Side Effects of Drugs Annual 32
HONORARY EDITOR Prof. M.N.G. Dukes, Oslo, Norway
ADVISORY EDITORIAL BOARD Prof. F. Bochner, Adelaide, Australia Prof. I.R. Edwards, Uppsala, Sweden Prof. G.P. Velo, Verona, Italy
SIDE EFFECTS OF DRUGS ANNUAL 32 A worldwide yearly survey of new data and trends in adverse drug reactions and interactions EDITOR
J.K. ARONSON MA, DPhil, MBChB, FRCP, FBPharmacolS, FFPM (Hon) Reader in Clinical Pharmacology University Department of Primary Health Care Old Road Campus, Headington, Oxford OX3 7LF, UK
Amsterdam – Boston – Heidelberg – London – New York – Oxford Paris – San Diego – San Francisco – Singapore – Sydney – Tokyo
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Contributors
SARAH ABBAS Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK M.C. ALLWOOD, BPHARM, PHD Pharmacy Academic Practice Unit, School of Biological, Forensic and Pharmaceutical Sciences, University of Derby, Mickleover, Derby, UK. E-mail:
[email protected] BRIAN J. ANGUS, MD John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK. E-mail:
[email protected] J.K. ARONSON, MA, MBCHB, DPHIL, FRCP, FBPHARMACOLS, FFPM (HON) University Department of Primary Health Care, Old Road Campus, Headington, Oxford OX3 7LF, UK. E-mail:
[email protected] V.V. BANU REKHA Tuberculosis Research Centre, Mayor VR Ramanathan Road, Chetpet, Chennai 600031, India. E-mail:
[email protected] MATTHIAS BEHREND, MD, PHD Klinik für Viszeral-, Gefäß-, Thorax- und Kinderchirurgie, Klinikum Deggendorf, Perlasberger Str. 41, D-94469 Deggendorf, Germany. E-mail:
[email protected] KRISTIEN BOELAERT, MD, PHD, MRCP MRC Clinician Scientist and Honorary Consultant Endocrinologist, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, IBR Building 2nd floor, University of Birmingham, Birmingham B15 2TT, UK. E-mail:
[email protected] FELIX BRAUN, MD, PHD Klinik für Allgemeine Chirurgie und Thoraxchirurgie, Zentrum Chirurgie, Universität Schleswig-Holstein, Campus Kiel, Arnold-Heller Strasse 7, 24105 Kiel, Germany. E-mail:
[email protected] DIETER C. BROERING, MD, PHD Klinik für Allgemeine Chirurgie und Thoraxchirurgie, Zentrum Chirurgie, Universität Schleswig-Holstein, Campus Kiel, Arnold-Heller Strasse 7, 24105 Kiel, Germany. E-mail:
[email protected] TEHREEM F. BUTT, MBCHB, MRCP (UK) Department of Clinical Pharmacology, College of Medical and Dental Sciences, Univer sity of Birmingham, Edgbaston, Birmingham B15 2TT, UK. E-mail:
[email protected]
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vi
Contributors
ANDREW BYRNE, BA, MB, BCH, BAO, MRCPSYCH, MMEDSCI Fieldhead Hospital, South West Yorkshire Mental Health NHS Trust, Ouchthorpe Lane, Wakefield, WF1 3SP, UK. E-mail:
[email protected] ALFONSO CARVAJAL, MD, PHD Instituto de Farmacoepidemiología, Facultad de Medicina, 47005 Valladolid, Spain. E-mail:
[email protected] K. CHAN, PHD, DSC, FSB, FCP, FRPHARMS, FRSM Herbal Medicines Research and Education Centre (HMREC) Faculty of Pharmacy, The University of Sydney, NSW2006; and CompleMED, College of Science & Health, University of Western Sydney, NSW2560, Australia. E-mail:
[email protected] N.H. CHOULIS, MD, PHD LAVIPHARM Research Laboratories, Agias Marinas Street, 19002 Peania, Attika, Greece. E-mail:
[email protected] JAMIE J. COLEMAN, MBCHB, MA(MED ED), MD, MRCP(UK) Department of Clinical Pharmacology, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. E-mail:
[email protected] NATASCIA CORTI, MD University Hospital Zurich, Department of Medicine, Division of Infectious Diseases and Hospital Epidemiology, Rämistrasse 100, CH-8091 Zürich, Switzerland. E-mail:
[email protected] J. COSTA, MD Clinical Pharmacology Department, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Ctra. de Canyet s/n, 08916 Badalona, Spain. E-mail:
[email protected] STEPHEN CURRAN, BSC, MBCHB, MMEDSC, MRCPSYCH, PHD Fieldhead Hospital, South West Yorkshire Mental Health NHS Trust, Ouchthorpe Lane, Wakefield, WF1 3SP, UK. E-mail:
[email protected] H.R. DALTON, BSC, DPHIL, FRCP, DIPMEDED Department of Gastroenterology, Royal Cornwall Hospital, Truro, Cornwall, TR1 3LJ, UK. E-mail:
[email protected] GWYNETH A. DAVIES, MD, MRCP Senior Clinical Lecturer, Asthma & Allergy, School of Medicine, Swansea University, Swansea, Wales, UK. E-mail:
[email protected] JANE DEMOCRATIS Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK S. DITTMANN, MD, DSCMED 19 Hatzenporter Weg, 12681 Berlin, Germany. E-mail:
[email protected]
Contributors
vii
IDA DUARTE Santa Casa de São Paulo Medical School, Sao Paulo, Brazil. E-mail:
[email protected] M.N.G. DUKES, MD, MA, LLM Trosterudveien 19, 0778 Oslo, Norway. E-mail:
[email protected] RIF S. EL-MALLAKH, MD Director, Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, MedCenter One, 501 E Broadway, Suite 340, Louisville, KY 40202, USA. E-mail:
[email protected] M. FARRÉ, MD Unitat de Farmacologia, Institut Municipal d’Investigació Mèdica (IMIM)-Hospital del Mar, Universitat Autònoma de Barcelona, Doctor Aiguader 88, 08003 Barcelona, Spain. E-mail:
[email protected] M.G. FRANZOSI, PHD Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via Eritrea 62, 20157 Milan, Italy. E-mail:
[email protected] S. GALEA, MD, MRCPSYCH, MSC (ADDICTIVE BEHAVIOUR), DIP (FORENSIC MENTAL HEALTH), ASSOCIATE FELLOW, ICDP Centre for Addiction Studies, St George’s Hospital Medical School, 6th Floor, Hunter Wing, Cranmer Terrace, London SW17 0RE, UK. E-mail:
[email protected] YONGLIN GAO, MD Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, MedCenter One, 501 E Broadway, Suite 340, Louisville, KY 40202, USA. E-mail:
[email protected] A.H. GHODSE, MD, PHD, FRCP, FRCPSYCH Centre for Addiction Studies, St George’s Hospital Medical School, 6th Floor, Hunter Wing, Cranmer Terrace, London SW17 0RE, UK. E-mail:
[email protected] FREYA A. GOUMAS, MD Klinik für Allgemeine Chirurgie und Thoraxchirurgie, Zentrum Chirurgie, Universität Schleswig-Holstein, Campus Kiel, Arnold-Heller Strasse 7, 24105 Kiel, Germany. E-mail:
[email protected] ANDREAS H. GROLL, MD Infectious Disease Research Program, Center for Bone Marrow Transplantation and Depart ment of Hematology/Oncology, University Children’s Hospital, Albert-Schweitzer-Strasse 33, 48129 Muenster, Germany. E-mail:
[email protected] PETER M. HADDAD, BSC, MBCHB, FRCPSYCH, MD Greater Manchester West Mental Health NHS Foundation Trust, Cromwell House, 32 Cromwell Road, Eccles, Salford M30 0GT, UK. E-mail:
[email protected] A. HALL, BSC, MBCHB, FRCA School of Clinical Science, University of Liverpool, The Duncan Building, Daulby Street, Liverpool, L69 3GA, UK. E-mail:
[email protected]
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Contributors
ALEXANDER IMHOF, MD University Hospital Zurich, Department of Medicine, Division of Infectious Diseases and Hospital Epidemiology, Rämistrasse 100, CH-8091 Zürich, Switzerland. E-mail:
[email protected] NATALIA JIMENO, MD, PHD Instituto de Farmacoepidemiología, Facultad de Medicina, 47005 Valladolid, Spain. E-mail:
[email protected] OLIVER KOCH Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. E-mail:
[email protected] SARAH LANGENFELD, MD University of Massachusetts Medical School, Department of Psychiatry, 361 Plantation Street, Worcester, MA 01605, USA. E-mail:
[email protected] R. LATINI, MD Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via Eritrea 62, 20157 Milan, Italy. E-mail:
[email protected] ROSANA LAZZARINI Santa Casa de São Paulo Medical School, São Paulo, Brazil. E-mail:
[email protected] MARTIN LEUWER, MD University Department of Anaesthesia, University of Liverpool, The Duncan Building, Daulby Street, Liverpool, L69 3GA, UK. E-mail:
[email protected] KEIR E. LEWIS, MD, MRCP Senior Clinical Lecturer, School of Medicine, Swansea, Wales, UK. E-mail:
[email protected] Z.X. LIN, BSC, PHD School of Chinese Medicine, Faculty of Science, The Chinese University of Hong Kong, 1/F, Sino Building, CUHK, Shatin, N.T., Hong Kong SAR, PR China. E-mail:
[email protected] PAM MAGEE, BSC, MSC, MRPHARMS Director of Pharmaceutical Services, University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry CV2 2DX, UK. E-mail:
[email protected] LUIS H. MARTÍN ARIAS, MD, PHD Instituto de Farmacoepidemiología, Facultad de Medicina, 47005 Valladolid, Spain. E-mail:
[email protected] R.H.B. MEYBOOM, MD, PHD Department of Pharmacoepidemiology and Pharmacotherapy, Faculty of Pharmacy, Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands. E-mail:
[email protected]
Contributors
ix
MARK MIDDLETON, PHD, FRCP University of Oxford, Department of Medical Oncology, Churchill Hospital, Oxford OX3 7LJ, UK. E-mail:
[email protected] TORE MIDTVEDT, MD, PHD Department of Microbiology, Tumor and Cell Biology (MTC), Von Eulers v. 5, Karolinska Institutet, Box 60 400, S-171 77 Stockholm, Sweden. E-mail:
[email protected] SHABIR MUSA, MBCHB, MRCPSYCH Fieldhead Hospital, South West Yorkshire Mental Health NHS Trust, Ouchthorpe Lane, Wakefield, WF1 3SP, UK. E-mail:
[email protected] R.C.L. PAGE, MD, FRCP, MA (ED) Endocrine Unit, Dundee House, City Hospital, Hucknall Road, Nottingham NG5 1PB. E-mail:
[email protected] JAYENDRA K. PATEL, MD University of Massachusetts Medical School, Department of Psychiatry, 361 Plantation Street, Worcester, MA 01605, USA. E-mail:
[email protected] CH. P. PESCOTT, MD Sanquin Blood Supply Foundation, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. E-mail:
[email protected] HARI KRSHNAN, MBBS, FANZCA MMED Department of Anaesthesia & Intensive Care, Kuala Lumpur General Hospital, Jalan Pahang, 50160 Kuala Lumpur, Malaysia. E-mail:
[email protected] R. RAMNARACE, MBBS, MRCP Department of Gastroenterology, Royal Cornwall Hospital, Truro, Cornwall, TR1 3LJ, UK. E-mail:
[email protected] NADJA RIFAIE Klinik für Allgemeine Chirurgie und Thoraxchirurgie, Zentrum Chirurgie, Universität Schleswig-Holstein, Campus Kiel, Arnold-Heller Strasse 7, 24105 Kiel, Germany. E-mail:
[email protected] RONA J. ROBERTS, MD Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, MedCenter One, 501 E Broadway, Suite 340, Louisville, KY 40202, USA. E-mail:
[email protected] ANITA ROTTER Clinic of Dermatology, Santa Casa de São Paulo, São Paulo, Brazil. E-mail:
[email protected] AMI SABHARWAL University of Oxford, Department of Medical Oncology, Churchill Hospital, Oxford OX3 7LJ, UK. E-mail:
[email protected]
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Contributors
CATHERINE SARGENT Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK. E-mail:
[email protected] MICHAEL SCHACHTER, MD Department of Clinical Pharmacology, National Heart and Lung Institute, Imperial College, St Mary’s Hospital, London W2 1NY, UK. E-mail:
[email protected] JURGEN SCHIEFERMUELLER Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK J.S.A.G. SCHOUTEN, MD Department of Ophthalmology, Maastricht University Hospital, PO Box 5800, 6202 AZ Maastricht, The Netherlands. E-mail:
[email protected] DOMINIK SCHREY Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Hematology/Oncology, University Children’s Hospital, Albert-SchweitzerStrasse 33, 48129 Muenster, Germany. E-mail:
[email protected] STEPHAN A. SCHUG, MD, FANZCA, FFPMANZCA Level 2, MRF Building G Block, Royal Perth Hospital, GPO Box X2213, Perth, WA 6847, Australia. E-mail:
[email protected] REGINALD P. SEQUEIRA, PHD, FCP Department of Pharmacology & Therapeutics, College of Medicine & Medical Sciences, Arabian Gulf University, PO Box 22979, Manama, Bahrain. E-mail:
[email protected] SUSANNE SHEEHY Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK. E-mail:
[email protected] DOMENIC A. SICA, MD Section of Clinical Pharmacology and Hypertension, Division of Nephrology, Medical College of Virginia of Virginia Commonwealth University, Box 980160 MCV Station, Richmond, VA 23298-0160, USA. E-mail:
[email protected] OSCAR OZMUND SIMOOYA, BSC, MBCHB, MSC The Copper belt University, Health Services Division, PO Box 21692, Kitwe, Zambia, Central Africa. E-mail:
[email protected];
[email protected] S. STRAUBE, BM, BCH, MA, DPHIL Department of Occupational and Social Medicine, University of Göttingen, Waldweg 37 B, D-37073 Göttingen, Germany. E-mail:
[email protected] P.F.W. STRENGERS, MD Sanquin Blood Supply Foundation, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. E-mail:
[email protected]
Contributors
xi
SOUMYA SWAMINATHAN, MD Tuberculosis Research Centre, Mayor VR Ramanathan Road, Chetpet, Chennai 600031, India. E-mail:
[email protected] GIJSBERT B. VAN DER VOET, PHD, ERT Health Council of The Netherlands, Parnassusplein 5, 2511 VX The Hague, The Netherlands. E-mail:
[email protected] P.J.J. VAN GENDEREN, MD, PHD Havenziekenhuis and Institute of Tropical Diseases, Department of Internal Medicine, Harbour Hospital, Haringvliet 2, 3011 TD Rotterdam, The Netherlands. E-mail:
[email protected] R. VERHAEGHE, MD Center for Vascular Diseases, University of Leuven, Herestraat, 49, 3000 Leuven, Belgium. E-mail:
[email protected] P. VERHAMME, MD Center for Vascular Diseases, University of Leuven, Herestraat, 49, 3000 Leuven, Belgium. E-mail:
[email protected] GARRY M. WALSH, MSC, PHD School of Medicine, Institute of Medical Sciences Building, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK. E-mail:
[email protected] THOMAS J. WALSH, MD Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. E-mail:
[email protected] CHRISTA WENGER, MD University Hospital Zurich, Department of Medicine, Division of Infectious Diseases and Hospital Epidemiology, Rämistrasse 100, CH-8091 Zürich, Switzerland. E-mail: christa.
[email protected] C. WILLIAMS, BSC, MBCHB, FRCA Department of Anaesthesia, 12th Floor, Royal Liverpool University Hospital, Prescot Street, Liverpool, L7 8XP, UK. E-mail:
[email protected] EILEEN WONG, MD Harvard Medical School, Massachusetts Mental Health Center, Department of Psychiatry, Jamaica Plain, MA 02130, USA. E-mail:
[email protected] GAETANO ZACCARA, MD U.O. Neurologia, Ospedale S Giovanni di Dio, Via Torregalli, 50100 Firenze. E-mail:
[email protected]
Special reviews
Antidepressants and emergent suicidality Adverse effects of antidepressants in pregnancy SSRIs and gastrointestinal bleeding Lithium in neuroprotection Ecstasy and neurocognition Deaths associated with antipsychotic drug treatment Serious skin reactions to carbamazepine Overdose of valproate and its management Frequency of adverse reactions to opioid analgesics Levacetylmethadol (levo-a-acetylmethadol, LAAM) Oxymorphone Pholcodine An update on cardiovascular and gastrointestinal adverse effects
of non-selective NSAIDs and coxibs Stereoisomers of arylpropionic acids Adrenal suppression from etomidate Management of adverse drug reactions to local anesthetics with lipid emulsion Sugammadex Tolcapone Dimethyl fumarate Inhaled glucocorticoids and the risk of pneumonia Inhaled glucocorticoids: update on skeletal adverse effects Indacaterol The cardiovascular risks of anticholinergic drugs Zileuton Mortality during treatment of atrial fibrillation with digoxin Dyspnea and bronchospasm associated with adenosine Enhanced eryptosis as a possible mechanism of action of amiodarone Pilsicainide Quality of life and adherence to antihypertensive drugs ACE inhibitors and angioedema Thiamine deficiency due to diuretics Resistance to antibacterial drugs Intrapartum antibiotics for mothers with group B streptococcal colonization:
to treat or not to treat? Drug-drug interactions with antifungal azoles The use of pyrimethamine þ sulfadoxine in intermittent preventive regimens in malaria Hepatotoxicity of antituberculosis drugs Dosages of antituberculosis drugs in children Antituberculosis drug treatment in transplant recipients Pharmacovigilance of antihelminthic drugs in developing countries Adverse effects of vaccine adjuvants The benefit to harm balance of drotrecogin alfa (activated) Tetrahydrobiopterin and sapropterin
xvi
29
31
33
41
63
89
129
157
183
193
203
206
225
229
249
261
275
289
295
311
312
317
318
322
333
337
339
348
375
380
401
445
446
497
523
555
557
559
571
577
591
609
Special reviews
xvii
Heparin-induced thrombocytopenia type II in different populations of patients Danaparoid sodium Withdrawal of aprotinin TGN1412 Hormone replacement therapy and ovarian cancer Long-term medical and social consequences of androgenic anabolic steroid abuse Reduced bone density and risk of fracture due to thiazolidinediones Peroxisome proliferator-activated dual receptor agonists Torcetrapib Monofunctional alkylating agents Photodynamic therapy in the treatment of cancers Sialadenitis due to iodinated contrast media Contrast medium-induced nephrotoxicity Systemic fibrosis due to gadolinium-based contrast agents Injectable formulations of Chinese medicines
626
631
642
691
740
751
779
782
816
827
832
845
846
852
880
Cumulative indexes of special reviews, Annuals 12–31 1. Index of drugs Note: the format 31.352 refers to SEDA-31, p. 352. Abetimus, drug development, 29.460 ACE inhibitors acetylsalicylic acid, interaction, 28.124 angioedema, 22.225, 29.207, 31.352 cough, 19.211 indications, 24.233 Acetaminophen, see Paracetamol Acetylsalicylic acid, 21.100 ACE inhibitors, interaction, 28.124 antithrombotic effectiveness, 12.74 benefit to harm balance in preventing strokes and heart attacks, 27.109
co-medication, 26.423
gastrointestinal effects, 17.95, 18.90
Reye's syndrome, 11.79, 15.85
rhinosinusitis/asthma, 17.94
respiratory disease, 31.193
sensitivity, 12.75
Acupuncture incidence of adverse effects, 29.589 traumatic effects, 29.590 Adrenaline, myocardial infarction and vasospasm, 31.259 Aerosols, delivery, 27.172 Albumin, human, anaphylaxis, 14.296 Alcohol, 31.757 vitamin A, beta-carotene, interaction, 24.442 Aldosterone antagonists, in heart failure, 24.246 Alkylating drugs, 31.721 Aluminium in albumin solutions, 23.359
toxicity in children, 12.185
tumorigenicity, 31.383
Aminoglycoside antibiotics, 17.304 contact dermatitis, 13.225 dosage regimens, 20.234, 21.265, 23.264 nephrotoxicity, 15.268, 17.305 ototoxicity, 14.222, 18.268 and ribostamycin, 15.270
xviii
Amiodarone, dysrhythmias, 25.211 respiratory toxicity, 15.168 thyroid disease, 27.192, 31.327 Amphetamines, 29.3 Amphotericin, liposomal, 17.319 nephrotoxicity, 13. 231, 14.229, 27.276 Anabolic steroids, abuse in sport, 29.508 Analgesics agranulocytosis and aplastic anemia, 11.87 choice of drug and dose, 12.63 headache, 21.95 headaches in children, 23.114 nephropathy, 21.98 Androgens, in women, 24.477 Anesthesia, dental, safety of, 16.122 Anesthetics halogenated, renal damage, 20.106
local, combinations, 20.121
local, lipid rescue, 31.231
local, neurotoxicity, 21.129, 25.152
ocular, 17.542
Angiotensin II receptor antagonists, angioedema 30.238 Anisoylated plasminogen-streptokinase activator complex (APSAC), 12.313 Anorectic drugs cardiac valvulopathy 22.3, 23.2, 24.4, 25.5 primary pulmonary hypertension, 18.7, 21.2, 23.2, 25.5 Anthracyclines, 25.533 Antiallergic drugs, ocular treatment, 11.420 Antibacterial drugs, resistance, 31.413 Anticancer antimetabolites, 29.531 Anticholinergic drugs, 22.507, 31.273 Anticoagulants, oral, skin necrosis, 29.358 Anticonvulsants, see Antiepileptic drugs Antidepressants, see also individual agents during and after pregnancy, 21.17
mania, 29.18
overdose, 28.14
relative risks, 11.16
Cumulative indexes of special reviews, Annuals 12–31 Antidysrhythmic drugs in atrial fibrillation, 24.197 prodysrhythmic effects, 17.218, 23.196 Antiepileptic drugs bone loss, 27.74 comparison, 25.78 death, 23.83 overdosage, 22.84 psychiatric effects, 22.82, 27.72 Antiestrogens, genotoxicity and tumorigenicity, 27.429 Antifungal drugs drug interactions (azoles), 24.318, 28.299, 29.282, 30.320, 31.459 Pneumocystis jiroveci (carinii) pneumonia, 18.289 Antihelminthic drugs, Mazzotti reaction, 31.507 Antihistamines cardiovascular adverse effects, 17.196, 22.176, 25.183, 26.180 drowsiness/sedation, 21.170, 23.171, 26.182 Antihypertensive drugs, 19.209 in diabetes mellitus, 28.226 fixed-dose combinations, 22.224 individualizing therapy, 17.246 Antimalarial drugs, 14.237, 17.325, 20.257 adjunctive treatments, 24.330 prophylaxis, 13.239, 23.304 Antimicrobial drugs, see also different types allergic reactions, 23.251 coagulation disorders, 18.258 colitis, 12.216, 17.303 intestinal motility, 13.220 male fertility, 16.262 new, 13.210 new, with adjuvants, 17.296 the pill and pregnancy, 24, 274 policies and politics, 16.273 pregnancy, 11.231 prescribing, 15.254 preterm infants, 21.258 prudent use, 25.279 , 27.242, 28. 265 resistance, 12.206, 13.210, 19.237, 20.228, 21.257, 22.265, 23.250, 24.273, 29.244, 31.413
seizures, 18.261
side chains, 16.264
Antioxidant vitamins, 20.363 Antiprotozoal drugs African trypanosomiasis, 18.293 toxoplasmosis, 20.262 Antipsychotic drugs comparisons of different types 25.53, 27.50 diabetes mellitus, 28.60 use in conditions other than schizophrenia, 27.49 use in elderly patients, 30.59 weight gain, 26.56 Antiretroviral drugs, metabolic complications, 28.329
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Antischistosomal drugs, 12.261 Antithyroid drugs, pregnancy, 13.377 Antituberculosis drugs, 16.341, 31.500 genetic susceptibility, 28.342 hepatotoxicity, 25.363, 26.339, 31.495 Mycobacterium avium–complex infection, 20.278 Appetite suppressants cardiac valvulopathies, 22.3, 23.2, 24.4, 25.5 primary pulmonary hypertension, 18.7, 21.2, 23.2, 25.5 Aripiprazole, 31.70 Aspirin, see Acetylsalicylic acid Asthma medications, exacerbation of asthma, 20.165 Atovaquone, 19.266 Avoparcin lessons from, 27.242 resistance, 29.244 Azathioprine, see Thiopurines Azoles, see Antifungal drugs Baclofen, withdrawal syndrome, 26.152 Bambuterol, cardiac failure, 23.181 Benzodiazepines brain damage, 14.36
dependence, 12.41
depression, 17.43
medicolegal aspects, 13.33
Beta2-adrenoceptor agonists, 18.159 asthma, 19.178, 21.179 asthma deaths, 17.164 long-acting, respiratory adverse effects, 30.198, 31.309
long-acting, genetic susceptibility factors,
30.199, 31.310
Beta-adrenoceptor antagonists arthralgia, 11.164 sexual function, 15.188 Beta-carotene, see also Vitamin A alcohol, vitamin A, interaction, 24.442 tumorigenicity, 25.454 Beta-lactam antibiotics effects on eukaryotic cells, 13.212 immediate hypersensitivity reactions, 14.211 pregnancy, 25.280 Blood, see Transfusions Botulinum toxin A, use in primary axillary hyperhidrosis, 27.161 Budesonide, children, susceptibility factors, 30.194 Calcium antagonists, long-term safety, 20.185, 21.208, 22.214 Carnitine, 13.269 Carotenoids, tumorigenicity, 25.454 Ceftriaxone, 15.258 nephrolithiasis, 29.246
xx Cephalosporins immunological reactions, 28.267 hypersensitivity reactions, cross-reactivity with penicillins, 30.280 and vitamin K, 12.210 Charcoal, activated, in digitalis overdose, 24.201 Chloramphenicol, children, 15.267 Chloroquine, 15.286 Chondroprotective agents, 14.439 Chymopapain, 11.279, 14.264 Ciclesonide, 30.196 Ciclosporin, urinary system, 19.348 Clozapine, 15.50 agranulocytosis, 22.1359 Cocaine cardiovascular effects, 18.5 fetotoxicity, 29.41, 30.35 prenatal exposure and perinatal effects, 27.1 second-generation effects, 20.24 Cocamidopropylbetaine, allergy, 19.151 Complementary and alternative therapies, indirect risks, 27.521 esophagus, adverse effects on, 14.442 Contrast media adverse effects, 13.431, 24.525 anaphylactoid and allergic reactions, 20.422 delayed reactions, 26.513 in magnetic resonance imaging, 20.419 nephrotoxicity, 27.500, 28.556, 29.575, 31.731, 31.735 Codeine, breast feeding, 31.154 Corticosteroids, see Glucocorticoids Cosmetics adverse effects, 13/117
contact allergy, 11.142, 16.150, 19.151
ingredient labeling 22.159
Co-trimoxazole, hypersensitivity reactions, 20.264 COX-2 inhibitors, 24.115, 25.126, 26.116 vascular disease, 29.116 Daptomycin, muscle damage, 30.309 Deferiprone, cardiac siderosis, 29.235 Deferoxamine, 16.247 bone dysplasia, 23.241
cardiac siderosis, 29.235
bone dysplasia, 23.241
cardiac siderosis, 29.235
yersiniosis, 11.215
Diamorphine, progressive spongiform leukoencephalopathy, 24.40 Diclofenac, liver damage, 20.91 Diethylstilbestrol, transgenerational effects, 31.657 Digitalis, in atrial fibrillation, 24.197 Digoxin, compared with other drugs in heart failure in sinus rhythm, 14.141 compared with other drugs in chronic uncomplicated atrial fibrillation, 14.144
Cumulative indexes of special reviews, Annuals 12–31
in heart failure in sinus rhythm, 18.196
Dipeptidyl peptidase IV inhibitors, 30.498
Diuretics
diabetes mellitus, electrolyte abnormalities, and the ALLHAT trial, 27.219
hyponatremia, 29.219
interactions with NSAIDs, 12.80
renal cell carcinoma, 23.225
renal insufficiency, 25.250
DNA alkylating drugs, 31.721
Dofetilide, 26.208
Dopamine receptor agonists
pathological gambling, 30.174
sleep disorders, 26.160, 27.149
Doxylamine, overdose and rhabdomyolysis,
31.298 Ecstasy, see MDMA
EDTA, pseudothrombocytopenia, 21.250
Endothelin receptor antagonists, in
hypertension, 26.233 Enzyme inhibitors, 15.337 Epinephrine, see Adrenaline Erythromycin, versus the new macrolides, 21.269 Erythropoietin, pure red cell aplasia, 27.348 status and safety, 16.400
Ethambutol, optic neuropathy, 30.358
Ethylene oxide, dialyser hypersensitivity,
11.219
Etoposide, 27.477
Etretinate, ossification, 12.127
Euxyl K 400, contact allergy, 16.150
Fat emulsions, priapism, 11.313 Felbamate
aplastic anemia, 19.68, 22.86
risk/benefit ratio, 23.86
Fenfluramine cardiac valvulopathies, 22.3, 23.2, 24.4, 25.5 primary pulmonary hypertension, 18.7, 21.2, 23.2, 25.5 Fenoterol, safety in severe asthma, 23.182 Fentanyl, buccal and transdermal administration, 20.77 Fertility drugs
malignant melanoma, 26.434
ovarian cancer, 24.474
Finasteride, 30.480
Fish oil, 13.460
Flecainide, in supraventricular dysrhythmias,
21.200
Fluoroquinolones, 12.250, 18.271
Fluorouracil, adverse effects, 23.476
Folic acid, dietary supplementation, 19.369
safety aspects, 27.407
Formoterol, tolerance, 24.187
Fragrances, contact allergy, 20.149
Cumulative indexes of special reviews, Annuals 12–31 Gadolinium salts, nephrotoxicity, 28.561, 31.735 General anesthetics, see Anesthetics Germanium, 16.545 Glucocorticoids bone, 16.447, 22.182, 25.195 contact allergy, 15.139, 21.158 effective dose and therapeutic ratio, 23.175 and eyes, 29.481 and growth, 14.335 inhaled, children, risks in, 27.174 inhaled, effects on mouth and throat, 29.168 inhaled, effects on skin, 29.169 inhaled, fracture risk, 31.307 inhaled, growth inhibition, 26.186 inhaled, hypothalamic–pituitary–adrenal gland function, 31.305 inhaled, systemic availability, 24.185, 26.187 musculoskeletal adverse effects, 21.417 osteoporosis and osteonecrosis, 16.447, 19.377, 20.374, 21.417, 22.182, 28.473 preterm infants, 17.445 Glucose solutions, hypophosphatemia, 11.312 Grapefruit juice, drug interactions 23.519 Growth hormone adults, 16.501
Creutzfeldt-Jakob disease, 11.371
insulin resistance, 24.504
malignancy, 23.468
Heparin low-molecular-weight, 12.311 thrombocytopenia, 30.404 Hepatitis B vaccine, demyelinating diseases, 21.331, 22.346, 24.374 Herbal medicines, warfarin, interactions, 30.400 Heroin, see Diamorphine Histamine (H2) receptor antagonists, 13.330, 15.393 HIV-protease inhibitors insulin resistance, 22.317 lipodystrophy, 22.317 HMG Co-A reductase inhibitors, interactions, 25.530, 30.517 Hormone replacement therapy, cardiovascular effects, 31.659 Hormones, sex breast cancer 11.346 tumors, 22.465 HRT, see Hormone replacement therapy 5-HT, see Serotonin Hydrochlorothiazide, non-cardiogenic pulmonary edema, 31.373 Hypnotics, 20.30 avoiding adverse effects, 21.37 Hypoglycemic drugs, combinations of, 27.458, 28.521
xxi
Immunization adverse effects, 24.364 and autoimmune disease, 27.336 bioterrorism, 25.378, 26.354 multiple, 27.334 surveillance after, 15.340, 22.333, 23.335, 24.364, 25.376, 26.353, 27.334 Immunotherapy, in leishmaniasis, 15.299 Incretin mimetics, 29.528 Indometacin, fetal and neonatal complications, 18.102 Influenza vaccine, 29.332 Inhalations, 11.151 Insulin edema, 11.364
human, and hypoglycemia, 15.452
inhalation, 30.495
modes of administration, 26.464
resistance, and growth hormone, 24.504
synthetic analogues, 24.489
Interferon þ ribavirin, 30.344
Interferons, psychological and psychiatric effects,
29.384 Interleukin-2, 14.325 Ipecacuanha, myopathy, 11.422 Irinotecan, 27.477 Iodine, radioactive, 11.358 Iron chelators, combinations, 31.399 Isoniazid genetic susceptibility factors, 12.257
prophylactic, toxicity, 24.352
Kathon® CG, 31.134 Kava kava liver damage, 27.518 adverse effects, 28.579 Ketoconazole, hepatotoxicity, 12.229 Ketorolac, risk of adverse effects, 17.110 Khat, 30.43 Lamotrigine, skin rashes, 20.62, 24.88 Latex, allergy, 31.761 Laxatives, abuse, 13.336 Leflunomide, 29.435 Leukotriene receptor antagonists, Churg–Strauss syndrome, 24.183, 27.177, 29.174 Levodopa, and malignant melanoma, 31.267 Lipid-lowering drugs, 13.402, 15.479 Lithium adverse effects, prevention and treatment, 13.17, 17.28 beneficial uses other than in bipolar disorder, 27.19 efficacy, comparisons with other agents, 30.23 interactions, 16.13, 18.30 intoxication, prevention and treatment, 17.29 monitoring therapy, 11.24, 18.25
xxii Lithium (cont) mortality, 19.14 urinary system, 14.18, 19.16 thyroid, 12.26 Local anesthetics, see Anesthetics Loop diuretics, see Diuretics Lorenzo's oil, 27.475 Lyme disease vaccine, autoimmune disease, 24.366 Macrolides, drug interactions, 14.220 intestinal motility, 18.269 Malaria vaccines, 22.306 Mannitol, 28.236 MAO inhibitors, see Monoamine oxidase inhibitors MDMA (ecstasy) cognitive effects, 26.32 deaths, 24.32 epidemiology of use, 30.37 Measles immunization see also MMR autism, 23.350 Crohn’s disease, 23.350 neurological adverse effects, 23.348 subacute sclerosing panencephalitis, 29.335 Mebendazole, hypersensitivity reactions, 12.263 Melatonin, 25.523 Mercaptopurine, see Thiopurines Metamfetamine, 29.3 Metformin contraindications, 28.515 lactic acidosis, 23.459, 29.526 Methyldibromoglutaronitrile, contact allergy, 16.150, 19.151 Methylphenidate, effects at different ages, 31.6 Methylthiotetrazole, 11.226 Mibefradil, drug interactions, 23.210 Midazolam, 15.112 Midodrine, 26.159 Milrinone, intravenous, acute heart failure, 21.196 MMR immunization autism, 23.350, 25.387, 28.363 Crohn’s disease, 23.350, 25.387 Mometasone furoate, 30.197 Monoamine oxidase inhibitors, 12.8, 13.6, 17.361 Morphine, managing adverse effects, 26.98 Muscle relaxants emergency medicine, 20.133
eyes, 21.145
hypersensitivity reactions, 27.138
intensive care, 19.140
Neuromuscular blocking agents, anaphylaxis, 29.145 non-depolarizing neuromuscular blockers, 15.127
recovery in intensive care, 12.114
Cumulative indexes of special reviews, Annuals 12–31
residual paralysis, 27.139
Niacin, extended-release, 16.440
N-Lost derivatives, 31.721
Nomifensine, 11.15
NSAIDs, see also COX-2 inhibitors
acute renal insufficiency, 28.122 blood pressure, 19.92, 27.102 children, 19.96 current controversies, 17.102 COX-2 inhibitors, 24.115, 25.126, 26.116 dyspepsia, 28.120 gastrointestinal adverse effects, 14.79, 17.95, 18.90, 18.99, 20.86, 21.96, 22.108, 23.114 gastrointestinal damage, role of Helicobacter pylori, 27.105 gastrointestinal damage, reducing, 30.125 gastrointestinal toxicity, prevention, 19.93 inflammatory bowel disease, 25.131 inhibiting cardioprotective effects of acetylsalicylic acid, 28.118 interactions with diuretics, 12.80 intracerebral hemorrhage, 28.119 necrotizing fasciitis, 28.121 nephrotoxicity, 11.82, 18.100, 20.89, 24.120, 26.111
osteoarthritis, 11.87
skin reactions, 13.72
topical, 18.163
Ocular drugs
allergic reactions, 21.486
geriatric patients, 16.542
risk factors for adverse effects, 22.507
Omeprazole, tumors, 16.423 Opioids
abuse, 29. 44
adverse effects, prevention, 24.100
death, 25.37
obstetric use, 24.102
routes of administration, 30.106
tolerance in neonates, 23.97
Oral contraceptives
antimicrobial drugs, and pregnancy, 24.274
and breast cancer, 15.426
formulations, 24.472
third-generation, 25.484, 26.442
venous thromboembolism, 23.442
Orlistat, 30.429 Paclitaxel, adverse effects, 21.463
Pancreatic enzyme supplements, fibrosing
colonopathy, 20.322
Paracetamol
asthma, 30.129
hepatotoxicity in alcoholism, 12.76
liver damage, 17.98, 18.94
overdose, 13.68, 23.117
Cumulative indexes of special reviews, Annuals 12–31 Parenteral nutrition bone effects, 22.378 cholestasis, 22.376 infections 22.379 Penicillins acute desensitization, 23.252 hypersensitivity reactions, cross-reactivity with cephalosporins, 30.280 immunological reactions, 28.267 Peritoneal dialysis fluids, effects on peritoneum, 22.381 Pertussis vaccine, 11.284, 11.285 Phentermine, cardiac valvulopathies, 24.4 Phytoestrogens, in foodstuffs, 31.655 Piroxicam gastrointestinal effects, 11.97, 12.91 Pivalic acid, and carnitine, 12.209 Platinum compounds, 26.490 Polio vaccine, AIDS, 23.352 Polyaspartic acid, protective against nephrotoxicity, 17.305 Polyethylene glycol, electrolyte, mineral, metal, and fluid balance, 29.376 Polystyrene sulfonates, 25.271 Polyvinylpyrrolidone, storage disease, 22.522 Pregabalin, 30.86 Propofol infusion syndrome, 26.135 prevention of pain, 30.143 Propolis, allergy, 17.181 Proton pump inhibitors, tumors, 23.383 Psilocybin, 31.49 PUVA, malignant melanoma, 22.166 Pyrazinamide, in latent pulmonary tuberculosis, 27.323 Quinidine, versus quinine, 15.295 Quinine, versus quinidine, 15.295 Rasagiline, 31.270 Rasburicase, 31.203 Renin inhibitors, 30.242 Rhesus anti-D, prophylaxis, 13.297 Ribavirin þ interferon, 30.344 Ribostamycin, and aminoglycosides, 15.270 Rocuronium, allergic reactions, 26.150 and pholcodine, 31.249 Rotashield, intussusception, 23.354 Rotavirus vaccine, Kawasaki disease, 31.522 Rubella vaccine, joints, 11.295 Salbutamol, adrenoceptor genotypes, 29.173 Salmeterol, tolerance, 24.187 Sedatives, 29.128 Sex hormones, tumors, 22.465 Serotonin receptor antagonists, 15.391
xxiii
selective serotonin reuptake inhibitors, drug interactions, 22.13 selective serotonin reuptake inhibitors, suicidal behavior, 29.19, 31.18 Smallpox vaccination, 27.339 Somatostatin, 15.468 Spinal manipulation, adverse effects, 29.591 SSRIs, see Serotonin Statins, see HMG Co-A reductase inhibitors Steroids, see Glucocorticoids Stimulants, in ADHD, 31.4 Sulfonamide derivatives, hypersensitivity reactions, 30.252 Sumatriptan, 17.171 Suprofen, nephrotoxicity, 12.88 Suramin, patients with prostate cancer, 20.283 Surgam, gastric effects, 12.89 Suxamethonium, postoperative myalgia, 28.155 Tamoxifen, versus aromatase inhibitors, 30.475 Teniposide, 27.477 Tetracyclines adverse effects, 12.212, 26.268
chemically modified, 31.419
comparative toxicity, 22.268
and metalloproteinases, 26.266
non-antimicrobial properties, 30.288
in pregnancy, 25.280
in rheumatology, 23.255
therapeutic effects, 24.278
Theophylline, asthma, 17.2, 18.1, 18.2 Thiazides, see Diuretics Thiazolidinediones cardiovascular effects, 31.697 peripheral edema, 29.531 Thiomersal, in vaccines, 28.357 Thiopurines, genetic susceptibility, 31.634 Thyroid hormones, 29.464 Thyroxine, drug interactions, 24.484 Tiaprofenic acid, cystitis, 18.106 TNF, see tumor necrosis factor Topiramate, cognitive effects, 26.81 Topoisomerase inhibitors, 27.477 Topotecan, 27.477 Transfusions AIDS, 12.298 complications, 12.300 Tretinoin, topical, teratogenicity, 18.164 Triazolam, 16.33 Tricyclic antidepressants endocrine effects, 11.12 mania, 13.8 L-tryptophan, eosinophilia-myalgia syndrome, 15.514 Tumor necrosis factor antagonists, infection risk, 29.395, 31.594 Tyrosine kinase inhibitors, 30.520
xxiv
Cumulative indexes of special reviews, Annuals 12–31
Vaccines, see also individual agents autism, 31.516 combinations, 29.327, 30.369 Guillain–Barré syndrome, 31.515 HIV-infected individuals, 12.269 Kawasaki disease, 31.522 national compensation systems, 12.271 poliomyelitis, 22.352 thiomersal in, 28.357 Valproate, polycystic ovary syndrome, 26.81 Vancomycin lessons from, 27.242 resistance, 29.244 Vigabatrin psychosis and abnormal behavior, 18.71 visual field defects, 21.78, 24.95, 25.98, 26.82 Vinca alkaloids, 28.538
Vitamin A, 17.436
alcohol, beta-carotene, interaction, 24.442
hypervitaminosis, 15.411
in pregnancy, 21.405
and prostate cancer, 13.346
Vitamin B6, debate, 23.420
Vitamin E, co-medication, 26.423
Vitamin K
cancer, 23.424
skin reactions, 25.461
Vitamins, in old age, 22.431
2. Index of adverse effects
asthma deaths, beta2-adrenoceptor agonists, 17.164 asthma exacerbation, asthma medications, 20.165 beta2-adrenoceptor agonists, long-acting, 30.198 bronchoconstriction, paradoxical, nebulizer solutions, 13.134 Churg–Strauss syndrome, leukotriene receptor antagonists, 24.183, 27.177, 29.174 cough, ACE inhibitors, 19.211 long-acting beta2-adrenoeceptor agonists, 31.309 primary pulmonary hypertension, appetite suppressants, 18.7, 21.2, 23.2, 25.5 pulmonary edema, non-cardiogenic, hydrochlorothiazide, 31.373 rhinosinusitis, acetylsalicylic acid, 17.94 Ear, nose, throat glucocorticoids, inhaled, 29.168 Nervous system anticholinergic effects, 31.273 brain damage, benzodiazepines, 14.36 Creutzfeldt–Jakob disease, growth hormone, 11.371 demyelinating diseases, hepatitis B vaccine, 21.331, 22.346, 24.374 drowsiness/sedation, antihistamines, 21.170, 23.171, 26.182 Guillain–Barré syndrome, vaccines 31.515 headache, analgesics, 21.95, 23.114 intracerebral hemorrhage, NSAIDs, 28.119 neuroleptic malignant syndrome, 11.47, 20.41 neurotoxicity, anesthetics, local, 21.129 neurotoxicity, measles immunization, 23.348 overdosage, antiepileptic drugs, 22.84 pain, propofol, 30.143 poliomyelitis, vaccines, 22.352 progressive spongiform leukoencephalopathy, diamorphine, 24.40
Cardiovascular atrial fibrillation, antidysrhythmic drugs, 24.197 atrial fibrillation, digitalis, 24.197 cardiac failure, aldosterone antagonists, 24.246 cardiac failure, bambuterol, 23.181 cardiac siderosis, deferoxamine/deferiprone, 29.235 cardiotoxicity, antihistamines, 17.196, 25.183, 26.180 cardiotoxicity, calcium antagonists, 20.185 cardiotoxicity, cocaine, 18.5 cardiotoxicity, coxibs, 29.116 cardiotoxicity, hormone replacement therapy, 31.659 cardiotoxicity, propofol, 26.135 cardiotoxicity, thiazolidinediones, 31.697 dysrhythmias, antihistamines, 22.176 dysrhythmias, amiodarone, 25.211 hypertension, NSAIDs, 19.92, 27.102 myocardial infarction, acetylsalicylic acid, 27.109 myocardial infarction, adrenaline, 31.259 prodysrhythmic effects, antidysrhythmic drugs, 17.218, 23.196 QT interval prolongation, 24.54 valvulopathies, fenfluramine, 22.3, 23.2, 24.4, 25.5 valvulopathies, phentermine, 24.4, 25.5 vasospasm, adrenaline, 31.259 venous thromboembolism, oral contraceptives, 23.442 Respiratory amiodarone, 15.168
asthma, acetylsalicylic acid, 17.94, 31.193
asthma, fenoterol, 23.182
asthma, paracetamol, 30.129
asthma, in pregnancy, 28.186
Warfarin, herbal medicines, interactions, 30.400 Ximelagatran, hepatotoxicity, 30.411 Zidovudine, 13.246
Cumulative indexes of special reviews, Annuals 12–31 seizures, antimicrobial drugs, 18.261 sleep disorders, dopamine receptor agonists, 26.160, 27.149 strokes, acetylsalicylic acid, 27.109 strokes, risperidone, 28.76 subacute sclerosing panencephalitis, measles vaccine, 29.335 tardive dyskinesia, 14.47, 20.38 tardive syndromes, 17.54 transient symptoms, intrathecal anesthetics, 25.152 Neuromuscular residual paralysis, neuromuscular blocking drugs, 27.139 Sensory systems eye effects, drug abuse, 12.33 eye effects, glucocorticoids, 29. 481 eye effects, muscle relaxants, 21.145 optic neuropathy, ethambutol, 30.358 ototoxicity, aminoglycosides, 14.222, 18.268 visual field defects, vigabatrin, 21.78, 24.95, 25.98, 26.82 Psychological cognitive effects, MDMA, 26.32 cognitive effects, metamfetamine, 29.3 cognitive effects, topiramate, 26.78 gambling, dopamine receptor agonists, 30.174 interferons, 29.384 Psychiatric antiepileptic drugs, 22.82, 27.72 autism, MMR/measles immunization, 23.350, 25.387, 28.363, 31.516 depression, benzodiazepines, 17.43 mania, antidepressants, 13.8, 29.18 interferons, 29.384 psychosis and abnormal behavior, vigabatrin, 18.71
suicidal behavior, SSRIs, 29.19, 31.18
Endocrine diabetes mellitus, antihypertensive drugs, 28.226 diabetes mellitus, antipsychotic drugs, 28.60 diabetes mellitus, diuretics, 27.219 hypothalamic–pituitary–adrenal gland function, inhaled glucocorticoids, 31.305 insulin resistance, growth hormone, 24.504 insulin resistance, HIV-protease inhibitors, 22.317
ovarian hyperstimulation syndrome,
valproate, 26.477 polycystic ovary syndrome, valproate, 26.81 thyroid disease, amiodarone, 27.192, 31.310 thyroid disease, lithium, 12.26 tricyclic antidepressants, 11.12 Metabolism antiretroviral drugs, 28.329
hyperlactatemia, 29.302
xxv
hypoglycemia, insulin, 15.452 lactic acidosis, metformin, 23.459, 29.526 lipoatrophy, 29.302 lipodystrophy, HIV-protease inhibitors, 22.317 metabolic acidosis, propofol, 26.135 mitochondrial toxicity, 29.302 polyvinylpyrrolidone storage disease, 22.522 weight gain, antipsychotic drugs, 26.56 Electroyte balance electrolyte abnormalities, diuretics, 27.219, 29.219
polyethylene glycol, 29.376
Mineral balance hypophosphatemia, glucose solutions, 11.312 polyethylene glycol, 29.376 Metal balance polyethylene glycol, 29.376 Fluid balance edema, insulin, 11.364
edema, thiazolidinediones, 29.531
polyethylene glycol, 29.376
Hematologic agranulocytosis, analegsics, 11.89 agranulocytosis, clozapine, 22.59 aplastic anemia, analegsics, 11.89 aplastic anemia, felbamate, 19.68, 22.86 coagulation disorders, beta-lactam antibiotics, 18.258 eosinophilia-myalgia syndrome, tryptophan, 15.514 hemolytic disease of the newborn, anti-D prophylaxis, 12.293 hemostasis, cephalosporins, 12.210 pseudothrombocytopenia, EDTA, 21.250 pure red cell aplasia, erythropoietin, 27.348 thrombocytopenia, heparin, 30.404 Mouth Glucocoricoids, inhaled, 29.168 Gastrointestinal bleeding, acetylsalicylic acid, 17.95, 18.90 cholestasis, total parenteral nutrition, 22.376 colitis, antimicrobial drugs, 12.216, 17.303 Crohn's disease, MMR/measles immunization, 23.350, 25.387 dyspepsia, NSAIDs, 28.120 fibrosing colonopathy, pancreatic enzyme supplements, 20.322 inflammatory bowel disease, NSAIDs, 25.131 intestinal motility, antimicrobial drugs, 13.220 intestinal motility, macrolides, 18.269 intussusception, Rotashield, 23.354 piroxicam, 12.91 Surgam, 12.89 ulceration, bleeding and perforation, NSAIDs, 11.97, 14.79, 16.103, 17.95, 18.90, 18.99, 19.93, 20.86, 21.96, 22.108, 23.114, 27.105, 30.125
xxvi Liver hepatotoxicity, alcohol/vitamin A/beta carotene, 24.442 hepatotoxicity, antituberculosis drugs, 25.363, 26.339, 31.495 hepatotoxicity, diclofenac, 20.91 hepatotoxicity, kava kava, 27.518 hepatotoxicity, ketoconazole, 12.229 hepatotoxicity, paracetamol, 12.76, 17.98, 18.94 hepatotoxicity, ximelagatran, 30.411 Reye's syndrome, acetylsalicylic acid, 11.79, 15.85 Urinary tract acute renal insufficiency, NSAIDs, 28.122 cystitis, tiaprofenic acid, 18.106 nephrolithiasis, ceftriaxone, 29.246 nephrotoxicity, aminoglycosides, 15.268, 17.305 nephrotoxicity, amphotericin, 13.231, 14.229, 27.276
nephrotoxicity, analgesics, 21.98
nephrotoxicity, anesthetics, halogenated,
20.106 nephrotoxicity, ciclosporin, 19.348 nephrotoxicity, contrast media, 27.500, 28.556, 29.575, 31.731, 31.735 nephrotoxicity, gadolinium salts, 28.561 nephrotoxicity, lithium, 14.18, 19.16 nephrotoxicity, NSAIDs, 11.82, 18.100, 20.89, 24.120, 26.111
nephrotoxicity, suprofen, 12.88
renal cell carcinoma, diuretics, 23.225
renal insufficiency, diuretics, 25.250
Skin contact allergy, 23.160 contact allergy, glucocorticoids, 15.139 contact dermatitis, aminoglycosides, 13.225 cutaneous reactions, NSAIDs, 13.72 glucocorticoids, inhaled, 29.169 necrosis, oral anticoagulation, 29.358 rashes, lamotrigine, 20.62, 24.88 vitamin K1, 25.461 Serosae peritoneum, peritoneal dialysis, 22.381
pleurodesis, 25.189
Musculoskeletal arthralgia, beta-adrenoceptor antagonists, 11.164 arthralgia, rubella vaccination, 11.295 bone, total parenteral nutrition, 22.378 bone dysplasia, deferoxamine, 23.241 bone loss, antiepileptic drugs, 27.74 bone mineral density, glucocorticoids, 25.195 eosinophilia-myalgia syndrome, tryptophan, 15.514
fractures, inhaled glucocorticoids, 31.307
Cumulative indexes of special reviews, Annuals 12–31
growth in children, inhaled glucocorticoids, 26.186 growth in children, oral glucocorticoids, 14.335 growth in children, stimulants, 31.4 muscle damage, daptomycin, 30.309 myopathy, ipecacuanha, 11.422 ossification, etretinate, 12.127 osteoarthritis, NSAIDs, 1187 osteoporosis and osteonecrosis, glucocorticoids, 16.447, 19.377, 20.374, 21.417, 22.182, 28.473 rhabdomyolysis, doxylamine overdose, 31.298 rhabdomyolysis, propofol, 26.135 postoperative myalgia, suxamethonium, 28.155 Sexual function beta-adrenoceptor antagonists, 15.188 priapism, fat emulsions, 11.313 Immunologic allergic reactions, antimicrobial drugs, 23.251 allergic reactions, contact allergy, cosmetics, 11.142 allergic reactions, contact allergy, Kathon® CG, 11.134 allergic reactions, latex, 31.761 allergic reactions, rocuronium, 26.150 allergy testing, chymopapain, 11.279 anaphylaxis, human albumin, 14.296 anaphylaxis, neuromuscular blocking agents, 29.145 angioedema, ACE inhibitors, 22.225, 29.207 aspirin sensitivity, 12.75 autoimmune disease, immunizations, 27.336 autoimmune disease, Lyme disease vaccine, 24.366
cocamidopropylbetaine, 19.151
contrast agents, 20.422
cosmetics, 16.150, 19.151
co-trimoxazole, 20.264
desensitization, penicillin, 23.252
Euxyl K 400, 16.150
fragrances, 20.149
glucocorticoids, 21.158
hypersensitivity reactions, beta-lactam
antibiotics, 14.211, 30.280 hypersensitivity reactions, ethylene oxide, 11.219 hypersensitivity reactions, muscle relaxants, 27.138
hypersensitivity reactions, mebendazole,
12.263 hypersensitivity reactions, rocuronium, 31.249 hypersensitivity reactions, sulfonamide derivatives, 30.252 immune reconstitution disease, 29.315 Kawasaki disease, rotavirus vaccine, 31.522 Mazzotti reaction, antihelminthic drugs, 31.507 methyldibromoglutaronitrile, 16.150, 19.151
Cumulative indexes of special reviews, Annuals 12–31 ocular drugs, 21.486
propolis, 17.181
red man syndrome, 17.312
Autacoids angioedema, angiotensin converting enzyme inhibitors, 31.352 angioedema, angiotensin II receptor antagonists, 30.238 Infection risk AIDS, polio vaccine, 23.352 AIDS, transfusions, 12.298 necrotizing fasciitis, NSAIDs, 28.121 total parenteral nutrition, 22.379 tumor necrosis factor antagonists, 29.395, 31.594
yersiniosis, deferoxamine, 11.215
Body temperature malignant hyperthermia, 18.112 Trauma acupuncture, 29.590 Death antiepileptic drugs, 23.83
calcium antagonists, 22.214
ecstasy, 24.32
lithium, 19.14
opiates, 25.37, 29.44
Drug abuse anabolic steroids in sport, 29.508 Drug tolerance antimicrobial drug resistance, 11.223,
12.208, 19.237, 20.228, 21.257,
22.265, 23.250, 24.273, 25.279,
29.244, 31.413
opioids in neonates, 23.97 Drug dependence benzodiazepines, 12.41 Drug withdrawal baclofen, 26.152 Genotoxicity antiestrogens, 27.429 Tumorigenicity alcohol/vitamin A/beta-carotene, 24.442 aluminium, 31.383 antiestrogens, 27.429 beta-carotene, 25.454 carotenoids, 25.454 fertility drugs, 24.474, 26.434 growth hormone, 23.468 levodopa, 31.267 omeprazole, 16.423 oral contraceptives, 11.346, 15.426 proton pump inhibitors, 23.383 PUVA, malignant melanoma, 22.166 sex hormones, 22.465 vitamin K, 23.424 Fertility fertility, male, antimicrobial drugs, 16.262
xxvii
Pregnancy affective disorders in, 21.17
antibiotics, 11.231
antimicrobial drugs and the pill, 24.274
antithyroid drugs, 13.377
asthma, 28.186
beta-lactams, 25.280
cocaine, 27.1
opioids, 24.102
tetracyclines, 25.280
vitamin A, 21.405
Teratogenicity antibiotics, 11.231
tretinoin, topical, 18.164
Fetotoxicity cocaine, 20.24, 27.1, 29.41, 30.35 diethylstilbestrol, transgenerational effects, 31.657
indometacin, 18.102
Lactation cocaine, 31.154 Susceptibility factors age, methylphenidate, 31.6 children, aluminum, 12.185 children, budesonide, 30.194 children, inhaled glucocorticoids 27.174 children, NSAIDs, 19.96 elderly patients, antipsychotic drugs, 30.59 genetic susceptibility, antituberculosis drugs, 28.342 genetic susceptibility, beta-adrenoceptor agonists, 29.173, 30.199, 31.310 genetic susceptibility, isoniazid, 12.257 genetic susceptibility, thiopurine toxicity, 31.634 HIV infection, immunization, 12.269 intensive care, muscle relaxants, 19.140 neonatal complications, indometacin, 18.102 ocular drugs, 22.507 old age, vitamins, 22.431 preterm infants, beta-lactam antibiotics, 21.258 Drug administration delivery of aerosols, 27.172 dosage regimens, aminoglycosides, 23.264 errors, 28.587, 29.596 formulations, oral contraceptives, 24.472 inhaled glucocorticoids, systemic availability, 24.185 inhaled insulin, 30.495 intravitreal and parabulbar injection, 29.581 labeling problems, cosmetics, 22.159 opioids, 30.106 Drug overdose antidepressants, 28.14
digitalis, charcoal, 24.201
paracetamol, 23.117
xxviii Drug formulations enantiomers and racemates, 13.442 Drug–drug interactions acetylsalicylic acid/ACE inhibitor, 28.124
acetylsalicylic acid/NSAIDs, 28.118
alcohol/vitamin A/beta-carotene, 24.442
antimicrobial drugs/the pill, 24.274
antifungal azoles, 24.318, 28.299, 29.282,
30.320, 31.459 diuretics/NSAIDs, 12.80 grapefruit juice, 23.519 herbal medicines/warfarin, 30.400 HMG Co-A reductase inhibitors, 25.530, 30.517 lithium, 16.13 lithium/selective serotonin reuptake inhibitors, 18.30
macrolides, 14.220
Cumulative indexes of special reviews, Annuals 12–31
mibefradil, 23.210 monoamine oxidase inhibitors/foods, 13.6 NSAIDs/ACE inhibitors, 28.122 paracetamol, 13.68 selective serotonin reuptake inhibitors, 22.13 thyroxine, 24.484 Methods ethnopharmacology, 14.429
eukaryotic cells, effects of beta-lactams,
13.212 hemolytic disease of the newborn, prophylaxis, 13.297 lithium, monitoring, 11.24 local anesthetic toxicity, lipid rescue, 31.231 onchocerciasis, treatment, 14.261 post-marketing surveillance, 14.210, 15.266, 24.274
Table of Essays, Annuals 1–31
SEDA
Author
Country
Title
1 2 3
M.N.G. Dukes K.H. Kimbel L. Lasagna
The Netherlands Germany USA
4 5
The Netherlands UK Hungary Canada Denmark UK Denmark Denmark Switzerland UK Denmark
Science vs practice and/or practice vs science Adverse reactions: some pitfalls and postulates The seven pillars of foolishness Let’s get our act together Integrated medicine, safer medicine and “AIDS” Hark, hark, the fictitious dogs do bark Both sides of the fence On our side of the fence The great cholesterol carousel
15
M.N.G. Dukes J.P. Griffin, P.F. D’Arcy I. Bayer E. Napke M.N.G. Dukes W.H.W. Inman S. Van Hauen M.N.G. Dukes M.C. Cone C. Medawar M.N.G. Dukes, E. Helsing P. Tyrer
The moments of truth Drug monitoring: why care? Wanted and unwanted drug effects: the need for perspective The van der Kroef syndrome Adverse reactions to drugs – the information lag
UK
16 17 18
M.N.G. Dukes M.N.G. Dukes R.D. Mann
Denmark Denmark UK
19
A. Herxheimer
UK
20
E. Ernst
UK
21
H. Jick
USA
22
UK
24
J.K. Aronson, R.E. Ferner K.Y. Hartigan-Go, J.Q. Wong I. Palmlund
UK
25 26
L. Marks D.J. Finney
UK UK
26 27 27 28 29
L.L. Iversen J.K. Aronson H. Jick J.K. Aronson M. Hauben, A. Bate J.K. Aronson J. Harrison, P. Mozzicato
UK UK USA UK USA/Sweden
The nocebo effect – poorly known but getting stronger Good enough for Iganga? The mists of tomorrow Databases, privacy, and confidentiality – the effect of proposed legislation on pharmacoepidemiology and drug safety monitoring Side effects: freedom of information and the communication of doubt Complementary/alternative medicine: what should we do about it? Thirty years of the Boston Collaborative Drug Surveillance Program in relation to principles and methods of drug safety research Errors in prescribing, preparing, and giving medicines: definition, classification, and prevention Inclusion of therapeutic failures as adverse drug reactions Secrecy hiding harm: case histories from the past that inform the future The pill: untangling the adverse effects of a drug From thalidomide to pharmacovigilance: a personal account How safe is cannabis? Louis Lewin – Meyler’s predecessor The General Practice Research Database Classifying adverse drug reactions in the 21st century Data mining in drug safety
UK USA
Drug withdrawals because of adverse effects MedDRA®: the tale of a terminology
6 7 8 9 10 11 12 13 14
23
30 31
Philippines
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Classifications of adverse drug reactions Adverse drug reactions are classified in SEDA using two complementary systems, EIDOS and DoTS (1–3). These two systems are illustrated in Figures 1 and 2.
1. EIDOS The EIDOS mechanistic classification of adverse drug effects has five elements: • • • • •
the Extrinsic species that initiates the effect (Table 1); the Intrinsic species that it affects; the Distribution of these species in the body; the (physiological or pathological) Outcome (Table 2); the Sequela, which is the adverse effect.
Extrinsic species This can be the parent compound, an excipient, a contaminant or adulterant, a degradation product or a derivative of any of these (e.g. a metabolite) (for examples see Table 1). Intrinsic species This is usually the endogenous molecule with which the extrinsic species interacts; this can be a nucleic acid, an enzyme, a receptor, an ion channel or transporter or some other protein. Distribution A drug will not produce an adverse effect if it is not distributed to the same site as the target species that mediates the adverse effect. Thus, the pharmacokinetics of the extrinsic species can affect the occurrence of adverse effects. Outcome Interactions between extrinsic and intrinsic species in the production of an adverse effect can result in physiological or pathological changes (for examples see Table 2). Physiological changes can involve either increased actions (e.g. clotting due to tranexamic acid) or decreased actions (e.g. bradycardia due to beta-adrenoceptor antago nists). Pathological changes can involve cellular adaptations (atrophy, hypertrophy, hyper plasia, metaplasia and neoplasia), altered cell function (e.g. mast cell degranulation in IgE-mediated anaphylactic reactions) or cell damage (e.g. cell lysis, necrosis or apoptosis). Sequela The sequela of the changes induced by a drug describes the clinically recogniz able adverse drug reaction, of which there may be more than one. Sequelae can be classified using the DoTS system.
xxx
Classifications of adverse drug reactions
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1. EIDOS: a mechanistic classification
2. DoTS: a clinical classification
Drug
Dose-relatedness
Drug Extrinsic
Intrinsic Patient
Outcome Adverse reaction
Patient Susceptibility factors
Adverse reaction Time course
Fig. 1. Classifying adverse drug reactions – two complementary systems. Note that the triad of drug–patient– adverse reaction appears outside the triangle in EIDOS and inside the triangle in DoTS.
Fig. 2. Classifying adverse drug reactions – two complementary systems. Here the two triangles in Figure 1 are superimposed, to show the relation between the two classification systems. An adverse reaction occurs when a drug is given to a patient (Gothic letters). Adverse reactions can be classified mechanistically (EIDOS; sans-serif letters) by noting that the extrinsic (drug) species, when co distributed with an intrinsic (patient) species, has a pharmacological or other effect (the outcome), producing the adverse effect (the sequela). The sequela can be further classified (DoTS; serif letters) by considering the three main features of the adverse reaction – its dose-relatedness, its time-course, and individual susceptibility.
Classifications of adverse drug reactions
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Table 1. The EIDOS mechanistic classification of adverse drug effects Feature
Varieties
Examples
E. Extrinsic species
1. The parent compound 2. An excipient 3. A contaminant
Insulin Polyoxyl 35 castor oil 1,1-Ethylidenebis [L-tryptophan] Lead in herbal medicines Outdated tetracycline
4. An adulterant 5. A degradation product formed before the drug enters the body 6. A derivative of any of these (e.g. a metabolite) I. The intrinsic species and the nature of its interaction with the extrinsic species: (a) Molecular
1. Nucleic acids • DNA • RNA 2. Enzymes • Reversible effect • Irreversible effect 3. Receptors • Reversible effect • Irreversible effect 4. Ion channels/transporters 5. Other proteins • Immunological proteins • Tissue proteins
(b) Extracellular
(c) Physical or
physicochemical
D. Distribution
O. Outcome (physiological or pathological change) S. Sequela
1. Water 2. Hydrogen ions (pH) 3. Other ions 1. Direct tissue damage 2. Altered physicochemical nature of the extrinsic species 1. Where in the body the extrinsic and intrinsic species occur (affected by pharmacokinetics) The adverse effect (See Table 2) The adverse reaction (Dose, Time, Susceptibility [DoTS] classification)
Acrolein (from cyclophosphamide)
Melphalan Mitoxantrone Edrophonium Malathion Prazosin Phenoxybenzamine Calcium channel blockers; digoxin and Na+/K+-ATPase Penicilloyl residue hapten N-acetyl-p-benzoquinone imine (paracetamol [acetaminophen]) Dextrose 5% Sodium bicarbonate Sodium ticarcillin Intrathecal vincristine Sulindac precipitation Antihistamines cause drowsiness only if they affect histamine H1 receptors in the brain – –
Classifications of adverse drug reactions
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Table 2. Examples of physiological and pathological changes in adverse drug reactions (some categories can be broken down further) Type of change 1. Physiological changes (a) Increased actions (b) Decreased actions
Examples
Hypertension (monoamine oxidase inhibitors); clotting (tranexamic acid) Bradycardia (beta-adrenoceptor antagonists); QT interval prolongation (antiarrhythmic drugs)
2. Cellular adaptations (a) Atrophy Lipoatrophy (subcutaneous insulin); glucocorticosteroid-induced myopathy (b) Hypertrophy Gynecomastia (spironolactone) (c) Hyperplasia Pulmonary fibrosis (busulfan); retroperitoneal fibrosis (methysergide) (d) Metaplasia Lacrimal canalicular squamous metaplasia (fluorouracil) (e) Neoplasia • Benign Hepatoma (anabolic steroids) • Malignant – Hormonal Vaginal adenocarcinoma (diethylstilbestrol) – Genotoxic Transitional cell carcinoma of bladder (cyclophosphamide) – Immune Lymphoproliferative tumors (ciclosporin)
suppression
3. Altered cell function IgE-mediated mast cell degranulation (class I immunological reactions) 4. Cell damage (a) Acute reversible damage • Chemical damage Periodontitis (local application of methylenedioxymetamfetamine [MDMA, ‘ecstasy’]) • Immunological Class III immunological reactions
reactions
(b) Irreversible injury • Cell lysis Class II immunological reactions • Necrosis Class IV immunological reactions; hepatotoxicity (paracetamol, after apoptosis) • Apoptosis Liver damage (troglitazone) 5. Intracellular accumulations (a) Calcification Milk-alkali syndrome (b) Drug deposition Crystal-storing histiocytosis (clofazimine); skin pigmentation (amiodarone)
2. DOTS In the DoTS system (SEDA-28, xxvii–xxxiii) adverse reactions are classified according to the Dose at which they usually occur, the Time-course over which they occur and the Susceptibility factors that make them more likely, as follows: • Relation to dose – Toxic reactions (reactions that occur at supratherapeutic doses) – Collateral reactions (reactions that occur at standard therapeutic doses) – Hypersusceptibility reactions (reactions that occur at subtherapeutic doses in susceptible individuals) • Time course – Time-independent reactions (reactions that occur at any time during a course of therapy) – Time-dependent reactions * Immediate or rapid reactions (reactions that occur only when a drug is administered too rapidly)
Classifications of adverse drug reactions
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First-dose reactions (reactions that occur after the first dose of a course of treatment and not necessarily thereafter) * Early reactions (reactions that occur early in treatment then either abate with continuing treatment, owing to tolerance or persist) * Intermediate reactions (reactions that occur after some delay but with less risk during longer term therapy, owing to the ‘healthy survivor’ effect) * Late reactions (reactions in which the risk increases with continued or repeated exposure) * Withdrawal reactions (reactions that occur when, after prolonged treatment, a drug is withdrawn or its effective dose is reduced) * Delayed reactions (reactions that occur some time after exposure, even if the drug is withdrawn before the reaction appears) • Susceptibility factors – Genetic – Age – Sex – Physiological variation (e.g. weight, pregnancy) – Exogenous factors (e.g. the effects of other drugs, devices, surgical procedures, food, smoking) – Diseases The following reactions have been classified in previous issues of SEDA using the DoTS system; in the italicized references to SEDA-31, the EIDOS and DoTS systems have both been used: ACE inhibitors: angioedema Adrenaline: hypertension Adrenaline: myocardial infarction Angiotensin II receptor antagonists: angioedema Anticoagulants, oral: skin necrosis Antipsychotic drugs: diabetes mellitus Antituberculosis drugs: hepatotoxicity Bisphosphonates: osteonecrosis of the jaw Cocaine: myocardial infarction Contrast media: nephrotoxicity Diuretics, loop and thiazide: hyponatremia Dopamine receptor agonists: pathological gambling Dopamine receptor agonists: sleep attacks Ephedrine: vasospasm Ergot-derived dopamine receptor agonists: fibrotic reactions Ethambutol: optic neuropathy Exenatide: nausea Fluvastatin: hepatitis and cholestatic hepatitis Gadolinium salts: nephrogenic systemic fibrosis Glucocorticoids: osteoporosis Heparin: type II thrombocytopenia Nitrofurantoin: lung disease Pseudoephedrine: toxic epidermal necrolysis SSRIs: suicidal behaviour Statins: acute pancreatitis Statins: myopathy and rhabdomyolysis Thionamides: agranulocytosis Vigabatrin: visual field loss Ximelagatran: liver damage
29.207 30.170 31.259 30.238 29.358 28.60 31.495 30.562 29.38 29.575, 30.535, 31.732 29.219 30.174, 31.269 28.162 30.171 30.176, 31.268 30.358 30.499 31.717 28.561, 31.735 28.185, 31.306 30.404, 31.439 30.303 30.172 29.19 31.715 30.516, 31.716 29.520, 30.490, 31.685 28.101, 29.99, 30.98, 31.137 30.411
Classifications of adverse drug reactions
xxxv
References 1. Aronson JK, Ferner RE. Joining the DoTS. New approach to classifying adverse drug reactions. BMJ 2003;327:1222–5. 2. Aronson JK, Ferner RE. Clarification of terminology in drug safety. Drug Saf 2005;28(10):851–70. 3. Ferner RE, Aronson JK. EIDOS: A mechanistic classification of adverse drug effects. Drug Saf 2010;33(1):13–23.
How to use this book THE SCOPE OF THE ANNUAL Volumes in the Side Effects of Drugs Annual (SEDA) series have been published since 1977. The series is designed to provide a critical account of new information relating to adverse drug reactions and interactions from the clinician’s point of view. It complements the standard encyclopedic work in this field, Meyler’s Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions, the 15th edition of which was published in 2006.
PERIOD COVERED The present Annual reviews all reports that presented significant new information on adverse reactions to drugs during 2007 and the first half of 2008; the next volume (SEDA-33) will cover the second half of 2008 and all of 2009. During the production of this Annual, some more recent papers have also been included; older literature has also been cited when it is relevant. Special reviews (see below) often cover a much wider range of literature.
SELECTION OF MATERIAL In compiling the Side Effects of Drugs Annual particular attention is devoted to publications that provide essentially new information or throw a new light on problems already recognized. Some confirmatory reports are also described. In addition, some authoritative new reviews are listed. Publications that do not meet these criteria are omitted. Readers anxious to trace all references on a particular topic, including those that duplicate earlier work, or to cross-check an electronic search, are advised to consult Adverse Reactions Titles, a monthly bibliography of titles from about 3400 biomedical journals published throughout the world, compiled by the Excerpta Medica Interna tional Abstracting Service.
Special reviews The special reviews deal in more detail with selected topics, often interpreting conflicting evidence, providing the reader with clear guidance. They are identified by the traditional prescription symbol and are printed in italics. This volume includes a Cumulative Index of the Special Reviews that were published in SEDA-11 to SEDA-31 and a list of the Special Reviews that appear in the current Annual.
CLASSIFICATION OF DRUGS Drugs are classified according to their main field of use or the properties for which they are most generally recognized. In some cases a drug is included in more than one chapter (e.g. lidocaine is mentioned in Chapter 11 as a local anesthetic and in Chapter 17 as an antidysrhythmic drug). Fixed combinations of drugs are dealt with according to their most characteristic component or as a combination product.
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How to use this book
xxxvii
DRUG NAMES Drugs are usually called by their recommended or proposed International Non-proprietary Names (rINN or pINN); when these are not available, chemical names have been used. If a fixed combination has a generic combination name (e.g. co-trimoxazole for trimethoprim + sulfamethox azole) then that name has been used; in some cases brand names have been used instead.
SYSTEM OF TAGGING REFERENCES References in the text are tagged using the following system, which was introduced in SEDA-24: M A R r C c H E S
A meta-analysis or other form of systematic review;
An anecdote or set of anecdotes (i.e. case histories);
A major review, including non-systematic statistical analyses of published studies;
A brief commentary (e.g. an editorial or a letter);
A major randomized controlled trial or observational study;
A minor randomized controlled trial or observational study or a non-randomized study;
A hypothesis article;
An experimental study (animal or in vitro);
Official (e.g. Governmental, WHO) statements.
The various editions of Meyler’s Side Effects of Drugs are cited in the text as SED-l4, SED-15, etc.; the Side Effects of Drugs Annuals 1–31 are cited as SEDA-1, SEDA-2, etc.
INDEXES Index of drugs: this index provides a complete listing of all references to a drug for which adverse effects and/or drug interactions are described. Index of adverse effects: this index is necessarily selective, since a particular adverse effect may be caused by very large numbers of compounds; the index is therefore mainly directed to adverse effects that are particularly serious or frequent, or are discussed in special detail; before assuming that a given drug does not have a particular adverse effect, consult the relevant chapters. For indexing purposes American spelling has been used, for example anemia, estrogen rather than anaemia, oestrogen.
Kelvin Chan1 SIDE EFFECTS OF DRUGS ESSAY
Regulating complementary and alternative medicines Over the past decade, the increasing popularity of complementary and alterna tive medicines (CAM) and over-the counter (OTC) health foods and supple ments, nutraceuticals and medicinal pro ducts from plants or other natural sources (inclusively known as botanicals, includ ing herbal medicines, or phytomedicines) has also brought concerns about the pro fessionalism of practitioners, and about the quality, efficacy, and safety of their treatment methods and the available pro ducts that are derived from herbal and natural sources (1R). These OTC products may contain excessive or banned pesticides, microbial contaminants, chemical toxins and other contaminants or adulterants, such as heavy metals, and pharmaceuticals. Con taminants can come from locations where the plants are grown, collected, or pro cessed. Toxins can come from poor storage conditions. The presence of pharmaceuti cals may be illogically claimed to be due to accidental contamination during produc tion; however, such products are also 1
The author of this year’s Side Effects of Drugs Essay is Kelvin Chan PhD, DSc, FSB, FCP, FRPharmS, FRSM. Professor Chan is Joint Chair Professor in Traditional Chinese Medicine at Faculty of Pharmacy, University of Sydney, NSW2006, and at the College of Health and Science, University of Western Sydney, NSW2560, Australia.
xxxviii
manufactured unprofessionally and are deliberately adulterated (2R). Environment-related factors can be con trolled by implementing standard operat ing procedures (SOP), leading to Good Agricultural and Collection Practice (GACP), Good Laboratory Practice (GLP), Good Supply Practice (GSP), and Good Manufacturing Practice (GMP) for producing these medicinal products, before Good Clinical Trial Practice (GCTP) for evaluation of efficacy. There fore, regulatory policies should be set up to oversee the quality and safety of these products before they are made available to the public as OTC medicines, or for prescription. The public’s faith in herbal and natural products, which they believe (often incorrectly) to be safer than syn thetic pharmaceutical medicines, can only be rewarded by instituting regulatory con trols on these products, which demand that they should provide traceability of their sources and manufacture, using good codes of practice. Some national govern ment authorities have set up regulatory controls over the starting materials that are supplied to herbal companies for the manufacture of herbal products in order to safeguard the interests of the public. In this essay I focus on the progress of regulatory standards (3S–5S). Some aca demic and professional bodies have also taken initiatives to build reliable and repu table databases for monitoring the adverse
Regulating complementary and alternative medicines
effects of CAM, and we shall summarize the key reviews that have been published (6R, 7R).
Australia and New Zealand (3 S) In Australia and New Zealand comple mentary medicines, including herbal, minerals, nutritional/dietary supplements, aromatherapy oils and homeopathic med icines, are regulated under therapeutic goods/products legislation. The Thera peutic Goods Administration (TGA), a division of the Commonwealth Depart ment of Health and Ageing, is responsi ble for administering the provisions of the legislation in Australia. The New Zealand Medicines and Medical Devices Safety Authority (Medsafe) administers the provision of legislation in New Zealand. In December 2003 the Australian and New Zealand governments signed a treaty to establish a single, binational agency to regulate therapeutic products, including medical devices prescription, OTC medicines and complementary medicines. The single agency has replaced Medsafe in New Zealand and the TGA in Australia. The role of this agency is to safeguard public health through regulation of the quality, safety and efficacy or performance of therapeutic products in both countries. The major activities of the new joint A ustralia New Zealand Therapeutic Pro ducts Agency are in product licensing, specifying labelling standards and setting advertising schemes, as well as determin ing the risk classes of medicines and creating an expanded list of ingredients permitted in Class I medicines. A new, expanded definition of comple mentary medicines has been proposed, and this definition is currently under con sultation. Related Australian and New Zealand legislation is being developed to
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implement the joint scheme. Once this leg islation is passed, the Treaty will come into force and the new joint regulatory scheme will begin. The agency was originally expected to commence operation no later than 1 July 2006 and to result in a single agency to regulate CAM. However, con sultation continues. In Australia, there has been an initiative to introduce nationwide registration of traditional Chinese medi cine (TCM) practitioners by 2012.
China (4S) China’s National Center for Adverse Drug Reaction (ADR) Monitoring was estab lished in 1989, before China joined the World Health Organization’s Programme for International Drug Monitoring in 1998. In March 2004, China formally promul gated the final version of the Regulations on Adverse Drug Reaction Reporting and Monitoring. This modern system supple ments an informal reporting system in scholarly publications. Procedurally, the formal Chinese mon itoring system requires pharmaceutical companies and health-care professionals to report most adverse events quarterly. However, new, uncommon, serious or ‘group’ adverse events are required to be reported within a shorter period. Reports are made to local centres, which then analyse and transmit them to a national ADR centre operated by China’s State Food and Drug Administra tion (SFDA). The national authority is then empowered to authorize further stu dies, publish formal warning announce ments or prohibit the use of a product. TCM products are also regulated as drugs in China. Because the use of TCM products is increasing worldwide, Chinese adverse reactions monitoring is particu larly, if not uniquely, useful in reporting
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Regulating complementary and alternative medicines
of TCM-related adverse drug reactions. A survey of Chinese ADR alerts and findings regarding TCMs and other sub stances is included, providing an overview of the breadth and timeliness of the infor mation available from China’s increasing pharmacovigilance activity. Overall, the system shows considerable progress and promise, especially if awareness of the procedures for reporting suspected ADRs continues to grow among China’s healthcare professionals and public.
take part in experimental and research work in setting standard guidelines and monographic standards for the quality and safety of Chinese medicinal materials (CMM) available in Hong Kong and Mainland China. The standard criteria include chromato graphic fingerprints and assay values of markers of Chinese medicinal materials, together with all the required monographic data in established pharmacopoeias, such as the British, Chinese, European, Japanese, and US Pharmacopeias. Generation of these data is overseen and advised by an International Advisory Board of renowned experts from various countries and regions in Australia, Canada, China, Germany, Japan, Thailand, the UK, and the USA. A recent ‘Commentary article’ has given an overview of the encouragement of a global agreement on harmonizing pharmacopeia monographic standards of
Hong Kong Chinese Materia Medica Standards (HKCMMS) (5S) The Department of Health (DOH) in Hong Kong’s SAR Government initiated the HKCMMS project in 2003 and com missioned experts available in the local universities and research institutes to
Table 1. Pharmacopoeia or standards of various countries or regions that have monographic standards for
Chinese medicinal materials (modified from reference 6)
Pharmacopoeia or monograph
Authority
Status and remarks
WHO Monographs on Selected Medicinal Plants Pharmacopoeia of the People’s Republic of China (CP) Australian Regulatory Guidelines for Complementary Medicines European Pharmacopoeia
World Health Organization, Geneva
Four volumes; unofficial
State Food and Drug Administration (SFDA), PR China Therapeutic Goods Administration (TGA), Australia European Directorate for the Quality Medicines & Healthcare (EDQM) Department of Health, Hong Kong SAR, PR China The Pharmaceutical Affairs Thai Food and Drug Administration, Ministry of Public Health British Pharmacopoeia Commission, MHRA, UK Dietary Supplements Health and Education Act (DSHEA) decides that botanicals are treated as food supplements Kotzting/Bayer. Wald, Germany
Official
Hong Kong Chinese Materia Medica Standards Japan Pharmacopoeia Thai Herbal Pharmacopoeia British Pharmacopoeia American Herbal Pharmacopeia (AHP); contains some monographs on Chinese medicinal materials Chinese Drug Monographs and Analysis
TGA, Official Official Official Official Official Official Unofficial
Verlag f€ ur Ganzheitliche Medizin – Dr Erich Wuhr GmbH; unofficial
Regulating complementary and alternative medicines
Chinese medicinal materials, such that the quality of these starting herbal ingre dients can be assured for the practice of TCM and the manufacture of Chinese medicinal products (6R). Table 1 summarizes the major stan dards in various countries and regions for reference.
Initiative on International Standards for Data Collection (7R) Research on morbidity from TCM is an emerging field. Currently, not much is known and there is a lack of international standards for data collection and reporting. Based on the experience of developing a computerized system for patient data collection by colleagues at the University of Technology Sydney (UTS) Acupunc ture Clinic and reporting results from that database, a start can be made towards developing guidelines for reporting simi lar results from TCM clinical audits. This study has reported data relating to 5735 patients who had undergone 29 697 courses of treatment. Patient information is collected by a computerized database recording the International Classification of Primary Care (ICPC), reason for encounter (RFE) and symptom for encounter (SFE) data, and TCM tongue, pulse, diagnostic, and treatment data. Data coding is automated, and systems for reliability testing and error reporting
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have been developed. The UTS database has a 2.7% error rate and is within inter national standards of 5% error. Musculoskeletal disorders are the most common presentation (41%) of all RFE, followed by general disorders (13%) and digestive disorders (8.1%). International standards must be set for TCM morbidity data collection methods and reporting. It is hoped that the meth ods described and reported in this paper are an initial step in the setting of such standards and that they will be adopted by other researchers. In particular, meth ods for testing and reporting data relia bility must be adopted if TCM morbidity studies are to maintain any credibility.
Conclusion Differences among national or regional regulations on the import and export of medicinal plants can affect the quality control of herbal products. The same med icinal plant products may be classified as foods, food supplements, functional foods, nutriceuticals, or prescribed herbal medi cines in different countries or regions. A harmonized regulatory system in phar macopeial standards of herbal materials generated from medicinal plants would improve the quality of herbal materials, thereby ensuring the safety of manufac tured herbal products and assisting herbal practitioners.
References 1. Chan K. Chinese medicinal materials and their interface with western medical concepts. J Ethnopharmacol 2005;96:1–18. 2. Chan K. Some aspects of toxic contaminants in herbal medicines. Chemosphere 2003; 52:1361–71.
3. Ghosh D, Skinner M, Ferguson LR. The role of the Therapeutic Goods Administration and the Medicine and Medical Devices Safety Authority in evaluating complementary and alternative medicines in Australia and New Zealand Toxicology. Toxicology 2006; 221:88–94.
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4. Zhou Y-B, Miller V, Hogan M, Callahan L. An overview of adverse drug reaction moni toring in china. Int J Pharmaceut Med 2006;20(2):79–85. 5. Hong Kong Chinese Materia Medica Stan dards (HKCMMS) Chinese Medicine Divi sion of the Department of Health Hong Kong SAR China Government. http://www. dh.gov.hk/english/main/main_cm/main_cm_ hkcmms.html.
6. Chan K, Leung KSY, Zhao SS. Harmoniza tion of monographic standards is needed to ensure the quality of Chinese medicinal mate rials. BioMed Central: Chin Med 2009;4:18. http://www.cmjournal.org/content/4/1/18. 7. Meier P, Rogers C. Reporting traditional Chinese medicine morbidity – a University of Technology, Sydney, project with an emphasis on developing standards for testing and report ing data. J Alt Compl Med 2006;12(6): 529–34.
Reginald P. Sequeira
1
Central nervous system stimulants and drugs that suppress appetite
(SED-15, 180;
SEDA-29, 1; SEDA-30, 1; SEDA-31, 1)
AMPHETAMINES
Note on spelling: In International Nonpro prietary Names (INNs), the digraph -ph- is usually replaced by -f-, although usage is not consistent, and -ph- is used at the beginnings of some drug names (e.g. compare fenflura mine and phentermine) or when a name that begins with a ph- is modified by a prefix (e.g. chlorphentermine). For the amphetamines the spellings that are used in SEDA are as follows: amfetamine, benzfetamine, dex amfetamine, metamfetamine (methylampheta mine) and methylenedioxymetamfetamine (ecstasy); however, for the general term for the group of drugs the more common spelling ‘amphetamines’ is used.
segment depression. Her troponin concentration was raised at 7 ng/ml. An echocardiogram showed an ejection fraction of 20% with basal akinesia and moderate mitral and tricuspid regurgitation. She responded well to diuretic therapy. Ventriculography showed reverse apical ballooning with a hyperdynamic apex and akinetic basal walls. Angiography showed normal coronary arteries. She was discharged taking an angiotensin converting enzyme (ACE) inhibitor and metoprolol, and an electrocardiogram 2 weeks later showed complete recovery of left ventricular function.
• A 25-year-old woman developed shortness of breath shortly after inhaling amfetamine. She had a sinus tachycardia (140/minute), a raised blood pressure (160/90 mmHg) and pulmonary edema. An electrocardiogram showed ST
Transient left ventricular apical ballooning syndrome was first described in Japan as ‘Takotsubo cardiomyopathy’. Many varia tions of this syndrome have been reported, but the reverse type of this syndrome, with a hyperdynamic apex and complete akinesia of the base (as opposed to classical apical ballooning), is rare. The term ‘stress cardio myopathy’ is now commonly used to describe all varieties of this condition, defined as reversible left ventricular systolic dysfunction triggered by an acute stressful event without significant coronary artery disease. This syndrome can involve any segment of the left ventricular wall and has been classified into four types. The authors postulated that amfetamine-induced tachycardia and hypertension triggered reverse Takotsubo cardiomyopathy in this patient.
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32001-0 2010 Elsevier B.V. All rights reserved.
Drug abuse Adderall (see also Drug formulations below), a treatment that has been approved by the FDA for attention deficit disorder (ADD)/attention deficit hyperactivity disorder (ADHD) in the
Amfetamine (SEDA-29, 2; SEDA-30, 1) Cardiovascular A rare case of reverse left ventricular apical ballooning syndrome has been attributed to amphetamines (1A).
1
2
USA, consists of a mixture of the neutral sulfate salts of dexamfetamine and amfeta mine, with the dextrorotatory isomer of amfetamine saccharate and d-levo amfetamine aspartate monohydrate. Of all calls related to Adderall received by several poison control centers in Texas during 1998–2004, 12% involved drug abuse (2c). There were 5140 calls about Adderall, including 3152 (61%) human exposures, 221 (4.3%) animal exposures, 1220 (24%) drug identification calls, and 547 (11%) requests for other information. Of the 3152 human exposures, 391 (12%) involved abuse. The number of calls received per year increased during the first half of this period but then fell. Most of the patients were male and the most frequently reported adverse effects were neurological, followed by cardiovascu lar and gastrointestinal. Adderall abuse exposures were more likely to involve almost all of the categories of adverse clin ical effects, and in particular the adverse effects of chest pain, hypertension, tachy cardia, nausea, dizziness, numbness, and tremor. When compared with non-abuse exposures, Adderall abuse exposures were more likely to (a) involve children under 13 years of age; (b) occur at others’ residences, schools and public areas; (c) be managed at health-care facilities; (d) involve more ser ious medical outcomes; (e) involve adverse clinical effects. This suggests that reported abuse exposures are more severe than reported after non-abuse exposures. This might be because of the use of higher doses of Adderall by abusers. Alternatively, Adderall abuse exposures might reflect reluctance for instances of abuse to be reported to poison control centers, unless thought to be severe. Lactation Dexamfetamine readily passes into human breast milk. In four women taking dexamfetamine the relative infant dose was <10% in their breast-fed infants, which is within a range that is generally accepted as being safe in the short term (3S). The median maternal dose was 18 (range 15–45) mg/day. In three infants tested, dexamfe tamine was undetectable in the plasma in one and present at 18 and 2 µg/l in the other two (4c).
Chapter 1
Reginald P. Sequeira
Nevertheless, given the broad range of cardiovascular and central nervous sys tem effects of amphetamines, and the fact that two of three infants examined had significant plasma concentrations of dexam fetamine, it is prudent to exercise caution.
Drug formulations Adderall XR® (mixed amfetamine salts in an extended-release cap sule formulation; MAS-XR) releases the first half of the dose after ingestion, and delayedrelease pellets begin to release the active drug about 4 hours later. The capsule contains the same 3:1 ratio of dexamfetamine to levoamfe tamine immediate-release tablets containing mixed salts of amphetamine (MAS-IR; Adderall). The systemic availability and phar macokinetic profiles of MAS-XR 20 mg/day are comparable to those associated with twice-daily MAS-IR 10 mg (5c). In a prospective, open, non-comparative, community-based study, the cardiovascular safety of MAS-XR was evaluated in 2968 children, aged 6–12 years, with ADHD (6c). Subjects whose symptoms were well con trolled with stimulant medication main tained their established treatment regimens for 2 weeks before enrolment. They were then converted to an approximately equiva lent once-daily dose of MAS-XR 10, 20, or 30 mg/day according to a medicationconversion algorithm, which could be adjusted to 40 mg/day for optimal efficacy and tolerabil ity. There were no clinically significant changes in blood pressure or pulse rate. One subject had QT interval prolongation > 25%, although there was no clinically significant pro longation of the mean QT interval. About 2.5% of the subjects had two consecutive sys tolic blood pressures (SBPs) or diastolic blood pressures (DBPs) > 95th percentile for age, sex, and height, and in 3.6% the pulse rate rose by 25–110/minute. There were no serious cardiovascular adverse events. In general, 151 subjects (5.1%) had a treatment-related adverse event that resulted in withdrawal of MAS-XR; of these, seven (0.2%) had cardio vascular events, including hypertension, bouts of palpitation, and tachycardia. Nine subjects reported treatment-related
Central nervous system stimulants and drugs that suppress appetite
cardiovascular adverse events of moderate to severe intensity. The cardiovascular events reported by five of these nine subjects were deemed to be possibly or probably related to treatment with MAS-XR. There were no deaths. The product labelling of MAS-XR was revised in August 2004 to include a warn ing that sudden death had occurred in asso ciation with amfetamine treatment in children with structural cardiac abnormal ities. In February 2005, Health Canada reviewed the safety data and suspended the sale of MAS-XR in Canada. Subse quently, the FDA re-evaluated the data on sudden deaths in patients taking MAS XR, based on about 30 million prescrip tions ordered between 1999 and 2003 (7S). The incidence rate of sudden death in chil dren and adolescents was on average 3.3/ 100 000 per year, and more than half of these deaths were linked to hereditary con duction and cardiac structural abnormal ities. In August 2005, Health Canada reinstated the marketing authorization of MAS-XR. Given the minor cardiovascular effects of ADHD treatment with MAS-XR, patients should undergo routine cardiac monitoring. MAS-XR should not be used in patients with structural cardiac abnormalities. It should be used only after thorough exami nation in patients with a history of unexplained syncope, shortness of breath, a history of unexplained seizure or a history of chest pain on exertion (8S). Taken together, these results (6c–8S) support those previously published (9C, 10C) and further demonstrate that the cardiovascular profile of MAS-XR is associated with small divergences from age-specific population norms that pose very limited risks in otherwise healthy patients with ADHD.
Ecstasy (3,4-methylenedioxymet amfetamine, MDMA) See Chapter 4.
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Metamfetamine (SEDA-29, 3; SEDA-30, 2; SEDA-31, 1) Metamfetamine hydrochloride, or ‘crystal meth’ or ‘ice’, is a potent and addictive form of amphetamine. Smoking metamfeta mine is associated with a rapid high similar to other sympathomimetic stimulant drugs. In a retrospective study of enquiries to two poisons centers and the UK National Poi sons Information Service relating to all recreational drugs, metamfetamine, and ecstasy, there was a small increase in the number of metamfetamine-related calls from 0.1% of all recreational drugs cases in 2000 to 1.23% in 2006; however, it was still uncommon compared with ecstasy (17–43% of all recreational drugs cases) (11C). In 2005–2006, there were 12 enqui ries related to metamfetamine compared with 455 for ecstasy (0.014% and 0.52% of all enquiries respectively). There were five presentations at emergency departments over 15 months compared with 171 for ecstasy. Of 254 440 urine samples screened at the workplace from 2000 to 2006, three were positive for metamfetamine and 147 for ecstasy. Observational studies Intranasal metam fetamine produced predictable effects on multiple behavioral and physiological mea sures before peak plasma concentrations were observed (12c). In 11 non-treatment seeking metamfetamine abusers, placebo or one of three doses of metamfetamine (12, 25, and 50 mg/70 kg) was administered double-blind, and metamfetamine plasma concentrations, cardiovascular subjective effects and psychomotor/cognitive perfor mance effects, were assessed. Metamfeta mine increased cardiovascular measures and positive subjective effects, with peaks at 5–15 minutes after drug insufflation, when plasma concentrations were still ris ing. Cognitive performance on less compli cated tasks improved with all doses of metamfetamine, whereas performance on more complicated tasks improved only by 12 and 25 mg doses.The dissociation between metamfetamine plasma concentra tions with cardiovascular measures and
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positive subjective effects has important implications for potential toxicity after repeated doses. Cardiovascular Metamfetamine has been associated with cardiomyopathy in young patients in a case–control study based on chart review of discharges between 2001 and 2004 from a tertiary care facility, in which 107 cases and 114 controls were iden tified (13R). Metamfetamine users had 3.7 times increased odds ratio (95% confidence interval (CI) = 1.8, 7.8) for cardiomyopathy adjusted for age, body mass index, and renal failure; 4 of 10 patients with cardiomyopathy and aged 45 years or over had used metam fetamine. This study suggested that young patients who use metamfetamine are not only at a greater risk of cardiomyopathy but also of a more severe form of cardio myopathy, confirming the findings of a case series from Honolulu (14c). Because a his tory of drug use is inconsistently documen ted in medical records, a control group with a random selection of patients from medical records alone would underestimate the pre valence of drug use. Since fewer cases than controls (38% versus 55%, P = 0.02) had urine tested for toxicology at admission, the results probably underestimate the true effect size for metamfetamine. It is concei vable that hospitalized metamfetamine users with cardiomyopathy represent patients with more severe disease. If so, it would suggest that there is a larger propor tion of non-hospitalized metamfetamine users with subclinical cardiomyopathy. The findings of this study are applicable only to the smoked form of metamfetamine, as this was the more common method of abuse. Obtaining a detailed history of substance abuse, especially of metamfetamine, and toxicology screening in young patients with cardiomyopathy or heart failure is recommended. Nervous system It has been suggested that a history of chronic metamfetamine abuse is associated with motor neuron disease (15c). Among 61 patients with motor neuron disease seen over a period of 30 months in Arkansas, 6 admitted to metamfetamine
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abuse. The age at onset was 31–41 years, mostly men, with bulbar onset. The sole woman abuser had progressive bulbar palsy; the other five had definite (n = 3) or probable (n = 2) progressive amyotrophic lateral sclerosis. None was HIV positive. Abusers smoked or snorted metamfeta mine; the most extensive abuser had used it daily for 10 years. Four patients devel oped symptoms while still abusing the drug; one of them had been abstinent for 1 year and one for 6 years when symptoms began. One had abused solely metamfetamine, three had also smoked marijuana, and two had abused multiple substances. Whether metamfetamine per se or a contaminant is the actual culprit remains to be determined. Physicians caring for patients with motor neuron disease should obtain a detailed his tory of substance abuse and environmental toxin exposure to shed further light on the mechanism of the underlying motor neuron disease. In a study of abstinent metamfetamine abusers (n = 32) and healthy controls (n = 30) in Korea, the metamfetamine abusers had disrupted integrities in frontal white matter associated with clinical manifestations, including impairment of frontal executive function (16c). Furthermore, disrupted fron tal white matter integrities were found only in male metamfetamine abusers, suggesting that men are more vulnerable to metamfeta mine-induced effects on frontal white mat ter. The estimated cumulative intravenous metamfetamine dose was in excess of 50 g. Considering the small sample size, the sex difference observed in this study should not be taken to imply that metamfetamine abuse does not harm women of reproductive age. The confounding effects of age and the higher prevalence of current smoking among metamfetamine abusers also need to be addressed. Moreover, the metamfetamine abusers in the study may not have been representative of ‘typical’ metamfetamine abusers, as a number of metamfetamine abusers commonly have co-morbid psychia tric disorders. These criticisms limit general ization of the findings of this study. Metamfetamine-related abnormalities may, in part, recover with abstinence, in
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grey matter, but not in white matter (17c). In 30 abstinent metamfetamine abusers and 20 healthy subjects, proton magnetic resonance spectroscopy was used to deter mine the concentrations of brain metabo lites, such as N-acetylaspartate and myoinositol, which are markers for neuro toxicity. The total cumulative lifetime dose of metamfetamine was estimated at around 100 g and the duration of abstinence at about 6 months. The self-reported nature of drug use and a lack of information regarding metamfetamine purity are caveats for interpreting the findings of this study. Another limitation of this study is that participants were not screened for HIV, and HIV infection in metamfetamine abusers has been reported to have additive effects on metabolic abnormalities in the brain (18c). Psychological The neural substrate dysfunc tions and disrupted cognitive, affective, and experiential processes observed in metam fetamine- and cocaine-dependent indivi duals have been reviewed (19R). Stimulant dependence is characterized by attenuated anterior and posterior cingulate activation, reduced inferior frontal and dorsolateral prefrontal cortex activation, and altered posterior parietal activation, suggesting inadequate demand-specific processing of information. Processes that have been most consistently reported to be deficient in functional neuroimaging studies include inhibitory control, executive functioning, and decision making. The authors con cluded that an emerging theme is that stimulant-dependent individuals show spe cific, rather than generic, brain activation differences, i.e. instead of showing more or less brain activation regardless of task, they have process-related brain activation differ ences that are consistent with a shift from context-specific, effortful processing to a more stereotyped habitual response generation. Fetotoxicity Prenatal metamfetamine expo sure has been associated with neuro behavioral patterns of reduced arousal, increased stress, and poor quality of move ment in neonates. In the Infant
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Development, Environment and Lifestyle (IDEAL) study, 13 808 subjects were screened and 1632 were eligible and con sented; 166 (of whom 74 had been exposed) were followed up (20c). Exposure was determined by detection in the meconium and self-reporting. The NICU Network Neurobehavioral Scale (NNNS) was admi nistered in the first 5 days of life. In heavy users of metamfetamine, there was lower arousal, more lethargy, and increased phy siological stress. First trimester use was related to increased stress abstinence and third trimester to poorer quality of move ment. Higher concentrations of ampheta mine metabolites in the meconium were associated with increased nervous system stress. It is unclear whether the observed neurobehavioral effects in neonates repre sented adverse effects of metamfetamine or acute withdrawal-like effects. The subtle effects observed in children exposed to pre natal metamfetamine have both short-term and potentially long-term implications. However, because of limitations, caution needs to be exercised when interpreting these preliminary results of the IDEAL study, and a ‘rush to judgement’ regarding the long-term outcomes of these children should be avoided (21c). Periventricular leukomalacia has been reported in a preterm infant with no other known susceptibility factors after in utero exposure to metamfetamine (22A). Longterm follow up at 24 months showed severe developmental delay, with spastic quadri plegic cerebral palsy that required baclofen. It is unclear whether other unknown con founding prenatal factors, including contami nants in the metamfetamine, contributed to this effect. The authors’ recommendation that premature infants exposed prenatally to metamfetamine should be screened for periventricular leukomalacia is justified. Susceptibility factors Genetic A family his tory of psychiatric illness may further increase the risk of recurrent psychotic symptoms associated with metamfetamine abuse. There was a positive correlation between the frequency of metamfetamine-related psy chotic episodes and scores on the Wender
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Utah Rating Scale, a scale that retrospec tively measures childhood behaviors relevant to ADHD. These findings were based on a study of behavioral characteristics in 39 drug-abstinent metamfetamine-dependent subjects who experienced psychotic symp toms associated with metamfetamine abuse (23c). However, the correlational patterns reported do not necessarily imply causality. A PICK1 (protein interacting with C kinase) gene has been implicated in the pathophysiology of metamfetamine psycho sis (24C). PICK1 plays a role in the targeting and localization of synaptic membrane pro teins, such as the dopamine transporter, and also interacts with alpha amino-3-hydroxy 5-methyl-4-isoxazole propionate (AMPA) receptors and metabotropic glutamate receptors, which have been implicated in the pathophysiology of substance abuse as well as schizophrenia. The association between PICK1 gene polymorphisms and metamfetamine abuse has been explored in 208 Japanese metamfetamine abusers and 218 healthy subjects. The effects of four highly frequent single nucleotide poly morphisms (SNPs), rs737622 (–332 C/G) and rs3026682 (–205 G/A) in the promoter region, rs713729 (T/A) in intron 3, and rs2076369 (T/G) in intron 4, were studied. Of these SNPs, rs713729 was significantly associated with metamfetamine abuse in gen eral and rs713729 and rs2076369 were signif icantly associated with spontaneous relapse of psychosis. The specific haplotypes of these SNPs were associated with metamfeta mine abuse. A gene reporter assay showed that the two SNPs in the promoter region significantly altered transcriptional activity. Sex Sex differences in susceptibility to metamfetamine neurotoxicity have been reported (25E, 26E), and estrogens may have played a neuroprotective role. Drug overdose Metamfetamine body packing can be fatal. Three Nigerian men were found to have concealed packages of metamfetamine HCl in their stomach, in quantities ranging from 73 to 498 g (27A). One died with acute poisoning from an estimated 20 g of metamfe tamine that had leaked into the stomach. His
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plasma concentration was 8.6 µg/ml when he was hospitalized, 17 hours before he died. An autopsy showed extreme pulmonary conges tion and edema, moderate hepatic edema, and petechiae. Analysis by GC/MS showed extre mely high concentrations of metamfetamine and its metabolite amfetamine in cardiac blood, urine, gastric contents, and all other autopsy samples. Impurity-profiling analysis of the seized metamfetamine showed that the metamfetamine smuggled by the three suspects originated from the same batch. Metamfetamine plasma concentrations in the other two suspects, who survived, were 8.6 and 7.8 µg/ml. In another study, a shift towards the use of alternative precursors for illicit manufacture of metamfetamine in Korea between 1997 and 2005 has been shown by determining the enantiomer ratio in the samples. This finding has considerable implications for profiling international trafficking of metam fetamine (28H). As a consequence of regula tory restrictions, clandestine laboratories have difficulties in obtaining pure ephedrine, and alternative precursors are increasingly being used. Accidental exposure With increasing preva lence of metamfetamine use and clandestine production at home, children are at risk of injuries resulting from living in a drugendangered environment. Chemicals used for clandestine metamfetamine production (such as precursors, solvents, reducing agents, bases, and acids) can be responsible. In homes where metamfetamine was being produced, two young children suffered che mical burns after ingesting commercial clea ners containing sulfuric acid (29A). In both cases metamfetamine and amfetamine were detected, confirming exposure. Several find ings led medical personnel to suspect a drugendangered environment. • A 5-year-old girl was found gasping and vomiting in the kitchen near an open bottle of Liquid Fire, a commercial cleaner containing sulfuric acid used as a drain opener. Her lips, tongue, and oropharynx were severely burned and there were partial-thickness burns on her hands. She had multiple healed marks on her chest, abdomen, left flank, and back. Arterial
Central nervous system stimulants and drugs that suppress appetite blood gas analysis showed a metabolic acidosis. Flexible esophagogastroscopy showed significant edema of the anterior and posterior oropharynx with esophagitis and gastritis. Microlaryngoscopy and bronchoscopy showed extensive burns on the uvula, tonsils, epiglottis, vallecula, vocal cords, and arytenoids. Her hair tested positive for metamfetamine and amfetamine. • A 2-year-old child ingested Liquid Lightening, which contained sulfuric acid used as a drain opener, and developed drooling, stridor, and skin blistering on the neck, chest, and abdomen. There were partial-thickness burns on the neck, chest, abdomen, lips, and anterior oral cavity. The child had a metabolic acidosis. Urine toxicology was positive for metamfetamine and amfetamine.
These children had suffered severe caustic ingestion in homes where metamfetamine was being produced. Although ingestion of household cleaners is usually accidental and not a result of illicit drug use or production, medical providers need to be aware of the chemicals associated with illicit drug pro duction to identify patients harmed in this environment.
Fenfluramines
(SED-15, 1333; SEDA-29, 11; SEDA-30, 7)
Cardiovascular Seven years after fenflura mines were withdrawn, reports of mitral and aortic valvular disease continue to appear (30A). • When a 39-year-old woman developed pneumonia, her systolic and diastolic murmurs, which had been previously detected, were re-evaluated. Echocardiography showed grade III mitral regurgitation and grade II/III aortic regurgitation. The valves were pearly white and retractile, with no commissural symphysis or calcification. From the age of 19 years she had taken intermittent treatment with anorectics for 10 years (cumulative total of 34 months of fenfluramine 60 mg/day and 3 months of dexfenfluramine 45 mg/day). The murmurs were first detected at the age of 25 years, 6 years after she had started taking anorectics. Histological examination of the resected valves showed proliferation of myofibroblasts expressing smooth muscle a-actin.
This case suggests that severe valvular re gurgitation associated with fenfluramines can
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occur late. Long-term health surveillance of anorectic exposed subjects may be necessary. The evidence implicating ion channels in pulmonary artery smooth muscle vaso constriction, proliferation, and/or reduced apoptosis has been reviewed (31R). Pulmonary arterial hypertension may be considered as a form of vascular channelo pathy. Experiments performed on cloned, voltage-activated potassium channels (Kv channels) in expression systems have con firmed that dexfenfluramine inhibits cloned Kv2.1 channels expressed in Xeno pus laevis oocytes (32E); a number of anor ecticdrugs, including aminorex, dexfenfluramine, phentermine, and sibu tramine, inhibit Kv1.5 channels expressed in CHO cells (33E). To reduce the risk of future epidemics of pulmonary arterial hypertension, it has been suggested that potential appetite-suppressant molecules should be screened in heterologous Kv channel expression systems. Nervous system Direct evidence of fenflur amine neurotoxicity in humans has emerged (34c). Using quantitative positron emission tomography (PET) with (14C)McN5652, a serotonin transporter ligand, global, and regional distribution volumes of the ligand were compared in 15 subjects who had pre viously used fenfluramine for weight loss and 17 age-matched controls. There was a significant reduction in ligand binding in 14 of the 15 brain regions of interest, more than 4 years after drug withdrawal. How ever, the study only showed an association between fenfluramine use and reduction in brain 5HT transporter density and did not prove that fenfluramine had caused this reduction. The fenfluramine-exposed group were mostly women, whereas the controls were men, leaving the possibility that sex differences might have played a part. Most of the subjects in the fenflura mine group had also been exposed to phen termine as part of a ‘Fen/Phen’ combination for weight loss for variable periods (average duration 8.3 months). Whether these changes are reversible cannot be deduced from this study, because the time since the last use of fenfluramine varied. Given the
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important role of 5HT neurons in various brain functions, reductions in 5HT transpor ter binding density associated with fenflur amine might be anticipated to predispose an individual to behavioral disturbances.
Atomoxetine Systematic reviews The efficacy and safety of atomoxetine in children and adolescents have been evaluated in a systematic review of nine randomized placebo-controlled trials (35M). Atomoxetine (n = 1150) was superior to placebo (n = 678) in reducing ADHD symptoms. The NNTB values for treatment response and relapse prevention were 3.43 (95% CI = 2.79, 4.45) and 10.3 (95% CI = 5.89, 40.62), respectively. The most common adverse events were gastro intestinal (reduced appetite, NNTH = 9; abdominal pain, NNTH = 22; vomiting, NNTH = 30; dyspepsia, NNTH = 49) and somnolence (NNTH = 19). Young age and high baseline hyperactive/impulsive symp toms were associated with more adverse events, and ADHD inattentive subtype was associated with fewer adverse events. Cardiovascular Since atomoxetine is a selec tive noradrenaline transport blocker, it could cause increased blood pressure by increasing noradrenaline concentrations in peripheral sympathetic neurons, an effect that could be masked in healthy subjects by central sympatholytic mechanisms. The pressor effect of atomoxetine (18 mg) has been studied in 21 patients with impaired central (n = 10) and peripheral (n = 11) autonomic nervous system functions in a randomized, crossover, placebo-controlled study (36C). Atomoxetine acutely increased sitting and standing SBPs in patients with central autonomic impairment by 54 and 45 mmHg respectively, compared with pla cebo. However, in those with peripheral autonomic impairment, atomoxetine had no pressor effect. The authors proposed that this suggests that a functional central sympatholytic pathway is essential to avoid hypertension in patients taking
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atomoxetine. They suggested caution when atomoxetine is used in patients with auto nomic impairment. Nervous system Seizures and seizurerelated symptoms have been studied using two of the manufacturers’ databases: the atomoxetine clinical trials database and the atomoxetine post-marketing spontaneous adverse event database (37c). The crude incidence rates of seizure adverse events with atomoxetine, methylphenidate, and placebo did not differ. In two children with ADHD, aged 6 and 8 years, relatively low doses of atomoxetine exacerbated and precipitated tics, which improved after withdrawal (38A). A 13 year-old boy was similarly affected (39A). Two cases of neurological complications requiring hospitalization occurred when atomoxetine was added to other psycho active drugs (40A). A 9-year-old taking cloni dine and dexamfetamine developed a psychosis, abnormal involuntary movements, and insomnia. An 18-year-old who took venlafaxine developed facial tics, tremors, and speech disturbance. The acute symptoms did not respond to diphenhydramine in either case, but resolved after atomoxetine and other medications were withdrawn. The possible explanations proposed by the authors included atypical atomoxetine effects, excess atomoxetine or metabolites due to poor CYP2D6 metabolizer status, drug–drug interactions leading to raised drug concentrations, or excess synaptic nora drenaline or dopamine concentrations. They suggested that there may be a risk of dyski nesias when atomoxetine is combined with dopaminergic, noradrenergic or serotonergic medications. Psychological Potential aggression and hostility have been studied in a meta-analysis of 14 acute clinical trials of atomoxetine for ADHD in children (atomoxetine, n = 1308; placebo, n = 806), active compara tor databases in children (atomoxetine, n = 566; methylphenidate, n = 472), and pla cebo-controlled studies in adults (atomoxe tine, n = 541; placebo, n = 405) (41M). In the placebo-controlled database, 21 patients
Central nervous system stimulants and drugs that suppress appetite
taking atomoxetine and 9 taking placebo had aggression/hostility events. In the active comparator database, there were seven events in patients taking atomoxetine and four in patients taking methylphenidate. In the adult database, there was one event in a patient taking placebo. The authors con cluded that events related to aggression or hostility occurred in less than 2% of patients and were not significantly more frequent in patients taking atomoxetine or methyl phenidate compared with placebo. Psychiatric Suicide-related events in 14 acute, double-blind, and placebo- or active comparator-controlled trials with atomoxe tine in children have been reviewed (42M). There were no completed suicides. The fre quency of suicidal ideation was 0.37% (5/1357) with atomoxetine versus 0% (0/851) with placebo (RR = 2.92; 95% CI = 0.63, 13). Frequencies of suicide-related events did not differ between methylphenidate and atomoxetine. The NNTH for an additional suicide-related event was 227 compared with the NNTB of 5 to achieve remission of ADHD symptoms. Electrolyte balance Hyponatremia has been attributed to atomoxetine (43A). Salivary glands Salivary stones have been associated with atomoxetine (44A). Gastrointestinal Atomoxetine has been given to 13 individuals who were seeking treatment for marijuana dependence in an 11-week open study; 8 completed the trial. Atomoxetine was associated with a large number of gastrointestinal adverse events: 10 of 13 subjects had mild to moderate adverse events, including nausea, vomiting, dyspepsia, and loose stools (45c). Liver Case reports that mentioned potential hepatobiliary events have been identified by a computerized search of the manufac turers’ spontaneous adverse events and clin ical trials databases (46c). Of 7961 children and adults who received atomoxetine in clinical trials, 41 had hepatobiliary events requiring additional analysis. Most were
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slight increases in transaminase activities. None progressed to liver failure. During the 4 years after marketing, 351 sponta neous reports of adverse events were related to the liver, of which 69 had other explanations unrelated to atomoxetine. Of the other 282 cases, 133 had possible con founding factors and were thought to be possibly related and 146 included too little information to assess. Three implicated ato moxetine as a probable cause of liver damage, one of whom had a positive rechal lenge; all three recovered after drug with drawal. The authors concluded that atomoxetine should be withheld in patients with jaundice or laboratory evidence of liver damage and should not be restarted. • An 8-year-old girl with ADHD was given atomoxetine hydrochloride. She complained of increased abdominal pain and occasional vomiting. Her transaminase activities and bilirubin concentration were markedly raised. Atomoxetine was withdrawn and a liver biopsy showed hepatitis with moderate piecemeal necrosis. She improved over 13 days.
The authors rated this as a probable adverse effect of atomoxetine (47A). Musculoskeletal The effects of atomoxetine on growth during long-term treatment for ADHD have been studied in 1312 patients, aged 6–17 years, of whom 61 were studied for 5 years (48C). The patients were slightly shorter than expected after 12 months and reached a maximum shortfall at 18 months; however, they returned to expected height by 24 months. Susceptibility factors The effects of CYP2D6 on the efficacy, safety, and tolerability of atomoxetine has been studied in children and adolescents using pooled data from atomoxetine clinical trials (49M). Poor meta bolizers had markedly greater reductions in mean symptom severity scores than exten sive metabolizers. Poor metabolizers had greater increases in heart rate and diastolic blood pressure and smaller increases in weight than extensive metabolizers. Several adverse events, including reduced appetite
10
and tremor, were more frequent in poor metabolizers. Drug overdose Pediatric cases of atomoxe tine ingestion reported to Texan poison control centers during 2003–2005 have been analysed (50c). There were higher rates of serious outcomes at a maximum dose of > 2.8 mg/kg or > 200 mg or more than four tablets. Serious outcomes were also more common if the exposure involved intentional self-harm. • A 17-year-old girl took 2840 mg of atomoxetine in an attempt to kill herself, and about 3 hours later she had a tonic–clonic seizure lasting 1 minute (51A). The serum atomoxetine concentration was 1995 µg/l and the serum naproxen concentration was 12 µg/l. • A 16-year-old girl with ADHD took 15 tablets of Concerta (modified-release tablets of methylphenidate 54 mg each), 5–10 tablets of Ritalin (methylphenidate 10 mg each) and 8 tablets of Strattera (atomoxetine 40 mg each) (52A). About 2 hours later she was awake and oriented but with a fluctuating level of consciousness. She complained of dizziness and had periodic jerks in the lower limbs and tremor in both hands. The serum atomoxetine concentration about 6 hours after intake was 6410 µg/l (usual target range 13–204). In a second blood sample taken about 21 hours after intake, the serum concentration was 2902 µg/l. Methylphenidate concentrations were 174 and 9 µg/l (usual target range at tmax 2–17 µg/l). She recovered with supportive therapy. Her CYP2D6 genotype was *4/*5; the *4 polymorphism is a splice-site mutation that yields inactive enzyme, and *5 is a gene deletion.
The authors of the second case concluded that intoxication with atomoxetine can take a benign course, even in CYP2D6 poor metabolizers.
Methylphenidate (SED-15, 2307; SEDA-29, 10; SEDA-30, 4; SEDA-31, 3) Two reviews have comprehensively addressed the adverse effects of drugs used in the treatment of ADHD (53R, 54R). Observational studies The effects of methyl phenidate have been studied in 303 children
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aged 3–5.5 years with ADHD. Methyl phenidate was effective in preschool children with ADHD, but was associated with a high rate of adverse events (55C). The strengths of the study included a meticulous diagnostic process, participation of all parents in an intensive behavioral management programme before considering medication, randomization to different doses of medica tion (1.25, 2.5, 5.0, and 7.5 mg immediaterelease methylphenidate tds) and long-term follow-up to assess safety. The diagnosis of ADHD remains a chal lenge, because the core symptoms – hyper activity, impulsivity, and inattentiveness – are consistent with developmental variations in preschool children. Clinicians must decide which of these children fall outside expected behavioral norms and should weigh the potential benefits of methylphenidate against the relatively high rate of adverse events (56r). Comparative studies Immediate-release methylphenidate versus modified-release methylphenidate Based on a chart review, switching from immediate-release methyl phenidate to OROS methylphenidate in adults with ADHD was associated with improved treatment adherence and effec tiveness. There were no differences between the two formulations in terms of tolerability (57c). The most common adverse events with immediate-release and OROS methylphenidate were headache (21% versus 26%), reduced appetite (24% versus 20%), tachycardia (13% versus 31%), and insomnia (21% versus 18%). Although the reports of tachycardia and mood instability were more common in patients taking OROS methylphenidate, they were not significantly so. This study had limita tions, particularly (a) potential reporter bias due to non-blind design and (b) adherence assessment based on self-reporting without objective measures such as methylphenidate serum concentrations. Modified-release methylphenidate versus atomoxetine A modified-release formula tion of methylphenidate has been compared with atomoxetine in a large randomized,
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controlled trial in children and adolescents with ADHD (58C). The study incorporated many desirable features, including rando mized design, a placebo arm, a large num ber of subjects, and optimal formulations and dosing strategies. The results suggested that while both drugs were better than pla cebo, methylphenidate was more effective in reducing the symptoms of ADHD than atomoxetine. Methylphenidate had a large effect size with a highly favorable NNTB of 3. Atomoxetine had a medium effect size and a less favorable, but still acceptable, NNTB of 5. Sleep difficulties were more frequent with methylphenidate, and somno lence with atomoxetine. Both drugs caused reduced appetite, but weight loss was greater with methylphenidate. Both increased diastolic blood pressure, but atomoxetine increased heart rate as well. The short dura tion of treatment (6 weeks) was adequate for detecting acute effects but was too short for measuring the effects on level of func tioning or on long-term adverse effects, such as growth suppression. A potential bias was introduced by including responders to previous methylphenidate treatment, while excluding patients who had not responded or could not tolerate it. Other limitations were the asymmetrical crossover after the initial 6-week trial, as only the methylphenidate group was switched to ato moxetine, and the lack of placebo control during this phase of the study. However, these data confirm that stimulants and ato moxetine, consistent with adrenergic activ ity, cause cardiovascular changes, which are on average small but whose long-term impact is unknown (59r). Methylphenidate versus clonidine Cloni dine, used alone or in combination with methylphenidate, has been evaluated in ADHD in a 16-week, randomized, doubleblind, placebo-controlled trial in 122 children aged 7–12 years with any type of ADHD (60C). The primary outcome was measured using Conners Teachers Abbreviated Symp tom Questionnaire (CTASQ) and the sec ondary outcome with Conners Abbreviated Symptom Questionnaire for Parents and the Children’s Global Assessment Scale
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(CASQPCGAS). On the CTASQ, clonidine did not improve the symptoms of ADHD, whereas methylphenidate gave significant improvement. On the CASQPCGAS score, clonidine not only improved the symptoms, but also caused more sedation, which never theless abated after 8 weeks, suggesting that it is more an acute than a long-term problem. In general, these findings should be viewed cautiously in the light of the differential rates of attrition across groups. The rate of attri tion was high in the placebo group, owing to lack of perceived efficacy or parental request or loss to follow-up. The findings were also limited by the exclusion of children with cer tain co-morbidities, such as mood and anxi ety disorders. Given that all of the subjects participated in psychoeducational and beha vioral interventions as part of the protocol, these results may be limited to settings in which these behavioral interventions are used. A further comparison of groups in terms of adverse events and changes from base line to week 16 showed that there were more instances of bradycardia (defined as a heart rate under 60/minute) in those who took clonidine (18% versus 3.4%), but no other significant group differences regard ing electrocardiography and other cardio vascular outcomes. Moderate and severe adverse events were more common in those taking clonidine (79% versus 49%) but not associated with higher rates of early withdrawal from the study. Drowsi ness was more common with clonidine, but generally resolved by 6–8 weeks. It is pru dent to monitor bradycardia and advise patients about the high likelihood of initial drowsiness. However, the safety of clonidine alone or with methylphenidate in children with ADHD and cardiac problems is not established. It is important to note that rare but important adverse events, either cardio vascular or psychiatric, may only be captured in a much larger sample. Should bradycardia or other intolerable adverse effects occur, clinicians can try lowering the dose of cloni dine gradually to see whether they resolve, but should avoid abrupt withdrawal of clo nidine, especially when patients are taking higher doses, to avoid rebound.
12
Cardiovascular In a retrospective cohort analysis 10 years (1994–2004) of Florida Medicaid, claims data were cross-linked to the Vital Statistics Death Registry data (61cr). The cohort included subjects aged 3–20 years. During 124 932 person-years of observation (n = 55 383), 73 youths died, 5 from cardiac causes. No cardiac death occurred during 42 612 person-years of sti mulant use. Hospital admissions from car diac causes occurred in 27 children (8 due to stimulant use, 11 during 35 671 person-years of former use, and 8 during 46 649 personyears of non-use); and 1091 children visited the emergency department for cardiac causes (8.7 per 1000 person-years). Current stimulant use was associated with a 20% increase in the hazard for emergency department visits compared with non-use. There was no increased risk for periods of former use compared with non-use. Two important findings emerged from this study. First, the use of stimulants was asso ciated with an increased incidence of car diac symptoms. Second, the incidence of fatal and serious events from circulatory causes was low and seemed to be similar to national background rates. Although multivariate analysis showed that cardiac risk factors were adjusted, unmeasured con founders may have been missed. This could have included concomitant use of other medications with cardiac adverse effects that were not reimbursed by Medicaid, such as oral decongestants or appetite sup pressants, or the presence of undiagnosed congenital heart disease. Thus, a direct comparison between non-use and current use periods may be biased. However, addi tional analysis of former use mitigated such bias, because the hazard rates of periods of former use and of non-use were almost identical. It is important to note that ato moxetine was not included in this analysis. Nervous system Acute and transient dys kinesia occurred within hours of taking modified-release methylphenidate in a stimu lant-naïve 7-year-old boy who had recently stopped taking risperidone; rechallenge resulted in recurrence of the dyskinesia (62A). An interaction between supersensitive
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dopamine receptors and acute exposure to an indirect dopamine receptor agonist could have caused this adverse reaction. The authors suggested slow neuroleptic drug withdrawal followed by an extended wash out period before starting a psychostimulant in a low dose, with immediate withdrawal of the psychostimulant if dyskinesia should occur. Psychiatric An acute psychosis has been attributed to methylphenidate (63A). • A 10-year-old boy with ADHD and a chronic pattern of somatization developed somatic hallucinations after an increase in the dose of methylphenidate. He had a history of prenatal exposure to cannabis and cocaine, leading to foster placements before adoption. He had been taking OROS methylphenidate 36 mg/ day for 2 years but, because of disruptive behavior, was switched to regular-release methylphenidate 10 mg bd and then titrated to 15 mg bd Within 2 days after dose titration, his somatic symptoms intensified and became overtly hallucinatory, incorporating new themes and bodily functions. He believed that his genitalia were deformed and that urine was constantly trickling down his legs. Over the next several days he developed delusional parasitosis – tactile hallucinations of bugs crawling beneath his skin. His treatment was switched to clonidine and he had no somatic complaints at follow-up 1 year later.
Methylphenidate has been known to pro duce psychotic symptoms, in particular tac tile hallucinations (64A), at therapeutic doses. These are rare and usually of acute onset, and they may occur in the context of underlying psychotic disorder or substance abuse (65A). • A 7-year-old girl with ADHD and mild mental retardation displayed excessive masturbation and hypersexual behavior during After methylphenidate therapy (66A). withdrawal of methylphenidate, her ADHD symptoms increased as expected, but her sexual behavior improved rapidly and disappeared completely in 1 week.
Hypersexuality and masturbation were deemed to have been direct effects of methylphenidate, on the grounds that there was no history of such behavior before methylphenidate and that it increased in
Central nervous system stimulants and drugs that suppress appetite
proportion with the increase in methylpheni date dose. In addition, the behaviors abated during drug holidays and completely disap peared shortly after drug withdrawal. Liver Hepatitis has been attributed to methylphenidate after liver transplantation (67A). • A 57-year-old Caucasian man, who had had an orthotopic liver transplantation 4 years before for chronic hepatitis C infection, developed liver function abnormalities. He had been maintained on cyclosporin, venlafaxine, omeprazole, hydrochlorothiazide, fosinopril, and a multivitamin formulation during the previous year. He denied using any herbal medications. In the months before presentation his liver function had been stable. His doctor had given him a long-acting formulation of methylphenidate 1 month earlier for impaired concentration and depressive symptoms refractory to venlafaxine. He had a raised antinuclear antibody titre (1:80) with a nucleolar pattern and anti-smooth-muscle antibodies (1:40). A liver biopsy showed a lobular and periportal necro-inflammatory infiltrate with predominant lymphocytes, plasma cells, and eosinophils, consistent with autoimmune hepatitis. On withdrawal of methylphenidate his liver function improved. He continued to take his previous medications plus prednisone 10 mg/day. His liver function normalized after a few months and the prednisone was withdrawn. He was also given a dexamfetamine/amfetamine combination. A liver biopsy 1 year after the acute episode of hepatitis showed marked improvement in the inflammatory infiltration.
Hematologic Hematological changes over the course of a 2-year trial of once-daily OROS methylphenidate in otherwise healthy children, aged 6–13 years, with ADHD, have been investigated (68C). Of 407 subjects, 289 completed 12 months and 229 completed 21 months. There were no clinically significant changes from baseline. These data suggest that long-term therapy with OROS methylphenidate has no clini cally relevant hematological effects, chal lenging the practice of routine hematological monitoring in otherwise healthy children with ADHD. Although rare cases of thrombocytopenia and easy bruisability, epistaxis, gingival bleeding, leucopenia, anemia, and
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eosinophilia have been reported in patients taking methylphenidate, a causal relation with the drug has not been established. Drug abuse The abuse potential of a single dose of OROS methylphenidate has been compared with that of immediate-release methylphenidate and placebo in healthy subjects with a history of recreational stimu lant use. Although requiring epidemiologi cal confirmation, the results suggested that OROS methylphenidate, with its character istic slow-ascending plasma concentration profile, may have less abuse potential. This conclusion was supported by fewer subjec tive responses during early hours compared with the immediate-release formulation, with its rapid drug delivery and accompany ing greater subjective effects (69C). This study did not pretest if the subjects could reliably report the effects of stimulants. This would have contributed to increased overall intersubject variation in subjective effects and a reduction in study power. Genotoxicity A threefold increase in geno mic damage in 12 children after 3 months of therapy with methylphenidate (70c) could not be replicated in a later study (71C). In a prospective study, genomic damage was studied in 38 children with ADHD before and after 1 month (n = 30), 3 months (n = 21), and 6 months (n = 8) after starting methylphenidate treatment. The measure of genomic damage was the frequency of micronuclei, a subset of chromosomal aber ration in peripheral lymphocytes. There were no changes in the number of micronucleated cells after methylphenidate treat ment at any time. The reasons for the discrepancies in the results of these studies have not been adequately addressed. The lack of supporting data should mitigate con cerns about the risk of cancer (72c, 73cr). Drug–drug interactions Disulfiram A possi ble drug–drug interaction of methylpheni date with disulfiram has been reported (74A). • A 33-year-old man with alcohol abuse and ADHD was given disulfiram 400 mg/day
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14 without any noticeable adverse effects. He was then given OROS methylphenidate 36 mg/day. After taking the first dose of methylphenidate, he rapidly experienced a psychotic episode that lasted several hours. He stopped taking methylphenidate, continued to take disulfiram and vitamins, and recovered fully. Three months later, disulfiram was withdrawn and he was again treated with OROS methylphenidate, after which he experienced no psychosis, even after increasing the dose to 54 mg/day.
It is important to have a washout period in patients taking disulfiram before starting methylphenidate. Risperidone Three children developed severe hyperactivity, agitation, and irritabil ity on taking methylphenidate after with drawal of risperidone. These adverse reactions resolved on withdrawal of methyl phenidate; rechallenge with methylpheni date in two of these patients did not produce adverse effects after a risperidone free interval (75A). As atypical antipsycho tic drugs are being increasingly used in the treatment of childhood behavioral disor ders, either alone or in combination, their safety needs to be established. Functional adaptations in receptors during risperidone treatment may lead to altered behavioral responses on switching to methylphenidate. Tapering the dosage of the antipsychotic drug and a drug-free interval are recom mended.
Reginald P. Sequeira
nearly sleepless. Modafinil was withdrawn, and the hallucinations resolved within 1 week.
According to the Naranjo Scale, modafi nil was possibly the cause of this patient’s hallucinations. There have been two other case reports of the potential of modafinil to trigger or exacerbate psychotic symptoms in a schizophrenic patient receiving clozapine (77A) and in a healthy man who partici pated in a research project (78A). Drug–drug interactions Monoamine oxidase inhibitors Although a case report has suggested that modafinil combined with tranylcypromine is safe (79A), another report has illustrated the need for a study on the safety of combining modafinil with non-selective monoamine oxidase inhibitors. • A 34-year-old Caucasian woman developed chorea and confusion. She had a 15-year history of depression, stable with tranyl cypromine 80 mg/day. Three days before admission she had started to take modafinil 200 mg/day to improve wakefulness. She became restless and had tics, severe choreiform movement of all limbs, lip smacking and rhythmic rapid tongue protrusions. Her neck was in opisthotonus with rhythmic bilateral rotations. She was treated with cyproheptadine for presumed serotonin syndrome. The symptoms resolved in 48 hours (80A).
Overdose Combined overdose with methyl phenidate and atomoxetine has been reported (see above, under Atomoxetine).
METHYLXANTHINES (SEDA-29, 1; SEDA-30, 5; SEDA-31, 8)
Modafinil
(SED-15, 2369; SEDA-29, 10; SEDA-30, 6; SEDA-31, 7) Nervous system Hallucinations have been attributed to modafinil (76A).
• A 53-year-old man with a 10-year history of unipolar major depression without psychotic symptoms or substance abuse took venlafaxine 225 mg/day for 3 months. Modafinil was added, titrated up to 200 mg/ day. Three weeks later, he developed severe visual and coenesthetic primary hallucinations and became increasingly fearful, agitated, and
Caffeine
(SED-15, 588; SEDA-29, 1; SEDA-30, 5; SEDA-31, 8)
Fetotoxicity The premature neonate of an Argentinian mother who reported drinking yerba maté (the traditional name for the Ilex paraguariensis shrub, family Aquifolia ceae) during pregnancy developed jitteri ness and irritability, a high pitched cry, hypertonia in the limbs and brisk tendon reflexes, consistent with a neonatal with drawal syndrome (81A). There were high
Central nervous system stimulants and drugs that suppress appetite
concentrations of caffeine and theobromine in the placenta, cord blood, neonatal urine, maternal and neonatal hair, meconium, and breast milk, demonstrating both acute and chronic prenatal and postnatal exposure to methylxanthines, present in high amounts in home-brewed maté. The symptoms gradu ally resolved at 84 hours of age, although residual irritability persisted at 24 days of age. Plant extracts containing caffeine and other methylxanthines have become popu lar in North America and Europe as com ponents of ‘energy dietary supplements’. The authors noted that because of migration, doctors are seeing increasing number of South American pregnant women who consume yerba maté during pregnancy in Europe. Furthermore, highly variable amounts of methylxanthines in plants (because of differ ent methods of preparation) make it difficult to recommend intake limits for popular herbbased drinks. It has been suggested that there is an association between maté drinking dur ing pregnancy and a risk of preterm and smallfor-gestational-age birth (82A). Drug–drug interactions Regadenoson Rega denoson is a selective adenosine A2A receptor agonist. Regadenoson-induced coronary blood flow reserve was not significantly affected by prior caffeine ingestion 200 mg in the majority of 41 subjects studied in a phase II, double-blind, randomized, placebo-controlled, crossover study (83C). Caffeine blunted the coronary vasodilatory effect of adenosine but had a limited effect on regadenoson. How ever, it attenuated the severity of adverse effects and improved the tolerability of rega denoson. Moderate coffee consumption does not seem to interfere with regadenoson stress myocardial perfusion imaging. Synephrine Dietary supplements promoted to enhance athletic performance often con tain herbal sympathomimetics, such as Citrus aurantium (synephrine) and caffeine. In a three-arm, double-blind, placebo-controlled, crossover study, 10 healthy adults aged 20–31 years took one dose of a dietary supplement (Ripped Fuel Extreme Cut®), containing synephrine 21 mg and caffeine 304 mg (84c). There were significant increases in post
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exercise diastolic blood pressure and post prandial plasma glucose concentrations. Peak plasma concentrations of synephrine after a single oral dose averaged <2 µg/l and caffeine concentrations averaged 6 mg/l. The kinetics of caffeine and synephrine were not altered by exercise. These results cannot be generalized to other individuals, such as those who are sedentary or overweight or have pre-existing conditions such as hyper tension. Such individuals could have exagger ated cardiovascular responses to ergogenic supplements, and different effects on exercise tolerance. Given the wide range of weight loss supplements, many of which contain no sympathomimetics (85r), diligent attempts to make an informed decision are hindered by vague product labelling that often provides no information on the content or dose of active ingredients (86r). Theanine L-Theanine, an amino acid in tea, which is structurally related to glutamate, antagonized the effect of caffeine on blood pressure but did not significantly affect jit teriness, alertness or other aspects of mood; it also slowed overall reaction time on the visual probe task (87c). In another rando mized, placebo-controlled, double-blind, balanced, crossover study, a combination of caffeine and theanine improved rapid visual information processing, numeric working memory, and delayed word recognition reac tion time. These results have implications in understanding differences between the effects of tea and coffee (88c). Zolpidem Caffeine partially reversed many effects of zolpidem, particularly the sedative and performance-impairing effects (89c). The mechanism for the interaction is not likely to be pharmacokinetic. Caffeine can not be considered as an antidote to zolpidem.
Theophylline (SED-15, 3361; SEDA-29, 1; SEDA-30, 5; SEDA-31, 8) Nervous system In eight children with idiopathic low seizure threshold and fever, theophylline possibly triggered seizures.
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The seizure patterns, electroencephalo graphy, brain single-photon emission com puted tomography (SPECT), cranial magnetic resonance imaging (MRI), and neurological outcomes have suggested that some kind of cerebrovascular involvement is related to theophylline-associated sei zures in young children (90A). Intermittent exposure to theophylline might be an addi tional susceptibility factor (91c). Diagnosis of adverse drug reactions The ‘Inje cocktail’ (92c), developed and vali dated in Korea, can be used as a tool to phenotype the in vivo enzyme activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A with only 4-hour blood sam pling and 8-hour urine collection after simultaneous single oral administration of five probe drugs (caffeine, losartan, ome prazole, dextromethorphan and midazo lam). This modified cocktail can be useful in countries where some of the probe drugs in the Cooperstown cocktail (93c) and Kar olinska cocktail (94c) are not readily avail able, and can be used as a convenient tool in studying drug–drug interactions or food– drug interactions involving possible enzyme induction or inhibition, including gastro intestinal xenobiotic metabolism.
DRUGS THAT SUPPRESS APPETITE (SEDA-29, 11; SEDA-30, 7; SEDA-31, 9) Systematic reviews The long-term effects of weight-reducing interventions in hyperten sive patients, specifically the effects of (a) dietary interventions intended to reduce body weight, (b) pharmacologically induced reductions in body weight, and (c) body weight reduction through invasive interven tions, have been assessed (95M). Seven studies (38 publications) involved dietary interventions. In eight studies (10 publica tions) pharmacological interventions (orlistat or sibutramine) were compared with placebo. There were no studies of surgical
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interventions or rimonabant that satisfied the inclusion criteria, mainly because the studies were not randomized, had a duration of less than 24 weeks, or did not allow extrac tion of results from hypertensive patients. The outcomes of primary interest were total mortality, cardiovascular morbidity and adverse events. Other outcome mea sures were the duration and magnitude of reductions in blood pressure and body weight. The reduction in blood pressure was greater in patients who used weight loss diets (systolic blood pressure weighted mean difference –6.3 mmHg; diastolic blood pressure –3.4 mmHg) or orlistat (–2.5 and –2 mmHg, respectively). Systolic blood pres sure rose by 3.2 mmHg with sibutramine. In patients with essential hypertension, therapy with a weight loss diet or orlistat resulted in reductions in body weight and blood pressure. Although sibutramine treatment reduced body weight, it did not lower blood pressure. This systematic review shows that there are no randomized controlled trials designed to determine the long-term effects of weight loss through dietary, pharmacolog ical or invasive interventions on patientrelevant endpoints, such as death and cardio vascular complications in obese patients and essential hypertension in those taking antihypertensive drugs. Although these results show that orlistat may be a helpful option in the antihypertensive therapy of obese hypertensives, some questions still remain. First, patients taking orlistat had adverse effects to a greater degree, espe cially gastrointestinal. Furthermore, it is unclear whether blood pressure remains low for longer once the medication is with drawn, because there is evidence that after 1 year body weight may increase, despite continued orlistat treatment. Rimonabant 5 mg/day had inconsistent effects on blood pressure changes, but 20 mg/day produced more consistent find ings, with greater reductions in systolic and diastolic blood pressures. A reduction in body weight of about 4 kg was necessary to achieve a reduction of about 6 mmHg in systolic blood pressure with dietary treat ment and of about 2.5 mmHg with orlistat. Although sibutramine reduced body weight,
Central nervous system stimulants and drugs that suppress appetite
it did not lower or might even have increased blood pressure. None of the studies has pro vided data to answer the question whether the risk of mortality or other patient-relevant end points can be lowered by weight reduction.
Phentermine
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more severe when present. Dilatation of the pulmonary ring, resulting from raised pul monic pressures, with subsequent pulmon ary regurgitation and reduced pulmonary artery pressures, appears to be a functional change in the hearts of these individuals with unknown long-term consequences.
(SED-15, 2804;
SEDA-31, 9) Cardiovascular Combined use of fenflura mine and phentermine (‘Fen–Phen’) has been associated with varying degrees of valvular regurgitation and pulmonary hyper tension. In 57 men and women (30 taking Fen–Phen and 27 controls matched for BMI) chamber dimensions, wall motion, diastolic function, valvular abnormalities, left ventricular ejection fraction, and pul monary artery pressures were measured (96c). Those taking Fen–Phen were studied shortly after they stopped taking it and again 6–12 months later. The results in these subjects were then compared with the findings in 660 randomly selected car diac patients with heart disease that was not caused by Fen–Phen. Valvular regurgitation was greatest among patients who had recently stopped taking Fen–Phen, 57% of all valves having regurgitation, 88% of which were ‘mild’; they also had the largest left ventricles at end diastole (5.03 cm) and systole and higher pulmonary artery pres sures (29 mmHg), associated with a lower incidence (14%) of pulmonic regurgitation. The number of people with aortic regurgita tion fell with time after the withdrawal of Fen–Phen. However, among those who con tinued to have aortic regurgitation, there was an increase in the number of those who progressed from mild to moderate regurgitation, with an associated increase in left ventricular end-diastolic and endsystolic dimensions and left ventricular ejection fraction. There was an increase in the incidence of pulmonic regurgitation with time and a fall in pulmonary artery pressure from 29 to 14 mmHg. The inci dence of tricuspid and mitral regurgitation fell with time, while pulmonic and aortic regurgitation tended to increase or become
Sibutramine
(SED-15, 3131; SEDA-29, 11; SEDA-30, 7; SEDA-31, 9)
The FDA has listed the names of 69 pro ducts marketed for weight loss that have not been approved by the Agency and has alerted consumers not to purchase or con sume these products. They contain unde clared, active pharmaceutical ingredients that pose serious health risks (e.g. high blood pressure, seizures, tachycardia, palpi tation, heart attacks or strokes). These ingre dients include sibutramine, rimonabant, phenytoin, phenolphthalein, and bumeta nide, some in amounts that far exceed the FDA’s recommended doses (97S). The FDA has also warned consumers not to take a product named Venom Hyperdrive 3.0, which was sold as a dietary supplement con taining undeclared sibutramine (98S). The product has been sold in various countries, including the USA, the UK, Canada, Swe den, France, the Netherlands, and Poland. The Swiss Agency for Therapeutic Pro ducts has also issued a warning regarding the serious health risks of the slimming pro duct ‘Zhen de Shou Fat Loss Capsules’, which contains sibutramine and has been sold via the Internet (99S). Cardiovascular The Sibutramine Cardio vascular Outcomes (SCOUT) trial has reported the effect of sibutramine 10 mg/day plus weight management on cardiovascular responses and weight loss in an initial single-blind, 6-week lead-in period (100C). Of 10 742 subjects, 97% had cardiovascular dis ease, 88% hypertension and 84% type 2 dia betes. Body weight fell (median 2.2 kg; 95th percentile changes 6.2, 0.5); waist circumfer ence was reduced by 2.0 cm (men: –8.5, 2.9;
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women: –9.0, 3.0), SBP fell by 3 mmHg (–24, 13) and diastolic by 1 mm Hg (–14, 10). Pulse rate increased by 1.5/minute (–11, 14). All changes were statistically sig nificant. Two consecutive increases in blood pressure or pulse rate of > 10 mmHg/bpm were observed in 4.7 and 3.5% of subjects, respectively. Fifteen subjects died; 10 deaths were attributed to a cardiovascular cause, equivalent to 1.2 and 0.8 deaths per 100 years of exposure respectively. A further analysis of a subgroup in this trial showed that despite an initial lower body weight, older women with cardio vascular disease and diabetes mellitus appear to lose as much weight as men. The adverse effects profile of sibutramine in this older at-risk population was similar to that pre viously observed in younger patients (101C). The SCOUT trial is a double-blind, ran domized, placebo-controlled, parallel group trial conducted at 300 centers in 16 coun tries, predominantly in Europe. The overall dropout rate due to adverse events was 6.8% during the lead-in phase. Cardiac dis orders (0.6%) and blood pressure increases (0.2%) caused a minority of withdrawals, whereas others were due to previously reported and well-known adverse effects of sibutramine. All these numbers are much lower than anticipated. The benefit to-harm balance needs to be assessed, since many patients with manifest cardiovas cular disease, and in particular those at high risk (i.e. diabetics with metabolic syndrome), actually have the problem of obesity (102r). Sibutramine had comparable effects in men and women, as well as in those taking or not taking b-blocker. Although the authors of SCOUT study highlighted the potential of b-blockers to protect against disadvantageous changes in blood pressure and heart rate, there are no ambulatory blood pressure data to support this claim. Identifying the subgroups that would parti cularly benefit from sibutramine might emerge when the complete trial results are available. The concomitant use of sibutramine and b-blockers raises two conflicting problems. The Hypertension–Obesity–Sibutramine (HOS) study has shown the effects of
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Reginald P. Sequeira
different antihypertensive regimens (felodi pine þ ramipril versus trandolapril þ vera pamil versus metoprolol þ hydrochloro thiazide). Although the antihypertensive effects were not significantly different, those who took metoprolol þ hydrochlor othiazide had the greatest falls in blood pressure. More importantly, metoprolol þ hydrochlorothiazide attenuated the effect of sibutramine on weight loss and waist cir cumference. This treatment abrogated the improvement in glucose tolerance, as assessed by an oral glucose tolerance test, suggesting that this combination of antihy pertensive drugs was associated with wor sening of the metabolic syndrome (103C). Weight gain associated with b-blockers, mostly due to an increase in body fat (104c), is a disadvantage for combining them with sibutramine in patients with the metabolic syndrome and coronary artery disease. Thus, a prognostic benefit of com bining sibutramine with a b-blocker has yet to be confirmed. Two women developed myocardial infarctions with acute ST segment elevation associated with the use of sibutramine and phentermine (105A). The absence of cardio vascular risk factors and the negative results of other investigations suggested that the use of appetite suppressants may have been responsible. Respiratory In an open study in 87 middleaged men with obesity (BMI = 34 kg/m2) and symptomatic obstructive sleep apnea, moderate weight loss (~10%) with sibutra mine and a weight loss programme improved the severity of sleep apnea with out increasing the blood pressure (106c). However, there was a small increase in rest ing heart rate. Given the high prevalence of hypertension in patients with sleep apnoea, it is important first to establish whether con cerns about the risks of using sibutramine are justified. Paradoxically, there was a ten dency for the SBP to fall during sibutramine therapy and then revert to baseline after drug washout. This finding is in keeping with the inhibitory clonidine-like effect of sibutramine on the central nervous system (107c).
Central nervous system stimulants and drugs that suppress appetite
Psychiatric Two reports have described another three cases of psychosis probably induced by sibutramine that responded to antipsychotic drugs (108A, 109A). Although causality is not yet established, sibutramine could be a susceptibility factor for people who are vulnerable to psychosis (110H). Drug–drug interactions Lorazepam Con current use of sibutramine 10 mg and loraz epam 2 mg resulted in hypoglycemic coma after less than 12 hours of fasting (111A). There was no other attributable cause, such as medication errors, ethanol ingestion, neoplasms, or liver disease.
Rimonabant The most frequent adverse effects of this endocannabinoid receptor antagonist are nausea, dizziness, diarrhea, and insomnia, each 1–9% more often than with placebo. Adverse effects leading to drug withdrawal occurred in 13–16% of patients taking the 20-mg dose (112C–115C). In the RIO-Europe, RIO-North America, and RIO Lipids clinical trials, drug withdrawal due to depression occurred in 6–7% of those tak ing rimonabant and an absolute increase of 2–5% over placebo. Because patients with mental illnesses were excluded from the RIO programme, these estimates of the potential of psychiatric adverse effects of this drug are conservative (116R, 117M).
DRUGS USED IN ALZHEIMER’S DISEASE (SEDA-29, 12; SEDA-30, 8; SEDA-31, 10)
Donepezil
(SED-15, 1179; SEDA-29, 12; SEDA-30, 8; SEDA-31, 10) Placebo-controlled studies In a multi national, double-blind, placebo-controlled trial at 98 sites, donepezil preserved
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cognition and global function in patients with severe Alzheimer’s disease (118C). Adverse events were consistent with the known cholinergic effects of donepezil, similar to those encountered in patients with mild to moderate Alzheimer’s disease. Furthermore, the Swedish Alzheimer Treat ment Study (SATS) has shown that 3-year treatment with donepezil had positive global and cognitive outcomes in the routine clin ical setting (119C). Since this study enrolled patients with concomitant diseases and medications, the 3-year-completion rate was 38%, comparable with earlier studies. Treatment with donepezil for 12 weeks has no significant advantage for donepezil over placebo in the treatment of clinically signifi cant agitation in patients with Alzheimer’s disease (120C). Sensory systems Intraoperative floppy-iris syndrome associated with long-term donepezil has been reported (121A). • A 75-year-old white man, who had taken donepezil for 8 years, had phacoemulsification under general anesthesia. Mydriasis was achieved preoperatively with topical cyclo pentolate, phenylephrine, and diclofenac. During surgery, the features of floppy-iris syndrome developed, such as billowing of the iris, which also prolapsed through the phaco and side-port incisions with progressive miosis. Phacoemulsion was continued with a low vacuum, a low flow rate and injection of 2.3% sodium hyaluronate to achieve good mechanical pupil dilatation and keep the iris away from the incision. The surgery was uneventful, and the patient had a visual acuity of 6/6.
Identifying drugs that can influence the out come of cataract surgery is crucial, and the authors stressed the importance of thor oughly evaluating a patient’s medication history preoperatively. Drug–drug interactions Atracurium Don epezil can prevent neuromuscular blockade due to atracurium during general anesthe sia. The authors recommended withdrawal of cholinesterase inhibitors 3–4 weeks before anesthesia in patients with Alzhei mer’s disease (122A).
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Memantine
(SED-15, 2250)
Systematic reviews There is considerable interest in assessing drugs used in the treat ment of Alzheimer’s disease for other types of dementias. Cholinesterase inhibitors and memantine do not have regulatory approval in most countries for treating vascular dementia. The available evidence has been examined in a systematic review (123M). The authors concluded that cholinesterase inhibi tors and memantine produce little benefit on cognition in patients with mild to moderate vascular dementia. Three donepezil, two galantamine, one rivastigmine, and two memantine clinical trials, comprising 3093 patients receiving drug therapy and 2090 patients on placebo, were included in this analysis. Compared with placebo, there were more dropouts and adverse effects, such as anorexia, nausea, vomiting, diarrhea, and insomnia, with cholinesterase inhibitors but not with memantine. The trials included in this meta-analysis lasted 6 months and were designed specifi cally to assess symptomatic rather than neuroprotective effects. Although the risk of adverse events with memantine seemed to be less than with cholinesterase inhibi tors, reporting was more limited, precluding full assessment. The clinical heterogeneity of patients with vascular dementia limits generalizability of the trial’s outcomes, because the effect of treatment on specific patients or subgroups cannot be defined.
Rivastigmine (SED-15, 3072; SEDA-30, 10; SEDA-31, 11) Observational studies There were no signif icant benefits of rivastigmine on the pro gression rate of mild cognitive impairment to Alzheimer’s disease or on cognitive func tion over a span of 4 years in patients with mild cognitive impairment (124C). Rivastigmine was not associated with any significant safety concerns. Placebo-controlled studies In the IDEAL (Investigation of Trans-Dermal Exelon in
Reginald P. Sequeira
Alzheimer’s disease) study, rivastigmine transdermal patches were compared with rivastigmine capsules and placebo in a 24 week double-blind, double-dummy, pla cebo- and active-controlled trial (125C). Patients with Alzheimer’s disease were ran domized to placebo or one of three active treatments: a 10-cm2 rivastigmine patch (delivering 9.5 mg/day), a 20-cm2 rivastig mine patch (17.4 mg/day) or rivastigmine capsules 6 mg bd A total of 1195 patients participated. The 10-cm2 patch showed similar efficacy to the capsules, with about two-thirds fewer reports of nausea (7.2% versus 23%) and vomiting (6.2% versus 17%), incidences that were not statistically different from placebo (5.0 and 3.3% for nausea and vomiting respectively). The 20-cm2 patch produced earlier improve ment and numerically superior scores com pared with the 10-cm2 patch and similar tolerability to the capsules. There was excel lent adhesion of the patch, even in tropical countries, where sweating is expected at the site of application of the patch. There was no skin irritation. Cardiovascular Complete heart block has been attributed to rivastigmine (126A). • A 67-year-old Turkish woman with Alzheimer’s disease developed dizziness and syncope. She had taken amlodipine 5 mg/day for hypertension and nateglinide 120 mg/day for diabetes mellitus for over 5 years and oral rivastigmine 6 mg/day for 5 months. She had had dizziness since she had started to take rivastigmine. Her blood pressure was 90/ 60 mmHg and her pulse rate 34/minute. An electrocardiogram showed complete atrio ventricular (AV) block. Echocardiography, serum electrolytes, cardiac biochemical markers and the coronary arteries were normal. A temporary transvenous pacemaker was implanted, and amlodipine and rivastigmine were withdrawn. Two days later, the AV block reverted spontaneously to sinus rhythm. Complete AV block recurred after rivastigmine 6 mg/day was restarted and she required a permanent pacemaker.
According to the Naranjo Scale, there was a probable association between rivas tigmine therapy and complete AV block. Other cholinesterase inhibitors used for
Central nervous system stimulants and drugs that suppress appetite
treating Alzheimer’s disease can also cause AV block in susceptible individuals. Nervous system Therapy with rivastigmine in patients with mild Alzheimer’s disease induces remodelling of the cholinergic and related neuronal networks in the brain, which is clinically manifested by reduced progression of the disease. Changes in 11 C-nicotine binding have been assessed by dual-tracer PET scanning in 10 patients with mild Alzheimer’s disease (127c). The main cognitive domain associated with nico tinic receptors after treatment was the attention domain. Drug formulations The pharmacokinetics of rivastigmine from a transdermal patch cor related with inhibition of plasma butyrylcholinesterase enzyme activity in 51 patients. Average exposure with a 10-cm2 patch was comparable with rivastigmine capsules 6 mg bd. In those who used the 10-cm2 patch, nausea and vomiting occurred in 8 and 4% of patients respectively. In those who used capsules 12 mg/day, nausea and vomiting occurred in 28 and 17% respectively. In total, 16 patients withdrew because of adverse events, mainly gastrointestinal. Drug administration route The regional variation in transdermal availability of rivas tigmine has been explored (128c). Taking the upper back as the reference site, the relative availability of rivastigmine from the other anatomical sites was 100% for the chest, 92% for the upper arm, 80% for the abdo men and 71% for the thigh. From all body sites, rivastigmine was detectable in less than an hour after application of the patch. Drug–drug interactions Memantine Conco mitant administration of memantine did not alter the extent of systemic exposure to riv astigmine and its metabolite NAP226-90 at steady state in an open single-center study in patients with mild to moderate Alz heimer’s disease (129c). The combination was well tolerated when a gradual step-up approach was used to increase the dose of
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21
memantine in patients already stabilized on rivastigmine.
Tacrine
(SED-15, 3279; SEDA-27, 7)
Susceptibility factors Genetic In 69 patients of Caucasian origin taking tacrine for Alz heimer’s disease, 241 SNPs in 19 candidate genes potentially related to hepatotoxicity have been genotyped (130c). The data sug gested, but did not prove, an association between tacrine-induced transaminase rises and genetic variants in ABCB4, which encodes the phosphatidylcholine transpor ter multidrug resistance protein 3 (MDR3). Tacrine, however, does not seem to be either a substrate or an inhibitor of MDR3. The mechanisms by which tacrine interacts with MDR3, phosphatidylcholine transport, and possibly membrane fluidity, requires further investigation. This study has also highlighted the limitations of genetic studies of rare adverse events, since genotyping strategies that evaluate multiple genes or whole genomes will have limited statistical power. Hepatic gene expression has been deter mined using microarray in rats treated with single dose of tacrine (131Ec]. The interleukin 6 gene was identified as a potential candidate for susceptibility to changes in transaminases. In the same study, 69 patients with Alzhei mer’s disease taking tacrine, with or without altered transaminases, were genotyped for 17 interleukin-6 gene polymorphisms. The results suggested that the interleukin-6 geno type may be a susceptibility factor. An obvious limitation of this study was the small number of patients and the large number of SNPs investigated, raising the possibility of false-positive associations. Moreover, one cannot exclude the possibility that the associa tion with interleukin-6 is due to linkage dis equilibrium with a neighboring gene on chromosome 7. Given that tacrine is no longer used in clinical practice, further investigations will be of limited value. However, the role of acute dosing in rats in identifying candidate genes associated with drug-induced liver damage in humans merits further study.
22
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95. Horvath K, Jeitler K, Siering U, Stich AK, Skipka G, Gratzer TW, Siebenhofer A. Long term effects of weight reducing inter ventions in hypertensive patients. Arch Intern Med 2008;168:571–9. 96. Fleming RM, Boyd LB. The longitudinal effects of fenfluramine–phentermine use. Angiology 2007;58:353–9. 97. Anonymous. Weight loss pills. Warning about serious health risks. WHO Newslett 2009;1:7. 98. Anonymous. Dietary supplements contain ing undeclared drug. WHO Newslett 2009;2:7. 99. SwissMedic. Swiss Agency for Therapeutic Products. Dangerous side effects of the ille gal slimming product ‘Zhen de Shou’. http:// www.swissmedic.ch/aktuell/00003/00687/ index.html?lang=en. 100. Torp-Pedersen C, Caterson I, Coutinho W, Finer N, Van Gaal L, Maggioni A, Sharma A, Brisco W, Deaton R, Shepherd G, James P, SCOUT Investigators Cardiovascular responses to weight management and sibu tramine in high-risk subjects: an analysis from the SCOUT trial. Eur Heart J 2007;28:2915–23. 101. Coutinho WF. The obese older female patient: CV risk and the SCOUT study. Int J Obesity 2007;31:S26–30. 102. von Haehling S, Lainscak M, Anker SD. Sibutramine in cardiovascular disease: is SCOUT the new STORM on the horizon? Eur Heart J 2007;28:2830–1. 103. Scholze J, Grimm E, Herrmann D, Unger T, Kintscher U. Optimal treatment of obesityrelated hypertension. The Hypertension– Obesity–Sibutramine (HOS) study. Circulation 2007;115:1991–8. 104. Lainsack M, Keber I, Anker SD. Body composition changes in patients with systo lic heart failure treated with beta blockers: a pilot study. Intl J Cardiol 2006;106:319–22. 105. Azarisman SM, Magdi YA, Noorfaizan S, Oteh M. Myocardial infarction induced by appetite suppressants in Malaysia. N Engl J Med 2007;357:1873–4. 106. Yee BJ, Phillips CL, Banerjee D, Caterson I, Hedner JA, Grunstein RR. The effect of sibutramine-assisted weight loss in men with obstructive sleep apnea. Int J Obesity 2007;31:161–8.
Central nervous system stimulants and drugs that suppress appetite 107. Birkenfeld AL, Schroeder C, Pischon T, Tank J, Luft FC, Sharma AM, Jordan J. Paradoxical effect of sibutramine on auto nomic cardiovascular regulation in obese hypertensive patient. Clin Autonom Res 2005;15:200–6. 108. Rosenbohm A, Bux CJ, Connemann BJ. Psychosis with sibutramine. J Clin Psycho pharmacol 2007;27:315–7. 109. Litvan L, Alcoverro-Fortuny O. Sibutra mine and psychosis. J Clin Psychopharma col 2007;27:726. 110. Fern´andez P, Peiró AM. A sibutramineinduced delusional disorder relapse. J Neu ropsychiatry Clin Neursosci 2007;19:88–9. 111. Lin Y-Y, Hsu C-W, Chu S-J, Tsai S-H. Another dangerous combination for hypogly cemic coma: Concurrent use of sibutramine and lorazepam. Q J Med 2008;101:243–4. 112. Després JP, Golay A, Sj¨ostrom ¨ L, Rimonabant in Obesity–Lipids Study Group. Effects of rimonabant on metabolic risk fac tors in overweight patients with dyslipide mia. N Engl J Med 2005;353:2121–4. 113. Van Gaal LF, Rissanen AM, Sheen AJ, Ziegler R, Rossner S, for the RIO–Europe Study Group. Effects of cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1 year experience from the RIO–Europe study. Lancet 2005;365:1389–97. 114. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J. RIO–North Amer ica Study Group. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in over weight or obese patients. J Am Med Assoc 2006;295:761–5. 115. Scheen AJ, Finer N, Hollander P, Jensen MD, van Gaal LF, RIO–Diabetes Study Group. Group efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes. Lancet 2006;368:1160–72. 116. Padwal RS, Majumdar SR. Drug treatments for obesity: orlistat, sibutramine, and rimo nabant. Lancet 2007;369:71–7. 117. Curioni C, Andre C. Rimonabant for over weight or obesity. Cochrane Database Syst Rev 2006;18:CD 006162(4). 118. Black SE, Doody R, Li H, McRae T, Jambor KM, Xu Y, Sun Y, Perdomo CA,
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Richardson S. Donepezil preserves cognition and global function in patients with severe Alzheimer’s disease. Neurology 2007;69:459–69. Wallin AK, Andreasen N, Eriksson S, Bats man S, Nasman B, Ekdahl A, Kilander L, Grut M, Ryden M, Wallin A, Jonsson M, Olofsson H, Londos E, Wattmo C, Jonhagen ME, Minthon L, Swedish Alzheimer Treat ment Study Group. Donepezil in Alzheimer’s disease: what to expect after 3 years of treat ment in a routine clinical setting. Dementia Geriatr Cognitive Disord 2007;23:150–60. Howard RJ, Juszczak E, Ballard CG, Ben tham P, Brown RG, Bullock R, Burns AS, Holmes C, Jacoby R, Johnson T, Knapp M, Lindesay J, O’Brien JT, Wilcock G, Katona C, Jones RW, DeCesare J, Rodger M, CALMAD Trial Group. Donepezil for the treatment of agitation in Alzheimer’s dis ease. N Engl J Med 2007;357:1382–92. Papadopoulos R, Bachariou A. Intraopera tive floppy-iris syndrome associated with chronic intake of donepezil. J Cataract Refract Surg 2007;33:1997–8. Baruah J, Easby J, Kessel G. Effects of acetylcholinesterase inhibitor therapy for Alzheimer’s disease on neuromuscular block. Br J Anaesth 2008;100:420. Kavirajan H, Schneider LS. Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomized controlled trials. Lancet Neurol 2007;6:782–92. Feldman HH, Ferris S, Winblad B, Sfikas N, Mancione L, He Y, Tekin S, Burns A, Cummings J, der Ser T, Inzitari D, Orgo gozo JM, Sauer H, Scheltens P, Scarpini E, Herrmann N, Farlow M, Potkin S, Charles HC, Fox NC, Lane R. Effect of rivastigmine on delay to diagnosis of Alzheimer’s disease from mild cognitive impairment: the InDDEx study. Lancet Neurol 2007;6:473–5. Winblad B, Grossberg G, Frolich L, Farlow M, Zechner S, Nagel J, Lane R. IDEAL A, 6-month, double-blind, placebo controlled study of the first skin patch for Alzheimer’s disease. Neurology 2007;69:S14–2. Kayrak M, Yazici M, Ayhan SS, Koc F, Ulgen MS. Complete atrioventricular block associated with rivastigmine therapy. Am J Health-Syst Pharm 2008;65:1051–3.
28 127. Kadir A, Darreh-Shori T, Almkvist O, Wall A, Langstrom B, Nordberg A. Changes in brain 11C-nicotine binding sites in patients with mild Alzheimer’s disease following rivastigmine treatment as assessed by PET. Psychopharmacology 2007;191:1005–14. 128. Lefevre G, Sedek G, Huang HA, Saltzman M, Rosenberg M, Kiese B, Fordham P. Pharmacokinetics of a rivastigmine trans dermal patch formulation in healthy volun teers: relative effects of body site application. J Clin Pharmacol 2007;47:471–8. 129. Shua-Haim J, Smith J, Picard F, Sedek G, Athalye S, Pommier F, Lefevre G. Steadystate pharmacokinetics of rivastigmine in patients with mild to moderate Alzheimer’s
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disease not affected by co-administration of memantine. An open label, cross-over, sin gle-center study. Clin Drug Invest 2008;28:361–74. 130. Alfirevic A, Mills T, Carr D, Barratt BJ, Jawaid A, Sherwood J, Smith JC, Tugwood JD, Hartkoorn R, Owen A, Park KB, Pir mohamed M. Tacrine-induced liver damage: an analysis of 19 candidate genes. Pharmacogenet Genomics 2007;17:1091–9. 131. Carr D, Alfirevic A, Tugwood JD, Barratt BJ, Sherwood J, Smith J, Pirmohamed M, Park BK. Molecular and genetic association of interleukin-6 in tacrine-induced hepato toxicity. Pharmacogenet Genomics 2007; 17:961–72.
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Antidepressant drugs
GENERAL Antidepressants and emergent suicidality Before reviewing recent publications in this controversial area, it will be helpful to review the background briefly. The term ‘emergent suicidality’ refers to suicidal thoughts or behaviors that occur soon after an anti depressant is introduced. Emergent suicidality may be a symptom of the underlying psy chiatric illness, e.g. depression, that led to use of the antidepressant, but the possibility that antidepressants may paradoxically cause or increase suicidality in some individuals has been periodically raised for decades. This most recently came to attention in 2005 when the US Food and Drug Administration (FDA) issued a black-box warning that all antidepressants increase the risk of suicidal thinking and behavior in children and ado lescents. The warning was based on a meta analysis of randomized placebo-controlled trials that showed that in younger people suicidal thinking and behavior occurred twice as often in those taking an antidepres sant as it did in those taking placebo; however, within this data set there were no completed suicides in either group (1M). Sub sequent analyses of suicidality in placebocontrolled antidepressant trials in adults have shown that the risk of both suicidal behaviour (completed suicide, attempted suicide, or preparatory acts) and suicidal ideation are age dependent (2M). Compared Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32002-2 � 2010 Elsevier B.V. All rights reserved.
with placebo, antidepressant use is associated with an increased risk of suicidal behavior and ideation among those under the age of 25 years (i.e. children, adolescents, younger adults). Among those aged 25–64 years, there is a neutral effect on suicidal behavior and possibly a protective effect on suicidal ideation. Among those aged 65 years and older, antidepressants are associated with a reduced risk of suicidal behavior and idea tion compared with placebo (2M). An updated meta-analysis conducted by Lilly, the manufacturers of fluoxetine, assessed suicidality in a database that brought together results from 18 double-blind, placebo-controlled fluoxetine trials in adults (fluoxetine, n = 2200; placebo, n = 1551) (3M). Fluoxetine treatment led to greater improve ment and faster resolution of suicidal idea tion than placebo. Of course, this result does not exclude the possibility that there may be individual patients in whom the opposite occurs, i.e. the result is still compatible with there being adults in whom fluoxetine leads to increased suicidal ideation. In a secondary analysis of data from an open 12-week trial of fluoxetine 20 mg/day in out-patients with an episode of non-psychotic major depression, 59 of 414 subjects (14%) without suicidal ideation at baseline reported suicidal ideation on at least one subsequent visit (4c). Independent factors associated with suicidal ideation included emergence of acti vation, worsening of depression, female sex, younger age, and having thoughts that life was not worth living before treatment. Emer gent suicidal ideation was associated with treatment resistance, i.e. depression that was more difficult to treat. The authors concluded that emergence of suicidal ideation was rela tively common, at least in this trial of fluox etine, and was associated with the emergence
29
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of activation and overall symptomatic wor sening. The lack of a placebo group means that one cannot determine to what extent the emergence of suicidal ideation in this study reflected the natural history of the underlying depressive illness, an effect of fluoxetine treat ment or both. However, the association of suicidal ideation with symptomatic worsening strongly suggests that suicidal ideation was a symptom of the underlying depressive illness. Elderly patients with major depression who took either paroxetine or nortriptyline were divided into four groups: those with no suici dal ideation, those with emergent suicidal ideation, those with persistent suicidal idea tion, and those who had resolved suicidal ideation (5c). The rates of emergent, persistent, and resolved suicidality were 7.8, 13, and 16%, respectively. The rates of emergent suicidal ideation were the same in those who took paroxetine or nortriptyline. Patients with emergent suicidality had lower selfesteem than non-suicidal patients at the start of treatment, were more likely to maintain higher depression scores, and had higher levels of anxiety and agitation during treat ment than patients with resolved suicidality. Emergent suicidal ideation was not asso ciated with akathisia. Emergent suicidal idea tion was associated with treatment resistance, i.e. depression that was more difficult to treat. In a retrospective cohort study using the UK General Practice Research Database, the risk of completed suicide and suicide attempts in adults aged 18–89 years taking venlafaxine was compared with the risk associated with citalopram, fluoxetine, and dothiepin (6c). Venlafaxine was associated with an increased unadjusted risk of completed suicide and attempted suicide. However, compared with patients taking other antidepressants, those who took venlafaxine were more likely to have susceptibility factors for suicide, includ ing a prior suicide attempt, and markers for severe or treatment-resistant depression. After adjustment for these confounders, the risks of both completed and attempted suicide with venlafaxine were substantially reduced. In summary, the increased risk of attempted and completed suicide in patients taking ven lafaxine compared with other antidepressants appears to be largely due to the increased
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likelihood that it will be prescribed for patients at higher risk of suicide rather than an increased likelihood that it causes suicidality. Liver A detailed review of antidepressantmediated liver damage has highlighted that the mechanisms are not understood (7R). In some reports it was not possible to estab lish causality, because of underlying liver damage or the concurrent use of other drugs. Among selective serotonin re-uptake inhibitors (SSRIs) there were more cases of hepatotoxicity with paroxetine than with other SSRIs. The most serious cases of hepa tic damage were seen with nefazodone, a serotonin–noradrenaline re-uptake inhibitor (SNRI), which led to its withdrawal in 2003 and 2004. Reports of hepatotoxicity were also noted with monoamine oxidase inhibi tors (MAOIs) and tricyclic antidepressants. The authors concluded that most anti depressant agents can produce hepatic damage. The key to management is prompt recognition followed by withdrawal of the causal antidepressant. Musculoskeletal The association between the risk of a fracture and the use of three classes of psychiatric drugs – anxiolytics and sedatives (including benzodiazepines), anti psychotic drugs, and antidepressants – has been investigated in a case–control study (8C). Both anxiolytics/sedatives and anti psychotic drugs were associated with a small increase in the overall risk of fracture, but there was no dose–response relationship, throwing some doubt on the findings. By contrast, antidepressants showed a dose–response relationship for the risk of fracture. The risk of fracture was higher with SSRIs than with tricyclic antidepressants. Whether the increased risk of fracture seen with the three medication groups represents a causal relationship with drug use is unclear. For example, impaired attention and concen tration, a common symptom of many psychia tric disorders, could lead to an increased risk of falls and fractures. Conversely, there are several mechanisms whereby psychiatric medications could increase the risk of frac ture. For example, sedation may increase the
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risk of falls and some antipsychotic drugs can cause hyperprolactinemia, which when marked can cause secondary hypogonadism, which in turn can lead to reduced bone mineral density and an increased risk of fracture when a fall occurs (9R). The existence of a dose–response relationship with anti depressants and fracture-risk in this study suggests that the relationship may be causal, but this requires further investigation. Drug withdrawal Withdrawal symptoms can occur with all the major antidepressant classes. These symptoms are usually mild and self-lim iting and resolve within a few days without treatment; however, occasionally they are severe, disabling, and of longer duration (10R). In an attempt to minimize or prevent their occurrence, most guidelines for antide pressant drug treatment recommend that if an antidepressant drug is withdrawn when a patient is well, it should be withdrawn gradu ally over several weeks rather than stopped abruptly. Whether or not dosage tapering is needed when switching between antidepres sants will depend on the pharmacological pro files of the two antidepressants, the one that is being stopped and the one that is being started. Abrupt switching is generally safe when switching between antidepressants with simi lar pharmacological actions. Although one would intuitively expect tapering to reduce the incidence of withdrawal symptoms, few studies have assessed whether that is the case. In a small study, patients taking SSRIs or venlafaxine who were still currently depressed were randomized to a 3-day (short) or 14-day (longer) antidepressant taper and openly assessed after a drug-free washout period for 5–7 days (11c). The patients were assessed for a third time after 7 days of treatment with a new antidepressant of the clinician’s choice. This is currently the only published rando mized study to have assessed the effect of taper length on the incidence of antidepres sant withdrawal symptoms. There was a ‘dis continuation syndrome’ (three or more new symptoms on the Discontinuation Emergent Signs and Symptoms checklist) in 46% of patients, with similar frequencies in those who had had the short or longer taper. Anti depressant withdrawal symptoms included
31
worsening depression and increased suicida lity. In keeping with the results of other stu dies, patients who were initially treated with a short half-life antidepressant had significantly greater increases in withdrawal and depres sive symptoms than those who stopped taking fluoxetine (a long half-life antidepressant). The results support the importance of halflife in the etiology of withdrawal symptoms and suggest that there is no advantage to a 2 week taper over a 3-day taper when switching or stopping antidepressants. Drug overdose The effect of a single dose of activated charcoal on the risk of QT interval prolongation after citalopram over dose has been studied in a retrospective case-note review (12c). Data from eight emergency departments were combined to yield two groups of patients who presented with citalopram overdose, those who were treated with activated charcoal and those who were not. The two groups were similar in terms of age, sex, citalopram dose, and co-ingested cardiotoxic drugs. No patient in either group developed torsade de pointes. The relative risk of QT prolongation was significantly less in the charcoal group than in those who did not receive charcoal. The authors concluded that a single dose of activated charcoal may be effective in reducing the risk of QT interval prolonga tion in patients after citalopram overdose.
Adverse effects of antidepressants in pregnancy When a mother develops a depressive illness during pregnancy, the decision of whether to prescribe an antidepressant requires a bal ancing of the risks that the antidepressant will harm the fetus and the mother against the risks to both mother and child from an untreated depressive illness, both during pregnancy and after delivery. A similar question applies when a woman taking a maintenance antidepressant becomes pregnant – do the benefits of medica tion in terms of reducing the risk of a depres sive recurrence outweigh the potential adverse effects of the medication?
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Teratogenicity A study from UnitedHealth care (www.uhc.com), a large US insurer, has shown that first-trimester exposure to paroxe tine was associated with an increased risk of congenital malformations compared with other antidepressants (13c). A population reg ister study from Quebec showed that neither paroxetine nor other SSRIs were associated with an increased risk of congenital cardiac malformations compared with non-SSRI antidepressants (14c). However, when the effect of dose was investigated, first-trimester use of paroxetine in doses over 25 mg/day was associated with an increased risk of major congenital malformations and major cardiac malformations. This study highlights the fact that drug dosage is an important variable that needs to be considered when assessing potential teratogenic risk. A meta-analysis concluded that first-trimester exposure to paroxetine was associated with an increased risk of cardiac malformations (15M). An increased risk of cardiovascular defects following exposure to bupropion during pregnancy has been reported in the GlaxoSmithKline Bupropion Pregnancy Registry. A further study using data from UnitedHealthcare compared the prevalence of congenital malfor mations in infants with first-trimester exposure to bupropion to that seen with (i) other anti depressants in the first trimester and (ii) bupro pion outside the first trimester (16c). The rate of all congenital malformations, and also that of cardiovascular malformations, did not differ significantly between the three groups. In sum mary, this study did not find evidence that firsttrimester bupropion exposure was teratogenic. Fetotoxicity An increased rate of symptoms has been reported in neonates whose mothers had taken antidepressants up to delivery com pared with the offspring of mothers who had not taken antidepressants. There has been a debate whether the underlying mechanism represents an antidepressant withdrawal syn drome, serotonin toxicity, or a combination of the two (17R). Previous reports have high lighted the fact that these neonatal symptoms are self-limiting and resolve, usually within a few days, without treatment. These findings have been confirmed in a retrospective cohort that compared mothers who had taken SSRIs or venlafaxine during the third trimester and
Peter M. Haddad
mothers who had not been given an anti depressant or any psychotropic agent at the time of delivery (18c). Data from 76 mothers taking antidepressants and 90 untreated mothers and their neonates were analysed. Signs involving the central nervous and the respiratory systems were more frequent in the antidepressant-exposed infants (63% versus 41%). In the antidepressant-exposed group signs appeared within 24 hours of delivery, had a median duration of 3 days, and were more common in those who were premature than in those born at full term. This last result suggests that premature infants may be more vulnerable than full-term infants to the effects of exposure to SSRIs and venlafaxine during the third trimester. There was recurrent hypothermia until day 10 of life in concordant monozygotic twins born to a mother who had taken mir tazapine during pregnancy (19A). The twins were born at 35 weeks’ gestation with birth weights of 2426 and 2355 g. Other causes were excluded. The authors suggested that hypothermia had been due to adrenergic and serotonergic receptor antagonism.
MONOAMINE OXIDASE INHIBITORS (SED-15, 2371; SEDA-29, 19) Drug overdose Drug-induced myocarditis is a rare adverse effect that has been asso ciated with various drugs, including amitripty line (20A), clozapine (21R), and cocaine (22R). The Scottish Poisons Information Bureau has suggested that myocarditis may also be a complication of phenelzine overdose (23A). • A 23-year-old woman, previously physically healthy and with no history of cardiovascular disease, took a very large overdose of phenelzine (2760 mg) plus olanzapine 50 mg, two glasses of beer, and a glass of wine. In addition to the recognized clinical features of overdosage with phenelzine (impaired consciousness, tachycardia, seizures), she developed severe hypotension and reduced left ventricular function and died after a few days. Post-mortem toxicology showed
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a high serum phenelzine concentration (4.1 mg/l) and histology showed the characteristic features of drug-induced myocarditis.
SELECTIVE SEROTONIN RE-UPTAKE INHIBITORS (SED-15, 3109; SEDA-29, 19; SEDA-30, 16; SEDA-31, 18) Nervous system Given the association of SSRIs with an increased risk of gastrointes tinal bleeding, the risk of hemorrhagic stroke in users of SSRIs has been studied in the USA (24c). The use of SSRIs was not associated with an increased risk of either intracerebral hemorrhage (n = 500) or sub arachnoid hemorrhage (n = 416). This is in keeping with the results of a previous study (25C). However, owing to limited power and the association between the use of SSRIs and bleeding at other sites, it is important that larger population studies be conducted to confirm or refute this finding. Endocrine The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a rare but well-recognized complication of many drugs, including antidepressants (26R). With antidepressants it usually occurs in the first weeks after starting treatment and is more common in elderly patients. A case of SIADH involving citalopram has been reported (27A). • A 54-year-old woman with hypertension took diuretics and a salt-restricted diet. After starting to take citalopram, she became drowsy and developed paresthesia, fatigue, nausea, vomiting, and visual hallucinations. She had hyponatremia (97 mmol/l) and hypokalemia (2.3 mmol/l). Her symptoms resolved after withdrawal of citalopram and fluid restriction, and the serum sodium and potassium concentrations increased to 137 and 5.2 mmol/l respectively.
The authors suggested that salt restriction may have increased her susceptibility to SIADH due to citalopram.
33 • A 58-year-old man with schizophrenia and a long history of excessive water intake developed nausea, fatigue and irregular fluctuating pyrexia soon after starting to take fluoxetine (28A). His symptoms improved after fluid restriction and withdrawal of fluoxetine.
It is possible that long-standing psychogenic polydipsia made this patient more vulner able to fluoxetine-induced SIADH.
SSRIs and gastrointestinal bleeding Reports have linked SSRIs to bleeding at sev eral body sites (29AR). Reported reactions range from mild spontaneous bleeding, includ ing bruising and nose bleeds, to serious events, including gastrointestinal bleeding, genito urinary bleeding and in one study an increased risk of bleeding and subsequent need for blood transfusion during orthopedic surgery (30c). In population-based cohort studies, SSRI users have been shown to be more likely to have upper gastrointestinal bleeding than non-users (31C, 32C), and in one study the risk of lower gastrointestinal bleeds was also increased (33c). The increased risk of bleeding is thought to reflect inhibition of the serotonin re-uptake transporter in platelet plasma membranes. The transporter allows the uptake of sero tonin into platelets, which cannot themselves synthesize it. Platelets release serotonin in response to vascular injury. The serotonin is responsible for vasoconstriction and a change in platelet shape, which, in the presence of other agents, such as collagen or adrenaline, leads to aggregation and clot formation. By depleting platelets of serotonin, SSRIs impair clot formation and so increase the risk of bleeding from pre-existing lesions, particu larly in the gastrointestinal tract, or from a new injury. This mechanism is supported by various studies, including a cohort study, in which the increased risk of abnormal bleeding was strongly associated with the degree of serotonin re-uptake inhibition (34C). There is no evidence that SSRIs cause direct injury to the gastrointestinal mucosa.
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A meta-analysis, using data from four observational studies involving 153 000 patients, has shown that SSRIs increase the risk of upper gastrointestinal hemorrhage and that the risk is further increased if the SSRI is used in combination with a non-steroidal anti inflammatory drug (NSAID) (35M). The odds ratio for an association of SSRIs with upper gastrointestinal hemorrhage was 2.36 (95% CI = 1.44, 3.85); for an SSRI co-prescribed with an NSAID the odds ratio was 6.33 (95% CI = 3.40, 12). In patients aged over 50 years, with no risk factors for upper gastrointestinal hemorrhage, the NNTH per year was 411 for SSRIs alone and 106 for SSRIs co-prescribed with an NSAID. A further study using the General Practice Research Database (GPRD) confirmed that SSRIs were associated with an increased risk of upper gastrointestinal hemorrhage (36C). However, unlike several earlier studies, the authors controlled for the confounding effect of heavy alcohol consumption. The excess risk of upper gastrointestinal hemorrhage with SSRIs was smaller than previously reported (rate ratio, RR = 1.3; 95% CI = 1.1, 1.6). There was no increase in the estimated risk of upper gastrointestinal hemorrhage with tricyclic antidepressants, but the risk with venlafaxine was the highest of the three antidepressant groups assessed. In summary, this study showed that SSRIs increase the risk of upper gastrointestinal hemorrhage but sug gested that earlier studies may have overesti mated the risk by failing to account for the confounding effect of heavy alcohol intake. Although there is some controversy about the magnitude of the risk, the association of SSRIs with an increased risk of upper gastro intestinal hemorrhage is a consistent finding across studies. The risk is increased in patients who also take NSAIDs, including aspirin. This is an important interaction, given the widespread use of NSAIDs and SSRIs and the seriousness of upper gastrointestinal hemorrhage. There are several clinical impli cations. SSRIs should be used with caution in patients with a history of bleeding disorders or risk factors for bleeding, e.g. cirrhosis. When possible, the combination of an SSRI and an NSAID should be avoided. Paraceta mol is a safer alternative if regular analgesia
Peter M. Haddad
is required. If the combination of an SSRI and an NSAID is required, the patient should be informed of the risks and asked to report any bleeding; the prescription of a gastro protective agent such as ranitidine or omepra zole should also be considered. However, it should be noted that no studies have inves tigated whether this approach reduces the risk of bleeding with SSRIs. Skin Mild skin reactions are well recognized with antidepressants, but serious skin reac tions are rare. Toxic epidermal necrolysis probably reflects cell-mediated hypersensi tivity and can occur with many drugs, includ ing antibiotics and anticonvulsants (37R). It is characterized by extensive cutaneous lesions, and the diagnosis is made when more than 30% of the epidermis is affected. The mucous membranes are often involved, systemic signs can occur and there can be multiple complications. Not surprisingly, mortality is high. A case of toxic epidermal necrolysis has been reported in a 34-year-old patient in association with fluoxetine (38A).
SEROTONIN AND NORADRENALINE RE-UPTAKE INHIBITORS (SNRIs) Duloxetine Cardiovascular Pre-existing heart failure worsened after the introduction of duloxetine in a 68-year-old man (39A). The resulting tachycardia remitted after drug withdrawal. Duloxetine is an SNRI, and increased con centrations of noradrenaline may be the underlying mechanism for the worsened heart failure. The authors recommended that SNRIs be avoided or used with caution and regular monitoring in patients with heart failure. Drug–drug interactions Interactions involving CYP2D6 The relative effects of escitalo pram 20 mg/day, duloxetine 60 mg/day, and
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sertraline 100 mg/day on the activity of CYP2D6 have been studied in young healthy adults by measuring changes in the pharmacokinetics of metoprolol, a substrate of CYP2D6 (40C). All three antidepressants produced statistically significant changes in metoprolol pharmacokinetics, but the size of the effect was greatest with duloxetine and least with sertraline. The change seen with duloxetine was significantly greater than with sertraline. The changes produced by escitalopram and sertraline were similar. The study confirms that dulox etine is a moderate inhibitor of CYP2D6 and that caution is needed when duloxetine is co-prescribed with drugs that are predominantly metabolized by CYP2D6 (e.g. risperidone, tricyclic antidepressants), particularly if they have a narrow thera peutic index.
Venlafaxine
(SED-15, 3614; SEDA-29, 24; SEDA-30, 19; SEDA-31, 22)
Cardiovascular Venlafaxine is associated with increased blood pressure. By contrast, hypotension associated with venlafaxine is much rarer. A physically healthy woman, taking no other medication, developed hypo tension with venlafaxine (41A). There was a temporal and a dose–response relation between the hypotension and the use of ven lafaxine, supporting a causal association. Pre-existing heart failure worsened after the introduction of venlafaxine in a 39-year-old woman (39A). The resulting tachycardia remitted after drug withdrawal. Venlafaxine is an SNRI, and increased concentrations of noradrenaline may be the underlying mechanism for the worsened heart failure. The authors recommended that SNRIs be avoided or used with caution and regular monitoring in patients with heart failure. Drug overdose The features of venlafaxine toxicity in overdose have been investigated in a retrospective case-note review of 235 patients admitted to a Scottish hospital after venlafaxine overdose between January 2000 and June 2006 (42c). Seizures occurred
35
in 8.9%. Patients who had seizures had taken significantly larger amounts of venla faxine than those who did not develop sei zures: median (interquartile range) 2800 (2006–4350) mg versus 1500 (900–2700) mg. There was a positive correlation between the amount of venlafaxine ingested and creatine kinase activity both across the whole group and in those without seizures, suggesting that venlafaxine overdose is associated with acute muscle damage irrespective of the occurrence of seizures.
OTHER ANTIDEPRESSANTS Bupropion (amfebutamone)
(SED
15, 108; SEDA-29, 24; SEDA-30, 20; SEDA-31, 22) Liver There have been rare reports of severe but non-fatal hepatotoxicity associated with bupropion, and in one case an auto immune mechanism appeared to be involved (43A). Fatal hepatotoxicity related to bupro pion has been reported (44A). This appeared to involve an autoimmune mechanism. • A 55-year-old man developed jaundice and severe hepatic damage about 6 months after starting to use bupropion for smoking cessation. Laboratory investigations showed a mixed picture of hepatocellular injury and cholestasis and were positive for autoimmune markers. Liver biopsy was consistent with drug-induced severe hepatic injury. Steroid treatment led to an initial improvement in his clinical condition, but he subsequently died of infectious complications.
Bupropion should be added to the list of drugs that can cause hepatocellular jaundice. Teratogenicity
See Special review above.
Drug–drug interactions Lopinavir þ rito navir The potential interaction of a single 100 mg dose of modified-release bupropion with the combination of lopinavir þ ritona vir 100 mg bd has been studied in 12 healthy volunteers (45C). Lopinavir þ ritonavir significantly reduced the Cmax of bupropion by 57% and the area under the curve (AUC)
36
infinity. The Cmax and AUC infinity of the active metabolite hydroxybupropion were also reduced. The proposed mechan ism is induction of CYP2D6 and UDP-glucuronosyltransferase. The authors suggested that the interaction may require as much as a doubling of the dose of bupropion in patients who are concur rently taking lopinavir þ ritonavir.
Reboxetine
(SED-15, 3028; SEDA-30, 21; SEDA-31, 22)
Endocrine Pseudopheochromocytoma has been attributed to reboxetine (46A).
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Peter M. Haddad
mirtazapine had no beneficial effect (48C). There were frequent withdrawals because of lethargy (2 in the first study, 15 in the second). Weight gain was significantly greater with mirtazapine than with placebo in both trials. Nervous system Worsening of seizures has been attributed to mirtazapine in a patient stabilized on phenytoin (49A). • A 50-year-old woman with simple partial seizures and secondarily generalized tonic– clonic seizures, occasionally precipitated by fever, took phenytoin 200 mg/day for 11 years and was seizure free. She then developed a low mood, anhedonia, pessimistic views about the future, anergia, and insomnia and was given mirtazapine 7.5 mg/day. After taking one dose of mirtazapine, she had two partial motor seizures with secondarily generalized tonic– clonic seizures while asleep. The following night, after a second dose she had another similar episode. Mirtazapine was withdrawn and she was given escitalopram. Her seizures did not recur.
• A 47-year-old man, who was taking colchicine for familial Mediterranean fever, developed major depression and was given reboxetine 8 mg/day, fluoxetine 20 mg/day, and clonazepam 2 mg/day. After 1 year, he developed episodic dizziness and syncope with asymptomatic runs of sinus tachycardia (118/minute) lasting up to 4 minutes. He was given metoprolol 50 mg/day but continued to have symptoms. His lying blood pressure was 148/85 mmHg, with a marked fall to 100/50 on standing, when his heart rate rose from 84 to 114/minute. Pheochromocytoma was suspected, and urinary collections for catecholamines and their metabolites showed very high concentrations. Reboxetine and fluoxetine were withdrawn and the urinary catecholamines and metabolites became normal. He was free of symptoms 2 years later.
The mechanism of this effect is unclear. Mirtazapine does not alter the metabolism of phenytoin, and in any case the event occurred too quickly to be explained kinetically. The seizures may have reflected the epileptogenic action of mirtazapine, though the existing literature suggests it has a very low seizureinducing potential. Alternatively a pharma codynamic interaction of mirtazapine with phenytoin could have been responsible.
Sexual function Erectile dysfunction and seminal emission and ejaculation during defecation and micturition have been attrib uted to reboxetine (47A).
Psychiatric Adding mirtazapine to a sero tonin re-uptake inhibitor may increase its antidepressant effects and is more likely to cause a switch to a manic phase.
• A 44-year-old man with depression but without any sexual dysfunction was given venlafaxine, but because of delayed ejaculation and occasional episodes of absent ejaculation he was switched to reboxetine. After 2 weeks he reported erectile dysfunction and premature ejaculation; seminal emission and ejaculation during defecation and micturition occurred after 8 weeks. He was given sertraline 50 mg/day instead, and his sexual dysfunction resolved after 2 weeks.
• A 66-year-old woman with type II diabetes mellitus, hypertension, hyperlipidemia, chronic renal insufficiency, unstable angina, and osteoporosis, but no history of mania, hypomania, or major depression, became depressed, irritable, and agitated and was given fluoxetine 20 mg/day. Her feelings persisted and she was switched to mirtazapine 30 mg/day, without a period of tapering off, washout, or cross-titration. Three days later, her selfesteem was inflated and her irritability, agitation, and argumentativeness worsened. She slept less but was energetic and talkative. After 6 days she developed vivid grandiose delusions with religious content. Her mood was elated and labile. After 8 days she had become violent and uncooperative. She asserted that she was free from all physical illnesses and could save her country and help all people
Mirtazapine Placebo-controlled studies In two rando mized, double-blind, placebo-controlled trials of mirtazapine (7.5, 15, 30, or 45 mg) for obstructive sleep apnea in 20 and 65 patients,
Antidepressant drugs
Chapter 2
rise to higher levels, spiritually and materially. Her speech was pressured and she was elated. Mirtazapine was withdrawn and valproate and low-dose risperidone begun. Her manic symptoms subsided gradually during the next 2 weeks.
The authors suggested that because of its long half-life fluoxetine might have persisted in the body after withdrawal and inhibited the metabolism of mirtazapine or produced a pharmacodynamic interaction (50A). Electrolyte balance A 61-year-old man and a 79-year-old woman developed profound hyponatremia (sodium 112 and 113 mmol/l) 7 and 10 days after starting to take mirtaza pine for depression (51Ar). Investigations excluded other causes, and withdrawal of mirtazapine led to recovery of sodium con centrations to at least 132 mmol/l after 7 and 10 days respectively. The authors graded the likelihood that mirtazapine had caused hypo natremia in these cases as ‘probable’ accord ing to the Naranjo criteria. A review of published cases showed that mirtazapine associated hyponatremia occurs in patients aged over 60 years, after a mean of 6.5 days, and with doses as low as 7.5 mg/day. The sodium concentration fell to a mean of 117 mmol/l, and after withdrawal of mirtaza pine the mean time to recovery was 11 days. Liver Mirtazapine has been associated with dose-related asymptomatic rises in hepatic enzymes (52c). Pancreas Pancreatitis is a rare complica tion of many drugs. Recurrent pancreatitis, thought to be due to mirtazapine, has been reported (53A). Fetotoxicity
See special review above.
Lactation The transfer of mirtazapine and desmethylmirtazapine into breast milk has been investigated in eight breast-feeding women who were taking a median dose of 38 mg/day and in four of their infants (54c). The mean infant doses of mirtazapine and desmethylmirtazapine were 1.5 and 0.4%, respectively. The mean milk-to-plasma ratios (AUC) were 1.1 for mirtazapine and 0.6 for desmethylmirtazapine. There were no adverse effects. Mirtazapine was detected in only one of the four infants tested (1.5 µg/l).
37
The authors concluded that it is probably safe for lactating women to use mirtazapine. Susceptibility factors Genetic Mirtazapine is given as a racemic mixture of Sþ and R– mirtazapine (55c). It is absorbed from the gut with a rate constant of 0.2/minute (half life 3.5 minutes) for the Sþ isomer and 0.08/ minute (half-life 9 minutes) for the R– isomer. The kinetics of R– mirtazapine are not related to CYP2D6 genotype, but the total clearance of the Sþ enantiomer is 1.3, 2.3, and 3.4 l/minute in poor, extensive, and ultrarapid metabolizers of CYP2D6 respec tively; there was substantial first-pass meta bolism in rapid and ultrarapid metabolizers. The effects of mirtazapine on heart rate and blood pressure correlated better with R– than Sþ concentrations, but sedation corre lated equally with the two enantiomers. Drug overdose In a retrospective chart review of 71 patients who took an overdose of mirtazapine reported to a poison centre during 2004, 33 isolated exposures were reviewed (56c). The average age was 27 (range 6–82) years. The mean dose ingested was 343 (range 15–1500) mg. The most common neu rological symptom was drowsiness, which occurred in eight patients; one became agi tated and 14 had no abnormal neurological findings. There were cardiovascular effects in four patients: three had tachycardia and one had bradycardia and hypotension. There were no deaths. In another retrospective case analysis of overdoses over a 5-year period, there were 117 cases (57c). The median (interquartile range) dose ingested was 450 (240–785) mg. Consciousness was impaired in 27% and there was a higher incidence of tachycardia (30%) than predicted. There were no other significant clinical, laboratory or electro cardiographic abnormalities. These reports suggest that mirtazapine is relatively safe in overdose and are consis tent with earlier reports (58R). Declaration of potential conflicts of interest In the past 3 years PMH has received fees for lecturing and/or consultancy from the manufacturers of various antide pressants, including Eli-Lilly and Servier.
38
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Peter M. Haddad
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49. Zia UI, Haq M, Prakash R, Akhtar S. Mirta zapine precipitated seizures: a case report. Prog Neuropsychopharmacol Biol Psychiatry 2008;32(4):1076–8. 50. Liu CC, Liang KY, Liao SC. Antidepressantassociated mania: soon after switch from fluox etine to mirtazapine in an elderly woman with mixed depressive features. J Psychopharmacol 2009;23(2):220–2. 51. Cheah CY, Ladhams B, Fegan PG. Mirtaza pine associated with profound hyponatremia: two case reports. Am J Geriatr Pharmac other 2008;6(2):91–5. 52. Adetunji B, Basil B, Mathews M, Osinowo T. Mirtazapine-associated dose-dependent and asymptomatic elevation of hepatic enzymes. Ann Pharmacother 2007;41 (2):359. 53. Hussain A, Burke J. Mirtazapine associated with recurrent pancreatitis – a case report. J Psychopharmacol 2008;22(3):336–7. 54. Kristensen JH, Ilett KF, Rampono J, Kohan R, Hackett LP. Transfer of the antidepres sant mirtazapine into breast milk. Br J Clin Pharmacol 2007;63(3):322–7. 55. Brockmo¨ ller J, Meineke I, Kirchheiner J. Pharmacokinetics of mirtazapine: enantio selective effects of the CYP2D6 ultra rapid metabolizer genotype and correlation with adverse effects. Clin Pharmacol Ther 2007;81(5):699–707. 56. LoVecchio F, Riley B, Pizon A, Brown M. Out comes after isolated mirtazapine (Remeron) supratherapeutic ingestions. J Emerg Med 2008;34(1):77–8. 57. Waring WS, Good AM, Bateman DN. Lack of significant toxicity after mirtazapine over dose: a five-year review of cases admitted to a regional toxicology unit. Clin Toxicol (Phila) 2007;45(1):45–50. 58. Kelly CA, Dhaun N, Laing WJ, Strachan FE, Good AM, Bateman DN. Comparative toxi city of citalopram and the newer antidepres sants after overdose. J Toxicol Clin Toxicol 2004;42(1):67–71.
Rif S. El-Mallakh, Rona J. Roberts, and Yonglin Gao
3 Uses The therapeutic use of lithium appears to be declining. In a study of in patient prescribing practices in 63 German, Austrian, and Swiss hospitals over a 10-year period from 1994 to 2004, the use of lithium for acute mania declined significantly from 43 to 35% (1M). This decline was more than offset by an increase in the use of both anticonvulsants (from 40 to 61%) and sec ond-generation antipsychotic drugs (from 19 to 44%). In the USA the use of lithium in outpatient Medicaid populations (n = 26 133) in the early 2000s was 13–25% of bipo lar subjects (2M, 3M). Yet when the entire weight of evidence is taken into account, lithium appears to be both underused and underappreciated (4r). Thus, it is not sur prising that in some areas (e.g. Spain), lithium use has actually increased, while in others (e.g. England), it is still commonly used (5r).
Lithium in neuroprotection Several animal and in vitro studies have demon strated a neuroprotective effect of lithium against a wide array of toxic insults (6E, 7E). Several magnetic resonance imaging (MRI) studies in patients have found increases in hippocampal volume. In humans, grey matter density was greater in 20 lithium-treated patients compared with 8 patients not taking lithium and 29 matched healthy controls, Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32003-4 2010 Elsevier B.V. All rights reserved.
Lithium particularly in the right anterior cingulate (8c). In 12 bipolar patients who took lithium for 2–4 years there was improvement in verbal memory performance and increased volume of the hippocampus (9E). Similarly, in 33 bi polar patients (12 unmedicated and 21 taking lithium) and 62 matched healthy controls, the total hippocampal volume was 10% larger in the lithium-treated patients and 14% larger than in unmedicated bipolar patients (10E). In a third study, of 12 patients who had taken lithium for 1–8 years (mean age 16 years, 7 male), 9 unmedicated and medica tion naïve patients (14 years, 3 male), 7 bipo lar subjects receiving anticonvulsants (26 years, 3 male), and 30 healthy controls (25 years, 14 male), the authors reported that both the hippocampal head and tail were increased in those taking lithium compared with all the other groups (11E). The authors were surprised that a neuroplastic change occurred so quickly. While collectively these studies might suggest a neurotrophic effect, none of the studies corrected for the effect of lithium on water. Lithium has the highest energy of hydration of all the alkali metals, and is consequently surrounded by a large amount of water, so as to make its hydrated size equivalent to that of calcium (12R). Con sequently, when rats are given lithium, the frontal cortical grey matter experiences an increase of 3.1% water (13E). However, lithium does induce synaptic plasticity in rats (14E). Lithium may have a neurotrophic effect by several mechanisms. Lithium treatment is asso ciated with elaboration of a variety of growth factors. It attenuates the reduction that is observed in bipolar subjects in the receptors for insulin-like growth factors in the prefrontal cortex (15E); lithium prevents the reduction in vascular endothelial growth factor (VEGF)
41
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Chapter 3
that is normally seen in stressed rats (16E); it increases expression of brain-derived neuro trophic factor (BDNF) in cultured rat neurons (17E); and finally, it reduces the activity of proapoptotic glycogen synthase kinase-3 (GSK3) (17E, 18E). Furthermore, lithium reduced basal ganglia glutamate/glutamine concentrations, as measured by magnetic reso nance spectroscopy in eight healthy controls who took lithium for 2 weeks (19c). Addition ally, lithium increased dorsomedial frontal cortical glucose utilization as measured with fluorodeoxyglucose positron emission tomo graphy in 20 healthy volunteers who took lithium for 4 weeks (20c). Finally, lithium may have an antioxidant effect. It reduced superoxide dismutase activity, catalase activity, and thiobarbituric acid reactive substances in 15 bipolar patients (21c, 22c). Lithium reduced total plasma antioxidant activity in 15 subjects who took it alone (for 6 months) or in combination with olanzapine (for an additional 6 months) (23c). Thus, it is not sur prising that lithium protected cognitive function in irradiated mice (24E) and reduced ischemic damage in a gerbil model of stroke (25E). In 66 elderly euthymic patients with bipolar illness, lithium was associated with a reduc tion in the risk of dementia compared with 48 similar patients not taking lithium (26C). The overall prevalence of dementia was 19% in the bipolar patients compared with only 7% in an age-matched general population; how ever, dementia was diagnosed in 5% of the lithium-treated patients compared with 33% in the non-lithium-treated sample. Several studies have attempted to correlate lithium activity with specific genes (27E–29E), but given that 1027 of 4474 genes tested chan ged significantly with lithium treatment (30E), it would be difficult to accept any single obser vation as being particularly important. Adherence to treatment Adherence to treatment recommendations reduces the risk of both mood relapse and toxicity. In a Veterans Administration study of 44 637 patients with bipolar disorder, 54% of the bipolar patients were fully adherent to mood stabilizer treatment (defined as a medication possession ratio of > 0.80), 25% were
Rif S. El-Mallakh, Rona J. Roberts, and Yonglin Gao
partially adherent (a medication possession ratio > 0.50 and <0.80) and 21% were nonadherent (31C). In a study of 106 outpatients with bipolar disorder, 86% were adherent to lithium, as documented by both self-report and a lithium concentration of 0.6–1.2 mmol/l; adherence to lithium treatment was positively correlated with scores on the Lithium Knowledge Test (32c). Self-report is highly correlated with objective measures of lithium adherence ( = 0.96) (33C). The median duration of adherence to lithium is 181 days (95% CI = 136, 181), based on a survey of the Medicinal Product Statistics database of the Danish Medical Register on Vital Statistics – a database that covers 5.3 million people (34C). Of all patients for whom lithium is prescribed, 25% stop it within 45 days. Women are more likely to stop taking lithium than men. However, one of the best predictors for lithium discontinuation is concurrent substance abuse. Among 115 subjects with bipolar disorder, of whom 58 had a substance abuse disorder, lifetime adherence to lithium was 85% in the absence of substance abuse and 66% in the presence of a substance abuse disorder (35C). Adherence to a regimen of monitoring by clinicians is almost as important. However, in a study of 121 subjects taking lithium, only 19% had a lithium concentration checked, only 39% had a thyroid-stimulating hormone (TSH) concentration checked, and 83% had renal function tests at the recommended semi-annual frequency (36c). Observational studies The usefulness of lithium in preventing recurrence of bipolar mood episodes has been examined in two studies. Of 213 patients who were stable for 2 years after a manic episode on lithium monotherapy, 54 chose to discontinue treatment for a wide range of reasons and were slowly tapered off the medications and followed for 1 year (37C). The risk of recurrence for those taking lithium was 0.15 compared with 0.45 off medication. The hazard ratio of relapse after lithium discontinuation was 4.85 compared with continuing lithium treatment. In another study of 120 type I and II bipolar subjects,
Lithium
Chapter 3
using a scale for retrospective analysis of prophylactic efficacy, a greater number of patients achieved a full response on lithium (30%) than with any other treatments, such as olanzapine (25%), valproate (13%), lamotrigine (11%), or carbamazepine (0%) (38C). Lithium has been examined as an aug mentation strategy in treatment-resistant major depression in two randomized open trials. In one study 29 elders with major depression inadequately responsive to ven lafaxine or a tricyclic antidepressant were randomly assigned to lithium augmentation or treatment with phenelzine (39C). Over the initial 6 weeks and the subsequent 2-year follow-up, the subjects who had had lithium added fared significantly better. One-third of the lithium-treated subjects achieved remission compared with none of the phenelzine-treated patients. Comparative studies In 20 patients with major depression who failed to respond to an antidepressant, lithium or quetiapine augmentation was randomly assigned. All improved, but those taking quetiapine improved significantly more than those taking lithium after 28 days (40C). Previous reports that lithium may have an antisuicidal effect have been expanded. Among 12 662 Oregon Medicaid patients with bipolar disorder treated between 1998 and 2003, there were 11 suicide deaths and 79 significant attempts (3M). Compared with lithium, the hazard ratio for suicide attempt was significantly greater at 2.7 for valproate and 2.8 for carbamazepine. In a smaller sam ple of 405 veterans with bipolar disorder followed for only 3 years, the rates of non lethal suicidal behavior were non-signifi cantly lower for lithium (2.49/100 patientyears) than carbamazepine (3.80/100 patient-years) and divalproex (4.67/100 patient-years) (41C). The antisuicidal effect appears to apply to non-bipolar patients as well. A meta-analysis of eight studies in 329 patients with major depressive disorder fol lowed for 1149 person-years on lithium and 1285 person-years off lithium showed that the risk of significant suicidal behavior was 89% lower with lithium (42C). However,
43
among 169 bipolar outpatients with bipolar disorder, 49% had a history of a suicide attempt. Most (84%) were taking more than one medication at the time of their suicide attempt, which included lithium in 36% (43C). Placebo-controlled studies New randomi zed trials continue to support the efficacy of lithium in mood disorders. In a double-blind, placebo-controlled, randomized study of 200 acutely manic subjects treated with either lithium (concentrations 0.7–1.0 mmol/l) or divalproex (concentrations 50–100 µg/ml) plus quetiapine (up to 800 mg/day) or placebo, the addition of quetiapine was not statistically superior to mood stabilizer monotherapy (44C). A meta-analysis was performed of all six placebo-controlled trials submitted to the Medicines Evaluation Board between 1997 and 2005 that examined acute mania and included lithium. These studies comprised 1032 subjects. The effect size for lithium at the end of 21 days was 0.4 (95% CI = 0.28, 0.53) (45M). Cardiovascular There have been several case reports that lithium can unmask or contribute to the development of Brugada type electrocardiographic changes (46A–50A) or conduction block (51A, 52A). Brugada syndrome is a cardiographic abnormality that predisposes subjects to sudden death. It is related to a genetic sodium channel dysfunction that has been identified as a loss of ankyrin G protein (53R). Bipolar illness may also be associated with anomalies of the ankyrin G gene (54E). However, these cases, as well as cases of lithium-associated bradycardia (55A) may also be related to the ability of lithium to lower abnormally raised intracellular sodium (56E) and prevent increased intracellular calcium (57E). Nervous system Lithium toxicity can cause an encephalopathy, with delirium or seizure activity, either convulsive or non-convulsive (58R). Further cases have been reported in which lithium was associated with nonconvulsive status epilepticus (59A) and a catatonic-like state (60A).
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Severe lithium-induced neurotoxicity is associated with permanent or long-lived cerebellar dysfunction (61R). Three new cases have been reported (62A). • A 52-year-old woman slowly developed toxicity with a serum concentration reaching 3.5 mmol/l; she still had ataxia, dysmetria, and dysarthria 2 years after the toxicity had resolved. • A 44-year-old woman slowly developed toxicity with a maximum concentration of 3.0 mmol/l; she still had dysarthria and dysmetria 9 years after the toxicity had resolved. • A 57-year-old man with depression and alcohol abuse overdosed on lithium with a maximum concentration of 1.98 mmol/l; he still had dysmetria, dysarthria, and ataxia 1 year after recovery.
Lithium has been reported to be associated with pseudotumor cerebri. The optic nerve changes that can occur with pseudotumor cerebri associated with lithium have been described (63A).
Psychological Cognitive dysfunction occurs in lithium-treated patients. In 20 patients with bipolar disorder taking lithium monotherapy who underwent neuropsychological testing, both processing speed and appropriate inhibition were significantly impaired compared with matched healthy controls (64C). In a study of neuropsychological function in 159 bipolar subjects taking a variety of medications, lithium had a more deleterious effect on cognition than lamotrigine or oxcarbazepine, but a less severe effect than topiramate, carbamazepine, or valproate (65C).
Endocrine Thyroid In a cross-sectional ultrasonographic study of the thyroid in 96 patients taking long-term lithium and 96 sexand age-matched controls, thyroid volume was significantly greater in the lithium-treated patients (24 ml versus 14 ml) and a signifi cantly greater fraction of lithium-treated sub jects had goiter (55% versus 20%) (66C). This effect may be beneficial in hyper thyroid patients who are intolerant to antith yroid medications. Six patients with
Rif S. El-Mallakh, Rona J. Roberts, and Yonglin Gao
hyperthyroidism secondary to either Graves’ disease (n = 5) or toxic multinodular goiter (n = 1) were successfully treated with lithium until more definitive treatments resulted in euthyroidism (67A). This antithyr oid effect reportedly hid hyperthyroidism in a 59-year-old bipolar woman who developed hyperthyroidism and refractory mania after lithium was withdrawn (68A) and in a 65-year-old woman whose subclinical hyperthyroidism worsened into overt hyper thyroidism when lithium was withdrawn (69A). Parathyroid Lithium is associated with an increased risk of hyperparathyroidism. • A 65-year-old woman who had taken lithium for 10 years developed a parathyroid adenoma and hyperthyroidism. Her hyperparathyroidism was successfully treated surgically, but her hyperthyroidism worsened after lithium withdrawal (69A).
In a retrospective examination of 1207 patients undergoing surgical exploration for primary hyperparathyroidism from 1995 to 2007, 16 subjects (1.3%) were found to have been taking lithium (70C). The rate of multiglandular disease was 25% in lithium-treated patients and 12% in non-lithium-treated patients. Among the 16 patients with lithium-associated hyper parathyroidism, 12 had a single adenoma. The use of quick intraoperative parathyroid hormone monitoring allowed unilateral surgical exploration in eight. Surgical treatment resulted in a ‘cure’ for the patients with lithium-associated hyperpar athyroidism, but the authors did not report if the patients continued their lithium treatment or not. If lithium withdrawal is not possible and surgical treatment not an option, cinacal cet, a calcimimetic, may be a reasonable option. Three patients with lithium-induced hypercalcemia and hyperparathyroidism were treated with cinacalcet 30–120 mg/day (dosage determined by laboratory tests); there was a significant fall in serum calcium concentration from 2.72 to 2.52 mmol/l (71A).
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Diabetes insipidus Hypernatremia due to diabetes insipidus and inadequate fluid intake can occur in lithium-treated patients in special circumstances. Three cases of postsurgical hypernatremia and hyperosmolarity with confusion have been reported. In one case, 25 l of hypotonic fluids were required to re-establish electrolyte balance (72A). In another case, a 55-year-old woman developed hyperosmolar coma due to hypernatremia (73A). In the last case, a serum sodium of 175 mmol/l was associated with lithium toxicity (serum concentration 2.79 mmol/l) (74A). Diabetes insipidus affects some 30% of patients taking long-term lithium (75A) and complicates the management of patients when they develop acute toxicity (76A). Alternatively, diabetes insipidus can contri bute to dehydration, which can induce prerenal renal failure and lead to lithium toxicity (77A). Delayed diabetes insipidus has been reported days (75A) or 3 years after lithium withdrawal (78A). Despite the fact that diabetes insipidus due to lithium is common, lithium treatment in bipolar subjects is associated with higher concentrations of arginine vasopressin (anti diuretic hormone) after the administration of dexamethasone 1.5 mg compared with bipolar subjects not taking lithium (1.0 pmol/l versus 0.5 pmol/l) (79C). Patients not taking lithium were no different from matched con trols (0.5 pmol/l versus 0.4 pmol/l). Electrolyte balance Since lithium is a cation, its accumulation in cases of toxicity can contribute towards a negative anion gap. Severe lithium toxicity in a 65-year-old man with a peak serum lithium concentration of 15 mmol/l was characterized by a negative anion gap of –2 mmol/l (reference range 7–13 mmol/l) (80A). Hematologic Lithium neutrophil leukocytosis.
can
cause
a
• A 55-year-old man with paranoid schizophrenia, who had been stable on clozapine treatment for more than 10 years, developed neutropenia. Since he did not do well after withdrawal of
clozapine, lithium 300 mg/day was started and clozapine re-started at a lower dose. The white cell count rose to 3.4 � 109/l and he was well during the next 14 months (81A).
Lithium may cause neutrophilia by atte nuating the surface chemokine receptor CXCR4 (82C) or by accentuating the func tion of CXCL12 (83H). Urinary tract Long-term lithium treatment is rarely associated with renal damage. • In a 51-year-old woman who had taken lithium for 30 years, the serum creatinine concentration started to rise, and lithium was withdrawn (84A). However, her creatinine continued to rise. An MRI scan of the kidneys showed normal sized kidneys with a large number of uniformly distributed fluid-filled microcysts.
It is not clear in this case whether the renal damage was due to lithium. However, it highlights the results of a previous study in 16 patients with lithium-related nephropa thy, who all had microcysts on MRI scans, suggesting that microcysts may be associated with lithium-associated nephropathy (85C). Renal cysts have been associated with rises in serum vasopressin concentrations (86E), so this may be the mechanistic link. Monitoring of renal function in patients taking lithium is suboptimal. In the USA 100 (83%) of 121 subjects taking lithium had renal function tests at the recommended semi-annual periodicity (36c); however, in France, among 1179 lithium-treated out patients, only 59% had at least one creatinine measurement over an 8-year period from February 1997 to December 2004 (87C). Skin Psoriasis is a relatively common skin reaction to lithium. • A 45-year-old man with bipolar illness and severe suicidal ideation developed severe psoriasis while taking lithium. Because of intense suicidality, it was elected to continue lithium and treat the psoriasis (88A). He was given etanercept 50 mg subcutaneously twice weekly and the psoriasis improved significantly.
Etanercept is a tumor necrosis factor-a (TNFa) inhibitor and is indicated in severe
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arthropathies, including psoriatic arthropa thy. This is the first report of the use of a TNFa inhibitor to treat lithium-induced psoriasis. Psoriasis is related to immunological changes. Lithium is associated with an increase in TNFa and interleukin-6 (IL-6) in vitro, which have been hypothesized to play a role in the induction of psoriasis (89E). However, at least IL-6 responds dif ferently in vivo, where lithium can actually reduce its production (90E). Thus, the mechanism of lithium-associated psoriasis remains to be elucidated. Musculoskeletal In 231 778 patients with fractures and matched controls, current lithium use was associated with a reduced risk of bone fracture (adjusted odds ratio (OR) = 0.75, 95% CI = 0.64, 0.88) (91C). Withdrawal of lithium was associated with an increase in fracture risk (OR = 1.35; 95% CI = 1.01, 1.79). The authors concluded that the underlying mental illness had increased the risk of fracture after lithium withdrawal, but it is also just as likely that there was a rebound effect that increased the risk. Reproductive system Metrorrhagia was observed in a 24-year-old woman with onset and offset within a few days of starting and stopping lithium 600 mg/day (serum concentration 0.87 mmol/l). The metrorrhagia recurred within a few days of rechallenge and abated within a few days of withdrawal (92A). This is the only reported case of metrorrhagia related to lithium. Sexual function In a study of sexual histories of 51 bipolar patients (mean age 33 years, 24 men) and 176 healthy controls (mean age 30 years, 96 men), sexual dysfunction was more common in bipolar subjects. Specifically, a greater fraction of bipolar patients reported ‘rare’ or ‘never’ for sexual intercourse (45% versus 20%), sexual fantasies (25% versus 14%), and desire (37% versus 9.5%), but sexual pleasure and satisfaction were both greater
Rif S. El-Mallakh, Rona J. Roberts, and Yonglin Gao
in bipolar patients than controls (73% versus 91% and 57% versus 83% respectively); 18% of the patients felt their sexual life was worse after the onset of the diagnosis, and 30% attributed their sexual dysfunction to the consumption of lithium (93C). In a previous study of 35 men taking lithium (mean age 43 years), 11 reported sexual dysfunction (94C). In rats given lithium (35 mg/kg/day for 21 days), the ultrastructure of the seminiferous tubules was altered significantly (95E).
Teratogenicity Of 837 women of child bearing age, 138 (16%) were identified as taking lithium, carbamazepine, or valproate, all known teratogens (96C). Counselling these women regarding the potential terato genicity of these drugs occurred only in 21%, and 24% were advised to use contraception; 10% became pregnant and 6% had a complication of pregnancy.
Lactation In 10 mother–infant pairs, maternal serum, milk and infant serum concentrations were measured. Maternal serum lithium concentrations averaged 0.76 mmol/l, while the concentration in milk was less than half, 0.35 mmol/l, and resulted in concentrations in infant serum that were less than 20% of those in the mothers (97c). These results challenge the recommendations of the American Academy of Pediatrics, which are based on anecdotal reports that infants’ serum concentrations are 30–50% that of their mothers (98S).
Drug overdose The severity of lithium toxicity is related to the speed at which the lithium concentration increases. In an investigation of 172 enquiries about lithium toxicity to a regional poison centre in Scotland, there were 101 acute ingestions, 38 acute-on-therapeutic ingestions and 33 cases of chronic toxicity (99C). The median lithium concentration achieved in each group was essentially the same, 2.4 (range 1.7–3.3), 2.1 (1.4–3.8), and 2.3 (1.9–3.3) mmol/l respectively. However, the fraction
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of subjects who had moderate or severe clinical toxicity was much lower after acute ingestion (9.9%), significantly higher after acute-on-therapeutic ingestion (26%), and higher still in those with chronic toxicity (55%). This study, and two additional cases in which lithium toxicity occurred at therapeutic concentrations (100A), highlights the fact that the intensity of lithium toxicity is not closely related to lithium concentrations. Overdosage is still the most common cause of lithium toxicity (99C), but it may be unintended. A dietary supplement avail able over the Internet called, Find Serenity Now, contains lithium orotate (each tablet contains 3.83 mg of elemental lithium versus 18.8 mg in a typical prescribed pill). An 18-year-old woman took 18 tablets of, Find Serenity Now, she developed signs of lithium toxicity (nausea and tremor) with a maxi mum lithium concentration of 0.4 mmol/l (101A). Overdosage with modified-release lithium formulations can prolong the course of lithium toxicity (102A). • A 32-year-old woman took about 16 g of modified-release lithium carbonate in a suicide attempt. Her initial lithium concentration was 3.2 mmol/l, but rose to 5.1 mmol/l 14 hours after the overdose. Despite hemodialysis (which lowered her lithium concentration to 2.54 mmol/l), her lithium concentration rose to 6.09 mmol/l 37 hours after the overdose, necessitating another round of hemodialysis, which reduced her concentration to 1.86 mmol/l.
Drug–drug interactions Amisulpride Lithium concentrations did not change when amisulpride was co-administered (103C), but lithium increased amisulpride concentrations (104A). However, this observation is of minimal clinical importance.
Angiotensin-converting enzyme (ACE) inhibitors Lithium toxicity as a conse quence of treatment with ACE inhibitors has previously been described (105A). In 20 hypertensive patients taking lithium, there was a 26% reduction in lithium clearance and a
47
36% increase in lithium concentrations after an ACE inhibitor was added (106c).
Angiotensin receptor antagonists Co administration of valsartan with lithium has been reported to increase the risk of lithium toxicity (107A). • A 60-year-old woman taking lithium 600 mg/day, valproate 1500 mg/day, clonazepam 2 mg/day, and valsartan 80 mg/day developed mania and was hospitalized. During her hospitalization she developed lithium toxicity with her concentration increased from 0.74 to 1.74 mmol/l, while her blood urea nitrogen rose to 14 mmol/l and her creatinine to 141 µmol/l.
The authors thought that lithium toxicity had been facilitated by valsartan. Risperidone Reports of potentiation or precipitation of lithium toxicity by psychotropic drugs are not infrequent. However, since co-administration of lithium with other psychotropic drugs is extremely common, these cases cannot be accepted at face value. Thus, reports that the antipsychotic risperidone caused encephalopathy and neuroleptic malignant syndrome (108A, 109A) have not been supported by larger studies (110C) and probably represent very special circumstances. Venlafaxine Reports that co-administration of venlafaxine with lithium can precipitate a serotonin syndrome-like state, particularly in elderly people (111A), are consistent with ol der reports (112A–114c). Monitoring therapy Lithium concentra tions vary with season. A total of 41 102 lithium concentrations were checked in 3054 patients over 8.5 years in the Netherlands. Serum lithium concentrations were highest in the summer (0.761 mmol/l) and lowest in winter (0.748 mmol/l) (115C). This may be directly related to the average temperature, since at the environmental temperature ranges of 15–20°C lithium concentrations
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are higher (0.762 mmol/l) than at cooler temperatures <0°C (0.741 mmol/l). Determination of the optimal lithium con centrations remains controversial. In a review of five long-term studies of random ized assignment to various lithium concen tration ranges, the authors concluded that there is evidence that lithium concen trations as low as 0.4 mmol/l confer protec tion against future relapse (116C). If a patient has a suboptimal response, increas ing the concentration to 0.6–0.75 mmol/l may yield additional benefit. Concentrations exceeding 0.75 mmol/l do not reduce the likelihood of relapse, but do reduce manic, but not depressive, interepisode symptoms. This last observation suggests that the dif ferent poles of bipolar illness may require different optimal lithium concentrations. This has been investigated in 86 euthymic bipolar subjects who had taken lithium monotherapy for 2.5 years (117C). The aver age serum lithium concentration before the reappearance of a manic or mixed epi sode was lower than the concentration before a depressive episode (0.53 mmol/l versus 0.66 mmol/l). A logistic regression analysis showed that manic symptoms occur at lower lithium concentrations, while depressive symptoms are more
Rif S. El-Mallakh, Rona J. Roberts, and Yonglin Gao
common at higher lithium concentrations. The authors concluded that higher lithium concentrations are required to prevent manic episodes than to prevent depressive episodes. However, the data could just as readily be interpreted to support the oppo site conclusion, namely that higher lithium concentrations are required for depressive symptoms. Specifically, if one considers that mania is a less severe manifestation of the illness than depression (118H), then at lower lithium concentrations the less severe man ifestation (mania) appears, which is less likely at higher concentrations. Lithium concentrations have long been measured in saliva, and multiple attempts have been made to make these determina tions reliable (119c), but without much suc cess. In a study of saliva and serum lithium concentrations 2 and 12 hours after dosing the half-life of lithium was longer in saliva (35 hours) than in serum (24 hours) (120c). This suggests that the rate of elimination of lithium from different body compartments is different, and may help explain the time course of both the therapeutic onset and offset and toxicity (121H), as well as enlighten optimization of salivary lithium measurements.
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45. Storosum JG, Wohlfarth T, Schene A, Elfer ink A, van Zwieten BJ, van den Brink W. Magnitude of effect of lithium in short-term efficacy studies of moderate to severe manic episode. Bipolar Disord 2007;9(8):793–8. 46. Fragakis N, Iliadis I, Papanastasiou S, Lam brou A, Katsaris G. Brugada type electrocar diographic changes induced by concomitant use of lithium and propafenone in patient with Wolff–Parkinson–White syndrome. Pacing Clin Electrophysiol 2007;30(6):823–5. 47. Laske C, Soekadar SR, Laszio R, Plewnia C. Brugada syndrome in a patient treated with lithium. Am J Psychiatry 2007;164(9):1440–1. 48. Oudit GY, Korley V, Backx PH, Dorian P. Lithium-induced sinus node disease at therapeutic concentrations: linking lithiuminduced blockade of sodium channels to impaired pacemaker activity. Can J Cardiol 2007;23(3):229–32. 49. Strohmer B, Schernthaner C. Brugada syn drome unmasked by lithium therapy. Wien Klin Wochenschr 2007;119(9–10):282. 50. Sandras R, Lesaffre F, Lacotte J, Nazeyrolias P. Un syndrome de Brugada majore par un traitement au lithium. [Brugada syndrome unmasked by lithium treatment.] Presse Med 2007;36(4 Pt 1):612–4. 51. Goldberger ZD. Sinoatrial block in lithium toxicity. Am J Psychiatry 2007;164(5):831–2. 52. Shiraki T, Kohno K, Saito D, Takayama H, Fujimoto A.Complete atrioventricular block secondary to lithium therapy Circ J 2008; 72:847–9. 53. Hashemi SM, Hund TJ, Mohler PJ. Cardiac ankyrins in health and disease. J Mol Cell Cardiol 2009;47(2):203–9. 54. Ferreira MA, O’Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L, Fan J, Kirov G, Perlis RH, Green EK, Smoller JW, Grozeva D, Stone J, Nikolov I, Cham bert K, Hamshere ML, Nimgaonkar VL, Moskvina V, Thase ME, Caesar S, Sachs GS, Franklin J, Gordon-Smith K, Ardlie KG, Gabriel SB, Fraser C, Blumenstiel B, Defelice M, Breen G, Gill M, Morris DW, Elkin A, Muir WJ, McGhee KA, William son R, MacIntyre DJ, MacLean AW, St CD, Robinson M, Van Beck M, Pereira AC, Kandaswamy R, McQuillin A, Collier DA, Bass NJ, Young AH, Lawrence J, Fer rier IN, Anjorin A, Farmer A, Curtis D,
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Scolnick EM, McGuffin P, Daly MJ, Corvin AP, Holmans PA, Blackwood DH, Gurling HM, Owen MJ, Purcell SM, Sklar P, Crad dock N. Wellcome Trust Case Control Con sortium. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 2008;40(9):1056–8. Waring WS. Delayed cardiotoxicity in chronic lithium poisoning: discrepancy between serum lithium concentrations and clinical status. Basic Clin Pharmacol Toxicol 2007;100(5):353–5. Huang X, Lei Z, El-Mallakh RS. Lithium normalizes elevated intracellular sodium. Bipolar Disord 2007;9(3):298–300. Gao YL, Lei Z, Lu C, Roisen F, El-Mallakh RS. Effect of elevated intracellular sodium concentration on the expression of the bipo lar candidate gene transient receptor poten tial protein melastatin subtype 2 (TRPM2). Presented at the Annual Meeting of the Society for Biological Psychiatry, 2008, Washington DC. Kaplan PW, Birbeck G. Lithium-induced confusional states: nonconvulsive status epi lepticus or triphasic encephalopathy. Epi lepsia 2006;47(12):2071–4. Yip KK, Yeung WT. Lithium overdose causing non-convulsive status epilepticus – the importance of lithium levels and the electroencephalography in diagnosis. Hong Kong Med J 2007;13(6):471–4. Desarkar P, Das A, Das B, Sinha VK. Lithium toxicity presenting as catatonia in an adolescent girl. J Clin Psychopharmacol 2007;27(4):410–2. El-Mallakh RS. Acute lithium neurotoxi city. Psychiatric Develop 1986;4:311–28. Niethammer M, Ford B. Permanent lithium-induced cerebellar toxicity: three cases and review of literature. Mov Disord 2007;22(4):570–3. Fujii S, Oku H, Takahashi R, Kanbara Y, Sugasawa J, Ikeda T. Optic nerve dysfunc tion secondary to long-term use of lithium carbonate. Jpn J Ophthalmol 2007;51:79–81. Mur M, Portella MJ, Martínez-Arán A, Pifarré J, Vieta E. Persistent neuropsycho logical deficit in euthymic bipolar patients: executive function as a core deficit. J Clin Psychiatry 2007;68(7):1078–86.
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65. Gualtieri CT, Johnson LG. Comparative neurocognitive effects of 5 psychotropic anticonvulsants and lithium. MedGenMed 2006;8(3):46. 66. Bauer M, Blumentritt H, Finke R, Schlatt mann P, Adli M, Baethge C, Bschor T, M€ uller-Oerlinghausen B, Berghöfer A. Using ultrasonography to determine thyroid size and prevalence of goiter in lithiumtreated patients with affective disorders. J Affect Disord 2007;104(1–3):45–51. 67. Akin F, Yaylali GF, Bastemir M. The use of lithium carbonate in the preparation for definitive therapy in hyperthyroid patients. Med Princ Prac 2008;17:167–70. 68. Lee CS-N, Hutto B. Recognizing thyrotox icosis in a patient with bipolar mania: a case report. Ann Gen Psychiatry 2008;7:3. 69. Dalan R, Leow MK, Jong M. Multiple endocrinopathies associated with lithium therapy. Endocr Pract 2007;13(7):758–63. 70. Carchman E, Ogilvie J, Hoist J, Yim J, Carty S. Appropriate surgical treatment of lithium associated hyperparathyroidism. World J Surg 2008;32(10):2195–9. 71. Gregoor PS, de Jong GM. Lithium hyper calcemia, hyperparathyroidism, and cina calcet. Kidney Int 2007;71(5):470. 72. Sze L, Ulrich B, Brändle M. Severe hypo natremia due to nephrogenic diabetes insi pidus – a life threatening side effect of chronic lithium therapy. Exp Clin Endocri nol Diabetes 2006;114(10):596–8. 73. Vergnaud E, Baudin O, Desachy A, Group ARCO. Une prise en charge périopératoire ‘usuelle’ peut conduire à un coma hyperos molaire chez les patients traités par lithium. [Standard perioperative management of patients treated with lithium can lead to hyperosmolar coma.] Ann Fr Anesth Rea nim 2007;26(2):168–70. 74. Leeman MF, Vuylsteke A, Ritchie AJ. Lithium-induced nephrogenic diabetes insi pidus after coronary artery bypass. Ann Thorac Surg 2007;84(2):656–7. 75. Paw H, Slingo ME, Tinker M. Late onset nephrogenic diabetes insipidus following cessation of lithium therapy. Anaesth Inten sive Care 2007;35(2):278–80. 76. Shen HC, Li JY, Lo YK. Lithium intoxicationinduced acute parkinsonism complicated with hyperparathyroidism and nephrogenic
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diabetes insipidus: report of a case. Acta Neurol Taiwan 2007;16(4):231–3. Abodo J, Seux V, Koffi-Dago P, Dalco O, Renaud-Lévy O, Tassy S, Million M, Lok rou A, Soubeyrand J, Retornaz F. Diabète insipide nephrogénique au cours d’une intoxication aiguë au lithium. [Nephrogenic diabetes insipidus during lithium acute intoxication.] Ann Endocrinol (Paris) 2007;68(6):467–9. Khairallah W, Fawaz A, Brown EM, El-Majj Fuleihan G. Hypercalcemia and diabetes insipidus in a patient previously treated with lithiumNat Clin Pract Nephrol 2007;3(7):397–404. Watson S, Gallagher P, Smith MS, Young AH, Ferrier IN. Lithium, arginine vasopres sin and the dex/CRH test in mood disor dered patients. Psychoneuroendocrinology 2007;32(5):464–9. Sood MM, Richardson R. Negative anion gap and elevated osmolar gap due to lithium over dose. Can Med Assoc J 2007;176(7):921–3. Kutscher EC, Robbins GP, Kennedy WK, Zebb K, Stanley M, Carnahan RM. Cloza pine-induced leucopenia successfully trea ted with lithium. Am J Health Syst Pharm 2007;64(19):2027–31. Kim HK, Kin JE, Chung J, Park KH, Han KS, Cho HI. Lithium down-regulates the expression of CXCR4in human neutrophils. J Trace Elem Med Biol 2007;21(3):204–9. Kast RE. How lithium treatment generates neutrophilia by enhancing phosphorylation GSK-3, increasing HIF-1 levels and how this path is important during engraftment. Bone Marrow Transplant 2008;41(1):23–6. Meier M, Beigel A, Schiffer L, Lotz J, Hiss M, Mengel M, Haller H, Schwarz A. Mag netic resonance imaging in a patient with chronic lithium nephropathy. Nephrol Dial Transplant 2007;22(1):278–9. Markowitz GS, Radhakrishnan J, Kambhan N, Valeri AM, Hines WH, D’Agati VD. Lithium nephrotoxicity: a progressive com bined glomerular and tubulointerstitial nephropathy. J Am Soc Nephrol 2000;11 (8):1439–48. Wang X, Wu Y, Ward CJ, Harris PC, Torres VE. Vasopressin directly regulates cyst growth in polycystic kidney disease. J Am Soc Nephrol 2008;19(1):102–8.
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87. Bassilios N, Martel P, Godard V, Froissart M, Gr€ unfeld J-P, Stengel B; Réseau Néphropar. Monitoring of glomerular filtration rate in lithium-treated outpatients – an ambulatory laboratory database surveillance. Nephrol Dial Transplant 2008;23:562–5. 88. Wachter T, Murach WM, Bröcker EB, Schön MP. Recalcitrant lithium-induced psoriasis in a suicidal patient alleviated by tumour necrosis factor-alpha inhibition. Br J Dermatol 2007;157(3):627–9. 89. Cen JP, Zhu KJ, Jin N, Lin AH, Cheng H. [Effects of drugs known to trigger psoriasis on HaCaT keratinocyte.] Yao Xue Xue Bao 2007;42(10):1041–4. 90. Knijff EM, Breunis MN, Kupka RW, de Wit HJ, Ruwhof C, Akkerhuis GW, Nolen WA, Drexhage HA. An imbalance in the production of IL-1beta and IL-6 by mono cytes of bipolar patients: restoration by lithium treatment. Bipolar Disord 2007;9 (7):743–53. 91. Wilting I, de Vries F, Thio BM, Cooper C, Heerdink ER, Leufkens HG, Nolen WA, Egberts AC, van Staa TP. Lithium use and the risk of fractures. Bone 2007;40(5):1252–8. 92. Even C, Thuile J, Rouillon F. Lithiuminduced menometrorrhagia. Psychiatry Clin Neurosci 2007;61:203. 93. Zuncheddu C, Carpiniello B. Disfunzioni sessuali e disturbo bipolare dell’umore: risul tati di uno studio su pazienti in trattamento a lungo termine con sali di litio. [Sexual dysfunctions and bipolar disorder: a study of patients submitted to a long-term lithium treatment.] Clin Ter 2006;157(5):419–24. 94. Aizenberg D, Sigler M, Zemishlany Z, Weizman A. Lithium and male sexual func tion in affective patients. Clin Neurophar macol 1996;19(6):515–9. 95. Zarnescu O, Zamfirescu G. Effects of lithium carbonate on rat seminiferous tubules: an ultrastructure study. Int J Androl 2006;29 (6):576–82. 96. James L, Barnes TRE, Lelliott P, Taylor D, Paton C. Informing patients of the terato genic potential of mood stabilizing drugs: a case note review of the practice of psychia trists. J Psychopharmacol 2007;21(8):815–9. 97. Viguera AC, Newport DJ, Ritchie J, Stowe Z, Whitfield T, Mogielnicki J, Baldessarini RJ, Zurick A, Cohen LS. Lithium in breast
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mild and nursing inftants: clinical implica tions. Am J Psychiatry 2007;164(2):342–5. American Academy of Pediatrics, Commit tee on Drugs. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108(3):776–89. Waring WS, Laing WJ, Good AM, Bateman DN. Pattern of lithium exposure predicts poisoning severity: evaluation of referrals to a regional poisons unit. QJM 2007;100:271–6. Habermeyer B, Hess M, Kozomara-Hocke P, Mager R, Kawahl W. Lithium intoxica tions at normal serum levels. Psychiatr Prax 2008;35:198–200. Pauzé DK, Brooks DE. Lithium toxicity from an Internet dietary supplement. J Med Toxicol 2007;3(2):61–2. Borrás-Blasco J, Sirvent AE, Navarro-Ruiz A, Murcia-López A, Romero-Crespo I, Enriquez R. Unrecognized delayed toxic lithium peak concentration in an acute poi soning with sustained release lithium pro duct. South Med J 2007;100(3):321–3. Canal M, Legangneux E, van Lier JJ, van Vliet AA, Coulouvrat C. Lack of effect of amisulpride on the pharmacokinetics and safety of lithium. Int J Neuropsychophar macol 2003;6(2):103–9. Bergemann N, Abu-Tair F, Kress KR, Pra zer P, Kopitz J. Increase in plasma concen tration of amisulpride after addition of concomitant lithium. J Clin Psychopharma col 2007;27(5):546–9. Meyer JM, Dollarhide A, Tuan IL. Lithium toxicity after switch from fosinopril to lisi nopril. Int Clin Psychopharmacol 2005;20 (2):115–8. Finley PR, O’Brien JG, Coleman RW. Lithium and angiotensin-converting enzyme inhibitors: evaluation of a potential inte raction. J Clin Psychopharmacol 1996;16 (1):68–71. Su YP, Chang CJ, Hwang TJ. Lithium intoxication after valsartan treatment. Psy chiatry Clin Neurosci 2007;61(2):204. Böker H, Brandenberger M, Neurotoxische SC. Enzephalopathie unter Kombinations behandlung mit Lithium und Risperidon bei einer Patientin mit schizoaffektiver Storung. [Neurotoxicity related to lithium–risperidone combination treatment in a patient with schi zoaffective disorder.] Psychiatr Prax 2007;34 (1):38–41.
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109. Kosehasanogullari SG, Akdede B, Akvar dar Y, Akan M, Tunca Z. Neuroleptic malignant syndrome caused by a combina tion of risperidone and lithium in a patient with multiple medical comorbidities. Prog Neuropsychopharmacol Biol Psychiatry 2007;31(5):1147–8. 110. Sachs GS, Grossman F, Ghaemi SN, Okamoto A, Bowden CL. Combination of a mood sta bilizer with risperidone or haloperidol for treatment of acute mania: a double-blind, pla cebo-controlled comparison of efficacy and safety. Am J Psychiatry 2002;159(7):1146–54. 111. Gillman K. Venlafaxine–lithium toxicity: suitability for use in the elderly. J Clin Pharm Ther 2007;32(5):529–31. 112. Liberek C, Aubry JM, Baud P. Manic switch and serotonin syndrome with ven lafaxine–lithium–valproate association. Therapie 2006;61(6):531–3. 113. Adan-Manes J, Novalbos J, LópezRodríguez R, Ayuso-Mateos JL, Abad-San tos F. Lithium and venlafaxine interaction: a case of serotonin syndrome. J Clin Pharm Ther 2006;31(4):397–400. 114. Bertschy G, Ragama-Pardos E, Aït-Ameur A, Muscionico M, Favre S, Roth L.Lithium augmentation in venlafaxine non-responders: an open study. Eur Psychiatry 2003;18(6): 314–7.
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115. Wilting I, Fase S, Martens EP, Heerdink ER, Nolen WA, Egberts AC. The impact of environmental temperature on lithium serum levels. Bipolar Disord 2007;9 (6):603–8. 116. Severus WE, Kleindienst N, Seem€ ullere F, Frangou S, Möller HJ, Greil W. What is the optimal serum lithium level in the long-term treatment of bipolar disorder – a review? Bipolar Disord 2008;10:231–7. 117. Kleindienst N, Severus WE, Greil W. Are serum lithium levels related to the polarity of recurrence in bipolar disorder? Evidence from a multicenter trial. Int Clin Psycho pharmacol 2007;22(3):125–31. 118. El-Mallakh RS, Wyatt RJ. The Na, K-ATPase hypothesis for bipolar illness. Biol Psychiatry 1995;37:235–44. 119. El-Mallakh RS, Linder M, Valdes Jr. R, Looney S. Dialysis of saliva improves accu racy of saliva lithium determinations. Bipo lar Disord 2004;6(1):87–9. 120. Serdarevic´ N, Kozjek F, Malesic I. Saliva and serum lithium monitoring in hospita lized patients and possibility to replace serum to saliva. Bosn J Basic Med Sci 2006;6(4):32–5. 121. El-Mallakh RS. Ion homeostasis and the mechanism of action of lithium. Clin Neuro sci Res 2004;4:227–31.
Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong
4
Drugs of abuse
Benzylpiperazine and related compounds
piperazine derivatives are known as ‘pep pills’.
A new class of designer drugs, piperazine derivatives, which include 1-benzylpipera zine, 1-(3,4-methylenedioxybenzyl)pipera zine, 1-(3-chlorophenyl)piperazine, and 1-(4-methoxyphenyl)piperazine, have amfe tamine-like effects; 1-benzylpiperazine was initially developed as a veterinary antihelminthic compound and has a chemical structure very similar to amfetamine. A mixture of 1-benzylpiperazine and 1-(3-trifluoro-methylphenyl)piperazine mimics the molecular mechanism of 3,4-methyle nedioxymetamfetamine (MDMA) (1c, 2c). Commonly, piperazines are sold as party pills on the black market or over the Internet, and generally piperazine blends are consumed (3r). Several countries (USA, Australia, Japan, and countries in the European Union) regulate benzylpiperazine derivatives under drug control legislation (4r). Many clinicians are unaware of emerging classes of drugs of abuse. Piperazines and amfetamine are similarly marketed, con sumed by the same population and have similar pharmacological effects (5A). There fore, piperazine poisoning can easily be misdiagnosed as amfetamine poisoning. Furthermore, piperazines are not detected by immunochemical screening procedures for drugs of abuse, but require toxicological analysis by gas chromatography/mass spec trometry (6E). Formulations containing
Drug overdose Poisoning due to 1-benzyl piperazine, resulting in convulsions and collapse, has been reported (5A).
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32004-6 2010 Elsevier B.V. All rights reserved.
• An 18-year-old woman purchased tablets thought to be ecstasy or amfetamine at a London nightclub (4A). After taking five tablets she collapsed and appeared to have a seizure lasting 10 minutes. She became agitated and had dilated pupils, a sinus tachycardia and a blood pressure of 150/51 mmHg. Her Glasgow Coma Score was 15 and she was apyrexial. She was one of seven patients who attended the hospital that night with a similar presentation. She was given high doses of benzodiazepines. A blood sample contained 1-benzylpiperazine, which was also found in a tablet that she had on her.
This patient’s presentation was consistent with previous reports. The authors suggested that clinicians should be vigilant for the presence of piperazines based on the clinical presentation, particularly as some drug tests do not detect them. Patients suspected of having ingested piperazines should be monitored for cardiotoxicity as well as seizures.
CANNABINOIDS (SED-15, 614; SEDA-29, 35; SEDA-30, 31; SEDA-31, 33) Cardiovascular In a case of cannabisassociated arteritis, aspirin treatment resulted in revascularization (7A). • A 48-year-old woman developed necrosis of the right big toe, and ultrasound showed complete
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occlusion of the large arteries below the knees bilaterally, but without atherosclerosis of the iliofemoral arteries, which might be expected in peripheral vascular disease. She stopped using marijuana and took aspirin 100 mg/day. Within 6 months all the arteries in the leg were patent and the toe had healed.
The authors suggested that aspirin could be effective in early intervention for cannabisassociated arteritis, making it important to distinguish arteritis from peripheral vascular disease. Cerebrovascular disease has been attribu ted to cannabis (8A). • A 34-year-old woman who used 2-6 cannabis cigarettes per day and took buprenorphine 5 mg/day developed temporal lobe hemorrhage. Angiography showed multifocal narrowing of arteries, without arteriovenous malformations or aneurysms. She reduced the dose of buprenorphine to 2 mg/day and reduced her consumption of cannabis to 3-4 cigarettes per week, and 3 months later angiography showed no narrowing or other abnormality in the cerebral vessels, leading the authors to conclude that the abnormality was associated with one or both drugs.
The dysrhythmogenic properties of can nabis appear to be influenced by the effects of tetracannabinol on action potential short ening and on vagal tone hyperstimulation. A case of Brugada-like syndrome has been reported (9A). • A healthy 19-year-old man suffered an attack of syncope lasting 2 minutes after heavy cannabis smoking. An electrocardiogram showed 2-mm ST-segment elevation in leads V1 and V2. Two-dimensional echocardiography showed normal left ventricular function without any structural abnormalities. Investigation of vasovagal-mediated syncope was negative. Urine and blood toxicology showed tetrahydrocannabinol. After resolution of the ST-segment abnormalities, a procainamide induction test failed to elicit ST-T wave changes.
The authors suggested that the ST-segment abnormalities may have been related to par tial sodium channel opening secondary to marijuana. Respiratory In 10 marijuana smokers with respiratory problems (mean age 41 years, 8 men), who had smoked marijuana regularly for at least 12 months, bullous lung disease was
Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong
identified by high-resolution CT scanning (10A). Their presenting problems included dyspnea (n = 4), pneumothorax (n = 4), and lung infection (n = 2). In four patients the chest X-ray was normal; in five cases lung function tests were normal. The authors suggested that people who smoke cannabis present at a young age with significant respira tory problems and changes. Psychological Cannabis use is associated with impaired memory and learning, and cannabinoid neuroreceptors are present in especially high density in the hippocam pus, which has a role in forming episodic memories or new associations. Deficits in learning and memory and hippocampal func tioning have been studied in cannabis users (11C). In the first experiment, 35 current cannabis users and 38 controls were given a neuropsychological test, a face–name task, which measures a person’s ability to associate faces and names and assesses hippocampal function. The cannabis users performed sig nificantly worse in learning and short- and long-term memory performance. In the sec ond experiment, 14 current cannabis users and 14 controls were tested in a modified face–name task. Cortical and parahippocam pal activities were examined by fluorescent magnetic resonance imaging (fMRI). Although the two groups performed similarly in learning, the marijuana users had hypoactivity or lower Blood Oxygen LevelDependent (BOLD) activity in the frontal and temporal cortices and hyperactivity or higher BOLD activity in the parahippocam pus. The authors suggested that deficits in learning involve dysfunction in the prefrontal and the parahippocampal regions. The effect of cannabis use on cerebellar function has been investigated (12c). The cerebellum has a role in motor coordination and some forms of associative learning and a key role in temporal operations, such as time estimation and rhythm production. Eye-blink conditioning (EBC) studies permit assessment of cerebellar-based timing defi cits. In 14 chronic cannabis users (24-hour abstinence before study) and 10 healthy drug-free controls, an EBC task was admi nistered, in which a conditioned stimulus (400 ms tone) was followed by a corneal air
Drugs of abuse
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puff unconditioned stimulus (50 ms), eliciting a conditioned blink response. The cannabis group had significantly fewer and more poorly timed conditioned blink responses compared with controls. The two groups had no detectable differences in an EEG measure of selective attention to the condi tioned stimulus (N100 auditory event-related potentials, ERPs) or the unconditioned response. It appeared that cannabis was associated with cerebellar disruption that was specific only to the acquisition of con ditioned blink responses. The authors noted that this finding corroborated recent work in mice (13E). They also observed that it is not known whether cannabis absti nence results in the recovery of cannabisinduced cognitive impairments. Psychiatric In a systematic review of popu lation-based or case-controlled longitudinal studies, the authors (14M) identified 4804 references to studies that provided infor mation about the risk that cannabis users versus non-cannabis users would develop a psychosis (including schizophrenia, schizoaffective disorder, psychotic disorder not otherwise specified, or psychotic symp toms) or affective disorders (affective mood or bipolar disorder, affective disorder not otherwise specified, depression, suicidal ideation, suicide attempts, anxiety, neurosis, or mania); 175 references seemed ade quately detailed, but 143 were excluded on reading the full paper. There were 11 papers that reported 7 cohort studies of psychosis and 24 papers that reported 15 cohort studies of affective outcomes. The authors found no evidence of publication bias among the papers they selected. This meta-analysis dif fered from previous meta-analyses, in that it did not include cross-sectional studies, included unadjusted results, and did not dif ferentiate people who ever used cannabis from those who regularly used it. The risk of psychosis, which was defined as a range of symptoms from self-reported psychotic symptoms to a clinical diagnosis of schizo phrenia, was increased in those who had ever used cannabis, with an odds ratio of 1.41 (95% CI = 1.21, 1.65). Six of the stu dies examined the effect of frequency; pool ing these data showed a dose–response
57
relationship, with an odds ratio of 2.09 (CI = 1.54, 2.84) for those who had used cannabis most often (defined differently in the studies as daily, weekly, > 50 times, or meeting dependence criteria). The studies excluded people with a psychosis at base line. The authors cautioned that the odds ratio did not imply causation. Affective outcomes were examined in 15 cohorts, but because of heterogeneity in the defini tion of cannabis use across the studies, no meta-analysis was performed. The authors found that these studies showed a slight increase in affective outcomes, although the confidence intervals were consistent with no effects. They concluded that there is now adequate evidence to justify issuing a warning that cannabis exposure will increase the risk of psychotic disorders. Endocrine A relationship between can nabis use and gynecomastia or breast tissue growth was first reported in 1972 (15A). Subsequent research has shown that there may be an association (16A) or not (17c). Dronabinol-induced gynecomastia has now been reported (18A). • A 48-year-old man with a lengthy gastrointestinal history and severe recurrent nausea was given dronabinol (Marinol) 5 mg/day for 1 month. He had a history of testicular cancer treated with unilateral orchidectomy and 20 years before had had a benign contralateral breast mass, consistent with gynecomastia, removed. He now presented with a new right retroareolar breast mass. The mass was mobile and tender to palpation; there was no lymphadenopathy. Mammography and ultrasonography showed that the mass was a small dense focus of retro areolar parenchyma without microcalcifica tion. Fine-needle aspiration of the mass showed normal breast tissue. Serum concentrations of testosterone, prolactin, and thyroxine were normal, as were liver function tests.
Drug contamination Over 3–4 months, 29 patients, aged 16–33 years, all regular users of marijuana, presented to a German uni versity hospital with lead poisoning, includ ing one with a severe encephalopathy and a permanent palsy in his forearm (19A). When samples of the marijuana in the patients’ homes were examined, lead parti cles were visible. The lead may have been used to increase the weight of the marijuana
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(which is sold by weight) and therefore increase profits to the dealer. Contaminated marijuana could be considered when seek ing a source for lead intoxication.
(SED-15, 848; SEDA-30, 31; SEDA-31, 37)
COCAINE
Cardiovascular Ischemic cardiac events due to cocaine EIDOS classification: Extrinsic moiety: Adrenaline Intrinsic moiety: a-Adrenoceptors Distribution: Myocardium Outcome: Vasospasm Sequela: Ischemic cardiac events due to cocaine DoTS classification: Dose relation: Toxic Time course: Time independent Susceptibility factors: Not known The cardiovascular toxicity of cocaine has been reviewed, providing an explanation of its ischemic and prothrombotic effects, accelerated coronary atherosclerosis, coron ary vasoconstriction, and dysrhythmias, including sinus tachycardia or bradycardia, ventricular fibrillation, ventricular tachy cardia, prolongation of the QTc interval, and torsade de pointes (20R). Prolongation of the QT interval after cocaine use has previously been reported to resolve within 72 hours, but a case in which it persisted for 5 days has been reported (21c). • A 59-year-old African American woman developed syncope after using cocaine for 4 days. She had bradycardia, a left-sided carotid bruit and a QTc interval of 600 ms, which was attributed to cocaine. She was taking no medications known to prolong the QT interval and she had no family history of similar events. Serial cardiac enzymes were within the reference ranges. Two-dimensional echocardiography showed left ventricular hypertrophy and normal left ventricular systolic function. Carotid angiography showed 90% stenosis in the left internal carotid artery.
Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong
The authors attributed the syncopal episode to cocaine-associated dysrhythmias. They speculated that cocaine affects cardio vascular physiology by preventing synaptic re-uptake of noradrenaline; it also acts like a type 1 antidysrhythmic agent, inhibiting membrane repolarization and preventing cardiac repolarization by blocking potas sium channels. Neonatal heart rate and heart rate varia bility are used to detect a variety of patho physiological alterations in the autonomic nervous system regulation of cardiac func tion. The effects of prenatal cocaine exposure on heart rate and heart rate variability have been studied in the presence of orthostatic stress in near-term and full-term neonates (22c). Infants with prenatal cocaine exposure (n = 21) and controls (n = 23) were enrolled within 120 hours of birth. An electrocardio gram was recorded for 1 hour during quiet sleep, for 30 minutes in supine and then for 30 minutes in an inclined position. Compared with controls, the infants with prenatal cocaine exposure had a delayed and pro longed reaction to orthostatic stress. The results suggested that the effects of prenatal cocaine exposure on the development of the sympathetic and parasympathetic nervous systems could alter cardiovascular function. Therapeutic hypothermia has been suc cessfully used in cocaine-induced cardiac arrest (23A). • A 28-year-old woman had a cardiac arrest with pulseless electrical activity after consuming cocaine. Despite treatment with chest compression, adrenaline and atropine or vasopressin, she had two further episodes of pulseless electrical activity and was given an infusion of noradrenaline. When her vital signs returned, she was comatose with ventricular fibrillation. Hypothermia was initiated, lowering her body temperature from 34.7°C (94.4°F) to 32–33°C (89.6–91.4°F) for 24 hours. She was then gradually re-warmed over 6 hours and was extubated. She had nearcomplete neurological recovery with mild deficits in short-term memory and orientation.
Although hypothermia has been shown to be a positive intervention in comatose survi vors of cardiac arrest, drug overdose was an exclusion criterion in previous studies.
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A Brugada-like syndrome has been reported in a patient with cocaine toxicity and was initially interpreted as acute ST-segment-elevation myocardial infarction (24Ar). The authors postulated that the elec trocardiographic changes may have been due to uncovering by cocaine of an under lying genetic predisposition or because of a direct effect on cardiac sodium channels. Cocaine can cause myocardial infarction by multiple mechanisms, including coronary vasoconstriction, increasing heart rate and blood pressure, platelet activation, and possi bly accelerated atherosclerosis (25R, 26R). The incidence of myocardial infarction after cocaine ingestion is estimated to be 0.7–6%. Evaluation of cocaine-associated chest pain is similar to evaluation in those who do not use cocaine; however, because cocaine can cause rhabdomyolysis, creatine kinase activ ity is not as reliable as other tests (26R). TIMI risk scores, which are used to predict 14-day mortality in unstable angina and nonST-elevation myocardial infarction, are not helpful in predicting outcomes in those with cocaine-associated chest pain. In a prospec tive cohort study of 261 patients with cocaine-associated chest pain, TIMI scores did not correlate with acute myocardial infarction, revascularization or death in the 30 days from the index visit (27c). There is a debate about the role of b-block ers in treating cocaine-associated myocardial infarction. The American Heart Association’s treatment guidelines (26R) and a recent review (25R) are consistent with the prior clinical convention that cautions against the use of b-blockers, because of concern that the b-blocking actions of cocaine on the coronary arteries will leave the a-adrenergic effects unopposed, leading to coronary vasospasm. This was based on an observation in 30 healthy adults that vasoconstriction after intranasal cocaine worsened after administra tion of a b-blocker (28c). A literature review of three case reports, two placebo-controlled trials and three national guidelines did not find evidence or opinion favouring the use of b-blockers after cocaine exposure (29R). However, a retrospective cohort study has shown possible benefit of b-blockers in reducing the risk of myocardial infarction
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after cocaine use, calling this into question (30c). Records from 363 consecutive admis sions (307 individual patients) to telemetry and intensive care units that had urine toxi cology studies positive for cocaine were reviewed for the effects of b-blockers on the development of myocardial infarction or death. Myocardial infarction was defined as a serum troponin concentration greater than 0.10 or ST elevation in two contiguous electrocardiogram leads. Patients who had received b-blockers as out-patients and patients with missing troponin measurements were excluded, leaving 310 admissions and 296 patients. Beta-blockers were used in 33 cases. Two patients who received a b-blocker developed a myocardial infarction and one died (incidence 1.7%), whereas 72 who did not receive a b-blocker developed a myocar dial infarction and 13 died (incidence 4.5%). Those who received a b-blocker were more likely to have a history of heart failure and higher blood pressures and glucose concen trations, although these differences are more apt to increase the risk of myocardial infarc tion. This was a small study, and the results were somewhat limited by its retrospective design and because no data were available about the time of cocaine ingestion; however, it did provide preliminary information in favour of using b-blockers. While some have called for a prospective randomized trial to evaluate b-blockers in this setting, others have cautioned that this would be dangerous (31r). In a review, the American Heart Associa tion (AHA) found no randomized controlled studies of treatment for cocaine-associated myocardial infarction. Management is in gen eral similar to that of non-cocaine-associated myocardial infarction, with a few exceptions. While the AHA does not recommend b-blockers, it does recommend intravenous benzodiazepines and the use of glyceryl trinitrate (nitroglycerin) and calcium channel blockers or phentolamine to treat hyperten sion (26R). The use of cocaine may be associated with higher risk of stent thrombosis after coronary stenting. Of 247 consecutive patients who received coronary stents, 12 were actively using cocaine (4.9%); four developed stent thrombosis; in three cases thrombosis
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occurred more than 30 days after stenting. Only two of the 235 patients without documen ted cocaine use (0.85%) had stent thrombosis during the same period (32C). An accompany ing editorial advised including cocaine among the risk factors for stent thrombosis and sug gested that drug-eluting stents, which are asso ciated with poorer endothelialization, should be avoided in cocaine users (33r). Cocaine has been associated with aortic dissection, thought to be due to shearing forces from hypertension and tachycardia. In a retrospective chart review of 164 patients admitted with acute aortic dissection over 15 years, 16 patients (9.8%) had used powdered cocaine intranasally or had smoked crack within 24 hours before the onset of symptoms (by self-report or positive urine toxicology) (34R). The mean time from drug use to symp toms was 13 hours. The cocaine users were significantly younger than those who had not used cocaine (mean age 47 versus 62 years). Outcomes, including length of hospital stay and mortality, were similar, with the excep tion of an increased rate of pulmonary com plications in those who had used cocaine, postulated to be due to cocaine- or cigaretteinduced pre-existing lung damage. Nervous system Fatal toxic encephalopa thy occurred in a 21-year-old man after an overdose of intravenous cocaine in a pre sumed suicide attempt (35c). He died 24 days after admission without gaining consciousness. Autopsy showed a severe leukoencephalopathy with pronounced demyelination, lipid-loaded macrophages, and liquefaction of the central cerebral white matter. The authors said that this was the first published report of fatal en cephalopathy after a single dose of cocaine. Sensory systems Eyes Pre-retinal hemor rhage has been attributed to use of cocaine. • A healthy 25-year-old man developed painless loss of vision in his right eye after using cocaine the night before (36c). His visual acuity was 1.0 in his left eye and 0.05 in his right eye. There was pre-retinal hemorrhage in the right eye. Visual acuity did not improve over the next 2 weeks and the macular hemorrhage continued to spread. He therefore underwent pars plana vitrectomy. The visual acuity in his right eye improved to 0.9.
Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong
Respiratory Cocaine has been associated with necrosis of the nasal septum and necro sis of the hard palate (37c). • A combination of intranasal cocaine and paracetamol þ oxycodone (Percocet) led to necrosis of the entire soft palate and most of the uvula in a 33-year-old woman, who developed oronasal reflux, voice changes, dysphagia, and partial hearing loss. Other causes of soft palate necrosis, including granulomatous disease and active infection, were ruled out. She underwent pharyngeal flap reconstruction, which addressed the velopharyngeal insufficiency, with improvement in speech intelligibility and reduced hypernasal speech.
The authors attributed this rare case of soft palate necrosis, without involvement of the hard palate, to inhalation of cocaine and Percocet. Teratogenicity and fetotoxicity The neuro developmental consequences of cocaine exposure have been studied in the Maternal Lifestyles Study, a multi-site study of mother– infant pairs (‘dyads’) screened and recruited after delivery (38R). Infants who had been exposed to cocaine or opiates were identified either by maternal admission of cocaine use during pregnancy or by positive laboratory tests for cocaine metabolites; 658 pairs were included in the exposed group and were matched to 730 pairs in the unexposed com parison group. The mothers were evaluated using the Addiction Severity Index (ASI) for current and lifetime substance use; the same tool, although not a screening instrument for depression, was used to identify those who had had serious depression in the past 30 days and those who had had a lifetime history of depression. The infants were assessed at 1 month of age using the NICU Network Neurobehavioral Scale, which evaluates three areas: neurological, behavioral, and stress. The authors found no significant differ ences in the proportion of women depressed in the previous 30 days when they compared the cocaine users with the abstinent group (19% versus 16%). They initially hypothe sized that infants exposed to depression would perform less well on neurobehavioral screening and that those with prenatal cocaine exposure would have worse outcomes than those without exposure. This hypothesis was
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only partly confirmed: the infants of depressed mothers had worse outcomes in terms of selfregulation, stress signs, excitability and arou sal; however, these findings were only evident in those infants who had not been exposed to cocaine. The authors were surprised by the absence of these negative effects in cocaineexposed infants. They postulated that cocaine exposure before birth may have affected development of the monoamine system in a way that was somehow protective. There were negative effects of cocaine on language development in 209 exposed chil dren compared with 189 unexposed, who were studied prospectively from birth (39R). Receptive, expressive, and total language skills were evaluated at 1, 2, 4, and 6 years of age. The cocaine-exposed children had poorer scores in all areas and did not make up for these differences over time. In utero cocaine exposure may also have a long-term effect on growth. In a prospective cross-sectional analysis of 99 children exposed to cocaine in the first trimester and 125 who were not, growth curves were eval uated at 1, 3, 7, and 10 years of age (40R). The exposed children were smaller than the nonexposed children at ages 7 and 10 and grew at a slower rate over the course of the study; there were no significant differences at ages 1 and 3. Cocaine exposure in utero may affect rest ing cerebral blood flow in adolescents. In a functional MRI study of a longitudinal cohort of 24 adolescents who had been exposed to cocaine in utero and 25 matched, nonexposed controls, the former had reduced resting global cerebral blood flow, especially in the posterior and inferior regions of the brain (41R). When global blood flow was controlled for, some anterior and superior regions, such as the prefrontal, cingulate, and amygdala, had relative increases in blood flow, hypothesized by authors as a compensatory mechanism in response to the reduction in global cerebral blood flow, which may have occurred in these areas because they mature later during brain development. Drug–drug interactions Quetiapine Cocaine is used in combination with other drugs, such as heroin, to modify the experi ence of intoxication; combination of cocaine
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with the prescription medication quetiapine has also been reported (42c). • A 33-year-old Caucasian man combined cocaine with 400–800 mg of crushed quetiapine, which was then heated and administered intra venously, seeking a hallucinogenic effect.
The authors speculated that the patient had replaced heroin with quetiapine to develop ‘Q-ball’, as the sedative effects of quetiapine may mitigate the dysphoria associated with cocaine withdrawal and might provide a hal lucinogenic effect.
Ecstasy (3,4 methylenedioxymetamfetamine, MDMA) (SED-15, 180; SEDA-29, 1; SEDA-30, 37; SEDA-31, 41; for other amphetamines see Chapter 1) Clinical uses The potential psychotherapeu tic role of ecstasy has been reviewed, since it is a powerful central nervous system (CNS) stimulant that affects several neuro transmitter systems and intensifies a range of psychobiological functions (43R). Alexander Shulgin – regarded as the father of ecstasy – suggested that ecstasy might prove to be an effective psychotherapeutic agent in the 1980s, based on its positive life-enhancing acute effects on mood, with affirmative cog nitive effects that endure well afterwards. Subsequently, ecstasy has been explored as a potential tool for enhancing psychotherapy. Psychotherapists have found that setting, intention, and expectations are crucial for a positive outcome, but these factors cannot be guaranteed. However, there are significant negative and potential antitherapeutic effects of ecstasy, which are important and need to be recognized. Moreover, stimulants like ecstasy, in patients with psychiatric predispo sition, may increase the likelihood of acute and chronic drug abreactions. The biological underpinnings of the psychodynamic expla nations proposed for ecstasy-assisted therapy still require further explorations to develop a neurochemical model to propose how it might relieve psychiatric distress. The author suggested that issues such as set and expecta tions should be addressed before it can be
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argued that ecstasy might be clinically useful for psychotherapy. Respiratory Spontaneous pneumomediasti num has been reported after use of ecstasy (44A). • A 21-year-old previously healthy man developed pleuritic chest pain and dysphagia nearly 1 day after taking an unknown quantity of ecstasy. He had taken ecstasy the previous afternoon followed by several hours of sexual intercourse for the remainder of the evening. He became symptomatic at night. He did not have vomiting, dyspnea, dysphonia, or odynophagia. He was comfortable, with normal vital signs; his trachea was central and there was crepitus in the anterior neck. Hamman’s sign was absent and the heart sounds were normal. A CT scan of the chest and neck showed free air in the mediastinum and retropharyngeal soft tissues of the neck. He was discharged after a brief period of observation.
The authors speculated that several hours of sexual intercourse may have caused exces sive positive airway pressure, resulting in overinflation and alveolar rupture. In a retrospective review of 56 cases of pneumomediastinum seen in two inner city hospitals between January 1999 and Decem ber 2004, six met the criteria of ecstasy use in the 24 hours before presentation (45cr). There were three men and three women aged 19–27 years. Five presented after dan cing or a rave party. Two did not smoke or have underlying lung disease; three were smokers and one had asthma. One had a concurrent pneumothorax. All were treated conservatively initially with intravenous fluids. The authors reviewed the literature and found 13 reports (15 cases) since 1993. All had been treated conservatively without any reported sequelae. Spontaneous pneumo mediastinum occurs when intrabronchial and intra-alveolar pressures rise because of forced expiration against a closed glottis. When the pressure is raised excessively, alveoli burst and air tracks along broncho alveolar fascia planes to reach the mediasti num. From there, air can track along the path of least resistance towards the neck and chest wall causing surgical emphysema. The authors suggested that this cannot be a direct effect of the drug and wondered if
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it could be explained by impurities. However, it appears that overexertion and extreme phy sical activity over prolonged periods at rave and other dancing parties may explain it. Nervous system A selective myelopathy has been reported after intranasal insufflation of ecstasy and heroin (46A). • A 17-year-old girl became drowsy and was unable to walk after an overdose of intranasal insufflated heroin and amphetamines. After a few hours, her drowsiness progressed to stupor and she became progressively weak in all four limbs, mainly the legs. Her creatine kinase activity was markedly raised and she had acute renal and hepatic failure. She had used cannabinoids and ecstasy since age 12, but during the past week she had insufflated heroin about once a day and on the previous night had taken a double dose of heroin and a high dose of ecstasy (about 1 g intranasally). The next day she was alert but reported diffuse muscle pain and tenderness, mostly in the legs, where weakness rapidly worsened to flaccid, areflexic paralysis. Ecstasy and opiates were found in her urine. The acute renal failure normalized by day 10 with resumption of normal diuresis, and the myalgia also disappeared. The muscle weakness in the arms promptly improved, but flaccid paralysis persisted in the legs. There were no sensory effects and no sphincteric abnormalities. Motorevoked potentials recorded from muscles in the feet were absent from day 9 onwards. On day 16, electromyography showed complete non-excitability of the leg motor nerves together with fibrillation potentials without any voluntary activity in all lower limbs and paraspinal muscles innervated by the L3–S1 roots. An MRI scan at the start of the symptoms was negative, but 1 month later showed selective T2 hyperintensity in the anterior horns and signal alteration in the lumbar roots, associated with volume increase and intense gadolinium enhancement. The skin sympathetic reflex, the quantitative sensory test and the urodynamic test were all normal. Intravenous high-dose steroids produced no clinical benefit and 4 months later she was still paraplegic.
The authors reviewed the literature and reported that although some of the symp toms mentioned in this case are well-known complications of intravenous heroin use, no cases of myelopathy after use of ecstasy have been described. However, their report high lighted selective involvement of the lumbar motor neurons and a unique MRI pattern that has never been reported previously.
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The MRI pattern did not suggest spinal infarction. The clinical, neuroradiological, and neurophysiological data suggested that the pathological process primarily affected spinal anterior horns, conditioning motor neuron cell death and then nerve roots and the lumbar plexus because of Wallerian degeneration. The authors speculated that a pathogenetic role of ecstasy could not be excluded and may have contributed towards some of the atypical features — e.g. the lack of a clear period of abstinence from heroin in their patient, which has been described in most cases of opiate toxic myelopathy, and the unusually high dose of ecstasy inhaled. They supported their hypothesis by suggest ing that the lumbar motor neurons express large numbers of serotonin receptors that could mediate the effects of ecstasy, whereas opioid receptors are three times more highly represented in the dorsal horns than in the ventral horns of the spinal cord.
Ecstasy and neurocognition Numerous meta-analyses, reviews, and reports have focused on neurocognition and the use of ecstasy. However, the data are not conclu sive and demand more rigorous research. The data on ecstasy-induced neurotoxicity in rats have been reviewed (47R). In animals, high-dose ecstasy produces deficits in sero tonin neurons, interpreted as neurotoxicity. However, whether such serotonin deficits actu ally reflect neuronal damage is a matter of debate. Ecstasy has neurochemical, endocrine, and behavioral effects in rats and humans at equivalent doses, e.g. 1–2 mg/kg, suggesting that there is no reason to adjust doses between these species when interpreting data. Doses that do not cause long-term serotonin depletion can have protracted effects on behavior, suggesting that even moderate doses may pose risks. For example, ecstasy in rats induces persistent anxi ety-like behaviors in the absence of measurable serotonin deficits. While ecstasy has been con sidered predominantly to be a serotonergic agent, certain adverse effects, including cardiovascular stimulation and hyperthermia, probably also involve noradrenaline and
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dopamine neurotransmission. While ecstasy in high enough doses can produce bona fide neurotoxicity, the neurotoxicity is not always synonymous with axonal death, because there is no associated silver-positive staining, reactive gliosis or loss of SERT protein in rat models. Heavy ecstasy use has been associated with neurocognitive deficits in various beha vioral and brain imaging studies. However, this association is not conclusive, owing to confounding by polysubstance abuse. The specific effects of ecstasy on working mem ory, attention, and associative memory have been investigated using functional MRI in 33 heavy ecstasy users (mean 322 pills lifetime) and 38 non-ecstasy users (48c). The indepen dent effects of the use of ecstasy, amfetamine, cocaine, cannabis, alcohol, and tobacco and of sex and IQ were assessed and separated by multiple regression analysis. Ecstasy had no effect on working memory and attention, but drug use was associated with reduced associative memory performance, which was affected by amfetamine much more than by ecstasy. Both amfetamine and ecstasy affected associative memory-related brain activity, but the effects were consistently in opposite directions, suggesting different mechanisms – serotonin by ecstasy and dopamine by amfe tamine. There were several limitations to this study. A consistent criticism of cross-sectional designs is that neurocognitive abnormalities might actually predate and place individuals at risk of drug abuse rather than being the result of abuse. Several studies have shown dose–effect relationships between cumulative lifetime ecstasy use and memory deficits, supporting the idea that ecstasy use causes neurocognitive impairment (49c). This study relied on statements by the subjects regarding their current and earlier consumption habits, with questionable reliability, although hair analysis confirmed previous ecstasy use in 86% of those who reported having used ecstasy. However, analysis of hair does not yield information on patterns of ecstasy use, such as frequency, dosage, and cumulative life time dose, but the results support the plausibil ity of self-reported data. In the absence of satisfactory sample stratification, the correla tions between the use of ecstasy and amfeta mine and cocaine were reduced. Hence, full
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independence between predictors cannot be claimed. Notwithstanding these caveats, there is reasonable evidence to conclude that polysubstance ecstasy users have reduced associa tive memory performance, but this impairment is largely due to concomitant amfetamine use, and not to ecstasy. The role of serotonin 5HT1A receptors and use of psychostimulants have been reviewed (50R). The 5HT1A receptors are not the only central mediators of increases in psychostimu lant-induced serotonin that affect behavior, but rather contribute to the effects of the whole serotonin system. As somatodendritic autoreceptors, they control the activity of serotonin neurons, and as post-synaptic recep tors, they control activity in terminal areas. The 5HT1A autoreceptors mainly facilitate psychostimulant addiction-related behaviors by limiting 5HT responses in terminal areas. By contrast, post-synaptic 5HT1A receptors predominantly inhibit the expression of various addiction-related behaviors directly. In a meta-analysis of the impact of recrea tional ecstasy use on short-term memory, longterm memory and verbal and visual memory, 26 studies were located containing memory data for ecstasy and non-ecstasy users (51M). These studies provided measures of short-term and long-term memory in 610 and 439 ecstasy users, respectively, and showed moderate to large effect sizes (Cohen’s d = 0.63 and 0.87 respectively). The difference between short-term and long-term memory was not significant. This corroborates the view that recreational use of ecstasy is associated with considerable memory impairment, signifi cantly affecting both short-term and long-term memory. The effect size for verbal memory was large (d = 1.00) and significantly larger than the effect size for visual memory (d = 0.27). The analysis suggested that visual memory may be affected more by concurrent cannabis use. The authors reported that the total lifetime number of ecstasy tablets con sumed did not significantly predict memory performance. However, it was not clear how clinically relevant the memory effects were. Contrary to the previous report, another meta-analysis of 35 studies showed that total lifetime ingestion of ecstasy was negatively associated with performance on tasks ranging
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from attention and concentration to learning and memory (52M). However, most primary studies have important inherent method ological problems. One of the most serious confounders is the widespread pattern of poly-drug use, which makes it difficult to relate the findings in user populations to one specific drug. The drugs that are most commonly used concurrently are alcohol, cannabis, and psychostimulants. Stimulants add to the neurocognitive insults and act synergistically. Cannabis use is described as more complex. Furthermore, ecstasy-related factors, such as acute and chronic tolerance, prolonged dan cing and the effect of body temperature on cognition, may contribute too. Concerns about ecstasy-associated longterm cognitive and psychiatric effects have been reviewed (53R). Although many studies have suggested a correlation between ecstasy exposure and psychopathology, and that the psychotropic effects may be long lasting or permanent, the authors cautioned that it is not possible to conclude that there is a causal rela tionship between exposure and the increased psychopathology observed in ecstasy users. They reported that a significant body of cir cumstantial evidence suggests that ecstasy, and especially frequent use of high doses, may cause cognitive and psychiatric symp toms, and that these symptoms do not lend themselves readily to reversal on quitting. Pos sible confounding factors include concomitant use of other drugs. Ecstasy use and neurocognition have been evaluated in a meta-analysis using two sets of inclusion/exclusion criteria (54M). In the stu dies that met the relatively stringent criteria for this review as well as those that met the relatively lenient inclusion/exclusion criteria, the use of ecstasy was associated with neuro cognitive deficits in each domain. Small to medium effects were generally observed. A comparison of effect sizes across the two sets of analyses did not show significant dif ferences. Thus, the authors concluded that use of ecstasy is associated with neurocogni tive deficits. As observed by others, concur rent drug use was a confounder. The authors inferred that recreational use of ecstasy is associated with poorer performance on neurocognitive measures.
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The long-lasting neurotoxic effects of ecstasy have been explored using auditory P300 event-related potentials in 14 current ecstasy poly-drug users, 13 current cannabis users, and 22 controls who were free of illicit drugs in two evaluations during 1 year (55cr). There were significant differences between ecstasy users and controls on cognitive mea sures of semantic word fluency, processing speed, and verbal memory recognition after 1 year. However, there were no significant differences in cognitive tests between ecstasy users and cannabis users or between cannabis users and controls. Lifetime ecstasy use was associated with poorer verbal memory recog nition. There were significant correlations between P3 latency and cannabis lifetime use, suggesting that lifetime higher use of can nabis was related to faster latency (a paradox ical effect), which was not seen with ecstasy exposure. These data suggest mild long-term cognitive deficits among ecstasy poly-drug users. According to the authors, both ecstasy use and the dynamic interaction between the effects of ecstasy and cannabis may account for these deficits. There were no significant P3 alterations in ecstasy users or in the other two groups, and the data were within the reference ranges, suggesting absence of impairment of neuroelectric brain activation in ecstasy users. Thus, this study, unlike other studies men tioned above, failed to find neurotoxic changes attributable to prolonged recreational use of ecstasy. There were more subclinical cognitive deficits relating to memory, executive func tions, and information processing speed in chronic ecstasy poly-drug users than in drugnaïve controls after 1 year, even after adjusting for sex and IQ. The cognitive deficits were stable and did not progress after 12 months in ecstasy users. These group differences seem to have limited consequences, insofar as poorer cognitive performance by ecstasy users suggests subclinical impairment, because the results were within standard norms and because neuroelectric brain activation was similar in all three groups. However, there were limitations to this study, including the small sample size. The effects of both prolonged abstention from ecstasy use and current use on cognitive function have been investigated, while control ling for the regular use of other recreational
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drugs, in order to overcome some of the research methodological limitations men tioned above (56C). The study included 25 current ecstasy users, 28 ex-ecstasy users absti nent for about 1 year, 29 poly-drug controls, and 27 drug-naïve controls. Most of the tests showed no group differences. There was an overall tendency for impaired verbal learning and memory in both current ecstasy users and poly-drug controls. There was evidence of reduced response inhibition in the current ecstasy users and poly-drug controls, which appeared to be related to the recency of drug use. The authors concluded that recreational drug use in general, rather than ecstasy use per se, can lead to subtle cognitive impairment and that recent drug use appears to have the strongest effect on cognitive performance. Thus, they cautioned that future studies of the effects of ecstasy on cognitive functions should control for use of all recreational drugs and in particular recent drug use. From all these data, one can infer that there is an active debate about whether ecstasy has neurotoxic effects on the human brain and if so what the magnitude of the effects is. Another debate relates to whether use of low-dose ecstasy is neurotoxic. In a prospec tive study of the effect of low-dose ecstasy on the brain in ecstasy-naïve volunteers using a combination of advanced MR techniques and self-report on psychopathology, 30 sub jects were evaluated in two sessions before and after first use of ecstasy (57C). The inter val between baseline and follow-up was on average 8.1 months and the time between last ecstasy use and follow-up was 7.7 weeks. There were no significant changes in the concentrations of N-acetylaspartate (NAA), choline, myoinositol, or creatinine, or in the ratios of NAA, choline, and myoinositol rela tive to creatinine. However, use of ecstasy was followed by a sustained 0.9% increase in fractional anisotropy in frontoparietal white matter, a 3.4% reduction in apparent diffusion in the thalamus, and a sustained reduction in relative regional cerebral blood volume in the thalamus, dorsolateral frontal cortex, and superior parietal cortex. After correction for multiple comparisons, only the relative regio nal cerebral blood volume reduction in the dorsolateral prefrontal cortex remained
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significant. There was increased impulsivity and less depression in novel ecstasy users, although the effect sizes were small and their clinical relevance unclear. There was no exten sive neuronal damage with this degree of ecstasy use, although it did cause prolonged vasoconstriction in some brain areas. In another study, the same group assessed the effects of low-dose ecstasy on human brain cognitive functioning using functional MRI (58c). In this prospective study, the sus tained effects of a low dose of ecstasy were studied in 25 subjects before and after their first episode of ecstasy use and in compari son with 24 persistent ecstasy-naïve controls, also measured twice and matched with the novice users for age, sex, IQ, and cannabis use. Cognitive brain function was measured in the domains of working memory, selective attention, and associative memory using fMRI. There were no significant effects of a low dose of ecstasy on working memory, selective attention, or associative memory, either at the behavioural level or at the neurophysiological level. Ecstasy neuroimaging research in humans has been reviewed to provide a background for interpreting these data (59R). The authors concluded that the current state of neuro imaging in ecstasy users does not permit conclusions regarding the long-term effects of ecstasy exposure. Of the existing neuro imaging studies in human ecstasy users, few experimental designs have been replicated across different research groups. Only studies that have used nuclear imaging methods to assay brain serotonin transporters densities have been replicated. These studies have found reduced numbers of transporters in recently abstinent ecstasy users, with some evidence for normalization of serotonin trans porter numbers with prolonged abstinence. However, the sensitivity of these methods is unknown. The acute and long-term responses to ecstasy during perinatal, adolescent, and adult periods have been reviewed (60R). Weight reduction was evident at all ages. Learning and working memory appeared to be altered independent of the development stage of exposure. Evidence suggests that adults are more sensitive to long-term serotonin
Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong
depletion after ecstasy, but younger patients have substantial and rapid neuroplasticity. The effects of ecstasy taken at night have been examined in a double-blind, placebocontrolled, two-way, within-subject study in 14 subjects (61c). Ecstasy impaired perfor mance in a simple tracking task and in a divided attention task. These performance impairments were additive to those produced by sleep loss secondary to ecstasy. Young recreational ecstasy users in Wes tern society have been studied, focusing on potentially modifiable determinants of ecstasy use-related behaviour, with the rationale that the factors that influence behaviour may be population specific (62M). Of 15 studies, 6 were excluded after having been thoroughly examined, and one more study was added after using the descendancy approach. The meta-analysis showed that the main predictors of intention to use and actual ecstasy use were (a) ‘attitude’ (specifically positive outcomes regarding mood control and social facilitation and negative outcomes regarding escalating use and physical and mental adverse effects); (b) subjective and descriptive norms regard ing one’s friends, partner, and peers; (c) perceived control regarding obtaining ecstasy and control in relation to being with friends who use it, going out dancing, being offered ecstasy, and having it available, and (d) habit, moral norm, and anticipated regret. Accord ing to the authors, these data lend support to a theory of planned behavior and expec tancy models. These findings also suggest that some expectations underlying attitude may be irrelevant; for example, ecstasy enhances sexual experience and norms relat ing to some social referents (e.g. parents and perceived control regarding ecstasy-related behaviors, such as taking ecstasy). They sug gested that as it is now clear which determi nants best predict intention to use ecstasy and actual use, these determinants seem advisable intervention targets. However, not all determinants are equally easy to modify. Simply presenting information about negative outcomes (‘fear appeals’) has been shown not to work, or even to work inversely. These data are limited by the small number of studies. However, the authors suggested that there is a sufficient
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evidence base to guide the development of interventions so that evidence-based practice is developed. The priorities for interventions should be negative expectations, perceived behavioral control, and anticipated regret. Psychiatric The controversies surrounding abuse of ecstasy have been brought into the realm of drug policy and intervention. Does the onset of mental illness or vulnerability to mental illness precede the use of ecstasy? Does use of ecstasy result in an increase in psychiatric symptoms? Some have suggested that there is not much evidence to support the notion that use of ecstasy causes long-term psychiatric symptoms or disorders (63r). How ever, they caution that they do not mean to imply that future studies will not reveal such a relationship or that use of ecstasy does not pose significant health risks. They acknowl edge that morbidities and mortality are asso ciated with ecstasy. However, as there is no compelling evidence that use of ecstasy typi cally causes long-term psychiatric difficulties, they have recommended that health-care professionals and drug education packages should not mention this putative link. Suicide with the use of ecstasy, a rare event, has been reported (64A). • A 24-year-old man informed his brother that he had taken an overdose of ecstasy for suicidal purposes. He was traced using his cell phone, but it was too late. At autopsy, he had superficial cuts on his wrists and neck. His brain had signs of edema. Other major organs showed signs of congestion. He had also aspirated. The autopsy findings were consistent with cardiovascular failure, leading to hypoxic brain injury and terminal vomiting and aspiration. His body fluids contained MDMA, as well as 3,4-Methylenedioxy N-Ethylamphetamine (MDEA) and 3,4-Met hylenedioxyamphetamine (MDA), metabolities of ecstasy. A large stash of ecstasy pills confiscated at around the time of this event also contained a combination of MDMA and MDEA.
The communication of intent by the patient, the absence of any signs of foul play at autopsy and the signs of shock suggested that there had been a time interval between the ingestion of pills and death. The author reported that the serum concentration of
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MDMA (13 mg/l) was among the highest reported. Most cases of toxicity and death are associated with concentrations between 0.5 and 10 mg/l. The question of whether recreational use of ecstasy is associated with higher levels of depressive symptoms has been reviewed in an evaluation of 22 studies for depressive symptoms associated with ecstasy use (65M). Eleven studies initially reported significantly higher depression scores in ecstasy users com pared with controls. However, only three stu dies ultimately revealed significantly higher depression scores compared with cannabis or poly-drug controls. There are methodological problems with these studies, and some studies have not shown differences compared with normative groups. The author therefore con cluded that the evidence for a specific associa tion between ecstasy use and higher levels of depressive symptoms is not convincing, except when ecstasy is used with other illicit drugs. Reportedly higher levels of depression could be related to poly-drug use in general, either as an individual effect of illicit drug use besides ecstasy, as combined effects of ecstasy and other drugs, or because of some other pre-existing differences in these patients. Body temperature The effective use of dantrolene in the management of hyperther mia following acute ecstasy toxicity has been reported (66A). • A 21-year-old man collapsed with generalized rigidity, tachycardia (160/minute), hypertension (170/120 mmHg), tachypnea (40/minute), and hyperthermia (41.7°C) after using ecstasy. Cold intravenous fluids, ice packs, diazepam, and paracetamol failed to relieve the hyperthermia, and as his condition was deteriorating he was given dantrolene 1 mg/kg. His rigidity improved almost immediately and his body temperature normalized after 90 minutes. He recovered fully.
The authors advocated the early use of dan trolene in the management of hyperthermia due to ecstasy. Drug–drug interactions Cannabis Over 90% of recreational ecstasy users also use cannabis. Most studies try to deal with the confounding effects of these drugs by remov ing the effects statistically. Their co-use and
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opposing effects have been reviewed (67R). Ecstasy is alerting whereas cannabis is sedat ing. Ecstasy is hyperthermic whereas cannabis is hypothermic. Ecstasy increases oxidative stress, whereas cannabinoids are antioxidants. The authors suggested that future research needs to evaluate whether these effects are additive or interactive. Serotonergic drugs Ecstasy can cause signif icant serotonin release within 4 hours, and combined use of ecstasy and other sero tonergic substances, such as antidepressants, can cause potentially life-threatening com plications. The risk has been reviewed, with a focus on serotonin syndrome, using a hierarchy of risk (68Hr). Substances that inhibit serotonin re-uptake are not likely to increase serotonin to life-threatening con centrations if used with ecstasy and are thus labelled as being of ‘less risk’; these include SSRIs, SNRIs, opioid analgesics, and anti histamines. These drugs differ from other serorimtonergic drugs, in that they compete with ecstasy at serotonin receptors and there fore reduce the effects of ecstasy. Bupropion is also less likely to increase the risk. When ecstasy is used with other ampheta mines and cocaine, the risk increases to ‘intermediate’. Specifically, dexamfetamine and methylphenidate are relatively potent releasers of serotonin and have some inhibitory effects on serotonin re-uptake. Metamfetamine can increase the risk if used concurrently. The serotonin precursors 5 hydroxytryptophan and L-tryptophan have a theoretical risk of causing serotonin syndrome with ecstasy, but no cases have been reported. The use of ecstasy with monoamine oxidase (MAO) inhibitors and RIMA antidepressants (Reversible Inhibitors of Monoamine oxidase type A), such as moclobemide, which prevent the breakdown of serotonin, is likely to lead to serious increases in serotonin, and deaths have been reported. Thus, these interactions are listed as being of ‘high risk’. St John’s wort, lysergic acid diethylamide (LSD), and antimigraine drugs such dihydroergotamine, bromocriptine and lithium salts, are labelled as being of ‘unknown risk’, as these com pounds interact with serotonin systems but have not been reported as causing drug interactions.
Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong
Drug contamination Two new cases of con tamination of ecstasy tablets have been reported. One involved 1-benzylpiperazine (see above) and the other the amphetamine derivative 3,4-methylenedioxy-N,N-dimethyl amfetamine (MDDM or MDDA) (69A). • A 31-year-old man was found dead at home in an advanced state of putrefaction. The post mortem examination suggested that death had occurred 7 days before. There was 600 ml of bloody fluid in the pleural cavities. He had generalized visceral congestion and a somewhat enlarged heart. Putrefaction prevented detailed microscopical examination. Toxicological screening showed MDEA and MDDM in various tissues, including urine, with higher concentrations in the left ventricle than in the peripheral blood.
The authors speculated that MDDM had been formed as a synthesis by-product or impurity in the ‘ecstasy’ tablets taken by the victim. They suggest that MDDM can be formed during the clandestine manufacture of MDMA by reductive amination of 3,4 methylenedioxyphenyl-2-propane (MDP2P) by dimethylamine. MDDM is formed because of the presence of dimethylamine as a contaminant in methylamine. They also suggested that MDDM could have been ingested separately and earlier.
Gamma-hydroxybutyric acid (SED-30, 1479) Gamma-hydroxybutyric acid (GHB) is natu rally produced in the body, and there are g-hydroxybutyrate receptors in the brain (70E). It was synthesized in 1874 (71E), but major research in human use was conducted in the early 1960s (72c) in order to study the neurotransmitter g-aminobutyric acid (GABA). GABA, or its sodium salt sodium oxybate, has been used as a general anes thetic to treat conditions such as insomnia, depression, narcolepsy (73R, 74R) and alco holism (75c, 76c) and to improve athletic performance. GHB can cause euphoria, increased libido, sociability and intoxication and in high doses nausea, dizziness, agita tion, respiratory depressed, amnesia, uncon sciousness, and death. In succinate semi-aldehyde dehydrogen ase (SSADH; ALDH5a1) deficiency, urinary
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concentrations of GHB are increased. The condition is associated with a wide range of neurological and psychiatric abnormalities, including psychomotor retardation, delayed speech development, epileptic seizures, and behavioral disturbances (77R, 78A). Endocrine Cushing’s syndrome has been attributed to GBH abuse (79A). • A 35-year-old woman who had used increasing daily doses of GHB gained weight and became hypertensive. Adrenocorticotrophic Hormone plasma concentrations were in the upper reference range (41 ng/l), and the plasma cortisol concentration was normal (0.36 µmol/ l), but dexamethasone did not suppress cortisol secretion and urinary excretion of free cortisol was increased. A CT scan showed normal adrenal glands. After stopping GHB, she lost 7 kg body weight and her BP normalized.
The authors hypothesized that GHB may bind to GABAB receptors in the pituitary gland causing overproduction of ACTH. Drug abuse The potential for abuse of GHB and its effects on psychomotor performance has been evaluated in a randomized, doubleblind, double-dummy, crossover study in 12 healthy male recreational users (80c). They took a single oral dose of GHB (40 or 60 mg/kg), ethanol (0.7 g/kg), flunitrazepam (1.25 mg), and placebo. Vital signs (blood pressure, heart rate, oral temperature, pupil lary diameter), psychomotor performance (digit symbol substitution test, balance, Mad dox–Wing), subjective effects, and pharmaco kinetics were studied. All active conditions produced positive effects related to their abuse potential. GHB produced euphoria and pleasurable effects, with slightly higher ratings than those observed with flunitraze pam and ethanol. It had a biphasic time pro file, with an initial stimulant-like effect related to the rise in plasma concentration and a latter sedative effect not related to GHB kinetics. GHB increased blood pressure and pupil diameter. GHB and flunitrazepam impaired psychomotor performance and performance in the digit symbol substitution test and the balance task, whereas ethanol had only mild effects exclusively affecting the balance task. Drug overdose Of 3775 adults who contacted health-care services because of acute
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poisoning (3025 episodes) during 1 year in Oslo, irrespective of intention, 947 (31%) were hospitalized (81c). The annual incidences were 1.9 per 1000 men and 2.1 per 1000 women. The median age was 36 (range 16–89) years and 54% were women. Benzo diazepines (18%), ethanol (17%), paraceta mol (12%), opioids (7%), and GHB (7%) were most often taken. There was suicidal intent in 29% of admissions.
Khat
(SEDA-30, 43; SEDA-31, 48)
The adverse effects of khat have been reviewed. They include mental health effects, such as depression, insomnia, aggravation of psychotic disorders; cardiovascular effects, such as increased blood pressure and heart rate; stomatitis; an increased risk of carci noma of the mouth and esophagus; gastro oesophageal reflux; anorexia; constipation; liver toxicity, which may be due to pesticides rather than the khat itself; and an increased risk of low birth weight in infants born to women using khat (82R). Psychiatric In a systematic review of the potential causal link between use of khat and mental illness, 24 papers were identi fied, including quantitative studies and case reports (83R). The quantitative studies did not claim a direct causal role for khat in causing mental illness, but four papers noted an association between heavy use of khat and mental illness. The authors con cluded that there may be an association between heavy use of khat and increasing vulnerability to mental illness, but those studies have not yet proven direct causality.
OPIOID ANALGESICS See Chapter 8, in which both therapeutic and abuse aspects of the opioids are covered.
Psilocybin
(SEDA-31, 49)
Cardiovascular An acute coronary syndrome with ST-segment elevation has been reported
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in the absence of coronary artery disease after abuse of psychoactive fungi, commonly referred to as ‘magic mushrooms’ (84A). • A 17-year-old boy developed chest pain and dyspnea at rest after consuming Psilocybe semilanceata. His blood pressure was 120/60 mmHg and his heart rate 93/minute. In a 12-lead electrocardiogram there were right bundle branch block and ST-segment elevation in leads I, II, aVL, aVF and V3–V6. Serum troponin T concentration and creatinine kinase (CK) activity were raised, as was the CK-MB fraction. Drug screening excluded other substances. He had no cardiovascular risk factors. Coronary angiography showed normal coronary arteries, but left ventriculography showed a regional wall motion abnormality in the apical segment and a reduced ejection fraction. Cardiovascular MRI scanning confirmed the contractile pattern. There was a pericardial effusion. Left ventricular function normalized after 6 days and the pericardial effusion resolved with anti-inflammatory drug therapy.
The authors attributed this presentation to Takotsubo cardiomyopathy (left ventricular ballooning syndrome) due to psilocybin, probably resulting from its catecholaminelike action. Psychological Psilocybin and other hallucino genic drugs cause alterations of time perception, such as ‘time standing still’ and mystical or ecstatic states. In a placebocontrolled study of two doses of psilocybin (115 and 250 micrograms/kg) on temporal processing, using tasks of temporal reproduc tion, sensorimotor synchronization, and tapping tempo in 12 healthy volunteers, psilo cybin significantly impaired their ability to reproduce interval durations longer than 2.5 seconds and to synchronize to inter-beat inter vals longer than 2 seconds; it also caused sub jects to be slower in their preferred tapping
Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong
rate (85C). These effects were accompanied by deficits in working memory and subjective changes in conscious state (increased reports of depersonalization and derealization, including disturbances in subjective time sense). The authors proposed that these results suggest that the serotonin system is selectively involved in duration processing of intervals longer than 2–3 seconds and in the voluntary control of the speed of move ment. They speculated that selective disrup tion of longer intervals by psilocybin is likely to result from interactions with cognitive dimensions of temporal processing, presum ably via 5HT2A receptor stimulation. The action of psilocybin on internal time representation has been investigated in two double-blind, placebo-controlled studies, in 12 subjects with graded doses and in 9 subjects at a very low dose (86c). The effects were assessed by measuring , a parameter of the dual klepsydra model of internal time repre sentation, fitted to individual response data and intra-individually normalized with respect to initial values. In both experiments, was significantly prolonged by psilocybin at 90 minutes, indicating a higher loss rate of internal duration representation. The authors suggested that this effect may be linked to the effects of psilocybin on subjective time. Psilocybin-containing mushrooms can sometimes cause a ‘bad trip’, a psychotic reaction accompanied by fear, panic, and dangerous behavior, especially when used in combination with other drugs and alcohol or by psychiatrically unstable patients. Two young men, aged 25 and 32 years, automuti lated with knives after consuming hallucino genic mushrooms; the first had also used cocaine, cannabis and alcohol, but the sec ond had used only the mushrooms (87A).
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87.
R. Relative abuse liability of gamma hydroxybutyric acid, flunitrazepam, and ethanol in club drug users. J Clin Psycho pharmacol 2007;27(6):625–38. Hovda KE, Bjornaas MA, Skog K, Opdahl A, Drottning P, Ekeberg O, Jacobsen D. Acute poisonings treated in hospitals in Oslo: a oneyear prospective study (I): pattern of poison ing. Clin Toxicol (Phila) 2008;46(1):35–41. Hassan NAGM, Gunald AA, MurrayLyon IM. Khat (Catha edulis): health aspects of khat chewing. East Mediterr Health J 2007;13(3):706–18. Warfa N, Klein A, Bhui K, Leavey G, Craig T, Stansfeld SA. Khat use and mental illness: A critical review. Soc Sci Med 2007;65:309–18. Nef HM, Mo¨ llmann H, Hilpert P, Krause N, Troidl C, Weber M, Rolf A, Dill T, Hamm C, Elsässer A. Apical regional wall motion abnormalities reminiscent to Tako-Tsubo cardiomyopathy following consumption of psychoactive fungi. Int J Cardiol 2009;134 (1):e39–41. Wittmann M, Carter O, Hasler F, Cahn BR, Grimberg U, Spring P, Hell D, Flohr H, Vollenweider FX. Effects of psilocybin on time perception and temporal control of beha viour in humans. J Psychopharmacol 2007;21 (1):50–64. Wackermann J, Wittmann M, Hasler F, Vollenweider FX. Effects of varied doses of psilocybin on time interval reproduction in human subjects. Neurosci Lett 2008;435 (1):51–5. Attema-de Jonge ME, Portier CB, Frans sen EJ. Automutilatie na gebruik van hal lucinogene paddenstoelen. [Automutilation after consumption of hallucinogenic mush rooms.] Ned Tijdschr Geneeskd 2007;151 (52):2869–72.
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5
Hypnosedatives and anxiolytics
AZASPIRONES
(SEDA-28, 52;
SEDA-29, 51)
Buspirone
(SED-15, 575; SEDA-29, 51)
Psychological The acute subjective and cognitive effects of buspirone 20 or 30 mg have been assessed in a double-blind, placebo-controlled study in 60 healthy men (1C). Subjective ratings (visual analogue skills) were completed at baseline and at 1.5 and 3.5 hours after treatment. Cognitive assessment was undertaken at between 1.5 and 3.5 hours, including tests of memory, executive planning, impulse control, decision making and cognitive flexibility. Buspirone 30 mg produced significantly higher subjective ratings of contentedness at 3.5 hours relative to placebo. The treatment and placebo groups did not differ significantly in cognitive measures. In contrast to benzodiazepines, the anxiolytic buspirone in therapeutic doses appears to have less detectable deleterious effects on cognition when given acutely.
BENZODIAZEPINES (SED-15, 429; SEDA-29, 51; SEDA-30, 49; SEDA-31, 57)
Alprazolam (SED-15, 91; SEDA-29, 51; SEDA-30, 49; SEDA-31, 57) Psychological The effects of extendedrelease (XR) alprazolam 1 mg and immediate-release (IR) alprazolam 1 mg on Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32005-8 � 2010 Elsevier B.V. All rights reserved.
actual driving ability and cognitive function have been investigated in a double-blind, placebo-controlled, three-way crossover study in 18 healthy volunteers aged 20–45 years (2C). At 4 hours after the dose, the subjects performed a standardized driving test on a primary highway in normal traffic. Cognitive and psychomotor tests were assessed at 1, 2.5, and 5.5 hours. Memory function was measured after 1 hour. Both formulations severely impaired driving performance at 4–5 hours. The magnitude of impairment in the driving test observed with alprazolam XR was about half that observed with alprazolam IR. Laboratory test results were in line with the driving data. The acute impairing effects of alprazolam XR 1 mg on driving and psychomotor functions were generally less than the IR equivalent, but still of sufficient magnitude to increase the risk of traffic accidents.
Diazepam
(SED-15, 1103; SEDA-29, 54; SEDA-30, 50; SEDA-31, 57)
Comparative studies Intravenous sodium valproate has been compared with an infu sion of diazepam for control of refractory status epilepticus in an open, randomized study in 40 children with refractory status epilepticus at a tertiary care teaching hospi tal (3C). Refractory status epilepticus was controlled by valproate in 80% and by diazepam in 85% of the patients. The median time to control refractory status epilepticus was less with valproate (5 min utes) than with diazepam (17 minutes). None of the patients who were given valproate required ventilation or developed hypotension, whereas of those given
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diazepam 60% required ventilation and 50% developed hypotension after starting the infusion. There were no adverse effects on liver function with valproate. Nervous system A study has been con ducted to clarify whether subjective sleepi ness in older people accurately reflects a benzodiazepine-related reduction in psychomotor function (4c). Placebo or diazepam 5 or 10 mg was given orally in a single-blind crossover manner to eight healthy young men (mean age 20 years) and placebo and diazepam 5 mg were given to seven healthy older men (mean age 61 years). The following were monitored every 20 minutes from 10.00 h until 16.00 h (the drug having been given at 12.00 h): plasma drug concentration, choice reaction time as an objective measure of psychomotor func tion, and the Stanford Sleepiness Scale as a measure of subjective sleepiness. The phar macokinetics of diazepam did not differ significantly between the two groups. Dia zepam 10 mg in the young men produced significant increases in both the choice reac tion time and sleepiness score. Diazepam 5 mg had no significant effect on sleepiness in either group but did produce a significant increase in choice reaction time only in the older subjects, matching that in the young subjects given diazepam 10 mg. The older subjects suffered from dissociation between subjective sleepiness and objective psycho motor impairment after diazepam. Older individuals may underestimate the detri mental effects of benzodiazepines on brain function. Drug dependence The effects of co administration of diazepam with methadone or buprenorphine have been investigated in a double-blind, randomized, 2 2 cross over study (5c). The effects of diazepam dose (0 mg versus 40 mg) and opioid dose (100% versus 150% of the normal dose) were examined over four sessions in four methadone- and seven buprenorphine maintained patients without concurrent dependence on other substances or signifi cant medical co-morbidities. Physiological measures (pulse rate, blood pressure, pupil
Andrew Byrne, Shabir Musa, and Stephen Curran
size, respiratory rate, and peripheral SpO2), subjective measures (Addiction Research Centre Inventory, ARCI) and performance (reaction time, cancellation task, and Digit Symbol Substitution Test, DSST) were taken before and for 6 hours after dosing. High-dose diazepam was associated with time-dependent increases in the inten sity of subjective drug effects (strength of drug effect, sedation) and reductions in psychological performance (reaction time, DSST) in patients taking methadone or buprenorphine. These effects were gener ally independent of the dose of opioid. The authors concluded that high-dose dia zepam significantly alters subjective drug responses and psychological performance in patients maintained on methadone and buprenorphine.
Lorazepam
(SED-15, 2163; SEDA-29, 55; SEDA-30, 51; SEDA-31, 58)
Psychological The effect of lorazepam on deductive reasoning has been investigated in a double-blind, placebo-controlled, cross over study of acute oral doses of lorazepam 2 mg in 14 healthy volunteers (6C). The study focused on the response delay of three separable phases of deductive reasoning (premise processing, premise integration, and validation). The authors matched working memory tasks (which involved only maintenance of informa tion), in which reasoners decide whether a conclusion logically follows from the premises (reasoning task) or is identical to one of the premises (maintenance task). Lorazepam slowed responses as memory load increased. It also specifically slowed validation in reasoning problems with visual relations and increased valida tion time in problems with subiconic rela tions. Acute lorazepam affected reasoning in two ways: it slowed processing nonspecifically when the demands of working memory increased and it augmented vali dation time depending on the difficulty in generating and/or manipulating mental representations by the central executive.
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Lormetazepam (SED-15, 2167; SEDA-29, 55) Comparative studies Lormetazepam 0.5 mg with sleep hygiene training or the latter alone has been compared in a 2-week open study in 30 elderly outpatients with insomnia (7c). The patients recorded details of sleep latency, numbers of awakenings and freshness on awakening in a daily sleep diary. The Epworth Sleepiness Scale and Stanford Sleepiness Scale were used to measure daily sleepiness. The addition of lormetazepam to sleep hygiene training improved all sleep parameters compared with sleep hygiene training alone. Mean duration of sleep improved significantly from baseline in the combined group after 2 weeks of treatment, but fell significantly in those who received sleep hygiene training alone. The mean duration of sleep increased by about 150 minutes each night in the com bined group, but fell by more than 30 min utes in those who used sleep hygiene training only. Improvement in sleep quality from baseline was statistically significant only in the combined group both for deepness of sleep and for the perception of waking refreshed. Sleep latency also shortened significantly in the combined group after 2 weeks. Sleepiness scores also improved significantly in the combined group. By contrast, in those who used sleep hygiene training only, the mean Epworth Sleepiness Scale score worsened signifi cantly from baseline, although the mean Stanford Sleepiness Scale score remained relatively constant. Rebound insomnia was not reported during follow-up for 1 week in patients in the combined group. Vital signs did not change from baseline and no adverse events were reported in either group.
Midazolam
(SED-15, 2337; SEDA-29, 56; SEDA-30, 51; SEDA-31, 59)
Comparative studies Buccal midazolam 0.2 mg/kg has been compared with nitrous oxide/oxygen inhalation for orthodontic extractions in 36 dental patients aged
77
10–16 years in a randomized, crossover trial (8C). The maximum level of sedation was achieved with buccal midazolam in a mean time of 14 minutes, compared with 7 minutes with inhalation sedation. Vital signs remained within acceptable limits with both types of sedation and the reported adverse effects were of no clinical significance. Buc cal midazolam was acceptable by 66% of patients but only 29% preferred it, the main disadvantage being the taste of the solution. The effects of midazolam and diazepam alone or combined with clonidine have been investigated in 160 patients with suspected coronary artery disease undergoing hemo dynamic studies in a double-blind, rando mized, controlled, prospective study (9C). The participants were divided into five groups of 32 patients each, according to the drug used: • group C (clonidine 0.5 micrograms/kg); • group M (midazolam 40 micrograms/kg); • group MC (combination of midazolam 40 micrograms/kg and clonidine 0.5 micrograms/ kg); • group D (diazepam 40 micrograms/kg); • group DC (combination of diazepam 40 micrograms/kg and clonidine 0.5 micrograms/kg).
Sedation was evaluated based on the Ramsay Sedation Scale and on the use of pethidine 0.04 mg/kg. Invasive blood pres sure monitoring, heart rate and the sedation score were analysed every 5 minutes at four different times. Those who received mida zolam had higher sedation scores and greater heart rate and blood pressure varia tion. Those who received diazepam or clonidine had lower sedation scores, which were more satisfactory for the performance of the procedure, and had less heart rate and blood pressure variation. The role of midazolam 0.24 mg/kg when combined with fentanyl 1.68 micrograms/kg or ketamine 1.4 mg/kg for insertion of central lines has been investigated in a ran domized trial in children aged 0–14 years (10c). Ketamine produced a quicker onset of sedation but had no effect on recovery, and there was a higher incidence of minor complications (21% versus 3.5%), including
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excessive secretions, desaturation, and hiccups; there were no major complications and no one required advanced airway management. Susceptibility factors Children The safety of intravenous midazolam in sedation for gastrointestinal endoscopy has been investi gated in a prospective study of 2635 endos copies, of which 1717 were outpatient procedures with the patient under intrave nous sedation (11C). Sedation data were available on 1578 procedures. The median dose of fentanyl was 2.77 micrograms/kg and the median dose of midazolam was 0.11 mg/kg. The mean recovery time was 118 minutes. Ten patients (0.8%) failed intravenous sedation. There were serious adverse events (apnea) in two patients. Mild or moderate adverse events included desaturation below 92% for less than 20 seconds (100 patients, 9%), vomiting (n = 64, 5%), agitation (n = 15, 1%), desaturation below 92% for more than 20 seconds (n = 12, 0.7%), and rash (n = 8, 0.7%). Cardiopulmonary resuscita tion and sedation reversal were not required. Patients under 6 years of age were more likely to develop respira tory adverse events. The authors con cluded that intravenous sedation with midazolam and fentanyl is safe for pae diatric gastrointestinal endoscopy. Serious adverse events were rare. Drug administration route Low-dose intranasal midazolam 1 or 2 mg and oral mid azolam 7.5 mg have been compared in 72 claustrophobic patients undergoing routine body magnetic resonance imaging (MRI) in a prospective study (12C). The oral midazo lam was given 15 minutes before MRI and the nasal spray immediately before. With oral midazolam, 18 of 36 MRI examinations had to be cancelled and the reduction in anxiety was insufficient in 12 of the other 18. With nasal midazolam, 35 of 36 MRI examinations were completed successfully, without adverse effects. Drug–drug interactions Roflumilast The effects of roflumilast, an investigational
Andrew Byrne, Shabir Musa, and Stephen Curran
PDE4 inhibitor for the treatment of chronic obstructive pulmonary disease (COPD) and asthma, on the pharmaco kinetics of the CYP3A probe drug mida zolam and its major metabolites have been investigated in an open, randomized study in 18 healthy men, who received single doses of midazolam alone 2 mg orally and 1 mg intravenously 1 day apart, repeated doses of roflumilast alone 500 micrograms/ day for 14 days and repeated doses of roflumilast together with single doses of midazolam (13c). Point estimates (90% CI) were 0.97 (0.84, 1.13) for the area under the curve (AUC) of intravenous midazolam and 0.98 (0.82, 1.17) for that of oral midazolam with and without roflu milast. These results suggest that roflumi last is unlikely to alter the clearance of drugs that are metabolized by CYP3A4.
Quazepam (SED-15, 2295; SEDA-31, 60) Drug–food interactions The effects of a light meal on the pharmacokinetics and pharmacodynamics of three benzodiaze pines have been investigated in 21 subjects who were randomized to quazepam 20 mg, diazepam 5 mg, or nitrazepam 5 mg (14c). Each took a single oral dose of the assigned drug after an overnight fast and on a separate occasion after a light meal. Blood samples were collected for 72 hours. Reaction time, critical flicker fusion threshold and visual analogue scale response were measured. The Cmax and AUC of quazepam were increased 1.2-fold (90% CI = 1.1, 1.5) and 1.5-fold (90% CI = 1.3, 1.9) respectively by food. For nitrazepam and diazepam, the tmax was delayed about 1 hour in the fed condition. Reaction time after quazepam with food was prolonged at 4 and 6 hours after dosing and its area under the effect-time curve from 0 to 10 hours was increased. The authors concluded that a light meal increased the systemic availability of qua zepam and affected psychomotor perfor mance. A light meal delayed the tmax of nitrazepam and diazepam.
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Chapter 5
Triazolam (SED-15, 3486; SEDA-31, 60) Psychological Triazolam alone (0.25 or 0.50 mg/70 kg), dexamfetamine sulphate alone (20 or 30 mg/70 kg), and triazolam þ dexamfetamine sulfate in all dose combina tions have been compared in a doubleblind, staggered-dosage, placebo-controlled, crossover study in 18 healthy adults across nine sessions (15c). Relative to the sedative measures, the effects of triazolam on mem ory were generally less extensively reversed by dexamfetamine. The memory measures ranged in degree of reversal: the greatest degree of reversal was observed for reaction time on the n-back Working Memory Task, and the least for accuracy on the Sternberg Working Memory Task; most of the mea sures showed an overall pattern of partial reversal. Benzodiazepines have specific effects on memory that are not merely a by-product of sedative effects, and the degree to which the sedative effects contri bute to the amnestic effects varies as a func tion of the particular memory process being assessed.
OTHER HYPNOSEDATIVES Chloral hydrate
(SED-15, 705; SEDA 30, 52; SEDA-31, 60)
Susceptibility factors Children The effi cacy of a sequential approach to rescue failed chloral hydrate sedation and obtain a low rate of adverse events along with predictable timings has been studied retrospectively in 862 neurologically impaired children weigh ing less than 26 kg undergoing MRI (16c). If the desired sedation score (3 on the Skeie Scale) was not reached within 30 minutes after oral administration of chloral hydrate, sedation was considered as potentially failed, and sevoflurane, ketamine, or pentobarbital and midazolam were started. Excessive movement caused failure in 27 sessions. Mean induction time was significantly higher in patients who received supplementation (52 minutes versus 39 minutes), whereas there
79
were no differences in recovery and total sedation times. Supplementation significantly increased the incidence of respiratory obstruction (4.6% versus 2.4%), although the incidence of other adverse events was unaffected. Administering up to 1.5 g of chloral hydrate without supplementation was associated with a failure rate of about 20%, but the proposed sequential approach enabled most of the failed sedations to be rescued while maintaining an acceptably low incidence of adverse events.
Ramelteon Ramelteon is a selective melatonin receptor agonist with a complex propionamide struc ture. It has particularly high affinities for MT1 and MT2 receptors, through which melatonin promotes sleep and creates circa dian sleep–wake cycle rhythms. Ramelteon can be used to treat insomnia. The most common adverse effects in clinical trials have been somnolence, headache, fatigue, dizziness, and nausea. Ramelteon has also been associated with raised prolactin con centrations. In other studies, ramelteon caused no next-day residual effects. Placebo-controlled studies The efficacy and safety of nightly ramelteon 8 or 16 mg have been evaluated in 405 adults with primary chronic insomnia (DSM-IV-TR) in a multi-center, double-blind, rando mized, placebo-controlled trial (17C). Latency to persistent sleep, total sleep time, sleep efficiency, wake time after sleep onset, and number of awakenings were measured by polysomnography. Sleep latency at week 1 (the primary out come) was significantly shorter with ramel teon 8 mg than placebo. Significant improvements in sleep latency were main tained at weeks 3 and 5. Total sleep time was significantly longer with both doses of ramelteon at week 1. Self-reported sleep latency was significantly shorter with ramelteon 8 mg at weeks 1, 3, and 5 and with ramelteon 16 mg at weeks 1 and 3. Wake time after sleep onset and number
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of awakenings were not significantly differ ent with ramelteon 8 or 16 mg. Subjective total sleep time was significantly longer with ramelteon 8 mg at weeks 1, 3, and 5 and with ramelteon 16 mg at week 1. Ramelteon had no effect on sleep architec ture, next-morning psychomotor tasks, alertness, or ability to concentrate. There were no withdrawal or rebound effects. Respiratory The potential effects of ramel teon 16 mg on apneic and hypopneic events and arterial oxygen saturation (SaO2) have been assessed in a double-blind, randomized, placebo-controlled, crossover study in 26 adults with mild to moderate obstructive sleep apnea (18C). The treatments were administered 30 minutes before the usual bedtime. Respiratory effort was monitored using respiratory inductance plethysmogra phy, SaO2 was measured by pulse oximetry and sleep onset and duration were measured by polysomnography and a post-sleep ques tionnaire, which also measured next-day resi dual effects. The apnea–hypopnea index was similar with ramelteon and placebo (11.4 ver sus 11.1; CI = –2.1, 2.6). Ramelteon had no effect on the number of episodes of central, obstructive, or mixed apnea. There were no significant differences in SaO2 during the entire night between ramelteon and pla cebo (95.1% versus 94.7%). Ramelteon did not affect sleep when evaluated by poly somnography and post-sleep questionnaire. Compared with placebo, ramelteon had no significant effect on next-day residual effects. Adverse events were reported by three of those who took ramelteon: headache (n = 2) and urinary tract infection (n = 1). No adverse events were reported with placebo. Ramelteon was well tolerated and, as expected, did not worsen sleep apnea when taken by subjects with mild to moderate obstructive sleep apnea. Susceptibility factors The effects of age and sex on the pharmacokinetics and pharmaco dynamics of ramelteon 16 mg have been evaluated in healthy young volunteers (18–34 years) and elderly volunteers (63–79 years) (19C). The pharmacokinetics of oral
Andrew Byrne, Shabir Musa, and Stephen Curran
ramelteon were studied in an open phase and the pharmacodynamics in a doubleblind, randomized, placebo-controlled, cross over study of ramelteon 16 mg. Ramelteon clearance was significantly reduced in the elderly volunteers (384 ml/minute/kg versus 883 ml/minute/kg) and the half-life was signif icantly increased (1.9 hours versus 1.3 hours). There were no sex differences in clearance or half-life. Ramelteon was extensively trans formed to its hydroxylated M-II metabolite, whose serum AUCs averaged about 30 times those of the parent drug. Compared with pla cebo, ramelteon increased self- and observerrated sedation, but age and sex did not influ ence the magnitude of the ramelteon/placebo difference. Ramelteon did not significantly impair digit-symbol substitution test perfor mance or information acquisition and recall. Thus, the reduced clearance and higher serum concentrations of ramelteon in elderly subjects were not associated with enhanced pharmacodynamic effects. The usually recommended clinical dose of ramelteon (8 mg) does not require modification based on age or sex.
Zolpidem
(SED-15, 3723; SEDA-29, 57; SEDA-30, 53; SEDA-31, 61)
Placebo-controlled studies In a doubleblind crossover study, seven athletes took zolpidem 10 mg or placebo in two sessions over two nights (20c). Residual effects on subsequent daytime functions were evalu ated both objectively (by measuring psycho motor and physical performance, using a combined test of finger dexterity, a simple discriminatory reaction test, critical flicker fusion test, vertical jump, and a 50-m sprint) and subjectively (by visual analogue scales). Zolpidem shortened self-estimated sleep latency and increased total sleep. There was no change in alertness and fatigue scales on the following day after zolpidem, but daytime well-being was slightly wor sened. The critical flicker fusion test showed significantly better results after zolpidem than placebo. Zolpidem did not have effects on athletic evaluation. Zolpidem has a
Hypnosedatives and anxiolytics
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81
hypnotic activity without disturbing psycho motor and physical performance on the fol lowing day when given to healthy adults, suggesting that it could be used in healthy athletes to adjust their extrinsic sleep dis turbances and their consecutive psychomo tor and physical impairments.
concerning the behavioural effects of zolpi dem. Data from the CEIP and the 53 litera ture case reports highlighted a significant dependence and abuse potential of zolpi dem. This study adds to the growing evi dence that zolpidem has the potential for abuse and dependence.
Susceptibility factors Age Three hypnotic drugs, zolpidem 10 mg/day, triazolam 0.125–0.25 mg/day, or oxazepam 15 mg/day, were used for the treatment of insomnia in 60 elderly people with a history of concomi tant diseases (depression, dementia, and behavioral disturbances) (21c). All three drugs were effective and safe. There were no paradoxical effects.
Drug–drug interactions Caffeine The kinetic and dynamic interactions of caffeine 250 or 500 mg and zolpidem 7.5 mg have been evaluated in a double-blind, placebocontrolled, single-dose, six-way crossover study (23c). Caffeine co-administration increased the Cmax and AUC of zolpidem by 30–40%; zolpidem had no effect on the pharmacokinetics of caffeine or its metabo lites. Zolpidem plus placebo significantly increased sedation, impaired digit-symbol substitution test performance, slowed tapping speed and reaction time, increased electroencephalogram (EEG) relative beta amplitude, and impaired delayed recall. Caffeine partially, but not completely, reversed most of the pharmacodynamic effects of zolpidem. Thus, caffeine only incompletely reverses zolpidem’s sedative and performance-impairing effects and cannot be considered as an antidote to ben zodiazepine agonists.
Drug abuse and drug dependence An offi cial enquiry was carried out in Nantes by the Centre for Evaluation and Information on Pharmacodependence (CEIP) to deter mine whether the non-benzodiazepine hyp notic zolpidem has a higher abuse potential than previously documented (22R). The authors reviewed the literature and analysed French data corresponding to the drug’s post-marketing period collected by the CEIP network from 1993 to 2002. The literature review yielded mixed results
References 1. Chamberlain SR, M€ uller U, Deakin JB, Corlett PR, Dowson J, Cardinal RN, Aitken MRF, Robbins TW, Sahakian BJ. Lack of deleterious effects of buspirone on cognition in healthy male volunteers. J Psychopharma col 2007;21(2):210–5. 2. Leufkens TRM, Vermeeren A, Smink BE, van Ruitenbeek P, Ramaekers JG. Cognitive, psychomotor, and actual driving performance in healthy volunteers after immediate- and extended-release formulations of alprazolam 1 mg. Psychopharmacology 2007;191(4):951–9. 3. Mehta V, Singhi P, Singhi S. Intravenous sodium valproate versus diazepam infusion for the control of refractory status epilepticus
in children: a randomized controlled trial. J Child Neurol 2007;22(10):1191–7. 4. Echizenya M, Mishima K, Satoh K, Kusanagi H, Ohkubo T, Shimizu T. Dissociation between objective psychomo tor impairment and subjective sleepiness after diazepam administration in the aged people. Hum Psychopharmacol Clin Exp 2007;22(6):365–72. 5. Lintzeris N, Mitchell TB, Bond AJ, Nestor L, Strang J. Pharmacodynamics of diazepam co-administered with methadone or bupre norphine under high dose conditions in opioid-dependent patients. Drug Alcohol Depend 2007;91(2–3):187–94.
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6. Pompéia S, Manzano GM, Pradella-Hallinan M, Bueno OFA. Effects of lorazepam on deductive reasoning. Psychopharmacology 2007;194(4):527–36. 7. De Vanna M, Rubiera M, Luisa Onor M, Aguglia E. Role of lormetazepam in the treatment of insomnia in the elderly. Clin Drug Invest 2007;27(5):325–32. 8. Wilson KE, Welbury RR, Girdler NM. Com parison of transmucosal midazolam with inhala tion sedation for dental extractions in children. A randomized, cross-over, clinical trial. Acta Anaesthesiol Scand 2007;51(8):1062–7. 9. Nascimento JS, Modolo NS, Silva RC, Santos KP, Carvalho HG. Sedative and cardiovascular effects of midazolam and diazepam alone or combined with cloni dine in patients undergoing hemodynamic studies for suspected coronary artery dis ease. Arq Bras Cardiol 2007;89(6):403–8. 10. Lucas da Silva PS, Oliveira Iglesias SB, Leao FV, Aguiar VE, Brunow de Carvalho W. Procedural sedation for insertion of central venous catheters in children: comparison of midazolam/fentanyl with midazolam/ketamine. Paediatr Anaesth 2007;17(4):358–63. 11. Mamula P, Markowitz JE, Neiswender K, Zimmerman A, Wood S, Garofolo M, Nieberle M, Trautwein A, Lombardi S, Sargent-Harkins L, Lachewitz G, Farace L, Morgan V, Puma A, Cook-Sather SD, Liacouras CA. Safety of intravenous midazo lam and fentanyl for pediatric GI endoscopy: prospective study of 1578 endoscopies. Gas trointest Endosc 2007;65(2):203–10. 12. Tschirch FTC, Gapfert K, Fro¨ hlich JM, Brunner G, Weishaupt D. Low-dose intrana sal versus oral midazolam for routine body MRI of claustrophobic patients. Eur Radiol 2007;17(6):1403–10. 13. Nassr N, Lahu G, von Richter O, Reutter F, Knoerzer D, Zech K, Erb KA, Schug B, Blume H, Hermann R. Lack of a pharmaco kinetic interaction between steady-state roflumilast and single-dose midazolam in healthy subjects. Br J Clin Pharmacol 2007;63(3):365–70. 14. Yamazaki A, Kumagai Y, Fujita T, Hasunuma T, Yokota S, Maeda M, Otani Y, Majima M. Different effects of light food on
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pharmacokinetics and pharmacodynamics of three benzodiazepines, quazepam, nitraze pam and diazepam. J Clin Pharm Ther 2007;32(1):31–9. 15. Mintzer MZ, Griffiths RR. A triazolam/ amphetamine dose–effect interaction study: dissociation of effects on memory versus arou sal. Psychopharmacology 2007;192(3):425–40. 16. Cortellazzi P, Lamperti M, Minati L, Falcone C, Pantaleoni C, Caldiroli D. Sedation of neurologically impaired children undergoing MRI: a sequential approach. Pediatr Anesth 2007;17(7):630–6. 17. Zammit G, Erman M, Wang-Weigand S, Sainati S, Zhang J, Roth T. Evaluation of the efficacy and safety of ramelteon in sub jects with chronic insomnia. J Clin Sleep Med 2007;3(5):495–504. 18. Kryger M, Wang-Weigand S, Roth T. Safety of ramelteon in individuals with mild to mod erate obstructive sleep apnea. Sleep Breath 2007;11(3):159–64. 19. Greenblatt DJ, Harmatz JS, Karim A. Age and gender effects on the pharmacokinetics and pharmacodynamics of ramelteon, a hypnotic agent acting via melatonin recep tors MT1 and MT2. J Clin Pharmacol 2007;47(4):485–96. 20. Ito SU, Kanbayashi T, Takemura T, Kondo H, Inomata S, Szilagyi G, Shimizu T, Nishino S. Acute effects of zolpidem on daytime alert ness, psychomotor and physical performance. Neurosci Res 2007;59(3):309–13. 21. Cotroneo A, Gareri P, Nicoletti N, Lacava R, Grassone D, Maina E, De Sarro G, Cabodi S. Effectiveness and safety of hypnotic drugs in the treatment of insomnia in over 70-year-old people. Arch Gerontol Geriatr 2007;44(1):121–4. 22. Victorri-Vigneau C, Dailly E, Veyrac G, Jolliet P. Evidence of zolpidem abuse and dependence: results of the French Centre for Evaluation and Information on Pharma codependence (CEIP) network survey. Br J Clin Pharmacol 2007;64(2):198–209. 23. Cysneiros RM, Farkas D, Harmatz JS, von Moltke LL, Greenblatt DJ. Pharmacokinetic and pharmacodynamic interactions between zolpidem and caffeine. Clin Pharmacol Ther 2007;82(1):54–62.
Alfonso Carvajal, Luis H. Martín Arias, and Natalia Jimeno
6 GENERAL
Antipsychotic drugs (SED-15, 2438)
The adverse effects of antipsychotic drugs as outcome measures have been reviewed (1R). The sources included randomized con trolled trials, post-marketing surveillance, and observational studies. The authors con cluded that adverse effects are inconsis tently reported, hampering cross-study comparisons. They suggested that total withdrawal rates provide a useful global outcome measure, incorporating tolerability and efficacy, as well as patients’ and clini cians’ viewpoints. Clinical uses In spite of the current debate about the therapeutic role that different types of antipsychotic drugs should have, the American Society of Health-System Pharmacists has encouraged health-care professionals to consider the use of secondgeneration antipsychotic drugs as first-line treatments for individuals with psychotic dis orders (2RS). However, a consensus panel has developed a statement outlining the metabolic risks of treatment with atypical antipsychotic drugs, recommending careful consideration of the metabolic risks and con sideration of switching antipsychotic drugs in patients who gain 5% or more of their initial weight, have hyperglycemia, or develop wor sening hyperlipidemia (3S).
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32006-X � 2010 Elsevier B.V. All rights reserved.
A review of 84 published studies showed a lack of high-quality evidence to support off-label use of atypical antipsychotic drugs, which is thus likely to yield even less benefit per dollar expended (4R). Observational studies Conventional anti psychotic drugs and clozapine seem to con stitute the current mainstream for the treatment of schizophrenia in China, according to a cross-sectional chart review in 503 in-patients who met ICD-10 diagnos tic criteria for schizophrenia (5c). Most of them (91%) were receiving antipsychotic drug monotherapy, clozapine being the most commonly used medication (30%); the subset of patients treated during the course of a first episode of psychosis, or with less than 5 years of illness, were more likely to be treated with atypical antipsycho tic drugs than with conventional ones. Comparative studies In an open random ized trial in patients with schizophrenia, treated with atypical antipsychotic drugs or haloperidol, there were no differences between treatments in symptom reductions after 1 year (6C). More patients on haloper idol had signs of parkinsonism than those assigned to an atypical antipsychotic drug; by contrast, the proportion of patients who were overweight was higher with olanzapine than with haloperidol. With haloperidol 72% of patients discontinued treatment for any cause within the 12 months (dose range 1–4 mg/day; n = 103), with amisulpride 40% (dose range 200–800 mg/day; n = 104), with olanzapine 22% (5–20 mg/day; n = 105), with quetiapine 53% (200–750 mg/day;
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n = 104) and with ziprasidone 45% (40–160 mg/day; n = 82). Rates of admission to hospital were 7–23% and did not differ significantly between treatments. Since the study was open, the psychiatrists’ expec tations could have led to haloperidol being withdrawn more often. The study was sup ported by the Marketing Authorization Holders of some of the antipsychotic drugs studied, AstraZeneca, Pfizer and SanofiAventis. The effectiveness of different combina tions of drugs for tranquillizing and sedating people who are violent or agitated as a result of psychiatric disorders have been assessed in two randomized controlled trials in India and Brazil (7c, 8c). In the Indian trial, the tranquillizing and sedative effects of a single intramuscular dose of either olanzapine 10 mg or a combination of halo peridol 10 mg plus promethazine 50 mg were compared in 300 aggressive or agi tated patients; the observation period lasted for 4 hours only and patients were followed up for just 2 weeks. Revisits by consultants and the use of additional drugs were less frequent with the combination; the need for physical restraint and the adverse effects of drugs did not differ significantly between treatments. There were no cases of dystonia. In the Brazilian study, the combination of haloperidol 5–10 mg þ promethazine up to 50 mg was more likely to tranquillize or induce sleep than haloperidol alone at 20 min utes; the groups did not differ in this or other measures at later assessments up to 24 hours. There were three seizures within 24 hours of the administration of haloperidol alone (two events) or of haloperidol þ promethazine (one event); nine patients, all allocated to haloperidol alone, had acute dystonias. Quality of life has previously been addressed in an independent study (CUtLASS; SEDA-31, 65). Assessment of quality of life in out-patients with schizo phrenia has now also been performed in a 12-month prospective study in Germany in 1462 patients who were given a new anti psychotic drug or switched to another (9c). The Subjective Well-Being under Neuro leptics Scale (used by the patients them selves) and the Quality of Life Scale (used
by the psychiatrists) were used. Quality of life, as assessed by both patients and doctors, improved with all treatments. Patients’ and psychiatrists’ scale responses were respec tively 52 and 58% (patients treated with olanzapine monotherapy, n = 1007), 39 and 45% (another atypical antipsychotic drug as monotherapy, n = 335), 31 and 59% (a typi cal antipsychotic drug as monotherapy, n = 32) and 44 and 41% (combination therapy with more than one antipsychotic drug, n = 88). Symptom severity, as assessed by the Clinical Global Impression scale, also improved over time regardless of the type of antipsychotic drug. Median body mass index (BMI) increased only with olanzapine, from 25 to 26. The study was promoted by Lilly. Since there was no comparator group, the real contribution of antipsychotic medication to a better quality of life remains unknown. Systematic reviews of comparative studies A meta-analysis has been per formed of 24 randomized controlled com parisons in 6187 patients of atypical antipsychotic drugs with placebo, typical antipsychotic drugs, or mood stabilizers in the treatment of acute mania (10M). Most of the studies lasted 3 weeks. Atypical antipsychotic drugs versus placebo There was a significantly lower global dropout rate in those who received olanzapine and risperidone but not with aripiprazole, quetiapine and ziprasidone; dropouts due to adverse events did not differ between treatments; weight gain was significantly greater in patients who received olanzapine and quetiapine but not with the other atypical drugs. All the atypical antipsychotic drugs produced significantly higher rates of somnolence. Atypical antipsychotic drugs versus halo peridol The analysis showed a signifi cantly lower global dropout rate in patients who received aripiprazole and a trend towards a higher rate in patients treated with quetiapine. Adverse effects such as somnolence, weight gain and
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extrapyramidal symptoms had an impact on treatment adherence. Atypical antipsychotic drugs versus mood stabilizers All the trials together indicated a trend towards superiority of atypical anti psychotic drugs compared with mood stabilizers. Combination therapy (atypical antipsycho tic drugs plus mood stabilizers) versus mood stabilizers The global dropout rate was significantly lower in patients treated with mood stabilizers þ quetiapine or ris peridone than in those treated with mood stabilizers þ placebo. There were no differ ences for olanzapine or ziprasidone. Analy sis of all the trials showed a significantly reduced global dropout rate in patients treated with combination therapy. The effectiveness of co-therapy compared with monotherapy for people with bipolar mania has been assessed in another meta analysis of randomized clinical trials (11M). Eight studies were included (n = 1124). There were significant reductions in mania (Young Mania Rating Scale, YMRS) scores with haloperidol, olanzapine, risperidone and quetiapine as co-therapy compared with monotherapy with a mood stabilizer. YMRS scores were 5.2 (1.1–9.3) points lower with haloperidol, 4.0 (2.0–6.1) points lower with olanzapine, and 5.2 (2.3–8.0) points lower with risperidone; significantly more participants taking co-therapy met the response criterion (at least a 50% reduction in YMRS score; RR = 1.5; 95% CI = 1.3, 1.8). For haloperidol, olanzapine and quetiapine there was no significant difference in the num ber of withdrawals between adjunct and monotherapy: respectively 30% fewer (81% fewer to 166% more), 3% more (27% fewer to 47% more), and 12% fewer (36% fewer to 20% more). With some drugs, co-therapy reduced tolerability compared with monotherapy and resulted in greater weight gain. Cardiovascular The CYP1A2*1F poly morphism may contribute to the risk of prolongation of the QT interval in patients taking higher dosages of antipsychotic drugs
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(12c). This has been observed in 72 patients (mean age 53 years; men 83%), mainly Chinese (n = 61), who were genotyped for CYPA2*1C and CYPA2*1F; mean QTc intervals in those with different CYPA2*1F genotypes (chlorpromazine-equivalent doses > 300 mg/day) were 400 ms (A/A), 426 ms (A/C) and 427 ms (C/C). The QT interval in children taking psy chotropic drugs has been extensively reviewed in the light of the increased use of these medications and reports of several cases of sudden death in children (13R). It is recommended that before prescribing a psy chotropic drug a detailed past medical and family history should be taken, looking spe cifically for a family history of sudden death, a personal or family history of unex plained syncope or seizures, a history of congenital heart disease, deafness or disor ders involving electrolyte imbalance, and use of medications that can cause electro lyte imbalance, interfere with the metabo lism of other drugs, or cause QT interval prolongation themselves. In a retrospective case-control study, in which the records of 700 patients receiving in-hospital care between 1995 and 2003 were analysed, haloperidol was associated with car diac arrest (adjusted OR = 3.8; 95% CI = 1.6, 9.2) (14C). Cardiac arrest was defined as cir culatory arrest in patients for whom interven tion of the advanced life support resuscitation team was requested (n = 140). Nervous system Sedation and mental clouding may be implicated in social with drawal, but their severity may be under estimated by psychiatrists. Accordingly, consultations with consenting patients were taped and transcribed to explore these adverse effects in relation to antipsychotic drugs (15c). These problems were raised as topics in 39 of 92 consultations, more often by patients than by doctors. The authors suggested that presentation of this material sheds light on why patients often complain about not being told enough about adverse drug effects. The risk of extrapyramidal symptoms in schizophrenic patients taking antipsychotic
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drugs has been studied using a populationbased claim database detailing a total of 98 320 hospitalizations in 40 561 patients with a diagnosis of schizophrenia (male 59%; mean age 36 years) between 1999 and 2003 in Taiwan (16C). Antiparkinsonian drugs, an indirect indicator of extrapyramidal symptoms, were frequently co-prescribed, but fell over the years, with a 15% reduction during the study period. The adjusted relative risk of antiparkinsonian drug prescribing in those taking typical antipsychotic drugs was 1.8 (95% CI = 1.7, 1.8) compared with those taking atypical antipsychotic drugs; hospitalizations that involved a higher-than-recommended dose (prescribed daily dose > defined daily dose) were also associated with more use of antiparkinsonian drugs (RR = 1.8, 95% CI = 1.8, 1.9). The ranking of the crude co-prescribing rate of antiparkinsonian drugs after adjustment for covariates, in increasing order, was clozapine (31%), quetiapine (33%), olanzapine (36%), thioridazine (66%), chlorpromazine (69%), zotepine (72%), risperidone (75%), clotia pine (82%), sulpiride (83%), flupentixol (91%), haloperidol (94%), zuclopenthixol (95%), loxapine (96%) and trifluoperazine (97%). The evolution of antipsychotic druginduced extrapyramidal symptoms during long-term treatment has also been studied twice: in 1975 in in-patients taking regular typical antipsychotic drugs and/or clozapine (n = 200; mean age, 42 years; mean duration of illness, 16 years) with regard to the presence of extrapyramidal effects and again in 2003/2004 (n = 83); the respective prevalences were 17 and 29% for parkin sonism, 14 and 14% for akathisia, and 24 and 13% for tardive dyskinesia (17c). In a multivariate analysis, there was a tendency for the long-term evolution of tardive dys kinesia to depend on illness duration as the only variable; considering the category of uncertain dyskinesia, there was worsening of the syndrome in 11 patients and improve ment in 22; thus, the authors stated that tardive dyskinesia is not always persistent or irreversible. As the type of antipsychotic drug or combination used changed during the study, and since there might have been a
survival bias, it is difficult to draw firm con clusions from these results. Rabbit syndrome Rabbit syndrome is a movement disorder that is associated with long-term exposure to neuroleptic drugs. In a search carried out in MEDLINE and PubMed (1972–2006), 34 cases of rabbit syndrome associated with different typical antipsychotic drugs and 11 cases with atypi cal drugs have been identified (18M); of the latter, all but three were associated with risperidone. It is said that, unlike tardive dyskinesia, rabbit syndrome responds favourably to anticholinergic agents, such as benzatropine, biperiden, procyclidine and trihexyphenidyl. Tardive dyskinesia Tardive dyskinesia is a hyperkinetic movement disorder induced by dopamine receptor antagonists. It not only typically presents with stereotypy or dysto nia, but can also cause akathisia, myoclonus or tremor. However, there have been no detailed reports of gait abnormalities. Three patients exposed to dopamine receptor antagonists for long periods developed ‘tard ive gait’; one, a 73-year-old woman, had a dancing gait – a repetitive pattern of several short steps on her toes, followed by a long step; the other two, 58- and 78-year-old women, had a ‘duck-like’ gait – a short stride length and initial contact with the ground by the toes instead of the heels at the end of the swing phase (19Ar). There was no association with DRD1 and DRD2 polymorphisms and extrapyramidal adverse effects in two studies in 130 out patients in stable remission who met the DSM-IV criteria for schizophrenia spectrum disorders and were receiving long-term main tenance therapy with haloperidol, fluphena zine, zuclopenthixol or risperidone (20c) and in 47 in-patients receiving perphenazine (21c). However, in the latter study, the 102C allele of HTR2A and the –697C and 23Ser alleles of HTR2C were more frequent among patients with extrapyramidal symptoms (n = 25) than in patients without these symp toms (n = 22) (OR = 3.2, 95% CI = 1.1, 8.7; and OR = 4.3, 95% CI = 1.4, 13.0 for the two alleles, respectively); the difference remained
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significant after multiple model analyses, including age, sex and duration of anti psychotic drug treatment as covariates. Psychological Working memory is a multi faceted cognitive construct that includes the internal maintenance, manipulation and sequencing of information; the oculomotor delayed response task is a translational paradigm that is used to examine the main tenance of spatial location information of working memory. In 14 antipsychotic drugnaïve patients with schizophrenia, an oculo motor delayed response task was performed before and 6 weeks after antipsychotic drug treatment (risperidone n = 11; olanzapine n = 3); they were compared with 15 matched healthy individuals (22c). The pre-treatment deficit in accurately remem bering spatial locations was exacerbated by antipsychotic drug treatment; however, this occurred only when covert attention was directed away from remembered locations during delay periods. The authors stated that disruption in the allocation of covert attention might contribute to patients’ decline in spatial working memory after antipsychotic drug treatment, which they explained as alterations in prefrontal dopa minergic systems or reduced thalamocorti cal drive. Blockade of dopamine D2 receptors, which is thought to mediate antipsychotic drug efficacy, has also been implicated in adverse subjective experiences. The relation ship between striatal and extrastriatal dopa mine D2 receptor binding potential and occupancy and adverse subjective experi ences has been examined in a double-blind controlled study (23c). Patients with recentonset psychoses (n = 12) were randomly assigned to olanzapine 2.5 or 15 mg/day or risperidone 1 or 4 mg/day. Subjective experi ences, motor adverse effects and striatal and extrastriatal dopamine D2 receptor numbers (respectively determined by [11C]raclopride and [11C]FLB 457 PET scans) were evalu ated after 2 weeks of continuous antipsycho tic drug treatment. D2 occupancy was 50–91% in the striatum and 4–95% in the different extrastriatal regions. There was a
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significant association between striatal block ade and mental functioning; higher dopa mine D2 receptor occupancy in the striatal, temporal and insular regions was negatively associated with subjective experiences when patients were receiving stable doses of anti psychotic drugs. Endocrine Autoimmune thyroiditis was observed in a study in 74 consecutive, clini cally stable out-patients with schizophrenia who had received stable doses of different antipsychotic drugs for at least 3 months (mean age 40 years) and had no history of overt thyroid disease. Mean serum prolactin concentrations were significantly higher in patients with thyroid autoantibodies (n = 11; mean age 37 years) compared with patients without (n = 63; mean age 40 years) (24c). Metabolic Weight gain and diabetes mellitus due to antipsychotic drugs EIDOS classification: Extrinsic moiety: Antipsychotic drugs Intrinsic moiety: 5HT2C receptors Distribution: Adipocytes and other cells Outcome: Altered physiology (leptin secretion, insulin resistance, impaired glucose tolerance) Sequela: Weight gain and diabetes mellitus due to antipsychotic drugs DoTS classification: Dose relation: Collateral reaction Time course: Intermediate Susceptibility factors: Genetic (African American origin); sex (male) In an observational study, 98 out-patients with newly diagnosed first-episode psy choses receiving antipsychotic drugs gained significantly more weight during 1 year than 30 healthy controls and seven untreated patients (25C). BMI increased by 2.2 in the treated patients (mean age 27 years), by 0.4 in the healthy controls (mean age 21 years) and by 0.5 in the untreated patients (age not stated); olanzapine, risperidone, haloperi dol and perphenazine were associated with BMI gains of 5.5 (n = 11), 2.5 (n = 43),
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1.4 (n = 24) and 0.5 (n = 13) respectively. There was more weight gain in younger patients and in those with more negative symptoms at baseline; higher individual total co-medication counts and antidepressant co-prescriptions were also associated with weight gain independent of antipsychotic drug therapy. The authors stated that beha vioral treatments have been successful at con trolling weight in chronic schizophrenia patients and may also be appropriate interven tions in patients with first-episode psychoses. In 99 patients with first-episode schizo phrenia (mean age 26 years) and 51 healthy matched controls (mean age 28 years), fol lowed up for 6 weeks to explore the predictors of antipsychotic drug-induced weight gain, there were significant changes in waist circum ference, weight and BMI between baseline and end-point, influenced by the presence of the disease (versus healthy controls) (26C). There were significant negative correlations between weight at baseline and both waist circumference changes and BMI. The BMI at baseline influenced clinically significant weight gain (>7% above baseline); patients with lower BMI scores of below 18.5 gained more weight (71%, n = 38) than those between 18.5 and 23 (45%, n = 51) and those between 23 and 27 (50%, n = 10). Among the antipsychotic drugs, more of the patients who were taking olanzapine had significant weight gain (77%, n = 35) than those who were tak ing risperidone (64%, n = 33) or haloperidol (23%, n = 31). Weight gain over time has been also compared in 32 boys with tics taking tetra benazine (mean age 13 years) and an agematched group of 41 patients (33 boys) with tics taking only antipsychotic drugs (mean age 12 years) (27c). Weight gain with tetra benazine was 0.36 kg/month (mean follow-up duration 25 months) and with antipsychotic drugs 0.75 kg/month (mean follow-up dura tion 19 months). In patients with severe mental disorders who were on monotherapy with olanzapine or clozapine (n = 80), monotherapy with other antipsychotic drugs (n = 80) or un medicated (n = 82), and despite similar BMIs, dyslipidemia (high triglycerides and low high-density lipoprotein (HDL)
cholesterol) was significantly more prevalent in those who received antipsychotic drugs than in unmedicated subjects (28c). There were no significant intergroup differences in the prevalence of metabolic syndrome, obe sity, hypertension or hyperglycemia. After adjusting for age and body mass, olanzapine and clozapine-treated patients had signifi cantly higher prevalence of dyslipidemia than unmedicated patients; they also had sig nificantly higher mean triglyceride concentra tions and lower mean HDL cholesterol concentrations; patients taking other antipsy chotic drugs had intermediate values. Although the cross-sectional design of this study precluded conclusions about causality, the authors stated that these results suggest a primary effect of some antipsychotic drugs on lipid regulation that may be important in the development of cardiovascular disease. Compared with patients receiving conven tional antipsychotic drugs, the risk of newonset diabetes was greatest among patients taking risperidone (HR = 3.8; 95% CI = 2.7, 5.3), olanzapine (HR = 3.7; 95% CI = 2.5, 5.3) and quetiapine (HR = 2.5; 95% CI = 1.4, 4.3) in a retrospective nested case-control study in which cases were patients with diabetes (n = 283) who were matched by age, sex and index date with 1134 controls (29C). The cases and controls had bipolar disorder and all had been exposed for at least 3 months to either conventional or atypical antipsychotic drugs or three filled prescriptions for treatment disorders. The relationship between drug-induced weight gain and the risk of diabetes has been reviewed (30R). The degree of adipos ity during antipsychotic drug treatment was strongly related to insulin in a study, in which 63 non-diabetic patients with schizo phrenia taking different antipsychotic drugs were compared with 14 age- and BMImatched controls (31c). BMI and waist cir cumference explained on average 33–34% of the variance in insulin sensitivity, with possible additional contributions from geno type and degree of fitness. Gastrointestinal Dysphagia has been attri buted to antipsychotic drugs (32A).
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• A 53-year-old man with paranoid schizophrenia was treated with haloperidol 15 mg/day, diazepam 15 mg/day and levomepromazine 150 mg/day and 14 days later complained of disturbed swallowing and food getting stuck in the throat. He was given biperiden 4 mg/day, without improvement. His antipsychotic medication was changed to risperidone 6 mg/day, but he became agitated and aggressive, and had paranoid delusions 1 week later. He was given fluphenazine 10 mg/day and diazepam and levomepromazine were continued. His psychotic symptoms disappeared and the dysphagia improved.
Liver Antipsychotic drugs commonly cause asymptomatic increases in liver enzymes and serum bilirubin concentrations. In a retrospective study, the charts of 110 psychiatric patients (age range 12–65 years) were reviewed to evaluate the effect of the atypical antipsychotic drugs olanzapine (n = 33), risperidone (n = 29) and quetiapine (n = 48) on liver enzymes and serum biliru bin concentrations after 1 and 6 months (33c). Of the 110 patients, 31 had asympto matic increases in transaminases, gamma glutamyltranspeptidase activity, and serum bilirubin concentrations in the first month of the study; after 6 months there were abnormalities in liver function tests in 27 patients; there were no significant differ ences among the three groups. Two of the 110 patients had high increases and stopped treatment. Musculoskeletal Bone mineral density can be negatively influenced by hyper prolactinemia (34A). • A 52-year-old woman had a spontaneous rib fracture after taking antipsychotic drugs for several years (mainly risperidone 2 mg/day), antidepressants (mainly sertraline 50 mg/day) and anxiolytics (mainly lorazepam 2.5 mg/ day). At the time of the fracture, there was severe osteoporosis (T score at L2–L4 = –3.35) and a markedly increased plasma prolactin concentration (117 ng/ml; reference range 3–24 ng/ml). The latter normalized 2 months after withdrawal of sertraline and risperidone.
In young women maintained on either prolactin-raising antipsychotic drugs (e.g. risperidone, amisulpride; n = 20) or olanzapine,
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a prolactin-sparing drug (n = 12), there was an overall gain in lumbar bone mineral den sity over 1 year in the latter compared with overall loss in the former (35c).
Deaths associated with antipsychotic drug treatment Both atypical and conventional antipsycho tic drugs are associated with an increased risk of cerebrovascular adverse events when used in elderly people with dementia (36S). Furthermore, atypical antipsychotic drugs are associated with increased mortality in this population (SEDA-30, 60). There has been growing concern that physicians may switch patients to conventional antipsychotic drugs, based on absence of evidence of risk rather than evidence of absence of risk. A number of observational studies have been conducted in an attempt to determine whether or not conventional antipsychotic drugs, like atypical antipsychotic drugs, are associated with increased mortality when used in elderly people with dementia. For instance, short-term mortality among elderly people who received conventional and atypi cal antipsychotic drugs has been assessed in a large population-based cohort (37C). Linked health-care utilization data of all British Columbia (Canada) residents were used to identify a cohort of people aged 65 years and older who began taking antipsy chotic drugs between January 1996 and December 2004 and had no cancers. The 180-day all-cause mortality rates among resi dents taking conventional antipsychotic drugs (n = 12 882) and those taking atypical antipsychotic drugs (n = 24 359) were com pared; 1822 patients (14%) in the conven tional drug group died, compared with 2337 (9.6%) in the atypical drug group (adjusted mortality ratio = 1.3, 95% CI = 1.2, 1.4). Compared with risperidone, haloperidol was associated with the greatest increase in mortality (mortality ratio = 2.1; 95% CI = 1.9, 2.4) and loxapine with the lowest (mortality ratio = 1.3; 95% CI = 1.2, 1.4). The greatest increase in mortality occurred among those who were taking higher (above
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median) doses of conventional antipsychotic drugs (mortality ratio = 1.7; 95% CI = 1.5, 1.9) and during the first 40 days after the start of drug therapy (mortality ratio = 1.6, 95% CI = 1.4, 1.8). In another population-based, retrospective cohort study carried out in other province of Canada, older adults with dementia were fol lowed up between 1 April 1997 and 31 March 2003 (38C). A total of 27 259 matched pairs were identified. New use of atypical antipsy chotic drugs was associated with a statistically significant increase in the risk of death at 30 days compared with non-use in both the com munity-dwelling cohort (adjusted hazard ratio = 1.3; 95% CI = 1.0, 1.7) and the longterm care cohort (adjusted hazard ratio = 1.5; 95% CI = 1.1, 2.1). The excess risk persisted to 180 days, but unequal rates of censoring over time may have affected these results. Relative to atypical antipsychotic drug use, conventional antipsychotic drug use was asso ciated with a higher risk of death at all times. A sensitivity analysis showed that unmea sured confounders that increase the risk of death could reduce or eliminate the observed associations. In this regard, there is a state ment from the European Medicines Agency (EMA) (39S). By contrast, neither atypical nor conven tional antipsychotic drugs increased mortal ity or hospital admissions in a sample of 254 very frail patients with dementia (mean age 86 years) (40C). Medical records were exam ined to provide information on the use of daily antipsychotic drugs, and central regis ters confirmed mortality for up to 2 years. Nearly a half (48%) of the patients used antipsychotic drugs (typical antipsychotic drugs, n = 95; atypical drugs, n = 28). The mean number of hospital admissions was higher among the non-users than among the users of conventional or atypical antipsycho tic drugs. Of the users of atypical antipsycho tic drugs (risperidone, olanzapine), 32% died within 2 years; the respective figures for users of conventional neuroleptic drugs were 45%, and for non-users 50%. In the Cox proportional hazard model, only a high number of medications and the use of physical restraint predicted higher mortality at 2 years. Furthermore, other data did not
show an increased mortality risk from anti psychotic drugs in adults with schizophrenia. Mortality rates have also been assessed in adults with schizophrenia, by reviewing safety data from clinical trials conducted from approximately 1982 to 2002 (41M). These trials involved 16 791 adults with schizophre nia (DSM-III or DSM-IV criteria) in the FDA’s Summary Basis of Approval reports for six antipsychotic drugs. The mortality rate for patients assigned to placebo was signifi cantly higher than for either the investiga tional antipsychotic drug (OR = 0.2; 95% CI = 0.1, 0.4) or the active control group (OR = 0.2; 95% CI = 0.1, 0.4).
Fetotoxicity In an analysis of 22 843 cases carried out by the Hungarian Case-Control Surveillance of Congenital Abnormalities during 1980–1996, 25 congenital abnormal ities were identified; 3648 (16%) were born to mothers treated orally with promethazine during pregnancy (42C). Of 38 151 matched population controls without congenital abnormalities, 6025 (16%) had mothers who had taken promethazine during pregnancy. There were higher rates of cleft lip ± cleft palate (adjusted OR = 1.5; 95% CI = 1.1, 2.0) and poly/syndactyly (adjusted OR = 1.3; 95% CI = 1.0, 1.8) after promethazine treat ment during the 2nd and 3rd months of gesta tion. Since these associations were not confirmed after evaluation of only medically recorded uses of promethazine, these risks were explained by recall bias. Susceptibility factors Genetic The effects of CYP2D6 genotypes on the occurrence of neuroleptic malignant syndrome have been tested in 53 patients who had experienced the condition and 112 healthy individuals (43c). There was a higher prevalence of the CYP2D6*5 allele in the group of patients with neuroleptic malignant syndrome, although the difference was not statistically significant (10% versus 5.4%; OR = 2.0, 95% CI = 0.9, 4.8). However, the preva lence of the CYP2D6*5 allele in the 29 patients who developed neuroleptic
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malignant syndrome as a result of having taken CYP2D6 substrates was significantly higher than in the controls (16% versus 5.4%; OR = 3.2, 95% CI = 1.3, 8.1). The CYP2D6 genotype contributed to the development of acute extrapyramidal symptoms in 79 patients receiving anti psychotic drugs in hospital compared with 188 controls (44c). There was a significant association between the risk of antipsychotic drug-induced acute extrapyramidal symp toms and the homozygous CYP2D6*4 polymorphism (OR = 4.1; 95% CI = 1.0, 16.0) and the heterozygous CYP2D6*6 poly morphism (OR = 5.4; 95% CI = 1.1, 18.0). Age The efficacy and tolerability of antipsy chotic drugs in children and adolescents with psychoses have been reviewed (45R–47R). There are few comparative data on whether there are differences among the different antipsychotic drugs in clinical effectiveness; the available data from short-term studies suggest that young subjects might be more likely than adults to develop antipsychotic drug-related adverse effects (e.g. extrapyra midal adverse effects, sedation, raised prolac tin, weight gain). In addition, preliminary data suggest that atypical antipsychotics can lead to the development of diabetes in some young subjects. Such a substantial risk points to the urgent need to develop therapeutic strategies to prevent and/or mitigate weight gain and diabetes early in the course of treatment in this population. A few results from one study favoured clozapine over haloperidol in treating treatment-resistant childhood-onset schizophrenia (n = 21, WMD Bunney–Hamburg Psychosis Rating Scale –3.6, 95% CI –6.6, –0.6). However, those who took clozapine were more likely to have drowsiness (n = 21; RR = 3.3, 95% CI = 1.2, 8.8; NNTH = 2, 95% CI = 2, 17) and half of the children who took clozapine had neutropenia (n = 21; RR = 12, 95% CI = 0.7, 193). Drug overdose The impact of legislative changes on patterns of antipsychotic drug prescribing and self-poisoning in Scotland during 2000–2006 has been analysed (48c).
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During that period, regulatory authorities in the UK restricted the use of thioridazine because of cardiotoxicity (SEDA-24, 55). The prescribing pattern then changed; there was a fall in the use of typical anti psychotic drugs, whereas the use of atypical antipsychotic drugs increased. In general, the number of hospital admissions associated with atypical antipsychotic drug overdose was low, representing 1.5 (95% CI = 1.3, 1.7) admissions per 1000 prescriptions during that period; admissions after typical antipsychotic drug ingestion were significantly higher, representing 3.4 (95% CI = 2.7, 4.0) per 1000 prescriptions. Management of adverse drug reactions Dyskinesias Tetrabenazine inhibits vesi cular monoamine transporter 2, leading to depletion of dopamine and other monoa mines in the central nervous system. In a retrospective chart review, 448 patients who had used tetrabenazine between 1997 and 2004 (mean age at onset of the movement disorder, 43 years; 42% men) were treated for a variety of hyperkinesias, including tardive dyskinesia (n = 149), dystonia (n = 132), chorea (n = 98), tics (n = 92) and myoclonus (n = 19) (49c). They were treated for a mean of 2.3 years and efficacy was sustained in most cases. Common adverse effects included drowsiness (25%), parkinsonism (15%), depression (7.6%) and akathisia (7.6%). Although it has repeatedly been observed that tetrabena zine alleviates hyperkinetic movements, it can worsen parkinsonism (50R). Weight gain In a 12-week double-blind, placebo-controlled, randomized trial of sibu tramine on clozapine-associated weight gain, there were no significant differences in changes in weight, BMI, abdominal and waist circumferences, glycated hemoglobin (HbA1), fasting glucose or cholesterol con centrations between sibutramine (n = 11) and placebo (n = 10) (51c). Other specific interventions for weight gain associated with olanzapine have been proposed, including reboxetine (52c) and metformin (53c).
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• A 49-year-old African American woman with a schizoaffective disorder, hypertension, type II diabetes, stress incontinence and obesity was given topiramate to treat weight gain over three distinct trials, followed by a 4-week washout before starting acetazolamide (54A). The weight changes with topiramate in the successive trials were 1.9 kg (3 months), 0.2 kg (4 months), 6.7 kg (12 months) and for acetazolamide 5.0 kg (2 months).
The authors suggested that acetazolamide was as effective as topiramate in reversing weight gain due to antipsychotic drugs; however, they stated that, since there are no clearly effective treatments, cognitive behavioral programmes should be recom mended for motivated patients.
INDIVIDUAL DRUGS Amisulpride
(SED-15, 173; SEDA-29, 65; SEDA-31, 69)
Observational studies Of 106 consecutive out-patients with cancers and depressive symptoms in a prospective 4-week study with low doses of amisulpride 50 mg/day, two withdrew owing to an adverse event (weight gain and excessive activation, one each) (55c). Scores on the Montgomery– Asberg Rating Scale for depression improved significantly from baseline to endpoint, includ ing both emotional and physical aspects.
Comparative studies In an open study, patients with stable schizophrenia and a major or minor depressive episode taking risperidone were randomized into a risperi done continuation group (n = 45; mean age 38 years) or an amisulpride switch group (n = 42; mean age 33 years) (56c). The main outcome measures were changes from base line on the Calgary Depression Scale for Schi zophrenia and the Beck Depression Inventory. The mean dose at 12 weeks was 4.2 mg/day for risperidone and 458 mg/day for amisulpride. Improvements were significantly greater in the amisulpride switch group than
in the risperidone continuation group at weeks 8 and 12. Mean changes in body weight did not differ significantly between groups (þ0.2 kg for amisulpride and –0.6 kg for risperidone); mean serum prolactin concentrations increased with amisulpride (71–83 ng/ml) and fell slightly with risperi done (71–67 ng/ml). Extrapyramidal symp toms did not significantly differ between groups from baseline to endpoint; akathisia (n = 18 versus n = 15), tremor (n = 8 versus n = 7). Other effects were oligomenorrhea (n = 6 and n = 5; one new case in each group); somnolence (n = 5 in both groups) and lassitude (n = 6 versus n = 3). Nervous system Extrapyramidal symp toms in patients taking amisulpride have been reported (SEDA-29, 65). These symp toms were associated with higher amisul pride plasma concentrations in a drug monitoring survey in 378 schizophrenia patients, supported by Sanofi-Aventis (57c). Patients taking amisulpride (dosage range 100–1550 mg/day) who experienced extra pyramidal symptoms (15%) had signifi cantly mean higher amisulpride plasma concentrations (377 ng/ml) than patients without extrapyramidal symptoms (305 ng/ml), despite similar doses (595 mg/day versus 594 mg/day). Mean amisulpride daily doses (594 mg/day) and plasma concentrations (315 ng/ml) were significantly correlated. Tardive dyskinesia has been associated with amisulpride (58A). • A 37-year-old woman with schizophrenia tak ing haloperidol developed acute extrapyrami dal symptoms, including muscle rigidity and tremor. Amisulpride monotherapy was started, increasing up to 800 mg/day, and her symptoms improved. After 6 months she developed involuntary movements periorally and in the left upper limb. Amisulpride was maintained at the same dose and the intensity and fre quency of the abnormal movements increased; she also developed periodic involuntary oral– buccal–lingual movements and choreoathetoid movements in her left arm, wrist and fingers. The symptoms gradually remitted throughout the next 3 months after amisulpride was with drawn and treatment was given with quetiapine 300 mg/day, clonazepam, amantadine hydro chloride and vitamins E and B6.
Antipsychotic drugs
Aripiprazole
Chapter 6
(SEDA-30, 61;
SEDA-31, 70) Drug combination studies A fixed dose of aripiprazole 15 mg/day added to previous clozapine (mean dose 478 mg/day) resulted in significant improvement on PANSS scores in 27 clinically stabilized patients with chronic schizophrenia (22 men; mean age 42 years) in a 16-week open uncon trolled study (59c). There were no signifi cant changes from baseline to end-point in extrapyramidal symptoms, body weight or prolactin concentrations; none of the four dropouts was due to adverse events. Placebo-controlled studies Aripiprazole (15 mg/day, n = 19) has been compared with methylphenidate (54 mg/day, n = 17) and placebo (n = 17) in patients with amphetamine dependence in a randomized 20-week study (60c). The study was termi nated prematurely owing to unexpected results of an interim analysis; patients allo cated to aripiprazole had significantly more amphetamine-positive urine samples than patients in the placebo group (OR = 3.8, 95% CI = 1.5, 9.2), whereas patients who were taking methylphenidate had signifi cantly fewer (OR = 0.5, 95% CI = 0.3, 0.8). Nervous system Although aripiprazole seems to produce fewer extrapyramidal symptoms than other antipsychotic drugs, symptoms have occasionally been associated with it (SEDA-30, 61; SEDA-31, 75). New cases have appeared (61A, 62A). • A 54-year-old woman with bipolar disorder who had taken lithium for 25 years and olanzapine for 1 year was changed to lithium and amisulpride up to 200 mg/day because of increased appetite and weight gain. Since the weight gain persisted, amisulpride was replaced by aripiprazole (up to 10 mg/day). She suddenly developed an akinetic hypertonic parkinsonian syndrome, with shaking of the upper limbs and stiffness of all four limbs, impeding her usual daily movements; she later developed facial, oral and axial dystonia, as well as recurrent psychotic symptoms. Aripiprazole was then withdrawn and she was given trihexyphenidyl
93 15 mg/day, olanzapine 5 mg/day and lithium. After 3 months, her motor and psychotic symptoms disappeared and her appetite returned. • A 54-year-old woman with a history of breast cancer, who had taken tamoxifen for 4 years and olanzapine for 5 years for a schizoaffective disorder, developed weight gain. The olanzapine was replaced by aripiprazole (up to 20 mg/day). Ten months later, she developed ‘tongue heaviness’, a lisp, lip smacking, tongue protrusion and lingual writhing movements. Aripiprazole was withdrawn and the dyskinetic movements resolved completely within 1 month. She was successfully maintained on quetiapine without recurrence of dyskinesias for 1 year.
Surprisingly, aripiprazole has been reported to improve haloperidol-induced dyskinesia (SEDA-31, 75) and has also been reported to improve tics associated with risperidone in a 31-year-old man (63A). Endocrine In a randomized, double-blind study, 56 patients with hyperprolactinemia taking haloperidol monotherapy were assigned to either haloperidol þ aripiprazole (n = 26; 11 men; mean age 38 years) or halo peridol þ placebo (n = 28; 11 men; mean age 41 years) (64C). There were no significant differences in haloperidol mean doses; ari piprazole was prescribed in a fixed dose of 15 mg/day during weeks 1–4 and 30 mg/day during weeks 5–8. Baseline prolactin concen trations were not significantly different between the two groups; prolactin concen trations in the aripiprazole group, compared with placebo, were significantly lower during the study, with a significant time effect. Reductions in prolactin concentrations in the aripiprazole-treated patients were 77 and 84% from baseline at weeks 4 and 8 respectively. At week 8 in the aripiprazole group 89% of patients had normal prolactin concentrations compared with 3.6% of patients receiving placebo; the change in prolactin concentrations from baseline to end-point was not significantly different between men and women. Plasma concen trations of haloperidol were not significantly altered. Furthermore, of the 11 women with menstrual disturbances randomly assigned to aripiprazole, seven regained menstruation during the study, whereas none receiving
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placebo did. The mean prolactin concentra tions in patients randomly assigned to ari piprazole who regained menstruation were 94 ng/ml at baseline, 32 ng/ml at week 4, and 19 ng/ml at week 8. Five women had galac torrhea at baseline; two were randomly assigned to aripiprazole and three to pla cebo. At week 8, one of the two patients taking aripiprazole no longer complained of signs or symptoms of galactorrhea, whereas all three who were taking placebo continued to experience it. No patients had gynecomas tia during the study. Cumulative adverse effects in the study in patients randomly assigned to aripiprazole were: insomnia (42%), dry mouth (31%), headache (23%), sedation (12%) and weakness (8%). In the placebo group, the adverse events were dry mouth (21%), sedation (18%) and insomnia (18%). Insomnia, dry mouth and sedation occurred more often during treatment with aripiprazole 15 mg/day compared with the last 4 weeks of the study, when the dose was 30 mg/day. Insomnia (42%), dry mouth (31%), headache (23%), sedation (12%) and weakness (8%) were also reported in patients taking aripiprazole, and dry mouth (21%), sedation (18%), and insomnia (18%) in those taking placebo.
Metabolism Hyperglycemia has been described in a 7-year-old child with a family history of diabetes mellitus while taking aripiprazole (65A). • An overweight 7-year-old boy (34.7 kg, BMI 21 kg/m2, 98th percentile) with attention deficit hyperactivity disorder, mood disorders and a family history of type II diabetes mellitus, had been treated with methylphenidate up to 54 mg/day. Because of worsening mood lability and aggression, methylphenidate was replaced by aripiprazole 2.5 mg/day. Four weeks later, he developed polydipsia, polyuria and poly phagia; his blood glucose concentration was 37 mmol/l (reference range 3.9–5.8 mmol/l) (659 mg/dl; 70–105 mg/dl), triglycerides 2.88 mmol/l (0.84–2.25 mmol/l) (255 mg/dl; 74–199 mg/dl) and mild ketonuria (150 mg/l). Aripiprazole was withdrawn and insulin was started; 4 weeks later, the blood sugar had normalized and insulin was withdrawn, but 6 months later he developed insulin-dependent diabetes.
Susceptibility factors Genetic An unusual aripiprazole blood concentration has been reported in a patient with genetic suscep tibility factors (66A). • A 51-year-old woman with schizophrenia taking aripiprazole 15 mg/day was changed to 30 mg per day because of lack of efficacy. Within 2 weeks, she developed progressive symptoms of lethargy and memory loss. The serum aripipra zole concentration was 2990 ng/ml, about seven times the expected plasma concentration at a dosage of 30 mg/day. She had a genetic polymorphism in the CYP2D6 gene, consisting in substitution of G1934!A on both alleles (homozygote CYP2D6*4/*4), and correspond ing to poor metabolism.
Clozapine
(SED-15, 823; SEDA-29, 66; SEDA-30, 61; SEDA-31, 78)
Observational studies The prescription patterns of clozapine use in China (Hong Kong and Beijing) have been investigated in a randomly selected group of 398 patients taking antipsychotic drugs (67c). Clozapine was prescribed for 16% of patients. On multi ple logistic regression analysis, the number of hospitalizations, place (Hong Kong versus Beijing), use of typical antipsychotic drugs, polypharmacy and co-prescription with antic holinergic drugs were significantly associated with the prescription of clozapine. There were no significant differences between the cloza pine and non-clozapine groups with regard to any of the quality-of-life domains. The patterns of clozapine use in New Zealand have been studied in 2796 patients with schizophrenia, of whom 917 (33%) were given clozapine, at a mean dosage of 372 mg/day and an average duration of ill ness of 9.7 years before starting clozapine (68c). Patients who had started treatment after clozapine was funded by the govern ment (n = 1658; 59%) and had received a median of three antipsychotic drugs before starting clozapine; most of the treatment regimens included one second-generation antipsychotic drug (91%). Clozapine-treated patients were less likely to have another anti psychotic drug co-prescribed compared with non-clozapine-treated patients (11.7% versus 17.6%). Both the clozapine and non
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clozapine treated groups had fewer psycho tropic medications prescribed (median 2); for clozapine-treated patients, the second drug was most probably for the treatment of hypersalivation. The case notes of 17 consecutive patients with schizophrenia given compulsory treat ment with clozapine have been retrospec tively rated (69C). At the last observation, 10 of the 11 patients still taking clozapine were classified as being much to very much improved; the degree of custodial restriction at the last observation was improved in 11 patients and there was no change in six. There were no serious adverse events; sialorrhea was reported in two patients, and somnolence and speech disorder in one. Two patients taking 150 and 225 mg/day devel oped local swellings and one had backflow of clozapine solution at the injection site. Transient leukopenia in one patient led to withdrawal of clozapine. Comparative studies The effectiveness and safety of clozapine versus high-dose olanzapine (up to 30 mg/day) have been evaluated in treatment-refractory adoles cents with schizophrenia aged 10–18 years (70C). They were randomized to 12 weeks of double-blind, flexibly dosed treatment with clozapine (n = 18) or olanzapine (n = 21). Significantly more clozapine-treated adolescents (66%) than olanzapine-treated subjects (33%) met the response criteria. Clozapine was superior to olanzapine in terms of reduced psychosis and negative symptoms from baseline to end-point. Both treatments were associated with sig nificant weight gain and related metabolic abnormalities; five of 39 participants (three clozapine, two olanzapine) gained > 7% of their baseline body weight by the end of the study. One olanzapine-treated patient developed neutropenia, as did four cloza pine-treated patients. Systematic reviews A meta-analysis of randomized, placebo-controlled trials of clozapine augmentation with another anti psychotic drug in patients with schizophrenia
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who partially responded to clozapine has been performed (71M). The four identified studies (n = 166) had clinically important heterogeneity. The two studies lasting 10 weeks or more gave an odds ratio of response to treatment of 4.4 (95% CI = 1.4, 14). The same pattern of response was seen in eight open studies. The main treatment-related adverse effects were extrapyramidal adverse effects and raised serum prolactin. Cardiovascular Cardiomyopathy has been associated with clozapine; an incidence of 0.2% in the first month has been estimated (SED-15, 824). • A 33-year-old woman without cardiac history or other susceptibility factors developed heart failure after taking clozapine and olanzapine for 6 weeks (72A). After withdrawal of the two drugs, her heart function improved significantly. • Atypical clozapine-induced cardiomyopathy occurred in a 28-year-old man who presented with a panic attack (73A). • A 34-year-old man developed hypokinetic cardiomyopathy while taking clozapine and was successfully treated with carvedilol and captopril (74A).
The authors of the last case suggested that beta-blockers and angiotensin-converting enzyme (ACE) inhibitors may allow resump tion of clozapine in refractory schizophrenia in which it has been withdrawn because of cardiotoxicity. Myocarditis has been estimated to occur in 0.01–0.19% of patients taking clozapine (SEDA-31, 79). • A 32-year-old man developed myocarditis, documented by late gadolinium enhancement cardiovascular MRI, after taking clozapine for 1 week (75A). The condition gradually resolved 5 weeks after withdrawal of clozapine.
Pericardial effusion accompanied by pleural effusion has been associated with clozapine (SEDA-29, 67). • A 33-year-old man developed pericarditis and a pericardial effusion after taking clozapine 200 mg bd for 10 weeks (76A). The symptoms disappeared within 1 week after withdrawal of clozapine.
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• A 47-year-old man developed an effuso constrictive pericarditis associated with clozapine; his symptoms improved after drug withdrawal (77A). • A 60-year-old woman developed polyserositis with a pericardial effusion and bilateral pleural effusions after taking clozapine for 13 months (78A). • A 43-year-old woman developed clozapine associated polyserositis (pleuritis and serositis) and hepatitis, although an electrocardiogram and a transthoracic echocardiogram were normal (79A).
Nervous system It is believed that cloza pine causes less tardive dyskinesia than haloperidol and may even improve the pre-existing dyskinesia; however, isolated cases have been associated with clozapine (SEDA-31, 79). Dystonia in a 34-year-old man associated with clozapine satisfied the criteria for antipsychotic drug-induced tardive dyskinesia (80A), and there has been another report of blepharospasm, a type of focal tardive dystonia that is usually considered to be a variant of tardive dys kinesia, in a 46-year-old woman (81A). On the other hand, an antidyskinetic effect of zotepine on clozapine-associated tardive dyskinesia has been reported (82c). The low prevalence of akathisia in patients taking clozapine has led to a pro posal that clozapine should be used in patients with antipsychotic drug-induced chronic akathisia (SED-15, 826). However, a case of acute nocturnal akathisia has been reported in a 43-year-old man taking cloza pine who was successfully treated with betablockers (83A). Restless legs syndrome is a neurological disorder characterized by irresistible move ments and dysesthetic sensations in the legs. A case associated with clozapine has been described, supposedly for the first time (84A). • A 26-year-old man developed severe extrapyramidal symptoms characterized by tremor, bradykinesia and sialorrhea while taking haloperidol 20 mg/day and valproate 1400 mg/day. Haloperidol was replaced by clozapine 50 mg/day and valproate was continued. After 3 days he started to have unpleasant sensations in his calves and burning sensations over his feet.
Several cases of stuttering have been associated with clozapine and it can occur before a generalized epileptic seizure (SEDA-27, 56). A further report has now been published, describing two patients who developed stuttering while taking clozapine (85A). Two additional cases of stuttering have emerged; the first, in a 40-year-old man started to stutter when his clozapine dosage was increased from 400 mg/day; it was also associated with a marked increase in seizure activity (86A). The other case was in a 44-year-old man whose clozapine-induced speech dys fluency disappeared when clozapine was withdrawn (87A). Electroencephalographic abnormalities and stuttering may be harbingers of seizures and clozapine is thought to increase the risk of this (SEDA-27, 56). Two cases have been reported in a 74-year-old man and a 56 year-old man, both with non-epileptic clo zapine-induced drop attacks, bouts of sud den collapse without loss of consciousness, and symptoms of posterior circulation dis ruption (88A). Cataplexy, an abnormal state character ized by atonia and believed to represent dis sociated rapid eye movement (REM) sleep phenomena that intrude into wakefulness, has been reported in a 29-year-old woman taking clozapine (89A). Psychiatric Eating disorders can be induced or aggravated by clozapine. Food craving and binge eating have been studied in patients who were randomized to cloza pine (n = 15) or olanzapine (n = 15) (90c). There were no differences in improvement in clinical symptoms and severity of illness. Adverse effects occurred significantly less often with olanzapine than with clozapine. The likelihood of food craving at any time during drug treatment tended to be higher with olanzapine (49%) than with clozapine (23%), and the likelihood of binge eating at any time during drug treatment was higher, but not significantly so, with olanzapine (17%) than with clozapine (9%). In another open observational study, patients taking clozapine (n = 33) or
Antipsychotic drugs
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olanzapine (n = 31) were screened to iden tify subjects with prior eating disorders (91c). The authors concluded that both drugs might induce recurrence or deteriora tion of binge eating or full-blown eating disorders in those who had the conditions before the start of treatment. Metabolism Weight gain is a common and well-known adverse effect of clozapine (SEDA-29, 67; SEDA-30, 62; SEDA-31, 79). The possible variables associated with weight gain have been analysed in 50 treatment-refractory patients with schizo phrenia who were randomized to clozapine 100, 300 or 600 mg/day in a 16-week, doubleblind study (92C). Weight gain varied across three baseline body mass index (BMI) cate gories: normal weight (þ4.1 kg), overweight (þ2.6 kg), and obese (þ0.4 kg), and accord ing to dosing: 600 mg (þ4.4 kg), 300 mg (þ2.6 kg) and 100 mg (þ1.3 kg). Sex had no effect after controlling for baseline BMI and dose, but African American ethnicity had a strong significant effect, despite the small number included in the sample (n = 6). Plasma norclozapine concentration was not significantly correlated with weight gain. Hematologic Agranulocytosis, leucopenia and neutropenia associated with clozapine have been extensively studied and discussed (SED-15, 829; SEDA-31, 80). Severe neutro penia can occur unexpectedly and suddenly during a quiet laboratory monitoring period, as illustrated by the case of a 36-year-old man who developed sudden, unpredictable, lateonset, clozapine-related, life-threatening agranulocytosis, with a nadir of 14 106/l polymorphonuclear cells (93A). Rates of leukopenia and agranulocytosis as reasons for withdrawal of clozapine have been examined retrospectively in 1875 patients who took clozapine between 1989 and 1999 (94c). No African American patient developed agranulocytosis, whereas eight Caucasian patients (0.62%) did; how ever, 5.3% of the African American cohort versus 2.4% of the Caucasian cohort had to
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stop taking clozapine treatment because of leukopenia. The authors suggested that it is likely that the African American patients had clozapine withdrawn unnecessarily because of benign ethnic neutropenia, within a lower reference range for white blood cell count. Patients with neutropenia secondary to clozapine are supposed to be at high risk of recurrent neutropenia and, which is more important, agranulocytosis if re-exposed. Nevertheless, cases of negative or positive rechallenge in patients with neutropenia with prior agranulocytosis have appeared (SED-15, 830; SEDA-30, 63; SEDA-31, 80). • A 40-year-old woman with clozapine-induced neutropenia prolonged by subsequent use of olanzapine was successfully rechallenged with both olanzapine and then clozapine (95A).
Patients with leukopenia associated with clozapine have been successfully treated with lithium carbonate (SEDA-29, 68), and another case has been reported in a 55-year old man (96A). Salivary glands Sialorrhea has commonly been associated with clozapine, and var ious drugs, such as antimuscarinic agents, adrenoceptor antagonists, and adrenocep tor agonists, have been used to treat it, although no drug has been found to be superior (SED-15, 831; SEDA-29, 68; SEDA-30, 63; SEDA-31, 80). The effec tiveness of glycopyrrolate 4 mg day, an anticholinergic drug that is structurally related to atropine, has been reported, sup posedly for the first time, in a 40-year-old man with clozapine-induced sialorrhea (97A). Glycopyrrolate 4–8 mg has also been successfully used in three adolescent girls (aged 13–16 years) who developed sialorrhea secondary to clozapine (98A). Glycopyrrolate was generally well toler ated; however, one patient reported con stipation and another reported dry mouth. Gastrointestinal A case of clozapine induced microscopic colitis, a condition that can occasionally be life-threatening,
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has been reported, supposedly for the first time (99A). • A 37-year-old man taking clozapine up to 500 mg/day, with no other medications, devel oped intermittent severe watery diarrhea after 3 months. Microscopic colitis was diagnosed by colonic biopsy. Clozapine was withdrawn and he gradually improved; multiple colonic biopsies taken 7 days later were normal.
Sexual function The frequency and course of sexual disturbances associated with cloza pine have previously been studied (SED-15, 832). Priapism has occasionally been described (SEDA-19, 54). Recurrent priap ism requiring surgical intervention has also been reported in a 33-year-old man taking clozapine 300 mg/day and lithium carbonate 1800 mg, and also while he was taking quetia pine or haloperidol (100A). The authors speculated that some individuals are more susceptible for unknown reasons. Teratogenicity and fetotoxicity Neuro developmental disorders, particularly delayed speech, have been described in a baby, whose mother, a 30-year-old woman with schizophrenia, took clozapine treat ment throughout her 9 months of pregnancy and during lactation (101A). Susceptibility factors Sex Only sex signifi cantly affected clozapine concentrations in a retrospective study in Chinese patients with schizophrenia, in which dosages and plasma clozapine concentrations in 116 men and 77 women, younger (<40 years, n = 82) and older patients (> 40 years, n = 111) and cur rent male smokers (n = 50) and non-smokers (n = 66) were analysed (102c). Women had significantly higher concentrations than men. Drug overdose Fatal and non-fatal cases of clozapine overdose have been reported (SED-15, 833; SEDA-30, 63). The notes of 47 patients who attempted suicide by ingest ing large amounts of clozapine have been analysed retrospectively (103c). Of the 20 unconscious patients with plasma clozapine
concentrations of more than 2000 ng/ml, 14 were given a combination of hemoperfusion and symptomatic treatment, whereas the other six and the remaining 27 patients received only symptomatic treatment. One patient died of pulmonary edema and subse quent heart failure, but the others recovered without any sequelae. Patients who received hemoperfusion regained consciousness signif icantly faster than their counterparts with the same clozapine plasma concentration who did not receive hemoperfusion. Fatal poisoning has been reported in a neo nate in the final stage of gestational life. His mother, when 9 months pregnant, took a toxic dose of clozapine intending to commit suicide (104A). Analysis of post-mortem blood speci mens collected from the neonate showed clo zapine and its two metabolites, norclozapine and clozapine-N-oxide. The woman was also severely poisoned, but her life was saved. Drug–drug interactions Aluminium hydroxide An interaction of clozapine with aluminium hydroxide has been reported, supposedly for the first time (105A). • A 26-year-old man almost doubled his plasma clozapine concentration after he stopped tak ing aluminium hydroxide. The clozapine serum concentration had been previously stable at 382 ng/ml. A few weeks later, he became sleepier and was drooling a lot more than before; the plasma clozapine concentra tion was 739 ng/ml.
Chemotherapy Seven references report ing no synergistic effect of clozapine and chemotherapy on blood counts have been reviewed (106r). A 39-year-old man was successfully restarted on clozapine while receiving ablation chemotherapy and an autologous stem cell transplant for Hodg kin’s lymphoma (107A). Ciprofloxacin Another case of an inter action of clozapine with ciprofloxacin has been reported (108A). CYP inhibitors A series of five case of drug–drug interactions involving clozapine, each of which illustrates a different
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mechanism by which the metabolism of cloza pine can be altered, has been reported (109A). Four were with fluoxetine, ciprofloxacin, ethinylestradiol and cimetidine, and one was with smoking. Fluoxetine can reasonably be considered a CYP pan-inhibitor, much like cimetidine; thus, the addition of fluoxetine led to moderate inhibition of CYP1A2, CYP2C9/19, CYP2D6 and CYP3A4, causing increased clozapine and norclozapine concen trations. Similarly, ethinylestradiol inhibits both CYP1A2 and CYP2C19. Levomepromazine Two cases of suspected interaction between levomepromazine and clozapine, with lack of therapeutic efficacy of clozapine, have been reported (110A). Rifampicin Rifampicin and clozapine may interact, as illustrated by the case of a 30-year-old man with pulmonary tuberculosis, whose psychiatric symptoms worsened after introduction and improved after withdrawal of rifampicin (111A). Rifampicin induces sev eral CYP isoforms, which would have caused a reduction in clozapine serum concentration. Drug–smoking interactions It is generally believed that plasma concentrations of clo zapine are lower in smokers than in non smokers (SEDA-31, 81). • A 27-year-old man with schizophrenia failed trials of haloperidol, tiotixene, olanzapine, ari piprazole and quetiapine, and was given cloza pine, which was titrated to 500 mg/day, giving a clozapine concentration of 417 ng/ml (109A). Over the next several weeks, he improved and was discharged from hospital. He then started smoking again (2 packs/day), and 3 weeks later his paranoia and hallucinations returned. The clozapine concentration was only 192 ng/ml, even though he was said to be consistently compliant with his medication. The dosage of clozapine was increased to 900 mg/day and his clozapine concentration rose to 392 ng/ml.
The authors attributed this effect to induction of CYP1A2, and noted that chew ing-tobacco, nicotine patches and nicotine inhalers do not do this. Monitoring therapy Prediction of response to clozapine by measurement of peripheral
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biochemical markers, such as plasma serotonin, platelet serotonin and platelet monoamine oxidase (MAO) activity, has been examined in 20 patients taking clozapine and 20 healthy controls matched for age, sex and smoking (112c). After 8 weeks, plasma serotonin and platelet MAO increased significantly in those taking clozapine; platelet serotonin concentrations fell significantly. Baseline platelet MAO explained 22% of the variance in the Clinical Global Impression Improvement Scale and in improvement in attention, whereas baseline platelet serotonin predicted 23% of the variance in the improvement in positive symptoms. The authors concluded that clozapine might reverse or compensate for a pre-existing alteration in serotonin neurotransmission in schizophrenic patients.
Olanzapine (SED-15, 2598; SEDA-29, 70; SEDA-30, 64; SEDA-31, 81) Observational studies In a 12-month uncontrolled study in different Asian coun tries, olanzapine (mean dose at baseline 8.4 mg/day, at end-point 9.3 mg/day) was given to refractory outpatients with schizo phrenia (n = 1267, mean age 33 years, 53% men) (113C). A total of 954 patients (75%) completed the study and 87% of them responded to treatment as assessed by at least a 30% reduction in the Brief Psychiatric Rating Scale. Concomitant medications from baseline to end-point changed from 10 to 4.5% for other antipsychotic drugs and from 49 to 27% for other drugs. Only seven patients dropped out because of adverse events. Across the study period, mean scores in the Abnormal Involuntary Movement Scale fell markedly and mean weight increased signifi cantly from 62 to 65 kg; 39% of subjects (ran ging from 32% in Korea to 43% in China) gained 7% of body weight or more. Comparative studies Olanzapine and haloperidol In a study in which patients were randomized to either intramuscular olanzapine or haloperidol þ promethazine
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(n = 150 in each group), both drugs were effective for rapid sedation or sleep induc tion at 15 and 240 minutes in patients with agitated or violent behavior (7C). Adverse events included akathisia (one patient tak ing olanzapine) and dehydration (one patient taking haloperidol); after 2 weeks, one patient taking olanzapine who had been switched to clozapine developed intestinal obstruction. Olanzapine and lithium Chinese patients with bipolar acute mania were randomized to olanzapine (n = 69, mean dose 18, range 5–20 mg/day) or lithium carbonate (n = 71, mean dose 1110, range 600– 1800 mg/day) in a 4-week, multi-center, double-blind, randomized study (114C). The study was completed by 91% of patients taking olanzapine and 79% of those taking lithium; there was a signifi cantly greater mean change in patients taking olanzapine as measured by differ ent scales. Adverse events occurred in 55 and 42% of the patients respectively. The most common events with olanzapine were constipation (13%), nausea (7.2%) and somnolence (7.2%); with lithium, there were nausea (13%) and nasophar yngitis (5.6%), and one patient dropped out because of abnormal hepatic function. Mean weight gain was 1.85 kg with olan zapine and 0.73 kg with lithium; 16% of those taking olanzapine and 2.9% of those taking lithium had significant weight gain ( 7% of baseline). A high blood glucose concentration was reported in one patient taking olanzapine and high total cholesterol concentrations in four patients (three taking olanzapine). Olanzapine and quetiapine In a prospec tive 12-month study, adults with schizophre nia previously treated with first-generation antipsychotic drugs were randomized to olanzapine (n = 42; mean dose 17 mg/day) or quetiapine (n = 43; mean dose 613 mg/ day) (115c). Clinical improvements were similar in the two groups. Cognitive assess ment with the computer-assisted test bat tery COGLAB showed a significantly better performance in attention tasks only
in patients taking quetiapine. Neurological adverse effects abated in both groups from baseline to end-point according to scores in the scales UKU-SR, SAS and AIMS; mean weight increases were 7.2 kg in patients tak ing olanzapine and 2.8 kg in those taking quetiapine; olanzapine caused dysglycemia, defined as a fasting plasma glucose of at least 5.6 mmol/l (one case at baseline and 13 at end-point) but quetiapine did not (three and four cases respectively). Olanzapine, quetiapine and risperidone Subjects with schizophrenia who had been randomly assigned to and then discontinued perphenazine in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study (SEDA-30, 59) were randomly reas signed to double-blind treatment with olan zapine 7.5–30 mg/day (n = 38); quetiapine 200–800 mg/day (n = 38) or risperidone 1.5–6.0 mg/day (n = 38) (116C). Time to discontinuation was longer in those taking olanzapine (7.1 months) and quetiapine (9.9 months) than in those taking risperidone (3.6 months); discontinuation rates were 58% for quetiapine, 61% for olanzapine and 84% for risperidone. There were no significant differences in reasons for drop out, including lack of efficacy, intolerability or patient decision. There were no notable differences in total scores on the Positive and Negative Syndrome Scale (PANSS) among the treatment groups at any time, nor in CGI global severity at 6 or 12 months. Adverse events, detected by systematic inquiry, ranged from 42% of those taking risperidone (n = 16) to 69% of those taking olanzapine (n = 27); the most frequent were anticholinergic effects (n = 13) and hypersomnia (n = 10) with olanzapine; hypersomnia (n = 16), insomnia, sexual dysfunction and orthostatic faintness (n = 18 for each event) with quetiapine, and anticholinergic effects (n = 24), hypersomnia (n = 6), and insomnia (n = 6) with risperidone; rashes were reported by three, one and four patients respectively. Mean body weight gains across the study were higher for olanzapine (4.1 kg, range –3 to 33) than for risperidone (3.6 kg, range –16 to 22)
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and quetiapine (0.9 kg, range –32 to 33); rates of weight change were þ0.7 kg/month for olanzapine, þ0.2 kg/month for risperidone and –0.2 kg/month for quetiapine. Choles terol and triglyceride concentrations increased significantly in patients taking olanzapine and moderately in those on risperidone and quetiapine. Olanzapine, quetiapine and risperidone have also been compared in a doubleblind, multi-center study in patients with schizophrenia and other psychoses (mean age 25 years, 63% men), who were randomi zed to olanzapine (n = 133), quetiapine (n = 134) or risperidone (n = 133) (mean modal doses 12, 506 and 2.4 mg/day respec tively) (117C). At week 52, discontinuation rates were 68% for olanzapine, 71% for quetiapine and 71% for risperidone; med ian times to discontinuation (25–27 weeks) did not differ significantly. The three groups had reduced scores in total PANSS. Adverse effects accounted for 40 dropouts (olanzapine, n = 14; quetiapine and risperidone, n = 13 each); patient deci sion was also a reason for withdrawal (n = 57, 52 and 57 respectively). There were 18 serious adverse events during the 52-week follow-up, four with olanzapine and seven each with quetiapine and risper idone; these events included two suicide attempts and one alleged homicide in those taking olanzapine, two completed suicides and one case of suicidal ideation in those taking quetiapine, and one suicide attempt in those taking risperidone. As expected, olanzapine was associated with a higher proportion of patients with a weight gain of at least 7%; at week 52 this increase was apparent in 80% of patients taking olanzapine compared with 50% of those taking quetiapine and 58% of those taking risperidone. In women, ris peridone was significantly associated with greater increases in weight and BMI than quetiapine. Quetiapine and olanzapine were associated with greater rises in fasting concentrations of triglycerides and cholesterol than risperidone. Prolactin concentrations rose with risperidone. Extrapyramidal symptoms were infrequent and did not differ significantly across the
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groups; nevertheless, these data should be interpreted cautiously, because of the final reduced group sample sizes at week 52: 37 for olanzapine and risperidone each and 44 for quetiapine. In an 8-week study, 75 patients with schizophrenia were randomized to olanza pine, quetiapine or risperidone (25 in each group; mean doses at end-point 15, 590 and 5.1 mg/day, respectively) (118c). There were no significant differences in efficacy among the three drugs, as measured by the PANSS scale. Risperidone was associated with significantly worse scores on the Simp son–Angus Scale for extrapyramidal symp toms at week 3. Weight gains of at least 7% from baseline were more frequent in patients taking olanzapine (29%) than in those taking quetiapine or risperidone (8% each). Olanzapine, quetiapine, risperidone and haloperidol In 101 patients with psy choses allocated to olanzapine, risperi done, quetiapine or haloperidol for acute agitation, aggressive behaviour, as mea sured by the Modified Overt Aggression Scale and the Hostility-suspiciousness factor derived from the Brief Psychiatric Rating Scale, improved significantly in all groups, with no significant between-group differences (119c). Extrapyramidal symp toms were more common in those who took haloperidol; somnolence was the most common adverse event in the other three groups.
Olanzapine and risperidone done below.
See Risperi
Drug combination studies Patients with schizophrenia stabilized on olanzapine were randomized to dehydroepiandroster one or placebo (n = 20 in each group) for 12 weeks in a double-blind study (120c). Negative symptoms improved in those who took dehydroepiandrosterone, even when baseline scores were controlled as a co-variate, and there was some improvement
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in parkinsonism and akathisia compared with baseline. Body weight did not change signifi cantly in either group. Placebo-controlled studies In a 3-week, multi center, double-blind study, adoles cents of both sexes with bipolar mania were randomized to olanzapine (n = 107, mean modal dose 11 mg/day) or placebo (n = 54) (121C). The mean change from baseline to end-point in the Young Mania Rating Scale total score was significantly greater in patients who took olanzapine. Olanzapine caused significant weight gain and increases in the serum concentrations of prolactin, fasting glucose, fasting total cholesterol and uric acid. Olanzapine was not effective in video poker pathological gamblers (n = 9) com pared with placebo (n = 12) (122c). Two subjects stopped taking olanzapine because of sedation. Cardiovascular Pulmonary thrombo embolism has been associated with olanza pine and risperidone (123A); 5HT2 receptor antagonism may be the mechanism. • A 25-year-old man with schizoaffective disor der, otherwise healthy, and not overweight, but a smoker (1 pack/day) and without a personal or familial history of venous thromboembolism, was given olanzapine 20 mg/day, paroxetine 20 mg/day and valproate 2000 mg/day; 12 weeks later he developed sud den back pain radiating to the thorax with dyspnea and hemoptysis. A CT scan showed bilateral pulmonary embolism, and he was given anticoagulants. Olanzapine was withdrawn, but he was then given risperidone. A second episode of thromboembolism was attributed to non-adherence to anticoagulant treatment, but after a third event risperidone was changed to amisulpride, which does not affect 5HT2 receptors.
Nervous system Although it is unusual, somnambulism has been associated with olanzapine (124A). • A 52-year-old man with bipolar disorder, who had taken valproic acid and lithium for years, had his doses increased to 1000 mg/day and
900 mg/day respectively, because of a manic episode; olanzapine was also titrated up to 20 mg/day. Six days later he developed episodes of somnambulism with subsequent amnesia; dosage reduction of olanzapine to 15 mg/day caused a reduction in the number of episodes.
The authors suggested that this had hap pened because of an interaction of olanza pine with both valproate and lithium.
Endocrine Hyperprolactinemia and amen orrhea associated with olanzapine have been reported (SEDA-29, 73) and a new case has appeared (125A). • A 35-year-old woman with psychotic depres sion was given olanzapine up to 30 mg/day and citalopram 40 mg/day. After 4 weeks she developed amenorrhea and her serum prolactin was 253 ng/ml (reference range, 2.8–29 ng/ml). The plasma olanzapine concen tration was 78 ng/ml (usual target range, 20–80 ng/ml). After the addition of aripipra zole 15 mg, her menstrual pattern and prolac tin concentrations normalized; 5 weeks later the improvement persisted.
Metabolism Insulin sensitivity fell signifi cantly from 5.7 to 4.7 ml/hour/kg in 14 healthy subjects taking olanzapine 10 mg/ day for 10 days, but not in a comparison group taking ziprasidone 80 mg/day (n = 15) (126c). Furthermore, hyperglycemia asso ciated with olanzapine 5 mg/day has been reported after 3 weeks in a 27-year-old patient with anorexia nervosa (127A). Finally, a case of hyperglycemia and diabetic ketoacidosis has been described in a 35-year old-woman with a urinary tract infection who had taken olanzapine 10 mg/day for 2 weeks (128A). Weight gain in relation to antipsychotic drugs, particularly olanzapine, has been addressed previously (SEDA-26, 56; SEDA-29, 74; SEDA-30, 66; SEDA-31, 81). However, weight loss has been observed in an open 12-month study, in which 26 patients with schizophrenia taking olanzapine standard oral tablets were switched to an orally disintegrating formu lation (129c). Mean weight loss was –2.5 kg
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at 3 months, –2.9 kg at 6 months, and –3.4 kg at 12 months; body mass index fell by 1.0 kg/m2 overall. In another study, there was a significantly smaller increase in weight after 6 weeks in patients taking orally disintegrating olanza pine (mean weight increase 3.3 kg) com pared with those taking standard tablets (mean weight increase 6.3 kg) (130c). In a prospective comparison of weight gain in children and adolescents taking clo zapine (n = 15), olanzapine (n = 15) or ris peridone (n = 15), average weight gain was significantly higher with olanzapine (þ4.6 kg) than with risperidone (þ2.8 kg) or clozapine (þ2.5 kg) at 6 weeks (131c). Olanzapine and risperidone, but not cloza pine, caused disproportionately greater weight gain in children and adolescents than in adults. Fluid balance Edema is unusual in patients taking olanzapine; a case with posi tive rechallenge has been described (132A). • A 34-year-old woman with bipolar disorder took olanzapine 10 mg/day for 4 months and developed bilateral pedal edema, which disap peared with slow withdrawal of olanzapine but recurred with reintroduction at 5 mg/day.
Urinary tract Acute urinary retention occurred in two elderly patients with previous benign prostatic hyperplasia when they took olanzapine (133A). Skin Skin reactions are not common in patients taking olanzapine; however, a gen eralized lichenoid eruption affecting the thighs, arms, hands, nails, feet and tongue affected a 73-year-old woman taking olan zapine 15 mg/day and escitalopram 20 mg/ day; the eruption disappeared after 3 weeks when olanzapine was replaced by risperi done (134A). Nails A 47-year-old woman developed photo-onycholysis 1 month after switching from chlorpromazine to olanzapine (135A).
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A change to aripiprazole further worsened the illness, which resolved after 4 months with avoidance of fingernail sun exposure. Musculoskeletal Treatment with olanza pine 15 mg/day and topiramate 40 mg/day for 8 weeks is suspected to have caused hyperthermia of 42.2°C and rhabdomyolysis in a 14-year-old girl who had exercised at high temperatures and became unrespon sive, with increases in creatine kinase (peak 11007 U/l), urine myoglobin (up to 5930 pg/l) and serum iron (1.53 ng/l); after withdrawal of both drugs, olanzapine was restarted for symptom recurrence, and was well tolerated for 2 weeks after discharge (136c). Fetotoxicity Cardiac and musculoskeletal abnormalities occurred in a neonate whose mother had been exposed to olanzapine (137A). • A 25-year-old primigravida took olanzapine 10 mg/day for schizophrenia and gave birth to a baby with an atrioventricular canal defect and unilateral clubfoot; the baby’s karyotype was 46XY and there were no other identifiable sources of teratogenicity. The baby recovered fully with a plaster cast and open heart surgery at 6 months.
Susceptibility factors Genetic Some genetic polymorphisms have been suggested as susceptibility factors for olanzapine associated weight gain, including genes for apolipoprotein E and apolipoprotein A4 (138c), an S promoter (SERTPR), a serotonin transporter variant (139c), an AG –2548 polymorphism in the leptin gene in Korean patients (140c), a G allele of the –1548 polymorphism in the leptin gene (141c) and the G allele of the prome lanin hormone gene (142c). Drug formulations Intramuscular olanza pine (mean dose 10 mg) was effective in severely agitated patients with bipolar mania (n = 22) or schizophrenia (n = 52) in
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a 1-week observational study (143c). Most of the patients (93%) received only one dose; antipsychotic drugs were the most fre quent concomitant medications (94%). Insomnia (9.5%), arthralgia (7.9%) and headache (6.3%) were the most commonly reported adverse events; there were no sig nificant changes in sitting pulse rate or blood pressure 1 day after the first injection. Drug overdose Olanzapine overdose in 37 patients was associated with tachycardia (73%), central nervous system depression (43%), miosis (39%) and delirium (54%) (144c). Delirium increased the length of hospital stay and the rate of admission to an intensive care unit. Drug–drug interactions Concomitant use of carbamazepine or lamotrigine signifi cantly altered plasma olanzapine concentra tions in 163 adults (145c). Drug–smoking interactions In a study in 163 adults, plasma olanzapine concentrations were 41% lower in smokers who were not taking lamotrigine compared with non smokers not taking lamotrigine (145c).
Perphenazine (SED-15, 2783; SEDA-29, 75) Drug–drug interactions Midodrine A 53 year-old woman who had been receiving perphenazine 4 mg/day for 4 years for major depression was given midodrine 7.5 mg/day for orthostatic hypotension (146A). After 3 days later she developed acute bilateral, unpredictable, repetitive involuntary movements of the perioral muscles and continuous tonic neck muscle contraction with head deviation to the right. Midodrine was immediately withdrawn and the dys tonic movements disappeared after 1 day. Midodrine is metabolized by CYP2D6 and inhibits it; it may therefore increase the concentrations of substances metabolized by CYP2D6, such as perphenazine.
Quetiapine (SED-15, 2995; SEDA-29, 75; SEDA-30, 67; SEDA-31, 87) A violation by AstraZeneca, consisting of oral and written promotion of quetiapine for major depressive disorder, an un approved use, has been denounced (147S). Observational studies The safety of que tiapine in general practice in England has been examined in a Prescription Event Mon itoring study in 1728 patients (median age 39 years, 53% women) (148C). Drowsiness/ sedation was the most frequently reported event during the first month of treatment (n = 47, 3% of the cohort) and the most common reason for stopping quetiapine (n = 51). There were low incidences of extra pyramidal symptoms (n = 21) and hyperpro lactinemia (n = 3). There was new-onset diabetes mellitus in three cases. There were six pregnancies and four live births, with no reported congenital abnormalities. From the 56 deaths reported during this study, the most frequently reported causes were cardi ovascular (n = 18) and respiratory (n = 15). There was a high discontinuation rate in an open study (68%, mean duration 18 weeks) in patients with rapid-cycling bipolar disorder who received quetiapine either as monother apy (n = 19) or as add-on therapy (n = 22) for up to 1 year (mean dose 196.6 mg/day, range 25–900 mg/day) (149c). Mean body weight fell from 91 kg at baseline to 86 kg at end point with quetiapine monotherapy but did not change in the whole sample. Placebo-controlled studies Up to four different re-analyses of the same four double-blind, placebo-controlled studies of quetiapine in mania (150c), agitation, and aggression in bipolar mania (151c), efficacy across a broad range of symptoms (152c) and target dose for efficacious treatment (153c) have been published; all were sup ported by AstraZeneca, the Marketing Authorization holder. Quetiapine was claimed to be well tolerated. In a 2-week, multi center, randomized, open study funded by AstraZeneca,
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patients with acute schizophrenia or schizoaffective disorder received quetiapine either rapidly (200 mg on day 1, 400 mg on day 2, 600 mg on day 3 and 800 mg on day 4; n = 139) or in a conventional regimen (50 mg on day 1, 100 mg on day 2, 200 mg on day 3, and 400 mg on day 4; n = 130) (154C). In both cases, treatment was followed by a flexible dosage of 400–800 mg/day (mean maximal dosages 786 mg/day and 508 mg/day respec tively). During week 1, the rates of patients who had at least one adverse event were 39% with the rapid regimen and 25% with the conventional regimen. The most com mon adverse events associated with quetia pine (somnolence, dizziness and orthostatic hypotension) occurred in 10 and 5.4% of patients in the rapid conventional regimens, respectively. The most common adverse events overall were hypotension (14% with the rapid regimen versus 7.7% with standard therapy), tachycardia (9.4% versus 10%), somnolence (6.5% versus 3.8%) and seda tion (5.8% versus 5.3%). There were no sig nificant differences in withdrawal rates due to adverse events (rapid regimen, n = 3, 2.1%; conventional regimen, n = 4, 3.1%). The only serious adverse event was agitation in the rapid initiation group. Comparative studies Quetiapine and lithium Quetiapine was more efficacious than lithium in Chinese bipolar patients in a 4-week, multi center, double-blind study supported by AstraZeneca, in which patients with acute mania were randomized to either quetiapine (n = 77, mean dose 648 mg/day, maximum 800 mg/day) or lithium (n = 77, mean serum concentration 0.80 mmol/l, maximum 2000 mg/day) (155C). The authors reported a significantly higher response rate, defined as a 50% reduction from baseline to day 28 in the YMRS total score, with quetiapine (78% versus 60% with lithium) and a higher remission rate. The most frequent adverse events with que tiapine were constipation (35%), dizziness (15%), diarrhea (10%), rises in alanine ami notransferase (9.0%) and palpitation (9.0%); in those taking lithium, they were nausea (17%), constipation (13%), vomiting
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(13%) and nasopharyngitis (12%). Adverse events led to withdrawal in three patients taking lithium. Extrapyramidal symptoms were similarly in the two groups (5.1% and 6.5%). Weight gain was 1.5 kg in patients taking quetiapine and 0.3 kg in those taking lithium. Quetiapine and risperidone Quetiapine and risperidone have been compared in patients with schizophrenia in a 12-week double-blind study supported by AstraZeneca (156c). Quetiapine (n = 19, mean final dose 569 mg/day) produced signifi cantly fewer extrapyramidal effects accord ing to the Simpson–Angus Scale than risperidone (n = 15, mean final dose 5.1 mg/day). Conversely, in a randomized study in patients with dementia, Simpson–Angus Scale scores did not change significantly from baseline after 8 weeks, in patients taking quetiapine (n = 38) or risperidone (n = 34); mean end-point dosages were 77 mg/day and 0.9 mg/day respectively (157c). There were no significant changes in blood pressure or body weight. Three patients taking quetiapine and one taking risperidone had a serious adverse events (quetiapine: thigh fracture, n = 2, a fall with contusions, n = 1; risperidone: halluci nations, n = 1); the most common adverse events were sedation (11%) and fatigue (7.9%) in patients taking quetiapine, and diarrhea and muscle rigidity (15% each) in those taking risperidone. Quetiapine, risperidone, chlorpromazine and haloperidol Data from 4956 patients with schizophrenia or related disorders in randomized, double-blind, controlled studies in the AstraZeneca clinical trials database have been re-analysed (158c). These data allowed comparison of quetiapine (mean doses 357–496 mg/day) with placebo, risper idone (5.5 mg/day), haloperidol (10 mg/day) or chlorpromazine (552 mg/day). When que tiapine (n = 536, median dose 419 mg/day) was compared with risperidone (n = 541, median dose 5.9 mg/day), the most common adverse events were headache (12% versus 15%) and sedation (13% versus 9.6%); the
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incidences of serious adverse events were similar in both groups (4.9 and 3.7% respec tively), as were the rates of withdrawal due to adverse events (8.6 and 8.7% respec tively). As expected, extrapyramidal symp toms were significantly less common (quetiapine 12.5%; risperidone 24.8%; OR = 0.4, 95% CI = 0.3, 0.6). In the compar ison of quetiapine (n = 347, median dose 552 mg/day) and chlorpromazine (n = 348, median dose 553 mg/day), insomnia (15% versus 13%) and agitation (12% versus 10%) were the most common adverse events; extrapyramidal symptoms consisted mainly of akathisia and tremor. In the com parison of quetiapine (n = 1177, median dose 321 mg/day) and haloperidol (n = 752, med ian dose 9.9 mg/day), insomnia (15% versus 18%) and headache (14% versus 11%) were the most common adverse events; akathisia (22% versus 5.3%) and tremor (18% versus 3.8%) were significantly more common with haloperidol than with quetiapine. Drug combination studies Quetiapine (mean dosage 182 mg/day) has been added to SSRIs or venlafaxine in an 8-week, dou ble-blind, placebo-controlled study in 58 patients with major depressive disorder (159c). Eight out of eleven dropouts in the quetiapine group were because of adverse effects (sedation/somnolence/lethargy, n = 6; weight gain and fatigue, n = 1; increased appetite, irritability and somnolence, n = 1; total dropouts, n = 11); two patients withdrew from the placebo group (sedation/ somnolence/lethargy, n = 1; increased irrit ability, n = 1). Quetiapine has been added to antidepres sants in elderly patients (n = 9, mean age 73 years) with major depressive disorder and cerebrovascular damage (160c), although it is not approved for this indication. Placebo-controlled studies Quetiapine (n = 963, median dose 300 mg/day) and placebo (n = 292) for patients with schizo phrenia have been compared in trials that have been re-analysed (158c). Headache was the most common adverse event in both
groups (18% versus 20%), followed by sedation, which was significantly more com mon with quetiapine (15% versus 6.2%; OR = 2.7, 95% CI = 1.6, 4.5); somnolence and orthostatic hypotension were also sig nificantly more common with quetiapine. The frequency of extrapyramidal symptoms was similar in the two groups (9.6 and 11% respectively). There was no clinical improvement accord ing to the Neuropsychiatric Inventory and the Clinical Global Impression of Change in elderly patients with Alzheimer’s disease and behavioral and psychological symptoms when they were randomized to quetiapine (n = 20, median dose 200 mg/day) or placebo (n = 20) in a 6-week double-blind trial (161c). Extrapyramidal effects did not differ signifi cantly between the groups. Nervous system Quetiapine reportedly caused generalized tonic–clonic seizures in a 16-year-old girl with ornithine transcarbamy lase deficiency and mental retardation and in a 7-year-old boy with autism (162A). Quetiapine might modulate human motor cortex excitability (163c). There was significant prolongation of the cortical silent period in 15 healthy subjects, using transcranial magnetic stimulation, after a single 100-mg dose of quetiapine compared with placebo; however, the difference did not remain significant during treatment with quetiapine 100 mg/day for 5 days. Endocrine Galactorrhea has been des cribed in a patient taking quetiapine (164A). • A 31-year-old woman with a personality disorder taking divalproex sodium 1250 mg/ day, gabapentin 900 mg/day and venlafaxine 150 mg/day was given quetiapine 100 mg/day. Ten days later she complained of heaviness in her breasts and galactorrhea; the symptoms disappeared when quetiapine was stopped and at 2 months’ follow-up.
Metabolism A patient with refractory schizophrenia and a fasting glucose concen tration of 6.8 mmol/l (123 mg/dl) at baseline developed diabetes mellitus during a
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12-week open study while taking quetiapine 1400 mg/day (165c). Haematologic Quetiapine has been asso ciated with leukopenia and thrombocytope nia (166A). • A 45-year-old man taking sodium valproate 1500 mg/day, zuclopenthixol depot 150 mg every 2 weeks, and quetiapine up to 600 mg/ day developed a white cell count of 2.7 109/l and a platelet count of 146 109/l after 7 weeks of treatment. The counts normalized after drug withdrawal.
Hair Alopecia has been associated with que tiapine, supposedly for the first time (167A). • A 34-year-old woman took citalopram 20 mg/ day and quetiapine up to 100 mg/day for 6 weeks and developed hair loss, which resolved when quetiapine was withdrawn.
Drug abuse Possible abuse of quetiapine has been previously reported (SEDA-30, 68), and two further cases have been pub lished (168A, 169A). • A 39-year-old male prisoner with hepatitis C and a history of opiate abuse was treated for generalized anxiety with quetiapine 800 mg/ day and clonidine 0.9 mg at bedtime. The psychiatrist was concerned about the risks of prescribing an antipsychotic drug for a patient with hepatitis without a serious mental disorder. The patient refused to discuss other treatment alternatives, stating, ‘I need my Seroquel’. Efforts to enlist his cooperation for a quetiapine taper were unsuccessful. He abruptly left a treatment team meeting and informed staff that he would purchase quetiapine illegally from other inmates, as he had done before. • A 33-year-old man with a history of polysubstance dependence, including alcohol, heroin and cocaine, regularly diverted quetiapine from his wife’s prescription and took 400–800 mg/day by crushing the tablets, mixing them with cocaine and water and injecting the mixture intravenously.
Drug overdose In a 5-year retrospective study using the California Poison Control System database, 945 cases of quetiapine
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acute ingestion were identified (median age 35 years; range 18–84 years; 45% men) (170C). Intentional ingestion accounted for 87% of cases. The clinical manifestations included drowsiness (76%), coma (10%), seizures (2%), tachycardia (56%), hypo tension (18%) and respiratory depression (5%). There were three deaths; all had coma, tachycardia and respiratory depres sion requiring ventilatory support. Com pared with overdose with all other antipsychotic agents as a group, quetiapine was more likely to cause hypotension (OR = 2.0, 95% CI = 1.5, 2.8), coma (OR = 2.2, 95% CI = 1.5, 3.2), respiratory depression (OR = 2.5, 95% CI = 1.4, 4.4) and a need for tracheal intubation (OR = 1.9; 95% CI = 1.4, 2.6); deaths and major medical outcomes were also more common (OR = 2.6; 95% CI = 1.8, 3.8).
Risperidone (SED-15, 3052; SEDA-29, 76; SEDA-30, 69; SEDA-31, 90) In June 2008, the US Food and Drug Administration approved the first generic versions of risperidone tablets (171S). It issued an amendment to the existing warn ing, based on increased mortality in elderly patients with dementia-related psychosis, stating that elderly patients with dementiarelated psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, showed that the risk of death in drug-trea ted patients was 1.6–1.7 times the risk of death in placebo-treated patients (172S). Over the course of a typical 10-week con trolled trial, the death rate in drug-treated patients was about 4.5%, compared with about 2.6% with placebo. Although the causes of death were varied, most appeared to be either cardiovascular (e.g. heart fail ure, sudden death) or infective (e.g. pneu monia). Observational studies have suggested that, similar to atypical antipsy chotic drugs, treatment with conventional antipsychotic drugs may increase mortality.
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The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Risperidone is not approved for patients with dementia-related psychosis. For a review of antipsychotic drugs in elderly patients see SEDA-30, 59. Observational studies Of 54 children with epilepsy and behavioural disorders (age range 2–18 years; 70% boys) treated with risperidone for 3 months (mean dose, 0.038 mg/kg/day) five withdrew because of adverse events (increased seizure fre quency, n = 2; agitation, n = 2; somnolence, n = 1) (173c). Risperidone and haloperidol In a retro spective study using medical reports in Japanese patients with delirium who were treated with risperidone (n = 39), oral halo peridol and intravenous or intramuscular haloperidol (n = 61) deaths during delirium were significantly more common with intra venous or intramuscular haloperidol (13%) than with oral haloperidol (2.1%) or risper idone (3.2%) (174c). Risperidone and olanzapine In a multi center, open, 53-week, two-phase study, patients were randomized either to longacting injectable risperidone (n = 318, initially 25 or 50 mg every 2 weeks) or olanzapine (n = 300, 5–20 mg/day) (175C). Long-acting risperidone was at least as effec tive as oral olanzapine. Adverse events resulted in treatment withdrawal in 3% of patients who took long-acting risperidone and 4% of those who took olanzapine. Ser ious adverse events were reported by 23% of the patients who took long-acting risperi done group and 21% of those who took olanzapine; the most frequent adverse events included psychosis (29 and 25%, respectively), insomnia (22 and 24%), depression (20 and 14%), anxiety (14 and 16%), agitation (10 and 5%) and headache (8 and 5%). Eight patients died during the study, two taking risperidone and six taking olanzapine. Mild extrapyramidal symptoms
were reported by 25% of those who took long-acting risperidone and 15% of those who took olanzapine. New tardive dyskine sia occurred in two patients in each group. Other relevant adverse events were nonpuerperal lactation (five and two respec tively), impotence (two in each group), diabetes mellitus (one in each group) and hyperglycemia (four in each group). Mean body weight increased by 1.7 kg in those who took long-acting risperidone group and by 4.0 kg in those who took olanzapine; there was weight gain of 7% or more in 20% of those who took long-acting risperidone and 36% of those who took olanzapine; there were reductions of 7% in 6% of patients in both groups. Risperidone, olanzapine and haloperidol In an open randomized trial, 145 patients had a first episode of psychosis and were assigned to haloperidol (n = 40, 4.2 mg/day), olanzapine (n = 41, 13 mg/day), or risperi done (n = 47, 3.6 mg/day) (176C). A total of 128 patients (88%) completed the 12-week study. There was significant weight gain with all three drugs. Mean increases were haloperidol 3.8 kg, olanzapine 7.5 kg and risperidone 5.6 kg. All three drugs caused significant increases in total cholesterol and low-density lipoprotein (LDL) cholesterol concentrations but only olanzapine caused a significant increase in triglyceride concentra tion. There were no significant changes in parameters involving glucose metabolism. Placebo-controlled studies Augmentation therapy with risperidone has been investi gated in a multi center, double-blind, rando mized, placebo-controlled trial to determine whether it reduces symptoms and increases responses to antidepressant therapy and remission of depression in adults (177C). After a 4-week run-in period to ensure a response to standard antidepressants, 274 adults with major depressive disorder that was suboptimally responsive to antidepres sant therapy were randomly assigned to ris peridone 1 mg/day or placebo for 6 weeks; after 4 weeks, the dosage of risperidone was increased to 2 mg/day in some cases. Of the
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intention-to-treat population (268 patients), 81% (111 of 137) who took risperidone and 88% (115 of 131) who received placebo com pleted 6 weeks of double-blind treatment. Mean Hamilton Rating Scale for Depression scores improved significantly more with ris peridone augmentation than with placebo (13 versus 16). Significantly more risperidone recipients had remission of depression (25% versus 11%) and had a response (46% versus 30%). Headache (8.8% of risperidone recipi ents versus 15% of placebo recipients), som nolence (5.1% versus 1.5%) and dry mouth (5.1% versus 0.8%) were the most frequent adverse events. In an 8-week double-blind study, 55 autis tic children were randomized to either risper idone (mean dosage 1.37 mg/day; n = 27) or placebo (n = 28) (178c). Patients who took risperidone had significantly improved scores in the Aberrant Behavior Checklist Irritabil ity subscale (–13.4 versus –7.2). There was somnolence in 74% versus 7%; it was usually mild and resolved spontaneously. Adverse events were reported in all those who took risperidone and in 71% of those who took placebo; other events were upper respiratory infections (41% versus 18%), rhinitis (26% versus 7%) and fever (26% versus 18%). Weight increase was reported in two patients taking risperidone and none taking placebo; movement disorders, including extrapyrami dal symptoms, dyskinesia, hypokinesia and involuntary muscle contractions (n = 1 each), and hyperkinesia and tremor (n = 2 each) were also reported in patients taking risperidone; there were no changes in chem istry values or electrocardiography. Systematic review A meta-analysis of four randomized placebo-controlled trials in aged patients with dementia has been per formed (mean age 83 years; mostly women) (179M). The patients taking risperidone (n = 515) had significantly improved scores in the different scales compared with pla cebo (n = 380). Somnolence and extrapyra midal symptoms were significantly more common with risperidone than with placebo (18% versus 8% and 12% versus 5.8%, respectively). Death occurred in 16 patients
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(3.1%) taking risperidone and seven taking placebo (1.8%). Cerebrovascular disorder occurred in 1.6% versus 0.8%, respectively. In a Cochrane review of the use of risper idone and olanzapine in the treatment of schizophrenia, there were no significant dif ferences in efficacy (180M). Adverse events occurred in 75% of those who were given either drug, including anticholinergic symp toms in 20%. Both groups experienced insomnia, although this was more frequent with risperidone (n = 1588; five RCTs; RR = 1.4, 95% CI = 1.1, 1.7); about 30% experienced sleepiness (n = 1713; six RCTs; RR = 0.9, 95% CI = 0.8, 1.1). People given either drug often had some extrapyr amidal symptoms and 25% of those using risperidone required medication to alleviate these symptoms (n = 419; two RCTs; RR = 1.8, 95% CI = 1.2, 2.5; NNTH = 8, 95% CI = 4, 25). People allocated to risper idone were less likely to gain weight than those given olanzapine, and the weight gain was often considerable and of quick onset (n = 984; two RCTs; weight gain 7% in the short term, RR = 0.5, 95% CI = 0.4, 0.6; NNTH = 7, 95% CI = 6, 10). Patients taking risperidone were more likely to have abnor mal ejaculation (n = 370; two RCTs; RR = 4.4, 95% CI = 1.4, 14; NNTH = 20, 95% CI = 6, 176). Both drugs were asso ciated with high attrition rates; in the long term, consistent 66% of those allocated to risperidone left the study early compared with 56% given olanzapine (n = 1440; five RCTs; RR = 1.2, 95% CI = 1.1, 1.3; NNTH = 11, 95% CI = 7, 23). Randomized comparisons of risperidone and olanzapine for schizophrenia have also been reviewed (181M). Both drugs were commonly associated with adverse events and high attrition rates. Cardiovascular Acquired long QT syn drome associated with risperidone has again been reported (182A). • An 83-year-old woman with senile dementia and psychosis, who had taken risperidone 1.5 mg/day for the past 2 years and was also taking diltiazem 120 mg/day and torasemide 5 mg/day, developed a slow pulse. An electrocardiogram showed a
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phase 2 polymorphous ventricular tachycardia associated with torsade de pointes. Her family refused a pacemaker and she died.
Nervous system Risperidone-induced move ment disorders in children with disruptive behaviour and sub average intellectual func tioning have been retrospectively analysed using data from three 1-year, open studies (patients’ age range 4–14 years; 82% men; n = 668) (183C). About 70% of the patients completed the studies (mean risperidone dosage 1.6 mg/day). There were movement disorders in 23% of patients, although mean Extrapyramidal Symptom Rating Scale scores remained low; 4.3% required antiparkinsonian drugs. Fifty patients with drew owing to adverse events, 13 had a movement disorder; in five cases this was the only reported adverse event: dyskinesia, dyskinesia plus tardive dyskinesia, tardive dyskinesia, an extrapyramidal disorder plus hypertonia and hyperkinesia, and an extra pyramidal disorder. One subject met prede fined criteria for tardive dyskinesia after a dosage reduction; the symptoms persisted for 4 weeks and resolved with continued treatment and no further dosage change. Two other subjects were considered to have tardive dyskinesia, including a 7-year-old boy who had occasional mild movements of his lips after taking risperidone for 133 days; 7 days after a dosage reduction, he devel oped marked lip movements and recovered fully when risperidone was withdrawal. A re-analysis sponsored by Janssen showed that treatment with low-dose risperidone in children with disruptive behaviours disorder is associated with a low rate of tardive dyskinesia and other movement disorders. Salivary glands Sialorrhea or hyper saliva tion is an uncomfortable adverse effect that develops during treatment with antipsycho tic medications, especially clozapine (SEDA-29, 68). Sialorrhea associated with risperidone has been reported (184A). • An 18-year-old woman with schizophrenia who was taking risperidone 2 mg/day and lorazepam 1 mg/day gradually increased the
dosage of risperidone to 6 mg/day over 3 days. On day 4, her psychomotor agitation improved but she developed hypersalivation, associated mild speech impairment and mildly impaired postural reflexes. She responded to intramuscular biperiden.
Sexual function Sexual adverse effects of quetiapine and risperidone have been com pared in a 6-week, randomized, doubleblind trial in men with schizophrenia who had previously had risperidone-associated sexual dysfunction and were randomized to risperidone continuation (n = 12, mean dose = 4.3 mg/day) or quetiapine switch (n = 10, mean dose = 300 mg/day) (185c). There was a significant positive relationship between serum prolactin concentration and impairment of sexual function according to the Arizona Sexual Experience Scale total score only in those who took risperidone.
Sertindole (SED-15, 3120; SEDA-30, 72) Psychological In a 12-week trial, patients with schizophrenia were randomized to ser tindole (n = 17) or haloperidol (n = 17) (186c). Cognitive sub processes were inves tigated with the Reaction Time Decomposi tion method and the Wisconsin Card Sorting Test, at baseline and weeks 4 and 12. Sertindole reversed cognitive deficits significantly more than haloperidol; cogni tive processing improved independently of motor function. Death Sertindole has been associated with a prolonged QT interval in clinical trials; it was suspended because of an excessive rela tive reporting rate of sudden deaths in 1998 and then re-introduced in 2001 in Europe under certain restrictions (SEDA-26, 66). The European Sertindole Safety and Exposure Survey was a follow-up study of patients treated with sertindole in Germany, Austria, Belgium, Hungary, the Netherlands and the UK, aimed at identify ing deaths and their causes in those patients (187C); a nested case-control study of potential susceptibility factors was
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conducted within that study comparing patients with cardiac or unexplained deaths with randomly selected survivors matched for age and sex. A total of 8608 patients were identified as having taken sertindole, for 3819 person-years; 35 had died (all cause mortality rate, 0.9 per 100 personyears exposed. Eight deaths were suicides and 11 were cardiac deaths. On average, patients who died because of cardiac disor ders were older and patients who com mitted suicide were younger than the other patients who died; patients who had taken sertindole were at a higher risk of prema ture cardiac or unexplained death if they had hypertension or other cardiovascular disorders associated with diabetes or meta bolic disorder. The authors stated that the mortality rate was not higher than in clinical trials that had led to market authorization; in Belgium, where the drug was not mar keted and there was an exhaustive register of all patients treated, the all-cause death rate was 0.8.
Ziprasidone (SED-15, 3721; SEDA-29,
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In an open 12-week observational study of 276 patients with schizophrenia and schizoaffective disorder who took flexible of ziprasidone (40–160 mg/day) a high pro portion of patients withdrew (60%), most of them within the first 4 weeks (189c). This was explained by invoking initial and over all under-dosing; in those who completed the study, ziprasidone was associated with improvements in different scales. One treatment-emergent adverse event was experienced by 217 patients; in 30 patients (14%) the adverse event was severe. The most common severe event was re-emer gence or deterioration of psychotic symp toms (‘schizophrenic reactions’ and ‘psychoses’); other events were agitation, depression, insomnia, gastrointestinal syn dromes, dizziness, urticaria and intentional overdose. The incidence of extrapyramidal symptoms was 6%. Body weight fell on average by 1.3 kg. There was a non-signifi cant prolongation of the average QTc inter val from a mean of 392 ms at baseline to 395 ms; the maximum was 461 ms; there were no cases of torsade de pointes or other severe dysrhythmias.
81; SEDA-30, 72; SEDA-31, 94) Observational studies Several open stu dies, all promoted by Pfizer, have emerged; two deserve some attention because of the large numbers of patients included, allowing the identification of adverse reactions of very low frequency. In a multi center, 6-month, uncontrolled observational study, 1266 patients taking ziprasidone were enrolled (188c). Of those analysed at the end of the study (n = 1022), 47% had at least a 30% reduction in PANSS total score. In total, 453 patients (36%) withdrew; ziprasidone doses greater than 120 mg/day were asso ciated with a lower risk of withdrawal for any cause (OR = 0.5; 95% CI = 0.3, 0.6). About one-third (n = 374) of the 1260 patients evaluable for safety reported at least one adverse event. There were serious adverse events in 19 patients (1.5%), includ ing five deaths (three suicides, one sudden death, and one brain abscess). Adverse reac tions were elicited using an open-ended ques tionnaire, which can lead to under-reporting.
Nervous system Ziprasidone-induced extrapyramidal symptoms have previously been reported (SEDA-29, 81; SEDA-31, 95). Four new cases of dystonia associated with ziprasidone have now been published (190-2A); two of the patients used cocaine, which could have been a susceptibility factor. • A 31-year-old woman with schizophrenia, who had previously had acute dystonia with haloperidol and mild extrapyramidal symptoms with risperidone, took ziprasidone 120 mg bd, increased from 160 mg/day. Within 2 days of the dosage increase, she developed transient tongue dystonia, general body stiffness, and conjugate eye deviation on two separate occasions. She continued to take the increased dose and on day 4 had a severe acute dystonic reaction, including an oculogyric crisis, lockjaw, tongue protrusion, severe generalized body stiffness and respiratory difficulty. Her symptoms resolved with intravenous diphenhydramine 50 mg. • A 20-year-old man with a schizoaffective disorder and cocaine dependence was given
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divalproex sodium 500 mg/day, ziprasidone 60 mg/day and trazodone 100 mg at bedtime. On day 2, the dose of divalproex sodium was increased to 1000 mg/day and ziprasidone to 60 mg bd Two hours after the second dose of ziprasidone, he developed lateral flexion of the trunk towards the right side with slight rotation (Pisa syndrome), dysphonia and dysphagia. Benzatropine 1 mg intramuscularly produced rapid complete resolution. • An 18-year-old man with paranoid schizophrenia was given ziprasidone 20 mg bd, increasing to 40 mg bd on day 2 and 60 mg bd on day 3. He then started choking and had difficulty in speaking. His symptoms completely resolved within 15 minutes of a dose of benzatropine 1 mg intramuscularly. • A 37-year-old man with a psychotic disorder who had snorted cocaine intermittently for about 6 months was given three doses of ziprasidone 40 mg/day; 5 hours after the third dose he developed trismus, which resolved with benzatropine 1 mg intramuscularly.
Psychiatric Antipsychotic drugs have been associated with depression. Depression has been attributed to ziprasidone in three patients with schizophrenia (193A). How ever, since depression in patients with schi zophrenia is multi factorial, it is difficult to establish a causal relationship.
Endocrine Hyperprolactinemia has been attributed to ziprasidone (194A). • A 22-year-old woman took ziprasidone 60 mg/day and lithium 1500 mg/day for bipolar affective disorder, and after 40 days developed galactorrhea and breast pain. The plasma prolactin concentration was 135 ng/ml (reference range 3.4–24 ng/ml); after withdrawal of ziprasidone it fell to 18 ng/ml within 2 weeks.
Zuclopenthixol (SED-15, 3722) Placebo-controlled studies The effects of zuclopenthixol on aggressive behaviour in patients with intellectual disabilities have been investigated (195A). Of 49 patients who responded to zuclopenthixol during 6 weeks of open treatment, 39 took part in a 12-week randomized withdrawal trial. The placebo subgroup (n = 20) had significantly more aggressive behaviour, as indicated by outcomes observed by external raters on the Modified Overt Aggression Scale. The number of adverse events and possible symptoms of withdrawal, such as nausea, insomnia and diarrhea, did not differ between the groups.
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167. McLean RM, Harrison-Woolrych M. Alopecia associated with quetiapine. Int Clin Psychopharmacol 2007;22:117–9. 168. Pinta ER, Taylor RE. Quetiapine addic tion? Am J Psychiatry 2007;164:174–5. 169. Waters BM, Joshi KG. Intravenous quetia pine–cocaine use (‘Q-ball’). Am J Psychia try 2007;164:173–4. 170. Ngo A, Ciranni M, Olson KR. Acute quetia pine overdose in adults: a 5-year retrospective case series. Ann Emerg Med 2008;52:541–7. 171. Medical News Today. FDA approves first generic risperidone to treat psychiatric con ditions. http://www.medicalnewstoday.com/ articles/113701.php 172. US Food and Drug Administration. Risper dal (risperidone) Tablets, August 2008. http:/www.fda.gov/Safety/MedWatch/Safety Information/Safety-RelatedDrugLabeling Changes/ucm123246.htm 173. Holzhausen SP, Guerreiro MM, Baccin CE, Montenegro MA. Use of risperidone in children with epilepsy. Epilepsy Behav 2007;10:412–6. 174. Miyaji S, Yamamoto K, Hoshino S, Yama moto H, Sakai Y, Miyaoka H. Comparison of the risk of adverse events between risper idone and haloperidol in delirium patients. Psychiatry Clin Neurosci 2007;61:275–82. 175. Keks NA, Ingham M, Khan A, Karcher K. Long-acting injectable risperidone v. olan zapine tablets for schizophrenia or schizoaf fective disorder. Randomised, controlled, open-label study. Br J Psychiatry 2007; 191:131–9. 176. Perez-Iglesias R, Crespo-Facorro B, Amado JA, Garcia-Unzueta MT, RamirezBonilla ML, Gonzalez-Blanch C, MartinezGarcia O, Vazquez-Barquero JL. A 12 week randomized clinical trial to evaluate metabolic changes in drug-naive, first-epi sode psychosis patients treated with halo peridol, olanzapine, or risperidone. J Clin Psychiatry 2007;68:1733–40. 177. Mahmoud RA, Pandina GJ, Turkoz I, Kosik-Gonzalez C, Canuso CM, Kujawa MJ, Gharabawi-Garibaldi GM. Risperi done for treatment-refractory major depressive disorder: a randomized trial. Ann Intern Med 2007;147:593–602. 178. Pandina GJ, Bossie CA, Youssef E, Zhu Y, Dunbar F. Risperidone improves beha vioral symptoms in children with autism in
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a randomized, double-blind, placebo-con trolled trial. J Autism Dev Disord 2007;37:367–73. Katz I, de Deyn PP, Mintzer J, Greenspan A, Zhu Y, Brodaty H.The efficacy and safety of risperidone in the treatment of psychosis of Alzheimer’s disease and mixed dementia: a meta-analysis of 4 pla cebo-controlled clinical trials. Int J Geriatr Psychiatry 2007;22:475–84. Jayaram MB, Hosalli P, Stroup TS. Risper idone versus olanzapine for schizophrenia. Cochrane Database Syst Rev 2006;1: CD005237. Jayaram MB, Hosalli PM, Stroup TS. Risper idone versus olanzapine for treatment of schi zophrenia. Schizophr Bull 2007;33:1274–6. Raviña T, Raviña P, Gutierrez J. Acquired long QT syndrome: risperidone-facilitated triggered activity and torsades de pointes during complete AV blockI. Int J Cardiol 2007;116:416–20. Pandina GJ, Bossie CA, Zhu Y, Gharabawi GM. Evaluating movement disorders in pediatric patients receiving risperidone: a comparison of spontaneous reports and research criteria for TD. Child Adolesc Psy chiatry Ment Health 2007;1:3. Panagiotidis PT, Fountoulakis KN, Sia mouli M, Magiria S, Iacovides A, Kaprinis G. Risperidone-induced sialorrhea respon sive to biperiden treatment. Schizophr Res 2007;93:410–1. Nakonezny PA, Byerly MJ, Rush AJ. The relationship between serum prolactin level and sexual functioning among male outpa tients with schizophrenia or schizoaffective disorder: a randomized double-blind trial of risperidone vs. quetiapine. J Sex Marital Ther 2007;33:203–16. Gallhofer B, Jaanson P, Mittoux A, TanghÏj P, Lis S, Krieger S. Course of recovery of cognitive impairment in patients with schi zophrenia: a randomized double-blind study comparing sertindole and haloperi dol. Pharmacopsychiatry 2007;40:275–86. Peuskens J, Moore N, Azorin JM, Toumi M, Cochran J. The European Sertindole Safety and Exposure Survey: a follow-up study of 8600 patients. Pharmacoepidemiol Drug Saf 2007;16:804–11. Arango C, Gómez-Beneyto M, Brenlla J, Gastó C, Sarramea-Crespo F, Chamorro L,
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Masramon X, Díez T. On behalf of the ZIS Study Group. A 6-month prospective, observational, naturalistic, uncontrolled study to evaluate the effectiveness and tol erability of oral ziprasidone in patients with schizophrenia. Eur Neuropsychopharmacol 2007;17:456–63. 189. Kudla D, Lambert M, Domin S, Kasper S, Naber D. Effectiveness, tolerability, and safety of ziprasidone in patients with schizophrenia or schizoaffective disorder: results of a multi-centre observational trial. Eur Psychiatry 2007;22:195–202. 190. Rosenfield PJ, Girgis RR, Gil R. High-dose ziprasidone-induced acute dystonia. Prg Neuro-Psycopharmacol Biol Psychiatry 2007;31:546–7. 191. Duggal HS. Acute Pisa syndrome and pharingolaryngeal dystonia due to
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ziprasidone. J Neuropsychiatry Clin Neurosci 2008;20:108–9. Duggal HS. Ziprasidone-induced acute laryngeal dystonia. Prog Neuro-Psycho pharmacol Biol Psychiatry 2007;31:970. Kaptsan A, Dwolatzky T, Lerner V. Zipra sidone-associated depressive state in schizo phrenic patients. Clin Neuropharmacol 2007;30:357–61. Citil DY, Secuk E, Karlida R. Ziprasidone induced hyperprolactinemia: a case report. Prog Neuro-Psychopharmacol Biol Psychia try 2008;32:905–6. Haessler F, Glaser T, Beneke M, Pap AF, Bodenschatz R, Reis O. Zuclopenthixol Disruptive Behaviour Study Group. Zuclo penthixol in adults with intellectual disabili ties and aggressive behaviours: discontinua tion study. Br J Psychiatry 2007; 190:447–8.
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Antiepileptic drugs
GENERAL Hypersusceptibility adverse reactions to antiepileptic drugs have been reviewed, and their mechanisms of action and risk factors have been described (1R). These reactions include (1) immune-mediated hypersensitiv ity reactions, (2) reactions involving unusual non-immune-mediated individual hypersus ceptibility, often related to abnormal produc tion or defective detoxification of reactive cytotoxic metabolites, and (3) so-called ‘off target’ pharmacology, whereby a drug inter acts directly with a system other than that for which it is intended (reactions that are classified as collateral adverse reactions in the DoTS framework (2H). Comparative studies The long-term efficacy and tolerability of antiepileptic drugs in patients with newly diagnosed epilepsy need to be evaluated in comparative studies. Two randomized, unblinded, long-term studies have been published. In the first study carbamazepine, gabapentin, lamotrigine, oxcarbazepine, and topiramate were compared in 1721 patients with epilepsy for whom carbamazepine was deemed to be standard treatment (patients with partial epilepsies) (3C). In the second study, 716 patients for whom valproate was considered to be standard treatment were randomized to valproate, lamotrigine, or topiramate (4C). One of two primary outcomes was time to
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32007-1 � 2010 Elsevier B.V. All rights reserved.
treatment failure, which is a mixed measure of efficacy and tolerability. In the first study, time to treatment fail ure was significantly better for lamotrigine than for carbamazepine (HR = 0.78; 95% CI = 0.63, 0.97), gabapentin (0.65; 0.52, 0.80), and topiramate (0.64; 0.52, 0.79), and there was a non-significant advantage com pared with oxcarbazepine (1.15; 0.86, 1.54). Adverse events occurred in 45–53% (lamo trigine 45%, topiramate 53%). The most common adverse effect associated with treatment failure was rash (7% of patients taking carbamazepine, 6% of those taking oxcarbazepine and 3% of those taking lamotrigine). In the second study valproate was signifi cantly better than topiramate (HR = 1.57; 95% CI = 1.19, 2.08), but there was no sig nificant difference between valproate and lamotrigine (1.25; 0.94, 1.68). The adverse events associated with treatment failure were most commonly psychiatric symptoms, cognitive symptoms, tiredness, and fatigue, all of which were more common with topira mate. For lamotrigine, rash was the most common symptom associated with treat ment failure (4% of patients randomized), whereas for valproate weight gain was the most common symptom (4% of patients randomized).
Systematic reviews In a meta-analysis of the most frequent treatment-related central nervous system adverse effects of new antiepileptic drugs from double-blind, addon, placebo-controlled studies in adults with epilepsy 36 suitable studies were identified (5M). No meta-analysis was possible for oxcarbazepine and tiagabine. Gabapentin was significantly associated with somnolence
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and dizziness; lamotrigine with dizziness, ataxia, and diplopia; levetiracetam with somnolence; pregabalin with somnolence, dizziness, ataxia, and fatigue; topiramate with somnolence, dizziness, cognitive impairment, and fatigue; zonisamide with somnolence, and dizziness. Psychological Clinically important cognitive effects of anticonvulsants have been investigated in a double-blind, parallel group, randomized, placebo-controlled study of anticonvulsant drug withdrawal in subjects with completely controlled seizures taking a single anticonvulsant (6c). Drug withdrawal was associated with significant improvement in performance on the Controlled Oral Word Association Test and the Stroop ColourWord Interference Test. Psychiatric The association of Alzheimer’s disease and all types of dementia with epilepsy and the use of antiepileptic drugs has been investigated in 5376 elderly people (aged 65 years or older) with no prior evidence of dementia, defined as a Modified Mini-Mental State score of at least 78 (7C). Those who took antiepileptic drugs had a significantly higher risk of developing dementia but not Alzheimer’s disease. The association remained significant in those who took only phenytoin. Further investigation is warranted to determine whether it is indeed antiepileptic drug therapy or some underlying confounding pathology that is associated with the development of dementia in these patients. The adverse effects of antiepileptic drugs on mood have been reviewed (8RH). The barbiturates, vigabatrin, and topiramate are more likely than other antiepileptic drugs to be associated with depressive symptoms, which are present in up to 10% of patients taking these drugs. Tiagabine, levetiracetam, and felbamate present an intermediate risk, with a prevalence of depression of about 4% or less. For zonisamide, the data are less clear, but it seems that mood disorders may occur in up to 7% of patients, even though in most cases slow titration can significantly
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reduce the risk. Phenytoin, ethosuximide, carbamazepine, oxcarbazepine, gabapentin, sodium valproate, pregabalin, and lamotri gine are all associated with low risks of depression (<1%), and several of these have a positive effect on mood. Several mechanisms may be involved in this effect of antiepileptic drugs, including potentiation of GABA neurotransmission, folate defi ciency, pharmacodynamic interactions, and forced normalization. Epidemiological data show that the rate of suicide among patients with epilepsy is five fold higher than in the general population, while in temporal lobe epilepsy it is even higher. It has been hypothesized that since disturbances of serotonin metabolism are involved in the pathogenesis of suicidal behavior, they might also be a common link between depression, suicidality and epi lepsy (9RH). The authors suggested that anticonvulsants with certain serotonergic properties should reduce the risk of suicidal ity, whereas drugs that lack serotonergic mechanisms would not be effective in pre venting it. According to this hypothesis, phenobarbital, and phenytoin should be drugs with a proven risk, while carbamazepine, oxcarbazepine, valproate, and lamotrigine could be regarded as drugs with antisuicidal properties, because they all improve mood in epilepsy and have serotonergic mechanisms of action. Topiramate, tiagabine, vigabatrin, levetiracetam, and zonisamide all have negative effects on mood, and cognition. How ever, zonisamide has negative psychotropic effects, even though it has serotonergic proper ties, whereas gabapentin has positive psycho tropic effects on mood but is devoid of serotonergic properties. Endocrine In women with epilepsy taking antiepileptic drug monotherapy, valproate monotherapy is associated with more obesity and metabolic syndrome, while lamotrigine and topiramate may be safer in patients with a high risk of cardiovascular disease (10c). Metabolism In 25 children taking anticonvulsant drugs, in whom homocysteine,
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folic acid, and vitamin B12 concentrations were investigated, plasma homocysteine concentrations were higher than the normal cut-off point accepted for childhood in four, of whom three were taking carbamazepine and one valproate (11c). A significant drug-induced change in weight may increase morbidity and impair adherence to treatment. Changes in weight induced by antiepileptic drugs have been summarized (12r). Gabapentin, pregabalin, valproic acid, vigabatrin, and possibly carba mazepine have been associated with weight gain. Felbamate, topiramate, and zonisamide have been associated with weight loss. Lamo trigine, levetiracetam, and phenytoin have no effects on weight. In a systematic search for studies on changes in weight and/or glucose/lipid con centrations with mood-stabilizing drugs in children with bipolar disorder, 24 trials (684 patients) were identified (13M). The treat ments included lithium and antiepileptic drugs alone or in combination, and secondgeneration antipsychotic drugs alone or com bined with lithium or divalproex for 4–48 weeks. There was significant weight gain in 18 of the trials; in two studies of topiramate there was significant weight loss. In trials that lasted at least 12 weeks, weight gain was greater with second-generation antipsychotic drugs plus mood stabilizers than with mood stabilizer monotherapy. Combining antipsy chotic drugs with mood stabilizers led to greater weight gain than one or two mood stabilizers. Skin The relative incidence and predictors of antiepileptic drug-related rashes in patients taking all common antiepileptic drugs have been evaluated retrospectively using the charts of 1890 outpatients (14c). The average rate of antiepileptic drug-induced rash was 2.8%. Higher rates were seen with phenytoin (5.9%), lamotrigine (4.8%) and carbamazepine (3.7%). Lower rates were seen with felbamate (1%), levetiracetam (0.6%), gabapentin (0.3%), valproate (0.7%), topiramate (0.6%), and vigabatrin (0%). The only non-drug predictor that was significant in a multivariate analysis was the
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occurrence of another antiepileptic druginduced rash – 8.8% versus 1.7% in those without another rash (OR = 3.1; 95% CI = 1.8, 5.1). The incidence of skin reactions to current anticonvulsants has been studied retrospec tively in 663 consecutive patients with epilepsy (2567 exposures to 15 different antiepileptic drugs) (15C). There were skin reactions in 14% of patients (5% of expo sures); 97% of the reactions occurred in patients taking carbamazepine, phenytoin, lamotrigine, oxcarbazepine, or phenobarbi tal. Rashes occurred in 11% of those taking carbamazepine, 8% of those taking pheny toin, lamotrigine, or oxcarbazepine, and 2% of those taking phenobarbital. Skin reac tions were significantly more common in women than in men (19% versus 8%), and significantly less often in patients with learning disabilities than in other patients (7% versus 16%). The cross-reactivity of rashes from antiepileptic drugs with an aromatic ring has been investigated in another study in the same population of patients (16C). A history of an antiepileptic drug-related rash was sig nificantly associated with reactions to pheny toin, carbamazepine, and oxcarbazepine. A carbamazepine-induced rash was not signif icantly associated with a reaction to lamotri gine and vice versa. Less than one-third of the patients with a carbamazepine-associated rash also reacted to oxcarbazepine. The risk of severe cutaneous adverse reactions in patients taking antiepileptic drugs has been evaluated in a multinational case–control study of 379 reactions and 15 005 controls (17C). There were strong associations for lamotrigine (RR > 14), car bamazepine, phenobarbital, and phenytoin. In general, the risk was restricted to the first few weeks of drug exposure. Musculoskeletal The prevalence of abnormal bone mineral density, measured using dual X-ray absorptiometry, in an urban population has been investigated in a cross-sectional study of 130 consecutive patients with epilepsy (18C). There were T scores of –1 or worse (the criterion for
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osteopenia in postmenopausal women) in 55% of patients and scores below –2.0 in 15%, more than six times the number expected in the general population. Older age, menopause in women, longer duration of therapy, and a history of using phenytoin or phenobarbital were markers for reduced bone mineral density. Teratogenicity The incidence of congenital malformations and other pregnancy outcomes as a function of in utero antiepileptic drug exposure has been studied in a systematic review of 59 published studies involving 65 533 pregnancies in women with epilepsy and 1817024 in healthy women (19M). The calculated incidence of births with congenital malformations in women with epilepsy (7.1%) was significantly higher than that in healthy women (2.3%). The incidence was highest for antiepileptic drug polytherapy (16.8%), mainly when the combination included phenobarbital, phenytoin or valproate. Valproate was associated with the highest incidence (10%). The first results derived from analysis of the Australian register of antiepileptic drugs in pregnancy have been published (20C). The data were collected between 1999 and December 2006 and contained data on 1002 pregnancies in women with epilepsy. There was a significant dose-related increased risk of fetal malformations associated with valproate; a tendency towards lower birth weights in live-born malformed offspring and a substantially reduced risk of seizures in pregnancies in which there had been free dom from seizures for 1 year. It has been hypothesized that fetal genetic variations in the expression and activity of some transport proteins may influence fetal exposure to antiepileptic drugs and thus the risk of teratogenicity (21RH). Fetal exposure to antiepileptic drugs may be influenced by drug transporting proteins in the placenta, including P-glycoprotein, multidrug resis tance protein 1, and breast cancer resistance protein. The location of these proteins in the syncytiotrophoblast plasma membrane (the interface of the maternal and fetal circula tions) allows these transport proteins to
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efflux xenobiotics back to the mother and offers the fetus protection from medications taken during pregnancy. Two of four pregnant women who took valproic acid and had offspring with neural tube defects had reduced phosphopyridoxal concentrations compared with controls (22c). The woman with the greatest reduction in plasma phosphopyridoxal took periconcep tional pyridoxine with folic acid in a second pregnancy, which had a normal outcome. The authors suggested that other vitamins, such as vitamin B6, in addition to folate, may be involved in neural tube defects in patients taking antiepileptic drugs. Drug formulations The advantages and disadvantages of extended-release formulations of antiepileptic drugs have been discussed (23R). Such formulations are usually designed to reduce dosage frequency and maintain relatively constant or flat plasma drug concentrations. Flat plasma concentrations of an antiepileptic drug may improve efficacy and minimize concentrationrelated adverse effects. Furthermore, consistent plasma concentrations may simplify the management of antiepileptic drug therapy. However, while the possibility of taking a drug once or twice a day might be more convenient, it will not necessarily improve therapeutic coverage. In fact, the effect of a missed dose in this case is larger and the risk of breakthrough seizures higher during once-daily administration than twicedaily administration.
Carbamazepine (SED-15, 627; SEDA 29, 88; SEDA-30, 78; SEDA-31, 107) Comparative studies The cognitive effects of carbamazepine and topiramate have been compared in patients with epilepsy in an open, observer-blinded, parallel-group, randomized trial in children with benign rolandic epilepsy (24c). Topiramate was introduced at a dose of 12.5 mg/day, with a minimum target dose of 50 mg/day over 4 weeks. Carbamazepine was started at a dose
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of 10 mg/kg/day, with a minimum target dose of 20 mg/kg/day. Changes in neuropsychological tests performed at baseline and after 28 weeks of treatment showed that topiramate had slightly worse effects than carbamazepine. There were no differences in behavioral adverse effects between carbamazepine and phenobarbital in a randomized, controlled trial in 108 children with generalized tonic– clonic or partial and secondarily generalized seizures in Bangladesh (25c). Placebo-controlled studies The efficacy of carbamazepine in 89 subjects with unipolar depression who had never received antidepressants has been evaluated in a double-blind, randomized, placebo-controlled study (26C). The patients had had at least two major depressive episodes but had never had mania or hypomania. They were random ized to immediate-release carbamazepine 300–800 mg/day (n = 51) or placebo (n = 38) for 12 weeks. There was mild leukopenia in 14/46 of those taking the active drug and 2/37 of those taking placebo. There were rashes in 11% of those taking carbamazepine and in none of those taking placebo. Nausea, headache, tremor, blurred vision, and somnolence almost exclusively occurred in those taking carbamazepine. Dizziness occurred in similar percentages (13% and 16% respectively). Cardiovascular Complete atrioventricular block has been attributed to carbamazepine (27A). Carbamazepine-induced dysrhythmias have two distinct forms: sinus tachycardia in the setting of massive carbamazepine overdose (mainly seen in young adults) and bradydysrhythmias or atrioventricular block, which are almost exclusively seen in elderly women and at carbamazepine con centrations in the usual target range. Psychological The absolute effect of antiepileptic drugs on cognition can only be observed in healthy volunteers. The neuropsychological and neurophysiological
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effects of carbamazepine and levetiracetam have been compared in a double-blind, two-period, crossover, randomized study in 28 healthy adults (28C). Evaluations were conducted at times of screening, baseline pre-drug treatment, the end of each maintenance phase (4 weeks), and the end of each washout period. The dosage of carbamazepine was adjusted to achieve midtarget range concentrations. The dosage of levetiracetam was titrated to 2000 mg/day. An overall composite score showed significantly worse effects of carbamazepine compared with levetiracetam and for both drugs compared with non-drug treatment. Furthermore, carbamazepine was worse than levetiracetam in 15 of 34 variables and none favored carbamazepine. These results suggest that carbamazepine has more negative cognitive effects than levetiracetam at commonly used dosages and that these differences may be clinically significant in some individuals. Up to now, there has been no conclusive evidence in patients with epilepsy of a sig nificant difference between two different antiepileptic drugs, with some exceptions. The cognitive effects of carbamazepine and remacemide hydrochloride have been compared in a double-blind, parallel-group study in patients with newly diagnosed epilepsy, who were randomized to either carbamazepine 200 mg/day (n = 282) or remacemide 200 mg/day (n = 288) for 2 weeks and slowly titrated to a target dose of 600 mg/day of both drugs (29C). After the 6-week titration period, the patients entered a maintenance phase, with possible upward or downward dosage adjustments of 200 mg/day. Repeated assessments of neuro psychological function and mood were carried out using computerized and conven tional measures. The trial ended after 20 months, following the second interim analysis, which showed inferiority of rema cemide compared with carbamazepine in preventing seizure recurrence. The patients who took carbamazepine had consistently worse performances than those who took remacemide on measures of information pro cessing, psychomotor speed, and attention. The authors suggested that the observed
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differences may have been due to direct pharmacological effects of the treatments themselves and did not seem to be influenced by aspects such as seizure control and adverse events profiles. Sensory systems Conjunctival metaplasia has been associated with carbamazepine in a 22-year-old man (30A). Endocrine Carbamazepine affects the serum concentrations of thyroid hormones, typically reducing concentrations of circulating thyroxine, both total and free, with variable effects on triiodothyronine. In patients with no underlying thyroid pathology this is only exceptionally clinically important. However, in hypothyroid patients such changes may be significant. Thyrotropin, total thyroxine, and free thyroxine serum concentrations have been studied in 29 hypothyroid patients taking levothyroxine and in 19 patients with no thyroid disorders who were taking levothyroxine for other reasons; measurements were made before carbamazepine therapy and then weekly for 7 weeks (31c). In the first group, total thyroxine fell significantly by 15–25%, starting from the first week; the fall in free thyroxine was smaller (10–15%) and delayed. In contrast, thyrotropin concentrations increased only slightly and stayed within the reference range. In the second group there were similar falls in total and free thyroxine, but followed by a significant increase in thyrotropin. Hence, in patients with no thyroid pathology there was a compensatory reaction, leading to a new steady state. In patients who were taking levothyroxine for hypothyroidism, increased metabolic clearance of thyroid hormones may lead to worsening of hypothyroidism. Metabolism The possible association between the effects of carbamazepine on thyroid function and lipid profile has been studied in 18 children with epilepsy (32c). During carbamazepine monotherapy there was a significant association between serum
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low-density lipoprotein (LDL) cholesterol and thyrotropin concentrations at 6 and 12 months. These results suggest that the increase in LDL cholesterol concentrations that occur in patients taking carbamazepine may be the consequence of altered thyroid function. Hematologic A young patient with a bipolar disorder started carbamazepine and developed pure red cell aplasia (33A). Carbamazepine can cause pseudolymphoma, and there have also been iso lated reports of true lymphomas. • A 73-year-old patient with erythroderma had an anaplastic large cell lymphoma; he had started to take carbamazepine for diabetic neuropathy 3 months before the development of skin lesions (34A).
However, the time course in this case was very short, suggesting that carbamazepine was not implicated. In a 5-year-old boy intravascular hemoly tic anemia with erythroblastopenia was con sidered probably due to carbamazepine (35A). Subsequently reduced erythrocyte activity of the enzyme glutathione peroxi dase was found in the boy and his mother. The authors speculated that reduced activ ity of this enzyme confers a high risk of carbamazepine-induced hemolysis. Gastrointestinal Drug rash with eosinophilia and systemic symptoms (DRESS), also known as anticonvulsant hypersensitivity syndrome, is typically characterized by multiorgan involvement (blood dyscrasias, hepatitis, nephritis, myocarditis, thyroiditis, interstitial pneumonitis, and encephalitis). Carbamazepine is often implicated. Two cases of carbamazepine-induced eosinophilic esophagitis in the contest of DRESS have been reported (36A). The involvement of the esophagus in this contest had probably never been noted before. Urinary tract Urinary retention has been attributed to carbamazepine (37A).
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• A 38-year-old woman with a 2-year history of epilepsy taking carbamazepine 200 mg bd started to have urgency and dribbling of urine and 3 days later developed acute urinary retention. Mechanical obstruction and all other causes of urinary retention were ruled out. Carbamazepine was the only medication with anticholinergic properties that she was taking. It was withdrawn and replaced by valproic acid. Her symptoms did not recur.
Although similar cases have previously been described, this case was unique because there was no evidence of underly ing disease, such as long-standing diabetes mellitus with severe peripheral neuropathy or Fabry’s disease with autonomic dysfunc tion. Carbamazepine has anticholinergic effects which may explain this complication. Skin A 52-year-old woman took carba mazepine 600 mg/day for 2 months and developed a psoriasiform eruption on her palms and soles followed 1 month later by alopecia (38A).
Serious skin reactions to carbamazepine Drug reaction with eosinophilia and systemic symptoms (DRESS) Several cases of carbamazepine-induced DRESS have been reported (39A–43A). A 16-year-old girl with Bourneville tuberous sclerosis took carbamazepine monotherapy for 5 weeks and developed DRESS. The unique characteristic of this case is that the complication recurred 3 weeks after treatment with valproic acid, which was substituted for carbamazepine (44A). After an immunological reaction to carbamazepine, valproate, which has a non-aromatic structure, is often used instead. In this case cross-sensitivity between these two drugs has been considered as possible. Stevens–Johnson syndrome and toxic epidermal necrolysis Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are now considered to be the same disease presenting with differences
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in severity. SJS is less extensive and affects less than 10% of body surface area, whereas TEN involves more than 30% of body surface area. The association between mood stabilizers and other medications used in patients with a bipolar disorder and severe cutaneous reac tions, such as erythema multiforme, SJS, and TEN has been evaluated epidemiologically (45C). In a database of more than 12 000 patients with bipolar disorders, 72 patients had had a serious skin reaction; 288 patients matched for sex and age, who had not had a serious skin disease during the same time, were also selected. The use of carbama zepine and valproate significantly predicted erythema multiforme, SJS, and TEN. Other significant predictors were other anticonvul sants (phenytoin, phenobarbital, and lamo trigine) and other concurrent drugs. The combination of carbamazepine and parace tamol (acetaminophen) further increased the risk. Re-administration of a drug that previously caused SJS may lead to TEN, which has a very high mortality rate (46A). • A 26-year-old man with schizophrenia and a history of carbamazepine-induced SJS 5 years before was again given carbamazepine. After 3 days he developed TEN (body surface area >90%). Despite appropriate treatment, he died 5 days later due to multiple organ failure.
In the West the overall estimated risk of SJS/TEN associated with carbamazepine is fairly low at about 1–6 per 10 000 new users (47C,48C). In some Asian countries, the risk is about 10 times higher than in Caucasian populations. In a case–control study in Tai wan, 59 of 60 patients with SJS/TEN asso ciated with carbamazepine were positive for HLA-B*1502, far higher than the 4% incidence of HLA-B*1502 in carbamaze pine-tolerant controls (49C). These findings suggest an initial estimate of a 5% absolute risk of SJS/TEN in HLA-B*1502 positive patients exposed to carbamazepine. Further more, in a case series of European patients with SJS/TEN associated with carbamaze pine, patients with Asian ancestry were over-represented. Of 12 patients, 4 were of
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Asian ancestry and all were positive for HLA-B*1502 (50C). In a further study in Hong Kong all of four cases of SJS/TEN associated with carbamazepine occurred in patients positive for HLA-B*1502 (51C). On the other hand, HLA-B*1502 is largely absent in individuals not of Asian origin, and it has therefore not been found to be a susceptibility factor for SJS/TEN in Cauca sians (52C). HLA-B*1502, an inherited allelic variant of the HLA-B gene, is found almost exclu sively in some individuals across broad areas of Asia, including South-Asian Indians. However, the prevalence of HLA-B*1502 has not been studied in many regions of Asia. It has been roughly calculated that 10–15% of people living in some parts of China, Thailand, Malaysia, Indonesia, the Philippines, and Taiwan carry the allele (53S). Since tests for HLA-B*1502 are already used to check for compatibility before tissue transplantation, the FDA has recommended that patients with ancestry from areas in which HLA-B*1502 is prevalent should be screened for the HLA-B*1502 allele before starting treatment with carbamazepine. If they test positive, carbamazepine should not be used, unless the expected benefit clearly outweighs the increased risk of serious skin reactions. On the other hand, since over 90% of carbamazepine-treated patients who will experience SJS/TEN have this reaction within the first few months of treatment, patients of any ethnicity or genotype (includ ing HLA-B*1502 positive) who have been taking carbamazepine for more than a few months are at low risk of SJS/TEN from carbamazepine.
Musculoskeletal Bone mineral density has been measured in 21 patients taking carbamazepine monotherapy and 21 patients taking valproate; the former had an increased frequency of lower bone density (54c). Enthesitis and Staphylococcus aureus tendon sheath abscess occurred as complica tions of severe carbamazepine hypersensi tivity in a 10-year-old girl (55A).
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Immunologic Recurrent Herpes simplex virus encephalitis has been attributed to carbamazepine-induced hypogammaglobu linemia (56A). • A 40-year-old man developed rigors, nausea, vomiting, photophobia, visual hallucinations, and behavioral changes followed by a tonic– clonic seizure. Cerebrospinal Fluid (CSF) analysis showed a lymphocytosis and the presence of Herpes simplex virus DNA type 1. Serum immunoglobulin concentrations were normal. He completed 3 weeks of intravenous aciclovir therapy and was discharged taking carbamazepine. Seven months later he had another tonic–clonic seizure and became agitated, confused and febrile. The CSF, an MRI scan, and electroencephalography were consistent with viral encephalitis. He had profound hypogammaglobulinemia and Herpes simplex virus DNA type 1 in the CSF.
Secondary bronchiolitis obliterans organiz ing pneumonia with repeated respiratory infections has also been associated with carbamazepine-induced hypogammaglobu linemia (57A). Drug formulations Cmax and AUC, which reflect the extent of availability, are not sufficiently sensitive parameters for distinguishing between formulations of carbamazepine in terms of tolerability, since the speed of availability is crucial (see below). In a reanalysis of the results of a bioequivalence study, using a mixed-effects pharmacokinetic–pharmacodynamic model to describe the dependence of adverse events on carbamazepine concentration, there was rapid tolerance to most neurological adverse effects (58R). The authors proposed the use of alternative, more sensitive methods for measuring bioequivalence between generic and branded formulations of antiepileptic drugs. Drug dosage regimens Slow titration of the dose of carbamazepine reduces the frequency and intensity of some of its nervous system adverse effects. It is therefore of interest to study what happens when it is given in a loading dose. The safety and efficacy of carbamazepine have been evaluated after the administration of a oral loading dose
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of 8 mg/kg in 36 patients (42 oral loads) (59c). The mean plasma carbamazepine concentration 3 hours after administration was 6.5 mg/l. There were adverse effects in about 60% of patients. The most common were drowsiness (26%) and nausea (23%) and others included dizziness, nystagmus, abdominal pain, vomiting, ataxia, and double vision. This confirms the low tolerability of carbamazepine when it is given in therapeutic doses without titration. It should be noted that the peak plasma concentrations were at the lower end of the usual target range. Drug overdose In 62 cases of carbamazepine overdose there was a statistically significant relationship between the serum carbamazepine concentration at time of admission and the Glasgow Coma Scale (60c). Seizures occurred exclusively in patients with epilepsy and a serum carbamazepine concentration over 25 mg/l. The authors proposed a classification into three neurological severity ranks (minimal, moderate, and important). Treatment of carbamazepine overdose consists mainly of supportive measures, the administration of activated charcoal, and gas tric lavage. In patients poisoned with modified-release formulations, multiple doses of activated charcoal are recommended, to enhance the elimination of carbamazepine. Whole bowel irrigation has been suggested to be beneficial but is not yet accepted as routine treatment because of limited human data. Gastrointestinal decontamination has been reported to be of limited efficacy in a case of severe overdose with slow-release carbamazepine (61A). Three cases of carbamazepine overdose in adolescents were managed with standard low-flux hemodialysis in two cases and char coal hemoperfusion in one. The authors concluded that hemodialysis is a cheaper and easier alternative, with fewer adverse effects than hemoperfusion (62A).
Gabapentin
(SED-15, 1465; SEDA-29, 89; SEDA-30, 80; SEDA-31, 110)
Observational studies When gabapentin was used to chronic irritability and recurrent
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pain in 9 neurologically impaired children, care-givers reported marked improvement; one child developed nystagmus and withdrawal was required (63c). Of eight patients who were refractory to first-line treatment in whom gabapentin was used as second-line treatment for chronic cluster headache in a prospective study, six responded; one had transient drowsiness at high doses and one had sexual dysfunc tion (64c). Gabapentin (initially 900 mg/day, increas ing up to a maximum of 2400 mg/day) has been evaluated in 55 patients with lumbar spinal stenosis (65c). Gabapentin increased walking distance and improved pain scores. The most frequent adverse effects were drow siness and dizziness and two patients had transient ataxia. There were no withdrawals. Comparative studies The hypothesis that both amitriptyline and gabapentin are more effective in relieving neuropathic pain than diphenhydramine has been tested in a randomized, double-blind, triple crossover, 8-week trial in 38 adults with spinal cord injuries (66c). Maximum daily doses were 2600 mg for gabapentin and 150 mg for amitriptyline. Amitriptyline was more efficacious in relieving neuropathic pain than diphenhydramine. Withdrawal because of possible adverse effects occurred five times during gabapentin treatment: (1) shortness of breath; (2) dizziness, fatigue, and nausea; (3) increased spasticity and pain; (4) fatigue, drowsiness, constipation, and dry mouth, and (5) severe itching. The four most frequent adverse events were dry mouth, drowsiness, fatigue, and constipation, which were all more common with amitriptyline. Placebo-controlled studies The efficacy and safety of gabapentin in doses up to 2400 mg/day for neuropathic pain caused by traumatic or postsurgical peripheral nerve injury have been investigated in a doubleblind, crossover, randomized, placebocontrolled study in 120 patients (67C). There was no statistically significant difference in the primary outcome of efficacy, although
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gabapentin provided significantly better pain relief than placebo. In 11 patients treatment was withdrawn because of adverse events. During gabapentin run-in, one patient had diplopia, ataxia, amnesia, and dysarthria, one had nausea and vomiting, one dizziness and vertigo, and one erythema. During gabapentin maintenance treatment, one patient was withdrawn because of cough and another because of vertigo. The most commonly reported adverse events during the gabapentin period were dizziness and vertigo, reported by 33% of the patients, and malaise and tiredness (26%), compared with 7.5% and 14% during placebo treatment respectively. Gabapentin (1200–2400 mg/day) and pla cebo have been compared in a 12-week, dou ble-blind, randomized study in 150 patients with pain associated with fibromyalgia (68C). Gabapentin produced greater improvement in average pain severity scores. Adverse events necessitated withdrawal in 12 patients taking gabapentin and 7 taking placebo. Gabapentin was associated with significantly more dizziness (19 versus 7 patients), seda tion (18 versus 3), light-headedness (11 versus 1), and weight gain (6 versus 0). Gabapentin (300 mg/day initially, increas ing to a maximum of 4200 mg/day) and pla cebo have been compared in a 12-week randomized, placebo-controlled trial in 50 patients with chronic masticatory myalgia (69c). Gabapentin was better than placebo in reducing pain and masticatory muscle hyperalgesia. The most frequent adverse effects were dizziness (in seven patients taking gabapentin and two patients taking placebo), drowsiness (n = 7 and 5 respec tively), impairment of memory and cogni tion (4 and 1), dry mouth (3 and 1), and fatigue (3 and 2). The effects of gabapentin 800 mg and dexamethasone 20 mg on postoperative pain, given together or separately 1 hour before the start of varicocele surgery, have been investigated in a randomized, doubleblind, placebo-controlled trial in 60 patients (70c). Gabapentin þ dexamethasone improved postoperative analgesia and pre vented postoperative nausea and vomiting better than either drug alone. The most
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frequent adverse effects were vomiting, nau sea, and dry mouth, which were significantly more common with placebo. Headache and pruritus occurred with similar frequencies in all four groups. The effects of gabapentin 1200 mg alone and gabapentin 1200 mg þ paracetamol 20 mg/kg, 1 hour before surgery, on post operative pain and morphine consumption in patients undergoing abdominal hyster ectomy have been compared in a three-arm, double-blind, placebo-controlled study in 75 patients (71c). Gabapentin alone and in combination with paracetamol reduced opioid requirements and increased patients’ satisfaction postoperatively. There were no significant differences between the groups in terms of adverse effects. The analgesic effect of gabapentin 1.2 g before the operation has been studied in patients undergoing elective hand surgery with intravenous regional anesthesia in a double-blind, placebo-controlled study (72c). Gabapentin was significantly superior to placebo in several measures of efficacy. Two of those who were given gabapentin and three of those who were given placebo had nausea that required antiemetic drugs and two of those who were given gabapentin complained of dizziness. Another postopera tive complaint was dry mouth in four patients given gabapentin and two given placebo. None reported being excessively drowsy after surgery. Gabapentin 600 mg has been assessed in the prevention of high-altitude headache in a placebo-controlled randomized study at an altitude of 3500 m in 202 unacclimatized hotel guests aged 15–65 years (73c). The total incidence of headaches was not signi ficantly affected by gabapentin, but there was a reduction in the incidence of moder ate/severe high-altitude headache. Somno lence was the most common adverse effect and was more common among gabapentin users. Dizziness, fatigue, and gastrointestinal adverse effects were not significantly differ ent between the groups. Gabapentin 2400 mg/day and tiagabine 24 mg/day in reducing cocaine use have been evaluated in a three-arm, 10-week, double-blind, placebo-controlled study in
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76 cocaine-dependent methadone-treated patients (74c). Treatment retention was sig nificantly reduced by gabapentin, but it was ineffective in reducing cocaine use. Adverse effects were not reported. Gabapentin up to 1200 mg/day for 8 days has been evaluated as an alternative to benzodiazepines in the treatment of alco hol withdrawal in 35 non-treatment-seek ing alcoholic subjects in a double-blind placebo-controlled study (75c). Gabapentin had no overall effect on drinking or crav ing. However, no adverse effects of the combination of gabapentin with alcohol were reported. The effects of memantine 10–40 mg/day and gabapentin up to 2400 mg/day on con genital nystagmus have been studied in 48 patients in a randomized, three-arm, doublemasked, placebo-controlled study over 56 days (76c). Both drugs improved visual acuity and reduced the intensity of nystag mus. In 16 patients given gabapentin 9 had adverse effects: each felt dizzy, or tired, or sleepless, or light-headed, nauseated, forget ful, and shaky, had headaches or was depressed; two had to reduce the dosage. Of 15 subjects who took placebo, 5 had adverse effects (dizziness, tiredness, light headedness, nausea, and headaches). Nervous system Life-threatening myoclonic status has been attributed to gabapentin (77A). • A 57-year-old man who had hand tremors and jerks involving the upper limbs was given gabapentin 900 mg/day and after 3 days developed continuous, fast-frequency, highamplitude jerking of the trunk and extremities, which severely impaired his normal activities. Progressive confusion, agitation, and disorientation developed soon after. Five days later he was admitted to the hospital. He was afebrile and had high-frequency, continuous, erratic, multifocal myoclonus, which was asynchronous in different parts of the body. Electroencephalography showed diffuse theta slowing and multifocal spikes. The diagnosis was cortical tremor. He was given thiopental after intubation and ventilation. Gabapentin was withdrawn. Genetic studies showed that he had a haplotype that co-segregates with benign adult familial myoclonic epilepsy. He was treated with levetiracetam 1000 mg/day, which controlled his symptoms.
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There have been several reports of gaba pentin-induced chorea. A patient with Parkinson’s disease developed new-onset dyskinesia (choreoathetosis involving both upper and lower limbs) when gabapentin was introduced, with full resolution when it was withdrawn (78A). Three further cases of chorea have been reported in patients without extrapyramidal disorders taking gabapentin. • A 46-year-old woman developed chorea in her neck, trunk and limbs soon after taking gabapentin for complex regional pain syndrome in her left arm (79A). The chorea lasted for 1 year and resolved completely within 2 weeks of withdrawal of gabapentin. • A 68-year-old hypertensive woman, who reported lumbar pain radiated to the legs associated with paresthesia, developed chorea 30 days after starting to take gabapentin; it resolved 1 week after drug withdrawal (80A). • A 41-year-old man with a thoracic cord lesion and subsequent severe neuropathic pain had right-sided hemichorea after taking gabapentin; it abated gradually after drug withdrawal (81A). An MRI scan was normal but functional imaging of regional cerebral blood flow showed hypoperfusion of the left basal ganglia, especially the left caudate.
A 57-year-old woman with diabetes melli tus and uremia on regular hemodialysis, who had bilateral leg dysesthesia, developed severe dizziness and lethargy after a single dose of gabapentin 75 mg; she recovered rapidly after one session of hemodialysis (82A). Hematologic Leukopenia has attributed to gabapentin (83A).
been
• A 35-year-old woman who had taken gabapentin 300 mg/day for 2 months for a trapped nerve, developed leukopenia and bilateral cervical lymphadenopathy, which resolved within 2 days after drug withdrawal. An infective cause was excluded and the authors concluded that the illness had been caused by gabapentin.
Musculoskeletal A severe myopathy has been attributed to gabapentin (84A). • An 85-year-old woman with diabetes mellitus, severe pain in her legs and difficulty in walking
134 took gabapentin 150 mg tds On the first day she developed psychomotor agitation and gastric pain, which were treated with haloperidol 10 mg and lansoprazole 30 mg. During the next few hours, the muscle pain became more severe and she developed a myopathy with acute renal failure (CK 459 U/l, myoglobin 11 437 ng/ml, creatinine 406 µmol/l), which worsened despite withdrawal of haloperidol and lansoprazole. Gabapentin was then withdrawn and her condition rapidly improved with complete recovery within 10 days.
Severe myotonia and dystonia after general anesthesia has been attributed to gabapentin (85A). This is the first report to suggest that anesthesia may precipitate this rare gabapen tin-induced adverse effect. • A 55-year-old woman who had undergone uneventful general anesthesia on numerous previous occasions took gabapentin for neuropathic pain. Subsequently she developed severe movement disorders on emerging from general anesthesia, unrelated to the choice of anesthetic or antiemetic. The last and most important episode was observed after anesthesia that lasted for 20 minutes, in which sevoflurane 1.8–2.2%, oxygen, dexamethasone 8 mg, and fentanyl 0.1 mg were used. On emerging she developed violent dystonic movements affecting her torso and limbs, and nearly fell off the trolley. The dystonia came in episodes lasting 1–5 minutes, with myoclonic jerks of the arms, and then subsided for the same period. She was given benzodiazepines and the movement disorder gradually abated over 5 days. Before discharge, she reported that she had experienced ‘twitchiness’ on occasions after starting to take gabapentin, which was withdrawn.
Drug withdrawal In two cases abrupt withdrawal of gabapentin after long-term treatment with high doses resulted in withdrawal symptoms, characterized by confusion, tremors, agitation, hallucinations, and vegetative symptoms (tachycardia and fever) (86A). The symptoms promptly resolved after gabapentin was reintroduced.
Lamotrigine
(SED-15, 1990; SEDA-29, 90; SEDA-30, 80; SEDA-31, 113)
Comparative studies In about 100 patients with bipolar II disorder, randomized to
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lamotrigine or lithium, both drugs were effective, but lamotrigine had a better profile of tolerability (87A). In a similar study in 34 patients with unipolar depression, there were no differences in tolerability between lamotrigine and lithium (88c). In a small, open, randomized comparison of lamotrigine and sustained-release carba mazepine for the treatment of newly diag nosed symptomatic seizures after stroke in elderly people, lamotrigine was significantly better tolerated (89c). Lamotrigine and sustained-release carbamazepine have been compared in a double-blind, parallel-group study in patients over 65 years old with newly diag nosed epilepsy who had had at least two unprovoked seizures (90C). The trial lasted 40 weeks, with a 4-week dose escalation phase, during which doses were adjusted up to 500 mg/day for lamotrigine and 2000 mg/day for carbamazepine. The pri mary end-point was retention in the trial, which is a mixed measure of efficacy and tolerability; 68/93 (73%) and 61/92 (67%) of patients randomized to lamotrigine or carbamazepine respectively completed the study. There was a non-significant trend to higher seizure-free rates for carbamazepine and better tolerability for lamotrigine. Pre vious comparative studies in the same populations of elderly patients had shown significant findings in favour of better toler ability of lamotrigine. The explanation for this partial discrepancy may be that because a sustained-release formulation of carbama zepine was used initial target dosages were lower and carbamazepine titration was slower. In a double-blind comparison of lamotri gine 100 mg bd and amitriptyline 50 mg/day in 53 patients with diabetic neuropathy, the two drugs had equal efficacy and favourable tolerability (91c). Placebo-controlled studies There were positive effects on cognitive function and no adverse effects in a double-blind, placebocontrolled study in a small population of patients with schizophrenia in which lamotrigine was added to clozapine (92c).
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Systematic reviews In an analysis of five double-blind, randomized, placebocontrolled trials in the acute treatment of bipolar depression, lamotrigine monotherapy was not effective (93M). The incidences of mania, hypomania, or mixed episodes were low and did not differ between lamotrigine and placebo. Lamotrigine did not precipitate or worsen manic symptoms. The potential role of lamotrigine in patients with schizophrenia resistant to atypical antipsychotic drugs has been evalu ated in several studies. In an analysis of two multicenter, double-blind, placebocontrolled, parallel-group studies of a flexible dose of lamotrigine 100–400 mg/day as add-on treatment in more than 400 patients with schizophrenia and stable residual psychotic symptoms there were similar percentages of adverse effects in the two groups (94M). Serious adverse events were reported by 3 patients who took placebo and 11 who took lamotrigine; they mainly concerned worsening of psychiatric symptoms. Only one serious adverse event, a suicide attempt, was considered to be possibly related to lamotrigine.
135 • A 17-year-old boy with a long history of intractable secondarily generalized tonic– clonic seizures and a normal MRI scan took lamotrigine 25 mg/day initially and gradually increased the dose to 200 mg/day. His epileptic seizures were significantly improved. After 5 days he developed involuntary, continuous, jerky movements of all four limbs, gradually worsening to the point of causing excoriation and bruising of the legs and impaired walking. The disorder, which was thought to be consistent with bilateral ballismus, disappeared about 10 days after withdrawal of lamotrigine.
Two cases of aseptic meningitis have been attributed to lamotrigine (97A). In the first case it had been prescribed for prevention of seizures in an HIV-positive patient. In the second, it had been substituted for valproic acid in a pregnant woman with epilepsy. Myoclonus provoked by lamotrigine has been described in a patient with bipolar affective disorder (98A).
• A 4-year-old boy with cerebral palsy and epilepsy was treated with primidone 375 mg/day and valproic acid 500 mg/day. Since his seizures were not controlled, lamotrigine 250 mg/day (16 mg/kg) was added, and 3 weeks later he developed an intermittent fever and a rash. He became comatose and had generalized tonic–clonic seizures with marked hepatosplenomegaly. He had a low white blood cell count (2.1 109/l), a low hemoglobin concentration, and a low platelet count. Liver function and renal function were abnormal. A bone marrow biopsy showed hemophagocytosis. He was given intravenous immunoglobulin and glucocorticoids, and his liver function, renal function, and pancytopenia resolved within 2 weeks.
Psychiatric Of about 1400 patients with epilepsy taking lamotrigine, 6 developed a psychotic disorder, mainly, but not exclusively, consisting of paranoid– hallucinatory (schizophrenia-like) symptoms (99c). A clear cause and effect relationship could not be determined because of the retrospective nature of the data, even though there was rapid remission of the psychotic symptoms after dosage reduction or withdrawal. Lack of a history of previous psychotic episodes in all cases but one made the author consider that these disorders were de novo psychoses. Lamotrigine can cause positive psychotic symptoms in patients with epilepsy or bi polar disorder, and can exacerbate positive psychotic symptoms in patients with schizoaffective disorder. In two cases positive symptoms in paranoid schizophrenia were exacerbated (100A). There have been sporadic cases of delir ium, hallucinations, and mania in patients taking lamotrigine for various psychiatric conditions (101A–104A).
Nervous system Ballismus has been associated with lamotrigine in a patient with epilepsy (96A).
Mouth Mouth ulcers occurred in two patients taking lamotrigine in whom oxcarbazepine had been withdrawn some weeks before the
Cardiovascular A hemophagocytic synd rome has been attributed to lamotrigine in a high initial dose (95A).
136
observation of the supposed adverse effect (105A). The authors speculated that deinduction may have contributed to the pathogenesis of this adverse effect. Liver Lamotrigine-induced hepatitis has previously been described, is considered to be immune-mediated and is often part of an anticonvulsant hypersensitivity syndrome. A patient with a history of schizophrenia taking lamotrigine 200 mg/day and aripiprazole 15 mg/day developed acute hepatitis, which, according to the Naranjo Probability Scale for adverse drug reactions, was considered probably due to lamotrigine (106A). Other cases have been described (107A–109A). Skin Lamotrigine-induced skin reactions vary from mild urticarial/maculopapular eruptions to potentially life-threatening reactions. In 44 patients the rash recurred after rechallenge in only five cases (110M). The authors concluded that patients who develop a benign rash with lamotrigine can be rechallenged, often without adverse consequences. A patient developed lamotrigine-induced SJS after withdrawal of interferon and riba virin (111A). The authors hypothesized that withdrawal of the immunosuppressive medi cations may have triggered the complication. Musculoskeletal Bone mineral densities in 13 children who were taking lamotrigine monotherapy and who had never been exposed to other medications have been compared with measurements in 36 nonepileptic subjects and 40 epileptic patients who had taken polytherapy (112c). The Z scores of bone mineral density for lamotrigine and control subjects were similar and higher than in those taking polytherapy. These results suggest that lamotrigine does not interfere with bone metabolism. Death Four cases of sudden unexpected death in epilepsy (SUDEP) have been reported in non-hospitalized patients who
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were taking lamotrigine monotherapy (113A). All were women with generalized tonic–clonic seizures. Three had generalized forms of epilepsy and the fourth had an idiopathic localization-related form. Two were seizure free, one had monthly simple partial seizures, and the fourth had had two seizures during the previous week. In the three cases in which post-mortem lamotrigine blood concentrations were measured, the plasma concentrations were low in two and absent in the third. The authors speculated that certain patients with epilepsy may be at increased risk of torsade de pointes and sudden unexpected death when taking lamotrigine, and that the risk may be higher in women. Experimental studies have shown that lamotrigine and other antiepileptic drugs inhibit the cardiac rapid delayed rectifier potassium ion current (Ikr), and drugs with this effect may increase the risk of cardiac dysrhythmias and sudden unexpected death (114E). However, this hypothesis has been questioned, since not all drugs that inhibit potassium channels prolong the QT interval, in particular those that are also active at sodium channels (115H). Teratogenicity Following the publication of data from the UK pregnancy registry, which showed an increased risk of major birth defects in patients who had been exposed to daily doses of lamotrigine over 200 mg/ day, data from the International Lamotrigine Pregnancy registry were analysed to examine the effect of a maximal first trimester maternal dose of lamotrigine monotherapy on the risk of major birth defects (116C). Among 802 exposures, the frequency of these effects was 2.7% and the distribution of dose did not differ between infants with and without major birth defects up to a dose of 400 mg/day. Antiepileptic drugs increase the risk of birth defects by two to six times, and studies of individual drugs have been enabled by the establishment of drug registries. Two reports have yielded contradictory findings on the risk of orofacial clefts after in utero exposure to lamotrigine. The North American Antiepileptic Pregnancy Registry showed no
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overall risk of major malformations in 684 infants exposed to lamotrigine monotherapy, but an increased risk of orofacial clefts (7.3/1000) (117C). This was an 11-fold increased risk compared with a control group of 221 746 unexposed infants. In the same study, data from five registries showed that the risk of orofacial clefts was increased (2.5/1000) in 1623 infants exposed to lamo trigine monotherapy compared with the above-mentioned control group. However, this finding was not confirmed by the EUROCAT congenital anomaly reg ister, which covered 3.9 million births from 19 registries in Europe (118M). Among 72 lamotrigine-exposed births (40 monother apy and 32 polytherapy) the numbers of cases of orofacial clefts were not signifi cantly different between patients who had taken lamotrigine in the first trimester and non-epileptic, non-antiepileptic drug users. This disparity can be explained by the small numbers of children with cleft defects in the lamotrigine group or by bias of some sort. Further information is necessary to clarify the question (119H). Drug formulations A new formulation of lamotrigine (extended-release; XR), administered once daily, has been evaluated in a double-blind, parallel-group, placebocontrolled study in 239 drug-resistant patients with epilepsy (120C). This formulation was effective and particularly well tolerated. The most common adverse events were headache (lamotrigine XR 17%, placebo 15%) and dizziness (lamotrigine XR 18%, placebo 5%). Drug overdose Lamotrigine overdose is not often reported. Most patients present with varying degrees of lethargy, disorientation, ataxia, and stupor (121A). Seizures and status epilepticus can occur (122A–125A). • A 42-year-old woman developed a seizure disorder at the age of 7 years and took carbamazepine and subsequently lamotrigine. After a pregnancy ended in a spontaneous abortion, she took lamotrigine 4.1 g (41 tablets of 100 mg) in a suicide attempt. About 1–2 hours later she had a series of secondarily generalized
137 tonic–clonic seizures over 3 hours without full recovery of consciousness between seizures. The serum lamotrigine concentration was 47 µg/ml.
Drug–drug interactions Aripiprazole Stevens–Johnson syndrome occurred in two patients taking lamotrigine and aripiprazole for schizophrenia (126A). The authors suggested that the risk of a lamotrigine induced severe skin reaction was increased by an interaction between these two drugs. Management of adverse drug reactions Toxic epidermal necrolysis is difficult to treat. Several options have been tried, including systemic corticosteroids, thalidomide, pentoxifylline, ciclosporin, cyclophosphamide, and intravenous immunoglobulin, with different and controversial results (127Ar). One of the most important problems is to reduce the degree of exudation from denudated areas. In one case of TEN due to lamotrigine the application of amniotic membranes on areas of skin detachment reduced exudation and pain (128A).
Levetiracetam
(SED-15, 2035; SEDA 29, 91; SEDA-30, 82; SEDA-31, 116)
Observational studies In 2007 and the first half of 2008 more than 30 observational studies of levetiracetam in different populations of patients with epilepsy or other neurological and psychiatric diseases were published. In a prospective, 16-week, open study, levetiracetam was given as add-on therapy to 1541 adults with treatment-resistant partial seizures (129C). More than 80% (1346 subjects) completed the study, and 7.5% reported adverse events as the most important reason for withdrawing. The more common adverse effects were somnolence (19%), fatigue (14%), dizziness (8%), and headache (10%). There were serious adverse events attributed to levetiracetam in 1%. In a retrospective study of 301 patients who had taken levetiracetam since its intro duction, 138 (46%) stopped taking it during the 24-month follow-up period; adverse
138
events were responsible for 6% of cases of withdrawal (130c). The most commonly reported adverse effects at the time of with drawal were mood disorders, both activat ing (14%) and deactivating (13%), tiredness (14%), and sleepiness (8.5%). Behavioral adverse events were more common in patients with mental handicap. In a prospective, open study, levetirace tam was given as add-on therapy to adults with treatment-resistant partial seizures (131c). The dose was 500 mg bd initially, increasing to 1500 mg bd in a 4-week titra tion period, and followed by a 12-week maintenance period. Of 100 patients 92 com pleted the study and 4 withdrew because of adverse effects, the most common of which were somnolence (36%), dizziness (12%), and headache (8%). Of 379 critically ill patients studied retro spectively, 124 (35%) received levetiracetam 500–4000 mg/day, either orally or via a feed ing tube (132C). The adverse effects profile of levetiracetam was better than with other antiepileptic drugs, particularly phenytoin. For example, encephalopathy occurred in 40 patients (24%) who received phenytoin and in none who received levetiracetam. In a retrospective multicenter 4-year study of levetiracetam 8–100 mg/kg/day (mean 39 mg/kg) in 200 children with refractory epilepsies the retention rate was 49% at 1 year (133C). Adverse events were reported in 24% of the children and in no case were they serious. Emotional lability (7.5%), aggression (6%), depression (3%), and som nolence (2.5%) were the most frequently reported. There were pre-existing behavioral problems in 8%, and less than half of these children had relevant behavioral abnormal ities during follow-up. In a prospective, open, add-on, 26-week study in 33 children aged 4–16 years with refractory epilepsies, levetiracetam was given in an initial dose of 10 mg/kg/day and increased at 2-week intervals up to a maxi mum of 60 mg/kg/day (134c). The retention rate was 70%. Two children stopped taking levetiracetam because of aggressive behavior. All reported at least one behavioral, sleeprelated, cognitive, or physical problem in a standardized adverse effects questionnaire.
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The most common complaints were hyper activity (49%), somnolence (36%), irritability (33%), and aggressive behavior (27%). In a retrospective study in 81 children aged under 4 years with refractory epilep sies, levetiracetam was added to previous therapy in an initial dose of 10 mg/day and increased every week up to a maximum of 62 mg/kg/day (134c). There was at least one adverse event in 34%, most commonly drowsiness (45%), nervousness (36%), cog nitive disturbances (29%), loss of appetite (14%), and sleep disturbances (7%). There were no life-threatening adverse effects. In 129 children and adolescents with refractory epilepsy in a prospective, open, long-term study the retention rate among responders after 3 years was 23% (135c). The rate of adverse effects, which was similar in patients taking monotherapy or polytherapy, was 40% in all patients. The most frequent adverse effects during the first 6 months were fatigue (13%), gastrointestinal disorders (13%), and aggressiveness (7.8%). During long-term treatment no new adverse effects were mentioned by the parents or their care-givers. In a retrospective analysis of 122 children aged under 4 years, followed for at least 6 months, levetiracetam produced seizure remission in 70 (136c). Adverse effects occurred in 34% but required withdrawal in only 16%. The most frequent adverse effects were irritability or other behavioral disturbances (22%), somnolence (5%), diffi culty in sleeping (4%), increased seizure frequency (3.3%), and dizziness (2.5%). In a retrospective study, eight patients with non-convulsive status epilepticus were given levetiracetam, mostly via nasogastric tube, and titrated from a starting dose of 500/1000 mg bd up to a maximum dose of 2000 mg/day within 2 days (137c). The authors stressed the excellent tolerability of this drug compared with standard antiepileptic drugs in a similar population of 11 subjects treated with conventional intra venous medications. In a prospective study of 25 patients with advanced Alzheimer’s disease and new-onset epileptic seizures, levetiracetam was given in a dosage of 1000–1500 mg/day (138c). About
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70% were seizure free for at least 1 year. Four stopped taking levetiracetam because of adverse events. In two small open studies of the use of leve tiracetam for psychiatric diseases in elderly people there were excellent tolerability pro files (139c,140c). Comparative studies See also Topiramate. In a multicenter, double-blind, noninferiority, parallel-group comparison of levetiracetam and controlled-release carba mazepine as first treatments in newly diag nosed epilepsy, adults with at least two partial or generalized tonic–clonic seizures were randomly assigned to levetiracetam 500 mg bd (n = 288) or carbamazepine 200 mg bd (n = 291) (141C). The dosages were increased incrementally to maxima of levetiracetam 1500 mg bd and carbamaze pine 600 mg bd Similar percentages of patients were free of seizures at 6 and 12 months and retention at 12 months was similar in the two groups. Similar propor tions of patients in the groups had at least one adverse effect. However, fewer patients taking levetiracetam group (41/288; 14%) stopping taking therapy because of adverse effects than those assigned to carbamaze pine controlled release (56/291; 19%), although this difference was not significant. Placebo-controlled studies In a multicenter, randomized, double-blind, placebo-controlled, parallel-group study, adults and children with generalized epilepsies, who had tonic– clonic seizures despite stable doses of one or two antiepileptic drugs, were randomized to levetiracetam (target dose 3000 mg/ day for adults; 60 mg/kg/day for children; n = 80) or placebo (n = 84), and a 4-week titration period was followed by a 20-week evaluation period (142C). Levetiracetam produced a significantly greater reduction in seizure frequency. Adverse events caused withdrawal of therapy in 1.3% of patients compared with 4.8% on placebo, but the proportion of patients who had adverse effects was similar in the two groups (72% with levetiracetam and 68%
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with placebo). Psychiatric disorders were the most common drug-related adverse effects, in about 23% of patients treated with levetiracetam and 14% with placebo. Fatigue (10% levetiracetam versus 6.0% placebo), somnolence (5.1% versus 4.8%), headache (5.1%, versus 3.6%), and irritability (5.1% versus 1.2%) were reported in more than 5% of patients. Adolescents and adults with idiopathic generalized epilepsy, who had myoclonic seizures (juvenile myoclonic epilepsy or juvenile absence epilepsy) despite antiepi leptic drug monotherapy, were randomized to levetiracetam 3000 mg/day (n = 60) or placebo (n = 60) in a multicenter, doubleblind, placebo-controlled trial (143C). Two patients taking levetiracetam and one patient taking placebo withdrew because of adverse events and similar numbers of patients in each groups had at least one adverse event. Somnolence was reported in those taking levetiracetam during up-titration. In 22 children with tics, levetiracetam (max imum dose 30 mg/kg/day) or placebo were given for 4 weeks in a crossover, doubleblind, randomized, placebo-controlled trial with a 2-week washout period between treat ments (144c). Adverse effects observed during treatment with levetiracetam included irrit ability, hyperkinesia (only during the escala tion phase), insomnia, sadness, tiredness, verbal aggression, reduced school participa tion, anxiousness, and headache. Cardiovascular In a randomized, placeboand active-controlled, four-way crossover study in 52 healthy adult subjects there were no clinically important changes in the QTc interval after a single dose of levetiracetam 1000 or 5000 mg (145C). Nervous system A 28-year-old man with idiopathic epilepsy and generalized seizures developed an encephalopathy characterized by a slowing of electroencephalographic background activity, increased seizure fre quency, and worsening of neuropsychologi cal findings after starting treatment with
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levetiracetam 3000 mg/day, which had been added to valproate 2000 mg/day (146A). The effects resolved after levetiracetam withdrawal. A 5-year-old girl, with a drug-resistant symptomatic focal epilepsy developed status gelasticus after levetiracetam was added to oxcarbazepine and diazepam (147A). Psychological The effects of lamotrigine 400 mg/day and levetiracetam 2000 mg/day on anger/hostility and mood in patients with epilepsy have been compared in a randomized, double-blind, 8-week, parallelgroup study in 268 adults with drug-resistant partial seizures (148C). There were no significant differences in their effects on seizures and their overall tolerability profiles were similar. However, there were significant differences between the change from baseline to the end of the 12-week maintenance phase in the Anger–Hostility subscale score of the Profile of Mood States in favour of lamotrigine. Psychiatric Levetiracetam-induced halluci nations in the absence of underlying neurological or psychiatric disease have been reported (149A). In another case there was agitation, anxiety, and sleeplessness during treatment with valproate and levetiracetam (150A). Respiratory Interstitial pneumonitis has been attributed to a low dose of levetiracetam in a 9-year-old girl who had a history of epilepsy, cerebral palsy, mental retardation, asthma and repeated hospitalizations for presumed aspiration pneumonia (151A). Metabolism Significant weight loss associ ated with levetiracetam 500–2000 mg/day has been reported in 19 patients (152c). The authors hypothesized that significant weight loss may be a complication of treatment with levetiracetam but that it is probably limited to a small population of susceptible individuals, who remain to be characterized.
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Electrolyte balance A 76-year-old man with complex partial seizures developed asymptomatic hyponatremia after two levetiracetam challenges (153A). Hematologic In a review of studies conducted in healthy men to evaluate the effect of levetiracetam on bleeding time the authors concluded that levetiracetam does not produce clinically significant increases in bleeding time (154R). Thrombocytopenia has been attributed to levetiracetam (155A). • A 64-year-old patient with symptomatic epilepsy taking levetiracetam and valproate developed thrombocytopenia; it did not improve after valproate withdrawal but did after levetiracetam withdrawal.
Drug formulations In 2006, an intravenous formulation of levetiracetam was approved for patients with epileptic seizures who are unable to take oral medications. When intravenous infusions of levetirace tam (100 ml of a solution of 5–15 mg/ml bd over 15 minutes) were given instead of oral doses for 4 days in 25 patients with epilepsy drug-related adverse effects were dizziness, blurred vision, ear pain, dysuria, and reduced diastolic blood pressure in one case each (156c). Intravenous levetiracetam has been retro spectively assessed in 50 critically ill patients for seizure prophylaxis or treatment of seizures or status epilepticus (157c). There were no major adverse effects. Two patients without hematological disorders developed mild transient thrombocytopenia. In 18 episodes of benzodiazepine-refractory focal status epilepticus in 16 patients treated with intravenous levetiracetam (mean dose 944 mg usually given within 30 minutes) there were no severe adverse effects (158c). The use of further antiepi leptic drugs after intravenous levetiracetam was necessary in only two episodes. In two retrospective studies of the effects of intravenous levetiracetam 0–40 mg/kg/ every 8 hours for infants and every 12 hours for older children in small populations
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intravenous levetiracetam was not withdrawn because of adverse effects (159c,160c). In one study, minor adverse reactions in the days after the infusion were considered potentially related to the intravenous formulation. Most were behavioral adverse effects and in three cases there were small falls in white cell count. Drug dosage regimens In an observational study of the effects of an oral loading dose of levetiracetam 1500 mg in 37 adults with epilepsy, followed by a maintenance dose of 500–1000 mg bd starting 12 hours later, there were no spontaneous complaints of adverse effects (161c). On questioning, only four patients reported transient irritability, imbalance, tiredness, or light-headedness. Levetiracetam concentrations, performed in only some cases, were around 30 mg/l after 1–2 hours and 12 mg/l after 12 hours. Drug overdose In two children who acci dentally received doses 4 and 10 times hig her than the usual therapeutic dose of levetiracetam, there were no remarkable a dverse effects; levetiracetam was restarted after a few days with no adverse consequen ces (162A). Drug–drug interactions Antiepileptic drugs The effects of age and co-medications on levetiracetam pharmacokinetics have been retrospectively studied in 629 adult out-patients (163C). Older adults had lower clearances than younger adults and required a mean 40% lower dose to achieve the same serum concentration. Co-medication with enzyme-inducing antiepileptic drugs increased levetiracetam clearance by 24–37%. There were intolerable adverse events in about 32% of the younger patients and about 41% of the older. The most common adverse effects were drowsiness (12% versus 25%), psychiatric effects (depression, anxiety, behavioural changes) (10% versus 14%), cognitive effects (4.1% versus 7.7%), imbalance (1.2% versus 6.9%), dizziness (1.9% versus 4.4%), and headache (3.2% versus 1.9%).
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In a study of the pharmacokinetics of levetiracetam in children with epilepsy who were also taking carbamazepine or valproate, levetiracetam clearance was 7–13% faster and AUC was 15–24% less in those taking carbamazepine compared with valproate (164c). However, these small differences were not considered clinically important. Ciclosporin Lack of interaction between levetiracetam and ciclosporin has been described in a 14-year-old girl who underwent orthotopic heart transplantation, followed by antirejection therapy including ciclosporin (165A).
Oxcarbazepine (SED-15, 2646; SEDA 29, 93; SEDA-30, 83; SEDA-31, 118) Observational studies Oxcarbazepine monotherapy was given for at least 12 weeks to 35 patients with idiopathic trigeminal neuralgia unresponsive to carbamazepine (166c). There was a significant reduction in pain frequency and improved patient satisfaction, but 14 patients reported adverse effects, the most common of which were vomiting (19%), dizziness (17%), nausea (17%), and somnolence (15%). Four patients withdrew because of adverse effects. There was hyponatremia in 10 patients, but none had a sodium concentration below 125 mmol/l. Of 147 epileptic patients taking oxcarba zepine monotherapy for a median of 18 (range 14–36) months, about 60% were sei zure free for at least 12 months and under 40% were unresponsive (167c). There were intolerable adverse effects leading to drug withdrawal in about 9% of patients: Stevens– Johnson syndrome (n = 2); fatigue and drow siness (n = 2); dizziness, nausea and vomiting with normal laboratory tests (n = 2); hypona tremia (<130 mmol/l; n = 5); and raised serum -glutamyl transferase activity (n = 1). Two studies of the use of oxcarbazepine in patients with diabetic neuropathy have been reviewed, a multicenter, open study in 497 patients and an open extension of a double-blind study in 96 patients (168r).
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The initial dose was 300 mg/day, with titra tion over 4 weeks to the maximal tolerated dose or a maximum dose of 900 mg bd. Adverse events most frequently affected the nervous and gastrointestinal systems: 21 and 22% of patients withdrew because of intolerable adverse events in studies 1 and 2 respectively. Serious adverse events were reported in 14% of the patients in each study. Comparative studies Oxcarbazepine in different dosages has been compared with naltrexone in a 90-day randomized open trial for prevention of relapse in 84 detoxified alcohol-dependent patients, of whom 27 received naltrexone 50 mg, 28 received oxcarbazepine 600–900 mg, and 29 received oxcarbazepine 1500–1800 mg (169c). Significantly more subjects remained alcohol free in the oxcarbazepine high-dose group (59%) than in the oxcarbazepine low-dose (43%) and the naltrexone groups (41%). The overall rate of withdrawals because of adverse events was 0.3% in the oxcarbazepine high-dose group and 18.5% in the naltrexone group. Headache (n = 3) and a superficial rash (n = 1) were the only adverse events in patients who took oxcarbazepine. In the oxcarbazepine high-dose group sodium concentrations fell from 140 to 138 mmol//l. Placebo-controlled studies Oxcarbazepine 900 mg/day for the treatment of the symptoms of alcohol withdrawal has been investigated in 50 patients in a double-blind, randomized, placebo-controlled pilot study for 6 days (170c). The amount of rescue medication of clomethiazole capsules needed was the primary end-point. The numbers of adverse events did not differ significantly between the groups, and there were no cases of dosage adjustment or permanent withdrawal. The effects of oxcarbazepine in migraine have been studied in a multicenter, doubleblind, randomized, placebo-controlled, parallel-group trial consisting of a 4-week single-blind baseline phase, a 6-week titra tion period and an 8-week maintenance
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period in 170 patients (171c). The initial dose was 150 mg/day, increasing by 150 mg/day every 5 days to a maximum tolerated dose of 1200 mg/day. There was no difference between oxcarbazepine placebo in mean change in the number of migraine attacks. There were adverse events in 68 oxcarbaze pine-treated patients and 55 placebo-treated patients. The most frequent were fatigue (20% with oxcarbazepine versus 6% with pla cebo), dizziness (18% versus 6%), and nausea (17% versus 4%). Nine patients taking oxcar bazepine and four (4.7%) taking placebo withdrew because of adverse events. Mean sodium concentrations were similar (oxcar bazepine 139 mmol/l; placebo 140 mmol/l). One patient taking oxcarbazepine had clini cally significant hyponatremia (defined as 125 mmol/l) and withdrew. Oxcarbazepine has been studied in the long-term prophylaxis of bipolar I and II dis orders in a 52-week, double-blind, parallelgroup, randomized, placebo-controlled trial in 55 patients who were also taking lithium (172c). The initial dose was 300 mg/day, increasing at 300 mg increments every 4 days up to a total daily dose of 1200 mg/day, which was maintained for 49 weeks. The average time until first recurrence of any type was significantly longer for oxcarbaze pine. There were adverse events considered to be related to treatment in 8 patients taking oxcarbazepine and 12 taking placebo. Series of serum lithium and sodium determinations were carried out during the study and did not change in either group. One patient tak ing oxcarbazepine had clinically significant hyponatremia and withdrew. Nervous system In a retrospective analysis of 290 patients taking oxcarbazepine, 12 had new-onset seizures, all with initially normal neurological examinations and normal electroencephalography; they developed either worsening of pre-existing seizures, new seizure types, and/or electroencephalographic deterioration after the introduction of oxcarbazepine monotherapy (173c). All were otherwise healthy and had no significant cognitive impairment. None of these patients had susceptibility factors for aggravation of
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epilepsy (polytherapy, epileptic enceph alopathy, cognitive impairment, high seizure frequency, multifocal epileptiform electro encephalographic activity). Three patients with migraine and epi lepsy (both under control) developed status migrainosus after the introduction of oxcar bazepine, as part of a switch from carbama zepine; all, despite the use of different drugs, had intractable headache, which recovered only after oxcarbazepine with drawal (174A). • A 70-year-old woman developed chronic daily headache after treatment with oxcarbazepine for control of seizures secondary to a meningioma; the headache resolved after withdrawal of the drug, and was ultimately attributed to oxcarbazepine (175A).
Malignant neuroleptic syndrome has been observed after oxcarbazepine was given to a patient who was already taking amisulpride (176A). • Oxcarbazepine was added and progressively titrated up to 1200 mg/day in a 31-year-old man who was taking amisulpride 800 mg/day for chronic schizophrenia. After 1 month he developed rigidity, tremors, altered consciousness, a mask-like facies, slow movements, sweating, high blood pressure, and pulse fluctuations. He had a mild leukocytosis, mild increases in aminotransferase activities and markedly raised CK and lactate dehydrogenase activities (3038 and 727 U/l respectively). He remained afebrile throughout the entire episode. Other laboratory results were normal and there was no evidence of infection, drug toxicity or thyroid disease. Amisulpride was withdrawn and the dose of oxcarbazepine was reduced to 600 mg/day. Amantadine and levodopa were added, and his symptoms gradually improved and finally resolved after 7 days.
In this case, two of the three major manifes tations of malignant neuroleptic syndrome were present (muscle rigidity and raised serum CK activity) and there were several minor manifestations. Other cases have been described during simultaneous treat ment with both neuroleptic drugs and carbamazepine but this could be the first case involving oxcarbazepine.
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Psychological In a multicenter, open, randomized, active-control, three-arm, parallel-group, 6-month comparison of the effects of oxcarbazepine, carbamazepine, and valproate on cognitive function in 112 children and adolescents with newly diagnosed partial seizures, of whom 99 completed the study (177C). Cognitive function was not impaired. The most common adverse events were fatigue (13% oxcarbamazepine, 14% carbamazepine and 7% valproate), and headache (11, 7, and 24%). Psychiatric Oxcarbazepine-induced psy chosis has been reported in a 71-year-old man with Parkinson’s disease who had also previously had psychotic episodes during dopamine agonist therapy (178A). The authors speculated that this adverse effect might have been caused by a dopaminergic effect of oxcarbazepine and its active metabolite. Electrolyte balance In a retrospective analysis of 414 consecutive patients with epilepsy treated with oxcarbazepine monotherapy or add-on therapy, there was hyponatremia in 9.2% of cases; those who had this adverse effect were significantly older than those who did not (179c). Mineral balance The effects of oxcarbazepine monotherapy on bone turn over have been studied in 34 prepubertal and pubertal children with newly diagnosed idiopathic partial epilepsy (180c). Concentrations of 25-hydroxyvitamin D were significantly reduced after 18 month compared with baseline while gamma glutamyl transferase activity and osteocalcin concentration rose significantly. Parathyroid hormone, calcitonin, phosphorus, alkaline phosphatase, parathyroid hormone, and calcitonin also increased, although non significantly. Three patients who at the start of treatment with oxcarbazepine had had low bone mineral densities (Z-T scores worse than –1.5) developed osteopenia. There were no correlations between bone mineral density and increased osteocalcin
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concentrations or reduced 25-hydroxy vitamin D concentrations. The mechanism of oxcarbazepine-induced osteopenia has n ot been clarified. Hematologic Leukopenia and thrombocy topenia have previously been observed in association with oxcarbazepine, and pancy topenia has also been reported (181A). Hemolytic anemia occurred in a 75-year old man after 3 months of oxcarbazepine therapy and resolved after withdrawal (182A). A woman with a schizoaffective disorder took oxcarbazepine for 2 weeks for treat ment of aggression and developed a fever with lymphadenopathy, leukopenia, and thrombocytopenia, which subsided a few days after oxcarbazepine withdrawal and glucocorticosteroid treatment (183A). Liver A 16-year-old girl taking oxcarbazepine for a seizure disorder developed a giant hepatic adenoma (184A). The authors hypothesized that this benign tumor, which is known to be hormone regulated, had been induced by alterations in normal hormone concentrations by oxcarbazepine. An association between hepatic adenomas and oxcarbazepine has also been observed in animals (185S). Skin Oxcarbazepine-associated angio edema is a rare but potentially lifethreatening reaction. Nine cases have been identified through the FDA’s Adverse Event Reporting System and a literature search; the reporting rate for angioedema was calculated to be 9.8 cases per million children (186A). The delay between the start of drug use to the onset of the event ranged from 30 minutes to 7 months. All the patients recovered after drug withdrawal and in some instances following treatment with glucocorticoids. • A 4½-year-old child, weight 18.5 kg, with hydrocephalus and a seizure disorder developed acute dyspnea and stridor 30 minutes after swallowing a first dose of an oral suspension of
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oxcarbazepine. The symptoms worsened and facial swelling appeared over the next 2 hours. He was afebrile, tachycardic, and tachypneic; his pharynx was not erythematous and his tonsils were not enlarged. The airway showed subglottic narrowing and a thickened epiglottis. He was given dexamethasone and adrenaline by nebulizer and improved over 2 hours.
From January 2001 to September 2006, only seven cases of oxcarbazepine-induced DRESS, compared with 86 cases related to carbamazepine, were notified to the French Pharmacovigilance network (187C). This dif ference was considered to have been related to lower oxcarbazepine sales. Patients taking oxcarbazepine had cutaneous eruptions that were erythematous, morbilliform, papular or eczematous and appeared between 11 and 49 days after the start of treatment. Lymphade nopathy (n = 4) and hypereosinophilia were also present. Two patients had cholestatic hepatitis. One had interstitial pneumonia. All recovered within an average of 4 weeks. Oxcarbazepine was the only prescribed drug in three cases; in the other four cases causality assessment was higher for oxcarbazepine than other medications. Oxcarbazepine-induced DRESS has also been reported in a 13-year-old boy (188A) and in a 46-year-old woman with Crohn’s disease and a polyneuropathy (189A). Immunologic Drug-induced lupus-like syndrome has been reported in a child with epilepsy who was receiving oxcarbazepine and valproic acid (190A). Oxcarbazepine was withdrawn, the dose of valproate was reduced, and glucocorticoid treatment was started. The symptoms resolved after 2 days.
Teratogenicity A girl was born with micrognathia, low-set ears, facial dimorphism, and unilateral radius aplasia to a mother who had taken lamotrigine and oxcarbazepine during pregnancy (191A). Drug overdose The concentrations of oxcarbazepine and its active metabolite, 10-hydroxycarbazepine, were measured in
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various organs and tissues in a 27-year-old woman with epilepsy who was found dead in bed and in whom oxcarbazepine intoxication was suspected (192A). The concentrations of 10-hydroxycarbazepine were femoral blood 66 mg/kg; muscle 40 mg/kg; liver 62 mg/kg; gastric contents 27 mg/kg; vitreous humor 25 mg/kg. In 26 post-mortem cases involving oxcarbazepine concentrations of the active metabolite ranged from 2.2 to 48 mg/kg with a median of 25 mg/kg. In only two cases with high metabolite concentration was the drug judged to have contributed to death.
Phenobarbital and primidone (SED-15, 2798; SEDA-29, 95; SEDA-30, 85) Comparative studies In a 12-month, double-blind, randomized comparison of the behavioural adverse effects of phenobarbital (n = 54) and carbamazepine (n = 54) in Bangladeshi children with epilepsy (193c), 10 children developed excessive restlessness and hyperactivity. Four were taking phenobarbital and six carbamazepine. These were considered unacceptable in one patient taking phenobarbital and in three taking carbamazepine. There was no excess of behavioral adverse effects associated with phenobarbital. Hematologic A 22-year-old woman devel oped aplastic anemia after taking phenobarbi tal for 6 years (194A). Liver In two patients with a long history of epilepsy taking phenobarbital who suddenly died, the liver parenchyma showed rich portal inflammatory infiltrates and inflammatory reactions in the biliary ducts (195A). The authors speculated that chronic liver damage in these patients had been caused by phenobarbital. Drug–drug interactions HIV protease inhibitors In vitro studies have suggested
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that tipranavir inhibits CYP2C9 and CYP2C19 and that ritonavir induces oxidation by these two isoenzymes. A 49-year-old white man with AIDS and epilepsy had a seizure and reduced phenobarbital concentrations after treatment with tipranavir þ ritonavir (196A). The authors concluded that the net effect of the co-administration of these two drugs is induction of CYP2C9 and/or CYP2C19.
Phenytoin and fosphenytoin
(SED 15, 2813; SEDA-29, 95; SEDA-30, 85; SEDA-31, 120)
Comparative studies In a randomized open comparison of intravenous phenytoin (n = 50) and intravenous valproate (n = 50) in patients with benzodiazepine-refractory status epilepticus the adverse effects attributed to phenytoin were hypotension in six cases and respiratory depression in two (197c). Cardiovascular Phenytoin in supratherapeutic concentrations can unmask an electrocardiographic Brugada pattern, which is a susceptibility factor for sudden death (198A). • An 81-year-old Caucasian man with dementia and seizures taking phenytoin developed new right bundle branch block with coved ST segment elevation in leads V1–3, consistent with a type 1 Brugada pattern. The serum phenytoin concentration was 22 mg/l (usual target range 10–20). Phenytoin was withdrawn and the electrocardiogram returned to baseline after 24 hours. The patient remained free of cardiac events for 3 years afterwards.
Nervous system Cerebellar atrophy and skull thickening has been described as a result of chronic phenytoin intoxication (199A). Cerebellar symptoms have also been described (200A, 201A). Skin Prophylactic use of phenytoin during cranial irradiation caused erythema multiforme in a 60-year-old woman with an
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intraductal adenocarcinoma of the breast and cerebral metastases (202A). Phenytoin-induced toxic epidermal necrolysis has been described in two patients. In one the rash occurred a few days after the start of prevention of postsurgical seizures (203A) and in the other in a patient under going brain radiotherapy (204A). DRESS, attributed to phenytoin, showed cross-reactivity to phenobarbital confirmed by a positive patch test (205A). Musculoskeletal Phenytoin-induced osteo malacia has again been reported, with severe bone pain and multiple pathological pseudofractures (206A). Immunologic In 25 patients taking phe nytoin, folic acid 1 mg/day failed to ame liorate phenytoin-induced salivary IgA hyposecretion (207c). Drug–drug interactions Efavirenz An unexpected interaction between phenytoin and efavirenz resulted in a dramatic reduction in efavirenz plasma concentrations in a 35-year-old man with newly diagnosed HIV-1 infection (208A). Erlotinib Inhibition of phenytoin meta bolism caused by erlotinib has been described in a patient with a non-small-cell lung cancer and cerebral metastases (209A). • A 70-year-old man taking phenytoin took TS-1 (a combination formulation of tegafur, gimeracil, and oteracil potassium) for gastric cancer and after 1 month developed light headedness and had repeated falls associated with increased serum phenytoin concentrations (33 mg/l, 132 µ mol/l) (210A).
Management of adverse drug reactions A 12-year-old boy with frontal lobe epilepsy and paroxysmal kinesigenic choreoathetosis had a phenytoin-induced maculopapular eruption. Desensitization was attempted using phenytoin powders mixed with lactose (211A). The starting dose was 1 mg/day, and
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the dose was doubled every 2 days. A druginduced lymphocyte transformation test before desensitization was negative, with a sti mulation index of 130%. Before desensitiza tion, the proportion of carboxyfluorescein succinimidyl ester low CD4þ cells in whole CD4þ was 3%; After desensitization, pheny toin-specific carboxyfluorescein succinimidyl ester low CD4þ cells fell to background level. The authors proposed that this techni que can be used to diagnose and monitor desensitization of drug hypersensitivity.
Pregabalin (SEDA-28, 56; SEDA-30, 86) Observational studies Clinical experience with pregabalin when used as add-on therapy in 101 adult patients with refractory partial epilepsy followed for at least 1 year has been reviewed retrospectively (212c). Adverse effects required withdrawal in 15 patients and 9 withdrew because of inefficacy and adverse events. The most common adverse events were weight gain (26%), dizziness/ataxia (20%), lower limb edema (9.9%), and blurred vision (3.9%). In a randomized study of the quality of analgesia in women undergoing day-case gynecological laparoscopic surgery, preme dication with pregabalin 75 mg (n = 30) or 150 mg (n = 26) was compared with diaze pam 5 mg (n = 28) (213c). Analgesia was better after pregabalin 150 mg than diaze pam 5 mg. Dizziness occurred in 64% of those treated with diazepam, 53% of those treated with pregabalin 75 mg and 80% of those treated with 150 mg. Headache occurred in 32, 27 and 19% of patients respectively; blurred vision in 11, 20, and 27%; lack of concentration in 74, 67, and 85% and pruritus in 7, 23 and 19%. A flexible-dose regimen of pregabalin has been assessed in 217 patients with dia betic peripheral neuropathy or postherpetic neuralgia in an open study (214c); 125 had at least one adverse event, including a psy chotic disorder in one subject. The most frequent adverse effects were dizziness (n = 33) and fatigue (n = 31). Increased
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weight and peripheral edema occurred in 18 and 11 subjects respectively. In all, 17 sub jects withdrew because of adverse effects.
malaise. Four dropouts in the placebo group were due to fatigue, palpitation and withdrawal of consent.
Placebo-controlled studies The effect of pregabalin on pain has been evaluated in three double-blind, placebo-controlled, parallel-group studies with similar designs. In the first study, 395 adults with posther petic neuralgia were randomized to placebo or pregabalin 150, 300, or 600 mg/day (n = 96, 99, 99, and 101); adverse events caused withdrawal in 3, 5, 11, and 13 patients in the respective groups (215C). The most common adverse events were diz ziness (2 patients randomized to placebo versus 3, 9, and 14 patients randomized to the increasing doses of pregabalin), periph eral edema (2 versus 5, 9, and 10) and somnolence (1, 5, 4, and 8). The NNTH (withdrawal because of adverse events) was 10 for pregabalin 600 mg/day. In a second study pregabalin was evalu ated in 748 patients with pain associated with fibromyalgia, who were randomized to placebo or pregabalin 300, 450, or 600 mg/day bd adverse events caused with drawal in 19, 35, 41 and 62 patients in the respective groups (216C). The most com mon adverse events were dizziness (n = 16, 60, 80, and 88), somnolence (10, 39, 44, and 53) and weight gain (5, 15, 16, and 26). In a third study (217C) 40 patients with central neuropathic pain caused by brain or spinal cord injuries received escalating doses of either pregabalin (150, 300, and 600 mg/day; n = 20) or matching placebo capsules (n = 20). Three patients rando mized to pregabalin and three randomized to placebo withdrew because of adverse effects. The most common adverse effects were nausea (6 and 4), worsening cognitive performance (6 and 8), somnolence (9 versus 9), dizziness (7 and 6) and confusion (7 and 4). In a double-blind, randomized, placebocontrolled study of pregabalin in essential tremor in 20 patients, pregabalin produced a significant reduction in tremor amplitude (218c). Three patients who took pregabalin withdrew because of dizziness, flu and
Systematic reviews A model has been used to describe the relationship between pregabalin exposure and the adverse event of dizziness; data from six double-blind clinical studies were used (219H). Cardiovascular Four patients with chronic heart failure and left ventricular systolic dysfunction had exacerbation of heart failure after they started to take pregabalin for neuropathic pain (220A, 221A). The authors hypothesized that pregabalin has a deleterious effect on failing myocardium through blockade of calcium channels. • A 69-year-old man with ischemic cardiomyopathy and a left ventricular ejection fraction of 40% was treated with furosemide 40 mg/day, bisoprolol 5 mg/day, glyceryl trinitrate patches 10 mg, eplerenone 25 mg/day, atorvastatin, lansoprazole, insulin, diltiazem, and nicorandil. He was given pregabalin for neuropathic pain related to diabetes. Over the next 4 weeks he became increasingly short of breath and noticed weight gain. He had a raised jugular venous pressure, pitting ankle edema, and increased concentrations of B type natriuretic peptide. The dosage of furosemide was increased and pregabalin was withdrawn. After 3 days he started to improve. • A 92-year-old patient with a history of paroxysmal fibrillation developed a sinus tachycardia followed by atrial fibrillation and congestive heart failure 15 hours after a first dose of pregabalin (222A).
Nervous system Pregabalin can evoke myoclonic jerks in patients with focal epilepsies and in patients with severely impaired renal function. Two patients with arteriosclerotic encephalopathy, who had never had seizures before, developed generalized status epilepticus while taking pregabalin for chronic pain (223A). The authors suggested that old age, cognitive impairment, and reduced creatinine clearance may predispose to this complication.
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Hematologic A 45-year-old woman taking pregabalin developed mild neutropenia after 2 days and gradually recovered after pregabalin withdrawal (224A). Liver Cholestasis was attributed to pregabalin in a 61-year-old man (225A). Drug overdose Intentional overdose with lamotrigine and pregabalin in a 29-year-old man caused seizures and a reduced level of consciousness, with peak drug concentrations of 45 mg/l (lamotrigine) and 60 mg/l (pregabalin) (226A). Drug–drug interactions Antiepileptic drugs The effects of dose, sex, age, and co-medications on serum pregabalin con centrations have been studied in 198 samples from 167 patients (227c). The relationship between pregabalin weightcorrected doses and serum concentrations was nearly linear. The serum pregabalin concentrations were higher in older patients but were not affected by sex. They were significantly reduced by carbamazepine, phenytoin and oxcarbazepine, but not altered by phenobarbital, levetiracetam, or valproate. Management of adverse drug reactions Weight gain is a characteristic adverse effect of pregabalin. In a randomized controlled trial, the effects of extended versus standard patient counselling on the risk of weight gain was assessed in 98 adults with epilepsy eligible for pregabalin add-on treatment (228c). Weight gain correlated with the number of anticonvulsant drugs but there was no effect of extended counselling.
Tiagabine
(SED-15, 3419; SEDA-29, 95; SEDA-30, 89; SEDA-31, 123)
Observational studies In an open study, in which tiagabine monotherapy was substituted
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for SSRI or SNRI antidepressants in 26 patients with generalized anxiety disorders who had antidepressant-induced sexual dysfunction (229c) the symptoms of sexual dysfunction improved. The most commonly reported adverse events were dizziness/ light-headedness (23%), nausea (23%), and fatigue (8%). Tiagabine has been evaluated in 54 patients with social anxiety disorder in an open study (230c). The most common adverse effects were somnolence (n = 12), dizziness (n = 10), and nausea/vomiting (n = 6). Placebo-controlled studies In a 12-week, double-blind, placebo-controlled study of the efficacy of tiagabine in 141 subjects with cocaine dependence there was reduced cocaine craving and improved global functioning (231c). Those who took tiagabine were significantly more likely to have dizziness, fatigue, and influenza. In a 12-week, multicenter, double-blind, placebo-controlled study of the effects of tiagabine in 232 patients with post traumatic stress disorder, tiagabine was not associated with weight gain, changes in sexual function or worsening of depressive symptoms (232C). Systematic reviews The results of three 10-week, double-blind, placebo-controlled studies in adults with generalized anxiety disorder have been reviewed (233R). A total of 20 serious adverse events were reported across the three studies by 13 of 1106 patients (1.2%) who took tiagabine and 6 of 684 patients (0.9%) who took placebo. The most common adverse events were dizziness, headache, nausea, fatigue, and somnolence. Between 9 and 16% of patients withdrew because of adverse events in the fixed dose study compared with 10% of those who took placebo. In the two flexible dose studies 11–15% of those randomized to active treatment and 4–8% of those randomized to placebo withdrew because of adverse events.
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Nervous system Myoclonic status epilepticus has been described in a nonepileptic patient taking tiagabine(234A). Tremor is one of the most typical adverse effects associated with tiagabine. • A 66-year-old man with a 10-year history of essential tremor took tiagabine 2 mg bd for off-label treatment of anxiety and developed marked exacerbation of his tremor after 10 days (235A).
Drug overdose Tiagabine overdose with an unusual presentation and the highest serum drug concentration ever reported (4600 µg/l, 1725 mmol/l) has been described (236A). • A 44-year-old woman took 100 tiagabine 15 mg tablets (1500 mg; 25 mg/kg) and deve loped vomiting, coma, myoclonus, generalized rigidity, bradycardia, hypertension, hyper salivation and generalized piloerection. Coma lasted 10 hours and was followed by severe agitated delirium. She recovered fully within 26 hours.
Topiramate
(SED-15, 3447; SEDA-29, 96; SEDA-30, 89; SEDA-31, 124)
Observational studies Topiramate as addon therapy in 450 epileptic patients has been assessed in an open prospective study (237C). Only 5% of patients withdrew because of an adverse event. The most common treatment-related adverse events were impaired memory (4.2%), somnolence (3.6%), dizziness (2.7%), weight loss (2%), and depressive symptoms (2%). In 320 patients (275 adults and 45 chil dren) with epilepsy in a prospective, open, long-term (36 months) trial of topiramate given either as monotherapy or adjunctive therapy there were topiramate-associated adverse events in 98 patients (31%) (238C). The most common were weight loss (8.4%), paresthesia (7.2%), poor memory (3.8%), and dizziness (2.8%). Topiramate was withdrawn because of adverse events in 13 patients (4.1%). The rate of adverse events was significantly higher in patients
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treated with topiramate monotherapy (48%) than in those on polytherapy (16%). In a 20-week, multicenter, open trial of topiramate as primary or adjunctive therapy for infantile spasms in 544 patients, adverse effects occurred in 211 (39%) (239C). The most common were anorexia and somnolence. Comparative studies The effect of topiramate on cognitive function and behaviour has been compared with that of carbamazepine in a 4-week, multicenter, open, parallel-group, randomized, observerblinded trial in 88 children with benign rolandic epilepsy (24c, 59c). The minimum target dose of topiramate was 50 mg/day and that of carbamazepine 20 mg/kg/day. Of all cognitive variables measured, arithmetic showed significant worsening with topiramate and a maze test showed a significantly greater improvement with carbamazepine. Of behavioral variables, there were no significant changes, but the scores had a negative trend for topiramate. In a retrospective analysis of all patients referred to a tertiary epilepsy centre who had been taking topiramate (n = 429) or levetir acetam (n = 301) the retention rates after 12 and 24 months of treatment were higher with levetiracetam (66% and 46% respectively) than topiramate (52% and 38% respectively) (240C). The adverse effects profiles were different. Levetiracetam was associated with mood disorders such as agitation, aggression, and hyperirritability (14%), tiredness (14%), and depression or apathy (13%). Topiramate was more often associated with mental slowing (28%), dysphasia (15%), sleepiness (8.5%), gastrointestinal complaints (11%), paresthesia (7.5%), loss of appetite (7.0%), skin complaints (6.6%), and weight loss (6.2%). Sibutramine 5–15 mg/day and topiramate 25–600 mg/day have been compared as adjunctive treatments for psychotropic drug-associated weight gain in 46 over weight or obese patients with bipolar disor der in a 24-week, open, flexible-dose trial (241c). Only four patients taking sibutra mine and six taking topiramate completed the trial. Worsening of mood was the most
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common reason for withdrawal of both drugs. With topiramate, other reasons for withdrawal were cognitive impairment, visual problems, ear pressure, dry mouth, and tremor. In a double-blind, dose-controlled study of topiramate as monotherapy in 470 newly diagnosed children or adolescents with epi lepsy, eligible patients were randomized to topiramate 50 mg/day (n = 74) or 400 mg/ day (n = 77) and followed for at least 6 months (242C). The probability that patients remaining in the study were seizure free at 6 months was 78% with 50 mg/day and 90% with 400 mg/day. The incidence of treatment-limiting adverse events was 4% in the former and 14% in the latter. The most common adverse events were headache, reduced appetite, weight loss, somnolence, dizziness, difficulty in concen tration/attention, and paresthesia. Placebo-controlled studies Low doses of lamotrigine 50 mg/day and topiramate 50 mg/day have been compared in a fourphase, 1-month, crossover, placebocontrolled study in migraine prophylaxis in 60 patients with frequent migraine (243c). No patients withdrew because of adverse effects. During treatment with topiramate, 15% of patients had adverse effects, of which the most common were paresthesia, sleepiness, and gastrointestinal disturbances. Adverse effects were not significantly more common with either drug versus placebo. Topiramate 100 mg/day for chronic migraine has been evaluated in a 16-week, parallel-group, multicenter, double-blind, randomized, placebo-controlled trial in 306 patients (244C). Topiramate significantly reduced the number of migraine headache days. Treatment-related adverse events occurred in 65% of those taking topiramate and in 43% of those taking placebo. The most common were paresthesia (29% versus 7.5%), fatigue (11% versus 9.3%), difficulty in concentrating (9.4% versus 2.5%), and dry mouth and nausea (8.1% for both events versus 2.5% and 5.6% with placebo). Patients randomized to topiramate experi enced weight loss of 2.3–2.9 kg.
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Withdrawal of migraine prophylaxis with topiramate versus continuation has been the subject of a double-blind, placebocontrolled study in 818 patients who first received topiramate 50–200 mg/day in a 26-week open phase and were then randomly assigned to continue this dose or switch to placebo for a 26-week double-blind phase (245c). Patients in the placebo group had more days on acute medication for migraine episodes than those who took topiramate. The most common adverse events in the open phase were paresthesia (50%), fatigue (12%), impaired attention (12%), anorexia (11%), weight loss (9%), nausea (9%), dysgeusia (6%) and dizziness (6%). In the subsequent double-blind phase, these adverse events were less frequent. For example, paresthesia was present in 77 (30%) patients with the active drug and in 55 (21%) patients treated with placebo, fati gue in 7% versus 4%, impaired attention in 4% versus 5%, anorexia in 5% versus 3%, and weight loss in 9% versus 7%. Few serious adverse events were reported, and there was no difference between those who took topir amate or placebo. In a 14-week, double-blind, randomized, placebo-controlled trial in 371 patients with alcohol dependence, topiramate was more efficacious than placebo in reducing the per centage of heavy drinking days from base line (246c). The most common treatmentrelated adverse events were paresthesia (51% versus placebo 11%), headache (24% versus 32%), taste disturbance (23% versus 4.8%), fatigue (22% versus 18%), anorexia (20% versus 6.9%), insomnia (19% versus 16.%), impaired concentra tion/attention (15% versus 3.2%), nervous ness (14% versus 7.5%), impaired memory (13% versus 6.9%), somnolence (12% versus 10%), diarrhea (12% versus 8.5%) and dizziness (12% versus 5.3%). In a 14-week, multicenter, double-blind, randomized, controlled study of the effects of topiramate up to 300 mg/day in 371 alco hol-dependent subjects, topiramate signifi cantly reduced obsessional thoughts and compulsions about using alcohol (247C). Dropout rates due to adverse events were 19 and 4.3% for topiramate and placebo
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respectively. The most common adverse events were paresthesia (51% topiramate versus 11% placebo), headache (24% versus 32%), taste disturbance (23% versus 4.8%), fatigue (22% versus 18%), anorexia (20% versus 6.9%), nausea (10% versus 17%), insomnia (19% versus 16%), impaired concentration/attention (15% versus 3.2%), nervousness (14% versus 7.4%), impaired memory (13% versus 6.9%), and somno lence (12% versus 10%). Topiramate has been evaluated in a 16-week, multicenter, parallel-group, flexible-dose, placebo-controlled trial in 394 patients with binge eating disorder asso ciated with obesity (248c). Topiramate sig nificantly reduced binge eating, weight, and BMI. Withdrawal rates for adverse events were 16% for patients taking topiramate and 8% for those taking placebo. The most common adverse events were par esthesia (56% versus placebo 12%), somno lence (17% versus 13%), nausea (16% versus 12%), taste disturbance (14% versus 1.0%), dry mouth (13% versus 11%), impaired concentration/attention (13% ver sus 2.5%), impaired memory (12% versus 5.9%), and headache (12% versus 14%). Systematic reviews In a pooled analysis of three large multicenter, randomized, double-blind, placebo-controlled trials the time course of adverse events associated with topiramate has been evaluated in the prevention of migraine (249R). In all randomized studies, patients (topiramate 100 mg/day, n = 386; placebo n = 372) had a 4-week titration period and a 22-week maintenance period. Adverse events led to treatment withdrawal in 25% of patients taking topiramate and 11% of those taking placebo. Paresthesia, any cognitive symptoms, nausea, and loss of appetite were more common with topiramate. Adverse events that lead to withdrawal of topiramate are more likely to occur during dose titration. Patients who do not have adverse events within the first 6 weeks of treatment are unlikely to have them later. In other words, the adverse effects of topiramate have an intermediate time course (250H).
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Nervous system The relation between paresthesia, a typical adverse effect of topiramate 100 mg/day, and headache has been studied in 133 migraineurs in a prospective, open study, and treated with topiramate (251c). Patients who developed paresthesia (n = 73) had fewer headache days than those who did not (n = 60), and had a higher responder rate (58% versus 38% and 66% versus 42% after 3 and 6 months of treatment respectively). Dementia has been attributed to topira mate (252A). • A 77-year-old woman took topiramate up to 200 mg/day for a depressive disorder. Although her symptoms improved, after 1 month she gradually developed a dementing disorder characterized by forgetfulness, language problems and difficulty in performing daily activities. She was disoriented in time, recalled only a few items and had difficulty in naming objects. Her score on the Mini-Mental State Examination was 18. An MRI scan of the brain and all other examinations routinely performed in patients with dementia were normal. Topiramate was withdrawn, and 1 week later she had improved, with a MiniMental State Examination score of 29.
There have been two reports of restless legs syndrome in patients taking topiramate (253A). • When a 26-year-old woman with post-traumatic epilepsy, whose seizures were not controlled by phenobarbital, was given topiramate 50 mg bd she developed nocturnal leg discomfort during inactivity with an urge to move her legs. All investigations were unremarkable and neurography excluded a neuropathy. Topiramate was gradually switched to carbamazepine and the restless leg syndrome disappeared.
Two patients developed reversible facial myoclonus following treatment with topira mate (254A). • A 28-year-old man with partial epilepsy was converted from phenytoin to topiramate monotherapy, but 4 days after taking 75 mg bd he started to have symmetrical synchronous twitching of his facial muscles, predominantly involving the forehead. Electromyography showed that the twitches occurred in clusters lasting up to 10 seconds,
152 with a frequency of 6–8 Hz, and each jerk lasted between 50 and 100 ms. Neurological examination was normal. Gradual withdrawal of topiramate led to improvement and disappearance of facial myoclonus, with no recurrence over 10 months of oxcarbazepine monotherapy.
In a subsample of 67 adult patients with partial seizures participating in a random ized, double-blind comparison of adjunctive lamotrigine and adjunctive topiramate, a self-administered computer task was used to measure divided attention (255c). The results of this test correlate with driving performance. Adjunctive topiramate nega tively affected both simple target identifica tion and divided attention performance. The authors concluded that therapeutic doses of adjunctive topiramate compromise driving-related visual and cognitive skills. Psychological In an observational study of the cognitive adverse effects of levetiracetam and topiramate in 30 consecutive patients with focal epilepsy taking levetiracetam and 21 taking topiramate either as monotherapy or as add-on medication, the patients did not differ significantly with respect to cognitive performance at the start of treatment (256c). The initial dosage of levetiracetam was 500 mg/day, and 250 mg was added every 3 days; the initial dosage of topiramate was 25 mg/day, and the speed of titration was 25 mg every 4 days. Those who took topiramate had impaired cognitive speed, verbal fluency, and short-term memory; those who took levetiracetam had no changes in cognitive performance.
Psychiatric In a systematic analysis of a case registry of over 800 patients who had psychiatric adverse events during trials with topiramate and levetiracetam, 108 patients had a trial with both drugs, of whom 9 developed psychiatric disturbances with both drugs and 71 did not with any of them (257R). Comparison of these two groups of patients did not show any difference in epilepsy-related variables. This analysis suggests that a subgroup of patients is
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generally susceptible to psychiatric disturbances during antiepileptic drug treatment, despite different pharmacological properties of these molecules. A young woman had several panic attacks while taking topiramate (258A). The panic attacks ended after drug with drawal and recurred after reintroduction, supporting a cause-and-effect relation. Delusional parasitosis is characterized by the conviction that small organisms are infesting the body, despite the absence of confirmatory evidence; it can occur in a wide variety of organic and psychiatric disorders and has been attributed to topiramate (259A). • A 48-year-old woman with temporal lobe epilepsy took topiramate and developed intense pruritus and the firm belief that her skin was infected by parasites. Topiramate was withdrawn and her unshakeable conviction abated completely without the use of antipsychotic drugs.
Hypomania has been attributed to topir amate (260A). • A 30-year-old woman with no history of psychiatric disorders took topiramate for migraine prophylaxis and suddenly developed hypomania after an increase in topiramate dosage to 200 mg/day. This association has been reported before (261C).
Sensory systems Suprachoroidal effusions have been attributed to topiramate. • A 27-year-old woman developed impaired vision in both eyes due to acute myopia 2 weeks after starting to take topiramate (262A). Ultrasound showed that she had suprachoroidal effusions in both eyes. The symptoms and clinical findings resolved completely after withdrawal of topiramate and administration of topical atropine 1% and prednisolone acetate 1%.
Severe acute bilateral angle closure glau coma with complete visual loss after dou bling the dosage of topiramate has been described (263A). Metabolism Topiramate-induced longterm weight changes have been studied in
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120 children and adults who took topiramate for 1–5 years (264c). At 1, 2, 3, 4, and 5 years BMI was 97.6%, 95.5%, 97.6%, 97.4%, and 109% of baseline. At 1 year, the patients with higher baseline BMI and who were younger had lost more weight. Doses over 6 mg/kg/day were associated with a greater fall in BMI.
The effect of combining topiramate and olanzapine on body weight has been studied in a long-term follow-up study of a previous double-blind trial (269c). All those who had taken topiramate þ olanzapine (n = 25) or olanzapine alone (n = 18) were observed in an 18-month open study. Topiramate reduced olanzapine-related adiposity.
Acid–base balance A critically ill patient treated with topiramate for a refractory seizure disorder developed central neurogenic hyperventilation, as a result of cerebrospinal fluid acidosis (265A). Alkalosis due to hyperventilation has been attributed to topiramate (266A).
Management of adverse drug reactions Choroidal drainage was performed in one eye of a patient who, 2 weeks after starting to take topiramate, had had acute bilateral angle closure secondary to cilio-choroidal effusion (270A). After choroidal drainage, the anterior chamber deepened, the corneal edema resolved, and intraocular pressure was controlled without medication.
• A 42-year-old woman with a history of migraine without aura was given topiramate 25 mg/day, increasing by 25 mg per week up to 100 mg/day. While taking 50 mg/day she developed exerciseinduced dyspnea, which became severe at 100 mg/day. Physical examination was normal, but blood gas analysis showed a respiratory alkalosis, probably due to hyperventilation, with hyperoxia and hypocapnia. Pulmonary function tests and a chest X-ray were normal. Topiramate was withdrawn and her dyspnea disappeared within 2 days.
Fetotoxicity Two siblings whose mother took topiramate during both pregnancies both developed neonatal hypocalcemic seizures (267A). The authors proposed that topiramate exposure in utero can cause hypoparathyroidism and subsequent hypocalcemia. Drug–drug interactions Antipsychotic drugs Topiramate, gradually titrated up to a final dosage of 200 mg/day for 6 weeks, was given to 38 outpatients with schizophrenia or bipolar disorder taking long-term clozapine (250–500 mg/day, n = 10), olanzapine (10–20 mg/day, n = 12), risperidone (3–6 mg/ day, n = 9), or quetiapine (200–600 mg/day, n = 7) (268c). Plasma concentrations of clozapine and its metabolite norclozapine, olanzapine, risperidone and its metabolite 9-hydroxyrisperidone, and quetiapine did not change significantly.
Valproate sodium and semisodium (divalproex) (SED-15, 3579; SEDA-29, 97; SEDA-30, 92; SEDA-31, 126) Observational studies In an open, prospective study of first-line monotherapy with valproate in 1192 adults and 792 children with focal onset epilepsy, the overall retention rate at 6 months was 90% and 77% of subjects were seizure free (271c). Comparative studies In an open study, 100 patients with a status epilepticus refractory to benzodiazepines were randomly assigned to intravenous valproate or phenytoin (272c). Valproate was successful in 88% and phenytoin in 84%. There were adverse effects in four patients treated with valproate, in all cases characterized by small rises in liver enzymes. Eight patients treated with phenytoin had either hypotension (6 cases) or respiratory depression (2 cases). Intravenous sodium valproate or diaze pam have been compared in 40 children with for control of refractory status epilep ticus in an open study (273c). Status epilep ticus was controlled in 80% with valproate
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and 85% with diazepam. None of the patients who were given valproate required ventilation or developed hypotension, whereas of those who received diazepam 60% required ventilation and 50% devel oped hypotension after starting the infu sion. There were no adverse effects of valproate on liver function. Subcutaneous histamine (n = 46) has been compared with oral valproate 500 mg/day (n = 46) in patients with migraine in a 12-week, double-blind, con trolled trial (274c). Histamine caused a sig nificantly greater reduction in the intensity and duration of attacks of migraine. Six patients stopped taking valproate because of adverse effects, the most common of which was nausea (37%). Other adverse effects included tremor (34%), weight gain (24%), and alopecia (12%). Placebo-controlled studies The use of valproate 1000 mg/day in chronic migraine or chronic tension-type headache has been studied in a 12-week, double-blind, placebocontrolled trial in 70 patients (275c). Adverse effects were rare. One patient had somnolence and tremor, one impotence, and one hair loss. Valproate as Epilim Chrono has been studied in a 6-week double-blind, placebocontrolled study in 80 men with a general ized anxiety disorder without psychiatric co-morbidity (276c). Valproate was signifi cantly more effective. Four patients with drew early because of adverse events. The two common adverse effects leading to with drawal of valproate were dizziness and nausea. Nervous system Histone acetyltransferase and histone deacetylase play important roles in gene expression, and consequently affect cell function, differentiation and proliferation. There is altered activity of these enzymes in several types of cancer. Valproate inhibits histone deacetylase and induces proteasomal degradation, leading to cellular differentiation and arrest of growth. In an open study of the use of
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valproic acid, 26 patients with progressing solid tumours were enrolled in doseescalating, three-patient cohorts, starting at a dosage of 30 mg/kg/day up to 300 mg/kg/ day (277c). Valproate was given as a 1-hour infusion daily for 5 consecutive days in a 21-day cycle. Neurocognitive impairment dominated the toxicity profile and was dose limiting in eight patients. Confusion or disorientation was dose limiting in seven cases. Five patients had neurovisual or neuroacustical adverse effects and five had vertigo. Somnolence occurred in 21 patients and was dose limiting in two. All these neurological adverse effects resolved after withdrawal. Hematological adverse effects were mild and characterized by leukopenia and thrombocytopenia. Nausea and/or vomiting occurred in 13 and five had fatigue. The prevalence of parkinsonism and sus ceptibility factors has been studied in 201 patients taking antiepileptic drugs, mainly valproate (278c). The odds of having par kinsonism were five times higher with valproate than with other antiepileptic drugs and none of the newer antiepileptic drugs was associated with movement disorders. The prevalence of valproate-induced par kinsonism has also been studied in 226 patients with epilepsy who were managed in epilepsy referral centers (279c). There was a significantly higher prevalence of patients with parkinsonism among those taking valproate than those who were tak ing other antiepileptic drugs (6 of 119 versus none of 107). Valproate dosages were reduced in four patients and discontinued in two patients and they improved after a few months. A patient with an acute schizoaffective episode developed severe cervical dystonia while being treated with quetiapine and val proic acid (280A). • A 60-year-old woman with diagnosis of acute schizoaffective disorder was treated with quetiapine 800 mg/day. The plasma concentration of quetiapine was 0.15 mg/l (usual target range 0.05–0.17 mg/l). Since she had two generalized seizures, valproate was added and the dosage of quetiapine was reduced to 600 mg/day. Four days later, she
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developed severe cervical dystonia. The plasma concentration of quetiapine was 0.24 mg/l and the valproic acid concentration was 76 mg/l (50–100 mg/l). The cervical dystonia resolved after reduction of the dosages of both quetiapine and valproic acid.
Five elderly patients with underlying cere brovascular diseases or dementia and symp tomatic seizures started to take valproate and developed an encephalopathy, reversible in all cases but one and characterized by altered consciousness, a possible increase in seizure frequency, and raised ammonia concentra tions (281A). In all cases electroencephalo graphy showed generalized slow-wave activity, which in some patients was associated with worsening or appearance of epileptic discharges. A child with juvenile absence epilepsy had a paradoxical exacerbation of seizures after intravenous administration of valproic acid (282A). Psychiatric Two children taking valproate and risperidone developed manic behavior, which was resolved by valproate withdrawal (283A). The authors speculated that the hyperammonemia that occurred when these drugs were given in combination, may have caused this psychiatric complication. Sensory systems A 22-year-old woman had a bilateral concentric visual field defect during long-term therapy with valproate, attributed to a GABAergic effect (284A). Endocrine The effect of long-term sodium valproate therapy on reproductive endocrine function has been studied in 30 women with generalized epilepsy (285c). There was weight gain in 40%, hirsutism in 20%, menstrual abnormalities in 24%, polycystic ovaries in 16%, and polycystic ovarian syndrome in 20%. The menstrual abnormalities, hirsutism, and polycystic ovaries correlated significantly with the weight gain. These abnormalities persisted over the subsequent 2 years in the women who were followed. Neither valproate nor lamotrigine monotherapy altered circulating androgenic
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hormones in 225 patients with newly diag nosed epilepsy followed for 1 year in a ran domized study (286c). The endocrine effects of valproate have been investigated in 88 consecutive adoles cent girls with epilepsy aged 6–20 years (28 premenarchic, 60 postmenarchic), of whom 45 were under taking valproate and 43 had not yet received treatment (287c). Mean testosterone concentrations were higher in the controls after the menarche. There were no between-group differences in rates of obesity, menstrual irregularities, hirsutism, or acne. The treated group had higher concentrations of thyroid-stimulating hormone and lower concentrations of free thyroxine than the untreated group, although still within the reference ranges. In consecutive patients with epilepsy there was subclinical hypothyroidism in 35 patients taking valproate (25%) and none of 35 control subjects (288A). Predic tors of subclinical hypothyroidism were younger age, duration of treatment and polytherapy with enzyme-inducing or non enzyme-inducing agents. Metabolism The effect of valproate on acylcarnitine has been assessed in children with epilepsy in a longitudinal study (289c). Specific changes in acylcarnitine subspecies were unequivocally associated with valproate and might be involved in the pathogenesis of hepatotoxicity. • A 45-year-old woman with a schizoaffective disorder had repeated episodes of altered consciousness for 3 weeks after starting to take valproate 1500 mg/day, due to hyperammonemic encephalopathy, with ammonia concentrations of 4450 g/l (reference range 190–870) (290A).
The effects of valproate monotherapy on weight and carbohydrate craving have been studied in 106 patients with epilepsy (55 women) (291c). There was significant weight gain in both men and women, but significantly higher serum leptin concentra tions in the women. The frequency of car bohydrate craving was 26% in women and 14% in men, even though more women tried to lose or control weight through diet
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(23% versus 7.1%). The authors hypothe sized that, in spite of higher frequency of dieting, women are more likely to gain weight than men, possibly because of leptin resistance and/or a higher frequency of car bohydrate craving. A 22-year-old man developed the syn drome of inappropriate secretion of antidiure tic hormone with hyponatremia while taking valproate (292A). The authors speculated that this might have been caused by a combi nation of factors, including serotonergic sti mulation of ADH secretion and reduced renal ability to conserve salt and water. Hematologic A 13-year-old girl had pure red cell aplasia and megakaryocyte dysplasia attributed to valproate (293A). Valproate can cause a variety of hemato logical abnormalities, including thrombocy topenia, impaired platelet aggregation, prolonged bleeding time, and reduced plasma concentrations of fibrinogen, von Willebrand factor, and factor XIII. However, the clinical relevance of these abnormalities is still debated. Four children with severe bleeding complications during treatment with valproate have been reported (294A). • A child with severe developmental retardation and epilepsy was given valproate 70 mg/kg/day for myoclonic astatic seizures. At the age of 5 years he underwent tonsillectomy and intraand postoperatively had severe diffuse oropharyngeal hemorrhage requiring blood transfusion. Thrombocytopenia was first detected at the time of bleeding and platelet function tests were not performed. Von Willebrand factor concentrations were normal. The serum valproate concentration post operatively was in the usual target range. The dosage of valproate was reduced to 50 mg/kg and 1 week later thrombocytosis was observed; it normalized during the next 2 weeks.
Unexplained severe postoperative bleed ing after routine coronary artery bypass grafting and aortic valve replacement was attributed to an effect on platelet count and function during long-term treatment with valproate (295A). Because cardiopulmonary bypass may itself have effects on platelet function and coagulation, the combination of valproate treatment with this cardiac
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surgical procedure should be considered a susceptibility factor for bleeding. In 26 children with epilepsy serum albu min concentrations, determined before and at 6, 12 and 24 months, fell during valproate monotherapy (296A). A patient developed acquired factor VII deficiency while taking valproate (297A). A 2-year-old girl developed marked pro liferation of immature myeloid precursors, simulating leukemia, during valproate ther apy (298A). Liver In a 2-year-old child, a combination of encephalopathy, bone marrow suppression, hepatopathy, and mild pancreatitis was associated with valproate, supposedly triggered by a simultaneous infection (299A). The serum valproate concentration was 87 mg/l. Valproate was withdrawn and intravenous carnitine 100 mg/kg was started. There was improvement during the next 10 days. A 2-year-old child with epilepsy developed reversible hepatic failure shortly after the start of valproate therapy; sequencing of the mitochondrial polymerase gamma gene (POLG1) revealed four heterozygous substi tutions, two of which have been identified in cases of Alpers–Huttenlocher disease (300A). Pancreas An 11-year-old child developed acute pancreatitis after taking valproate for 6 months; it resolved within 2 weeks of drug withdrawal (301A). The prognosis in valproate-associated acute pancreatitis depends mainly on early diagnosis and timely withdrawal of the drug. Reports of valproate-induced pancreatitis from 1979 to 2005 (n = 53) have been reviewed in a survey of all new cases (n = 16) observed in Germany from 1994 to 2003. (302R). The author hypothesized that this severe adverse effect is under-reported. Hair A 47-year-old white woman developed various changes in hair texture, probably related to valproate (303A). A 7-year-old boy had progressive changes in
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hair color and structure after taking valproate for 5 months (304A). His hair color changed from brown to ash blond and back to brown again 5 months after valproate withdrawal. Teratogenicity The risk of hypospadias in newborn infants exposed to valproate during the first trimester of pregnancy has been studied using data derived from the Spanish collaborative study of congenital malformations (305c). The sample included 2393 infants with hypospadias and 12 465 male controls. The unadjusted risk of hypospadias in infants prenatally exposed to valproate was 5.2 (95% CI = 2.3, 12). The calculated risk of hypospadias was 1 case in 97 births in mothers using valproate during the first trimester of pregnancy. The outcomes of pregnancies after in utero exposure to valproate have been stu died by the Israeli Teratology Information Service (306c). All women who called for information about gestational exposure to valproate between 1994 and 2004 were enrolled. The outcomes of 154 valproate exposed pregnancies were compared with those of 1315 pregnancies in women who had not been exposed to teratogenic sub stances. The rate of major anomalies in the valproate group was higher than in the con trols (6.7% versus 2.5%; RR = 2.66, 95% CI = 1.25, 5.65). There were five cardio vascular anomalies and two cases of hypo spadias; two children were mentally retarded and three were suspected of having fetal valproate syndrome. There were no cases of neural tube defects. An unusual case of trigonocephaly (a cra niosynostosis characterized by a triangular appearance of the head in association with ocular hypotelorism) has been described in a neonate whose mother had taken valpro ate during pregnancy (307A). Fetotoxicity Drug-induced gingival enlargement is one of several causes gingival hyperplasia observed at birth (308A).
157 • A 32-year-old mother with generalized epilepsy who took valproate 1 g/day gave birth at 32 weeks of gestation. The neonate had a coarse face; the nose had a broad flat bridge, the philtrum was long and flat, the vermilion thin, and the forehead broad; there was hypertelorism and posterior rotated ears. There was also gingival enlargement involving mainly the upper gum. Other causes of gingival hyperplasia, including metabolic and hereditary disorders, were excluded. Within 3 months the gingival enlargement had improved significantly.
Drug administration route Undiluted intravenous valproate, given at rates of 6 or 10 mg/kg/minute, has been investigated in 40 patients who received a loading dose of 20 or 30 mg/kg (309A). There were no significant changes in heart rate or mean arterial pressure. Some patients complained of transient local irritation lasting under 3 minutes. There was no effect on the level of consciousness. The safety of rapid intravenous valproate infusion has been investigated in 18 children aged 1–16 years, who received doses of 7.5–41.5 mg/kg at rates of 1.5–11 mg/kg/minute (310A). Of 48 intravenous administrations, there was only one adverse event, charac terized by burning at the infusion site. Electrocardiography during infusion did not show any effects and no abnormal laboratory results were reported.
Overdose of valproate and its management Clinical features Valproate overdose causes sedation, apathy, stupor, and confusion (311R). Coma can occur with doses in excess of 20 mg/kg and may be related to hyperammonemia. Other features include cerebral edema, asterixis, seizures, hypoten sion, nausea, vomiting, diarrhea, hypernatre mia, hypoglycemia, hypocalcemia, hypophosphatemia and metabolic acidosis. Bone marrow suppression, leukopenia, thrombocytopenia, pancreatitis, and rarely hepatotoxicity have also been reported. Unlike other antiepileptic drugs, dysarthria, nystagmus,
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and ataxia are not features of valproate poisoning. The clinical features, complications, and pharmacokinetics of valproic acid after inten tional acute overdose have been described in six patients (312c). The doses were 18, 24, 30, 50, and 60 g; in one case the dose was unknown. The nervous system was predominantly affected (6/6), followed by respiratory failure (5/6) and multiorgan failure (2/6). Mechanical ventilation was required in five of six patients because of respiratory depression or profound coma. Hemodialysis was used in 4/6 of the cases because of hyperammonemia, a worsen ing neurological condition, or organ dysfunc tion. Cerebral edema and hemorrhagic pancreatitis occurred in two patients and two died. The valproate peak concentration was 520–1700 mg/l (mean 1127 mg/l). Ammonia was raised in all cases (mean 5500 µg/l). All the patients had signs of impaired mitochon drial beta-oxidation, with increased serum con centrations of medium- and long-chain acylcarnitines. Pharmacokinetics Polish authors have studied the pharmacokinetics of valproic acid in five intoxicated patients who wanted to commit suicide (313c). Three were comatose (Glasgow coma scale 3); the other two were less severely affected. All recovered. Two had taken valproic acid alone and the other three had also taken other substances, including barbiturates, chlorprotixene, tricyclic antidepressants, cannabis, and alcohol. Valproate was absorbed rapidly, with maximum concentrations of 110– 724 mg/l after 3.5–5.6 hours. The fall in valproic acid concentrations in plasma was biphasic, with a terminal half-life of 8.8–31 hours. The calculated apparent volume of distribution was 0.17–0.72 l/kg. Case reports Several cases of valproate overdose have been reported, including fatal valproate overdose in a 26-day-old girl (314A). A diffuse encephalopathy has been attrib uted to severe valproic acid intoxication (315A).
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• A 41-year-old man with temporal lobe epilepsy taking valproic acid 1 g/day was found snoring and unresponsive. He was thought to have a post-epileptic state with hypothermia and rhabdomyolysis. Valproate was continued. However, electroencephalography showed triphasic waves consistent with diffuse encephalopathy due to a post-anoxic, metabolic, or toxic encephalopathy and the plasma valproate concentration was very high (1308 mg/l; usual target range 50–150 mg/l). Valproate was withdrawn and he was given activated charcoal 40 g 3-hourly and L-carnitine. He awoke after 36 hours and recovered without sequelae.
There was delayed clinical toxicity in three cases of valpromide overdose (316A). Since valpromide is a prodrug of valproic acid and a period of time is required for its conversion into the parent compound this delay in the onset of clinical symptoms was expected. Management of overdose Management of valproate overdose consists mainly of supportive care. Gastric lavage may be useful within 1 hour of the overdose. Various methods for increasing the rate of elimination of valproate and some methods for producing symptomatic relief from its adverse effects have been reported.
Carnitine Because valproate causes hyperammonemia, L-carnitine has been used in the treatment of acute poisoning. In five cases of valproate overdose with central nervous system depression and raised ammonia concentrations L-carnitine with supportive measures was used successfully (317A–319A). • A 14-year-old girl taking valproate 700 mg/day took 40 tablets of 500 mg Epilim-chrono (20 g, about 400 mg/kg). After 10 hours she was alert and all vital signs and physical examinations were normal. Her initial valproate concentration was 288 mg/l. The initial ammonia concentration was 74 µmol/l (reference range 11–51 µmol/l), with a peak concentration of 110 µmol/l at 34 hours. After 18 hours she became drowsy and was given three doses of intravenous L-carnitine 3 g each over the next 24 hours. She gradually improved and her mental status became normal 30 hours after ingestion.
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• A 15-month-old boy became comatose after accidentally taking 4000 mg (400 mg/kg) of valproate, which had been prescribed for his mother. His serum valproic acid concentration was 1316 mg/l (9125 µmol/l) and blood ammonia and liver function tests were normal, but analysis of urinary valproic acid metabolites showed abnormally low concentrations of beta-oxidation products and increased concentrations of omega- and omega-1-oxidation products. Administration of carnitine 100 mg/kg/day for 3 days by nasogastric tube was associated with a rapid return of the metabolite pattern towards normal. He regained consciousness after 3 days and was discharged on day 8.
Administration of intravenous L-carnitine in patients with valproic acid overdose and hyperammonemia is recommended at a dose of 50 mg/kg every 8 hours for the first initial 24 hours. Charcoal Activated charcoal can bind drugs in the gut and if a drug is excreted into the gut after absorption, by either biliary excretion or enteric secretion, repeated doses of charcoal can be useful (320R). This technique has been called ‘intestinal dialysis’. It has been used to treat toxicity with acetylsalicylic acid (321A), benzodiazepines (322A), carbamazepine (323A,324A), cardiac glycosides (325A), dothiepin (326A), phenobarbital (327A), and oleander seeds (328A). It has been suggested that repeated doses of activated charcoal may be beneficial in overdose with valproate, on the basis of a case report. • A 26-month-old boy who accidentally took a minimum of 4.5 g of enteric-coated valproic acid was given 20 g of activated charcoal 1.5 hours later (329A). At 4 hours after the overdose he became comatose, cyanotic, and apneic and was treated with intravenous naloxone. The serum valproic acid was 315 mg/l at the time and increased to 815 mg/l 2 hours later. Further charcoal was given by nasogastric tube (0.25 g/kg/hour), initially together with a cathartic. The serum valproic acid concentrations fell rapidly over 24 hours to 56 mg/l, and this was associated with complete recovery.
The rapid elimination of valproic acid in this patient (estimated half-life of about 4.8 hours) could have been explained by charcoal binding to enterally secreted drug.
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However, this suggestion has not been supported by a study in seven healthy volunteers, who took valproate syrup 300 mg followed by repeated doses of oral charcoal starting 4 hours after the drug and continuing up to 32 hours (total dose 80 g) (330C). Valproate was rapidly absorbed, with maximum concentrations at 1 hour after administration. The AUC0!48 was 408 hoursmg/l in the control phase and 398 hoursmg/l after charcoal. The half-life was 20 hours in the control phase, and 22 hours after charcoal. Thus, repeated doses of activated charcoal did not appear to increase the rate of elimina tion of sodium valproate after therapeutic doses. However, in overdose there may be more intestinal secretion of valproate, and this study does not rule out a possible beneficial effect in overdose. Hemodialysis, hemoperfusion, and hemodiafiltration These methods of removing valproate more quickly have all been tried, with varying results. • After valproate overdose a 27-year-old man developed seizures, hypernatremia, respiratory failure, metabolic acidosis, liver failure and bone marrow depression (331A). His plasma valproic acid concentration was 1414 mg/l. Treatment with hemodialysis was effective in enhancing valproic acid clearance, while hemoperfusion was relatively less effective, because of saturation of the column. Overall, the half-life of the drug was reduced from over 20 hours before treatment to less than 3 hours during hemodialysis/hemoperfusion; drug removal was probably favoured by saturation of drug binding to plasma proteins, which resulted in a low unbound fraction (32% at the start of treatment). He was comatose for 5 days but recovered fully thereafter. • A 19-year-old woman developed coma and lactic acidosis 6 hours after ingesting 18 g of valproate (332A). Her plasma valproic acid concentration was 800 mg/l. Metabolic studies suggested that the coma could have been related to inhibition of beta-oxidation of fatty acids. She was hemoperfused with activated charcoal, which shortened the half-life of valproic acid to 1.8 hours (compared with 4.4 hours before hemoperfusion). Over a period of about 6 hours, her valproic acid concentration fell from 471 to 45 mg/l, at which point she became alert.
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A beneficial effect of high-flux hemodialy sis without hemoperfusion has been described in valproate overdose (333A). • A 25-year-old white woman took an unknown amount of valproic acid, became comatose, and developed hypotension and lactic acidosis. Her valproic acid concentrations rose to over 8400 µmol/l. High-flux hemodialysis was performed for 4 hours; the calculated half-life during the procedure was 2.7 hours, compared with a post-hemodialysis value of 23 hours, suggesting that high-flux hemodialysis had increased the clearance rate of valproic acid. Her hemodynamic status and mental function improved in conjunction with the acute reduction in valproic acid concentrations.
In a case of severe valproate overdose continuous venovenous hemodiafiltration led to a significant reduction in serum con centrations (334A). Naloxone A patient developed acute confusion, a reduced level of consciousness and generalized myoclonic movements after valproate overdose (335A). Her plasma valproate concentration was 848 mmol/l. Administration of naloxone 0.8 mg led to rapid clinical improvement. Pentobarbital Cerebral swelling and raised intracranial pressure in severe valproate intoxi cations may respond to pentobarbital (336A). • A 25-year-old man with tonic–clonic epilepsy was found unconscious. His Glasgow coma scale score was 4 and his serum valproate concentration was over 10 000 µmol/l, falling to 4300 µmol/l by 28 hours after ingestion. A CT scan showed signs of cerebral swelling, with compression of the basal cisterns and convex sulci and increased attenuation of the major cerebral arteries. The intracranial pressure was over 50 mmHg, and electroencephalography showed isoelectric readings. He was given a high-dose pentobarbital infusion and his intracranial pressure gradually normalized. His level of consciousness was impaired for 2 months, but he gradually recovered with minor subjective cognitive deficits.
Drug–drug interactions Lamotrigine Valproate-induced hyperammonemic
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encephalopathy might have been caused by an interaction of valproate with lamotrigine, perhaps by inhibition of valproate glucuronida tion due to lamotrigine, causing the production of toxic valproate metabolites (337A). Levetiracetam Agitation, anxiety, and sleeplessness have been reported during treatment with valproate and levetiracetam (338A). The authors hypothesized that a pharmacodynamic interaction between these two antiepileptic drugs may have caused these behavioral abnormalities. Meropenem The interaction of valproate with meropenem has been retrospectively studied (339c). Meropenem reduced valproate plasma concentrations by 66% within the first 24 hours, and this interaction contributed to clinical deterioration in 11 cases. In two other cases meropenem caused a rapid fall in valproic acid concentrations, with adverse clinical consequences (340A). Oxcarbazepine Increased unbound blood concentrations of valproate, responsible for toxic symptoms, arose through co administration of oxcarbazepine (341A). The authors speculated that this interaction was due to inhibition of valproate metabolism by oxcarbazepine.
Vigabatrin (SED-15, 3623; SEDA-29, 99; SEDA-30, 98; SEDA-31, 136) Sensory systems Visual field loss from vigabatrin EIDOS classification: Extrinsic moiety: Vigabatrin
Intrinsic moiety: Nerve fibers
Distribution: Retina
Outcome: Atrophy
Sequela: Visual field loss from vigabatrin
DoTS classification: Dose-relation: Collateral reaction Time-course: Late Susceptibility factors: Age (more common in adults)
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The benefits and harms of vigabatrin therapy have been reviewed in the light of potential visual disturbance (342R). The authors made the following recommendations: 1. Vigabatrin should be considered for use in patients with demonstrable treatment resistance who are not candidates for other therapies. 2. Retinal function testing should be undertaken at baseline and throughout vigabatrin therapy. 3. The efficacy of vigabatrin should be assessed within 3 months of the start of treatment, which is well before the earliest time of onset of vigabatrin-related retinopathy. 4. The drug should be withdrawn in the absence of definitive seizure reduction during this trial period, to eliminate the potential for peripheral defects. 5. Clinicians should continue to perform retinal function assessment and visual field testing and inform patients who continue to take vigabatrin about the benefit to harm balance of treatment.
An interim analysis of a multinational, prospective, observational study aimed at clarifying the principal/major factors for visual field loss attributable to vigabatrin has been published (343C). The results were based on 563 participants, 432 of whom yielded one or more conclusive visual field examinations. Perimetry was undertaken at least every 6 months for up to 36 months and was performed in three groups of patients with refractory partial epilepsy, stratified by age (8–12 years; >12 years). Group I com prised participants treated with vigabatrin for at least 6 months; group II participants had previously taken vigabatrin for at least 6 months and had stopped taking it for at least 6 months; group III had never taken it. Visual field loss attributable to vigabatrin was associated with duration of therapy (OR = 14; 95% CI = 5.0, 41); mean dose (OR = 8.5; 95% CI = 2.2, 33) and male sex (OR = 2.1; 95% CI = 1.2, 3.7). The relation between vigabatrin-induced visual field loss and maximum daily dose, cumulative dose and duration of dose has been investigated in 34 patients, who under went standard automated static visual field examination of the central visual field. A regression model suggested that the maxi mum dose was the only factor significantly
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correlated with individual eye severity and symmetry of visual field defect (344c). Eight patients with epilepsy and visual field loss attributed to vigabatrin had their retinal nerve fibre layer evaluated by scan ning laser polarimetry (345A). With this tech nique it is possible to perform objective measurement of the thickness of the retinal nerve fibre layer. The thickness of the retinal nerve was significantly reduced in all patients. However, this finding did not correlate with cumulative dose or time on treatment. The authors suggested that scanning laser polarimetry can be used to screen patients taking vigabatrin, especially those who may not tolerate formal field testing well. Drug withdrawal Four patients with focal cortical dysplasia and asymmetric spasms that were easily controlled by first-line vigabatrin therapy benefited from normal development. Vigabatrin was withdrawn after 1–5 years but the spasms recurred in all cases, were refractory to vigabatrin, and led to severe mental retardation (346A).
Zonisamide
(SED-15, 3728; SEDA-29, 100; SEDA-30, 99; SEDA-31, 137)
Observational studies Zonisamide as long-term adjunctive therapy in Lennox– Gastaut syndrome has been evaluated in 62 children (347c). Two had somnolence and one had anorexia and weight loss. Zonisamide in a dosage of at least 6 mg/kg/day has been assessed for 16 weeks in 30 patients with refractory pro gressive myoclonic epilepsies, more than one-third of whom had at least a 50% reduction in myoclonic seizure frequency (348c). Five patients stopped taking zonisa mide because of adverse events, the most common of which were reduced appetite, somnolence, and weakness. Zonisamide 130 mg/day has been assessed for a mean of 27 weeks in 35 out patients with bipolar disorder (349c). The most common adverse effects were nausea (19%) and sedation (25%). Treatment was
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withdrawn in six patients owing to adverse effects (nausea in two cases, abdominal pain, pulmonary embolism, diarrhea and dizziness in one each). Seven patients, five of whom withdrew early, had worsening of manic symptoms. In an open study of zonisamide as adjunctive therapy in 24 mentally retarded and multiply handicapped patients with severe childhood-onset epilepsy, 10 were still taking it after 18 months and one became completely seizure free (350c). The most common adverse event was reduced appetite in five cases. Three patients had fatigue, one reported constipa tion, one nausea, and one behavioral change. Two stopped taking zonisamide because of loss of appetite. Placebo-controlled studies In a 16-week, randomized, double-blind, placebocontrolled, flexible-dose (100–600 mg/day) trial, 60 patients with binge eating disorders and obesity took zonisamide (n = 30) or placebo (n = 30) (351c). Zonisamide was associated with a significantly greater rate of reduction in binge eating, body weight and other outcomes. There was no statistically significant difference between the treatment groups in the incidence of any particular adverse event. The most frequent were dry mouth (13 versus 10 with placebo), somnolence (12 versus 7), headache (11 versus 9), nausea (11 versus 5), and nervousness (8 versus 3). In a double-blind, randomized, placebocontrolled study of zonisamide in 20 patients with essential tremor the initial dose was 100 mg/day, increasing to 200 mg at day 14 (352c). Tremor amplitude improved signifi cantly with zonisamide. Three patients taking zonisamide 100 mg/day withdrew because of adverse effects (headache and nausea, fatigue, diarrhea, and headache). Three others taking zonisamide 200 mg/ day developed adverse effects (fatigue in one patient on day 15, mild sleepiness and headache in one patient on day 22, and paresthesia and fatigue in one patient on day 22), but none withdrew.
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In a 12-week, multicenter, double-blind, parallel-treatment, placebo-controlled study, 347 patients with Parkinson’s disease were randomized to zonisamide 25 mg/day (n = 84), 50 mg/day (n = 87), 100 mg/day (n = 87), or placebo (n = 89) as adjunctive treatment (353c). There was significant improvement in the primary end-point with 25 and 50 mg/day versus placebo. There was no significant difference in the incidence of adverse events between 25 and 50 mg/day compared with placebo, but the incidence was significantly higher with 100 mg/day. Adverse events for which the incidence was greater in the total group of patients treated with zonisamide than in the placebo group were somnolence (11%), apathy (8.5%), weight loss (6.9%), and con stipation (6.5%). Respiratory It has been suspected that co-administration of zonisamide and valproate for epileptic spasms might have exacerbated interstitial pneumonitis in a 6 month-old girl (354A). Nervous system Restless legs syndrome has been associated with zonisamide and attributed by the authors to a dopaminergic effect of the drug (355A). Dopamine receptor agonists can cause neuroleptic malignant syndrome when they are withdrawn. A patient with epi lepsy, mental retardation, and aggressive behavior taking zonisamide and carbama zepine developed a neuroleptic malignantlike syndrome after abrupt withdrawal of zonisamide (356A). The authors suggested that abrupt withdrawal of zonisamide may have caused an imbalance in dopaminergic activity, resulting in the described symptoms. Psychological In a randomized open investi gation of the long-term effects of zonisamide monotherapy on cognition and mood in 43 patients with epilepsy the final doses were 100, 200, 300, and 400 mg/day (357A). Nine patients withdrew before the follow-up
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neuropsychological test. After 1 year, 16 patients complained of cognitive deficits and 5 had mood changes. Neuropsychological tests showed that zonisamide had several negative effects on cognition. Psychiatric A patient developed psychotic symptoms after starting to take zonisamide; they improved only after zonisamide was withdrawn and antipsychotic drugs were given (358A). Metabolism Zonisamide effectiveness and tolerability has been assessed for the treatment of obesity in euthymic bipolar disorder patients (359c). Weight change in 25 patients was assessed prospectively for a maximal duration of 6 months. The mean final dose of zonisamide was 375 mg/ day (range 75–800). Mean weight loss was 1.2 BMI points. Eleven patients withdrew because of altered mood (eight with depression, two with mania, and one with subsyndromal mixed symptoms). Urinary tract The prevalence of renal calculi in patients taking zonisamide has been studied by reviewing all reports of renal calculi from four double-blind, placebo-controlled trials, their long-term open extension phases, and the US/ European zonisamide clinical trial program (360C). Pooled safety data from all clinical trials identified 15/1296 (1.2%) patients with symptomatic renal calculi during treatment for up to 8.7 years. Postmarketing surveillance revealed 9 cases from 59 667 patient-years of exposure in the USA, and 14 from 709 294 patientyears of exposure in Japan. No cases of renal calculi were reported among 59 patients taking concomitant topiramate in the clinical trial population. In the postmarketing safety surveillance database, only one patient of 25 taking zonisamide and topiramate had a renal calculus. The authors concluded that the risk of renal calculi during zonisamide treatment is low and that data are still insufficient to
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determine whether concomitant treatment with topiramate increases this risk. Skin Xerosis and pityriasis associated with zonisamide treatment have been described (361A). • A 5-year-old child developed generalized dryness and asymptomatic hypopigmented macules on her face and trunk, some with minimal erythema, after taking zonisamide for 2 months for West’s syndrome. She was managed with emollients and zonisamide was withdrawn. Both the dryness and the skin lesions improved.
The authors suggested that hypohidrosis, due to zonisamide-induced inhibition of car bonic anhydrase, may have contributed to the sudden development of xerosis and pityriasis alba-like changes. Several reports have described a close relation between HHV-6 reactivation and drug rash with eosinophilia and systemic symptoms (DRESS). Toxic epidermal necrolysis associated with HHV-6 reactiva tion has been described in a patient taking zonisamide (362A). • A 71-year-old man developed a fever and a rash over his entire body. He had been taking zonisamide 300 mg/day, added to valproate, for 23 days for epilepsy. Zonisamide was withdrawn but his condition worsened and a diagnosis of toxic epidermal necrolysis was made clinically and histopathologically. Intravenous immuno globulin 5 g/day was given for 3 days and the progression of skin lesions appeared to slow. However, 9 days after the onset, the eruption recurred, accompanied by a high fever. HHV-6 IgG antibody titers and HHV-6 DNA concentration greatly increased between day 4 and day 22. Three weeks after the onset, the condition resolved.
Drug–drug interactions Antiepileptic drugs Zonisamide is mainly metabolized by CYP3A4. Relevant drug–drug interaction studies have been reviewed (363R). Zonisamide has no effect on the steady-state pharmacokinetics of carbamazepine, phenytoin, sodium valproate, or lamotrigine. However, enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and
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phenobarbital) increase its clearance and this interaction may necessitate a dosage increase. Lamotrigine Neither zonisamide nor lamotrigine concentrations are likely to be influenced by co-administration. Topiramate Zonisamide and topiramate are both weak inhibitors of carbonic
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anhydrase and may independently increase the risk of renal calculi. When they are co-administered, there is a theoretical poten tial for an adverse pharmacodynamic interaction. Valproic acid Valproic acid, which is an enzyme inhibitor, may marginally increase zonisamide concentrations without clinically significant effects.
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181 353. Murata M, Hasegawa K, Kanazawa I, Aizawa H, Kimura T, Kikuchi S, Baba M, Chida K, Hisanaga K, Toyoshima I, Kurita K, Suzuki Y, Yoshizawa K, Shoji S, Nakano I, Hirata K, Kamakura K, Shimizu T, Nogawa S, Utsumi H, Mizusawa H, Yokochi F, Hirabayashi K, Hasegawa K, Takahashi Y, Kuroiwa Y, Kameyama S, Komai K, Hashimoto T, Mizoguchi K, Mitake S, Yasuda T, Washimi Y, Tatsuoka Y, Matsumoto S, Abe K, Fujimura H, Hashiguchi H, Nakashima K, Takamatsu K, Yamada T, Nomoto M, Yuhi T, Yamada T, Ikezoe K, Sato A, Matsuo H, Tsuruta K, Arimura K, Yuasa T, Kawashima N, Ishikawa A, Yoshikawa N, Higashi Y, Ohnishi H, Yoshinaga J, Fujita H, Katagi R, Miyajima H, Ojika K, Kawamura M. Zonisamide improves motor function in Parkinson disease: a randomized, double-blind study. Neurology 2007;68 (1): 45–50. 354. Nikaido K, Kato T, Takayama R, Doi T. [Valproate sodium and zonisamide asso ciated interstitial pneumonitis in an infant.] No To Hattatsu 2007;39(1):44–8. 355. Velasco PEB, Goiburu JAZ, Pinel RS. Restless legs syndrome induced by zonisa mide. Mov Disord 2007;22(10):1517–8. 356. Azuma H, Negi A, Hattori M, Masayasu T, Akechi T, Furukawa TA. Neuroleptic malignant syndrome-like state in an epi leptic patient with organic brain comor bidity treated with zonisamide and carbamazepine. Epilepsia 2007;48(10): 1999–2001. 357. Park SP, Hwang YH, Lee HW, Suh CK, Kwon SH, Lee BI. Long-term cognitive and mood effects of zonisamide monother apy in epilepsy patients. Epilepsy Behav 2008;12(1):102–8. 358. Michael CT, Starr JL. Psychosis following initiation of zonisamide. Am J Psychiatry 2007;164(4):682. 359. Wang PW, Yang Y-S, Chandler RA, Now akowska C, Alarcon AM, Culver J, Ketter TA. Adjunctive zonisamide for weight loss in euthymic bipolar disorder patients: a pilot study. J Psychiatr Res 2008;42(6):451–7. 360. Wroe S. Zonisamide and renal calculi in patients with epilepsy: how big an issue? Curr Med Res Opin 2007;23(8):1765–73.
182 361. Kaliyadan F, Manoj J, Venkitakrishnan S. Xerosis and pityriasis alba-like changes associated with zonisamide. Indian J Der matol Venereol Leprol 2008;74(2):165–6. 362. Teraki Y, Murota H, Izaki S. Toxic epider mal necrolysis due to zonisamide asso-
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ciated with reactivation of human herpesvirus 6. Arch Dermatol 2008;144 (2):232–5. 363. Sills GJ, Brodie MJ. Pharmacokinetics and drug interactions with zonisamide. Epilep sia 2007;48(3):435–41.
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8
Opioid analgesics and narcotic antagonists
Note on receptor nomenclature: Opioid receptors, originally called , and µ recep tors, then OP1, OP2 and OP3 receptors, have also been called DOR, KOR and MOR respectively.
GENERAL The World Health Organization (WHO) guidelines for pain relief recommend a three-step analgesic ladder depending on persistent or increasing pain (1S). The effect of extending the WHO guidelines to include evaluation of adverse effects of opioids has been explored prospectively (2C). Patients may report lack of response to opioids not only because of poor analgesic efficacy but also because of intolerable adverse effects. The authors propose a five-step analgesic and adverse effects ladder, with opioid switching recommended if less than 30% pain relief from morphine has been achieved or if a patient has marked confu sion or hallucinations, marked drowsiness or a significantly dry mouth. Prescribing opioids, even in the longer term, for appropriate clinical indications is clinically appropriate and should be accom panied by adequate clinical inquiry and doc umentation (3R). However, physicians may be reluctant to prescribe opioids because of Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32008-3 2010 Elsevier B.V. All rights reserved.
fear of having to deal with inappropriate demands from patients, fear of monitoring by authorities, the risk of diversion and the risk of serious direct adverse events, such as respiratory depression and death. Continu ous opioid therapy is not indicated for the treatment of chronic headache. The role of anesthesiologists in facilitat ing recovery and reducing hospital stay has been reviewed (4R). Attention to minimiz ing the adverse effects of opioids, while ensuring adequate pain relief, is one aspect linked to improved patient care. The quality of pain management with opioids has been explored in 59 patients with cancer and the frequency of adverse effects described (5c). The most frequent adverse effects were constipation, nausea, vomiting, xerostomia, sweating, confusion, cognitive dysfunction, and sedation. Of these, only nausea, vomiting and constipation were treated, highlighting the potential for improv ing patients’ experiences of treatment.
Frequency of adverse reactions to opioid analgesics The prevalence of adverse consequences to continuous opioid administration has been reviewed (6R). The most common adverse effects in patients taking prescribed opioids for chronic non-malignant pain are nausea, vomiting, constipation, dry mouth, dry skin, pruritus, and drowsiness or dizzi ness. Longer-term adverse effects include cardiac problems, opioid-induced hyperalge sia, cognitive dysfunction, hypogonadism, immunosuppression, and drug dependence.
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Adverse effects tend to be experienced by about 50% of those taking the prescribed medication and about 20% stop treatment as a result. Those who take opioids conti nuously tend to have more adverse effects than those who take them intermittently (7R). In another review article a higher pre valence has been reported in 59% of those who have taken opioids for less than 3 months and 73–90% of those who have taken them for more than 3 months (3R). Opioid-induced adverse events affect the length of hospital stay and health-care costs. Among patients admitted for surgery, 1.8% had adverse events, causing 7.4% higher overall hospital costs and 10% longer hospi tal stays (8C). Rates of adverse effects vary with the opioid used (9C). In 5684 subjects taking long-acting opioid analgesics, including extended-release oxycodone, methadone, extended-release morphine, and transdermal fentanyl, those who took extended-release oxycodone were 33% less likely to require emergency treatment for adverse effects than those who took extended-release morphine and 23% less likely to require hospitaliza tion; they had a 41% lower risk of constipa tion and a 29% lower risk of death. Fentanyl was associated with higher requirements for emergency opioid-related treatment. Metha done was associated with a higher risk of overdose than extended-release morphine. Constipation occurs in 52–65% of those taking opioids and tolerance does not develop (3R). Those aged over 65 years are 7.33 times more likely to develop constipation if they take modified-release oxycodone rather than transdermal fentanyl (10R). There was a clear link between the use of opioids, in particular naturally occur ring opium alkaloids, and the risk of post operative paralytic ileus in a case-control study in 180 279 subjects (11C). The risk increased from 1 in 500 to 1 in 185 in patients using opioids during their hospital admission. Nausea occurs in 50–54% of patients, and tolerance develops after several days (3R). Vomiting occurs in 26–29% of patients (3R). Dizziness occurs in 24–25%. Tolerance to the sedating effects tends to develop
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within a week of starting treatment (3R). The use of morphine and other opiates is associated with a risk of fractures, due to falls related to dizziness (12R). The use of opioids in relation to the risk of fractures has been reviewed (10R). There are conflict ing views; one study reported a reduced risk of falls and fractures with opioids but another provided odds ratios that suggested an increased risk (morphine 1.47, fentanyl 2.23, methadone 1.39, oxycodone 1.36, tra madol 1.54, codeine 1.16, and buprenor phine 0.86). The most commonly abused opioids are oxycodone, hydrocodone, hydromorphone, methadone, and morphine. The prevalence of addiction in those treated with opioids for pain control is reported to be the same as in the general population (6–10%); how ever, the risk of diversion remains signifi cant, especially with some opioids, such as oxycodone (3R). Sustained-release oxycodone is reported to have the highest opioid attractiveness and fentanyl patches the lowest (7R). Oxytrex, a combination of oxycodone and naltrexone, minimized the potential for physical dependence (12R). Characteris tics associated with increased risk for abuse in chronic non-malignant pain include male sex, young age, a history of alcohol or cocaine abuse, associated mental health problems, multiple pain regions and pain from motor vehicle accidents (7R). Other vulnerable groups include anesthetists. In this group, second-hand exposure was offered as an explanation for the increased incidence of fentanyl abuse (12R).
Cardiovascular Cardiac problems associ ated with opioid use include QT interval prolongation, especially with methadone, and cardiac wall motion abnormalities and reduced left ventricular ejection fraction, which have been reported after abrupt withdrawal of oxycontin. QT interval prolongation has also been reported with buprenorphine and naloxone when combined with antiretroviral drugs in HIVnegative and opioid-dependent subjects (7R, 12R). The active metabolite of
Opioid analgesics and narcotic antagonists
Chapter 8
dextropropoxyphene, norpropoxyphene, causes prolongation of the QRS interval and ventricular dysrhythmias, including ventricular fibrillation. These effects of norpropoxyphene, combined with the respiratory depressant effects of dextro propoxyphene, increase the risk of death from overdose (13R). Respiratory Respiratory depression and drug-related deaths are linked to the amount of opioid ingested, the speed of absorption, the route of administration, the degree of tolerance of the individual and other modulating factors, such as sex and greater respiratory depressant effects being observed in women (13R, 14R). Other respiratory depressants, such as propofol, sevoflurane, midazolam, and ethanol, have synergistic effects on respiratory depression when they are combined with opioids (14R). Other conditions increase the risk of respiratory depression, including sleep apnea, pulmonary disease, and other serious medical conditions (3R). Naloxoneinsensitive respiratory depression can occur with high doses of buprenorphine, especially when it is combined with a benzodiazepine (12R). Tramadol has less respiratory depressant potential than equianalgesic doses of pethidine or oxycodone; however, tramadol-induced respiratory depression has been reported in patients with renal insufficiency (14R). Opioid toxicity and respiratory depres sion can occur in individuals who illegally carry drugs in packets inserted in the mouth, rectum and vagina (body packers). In one case 81 packets containing opium were inserted abdominally and required surgical removal; the individual had respiratory distress and loss of conscious ness (15A).
Nervous system Opioid-induced hyper algesia, generally attributed to morphine, can also be associated with other opioids, especially short-acting opioids, such as remifentanil. Opioids can cause hyperalgesia, even after short-term use,
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through triggering of a sensitization process that can last several days (10R, 16R). • A 54-year-old man with hepatocellular carcinoma was initially given oral oxycodone modified-release 800 mg 8-hourly with hourly rescue doses of 200 mg, switched to oral methadone 225 mg 8-hourly with buccal fentanyl 800 micrograms hourly as required and then switched to intravenous methadone 30 mg/hour with an additional 10 mg every 15 minutes as required; he developed opioidinduced hyperalgesia (17A).
The presence and nature of opioid-induced hyperalgesia has been studied in 110 patients (58 men and 52 women) with either cancerrelated or non-cancer-related pain (18C). There was no evidence of opioid-induced hyperalgesia in cold pain measures, but there was significantly less diffuse noxious inhibitory control in those who received opioids compared with those who did not. This difference was sex-specific and was sig nificant in men but not women. Psychological Opioid-treated individuals have impaired reaction times, psychomotor speed, and working memory (7R). However, such changes are generally modest. In one study there was modest impairment in digit span test and clock drawing test in 14 patients with cancers treated with opioids, indicating impaired attention, concentration, working memory, and executive abilities (19c). Such impairments could influence treatment comprehension and compliance. Despite modest changes, the differences were not significant, possibly because the sample was small. Impaired ability to drive has social and legal implications; however, most studies of opioids have failed to show impaired driv ing ability (3R). Psychiatric The association between opioid use and delirium, especially in patients with cancer, warrants recognition. In one study 114 hospitalized cancer patients had a 40% higher risk of delirium when receiving high doses of opioids (over 90 mg morphine equivalents/day)
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compared with lower doses. There were 667 delirium events (six per patient) (20C). Gastrointestinal Opioid-induced bowel dysfunction results in a range of symptoms, including constipation, bloating, abdominal cramps, delayed and reduced gastric emptying and formation of hard stools. It has been suggested that clinicians should encourage patients to discuss such adverse effects, to facilitate optimal management, pain control and medication compliance (21R). Sexual function Hypogonadism has been attributed to opioids, especially with intrathecal administration (7R, 10R, 22R). Reduced libido in both men and women, impotence in men and amenorrhea or irregular menstrual cycles have been reported. Sexual dysfunction is a recognized com plication in the treatment of opiate depen dence. The incidence of sexual dysfunction in those dependent on heroin has been com pared with that in those on methadone or buprenorphine treatment for opiate depen dence (23C). Those who used heroin (n = 30) and those who used methadone (n = 33) reported significantly higher levels of sexual dysfunction than those who used buprenorphine (n = 28). Forms of sexual dysfunction that occurred with statistically significant differences between buprenor phine, heroin, and methadone included loss of sexual desire (57% heroin, 58% methadone, 7.1% buprenorphine); loss of sexual fantasies (33% heroin, 15% metha done, 7.1% buprenorphine); erectile impo tence (33% heroin, 24% methadone, none with buprenorphine); premature ejaculation (57% heroin, 42% methadone, 21% bupre norphine); loss of penis angulation (50% heroin, 70% methadone, 21% buprenor phine); and loss of morning erection (47% heroin, 24% methadone, 11% buprenor phine). Other forms of dysfunction that did not differ across the drugs included loss of dream erection, inability to ejaculate and ejaculation with a soft penis.
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Immunologic Codeine, fentanyl, metha done, morphine, and remifentanil have the most immunosuppressive potential of all opioids, whereas hydromorphone, oxycodone and tramadol are less immuno suppressive and buprenorphine has no immunosuppressive effects (7R, 10R). Drug abuse The abuse of prescription drugs is on the increase. It is suggested that physicians set up systems that support safe prescribing, including measures such as use of tamper-proof prescription pads, monitoring and addiction screening to identify patients at risk of dependence (24r). In veterans taking opioids for chronic non-cancer pain, a history of nonopioid substance abuse is an uncommon but strong susceptibility factor for opioid abuse, whereas a history of mental health problems is common but presents only a moderate risk of opioid abuse (25C). Drug tolerance and dependence In most patients using prescribed opioids, dose escalation is needed because of tolerance, especially in younger patients with nociceptive pain, but does not tend to be a major problem (7R). Drug withdrawal Common symptoms of withdrawal in patients receiving opioids include deep bone pain, increased pain, and muscle aches (7R).
Susceptibility factors Diseases The manage ment of pain by individuals with cognitive impairment, such as dementia, is complicated by the fact that such individuals generally find it difficult to communicate clearly; in addition, adverse effects tend to be more prevalent in individuals with dementia (26R). Opioid-related adverse effects that tend to be more prevalent in this population include worsening of cognitive impairment, sedation, problems with balance and constipation. Pethidine has been associated with delirium, and
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propoxyphene with ataxia and dizziness. Such opioids should be avoided or prescribed with caution. Attention should also be paid to other associated problems, such as renal impairment, which could result in increased serum concentrations of opioids. Opioid rotation has been suggested as one way of mitigating adverse effects. Constipation tends to be a common problem and so the administration of prophylactic bowel regimens is recommended.
Drug overdose Chronic morphine pre treatment reduces the potential for morphine-induced, but not heroin-induced, death after overdose. Prescribing naloxone for injecting heroin-users as a public health measure has been reported to be associated with reduced heroin-related deaths. There was a positive correlation between methadone-related deaths and positive urine testing for tricyclic anti depressants and benzodiazepines (12R). In an epidemiological study on acute poi soning among the indigenous population of Tehran, opium (74%) was the most com mon cause of acute poisoning (27C). This prevalence is significantly higher than other causal agents such as hypnosedatives (33%), psychotropic drugs (27%), methanol (65%), and ethanol (35%). Other opioids included heroin (15%), morphine (3.4%), codeine (3.1%), methadone (2.3%) and pethidine (2.3%). The overall death rate was 1.3%.
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When alfentanil was used there was oxygen desaturation in 11, and 9 required supplementary oxygen, compared with 3 when ketamine was used. Drug–drug interactions Propofol The combination of propofol (2 mg/kg) and alfentanil (10 micrograms/kg), used as anesthesia in a 10-year-old child undergoing ambulatory laser therapy, was associated with bradycardia and cardiac arrest (29A). The child was taking long-term methylphenidate for attention deficit hyperactivity disorder. The authors postulated that chronic methylphenidate use depleted stored noradrenaline and dopamine, resulting in a blunted sympathetic response, which, in the presence of propofol and alfentanil, could have serious consequences.
Codeine
(SED-15, 880; SEDA-31, 156)
Drug formulations Tylenol No. 3, which contains paracetamol (acetaminophen), codeine and caffeine, has been compared with paracetamol and ibuprofen in the management of pain after outpatient general surgical procedures. Of those who received Tylenol No. 3 (n = 74), more had more adverse effects (58% versus 41%), mostly resulting from a higher incidence of nausea (16% versus 7%), and more withdrew because of adverse effects (11% versus 3%) (30C).
Dextromethorphan (SED-15, 1088; SEDA-29, 105; SEDA-30, 109; SEDA-31, 158) OPIOID RECEPTOR AGONISTS Alfentanil
(SED-15, 72; SEDA-31, 153)
Respiratory Alfentanil (20 micrograms/kg) and propofol (2 mg/kg) have been compared with propofol (2 mg/kg) and ketamine (1 mg/kg) in a prospective crossover study in 20 patients aged 2–15 years undergoing lumbar puncture (28c).
Psychiatric Dextromethorphan-induced psychosis has been described in a 66-year-old man with no previous history of psychiatric disorders who was a poor CYP2D6 metabolizer (31A). He developed auditory hallucinations associated with near fatal suicidal behavior, after taking excessive amounts of a cough syrup containing dextromethorphan (1575 mg/day, gradually increasing to up to 3150 mg/day). Cough syrup should be recommended with
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caution in elderly patients, who may be more susceptible to adverse effects. Drug overdose Dextromethorphan toxicity was reported in a 20-year-old man after free-basing of dextromethorphan using the ‘Agent Lemon’ technique (1 g of liquid free-base dextromethorphan) (32A). He became unresponsive shortly after ingestion and developed hypotension and shallow respiration, which did not respond to naloxone and flumazenil. He then developed flushing, axillary sweating, hypoactive bowel sounds and dilated pupils with a sluggish response to light. He became agitated and tremulous and had myoclonic jerks, hypertension and tachycardia. His symptoms abated after 13 hours.
Interference with diagnostic tests Dextro methorphan and its metabolites gave a false-positive result for phencyclidine using the ‘instant-view multi-test’ in a urine sample from a 24-month-old girl with ataxia and generalized seizures who had acciden tally ingested dextromethorphan; the urine concentration of dextromethorphan was 5.1 mg/l (33A).
Diamorphine (heroin) (SED-15, 1096; SEDA-28, 106; SEDA-29, 106; SEDA-30, 110; SEDA-31, 158) Cardiovascular Cardiomyopathy has been attributed to heroin. • A 23-year-old man developed generalized weakness and edema in both legs after using heroin. Over the next 24 hours he had reduced urine output and respiratory distress, which required intubation and mechanical ventilation. A chest X-ray showed pulmonary edema. Electrocardiography showed T wave inversion in leads V3–6. He had raised activities of AsT (1337 U/l), AlT (1732 U/l), LDH (5280 U/l), creatine kinase (72 500 U/l) and creatine kinase MB isoenzyme (2225 U/l), and raised serum concentrations of creatinine (600 µmol/l) and urea (27 mmol/l). An echocardiogram showed severe global systolic left ventricular dysfunction with
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an ejection fraction of 15%. Cardiac catheterization showed pulmonary edema. He was given intravenous dobutamine and continuous venovenous hemofiltration. His cardiac output gradually improved. On day 8 he developed abdominal pain and a fall in hematocrit. A large retroperitoneal hematoma was found on an abdominal computed tomography (CT) scan. Angiography showed multiple small aneurysms in the upper of the two left renal arteries. Embolization of the vessel was successful and he improved gradually. Four months later, he still had a reduced left ventricular ejection fraction of 45%.
Nervous system Neurotoxicity resulting from chronic heroin use has been explored in 15 heroin-dependent patients (34c). These patients had reduced concentrations of nerve growth factor and brain-derived neurotrophic factor, both of which are postulated to influence the survival of neurons, suggesting that they may have a role in neurotoxicity associated with heroin use. • A 45-year-old man developed a generalized dyskinetic syndrome, impaired vision and severe parkinsonism 24 hours after snorting heroin (35A). Brain imaging showed grey matter lesions in the basal ganglia and cerebral cortex. It is unclear whether these lesions were caused by the heroin itself or by additives.
Skin Necrolytic migratory erythema has been reported in a heroin smoker (36A). • An 18-year-old woman developed a rash similar to recurrent seborrheic dermatitis, with well-demarcated erythema, pustules, and hair loss over the scalp. Topical steroids, systemic antibiotics, antifungal agents and descaling measures produced some improvement. During the next 12 months, she had erythematous, scaly, weepy rashes, which waxed and waned in the axillae and toe webs. Skin scrapings were repeatedly negative for fungi. Two years later, she again developed the rash in the groins and perineal area as well. She admitted to smoking heroin, underwent detoxification, and enrolled in a methadone programme. Blood tests for hepatitis and HIV were negative. The rash persisted. Six months later, she developed septicemia secondary to cutaneous Herpes simplex and staphylococcal infection in the groin and had recurrent viral and bacterial infections. A biopsy from the groin area showed psoriasiform features and vacuolar
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changes. The methadone was slowly withdrawn and 4 months later the rash had cleared and her hair had completely re-grown. When she was re-challenged with methadone twice, the rash returned.
The role of opiates in the development of necrolytic migratory erythema is unclear; however, the association is important to recognize.
Musculoskeletal Rhabdomyolysis has been attributed to heroin in 3.6% of 181 patients (37c). • A 23-year-old man inhaled heroin and developed rhabdomyolysis and cardiogenic pulmonary edema, complicated by spontaneous rupture of a renal artery aneurysm, resulting in retroperitoneal hemorrhage (38A).
Infection risk Infection due to Clostridium botulinum following subcutaneous or intramuscular injection of heroin (‘skin popping’) by opiate-abusers has been described in 12 patients (39c). In 58% cranial nerves were affected, resulting in mydriasis, diplopia, dysarthria, and dysphagia, followed by paralysis of proximal muscles and respiratory muscles, requiring mechanical ventilation for a mean duration of 27 days. Five were given trivalent equine antitoxin. The authors speculated that contamination had probably occurred during the preparation of the heroin. Drug withdrawal Protracted abstinence syndrome following withdrawal of heroin, consisting of craving, negative mood, and physiological changes, has been investigated in 70 former heroin-users (40C). Some were using short-term methadone, others long-term methadone; some were in the 15–45-day period of being opiate-free after methadone-assisted detoxification and some were 5–6 months after methadone-assisted detoxification. The symptoms of protracted abstinence were worse in those within the 15–45 day period and best (especially mood) in those using long-term methadone.
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Fetotoxicity The use of heroin and methadone during pregnancy is associated with an increased risk of sudden infant death syndrome. In a study of 563 HIVinfected mothers over a 13-year period there were 24 infant deaths. Of these, 10 were associated with maternal opiate use during pregnancy and another 4 with use before pregnancy. The relative risk of sudden infant death syndrome was 69 in those with intra-uterine exposure, compared with the general population incidence of 0.82/1000 (41C). Diamorphine as a single dose of 7.5 mg intramuscularly during labor in 100 women was associated with low Apgar scores and resuscitation in neonates (42C). There were low Apgar scores in 20 neonates, and 14 needed resuscitation. The interval between the administration of diamorphine and deliv ery influenced adverse events. Susceptibility factors Genetic In 281 Spanish methadone-maintained heroindependent patients, there was an association with heroin dependence in the A1–A1 genotype, regardless of sex, and in the A1 allele in men (43C). Drug contamination Heroin intoxication causes a classical syndrome of respiratory and central nervous system depression with pupillary constriction. However, modification of the street drug with other substances can result in unusual or atypical presentations. Adulteration is the intentional addition of a pharmacologically active substance in an attempt to use less of the active drug without the user being aware. Aluminium The use of illicit heroin has been associated with aluminium (44c). Current (n = 27) and past (n = 23) users of illicit heroin had significantly higher concentrations of urinary aluminium than controls. This was believed to be due to drug contamination and volatilization, which facilitates passage of heroin into the blood.
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Clenbuterol Clenbuterol adulteration of heroin has been recognized as a public health problem in the USA (45c, 46A, 47r). Clenbuterol is a long-acting beta2 adrenoceptor agonist used to treat asthma and illegally by body-builders because of its anabolic properties. Exposure to clenbuterol-containing heroin can cause nausea, chest pain, palpitation, shortness of breath, and tremor. Physical findings include tachycardia and hypotension. Significant laboratory effects include hyperglycemia, hypokalemia, and lactic acidosis. The adverse effects of adulteration of her oin with clenbuterol in the context of heroin abuse have been reported in 34 probable cases of clenbuterol contamination (48c). Sympathomimetic effects, metabolic acidosis, and myocardial injury were described. Expo sure was confirmed in 13 patients, with clenbuterol concentrations of 2.4–26 µg/l in the blood and 9–13 µg/l in the urine. This study highlights the importance of a public health approach to identification of trends. In six cases there was evidence of myocardial damage from increased troponin concentra tions. In 10 cases beta-adrenoceptor antago nists caused resolution of symptoms. Fentanyl Substitution of fentanyl for heroin has resulted in morbidity and mortality (47r). During 12 months in 2006–2007, the Philadelphia County Medical Examiner’s office records included over 250 overdose deaths associated with fentanyl exposure. In this case, apparent heroin overdose is naloxone-resistant. Drug overdose Although heroin is responsible for most illicit drug-related deaths, the leading cause of death being accidental overdose, only 2–4% or about 1 in 20 overdoses end in death. Among the heroin-using population, serious clinical outcomes include bronchopneumonia, pulmonary edema, rhabdomyolysis, renal failure, cognitive loss and trauma. In a study in Australia, the pattern of non-fatal overdose and the effect on subsequent
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overdoses in heroin-users was investigated (49C). About 387 heroin-users, who were recruited for the Australian Treatment Outcome Study (ATOS), a study of treatment for heroin dependence, were interviewed at 12, 24, and 36 months. Before the ATOS, 55% had had a heroin overdose, 36% had had multiple overdoses and 40% had been given naloxone. Heroinusers not receiving treatment were also recruited. ATOS recruits were from programmes that provided methadone/ buprenorphine maintenance treatment, drug-free residential rehabilitation or detoxification. At 36 months, 52% continue to be enrolled in a treatment programme. Compared with the entry year, the rates of heroin overdose were substantially lower in the subsequent 3 years. In the first 12 months, rates of heroin use, overdose, and naloxone administration fell and then became stable. During follow-up, 19% reported a heroin overdose and 12% reported having received naloxone; 10 took more than one overdose. A history of an overdose in the previous year was the strongest predictor of a subsequent overdose. The authors suggested that the data and trends in overdose frequency justify screening heroin-users for histories of recent overdose for clinical management and prognosis. Diagnosis of adverse drug reactions A 39-year-old man with a 2-year history of regular heroin use died 6 days after heroin overdose. His bile contained morphine 21 mg/l and his hair 4.8 µg/g, but morphine was absent from blood, urine and the liver. These findings suggest that enterohepatic recycling does not play a role until about 144 hours after the last dose of heroin and that the gall bladder acts as a storage depot, in which high concentrations of morphine suggest regular use of heroin (50A).
Dihydrocodeine
(SED-15, 1125)
Comparative studies Dihydrocodeine has been compared with nabilone, a synthetic cannabinoid, in the treatment of chronic
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neuropathic pain (51C). Dihydrocodeine provided better pain relief and was associated with fewer adverse effects. Only tiredness and nightmares were more frequent with dihydrocodeine. Sexual function A 42-year-old woman with a 2-year history of dihydrocodeine abuse (600–750 mg/day with peak ingestion 1350 mg/day) developed secondary amenor rhea and serum gonadotrophin concentra tions consistent with hypogonadotrophic hypogonadism (52A). All other investigations were normal. Her menses returned sponta neously 3 months after dosage reduction.
Fentanyl
(SED-15, 1346; SEDA-29, 106; SEDA-30, 110; SEDA-31, 159)
Observational studies The addition of transdermal fentanyl in 226 patients with severe pain from rheumatoid arthritis improved pain relief, function, sleep, well-being, and patient satisfaction (53C). Adverse events were experienced by 39 patients (17%) and 10% stopped taking the treatment. The most frequent adverse events were nausea and vomiting; others included dizziness, sedation, and constipation. Combinations of varying doses of fen tanyl with bupivacaine have been com pared with bupivacaine alone in 58 infants undergoing lower abdominal and urologi cal surgery (54c). The treatments were 0.5% hyperbaric bupivacaine alone and bupivacaine þ fentanyl 0.25, 0.5 or 1 µg/kg. There was no significant difference in adverse effects across the groups. There was pruritus in three infants who received fentanyl. The safety and efficacy of patientcontrolled analgesia (PCA) using fentanyl 1 microgram/kg plus continuous intrave nous infusion of midazolam 2 micrograms/ kg/minute have been explored in 16 chil dren with moderate to severe postoperative pain (55c). Minor adverse effects occurred in 25%. Two had pruritus, one a
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maculopapular rash, and one vomiting. There were no problems related to PCA. In a similar study on PCA, fentanyl 1 microgram/kg/hour þ booster doses of intravenous fentanyl 1 microgram/kg were given to 18 children with moderate to severe pain (56c). Adverse effects were reported by 39% and included pruritus (17%), vomiting (11%) and rashes (11%); there were no major adverse effects. In a prospective open trial in 81 patients with moderate to severe osteoarthritis, transdermal fentanyl 25 micrograms/hour was associated with mild to moderate adverse effects (57c). Treatment was with drawn in 32 patients because of nausea, vomiting, or dizziness. Systematic reviews Transdermal ionto phoretic fentanyl was as effective as morphine PCA in the management of acute postoperative pain, but was associated with fewer treatment failures related to adverse events, less pruritus and less somnolence (58M). Cardiovascular Midazolam (median dose 0.11 mg/kg) and fentanyl (median dose 2.77 micrograms/kg) were given intravenously to 1226 children, mean age 9 years, undergoing endoscopy; there were mild to moderate cardiovascular events, mainly hypertension and hypotension, in 10% (59C). Patient-controlled epidural analgesia consisting of 0.16% ropivacaine þ 3.5 micro grams/ml fentanyl (n = 25) has been com pared with epidural boluses of 0.1% methadone 4–6 mg 8-hourly (n = 24), in con trolling acute post-thoracotomy pain (60c). Fentanyl þ ropivacaine caused more hypo tension during the first postoperative hour. Respiratory The combination of midazolam þ fentanyl in 100 children caused adverse events in 25%, with respiratory events in 9% (59C). Most of the respiratory events were mild to moderate, and apnea occurred in two patients.
192 • Severe respiratory depression simulating a stroke occurred in a 78-year-old woman on PCA with fentanyl after routine surgery for endoluminal graft repair for abdominal aortic aneurysm (61A). The fentanyl analgesia was programmed at 20-micrograms doses with 5 minutes lockout, resulting in administration of 600 micrograms of fentanyl 16 hours after the operation. She had a slightly impaired renal function (creatinine 167 µmol/l) and a history of obstructive sleep apnea, which together with the fentanyl contributed to the development of respiratory depression.
Intravenous fentanyl is often associated with a reflex cough. In 300 adults under going elective surgery, intravenous fentanyl 2 micrograms/kg in 2 seconds was followed by cough in 39%. Perioperative administra tion of clonidine 2 micrograms/kg reduced the incidence of cough to 17% (62C). Low-dose intravenous ketamine (0.15 mg/kg) reduced fentanyl-induced cough and the time of onset of cough in a placebocontrolled study in 360 patients undergoing elective surgery who received fentanyl 1.5 micrograms/kg in 5 seconds (63C). Nervous system Serotonin syndrome occurred in a 25-year-old man who was given intrathecal fentanyl (64A). The authors suggested that the combination of fentanyl with dihydroergotamine, which the patient was taking for migraine, precipitated the serotonin syndrome and that his illicit use of 3,4-methylenedioxymetamfetamine and ephedrine exaggerated the clinical symptoms. In a comparison of propofol þ ketamine and propofol þ fentanyl for analgesia in children aged 5–60 months, both regimens produced sedation and analgesia, but there was more restlessness (in seven patients) among those who received propofol þ fentanyl (65c). Drug abuse Oral/transmucosal abuse of transdermal fentanyl patches has been reported and can be fatal. In seven cases of fentanyl-related deaths after oral administration of fentanyl patches, blood fentanyl concentrations were 7–97 µg/l
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(66c). Fentanyl alone was considered responsible for two of the deaths, and the combination of fentanyl, ethanol, other substances, and medical causes was causative in the others. Fetotoxicity Fentanyl can cause impaired infant feeding after birth (67R). Drug administration route A novel fenta nyl transdermal matrix patch 12.5 micro grams/hour has been studied in 87 patients with cancer pain; there was no increase in the incidence of adverse events (68c). Fentanyl buccal tablets using OraVescent® technology have improved the systemic availability and speed of drug delivery (69R). Adverse effects include local irritation, erythema, pain, and oral ulcers. Systemic adverse effects include nausea and dizziness. Accidental overdose can cause loss of consciousness. It is easy to swallow the tablet accidentally, and prescribing should be accompanied by appropriate education. The administration of bupivacaine þ fentanyl epidural analgesia during labor and Cesarean section precipitated transi ent Horner’s syndrome in a 29-year-old woman at 39 weeks gestation, perhaps because of upward spread of the anesthetic within the epidural space (70A). Drug overdose A 1-year-old girl died from fentanyl intoxication after accidental ingestion of a transdermal patch containing fentanyl 4.2 mg; the blood concentration of fentanyl was 5.6 µg/l and norfentanyl 5.9 µg/l (71A). Drug–drug interactions Antifungal azoles The interaction between fentanyl and the triazole antifungal drugs voricona zole and fluconazole has been explored in a randomized study in healthy volunteers (72c). Voriconazole reduced the clearance of intravenous fentanyl 5 micrograms/kg by 23% and fluconazole by 16%. This suggests that that continuous use of fentanyl could
Opioid analgesics and narcotic antagonists
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have resulted in 100% increase in fentanyl concentrations, potentially causing severe respiratory distress. Midazolam Midazolam and fentanyl are frequently co-administered to induce sedation in children undergoing gastrointes tinal endoscopy. In a prospective analysis of 1226 patients, respiratory adverse events were more likely in children under 6 years of age (73C). Within the whole sample, vomiting occurred in 5%, agitation in 1%, rashes in 0.7%, apnea in 0.2%, desaturation below 92% for more than 20 seconds in 0.7%, and desaturation below 92% for less than 20 seconds in 9%.
Hydromorphone (SED-15, 1703; SEDA-28, 47; SEDA-29, 107; SEDA-31, 162) Comparative studies Hydromorphone 10 micrograms/kg (n = 20) as caudal blockade has been compared with clonidine 2 micrograms/kg (n = 20) and morphine 50 micrograms/kg (n = 20) in children aged 6 months to 6 years undergoing ureteral reimplantation (74C). Those who were given hydromorphone and morphine had significantly more nausea and vomiting (90 and 80% respectively, compared with 50%) and pruritus (70 and 75% compared with 30%) than those who were given clonidine. Endocrine Secondary adrenocortical insufficiency and secondary amenorrhea due to hypogonadotrophic hypogonadism have been attributed to hydromorphone. • A 32-year-old woman taking hydromorphone 32 mg bd and up to 2.6 mg qds as required developed fatigue, weakness, dizziness, postural hypotension, loss of weight, and amenorrhea (75A). Abnormal investigations included low plasma adrenocorticotropic hormone (ACTH), reduced serum cortisol, reduced urinary cortisol excretion, and reduced estradiol. When she was given tramadol instead, the abnormal results and symptoms resolved.
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Drug formulations Once-daily hydromor phone OROS® was well tolerated by 336 patients with chronic non-malignant pain when they were switched to OROS® from other opioids (76c). The adverse effects were those expected from opioid treatment; they were mild to moderate and occurred in 79% of patients. The most common were nausea, vomiting, constipation, headache, dizziness, and somnolence. There were severe events in 4%, but most were not considered to be related to the treatment. Drug administration route Different routes of administration of hydromorphone for postoperative analgesia in patients undergoing transabdominal gynecological surgery have been compared: hydromor phone PCA 0.2 mg every 8 minutes (n = 37), scheduled intravenous hydro morphone every 3 hours (n = 48) or scheduled subcutaneous hydromorphone every 3 hours (n = 37) (77c). More morphine was used in the PCA group, more time was spent in treatment and there were higher rates of pruritus.
Levacetylmethadol (levo-a-acetylmethadol, LAAM) Levacetylmethadol, an MOR agonist, is a congener of methadone with a longer halflife. It was developed as an alternative to methadone for the management of opioid withdrawal (78R). However, it was removed from the market throughout the European Union in 2001 because of reports of prolon gation of the QT interval and 10 cases of life-threatening cardiac disorders, including torsade de pointes (79S). At the same time, in the USA, the Food and Drug Adminis tration (FDA) required the addition of a black box warning to the drug labelling in 2001. Electrocardiographic monitoring before and periodically during therapy was made compulsory and there was a conse quent marked drop in the use of the drug. The manufacturers therefore decided to stop marketing the drug in the USA in 2003,
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although it is still approved by the FDA (80r, 81r). During levacetylmethadol induction there is a delay in opioid activity as the long-acting metabolites are formed; withdrawal medica tion must therefore usually be given during the first 96 hours of treatment to suppress opioid withdrawal symptoms adequately and prevent self-administration by the patient. Comparative studies In a randomized comparison of levacetylmethadol three doses per week and daily methadone maintenance therapy for 26 weeks in 315 patients, those taking levacetylmethadol were less likely to test positive for opioid use, both during treatment and at 26 weeks (40% versus 60%) (82C). There were no adverse events, cardiological or otherwise. In a randomized, crossover trial, 62 patients stable on methadone received lev acetylmethadol on alternate days and daily methadone for 3 months each, followed by a further 6 months during which they were free to choose between the two drugs (83C). Levacetylmethadol mainte nance was associated with a lower rate of heroin use than methadone maintenance. Most of the subjects preferred levacetyl methadol rather than methadone (27 versus 12). Their main reasons were that it pro duced less withdrawal, fewer adverse effects and less craving for heroin, and entailed fewer pick-up days. Systematic reviews In a meta-analysis of 18 comparisons of levacetylmethadol and methadone (15 randomized controlled trials and 3 controlled prospective studies), 3 were excluded because of lack of data on retention, heroin use or mortality (84M). Opioid withdrawal (11 studies, 1473 participants) was better with levacetylmethadol (RR = 1.36; 95% CI = 1.07, 1.73; NNTB = 8). Non-abstinence was less with levacetylmethadol (5 studies, 983 participants; RR = 0.81, 95% CI = 0.72, 0.91; NNTB = 9). In 10 studies (1441 participants) there were 6 deaths from a range of causes, 5 in participants assigned
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to levacetylmethadol CI = 0.59, 8.9).
(RR = 2.28;
95%
Cardiovascular Reports of torsade de pointes attributed to levacetylmethadol started to appear in 2001 (85A). • A patient whose heroin dependency was being managed with high doses of levacetylmethadol developed a prolonged QT interval and polymorphic QRS complexes consistent with torsade de pointes. The patient was taking other drugs that prolong the QT interval (fluoxetine and intravenous cocaine), and others that inhibit the P450 enzymes that metabolize levacetylmethadol and its active metabolite (fluoxetine, cocaine, and marijuana).
In a 17-week randomized, controlled trial of equally effective doses of levacetylmethadol, methadone and buprenorphine in 154 opioid-addicted subjects with normal baseline QTc intervals, 12-lead electrocardiograms were collected at baseline and every 4 weeks (86C). Levacetylmethadol and methadone were significantly more likely to prolong the QTc interval to over 470 or 490 ms or to increase the QTc interval from baseline by more than 60 ms. In a randomized, controlled comparison of levacetylmethadol with racemic metha done in 53 patients, electrocardiographic recordings were made during a run-in period when all the patients were taking methadone and 24 weeks after randomization to metha done or levacetylmethadol (87C). After 24 weeks, the patients taking levacetylmethadol had a significant increase in QT interval (409 ms versus 418 ms), whereas there were no significant changes in patients taking methadone. The effects of levacetylmethadol on the cloned human cardiac potassium channels human ether-a-go-go-related gene (HERG), KvLQT1/mink, and Kv4.3 have been studied using patch clamp electrophysiology (88E). Levacetylmethadol inhibited HERG channel currents in a voltage-dependent manner, with an IC50 value of 3 µmol/l. Its major active metabolite, noracetylmethadol, inhibited HERG channels with an estimated IC50 of 12 µmol/l. Levacetylmethadol had little or no effect on Kv4.3 or KvLQT1/minK channel
Opioid analgesics and narcotic antagonists
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currents at concentrations up to 10 µmol/l. The authors concluded that the pro dysrhythmic effects of levacetylmethadol are due to block ade of the HERG cardiac potassium channel and suggested that noracetylmethadol might be a safer alternative in the treatment of opioid addiction. Respiratory Five occasional opioid-users took once weekly doses of either placebo, levacetylmethadol or methadone (15, 30, or 60 mg/70 kg) and then received naloxone (1.0 mg/70 kg intramuscularly) 24, 72, and 144 hours after agonist exposure (89c). Three were withdrawn because of greater than anticipated and clinically relevant respiratory depression after levacetylmethadol 60 mg. Naloxone did not fully reverse the pupillary constriction produced by levacetylmethadol 60 mg. Psychiatric Of 28 heroin addicts who received levacetylmethadol instead of methadone over 6 weeks in an out-patient detoxification programme, 9 withdrew early and crossed over to methadone (90c). They had a variety of complaints, ranging from anxiety about possibly receiving an experimental drug to withdrawal symptoms and dysphoria, which they had not experienced while taking methadone. Endocrine In nine male heroin addicts who took levacetylmethadol for 5 months there was no change in plasma concentrations of testosterone and luteinizing hormone 72 hours after a dose and during 2 weeks after abrupt withdrawal of levacetylmethadol (91c). Liver In 959 opioid addicts treated with levacetylmethadol for up to 36 months, there was no evidence of long-term hepatic toxicity or tumor formation as studied by liver function studies and liver–spleen imaging (92c). Genotoxicity Levacetylmethadol was genotoxic in the ad-3 forward-mutation test
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in Neurospora crassa and weakly mutagenic in the mouse lymphoma forward-mutation assay (93E). Analysis of the ad-3 mutants showed that they were the result of a parasexual phenomenon rather than forward mutation. There was one confirmed trans location carrier in the heritable translocation study, which by conservative interpretation might imply some germ-cell risk associated with exposure to LAAM. Drug dosage regimens In a randomized, double-blind trial, 180 male and female opioid-dependent patients were assigned to one of three doses of levacetylmethadol. Low-dose induction (25 mg) was constant from the start of treatment (n = 62), medium-dose induction (50 mg) lasted 7 days (n = 59) and high-dose induction (100 mg) lasted 17 days (n = 59) (94C). There were more agonist-related adverse effects in the high-dose group. All those who dropped out because of levacetylmethadol-related adverse effects were in the high-dose group (five women and three men). The adverse effects reported included anorexia, feeling over medicated, sedated/drowsy, nausea, and vomiting. The 31 patients who dropped out averaged 14 days in treatment and had a mean dose of 53 mg. One woman in the high-dose group died during the second week of treatment and toxicological analysis showed the presence of multiple drugs, although the concentrations of levacetylmethadol, norlevacetylmethadol, and dinorlevacetylmethadol were within the expected ranges. Drug–drug interactions Levacetylmetha dol is metabolized by CYP3A4-mediated N-demethylation and CYP3A-mediated inacti vation. Its metabolites are norleva cetylmethadol and dinorlevacetylmethadol. Patients who take CYP3A4 inducers (for example, rifampicin) are susceptible to increased metabolism, reduced plasma concentrations, and withdrawal. Those taking CYP3A inhibitors (for example, troleando mycin) are susceptible to reduced metabolism,
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increased plasma concentrations and toxicity (95R). However, unexpectedly, CYP3A induction reduced and inhibition increased the concentrations and clinical effects of the active metabolites, which suggests that there is a CYP3A-mediated metabolic pathway that leads to inactive metabolites, which predominates over CYP3A-dependent conversion to the active metabolites. Antiretroviral drugs In a study in 40 patients taking methadone or levacetyl methadol, delavirdine significantly reduced methadone clearance and increased metha done half-life, with a resultant increase in the area under curve (AUC) of 19% and Cmin of 29% (96C). Delavirdine significantly increased the AUC of the total concentration of levacetylmethadol and its active metabolites, norlevacetylmethadol and dinorlevacetylmethadol, by 43%, the Cmax by 30% and the Cmin by 59%, and reduced the tmax. There were no changes in cognitive function over the 7-day study period, measured by the Mini-Mental State Examination, no opioid withdrawal symptoms, measured by the Objective Opioid Withdrawal Scale and no complaints of adverse symptoms. Neither methadone nor levacetylmethadol altered delavirdine concentrations.
Ketoconazole In vivo inhibition of CYP3A by ketoconazole altered the pharmacokinetics and pharmacodynamics of levacetylmethadol 5 mg/70 kg in a singleblind, crossover, randomized study in 13 opioid-naive subjects (6 women and 7 men) (97C). Co-administration of ketoconazole resulted in 3.22-fold and 5.29-fold increases in the Cmax and AUC of levacetylmethadol. The tmax of norlevacetylmethadol and dinorlevacetyl methadol increased 2.43 and 11.6 times, respectively, and their Cmax values were reduced to 77 and 55%. The AUCs of norleva cetylmethadol and dinorlevacetylmethadol were increased 2.25 and 1.21 times respectively. Pupil diameter was significantly reduced by levacetylmethadol after both placebo and
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ketoconazole pretreatment; ketoconazole increased the tmax for miosis 2.92 times.
Methadone (SED-15, 2270; SEDA, 107; SEDA-30, 112; SEDA-31, 163) Cardiovascular Methadone-induced long QT syndrome associated with torsade de pointes can be effectively managed by the use of implantable cardioverter defibrillators, as has been shown in eight patients on methadone maintenance (98c). • In a 40-year-old woman, torsade de pointes after an increase in daily methadone dose to 135 mg for heroin addiction was treated with cardioversion and infusions of magnesium sulfate and lidocaine (99A). • In a 52-year-old HIV-positive woman, QT interval prolongation and torsade de pointes were associated with high-dose methadone (145 mg/day) (100A). Pulseless polymorphic ventricular tachycardia was reversed by car diopulmonary resuscitation. The QT interval shortened with eventual normalization when the dosage of methadone was reduced to 80 mg/day. She was not taking other medica tions that would have increased the serum methadone concentration. • A 53-year-old HIV-positive woman stopped taking lopinavir þ ritonavir and developed QT interval prolongation and torsade de pointes (101A).
In the last case, the authors suggested that withdrawal of the protease inhibitors had led to de-induction of metabolism of methadone and increased its blood concentration. In a cross-sectional study in heroin addicts, there was an association between methadone dosage and QT interval (102C). There was QT interval prolongation in 28% of the men and 32% of the women taking methadone, associated with a higher inci dence of syncope; a 50 mg higher dose of methadone increased the odds for syncope by 1.2 times. There was no association between buprenorphine treatment and QT interval. QT interval prolongation was also found in a neonate born to a mother taking metha done (103A). Bradycardia, tachycardia, or an irregular heart rate in neonates should
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increase the suspicion of the possibility of QT interval prolongation.
Respiratory The relation between metha done concentrations and respiratory effects has been highlighted by the case of a 44-year old man who took 240 mg of methadone, after which he became comatose, developed respiratory depression and had pinpoint pupils. The plasma concentration of R,S-methadone was 1204 µg/l. Concentrations of R- and S-methadone fell log-linearly over time (104A). Pulmonary edema secondary to non-fatal overdose of oral methadone has been described (105A). Methadone caused severe respiratory failure and non-cardiogenic pulmonary edema. Naloxone reversed the central nervous system and respiratory depression but did not reverse the pulmon ary edema.
Nervous system Methadone ingestion by children can have serious consequences (106A). • A 3-year-old girl took methadone and developed acute atypical severe cerebellitis. She was unresponsive, had labored breathing, and was hypothermic. CT and magnetic resonance imaging (MRI) scans showed cerebellar pathology with hypoxic-ischemic injuries in a watershed distribution.
Opioid-dependent patients (n = 23) had abnormal heat and pain perception for months after successful detoxification from methadone (107C) compared with 27 patients in remission. Stable opiate-dependent individuals (10 on methadone, 14 on buprenorphine) have been compared with healthy volun teers in investigation of dysfunction of the dorsal anterior cingulated cortex asso ciated with opiate addiction (108c). The opiate-dependent patients had more taskrelated activation of the frontal, parietal and cerebellar regions and reduced concentrations of N-acetylaspartate and
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glutamate/glutamine in the dorsal anterior cingulate cortex. The abnormalities were believed to have contributed to poor inhi bitory control, which is characteristic of addictive behavior. Fluid balance A 45-year-old woman with chronic back pain was given methadone 5 mg tds plus etodolac and gabapentin (109A). After 1 week she complained of feeling ‘drunk’, had leg swelling, and felt bloated. Etodolac and gabapentin were withdrawn and the dose of methadone was increased. The edema continued to worsen. Methadone was eventually withdrawn, resulting in resolution of the edema and bloatedness. Sexual function In men taking methadone maintenance treatment (n = 84) and buprenorphine maintenance treatment (n = 19), 53% of those taking methadone had erectile dysfunction, which was moderate to severe in 26% (110C). A similarly high prevalence of erectile dysfunction has been reported in another study (111C), with an overall prevalence of 58% in 201 men (85 taking methadone maintenance and 116 taking buprenor phine). There was severe erectile dysfunc tion in 19%, moderate dysfunction in 4.7%, mild to moderate dysfunction in 7.1% and mild dysfunction in 20% of those taking methadone. About half of those taking methadone did not have erectile dysfunc tion. Those taking buprenorphine had fewer problems with erectile dysfunction (severe in 18%, moderate in 1.8%, mild to moderate in 3.5%, mild in 13%); 64% had no problem at all. Death Methadone is a potent drug with potential lethal consequences (112r), and deaths due to methadone ingestion in children are steadily increasing in frequency, as in the case of a 22-month-old child who developed fatal posterior ischemic cerebral and cerebellar changes after methadone ingestion (113A).
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Drug tolerance Eight patients maintained on methadone had cross-tolerance to remifentanil (114c). They were given intravenous remifentanil in seven increasing doses of 0.5–3.5 micrograms/kg/minute 20 hours after their last dose of methadone (range 50–110 mg/day). Antinociception was achieved, but substantially higher doses than usual of remifentanil were required. The respiratory rate fell in a dose-related manner with remifentanil infusion and returned to baseline 25 minutes after the end of the infusion. There were opiate withdrawal effects after the end of the infusion.
maternal vagal reactivity (118C). There was no association with a history of maternal substance abuse, methadone maintenance, or psychotropic drug exposure. The severity and treatment require ments in neonatal abstinence syndrome was investigated in neonates born to opioid-maintained mothers, of whom 22 were on methadone maintenance, 17 on modified-release oral morphine, and 14 on buprenorphine (119C). Treatment was required by 32 neonates (60%), most being related to methadone maintenance (n = 15) and morphine maintenance (n = 14).
Drug withdrawal Opiate-dependent patients (n = 48) admitted to a specialist in-patient drug treatment service were withdrawn from opiates using a 10-day methadone reduction schedule (115c). Patients withdrawn from higher doses of methadone reported more severe withdrawal symptoms, but the effect was not strong.
Drug–drug interactions Aspirin A 42-year old man taking long-term methadone developed chest pain due to an acute myocardial infarction after taking aspirin 330 mg/day for 3 days (120A). The underlying mechanism was unclear but could have been due to paradoxical activation of major platelet receptors during chronic methadone exposure after exposure to aspirin.
Teratogenicity Horizontal nystagmus occurred in 12 infants who had been exposed to opiates (mainly methadone and heroin) in utero (116c). Fetotoxicity Fetal exposure to methadone (n = 35) has been compared with buprenorphine (n = 47) during treatment for opiate dependence in pregnancy (117C). Exposure to methadone was associated with a higher incidence of neonatal abstinence syndrome (78% compared with 40%) and more infants required treatment for withdrawal (53% compared with 15%). It was also associated with a low birth weight and a small birth height; buprenorphine exposure was not associated with abnormal birth weight. In another study of neonatal abstinence syndrome related to intra-uterine exposure to methadone, male infants had more pro found symptoms requiring pharmacother apy and neonatal abstinence was related to
Diazepam The interaction of diazepam 0–40 mg with methadone (mean dose 69 mg) has been explored in four patients (121c). The combination resulted in increased sedation and impaired reaction times, attention and psychomotor skills. These effects peaked within the first 2 hours of administration. Oxygen saturation was also reduced when higher doses of methadone (150% of the usual dose) were used in combination. Nevirapine Nevirapine altered the pharmacokinetics of methadone in 10 HIV-positive patients (122c). Nevirapine is a potent inducer of CYP3A4, resulting in significantly reduced plasma methadone concentrations and consequent opioid withdrawal symptoms, requiring an increase in methadone dose. Nevirapine 200 mg daily and 400 mg daily produced similar effects.
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Quetiapine The plasma concentration of (R)-methadone was increased by co-administration with quetiapine in 14 patients, probably because of an interaction with CYP2D6 or P glycoprotein (123c). Voriconazole Voriconazole 200 mg bd reduced the metabolism of (S)-methadone and (R)-methadone, with a larger effect on (S)-methadone in 23 patients (124c). Voriconazole should be prescribed with caution in patients taking methadone, and dose reduction should be given consideration.
Morphine
(SED-15, 2386; SEDA-29, 107; SEDA-30, 113; SEDA-31, 164)
Observational studies Lumbar plexus blockade reduced the dosage requirements of PCA morphine and produced improved analgesia, increased patient satisfaction and decreased nausea and vomiting compared with PCA morphine alone in 17 patients undergoing hip arthroplasty (125c). The incidence of adverse effects correlated with dose. One patient developed respiratory depression. Low doses (4–5 micrograms/kg) of intrathecal morphine for postoperative pain in 187 children were generally well tolerated, and there was no severe respira tory depression (126C). There was nausea and vomiting in 32%, pruritus in 37%, and urinary retention in 6%. The addition of small doses of ketamine to morphine in PCA reduces the amount of morphine required and improves respira tory function, reducing the potential for respiratory depression. In 50 patients undergoing lobectomy, intravenous mor phine 1 mg/ml was compared with intra venous morphine 1 mg/ml þ ketamine 1 mg/ml as PCA for postoperative analgesia (127C). The addition of ketamine resulted in a significant reduction in cumulative mor phine consumption and improved respira tory function.
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Alfentanil þ morphine has been com pared with morphine alone in the treat ment of postoperative pain in 453 patients (128C). The combination provided better and earlier patient comfort without increasing the incidence of adverse effects.
Systematic reviews In a systematic review of morphine regimens in children with postoperative pain, the most common adverse effects after intravenous administra tion were nausea, vomiting, and sedation; there was no relation to morphine dosage (129M).
Respiratory Morphine can be used as an alternative to general anesthesia in infants. In a retrospective study, 109 infants undergoing laser treatment for retinopathy of prematurity were given infusions of morphine (maximum rate 40 micrograms/ kg/hour) (130C). Mechanical ventilation for morphine-induced apnea was required in only three cases. There were minor alterations in oxygen saturation (<90%), bradycardia, or tachycardia in 65 cases. PCA using morphine (1 mg/bolus with 5 minutes lockout) (n = 14) was associated with higher transcutaneous carbon dioxide pressures, longer duration of hypercapnia, and lower respiratory rates compared with epidural analgesia with 0.1% bupiva caine þ fentanyl 2 micrograms/ml (n = 14) (131c). Transcutaneous CO2 pressure recording in patients on PCA morphine is a useful and sensitive monitor of respira tory depression. The case of a 53-year-old woman who developed unconsciousness and respiratory depression after morphine analgesia high lighted the superior sensitivity of sedation scores compared with respiratory rate in detecting opioid-induced respiratory depression (132A). The authors recom mended a maximum intrathecal morphine dose of 0.2 mg for postoperative analgesia in adults.
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Nervous system Downbeat nystagmus is a rare adverse effect of morphine (133A). • A 74-year-old gentleman was given epidural morphine 12 mg in 48 hours after radica cystoprostatectomy. He was given intraoperative general anesthesia and a continuous infusion of fentanyl 6 mg/ml without any complications, but 48 hours postoperatively he developed vertical oscillopsia of equal amplitude. This resolved 36 hours after morphine was withdrawn.
The authors discussed five other reported cases of downbeat nystagmus associated with morphine. Hyperalgesia has been attributed to morphine. • A woman developed hyperalgesia when the dosage of morphine for immunosuppressant drug-related neuropathic pain after intestinal transplantation was gradually increased over the course of 3 years from 15 to 100 mg/day (134A). The hyperalgesia responded to opioid withdrawal through rapid detoxification under general anesthesia. • A 49-year-old woman received intrathecal morphine þ clonidine for complex regional pain syndrome and developed escalating pain without a history of new pathology, suggestive of hyperalgesia (135A). Increases in the doses of morphine because of suspicion of tolerance worsened the pain. Pain relief was achieved only by withdrawal of morphine and the administration of ketamine.
There was no significant impairment in cog nitive ability after the administration of mor phine 10 mg to 18 healthy volunteers (136c). There were only subtle impairments in work ing memory, but these were marginal and did not affect other assessments of memory. Gastrointestinal A 75-year-old woman given transdermal fentanyl patches (25 micrograms/hour) and subcutaneous morphine 5 mg qds for painful ulcers due to systemic sclerosis developed ileus with duodenal perforation requiring surgery. Pain was later controlled with topical morphine (137A). In 100 patients with cancer pain there was a higher incidence of nausea, vomiting, and constipation in those who were given longterm oral modified-release morphine com pared with hydromorphone (138C).
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Constipation was reported by 72% of 274 patients taking oral morphine for cancer pain (139C). A large number (89%) of con stipated patients were not receiving ade quate treatment for constipation. During postoperative pain control after bone and soft tissue cancer surgery using standard morphine (1.5 mg/bolus) or a combination of morphine þ ketamine (1 þ 5 mg/bolus) as intravenous PCA, those who were given morphine only (n = 29) had more nausea and vomiting than those who received morphine þ ketamine (n = 28) (140c). Intrathecal morphine (100 µg) during labor reduced the need for analgesia for breakthrough pain after spinal–epidural analgesia with bupivacaine and fentanyl, but was associated with an increase in nausea in 17% (141c). Susceptibility factors Genetic The experi ence of morphine-related central adverse effects correlated with specific genotypes in 228 cancer patients receiving morphine (142C). The multidrug resistance-1 (MDR-1) gene was associated with moderate or severe drowsiness and confusion or hallucinations. The catechol O-methyltransferase (COMT) genotype also correlated with the adverse effects of morphine. Those with guanosine at position 2677 in exon 26 were less likely to have drowsiness, confusion or hallucinations than those with the thymidine or adenosine variants. Single nucleotide polymorphisms in intron 1, particularly at position –4873G, were also significantly associated with central adverse effects. This study goes a long way towards understanding individual variations in morphine-related adverse effects. Age Morphine should be used with caution in preterm infants, especially those under 28 weeks gestational age. In an observational study in 64 preterm infants who received a low dose of morphine to manage pain from continuous positive airway pressure, there were reductions in heart rate and respiratory rate (143c). There was no difference in the development of apnea, but the authors
Opioid analgesics and narcotic antagonists
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suggested that further studies are required to assess and quantify the risk. In this study, adequate analgesia was achieved with a very low dose of morphine (0.01 mg/kg). Morphine should also be used with cau tion in elderly people, especially in the pre sence of organ impairment. • A 70-year-old man with multiple myeloma required analgesia for back pain. He became drowsy, and hepatic impairment and poor renal function were believed to have contributed to the accumulation of morphine (144A).
Sex Women have more adverse effects from morphine than men. In a comparison of 211 women and 144 men, intravenous morphine 0.1 mg/kg caused adverse events in 18% of women and 11% of men (145C). Drug dosage regimens In a comparison of two different doses of morphine, 53 patients received an initial injection of 0.05 mg/kg followed by 0.025 mg/kg every 5 minutes and 53 received an initial injection of 0.1 mg/kg followed by 0.05 mg/kg every 5 minutes. The two regimens gave similar analgesic effects and comparable adverse effects, but those on the higher regimen had about twice the incidence of adverse effects and four times the amount of vomiting (146C). Different doses of intrathecal morphine 0–0.5 mg have been compared in 100 women undergoing Cesarean section (147C). The incidence of nausea and vomiting was the same in all groups, but pruritus increased with the increase in dose. None of the patients developed respiratory depression. Drug administration route Patientcontrolled epidural analgesia with local anesthetics and morphine after major surgery was associated with lower pain ratings, fewer adverse effects (respiratory depression, sedation, confusion, night mares, and hallucinations) and more technical difficulties than morphine as intravenous PCA (148r).
201
The use of morphine as PCA in 19 patients with 25 vaso-occlusive crises in sickle cell disease was associated with a lower total dose of morphine for adequate pain control and fewer adverse effects compared with continuous infusion of morphine (149c). Those who were given PCA morphine had cumulative morphine consumption of 33 mg (compared with 260 mg in the infusion group), less nausea and constipation, and shorter hospital stays. Intramuscular morphine 0.15 mg/kg has been compared with the same dose sub cutaneously to control pain after Cesarean section (150C). There was no significant dif ference in the incidence of adverse effects in both groups.
Drug overdose Electroencephalography after morphine overdose in a neonate was a useful way of monitoring the required dosage of naloxone (151A). • A 2-day-old full-term neonate was acciden tally given an overdose of morphine 5000 micrograms/kg to manage discomfort after complications at birth. He had respira tory depression and a period of apnea, seda tion, hypotonia, and pinpoint pupils, but soon resumed spontaneous breathing. He was given naloxone and gradually became more reactive. The overdose was associated with electroencephalographic changes in the form of continuous activity with sleep– wake cycling to discontinuous activity without sleep–wake cycling and a reduction in lower border amplitude from about 6 µV to about 3.5 µV. Naloxone reversed the electroencephalographic activity to continuous with sleep–wake cycling with a lower border amplitude of approximately 5 µV.
Drug–drug interactions Buspirone When buspirone was given to patients with morphine-induced respiratory depression, there was a significant increased in nausea. In 20 healthy volunteers who were given intravenous morphine 0.43 mg/ kg over 2 hours and buspirone 60 mg, there was no effect on respiratory depression (152c).
202
Oxycodone
(SED-15, 2651; SEDA-29, 108; SEDA-30, 115; SEDA-31, 167)
Comparative studies Oxycodone has been compared with fentanyl in the management of postoperative pain after laparoscopic cholecystectomy in patients who were randomized to oxycodone 5 or 10 mg (n = 39) or fentanyl 50–100 micrograms (n = 39), depending on pain severity (153c). Oxycodone produced better analgesia but more adverse effects, including moderate or severe nausea, vomiting, and sedation. The authors suggested that the doses of fentanyl and oxycodone were not equipotent. Drug formulations Controlled-release oxy codone (22 mg/day on day 1 to 40 mg/day on day 21) as first-line treatment for moderate to severe cancer pain has been studied in 390 Italian patients (154C). Adverse effects were mild to moderate in intensity, nausea, vomiting, and constipation being the most common. Adverse events were reported by 4% of the patients, and 10 patients withdrew because of adverse events. The use of controlled-release oxycodone has been studied in 216 Chinese patients with moderate to severe cancer pain (155C). The daily dose of oxycodone in most patients (89%) was 10–30 mg. There were adverse reactions in 30%, and the majority were experienced within the first week. The most common events included constipation, nausea, vomiting, drowsiness, dizziness, distension, and dysuria. The fre quency of adverse events fell over time. There were no severe events. In 116 patients with chronic neck pain and acute episodes of pain, randomized to controlled-release oxycodone 5–10 mg every 12 hours or placebo, oxycodone was associated with nausea (in 31%), constipa tion (in 22%), pruritus (in 19%), and dizzi ness (in 28%) (156C). The symptoms were transient in most patients, reported on day 7 and gradually diminishing. Persistent consti pation occurred in only two patients. One patient who took oxycodone withdrew because of intolerable pruritus and one
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who took placebo withdrew because of severe nausea. The efficacy and tolerability of controlled-release oxycodone in the treatment of gynecological cancer pain has been explored in 37 women with gradual titration to an optimal mean dosage of 19 mg/day (157c). There were adverse effects in 17 patients, the most frequent events being constipation, somnolence, and nausea. There was no vomiting, dizziness, confusion, or respiratory depression. In an open uncontrolled registry study in 233 patients taking controlled-release oxy codone over 3 years, adverse events were reported by 88% of those who took at least one dose of oxycodone, most commonly constipation (15%) and nausea (12%) (158C). Other events were somnolence (8%), vomiting (7%), and depression (2%), and 18% withdrew because of adverse events. One death was precipitated by an interaction of oxycodone with alcohol and phenylpropanolamine. The incidence of adverse events was highest in the first 3 months of treatment and fell thereafter. In a post-marketing surveillance study of oxycodone controlled-release tablets in moderate to severe non-cancer pain, 53 of 196 and 83 of 190 patients respectively had adverse events, mainly constipation, nausea, and dizziness, within the first week. The adverse events gradually diminished with time (159C). In a study of the use of oxycodone controlled-release tablets in postoperative analgesia, three patients withdrew because of adverse events (160c). Perioperative administration of oral controlled-release oxycodone 20 mg 12-hourly in 40 patients undergoing lumbar discect omy reduced postoperative intravenous morphine consumption for pain control and was associated with a reduced incidence of adverse effects (161c). Postoperative nau sea and vomiting were reduced and there was earlier recovery in bowel function. Psychological There was only marginal impairment in working memory in 18 healthy individuals after the administration
Opioid analgesics and narcotic antagonists
Chapter 8
of oxycodone 5 mg (136c). This subtle impairment was found in the nine women who took part.
Liver Cholestatic hepatitis occurred in a 34-year-old man who took oxycodone 40 mg in the morning and 20 mg at night for analgesia after T11 vertebrectomy (162A). He developed jaundice and severe pruritus, which resolved on withdrawal of oxycodone. All other causes of hepatotoxicity were eliminated. Drug–drug interactions Tramadol The interaction of oxycodone 10 mg with tramadol 100 mg has been explored in 10 healthy volunteers; tramadol did not alter the clearance of oxycodone (163E).
Oxymorphone Oxymorphone is a pyridine-ring unsubstituted pyridomorphinan, with greater analgesic potency than morphine, whose antinociceptive effects are mediated predominantly through DOR and MOR. It is a metabolite, by O demethylation, of oxycodone and is formu lated for administration as a separate com pound. Formulations include oral immediate-release tablets and modifiedrelease tablets (164R), parenteral solutions, and suppositories. The pharmacology, clinical pharmacology, efficacy, and adverse effects of oxymorphone have been reviewed (165R– 167R). It has a similar adverse effects profile to other potent MOR agonists, although in some studies it caused more nausea and vomiting than morphine when given by patient-controlled devices. There were no dif ferences in nausea and vomiting with the oral modified-release forms of oxymorphone and morphine, but oxymorphone caused more flatulence. Oxymorphone was also reported to provide a better quality of life. The common adverse effects of oxymor phone are nausea, pyrexia, constipation, diz ziness, pruritus, somnolence, and sedation.
203
With oxymorphone instant-release, nausea and pyrexia are the most common.
Observational studies In a 52-week, multi center, open study of a modified-release for mulation of oxymorphone in 153 patients with moderate to severe chronic osteoarthri tis-related pain, only 61 patients completed the study (168c). Common opioid-related non-serious adverse events caused most of the withdrawals, and about one-half occurred in opioid-naive patients who had received placebo in a previous trial and were given an initial dose of 20 mg every 12 hours. The authors suggested that toler ability could be improved by titrating from a lower initial dose.
Comparative studies In 39 patients under going elective gynecological surgery of at least 2 hours duration, fentanyl 6.5 micrograms/kg or oxymorphone 65 micrograms/kg was given before induction (169c). Blood pressure and heart rate were well controlled with both agents, but those who received oxymorphone needed less analgesia postoperatively and more naloxone. Morphine and oxymorphone have been compared in 32 patients who received tradi tional PCA after Cesarean delivery and 32 who received the same agents plus a basal infusion of the opioid (170c). Oxymorphone produced greater reduction in resting pain scores and both opioids reduced pain during movement.
Placebo-controlled studies In a doubleblind, multi center, randomized placebocontrolled, parallel group, dose-ranging study, three doses of immediate-release (IR) oxymorphone (10, 20, or 30 micrograms) were compared with placebo or oxycodone IR (10 micrograms) in 300 patients receiving total hip or knee replacements (171C). All the doses of oxymorphone IR were better at providing pain relief for 8 hours, with a significant analgesic dose response that was maintained over several days, and a safety
204
profile comparable to that of oxycodone IR. The most common adverse events in those who took oxymorphone IR were mild to moderate opioid adverse effects. In a placebo-controlled study of the effects of modified-release oxymorphone in 126 patients with moderate or severe pain after knee arthroplasty, oxymorphone was more effective than placebo (172C). Adverse events such as nausea and constipation were typical of opioids. In a multi center, double-blind, placebocontrolled, parallel-group, dose-ranging study of different doses of two different modifiedrelease formulations of oxymorphone in 491 patients, the adverse events in all the opioid groups included mild to moderate nausea, con stipation and somnolence (173C). In a 2-week, multi center, randomized, double-blind, placebo-controlled, dose-ran ging, Phase III trial in 370 patients with osteoarthritis of the hip or knee with chronic moderate to severe pain, the most frequently reported adverse events, occurring in at least 5% of patients, were nausea (39%), vomiting (24%), dizziness (23%), constipation (22%), somnolence (18%), pruritus (17%), and headache (15%); most were mild or moderate in intensity (174C). There were three serious events (urinary retention, ner vous system depression and pancreatitis) that were considered possibly or probably related to the medication. In 250 patients with chronic moderate to severe low back pain who were taking an opioid analgesic, an equi analgesic dose of modified-release oxymorphone was substi tuted, with slow dose titration (175C). Withdrawals because of adverse events were similar in the two groups (10% with placebo and 11% with oxymorphone). Opioid-related adverse events included constipation (6%), somnolence (3%), and nausea (3%). In two combined double-blind placebocontrolled trials of a modified-release formu lation of oxymorphone in 347 adults with chronic low back pain, the proportion of patients who had adverse events was signifi cantly greater with oxymorphone than with placebo (26 versus 16%) (176C). The most frequent treatment-related adverse
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A.H. Ghodse and S. Galea
events in those taking oxymorphone were nausea (8.0%), constipation (6.3%), vomit ing (4.6%), and diarrhea (4.0%); the adverse events in those who took placebo were nau sea (5.8%), diarrhea (4.7%), and increased sweating (2.3%). Respiratory Delayed postoperative respira tory depression has been associated with oxymorphone (177A). Susceptibility factors Age The pharma codynamics, pharmacokinetics, efficacy and tolerability of oxymorphone in elderly patients have been reviewed in a systematic review (178M). Dosage adjustment is recommended in elderly people. Renal disease Oxymorphone should be used with caution in people with renal insufficiency, as it is renally excreted (179C, 180A). Liver disease Oral oxymorphone is contraindicated in patients with moderate to severe hepatic impairment because it is extensively metabolized in the liver to oxymorphone-3-glucuronide and the active metabolite 6-hydroxyoxymorphone (181R). It should also be used with caution in patients with biliary tract disease. Drug formulations The pharmacokinetics and dose proportionality of four strengths (5, 10, 20, and 40 mg) of a modified-release formulation of oxymorphone after a single dose and at steady state have been studied in a randomized, three-period, four-sequence, crossover study in 24 healthy adults (182C). The kinetics were linear over the doses studied. Two different types of modified-release formulations of oxymorphone have been compared in 47 adults with moderate to severe cancer pain (183c). There were no significant differences in opioid-related adverse events between the groups. In a similar comparison in a multi center, randomized, double-blind, placebo-controlled
Opioid analgesics and narcotic antagonists
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205
study in 213 ambulatory patients with moder ate to severe chronic low back pain, adverse events in those who took the active drugs were similar, the most frequent being constipation and sedation (184C).
Cimetidine Confusion, disorientation, apnea, respiratory depression, and seizures can occur if oxymorphone is used with cimetidine. In the presence of seizure disorders, oxymorphone can precipitate seizures.
Drug administration route Intramuscular oxymorphone is about 6 times as potent as oral oxymorphone, but in terms of peak effect it is about 14 times as potent (185c). Intramuscular oxymorphone is 8.7 times as potent as morphine in terms of total analgesic effect and 13 times as potent in terms of peak effect. In a double-blind, twin-crossover com parison, single doses of oxymorphone by rectal suppository and intramuscular injec tion were evaluated in 136 patients with postoperative pain (186C). Rectal adminis tration resulted in lower and more delayed peak analgesia and a longer duration of action than intramuscular administration. For duration and intensity of analgesia, rectal oxymorphone was 1/10 as potent as the intra muscular form; in peak effect, it was only 1/16–1/20 as potent. However, because intra muscular oxymorphone is 9–10 times as potent as intramuscular morphine, oxymor phone 5–10 mg by suppository provides analgesia comparable to that provided by the usually used doses of parenteral narcotics. The intrathecal route of administration has been associated with edema of the legs and feet, owing to vasodilatation (187c).
Nervous system depressants Oxymorphone should be used with caution when in conjunction with other central nervous system (CNS) depressants, and the starting dose should be one-third to one half the usual starting dose with gradual titration. Similarly, it should be used with caution in patients with impaired respiratory function. Concomitant use of alcohol should be avoided.
Drug–drug interactions Interactions of oxymorphone with drugs that inhibit the activity of CYP isoenzymes have not been described (165R). Anticholinergic drugs There is an increased risk of urinary retention and con stipation if oxymorphone is combined with anticholinergic drugs. Buprenorphine Concomitant use of bupre norphine can reduce the analgesic effects of oxymorphone.
Papaverine
(SED-15, 2678; SEDA- 30, 115; SEDA-31, 168) Nervous system Papaverine is effective in the control of acute renal colic pain and is a good alternative when non-steroidal anti-inflammatory drugs (NSAIDs) are contraindicated. Only minor adverse effects, mainly dizziness and sleepiness, were reported in a randomized comparison of papaverine and sodium diclofenac in 86 patients with acute renal colic. These adverse effects were experienced by 4 of 29 patients who were given papaverine (188C).
Pentazocine
(SED-15, 2777; SEDA- 30, 115; SEDA-31, 168) Musculoskeletal Calcific myofibrosis has been attributed to pentazocine.
• A 42-year-old man abused pentazocine 60 mg/ day intramuscularly for about 6 years and developed progressive persistent stiffness, muscle wasting, and impaired mobility. There were multiple areas of soft tissue calcification, with hyperdense muscles and atrophy, and features suggestive of neurogenic involve ment without inflammatory signs. Muscle groups that had not been injected with penta zocine were involved. The patient had also
206 injected Phenergan® (promethazine hydro chloride), which may have had a contributory role (189A).
Pethidine (meperidine) (SED-15, 2791; SEDA-29, 108; SEDA-30, 115; SEDA-31, 168) Comparative studies The use of pethidine for pain control after abortion by manual vacuum aspiration was associated with more adverse effects than if pethidine were not used in 113 patients, in whom three different analgesic regimens were compared: diclofenac þ paracervical block, pethidine þ diclofenac and pethidine alone (190C). All three regimens achieved similar analgesia, but adverse effects were more common in those in whom pethidine was used. Nausea and dizziness were significantly more common. Nervous system Pethidine 80 mg given intravenously over 20 minutes in 100 ml of saline to an otherwise healthy 29-year old woman with low back pain caused reversible retrograde amnesia lasting about 3 hours and disorientation in time, place, and person (191A). A 27-year-old man with a history of acute myeloid leukemia developed serotonin syn drome after being given for sepsis and pethidine for rigors (192A). He received pethidine 90 minutes after the third dose of linezolid and developed the serotonin syndrome about 30 minutes later. The symptoms reversed when pethidine was withdrawn.
Fetotoxicity Maternal use of pethidine during labor can have adverse effects on the fetus. Effects on fetal heart rate variability and respiratory distress have been reported (193R). Neonatal depression persisting for 3–5 days after birth has been described, even after the administration of low doses of pethidine during labor (167R).
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Susceptibility factors Diseases It has been recommended that pethidine be avoided as premedication for endoscopic procedures in patients with Alzheimer’s disease and other patients with increased risk of seizures after a 63-year-old woman with Alzheimer’s disease developed tonic–clonic seizures almost immediately after intravenous injection of pethidine 50 mg (194A). The authors postu lated that a combination of factors had con tributed: the metabolite of pethidine, norpethidine; the pathological changes of Alzheimer’s disease; and other medications, particularly galantamine, a cholinesterase inhibitor, and memantine, an N-methyl-D aspartate receptor antagonist. Management of adverse drug reactions Dexamethasone (0.1 mg/kg intravenously), given before intrathecal pethidine, reduces the incidence of postoperative nausea and vomiting (195c). Only 2 of 29 who received dexamethasone developed nausea and vomiting, compared with 11 and 10 respec tively in the control group of 28.
Pholcodine Pholcodine (3-morpholinoethylmorphine), a semi-synthetic alkaloid, is an MOR ago nist with similar anti tussive properties to codeine (196R). It is metabolized to nor pholcodine and pholcodine-N-oxide, its main metabolite, but not to morphine, which may explain its lack of analgesic effect (197E). In healthy volunteers who took single oral doses of 20 mg and 60 mg, pholcodine was absorbed rapidly (tmax 1.6 hours) and eliminated slowly, with a mean half-life of 50 hours; its renal clearance was 137 ml/minute and correlated inversely with urine pH but not with urine flow rate; plasma protein binding was 24%; 26% of the dose was excreted as unchanged pholco dine (198C). The concentration of pholco dine in saliva was 3.6 times higher than in plasma. After long-term administration, the pharmacokinetics of pholcodine were not statistically different.
Opioid analgesics and narcotic antagonists
Chapter 8
Immunologic Hypersensitivity has been attributed to pholcodine (199). • A 33-year-old woman developed facial angio edema 8 hours after taking Respilène® syrup (which contains pholcodine, domperidone, tixo cortol and bacitracin). The symptoms resolved with an intravenous corticosteroid. An intrader mal test was positive for pholcodine but negative for domperidone, tixocortol and bacitracin. Open oral challenge with pholcodine 20 mg was positive.
This is believed to have been the first report of allergy to pholcodine. Anaphylaxis due to drugs can be mediated by immunoglobulin E (IgE) antibodies that bind quaternary ammonium ion epitopes, which are present in many drugs, including pholcodine. Pholcodine can cause an increase in serum IgE concentrations (200c). In 17 patients who were randomized to cough syrup containing either pholcodine or guai fenesin for 1 week, pholcodine increased IgE antibodies to pholcodine, morphine, and suxamethonium, the median proportional increases 4 weeks after exposure being 39, 39, and 93 times baseline respectively. The median proportional increase in IgE was 19-fold. Guaifenesin had no such effect.
Drug–drug interactions Activated charcoal In a randomized study of the effects of single and multiple doses of activated charcoal on the absorption and elimination of pholco dine 100 mg administered in a cough syrup, charcoal 25 g given immediately after the pholcodine significantly reduced the absorp tion of pholcodine; the AUC0!96 was reduced by 91%, the Cmax by 77% and the amount of pholcodine excreted in the urine by 85% (201). When charcoal was given 2 hours after pholcodine, the AUC0!96 was reduced by 26%, the Cmax by 23% and the urinary excretion by 28%. When it was given 5 hours after pholcodine, charcoal produced only a 17% reduction in the AUC0!96, but reduced the further absorption of pholcodine still present in the gastrointestinal tract at the time of charcoal administration, as measured by the AUC5!96.
207
Remifentanil
(SED-15, 3030; SEDA-29, 109; SEDA-30, 116; SEDA-31, 168)
Cardiovascular In 26 ventilated children who had undergone cardiac surgery, sedation was administered with midazolam 50 micrograms/kg/hour and remifentanil, starting at 0.8 micrograms/kg/minute for 1 hour and then reduced by 0.1 micrograms/ kg/minute every 20 minutes, until the patient awoke (202c). Three patients developed hypotension; one settled spontaneously, one responded to fluids and one had to have remifentanil withdrawn. The blood pressure in the last normalized on withdrawal. The addition of remifentanil infusion (range 0.1–0.4 micrograms/kg/minute) to propofol anesthesia has been investigated in 72 patients (203c). Remifentanil reduced the heart rate by 13–24% and did not reduce propofol requirements for anesthesia. • A 2-year-old boy with severe bradycardia due to mild brain edema and a small subdural hematoma following a head injury was stabilized over 5 days (204A). On day 6 his sedative/analgesic regimen was changed to midazolam 0.1 mg/kg/hour þ remifentanil 0.1 micrograms/kg/minute, and 5 minutes later his heart rate fell to 58/minute and continued to fall. Within 15 minutes of remifentanil withdrawal, the heart beat normalized and cardiac contractility improved.
Respiratory Remifentanil adverse respiratory effects.
can
cause
• A 60-year-old man weighing 61 kg was admitted for elective cholecystectomy, and during anesthesia was erroneously given remifentanil 567 micrograms epidurally over 10 minutes, the recommended dose being 1 microgram/kg intravenously (205A). He only developed respiratory depression and altered consciousness after the second and third doses.
The authors suggest that this could have been due to a delay in diffusion from the epidural space to the systemic circulation. • A 38-year-old woman with von Willebrand’s disease developed respiratory depression during labor while receiving a continuous infusion of remifentanil (0.025 micrograms/kg/minute for 15 minutes followed by 0.1 micrograms/kg/minute) (206A). About 3 minutes after the increase in dose, she became apneic and the fetal heart rate fell significantly.
208 • A 21-year-old man who was given remifentanil (1.2 micrograms/kg/minute for 60 seconds and 0.2 micrograms/kg/minute thereafter) for surgery developed prolonged apnea postoperatively for about 45 minutes; it responded to naloxone (207A).
The interest in the second case was the prolonged apnea despite a moderate dosage. The authors speculated that phar macogenetic variation could have caused this atypical presentation. Nervous system In a randomized study, 27 parturients received intravenous PCA with remifentanil and 25 received epidural analgesia with levobupivacaine and fentanyl (208c). Those who were given remifentanil had more sedation and lower hemoglobin oxygen saturations. The combination of remifentanil (0.5 micrograms/kg/minute) and propofol (1.5 micrograms/ml) resulted in synergistic analgesic effects but led to increased hyper algesia on withdrawal in 15 healthy volun teers (209c).
Sufentanil
(SED-15, 3210; SEDA-29, 110; SEDA-31, 169)
Comparative studies Sufentanil has been compared with remifentanil in fasttrack cardiac anesthesia in 120 patients who underwent coronary artery bypass graft surgery and/or cardiac valve surgery (210C). They were given either sufentanil (1 microgram/kg for induction, 0.5 micro grams/kg for incision and 0.02 micrograms/kg/ minute thereafter) or remifentanil (1 micro gram/kg/minute). The incidences of adverse events were similar in the two groups (48 versus 55) and most of the adverse events were of mild to moderate intensity. Drug administration route Continuous intrathecal analgesia with bupivacaine þ sufentanil has been compared with continuous epidural analgesia in 429 patients during labor. One developed respiratory depression coinciding with application of fundal pressure during
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A.H. Ghodse and S. Galea
Cesarean delivery (211c). The authors suggested that respiratory depression had resulted from spread of intrathecal sufentanil at a faster rate towards the head because of raised spinal fluid pressure. In a similar study 2.5 micrograms of intra venous sufentanil (n = 30) was compared with 2.5 µg of intrathecal sufentanil (n = 30) in patients undergoing elective Cesarean section (212C). Less sufentanil was required when it was used intrathecally, but there was more pruritus. Management of adverse drug reactions Postoperative nausea and vomiting asso ciated with sufentanil in patients undergoing total knee replacement was adequately con trolled by the addition of a small dose of epidural naloxone (213c).
Tramadol (SED-15, 3469; SEDA-29, 110; SEDA-30, 117; SEDA-31, 170) Observational studies Tramadol-induced adverse drug reactions were responsible for 10% (939) of all adverse drug reactions reported to the Iranian Pharmacovigilance Centre from April 2002 to February 2005 (214C). The average number of reactions per patient was 2.78. Most occurred in women aged 20–40 years. The most common adverse reactions were nausea, vomiting, dizziness, weakness, and hypotension. Respiratory reactions, such as dyspnea, bronchospasm, respiratory depression, and apnea, amounted to 65 of the reported reactions. The strength of injectable tramadol was changed from 100 to 50 mg, after which the incidence of adverse reactions fell. Comparative studies Tramadol (starting dose 200 mg/day) and hydrocodone þ paracetamol (starting dose 25/2500 mg/ day) have been compared in 118 patients with chronic cancer pain (215c). Those who received tramadol had more nausea, vomiting, loss of appetite, dizziness, and weakness. Tramadol, pethidine, and morphine PCA have been compared after abdominal
Opioid analgesics and narcotic antagonists
Chapter 8
209
hysterectomy (216C). Those who used mor phine (mean dose 26 mg over 24 hours; n = 39), pethidine (266 mg over 24 hours; n = 39), and tramadol (320 mg over 24 hours; n = 40) achieved similar levels of pain control, but those who used tramadol required more rescue doses of fentanyl. There were no significant differences in adverse effects: morphine 33%, pethidine 28%, and tramadol 30%.
lavage specimens (400 mg/l), by detection of tramadol and N-desmethyltramadol in post-mortem blood, liver and kidney speci mens and by the failure to detect other poi sons (221Ar). The authors reviewed other cases mentioned in the literature and high lighted the fact that virtually all cases were due to tramadol in conjunction with other substances, rather than tramadol alone.
Gastrointestinal Epidural tramadol 2 mg/kg with 5 ml of 1% mepivacaine preoperatively in seven Japanese patients undergoing upper abdominal surgery was associated with nausea in four patients; there were no other adverse effects (217c).
PARTIAL OPIOID RECEPTOR AGONISTS
Musculoskeletal An 86-year-old woman who had had restless legs syndrome for almost 30 years was given tramadol 50 mg/ day. After about 1 year the syndrome worsened and the dose of tramadol was increased, which led to further worsening (218A). The symptoms and polysomno graphic features improved when tramadol was withdrawn. Drug formulations The safety profile of modified-release tramadol is similar to that of immediate-release tramadol. The inci dence of adverse effects increases with increasing doses. Modified-release tramadol has a low potential for abuse and should be considered for management of moderate to severe chronic pain in patients in whom NSAIDs and cyclooxygenase-2 (COX-2) inhibitors are problematic (219R). Dizziness, nausea, constipation, somno lence, and flushing are reportedly the most common adverse effects of modified-release tramadol 100–300 mg/day (220r). Drug overdose Multiple-organ failure due to tramadol alone occurred in a 27-year-old Caucasian man with a history of M€ unchausen syndrome and stress incon tinence. Tramadol overdose was confirmed through the finding of high concentrations of tramadol in serum (8 mg/l) and gastric
Buprenorphine (SED-15, 571; SEDA-29, 111; SEDA-30, 118; SEDA-31, 171) The safety profile of buprenorphine has been reviewed (222R). Nausea and vomit ing occur in 10–20% and dizziness in 5%. Other adverse effects include dry mouth, mild respiratory depression and erythema and pruritus with transdermal buprenorphine. Comparative studies In patients under going long-term treatment for opiate addic tion, there were only minor adverse events in those taking buprenorphine (17 of 106) or methadone (9 of 107) (223C). The adverse effects included headache, constipa tion, somnolence, weakness, and insomnia with buprenorphine and weakness and con stipation with methadone. Psychological Buprenorphine caused sig nificant deficits in cognitive and psycho motor functioning in 23 volunteers who were given 0.6 mg intravenously over 150 minutes and underwent neuropsychological tests of working memory, psychomotor func tion, concentration, sustained attention, vigi lance, and information processing (224c). There was significant impairment, and the time of onset was determined by slow distri bution of the drug into the biophase. Other effects have been found in other studies, particularly deficits in higher taskrelated activation of the frontal, parietal, and
210
cerebellar regions, and reduced concentra tions of N-acetylaspartate and glutamate/glu tamine in the dorsal anterior cingulated cortex, which is believed to contribute to poor inhibitory control characteristic of addictive behavior (108c). Drug abuse Six heroin addicts who snorted buprenorphine as a method of substance abuse have been reported (225c). This method of administration tends to be popu lar among prison populations and is reported to produce a quicker onset, albeit with a shorter-lasting effect. Drug withdrawal Buprenorphine is pos tulated to have anti psychotic effects and withdrawal has been associated with psy chotic symptoms. • A 32-year-old man with a history of substance misuse and a psychotic disorder took bupre norphine 6 mg/day and developed agitation, paranoid ideation and auditory and visual hal lucinations on gradual withdrawal (226A). His symptoms resolved 24 hours after re-adminis tration of buprenorphine.
Susceptibility factors Diseases Low-dose buprenorphine injected into the sympathetic ganglia to treat patients with chronic upper body pain is generally well tolerated (227C). However, one patient with a history of dilated cardiomyopathy had fatigue and sweating, although vital signs remained stable. Drug dosage regimen When higher doses of transdermal buprenorphine were used in 10 patients who were no longer benefit ing from a dose of 70 micrograms/hour, analgesic benefit was achieved with no change in adverse effects (228c). Drug–drug interactions Benzodiazepines The concomitant use of buprenorphine with benzodiazepines is common among opiate addicts, both in and out of treat ment. Benzodiazepines enhanced the response to buprenorphine (mean dose 11 mg) in seven patients engaged in treat ment, influencing attention, psychomotor
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skills and sedation (121c). These changes peaked 1–2 hours after medication, sug gesting an appropriate period for clinical monitoring. Cannabinoids It has been postulated that the concomitant use of buprenorphine 5 mg/ day and cannabis 2–6 cigarettes/ day contributed to the development of brain hemorrhage and cerebral vasospasm in a 34-year-old woman who had previously tolerated both substances for a long time (229A). The association was supported by the fact that angiographic abnormalities disappeared when the doses were reduced. HIV protease inhibitors The interaction of atazanavir and atazanavir þ ritonavir with buprenorphine has been explored in 40 opioid-dependent HIV-negative volun teers taking buprenorphine þ naloxone (230c). Atazanavir and atazanavir þ ritona vir in recommended doses were associated with increased concentrations of buprenor phine and its main metabolite. This was associated with sedation in 30%, suggesting that a reduction in dosage may be appro priate and that monitoring is clinically war ranted. Concentrations of atazanavir and atazanavir þ ritonavir were not affected. Naloxone The addition of ultra-low doses of naloxone to buprenorphine in healthy subjects enhanced the analgesic effect without increasing the incidence of adverse effects; in fact, respiratory depression was less pronounced with the addition of naloxone in a 10:1 ratio (231c).
Butorphanol (SED-15, 582; SEDA-31, 172) Observational studies The actions of butorphanol alone and in combination with naltrexone have been explored in 10 healthy volunteers with a history of opioid abuse (232c). They participated in experimental tests of varying doses of oral naltrexone (0, 1, 3, 10, or 30 mg) given 60 minutes before varying doses of
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intramuscular butorphanol (0, 6, or 12 mg/ 70 kg). Butorphanol alone produced predominant MOR effects (for example, miosis and respiratory depression) and changes in mood. In combination with naltrexone, it produced a significant diuresis, suggesting the unmasking of KOR activity. One volunteer developed agitation, tonic–clonic seizures, and disorientation after administration of butorphanol.
Nalbuphine
(SED-15, 2416; SEDA-29, 111; SEDA-30, 119)
Endocrine Intravenous nalbuphine in analgesic doses increased secretion of the ante rior pituitary hormone prolactin in 15 healthy male cocaine-abusers (233c). Concentrations of adrenocorticotropin and cortisol were not altered. Individuals reported feeling ‘sick’, ‘bad’ and ‘dizzy’ at higher doses of nalbuphine (10 mg/70 kg), correlating with the increase in prolactin concentrations.
OPIOID RECEPTOR ANTAGONISTS Methylnaltrexone
(SED-15, 2307)
Managing adverse drug reactions Methyl naltrexone blocks the peripheral effects of o pioids, sparing their central analgesic effects. Methylnaltrexone produced a laxative effect in 133 patients with opioid-induced constipation, which had not been relieved by conventional laxatives, without affecting the analgesic effect (234C). There were mild to moderate adverse events, including abdominal pain, flatulence, nausea, incre ased body temperature, and dizziness. In another study methylnaltrexone pre vented or relieved nausea and pruritus and reversed opioid-induced urinary retention (235M). Healthy men were given intravenous remifentanil 0.15 micrograms/kg/minute and then intravenous methylnaltrexone
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0.3 mg/kg, naloxone or saline; urinary reten tion was reversed in 5 of 12 volunteers (236E).
Nalmefene
(SED-15, 2420; SEDA-29, 111; SEDA-30, 119)
Observational studies The neuropatho physiology and pharmacotherapy of patho logical gambling have been reviewed, including results from a multi center study on the efficacy and tolerability of nalme fene in the treatment of pathological gam bling. In this study, subjects who took nalmefene had adverse effects, including nausea, dizziness and insomnia; the higher doses of nalmefene (50 and 100 mg) resulted in intolerable effects (237R). Placebo-controlled studies In a 28-week randomized placebo-controlled study in 403 heavy drinkers, nalmefene caused more nausea, vomiting, sweating, muscle tightness, insomnia, dizziness, fatigue, malaise, impaired sense of taste, and hang over than placebo (95% versus 81%) (238C). One patient had pancreatitis, which was thought to have been related to treat ment. Dosage reduction and withdrawal of treatment were needed in 113 subjects taking nalmefene because of nausea and vomiting, insomnia, nightmares, dizziness, anxiety, agitation, and psychotropic effects (visual and auditory hallucinations, dissocia tion, and derealization).
Naltrexone (SED-15, 2423; SEDA-29, 112; SEDA-30, 120; SEDA-31, 172) Observational studies High-dose naltrex one 150 mg/day in the treatment of co-dependence on cocaine and alcohol was associated with mild to severe adverse events. The most frequent were headache (62%), anxiety/irritability (61%), and nau sea (40%); women were more likely to com plain of nausea than men were (239C). Comparative studies Naltrexone has been compared with oxcarbazepine in prevention
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of relapse in 84 alcohol-dependent patients (240C). Those who took naltrexone (n = 27) had nausea, vomiting, dizziness, and hypotension. Systematic reviews The use of naltrexone in the treatment of autism has been the subject of a systematic review (241M). In one study, high-dose naltrexone 150 mg/day was associated with an increase in stereotyped movements, sedation, and nausea. Low-dose naltrexone was associated with increased selfinjurious behavior. Nervous system In 17 patients with Crohn’s disease, low-dose naltrexone 4.5 mg/day had only minor adverse effects; there were sleep disturbances in 7 (242c). Psychiatric In heroin addicts in Western Australia naltrexone was not associated with increased suicide rates during treatment or fatal overdose after treatment (243R). Liver In a 6-month, randomized, pla cebo-controlled trial, actively drinking alcoholics were randomized to placebo (n = 209), naltrexone 190 mg (n = 210) or naltrexone 380 mg (n = 205) (244C). There was a low incidence of hepatic adverse events, including hepatomegaly in two patients taking naltrexone. These findings suggested that modified-release naltrexone in approved doses was not associated with hepatic dysfunction, did not interact with alcohol, triggering hepa totoxicity, was safe even in patients who were obese and was safe when used with NSAIDs.
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Drug–drug interactions Cannabinoids The interaction of naltrexone 12 mg with Δ9-tetrahydrocannabinol (THC) has been studied in 22 marihuana-users and 21 non-users (245c). Naltrexone was given 30 minutes before oral THC. The inter action had different effects in the groups. In marihuana-users, naltrexone blunted the effects of THC 20 mg, but anxiety ratings were high in those who used THC 40 mg. In non-users naltrexone had the opposite effects: it increased the intoxicating effects of THC 2.5 mg and reduced the anxiogenic effects of THC 10 mg.
MISCELLANEOUS COMPOUNDS Nefopam (SED-15, 2433; SEDA-28, 112) An analysis of the French PharmacoVigilance database has provided an overview of adverse reactions to nefopam (246C). Between 1995 and 2004 there were 114 adverse drug reac tions with imputability ratings of ‘plausible’, ‘likely’, or ‘very likely’. The most frequent ‘expected’ adverse drug reactions were sweat ing (n = 15 cases), nausea (n = 10), tachycar dia (n = 8), malaise (n = 6), and vomiting (n = 5). ‘Unexpected’ adverse drug reactions included hallucinations (n = 11), confusion (n = 11), skin reactions (seven cases of erythema, four of pruritus, three of urticaria), and anaphylactic reactions (six cases: two of angio edema and four of anaphylactic shock). There were 23 serious adverse drug reactions, including one case of fatal convulsions.
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223 pharmacokinetic, and pharmacodynamic focus on effectiveness and safety in patients with chronic/persistent pain. Am J Ther 2008;15:157–66. Hair PI, Curran MP, Keam SJ. Tramadol extended-release tablets in moderate to moderately severe chronic pain in adults: profile report. CNS Drugs 2007;21 (3):259–63. De Decker K, Cordonnier J, Jacobs W, Coucke V, Schepens P, Jorens PG. Fatal intoxication due to tramadol alone. Case report and review of the literature. Forensic Sci Int 2008;175:79–82. Russo MA, Wasiak J. A clinical snapshot of transdermal buprenorphine in pain man agement. Eur J Pain Suppl 2007;1:74–77. Maremmani I, Pani PP, Pacini M, Perugi G. Substance use and quality of life over 12 months among buprenorphine mainte nance-treated and methadone maintenancetreated heroin-addicted patients. J Subst Abuse Treat 2007;33:91–98. Jensen ML, Sjgren P, Upton RN, Foster DJ, Bonde P, Graae C, Skram U, Stevner L, Christrup LL. Pharmacokinetic–pharmaco dynamic relationships of cognitive and psychomotor effects of intravenous buprenorphine infusion in human volun teers. Basic Clin Pharmacol Toxicol 2008;103:94–101. George S, Moreira K. Subutex snorters: a case series. J Subst Use 2008;13(2):131–7. Karila L, Berlin I, Benyamina A, Reynaud M. Psychotic symptoms following bupre norphine withdrawal. Am J Psychiatry 2008;165(3):400–1. Goebel A, Lawson A, Allen S, Glynn C. Buprenorphine injection to the stellate ganglion in the treatment of upper body chronic pain syndromes. Eur J Pain 2008;12:266–74. Mercadante S, Ferrera P, Villari P. Is there a ceiling effect of transdermal buprenor phine? Preliminary data in cancer patients. Support Care Cancer 2007;15:441–4. Renard D, Gaillard N. Brain haemorrhage and cerebral vasospasm associated with chronic use of cannabis and buprenorphine. Cerebrovasc Dis 2008;25:282–3. McCance-Katz EF, Moody DE, Morse GD, Ma Q, DiFrancesco R, Friedland G,
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Pade P, Rainey PM. Interaction between buprenorphine and atazanavir or atazana vir/ritonavir. Drug Alcohol Depend 2007;91:269–78. La Vincente SF, White JM, Somogyi AA, Bochner F, Chapleo CB. Enhanced bup renorphine analgesia with the addition of ultra-low-dose naloxone in healthy subjects. Clin Pharmacol Ther 2008;83(1): 144–52. Walsh SL, Chausmer AE, Strain EC, Bige low GE. Evaluation of the mu and kappa opioid actions of butorphanol in humans through differential naltrexone blockade. Psychopharmacology 2008;196:143–55. Goletiani NV, Mendelson JH, Sholar MB, Siegel AJ, Skupny A, Mello NK. Effects of nalbuphine on anterior pituitary and adre nal hormones and subjective responses in male cocaine abusers. Pharmacol Biochem Behav 2007;86:667–77. Thomas J, Karver S, Cooney GA, Chamber lain BH, Watt CK, Slatkin NE, Stambler N, Kremer AB, Israel RJ. Methylnaltrexone for opioid-induced constipation in advanced ill ness. N Engl J Med 2008;358:2332–43. Yuan C-S. Methylnaltrexone mechanisms of action and effects on opioid bowel dys function and other opioid adverse effects. Ann Pharmacother 2007;41:984–93. Rosow CE, Gomery P, Chen TY, Stefano vich P, Stambler N, Israel R. Reversal of opioid-induced bladder dysfunction by intravenous naloxone and methylnaltrex one. Clin Pharmacol Ther 2007;82(1):48–53. Iancu I, Lowengrub K, Dembinsky Y, Kotler M, Dannon PN. Pathological gam bling: an update on neuropathophysiology and pharmacotherapy. CNS Drugs 2008;22 (2):123–38. Karhuvaara S, Simojoki K, Virta A, Rosberg M, Loyttyniemi E, Nurminen T, Kallio A, Makela R. Targeted nalmefene with simple medical management in the treatment of heavy drinkers: a randomized
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An update on cardiovascular and gastrointestinal adverse effects of non-selective NSAIDs and coxibs The risks associated with cyclo-oxygenase-2 (COX-2) selective and non-selective NSAIDs continue to dominate the literature. Earlier evidence in this area has been covered in detail in previous editions of this publication (SEDA-29, 116; SEDA-30, 125), but new evidence has emerged that helps to estimate the risks of cardiovascular and gastrointestinal adverse events with coxibs and non-selective NSAIDs. An update is therefore needed.
1. Risks of cardiovascular and cerebrovascular adverse effects of non-selective NSAIDs and coxibs
Some new analyses allow a more detailed description of the cardiovascular risk with coxibs. A pooled analysis of adjudicated data from 7950 patients in six trials compared celecoxib with placebo. For the combined end-point of cardiovascular death, myocardial infarction, stroke, heart failure, or thrombo embolic events, and with 16 070 patient-years
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32009-5 � 2010 Elsevier B.V. All rights reserved.
of follow-up, the hazard ratio (HR; combining doses of 400 mg/day, 200 mg bd or 400 mg b.d.) was 1.6 (95% CI = 1.1, 2.3) (1M). An analysis using two data sets from the Adenomatous Polyp Prevention on Vioxx (APPROVe) and the Adenoma Prevention with Celecoxib (APC) trials showed that rofecoxib and celecoxib similarly increased the relative risks (RRs) of myocardial infarction or sudden death from cardiac causes compared with placebo (2R). A meta-analysis of 55 trials (99 087 patients) showed that celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib were associated with higher risks of myo cardial infarction than placebo. This study also showed an increased risk with coxibs compared with non-selective NSAIDs overall. The pooled odds ratio for any coxib compared with other NSAIDs was 1.45 (95% CI = 1.09, 1.93). However, comparisons between individual agents showed that coxibs were not always worse than non-selective NSAIDs. For example, rofecoxib had a significantly higher risk of myocardial infarction than naproxen (OR = 5.39; 95% CI = 2.08, 14) but valdecoxib had a lower risk of myocar dial infarction than diclofenac (OR = 0.14; 95% CI = 0.03, 0.73) (3M). A history of previous cardiac events seems to have some effect on risk. A population-based cohort study of 122 079 elderly people with or without a previous myocardial infarction newly treated with an NSAID showed that both rofecoxib (RR = 1.59; 95% CI = 1.15, 2.18) and celecoxib (RR = 1.40; 95% CI = 1.06, 1.84)
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were associated with increased risks of acute myocardial infarction among current users with a history of myocardial infarc tion, but only rofecoxib was associated with a significantly increased risk of myocardial infarction in those without a previous myocardial infarction (RR = 1.23; 95% CI = 1.05, 1.45) (4C). In a study of incident stroke until 2004 in 7636 patients free of stroke at baseline (1991–93), there was an increased risk of stroke with current use of non-selective NSAIDs and coxibs; HRs were 1.72 (95% CI = 1.22, 2.44) for non-selective NSAIDs and 2.75 (95% CI = 1.28, 5.95) for coxibs. A comparison of individual agents showed that current use of naproxen (HR = 2.63; 95% CI = 1.47, 4.72) and rofecoxib (HR = 3.38; 95% CI = 1.48, 7.74) was associated with an increased risk of stroke. HRs for diclofenac (HR = 1.60; 95% CI = 1.00, 2.57), ibuprofen (HR = 1.47; 95% CI = 0.73, 3.00) and cele coxib (HR = 3.79; 95% CI = 0.52, 28, based on one case) were non-significant (5C). Ana lysis of data from an extended follow-up of the APPROVe trial showed an increase in the risk of ischemic stroke in patients randomized to rofecoxib rather than placebo (RR = 2.91; 95% CI = 1.15, 7.39) (6R).
2. Risks of gastrointestinal adverse effects of non-selective NSAIDs and coxibs
Comparative studies The risk of upper gastrointestinal bleeding is increased about four-fold by non-selective NSAIDs (7M). There is a substantial body of evidence that coxibs cause fewer gastrointestinal adverse effects than non-selective NSAIDs (8R). Recent evidence has added to this. In a ran domized controlled trial in 458 patients with active ankylosing spondylitis, the incidence of gastrointestinal adverse events was higher with diclofenac (28%) than celecoxib (15–17% depending on dose) (9C). The use or non-use of aspirin seems to have some influence on the RR of gastro intestinal complications with non-selective NSAIDs compared with coxibs. The risks
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of using non-selective NSAIDs and coxibs have been compared in a nested case–control study of 1561 patients with upper gastro intestinal complications matched to 10 000 controls (10C). The adjusted RRs of an upper gastrointestinal complication associated with current use compared with non-use were 3.7 (95% CI = 3.1, 4.3) for non-selective NSAIDs and 2.6 (95% CI = 1.9, 3.6) for cox ibs. Overall, the RR with coxibs compared with non-selective NSAIDs was 0.8 (95% CI = 0.6, 1.1). However, among non-users of aspirin, the RR associated with coxibs was 0.6 (95% CI = 0.4, 0.9). Hospitalization for gastrointestinal bleed ing associated with non-selective NSAIDs and coxibs among 332 491 elderly patients (66 or older) has been investigated retrospec tively in a cohort study using Quebec govern ment databases (11C). The results suggested that celecoxib without concurrent low-dose aspirin was less likely than a non-selective NSAID without concurrent low-dose aspirin to be associated with hospitalization due to a gastrointestinal perforation or bleed (HR = 0.41; 95% CI = 0.33, 0.50); celecoxib plus aspirin was also less likely to be associated with hospitalization than a non selective NSAID plus aspirin but with a slightly higher HR of 0.62 (95% CI = 0.48, 0.80). Hospitalization rates were similar for celecoxib plus aspirin and a non-selective NSAID without aspirin (HR = 1.01; 95% CI = 0.81, 1.25). A systematic review showed that com pared with non-selective NSAIDs, coxibs were associated with significantly fewer gastroduodenal ulcers (RR = 0.26; 95% CI = 0.23, 0.30), clinically important ulcer complications (RR = 0.39; 95% CI = 0.31, 0.50), and fewer treatment withdrawals caused by gastrointestinal symptoms. Sub group analyses suggested that concurrent use of aspirin reduced the gastrointestinal safety advantage of coxibs (12M). Mortality rates Knowing mortality rates associated with adverse events allows an estimation of their significance and can also help in explaining the risks to patients. A systematic review of mortality associated
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with gastrointestinal bleeding and perfora tion included data from 61 067 cases, of whom 5001 died. The mortality rate in all cases (taking NSAID or not) fell signifi cantly, from 12% (95% CI = 11.0, 12.2) in pre-1997 studies to 7.4% (95% CI = 7.2, 7.6) in studies published since 1997 (13M). In 5526 patients taking NSAIDs (including cox ibs) or aspirin (if used as an analgesic but excluding prophylactic low-dose aspirin), mortality increased from 15% (95% CI = 13.6, 15.8) before 1997 to 21% (95% CI = 18.8, 22.9) after 1997. This major reduction in mortality in all cases over time probably reflects improved standards of care. Mortality in the subgroup of NSAID users was significantly higher than for all cases, and even increased over time (perhaps reflecting changed demographics). NSAIDs not only increase the risk of upper gastro intestinal bleeding or perforation but also the mortality associated with such events to about 1 in 5 (using the latest data). Gastroprotection Gastroprotective strategies can reduce the gastrointestinal adverse effects of non-selective NSAIDs and result in similar rates of ulceration as coxibs. In a randomized, double-blind, endoscopic trial in 854 patients with osteoarthritis using low-dose aspirin, the rates of gastroduodenal ulceration were similar among those using celecoxib and those using naproxen plus lansoprazole (14C). In Tennes see Medicaid enrollees, use of gastroprotective therapy (a proton pump inhibitor, histamine H2 receptor antagonist, or misoprostol) concurrent with NSAID therapy reduced the rates of peptic ulcer hospitalization as much as coxibs (15C). In a retrospective cohort study of 1161508 prescriptions for celecoxib, 360799 for cele coxib plus a proton pump inhibitor, 715176 for non-selective NSAIDs and 148470 for non-selective NSAIDs plus a proton pump inhibitor, using the Government of Quebec health services administrative databases, the adjusted HRs of hospitalization for gastro intestinal perforation or bleeding were 0.69 (95% CI = 0.52, 0.93) for celecoxib plus a proton pump inhibitor versus celecoxib, 0.98 (95% CI = 0.67, 1.45) for non-selective
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NSAIDs plus proton pump inhibitor versus celecoxib and 2.18 (95% CI = 1.82, 2.61) for non-selective NSAIDs versus celecoxib. Cel ecoxib was clearly superior to non-selective NSAIDs. Using a proton pump inhibitor with a non-selective NSAID was as good as using celecoxib, but the effect of a proton pump inhibitor was also additive to that of celecoxib (16C). An analysis of the Manitoba Population Health Research Data Repository has con firmed that the use of coxibs together with proton pump inhibitors confers the greatest risk reduction in NSAID-related gastro intestinal complications (17C).
3. Balancing gastrointestinal and cardiovascular risks
The choice between non-selective NSAIDs and coxibs, given similar efficacy, is likely to be determined by considerations about their cardiovascular and gastrointestinal adverse effects. The balance between the cardiovascular risk associated with coxibs and the gastro intestinal benefit has been retrospectively analysed using data from Quebec in 510871 patients aged 65 or older taking an NSAID or paracetamol (18C). The outcome of inter est was hospitalization for either acute myocardial infarction or gastrointestinal bleeding. The results are shown in Table 1. Among non-users of aspirin, rofecoxib and naproxen carried the highest risks of hos pitalization for myocardial infarction compared with hospitalization for gastro intestinal bleeding; the risk profiles of cele coxib, ibuprofen and diclofenac were similar to that of paracetamol. However, for patients taking aspirin, celecoxib, naproxen and ibu profen were the best and rofecoxib again carried a high risk. Annualized event rates for gastrointestinal events and heart attacks or strokes with non selective NSAIDs or coxibs have been calcu lated in an analysis of randomized trials, meta-analyses of randomized trials and observational studies (19M). There were, in total, 439 complicated upper gastrointestinal
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Table 1. The balance of benefit to harm of various NSAIDs (hazard ratios of hospitalization for acute myocardial infarction to hospitalization for gastrointestinal bleeding; comparisons are with paracetamol without aspirin) Drug
Hazard ratio in patients not taking aspirin (95% CI)
Drug
Hazard ratio in patients taking aspirin (95% CI)
Paracetamol Celecoxib Ibuprofen Diclofenac Rofecoxib Naproxen
[reference case] 0.93 (0.83, 1.03) 1.05 (0.74, 1.51) 1.17 (0.99, 1.38) 1.27 (1.13, 1.42) 1.59 (1.31, 1.93)
Paracetamol Celecoxib Naproxen Ibuprofen Diclofenac Rofecoxib
1.29 (1.17, 1.42) 1.34 (1.19, 1.52) 1.35 (0.97, 1.88) 1.51 (0.95, 2.41) 1.69 (1.35, 2.10) 1.73 (1.52, 1.98)
events in 49 006 patient years of exposure and 948 serious cardiovascular events in 99400 patient-years of exposure. In an over all comparison, this analysis showed that for every 1000 patients treated for a year with coxibs rather than non-selective NSAIDs, there would be eight fewer complicated upper gastrointestinal events, but one more fatal or non-fatal heart attack or stroke. Indi vidual comparisons showed that for every 1000 patients treated for a year with cele coxib rather than a non-selective NSAID, there would be 12 fewer upper gastrointest inal complications and 2 fewer fatal or non fatal heart attacks or strokes. For rofecoxib there would be six fewer upper gastrointest inal complications, but three more heart attacks or strokes. For lumiracoxib there would be eight fewer upper gastrointestinal complications, but one more heart attack or stroke. The gastrointestinal benefits and cardio vascular harms of coxibs versus non-selec tive NSAIDs, specific for age, sex, and susceptibility factors, have been estimated using data from the General Practice Research Database in 155439 coxib users (20C). Based on event rates of gastrointes tinal and cardiovascular adverse effects from meta-analyses of randomized con trolled trials, the authors estimated that 179 cases of upper gastrointestinal events per 10000 patients treated for 4 years were prevented by coxibs; however, there would be an excess of 125 cases of myocardial infarction. Stratifying the cohort by baseline probabilities for upper gastrointestinal or
cardiovascular adverse events, the benefits of coxib use were largest in those with the highest baseline probability for upper gastro intestinal events but these patients also had more myocardial infarctions and strokes. It would be logical to use coxibs or non selective NSAIDs depending on individual patients’ risks of gastrointestinal or cardi ovascular adverse events. However, this may be more difficult than it seems. Restricting coxibs to patients with a low baseline probability of myocardial infarc tion would reduce the excess numbers of myocardial infarctions and strokes, but in that case the number of gastrointestinal adverse events prevented by coxibs would also be smaller.
4. Conclusions Because the harms from non-selective NSAIDs and coxibs occur in different body systems, the challenge for current clinical practice and future research is to weigh up these risks with individual patients in mind. Evidence is emerging that the risks are deter mined by patient characteristics that include concurrent medications (particularly aspirin) and medical history (previous myocardial infarction), but the picture is far from com plete. Given the within-class differences in risk profiles between individual non-selective NSAIDs or coxibs, evaluating individual drugs, rather than only comparing drug classes, is essential.
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ARYLALKANOIC ACID DERIVATIVES (SED-15, 2555; SEDA-28, 126; SEDA-31, 186)
Stereoisomers of arylpropionic acids The dextrorotatory stereoisomers of some arylpropionic acids, ibuprofen, indoprofen, and ketoprofen, have been marketed as indi vidual compounds, affording extension of patent life to their manufacturers. Reviews of these follow. There appear to be no major advantages of these compounds compared with the racemic mixtures in terms of efficacy or adverse effects. Furthermore, there is vari able conversion of dextrorotatory isomers in vivo to their levorotatory counterparts and vice versa, making it doubtful whether there are major advantages to administration of the single isomers. Dexibuprofen Dexibuprofen is the dex trorotatory isomer of ibuprofen. Clinical experience is still inadequate to judge its safety profile, although there are claims that it is of comparable safety to celecoxib (21c). Pharmacokinetics The pharmacokinetics of dexibuprofen 400 mg and ibuprofen arginate 600 mg have been compared in 24 healthy volunteers in an open, randomized, two-period, crossover study (22C). Ibuprofen arginate had a 45% higher Cmax and its tmax occurred 2 hours earlier, suggesting faster absorption. In 20 Chinese subjects who took single doses of racemic ibuprofen and dexibu profen 400 mg in a two-way, crossover, randomized study, the two formulations were pharmaceutically bioequivalent (23C). There was 25% conversion of R-(–)-ibuprofen in the racemic ibuprofen tablets to S-(þ) ibuprofen. Comparative studies Dexibuprofen and celecoxib Dexibuprofen 800 mg/day and celecoxib 200 mg/day have been compared in 148 adults with osteoarthritis of the hip in a randomized, parallel-group, doubleblind trial (24C). The overall incidence
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of adverse drug reactions was 12% with dex ibuprofen and 14% with celecoxib; 8.1% of those who took dexibuprofen and 9.5% of those who took celecoxib had gastrointest inal disorders. Dexibuprofen and diclofenac Oral dexibu profen 300 mg tds and diclofenac sodium 50 mg tds have been compared in a random ized, double-blind, parallel-group study for 15 days in 110 patients with painful osteoarthritis of the knee; 7.3% of the patients taking dex ibuprofen and 15% of those taking diclofenac sodium dropped out because of adverse effects (25C). Dexibuprofen and ibuprofen Dexibupro fen 200 or 400 mg tds and racemic ibupro fen 800 mg tds have been compared in a double-blind, randomized trial in 178 patients with painful osteoarthritis of the hip (26C). There were adverse drug reac tions, mainly gastrointestinal disorders, in 13–15% of those taking dexibuprofen and 17% of those taking racemic ibuprofen. Dexibuprofen 600 or 1200 mg/day and racemic ibuprofen 2400 mg/day have been compared in an open study for 1 year in 223 inpatients with osteoarthritis of the hip (27 c). The overall incidence of clinical adverse events was 15% (gastrointestinal tract 12%, nervous system 1.3%, skin 1.3%, others 0.9%). Dexibuprofen 5 and 7 mg/kg has been compared with ibuprofen 10 mg/kg in chil dren aged 6 months to 14 years with fever caused by upper respiratory tract infections (28c). There were no significant differences in efficacy or adverse drug reactions. Systematic reviews In a meta-analysis of five trials and three postmarketing surveil lance studies in 7133 patients, dexibuprofen was at least as efficacious as racemic ibu profen in rheumatoid arthritis, ankylosing spondylitis, osteoarthritis of the hip, osteoarthritis of the knee, lumbar vertebral syndrome, distortion of the ankle joint and dysmenorrhea (29M). Racemic ibuprofen had a 30% and diclofenac a 90% higher incidence of adverse drug reactions. The incidence of adverse drug reactions in the
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postmarketing surveillance studies was 5.5–7.4% and withdrawals were 2.3–2.7%. Nervous system Aseptic meningoencepha litis has been attributed to dexibuprofen in a 22-year-old woman with systemic lupus erythematosus (30A). Patients with systemic lupus erythematosus have increased suscept ibility to NSAID-induced aseptic meningitis or encephalitis. Hematologic The effects of dexibuprofen 800 mg/day and aspirin 100 mg/day on plate let function have been studied in 12 healthy volunteers; the effects were quantitatively simi lar, but the effect of aspirin persisted for 24 hours after the last dose whereas platelet aggregation returned to baseline within 24 hours after the last dose of dexibuprofen (31c). Gastrointestinal The effects of treatment with dexibuprofen, ibuprofen, and diclofenac for 2 weeks on plasma pepsinogen concentra tions and the gastrointestinal mucosa have been studied in 60 patients with rheumatolo gical diseases (32c). There were no differences in plasma pepsinogen concentrations or gastrointestinal injury between the groups. Adverse events occurred with similar frequen cies in the three groups (28, 38 and 34%). Drug–drug interactions Phenytoin Dex ibuprofen has been reported to cause pheny toin toxicity, presumably by inhibiting its metabolism (33). • A 70-year-old woman with epilepsy who had been fit-free while taking phenytoin 300 mg/ day, plasma concentrations 48–64 µmol/l, was given dexibuprofen 800 mg/day; 72 hours later, she developed severe nystagmus, vertigo, som nolence, blurred vision, and xanthopsia. Her total plasma phenytoin concentration was 122 µmol/l, unbound concentration 16 µmol/l. All medications were withdrawn and 2 weeks later the phenytoin concentration had fallen to 30 µmol/l (unbound 6.4 µmol/l).
Dexindoprofen Dexindoprofen is the dextrorotatory stereo isomer of indoprofen, to which it has a similar adverse effects pattern. Gastrointestinal and
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nervous system effects and skin reactions are the most frequent (34c).
Dexketoprofen Dexketoprofen is the dextrorotatory stereoi somer of ketoprofen. The analgesic effect of ketoprofen is due to the S-(þ)-enantiomer (dexketoprofen), while the R-(–)-enantiomer has no analgesic activity (35R) but may be ulcerogenic (36R). Thus, dexketoprofen should produce equivalent analgesia to twice the dose of ketoprofen, but with less risk of gastrointestinal damage. Pharmacokinetics Dexketoprofen is for mulated as the water-soluble salt dexketopro fen trometamol to improve its absorption (37c). The systemic availability of oral dex ketoprofen trometamol (12.5 and 25 mg) is similar to that of oral racemic ketoprofen (25 and 50 mg, respectively) (38R). Dex ketoprofen trometamol is rapidly absorbed, with a tmax of 0.25–0.75 hours compared with a tmax of 0.5–3 hours for the S-enantiomer after the racemic drug. Of the administered dose 70–80% is recovered in the urine during the first 12 hours, mainly as the acyl glucuroni dated parent drug. R-Ketoprofen is not found in the urine after administration of dexketoprofen, confirming the absence of stereoisomeric interconversion in vivo. Comparative studies Dexketoprofen and diclofenac In a randomized, doubleblind, parallel, active controlled, multicenter study in 370 outpatients with acute low back pain, intramuscular dexketoprofen 25 or 50 mg bd was compared with intramuscular diclofenac 75 mg bd for 2 days (39C). Five patients withdrew from the study because of adverse events (two who took dexketoprofen 25 mg, one who took dexketoprofen 50 mg, and two who took metamizole). Injection site reactions were common with dexketoprofen (19 patients in all, 9.3%) and did not occur with metamizole. Gastrointestinal disorders (abdominal pain, constipation, dyspepsia, nausea, vomiting, and dry mouth) occurred in 11 patients (5.4%). Otherwise, adverse effects were uncommon and similar in the
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three groups. There were 10 serious adverse events in those who were given dexketopro fen; most were recurrences of renal pain and none was considered to be drug-related. Dexketoprofen and racemic ketoprofen Dexketoprofen trometamol 50 mg has been compared with racemic ketoprofen 100 mg both given intravenously, every 8 hours over 2 days, in 252 patients with moderate to severe pain after hip or knee replacement surgery in a multi-center, double-blind, ran domized, parallel-group study (40C). Both groups needed rescue analgesia – 81% of those who received dexketoprofen and 87% of those who received ketoprofen. There were treatment-related adverse events in 16% of patients who were given dexketopro fen compared with 21% of those who were given ketoprofen. Dexketoprofen and ketorolac Dexketo profen trometamol 25 mg qds and ketorolac 10 mg qds have been compared in 115 patients with bone cancer pain in a multicenter, rando mized, double-blind, parallel-group study (41C). Fewer patients withdrew for any reason, including insufficient therapeutic effect or adverse events, among those who were given dexketoprofen. A total of 54 adverse events were reported by 39 (34%) of the 115 patients. The number of patients with treatment-related adverse events was slightly lower among those who were given dexketoprofen trometamol (16%) than among those who were given ketorolac (24%). Most of the adverse events were mild or moderate in intensity, the most frequent being gastrointestinal complaints, especially constipation, vomiting, and abdom inal pain; 3.5% had serious adverse events in each group. Only one of the five serious adverse events was considered to be related to the study treatment – gastrointestinal hemor rhage in one patient who received ketorolac. Six patients withdrew because of adverse events: one taking dexketoprofen died from progression of cancer and five who were given ketorolac withdrew because of gastroin testinal bleeding, diarrhea, feeling of hot/cold, erythematous rash, and abdominal pain.
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Dexketoprofen and metamizole A single intravenous dose of dexketoprofen trometa mol has been compared with an intravenous infusion of metamizole (dipyrone) in 308 patients with moderate to severe pain due to renal colic (42C). Dexketoprofen produced similar analgesia to metamizole but with a faster onset. Placebo-controlled studies Dexketoprofen and rofecoxib Rofecoxib 50 mg and dex ketoprofen trometamol 25 mg have been com pared in a double-blind, randomized, placebo-controlled trial in 120 patients under going surgical removal of a single mandibular third molar (43C). Adverse events were mild to moderate in intensity. There were 20 adverse events in 15 subjects: 6 with rofecoxib, 5 with dexketoprofen, and 4 with placebo. The most frequent events were nausea and vomit ing (n = 4), tiredness/drowsiness (n = 3), headache (n = 2), and feeling hot/feverish (n = 2). One patient who was given dexke toprofen reported profuse bleeding (not otherwise specified) starting 4 hours after the administration of dexketoprofen and lasting for 30 minutes. None of the reported events resulted in withdrawal from the study. Systematic reviews In a systematic review of trials in acute and chronic pain in 6380 patients, of whom 3381 took dex ketoprofen, 35 trials were included (44M). Almost all of them were of short duration in acute conditions or recent onset pain. In all 12 randomized trials that compared dexketoprofen (any dose) with placebo, dexketoprofen was statistically superior. Adverse event withdrawal rates, which are shown in Table 2, were low in postopera tive pain and higher in trials of longer duration; no serious adverse events, such as gastrointestinal bleeding, myocardial infarction, or death, were reported. Hematologic Neutropenia and thrombo cytopenia have been attributed to dexketo profen (45A). • A previously healthy 35-year-old woman had an episode of fever, neutropenia,
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Table 2. Adverse event withdrawal rates in trials involving dexketoprofen Drug
Placebo Dexketoprofen Tramadol Ketoprofen Diclofenac Paracetamol þ opioid
Withdrawals due to adverse events (%) (n) Dental and post-surgical pain
Other acute pain, back pain, arthritis
2.5 (236) 1.8 (652) 1.4 (72) 1.3 (301) 0.0 (80) 0.0 (100)
No data 3.2 (844) 9.7 (247) 7.9 (152) 3.7 (272) 1.2 (167)
thrombocytopenia and raised liver function tests 10 days after she started to take dexketoprofen trometamol. Infectious and autoimmune causes of neutropenia and viral or autoimmune hepatitis were excluded. She recovered after withdrawal of dexketoprofen.
Co-magaldrox, given 10 minutes before dexketoprofen trometamol, did not alter its pharmacokinetics. Food significantly incre ased the tmax and significantly reduced the Cmax of dexketoprofen trometamol, suggest ing a change in the rate of absorption, but did not alter the extent of absorption.
Skin Dexketoprofen has been reported to cause photosensitivity after oral therapy (46A). • A 27-year-old woman developed contact photo sensitivity after applying topical dexketoprofen trometamol for joint pains (47A). Photopatch testing for components of the gel was positive for ketoprofen trometamol only.
In another case a patient developed a cuta neous eruption in a photo-exposed area 1 week after topical treatment with dexketo profen (48A). Photopatch tests were positive for dexketoprofen, ketoprofen and piketo profen and a patch test was positive for piketoprofen. Control photopatch testing with dexketoprofen in 15 healthy volunteers was negative. Other reports have appeared (49A), and photoallergic contact dermatitis in patients taking dexketoprofen has also been discussed in the context of six cases (50c). Drug–drug interactions Co-magaldrox The effect of co-magaldrox (magnesium trisilicate þ aluminium hydroxide) on the pharmacokinetics of dexketoprofen trometa mol has been studied in a randomized, threeway, crossover study in 24 healthy volunteers who took three single doses of dexketoprofen trometamol 25 mg either fasting, after co magaldrox or after a high-fat breakfast (51C).
COX-2 SELECTIVE INHIBITORS (SEDA-29, 116; SEDA-30, 130; SEDA-31, 190) Comparative studies It has been unclear to what extent patients intolerant of non selective NSAIDs can tolerate coxibs. In a systematic review of 3304 patients with NSAID intolerance taking coxibs, 119 adverse events were identified (52M). All but two were allergic or urticarial reactions; none was lethal, but two were graded as lifethreatening. In an investigation of 206 patients with urticaria and/or angioedema due to non selective NSAIDs, there was some crossreactivity to coxibs (53c). Oral challenges were positive with celecoxib in 18%, with etoricoxib in 11%, with valdecoxib in 10% and with rofecoxib in 9.4%. In another study of 31 patients who had adverse reactions to NSAIDs, none reacted to etoricoxib (54c). Coxibs seem safe in most patients who are intolerant of non-selective NSAIDs, but some patients cross-react.
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Celecoxib
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glucocorticoids. The skin lesions resolved within 2 weeks.
Liver A case report has suggested that celecoxib can cause late-onset renal, hepa tic, or even combined toxicity (55A). • A 56-year-old hypertensive man taking ramipril was given celecoxib 200–400 mg/day for osteoar thritic pain and 10 months later developed inter mittent right upper quadrant abdominal pain, fatigue and reduced appetite. During the next 2 months his symptoms progressed to lethargy and jaundice, with dark urine and pale stools. He had increased blood urea nitrogen, creati nine, and bilirubin serum concentrations. Liver and renal biopsies suggested drug-induced toxicity and other causes were ruled out. After withdrawal of celecoxib, he rapidly improved.
Pancreas Acute pancreatitis attributed to celecoxib (56A).
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• A 57-year-old woman with osteoarthritis developed subumbilical pain after taking cele coxib 200 mg/day for 3 months. Her serum amylase and lipase activities were raised. An abdominal computed tomography (CT) scan showed diffuse peripancreatic fat infiltration with areas of necrosis. Celecoxib was with drawn and she recovered.
Sexual function Celecoxib and etoricoxib have been associated with erectile dysfunc tion (57A). • A 26-year-old man reported erectile dysfunc tion after taking celecoxib 100 mg for recurrent dental pain. The pain was relieved after 1 hour but he was unable to achieve an erection. He later recovered potency, but challenge with etoricoxib after the dental pain recurred pro duced the same result.
Sexual function See ‘Celecoxib’ above. Nimesulide Nimesulide is a sulfonamide derivative with relative selectivity for COX-2. Skin Selective hypersensitivity to nimesu lide has been reported, on the basis of a posi tive oral provocation test and a confirmation basophil activation test (59A). • A 23-year-old woman with no history of allergic diseases had two urticarial reactions 6 months apart within 15 minutes of administration of nimesulide 100 mg for headache. A placebocontrolled oral provocation test confirmed the causal relation; a basophil activation test was also positive. Placebo-controlled tolerability tests with aspirin, diclofenac, paracetamol, meloxicam, parecoxib and etoricoxib were negative.
Immunologic In 206 patients with urticaria and/or angioedema due to non-selective NSAIDs, oral challenges with nimesulide were positive in 31% (52c).
Rofecoxib Psychiatric Two cases of acute psychotic ill nesses (visual and/or auditory hallucinations) have been attributed to rofecoxib; in both cases the symptoms resolved after rofecoxib was withdrawn (60A).
Etoricoxib Skin Etoricoxib has reportedly better cutaneous tolerance than other coxibs; it may nonetheless cause potentially severe adverse skin reactions in susceptible indivi duals (58A). • A 69-year-old man took etoricoxib 90 mg/day for knee pain and after 7 days developed erythema multiforme-like eruptions in the groins. Herpes simplex and mycotic infections were ruled out. Etoricoxib was withdrawn and he was treated with potent topical
OXICAMS
(SEDA–15, 2555; SEDA– 28, 128; SEDA–29, 125; SEDA–30, 132)
Meloxicam Immunologic Of 21 patients with aspirin hypersensitivity, asthma and/or nasal polyps, only one reacted to meloxicam at a cumula tive dose of 7.5 mg. The authors of that
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study suggested that meloxicam was a safe alternative for patients with aspirin-hyper sensitive asthma and/or nasal polyps (61c). In 206 patients with urticaria and/or angioe dema due to non-selective NSAIDs oral challenges with meloxicam were positive in 21% (52c).
Piroxicam Skin A fixed drug eruption has been attributed to piroxicam (62A).
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risks of hepatotoxicity could be ameliorated by using a graded dosage increase, together with regular monitoring of liver function and concluded that the withdrawal of benz bromarone had not been in the best inter ests of patients with gout. Adverse effects associated with benzbro marone are relatively uncommon, but poten tially severe. It causes diarrhea (in 3–4% of patients), urate and oxalate stones, urinary sand, renal colic, and allergic reactions in a small number of patients (63R, 64R).
Benzbromarone (SEDA-15, 423)
Liver Several cases of benzbromarone induced hepatotoxicity have been published (65A–72A). It causes a chronic active hepati tis, which can be fatal (73A). The estimated risk of hepatotoxicity in Europe is about 1 in 17 000 patients, although it may be higher in Japan (63R). The mechanism of toxicity has been pro posed to be bioactivation of benzbromarone by CYP2C9 through sequential hydroxylation of the benzofuran ring, through 6-hydroxy benzbromarone, to a catechol, 5,6-dihydroxy benzbromarone, which can then be further oxidized to a reactive quinone intermediate capable of adducting protein (74E). The cellu lar effects included mitochondrial toxicity and induction of apoptosis and necrosis (75E).
Benzbromarone is a uricosuric drug that was introduced in the 1970s. However, in 2003 it was withdrawn by Sanofi-Synthélabo after reports of serious hepatotoxicity, although it is still marketed in several coun tries by other drug companies. The half-life of benzbromarone is about 3 hours, but it has a uricosuric metabolite, 6-hydroxybenz bromarone, with a much longer half-life (up to 30 hours). It is metabolized by CYP2C9 in the liver. The benefit-to-harm balance of benzbro marone has been assessed in the light of its clinical benefits, the efficacy of alternatives, such as allopurinol and probenecid, particu larly in patients with renal impairment, the risk of hepatotoxicity from benzbromarone and the risk of adverse reactions to allopur inol and probenecid. Lee et al. (63R) gave recommendations on the use of benzbro marone. They thought it likely that the
Drug–drug interactions Coumarins As benzbromarone is a coumarin derivative, it can potentiate the effects of anticoagulants that act as vitamin K antagonists. In patients taking both warfarin and benzbromarone, the latter was withdrawn for 1 week and then reintroduced (76c). After withdrawal of benzbromarone, the prothrombin time improved and factor II activity increased significantly while protein induced by vita min K absence-II (PIVKA-II) activity fell. Factor VIII, which is vitamin K-indepen dent, was unchanged. Total plasma warfarin concentration also fell significantly, but unbound warfarin concentration was unchanged. The mechanism of this interaction has been studied in patients with heart disease who took warfarin with (n = 13) or without (n = 18) oral benzbromarone 50 mg/day; in vitro effects were studied using human
• A 31-year-old woman who sometimes took piroxicam for myalgia developed recurrent painful lesions on her hands, feet, lips and genitalia; 1 hour after oral provocation testing with piroxicam the previous lesions became more prominent. Histological examination suggested a fixed drug eruption. She stopped taking piroxicam and the lesions did not return.
DRUGS USED IN THE TREATMENT OF GOUT
Anti-inflammatory and antipyretic analgesics and drugs used in gout
CYP2C9 and liver microsomes (77CE). The patients who took warfarin with benzbromar one required a 36% lower dose of warfarin than those who took warfarin alone (2.5 ver sus 3.9 mg/day) to attain similar values of the international normalized ratio (2.1 and 2.2 respectively), and S-warfarin clearance was about 50% lower. There was no effect on R-warfarin. Benzbromarone was a potent in vitro competitive inhibitor of S-warfarin 7-hydroxylation mediated by CYP2C9.
Febuxostat Febuxostat is a non-purine xanthine oxidase inhibitor (78R–82R). Its pharmacology, effi cacy and safety have been subjected to sys tematic review (83R). Its most common adverse effects include liver function test abnormalities, diarrhea, headache, nausea, vomiting, abdominal pain, and dizziness (84R). Pharmacokinetics In a Phase I study of oral febuxostat 10, 20, 30, 40, 50, 70, 90, 120, 160, 180, and 240 mg/day in 12 subjects at each dose (10 febuxostat plus 2 placebo), absorp tion was rapid, with a median tmax of 0.5–1.3 hours (85C). The pharmacokinetics were not time dependent and were linear in the 10–120 mg/day dose range but non-linear at higher doses. The mean apparent total clear ance was 10–12 l/hour and the apparent volume of distribution at steady state was 33–64 l. The half-life was 1.3–16 hours. Febuxostat was metabolized by glucuronida tion (22–44% of the dose) and oxidation (2–8%); only 1–6% of the dose was excreted unchanged via the kidneys. Comparative studies In 760 patients with gout and with serum urate concentrations of at least 480 µmol/l (8.0 mg/dl), febuxo stat 80 or 120 mg/day or allopurinol 300 mg/day was given for 52 weeks (86c). More of those who took high-dose febuxo stat withdrew than those who took allo purinol or low-dose febuxostat. Four of the 507 patients in the two febuxostat groups (0.8%) and none of the 253 patients in the allopurinol group died; all
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deaths were from causes that the investi gators (while still blinded to treatment) judged to be unrelated to the study drugs. In two double-blind, randomized trials in 762 and 1072 patients in which various doses of febuxostat were compared with a standard dose of allopurinol, febuxostat was associated with more attacks of gout during the first 2 months of treatment, despite preventive measures (30–35% versus 22%) (87C). At 3–6 months of treatment neither drug reduced the incidence of attacks of gout more effectively than placebo. In the short term, severe cardiac disorders were 4–5 times more frequent with febuxostat than with allopurinol. Treatment with drawals due to hepatic disorders were more frequent with febuxostat than with allopuri nol (2.8% versus 0.4%). The authors of that study concluded that patients with hyperur icemia should continue to take allopurinol as first-line treatment and probenecid as second-line treatment if allopurinol was ineffective. Placebo-controlled studies Febuxostat, allopurinol and placebo have been com pared for 28 weeks in 1072 subjects with hyperuricemia and gout, including some with impaired renal function (88C). Febuxo stat was used in one of three doses (80, 120, or 240 mg/day) and allopurinol in one of two doses (300 or 100 mg/day, based on renal function). The proportions of subjects who had any adverse event or serious adverse event were similar across the groups, although diarrhea and dizziness were more frequent in those who took febuxostat 240 mg/day. The primary reasons for withdrawal were similar across the groups except for gout flares, which were more frequent with febuxostat. Susceptibility factors Age and sex Age and sex had no clinically important effects on the pharmacokinetics, pharmaco dynamics and safety of once-daily oral febuxostat 80 mg in healthy men and women aged 18–40 years and over 65 years after 7 days (89c). Following multiple dosing with febuxostat, there were no
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statistically significant differences in the plasma or urinary pharmacokinetic or phar macodynamic parameters between subjects.
Rasburicase Respiratory Two cases of fatal respiratory arrest have been reported in patients who were taking rasburicase as part of leukemia treatment (90A). • A 51-year-old woman, who smoked 20 cigar ettes/day, developed dyspnea and cyanosis. Her temperature was 38.7°C and heart rate 120/minute. She had a leukocytosis (24.4 109/l), a low hemoglobin (7.4 g/dl), a low platelet count (34 109/l) and raised uric acid (800 µmol/l) and lactate dehydro genase (2479 IU/l). A diagnosis of acute myelogenous leukmia was made and she was given oxygen, hydration, allopurinol, and hydroxycarbamide (hydroxyurea). After 12 hours an infusion of rasburicase (0.20 mg/ kg/day) was begun. During the infusion she developed progressive dyspnea, had a cardi opulmonary arrest and died. • An obese 51-year-old man, who smoked 40 cigarettes/day and had a history of gingivitis, developed dyspnea and weakness. He was feb rile (38°C), and had gingival hyperplasia, a
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heart rate of 112/minute, a systolic murmur and edema of the face, eyelids, abdominal wall and legs. He was given oxygen, hydration, allopurinol, prednisone, and hydroxycarba mide and after 18 hours a dose of rasburicase. He remained dyspneic, but with good oxygen saturation. One day later, he was given a sec ond dose of rasburicase; during the infusion his dyspnea worsened and he had a cardio pulmonary arrest, became comatose, and died 3 days later.
Hematologic Methemoglobinemia and hemolytic anemia have been attributed to rasburicase administration in a child with Burkitt’s lymphoma (91A). The risk of this complication may be increased in subjects with low catalase activity who can accumu late high concentrations of hydrogen perox ide (92c). Susceptibility factors Renal disease The pharmacokinetics of rasburicase are not altered by impaired renal function (93c), and rasburicase has been used in patients with renal impairment (94c, 95c). It has even been suggested that it could be used to frag ment renal calculi and relieve obstructive uropathy (96A).
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nonsteroidal anti-inflammatory drugs. Int Arch Allergy Immunol 2007;143(2):103–8. 55. Tabibian JH, Tabibian N, Kaufman DM. Late-onset celecoxib-induced combined hepato-nephrotoxicity. Br J Clin Pharmacol 2008;66(1):150–1. 56. Mennecier D, Ceppa F, Sinayoko L, Corberand D, Harnois F, Thiolet C, Farret O. Acute pancreatitis after treatment by celecoxib. Gas troenterol Clin Biol 2007;31(8–9 Pt 1):668–9. 57. Dhikav V, Gupta S, Anand KS. Erectile dys function induced probably by celecoxib. Phar macoepidemiol Drug Saf 2008;17(2):211–2. 58. Thirion L, Nikkels AF, Piérard GE. Etori coxib-induced erythema-multiforme-like eruption. Dermatology 2008;216(3):227–8. 59. Viola M, Maietta G, Quaratino D, Rumi G, Gaeta F, Romano A. Selective hypersensitiv ity to nimesulide. Allergy 2008;63(5):624–6. 60. Sabolek M, Unrath A, Sperfeld AD, Conne mann BJ, Kassubek J. Rofecoxib-induced psychosis. Psychiatr Prax 2007;34(4):200–2. 61. Bavbek S, Dursun AB, Dursun E, Eryilmaz A, Misirligil Z. Safety of meloxicam in aspirinhypersensitive patients with asthma and/or nasal polyps. A challenge-proven study. Int Arch Allergy Immunol 2007;142(1):64–9. 62. G€ ul U, Gön€ ul M, Heper AO. Piroxicam induced fixed drug eruption. Eur J Dermatol 2008;18(1):96–7. 63. Lee MH, Graham GG, Williams KM, Day RO. A benefit–risk assessment of benzbro marone in the treatment of gout. Was its withdrawal from the market in the best inter est of patients? Drug Saf 2008;31(8):643–65. 64. Masbernard A, Giudicelli CP. Ten years’ experience with benzbromarone in the man agement of gout and hyperuricaemia. S Afr Med J 1981;59(20):701–6. 65. Babany G, Larrey D, Pessayre D, Degott C, Rueff B, Benhamou JP. Chronic active hepa titis caused by benzarone. J Hepatol 1987;5 (3):332–5. 66. Nakad A, Azzouzi K, Gerbaux A, Delcourt A, Sempoux C, Tamo F, Rahier J, Geubel AP. Hépatite à la benzarone: un deuxième cas. [Hepatitis caused by benzarone: a sec ond case.] Gastroenterol Clin Biol 1990;14 (10):782–4. 67. Sepulchre D, De Plaen JL, Geubel AP. Hépatite médicamenteuse liée à la benzar one (Fragivix): à propos d’une observation
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clinique. [Drug-induced hepatitis due to benzarone (Fragivix): apropos of a clinical case report.] Acta Gastroenterol Belg 1990;53(5–6):499–503. Gehenot M, Horsmans Y, Rahier J, Geubel AP. Subfulminant hepatitis requiring liver transplantation after benzarone administra tion. J Hepatol 1994;20(6):842. van der Klauw MM, Houtman PM, Stricker BH, Spoelstra P. Hepatic injury caused by benzbromarone. J Hepatol 1994;20 (3):376–9. Wagayama H, Shiraki K, Sugimoto K, Fuji kawa K, Shimizu A, Takase K, Nakano T, Tameda Y. Fatal fulminant hepatic failure associated with benzbromarone. J Hepatol 2000;32(5):874. Suzuki T, Suzuki T, Kimura M, Shinoda M, Fujita T, Miyake N, Yamamoto S, Tashiro K. [A case of fulminant hepatitis, possibly caused by benzbromarone.] Nippon Shoka kibyo Gakkai Zasshi 2001;98(4):421–5. Arai M, Yokosuka O, Fujiwara K, Kojima H, Kanda T, Hirasawa H, Saisho H. Fulminant hepatic failure associated with benzbromar one treatment: a case report. J Gastroenterol Hepatol 2002;17(5):625–6. Hautekeete ML, Henrion J, Naegels S, DeNeve A, Adler M, Deprez C, Devis G, Klöppel G. Severe hepatotoxicity related to benzarone: a report of three cases with two fatalities. Liver 1995;15(1):25–9. McDonald MG, Rettie AE. Sequential meta bolism and bioactivation of the hepatotoxin benzbromarone: formation of glutathione adducts from a catechol intermediate. Chem Res Toxicol 2007;20(12):1833–42. Kaufmann P, Török M, Hänni A, Roberts P, Gasser R, Krähenb€ uhl S. Mechanisms of ben zarone and benzbromarone-induced hepatic toxicity. Hepatology 2005;41(4):925–35. Shimodaira H, Takahashi K, Kano K, Mat sumoto Y, Uchida Y, Kudo T. Enhancement of anticoagulant action by warfarin–benzbro marone interaction. J Clin Pharmacol 1996;36(2):168–74. Takahashi H, Sato T, Shimoyama Y, Shioda N, Shimizu T, Kubo S, Tamura N, Tainaka H, Yasumori T, Echizen H. Potentiation of anticoagulant effect of warfarin caused by enantioselective metabolic inhibition by the
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uricosuric agent benzbromarone. Clin Phar macol Ther 1999;66(6):569–81. Hoskison TK, Wortmann RL. Advances in the management of gout and hyperuricae mia. Scand J Rheumatol 2006;35(4):251–60. Okamoto K. [Inhibitors of xanthine oxidor eductase.] Nippon Rinsho 2008;66(4): 748–53. Ichida K. [New antihyperuricemic medicine: febuxostat, Puricase, etc.] Nippon Rinsho 2008;66(4):759–65. Anonymous. Febuxostat (Uloric) for chronic treatment of gout. Med Lett Drugs Ther 2009;51(1312):37–8. Keenan RT, Pillinger MH. Febuxostat: a new agent for lowering serum urate. Drugs Today (Barc) 2009;45(4):247–60. Yu KH. Febuxostat: a novel non-purine selective inhibitor of xanthine oxidase for the treatment of hyperuricemia in gout. Recent Pat Inflamm Allergy Drug Discov 2007;1(1):69–75.
84. Pohar S, Murphy G. Febuxostat for preven tion of gout attacks. Issues Emerg Health Technol 2006;(87):1–4. 85. Khosravan R, Grabowski BA, Wu JT, Joseph-Ridge N, Vernillet L. Pharmaco kinetics, pharmacodynamics and safety of febuxostat, a non-purine selective inhibitor of xanthine oxidase, in a dose escalation study in healthy subjects. Clin Pharmaco kinet 2006;45(8):821–41. 86. Becker MA, Schumacher Jr. HR, Wortmann RL, MacDonald PA, Eustace D, Palo WA, Streit J, Joseph-Ridge N. Febuxostat com pared with allopurinol in patients with hyper uricemia and gout. N Engl J Med 2005;353 (23):2450–61. 87. Anonymous. Febuxostat: new drug. Hyper uricaemia: risk of gout attacks. Prescrire Int 2009;18(100):63–5. 88. Schumacher Jr. HR, Becker MA, Wortmann RL, Macdonald PA, Hunt B, Streit J, Lade macher C, Joseph-Ridge N. Effects of febuxo stat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, Phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum 2008;59(11):1540–8. 89. Khosravan R, Kukulka MJ, Wu JT, Joseph-Ridge N, Vernillet L. The effect
Anti-inflammatory and antipyretic analgesics and drugs used in gout of age and gender on pharmacokinetics, pharmacodynamics, and safety of febuxo stat, a novel nonpurine selective inhibitor of xanthine oxidase. J Clin Pharmacol 2008;48(9):1014–24. 90. Trujillo M, Morales M. Rasburicase-induced fatal respiratory arrest? Ann Oncol 2007;18 (2):399–400. 91. Borinstein SC, Xu M, Hawkins DS. Methemoglobinemia and hemolytic anemia caused by rasburicase administration in a newly diagnosed child with Burkitt lym phoma/leukemia. Pediatr Blood Cancer 2008;50(1):189. 92. Góth L, Bigler NW. Catalase deficiency may complicate urate oxidase (rasburicase) ther apy. Free Radic Res 2007;41(9):953–5. 93. Sestigiani E, Mandreoli M, Guardigli M, Roda A, Ramazzotti E, Boni P, Santoro A. Efficacy and (pharmaco)kinetics of one sin gle dose of rasburicase in patients with chronic kidney disease. Nephron Clin Pract 2008;108(4):c265–71.
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94. De Angelis S, Noce A, Di Renzo L, Cianci R, Naticchia A, Giarrizzo GF, Giordano F, Tozzo C, Splendiani G, De Lorenzo A. Is rasburicase an effective alternative to allo purinol for management of hyperuricemia in renal failure patients? A double blind-ran domized study. Eur Rev Med Pharmacol Sci 2007;11(3):179–84. 95. Hummel M, Reiter S, Adam K, Hehlmann R, Buchheidt D. Effective treatment and prophylaxis of hyperuricemia and impaired renal function in tumor lysis syndrome with low doses of rasburicase. Eur J Haematol 2008;80(4):331–6. 96. Segura Torres P, Borrego Utiel FJ, Pérez Del Barrio P, Gil Cunquero JM, Pérez Bañasco V. Eficacia de la rasburicasa en el fracaso renal agudo obstructivo por litiasis: una nueva opcion terapeutica. [Efficacy of rasburicase therapy in obstructive renal failure secondary to urolithiasis: a novel therapeutic option.] Nefrologia 2008;28 (1):102–5.
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10
General anesthetics and therapeutic gases
Immunologic The incidence of hypersensi tivity reactions during anesthesia has been underestimated, because clinical symptoms vary and the diagnosis is often not obvious. The incidence of allergic reactions during anesthesia has been estimated in a systema tic follow-up of patients for 2 years (70 000 anesthetics) (1C). When a hypersensitivity reaction was suspected or when there were unexplained adverse reactions during anesthesia, blood was sampled to measure histamine and tryptase and skin tests were performed 4–6 weeks later. Of the 39 patients enrolled, 8 were excluded because of lack of skin tests, 22 had clinical features compatible with immediate hypersensitivity reactions and 9 had reactions rated as ‘unex plained’ by the attending physician. After systematic investigation, 22 hypersensitivity reactions were detected (15 patients with obvious and 7 with unexplained reactions) during anesthesia. This increases the esti mated incidence of hypersensitivity reactions from 1:4667 to 1:3180 anesthetics. Tryptase concentrations were increased in only 50% of these patients, and the positive and nega tive predictive values of tryptase for a diag nosis of anaphylaxis were 100 and 60% respectively. Latex was the major causative agent, followed by neuromuscular blocking agents and antibiotics.
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32010-1 � 2010 Elsevier B.V. All rights reserved.
ANESTHETIC VAPORS (SEDA-27, 119; SEDA-29, 129; SEDA-30, 137; SEDA-31, 217) HALOGENATED VAPORS Gastrointestinal The incidence of post operative nausea and vomiting (PONV) after lumbar disc surgery has been investi gated in a prospective non-randomized cohort study in 625 patients who sequen tially received isoflurane, desflurane, and sevoflurane in an O2/air mix depending on the year of surgery (2c). They all received two antiemetics (metoclopramide and dexamethasone). The rates of PONV were similar with all three volatile anesthetics (i soflurane 9.3%, desflurane 11%, and sevo flurane 11%). Multiple logistic regression identified well-known independent risk factors for PONV, such as female sex, non smoking, a history of PONV and duration of anesthesia.
Desflurane (SED-15, 1072; SEDA-30, 137; SEDA-31, 217) Cardiovascular Desflurane 6% prolonged the QT interval to over 440 ms until 30 min utes after the end of inhalational anesthesia in 20 children undergoing inguinal hernia repair, all of whom had a normal preoperative electrocardiogram (3c). Sevo flurane 2% had no effect. Ear, nose, throat In 19 boys, mean age 7 years, middle ear pressure was measured in
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both ears at baseline, after 5, 10, and 15 minutes of desflurane administration and 10 minutes after withdrawal (4C). There was a significantly increased middle ear pres sure, even at 5 minutes, which peaked at 15 minutes and remained significantly raised at 10 minutes after withdrawal of desflurane. The authors thought that this might cause problems, such as tympanic rupture, displacement of tympanic mem brane grafts, hemotympanum or varying degrees of hearing loss. Liver Hepatotoxicity has been ascribed to desflurane (5A). A 15-month-old boy with Mo¨ bius syndrome (congenital oculofacial paralysis), who had had two previous uneventful general anes thetics with isoflurane and remifentanil, under went an uneventful Nissen fundoplication using desflurane and remifentanil. On the first postoperative day he had an upper gastro intestinal bleed and was found to have a coagulopathy with raised liver enzymes. However, liver ultrasound was unremarkable. A diagnosis of exclusion of desflurane hepato toxicity was made.
Other potential causes for hepatotoxicity were ruled out. Desflurane (and isoflurane) produce low concentrations of a trifluoro acetylated product, and this can be enough to produce hepatotoxicity in the sensitized patient. However, hepatic trifluoroacetylated microsomal proteins could not be measured. In another case, desflurane-induced hepatitis was associated with hapten and autoantigen-specific IgG4 antibodies (6A). A 22-year-old woman underwent uneventful exploratory laparotomy with general anesthe sia using desflurane. On day 17 she developed dark urine, pruritus and vomiting. On day 21 she developed jaundice and raised liver func tion tests, but normal liver ultrasonography. All viral screens were negative. She was tested for three antibodies known to be increased in volatile gas-associated hepatitis and was posi tive for all three (trifluoroacetyl-specific IgG4 (TFA IgG4) and 58 kDa endoplasmic reticulum protein and CYP2E1 autoantibodies).
The authors concluded that drug-induced liver injury may be an autoimmune response
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triggered by native hepatic proteins covalently linked to TFA IgG4. They identified sus ceptibility factors for drug-induced liver injury, including previous exposure, female sex, and a history of autoimmune disease.
Isoflurane
(SED-15, 1921; SEDA-30, 138; SEDA-31, 218) Drug withdrawal The effects of isoflurane withdrawal have been reported (7A).
An ex-premature infant girl, now 4 years old, developed status asthmaticus and was given isoflurane for bronchodilatation. After she had been weaned off other sedation, the isoflurane was also reduced. Each time severe bronchospasm occurred within a few hours of extubation, requiring rapid reintubation and subsequent tracheostomy, suggesting possible tolerance. After 20 continuous days of inhaled therapy (end tidal concentration up to 2%), she developed choreoathetoid movements on dosage reduction, precipitating bronchospasm. She was given a ‘weakening’ dose of cisatra curium (0.04 mg/kg/hour) to facilitate dosage reduction. After 18 days, the isoflurane was weaned and then subsequently the cisatracur ium. One year later there were no motor or new cognitive defects or abnormal movements.
Methoxyflurane (SED-15, 2290) Observational studies Methoxyflurane, which had fallen out of favor because of potential nephrotoxicity, has started to be used again for procedural and pre-hospital sedation in emergencies. Its use has been studied in adults and in children. In a prospective, non-randomized obser vational case series of 83 adults paramedics gave methoxyflurane via a hand-held pen throx inhaler delivering 0.2–0.4% (dilutor hole open) and 0.5–0.7% (hole closed) (8c). There was a statistically significant reduction in pain scores after 5 minutes with only minor adverse effects in 19%. The adverse effects included nausea (n = 7), euphoria (n = 3), dizziness (n = 2), and one each of headache, hallucinations, sore throat, and lip paresthesia. Ramsay sedation scores
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showed a mean of 2, and only one patient became significantly drowsy (Ramsay score 5). There was a moderately high level of satisfaction with the drug among the para medics (82%) and patients (72%). Methoxyflurane has also been studied in a prospective, observational case series of 14 children aged 6–13 years (9c). It was deliv ered using the hand-held penthrox inhaler, delivering 0.1–0.2% (with dilutor hole open) and 0.3–0.4% (dilutor hole closed). There were no major adverse events. However, five patients had minor adverse events, including agitation, euphoria, blurred vision, and dizziness, and two had cough, both of whom had the dilutor hole closed to increase the concentration of methoxyflurane.
Sevoflurane
(SED-15, 3123; SEDA-29, 129; SEDA-30, 138; SEDA-31, 218)
Cardiovascular In 54 patients the Tp-e (the time interval between the peak and the end of the T wave, a measure of transmural dispersion of repolarization), which is a more sensitive indicator of the risk of torsade de pointes than QT interval, was measured (10c). The patients were randomized to sevoflurane 1, 1.25 or 1.5 age-adjusted minimum alveolar concentration (MAC) after induction with 8% sevoflurane. There was a significant increase in QTc duration in all the groups compared with pre-induction. However, there were no significant increases in Tp-e after sevoflurane exposure, suggesting that sevoflurane has a low potential for causing torsade de pointes. The increase in QTc interval could be explained by the high dose of sevoflurane that was given at induction. Nervous system The epileptiform effects of sevoflurane have been studied under four different conditions, including tidal and vital capacity induction, 2 and 4% end tidal mini mal alveolar concentration and inclusion of hyperventilation in 40 patients (11c). There were epileptiform discharges in 12 patients, but there were no differences between the groups. These discharges were not associated with hemodynamic changes. Post hoc
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univariate analysis showed that female sex, increased dose of sevoflurane, and speed of onset of induction were statistically signifi cant susceptibility factors for epileptiform discharges. Emergence agitation after sevoflurane has been reported when propofol 1 mg/kg was added before the end of the procedure in two placebo-controlled studies in chil dren aged 2–7 years undergoing either MRI scanning (12C) or strabismus surgery (13C). In the first study there was a signifi cant reduction in emergence agitation (27% versus 4.8%) with the addition of propofol and no increase in adverse effects; time to eye opening and recovery room discharge were not different. In the second study there were also significant reductions in emergence agitation, but the time to removal of the laryngeal mask and emer gence time were significantly longer after propofol. There were no major adverse events or respiratory compromise and recovery room discharge times were equiva lent, suggesting that longer emergence times may not be clinically significant. Neuromuscular function The effects of sevoflurane 0, 1.7 and 3.4% on neuromuscular function have been studied in patients with myasthenia gravis undergoing anesthesia without neuromuscular blockade in a singlecenter cohort study (14c). T1 and the T4/T1 ratio were measured by electromyographic sti mulation of the ulnar nerve. Three groups were identified: a control group and two groups of patients with myasthenia gravis, those who initially displayed fade and those who did not. In all three groups, increasing concentrations of sevoflurane reduced the T4/T1 ratio but more significantly in the patients with myasthe nia gravis who displayed fade, thus implying that the effect of sevoflurane could be pre dicted in these patients and further negating the need for neuromuscular blockade. Liver The repeated use of sevoflurane has been associated with fatal hepatic failure (15A). A 69-year-old man with chronic renal insufficiency secondary to diabetes underwent general anesthesia with sevoflurane to repair a
246 subclavian artery after damage from an intravenous catheter. The procedure was uneventful but during the 20th postoperative hour he developed deep jaundice, abnormal liver function and a coagulopathy. Thoracotomy for suspected bleeding was negative. His clinical condition deteriorated rapidly, and he developed multiorgan failure with severe cerebral edema. He died on the 8th postoperative day. At post-mortem examination the liver was reduced in size, with multiple necrotic areas. Microscopic examination showed perivenular necrosis and intracellular calcium deposits.
The post-mortem findings were consis tent with previous studies that have proposed that hepatic damage may be due to disruption of intracellular calcium homeostasis, resulting in hepatic necrosis and a large amount of calcium deposition in hepatocellular cytoplasm. Musculoskeletal Malignant hyperthermia has again been reported in the case of a 7-year-old boy with three previous normal general anesthetics who underwent sevo flurane anesthesia without muscle relaxa tion for tympanoplasty (16A). Despite other classic signs of malignant hyperther mia (tachycardia and hyperthermia), there were no signs of muscle rigidity or masseter spasm and the rise in PECO2 was minor (4.8–5.2 kPa). Subsequent investigation showed that his father was susceptible to malignant hyperthermia but his mother was negative. Susceptibility factors Diseases Death occur red after volatile anesthesia in an infant w ith undiagnosed Duchenne muscular dystrophy (17A). An 8-month-old ex-premature boy who had previously undergone eight general anesthetics with volatile agents died 12 hours after closure of an ileostomy with hyperthermia and rhabdomyolysis. Perioperatively he had a per sistent tachycardia and hypercapnea un responsive to treatment. Postoperatively, he developed a fever, increased serum creatinine and a coagulopathy. He became hypotensive and required inotropic support. Echocardio graphy showed poorly contracting ventricles. Despite optimum therapy, he deteriorated and died. At post-mortem examination there were dilated renal tubules and raised serum
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creatinine kinase and lactate dehydrogenase activities (21 093 and 21 393 IU respectively). Immunohistochemical staining showed un diagnosed Duchenne muscular dystrophy.
Trichloroethylene (SED-15, 3488; SEDA-29, 130; SEDA-30, 140; SEDA-31, 219) Nervous system A link between trichloro ethylene, parkinsonism and mitochondrial neurotoxicity has been postulated (18cE). In a questionnaire study of 134 previous empl oyees of a factory in which trichloroethylene had been used, 65 responded. They were equally spread between those who reported no symptoms of parkinsonism, 1–2 symptoms or 3 or more. The authors further evaluated the symptomatic and very symptomatic groups, of whom about 60% consented to undergo neurological testing. Both groups had significantly slower movements than age-matched controls. The asymptomatic patients also had slower fine motor hand movements than those of the age-matched controls, albeit faster than those of the symptomatic patients. In a parallel study, rats that were exposed to trichloroethylene for 6 weeks had significantly inhibited mitochondrial function in the substantia nigra. Drug overdose There have been two case reports of trichloroethylene overdose, one fatal, secondary to abuse, and one non-fatal after an industrial accident. A 27-year-old man, a known thinner addict, developed chest and abdominal pain and drow siness. Imaging and blood investigations were normal apart from a respiratory alkalosis (19A). After 24 hours he developed increased liver enzymes (alanine transaminase 4920 IU/l and aspartate transaminase 9370 IU/l) and thrombo cytopenia (17 109/l). His liver enzymes continued to deteriorate and he developed dis seminated intravascular coagulation and a metabolic acidosis. All viral markers were nega tive. He was treated with respiratory and invasive hepatic support. His urinary trichloro acetate concentration was 24 mg/l (normally undetected). He subsequently developed renal insufficiency and cerebral edema. Electro encephalography showed flat waves and further brainstem testing confirmed the absence of brainstem reflexes. He died on the same day.
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Although no liver biopsy was performed, the very high AsT/AlT ratio suggested cen trilobular liver damage, which is the histo logical finding that has been found in animal studies and previous autopsy reports after poisoning with trichloroethylene. Severe hepatotoxicity with trichloroethylene alone is rare in humans and the patient may there fore have been exposed to other hepato toxic substances, such as alcohol. A 54-year-old man was found unconscious beside a metal-degreasing machine in which trichloroethylene was used as a solvent. His serum trichloroethylene concentration was 9 mg/l and rapidly fell over the first 24 hours (20A). The urinary trichloroethylene concentration exhibited two peaks at 7 and 14 hours. Excretion of total urinary protein and enzymes (glutamine synthetase and N-acetyl--D-glucosaminidase) coincided with urinary excretion of trichloroethylene. Plasma urea and creatinine remained stable and he recovered completely.
Based on the blood concentration of tri chloroethylene and its urinary excretion, the exposure level was around 150 ppm (three times higher than statutorily recom mended). Glutamine synthetase is a mito chondrial enzyme that is found in a variety of tissues, including the kidneys, and speci fically the S3 segment of the proximal tubule. Excretion of this protein in the urine is early indication of damage to this segment and a high excretion rate relates to necrosis. N-acetyl--D-glucosaminidase is a lysosomal enzyme, also segmentally located in the S3 segment of the proximal tubule. This report, therefore, suggests a link between trichloroethylene poisoning and dysfunction of a specific segment of the proximal tubule, segment S3.
OTHER VAPORS Nitrous oxide (SED-15, 2550; SEDA-29, 131; SEDA-30, 140; SEDA-31, 221) Metabolism Nitrous oxide (N2O) interferes with methionine synthesis via the oxidation of vitamin B12, causing bone marrow and
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nervous system changes. Reversible myelo neuropathy with previously undiagnosed per nicious anemia and a normal mean erythrocyte volume has been reported (21A). A 27-year-old otherwise fit and well woman developed ascending numbness and bilateral lower-extremity weakness developing over 2–3 months starting 3 months after nitrous oxide-based anesthesia for dental procedures. She had normal cognition, cranial nerves and upper limb and proximal lower strength, but light touch sensation was reduced in the arms and over the trunk. Her gait was widened and ataxic. Myeloneuropathy was diagnosed. She had a mild anemia (hemoglobin 11.9 g/dl) with an mean cell volume (MCV) of 86 fl, serum B12 290 pg/ml, homocysteine 17 mmol/l, and positive antibodies to intrinsic factor. Nerve conduction studies showed an axonal sensory and motor polyneuropathy. Needle electromyography showed 2þ fibrillation and positive sharp waves with normal motor unit action potentials. An MRI scan of the cervical spine showed patchy enhancement in the posterior regions. She improved with a 10-month course of intra muscular vitamin B12 100 micrograms/month.
Hematological parameters have been measured in 95 female theatre nurses who had been exposed to anesthetic gases in oper ating theatres for 5–26 years and 90 control nurses who worked elsewhere in the same hospital. Initial hemoglobin, mean cell hemo globin (MCH), mean cell volume (MCV), and mean corpuscular hemoglobin concen tration (MCHC) were normal in both groups (22c). Despite these normal hematological parameters, vitamin B12 concentrations were lower and homocysteine concentrations significantly higher in the exposed group. In nurses who worked in theatres that exceeded the quoted US and German government guidelines for anesthetic gas concentrations, vitamin B12 concentrations were statistically significantly lower and homocysteine con centrations significantly higher than those in nurses who worked in theatres where expo sure was within the guidelines. There was also a significant negative correlation between theater nitrous oxide concentrations and vitamin B12 concentrations and a significant positive correlation between theater nitrous oxide concentrations and homocysteine, but no correlation with duration of exposure to nitrous oxide. Hyperhomocysteinemia at
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these concentrations is an independent risk factor for cardiovascular disease and this may warrant further investigation.
Xenon Gastrointestinal Xenon is emetogenic. In a prospective, randomized trial in 142 patie nts who received either xenon anesthesia or propofol total intravenous anesthesia, the xenon group had statistically significantly greater incidences of nausea and vomiting both in the recovery area and in the first 24 hours, despite having received similar amounts of cumulative opioids; late nausea and vomiting did not differ between the groups (23c). As propofol has antiemetic properties (24C), its use may have mitigated the emetogenic effect of xenon found in this study. A comparison of xenon with another anesthetic vapor in addition would be desirable.
INTRAVENOUS AGENTS: NON-BARBITURATE ANESTHETICS Etomidate
(SED-15, 1302; SEDA-30, 140; SEDA-31, 221)
Cardiovascular Complete atrioventricular blockade after etomidate has been reported (25A). A 71-year-old woman was given atropine and etomidate 17 mg for electroconvulsive therapy (ECT), having undergone a full course uneventfully in the previous year. She devel oped complete heart block with an atrial rate of 100/minute and an intrinsic ventricular rate of 10/minute, which resolved spontaneously after 30 seconds. On three occasions she had had asymptomatic bradycardia (20/minute) after induction with etomidate 18 mg and sux amethonium 50 mg, which had been attributed to suxamethonium. On this occasion suxa methonium was not given and treatment was abandoned. Subsequent investigation showed no abnormalities and the event was attributed to etomidate.
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Etomidate is suspended in 35% propy lene glycol, which has been shown to cause atrioventricular dissociation in animals and rarely in humans (26E). It is possible that this may have been the causative agent rather than the etomidate itself. Nervous system Transient myoclonus is a reported adverse effect of etomidate, but a case report has suggested that it can cause more prolonged myoclonus (27A). A healthy 69-year-old man with treatmentrefractory depression, who had previously received etomidate for ECT, was again given etomidate 10 mg and developed severe sus tained myoclonus lasting 10 minutes. His vital signs were stable and oxygenation was easily maintained via a facemask. Anesthesia was s uccessfully induced 45 minutes later with 1% propofol.
Etomidate-induced myoclonus has been studied in a double-blind, placebo-con trolled trial of the benefit of pre-treatment with low-dose midazolam in 40 patients undergoing elective cardioversion for atrial fibrillation after cardiac surgery (28c). In those who were given placebo the incidence of myoclonus was 50%; it was mild in six patients, moderate in three, and severe in one. After pre-treatment with midazolam 0.015 mg/kg, only two patients out of 20 had mild myoclonus. Although etomidate is a proconvulsant and prolongs the duration of seizures during ECT, seizures are rare. Two cases have been reported (29c). A 49-year-old white man was given etomidate 20 mg and suxamethonium 120 mg uneventfully for ECT. Before a second course he was given the same dose of etomidate and had a general ized tonic–clonic seizure, which lasted 450 sec onds and ended spontaneously, associated with bradycardia, which responded to glycopyrro late. Electroencephalography was consistent with childhood benign occipital lobe epilepsy. On the next occasion he was given the same dose of etomidate and had a generalized tonic–clonic seizure. It lasted 450 seconds and ended spontaneously, but was associated with glycopyrrolate-responsive bradycardia. Electro encephalography was consistent with childhood benign occipital lobe epilepsy.
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A 38-year-old African woman with a schizoaffective disorder had been treated successfully with ECT. On each previous occasion, she had developed mild myoclonus after being given etomidate; however, on this occasion, after eto midate 18 mg the myoclonus developed into seizure activity. Bifrontal electroencephalogra phy showed possible epileptiform waves. The seizure activity resolved spontaneously after 4 minutes. Later electroencephalography showed no epileptiform activity.
The authors suggested that in patients at increased risk of etomidate-induced sei zures, propofol should be considered for induction of anesthesia.
Adrenal suppression from etomidate In a prospective, unblinded, randomized, controlled trial, adults with trauma were ran domized into two groups who received either etomidate 0.3 mg/kg (n = 18) or fentanyl 100 micrograms þ midazolam 5 mg (n = 12), both with suxamethonium 1 mg/kg (30c). Baseline and 6-hour serum cortisol were measured and an ACTH stimulation test was performed at 4–6 hours. Baseline serum cortisol was the same in the two groups (310 and 270 µg/l), but after 4–6 hours etomidate reduced serum cortisol (180 µg/l versus 280 µg/l). After the ACTH stimulation test, those who had received etomidate had a sig nificantly lower rise in cortisol (42 µg/l versus 112 µg/l), suggesting impaired adrenal func tion. Despite having the similar severity of injuries, those who received etomidate required significantly more units of red blood cells and fresh frozen plasma; they also had an increased duration of both ICU and hospital stay and an increased number of ventilator days. This study had many lim itations: it was small and unpowered and about 50% of the patients were withdrawn for a number of reasons, including problems with consent. This may have skewed the results, as 11 of the 31 patients who were withdrawn received etomidate. There was also a difference in blood and clotting products between the two groups. However, it is not clear why the authors felt that it could be accounted for by
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‘physiologic alterations’ between the two groups. Resuscitation of the patients was at the discretion of the attending physician, and perhaps this also had an influence. A prospective non-randomized observa tional study investigated 40 critically ill adults without septic shock who required intubation for respiratory distress, all had etomidate and suxamethonium for induction. Serial serum cortisol and 11-deoxycortisol concentra tions were taken at baseline and 60 minutes after corticotrophin stimulation tests per formed at 12, 24, 48, and 72 hours (31c); 80% of the patients fulfilled previously pub lished criteria for adrenal insufficiency (32c) at 12 hours and 46% at 24 hours. This fell to 9% and 7% at 48 and 72 hours respec tively. A subgroup analysis showed that the patients with adrenal insufficiency required significantly more noradrenaline support (1.8 mg/hour versus 0.2 mg/hour). The lack of a control group does not allow complete confidence in suggesting that it was etomi date rather than the pathology that caused the adrenal suppression. Also, patients who died within 12 hours were excluded, which may also have skewed the data. However, this study presents some evidence for a more prolonged period of adrenal insuffi ciency after the administration of a single dose of etomidate. The effects of propofol and etomidate have been compared in patients with severe aortic stenosis undergoing aortic valve repair in a double-blind, randomized study of 66 patients (33c). Hypotension was significantly more likely in those who received propofol (20/30 versus 8/30), although the range of doses of propofol to achieve a bispectral index of 60 was large (40–400 mg), which may have influenced vasopressor require ments. Pulmonary capillary wedge pressure, cardiac index, systemic vascular resistance index and stroke volume fell in both groups to a similar extent. More of those who were given propofol required phenylephrine at the time of induction, but those who required the drug in the two groups received the same dose. Cortisol concentrations were com parable preoperatively and on the first postoperative morning. Immediately post operatively those who were given etomidate
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had significantly lower serum cortisol con centrations (250 nmol/l versus 700 nmol/l). There was an inverse relation between the dose of etomidate and the total cortisol con centration. Cortisol stimulation tests were not performed. There were no differences in out come, length of stay and mortality, although the sample size was only powered to detect reductions in blood pressure and may have been too small to identify differences in mortality. Adrenal insufficiency after a single dose of etomidate has been reported (34A). A 74-year-old woman who underwent an uncomplicated abdominoperineal resection was induced with etomidate and suxametho nium and 6 hours postoperatively became leth argic, bradycardic and hypotensive. She did not respond to atropine and fluids. Transcutaneous pacing was initiated, and she improved hemo dynamically. Subsequently a temporary transvenous pacing wire was inserted. A random cortisol was 176 µg/l (although the temporal relation to the dose of etomidate was unclear). She was given intravenous hydrocortisone 100 mg tds and 6 hours after the first steroid dose did not need further pacing.
The authors concluded that adrenal insuf ficiency should be considered in patients with postoperative shock who have received etomidate who do not respond to fluids and vasopressors.
Acid–base balance Hyperosmolar, increased anion-gap metabolic acidosis and associated hyperglycemia have been reported after infusion of etomidate in propylene glycol (35A). A 33-year-old woman with a large subarachnoid hemorrhage and poorly controlled intracranial pressure (ICP) was given etomidate by infusion following failure of pentobarbital to control ICP. She also received intravenous dexamethasone 20 mg 12 hourly. Twenty-four hours after the start of the infusion she became markedly acidotic (pH 7.06, anion gap 23 mmol/l), hyperglycemic (36 mmol/l) and hyperosmolar (serum osmolarity 422 mOsm/l). Urinary ket ones were absent. Despite treatment, her meta bolic derangement returned to normal only when the etomidate infusion was stopped, after a total dose of 2800 mg in 508 g of propylene glycol.
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Propylene glycol is 45% excreted unchanged by the kidneys and the rest is metabolized by hepatic alcohol dehydro genase to pyruvate, lactate and acetate. Thus, in hepatic and renal impairment, propylene glycol toxicity can cause hyperosmolar acidosis with hyperglycemia from increased gluconeogenesis. Dexametha sone may also have contributed to the hyperglycemia by increasing insulin resis tance, although it was continued after withdrawal of etomidate and after her blood glucose normalized (36r).
Ketamine Observational studies The addition of ketamine to propofol is thought to counteract the cardiorespiratory depression that occurs when propofol is used alone, whereas propo fol is thought to reduce the psychometric and emetic effects of ketamine. In a prospective case series of 114 patients of all ages, a mix ture of propofol 10 mg/ml þ ketamine 10 mg/ ml (‘ketofol’) was used for procedural seda tion in an emergency department (37c). There was no standardization of the preprocedural analgesia used, and a large proportion (42/114) received intravenous or oral opioids. Only three patients required additional propofol to complete the proce dure. Eight had minor adverse events, includ ing three airway malalignments requiring manipulation, two emergence reactions, and one case of self-limiting atrial fibrillation. Four had major adverse events, including three patients with apnea and/or hypoxia requiring airway adjuncts and 100% oxygen, one of whom was acutely intoxicated and one had received narcotics. Comparative studies The effects of mida zolam on ketamine-induced emergence reactions have been investigated in 100 chil dren undergoing adenotonsillectomy (38c). All were given intramuscular ketamine 7 mg/kg and atropine 0.015 mg/kg and half were given midazolam 0.1 mg/kg. There were no severe adverse events in either group. In the immediate postoperative period, mild
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reactions were similar, but moderate reactions were less common in those who received midazolam (3.6% versus 25%). On day 1, mild reactions were frequent in both groups. On day 2, 71% of the children who received ketamine without midazolam had mild reactions, whereas 75% of those who received midazolam group had no emergence reactions. The incidence of immediate PONV (at 0–4 hours) was significantly reduced by midazolam, but this was reversed in the period up to 24 hours, when those who received midazolam had a higher incidence of vomiting. This may have been attributable to the relative half-lives of the drugs. Nervous system In a randomized, placebo-controlled study, 60 children aged 3–7 years had ketamine 0.5 mg/kg in 2 ml or placebo infiltrated into the tonsillar fossa after day case adenotonsillectomy (39c). Using the childrens’ hospital of eastern ontario pain score (CHEOPS), 26/30 in the ketamine group versus 3/30 in the placebo group had no pain in the immediate postoperative period. The time to first requirement for analgesia was significantly longer in those who received ketamine and the dose required was lower. There were no hallucinations or negative behaviors and the incidence of nausea and vomiting was the same in the two groups. There were no delayed discharges. Respiratory Prolonged apnea has been reported after the use of ketamine (40A). An 11-month-old, 7-kg full-term girl was given intramuscular ketamine 35 mg and glycopyrrolate 0.05 mg before elective plas tic surgery. She started to have ineffective respirations, followed by apnea requiring intubation. There was no laryngospasm or excessive secretions. Spontaneous respiration resumed after 90 minutes. There were no complications.
Respiratory depression has been noted before with high doses of intramuscular ketamine (10 mg/kg), or when it is co administered with other sedatives, or in neonates with electrolyte abnormalities.
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However, it is unusual with a low dose in an otherwise healthy subject.
Psychiatric The influence of adding an infusion of ketamine 0.1 mg/kg/hour to tramadol 0.2 mg/kg/hour has been assessed in a double-blind, randomized, placebocontrolled trial in 120 adults undergoing elective laparotomy (41C). Ketamine produced superior analgesia, with 54% less morphine consumption than in the placebo group. There were no differences in nausea and antiemetic drug use, psychomotor performance, sleep disturbance, or nondisturbing hallucinations. However, three patients withdrew from the study because of disturbing hallucinations; all had received ketamine. In a randomized, double-blind, placebocontrolled trial, 73 adults with trauma and severe acute pain (as defined by a visual analogue scale) received ketamine 0.2 mg/ kg or placebo (isotonic saline) in addition to morphine 0.1 mg/kg followed by 3 mg every 3 minutes. Ketamine significantly reduced morphine consumption (0.20 mg/kg versus 0.15 mg/kg), despite no differences in pain scores between the groups (42C). There were more adverse effects with ketamine, with an increased incidence of neuropsychia tric effects (hallucinations, dizziness, diplopia, and dysphoria). No patient required treat ment for these adverse effects and patient satisfaction was the same in the two groups. The investigation period was very short (30 minutes), and this may have skewed the identification of adverse effects, although the study was not powered to look at this. Gastrointestinal The addition of intra venous low-dose ketamine (2.5 micro grams/kg/minute) to a standard patientcontrolled morphine infusion has been stu died in 42 patients after elective bowel resection (43c). The mean time to passing flatus or stools, return of bowel sounds, or drinking without vomiting was the same in the two groups. There were significantly more adverse effects in those who were given ketamine, 32% of whom had
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hallucinations, perhaps because benzodia zepines were not used. There were no dif ferences between the groups with respect to nausea and nightmares. All the patients who had hallucinations wanted to remain in the study, as they thought that they were getting the active drug.
Urinary tract Patients with a history of recreational ketamine abuse commonly have urinary symptoms. The index case in a series of nine presented with a 6-month history of painful hematuria, dysuria, urgency, and post-micturition pain after taking daily ketamine (44A). Urinalysis, cultures, and cytology were normal. An abdominal CT scan showed a very small capacity bladder with marked inflammatory changes, and a biopsy showed chronic ulcerative cystitis with eosinophil infiltration. Antibiotics and glucocorticoids were ineffective, and the symptoms were partly controlled by withdrawal of ketamine. Another eight cases presented in a similar fashion, and if symptoms did not resolve completely with ketamine withdrawal, pentosan polysulphate (to supplement the glycosaminoglycan layer of the bladder) was effective. The mechanism of ketamine induced ulcerative cystitis is unclear. However, there were high concentrations of norketamine and hydroxynorketamine in the urine of recreational users, and these metabolites may cause bladder irritation. In four bladder biopsies there was a degree of eosinophil infiltration, which is considered the final common pathway for allergic cystitis mediated by IgE-activating mast cells.
Propofol
(SED-15, 2945; SEDA-29, 132; SEDA-30, 142; SEDA-31, 222)
Cardiovascular A mixture of propofol 1 mg/kg þ fentanyl 1 microgram/kg has been compared with spinal anesthesia with hyperbaric lidocaine 10 mg in american society of anesthesiologists (ASA) I and
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ASA II patients undergoing prostate biopsy (45c). Those who received propofol þ fen tanyl had significantly more hypotension a nd required increased boluses of ephedrine. Propofol and xenon have been compared in ASA III and ASA IV patients under going non-elective cardiac surgery (46c). Those who received propofol had lower mean arterial pressure after induction and poorer myocardial performance index and circumferential fiber shortening, suggesting impaired left ventricular function. However, xenon was associated with a significant increase in the rate of PONV. There have been contradictory results in studies of whether propofol has any effect on cardiac conduction (47A). A 49-year-old woman with a history of palpitations had a third molar extracted under propofol sedation and local anesthesia with lidocaine. Her preoperative electrocar diogram was normal, but shortly afterwards a delta wave appeared and persisted after injection of 2% plain lidocaine. She was hemodynamically stable, so surgery continued. She was given 2% lidocaine 3.6 ml with 1:80 000 adrenaline and 10 minutes later the delta wave resolved and she regained sinus rhythm. A postoperative electrocardiogram was normal.
This may have been due to reduced sympa thetic tone, sinus node automaticity, and atrial refractoriness. Systemic absorption of adrenaline may have shortened conduction in the atrioventricular node and accessory pathways, causing the delta wave to disappear. The oculocardiac reflex is a common pro blem during strabismus surgery, causing bradycardia and even asystole on manipula tion of the eye. The effect of intravenous anesthetics has been investigated in a dou ble-blind, randomized comparison of 120 children aged 3–9 years who were allocated to propofol 3 mg/kg or ketamine 1 or 2 mg/kg for induction. Ketamine significantly reduced the incidence of the oculocardiac reflex from 14/40 (placebo) to 4/40 (1 mg) and 1/40 (2 mg); it also significantly reduced the amount of rescue opioid analgesia required postoperatively (48c).
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Respiratory In 82 patients who underwent sedation with propofol for mainly minor orthopedic procedures, the mean starvation time was 5.5 hours and the mean initial dose was 0.5 mg/kg in those with and without complications (49c). There were 28 sedation events in 17 people. Hypoventilation was the commonest and nine developed brief hypox emia (mean 1.2 minutes, SpO2 < 90%); none required assisted ventilation. All the episodes resolved with simple airway adjust ments and supplementary oxygen. There were similar results in a larger retrospective audit of children undergoing radiotherapy for 3833 oncology procedures (50c). There were 49 complications (1.3%), of which one was hemodynamic instability; the others were airway complications, none of which required advanced airway interven tion. There were no episodes of laryngo spasm. Univariate analysis showed that the use of adjuncts (benzodiazepines, opioids, and ketamine) was significantly associated with an increased risk of complications. This has been reinforced by a report of aspiration pneumonitis in a patient who had eaten before the operation and received a large dose of propofol and opiates (51A). A 65-year-old woman needed reduction of an ankle fracture 5 hours after a large meal taken with alcohol. She received fentanyl 100 micrograms followed by 20–40 mg boluses of propofol (total 120 mg). Fracture reduction was unsuccessful. 20 minutes later she developed wheezing but had a normal chest X-ray. An hour later she was given further fentanyl 100 micrograms and propofol 60 mg and she vomited and aspirated. She became hypoxic and hypotensive and required intuba tion. There were patchy areas bilaterally on the chest X-ray. Recovery was uneventful.
In a prospective case series of procedural sedations in 404 starved and non-starved patients in an emergency department, the attending physician gave opiates in 63% of cases (52c). There were respiratory adverse effects in 22% after a mean bolus dose of propofol 0.82 mg/kg and a total dose of 1.78 mg/kg. All responded to basic airway manoeuvres and there were no cases of aspira tion, intubation, or unplanned admissions. A smaller non-randomized study in 37 patients also showed no major adverse
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effects (apnea, desaturation, airway com promise, or hypotension) after the use of propofol 0.5–1 mg/kg for sedation in the emergency department (53A). Again, most patients received variable amounts of opi ate analgesia. In a crossover study of children who received sedation for lumbar puncture with propofol 2 mg/kg plus either alfentanil 20 micrograms/kg or ketamine 1 mg/kg, those who were given alfentanil had a statis tically significant increase in respiratory depression, resulting in reduced oxygen saturation. However, advanced airway manoeuvres were not required (54c). There were no other differences between the groups. Nervous system Propofol withdrawal seizures have been reported (55A). A 51-year-old woman received propofol 150 mg followed by an infusion of 6.5 mg/kg/ hour for 90 minutes for a metatarsal bone graft. She also received fentanyl 100 micrograms and lidocaine 10 mg. During recovery she had tonic–clonic movements and was unresponsive for 3 minutes; she was treated with lorazepam. A second event occurred and further loraze pam and phenytoin were given. Afterwards she was post-ictal and had no recall of the events. Blood tests and electroencephalography were unremarkable postoperatively, except for a raised serum prolactin concentration.
Although propofol is usually described as being anticonvulsant (56c), there have been reports of seizure-like events after its administration. This description of a seizure-like event with a subsequent rise in prolactin may have indicated true seizure activity. A link between propofol and an antimuscarinic syndrome has been implied in a case report (57A). A 20-year-old healthy man became drunk, fell, and dislocated his elbow. He received therapeutic doses of pethidine and prometha zine several hours before reduction of the dislocation and was given bolus injections of propofol (total 160 mg over 5 minutes); 5 minutes after the last dose of propofol he be came agitated and confused and required midazolam. Mydriasis was absent but the
254 antimuscarinic syndrome was diagnosed and he was given physostigmine 1 mg four times, with almost immediate effect. A drug screen was positive for caffeine, cannabinoids, nico tine, and the administered drugs and their metabolites.
This man received several drugs that have antimuscarinic activity (pethidine, pro methazine, and propofol), and the addition of alcohol may have further impaired choli nergic transmission. Sleep disturbance has been reported after propofol/remifentanil compared with sevo flurane anesthesia in 39 infants undergoing cleft lip/palate surgery (58c). Sleep patterns in both groups were disturbed in the 2 weeks after surgery compared with pre operatively. With propofol, sleep duration was significantly shorter than with sevoflur ane but awakening and inconsolable episodes were similar.
Psychological In 19 patients who under went colonoscopy or gastroscopy, took validated psychological tests, and answered driving licence questions to assess their ability to drive after anesthesia. Propofol caused significantly impaired memory imm ediately after anesthesia (59c). Four subjects had scores compatible with medium organic disorder and six had scores compatible with a slight disorder. After 1 hour, 91% and after 2 hours 94% had either no or slight memory deficits, implying rapid recovery. Acid–base balance Prolonged infusion of propofol at high doses has been associated with the propofol infusion syndrome, a syn drome associated with unexplained metabolic acidosis, rhabdomyolysis and death (60c). Further cases have been reported (61A, 62A). A 36-year-old white woman developed intract able epilepsy 2 weeks post-partum. Despite infusion of high-dose propofol (4.2 mg/kg/hour), her myoclonic jerks and electroencephalographic epileptiform activity continued. The dose of propofol was increased to 7.2 mg/kg/hour to achieve burst suppression for 19 hours, and then reduced to 4.8 mg/kg/hour. After a further 24 hours her urine became dark and serum
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triglyceride concentrations and creatine kinase activity were raised. She developed a fever and hypotension requiring inotropic support. Propo fol was withdrawn, but she developed acute renal insufficiency and required dialysis. Echocardio graphy showed global biventricular dysfunction without four-chamber dilatation and she pro gressed to bradycardia and eventually asystole. An autopsy showed normal cerebral hemi spheres with no ischemic changes. There was acute skeletal muscle aseptic necrosis, rhabdo myolysis and myoglobin casts in the renal tubules. An 18-year-old man with a severe head injury after a high-speed road traffic accident was given an infusion of propofol 7.5 mg/kg/hour for more than 72 hours to control intracranial pressure. He developed dark urine and a rising creatine kinase, which peaked at 95 440 U/l, followed by acute renal insufficiency, a metabolic acidosis and cardiac arrest, from which he could not be resuscitated. A 29-year-old woman with a severe head injury from a fall and an intracranial pressure of 28 mmHg was given high-dose propofol 4– 12 mg/kg/hour for 5 days. She subsequently underwent decompressive craniotomy for impending herniation and intraoperatively was found to be severely acidotic (pH 7.01, base excess –24 mmol/l, bicarbonate 7 mmol/l). Propofol was thought to be the culprit and anesthesia was switched to thiopental; over the next 5 hours the acidosis resolved, although on the next day she developed myoglobinuria with a rising creatine kinase (6966 U/l). She died the next day.
In a retrospective analysis of the case notes of 301 patients who underwent non invasive radiofrequency ablation for atrial dysrhythmias, 55 had had arterial blood gas measurements during the procedure. The controls were 267 patients undergoing carotid endarterectomy who had baseline arterial blood gas measurements. There was documented metabolic acidosis (defined as a base excess worse than –2 mmol/l) in 8.2% of the controls and 91% of those who received propofol. The authors did not report sodium, chloride, or bicarbonate concentrations, but they com mented that there was no relation between rate of fluid administration and the maximal negative base excess in these patients. The serious flaws of this work were outlined in a letter (63r). The definition of metabolic acidosis was at the lower limit of the normal range. Of the 301 patients who had arterial
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blood gas measurements during radiofrequency ablation, 55 had poor respiratory status, making it impossible to interpret the metabolic picture. Furthermore, there was no temporal relation between propofol administration and the time of blood sam pling. Finally, the dose of propofol used was not high. It is therefore difficult to draw any conclusions from this study. The mechanism of propofol infusion syn drome is unknown. Some have described effects of high-dose propofol on mitochon dria, with changes in electron and calcium transport and oxidative phosphorylation. This suggests that the syndrome may be due to impaired fatty acid utilization in the mitochondria (61A). Others have shown dif fuse myonecrosis in both cardiac and skele tal muscle, suggesting susceptibility of muscle cells to the toxic effects of propofol because of high ATP requirements.
INTRAVENOUS AGENTS: BARBITURATE ANESTHETICS Thiopental sodium
(SED-15, 3395; SEDA-30, 146; SEDA-31, 226)
Respiratory The use of a laryngeal mask airway reduces pharyngeal discomfort and dysphonia compared with tracheal intuba tion. In a double-blind, randomized trial in 335 ASA I–III patients who received either propofol 2 mg/kg or thiopental 5 mg/kg without neuromuscular blockade, thiopental was associated with a greater incidence of sore throat at 2 and 12 hours (24% versus 13% and 15% versus 6% respectively) and more dysphagia at 2 hours (15% versus 3%) but no difference at 12 hours (64c). In those who required a second attempt at placement of a laryngeal mask airway, thiopental was associated with a significant increase in dysphagia (18% versus 9.5%). Thiopental caused more PONV (20% versus 11%). There was no difference in the use of supplementary analgesia,
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although peri-operative analgesia was not mentioned. Patient satisfaction was the same in the two groups. Electrolyte balance Thiopental is com monly infused during neurocritical care to achieve burst suppression in patients in whom control of intracranial pressure is difficult. A rare complication of this appears to be imbalance in potassium regulation (65A). A 32-year-old man with a large traumatic subarachnoid hemorrhage, an intraparenchy mal hematoma and hydrocephalus had raised intracranial pressure that was difficult to control. He was given thiopental 3 100 mg boluses a nd then 2.5 mg/kg/hour and subsequently 4 mg/ kg/hour. After 5 hours, his serum potassium concentration had fallen from 3.4 to 1.7 mmol/l. He was given potassium chloride 170 mmol over 14 hours, and 8 hours after the withdrawal of thiopental, the potassium had increased to 8.7 mmol/l. Renal function was normal. A 53-year-old man with a left-sided subdural hematoma and midline shift developed a raised intracranial pressure (over 40 mmHg) and was given thiopental 5 mg/kg and then 3.75 mg/kg/hour. During 141 hours of coma, his serum potassium fell from 3.8 to 2.0 mmol/ l and he was given potassium chloride 600 mmol. Thiopental was withdrawn and the potassium rose to 8.5 mmol/l. There was mildly impaired renal function (serum creatinine 258 µmol/l). A 24-year-old woman developed diffuse brain edema, a small posterior temporal contusion and raised intracranial pressure after a severe head injury. She was given thiopental 3 mg/kg followed by an infusion of 5 mg/kg/hour, which was reduced to 3 mg/kg/hour because of hemodynamic instability. A few hours later the serum potassium concentration fell from 3.7 to 2.8 mmol/l and she was given potassium chloride 330 mmol during the thiopental infusion. A few hours after the end of treatment, the potassium rose to 6.8 mmol/l associated with an unstable ventricular tachycardia, requiring DC cardioversion. Renal function was normal.
The implication of a fall in potassium concentrations without an increase in urinary excretion, and a sudden rise after withdrawal of thiopental in the absence of abnormal renal function, suggests a shift of potassium into the intracellular compart ment. Several hypotheses have been
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suggested. One is inhibition of phospho fructokinase at high doses of thiopental, resulting in reduced lactate and pyruvate production, increasing intracellular pH and reducing potassium concentrations (66E). Second, inhibition of voltage-dependent neu ronal potassium channels can occur (67E). The use of catecholamines, insulin, and
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mannitol in neurocritical care is common, and the reduction in potassium could there fore be multifactorial. Rebound hyperkale mia is less well described, and the authors suggested that rapid redistribution of the drug allows the concentrations of thiopental to fall rapidly, allowing redistribution of potassium to the extracellular environment.
References 1. Malinovsky JM, Decagny S, Wessel F, Guil loux L, Mertes PM. Systematic follow-up increases incidence of anaphylaxis during adverse reactions in anesthetized patients. Acta Anesth Scand 2008;52(2):175–81. 2. Wallenborn J,Rudolph C, Gelbrich G, Goer lich TM, Helm J, Olthoff D. The impact of isoflurane, desflurane, or sevoflurane on the frequency and severity of postoperative nau sea and vomiting after lumbar disc surgery. J Clin Anesth 2007;19(3):180–5. 3. Aypar E, Karagoz AH, Ozer S, Celiker A, Ocal T. The effects of sevoflurane and desflurane anesthesia on QTc interval and cardiac rhythm in children. Paediatr Anaesth 2007;17(6):563–7. 4. Ozturk O, Ilce Z, Demiraran Y, Iskender A, Guclu E, Yildizbas S. Effects of desflurane on middle ear pressure. Int J Pediatr Oto rhinolaryngol 2007;71(9):1439–41. 5. Cote G, Bouchard S. Hepatotoxicity after desflurane anesthesia in a 15-month-old child with Mobius syndrome after previous exposure to isoflurane. Anesthesiology 2007;107(5):843–5. 6. Anderson JS, Rose NR, Martin JL, Eger EI, Njoku DB. Desflurane hepatitis associated with hapten and autoantigen-specific IgG4 antibodies. Anesth Analg 2007;104(6):1452–3. Table of contents. 7. Cooper MK, Bateman ST. Cisatracurium in ‘weakening doses’ assists in weaning from sedation and withdrawal following extended use of inhaled isoflurane. Pediatr Crit Care Med 2007;8(1):58–60. 8. Buntine P, Thom O, Babl F, Bailey M, Ber nard S. Prehospital analgesia in adults using inhaled methoxyflurane. Emerg Med Australas 2007;19(6):509–14.
9. Babl F, Barnett P, Palmer G, Oakley E, Davidson A. A pilot study of inhaled methoxyflurane for procedural analgesia in children. Paediatr Anaesth 2007;17 (2):148–53. 10. Whyte SD, Sanatani S, Lim J, Booker PD. A comparison of the effect on dispersion of repolarization of age-adjusted MAC values of sevoflurane in children. Anesth Analg 2007;104(2):277–82. 11. Julliac B, Guehl D, Chopin F, Arne P, Burbaud P, Sztark F, Cros AM. Risk factors for the occurrence of electroencephalogram abnormalities during induction of anesthesia with sevoflurane in nonepileptic patients. Anesthesiology 2007;106(2):243–51. 12. Abu-Shahwan I. Effect of propofol on emer gence behavior in children after sevoflurane general anesthesia. Paediatr Anaesth 2008;18(1):55–9. 13. Aouad MT, Yazbeck-Karam VG, Nasr VG, El-Khatib MF, Kanazi GE, Bleik JH. A sin gle dose of propofol at the end of surgery for the prevention of emergence agitation in children undergoing strabismus surgery dur ing sevoflurane anesthesia. Anesthesiology 2007;107(5):733–8. 14. Nitahara K, Sugi Y, Higa K, Shono S, Hamada T. Neuromuscular effects of sevo flurane in myasthenia gravis patients. Br J Anaesth 2007;98(3):337–41. 15. Turillazzi E, D’Errico S, Neri M, Riezzo I, Fineschi V. A fatal case of fulminant hepatic necrosis following sevoflurane anesthesia. Toxicol Pathol 2007;35(6):840–5. 16. Bonciu M, de la Chapelle A, Delpech H, Depret T, Krivosic-Horber R, Aime MR. Minor increase of endtidal CO2 during
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sevoflurane-induced malignant hyperther mia. Paediatr Anaesth 2007;17(2):180–2. 17. Phadke A, Broadman LM, Brandom BW, Ozolek J, Davis PJ. Postoperative hyperther mia, rhabdomyolysis, critical temperature, and death in a former premature infant after his ninth general anesthetic. Anesth Analg 2007;105(4):977–80. 18. Gash DM, Rutland K, Hudson NL, Sullivan PG, Bing G, Cass WA, Pandya JD, Liu M, Choi DY, Hunter RL, Gerhardt GA, Smith CD, Slevin JT, Prince TS. Trichloroethylene: parkinsonism and complex 1 mitochondrial neurotoxicity. Ann Neurol 2008;63 (2):184–92. 19. Takaki A, Suzuki H, Iwasaki Y, Takigawa T, Ogino K, Matsuda H, Yagi T, Hanazaki M, Nakatsuka H, Katayama H, Matsumi M, Shoji B, Terada R, Kobashi H, Sakaguchi K. A 27-year-old man who died of acute liver failure probably due to trichloroethylene abuse. J Gastroenterol 2008;43(3):239–42. 20. Carrieri M, Magosso D, Piccoli P, Zanetti E, Trevisan A, Bartolucci GB. Acute, nonfatal intoxication with trichloroethylene. Arch Toxicol 2007;81(7):529–32. 21. Singer MA, Lazaridis C, Nations SP, Wolfe GI. Reversible nitrous oxide-induced myelo neuropathy with pernicious anemia: case report and literature review. Muscle Nerve 2008;37(1):125–9. 22. Krajewski W, Kucharska M, Pilacik B, Fob ker M, Stetkiewicz J, Nofer JR, WronskaNofer T. Impaired vitamin B12 metabolic status in healthcare workers occupationally exposed to nitrous oxide. Br J Anaesth 2007;99(6):812–8. 23. Coburn M, Kunitz O, Apfel CC, Hein M, Fries M, Rossaint R. Incidence of postoperative nausea and emetic episodes after xenon anesthesia compared with propofol-based anesthesia. Br J Anaesth 2008;100(6):787–91. 24. Apfel CC, Korttila K, Abdalla M, Kerger H, Turian A, Vedder I, Zernak C, Danner K, Jokela R, Pocock SJ, Trenkler S, Kredel M, Biedler A, Sessler DI, Roewer N: IMPACT Investigators. A factorial trial of six interven tions for the prevention of postoperative nausea and vomiting. N Engl J Med 2004;350(24):2441–51.
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25. Combeer A. Complete atrioventricular block following etomidate. Eur J Anesthesiol 2007;24(12):1067–8. 26. Stowe DF, Bosnjak ZJ, Kampine JP. Com parison of etomidate, ketamine, midazolam, propofol, and thiopental on function and metabolism of isolated hearts. Anesth Analg 1992;74(4):547–58. 27. Kuczkowski KM, Hastings BH. Severe myoclo nus prior to electroconvulsive therapy following intravenous etomidate. AANA J 2007;75(2):88. 28. Huter L, Schreiber T, Gugel M, Schwarzkopf K. Low-dose intravenous midazolam reduces etomidate-induced myoclonus: a prospective, randomized study in patients undergoing elective cardioversion. Anesth Analg 2007;105(5):1298–302. Table of contents. 29. Griffeth BT, Mehra A. Etomidate and unpredicted seizures during electroconvul sive therapy. J ECT 2007;23(3):177–8. 30. Hildreth AN, Mejia VA, Maxwell RA, Smith PW, Dart BW, Barker DE. Adrenal suppres sion following a single dose of etomidate for rapid sequence induction: a prospective ran domized study. J Trauma 2008;65(3):573–9. 31. Vinclair M, Broux C, Faure P, Brun J, Genty C, Jacquot C, Chabre O, Payen JF. Duration of adrenal inhibition following a single dose of etomidate in critically ill patients. Inten sive Care Med 2008;34(4):714–9. 32. Annane D, Sebille V, Troche G, Raphael JC, Gajdos P, Bellissant E. A 3-level prognostic classification in septic shock based on corti sol levels and cortisol response to corticotro pin. J Am Med Assoc 2000;283(8):1038–45. 33. Bendel S, Ruokonen E, Polonen P, Uusaro A. Propofol causes more hypotension than etomidate in patients with severe aortic ste nosis: a double-blind, randomized study com paring propofol and etomidate. Acta Anesthesiol Scand 2007;51(3):284–9. 34. Lundy JB, Slane ML, Frizzi JD. Acute adre nal insufficiency after a single dose of etomi date. J Intensive Care Med 2007;22(2):111–7. 35. Ganesh A, Audu P. Hyperosmolar, increased-anion-gap metabolic acidosis and hyperglycemia after etomidate infusion. J Clin Anesth 2008;20(4):290–3. 36. Valladolid G, Varon J. Etomidate infusion: a cause of hyperglycemia? J Clin Anesth 2008;20(4):245–6.
258 37. Willman EV, Andolfatto G. A prospective evaluation of ‘ketofol’ (ketamine/propofol combination) for procedural sedation and analgesia in the emergency department. Ann Emerg Med 2007;49(1):23–30. 38. Erk G, Ornek D, Donmez NF, Taspinar V. The use of ketamine or ketamine–midazo lam for adenotonsillectomy. Int J Pediatr Otorhinolaryngol 2007;71(6):937–41. 39. Erhan OL, Goksu H, Alpay C, Bestas A. Ketamine in post-tonsillectomy pain. Int J Pediatr Otorhinolaryngol 2007;71(5):735–9. 40. Jonnavithula N, Kulkarni DK, Ramachan dran G. Prolonged apnea with intramuscular ketamine: a case report. Paediatr Anaesth 2008;18(4):330–1. 41. Webb AR, Skinner BS, Leong S, Kolawole H, Crofts T, Taverner M, Burn SJ. The addi tion of a small-dose ketamine infusion to tramadol for postoperative analgesia: a dou ble-blinded, placebo-controlled, randomized trial after abdominal surgery. Anesth Analg 2007;104(4):912–7. 42. Galinski M, Dolveck F, Combes X, Limoges V, Smaïl N, Pommier V, Templier F, Catineau J, Lapostolle F, Adnet F. Management of severe acute pain in emergency settings: ketamine reduces morphine consumption. Am J Emerg Med 2007;25(4): 385–90. 43. McKay WP, Donais P. Bowel function after bowel surgery: morphine with ketamine or pla cebo; a randomized controlled trial pilot study. Acta Anesthesiol Scand 2007;51(9): 1166–71. 44. Shahani R, Streutker C, Dickson B, Stewart RJ. Ketamine-associated ulcerative cystitis: a new clinical entity. Urology 2007;69(5):810–2. 45. Nishikawa K, Yoshida S, Shimodate Y, Igar ashi M, Namiki A. A comparison of spinal anesthesia with small-dose lidocaine and general anesthesia with fentanyl and propo fol for ambulatory prostate biopsy proce dures in elderly patients. J Clin Anesth 2007;19(1):25–9. 46. Baumert JH, Hein M, Hecker KE, Satlow S, Neef P, Rossaint R. Xenon or propofol anesthesia for patients at cardiovascular risk in non-cardiac surgery. Br J Anaesth 2008;100(5):605–11. 47. Wakita R, Takahashi M, Ohe C, Kohase H, Umino M. Occurrence of intermittent Wolff-Parkinson-White syndrome during intravenous sedation. J Clin Anesth 2008;20 (2):146–9.
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48. Choi SH, Lee SJ, Kim SH, Kim JH, Kwon HH, Shin YS, Lee KY. Single bolus of intra venous ketamine for anesthetic induction decreases oculocardiac reflex in children undergoing strabismus surgery. Acta Anesthesiol Scand 2007;51(6):759–62. 49. Weaver CS, Hauter WE, Brizendine EJ, Cordell WH. Emergency department proce dural sedation with propofol: is it safe? J Emerg Med 2007;33(4):355–61. 50. Anghelescu DL, Burgoyne LL, Liu W, Han kins GM, Cheng C, Beckham PA, Shearer J, Norris AL, Kun LE, Bikhazi GB. Safe anesthesia for radiotherapy in pediatric oncology: St. Jude Children’s Research Hos pital Experience, 2004–2006. Int J Radiat Oncol Biol Phys 2008;71(2):491–7. 51. Cheung KW, Watson ML, Field S, Campbell SG. Aspiration pneumonitis requiring intu bation after procedural sedation and analge sia: a case report. Ann Emerg Med 2007;49 (4):462–4. 52. Bell A, Treston G, McNabb C, Mony penny K, Cardwell R. Profiling adverse respiratory events and vomiting when using propofol for emergency department procedural sedation. Emerg Med Australas 2007;19(5):405–10. 53. Dunn T, Mossop D, Newton A, Gammon A. Propofol for procedural sedation in the emergency department. Emerg Med J 2007;24(7):459–61. 54. Crea F, Ruggiero A, Genovese O, Tortorolo L, Zorzi G, Chiaretti A. Safety and efficacy of two protocols for sedation in pediatric oncology procedures. Central Eur J Med 2008;3(1):77–82. 55. Zeiler SR, Kaplan PW. Propofol withdrawal seizures (or not). Seizure 2008;17(7):665–7. 56. Brown LA, Levin GM. Role of propofol in refractory status epilepticus. Ann Pharmaco ther 1998;32(10):1053–9. 57. Snow KA, Clements EA, Eppert AJ, Judge BS. Antimuscarinic syndrome after propofol administration in the emergency department. J Emerg Med 2007;33(1):29–32. 58. Steinmetz J, Holm-Knudsen R, Eriksen K, Marxen D, Rasmussen LS. Quality differ ences in postoperative sleep between propo fol-remifentanil and sevoflurane anesthesia in infants. Anesth Analg 2007;104(4):779–83. 59. Seidl S, Hausmann R, Neisser J, Janisch HD, Betz P. Severity and duration of mental
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61.
62.
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deficiency symptoms after intravenous administration of propofol. Int J Legal Med 2007;121(4):281–5. Cravens GT, Packer DL, Johnson ME. Inci dence of propofol infusion syndrome during noninvasive radiofrequency ablation for atrial flutter or fibrillation. Anesthesiology 2007;106(6):1134–8. Zarovnaya EL, Jobst BC, Harris BT. Propo fol-associated fatal myocardial failure and rhabdomyolysis in an adult with status epi lepticus. Epilepsia 2007;48(5):1002–6. Rosen DJ, Nicoara A, Koshy N, Wedder burn RV. Too much of a good thing? Tracing the history of the propofol infusion syn drome. J Trauma 2007;63(2):443–7. Rozet I, Lam AM. Propofol infusion syn drome or probable overinterpretation syn drome? Anesthesiology 2008;108(2):330. Author reply 331–2.
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64. Chia YY, Lee SW, Liu K. Propofol causes less postoperative pharyngeal morbidity than thiopental after the use of a laryngeal mask airway. Anesth Analg 2008;106 (1):123–6. 65. Bouchard PM, Frenette AJ, Williamson DR, Perreault MM. Thiopental-associated dys kalemia in severe head trauma. J Trauma 2008;64(3):838–42. 66. Nordstrom CH, Messeter K, Sundbarg G, Schalen W, Werner M, Ryding E. Cerebral blood flow, vasoreactivity, and oxygen con sumption during barbiturate therapy in severe traumatic brain lesions. J Neurosurg 1988;68(3):424–31. 67. Friederich P, Urban BW. Interaction of intravenous anesthetics with human neuro nal potassium currents in relation to clinical concentrations. Anesthesiology 1999;91 (6):1853–60.
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11
Local anesthetics
GENERAL Management of adverse drug reactions to local anesthetics with lipid emulsion Publications on the use of lipid emulsion as a rescue medication for local anesthetic toxi city, discussed in detail in SEDA 31 (p. 231), continue to appear; increasingly lipid emulsion is reported to be used early in cases of toxicity. This is not surprising, as local anesthetic-induced cardiotoxicity is a serious complication of regional anesthesia, for which no specific treatment was previously available. In a report of severe dysrhythmias induced by bupivacaine toxicity, administra tion of Intralipid within 3 minutes of the onset of the dysrhythmias resulted in restora tion of sinus rhythm and spontaneous circulation (1A). In another report the use of Intralipid has been described in a patient with cardio vascular and nervous system toxicity due to combined use of mepivacaine and prilo caine (2A). • A 91-year-old man (57 kg, 156 cm, ASA III) received an infraclavicular brachial plexus block for surgery for olecranon bursitis, and 20 minutes after injection of 30 ml of mepiva caine 1% and 5 minutes after axillary supple mentation with 10 ml of prilocaine 1%, he developed nervous system symptoms (agita tion, dizziness, then unresponsiveness to
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32011-3 2010 Elsevier B.V. All rights reserved.
verbal commands) and supraventricular extra beats with bigeminy. He was given 20% Intralipid 200 ml by infusion and his symptoms disappeared within 5 and 15 minutes. He then underwent the scheduled procedure uneventfully.
Intralipid has also been used to treat dys rhythmias in a child (3A). • A 13-year-old girl scheduled for knee surgery under general anesthesia with posterior lumbar plexus block using a combination of lidocaine and ropivacaine developed a ventricular dysrhythmia 15 minutes after local anesthetic injection. Intralipid 20% converted the ventricular dysrhythmia to sinus rhythm.
The use of Intralipid in pregnancy has again been reported (4A). • An 18-year-old primigravida at 38 weeks ges tation had a lumbar epidural catheter for analgesia during labor. After a test dose to detect intravascular or spinal placement, she needed an emergency Cesarean section. Within 90 seconds after an anesthetic top-up she became restless and agitated and no longer obeyed commands. Within 30 seconds of a bolus dose of Intralipid 20%, she regained full consciousness and an uneventful emergency Cesarean delivery was performed.
Intralipid has also been used successfully to treat seizures and cardiovascular collapse caused by levobupivacaine toxicity (5A). In a survey of consultant-led labor wards in the UK, replies from 195 (86%) of the labour wards showed that only in 40% of the 107 wards with treatment guidelines was lipid emulsion included. Lipid emulsion was readily available on only 95 labor wards (49%) (6C). The increasing use of Intralipid and other lipid emulsions for the treatment of local anesthetic toxicity has led to a discussion of its safety. While there are many potential
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adverse effects, only allergic reactions, including anaphylaxis (in particular due to soy bean oil), are a concern with acute shortterm use for this indication (7R). There is therefore no reason to withhold lipid emul sion treatment in severe local anesthetic toxi city, and the authors of this review repeated the previous recommendation that lipid emulsion should be readily available in all locations in which regional anesthesia is performed.
Immunologic True immunological reactions to local anesthetics are rare and account for less than 1% of all adverse reactions. • A 25-year-old woman had bupivacaine, lidocaine, and methylprednisolone acetate infiltrated for the third time for back pain (8A). She developed a vagal reaction followed by a pruriginous rash, tongue edema, and severe bronchospasm, requiring adrenaline and intubation. She was atopic, with allergy to multiple pollens, animals, possibly kiwi, and also penicillin and sulphonamides. She had positive skin prick tests to lidocaine, bupivacaine, and procaine.
Three patients developed localized edema after dental anesthesia with various local anesthetics (9A). All had negative tests on evaluation at 1 hour, but positive patch tests with delayed swelling at 24 and 48 hours after challenge. The authors recom mended that patients who react to multi ple amide anesthetics, who have delayed swelling or who have a history of severe contact dermatitis should be screened for features and susceptibility factors asso ciated with type IV reactions. They also reiterated that patients who react to ben zocaine can tolerate lidocaine and that lidocaine-allergic individuals can tolerate ester anesthetics. Drug–drug interactions Halothane In animals, administration of general anesthesia with halothane significantly altered the regional and whole-body pharmacokinetics of six commonly used amide local anesthetics (10E). In another animal study general anesthesia led to more
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severe cardiovascular depression by these local anesthetics, but improved survival in toxic episodes (11E).
EFFECTS RELATED TO MODES OF USE (SED-15, 2121; SEDA-29, 135; SEDA-30, 152; SEDA-31, 233)
Brachial plexus anesthesia Nervous system Horner’s syndrome (a triad of miosis, ptosis, and enophthalmos, associated with vasodilatation and anhidro sis), which can occur as a complication of brachial plexus anesthesia, is caused by blockade of the ipsilateral sympathetic cervi cal chain (stellate ganglion). Interscalene and supraclavicular blocks of the brachial plexus are the main techniques associated with this syndrome. Late Horner’s syndrome has been reported during postoperative continuous infraclavicular brachial plexus analgesia (12A). • A 33-year-old healthy woman (55 kg, 170 cm) was given analgesia via a continuous infraclavicular brachial plexus catheter after osteosynthesis of a complex fracture of the elbow. On the second postoperative night, about 50 hours after catheter placement, she developed nasal congestion. She had classical Horner’s syndrome and the perineural infusion was stopped (568 ml of 0.2% ropivacaine in all). The Horner’s syndrome vanished about 2 hours later.
The authors assumed that the delayed presentation had been due either to accu mulation of solution during the infusion or to atypical proximal migration of the solution to the supraclavicular paraverteb ral area. In another rather unusual case, a patient developed motor and sensory blockade in all four limbs, other than the ipsilateral arm, after an axillary brachial plexus block (13A). Epidural blockade was suspected after ruling out nervous system events such as a stroke.
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CAUDAL, EPIDURAL, AND SPINAL ANESTHESIA Caudal anesthesia Cardiovascular During administration of a test dose of bupivacaine and adrenaline to exclude intravascular injection, the recommended signs to look for are increased amplitude of the electrocardiographic T wave by 25% or an increased heart rate by more than 10/minute. In three children there were no changes in the electrocardiogram or heart rate, despite intravascular administra tion (14A). The authors offered a range of possible explanations, including too low a dose of adrenaline, too short a time taken to assess the effect of the test dose or lack of atropine pretreatment. They also recommended repeated aspiration during injection, as in all three cases blood could be aspirated with this approach.
Epidural anesthesia Nervous system Trigeminal nerve palsy has been reported on a few occasions after lumbar epidural anesthesia. Horner’s syndrome is also a rare complication of epidural blockade, but it is more common in obstetric patients (0.4–5%). There has been a report that subdural placement of an epidural catheter caused both of these complications (15A). The subdural space is a potential space containing a small volume of serous fluid between the dura mater and arachnoid mater, and in this case the authors confirmed the subdural position of the catheter by repeat injection and epidurography.
Spinal (intrathecal) anesthesia Nervous system Trigeminal nerve involve ment and Horner’s syndrome are rare complications of spinal anesthesia (16A). • A 28-year-old healthy woman received spinal anesthesia with bupivacaine 8.5 mg and fentanyl 20 micrograms for elective Cesarean
263 delivery. Sensory block at the level of T4 was achieved and surgery proceeded without complications. An hour later, she developed a left-sided Horner’s syndrome, a runny nose, lacrimation, and conjunctival injection on the contralateral side. Both the Horner’s syndrome and the contralateral trigeminal parasympa thetic manifestations resolved spontaneously within 8 hours.
Recurrence of spinal anesthesia has previously been reported. It has been specu lated that pooled hyperbaric lidocaine can remix with the cerebrospinal fluid through Valsalva manoeuvres that precede rises in the sensory levels. In a newly reported case spinal anesthesia recurred without an asso ciated Valsalva manoeuvre (17A). • Two hours after induction of spinal anesthesia for knee arthroscopy in a 66-year-old man, his motor strength returned to the legs. When his head was raised to 30 degrees, his legs became weak and he became hypotensive. One hour later, his strength returned.
The authors speculated that the reappear ance of spinal anesthesia may have been secondary to remixing of the cerebrospinal fluid with the pooled local anesthetic or transfer of the local anesthetic from the subdural to the subarachnoid space with movement of the patient. Spinal myoclonus, presenting as sudden involuntary muscle contractions, is usually caused by spinal cord pathology. However, it can also be induced by intrathecal drug administration, including spinal anesthesia (18A, 19A). • A 53-year-old Caucasian woman with no history of neurological disease had spinal anesthesia with 2.5 ml bupivacaine heavy and diamorphine 300 micrograms for surgical repair of a cystocele and uterine prolapse. Previous general and spinal anesthesia had been uneventful. Three hours after successful spinal anesthesia and surgery, she developed bilateral myoclonus of the legs, which resolved completely with midazolam 4 mg within 30 minutes. The total duration of myoclonus was 2 hours. Follow-up for 3 days and then after 10 days revealed no myoclonus or other neurology. Laboratory results were normal, except for a low serum vitamin B12 concentration 191 ng/l (reference range 200–900 ng/l). • A patient of unknown age and sex had spinal anesthesia with 0.5% hypobaric bupivacaine
264 2.5 ml for excision of a Baker’s cyst. One hour later the patient developed myoclonic move ments in both legs, and surgery was inter rupted. The myoclonus was not responsive to diazepam 20 mg and thiopental 175 mg, but resolved after recovery from spinal anesthesia 50 minutes later. Later investiga tions, including neurological examination, electromyography, and electroencephalography, were normal.
The authors found no obvious explanation for this complication, although the authors of the first case speculated about a contribu tion of chronic glucocorticoid therapy or vitamin B12 deficiency. They also suggested midazolam as the treatment of choice. Complications of spinal anesthesia include transient urinary incontinence (20A); how ever, a report of permanent urinary incon tinence is more disconcerting (21A). • A 70-year-old woman with no relevant medical history received spinal anesthesia in the sitting position via a 22-gauge Quincke spinal needle at the L3–4 interspace (0.5% hyperbaric bupivacaine, no volume specified) for hammer toe surgery. After sensory and motor recovery, she continued to complain of urinary incontinence, which persisted for more than 2 years.
The authors assumed that nerve root toxi city due to hyperbaric local anesthesia had caused the complication.
Dental anesthesia Cardiovascular In 54 patients with coronary artery disease undergoing dental extraction under local anesthesia randomized to two groups with and without adrenaline 1:100 000 (22c), three had ST segment depression after administration of adrena line and two others had increased CK-MB activity. Surprisingly, the authors concluded that dental extraction performed under local anesthesia with 1:100000 adrenaline does not imply additional ischemic risks. Nervous system Inferior alveolar blockade is commonly used in dental practice. However, a rare case of upper lip blanching
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with temporary lateral rectus nerve palsy, leading to diplopia, has been reported (23A).
Infiltration anesthesia Death Tumescent local anesthesia (the subcutaneous infusion of large volumes of diluted local anesthetic with adrenaline) is widely used to provide anesthesia for cosmetic procedures, in particular liposuction. However, severe complications, including fatalities, have been reported (24A). • A 38-year-old woman underwent liposuction under tumescent local anesthetic infusion of unspecified amounts of lidocaine and mepiva caine as an outpatient. After 30 minutes she developed generalized seizures and then asys tole; resuscitation was unsuccessful. Heart blood concentrations of lidocaine and mepivacaine were 4.9 and 16 mg/l respectively.
Local anesthetic toxicity was determined as the cause of death; a legal finding of invo luntary homicide due to gross negligence was made. Management of adverse drug reactions The authors of a systematic review aimed to establish whether warming local anesthetic solutions reduces pain on injection (25M). They concluded, based on the best evidence available, that warming local anesthetics, either alone or in combination with buffering, does significantly reduce the pain of local infiltration.
Interpleural anesthesia Cardiovascular Continuous infusion of local anesthetics via an interpleural catheter can be used to provide effective postoperative pain relief after breast surgery. Bradycardia and asystole have been reported with this technique (26A). • An otherwise fit 51-year-old woman had an elective free transverse rectus abdominis myo cutaneous (TRAM) flap breast reconstruction following right mastectomy, with interpleural
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administration of bupivacaine þ adrenaline for postoperative analgesia. On the first postopera tive day she developed symptomatic bradycardia leading to hypotension, which progressed to asystole. The electrocardiogram showed thirddegree block with ventricular arrest, which was treated with a temporary pacemaker.
No cardiac abnormalities were found, and it was assumed that these symptoms reflected local anesthetic toxicity.
Intravenous regional anesthesia Immunologic In intravenous regional anesthesia a tourniquet is used to restrict blood flow to an exsanguinated limb, which is then injected with a local anesthetic. Prilocaine is the drug of choice with regard to cardiovascular safety. However, allergic reactions can occur (27A). • In a 60-year-old woman intravenous regional anesthesia was induced with 0.5% prilocaine 3 mg/kg diluted with saline to a total of 40 ml for surgical treatment of carpal tunnel syndrome. Laboratory tests were normal and she had no history of allergic reactions. Severe erythema and edema developed in the whole limb below the tourniquet within 2–3 minutes. After intravenous hydrocortisone, tourniquet cuff deflation 20 minutes later, and postponement of the operation, the skin symptoms disappeared within an hour. There were no reaction symptoms above the level of the tourniquet, nor systemic effects after removal of the tourniquet. Three weeks later a skin prick test to 0.5% prilocaine was slightly positive. Intradermal injection of 0.5% prilocaine resulted in an immediate erythematous wheal 1 cm in diameter.
Obstetric anesthesia Fetotoxicity Neonatal intoxication from local anesthetics administered by pudendal nerve block to the mother has been reported with lidocaine in three neonates, who developed hypotonia, pupillary mydriasis fixed to light, apnea, cyanosis, and seizures; two required mechanical ventilation (28A). In all three cases recovery was complete.
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Ocular anesthesia Nervous system The use of local anes thetics for cataract surgery and the inci dence of serious complications have been surveyed in a prospective 13-month study of routine practice in the UK (29C). Cataract surgery was performed under gen eral anesthesia in only 4.1% of cases; local anesthesia without sedation was used in 92%, with sedation in 3.9%. Of an esti mated 375000 operations performed under local anesthesia, 43% were sub-Tenon’s blocks, 31% were peribulbar, 11% topical– intracameral, 9.9% topical, 3.5% retrobul bar, and 1.7% subconjunctival. Of eight neurological complications consistent with brainstem anesthesia, seven occurred with peribulbar or retrobulbar local anesthesia. The authors suggested that because there is a lower rate of reported serious complica tions with sub-Tenon’s, topical, and topical– intracameral administration, these methods may be preferable for routine cataract surgery. Brainstem anesthesia as a complication of retrobulbar block has again been described (30A). • A 75-year-old man received 0.5% bupivacaine 4 ml for retrobulbar block. He immediately became unresponsive, apneic, tachycardic, and hypertensive, and had seizures. He was resuscitated and intubated. He recovered fully by day 4.
This case illustrates the need for access to resuscitation equipment and properly trained personnel, when such blocks are performed, in particular in day-case surgical centers. Sub-Tenon’s block is increasingly becom ing the local anesthetic technique of choice for many ophthalmic surgical procedures, in particular ambulatory cataract surgery. In a double-blind, randomized, controlled study of the effect of warming the local anesthetic solution before sub-Tenon’s block in 140 patients, who were randomly allocated to local anesthetic either stored at room tem perature or warmed to 37°C, there was no significant difference in pain scores between the two groups (31C).
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Hematologic Sub-Tenon’s anesthesia is widely regarded as safe, and prospective studies have failed to show significant blockrelated complications, even in patients taking oral anticoagulants. However, retrobulbar hemorrhage as a result of sub-Tenon’s block in a patient taking oral anticoagulants has been reported (32A).
The authors assumed that the factors that contributed to this complication were the relatively large volume of a high concentra tion of bupivacaine and pressure applied above the point of injection.
• A 45-year-old woman with type 1 diabetes taking clopidogrel and aspirin had a sub Tenon’s block for vitrectomy and 5 minutes later described intense pain and nausea. Retrobulbar hemorrhage was diagnosed and treated by emergency lateral canthotomy and inferior cantholysis. This led to an immediate reduction in her pain and nausea and normalization of the intraocular pressure.
INDIVIDUAL COMPOUNDS
It has been suggested that the Sandwell technique (using the soft plastic sheath of an intravenous cannula to deliver a local anesthetic into the sub-Tenon space) minimizes hemorrhagic complications (33r). The authors hypothesized that this approach prevents injury to blood vessels in a highly vascular region during an essen tially blind procedure. Death Despite the perceived safety of sub-Tenon’s block, death has been reported (34A). • An 82-year-old patient had a generalized tonic–clonic seizure and then refractory ventricular fibrillation 1 minute after injection of local anesthetic for sub-Tenon’s block. Resuscitation was unsuccessful. Severe triple vessel coronary artery disease was found at post-mortem.
Peripheral nerve block Nervous system Concurrent femoral nerve block after ilioinguinal nerve block is rare, but can occur (35A). • A 63-year-old man had an ilioinguinal nerve block with 0.5% plain bupivacaine 20 ml after induction of general anesthesia for inguinal hernia repair as a day case. Four hours later, he continued to be unable to bear weight and could not be discharged. He recovered completely over 36 hours.
Articaine
(SED-15, 348; SEDA-30, 158)
Cardiovascular The cardiovascular safety profiles of 4% articaine 1.8 ml with adrenaline 1:200 000 or 2% lidocaine with adrenaline 1:100 000 for dental treatment have been compared in a randomized study in 50 patients with cardiovascular risk factors (36c). There were no severe adverse effects and no differences in any measurements. Nervous system A literature search to appraise the safety and suitability of articaine as a substitute for lidocaine (37R) has confirmed the role of articaine as an effective and well-tolerated anesthetic for dental use, but highlighted a potential, as yet unproven, risk of neurotoxicity of articaine 4%.
Benzocaine
(SED-15, 427; SEDA-30, 158; SEDA-31, 239) Hematologic Methemoglobinemia EIDOS classification: Extrinsic moiety: Benzocaine
Intrinsic moiety: Hemoglobin
Distribution: Erythrocytes
Outcome: Oxidation of iron in
hemoglobin
Sequela: Methemoglobinemia due to
benzocaine
DoTS classification: Dose-relation: Hypersusceptibility
Time-course: Immediate
Susceptibility factors: Sepsis, anemia
Methemoglobinemia, a well-known adverse effect of benzocaine, can be fatal. Of 28 478
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patients undergoing transesophageal echocar diography at the Mayo Clinic under topical local anesthesia with benzocaine, there were 19 patients with methemoglobinemia (1 in 1500), 18 of whom were treated with methylthioninium chloride; all had a good outcome (38C). Susceptibility factors were sepsis, anemia, and hospitalization; the authors recommended avoidance of benzo caine in such patients. There have been other reports of methe moglobinemia after the use of a topical anesthetic spray containing benzocaine (39A), including oral spray (40A). The authors of the latter report suggested that the suspicion of methemoglobinemia should be raised if the arterial blood gas with a normal partial pressure of oxygen is incon sistent with a low-pulse oximeter reading and with the physical appearance of the patient. The appropriateness of this has been confirmed in another case (41A). • A 23-year-old woman with temporomandibular joint pain had fiberoptic intubation while awake for intermedullary maxillary fixation using benzocaine topical anesthesia. Her oxygen saturation on pulse oximetry remained in the range of 91–93% despite ventilation with 100% oxygen and cyanosis of the lips and nail beds. Based on the clinical signs and blood gas analysis, methemoglobinemia was diagnosed.
Bupivacaine
(SED-15, 568; SEDA-30, 159; SEDA-31, 239)
Cardiovascular Bupivacaine cardiac toxicity mimicking an acute non-ST segment elevation myocardial infarction has been reported (42A). • A healthy young woman was given a spinal anesthetic with bupivacaine 6 mg for hemor rhoidectomy, and she immediately developed hypotension and an accelerated idioventricular rhythm, with ST segment depression. Trans thoracic echocardiography showed a reduced left ventricle systolic ejection fraction (about 27%), regional wall motion abnormality of the left ventricle and increased cardiac markers. The presentation mimicked a non-ST segment elevation myocardial infarction. She improved gradually and 7 days later had normal cardiac function and normal coronary angiography.
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The authors assumed that a direct effect of bupivacaine on the myocardium had caused this presentation, although this seems extre mely unlikely after a dose of 6 mg given intrathecally. Immunologic There has been a report of delayed type IV hypersensitivity to bupiva caine (43A). • A 33-year-old woman developed an eczem atous reaction 3 days after continuous lumbar epidural analgesia with bupivacaine 0.075% during labour. The skin responded to topical steroids. A patch test 4 months later was positive to bupivacaine.
Lidocaine
(SED-15, 2051; SEDA-30, 160; SEDA-31, 240) Nervous system Seizures in a 3-month-old boy occurred after an overdose of lidocaine for circumcision (44A).
Hematologic Methemoglobinemia is a common adverse effect of prilocaine (see also benzocaine above). In a retrospective cohort study of 50 children aged 3–31 months undergoing infiltration anesthesia of the scalp before craniofacial surgery, lidocaine 1% with adrenaline caused this complication in 10 children (45c). The methemoglobin concentrations were low and in the range 2.2–18% (median 6%). In eight children, the methemoglobinemia resolved spontaneously within 12 hours. Only two children were given methyl thioninium chloride (methylene blue). No cause other than lidocaine could be identified. There was no correlation between the dose of lidocaine and the occurrence of methemoglobinemia. Immunologic True type I hypersensitivity to lidocaine is extremely unusual, but a report of such a reaction has been published (46A). Reports of allergic contact dermatitis and other delayed type IV hypersensitivity
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reactions are almost always related to ester local anesthetics, and rarely to amide local anesthetics such as lidocaine. Contact dermatitis to lidocaine has been reported in 16 patients aged 28–77 years (47c). The der matitis involved the hands or the hands and feet in eight, the arms in three, and the face and the groin in one case each; it was dis seminated in five patients. Drug overdose A rare case of suicide in a 31-year-old woman after oral ingestion of lidocaine is reported (48A). Lidocaine concentrations were extremely high: blood 31 g/l, gastric contents 2.5 g, liver 10 mg/g, kidney 12 mg/g, brain 9 mg/g, spleen 24 mg/ g, lung 84 mg/g, heart 9 mg/g, urine 9 g/l, and bile 6 g/l. No other drugs or alcohol were detected.
Mepivacaine
(SED-15, 2256;
SEDA-30, 160) Immunologic A type I hypersensitivity reaction to mepivacaine has been reported (49A). • A 31-year-old woman received mepivacaine 66 mg for dental anesthesia and within a few minutes developed intense pruritus of her hands and feet accompanied by erythema and swelling of the hands and nausea. These symptoms responded to parenteral and oral antihistamines. An in vitro test specific for IgE against mepivacaine was positive.
Prilocaine and EMLA® (prilocaine þ lidocaine)
(SED-15, 2916; SEDA-31, 240) Cardiovascular An unusual case of cardiovascular collapse as a result of topical local anesthetic administration has been reported (50A). • In a 37-year-old woman the use of EMLA cream on intact, non-inflamed skin before planned laser hair removal in a circum scribed area measuring 5 5 cm on her left cheek resulted in tinnitus, perioral tingling,
Stephan A. Schug and Hari Krshnan
and cyanosis after 30 minutes. Despite thor ough washing of the skin with saline and distilled water, she developed a dys rhythmia and then cardiovascular collapse. Methemoglobinemia was confirmed and she recovered completely.
Hematologic Prilocaine continues to be linked to methemoglobinemia, in particular in infants (see also benzocaine above). • A 42-day-old boy developed cyanosis after receiving local anesthesia with prilocaine for circumcision (51A). The methemoglobin concentration was 45%. The cyanosis resolved after intravenous administration of ascorbic acid. • A 28-day-old girl developed fever and was scheduled for lumbar puncture, in preparation for which EMLA cream was applied to her lower back and covered by a gauze pad (52A). However, as there were no other findings, lumbar puncture was not performed. She developed cyanosis 18 hours later, and pulse oximetry showed a saturation of 88%, which did not improve with oxygen supplementation. Discrepancies in the arterial blood gas analysis led to a diagnosis of methemoglobinemia. Treatment with methylthioninium chloride was successful.
Despite the known risk and the recommen dation that prilocaine should not be used in children under 3 months of age, it continues to be used for procedures in neonates. Skin While EMLA cream is widely used to reduce procedural pain related to leg ulceration, progression of necrotic ulcers after application has been reported (53A). • EMLA cream was applied topically in a 63-year-old woman with leg ulcers before wound debridement and 90 minutes later a hemorrhagic livid margin developed around the ulcer, which turned necrotic over days.
The authors regarded this observation as a pathological reaction of the small cutaneous blood vessels to EMLA cream, possibly aggravated by a connective tissue disease with microvascular involvement. They advised caution when using EMLA cream to treat patients with a known disorder of the microcirculation.
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Drug–drug interactions Barbiturates Methemoglobinemia has been reported after a rather low dose of prilocaine in an adult and associated with an interaction with a barbiturate (54A).
elevation of a1-acid glycoprotein concentra tions could have altered the pharmaco kinetics of ropivacaine and possibly contributed to unexpected toxicity.
• An 18-year-old woman received prilocaine 300 mg by subcutaneous infiltration to enable insertion of a halo frame, after she had received pentobarbital infusion for 7 days for increased intracranial pressure. Within minutes her arterial oxygen saturation on pulse oximetry fell to 88% and the methaemoglobin was 14%; the plasma pentobarbital concentration was 14 mg/l. She recovered after 6 hours with no treatment besides oxygen.
Death Death due to ropivacaine has been attributed to vascular disease, with insuffi cient cerebral perfusion during resuscitation after cardiac arrest (57A).
The authors assumed that enzyme induction by pentobarbital had resulted in increased formation of o-toluidine causing methemo globinemia.
Ropivacaine
(SED-15, 3078; SEDA-30, 161; SEDA-31, 240) Cardiovascular Ventricular tachycardia has been reported after epidural ropivacaine (55A).
• A 39-year-old primipara with an 11-year his tory of Takayasu’s disease had epidural anesthesia for an elective Cesarean section with 1% ropivacaine 20 ml, injected through an epidural catheter after a test dose. Within 22 minutes she developed pulseless ventricular tachycardia and a generalized seizure. Immediate defibrillation was successful and a healthy boy was delivered. There were no sequelae for mother and child.
Nervous system Nervous system toxicity of ropivacaine after ultrasound-guided interscalene block has been reported (56A). • A 76-year-old woman with multiple myeloma received ultrasound-guided interscalene plexus block with ropivacaine for open reduc tion and internal fixation after a pathological fracture of her left upper humerus. She devel oped nervous system toxicity 15 minutes after the injection, although the total ropivacaine plasma concentration was only 3.68 mg/l.
The authors speculated that advanced age, malnutrition, adrenaline, and possible
• A 45-year-old dialysis patient with significant vascular disease and a previous transient ischemic attack had a cardiac arrest 5 minutes after axillary plexus block with ropivacaine 190 mg, most probably due to accidental intra vascular injection. Despite successful resusci tation and return of spontaneous circulation within 20 minutes, the patient sustained severe hypoxic brain damage and died 18 days later.
Drug–drug interactions CYPD26 inhibitors Ropivacaine and one of its metabolites, pipecoloxylidide, inhibits CYP2D6 in human liver microsomes. The effect on CYP2D6 activity of continuous epidural infusion of ropivacaine 2 mg/ml at a rate of 14 ml/hour for 50 hours has been investigated (58C). CYP2D6 activity was inhibited in extensive metabolizers, but the effects were unlikely to be of major clinical importance.
Tetracaine
(SED-15, 3327; SEDA-30, 161; SEDA-31, 241) Susceptibility factors Genetic Malignant hyperthermia has been attributed to spinal anesthesia with tetracaine in a susceptible patient (59A).
• A 62-year-old man had spinal anesthesia with tetracaine 12 mg for transurethral resection of the prostate. Within 1 hour he developed tachypnea and generalized muscle rigidity, accompanied by tachycardia and fever. He lost consciousness and required cardiopulmon ary resuscitation. Malignant hyperthermia was diagnosed and he was given dantrolene. He responded within 1 hour and his vital parameters normalized. There were no sequelae.
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References 1. McCutchen T, Gerancher JC. Early Intralipid therapy may have prevented bupiva caine-associated cardiac arrest. Reg Anesth Pain Med 2008;33(2):178–80. 2. Whiteside J. Reversal of local anaesthetic induced CNS toxicity with lipid emulsion. Anaesthesia 2008;63(2):203–4. 3. Ludot H, Tharin JY, Belouadah M, Mazoit JX, Malinovsky JM. Successful resuscitation after ropivacaine and lidocaine-induced ventricular arrhythmia following posterior lumbar plexus block in a child. Anesth Analg 2008;106 (5):1572–4. 4. Spence AG. Lipid reversal of central nervous system symptoms of bupivacaine toxicity. Anesthesiology 2007;107(3):516–7. 5. Foxall G, McCahon R, Lamb J, Hardman JG, Bedforth NM. Levobupivacaine-induced seizures and cardiovascular collapse treated with Intralipid. Anaesthesia 2007;62(5):516–8. 6. Williamson RM, Haines J. Availability of lipid emulsion in obstetric anaesthesia in the UK: a national questionnaire survey. Anaesthesia 2008;63(4):385–8. 7. Brull SJ. Lipid emulsion for the treatment of local anesthetic toxicity: patient safety impli cations. Anesth Analg 2008;106(5):1337–9. 8. Caron AB. Allergy to multiple local anes thetics. Allergy Asthma Proc 2007;28 (5):600–1. 9. Melamed J, Beaucher WN. Delayed-type hypersensitivity (type IV) reactions in dental anesthesia. Allergy Asthma Proc 2007;28 (4):477–9. 10. Copeland SE, Ladd LA, Gu XQ, Mather LE. The effects of general anesthesia on whole body and regional pharmacokinetics of local anesthetics at toxic doses. Anesth Analg 2008;106(5):1440–9. 11. Copeland SE, Ladd LA, Gu XQ, Mather LE. The effects of general anesthesia on the cen tral nervous and cardiovascular system toxi city of local anesthetics. Anesth Analg 2008;106(5):1429–39. 12. Salengros JC, Jacquot C, Hesbois A, Vandesteene A, Engelman E, Pandin P. Delayed Horner’s syndrome during a contin uous infraclavicular brachial plexus block. J Clin Anesth 2007;19(1):57–9.
13. Shinn HK, Kim TJ, Lee CS, Cha YD, Eum SH, Ryu SH, Song JH. Motor and sen sory block of both upper and lower extremi ties following axillary brachial plexus block using a transarterial approach. Acta Anaes thesiol Scand 2007;51(4):514. 14. Timmerman L, Megens JH. Detecting intra vascular injection during caudal anaesthesia in children. Eur J Anaesthesiol 2007;24 (12):1060–2. 15. De la Gala F, Reyes A, Avellanal M, Baticon P, Gonzalez-Zarco LM. Trigeminal nerve palsy and Horner’s syndrome following epidural analgesia for labor: a subdural block? Int J Obstet Anesth 2007;16(2):180–2. 16. Lavi R. Spinal anesthesia for cesarean deliv ery associated with Horner’s syndrome and contralateral trigeminal parasympathetic activation. Anesth Analg 2007;104(2):462. 17. Deleon AM, Benzon HT, Eisenman TS, Doty Jr. RA, Newell B, McLaughlin K. A case report of reappearance of spinal anesthe sia. Reg Anesth Pain Med 2008;33(3): 271–2. 18. Alfa JA, Bamgbade OA. Acute myoclonus following spinal anaesthesia. Eur J Anaes thesiol 2008;25(3):256–7. 19. Lin CS, Wei-Hung C, Lee YW. Transient spinal myoclonus after spinal anaesthesia with bupivacaine in the perioperation period. Anaesthesist 2008;57(5):518. 20. Basaranoglu G, Comlekci M, Pekel AF, Kosker T, Inan B, Saitoglu L. Transient urin ary incontinence after subarachnoid anesthe sia with 0.5% heavy bupivacaine. Anesth Analg 2006;103(4):1051. 21. Di Genova E, D’Andrea G. Permanent urin ary incontinence after subarachnoid anesthe sia with 0.5% hyperbaric bupivacaine. Anesth Analg 2007;105(5):1517–8. 22. Conrado VC, de Andrade J, de Angelis GA, de Andrade AC, Timerman L, Andrade MM, Moreira DR, Sousa AG, Sousa JE, Piegas LS. Cardiovascular effects of local anesthesia with vasoconstrictor during dental extraction in coronary patients. Arq Bras Cardiol 2007;88(5):507–13. 23. Scott JK, Moxham BJ, Downie IP. Upper lip blanching and diplopia associated with local
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anaesthesia of the inferior alveolar nerve. Br Dent J 2007;202(1):32–3. Martinez MA, Ballesteros S, Segura LJ, Garcia M. Reporting a fatality during tumes cent liposuction. Forensic Sci Int 2008;178 (1):e11–6. Sultan J. Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. The effect of warming local anaesthetics on pain of infiltration. Emerg Med J 2007;24(11):791–3. Jagadeesan J, Kannan R, Dujon D. Ventri cular standstill: a complication of intrapleural anesthesia using bupivacaine in a patient with free transverse rectus abdominus myo cutaneous flap breast reconstruction. Ann Plast Surg 2007;59(4):445–6. Dogramaci Y, Dogramaci AC, Esen E, Korkmaz T. Severe allergic reactions to pri locaine during intravenous regional anesthe sia. Eur J Dermatol 2008;18(4):462–3. Pages H, de la Gastine B, Quedru-Aboane J, Guillemin MG, Lelong-Boulouard V, Guillois B. Intoxication néonatale à la lido caine après analgésie par bloc des nerfs honteux: à propos de trois observations. [Lidocaine intoxication in newborn following maternal pudendal anesthesia: report of three cases.] J Gynecol Obstet Biol Reprod (Paris) 2008;37(4):415–8. Eke T, Thompson JR. Serious complications of local anaesthesia for cataract surgery: a 1 year national survey in the United Kingdom. Br J Ophthalmol 2007;91(4):470–5. Dahle JM, Iserson KV. ED treatment of brainstem anesthesia after retrobulbar block. Am J Emerg Med 2007;25(1):105–6. Allen MJ, Bunce C, Presland AH. The effect of warming local anaesthetic on the pain of injection during sub-Tenon’s anaesthesia for cataract surgery. Anaesthesia 2008;63(3):276–8. Subbiah S, McGimpsey S, Best RM. Retro bulbar hemorrhage after sub-Tenon’s anesthesia. J Cataract Refract Surg 2007;33 (9):1651–2. Ghosh YK, Van Vuuren A, Aggarwal SP, Dubash D. Prevention of retrobulbar hemor rhage after sub-Tenon anesthesia. J Cataract Refract Surg 2008;34(3):347. Quantock CL, Goswami T. Death potentially secondary to sub-Tenon’s block. Anaesthesia 2007;62(2):175–7.
271 35. Salib Y, Kukreja PK, Parikh MK. Prolonged femoral nerve palsy after ilio-inguinal nerve block. Reg Anesth Pain Med 2007;32(3):271. 36. Elad S, Admon D, Kedmi M, Naveh E, Benzki E, Ayalon S, Tuchband A, Lutan H, Kaufman E. The cardiovascular effect of local anesthesia with articaine plus 1: 200,000 adre nalin versus lidocaine plus 1: 100,000 adrena lin in medically compromised cardiac patients: a prospective, randomized, double blinded study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105(6):725–30. 37. Wells JP, Beckett H. Articaine hydrochlor ide: a safe alternative to lignocaine? Dent Update 2008;35(4):253–6. 38. Kane GC, Hoehn SM, Behrenbeck TR, Mulvagh SL. Benzocaine-induced methemo globinemia based on the Mayo Clinic experience from 28 478 transesophageal echocardiograms: incidence, outcomes, and predisposing factors. Arch Intern Med 2007;167(18):1977–82. 39. Throm MJ, Stevens MD, Hansen C. Benzo caine-induced methemoglobinemia in two patients: interdisciplinary collaboration, management, and near misses. Pharma cotherapy 2007;27(8):1206–14. 40. Young B. Intraoperative detection of methe moglobinemia in a patient given benzocaine spray to relieve discomfort from a nasogastric tube: a case report. AANA J 2008;76(2):99–102. 41. Gutta R, Louis PJ. Methemoglobinemia – an unusual cause of intraoperative hypoxia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103(2):197–202. 42. Ryu HY, Kim JY, Lim HK, Yoon J, Yoo BS, Choe KH, Lee SH. Bupivacaine induced car diac toxicity mimicking an acute non-ST seg ment elevation myocardial infarction. Yonsei Med J 2007;48(2):331–6. 43. Nettis E, Colanardi MC, Calogiuri GF, Foti C, Priore MG, Ferrannini A, Vacca A. Delayed-type hypersensitivity to bupiva caine. Allergy 2007;62(11):1345–6. 44. Rezvani M, Finkelstein Y, Verjee Z, Railton C, Koren G. Generalized seizures following topical lidocaine administration during circumcision: establishing causation. Paediatr Drugs 2007;9(2):125–7. 45. Neuhaeuser C, Weigand N, Schaaf H, Mann V, Christophis P, Howaldt HP, Heckmann M. Postoperative methemoglobinemia following
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46.
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49.
50.
51.
52.
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infiltrative lidocaine administration for com bined anesthesia in pediatric craniofacial sur gery. Paediatr Anaesth 2008;18(2):125–31. Haugen RN, Brown CW. Case reports: type I hypersensitivity to lidocaine. J Drugs Der matol 2007;6(12):1222–3. Amado A, Sood A, Taylor JS. Contact allergy to lidocaine: a report of sixteen cases. Dermatitis 2007;18(4):215–20. Centini F, Fiore C, Riezzo I, Rossi G, Fineschi V. Suicide due to oral ingestion of lidocaine: a case report and review of the literature. Forensic Sci Int 2007;171(1):57–62. Venemalm L, Degerbeck F, Ig SW. E-mediated reaction to mepivacaine. J Allergy Clin Immunol 2008;121(4):1058–9. Elsaie ML. Cardiovascular collapse develop ing after topical anesthesia. Dermatology 2007;214(2):194. Boran P, Tokuc G, Yegin Z. Methemoglobi nemia due to application of prilocaine during circumcision and the effect of ascorbic acid. J Pediatr Urol 2008;4(6):475–6. Shachor-Meyouhas Y, Galbraith R, Shavit I. Application of topical analgesia in triage: a potential for harm. J Emerg Med 2008;35 (1):39–41. Stahl M, Meyer C, Haas E, Glaenz T, Zutt M. Leg ulcer progression caused by topical anesthesia with EMLA cream. J Dtsch Der matol Ges 2008;6(7):566–8.
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54. Kreeftenberg Jr. HG, Braams R, Nauta P. Methemoglobinemia after low-dose prilo caine in an adult patient receiving barbitu rate comedication. Anesth Analg 2007;104 (2):459–60. 55. Yoshida M, Matsuda H, Fukuda I, Furuya K. Sudden cardiac arrest during cesarean sec tion due to epidural anaesthesia using ropi vacaine: a case report. Arch Gynecol Obstet 2008;277(1):91–4. 56. Dhir S, Ganapathy S, Lindsay P, Athwal GS. Case report: ropivacaine neurotoxicity at clinical doses in interscalene brachial plexus block. Can J Anaesth 2007;54(11):912–6. 57. Lascarrou JB, Thibaut F, Malinovsky JM. Arrêt cardiorespiratoire dans les suites immediates d’un bloc plexique axillaire à la ropivacaine chez une insuffisante rénale chronique dialysée. [Cardiac arrest after axil lary plexic anaesthesia with ropivacaine in a chronic kidney failure dialysis patient.] Ann Fr Anesth Reanim 2008;27(6):495–8. 58. Wink J, Veering BT, Kruit M, Burm AG, Huledal GA, Ekstrom GY, Stienstra R, van Kleef JW. The effect of a long term epidural infusion of ropivacaine on CYP2D6 activity. Anesth Analg 2008;106(1):143–6. 59. Sheu CC, Tsai JR, Hung JY. Possible malignant hyperthermia during spinal anaes thesia with tetracaine. Anaesthesia 2007;62 (2):200–1.
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Neuromuscular blocking agents and skeletal muscle relaxants
DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS
(SED-15, 2489; SEDA-28, 155; SEDA-31, 247)
Suxamethonium Electrolyte balance Hyperkalemia after the administration of suxamethonium is usually mild, but can occasionally be severe (1A, 2A). • A 61-year-old obese man with hypertension and type 2 diabetes was scheduled to undergo resection of his distal colon and rectum for rectal adenocarcinoma, after receiving preoperative lower abdominal and pelvic irradiation and adjuvant chemotherapy over 6 weeks. Suxamethonium 1.5 mg/kg was used to facilitate endotracheal intubation. The serum potassium concentration before induction of anesthesia was 4.5 mmol/l; after the start of surgery it rose to 6.4 mmol/l. Hyperkalemia was treated with sodium bicarbonate, dextrose and insulin. • Hyperkalemia and cardiac arrest followed the administration of suxamethonium in a 16-year-old boy with acute non-lymphoblastic leukemia and sepsis. His potassium concentration was normal before the administration of suxamethonium.
As the first patient had no other susceptibil ity factors for hyperkalemia after the Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32012-5 � 2010 Elsevier B.V. All rights reserved.
administration of suxamethonium, it was attributed to muscle damage associated with radiotherapy; the authors suggested further investigation of possible suxametho nium-induced hyperkalemia after chemo radiotherapy. The susceptibility factors in the second case were immobility and sepsis. Immunologic Blood samples were collected from 15 patients (3 men and 12 women, age range 20–60 years) with suspected anaphylaxis during general anesthesia (3c). Serum concentrations of IgE antibodies against suxamethonium in blood samples collected up to 6 hours after the reaction were not different from those in samples drawn before or days and weeks after the occurrence of anaphylaxis. This was a small study, but the authors concluded that a serum sample intended to trace the drug involved in an IgE-mediated reaction can be taken at the same time as the reaction. Susceptibility factors Genetic The tetra meric glycoprotein butyrylcholinesterase is one of two enzymes that hydrolyse choline esters. The controlling gene (BCHE) has four coding exons and is located on chro mosome 3q26. Based on butyrylcholines terase activity in the presence and absence of dibucaine, two gene products have been distinguished – the usual product (designated U) and an atypical product (designated A). Homozygotes for the A gene product are at risk of prolonged
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apnea after exposure to suxamethonium or mivacurium. In a prairie Hutterite kindred there were two BCHE mutations, c.209A> G p. D70G and c.1615G> A p. A539T (4c). Homozygotes for the for mer (i.e. atypical or A) are the only indi viduals whose butyrylcholinesterase activity could lead to adverse reactions to suxamethonium.
NON-DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS (SED-15,
C. Williams and M. Leuwer
concluded that suxamethonium creates excellent intubation conditions more reliably than rocuronium and should still be used as a first-line muscle relaxant for rapidsequence induction intubation. If an alternative agent is required, rocuronium can be used to create acceptable intubation conditions, but it should only be used as a second-line treatment. However, only a few studies used a dose of 1.2 mg/kg, which significantly shortens onset time compared with 0.6 mg/kg. The ability of sugammadex to reverse deep neuromuscular blockade under rocuronium may alter the benefit to harm balance in comparison with suxamethonium, which was not considered in the review.
2489; SEDA-28, 155; SEDA-31, 248)
Mivacurium
(SED-15, 2363;
SEDA-28, 155) Susceptibility factors Genetic Prolonged postoperative paralysis after anesthesia with mivacurium was successfully treated with transfusion of fresh frozen plasma, with reversal of the respiratory paralysis and complete recovery (5A). There was reduced cholinesterase activity because of a homozygous atypical and heterozygous K variant of the cholinesterase gene. Fresh frozen plasma is rarely indicated in such cases, because of the risks of transmitting infection.
Rocuronium
(SED-15, 3073;
SEDA-31, 248) Systematic reviews Because of its fast onset of action, rocuronium is a potential alternative to suxamethonium for rapidsequence intubation in patients with an increased risk of aspiration. The Cochrane review of rocuronium versus suxamethonium for rapid-sequence intubation has been updated with the inclusion of 11 additional studies (6M). When rocuronium was used, the relative risk for excellent intubating conditions was 0.86, with a NNTH of 8. The authors
Neuromuscular Prolonged paralysis has been reported after a single intubating dose of rocuronium, highlighting the clinical impact of interindividual variations in pharmacokinetics and pharmacodynamics (7A). • An 84-year-old woman, with no known co-morbidities, who was not taking any regular medications, received rocuronium 0.6 mg/kg for induction of anesthesia to facilitate endotracheal intubation. After 2 hours there was no twitch response to train of-four stimulation of the ulnar nerve, but the post-tetanic count was 8. After 193 minutes one twitch response to train-of-four stimulation was recorded, and after 215 minutes a second twitch response appeared. At this time, neostigmine 0.05 mg/ kg was given for reversal, and 8 minutes later a train-of-four ratio >0.9 was observed. She was extubated without signs of residual paralysis.
The authors suggested that the unusually long duration of action of rocuronium in this case had been caused by a combination of factors, including genetically increased sensitivity to rocuronium, advanced age, reduced liver function, female sex, and the use of sevoflurane. However the extent of prolonged paralysis after rocuronium in this patient was far outside the normal range and was not easily explained by the combination of factors listed by the authors. Muscle disease, such as mitochon drial myopathies, can cause pronounced
Neuromuscular blocking agents and skeletal muscle relaxants
sensitivity to non-depolarizing neuromus cular agents and all cases of extreme sensi tivity to muscle relaxants in apparently healthy individuals warrant further investigation.
Sugammadex Sugammadex is a modified -cyclodextrin designed to reverse the effects of rocuro nium selectively by encapsulating the aminosteroid within its lipophilic core. It is the first selective agent for binding a muscle relaxant. Sugammadex forms a stable com plex in plasma, resulting in a rapid reduc tion in effector site concentration at the neuromuscular junction. This is in contrast to conventional anticholinesterase reversal agents, such as neostigmine, which prolong the action of acetylcholine at the neuro muscular junction. Its pharmacology has been reviewed (8R–10R). Sugammadex was licensed for clinical use in the European Union in 2008. Observational studies The first exposure of sugammadex (then Org 25969) in 29 healthy volunteers produced nine adverse events (11c). All those related to sugammadex were reported to be of limited duration and mild intensity, except for a period of paresthesia of moderate intensity at the intravenous cannula site. In a phase II, dose-finding trial involving 80 ASA I and ASA II adults four adverse effects were attributed to sugammadex: one instance each of short-lived moderate tachycardia, delayed awakening by 5 minutes, erythema, and abdominal discomfort (12c). There were no serious adverse reactions. The investigators did not comment on the biological plausibility of the adverse reactions reported. Delayed awakening from anesthesia by 5 minutes would be within the variation seen in clinical practice. In a phase II dose-finding and safety study in 45ASA I–II adults there were two adverse events (diarrhea and light
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anesthesia) associated with sugammadex (13c). Light anesthesia maybe related to rapid reversal of neuromuscular block by sugammadex. In a phase I safety trial of the effect of sugammadex on the QT interval in 16 healthy volunteers there were 23 adverse events, none of which was serious (14c). All were mild or moderate in intensity and all resolved by the end of the study. Comparative studies The speed of reversal of rocuronium by sugammadex has been compared with reversal of cis-atracurium by neostigmine in 84 ASA I–III adults (15c). Four patients who were given sugammadex group (nausea in one, shivering in one, increased urinary N-acetyl glucosaminidase in two, and altered facial sensation in one patient) and one given neostigmine group (nausea) had at least one adverse reaction that the investigators attributed to the study drugs. Most of the adverse events were not considered to be related to the study drugs. Nausea and shivering after anesthesia are common adverse events. The authors did not explain their rationale for attributing nausea and shivering to sugammadex. Postoperative urinary N-acetyl glucosaminidase was raised in seven of those who received sugammadex and one of those who received neostigmine. No inferential analysis was performed on these data. Endocrine Sugammadex could encapsulate other steroidal drugs and endogenous steroids. However, the clinical relevance of this is likely to be small, as the affinity of sugammadex for these substances is up to 700 times less than for rocuronium (16E).
Susceptibility factors In a study of the safety and efficacy of sugammadex in 15 patients with end-stage renal failure (creatinine clearance less than 30 ml/minute) and 15 control patients with normal renal function there were no serious adverse effects (17c). Currently, sugammadex is not recommended for use in patients with
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significant renal impairment and further safety studies are warranted.
toxicity after accumulation of the drug secondary to acute renal insufficiency (23A).
Drug overdose A healthy volunteer who received an accidental overdose of sugammadex 40 mg/kg had no adverse effects in the 7 days after the event (18A).
Botulinum toxins
SKELETAL MUSCLE RELAXANTS Baclofen
(SED-15, 408; SEDA-30, 164; SEDA-31, 250) Observational studies In a trial of baclofen in suppressing alcohol consumption in 148 alcohol-dependent subjects with alcoholic liver cirrhosis it was well tolerated (19c).
Cardiovascular system Extreme bradycardia and hypotension has been reported in a tetraplegic patient given oral baclofen (20A). Another dose resulted in the same complications. However, this patient had a history of autonomic dysreflexia. Nervous system Recurrent transient global amnesia has been reported in a middle-aged woman after intrathecal baclofen (21A). The episodes were reduced by fludrocortisone and terminated by sublingual glyceryl trinitrate. This association has not previously been reported. Baclofen reduced hot and cold tempera ture perception in patients with spinal cord injuries (22c), consistent with experimental data in animals. This suggests a role for baclofen in the treatment of neuropathic pain. The authors did not comment on any potential adverse effects of reduced tem perature perception. Drug overdose Bicarbonate hemodialysis cleared baclofen in a patient who developed
(SED-15, 551; SEDA-29, 156; SEDA-30, 165; SEDA-31, 252) Uses The authors of a literature review of the safety and efficacy of botulinum toxin in movement disorders concluded that it should be offered as a treatment of cervical dystonia, may be offered as a treatment for blepharospasm, focal upper extremity dystonia, adductor laryngeal dystonia, and upper extremity essential tremor, and may be considered for hemifacial spasm, focal lower limb dystonia, and motor tics (24R). In a study of the role of botulinum toxin in autonomic disorders and pain the authors concluded that botulinum toxin should be offered for the treatment of axillary hyper hidrosis and detrusor overactivity (25R).
Observational studies The FDA has issued an early communication about its review of botulinum toxin A (Botox and Botox Cosmetic) and botolinum toxin B (Myobloc) (26S). The Agency says that it has received reports of adverse reactions associated with the use of these products, including respiratory compromise and death, suggestive of botulism. Most of the reported cases involved children who had received the drugs for limb spasticity in cerebral palsy, a condition for which botulinum toxins are not approved in the USA in children under 12 years. The FDA’s Adverse Event Reporting Sys tem database and the medical literature con tain reports of iatrogenic botulism in patients aged under 16 years, with serious outcomes, including hospitalization and death. No deaths were reported among adults. In cases of botulism the dose of botulinum toxin A was 6.25–32 U/kg in children and 10–700 U/kg in adults, and the doses of botu linum toxin B were 388–625 U/kg in children and 10 000–20 000 U/kg in adults.
Neuromuscular blocking agents and skeletal muscle relaxants
The Australian Adverse Drug Reaction Advisory Committee has emphasized the importance of adherence to the indications and dosing instructions in the use of botulinum toxin-containing products (27S). Botulinum toxin type A (Botox, 100 U/vial) is used for treatment of strabismus, blepharospasm, facial nerve disorders, spasmodic torticollis, various spasticity disorders, spasmodic dysphonia, axillary hyperhidrosis, and brow furrow lines. A hemagglutinating complexed form of botu linum toxin A has similar but more limited indications. Since 1994, the Therapeutic Goods Administration in Australia has received 45 reports in connection with the use of botulinum toxin, none of which have described a fatal outcome. The reactions reported are most commonly of muscle weak ness (n = 16) at sites adjacent to or distant from the injected area, including dysphagia (n = 8), respiratory failure or dyspnea (n = 3), and generalized muscle weakness (n = 7). Other reactions have included rashes or other allergic reactions, diplopia, and fatigue. Seven reports cited off-label use and 17 cited use for cosmetic reasons, but the others cited use according to approved indications. Nervous system In a double-blind, randomized, placebo-controlled trial of botulinum toxin type A injections for 12 weeks in 40 patients with writer’s cramp, the reported adverse effects were hand weakness, which was mostly mild and always transient, and pain at the injection site (28C). Despite weakness in the hand, most of the patients preferred to continue treatment. Infection risk Fournier’s gangrene has been reported in an elderly diabetic patient after an injection of botulinum toxin into the anal sphincter (29A). Diabetes mellitus in this patient probably increased the risk of this complication. Chlorzoxazone (SED-15, 735; SEDA-31, 253) Liver Chlorzoxazone has been used as a centrally acting muscle relaxant for several
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decades. However, it can cause liver damage, as highlighted by a report of severe liver necrosis requiring liver transplant (30Ar). • A 38-year-old woman developed nausea, vomiting, scleral icterus, confusion, and lethargy after taking chlorzoxazone 500 mg for 6 weeks. Serum alanine and aspartate transaminases and bilirubin were markedly raised and a transjugular liver biopsy showed acute hepatitis with bridging necrosis, severe hepatocyte ballooning degeneration, and a mixed inflammatory cell infiltrate, suggestive of drug-induced injury. As her condition did not improve, she underwent orthotopic liver transplantation. Extensive exploration revealed no other causes of liver damage.
The authors reviewed chlorzoxazone-asso ciated liver damage. So far, few cases have been reported, but some have been severe, including fulminant liver failure and death, with no obvious relation to dose. Surveil lance studies did not identify hepatotoxicity as a problem and there were no recommen dations for routine monitoring of liver enzymes.
Tetrabenazine Nervous system Tetrabenazine inhibits vesicular monoamine transporter 2, leading to depletion of dopamine and other monoamines in the central nervous system. In a retrospective chart review, 448 patients who had used tetrabenazine between 1997 and 2004 (mean age at onset of the movement disorder, 43 years; 42% men) were treated for a variety of hyperkinesias, including tardive dyskinesia (n = 149), dystonia (n = 132), chorea (n = 98), tics (n = 92), and myoclonus (n = 19) (31c). They took treatment for a mean of 2.3 years and efficacy was sustained in most cases. Common adverse effects included drowsiness (25%), parkinsonism (15%), depression (7.6%), and akathisia (7.6%). Although it has repeatedly been observed that tetrabenazine alleviates hyperkinetic movements, it can worsen parkinsonism (32R).
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Metabolism Weight gain over time has been compared in 32 boys with tics taking tetrabenazine (mean age 13 years) and an age-matched group of 41 patients (33 boys) with tics taking only antipsychotic drugs (mean age 12 years) (33c). Weight gain with tetrabenazine was 0.36 kg/month (mean follow-up duration 25 months) and with antipsychotic drugs 0.75 kg/month (mean follow-up duration 19 months).
drug safety, and effectiveness in healthy subjects and patients have been reviewed (34R). There is evidence that the relation between plasma concentrations of tizanidine and dose is linear and that the most common adverse events are related to drug concentration. A low therapeutic index and wide interpatient variability in plasma concentrations make it necessary to individualize therapy.
Tizanidine
Susceptibility factors Liver disease Tizanidine is a substrate of hepatic CYP1A2 and caused hypotension in a patient with liver cirrhosis (35A). Serum concentrations of the drug were raised.
(SED-15, 3436; SEDA-28, 157; SEDA-29, 146) Pharmacokinetics Tizanidine hydrochlor ide dose relationships to pharmacokinetics,
References 1. Holak EJ, Connelly JF, Pagel PS. Suxametho nium-induced hyperkalemia 6 weeks after chemoradiotherapy in a patient with rectal carcinoma. Br J Anaesth 2007;98(6):766–8. 2. Piotrowski AJ, Fendler WM. Hyperkalemia and cardiac arrest following succinylcholine administration in a 16-year-old boy with acute nonlymphoblastic leukemia and sepsis. Pediatr Crit Care Med 2007;8(2):183–5. 3. Guttormsen AB, Johansson SGO, Öman H, Wilhelmsen V, Nopp A. No consumption of IgE antibody in serum during allergic drug anaphylaxis. Allergy 2007;62(11):1326–30. 4. Zelinski T, Coghlan G, Mauthe J, TriggsRaine B. Molecular basis of succinylcholine sensitivity in a prairie Hutterite kindred and genetic characterization of the region con taining the BCHE gene. Mol Genet Metab 2007;90(2):210–6. 5. van Gammeren AJ, Cobbaert CM, Schrau wen CJ, Voets MA, Ermens AA. Fresh frozen plasma transfusion for reversal of pro longed post-anesthesia apnea. Transfus Med 2008;18(2):134–6. 6. Perry JJ, Lee JS, Sillberg VA, Wells GA. Rocuronium versus succinylcholine for rapid
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sequence induction intubation. Cochrane Database Syst Rev 2008;16(2):CD002788. Claudius C, Karacan H, Viby-Mogensen J. Prolonged residual paralysis after a single intubating dose of rocuronium. Br J Anaesth 2007;99:514–7. Hunter JM, Flockton EA. The doughnut and the hole: a new pharmacological concept for anesthetists. Br J Anaesth 2006;97(2):123–6. Naguib M. Sugammadex: another milestone in clinical neuromuscular pharmacology. Anesth Analg 2007;104:575–81. Bom A, Hope F, Rutherford S, Thomson K. Preclinical pharmacology of sugammadex. J Crit Care 2009;24:29–35. Gijsenbergh F, Ramael S, Houwing N, van Iersel T. First human exposure of Org 25969, a novel agent to reverse the action of rocur onium bromide. Anesthesiology 2005;103 (4):695–703. Suy K, Morias K, Cammu G, Hans P, van Duijnhoven WG, Heeringa M, Demeyer I. Effective reversal of moderate rocuronium or vecuronium-induced neuromuscular block with sugammadex, a selective relaxant bind ing agent. Anesthesiology 2007;106(2):283–8.
Neuromuscular blocking agents and skeletal muscle relaxants 13. de Boer HD, Driessen JJ, Marcos MAE, Kerkkamp H, Heeringa M, Klimek M. Reversal of rocuronium-induced (1.2 mg/kg) profound neuromuscular block by sugamma dex: a multicenter, dose-finding and safety study. Anesthesiology 2007;107(2):239–44. 14. Cammu G, De Kam PJ, Demeyer I, Decoop man M, Peeters PAM, Smeets JMW, Fou bert L. Safety and tolerability of single intravenous doses of sugammadex adminis tered simultaneously with rocuronium or vecuronium in healthy volunteers. Br J Anaesth 2008;100(3):373–9. 15. Flockton EA, Mastronardi P, Hunter JM, Gomar C, Mirakhur RK, Aguilera L, Giunta FG, Meistelman C, Prins ME. Reversal of rocuronium-induced neuromuscular block with sugammadex is faster than reversal of cisatracurium-induced block with neostig mine. Br J Anaesth 2008;100(5):622–30. 16. Zhang MQ. Drug-specific cyclodextrins: the future of rapid neuromuscular block rever sal? Drugs Future 2003;28(4):347–54. 17. Staals LM, Snoeck MM, Driessen JJ, Flockton EA, Heeringa M, Hunter JM. Multicen tre, parallel-group, comparative trial evaluating the efficacy and safety of sugam madex in patients with end-stage renal fail ure or normal renal function. Br J Anaesth 2008;101(4):492–7. 18. Molina AL, de Boer HD, Klimek M, Heeringa M, Klein J. Reversal of rocuro nium-induced (1.2 mg kg–1) profound neuro muscular block by accidental high dose of sugammadex (40 mg kg–1). Br J Anaesth 2007;98(5):624–7. 19. Addolorato G, Leggio L, Ferrulli A, Cardone S, Vonghia L, Mirijello A Abenavoli L, D’Angelo C, Caputo F, Zambon A, Haber PS, Gasbarrini G. Effectiveness and safety of baclofen for maintenance of alcohol absti nence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind con trolled study. Lancet 2007;370(9603):1915–22. 20. Smit CAJ, Slim EJ. Heart conduction pro blems in a tetraplegic patient caused by a single therapeutic dosage of Baclofen. Spinal Cord 2008;46(4):317–8. 21. Grande LA, Loeser JD, Samii A. Recurrent transient global amnesia with intrathecal baclofen. Anesth Analg 2008;106(4):1284–7.
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22. Oliviero A, Rubio-Esteban M, Foffani G, Aguilar J, Lopez-Dolado E, Arzoz-Lezaun T, Godino-Duran JA, Gómez-Arg€ uelles JM, Pérez-Borrego Y, Sebastia´n de la Cruz F, Di Lazzaro V. Effects of baclofen on tem perature perception in humans. Neurosci Res 2007;59:89–92. 23. Brvar M, Vrtovec M, Kovač D, Kozelj G, Pezdir T, Bunc M. Haemodialysis clearance of baclofen. Eur J Clin Pharmacol 2007;63 (12):1143–6. 24. Simpson DM, Blitzer A, Brashear A, Comella C, Dubinsky R, Hallett M, Jankovic J, Karp B, Ludlow CL, Miyasaki JM, Naumann M, So Y. Botulinum neurotoxin for the treatment of movement dis orders (an evidence-based review). Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2008;70(19):1699–706. 25. Helmstaedter V, Wittekindt C, Huttenbrink K-B, Guntinas-Lichius O. Safety and efficacy of botulinum toxin therapy in otorhinolaryn gology: experience from 1,000 treatments. Laryngoscope 2008;118(5):790–6. 26. Anonymous. Botulinum toxins. Report of systemic adverse reactions. WHO Newslett 2008;2:7. 27. Anonymous. Botulinum toxin type A. Adverse reactions such as muscle weakness. WHO Newslett 2009;2:2. 28. Kruisdijk JJ, Koelman JH, Ongerboer de Visser BW, de Haan RJ, Speelman JD. Botu linum toxin for writer’s cramp: a randomised, placebo-controlled trial and 1-year followup. J Neurol Neurosurg Psychiatry 2007;78 (3):264–70. 29. Mallo-Gonzalez N, Lopez-Rodriguez R, Fentes DP, Campos-Franco J, Lado FL, Alende-Sixto MR. Fournier’s gangrene fol lowing botulinum toxin injection. Scand J Urol Nephrol 2008;42(3):301–3. 30. Jackson J, Anania FA. Chlorzoxazone as a cause of acute liver failure requiring liver transplantation. Dig Dis Sci 2007;52:3389–91. 31. Kenney C, Hunter C, Davidson A, Jankovic J. Short-term effects of tetrabena zine on chorea associated with Huntington’s disease. Mov Disord 2007;22:10–3. 32. Morgan JC, Sethi KD. Drug-induced tre mors. Lancet Neurol 2005;4:866–76.
280 33. Ondo W, Jong D, Davis A. Comparison of weight gain in treatments for Tourette syn drome: tetrabenazine versus neuroleptic drugs. J Child Neurol 2008;23:435–7. 34. Henney III HR, Runyan JD. A clinically relevant review of tizanidine hydrochloride dose relationships to pharmacokinetics, drug
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safety and effectiveness in healthy subjects and patients. Int J Clin Pract 2008;62 (2):314–24. 35. Momo K, Homma M, Abei M, Hyodo I, Kohda Y. Tizanidine-induced hypotension in patients with liver cirrhosis. Eur J Clin Pharmacol 2008;64(6):6478.
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Drugs that affect autonomic functions or the extrapyramidal system
DRUGS THAT STIMULATE BOTH ALPHA- AND BETA-ADRENOCEPTORS (SEDA-27, 145; SEDA-29, 148; SEDA 30, 170; SEDA-31, 259)
Adrenaline (epinephrine) (SED-15, 41; SEDA-29, 148; SEDA-30, 170; SEDA 31, 259) Cardiovascular Ischemic heart disease EIDOS classification: Extrinsic moiety: Adrenaline Intrinsic moiety: Alpha-adrenoceptors Distribution: Myocardial blood vessels Outcome: Vasospasm Sequela: Ischemic heart disease due to adrenaline DoTS classification: Dose-relation: Toxic Time-course: Time-independent Susceptibility factors: Diseases (pre existing ischemic heart disease) In 54 patients with coronary artery dis ease undergoing dental extraction under local anesthesia, who were randomized to two groups with and without adrenaline Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32013-7 � 2010 Elsevier B.V. All rights reserved.
1:100 000, three had ST-segment depression after administration of adrenaline and two others had increased CK-MB activity (1c). Surprisingly, the authors concluded that dental extraction performed under local anesthesia with 1:100 000 adrenaline does not imply additional ischemic risks. Hypotension Local administration of adrenaline can cause serious problems. For instance, a solution containing lidocaine þ adrenaline is widely used for scalp infiltration before craniotomy. A group in China have compared the hemodynamic effects of scalp infiltration of 1% lidocaine (16 ml) combined with adrenaline 40, 80, or 160 micrograms, or no adrenaline at all (n = 40 in each group) (2C). In each of the adrenaline-treated groups there was a similar and significant fall in mean arterial pressure of 17–19 mmHg at 1.5 minutes after administration, with full recovery by 3 minutes. Heart rate increased by about 12/minute over the same time. It is important that clinicians are aware that this is likely to happen and do not attempt to treat a self-limiting response, although in some patients even this brief period of hypotension can be hazardous. Drug administration route The use of intravenous adrenaline should be considered very carefully even in emergencies, as a case report from Korea shows (3A). • A 36-year-old man, with no previous history of allergy, became hypotensive (80/50 mmHg) after multiple bee stings and did not respond
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282 to subcutaneous adrenaline 0.3 mg. He was then given a further 1 mg of adrenaline by intravenous infusion, in a total volume of 2200 ml. He improved and was discharged, but was readmitted unconscious after 27 hours, shortly after complaining of a severe headache and having a tonic–clonic seizure. His blood pressure was 180/80 mmHg, which was lowered by unspecified medication to 90/60 mmHg. A CT scan showed subarachnoid and intraventricular hemorrhages. He was ventilated but did not regain consciousness and died 7 days later.
Although the authors argued that this event was caused by a specific interaction between the bee stings and adrenaline, it is more likely that the adrenaline itself caused a hyperten sive crisis, leading to rupture of a pre-existing aneurysm, and that it would have been better not to have given the drug intra venously, or at least not in such a high dose.
Noradrenaline (norepinephrine) (SED-15, 2582) Comparative studies In a multicenter, double-blind study in 778 patients who were given noradrenaline 5–15 micro grams/minute or low-dose vasopressin 0.0 1–0.03 U/minute in addition to open vasopressors, there was no significant difference between the two groups in 28 day mortality (39 and 35% respectively) or in 90-day mortality (50 and 44%) (4C). There were no significant differences in the overall rates of serious adverse events (Table 1).
Ephedra and ephedrine (SED-15, 1221; SEDA-29, 148; SEDA-30, 171; SEDA-31, 262) Cardiovascular Myocardial infarction EIDOS classification: Extrinsic moiety: Ephedrine Intrinsic moiety: Alpha-adrenoceptors Distribution: Myocardial blood vessels Outcome: Vasospasm Sequela: Ischemic heart disease due to ephedrine
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Michael Schachter
DoTS classification: Dose-relation: Toxic Time-course: Time-independent Susceptibility factors: Diseases (pre existing ischemic heart disease) Acute myocardial infarction in a young athlete who had used ephedrine over the previous 5 years to improve physical perfor mance was associated with an intracoronary thrombus in the left anterior descending cor onary artery; after removal of the thrombus, only an intact non-obstructive atherosclero tic plaque was found (5Ar). The authors suggested that in this case there was a patho genetic link between non-obstructive coron ary atherosclerosis, focal vasoconstriction and obstructive thrombosis. Drug overdose Intractable ventricular fibrillation, requiring frequent defibrillation, has been reported in a patient who took an overdose of a dietary supplement containing Ephedra and caffeine (6A).
Pseudoephedrine (SED-15, 1221; SEDA-29, 149; SEDA-30, 171; SEDA-31, 263) Urinary tract Acute urinary retention has been attributed to pseudoephedrine in a 3-year-old boy (7A). Skin Acute generalized exanthematous pus tulosis has been attributed to pseudo ephedrine (8A). Death The Office of the Philadelphia Medical Examiners has reported 15 deaths between February 1999 and June 2005 of infants and toddlers aged 16 months and younger in which 10 different drugs commonly found in over-the-counter cold remedies were detected: pseudoephedrine, dextromethorphan, paracetamol, bromphe niramine, carbinoxamine, chlorphenamine, ethanol, doxylamine, phenobarbital, and phenytoin (9c). Pseudoephedrine was detec ted in all cases, with blood concentrations of
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Table 1. Numbers (%) of serious adverse events in patients with septic shock (4C)
Event
Noradrenaline (n = 382)
Vasopressin (n = 396)
At least one serious adverse event Acute myocardial infarction or ischemia Cardiac arrest Life-threatening dysrhythmia Acute mesenteric ischemia Digital ischemia Hyponatremia Stroke
40 (11) 7 (1.8) 8 (2.1) 6 (1.6) 13 (3.4) 2 1 1
41 (10) 8 (2.0) 3 (0.8) 8 (2.0) 9 (2.3) 8 1 1
0.10–17.0 (mean 3.34) mg/l; it was the only drug detected in three cases. A 31-year-old woman took over-the-coun ter pseudoephedrine, had a hypertensive cri sis with congestive heart failure, and died of a cardiac dysrhythmia and shock (10A). At autopsy a right adrenal pheochromocytoma was found and there was evidence of congestive heart failure and catecholamineinduced cardiomyopathy. The authors sug gested that her death was linked to the use of pseudoephedrine in the presence of an undiagnosed pheochromocytoma. They also suggested that over-the-counter packaging should include a warning about the dangers of using pseudoephedrine in those with a pheochromocytoma or a family history. Drug–drug interactions Selegiline In 25 healthy volunteers transdermal selegiline had no effects on the pharmacokinetics or pharmacodynamics of pseudoephedrine or phenylpropanolamine (11c).
DRUGS THAT PREDOMINANTLY STIMULATE ALPHA1 ADRENOCEPTORS (SEDA-27, 147; SEDA-29, 150; SEDA-30, 172; SEDA-31, 264)
Dopamine In low doses the effects of dopamine are generally limited to dopamine receptors; at
higher doses it also has beta-adrenoceptor agonist effects, and at higher doses still is an alpha-adrenoceptor agonist. A report from Bulgaria suggests that the last of these actions can nevertheless occur at relatively low doses (12A). • A 64-year-old man with diabetes mellitus developed septicemia and toxic shock second ary to gangrene in the right leg. Because of p oor renal function he was given an infusion of dopamine, initially 1.25 micrograms/kg/minute, increasing to 2.5 micrograms/kg/minute beca use of a poor response. There was a good di uretic response, but after 36 hours all the fingers of both hands, except the thumbs, had become ischemic, as had the previously normal left leg. In fact the right leg was amputated, possibly because of dopamine-exacerbated is chemia but this was unclear. Dry gangrene also developed in the affected fingers, although it is also unclear whether they were saved.
This was clearly an alpha-adrenergic effect of dopamine, though as the authors here point out this is seldom seen at doses below 5 micrograms/kg/minute.
Phenylephrine (SED-15, 2808; SEDA 30, 172; SEDA-31, 264) Cardiovascular The selective alpha-adreno ceptor agonist phenylephrine is used in some clinical settings to reverse hypotension. An example is spinal anesthesia for cesarean sections, as described in a report of cardiac dysrhythmias (13A). • A 31-year-old woman who required emer gency cesarean section after failure to progress during labor was given phenylephrine
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284 200 micrograms by infusion immediately after intrathecal injection of bupivacaine and dia morphine; the dose was repeated whenever the blood pressure fell below baseline. Within seconds of starting the infusion she developed ventricular bigeminy at a rate of 94/minute, which persisted until delivery, sinus rhythm returned without treatment. The blood pres sure was between 122/76 and 143/80 mmHg.
The mechanism of this effect was unclear. The authors suggested that there may have been increased after-load, leading to increased ven tricular stretch, but this was speculative. The rise in blood pressure that phenyl ephrine causes may itself be hazardous, even if it is not given systemically, or at least not intentionally (14A). • A 23-year-old African American man devel oped ischemic priapism as a result of sickle cell disease. After intracavernosal injection of phe nylephrine 500 micrograms he complained of very severe headache and a CT scan showed subarachnoid hemorrhage. His blood pressure was 180/100 mmHg, compared to his baseline reading of 130/88 mmHg. He was given enalapril (dose not stated) and his blood pressure fell. Fortunately, he had no neurological symptoms then or later.
The authors very reasonably suggested reducing the standard dose to be injected in these circumstances to 200 micrograms, to be repeated if necessary. Skin Local phenylephrine as an insert caused an acute blepharoconjunctivitis with eyelid eczema (15A), confirmed by patch testing. Generalized eczema can develop when phenylephrine is given intravenously.
Michael Schachter
extensive. They included 940 patients with hemorrhagic stroke that occurred between October 2002 and March 2004 and 1880 matched controls. Of those who had had a stroke, 16 (1.7%) had been exposed to phenylpropanolamine in the preceding 2 weeks, compared with 14 (0.74%) of the controls. There were no significant differen ces in the men (50% of each group), but in the women there was an increased risk of stroke associated with exposure to phenyl propanolamine, and this was graded accord ing to dose, more recent date of exposure and longer duration. The overall odds ratios were about 2 for exposure versus no expo sure; over 5 for an exposure within 3 days; over 3 for an exposure of greater than 3 days; and over 2 for a dose of greater than 75 mg/day. The risk was much greater in women. In a previous study the risk of stroke associated with phenylpropanolamine was significant only in women, but only women reported using appetite suppressants con taining phenylpropanolamine (17C). How ever, the ABBA study suggested that the more evident risk in women cannot be attributed to a difference in the exposure rate between the sexes.
DRUGS THAT STIMULATE BETA 1-ADRENOCEPTORS (SEDA-29, 150; SEDA-30, 173; SEDA-31, 265)
Dobutamine Phenylpropanolamine
(SED-15, 2811; SEDA-29, 150; SEDA-30, 173; SEDA-31, 264)
Nervous system Korean authors have analysed the risk of hemorrhagic stroke in individuals taking phenylpropanolamine as a cold remedy (16M). This drug has been withdrawn nearly everywhere in the world largely for this reason, although the previous data were less systematic and less
(SED-15, 1169; SEDA-29, 150; SEDA-30, 173; SEDA-31, 265) Cardiovascular Dobutamine stress testing is widely used in cardiology, but it is timeconsuming and efforts continue to produce new protocols that are quicker but retain diagnostic utility while being at least as safe as the standard procedure. An accelerated protocol has been described, in which the starting dose of dobutamine was 20 micrograms/kg/ml, escalating in one step to 40 micrograms/kg/ml after 3 minutes, with
Drugs that affect autonomic functions or the extrapyramidal system
administration of atropine after 1 minute if the target heart rate was not reached at the higher dose of dobutamine (18C). In contrast, the standard protocol started at a dose of 10 micrograms/kg/ml, with 10 micrograms/kg/ml increments every 3 minutes, usually to 40 but sometimes to 50 micrograms/kg/ml, with atropine given towards the end of this process. In all, 164 patients were allocated alternately to one of the protocols. The total test time was reduced in the new protocol from over 19 minutes to about 12 minutes, while the average duration of symptoms was just over 3 minutes rather nearly 6 minutes. In both protocols women had shorter test times than men. The incidence of dysrhythmias of all types was about 50% with both protocols. Cardiologists from Rio de Janeiro have described another approach to this problem (19C). They used the same standard proto col for comparison, while the accelerated version differed in that atropine was given after the lowest dose of dobutamine (10 micrograms/kg/ml). In all, 168 patients were allocated alternately to the two proce dures. As expected, the total test time was shorter with the new protocol (about 16 minutes versus 20 minutes). There were considerably fewer adverse effects, mainly dysrhythmias, in patients who received the accelerated protocol (35 versus 55). There were no sex differences. These reports, taken together, support the case for accelerated protocols, which are as useful as the standard one, with equal or even superior safety and tolerability.
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Levodopa
had had the disease for at least 5 years. Five, of whom two were women, had had abnormal involuntary eye movements for 7–18 years; two were also taking dopamine receptor agonists. The abnormal move ments all occurred during the ‘on’ phase of therapy and had a common pattern. They consisted of stereotyped and repetitive move ments, upwards, sideways, or both. Some were phasic and others more sustained and tonic; in both cases they were usually (4/5) towards the side of the body more affected by the disease. The authors commented that this should be recognized as a particular type of dyskinesia, and one that may have a negative effect on postural stability. Although it seems intuitively likely that the dosage of levodopa will have a signifi cant effect on the incidence of dyskinesias, this topic has received surprisingly little attention. At the same time there is evi dence that patients in whom ropinirole or pramipexole are used initially are less likely to develop dyskinesias. Neurologists from England and France have used data from two comparisons of levodopa and ropinirole (056 and REAL-PET) in 430 patients (21C). These trials confirmed the much higher risk of dyskinesias in patients who started on levodopa rather than ropinirole – 35% of patients taking levodopa developed dyski nesia in 2–5 years compared with 5% of those taking ropinirole. Among those tak ing only levodopa there was a highly signif icant difference in dosage between those who developed dyskinesia and those who did not: 9.2 mg/kg versus 6.9 mg/kg. Logistic regression analysis showed that the only variables associated with the emergence of dyskinesia were age and levodopa dosage per kilogram.
Nervous system Levodopa-induced dys kinesia is very common. Neurologists from Geneva have examined the frequency and characteristics of a subtype of dyskinesia, abnormal involuntary eye movements (20C). They studied 32 patients with advanced Par kinson’s disease, all of whom had moderate to severe symptoms and dyskinesias, and
Drug dosage regimens Long-term levodopa therapy often causes complications, which can occasion great distress and diffi culty for patients. Some of these problems may arise from the intermittent nature of the therapy in most circumstances. How ever, John Nutt has reviewed this hypoth esis and on balance argued against it, noting that it does not avoid the problems of
(SED-15, 2039; SEDA-28, 162; SEDA-29, 151; SEDA-30, 174; SEDA 31, 266)
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hypersensitization and tolerance, that it encourages 24-hour attempts at treating th e motor effects of Parkinson’s disease and its therapies, and that it may therefore enc ourage excessive medication (22H). Never theless, he favours rigorous randomized clinical trials to test the hypothesis.
Dopamine receptor agonists
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about 1800 patients were included (25M). There was evidence of superior efficacy for pramipexole as well as greater tolerability. Specifically, the odds ratios for nausea, vomiting, and dizziness were significantly lower for pramipexole (0.37, 0.21, and 0.47 respec tively). Whether a direct comparison is likely to be carried out is doubtful, although not out of the question, as both drugs are or soon will be generic in most countries.
Neurologists from Pisa have briefly outlined the uses and role of dopamine receptor ago nists in the treatment of Parkinson’s disease and their major adverse effects, both periph eral and central; in the former category they discuss orthostatic hypotension, peripheral edema, and pleuropulmonary fibrosis (23R). However, they give a far more detailed analysis of fibrotic heart valve dis ease, though arguably their verdict on the ergoline derivatives is rather optimistic. The central adverse effects that they discuss include motor complications, but in much greater depth the problem of somnolence and sleep attacks. Pathological impulse dis orders, especially pathological gambling, are also discussed in detail.
Cardiovascular Fibrotic reactions
Observational studies Researchers from 11 countries have performed a 52-week open study of ropinirole 0.25–4 (mean 1.9) mg/day in 310 patients (24C). Although over 91% of the participants reported at least one adverse event, these led to drug withdrawal in only 8.7%. Nausea was by far the most common adverse effect (in over 55%), and vomiting, dizziness, fatigue, and somnolence had frequencies of 6–8%; somnolence was severe enough to lead to drug withdrawal in only two patients. Sleep attacks as such were not described or even specifically enquired about.
In the last few years the most important influence on dopaminergic drug prescribing has been the recognition that ergot-derived dopamine agonists are associated with cardiac valvulopathies. Two Japanese physicians have reviewed the evidence for the patho genetic mechanism and have agreed with the consensus view that stimulation of serotonin 5HT2B receptors is most probably responsible (26R). However, they have pointed out that ropinirole and pramipexole, which have little or no affinity for 5HT2B receptors, can very rarely cause fibrosis in other organs. They do not go as far as to advise the complete cessa tion of prescribing of the ergot derivatives, particularly if the doses used are low. In a Danish cross-sectional study of the association of ergot-derived dopamine ago nists with valvulopathy in Parkinson’s dis ease and the value of different screening approaches for this pathology 138 patients, median age 64 years, 62% men, were
Systematic reviews In a meta-analysis of the comparative efficacy and tolerability of ropinirole and pramipexole in restless legs syndrome, there were no direct headto-head comparisons, and only 14 studies of which 10 involved ropinirole were identified;
EIDOS classification: Extrinsic moiety: Dopamine receptor
agonists (especially pergolide and
cabergoline)
Intrinsic moiety: 5HT2B receptors Distribution: Serosae, cardiac valves Outcome: Hyperplasia (fibrosis) Sequela: Fibrotic reactions due to some ergot-derived dopamine receptor agonists DoTS classification: Dose-relation: Collateral Time-course: Late Susceptibility factors: Unknown
Drugs that affect autonomic functions or the extrapyramidal system
recruited (27C). All had taken dopamine receptor agonists for at least 6 months, either ergot-derived drugs (n = 85) or other dopaminergic agents (n = 53). They were screened for valvulopathy clinically and by assessor-blinded echocardiography. The main outcome was valvular regurgita tion as confirmed by the latter. Among those taking ergot derivatives, 22 had moder ate to severe regurgitation affecting the aor tic, mitral or tricuspid valves; the five severe cases all involved the aortic valve. Two of the patients taking other dopamine agonists had moderate valvular regurgitation. The authors calculated that the risk of at least moderate valvular regurgitation was 7.2% among those taking ergot-derived drugs. They concluded that clinical screening, including natriuretic peptide assays, have only about 62% sensi tivity and even lower specificity. Therefore, patients who take ergot derivatives should be followed up with echocardiography as well as clinical assessment. In a smaller series from Texas, echocardiography was used to study 36 patients with Parkinson’s disease taking pergolide 0.375–6 mg/day and a matched group taking ropinirole and pramipexole (28c). The authors calculated severity scores for regur gitation ranging from 1 (trace) to 4 (severe) for the aortic, mitral and tricuspid valves, with the following comparisons for ergot versus non-ergot drugs: aortic 0.83 versus 0.19; mitral 1.42 versus 0.39; tricuspid 1.43 versus 0.19. All these differences were highly significant and overall exposure to dopaminergic medication was similar in the two groups. These results clearly re inforce recommendations to avoid or with draw pergolide if at all possible, and similar considerations apply to cabergoline. Hypotension Apomorphine has a long history of parenteral usage in the treatment of severe Parkinson’s disease. It is being increasingly used, often in the patient’s home, for the treatment of acute ‘off’ episodes. In a multicenter study in the USA the efficacy and safety of apomorphine has been examined in 62 patients, half of whom were randomized to placebo and half to active drug (29C). They had all been using
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intermittent apomorphine for at least 3 months, at least twice daily, and the effect of a single dose was assessed. There was a significant improvement in motor function after 20 minutes. Apomorphine also reduced both heart rate and blood pressure, but the changes were smaller than with placebo. Orthostasis occurred in similar numbers of patients, 11 for apomorphine and 8 for placebo. Of course, baseline dopamine replacement therapy will itself produce postural hypotension. Nervous system Sleep attacks EIDOS classification: Extrinsic moiety: Dopamine receptor agonists Intrinsic moiety: Dopamine (?D2) receptors Distribution: Brain Outcome: Altered cell function (nature unknown) Sequela: Sleep attacks due to dopamine receptor agonists DoTS classification: Dose-relation: Collateral Time-course: Time-independent Susceptibility factors: Not known Dopamine receptor agonists are asso ciated with sleep attacks (30R). A 73-year old woman with Parkinson’s disease taking excessive doses of levodopa and pergolide had sleep attacks and her family noticed that each was heralded by slowness of speech (31A). In rats low doses of levodopa (1–5 mg/kg) and of the dopamine D2 recep tor agonists talipexole and quinpirole (0.1 mg/kg) caused delayed increases in delta and theta power on electroencephalo graphy (32E). Higher doses led to immedi ate stable reductions in alpha1, alpha2 and beta1 power, as reported with dopamine D1 receptor agonists. Administration of the D2 antagonist sulpiride 10–20 mg/kg resulted in increased alpha2 power. The authors sug gested that since delayed increases in delta and theta activity are thought to originate from heterosynaptic, presynaptic dopamine
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D2 receptors on cholinergic neurons, these effects could explain daytime tiredness or sudden sleep attacks in patients with Par kinson’s disease.
Psychiatric Pathological gambling EIDOS classification: Extrinsic moiety: Dopamine receptor
agonists
Intrinsic moiety: Dopamine (?D1/D3)
receptors Distribution: Brain Outcome: Altered cell function (nature unknown) Sequela: Pathological gambling due to
dopamine receptor agonists
(particularly pramipexole)
DoTS classification: Dose-relation: Collateral
Time-course: Intermediate
Susceptibility factors: Genetic
(dopamine D1 receptor gene allele DRD1-800 T/C); age (younger age of onset of Parkinson’s disease); sex (male); drugs (combined therapy with levodopa) An extraordinary range of behavioral adverse reactions have been associated with dopaminergic therapies. Pathological gam bling is well known and has previously been reviewed in SEDA (SEDA-30, 174). Neurol ogists and psychiatrists from the Mayo Clinic have studied 11 patients with Parkinson’s dis ease who developed excessive gambling behaviour and 37 patients matched for age, sex and duration of disease (33c). Combined therapy with levodopa and pramipexole did not increase the risk of gambling, but prami pexole itself was apparently associated with such an increase, with an odds ratio of 3.6, which approached but did not quite reach significance. This is largely in agreement with the literature, although the authors noted that the cause has not been established. Early in the history of levodopa therapy for Parkinson’s disease it was noted that
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hypersexuality was a complication, especially in younger patients, although it was not until the late 1980s that this was put in the wider context of compulsive behaviours. The use of dopaminergic drugs for restless legs syn drome is much more recent, and neurologists at the Mayo Clinic in Arizona have examined whether similar behaviours occur in this con text (34C). They sent questionnaires to 261 patients, of whom just over a third (97) replied: this relatively low rate may have introduced bias. On the 97 respondents, 77 were taking one or more dopaminergic medications; 3 reported an increase in sexual desire. Of the 70 patients who responded specifically to the gambling questions, 4 reported an increase in gambling activity after starting medication. One patient noted increases in both sexual desire and gambling behaviour. Although the numbers were small the authors concluded that the pattern of drug-induced behaviours in rest less legs syndrome resemble those in Parkin son’s disease. In an extraordinary case report from Gen eva, two patients are described, a man and a woman aged 70 and 71 years with advanced Parkinson’s disease who developed compul sive singing, each of one particular melody, while taking high-dose dopamine replace ment therapy (35A). The first was taking cabergoline 4 mg/day, levodopa/carbidopa 800/200 mg/day, and tolcapone 300 mg/day (high doses). The other was taking levo dopa/benserazide 1000/250 mg/day. Both were resistant to reductions in dosage. They can be regarded as suffering from dopamine dysregulation syndrome, a type of punding, that is to say repetitive stereotyped behaviors. Even so, the melodies were by Donizetti and Mozart, so not all discernment was lost.
DRUGS THAT STIMULATE BETA 2-ADRENOCEPTORS For the use of beta2-adrenoceptor agonists in respiratory disorders see Chapter 16.
Drugs that affect autonomic functions or the extrapyramidal system
Clenbuterol Respiratory Clenbuterol is used by body builders for its anabolic effects. A 33-year old man inhaled clenbuterol in powder form for unknown reasons (36A). He immediately complained of headache, chest pain, and palpitation, and vomited. His blood pressure was 116/27 mmHg with a regular pulse rate of 146/minute, in sinus rhythm. An electrocardiogram showed ST segment depression in the lateral leads and 6 hours later he developed acute respiratory failure, with oxygen saturation of 64% and pulmonary edema on chest X-ray. He required intubation for 4 days.
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Hematologic Ritodrine has rarely been associated with life-threatening maternal neutropenia and three such cases have been described in three primiparous women aged 23–36 years (39A). Intravenous ritodrine was given for 2–5 weeks in unspecified but presumably standard doses. In one patient there was agranulocytosis and in the two others very low neutrophil counts (50 and 500 106/l at their lowest). Ritodrine was withdrawn and recombinant granulocyte stimulating factor was given for 3–7 days. On average, neutrophils counts returned to normal within about 4 days. There were no infections or other complications and all the babies were normal.
Ritodrine Cardiovascular In a Turkish study of the echocardiographic findings in 30 women treated with intravenous ritodrine 50–300 micrograms for pre-term labour compared with 32 women with uncomplicated pregnancies, the results confirmed positive chronotropic and inotropic effects (37c). Heart rate rose from 76 to 106/minute and there was a modest but significant increase in fractional shortening form 40 to 41%. Systolic and diastolic blood pressures fell from 120/78 to 108/71 mmHg. The authors commented that changes in contractility and heart rate are likely to increase myocardial oxygen demand and they therefore recommended that ritodrine and similar drugs should be avoided in women with ischemic or structural heart disease. Respiratory In another Turkish study oral ritodrine 15 mg/day was given over months to prevent premature labour, but the patient was nevertheless hospitalized because of increasing uterine contractions, and the dose of ritodrine was increased to 80 mg/day (38A). On the 5th day she developed respiratory distress due to pulmonary edema, which responded to oxygen and furosemide. The authors noted that this is a very rare complication of ritodrine in any form, and that the mechanisms have not been defined.
OTHER DRUGS THAT INCREASE DOPAMINE ACTIVITY Catechol-O-methyl transferase inhibitors (SED-15, 1219; SEDA-29, 153)
Tolcapone The story of tolcapone is a fascinating one, not only in its own right but as a case history of assessment of the benefit to harm balance in therapeutics. Tolcapone is a selective inhibitor of catechol-O-methyl transferase (COMT), which catalyses a relatively minor pathway of dopamine metabolism. It there fore enhances the action of dopamine. Its introduction had a major impact on the man agement of Parkinson’s disease, and within months tens of thousands of patients throughout the world were taking it. Tolca pone was considered to be useful in prolong ing the half-life of levodopa, thereby allowing dosage reduction and possibly smoother therapeutic responses. In early studies the most frequent adverse effects of tolcapone were dyskinesias, nausea, sleep disorders, dystonia, orthostatic hypotension, diarrhea, dizziness, and
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hallucinations (40R). There was also a report of progressive vitiligo in a 50-year-old patient who took tolcapone 300 mg/day in combina tion with co-careldopa; the first depigmented lesions appeared a week after starting the drug, and the authors speculated that increased concentrations of dopamine may have interfered with melanin synthesis (41A). However, during clinical trials rises in liver enzyme were noted, and the health authorities withdrew tolcapone from most European countries following an EMEA rul ing in November 1998 (42R). Increases of more than three times the upper limits of the reference ranges for aminotransferase activ ities occurred in 1 and 3% of patients taking tolcapone 100 mg tds and 200 mg tds respec tively. Increases of more than three times the upper limits of the reference ranges for ami notransferase activities occurred in 0.3 and 1.7% of patients taking tolcapone 100 mg tds and 200 mg tds respectively. Subsequently there were three deaths from acute liver failure in patients taking tolcapone during a total exposure of 40 000 patient-years, leading to the complete withdrawal of the drug. An ear lier review, predating the withdrawal of tolca pone, had suggested that it could be safely used provided liver function was closely mon itored in the first 6 months of therapy (43R). Some neurologists believed that this course of action was reasonable because they regard tolcapone as being of superior efficacy to other COMT inhibitors and a useful addition to the therapeutic options in the management of Parkinson’s disease. In the USA the mar keting of tolcapone was severely restricted, and individual written consent and compul sory liver function monitoring was required for each patient. The background to these events was briefly reviewed soon after this happened (44R). Two American neurologists have commen ted on the events since then (45R). In more than 40 000 patient-years there have been only three cases of severe but reversible liver damage and no deaths. Another COMT inhibitor, entaca pone, was introduced after tolcapone was lar gely withdrawn, but the clinical consensus was that it had less efficacy than the older drug. As a result of the new data and of professional demand, tolcapone was marketed again, with
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strict guidelines regarding liver function mon itoring. This should be carried out every 2–4 weeks for the first 6 months of treatment and at the physician’s discretion thereafter. A multicenter, placebo-controlled trial from the late 1990s has been reported 10 years later (46C). It examined the tolerability and safety of tolcapone 100 mg tds in 677 patients with early Parkinson’s disease just starting levodopa therapy. Although it was originally intended to last 6 years, the trial was stopped after 15 months because of the safety problems mentioned above. There were increases in serum transaminase activ ities in 28% of the patients taking tolcapone but also in 20% of those taking placebo. There were increases of more than three times the upper limit of normal in only 1.2 and 1.8% of those taking placebo and tolca pone respectively. In 80% of those taking tolcapone liver enzymes returned to normal despite continuation of the drug. There were no cases of serious hepatotoxicity. Sympto matically the main problem with tolcapone therapy was diarrhea, which was reported in 29% of those taking tolcapone but only 11% of those taking placebo. This caused with drawal of treatment in 10% of the former, while overall 17% of patients stopped taking the drug for any reason: only 3% of those taking placebo stopped treatment.
DRUGS THAT AFFECT THE CHOLINERGIC SYSTEM (SEDA-29, 153; SEDA-30, 177; SEDA-31, 272)
Anticholinergic drugs
(SED-15, 264; SEDA-29, 153; SEDA-30, 153; SEDA-31, 273)
Observational studies In two large 12-week studies, from the USA and Germany, the adverse effects of extended-release formula tions of oxybutynin and tolterodine in patients with overactive bladder and urinary inconti nence were as expected from the pharmacolo gical actions of these drugs. The first study
Drugs that affect autonomic functions or the extrapyramidal system
involved 576 patients (94% women) and a parallel group of 399 patients taking extendedrelease tolterodine 4 mg/day (47C). The second study involved nearly 1700 patients (44% men) taking tolterodine 4 mg/day or placebo (48C). Dry mouth was by far the most common adve rse effect, although the prevalences were differ ent in the two series. In the German series it was 23% and in the US study 11%, about three times the rate in those taking placebo. The reason for this discrepancy was unclear. In bo th cases constipation was the next most com monly reported adverse event. No novel or unexpected problems emerged in either study. Urinary urgency and incontinence are fre quent problems, not only in older adults but also transiently in primary school-aged chil dren. There have been relatively few studies on the use of anticholinergic medications in this group, although there is general agree ment that they are efficacious. In a multina tional, 12-month, open study of extendedrelease tolterodine 2 mg/day in 318 children aged 5–11 years (54% boys), only 4 reported dry mouth and the most common adverse events were urinary tract infection (7%), nasopharyngitis (5%), and headache (5%) (49C). Whether the first two of these really were related to the treatment must be ques tionable. No fewer than 35% of the subjects withdrew from the study, mostly because of either symptomatic improvement or conver sely failure to respond; only 3% of the with drawals were due to adverse drug effects. Cardiovascular Although there have been no reports of a dysrhythmogenic effect of tolterodine, in vitro interactions with cardiac potassium channels have suggested that ventricular dysrhythmias could occur.
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Of 48 subjects recruited for a thorough study of the effect of tolterodine on the QT interval, 25 were men and 45% were poor metabolizers of tolterodine, largely because of low CYP2D6 activity; in a random sample of the population, only 7.5% of subjects would be in this category (50C). In a crossover design they were given tolterodine immediate-release 2 mg bd, a high dose of 4 mg bd, and as a positive control the qui nolone antibiotic moxifloxacin 400 mg/day, which is known to cause QT interval pro longation. The end-point was the Fridericia corrected QT interval on the fourth day of treatment at a time of peak drug expo sure. For moxifloxacin the mean prolonga tion of the QTc interval was 8.9 ms machineread and 19.3 ms manually. For the normal and high doses of tolterodine the readings were 1.2 and 5.6 ms machine-read, and 5.0 and 12 ms manually. None of the treatments came even close to the clinically relevant threshold of a 60 ms prolongation of QTc, reinforcing the clinical impression that tolterodine is safe even at high doses in poor metabolizers. Sensory systems Atropine 1% for topical use as an ointment is used to retard the development of myopia. Among 23 children (mean age 7.4 years) who used daily atropine for 1 year, one developed a mild allergic reaction, which resolved quickly after withdrawal (51c). In another study atropine was used to treat amblyopia and was compared with patching in patients aged 8–20 years (52c). Redness of the eye was observed more often in the atropine group. In one child the redness recurred after 6 months and the atropine was stopped and changed to patching on request of the parents.
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to treat Parkinson’s disease and the risk of gambling. Eur J Neurol 2008;15:350–4. 34. Driver-Dunckley ED, Nobel BN, Hentz JG, Evidente VGH, Caviness JN, Parish J, Krahn L, Adler CH. Gambling and increased sexual desire with dopaminergic medications in restless legs syndrome. Clin Neuropharmacol 2007;30:249–55. 35. Bonvin C, Horvath J, Christe B, Landis T, Burkhard PR. Compulsive singing: another aspect of punding in Parkinson’s disease. Ann Neurol 2007;62:525–8. 36. Schechter E, Hoffman RS, Stajic M, Tarabar A. Pulmonary edema and respiratory failure asso ciated with clenbuterol exposure. Am J Emerg Med 2007;25(735):e1–3. 37. Tulumbaci O, Onan MA, Turkoglu S, Kurdoglu M, Boyaci B, Tiras MB. Effects of ritodrine tocolysis on echocardiographic parameters. J Mat-Fet Neonat Med 2007; 20:751–5. 38. Findik S, Dirican A, Sengul B, Uzun O, Atici A, Erkan L. Acute pulmonary edema secondary to long-term use of oral ritodrine in a woman with triplet pregnancy. Int J Gynecol Obstet 2007;96:208–11. 39. Kikkawa M, Matsubara S, Takatoku M, Kuwata M, Ohkuchi A, Izumi A, Watanabe T, Suzuki M. Granulocyte-colony stimulating factor for the treatment of ritodrine-induced neutropenia. J Obstet Gynecol Res 2008;34:286–90. 40. Micek E. Tolcapone: a novel approach to Parkinson’s disease. Am J Health-Syst Pharm 1999;56(21):2195–205. 41. Sabaté M, Bosch A, Pedrós C, Figueras A. Vitiligo associated with tolcapone and levodopa in a patient with Parkinson’s disease. Ann Pharmacother 1999;33:1228–9. 42. Watkins P. COMT inhibitors and liver toxi city. Neurology 2000;55(Suppl 4):S51–2. 43. Olanow CW. Tolcapone and hepatotoxic effects. Arch Neurol 2000;57:263–7. 44. Colosimo C. The rise and fall of tolcapone. J Neurol 1999;246:880–2. 45. Olanow CW, Watkins PB. Tolcapone: an efficacy and safety review (2007). Clin Neu ropharmacol 2007;30:287–94. 46. Lees AJ, Ratziu V, Tolosa E, Oertel WH. Safety and tolerability of adjunctive tolca pone treatment in patients with early
294 Parkinson’s disease. J Neurol Neurosurg Psy chiatry 2007;78:944–8. 47. Armstrong RB, Dmochowski RR, Sand PK, MacDiarmid S. Safety and tolerability of extended-release oxybutynin once daily in urinary incontinence: combined results from two phase 4 controlled clinical trials. Int Urol Nephrol 2007;39:1069–77. 48. Dmochowski R, Abrams P, MarschallKehrel D, Wang JT, Guan Z. Efficacy and tolerability of tolterodine extended release in male and female patients with overactive bladder. Eur Urology 2007;51: 1054–64. 49. Nijman RJM, Borgstein NG, Ellsworth P, Siggaard C. Long-term tolerability of tolterodine extended release in children 5–11 years of age: results from a 12
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month, open-label study. Eur Urol 2007;52:1511–7. 50. Malhotra BK, Glue P, Sweeney K, Anziano R, Mancuso J, Thorough WP. QT study with recommended and supratherapeutic doses of tolterodine. Clin Pharmacol Ther 2007; 81:377–85. 51. Fan DSP, Lam DSC, Chan CKM, Fan AH, Cheung EYY, Rao SK. Topical atropine in retarding myopic progression and axial length growth in children with moderate to severe myopia: a pilot study. Jpn J Ophthal mol 2007;51:27–33. 52. Menon V, Shailesh G, Sharma P, Saxena R. Clinical trial of patching versus atropine penalization for the treatment of aniso metropic amblyopia in older children. J AAPOS 2008;12:493–7.
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Dermatological drugs, topical agents, and cosmetics
Editor’s note: The adverse effects of many drugs that are used to treat some skin diseases are covered in other chapters, for example, monoclonal antibodies in Chapter 37 and non-topical corticosteroids in Chapter 39. Vitamin A (carotenoids) is covered in Chapter 34.
Dimethyl fumarate
sufficient to inhibit NF�B1–RelA binding to NF�B consensus oligonucleotides in DNAbinding assays (10E). It has also been used to treat disseminated granuloma annulare (11c), alopecia areata (12c), necrobiosis lipoidica (13c), pityriasis rubra pilaris (14c), multiple sclerosis (15C), and non-infectious uveitis (16c). Observational studies In a retrospective study of 58 patients (25 women, 33 men) who had received fumaric acid esters for severe psoriasis, adverse events were reported in 66% (17 c). They mainly consisted of abdominal pain (61%), diarrhea (55%), flushing (45%), nausea (21%) and malaise (15%). Withdrawal of treatment was required in 15 patients after a mean period of 4.7 months. Lymphocytopenia occurred in 57% of patients, all of whom had had a baseline value within the reference range, but in only one case was it considered severe enough to warrant withdrawal. Eosinophilia is also common (18C).
Dimethyl fumarate is a fumaric acid deriva tive that is used to treat psoriasis (1c, 2C, 3C). After oral administration it is quickly hydro lysed at alkaline pH in the blood to methyl hydrogen fumarate (4E), which stimulates polarization of granulocytes and elastase release (5E). In transformed keratinocytes, dimethyl fumarate releases calcium mainly from intracellular stores into the cytoplasm and inhibits cell proliferation (6E). It reduces cell adhesion by inhibition of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin expression (7E) and inhibits expres sion of HLA-DR (8E). It inhibits the secretion of interleukin-6 (IL-6), transforming growth factor (TGF) alpha and interferon gamma in psoriatic cells (9E). It inhibits nuclear factor kappa B1 (NF�B1) nuclear localization in normal human dermal fibroblasts proved
Gastrointestinal A patient who took Fumaderm® (dimethyl fumarate þ monoethyl fumarate) for chronic plaque psoriasis developed abdominal pain and cramps, diar rhea, nausea and bloating, symptoms that disguised the fact that there was a bowel cancer and partial bowel obstruction (19A).
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32014-9 � 2010 Elsevier B.V. All rights reserved.
Skin Fumaric acid derivatives are potent contact sensitizers (20E) and occupational contact dermatitis has been reported (21A). Cases related to newly acquired sofas and
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chairs have surpassed the news threshold in some countries and the cause of the Chinese sofa/chair dermatitis epidemic is likely to have been contact allergy to dimethyl fuma rate (22A). Five patients with contact derma titis related to newly purchased chairs or sofas were studied. The chairs contained up to 470 micrograms/kg of dimethyl fumarate. The patients had strongly positive patch tests to upholstery fabric samples and to dimethyl fumarate, down to a concentration of 1 ppm in the most severe case.
DYESTUFFS Hair dyes Tumorigenicity Previous studies have sug gested an association between the use of hair dyes and some cancers (SED-15, 1573; SEDA-30, 182, SEDA-31, 288). Several studies have found an association of non Hodgkin’s lymphoma with the use of hair dyes, particularly permanent dark colors and use before 1980, when hair dye formu lations changed. The risk of non-Hodgkin’s lymphoma has been examined in relation to reported hair dye use among 1321 cases and 1057 controls from a US population-based multicenter study. DNA was extracted from blood or buccal cells to identify genetic variations in N-acetyltransferase 1 (NAT1) and 2 (NAT2), which encode enzymes that metabolize aromatic amine compounds found in hair dyes. There was a increased risk of non-Hodgkin’s lymphoma among women who used dark colored or intensetone permanent hair dyes before 1980 (23C).
Henna The crushed leaves of henna are used as a cosmetic agent worldwide, particularly in the Middle East. It causes a red-brown col oration of the skin. Lawsone (2-hydroxy-1,4 naphthoquinone) is a chemical present in henna.
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Hematological Percutaneous application of henna can cause hemolysis in blood cells deficient in glucose-6-phosphate de hydrogenase (G6PD). Hemolysis has been reported after application of henna (24A). • A 7-day-old boy developed mild pallor and jaundice 29 hours after the application of henna for prevention of nappy rash and for traditional cosmetic purposes. He was hypoactive and very icteric. About 50% of the skin surface had the red-brown color typical of henna. Screening revealed G6PD deficiency. Urinalysis was positive for protein, bilirubin, and hemoglobin.
Hemolysis in neonates with G6PD defi ciency is usually secondary to certain trigger ing factors. In this case, other medications, nutriments and infection that could have caused hemolytic anemia in G6PD defi ciency were excluded. The relatively thin newborn skin and the large application area used in this child could have resulted in enhanced percutaneous absorption of henna. Drug contamination Cutaneous deposi tion of mercury has been reported after application of henna that contained a red pigment (25A). • A 13-year-old boy developed a painful cutaneous granuloma and an abscess on the lateral aspect of his swollen arm. He had had a henna dye tattoo 4 months previously. The cutaneous granuloma was incised and mercury droplets were seen embedded in the subcutaneous tissues. Microscopic evaluation of the tissues also revealed zinc salt deposits in the chorion, with reactive granulomatosis.
This illustrates an adverse effect caused by heavy metal contamination of henna.
Paraphenylenediamine Skin In recent years contact dermatitis after henna tattoos has been attributed to the sensitizer paraphenylenediamine, which is used as an antioxidant and favours a longlasting effect of the henna (26A). The use of paraphenylenediamine in henna is responsible for early sensitization to it in children, and in some cases local hypopigmentation occurs in the tattoo (27A).
Dermatological drugs, topical agents and cosmetics
Immunomodulators, topical Tumorigenicity Tacrolimus and pimecroli mus, calcineurin inhibitors, inhibit the dephosphorylation of nuclear factors of activated T cells, causing reduced produc tion of proinflammatory cytokines, such as IL-2. Systemic absorption of topical pime crolimus and tacrolimus is low but detect able in a minority of patients. Although the reported incidence of malignancies in users of these agents has not increased compared with the general population, experts have advised that they be used with caution because of lack of long-term safety data. Two cases of interdigitating dendritic cell tumor have been reported in patients exposed to topical tacrolimus (Protopic) or pimecrolimus (Elidel) (28A). The tumors occurred in the regional lymph nodes draining the areas where the drugs had been applied. Although conclusions cannot be drawn as to the relation between these events, these presentations warrant further clinical observation and investiga tion into the carcinogenic potential of topi cal calcineurin inhibitors.
Pimecrolimus Skin Allergic contact dermatitis from pimecrolimus in a patient with tacrolimus allergy has been described, showing the possibility of cross-reactions among topical immunomodulators (29A). • A 15-year-old man with previously documented allergic contact dermatitis from tacrolimus had an allergic reaction to pimecrolimus, demonstrated by double-blind, right-versus-left provocative testing with pimecrolimus cream 1% versus inactive vehicle. The patient was also patch-tested and was weakly positive (1þ) with pimecrolimus cream 1% and negative with the vehicle. Patch tests on 30 control patients with pimecrolimus cream 1% were negative.
Molluscum contagiosum on the preauri cular area associated with the topical use of pimecrolimus in pityriasis alba has been reported (30A). Although clinical trials have not shown an increased risk of
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cutaneous infections, viral infections such as eczema herpeticum and molluscum eczema can be observed during treatment with pimecrolimus and tacrolimus.
Minoxidil Cardiovascular There have been reports of hypotension and tachycardia after chronic scalp application of minoxidil, suggesting that topical minoxidil can be systemically absorbed. Three young patients with alope cia areata treated with topical minoxidil 2% had cardiovascular adverse effects (31A). • A 12-year-old boy with extensive alopecia areata developed a tachycardia after using minoxidil 1% for 1 month. When minoxidil was withdrawn the tachycardia resolved. • A 10-year-old girl with alopecia totalis developed bouts of palpitation and dizziness after using topical minoxidil 1% for 1 month. The symptoms resolved on withdrawal. • A 14-year-old girl with alopecia areata developed bouts of palpitation and dizziness after using topical minoxidil 1% for 20 days.
Skin Oral minoxidil for the treatment of uncontrolled hypertension was associated with Stevens–Johnson syndrome in a 50-year-old man with chronic renal insuffi ciency (32A).
PHOTOTHERAPY AND PHOTOCHEMOTHERAPY (SED-15, 2823; SEDA-28, 171; SEDA-29, 158)
Aminolevulinic acid Nervous system Pain is the main adverse effect of photodynamic therapy. Each lesion is generally treated twice, and clinical expe rience suggests that the second treatment causes more pain than the first and becomes a therapy-limiting factor. Intrapatient varia tion in the experience of pain, between the first and second treatments, has been
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investigated in 38 patients (33c). The pain score was higher after the second treatment in 21 patients, was unchanged in 6 and was reduced in 11. The pain experienced after the first course of treatment may predict pain after subsequent treatments.
Nervous system Isolated sixth nerve palsy is rarely associated with drug treatment. A man developed diplopia secondary to iso lated sixth nerve palsy after the use of aci tretin for non-melanoma skin cancer chemoprophylaxis (36A).
Skin Topical photodynamic therapy has been used to treat non-melanoma skin can cer. The procedure involves light activation of an endogenous photosensitizer after topi cal application. Allergic contact dermatitis to the prodrug, a rare effect, has again been reported (34A).
Sensory systems Eyes A 33-year-old man with psoriasis vulgaris took oral acitretin 30 mg/day (37A). After 60 days he devel oped watery eyes, erythema and edema near the eyes. There was an excess of gran ulation tissue on the palbebral conjunctivae bilaterally. Microscopic examination was consistent with granulation tissue, which was believed to be related to the therapy. Acitretin was withdrawn, and 40 days later the effects resolved spontaneously. The excess granulation tissue reported with reti noids usually appears after 3–12 weeks of therapy, but there have been reports of reactions after 6 months. The reaction may resolve spontaneously after withdrawal of therapy or after reduction of the dose.
• An old woman developed acute eczema a few days after a fourth course of photodynamic therapy for a basal cell carcinoma on her left leg; the eczema rapidly became generalized over much of her body. After 3 months she had patch tests with a standard series, a textile and lower leg series, disodium ethylenediamine tetraacetate (EDTA), and 1, 5, and 10% aminolevulinic acid methyl ester cream in white soft paraffin. There was a positive reaction to the cream. In order to exclude a false-positive irritant reaction, the cream was applied to 30 consecutive healthy controls; no positive reactions were seen.
There is also a possibility in this case that allergy may have occurred to an untested excipient.
VITAMIN A (RETINOIDS) (SED-15, 3653; SEDA-29, 158; SEDA-30, 185; SEDA-31, 291; for vitamin A carotenoids see Chapter 34 )
Acitretin Cardiovascular Capillary leak syndrome is a rare and potentially life-threatening condi tion caused by a shift of intravascular fluid and proteins to the interstitial space. A patient with pustular psoriasis developed capillary leak syndrome after the start of aci tretin therapy (35A). In such cases, immediate withdrawal of retinoic acid is necessary and glucocorticoid therapy should be considered.
Isotretinoin Cardiovascular Cardiovascular adverse effects have been infrequently reported, but several case reports have suggested that isotretinoin can cause cardiac dysrhyth mias. These cases include patients with atrial tachycardia and incomplete right bun dle branch block, right bundle branch block associated with sinus tachycardia and tran sient sinus tachycardia (38A). • A 22-year-old man with nodular acne developed bouts of palpitation in the third week of a third course of isotretinoin. He took alcohol socially and denied other drug use. An electrocardiogram showed atrial tachycardia at a rate of 127/minute. He was given adenosine 6 mg, his response to which confirmed the diagnosis of atrial tachycardia. Over time there was a gradual fall in heart rate and an eventual return to sinus rhythm, consistent with the long half-life of isotretinoin. After 9 months he was asymptomatic.
Nervous system Accumulating evidence over the past decade has suggested that
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synthetic retinoids may affect both growth and differentiation of nervous tissue. Neuro logical examination and electroneuromyo graphy in 18 patients with various skin diseases before, at 3 months and at the end of isotretinoin treatment suggested the pre sence of a typical distal, length-dependent, predominantly sensory polyneuropathy (39c). The authors suggested that electro neuromyographic investigations should be performed in all patients who report symp toms (e.g. paresthesia, numbness, sensory loss), before and during oral isotretinoin treatment. The precise clinical significance of the isotretinoin-induced neurophysiologi cal alterations reported in this study remains to be determined. Cerebellar demyelination has been attrib uted to isotretinoin (40A). • A demyelinating lesion located in the left cerebellar region developed after treatment with oral isotretinoin for 3 months. One year before, the patient had had endocrinological problems and a brain magnetic resonance imaging (MRI) scan had been normal. However, 3 months after starting to take isotretinoin she reported lack of appetite, faintness and tinnitus. A second MRI scan showed a cerebellar lesion and isotretinoin was withdrawn. One month later the lesion became less prominent and after 3 months it had disappeared.
It is difficult to be sure that there was a causal association between the demyelina tion and isotretinoin in this case. Cerebral ischemia has been associated with isotretinoin (41A). • A 30-year-old right-handed man developed a left-sided facial paralysis and dysarthria. He had taken oral isotretinoin 45 mg/day for 3 months for severe acne. A cerebral CT scan showed a hypodensity in the right middle cerebral territory, suggesting cerebral ischemia. He reported having had a similar episode 7 years before, after taking oral isotretinoin for 3 months. No susceptibility factors were identified. Isotretinoin was withdrawn and the disorder resolved.
Isotretinoin seems to act on the coagulation process by a still-unexplained mechanism. Sensory systems Eyes Ocular adverse effects are common in patients taking
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isotretinoin, and have been comprehen sively reviewed (42R). Most are short-lived and usually resolve entirely on drug with drawal. They include abnormal meibomian gland secretion, sicca syndrome, blepharo conjunctivitis, reduced tolerance to contact lenses, photophobia, and keratitis. However, more significant and potentially persistent abnormalities can occur, including corneal opacities and raised intracranial pressure. Reduced retinal function has been reported, but in most patients it appears to improve on withdrawal. Typical symptoms include blurred vision, reduced night vision, and glare. In many cases patients are asympto matic or unaware of visual adverse effects, despite objectively demonstrable electro physiological abnormalities. Night blindness after the use of low-dose isotretinoin for a very short period has been reported (43A). • A 21-year-old, 60 kg female student was given isotretinoin 20 mg/day and 2 weeks later developed severe deterioration of night vision. Her serum concentrations of vitamin A and retinol binding protein were normal (2.2 µmol/l: reference range 1.4–4.0; and 39 µmol/l: reference range 32–60). She was given vitamin A 5000 units/day and by 4 months after stopping isotretinoin her night vision had recovered.
This case highlights the need to encourage all patients to report changes in night vision promptly, even in the earliest stages of iso tretinoin treatment. Patients such as pilots and commercial drivers, for whom the con sequences of even small changes in night vision would be serious, should be consid ered for electroretinography before and early during the course of isotretinoin ther apy. Measurement of serum concentrations of vitamin A and retinol binding protein can be helpful in assessing patients with impaired night vision, and vitamin A, even with normal serum concentrations, can help to speed recovery. Since isotretinoin is a retinoid, the mechanism of impaired night vision is likely to be interference with the retinol pathway, essential to the function of photoreceptors. Myopia has been attributed to isotreti noin (44A).
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• A 29-year-old Caucasian woman took isotretinoin 40 mg/day for acne and after 20 days suddenly noticed a marked reduction in visual sharpness. An ophthalmologist confirmed binocular myopia of 1.5 and 0.5 dioptres. Isotretinoin was discontinued 6 weeks later, but 13 months later she still had the same defect of refraction.
recovered baseline salivary flow 2 months after the end of treatment.
The authors could conclude that there was a certain relation between myopia and iso tretinoin, because it did not resolve after drug withdrawal. However, sudden onset of myopia in an adult without any previous ocular problem is remarkable.
• A 31-year-old African-Caribbean man was given oral isotretinoin 40 mg/day for dissecting cellulitis of the scalp and 4 weeks later developed sudden, sharp, right-sided chest pain, worse on deep inspiration. There was nothing abnormal on examinations and exhaustive hematological and biochemistry tests were normal, as was a chest X-ray. His chest pain lasted for 2 hours and resolved without pharmacological intervention. He stopped taking isotretinoin but started again 2 weeks later. After 1 week he had another episode of self-limiting right-sided pleuritic chest pain and stopped taking isotretinoin. An echocardiogram was normal. He later restarted isotretinoin and had a third admission with similar symptoms and negative investigations.
Hematologic Agranulocytosis has been attributed to isotretinoin (45A). • A 15-year-old girl with acne vulgaris developed a fever and odynophagia after taking isotreti noin 0.5 mg/kg for 5 weeks and then 1 mg/kg for 15 weeks. She had stopped taking isotretinoin 8 days before. Her hemoglobin was 13.7 g/dl, white blood cell count 1.2 109/l, and platelet count 145 109/l. There were no neutrophils. Bone marrow aspiration excluded malignancy. Antineutrophil antibodies were negative. Epstein–Barr virus, cytomegalovirus and human immunodeficiency virus (HIV) serologies were negative. Neutropenia was attributed to isotretinoin. She was given cefepime 150 mg/ kg/day and a single dose of recombinant human granulocyte colony stimulating factor (r-HuGCSF) subcutaneously. Her fever resolved and her white blood cell count rose to 7.7 109/l with a neutrophil count of 3.3 109/l. During the next year her neutrophil counts were normal.
Agranulocytosis is found in a variety of infectious diseases, but studies in this patient failed to reveal an infectious trigger. Teeth In a cohort study of the oral adverse effects of isotretinoin 0.5 mg/kg/ day salivary flow, the buffering capacity of the saliva, the number of pathogenic bac teria and the DMFT index (number of decayed, missing, and filled teeth) were assessed at each visit in 18 patients and 99 controls (46c). None of the measurements varied with time in the control group, whereas the DMFT index worsened signifi cantly in the treated group. Salivary flow gradually fell with time, but the patients
Serosae Non-musculoskeletal pleuritic chest pain has been associated with isotreti noin (47A).
The exact cause of the chest pain in this patient was undetermined, but the temporal association with isotretinoin on three occa sions and resolution of symptoms on with drawal suggests an association. Musculoskeletal Sacroiliitis and a sensori motor demyelinating polyneuropathy have been associated with isotretinoin (48A). • A 20-year-old otherwise healthy man developed bilateral hip pain. He had been using isotretinoin for acne for the previous 3 months (initial dose 30 mg/day for 2 months, increased to 40 mg/day for 1 month). The sacroiliac joints were very painful bilaterally and he had a Trendelenburg gait. His erythrocyte sedimentation rate was 50 mm/ hour (reference range 0–15); creatine kinase 1629 U/l (0–195), serum lead 160 µg/l (0–20), rheumatoid factor 22 IU/ml (0–15), and C-reactive protein 19 mg/l (0–5). He was HLA-B27 positive. An MRI scan of his sacroiliac joints showed bilaterally diffuse subarticular edema. Electromyography of the leg muscles showed a sensorimotor demyelinating polyneuropathy. Isotretinoin was withdrawn and he was given naproxen 500 mg/day. Within 4 weeks the laboratory results improved and the symptoms almost completely resolved. During 2 years of follow-up, the MRI findings fluctuated, showing presence and absence of sacroiliitis.
Dermatological drugs, topical agents and cosmetics Electromyography 2 years after the initial diagnosis showed mild improvement. A sural nerve biopsy showed demyelinating polyneuropathy with active regeneration.
Reproductive system Although there have been several reports of menstrual irre gularities related to isotretinoin, they were only mentioned as uncommon or trivial adverse effects. Of 40 women with acne patients who took isotretinoin 0.7–1.2 mg/ kg/day for 16 weeks or more, 8 had men strual irregularities during treatment (49c). They all denied previous menstrual irregula rities. Their hormone concentrations, including serum luteinizing hormone (LH), follicular stimulating hormone (FSH), thyroid-stimulating hormone (TSH), prolac tin, estradiol, and androgen, were within the reference ranges, and sonography showed no abnormalities. The progesterone withdrawal test using oral medroxyprogesterone 10 mg for 7 days resulted in bleeding. In all eight patients, menstruation regularity returned to normal after withdrawal of isotretinoin. The mechanism of menstrual irregularity induced by isotretinoin is unclear. Because this study examined women taking high doses of isotre tinoin (maintenance dose 1–1.2 mg/kg/day) for at least 16 weeks, it is difficult to draw a conclusion about the precise effect of treat ment duration and cumulative dose. How ever, normal hormone concentrations and a positive response to progesterone withdrawal in two patients suggested that the irregulari ties were caused by some disturbance in the pattern of pulsatile gonadotropin-releasing hormone (GnRH) secretion. Teratogenicity Of 8609 women aged 13–45 years with a first prescription for isotretinoin, 90 became pregnant, an annual incident preg nancy rate of 33 per 1000 person-years of treatment (95% CI = 27, 40) (50C). Of those 90 women, 76 had a termination, 3 had a spontaneous abortion (3%), 2 had trauma during delivery resulting in neonatal deaths (2%) and 9 had live births. Among the live births, only one had a congenital anomaly of the face and neck. Adjusting for potential confounders, predictors of becoming preg nant while taking isotretinoin were lower
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socio-economic class, one or more visits to the doctor or to the emergency department, or one or more episodes of hospitalization while taking isotretinoin; concomitant oral contraceptive use was preventive. This non interventional population-based study gener ated incidence rates of pregnancy while on isotretinoin four times greater than have been reported so far; elective abortion rates were also much higher.
Tretinoin (all-trans retinoic acid, ATRA) (SEDA-30, 186) In a multicenter, open evaluation of a gel formulation containing a crystalline suspen sion of clindamycin phosphate 1.2% þ tre tinoin 0.025% (called CLIN/RA) in 442 patients, the most frequent adverse events were acne (29/442; 7%, usually a flare), sun burn (12/442; 3%), hypersensitivity reactions (7/442; 2%), contact dermatitis (5/442; 1%), and desquamation at the site of application (3/442; 1%) (51r).
VITAMIN D ANALOGUES, TOPICAL (SED-15, 594; SEDA-29, 156; SEDA-31, 293; for oral vitamin D analogues see Chapter 34)
Tacalcitol Mineral metabolism Tacalcitol is a vitamin D analogue used as an ointment for psoriasis. It can cause hypercalcemia (52A). • A young man with severe psoriasis had an exacerbation of his skin disease (PASI = 68) and was given dithranol in alternation with tacalcitol (Curatoderm®). Tacalcitol was limited to 30% of body surface area once a day. On day 3 he developed severe abdominal pain and vomiting and admitted that he had already used tacalcitol for 3 months in a mean dosage of about 30 g/day. Thus, the cumulative dose was 2500–3000 g, exceeding the manufacturer’s guidelines by 8–10 times. He had severe hypercalcemia due to vitamin D intoxication, which was thought to have been responsible for acute pancreatitis.
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This patient had a very severe disease, in which scaling could have influenced drug absorption. However, he had also used a very high total dose, exceeding the manufac turer’s guidelines by 8–10 times and long-
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term exposure by 2–3 times. This is important, because the amount of drug absorption by the skin is often underestimated by patients and ointments are considered as relatively harmless compared with oral formulations.
References 1. Kolbach DN, Nieboer C. Fumaric acid ther apy in psoriasis: results and side effects of 2 years of treatment. J Am Acad Dermatol 1992;27(5 Pt 1):769–71. 2. Altmeyer PJ, Matthes U, Pawlak F, Hoffmann K, Frosch PJ, Ruppert P, Wassilew SW, Horn T, Kreysel HW, Lutz G Antipsoriatic effect of fumaric acid derivatives. Results of a multicenter doubleblind study in 100 patients. J Am Acad Der matol 1994;30(6):977–81. 3. Mrowietz U, Christophers E, Altmeyer P. Treatment of psoriasis with fumaric acid esters: results of a prospective multicentre study. German Multicentre Study. Br J Der matol 1998;138(3):456–60. 4. Litjens NH, van Strijen E, van Gulpen C, Mattie H, van Dissel JT, Thio HB, Nibbering PH. In vitro pharmacokinetics of anti-psoriatic fumaric acid esters. BMC Pharmacol 2004;4:22. 5. Nibbering PH, Thio B, Zomerdijk TP, Beze mer AC, Beijersbergen RL, van Furth R. Effects of monomethylfumarate on human granulocytes. J Invest Dermatol 1993;101 (1):37–42. 6. Thio HB, Zomerdijk TP, Oudshoorn C, Kempenaar J, Nibbering PH, van der Schroeff JG, Ponec M. Fumaric acid deriva tives evoke a transient increase in intracel lular free calcium concentration and inhibit the proliferation of human keratinocytes. Br J Dermatol 1994;131(6):856–61. 7. Vandermeeren M, Janssens S, Borgers M, Geysen J. Dimethylfumarate is an inhibitor of cytokine-induced E-selectin, VCAM-1, and ICAM-1 expression in human endo thelial cells. Biochem Biophys Res Com mun 1997;234(1):19–23. 8. Sebok B, Bonnekoh B, Vetter R, Schneider I, Gollnick H, Mahrle G. The antipsoriatic
dimethyl-fumarate suppresses interferon gamma-induced ICAM-1 and HLA-DR expression on hyperproliferative keratino cytes. Quantification by a culture platedirected APAAP–ELISA technique. Eur J Dermatol 1998;8(1):29–32. 9. Ockenfels HM, Schultewolter T, Ockenfels G, Funk R, Goos M. The antipsoriatic agent dimethylfumarate immunomodulates T-cell cytokine secretion and inhibits cytokines of the psoriatic cytokine network. Br J Derma tol 1998;139(3):390–5. 10. Vandermeeren M, Janssens S, Wouters H, Borghmans I, Borgers M, Beyaert R, Geysen J. Dimethylfumarate is an inhibitor of cyto kine-induced nuclear translocation of NFkappa B1, but not RelA in normal human dermal fibroblast cells. J Invest Dermatol 2001;116(1):124–30. 11. Weber HO, Borelli C, Ro¨ cken M, Schaller M. Treatment of disseminated granuloma annu lare with low-dose fumaric acid. Acta Derm Venereol 2009;89(3):295–8. 12. Venten I, Hess N, Hirschm€ uller A, Altmeyer P, Brockmeyer N. Treatment of therapy-resistant alopecia areata with fumaric acid esters. Eur J Med Res 2006;11(7):300–5. 13. Kreuter A, Knierim C, St€ ucker M, Pawlak F, Rotterdam S, Altmeyer P, Gambichler T. Fumaric acid esters in necrobiosis lipoidica: results of a prospective noncontrolled study. Br J Dermatol 2005;153(4):802–7. 14. Coras B, Vogt TH, Ulrich H, Landthaler M, Hohenleutner U. Fumaric acid esters therapy: a new treatment modality in pityriasis rubra pilaris? Br J Dermatol 2005;152(2):388–9. 15. Kappos L, Gold R, Miller DH, Macmanus DG, Havrdova E, Limmroth V, Polman CH, Schmierer K, Yousry TA, Yang M, Eraksoy M, Meluzinova E, Rektor I, Dawson KT, Sandrock AW, O’Neill GN,
Dermatological drugs, topical agents and cosmetics BG-12 Phase IIb Study Investigators. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebocontrolled phase IIb study. Lancet 2008;372 (9648):1463–72. 16. Heinz C, Heiligenhaus A. Improvement of noninfectious uveitis with fumaric acid esters: results of a pilot study. Arch Ophthal mol 2007;125(4):569–71. 17. Harries MJ, Chalmers RJ, Griffiths CE. Fumaric acid esters for severe psoriasis: a retrospective review of 58 cases. Br J Der matol 2005;153(3):549–51. 18. Nieboer C, de Hoop D, Langendijk PN, van Loenen AC, Gubbels J. Fumaric acid therapy in psoriasis: a double-blind com parison between fumaric acid compound ther apy and monotherapy with dimethylfumaric acid ester. Dermatologica 1990;181(1): 33–7. 19. Ng SY, Wilkinson J. A salutary case of Fuma derm potentially masking the symptoms of bowel cancer and partial bowel obstruction. Br J Dermatol 2007;157(4): 825–6. 20. de Haan P von Blomberg-van der Flier BM, de Groot J, Nieboer C, Bruynzeel DP. The risk of sensibilization and contact urticaria upon topical application of fumaric acid deri vatives. Dermatology 1994;188(2):126–30. 21. Foti C, Zambonin CG, Cassano N, Aresta A, Damascelli A, Ferrara F, Vena GA. Occupa tional allergic contact dermatitis associated with dimethyl fumarate in clothing. Contact Derm 2009;61(2):122–4. 22. Rantanen T. The cause of the Chinese sofa/ chair dermatitis epidemic is likely to be con tact allergy to dimethylfumarate, a novel potent contact sensitizer. Br J Dermatol 2008;159(1):218–21. 23. Morton LM, Bernstein L, Wang SS, Hein DW, Rothman N, Colt JS, Davis S, Cerhan JR, Severson RK, Welch R, Hartge P, Zahm SH. Hair dye use, genetic variation in N-acetyl transferase 1 (NAT1) and 2 (NAT2), and risk of non-Hodgkin lymphoma. Carcinogen esis 2007;28(12):1759–64. 24. Katar S, Devecioglu C, Ozbek MN, Ecer S. Henna causes life-threatening hyperbilirubi naemia in glucose-6-phosphate dehydrogenase deficiency. Clin Exp Dermatol 2006;32:235–6. 25. Mouzopoulos G, Tsouparopoulos V, Stamatakos M, Mihelarakis I, Pasparakis D,
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Agapitos E. Cutaneous mercury deposits after henna dye application in the arm. Br J Dermatol 2007;157(2):394–5. 26. Davies EEG, Grabczynska S. Para phenylenediamine allergy from a henna tat too. Arch Dis Child 2007;92(3):243. 27. Corrente S, Moschese V, Chianca M, Graziani S, Iannini R, La Rocca M, Chini L. Temporary henna tattoo is unsafe in atopic children. Acta Paediatr 2007;96(3):469–71. 28. Gordon MK, Kraus M, van Besien K. Inter digitating dendritic cell tumors in two patients exposed to topical calcineurin inhi bitors. Leuk Lymphoma 2007;48(4):816–8. 29. Shaw DW, Maibach HI, Eichenfield LF. Allergic contact dermatitis from pimecro limus in a patient with tacrolimus allergy. J Am Acad Dermatology 2007;56(2): 342–5. 30. Goksugur N, Ozbostanci B, Goksugur SB. Molluscum contagiosum infection associated with pimecrolimus use in pityriasis alba. Pediatr Dermatol 2007;24(5):63–5. 31. Georgala S, Befon A, Maniatopoulou E, Georgala C. Topical use of minoxidil in chil dren and systemic side effects. Dermatology 2007;214(1):101–2. 32. Callen EC, Church CO, Hernandez CL, Thompson ED. Stevens–Johnson syndrome associated with oral minoxidil: a case report. J Nephrol 2007;20(1):91–3. 33. Katrine EK, Lindeburg KEK, Brogaard HMV, Jemec GBE. Pain and photodynamic therapy (PDT). Dermatology 2007;215(3):206–8. 34. Harries MJ, Street G, Gilmour E, Rhodes LE, Beck MH. Allergic contact dermatitis to methyl aminolevulinate (Metvix) cream used in photodynamic therapy. Photoderma tol Photoimmunol Photomed 2007;23:35–6. 35. Vos LE, Vermeer MH, Pavel S. Acitretin induces capillary leak syndrome in a patient with pustular psoriasis. J Am Acad Dermatol 2007;56(2):339–42. 36. Arnault JP, Petitpain N, Granel-Brocard F, Cuny JF, Barbaud A, Schmutz JL. Acitretin and sixth nerve palsy. J Eur Acad Dermatol Venereol 2007;21(9):1258–9. 37. Bastos PR, Avelleira JCR, Cruz MA, de Oliveira NC, Azulay DR. Granulation tissue in palpebral conjunctivae associated with aci tretin therapy. J Am Acad Dermatol 2008;58 (2):S41–2.
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38. Dresden G. Atrial tachycardia associated with isotretinoin use. Arch Dermatol 2007;143(8):1084–5. 39. Aydogan K, Karli N. Effects of oral isotreti noin therapy on peripheral nerve functions: a preliminary study. Clin Exp Dermatol 2007;32(1):81–4. 40. Yaman M, Albayram S, Altintas A, Yeni SN, Karaagac N, Islak C. A cerebellar demyeli nating lesion following treatment of acne with isotretinoin. Clin Exp Dermatol 2008;33(2):118–21. 41. Laroche ML, Macian-Montoro F, Merle L, Vallat JM. Cerebral ischemia probably related to isotretinoin. Ann Pharmacother 2007;41(6):1073–6. 42. Taibjee SM, Charles-Holmes R. Pitfalls of pre scribing acne therapies including isotretinoin for pilots. Br J Dermatol 2008;158(3):653–5. 43. Halpagi P, Grigg J, Klistorner A, Damian DL. Night blindness following low-dose isotretinoin. J Eur Acad Dermatol Venereol 2008;22(7):893–4. 44. Martinez-Gonzalez MC, Garcia-Silva J, Sanchez MA, Castineiras I, Del Pozo J, Capdevila EF. Acute myopia while on oral isotretinoin treatment. J Eur Acad Dermatol Venereol 2007;21(7):977–8. 45. Ozdemir MA, Kose M, Karakukcu M, Ferahbas A, Patiroglu T, Koklu E. Isotretinoin induced agranulocytosis. Pediatr Dermatol 2007;24(4):425–6.
Ida Duarte, Rosana Lazzarini, and Anita Rotter
46. Lupi-Pegurier L, Muller-Bolla M, Fontas E, Ortonne JP. Reduced salivary flow induced by systemic isotretinoin may lead to dental decay. Dermatology 2007;214 (3):221–6. 47. Madan V, Muston HL, Marsland AM. Isotretinoin-induced pleuritic chest pain. Br J Dermatol 2007;157(2):385–6. 48. Eksioglu E, Oztekin F, Unlu E, Cakci A, Keyik B, Karadavut IK. Sacroiliitis and poly neuropathy during isotretinoin treatment. Clin Exp Dermatol 2008;33(2):122–4. 49. Kwon HJ, Lee JY, Cho BK, Park HJ. Menstrual irregularity during isotretinoin treatment. J Am Acad Dermatol 2007;21(4): 562–3. 50. Berard A, Azoulay L, Koren G, Blais L, Perreault S, Oraichi D. Isotretinoin pregnan cies, abortions and birth defects: a popula tion-based perspective. Br J Clin Pharmacol 2007;63(2):196–205. 51. Kircik LH, Peredo MI, Bucko AD, Loss Jr. RW, Fowler Jr. JF, Wortzman M, Neumaier GJ. Safety of a novel gel formulation of clindamycin phosphate 1.2%–tretinoin 0.025%: results from a 52 week open-label study. Cutis 2008;82(5): 358–66. 52. Knackstedt C, Winograd R, Koch A, Abuzahra F, Trautwein C, Wasmuth HE. Acute necrotic pancreatitis induced by severe hypercalcaemia due to tacalcitol ointment. Br J Dermatol 2007;156:575–612.
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15
Antihistamines (H1 receptor antagonists)
Histamine plays a prominent and diverse role in the pathophysiology of allergic disease, and therapeutic intervention is therefore typically focussed on blocking the effects of this biogenic amine. The histamine H1 recep tor is a heptahelical transmembrane molecule that transduces extracellular signals to intra cellular second messenger systems via G pro teins. Antihistamines act as inverse agonists that combine with H1 receptors, stabilizing them in the inactive form and shifting the equilibrium towards the inactive state (1R).
Brompheniramine
(SED-15, 562; see also dexbrompheniramine below)
Placebo-controlled studies Both sleepiness and hyperactivity were reported in children taking combinations of antihistamines þ decongestants (brompheniramine þ phenyl propanolamine and brompheniramine þ phenylephrine þ phenylpropanolamine) (2 C , 3 c ).
Cetirizine
(SED-15, 702; SEDA-29, 161; SEDA-30, 189; SEDA-31, 297) Cardiovascular The cardiotoxic effects of antihistamines are of concern in patients with long QT syndrome who also have allergies
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32015-0 � 2010 Elsevier B.V. All rights reserved.
(4R). In a randomized, single-blind study 15 asymptomatic patients with type 1 or type 2 long QT syndrome and 15 healthy volunteers were given placebo or cetirizine 10 mg (5A). Electrocardiography was performed at rest and after exercise. Cetirizine did not prolong the QT intervals either at rest or during exercise and recovery in either group. Thus, it may be safe in carriers of the gene mutations that cause long QT syndrome. Skin Fixed drug eruptions are the most frequent types of adverse cutaneous drug reaction; although fixed drug eruptions caused by systemic antihistamines are very rare, some have been previously reported with both cetirizine and levocetirizine (SEDA-31, 300), and another has been reported (6A). • A 45-year-old woman developed multiple, welldefined, round, erythematous, violaceous plaques, with central blisters on the trunk, forearms, and backs of the hands. She had taken oral cetirizine 10 mg for allergic rhinitis 4 hours before the lesions had appeared and reported three previous eruptions with the same morphology in the same sites, which had resolved spontaneously in 8–10 days, leaving only residual brown to grey hyperpigmentation, features typical of a fixed drug eruption. However, the previous episodes had not been associated with any medication. After an 8-day tapering regimen of methylprednisolone, starting with 32 mg/day, the lesions resolved. Six weeks later patch testing with cetirizine, levocetirizine, hydroxyzine, nimesulide, piroxicam, and vehicle controls produced positive reactions with cetirizine, levocetirizine, and hydroxyzine, but only on previously affected areas as defined by the residual hyperpigmented lesions. She was advised to avoid these three antihistamines and had no relapses.
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The authors concluded that cutaneous crossreactivity to cetirizine, levocetirizine, or hydroxyzine was due to the fact that they have the same chemical piperazine structure and similar pharmacological profiles. An urticarial reaction that was repro duced by challenge with cetirizine was not reproduced by levocetirizine (7A). • A 22-year-old man with chronic idiopathic urticaria, asthma and allergic rhinitis developed a severe exacerbation of generalized urticaria. He had previously taken cetirizine and hydroxyzine without aggravation of symptoms, and for the previous 3 months had taken only loratadine. He was given cetirizine and montelukast for nasal symptoms and asthma and 4 hours later developed severe generalized urticaria. Cetirizine and montelukast were withdrawn and the urticarial lesions disappeared spontaneously within 5 days. Subsequently, single-blind, placebo-controlled skin challenge tests were performed with cetirizine, levocetirizine, chlorphenamine, ebastine, fexofenadine, hydroxyzine, loratadine, montelukast, and placebo. Cetirizine and hydroxyzine reproduced the generalized urticaria after 3 and 4 hours respectively; levocetirizine and the other drugs and placebo had no effect. Drug-specific serum IgE was not found.
It is possible that dextrocetirizine, the dextrorotatory enantiomer of cetirizine, was the causative agent in this case, but this possibility was not directly tested.
Garry M. Walsh
urticaria (11C). Adverse events in those taking desloratadine were similar to events in those taking placebo. Because of a phenotypic polymorphism, about 6% of individuals have a reduced ability to metabolize desloratadine to the active metabolite 3-hydroxydesloratadine (12R). In one study three African American sub jects with normal liver function who were poor metabolizers of desloratadine had 2.6–6.5 times greater exposure to des loratadine than subjects with normal liver function and metabolism (13c). Adverse effects in those subjects were no more common than in those with nor mal metabolism.
Dexbrompheniramine
(SED-15, 1081; see also brompheniramine above) Placebo-controlled studies There were more cases of dizziness and dry mouth in patients taking dexbrompheniramine þ pseudephedrine (6 mg þ 120 mg bd for 7 days) (14c).
Dexchlorpheniramine (SED-15, 1081; SEDA-30, 162)
Teratogenicity In a prospective observa tional cohort study in 196 pregnant women exposed to cetirizine during the first trime ster and 1686 women who were not exposed to potential teratogens, cetirizine had no significant teratogenic effects (8C).
Desloratadine(SED-15, 1074; SEDA 29, 162; SEDA-30, 189; SEDA-31, 298; see also Loratadine below) Susceptibility factors Genetic Randomized trials have shown that desloratadine is effective and well tolerated in allergic rhinitis (9C, 10C) and chronic idiopathic
Nervous system First-generation sedating antihistamines such as dexchlorphenira mine and diphenhydramine readily cross the blood–brain barrier, resulting in block ade of histamine H1 receptors in the brain, which are responsible for maintaining a state of arousal, leading to drowsiness, fati gue, and psychomotor disturbances. The effect of first-generation antihistamines on a complex task such as car driving is well established. In a single-blind, placebocontrolled, crossover study the effect of oral dexchlorpheniramine 6 mg on regional cerebral blood flow responses, measured by positron emission tomography and (15O) H2O, was evaluated during a simulated car-driving task (15c). The numbers of lane
Antihistamines (H1 receptor antagonists)
Chapter 15
deviations were significantly increased by dexchlorpheniramine because of sup pression of visuospatial cognition and visuo motor coordination, rather than an effect on attention and motor functions. The authors reported no significant effect on subjective feelings of drowsiness, most probably because a modified-release formulation of dexchlorpheniramine (Repetab) was used in the study.
Diphenhydramine
(SED-15, 1134; SEDA-29, 163; SEDA-30, 189; SEDA-31, 298)
Drug overdose Diphenhydramine is inclu ded in many over-the-counter formulations for the treatment of allergic disease, insom nia, and symptoms of the common cold. Such medications are often used in chil dren, with the consequential risk of un intended diphenhydramine overdose. In a retrospective review of 25 012 cases of acute diphenhydramine overdose in young children, 926 met the following inclusion criteria: younger than 6 years, a single med ication ingested, a known quantity ingested, and a known clinical outcome (16c). The mean age was 30 months (range 1–72 months) and 49% were boys. The mean dose was 6.4 mg/kg (median 4.6). There were symptoms in 32%; most were minor (29%), 2.9 % had moderate symptoms, and 0.11% had severe symptoms. There was no relation between dose and symptom inten sity. A diphenhydramine dose of 7.5 mg/kg or more did not predict symptom severity; however, the authors concluded that patients who take a single dose greater than this should be referred to a healthcare facility. Overdosage in an adult has also been reported (17A). • A 47-year-old obese (110 kg) Caucasian man took 230 tablets of diphenhydramine (Benocten), giving a total dose of 10 mg/kg. He developed slight rotational nystagmus, opened his eyes only on command, and had no comprehensible speech. His Glasgow Coma Scale (GCS) score was 9. However, 3
307 hours after ingestion his cognitive state deteriorated to a GCS score of 5. He was intubated, sedated with propofol 100 mg/hour, and given activated charcoal 110 g over 6 hours through a nasogastric tube. After another 9 hours he awoke and remained asymptomatic thereafter.
The authors expressed surprise that a diphenhydramine plasma concentration above 15 µmol/l 8 hours after ingestion led to only a few hours of impaired conscious ness in this patient and no other symptoms. Severe symptoms, including coma, seizures, delirium, psychosis, agitation, and/or elec trocardiographic changes, are commonly expected with diphenhydramine doses above 1 g (18C).
Doxylamine
(SED-15, 1192;
SEDA-31, 298) Nervous system Giddiness and drowsiness were reported in adults taking Vicks Medi nite syrup (doxylamine þ dextromethor phan þ ephedrine þ paracetamol) (19c). Musculoskeletal Rhabdomyolysis is a potentially life-threatening complication of doxylamine overdose and in some cases leads to acute renal insufficiency, requiring dialysis. Most patients recover completely from rhabdomyolysis if it is recognized and treated promptly. Accordingly, early detec tion and management of patients at high risk of rhabdomyolysis after doxylamine overdose is important. In a prospective, observational study of 27 patients with doxylamine overdose, 16 developed rhabdomyolysis and 3 had acute renal insufficiency (20C). A dose of doxylamine greater than 20 mg/kg predicted rhabdomyolysis, with a sensitivity of 81%. As the authors acknowledged, the chief limitation of this study was the small number of subjects. However, they concluded that all patients with doxylamine overdose should be investigated for rhabdomyolysis and treated promptly to prevent progression to acute renal insufficiency.
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Levocetirizine (SED-15, 2038; SEDA-29, 163; SEDA-30, 190; SEDA-31, 300; see also Cetirizine above) Cardiovascular In a four-way, crossover, randomized, placebo- and positive-controlled trial of the effect of levocetirizine 5 and 30 mg/ day on the QT interval in 52 healthy men and women, levocetirizine had no significant effects on cardiac repolarization, in contrast to the effect of moxifloxacin (21C). Teratogenicity An analysis of safety data from the Early Prevention of Asthma in Atopic Children Study, in which 510 atopic children aged 12–24 months at entry received either levocetirizine 0.125 mg/kg bd or placebo for 18 months showed no significant adverse effects or treatment-associated drop outs associated with levocetirizine (22C). This comprehensive and well-constructed study confirms the long-term safety of levocetirizine in young atopic children.
Loratadine
(SED-15, 2162; SEDA-29, 164; see also Desloratadine above)
Garry M. Walsh
insomnia) were reported in 30% of those taking loratadine þ pseudoephedrine (5 mg 120 mg bd for 4 days) compared with 21% of those taking placebo (23C).
Rupatadine Rupatadine is a dual-acting compound that acts as both a histamine H1 receptor antago nist and a potent antagonist of the proinflammatory lipid mediator platelet activating factor (PAF). In randomized clin ical trials rupatadine has been effective and well tolerated in patients with allergic rhini tis (24C) and chronic idiopathic urticaria (25C, 26C). Placebo-controlled studies In a rando mized, double-blind, three-way, crossover study of the effect of rupatadine 10 mg on the actual driving performance of 20 healthy volunteers, it had no significant effect on lateral positioning, while the posi tive control hydroxyzine 50 mg significantly impaired it (27C).
Placebo-controlled studies Adverse events (including dry mouth, headache, and
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310 Pérez I, Izquierdo I, Arnaiz E. Once-daily rupatadine improves the symptoms of chronic idiopathic urticaria: a randomised, double-blind, placebo-controlled study. Eur J Dermatol 2007;17:223–8.
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27. Vuurman E, Theunissen E, van Oers A, van Leeuwen C, Jolles J. Lack of effects between rupatadine 10 mg and placebo on actual driving performance of healthy volunteers. Hum Psychopharmacol 2007;22(5):289–97.
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INHALED GLUCOCORTICOIDS (SEDA-29, 168; SEDA-30, 193; SEDA-31, 305)
Inhaled glucocorticoids and the risk of pneumonia
EIDOS classification:
Extrinsic species: Glucocorticoids
Intrinsic species: Not known
Distribution: Lungs
Outcome: Not known
Sequela: Pneumonia from inhaled
glucocorticoids in COPD
DoTS classification:
Dose-relation: Collateral reaction
Time-course: Early
Susceptibility factors: Age (over 55
years); physiological changes (low body mass index); diseases (severe COPD) A large cohort of patients with chronic obstructive pulmonary disease (COPD) using inhaled glucocorticoids has been stud ied in a retrospective, nested, case-control study (1c). Each subject who was hospita lized for pneumonia between 1988 and 2003 (n = 23 942) was age- and timematched with four control subjects (n = 95 768). After adjusting for co-morbidity and Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32016-2 � 2010 Elsevier B.V. All rights reserved.
severity of COPD, the rate ratio of hospita lization for pneumonia associated with cur rent use of inhaled glucocorticoids was 1.70 (95% CI = 1.63, 1.77); for hospitalization for pneumonia followed by death within 30 days the rate ratio was 1.53 (95% CI = 1.30, 1.80). The rate ratio of hospitalization for pneumo nia was greatest with the highest doses of inhaled glucocorticoids. For example, at a dosage equivalent to fluticasone 1 mg/day or more, the rate ratio was 2.25 (95% CI = 2.07, 2.44). All-cause mortality was similar for patients hospitalized for pneumo nia, whether or not they had used inhaled glucocorticoids (7.4 and 8.2%, respectively). The Towards a Revolution in COPD Health (TORCH) randomized controlled trial also reported that there was an excess of patients who developed pneumonia if they were using study medications containing inhaled glucocorticoids (either as monotherapy or in combination with a long-acting beta-adrenoceptor agonist) (2C). A post hoc analysis of their data showed that, after adjusting for time on treatment, there was a higher rate of pneumonia in those who used either fluticasone or salmeterol þ fluticasone (84 and 88 per 1000 treatment-years respec tively) compared with salmeterol only and pla cebo (52 and 52 per 1000 treatment-years respectively), despite a higher withdrawal rate in the placebo arm (3C). Susceptibility factors for pneumonia in those using inhaled glucocorticoids were age 55 years or more, more severe COPD with an FEV1 under 50% predicted, COPD exacerbations in the year before the study, worse Medical Research Council dyspnea scores and body mass index (BMI) under 25 kg/m2. There was no increase in pneumonia deaths
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with salmeterol þ fluticasone, but this could not be concluded for fluticasone alone. In a review of 18 randomized controlled trials involving 16 966 subjects with COPD, inhaled glucocorticoids were associated with a significantly increased risk of any pneumonia (RR= 1.60; 95% CI = 1.33, 1.92) and serious pneumonia (RR = 1.71; CI = 1.46, 1.99), but without a significantly increased risk of pneumonia-related mortality (RR = 1.27; CI = 0.80, 2.03) or overall mortality (RR = 0.96; CI = 0.86, 1.08) (4M). Moreover, inhaled glucocorticoids were associated with a significantly increased risk of serious pneu monia compared with placebo (RR = 1.81; CI = 1.44, 2.29) and also when the combination of inhaled glucocorticoids and long-acting beta-adrenoceptor agonists was compared with long-acting beta-adrenoceptor agonists alone (RR = 1.68; CI = 1.20, 2.34). In an analysis of pooled data from seven large trials comparing 3801 patients using inhaled budesonide (320–1280 micrograms/ day) with or without formoterol, with 5212 patient-years of exposure to treatment, versus 3241 patients in the control arms receiving placebo or formoterol alone, there was no significant difference in the occurrence of pneumonia (3% in both groups, adjusted HR = 1.05, 95% CI = 0.81, 1.37) or for time to pneumonia (log rank test = 0.94) (5M). The authors concluded that (in contrast to other inhaled glucocorticoids) budesonide used for 12 months did not increase the risk of pneumonia in patients with COPD. In summary, despite the benefits of inhaled glucocorticoids in the management of COPD, health-care providers should remain vigilant to the possibility of non-fatal pneumonia as a complication of inhaled glucocorticoids. Skin Cutaneous thinning and bruising have been reported in adults using inhaled glucocorticoids, but a double-blind, randomized, placebo-controlled trial of inhaled triamcinolone in COPD has provided more specific details on the exact prevalence of cutaneous adverse effects (6C). Bruising occurred in 11% of those who used inhaled glucocorticoids and 3.7% with placebo; delayed wound healing
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occurred in 2.4% and 0.5% respectively. These adverse effects were dose-related and increased with age.
Inhaled glucocorticoids: update on skeletal adverse effects The effects of inhaled glucocorticoids on osteoporosis and the risk of hip fracture were reviewed in SEDA-31 (p. 307), but more evidence is accruing about those who use inhaled glucocorticoids specifically for COPD. The dose–response relationship between inhaled glucocorticoids and the risk of frac ture in people with COPD, independent of confounders, has been investigated in a nested case-control study (7 c). Cases (people with a fracture identified from network data bases, n = 1235) were assigned up to four controls (n = 4598). The risk of fracture increased with increasing mean daily doses of inhaled glucocorticoids, and was most marked in those whose daily dose was at least 1.6 mg (OR = 1.80, 95% CI = 1.04, 3.11). This effect was virtually unchanged by adjustment for the degree of airflow obstruction and the annual prescription rate for oral glucocorticoids (adjusted OR for highest exposure = 1.74, 95% CI = 1.00, 3.01). The prevalence and progression of osteo porosis, specifically in patients taking inhaled glucocorticoids for COPD, was studied in a subset of 658 patients in the TORCH study (8C). This US subgroup had annual assess ments of bone mineral density. At baseline, 18% of the men and 30% of the women had osteoporosis and 42% of the men and 41% of the women had osteopenia. Annual changes in bone mineral density at the hip and lumbar spine over 3 years were small and there were no significant differences between treatment arms (adjusted mean percentage change from baseline at the hip was –3.1% for pla cebo, –1.7% for salmeterol only, –2.9% for fluticasone only, and –3.2% for the combina tion of salmeterol þ fluticasone; the respective changes at the lumbar spine were 0, 1.5, –0.3 and –0.3%). The incidence of fractures was low and similar with all treatments (5.1–6.3%). The authors concluded that
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osteoporosis is highly prevalent in patients with COPD, irrespective of sex, but there was no significant effect of standard doses of inhaled glucocorticoids on bone mineral density compared with placebo. In a case-control study of all patients with a fracture (n = 124 655), in the year 2000 in Denmark each with three age- and sexmatched controls randomly drawn from the general population (n = 373 962), COPD (OR = 1.19; CI = 1.13, 1.25), emphysema (OR = 1.31; CI = 1.16, 1.48), and other chronic lung diseases (OR = 1.20; CI = 1.00, 1.44) were associated with a higher relative risk of any fracture than asthma (OR = 1.06; CI = 1.01, 1.12) (9c). Oral glucocorticoids were associated with a dose-related increased risk of fractures. Apart from beta-adreno ceptor agonists (see below), other bronchodila tors and inhaled glucocorticoids at standard doses (up to 1 mg/day of beclometasone equiva lents) were not associated with a risk of fracture. From a sample of 10 941 adults who entered a Norwegian asthma study in 1995–1997, 2848 were interviewed, under went spirometry, and had their forearm bone mineral density assessed again in 2001; 528 had used inhaled glucocorticoids at both baseline and follow-up (10c). The yearly loss of adjusted forearm distal bone mineral density was higher in those who had used inhaled glucocorticoids at both baseline and follow-up compared with subjects with out respiratory symptoms. In women, the figures were 3.14 versus 2.26 mg/cm2, and in men they were 3.76 versus 1.92 mg/cm2. However, there was no significant associa tion between loss of bone mineral density and either daily dose or duration of use of inhaled glucocorticoids. Reduced lung func tion was an independent susceptibility factor for increased bone loss in both sexes, so residual confounding by disease severity could not be ruled out. Even if inhaled gluco corticoids did affect forearm bone mineral density in people with asthma, it should have minor clinical significance in most patients using low to moderate doses. In summary, there is growing evidence that inhaled glucocorticoids are associated with a small increase in the risk of fracture, but further reviews suggest that this occurs
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only at higher doses (11M), and such an effect has been confirmed by specific analysis in older adults, in whom the relative risk of non-vertebral fractures increases by about 12% for each 1 mg/day increase in the dose of beclometasone or equivalent (12M). The effect is stronger in COPD. Even then, the magnitude of this risk is considerably less than other common susceptibility factors for fracture in older adults.
Susceptibility factors Children The phar macokinetics, pharmacodynamics, efficacy, and adverse effects of different inhaled glucocorticoids in children with asthma have been reviewed (13R). Optimizing drug kinetics and metabolism is important in reducing adverse effects. An ideal inhaled glucocorticoid should have high pulmonary deposition; in this respect, des-ciclesonide is better than beclometasone with a hydrofluor oalkane (HFA) propellant. A longer lung residency time is also favorable, and this increases when both budesonide and des ciclesonide undergo reversible fatty acid ester ification. The clearance rate of des-ciclesonide is very high, increasing its safety profile. Fluti casone and mometasone have the highest receptor-binding affinity (18 and 22 times that of dexamethasone respectively), followed by budesonide (9.4; dexamethasone = 1). In low to medium doses, inhaled glucocorticoids hardly suppress the adrenal pituitary axis (see also SEDA-31, 305), but in high doses (e.g. 2 mg beclometasone equivalent), there is potential for significant adrenal suppression and adrenal crisis in children and adults. So, at the recommended doses, their effect on the adrenal glands is not clinically relevant, and the small change in cortisol concentrations that occurs reflects their presence in the blood. In several longitudinal studies in children, inhaled glucocorticoids have been con firmed to cause a small reduction in growth velocity (1–2 cm) during the first year of treatment. However, during follow-up of children who used budesonide for up to 10 years, there was no change in target adult height. Others have similarly concluded that growth velocity is slowed when inhaled
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glucocorticoids are used in younger chil dren, but this occurs only in the first months of treatment and is followed by a catch-up period and consistent data sup port the lack of a significant effect on final height (14R). However, close follow-up is warranted when doses of inhaled gluco corticoids higher than recommended are used.
BETA 2-ADRENOCEPTOR AGONISTS (SEDA-29, 171; SEDA-30, 198; SEDA-31, 308) Combination therapy Asthma guidelines recommend adding long-acting beta2 adrenoceptor agonists (LABAs) to inhaled glucocorticoids at step 3 in adults and adolescents before increasing the dose of beclometasone or other glucocor ticoids above 400 micrograms equivalents and certainly before increasing above 800 micrograms (15S, 16S). LABAs and combination therapy are licensed for chil dren over 5 years, but have not yet been adequately evaluated below this age. They should not be used in isolation in asthma but as add-on therapy to inhaled glucocor ticoids (17S). Comparative studies Arformoterol versus salmeterol Nebulized arformoterol (50 micrograms/day; n = 528) and salmeterol metered-dose inhaler (MDI; 42 micrograms bd n = 265) have been compared over 12 months in subjects with COPD (18C). There was no evidence of tolerance in either group – no increase in exacerbation rates or reduc tion in forced expiratory volume in 1 second (FEV1) response. Adverse events occurred in 91% with arformoterol and 88% with salmeterol. Tremor was more common with nebulized arformoterol (13%) than salme terol (1.1%). Formoterol versus salbutamol Formoterol (12 þ 12 micrograms via Aerolizer) has been compared with salbutamol (200 þ 200 þ
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200 micrograms via spacer) each at 20-minute intervals in 60 patients with acu te exacerbations of asthma in a doubleblind, randomized, placebo-controlled study (19C). Typical beta2-adrenoceptor mediated symptoms (reported as adverse events) occurred in 12 patients who used formoterol and 11 who used salbutamol. There was no significant difference in inci dence of adverse events between the two groups: dry mouth (38% versus 36%), dizziness (16% versus 7.1%), headache (9.4% versus 7.1%). The effects of formoterol Turbuhaler® (2 9 micrograms and 6 9 micrograms) and salbutamol Diskhaler® (3 400 micro grams and 9 400 micrograms) have been compared in 26 patients with asthma in a double-blind, crossover, randomized, pla cebo-controlled study (20C). Maximum heart rate and palpitation and tremor scores were statistically significant greater after sal butamol. Other systemic effects were com parable and the effects were brief. These findings need to be interpreted with caution, given the small size of the study. Adrenoceptor agonists versus glucocortic oids Combination therapy with salmeterol þ fluticasone propionate has been compared with increased doses of inhaled glucocor ticoids in patients with asthma in a meta analysis of 12 studies (5218 subjects) (21M). Combination therapy produced a statistically significant small improvement in lung function and symptoms but no significant reduction in exacerbations. Adverse events were less common with low-dose combination therapy (183/2522) than with increased doses of inhaled glu cocorticoids (263/2547) (OR = 0.85; n = 11; 95% CI = 0.76, 0.96). There were no sig nificant differences in hoarseness, oral can didiasis, upper respiratory tract infections or headache. Three previous systematic reviews (total n = 10 231) comparing LABAs þ inhaled glucocorticoids with different maintenance strategies using inhaled glucocorticoids in adults with asthma have been further combined (22M). The addition of a LABA
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to an inhaled glucocorticoid resulted in significantly better asthma control than maintenance inhaled glucocorticoids. The addition of a LABA to an inhaled gluco corticoid was associated with increased tre mor, which was both significant for initial therapy (NNTH = 21) and compared with higher doses of inhaled glucocorticoids (NNTH = 74). Headache and withdrawals caused by adverse events were similar. There were significantly fewer total withdrawals compared with a similar dose of an inhaled glucocorticoid alone (RR = 0.87; 95% CI = 0.77, 0.98). The authors concluded that the greatest benefit and least harm from using LABAs resulted from their addition to a similar dose of an inhaled glucocorticoid in adults with symptomatic asthma. Cardiovascular Concerns have been raised about the long-term safety of longacting beta2-adrenoceptor agonists; their overall adverse effects were reviewed in SEDA-30 (p. 198) and their respiratory adverse effects in SEDA-31 (p. 309). Subsequently, death from any cause was examined in the 3-year, multi center, rando mized, placebo-controlled TORCH trial in COPD, in which salmeterol þ fluticasone (50 and 500 micrograms bd) was compared with salmeterol alone, fluticasone alone, or placebo (n = 6184; 1542 in the salmeterol arm; mean age 65 years) (2C). All-cause mortality rates were 13% with the combina tion, 14% with salmeterol, 16% with fluti casone, and 15% with placebo. Although there was an 18% reduction in the risk of death with combination therapy compared with placebo, this did not quite reach statis tical significance (HR = 0.825; 95% CI = 0.681, 1.002). There was no significant difference in the cardiovascular causes of death (3% of patients) or in all-cause mortality between salmeterol and placebo. The incidence of cardiac disorders was not significantly increased by salmeterol (reported event rates per study year: 0.087 with combination therapy, 0.114 with salme terol alone, 0.102 with fluticasone, and 0.113 with placebo). Some have linked the use of
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beta2-adrenoceptor agonists to an increased risk of fractures, but the incidence of fractures was comparable across the groups. The risk of acute myocardial infarction in patients using beta2-adrenoceptor ago nists has been assessed in a nested casecontrol study (n = 2476) within a cohort of antihypertensive drug users in the Dutch PHARMO RLS database (23C). Current users had an increased risk of acute myo cardial infarction (crude OR = 1.36; 95% CI = 1.15, 1.61), but this risk was reduced after adjustment for the severity of asthma and COPD (adjusted OR = 1.18; 95% CI = 0.93, 1.49). Thus, only patients with ischemic heart disease with low cumulative exposure to beta2-adrenoceptor agonists had an increased risk of acute myocardial infarction (adjusted OR = 2.47; 95% CI = 1.60, 3.82). This excess risk was attributed to latent cardiovascular disease rather than to the direct effects of beta2 adrenoceptor agonists. Metabolism Lactic acidosis (peak serum concentration 5.2–13 mmol/l) has been described in a retrospective series of four children who were treated with nebulized beta2-adrenoceptor agonists for acute severe asthma (24A). However, it should be noted that a causal relationship was speculative; lactic acidosis may have been caused by mechanisms related to acute severe asthma. Musculoskeletal In a survey of all Danish patients who sustained fractures during 1 year (n = 124 655) compared with age- and sex-matched controls from the general population, the risk of fracture was assessed in patients with chronic lung diseases using bronchodilator drugs, inhaled glucocorticoids and oral glucocorticoids (9C). Inhaled short-acting beta2-adrenoceptor agonists (SABAs) were associated with an increased risk of fracture that was not dose-related: low doses were associated with an increased risk but higher doses were not. Inhaled LABAs (singly and in combination) and
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other bronchodilators were not associated with an increased risk. These results suggest that the increased risk of fracture may have been associated with the severity of the underlying lung disease rather than the drugs themselves. Susceptibility factors Genetic The effect of beta2-adrenoceptor gene (ADRB2) polymorphisms on the response to LABAs was reviewed in SEDA-31 (p. 310). There has since been a pharmacogenetic analysis of two randomized studies, to determine whether ADRB2 polymorphisms affect responses to LABAs in combination with inhaled corticosteroids (25M). In one 6-month, double-blind, randomized study (n = 2250), budesonide þ formoterol main tenance and reliever therapy, fixed-dose budesonide þ formoterol and fixed-dose fluticasone þ salmeterol were compared. Another study was of similar design (n = 405). In the first study, worsening asthma (the most common serious adverse event, n = 17) occurred at a comparable frequency across all the genotype groups. The Gly16Arg genotype did not influence adverse events or therapeutic responses in either study. In a double-blind, crossover, randomized, placebo-controlled study (n = 20), responses to subcutaneous terbutaline after treatment for 2 weeks with either terbutaline inhalation or placebo have been compared in patients with homozygous Arg16 or Gly16 in ADRB2 (26c). There were no genotypic dif ferences in the rise in FEV1 after subcuta neous terbutaline, whether or not it was preceded by terbutaline inhalation. For the Arg16 genotype only, subcutaneous terbuta line-induced hypokalemia was attenuated by pre-treatment with inhaled terbutaline (which resulted in an overall increase in baseline plasma potassium). However, it is difficult to extrapolate these differences to a general population, given the small size of this study. Prospective randomized con trolled trials are needed to clarify whether ADRB2 variance affects genetic susceptibil ity in relation to adverse events associated with beta2-adrenoceptor agonists.
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Age Adverse events relating to beta2 adrenoceptor agonists in older people (electrolyte disturbances, cardiac effects, tremor, tolerance, poor disease control, sudden life-threatening exacerbations, asth ma-related deaths, osteoporosis, nervous tension, headaches, sleep/behavior disturbance) have been reviewed (27R). Older people and those with co-morbidities were under-represented in drug trials, and caution must be exercised in interpreting these adverse events data.
Formoterol Placebo-controlled studies Racemic formo terol (6, 12, 24, and 48 micrograms) has been investigated over 5 days in 20 patients with COPD in a double-blind, crossover, randomized, placebo-controlled study (28C). There was a dose–response relationship with tremor, which increased with 24 and 48 micrograms. There was a statistically significant rise in mean heart rate after 48 micrograms but no dose–response rela tionship. The systemic effects at high doses were minimal. However, these findings should be interpreted with caution, given the small size of the study. Electrolyte balance High-dose therapy with 10 puffs of budesonide þ formoterol (100 þ 6 micrograms) or formoterol 6 micro grams during maintenance treatment with budesonide þ formoterol 2 puffs/day has been studied in 18 patients with asthma in a double-blind, three-way crossover, placebocontrolled study (29C). Formoterol was associated with a significantly greater reduc tion in serum potassium than budesonide þ formoterol or placebo (difference in mean minimum concentrations 0.11 and –0.15 mmol/l, respectively). There were no signifi cant differences in QTc interval, plasma lactate or vital signs. It should be emphasized that patients with asthma should not be treated with LABAs alone and that these should always be used as add-on therapy to inhaled corticosteroids (15S, 16S, 17S).
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Dosage regimens Once-daily versus twicedaily formoterol (total 24 micrograms/day) via Novolizer® have been compared over 12 weeks in 321 patients with moderate to severe COPD in a parallel-group, multi center, double-blind, randomized, active-controlled study (31C). The incidences of adverse events were comparable between groups and inclu ded tremor, confusional states, and insomnia. Over 96% of the patients and their physicians assessed tolerability as good or very good in both groups.
Indacaterol Indacaterol is a LABA. In contrast to sal meterol, which is a partial agonist with a duration of action of 12 hours, indacaterol is a full agonist with a duration of action of 24 hours (32RE, 33C, 34C). Comparative studies Indacaterol 200 or 1000 micrograms, salbutamol 200 or 1000 micrograms, salmeterol 50 or 2500 micro grams and placebo have been compared in 20 patients with persistent asthma, using single therapeutic and supra-therapeutic doses, in a randomized, open, crossover study (35c). There were few adverse events, and all were mild or moderate in intensity. The adrenoceptor agonists caused initial changes in glucose, potassium, heart rate, and QTc interval, but all values remained within the reference ranges. Placebo-controlled studies Indacaterol has been studied in 163 patients with moderate COPD in a 28-day, double-blind, randomized, placebo-controlled study (36C). They were randomized 2:2:1 to indacaterol 400 or 800 micrograms/day or placebo by singledose dry-powder inhaler, and 155 completed the study. There were no statistically significant differences between the groups in the overall incidence of adverse events (35%, 51% and 25%, respectively). Most of the adverse events were mild or moderate in intensity, and there were no drug-related
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serious adverse events. There were no statistically significant differences between indacaterol and placebo in mean pulse rate and QTc interval, and isolated statistically significant differences in mean blood pressure, blood glucose, and serum potassium. The effects of indacaterol 200, 400, or 600 micrograms have been assessed in 156 patients with asthma in a 28-day, multi cen ter, double-blind, randomized, placebo-con trolled study (37C). The most frequent adverse event was nasopharyngitis (15% with indacaterol 200 micrograms). Tremor was reported by two patients taking indaca terol 600 micrograms. There was a higher incidence of cough on treatment: four, seven and three patients using indacaterol 200, 400, and 600 micrograms, respectively, compared with one using placebo. There was no evidence of dose-related increases in the incidence of adverse events or of clinically significant hypokalemia or hyperglycemia. Mean changes in pulse rate were minor, with maximum changes from baseline at 1 hour of –3.7, –3.3, and –2.2/minute for indacaterol and –2.9/minute for placebo. Mean QTc interval was similar across the groups and there was a change from baseline of over 60 ms in only two patients. Indacaterol 400 and 800 micrograms/day via a single-dose dry powder inhaler has been investigated in 144 patients with persistent asthma in a 28-day, double-blind, parallelgroup, multi center, randomized, placebocontrolled study (38C); 135 completed the study. The incidences of adverse events were similar across the groups and when they occurred were mild or moderate in most cases. There was no dose-response relationship between indacaterol and the incidence of adverse events (400 micrograms 41%; 800 micrograms 37%; placebo 39%). There were small clinically unimportant differences between indacaterol and placebo in mean serum potassium and glucose. There was a trend to QTc interval prolongation with increas ing exposure (maximum mean change 8.9 ms). Indacaterol 50, 100, 200, or 400 micro grams via a multidose dry-powder inhaler (CertihalerTM), indacaterol 400 micrograms via a single-dose dry-powder inhaler and placebo have been compared in 436 patients
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with persistent asthma (39C). Most adverse events were mild to moderate and the most common were respiratory, thoracic, and mediastinal disorders. Cough was reported by 11–33% (1.4% of patients taking pla cebo) and was dose-related. Headache was reported by 0–7.9% of patients (2.8% of those taking placebo) and was not doserelated. One severe adverse event was con sidered to be related to indacaterol – severe palpitation, tachycardia, headache, vertigo, nausea, and insomnia in a patient taking 400 µg via the multi-dose inhaler. Another, taking indacaterol 100 micrograms/day, withdrew because of adverse events that were thought to be drug-related (erythema, anxiety, nausea, and tachycardia). There were no important differences between the groups in blood glucose, serum potassium, pulse rate, blood pressure or QTc interval and the incidences of other adverse events were comparable across the groups.
Ritodrine For the use of ritodrine in treating premature labor, see Chapter 13.
ANTICHOLINERGIC DRUGS (SEDA-29, 174; SEDA-30, 203; SEDA-31, 311)
The cardiovascular risks of anticholinergic drugs The Lung Health Study was the first randomi zed controlled trial to suggest that anti cholinergic drugs may increase the risk of adverse cardiovascular outcomes (40C). A subgroup analysis of hospitalizations and causes of death suggested that smokers randomized to inhaled ipratropium had a sig nificantly increased risk of cardiovascular death than smokers who used placebo (41C). However, the statistical tests used in this study were not adjusted for multiple tests and end
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points, no dose-effect relationship was estab lished and most of the cardiovascular deaths in the ipratropium group occurred in patients who were non-adherent. A later meta-analysis of 17 studies in a total of 13 645 patients, with follow-up dura tions of 6 weeks to 5 years, included systema tic reviews, regulatory authority studies, and randomized controlled trials of any inhaled anticholinergic drug for the treatment of COPD in which cardiovascular events were reported (42M). The primary outcome, a composite end point of cardiovascular deaths, myocardial infarction, or stroke, occurred in 134 of 6984 patients (1.9%) using inhaled anticholinergic drugs and 83 of 6661 patients (1.2%) using other therapies (RR = 1.60; CI = 1.22, 2.10). Among individual components of cardiovas cular risk, inhaled anticholinergic drugs signifi cantly increased the risk of myocardial infarction and cardiovascular deaths but not stroke. The secondary outcome of all-cause mortality was reported in 2.1% of the patients who used inhaled anticholinergic drugs and 1.6% of the controls (RR = 1.29; CI = 1.00, 1.65). A sensitivity analysis restricted to six long-term trials (lasting over 6 months) confirmed the significantly increased risk of cardiovascular death, myocardial infarction or stroke (RR = 1.73; CI =1.27, 2.35), suggest ing that inhaled anticholinergic drugs are associated with a significantly increased myocardial infarction risk among patients with COPD. Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT), the largest randomized con trolled trial of an anticholinergic drug, involved patients at least 40 years old with COPD (43C). It compared 4 years of therapy with either tiotropium (n= 2987) or placebo (n= 3006), and the patients were allowed to use all other respiratory medications (including combinations of long-acting beta agonists þ inhaled glucocorticoids), except inhaled anticholinergic drugs. In contrast to the pooled analyses, UPLIFT showed no difference in the rates of cardiovascular events but also no difference in the primary end point of rate of decline in lung function, despite other clinical improvements.
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A post-hoc, subgroup analysis of the UPLIFT data looked at the secondary end point of mortality in more detail during treatment and with follow-up of patients who withdrew (44C). An end-point commit tee adjudicated the causes of death. There were 792 deaths, with a lower risk in those who used tiotropium (HR = 0.84; 95% CI = 0.73, 0.97). There was a statistically significant difference in survival at the end of the protocol-defined treatment period, but not 30 days thereafter, possibly because of missing data. Adjustment by severity of lung function, sex, age, baseline smoking beha vior, and baseline respiratory medications did not alter the results. The HR for respira tory mortality was 0.86 (0.68, 1.09) and for cardiac mortality 0.86 (0.75, 0.99), suggest ing reduced risks. The most recent meta-analysis of cardio vascular adverse events in patients taking tiotropium concentrated only on large ran domized controlled trials, but noted short comings in all of them when evaluating cardiovascular risk, which none was designed specifically to do (45M). It is not certain why there is such a wide disparity in findings among the published studies in which the cardiovascular risks of inhaled anticholinergic drugs have been eval uated. The different findings may be explained by the use of composite end points in some but not all analyses, placebo controls being lumped together with active treatment controls in the comparator groups, and inac curate reporting of adverse events in reviews because of lack of access to source data; furthermore, differential dropout rates in the non-treatment arms could have resulted in shorter observational periods in these groups. Some have advocated caution in pre scribing anticholinergic drugs in patients with cardiovascular disease (46R), but nearly all agree that more prospective, adequately powered trials are needed to provide more evidence about the cardiovascular safety or otherwise of tiotropium and particularly ipratropium and to look for particular sus ceptibility factors associated with cardiovas cular events in people using anticholinergic drugs.
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Tiotropium bromide (SEDA-29, 174; SEDA-30, 203; SEDA-31, 311) Systematic reviews Following placebocontrolled studies and in ‘addition to stan dard treatment’ studies, ipratropium is increasingly being replaced by tiotropium, whose overall safety was reviewed in SEDA-31 (p. 311). Since then, there has been a pooled meta-analysis of adverse events data from 19 double-blind, rando mized, placebo-controlled trials in patients with obstructive lung disease treated with tio tropium (n = 4435) or placebo (n = 3384), contributing 2159 person-years of exposure to tiotropium and 1662 person-years of exposure to placebo (47M). There was a higher relative risk of dry mouth with tiotro pium (RR = 3.60; 95% CI = 2.56, 5.05), no difference in all-cause mortality (RR = 0.76; 0.50, 1.16), and no difference in either cardi ovascular mortality (RR = 0.57; 0.26, 1.26) or respiratory mortality (RR = 0.71; 0.29, 1.74). For urinary retention the RR was 11 (1.3, 95). This pooling of adverse events data from pre-approval and post-approval tiotro pium clinical trials increased the precision of effect estimates and suggested a relatively good safety profile of inhaled tiotropium. Post-marketing surveillance has since included rare case reports of possible asso ciations with photosensitivity reactions (48A) and acute angle-closure glaucoma (49A).
LEUKOTRIENE MODIFIERS (SEDA-29, 174; SEDA-30, 203; SEDA-31, 312)
Montelukast Comparative studies Montelukast 4 or 5 mg/ day has been compared with budesonide inhalation suspension 0.5 mg/day in 395 children aged 2–8 years with mild asthma or recurrent wheezing in a 12-month, multi center, randomized study (50C). There were similar increases in height from baseline to 12 months. The frequencies of adverse events
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were comparable, most being of mild to moderate intensity. In those who took montelukast (n = 198), there was one case each of headache, lower respiratory tract infection, and abnormal behavior, which were considered to be drug-related. Adverse events that were reported by at least 10% of patients using montelukast were upper respiratory tract infections (29%), pyrexia (23%), otitis media (17%), sinusitis (14%), nasopharyngitis (12%), headache (11%), and pharyngitis (10%). Five patients stopped taking montelukast because of adverse events, the commonest reasons for withdrawal being asthma or pneumonia. There were no deaths. Montelukast 5 mg/day and inhaled bude sonide 200 µg bd have been compared in a 3-week, crossover, randomized, placebocontrolled study in 71 children (aged 6–11 years) with mild asthma (51c). Montelukast did not significantly affect short-term lower leg growth rate, while budesonide was asso ciated with a reduced mean growth rate compared with placebo. Adverse events were comparable. No patients using monte lukast were thought to have had a drugrelated adverse event. Montelukast (10 mg/day) has been com pared with levocetirizine 5 mg/day for 2 consecutive days in 418 adults with ragweed-induced allergic rhinitis in a double-blind, parallel-group, randomized, placebo-controlled study (52C). Treat ment-related adverse events were more common with montelukast (18 of 156 patients) compared with placebo (8.6%) and levocetirizine (8.3%). Adverse events that were considered to be drug-related were more common with montelukast (5.8%) than levocetirizine (3.8%) or pla cebo (2.9%). There were no serious treat ment-related adverse events. Headache was the commonest adverse event with monte lukast (3.2%) and placebo (1.9%) but it was not reported in those taking levocetirizine. Somnolence was reported by one patient taking montelukast, two taking levocetiri zine, and none taking placebo.
glucocorticoids versus inhaled glucocorti coids alone or montelukast þ inhaled gluco corticoids versus active control þ inhaled glucocorticoids in adolescents and adults i ncluded 13 randomized controlled trials (duration at least 12 weeks) in a total of 2 746 331 patients (53M). Meta-analyses were performed where feasible. The addition of montelukast did not result in a greater overall rate of adverse events or increased withdrawal rates related to adverse events. When comparing montelukast with salmeterol as add–on therapy to inhaled glucocorticoids, the overall adverse event rates were comparable. However, separate meta-analyses of 12-week and 48-week trials suggested that montelukast was associated with a significantly lower rate of serious adverse events than salmeterol (RR = 0.68; 95% CI = 0.49, 0.94).
Systematic reviews A systematic review of comparisons of montelukast þ inhaled
Observational studies In a prescription event monitoring (PEM) study in 7976
Liver Hepatitis has been attributed to montelukast in a child with fatigue, nausea, vomiting and abdominal pain who had taken montelukast 5 mg/day for 2 years; resolution occurred within 2 weeks of drug withdrawal (54A). Susceptibility factors Age The single-dose pharmacokinetics of montelukast oral granules (4 mg and 8 mg/day) have been evaluated for 7 days in a placebo-controlled study in 12 infants aged 1–3 months with bronchiolitis or a history of bronchiolitis and asthma-like symptoms (55c). There was increased systemic exposure after a single dose of montelukast 4 mg compared with historical data: the population area under curve (AUC) estimate was 3.6 times higher than in infants aged 3–24 months. Three patients had transient drug-related increases in aspartate transaminase activity (montelukast 8 mg, n = 2; placebo, n = 1).
Zafirlukast
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patients for the period August 1998 to December 2000 (56c), general practitioners reported 152 adverse events in 120 patients (1.5%). The most frequent events were headache and nausea. Zafirlukast was withdrawn in 3148 patients (40%), the most frequent reason being that the drug was ineffective (2008 patients; 25%). Headache was the most common reason for withdrawal (82 patients; 1.0%). Exposure to zafirlukast during the first trimester was reported in 20 pregnancies, of which 9 live births with no recorded congenital abnormalities were reported. There was a total of 151 deaths (1.9%), 38% of which were related to the respiratory system (including COPD, asthma, and bronchopneumonia).
PHOSPHODIESTERASE
TYPE IV INHIBITORS (SEDA-29,
174; SEDA-30, 203; SEDA-31, 313)
Several strategies are currently being pur sued to improve the clinical efficacy and reduce adverse effects of phosphodiesterase type IV inhibitors, including delivery by inhalation, better understanding of the dis tinct tissue specificity of phosphodiesterase type IV isoforms and development of non-emetic inhibitors. New mixed inhibitors are reported to have an improved therapeu tic window, including tetomilast, oglemilast, and apremilast; clinical data on these are awaited.
Cilomilast
(SEDA-29, 174; SEDA-30, 203; SEDA-31, 313) Placebo-controlled studies A review of the efficacy and safety of cilomilast in five Phase III double-blind, parallel-group, randomized, placebo-controlled pivotal studies in over 6000 patients with COPD did not show any serious safety concerns, but neither there were consistent beneficial
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effects in a range of clinical and laboratory outcomes to replicate the promising early pre-clinical data (57R). These Phase III studies have led to termination of the development of cilomilast by its manufacturer.
Roflumilast (SEDA-29, 174; SEDA-30, 203; SEDA-31, 313) Placebo-controlled studies In two doubleblind, multi center, randomized, placebocontrolled studies in patients with moderate to severe COPD, oral roflumilast 500 micrograms/day alone or in addition to salmeterol, or placebo in addition to tiotropium, were compared (58M). Nausea, diarrhea, weight loss, and to a lesser extent headache were more frequent in patients who used roflumilast, but with no major difference between the studies using different comparator groups. In both trials, there was gradual weight loss with roflumilast (salmeterol þ roflumilast –2.0 kg, tiotropium þ roflumilast –1.8 kg) but little change in the placebo groups (salmeterol þ placebo þ 0.2 kg, tiotropium þ placebo þ 0.3 kg).
Systematic reviews A pooled analysis of two large randomized, controlled trials of patients with COPD, severe airflow limitation and exacerbations has suggested that those who used oral roflumilast 500 micrograms/day for 1 year in addition to long-acting beta agonists (n = 1537) had better lung function and less exacerbations than those who took placebo in addition to LABAs (n = 1554) (59M). Inhaled glucocorticoids and tiotropium were not allowed. Overall mortality was similar, with no differences in cardiovascular adverse events or dysrhythmias, pneumonia, or other pulmonary infections. Adverse events were more common with roflumilast (67%) than placebo (62%) and the probability of withdrawal was higher with roflumilast in the first 12 weeks;
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however, serious adverse events were similar (19% and 22%); 14% of the patients taking roflumilast and 12% of those taking placebo withdrew because of adverse events, diarrhea, nausea, and headache being the most common reasons. Vomiting was reported by 17 patients taking roflumilast and 11 taking placebo. Significantly more people taking roflumilast had weight loss (n = 8); the pooled analysis suggested a mean weight loss of 2.1 kg with roflumilast. The change in weight for roflumilast was the greatest in the first 6 months and was more likely to occur in those who reported diarrhea, nausea, vomiting, or headache. The largest absolute weight loss occurred in patients with a BMI of over 30 kg/m2. However, as many people with COPD are already underweight, this potential adverse effect needs careful investigation.
Zileuton
Keir E. Lewis and Gwyneth A. Davies
(FDA) approval, 2458 patients with asthma took zileuton 600 mg qds in addition to usual asthma care, and 489 patients received usual asthma care only (70C, 71C). Dyspep sia (17% versus 9.8%) and nausea (12% versus 5.7%) were more frequent with zileuton. Sinusitis was commoner in those receiving usual care and rates of infection were comparable. Withdrawals because of adverse events with zileuton comprised 20% compared with 2.2%. The commonest adverse events associated with withdrawal in the two groups were asthma exacerba tions (3.7 and 1%, respectively), raised levels of the liver enzyme Alanine transam minase (ALT) activity (2.7 and 0.2%), nau sea (2.4 and 0%), and dyspepsia (1.6 and 0%), Miscellaneous adverse events (not described) associated with withdrawal occurred in 9.3 and 1%. There were five deaths, which were considered unrelated to treatment and not associated with abnormal liver function. Changes in ALT activity in this study are discussed below.
(SEDA-15, 3717)
The 5-lipoxygenase pathway involves the metabolism of arachidonic acid and forma tion of leukotrienes, including leukotriene B4 (LTB4), 5-oxo-6E,8Z,11Z,14Z-eicosatetra noic acid, and the cysteinyl leukotrienes (LTC4, LTD4, and LTE4). It activates four leukotriene receptors: BLT1, BLT2, cysLT1, and cysLT2. Zileuton is an orally active specific inhibitor of 5-lipoxygenase and is the first of this class of medications to be used in the treatment of asthma in adults and children. It has bronchodilatory effects and attenuates induced bronchospasm. It can provide anti inflammatory or steroid-sparing effects with both single doses (800 mg) and during longterm treatment (400 and 600 mg qds) (60C, 61C, 62c, 63c, 64c). Pediatric data are currently limited. Adverse effects, including dyspepsia and raised liver enzymes, have been reported in about 3%. Zileuton has also been used to treat acne (65c), atopic dermatitis (66c, 67r), and the Sjo¨ gren–Larsson syndrome (68A, 69c). In a 12-month open study conducted before US Food and Drug Administration
Placebo-controlled studies Zileuton 800 mg bd or 600 mg qds has been studied in a 4-week, double-blind, parallel-group, randomized, pla cebo-controlled study in 139 patients with mild to moderate asthma (not using inhaled or oral glucocorticoids) (63c). The incidences of adverse events were comparable across the groups. Dyspepsia was reported by three patients taking zileuton 2.4 g/day and three taking 1.6 g/day, and in none taking placebo. There were no clinically significant changes in liver function. One patient developed urticaria and abnormal liver function tests after taking zileuton 1.6 g/day for 24 days, which resolved after drug withdrawal. Zileuton 400 or 600 mg qds has been studied in 401 patients with mild to moderate asthma (managed with inhaled beta2-adre noceptor agonists alone) in a 12-week, parallel-group, double-blind, randomized, placebo-controlled study (61C). Five patients taking zileuton 600 mg/day, three taking zileuton 400 mg/day, and none taking placebo developed abnormal liver function tests (over 3 times the upper limit of normal), which resolved after withdrawal (61C).
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Zileuton 400 or 600 mg qds has been studied in 373 patients with mild to moderate asthma (managed with inhaled beta2 adrenoceptor agonists alone) in a 24-week, multi center, parallel-group, double-blind, placebo-controlled study (60C). There were no dose-related adverse effects. The most common adverse events were acute exacer bation of asthma, infections, and headaches. Severe events occurred in 25 patients taking zileuton 600 mg/day, 23 taking 400 mg/day, and 10 taking placebo. Adverse events that occurred in 5% or more of the patients in any treatment group were worsening asthma, infections, headache, pharyngitis, flu-like syndromes, pain, sinusitis, back pain, dys pepsia, myalgia, nausea, weakness, diarrhea, rhinitis, bronchitis, accidental injury, and dizziness. These adverse events were not usually considered to be related to the study drug. Of 46 patients who left the study pre maturely, at least in part because of adverse events, 15 were taking zileuton 600 mg/day, 15 were taking zileuton 400 mg/day, and 16 were taking placebo. Rises in liver enzymes (to at least twice the upper limit of normal), including Aspartate transaminase (AST), glutamic–pyruvic transaminase, �-glutamyl transferase, and lactate dehydrogenase, or increases in total bilirubin occurred in 11 patients taking zileuton 600 mg/day, 9 taking zileuton 400 mg/day, and 12 taking placebo. There were mild rises in liver enzymes in 11 patients taking placebo (up to 2–3 times the upper limit of normal). Six patients taking zileuton 600 mg/day and five taking 400 mg/ day had either moderately or markedly increased enzyme activities (respectively 3–8 and over 8 times the upper limit of normal). There were no cases of jaundice or symptoms associated with these abnormal liver function tests, which resolved both during continuation or on withdrawal of the drug. Zileuton controlled-release 1200 mg bd added to usual care versus usual care alone has been studied in 926 patients with moder ate asthma in a multi center, double-blind, placebo-controlled study (72C). The ALT activity rose to over 3 times the upper limit of normal in 11 patients (1.8%) taking zileu ton and 2 patients (0.2%) taking placebo. These rises usually occurred in the first 3
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months of treatment and most resolved within 21 days of withdrawal. The incidence of gastrointestinal disorders was higher in the treatment group (31% versus 21%): nausea (9.2% versus 5.9%), diarrhea (5.3% versus 2.3%), and vomiting (5.0% versus 2.0%). Overall adverse events were comparable between the groups. Zileuton 600 mg qds has been studied in 40 patients with aspirin-intolerant asthma in a 6-week, crossover, double-blind, placebocontrolled study (73c). All the patients but one were using either medium-dose or highdose inhaled or oral glucocorticoids. Five had exacerbations of asthma during the pla cebo period and one while taking zileuton. There were no drug-related adverse effects. Unusually, liver function does not appear to have been monitored in this study. Comparative studies Zileuton versus beclometasone Zileuton 400 or 600 mg qds þ beclometasone dipropionate 200 micro grams bd has been compared with placebo þ beclometasone dipropionate 400 micrograms bd in 320 patients with persistent asthma in a 12-week, multi center, double-blind, randomized, active-control study (74C). The incidence and types of adverse events were similar in the three groups and included infections, exacerbation of asthma or eczema, headaches, rhinitis, flulike syndromes, dyspepsia, pharyngitis, and nausea. There were rises in ALT activity in two of those taking zileuton 2400 mg, two of those taking zileuton 1600 mg, and two of those taking beclometasone. Zileuton versus theophylline Zileuton has tended to have been studied in patients who require a daily inhaled beta2-adrenoceptor agonist; comparative studies are currently limited. Zileuton 400 or 600 mg qds has been compared with slow-release theophylline in 377 patients with chronic asthma in a 13-week, double-blind, multi center, randomized study (75C). One or more treatment-related adverse events were reported by comparable numbers in all the groups: zileuton 400 mg, 94%; zileuton
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600 mg, 94%; theophylline, 89%. Adverse events that were reported by at least 5% of patients were headache, infection, pharyngitis, flu-like syndromes, myalgia, dyspepsia, nausea, pain, back pain, sinusitis, and insomnia. One or more episodes of exacerbation of asthma were reported by about 75% of the patients across all treatment groups at some point in the 13-week double-blind phase. Of the 32 patients who left the study prematurely, 11 had adverse events that led to termination and were considered probably or possibly related to the study drug: three taking zileuton 400 mg/day (insomnia in one, raised liver enzyme activities in two), three taking zileuton 600 mg/day (dyspepsia in one, raised liver enzymes in two), and five taking theophylline. There were raised liver enzyme activities (to above twice the upper limit of normal) in 25 patients: eight taking zileuton 400 mg/day, nine taking 600 mg/day, and eight taking theophylline. Of those taking zileuton 400 mg/day, six had mild increases, one had a moderate increase, and one had a large increase. Of those taking zileuton 600 mg/day, the corresponding numbers were five, two, and two, and in those taking theophylline three, four, and one. No patient developed hepatotoxicity with jaundice. Hematologic In an in vitro study zileuton was associated with increased thromboxane B2 concentrations and platelet aggregation in 10 patients with asthma, with a theoretical thrombotic risk (76E). However, no thrombotic adverse effects have been reported. A study by the manufacturers of zileuton showed that there was no significant increase in thromboxane B2 concentrations when zileuton was given to healthy volunteers (77c). Liver In addition to all the studies quoted above, there have been reports of abnormal liver enzymes in patients taking zileuton. In 2947 patients at 233 centers in the USA randomly assigned in a 5:1 ratio to zileuton plus usual asthma care or usual asthma care alone, the patients who took zileuton had significantly fewer corticosteroid rescues,
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required less emergency care, had fewer hos pitalizations, and had greater increases in FEV1 (70C). They also had significantly greater improvements in asthma symptoms. There were increases in ALT activity to 3 times or more the upper limit of normal in 4.6% of patients taking zileuton and 1.1% of those receiving usual care; most of the increases occurred during the first 2–3 months. Hepatic damage was predominantly hepatocellular. Raised ALT activity was usually not associated with raised alkaline phosphatase and/or total bilirubin concen trations. Most of the liver enzyme abnormal ities in the treatment group (70%) occurred within the first 3 months. There was no cor relation between the time of onset and the height of the peak ALT activity. Women were more likely than men to have ALT activity over 8 times the upper limit of nor mal (1.8% versus 0.5%) and women aged over 65 years were at greater risk. Patients with ALT activity over 5 times the upper limit of normal continued treatment, and 53% successfully continued with resolution of ALT to below twice the upper limit of normal. For those who withdrew because of a raised ALT, the mean time to resolution was 4 weeks. Two developed mildly raised total bilirubin concentrations in association with raised ALT. There were no cases of jaundice, chronic liver disease, or liver fail ure. These data suggest that with appropriate monitoring the risk of irreversible liver injury appears to be low, but careful monitoring is indicated particularly in the first 3 months. Despite these changes in liver enzymes, jaundice is uncommon. There was a single reported case of jaundice among over 6000 patients taking zileuton (78R, 79R). The pattern of liver function abnormal ities suggests a mechanism relating to metabolic idiosyncrasy. In vitro and animal data suggest that hepatotoxicity is related to the biotransformation of zileuton to 2-acetylbenzothiophene (2-ABT) and further toxic metabolites (80E). 2-ABT is cytotoxic in a P450-dependent manner. Further in vitro work has implicated the reactive metabolite 2-ABT-S-oxide, which can cause irreversible alkylation of human serum albumin (81E).
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Chapter 16
Pregnancy There are animal data of concern regarding the use of zileuton in pregnancy, and guidelines recommend that leukotriene modifiers should not be begun in pregnancy (30S). In general these drugs would not be recommended in pregnancy, although their use could be considered in those with poorly controlled asthma who have previously demonstrated significant benefit (82S). There are no adequate human data. Drug dosage regimens Zileuton 600 mg qds for 8 weeks has been compared with zileuton 600 or 800 mg tds for 16 weeks followed by twice-daily treatment for 8 weeks in 278 patients with chronic asthma, in a multi center randomized study (83C). The commonest treatment-related adverse effects were headaches (23%), infections (22%), pain (10%), pharyngitis (8.3%), rhinitis (7.9%), flu-like syndromes (7.2%), and nausea (7.2%). Adverse effects caused 41 patients to withdraw: 11 had adverse effects that were probably zileuton-related, of which 4 were severe, and 20 had adverse effects that were possibly zileuton-related, of which 2 were severe. The other 10 patients had events that were unrelated to zileuton, of which 2 were severe. Four patients developed raised ALT activity during the first 2 months of treatment. All cases resolved, in one case during continuation of treatment and in three cases after withdrawal. Drug–drug interactions Zileuton is mainly eliminated by metabolism to zileuton glucuronides, but it can also be metabolized by cytochrome P450 isoenzymes. Drug interaction studies have suggested that interactions of zileuton with other drugs are mediated by inhibition of CYP1A2 (84E, 85R). Propranolol Patients taking propranolol should be closely monitored and doses may need to be reduced because of reduced clearance (86E). Terfenadine Zileuton should not be co administered with terfenadine because of
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increases in the plasma terfenadine concentration, but without significant prolongation of the QTc interval (87c). Theophylline In 16 healthy adult men who were given theophylline (Slo-Phyllin) 200 mg qds for 5 days and either zileuton 800 mg bd or placebo in a randomized, crossover, placebo-controlled study (88c), zileuton increased mean peak theophylline concentrations from 12 to 21 mg/l and reduced the apparent plasma clearance from 3.74 to 1.91 l/hour. The tmax of theophylline was delayed by 0.5 hours and the half-life was significantly prolonged by 1.5 hours. There were 44 mild to moderate adverse events in 14 subjects, possibly related to co-administration of zileuton, compared with eight who reported such events while taking placebo. Three volunteers who took theophylline þ zileuton withdrew prematurely. The authors advised that if theophylline is co-administered with zileu ton, dosages may need to be halved and plasma theophylline concentrations will require close monitoring. Warfarin Patients taking warfarin should be closely monitored and doses may need to be reduced because of reduced clearance (demonstrated for R-warfarin but not S-warfarin, the more active stereoisomer) (89E). Other drugs No significant interactions have been demonstrated between zileuton and digoxin, phenytoin, sulfasalazine, or naproxen (85R).
MUCOLYTICS Mucolytics are being increasingly pre scribed for COPD and bronchiectasis. In a Chinese multi center, randomized, placebocontrolled trial, carbocisteine 500 mg tds significantly reduced COPD exacerbations over 1 year (90C). Withdrawals occurred in 14% and 12% of patients in the two groups.
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There were 57 adverse events in those tak ing carbocisteine and 56 in those taking pla cebo, the most common (5 or more events) being gastrointestinal upsets (14 versus 5) and cardiac events (9 versus 5). There were no deaths.
Non-prescription cough and cold medicines (SEDA-31, 314) FDA guidance on non-prescription cough medicines was reviewed in SEDA-31 (p. 314). In particular it was noted that adverse events were often dose-related and that these preparations should not be used in children under 2 years unless speci fically advised by a health-care professional. For the adverse effects of proprietary cough medicines containing antihistamines, see Chapter 15. Placebo-controlled studies In a placebocontrolled study of the anti-tussive moguisteine (total daily dose 600 mg) for 3.5 days in 108 adults, there was an increased incidence of adverse events in the treatment group (22% versus 8%) (91c). The most frequent adverse events were nausea, vomiting, and abdominal pain, with four withdrawals in the treatment group because of adverse events.
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The adverse effects of guaifenesin (an expectorant) included nausea and urticaria (92C). Systematic reviews The effects of oral non-prescription cough medicines in 25 trials (17 in adults, 8 in children; 2876 adults and 616 children) in acute cough have been reviewed (93M). The data were conflicting and the number of studies in each category of cough medicines was small. The authors concluded that there was currently insufficient evidence for or against the effectiveness of non prescription cough medicines. Many studies failed to report adverse events. Counterfeit medicines Vicks Kingo is a proprietary cough medicine that contains guaiphenesin and cetylpyridinium chloride. The Tanzania Food and Drugs Authority (TFDA) has released a statement about counterfeit Vicks Kingo circulating in the market. The agency has taken a tough line on the matter and has threatened legal action against traders (94S). The counterfeit Vicks Kingo tablets are white instead of cream-colored and they do not have the menthol smell of the genuine tablets. The TFDA has urged anyone in possession of the counterfeit product to return it to the suppliers and report it to the nearest district health office or local TFDA.
References 1. Ernst P, Gonzalez AV, Brassard P, Suissa S. Inhaled corticosteroid use in chronic obstruc tive pulmonary disease and the risk of hospi talization for pneumonia. Am J Respir Crit Care Med 2007;176(2):162–6. 2. Calverley PM, Anderson JA, Celli B, Fergu son GT, Jenkins C, Jones PW, Yates JC, Vestbo J, TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356(8):775–89.
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5. Sin DD, Tashkin D, Zhang X, Radner F, Sjo¨ bring U, Thorén A, Calverley PM, Rennard SI. Budesonide and the risk of pneumonia: a meta-analysis of individual patient data. Lancet 2009;374(9691):712–9. 6. Anonymous. Cutaneous adverse effects of inhaled steroids. Prescrire Int 2007;16 (89):112–3. 7. Pujades-Rodriguez M, Smith CJ, Hubbard RB. Inhaled corticosteroids and the risk of fracture in chronic obstructive pulmonary disease. Quart J Med 2007;100(8):509–17. 8. Ferguson GT, Calverley PM, Anderson JA, Jenkins CR, Jones PW, Willits LR, Yates JC, Vestbo J, Celli B. Prevalence and pro gression of osteoporosis in patients with COPD: results from the TOwards a Revo lution in COPD Health study. Chest 2009;136(6):1456–65. 9. Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk in patients with chronic lung diseases treated with bronchodilator drugs and inhaled and oral corticosteroids. Chest 2007;132(5):1599–607. 10. Langhammer A, Forsmo S, Lilleeng S, John sen R, Bjermer L. Effect of inhaled corticos teroids on forearm bone mineral density: the HUNT study, Norway. Respir Med 2007;101 (8):1744–52. 11. Etminan M, Sadatsafavi M, Ganjizadeh Zavareh S, Takkouche B, FitzGerald JM. Inhaled corticosteroids and the risk of frac tures in older adults: a systematic review and meta-analysis. Drug Saf 2008;31(5):409–14. 12. Weatherall M, James K, Clay J, Perrin K, Masoli M, Wijesinghe M, Beasley R. Dose–response relationship for risk of nonvertebral fracture with inhaled corticoster oids. Clin Exp Allergy 2008;38(9):1451–8. 13. Gulliver T, Morton R, Eid N. Inhaled corti costeroids in children with asthma: pharma cologic determinants of safety and efficacy and other clinical considerations. Paediatr Drugs 2007;9(3):185–94. 14. Garcia-Marcos L, Ros-Lucas JA, SanchezSolis M. Inhaled corticosteroids in asthmatic children: are they as safe in infants and pre schoolers as in older children? A review. Curr Drug Saf 2008;3(1):35–45. 15. BTS/SIGN. British Guideline on the Man agement of Asthma. Thorax 2008;63(Suppl IV):iv1–121.
327 16. GINA. Global Strategy for Asthma Manage ment and Prevention 2008 http://www. ginasthmaorg. 17. Bacharier LB, Boner A, Carlsen KH, Eigen mann PA, Frischer T, Go¨ tz M, Helms PJ, Hunt J, Liu A, Papadopoulos N, Platts-Mills T, Pohunek P, Simons FE, Valovirta E, Wahn U, Wildhaber J, European Pediatric Asthma Group. Diagnosis and treatment of asthma in childhood: a PRACTALL consen sus report. Allergy 2008;63(1):5–34. 18. Donohue JF, Hanania NA, Sciarappa KA, Goodwin E, Grogan DR, Baumgartner RA, Hanrahan JP. Arformoterol and salmeterol in the treatment of chronic obstructive pul monary disease: a one year evaluation of safety and tolerance. Ther Adv Respir Dis 2008;2(2):37–48. 19. Najafizadeh K, Sohrab Pour H, Ghadyanee M, Shiehmorteza M, Jamali M, Majdzadeh S. A randomised, double-blind, placebocontrolled study to evaluate the role of formoterol in the management of acute asthma. Emerg Med J 2007;24(5):317–21. 20. Lotvall J, Ankerst J. Long duration of airway but not systemic effects of inhaled formoterol in asthmatic patients. Respir Med 2008;102 (3):449–56. 21. Li HT, Zhang TT, Zhou H, Qu XJ, Wu WM, Huang J. Combination therapy with the sin gle inhaler salmeterol/fluticasone propionate versus increased doses of inhaled cortico steroids in patients with asthma. Respiration 2007;74(1):33–43. 22. Gibson PG, Powell H, Ducharme FM. Dif ferential effects of maintenance long-acting beta-agonist and inhaled corticosteroid on asthma control and asthma exacerbations. J Allergy Clin Immunol 2007;119(2):344–50. 23. de Vries F, Pouwels S, Bracke M, Lammers JW, Klungel O, Leufkens H, van Staa T. Use of beta2 agonists and risk of acute myocardial infarction in patients with hypertension. Br J Clin Pharmacol 2008;65(4):580–6. 24. Koul PB, Minarik M, Totapally BR. Lactic acidosis in children with acute exacerbation of severe asthma. Eur J Emerg Med 2007;14 (1):56–8. 25. Bleecker ER, Postma DS, Lawrance RM, Meyers DA, Ambrose HJ, Goldman M. Effect of ADRB2 polymorphisms on response to longacting beta2-agonist therapy:
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329 55. Kearns GL, Lu S, Maganti L, Li XS, Migoya E, Ahmed T, Knorr B, Reiss TF. Pharmacoki netics and safety of montelukast oral granules in children 1 to 3 months of age with bronch iolitis. J Clin Pharmacol 2008;48(4):502–11. 56. Twaites BR, Wilton LV, Shakir SA. Safety of zafirlukast: results of a postmarketing sur veillance study on 7976 patients in England. Drug Saf 2007;30(5):419–29. 57. Rennard S, Knobil K, Rabe KF, Morris A, Schachter N, Locantore N, Canonica WG, Zhu Y, Barnhart F. The efficacy and safety of cilomilast in COPD. Drugs 2008;68 (Suppl 2):3–57. 58. Fabbri LM, Calverley PM, Izquierdo-Alonso JL, Bundschuh DS, Brose M, Martinez FJ, Rabe KF. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease trea ted with long-acting bronchodilators: two randomised clinical trials. Lancet 2009;374 (9691):695–703. 59. Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ, M2 124 and M2-125 Study Groups. Roflumilast in symptomatic chronic obstructive pulmon ary disease: two randomised clinical trials. Lancet 2009;374(9691):685–94. 60. Liu MC, Dubé LM, Lancaster J. Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month randomized multicenter trial. Zileuton Study Group J Allergy Clin Immunol 1996;98(5 Pt 1):859–71. 61. Israel E, Cohn J, Dubé L, Drazen JM. Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. A rando mized controlled trial. Zileuton Clinical Trial Group. J Am Med Assoc 1996;275(12):931–6. 62. Kearns GL, Lu S, Maganti L, Li XS, Migoya E, Ahmed T, Knorr B, Reiss TF. The effect of inhibition of 5-lipoxygenase by zileuton in mild-to-moderate asthma. Ann Intern Med 1993;119(11):1059–66. 63. Israel E, Rubin P, Kemp JP, Grossman J, Pierson W, Siegel SC, Tinkelman D, Murray JJ, Busse W, Segal AT, Fish J, Kaiser HB, Ledford D, Wenzel S, Rosenthal R, Cohn J, Lanni C, Pearlman H, Karahalios P, Drazen JM. The effect of inhibition of 5-lipoxygen ase by zileuton in mild-to-moderate asthma. Ann Intern Med 1993;119(11):1059–66. 64. Dahlén B, Nizankowska E, Szczeklik A, Zetterstro¨ m O, Bochenek G, Kumlin M,
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Mastalerz L, Pinis G, Swanson LJ, Boodhoo TI, Wright S, Dubé LM, Dahlén SE. Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirinintolerant asthmatics. Am J Respir Crit Care Med 1998;157(4 Pt 1):1187–94. Zouboulis CC, Nestoris S, Adler YD, Orth M, Orfanos CE, Picardo M, Camera E, Cun liffe WJ. A new concept for acne therapy: a pilot study with zileuton, an oral 5-lipoxygenase inhibitor. Arch Dermatol 2003;139(5):668–70. Woodmansee DP, Simon RA. A pilot study examining the role of zileuton in atopic der matitis. Ann Allergy Asthma Immunol 1999;83(6 Pt 1):548–52. Tas?kapan MO. Zileuton and atopic derma titis. Ann Allergy Asthma Immunol 2001;87 (2):162–3. Willemsen MA, Rotteveel JJ, Steijlen PM, Heerschap A, Mayatepek E. 5-Lipoxygenase inhibition: a new treatment strategy for Sj¨ogren–Larsson syndrome. Neuropediatrics 2000;31(1):1–3. Willemsen MA, Lutt MA, Steijlen PM, Cruysberg JR, van der Graaf M, Nijhuis van der Sanden MW, Pasman JW, Mayate pek E, Rotteveel JJ. Clinical and biochemical effects of zileuton in patients with the Sj¨ogren–Larsson syndrome. Eur J Pediatr 2001;160(12):711–7. Lazarus SC, Lee T, Kemp JP, Wenzel S, Dubé LM, Ochs RF, Carpentier PJ, Lancas ter JF. Safety and clinical efficacy of zileuton in patients with chronic asthma. Am J Manag Care 1998;4(6):841–8. Watkins PB, Dubé LM, Walton-Bowen K, Cameron CM, Kasten LE. Clinical pattern of zileuton-associated liver injury: results of a 12-month study in patients with chronic asthma. Drug Saf 2007;30(9):805–15. Wenzel S, Busse W, Calhoun W, Panettieri Jr. R, Peters-Golden M, Dubé L, WaltonBowen K, Russell H, Harris J. The safety and efficacy of zileuton controlled-release tablets as adjunctive therapy to usual care in the treatment of moderate persistent asthma: a 6-month randomized controlled study. J Asthma 2007;44(4):305–10. Dahlén B, Nizankowska E, Szczeklik A, Zetterstrom ¨ O, Bochenek G, Kumlin M, Mastalerz L, Pinis G, Swanson LJ, Boodhoo TI, Wright S, Dubé LM, Dahlén SE. Benefits
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from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirinintolerant asthmatics. Am J Respir Crit Care Med 1998;157(4 Pt 1):1187–94. 74. O’Connor BJ, Lofdahl CG, Balter M, Szczek lik A, Boulet LP, Cairns CB. Zileuton added to low-dose inhaled beclomethasone for the treatment of moderate to severe persistent asthma. Respir Med 2007;101(6):1088–96. 75. Schwartz HJ, Petty T, Dubé LM, Swanson LJ, Lancaster JF. A randomized controlled trial comparing zileuton with theophylline in moderate asthma. The Zileuton Study Group Arch Intern Med 1998;158(2):141–8. 76. Wu X, Dev A, Leong AB. Zileuton, a 5-lipoxygenase inhibitor, increases produc tion of thromboxane A2 and platelet aggre gation in patients with asthma. Am J Hematol 2003;74(1):23–5. 77. Rubin P, Dubé L, Braeckman R, Swanson L, Hansen R, Albert D, Carter G. Pharmacokinetics, safety, and ability to diminish leukotriene synthesis by zileuton, an inhibi tor of 5-lipoxygenase. Agents Actions Suppl 1991;35:103–16. 78. Wenzel SE, Kamada AK. Zileuton: the first 5-lipoxygenase inhibitor for the treatment of asthma. Ann Pharmacother 1996;30 (7–8):858–64. 79. Berger W, De Chandt MT, Cairns CB. Zileu ton: clinical implications of 5-lipoxygenase inhibition in severe airway disease. Int J Clin Pract 2007;61(4):663–76. 80. Joshi EM, Heasley BH, Chordia MD, Macdonald TL. In vitro metabolism of 2-acetylbenzothiophene: relevance to zileu ton hepatotoxicity. Chem Res Toxicol 2004;17(2):137–43. 81. Li F, Chordia MD, Woodling KA, Macdo nald TL. Irreversible alkylation of human serum albumin by zileuton metabolite 2-acet ylbenzothiophene-S-oxide: a potential model for hepatotoxicity. Chem Res Toxicol 2007;20(12):1854–61. 82. The use of newer asthma and allergy medica tions during pregnancy. The American College of Obstetricians and Gynecologists (ACOG) and The American College of Allergy, Asthma and Immunology (ACAAI). Ann Allergy Asthma Immunol 2000;84(5):475–80. 83. DuBuske LM, Grossman J, Dubé LM, Swan-
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zileuton in patients with moderate asthma: effect of reduced dosing frequency and amounts on pulmonary function and asthma symptoms. Zileuton Study Group Am J Manag Care 1997;3(4):633–40. 84. Machinist JM, Mayer MD, Shet MS, Ferrero JL, Rodrigues AD. Identification of the human liver cytochrome P450 enzymes involved in the metabolism of zileuton (ABT-077) and its N-dehydroxylated meta bolite, Abbott-66193. Drug Metab Dispos 1995;23(10):1163–74. 85. Dubé LM, Swanson LJ, Awni W. Zileuton, a leukotriene synthesis inhibitor in the man agement of chronic asthma. Clinical pharma cokinetics and safety. Clin Rev Allergy Immunol 1999;17(1–2):213–21. 86. Yoshimoto K, Echizen H, Chiba K, Tani M, Ishizaki T. Identification of human CYP iso forms involved in the metabolism of propra nolol enantiomers – N-desisopropylation is mediated mainly by CYP1A2. Br J Clin Pharmacol 1995;39(4):421–31. 87. Awni WM, Cavanaugh JH, Leese P, Kasier J, Cao G, Locke CS, Dubé LM. The pharma cokinetic and pharmacodynamic interaction between zileuton and terfenadine. Eur J Clin Pharmacol 1997;52(1):49–54. 88. Granneman GR, Braeckman RA, Locke CS, Cavanaugh JH, Dubé LM, Awni WM. Effect of zileuton on theophylline pharmacokinetics. Clin Pharmacokinet 1995;29(Suppl 2):77–83.
331 89. Awni WM, Hussein Z, Granneman GR, Patterson KJ, Dubé LM, Cavanaugh JH. Pharmacodynamic and stereoselective phar macokinetic interactions between zileuton and warfarin in humans. Clin Pharmacokinet 1995;29(Suppl 2):67–76. 90. Zheng JP, Kang J, Huang SG, Chen P, Yao WZ, Yang L, Bai CX, Wang CZ, Wang C, Chen BY, Shi Y, Liu CT, Chen P, Li Q, Wang ZS, Huang YJ, Luo ZY, Chen FP, Yuan JZ, Yuan BT, Qian HP, Zhi RC, Zhong NS. Effect of carbocisteine on acute exacerbation of chronic obstructive pulmon ary disease (PEACE study): a randomised placebo-controlled study. Lancet 2008;371 (9629):2013–8. 91. Adams R, Hosie J, James I, Khong T, Kohn H, Smith I. Antitussive activity and tolerability of moguisteine. Adv Ther 1993;10(6):263–71. 92. Robinson R, Cummings W, Deffenbaugh E. Effectiveness of guaifenesin as an expector ant: a cooperative double-blind study. Curr Ther Res 1977;22(2):284–96. 93. Smith SM, Schroeder K, Fahey T. Over the-counter medications for acute cough in children and adults in ambulatory settings. Cochrane Database Syst Rev 2008;(1): CD001831. 94. Anonymous. Counterfeit medicines. Regula tor tackles incident of fake Vicks Kingo. WHO Newslett 2008;4:1.
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1 7 Positive inotropic drugs and drugs used in dysrhythmias CARDIAC GLYCOSIDES (SED-15, 648; SEDA-29, 182; SEDA-30, 209; SEDA-31, 321) Observational studies Hospital admissions because of digoxin toxicity became signifi cantly less common from 1991 to 2004 in the USA and the UK in the former this was associated with a reduction in the use of digoxin, but in the latter there was no such change. However, in both countries, the num ber of prescriptions written for a dose of at least 250 micrograms fell (1C). Of 2 987 580 hospital admissions in the Netherlands during 2001–2004 there were 1286 cases of digoxin intoxication (0.04%) (2C). The incidence rate for admission related to digoxin intoxication was 49 per 100 000 prescriptions (95% confidence interval [CI] = 46, 51), corresponding to 1.94 admissions per 1000 treatment-years. Women had a 1.4-fold higher risk of intox ication than men (95% CI = 1.3, 1.6). The age- and sex-adjusted relative risk of death in patients with digoxin intoxication com pared with those admitted for other reasons was 0.7 (95% CI = 0.5, 0.8). Cardiovascular Digoxin toxicity has again been briefly reviewed in the context of two cases, one associated with sinus bradycardia and ventricular bigemini and one with second-degree heart block (3Ar). Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32017-4 2010 Elsevier B.V. All rights reserved.
Gastrointestinal Non-occlusive mesenteric ischemia secondary to digitalis is rare but has again been reported, in a 76-year-old woman with digoxin intoxication (serum concentration 6.0 µg/l) (4A).
Mortality during treatment of atrial fibrillation with digoxin There have been several studies of the risk of death during treatment of atrial fibrillation with digoxin. In a post-hoc analysis of the results of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study, the use of rhythm-control drugs was asso ciated with increased mortality after adjust ment for the other co-variates (hazard ratio [HR] = 1.49) and digoxin was associated with an increased risk of death (HR = 1.42; 95% CI = 1.09, 1.86) (5c). However, the authors suggested that that may have been caused by the use of digoxin in patients at a higher risk of death, such as those with heart failure, rather than by a deleterious effect of digoxin on survival. They also suggested that there may be other confounding factors in the reasons that physicians choose digoxin. Similarly, the survival of users and non users of digitalis has been investigated in a post-hoc analysis of data from the Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) III and V studies, in which 7329 patients with atrial fibril lation were randomized to warfarin or xime lagatran to prevent thromboembolism (6c). Users had a higher mortality than non-users
333
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(255/3911 versus 141/3418; 6.5% versus 4.1%; HR = 1.58; 95% CI = 1.29, 1.94). However, digitalis users also had more baseline risk fac tors, which would have confounded the results, even though after multivariate adjustment, the increased mortality persisted (HR = 1.53; 95% CI = 1.22, 1.92). The authors nevertheless sug gested that digitalis may increase mortality in patients with atrial fibrillation. Since both of these studies involved posthoc non-randomized analyses, they should be regarded as merely hypothesis generating. In a 1-year study using data from the Registry of Information and Knowledge about Swedish Heart Intensive care Admissions (RIKS-HIA), mortality was measured among 60 764 patients admitted to coronary care units with atrial fibrillation with or without congestive heart failure during 1995–2003 and adjusted for differences in background characteristics and other medications and treatments by propensity scoring (7c). Among those with atrial fibrillation without congestive heart failure there was a higher mortality rate in those who were discharged taking digoxin than in those who were not (adjusted RR = 1.42; 95% CI = 1.29, 1.56); there was no such difference among those who had con gestive heart failure with or without atrial fibrillation. The authors suggested that longterm therapy with digoxin may be an indepen dent susceptibility factor for death in patients with atrial fibrillation without congestive heart failure. However, as this study was based on registry data, confounding could have occurred. In 2824 patients with atrial fibrillation, who were studied prospectively for a mean of 4.6 years, information about medications was obtained from the local hospital registry and information about diagnoses, hospitali zations, and deaths from national registries (8c). Propensity score matching and Cox regression was used to account for con founding. Factors associated with the use of digoxin were permanent atrial fibrillation (HR = 3.2, CI = 2.7, 3.9), absence of a pace maker (HR = 2.3, CI = 1.6, 3.2), a history of heart failure (HR = 2.0, CI = 1.7, 2.5), treat ment in an internal medicine ward rather than a cardiology ward (HR = 1.6, CI = 1.3, 2.0), female sex (HR = 1.6, CI = 1.3, 1.9), and age 80 years or more (HR = 1.4, CI = 1.1, 1.7).
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Mortality was higher among those who used digoxin than among those who did not (51% versus 31%); however, after adjustment for co-variates there were no effects of digoxin on all-cause mortality, myocardial infarction, ischemic stroke, time to readmission to hospital, or days spent in hospital per year at risk. The authors concluded that the increased mortality associated with digoxin is attributable to its use in an elderly and frailer subset of patients with atrial fibrillation. Conclusion There is currently no good evi dence that the use of digoxin is associated with increased mortality in patients with atrial fibrillation, with or without concurrent congestive heart failure. A proper prospec tive randomized study would be necessary to confirm or refute this hypothesis. Susceptibility factors Sex In an analysis of adverse drug reactions in four German pharmacovigilance centres, which resulted in hospitalization of 3092 patients in 2000– 2004, 314 patients were admitted because of adverse effects associated with cardiac gly cosides. The incidence of adverse reactions was 1.9 (CI = 1.0, 3.3) per 1000 patients exposed to cardiac glycosides per 3 months exposure. More women were affected than men (244 versus 70) and oral digitoxin was involved in 296 (228 women). Women received significantly higher body weightrelated doses of digitoxin and had signifi cantly higher digitoxin plasma concentra tions than men. Doses were high (over 1 microgram/kg/day) in 71% of the women but in only 29% of the men. Those who had adverse reactions to cardiac glycosides had a significantly lower body weight and were significantly older than patients with other adverse drug reactions. Drug administration route In a retrospec tive analysis of 1795 pregnant women at 17–24 weeks’ gestation who received vary ing doses of digoxin by transabdominal intrafetal injection (up to 1.0 mg) or intraamniotic injection (up to 0.5 mg) to obtain fetal death in advance of elective termination in the second trimester, the overall failure
Positive inotropic drugs and drugs used in dysrhythmias
rate was 6.6% (9c). There were no failures using an intrafetal dose of 1.0 mg, but fail ures occurred with lower doses. Failure rates were higher with intra-amniotic administration of 0.5 mg (8.3%) than intrafetal administration (3.6%). There were no adverse maternal events. Drug overdose The management of over dose with cardiac glycosides when there are serious complications involves the use of Fab fragments of digoxin-specific anti bodies. However, in patients with severe renal impairment, the clearance of Fab– digoxin complexes is reduced, and plasma pheresis has been used to remove them (10A, 11A), as illustrated by another report (12A). However, it should be remembered that although plasma exchange removes digoxin–Fab complexes and prevents rebound digoxin toxicity, it does not increase the clearance of digoxin, which has a large apparent volume of distribution. Non-fatal self-poisoning with Digitalis purpurea, whose main constituent is digi toxin, occurs occasionally (13A, 14A), and unintentional poisoning can occur when the leaves of the plant are mistaken for those of comfrey (Symphytum officinale) (15A, 16A). Fatal self-poisoning with D. pur purea has been reported (17Ar). • A 64-year-old man ate a whole D. purpurea plant. He became nauseated and developed a junctional rhythm, with concave up-sloping ST segment depression; he later developed a bradycardia and runs of second-degree atrioventricular block, which rapidly progressed to a sinus pause lasting 3.5 seconds, followed by sinus arrest. The serum potassium concentration was 4.3 mmol/l and the serum glycoside concentration, measured using a digoxin assay, was 36 µg/l. Despite repeated doses of activated charcoal and administration of digoxin-specific antibodies, he had a cardiac arrest and died. At post-mortem examination there were undigested and partially digested foxglove plant parts in the stomach.
The reference to van Gogh in the title of this report is misleading (18r, 19r). Drug–drug interactions Calcium salts Although it has been suggested that intra venous calcium should be used to treat the
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hyperkalemia that can occur in digitalis intoxication (20R), this suggestion has been challenged, on the grounds that calcium salts may increase the risk of cardiac dys rhythmias in such cases (21r). However, evi dence that that is so is anecdotal, and counterexamples have also been published (22A, 23A, 24r). This question has been reviewed in the light of a case in which intravenous calcium gluconate was benefi cial in a patient with hyperkalemia and digoxin intoxication (25AR). The authors concluded that digoxin toxicity should be treated with digoxin-specific antibodies, when they are available (as they were not in their case). However, for patients with life-threatening hyperkalemia with loss of P waves, and especially if there is QRS widening, they recommended intravenous calcium. They also recommended that while slow infusion of calcium may be desirable, the speed of infusion should be determined by the urgency of the problem. Proton pump inhibitors There are several ways in which proton pump inhibitors might interact with digoxin. Inhibition of gastric acid secretion prevents hydrolysis of digoxin in the stomach, increasing its sys temic availability (26C). In one study ome prazole increased the average Cmax and area under curve (AUC) of digoxin by about 10% and slightly shortened the tmax, although in a few patients the effect was larger (up to 30%); the half-life was not changed, suggesting a change in availability rather than clearance (27C). Proton pump inhibitors also cause a transepithelial paracellular leak in the gas tric mucosa, which allows molecules as large as 4 kDa to cross (28c), although the effect is specific for certain molecules, as it allows the passage of digoxin but not phenytoin (29E). Omeprazole also inhibits P glycoprotein (30E), inhibition of which in the transepithe lial transport of digoxin in the intestine and kidney would reduce its clearance. There has been a single report of digoxin toxicity attributed to an interaction with omeprazole (31A).
336 • A 65-year-old woman developed weakness, loss of balance, nausea, and xanthopsia. She had been taking digoxin 0.0625 mg/day for paroxysmal atrial fibrillation and her serum digoxin concentration had been 1.1 µg/l. Omeprazole 20 mg/day had been added for gastroesophageal reflux disease and her serum digoxin concentration was 3.9 µg/l; renal function was normal. She was given antidigoxin antibody Fab fragments and quickly recovered.
Rabeprazole may also increase the effects of digoxin (32c). However, a single oral of pantoprazole 40 mg had no effect on the pharmacokinetics of oral beta-acetyldigoxin 0.2 mg bd in 18 healthy volunteers or on the electrocardiographic effects of digoxin (33c). Quinine The interaction of digoxin with quinine has only occasionally been described (SED-15, 664). It seems to have the same basis as the interaction of digoxin with quini dine. Torsade de pointes has now been attributed to this interaction in a 76-year-old man who was taking digoxin 0.5 mg/day, qui nine sulfate 750 mg/day, aspirin 100 mg/day, candesartan 8 mg/day, and amlodipine 10 mg/ day; the plasma digoxin concentration was 5 µg/l (6.4 µmol/l) (34A). Vildagliptin In an open, randomized, three-period, crossover study in 18 healthy subjects during co-administration of vilda gliptin 100 mg/day and digoxin (0.5 mg, then 0.25 mg/day on days 2–7), there were no effects on the exposure to either drug, assessed by AUC0!24h and Cmax, or on half-life or clearance (35c). Management of adverse drug reactions In a retrospective review of the records of 838 patients with raised serum digitalis con centration (digoxin > 1.95 µg/l or digitoxin > 23 µg/l), only 67 (8%) had received Fab fragments of antidigoxin antibody (36c). The authors concluded that the antibodies are underused in patients with raised digitalis con centrations and especially in those with chronic digitalis intoxication, who had a higher mortality rate than those with acute poisoning. They proposed that there should be identical criteria for the use of antidigoxin antibody after both acute and chronic poisoning.
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Monitoring therapy The reasons for mon itoring the plasma digoxin concentration have again been reviewed in the context of a case report (37Ar). In summary: • measure the plasma digoxin concentration to monitor adherence to therapy; • measure it to diagnose toxicity, if indicated by the patient’s clinical state; • measure it to monitor for potential toxicity if renal function changes, or after a change in dosage, or after the addition of another drug that affects the pharmacokinetics of digoxin; • always measure the serum potassium concen tration at the same time as the plasma digoxin concentration, because potassium depletion makes the plasma digoxin concentration unin terpretable, and toxicity should be assumed in the presence of hypokalemia, whatever the plasma digoxin concentration; • measure the serum potassium and renal function indices at intervals, depending on the patient’s clinical state and other drugs taken; • samples for digoxin measurement should be taken at least 6–12 hours after the last dose (ideally 11 hours); note that steady state takes 8–10 days to reach after any change in dose if renal function is normal, and longer in renal impairment; • plasma concentration monitoring is not necessary in clinically and biochemically stable patients.
OTHER POSITIVE INOTROPIC DRUGS
(SED-15, 2822; SEDA-29, 183; SEDA-30, 212; SEDA-31, 323)
Milrinone (SED-15, 2346; SEDA-29, 183; SEDA-30, 212; SEDA-31, 323) Drug administration route Milrinone by inhalation reduces pulmonary artery pres sure and its use has been studied retrospec tively in high-risk patients, mean age 64 years, to evaluate their postoperative course (38c). Milrinone 5 mg was given administered before (n = 30) or after (n = 40) cardiopulmonary bypass, which lasted a mean of 145 minutes, with crossclamping for 91 minutes. Those who received inhaled milrinone before the start of cardiopulmonary bypass had a lower
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pulmonary artery pressure after bypass and fewer needed emergency reinitiation of bypass after weaning (3% versus 23%). There were no detectable adverse effects.
ANTIDYSRHYTHMIC DRUGS Antidysrhythmic agents of class III have been reviewed, including the newer agents dofetilide, ambasilide, azimilide, chromanol 293B, dronedarone, ersentilide, ibutilide, sematilide, tedisamil, and trecitilide, as well as amiodarone, bretylium, and sotalol (39R).
ADENOSINE RECEPTOR AGONISTS (SED-15, 36; SEDA-29, 185; SEDA-30, 212; SEDA-31, 323)
Adenosine and analogues Cardiovascular In a retrospective review of 1948 adenosine stress myocardial perfusion studies, adenosine-induced atrial fibrillation occurred in eight (0.41%) cases 90–170 seconds after the infusion (40Ac). Three had a history of atrial fibrillation, two had a his tory of coronary artery disease, and seven had more than one risk factor for coronary artery disease. In three cases, the dysrhyth mia was preceded by bradycardia, adenosineinduced second-degree atrioventricular block, or sinus pauses. All converted spon taneously to sinus rhythm after 15 seconds to 6 hours. Pre-excited atrial fibrillation occurred in a 31-year-old woman with Wolff–Parkinson– White syndrome after the administration of adenosine (41A). The adverse effects of adenosine are usually transient, because it has a half-life of a few seconds. One patient developed a monomorphic ventricular tachycardia after termination of an atrioventricular nodal re-entrant tachycardia with intravenous
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adenosine 12 mg, which terminated sponta neously after 3 minutes (42A). Although not prolonged, this is longer than one would expect. Prolonged complete heart block requiring intubation and temporary pacing, after the administration of adenosine to a patient with an atrial flutter treated with metoprolol and diltiazem, has also been reported (43A). Accessory conduction pathways can be associated with dysrhythmias after the administration of adenosine. A 79-year-old man developed sustained second-degree atrioventricular block after adenosine infu sion for nuclear stress testing and required a permanent pacemaker (44A). In another case a non-sustained polymorphous ventri cular tachycardia occurred during adeno sine stress perfusion imaging in a patient with a pre-excitation electrocardiographic pattern (45A). Paradoxical coronary artery vasospasm with bursts of polymorphous tachycardia occurred after withdrawal of adenosine following a stress test in a patient with vasospastic angina (46A).
Dyspnea and bronchospasm associated with adenosine Asthma is a contraindication to the use of adenosine, which can cause bronchospasm in susceptible patients. In one case aden osine, 140 micrograms/kg/minute for 1 min ute, caused severe bronchospasm in a 78 year-old woman with pre-existing chronic obstructive pulmonary disease (COPD), but no evidence of reversible obstruction; it did not respond to repeated doses of inhaled salbutamol 100 micrograms but did respond to intravenous theophylline 50 mg (47A). However, the authors stressed that they did not want to discourage the use of adenosine in patients with COPD but no evidence of pre-existing reversible airway obstruction, as this adverse effect is rare in such patients. In another case, adenosine caused respiratory arrest in a patient with asthma (48A). In patients with a history of COPD or asthma, who were given adenosine
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140 mg/kg/minute for 4 minutes for stress myocardial perfusion scintigraphy, those with a history of asthma were given an inhaled bronchodilator before the administration of adenosine (49A). Most of the patients (24/46) did not have any dyspnea or chest pain during adenosine infusion. However, 14 had chest discomfort during adenosine and 9 complained of dyspnea. None required aminophylline or resuscitation. In a case-control study, patients with known or suspected mild asthma or COPD were pre treated with an inhaled beta2-adrenoceptor agonist and adenosine titrated up to a max imum of 140 micrograms/kg/minute over 6 minutes (50C). Of 1261 patients, 124 had known or suspected airway disease and 72 who were suitable for adenosine stress testing were compared with 72 controls. The most common adverse effects were dyspnea and chest pain; the former was significantly more common in those with asthma (38 versus 25 controls) but not the latter (14 versus 16 con trols); these effects were mostly mild and well tolerated. Bronchospasm occurred in five patients with asthma/COPD but resolved shortly after the end of the adenosine infusion; aminophylline was not required in any case. Because of the association of adenosine with bronchospasm, beta2-adrenoceptor agonist-induced supraventricular tachycardia in patients with asthma poses a therapeutic problem. In two boys with exacerbations of asthma and salbutamol-induced supraventri cular tachycardia, adenosine converted the rhythm without worsening the asthma (51A). This confirms previous reports that adenosine may be safe in such cases (52Ar, 53c). However, adenosine can cause dyspnea in the absence of bronchospasm, perhaps through stimulation of vagal C fibers in the airways and lungs. In 12 healthy subjects, mean age 32 years, intravenous adenosine 10 mg was given after inhalation of aerosoli zed lidocaine or placebo on two separate days (54C). After about 20 seconds, adenosine caused dyspnea, increased minute ventilation and caused transient bradycardia followed by tachycardia. The intensity of the dyspnea was markedly reduced by lidocaine, but the increased minute ventilation and heart rate responses were not affected.
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Of 54 patients, 7 of whom had mild COPD, 36 developed dyspnea during adenosine infu sion (55c). In those with mild COPD, respira tory resistance was significantly higher (0.48 versus 0.27 kPa/l/second), but neither those with nor those without COPD had a signi ficant increase in respiratory resistance during adenosine infusion. Respiratory resistance in those with dyspnea was insignificantly lower than in those without dyspnea. The authors concluded that bronchospasm had not been the cause of the dyspnea that their patients had suffered.
Adenosine receptor agonists (SEDA-30, 213; SEDA-31, 324) Observational studies In an open, rando mized, parallel-group, multicenter study in 133 adults who had completed diagnostic cardiac catheterization, the selective A2A adenosine receptor agonist binodenoson 0.3, 0.5 or 1 micrograms/kg/minute for 3 minutes or as a bolus injection of 1.5 or 3 micrograms/kg caused dose-related coron ary hyperemia within seconds (56c). All doses transiently caused reduced blood pressure, increased heart rate and an increased rate–pressure product. There were no adverse effects on the electrocardiogram. In an open dose-escalation study, the selective A2A adenosine receptor agonist regadenoson 10–500 micrograms by rapid intravenous bolus dose-relatedly increased peak intracoronary blood flow velocity in 34 subjects by up to 3.4 times (57c). Regade noson 400–500 micrograms increased heart rate by a mean of 21/minute and reduced systolic blood pressure by 5–24 mmHg and diastolic blood pressure by 8–15 mmHg. In another four subjects aminophylline 100 mg attenuated the increase in peak flow velocity but not the tachycardia caused by 400 micrograms of regadenoson. Adenosine and regadenoson in stress myocardial perfusion imaging have been compared in a database study of 2015 patients; regadenoson caused less chest pain, flushing, and throat, neck, or jaw
Positive inotropic drugs and drugs used in dysrhythmias
pain, but more headache and gastrointestinal discomfort (58c). Placebo-controlled studies In a crossover, randomized, double-blind, placebo-controlled trial, patients with asthma were challenged with adenosine monophosphate after rega denoson or placebo pretreatment (59C). The forced expiratory volume in 1 second (FEV1) was significantly higher at baseline at 10–60 minutes after treatment with regadenoson, but one patient had a 36% asymptomatic reduction in FEV1, which resolved spontaneously. The most common adverse events with regadenoson were tachy cardia (66%), dizziness (53%), headache (45%), and dyspnea (34%). Regadenoson increased the mean heart rate significantly (maximum 10/minute) compared with placebo. In a randomized, double-blind, placebocontrolled, crossover trial of regadenoson in 38 patients with moderate COPD and 11 patients with severe disease, there were no differences between regadenoson and pla cebo on multiple lung function parameters, including FEV1 and forced vital capacity, respiratory rate and oxygen saturation (60C). The mean maximum falls in FEV1 were 0.11 and 0.12 liters in patients who received regadenoson and placebo, respec tively, and there was new-onset wheezing in 6% and 12%. No patient required acute treatment with bronchodilators or oxygen.
Amiodarone
(SED-15, 148; SEDA-29, 185; SEDA-30, 213; SEDA-31, 324)
Enhanced eryptosis as a possible mechanism of action of amiodarone Eryptosis is a process of suicidal cell death undergone by erythrocytes, in which the pro cess known as scrambling of the cell mem brane occurs; erythrocyte shrinkage, exposure of membrane-bound phosphatidylserine, and annexin binding occur, mimicking features of
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apoptosis in nucleated cells (61R). The phos pholipids in erythrocyte plasma membranes are asymmetrically distributed; sphingo myelin and phosphatidylcholine are predomi nantly in the outer leaflet of the bilayer and phosphatidylserine and phosphatidylethano lamine in the inner leaflet. Alteration (‘scram bling’) of this asymmetry is an important feature of eryptosis. Eryptosis can be triggered by activation of calcium-permeable cation channels (62E–64E), with entry of calcium, which activates calcium-dependent potassium channels, leading to egress of potassium, chloride, and water, and thus to cell shrinkage (65E, 66E). These effects can be stimulated by the calcium ionophore iono mycin and by osmotic shock, oxidative stress, and glucose depletion. They are inhibited by inhibitors of the channels involved, such as amiloride and its analo gue ethylisopropylamiloride, charybdo toxin, chloride channel blockers such as niflumic acid, and antisense oligonucleo tides against the small-conductance cal cium-activated potassium channel isoform hSK4 (KCNN4); some of these effects are inhibited by phenylephrine, dobutamine, dopamine, catecholamines, and erythropoie tin. Calcium further triggers calcium-sensi tive scrambling of the cell membrane, causing breakdown of phosphatidylserine asymmetry, thought to result from activation of a so-called scramblase, which is sensitive to the intracellular concentration of free calcium (67E), with translocation of plasma membrane phospholipids and exposure of phosphatidylserine at the erythrocyte sur face. Cell membrane scrambling is also trig gered by ceramide (acylsphingosine) (68E). Erythrocytes in which membrane phosphati dylserine is exposed are rapidly eliminated from the blood, being engulfed by circulating macrophages (69E). Drugs that can stimulate eryptosis include chlorpromazine (70E), ciclosporin (71c), and paclitaxel (72c). Exposure of erythrocytes to lead (73E) and mercury (74E) does likewise. Several diseases are associated with acceler ated eryptosis, including sickle cell disease, thalassemia, and glucose-6-phosphate dehy drogenase deficiency (75c), hemolytic–uremic
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syndrome (76c), malaria (77E), in which it may contribute to accelerated removal of the erythrocytic form of the parasite (78E), sepsis (79c), phosphate depletion (80E), iron deficiency (81E), Wilson’s disease (82E), and amyloidosis (83E). When erythrocytes from healthy volun teers were exposed to amiodarone 1 µmol/l, the intracellular calcium concentration rose and annexin V binding was triggered (84E). However, amiodarone did not significantly affect ceramide formation, which is a feature of eryptosis. Amiodarone also increased annexin binding after hypertonic shock by the addition of sucrose 550 mmol/l but did not significantly alter the enhanced annexin binding after chloride removal by replace ment with gluconate. Thus, amiodarone appears to produce some of the effects that are associated with eryptosis and triggers phosphatidylserine exposure. However, it is not clear that the concentrations that produce this effect in vitro are relevant to in vivo therapy with amiodarone and specifically its adverse effects on the blood. Because eryptosis may be a mechanism whereby the clearance of Plasmodiuminfected erythrocytes are cleared, the effect of amiodarone on phosphatidylserine expo sure in Plasmodium-infected erythrocytes has been studied, in case it might affect the course of malaria (85E). Human erythro cytes were infected in vitro with Plasmodium falciparum, which increased annexin V bind ing, and this effect was significantly increased by amiodarone 10 µmol/l. Amiodarone also significantly reduced intraerythrocytic DNA/ RNA content and in vitro parasitemia. Fol lowing infection of mice with Plasmodium berghei, amiodarone 50 mg/kg significantly reduced the parasitemia and increased the survival of infected mice (from 0% to 70% 26 days after infection). Amiodarone also significantly increased the percentage of infected erythrocytes. Thus, amiodarone inhibited the intra-erythrocytic growth of Plasmodium falciparum, enhanced the suicidal death of infected erythrocytes, reduced parasitemia after Plasmodium bergheiinfection and supported host survival during malaria.
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Cardiovascular In the context of a case report it has been suggested that prolonga tion of the QT interval by amiodarone is the result of combined block of the rapid and slow components of the outward potassium current (IKr and IKs) in cardiac cells (86Ar). It has been proposed that activation of the IKs channel, for example with isoprenaline, could mitigate this adverse effect of amio darone (87A). The importance of susceptibility factors for cardiac dysrhythmias has been stressed in two cases. In one case intravenous amio darone unmasked congenital prolongation of the QT interval in a 62-year-old man with new-onset atrial fibrillation and no history of other dysrhythmias (88A). In another case torsade de pointes occurred in a 72-year old woman with pre-existing QT interval prolongation after the administration of amiodarone 300 mg/h for 3 hours (89A). Sinus bradycardia has been studied in 477 patients, mean age 49 years, taking amio darone, mean loading dose 809 mg/day, mean maintenance dosage 263 mg/day, mean duration of follow-up 21 months (90c). There was sinus bradycardia in 32% and 11% of patients during loading with amiodarone and maintenance treatment respectively. Phlebitis is a common complication when amiodarone is infused into a peripheral blood vessel, and although it may be possi ble to reduce the risk by using a low con centration (e.g. less than 2 mg/ml), the risk is still relatively high and has been esti mated at 14% (95% CI = 2.6, 25%) in a study in 273 patients, of whom 36 developed phlebitis (91c). When possible a large vein should be used for infusion of amiodarone. Respiratory Amiodarone-associated pneu monitis has again been reviewed in the context of case reports (92Ar, 93Ar). The hypothesis that aryl radical forma tion is involved in the adverse effects of amiodarone has been tested (94E). Photo lysis of anerobic aqueous solutions of amio darone and N-desethylamiodarone resulted in the formation of an aryl radical, as deter mined by spin-trapping and electron para magnetic resonance (EPR) spectroscopy.
Positive inotropic drugs and drugs used in dysrhythmias
The non-iodinated analogue, didesiodo amiodarone, did not form aryl radicals under identical conditions. The cytotoxicity of these compounds was also studied in human lung epithelioid HPL1A cells. Desethylamiodarone had a more rapid and potent effect (LC50 8 µmol/l) than amio darone (LC50 146 µmol/l), and dides iodoamiodarone was intermediate (LC50 26 µmol/l), suggesting that the iodine atoms play a minor part. Incubation of human lung epithelial cells with the spintrapping nitrones alpha-phenyl-N-t-butyl nitrone 10 mmol/l and alpha-(4-pyridyl N-oxide)-N-t-butylnitrone 5.0 mmol/l did not significantly protect against cytotoxicity. Intratracheal administration of amiodarone to hamsters produced pulmonary fibrosis by day 21, which was not prevented by 4 days of treatment with the spin-trapping nitrones. The authors suggested that although amiodarone can generate an aryl radical photochemically, its in vivo forma tion may not be a major contributor to toxicity. The mechanisms of amiodarone-induced lung toxicity have been studied in relation to interferon gamma, which inhibits pul monary fibroblast proliferation, and inter leukin-4 (IL-4), which increases fibroblast growth and collagen production (95c). The ratio of interferon gamma to interleukin-4 produced by activated peripheral cluster of differentiation 4 (CD4) T cells increased during treatment with amiodarone in 26 patients, 6 of whom had lung toxicity. The serum concentration of desethylamiodar one was lower in those with lung damage and was inversely proportional to the ratio of interferon gamma to interleukin, which was the most powerful indicator of amiodar one lung toxicity in a multilogistic regression analysis. In an analysis of 237 cases of amiodarone associated pulmonary toxicity (described as interstitial lung disease, pulmonary fibrosis, pulmonary infiltrates, pleural effusion, alveolitis fibrosis, pneumonitis, bronchiolitis obliterans organizing pneumonia, or crypto genic organizing pneumonia), only age and duration of therapy significantly affected the risk (96c). The authors suggested that
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targeted monitoring of patients aged over 60 years and those who have taken amio darone for 6–12 months may minimize the risk of morbidity and mortality secondary to lung complications. In the context of three men, all smokers, aged 75, 93, and 85 years, who developed diffuse interstitial pneumonitis after taking amiodarone 200 mg/day for an average of 6.6 months, the authors suggested that old age and pre-existing lung abnormalities caused by smoking could be associated with amio darone-related pulmonary toxicity (97Ar). In a patient with peripheral edema and respiratory crackles on auscultation, a diag nosis of cardiac failure was made. However, there was platypnea rather than orthopnea, and a computed tomography (CT) scan showed an interstitial pneumonitis, which was attributed to amiodarone (98A). In 15 patients with raised serum globulin concentrations who were taking amiodar one the serum globulin concentrations nor malized after drug withdrawal; 11 of these patients had amiodarone toxicity according to the authors, and 9 had amiodarone-asso ciated pneumonitis (99c). A pleural effusion has been attributed to the combination of amiodarone and hypo albuminemia in a patient with severe burns (100A), but could have been due to the hypoalbuminemia alone. There have been rare reports of isolated lung masses attributed to amiodarone, and another case has been reported (101A). The mass contained myofibroblasts, aggregates of foamy macrophages containing multiple lamellar bodies (typical of amiodarone), and chronic interstitial inflammatory cells. The lesion resolved completely within 3 months of amiodarone withdrawal. Following reports that the adverse effects of amiodarone on the lungs can occur after relatively short-term therapy (SEDA-30, 214; SEDA-29, 186), a prospective study has been conducted in 102 patients, who were admitted to an intensive care unit (ICU) after cardiac surgery and who received short-term prophylactic amiodar one if they were thought to be at high risk of atrial fibrillation (102c). They were given 900 mg/day intravenously for the first 2 days
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and 600 mg/day thereafter. There were no significant effects of amiodarone on respira tory function. In contrast, a rapidly fatal case of lung damage has been reported in a man who was given intravenous amiodarone. • A 72-year-old man who developed atrial fibrillation after three-vessel coronary artery bypass grafting was given an intravenous loading dose of amiodarone 5 mg/kg over 20 minutes and then an infusion at a rate of 750 mg/day. Sinus rhythm was restored after 2 hours, but he became increasingly breathless, with an oxygen saturation of 85% on oximetry. His breath sounds were reduced at the lung bases and there were bibasilar râles. Arterial blood gases showed a respiratory acidosis. His erythrocyte sedimentation rate was 156/hour and the leukocyte count was 16.5 109/l. A chest X-ray showed bilateral alveolo interstitial infiltrates. A CT scan showed prominent bilateral densities, mainly at the perihilar space, radiating to the periphery, with a ground-glass appearance. He died after an episode of ventricular fibrillation. Post mortem examination showed a diffusely deranged lung parenchyma with foamy cells typical of amiodarone toxicity, interstitial and intra-alveolar edema, and hyaline membranes with diffuse dilatation of the airways and hyperplasia of the alveolar cells.
In 500 consecutive Japanese patients tak ing amiodarone who were retrospectively evaluated, the mean follow-up period was 48 months and the mean maintenance dosage was 141 mg/day (103c). The cumula tive incidences of lung damage at 1, 3, and 5 years were 4.2%, 7.8%, and 11% respec tively. Multivariate analysis showed that age at the start (HR = 1.48; 95% CI = 1.13, 1.93) was a significant pretreatment suscept ibility factor. Age (HR = 1.64; 95% CI =1.29, 2.09), maintenance dosage (HR = 1.90; 95% CI = 1.45, 2.49) and plasma monodesethylamiodarone concen tration (HR = 1.30; 95% CI = 1.08, 1.58) were susceptibility factors during treatment. The diagnostic sensitivity and specificity of percent predicted diffusion capacity of carbon monoxide were 68% and 69% for at least a 15% reduction and 59% and 74% for at least a 20% reduction. The diagnostic sensitivity and specificity of a serum KL-6 concentration of at least 500 U/ml were 25% and 91% respectively. The authors
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concluded that amiodarone can cause sub stantial pulmonary toxicity even at low doses, particularly in older patients. Nervous system Cerebellar ataxia, with a wide-based gait, bilateral dysdiadochokinesia, and bilateral nystagmus, has been reported in a 95-year-old woman who had taken amio darone 200 mg/day for 8 months (104A). Sensory systems Eyes In vivo confocal microscopy has been performed in 20 eyes of 10 patients (6 men and 4 women) at different stages of amiodarone-induced ker atopathy (105c). There were brilliant intra cellular inclusions with high reflectivity in the basal epithelium layer in all cases. Patients with stage 2 and 3 changes had all corneal layers affected. There was thinning and increased tortuosity of the corneal nerves in patients with stage 2 and 3 changes. The authors concluded that the basal epithelium was most affected at any stage of keratopathy; in stage 1 only the superficial and basal epithelium are affected, while in stages 2 and 3 all the corneal layers are affected. With advancing keratopathy the corneal nerves became thinner and tortuous. Rarely, keratopathy can affect the whole cornea (106A). Amiodarone can cause optic neuropa thies (107Ar). The question of whether it can cause a non-arteritic anterior ischemic optic neuropathy at all has been briefly discussed (108r, 109r), and ischemic optic neuropathy has again been reported (110A). In a prospective, double-masked, rando mized study of amiodarone (n = 837) or pla cebo (n = 832) with a median follow-up in survivors of 46 months, there were no cases of bilateral visual loss (111C). The authors calculated that the maximum possible annual incidences of bilateral visual loss in subjects taking amiodarone continuously for 4 to over 60 months in daily doses of > 2.0 mg/kg (n = 696), > 3.0 mg/kg (n = 559), or > 4.0 mg/kg (n = 219) were 0.23%, 0.29%, and 0.74% respectively. Smell Anosmia has been attributed to amiodarone in a 66-year-old man who took amiodarone 200 mg/day for 3 years;
Positive inotropic drugs and drugs used in dysrhythmias
the symptom abated when the dosage was reduced to 100 mg/day (112A). Endocrine Thyroid There are two types of amiodarone-induced thyrotoxicosis: type 1 occurs in those with latent disease and is due to the iodine that amiodarone contains; type 2 is due to a destructive thyroiditis in a previously normal gland. The incidence and predictability of amiodarone-induced thyrotoxicosis and hypothyroidism have been studied in 72 patients with cardiomyopathy during a median follow-up period of 8 months (113c). The prevalence of thyroid dysfunc tion before the start of amiodarone therapy was 38% (n = 27), with almost equal distri bution between hypothyroidism and hyperthyroidism (n = 14 and 13). After treatment with amiodarone, thyroid dys function was diagnosed in 25 of the 44 patients without pre-existing dysfunction. Of these, nine developed either subclinical or overt hypothyroidism and 16 developed either subclinical or overt hyperthyroidism. Factors such as 99mTc-pertechnetate scan uptake, thyroid autoimmunity, age, thyroid autonomy, or abnormal thyroid morpho logy were not significantly associated with the development of thyroid dysfunction The usefulness of thyroid scintigraphy has been assessed in 27 consecutive patients (mean age 65 years, 13 women) with amio darone-associated hyperthyroidism (114c). All underwent 99mTc-pertechnectate thyroid scintigraphy and were classified according to the qualitative estimation of radiotracer uptake. Type 1, defined by increased/normal uptake, occurred in nine patients, all of whom responded to antithyroid drugs or radioiodine, except one with subclinical hyperthyroidism, who received no therapy. Type 2, defined by very low or undetectable uptake, occurred in 13 patients, 11 of whom responded to withdrawal of amiodarone or prednisone therapy. Hyperthyroidism was resistant in two patients and required antithyroid drugs or potassium perchlorate. The authors concluded that thyroid scinti graphy can establish the correct therapeutic approach in most cases of amiodarone induced hyperthyroidism.
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The usefulness of Doppler scanning in differentiating the two types has been eval uated in 84 healthy subjects, 30 euthyroid patients taking amiodarone, 14 patients with type 1 thyrotoxicosis, and 9 with type 2 thyrotoxicosis (115c). The two types were classified by 131I uptake and the clinical out come. The authors suggested that systolic peak velocity in the thyroid arteries could differentiate the two types of thyrotoxicosis. In another study of the usefulness of colorflow Doppler sonography, amiodarone associated thyrotoxicosis was classified as type 1 if there was increased blood flow (n = 11) and as type 2 if there was low or no blood flow (n = 10). Ten of the 11 patients in the first group had a hypervascular nodular pattern and one had a hypervascular parenchymal pattern; the clinical diagnoses were toxic nodular goiter and Graves’ disease respectively. Of the 10 patients in the second group, 6 had a normal thyroid volume, 3 a small diffuse goiter, and one a small multinodular goiter (116c). In a retrospective analysis of the preva lence and relative proportions of type 1 and type 2 amiodarone-associated thyrotoxico sis in 215 patients seen over 27 years in an Italian centre, type 1 was more frequent (60%) at the start but became less frequent with time; the annual mean number of patients with type 1 thyrotoxicosis was 3.6 at the beginning of the study period and 2.5 during the later years (117c). In contrast, the mean annual number of new cases of type 2 thyrotoxicosis progressively increased from 2.4 to 13. Likewise, the proportion of cases of type 2 thyrotoxicosis increased linearly, and by the end of the study was accounting for 89% of the cases. Patients with type 2 thyrotoxicosis were preponderantly male, had a higher serum free T4/free T3 (FT4/ FT3) ratio and lower 3 hour and 24 hour thyroid radioactive iodine uptake, and had taken a higher cumulative dose of amiodarone. The long-term risk of amiodarone induced thyroid dysfunction has been studied in 612 men who had taken part in a prospective, randomized, placebocontrolled trial of amiodarone and sotalol for persistent atrial fibrillation (118C).
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Subclinical hypothyroidism, with thyroidstimulating hormone (TSH) concentrations of 4.5–10 mU/L, occurred in 26% of those taking amiodarone and only 6.6% of the controls, and overt hypothyroidism (TSH > 10 mU/l) in 5.0% versus 0.3%; 94% of the cases of overt hypothyroidism were detected by 6 months, suggesting an inter mediate time-course. There was a trend towards a greater frequency of hyperthyr oidism (TSH < 0.35 mU/l) in those who took amiodarone (5.3% versus 2.4%). The histopathology of amiodarone-asso ciated hypothyroidism in a 66-year-old Japanese woman has been reported (119A). Most of the thyroid follicles were enlarged with dense colloid substance and lined by flattened follicular cells (involuted follicles). A few damaged follicles were infiltrated by macrophages, which were immunopositive for HAM56. Sudan IV staining showed many lipid droplets in folli cular cells. Ultrastructurally, the follicular cells contained large residual bodies com posed of abundant electron-lucent lipid dro plets of variable sizes. The methods by which different endocrin ologists manage amiodarone-induced thyr oid disease vary (SEDA-29, 186). In a questionnaire study the methods used by North American specialists (n = 115) have been compared with those of European specialists from a previous study (n = 101) (120c). Amiodarone-induced hyperthyroid ism was less frequent than amiodarone induced hypothyroidism in North America (34% and 66% of all cases of amiodarone induced thyroid dysfunction respectively, versus 75% and 25% in Europe). When hyperthyroidism is suspected, in North America hormonal assessment is mostly based on serum free T4 and TSH measure ments, and serum FT3 determination is requested less often than in Europe; thyr oid autoimmunity is included in the initial assessment less often than in Europe. The most commonly used other diagnostic pro cedures include, as in Europe, thyroid color-flow Doppler sonography, and to a lesser extent radioactive iodine uptake and thyroid scanning. Withdrawal of amioda rone is more often considered unnecessary
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in North America (21% versus 10% in type 1 hyperthyroidism and 34% versus 20% in type 2). In type 1, thionamides are the treatment of choice by both groups, but they are used as monotherapy in North America in 65% of cases com pared with 51% in Europe, where potas sium perchlorate is more often considered as a useful addition (31% versus 15% in North America). Glucocorticoids are the treatment of choice for type 2 hyperthyr oidism, alone (62% versus 46% in Europe) or in association with thionamides (16% versus 25% in Europe). After restoration of euthyroidism, thyroid ablation in the absence of recurrent thyrotoxicosis is recommended in type 1 hyperthyroidism less often in North America. If amiodar one therapy needs to be reinstituted, pro phylactic thyroid ablation is advised by 76% in type 1 hyperthyroidism, while a wait-and-see strategy is adopted by 61% in type 2 hyperthyroidism, similar to the European approach. The effects of potassium perchlorate on thyroid function have been retrospectively studied in 10 patients with amiodarone induced thyrotoxicosis without underlying thyroid disease while they continued to take amiodarone (121c). Potassium perchlorate restored euthyroidism in all patients within 28 (range 15–45) days, but after it was with drawn all the patients became thyrotoxic again after 45 (range 30–60) days. One patient developed a mild leukopenia and one had a slight increase in serum creatinine, which normalized after withdrawal of potas sium perchlorate. The authors recommended that potassium perchlorate should not be used as a first-line treatment for thyrotoxi cosis if amiodarone needs to be continued. The use of radioactive iodine to cause thyroid ablation has been studied in four patients with type 2 amiodarone-induced thyrotoxicosis who either were poor candi dates for surgery or had refused it (122c). They had been initially treated with thion amides and glucocorticoids and all but one had become euthyroid. All four patients received one dose of radioactive iodine (range 29–80 mCi) and were followed up for 12 months. There were no exacerbations of
Positive inotropic drugs and drugs used in dysrhythmias
thyrotoxicosis, but hypothyroidism occurred in three patients in the first 6 months. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) Hyponatremia due to SIADH has again been attributed to amiodarone (123A, 124A). Hematologic Amiodarone-associated bone marrow granulomata have been reviewed in the light of two further cases, in an 81-year-old man who developed leukopenia, thrombo cytopenia, and hepatosplenomegaly after tak ing amiodarone for 2 years and an 80-year-old man who developed pancytopenia after 2.5 years; both patients had non-caseating granulomata in the bone marrow (125Ar). The authors reviewed eight other published cases, one of which also featured hepatic granulomata. Liver Intravenous amiodarone can rarely cause acute hepatitis, and further cases have been reported, associated with very high rises in serum transaminases (126A, 127A). It is not clear whether this effect is due to the amiodarone itself or to the vehicle in which it is formulated, polysorbate (Tween) 80. The PPAR-Iþ/- gene may be a susceptibility factor. Pancreas Pancreatitis, a rare adverse effect of amiodarone, has again been reported (128Ar). • A 66-year-old woman who had taken amiodar one 200 mg/day for 1 month developed epigas tric pain radiating to both flanks associated with a raised serum lipase but a normal serum amylase. Endoscopic ultrasonography suggested pancreatitis. There were no asso ciated causal factors, such as biliary stones, hypertriglyceridemia or excess alcohol con sumption. Amiodarone was withdrawn. Her symptoms quickly resolved and the serum lipase activity fell. Three months later the abdominal pain had not recurred.
Urinary tract Renal damage associated with amiodarone-induced phospholipidosis has been reported; a renal biopsy showed lamellar lipid inclusions typical of amiodar one and there were also corneal microdepo sits (129A).
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Skin The blue-grey skin pigmentation in sun-exposed areas associated with amiodarone has been presumed to be due to deposition of lipofuscin. However, electron microscopy and high-performance liquid chromatogra phy have shown deposits of amiodarone in a sample of skin from a patient with such pigmentation, and no lipofuscin (130A). The authors therefore suggested that amiodar one-related skin pigmentation should be considered a skin storage disease that is secondary to drug deposition, i.e. a betweenthe-eyes reaction of type 1 (131H). Sexual function Another case of epididy mitis, a rare adverse effect of amiodarone, has been reported (132Ar). Immunologic The immunomodulatory properties of amiodarone in the inflamma tory response induced by cardiac surgery with cardiopulmonary bypass have been investigated in a double-blind, placebocontrolled trial in 20 patients (133c). They were given amiodarone 600 mg/day for 7 days orally before surgery and 45 mg/hour intravenously for 48 hours postoperatively. Fibrinogen formation was significantly increased by amiodarone, and plasma fibri nogen concentrations more than doubled by 96 hours after the start of surgery. The secretion of monocyte chemoattractant protein 1 transiently increased 4 hours after the start of surgery but rapidly fell there after; it was not affected by amiodarone. The plasma concentrations of C-reactive protein (CRP), tumor necrosis factor alpha (TNF-a), interleukin-6 (IL-6), and interleu kin-10 (IL-10) changed significantly, but were not altered by amiodarone. Although the authors suggested that amiodarone is associated with some proinflammatory actions, the data were not convincing. A hypersensitivity reaction to oral amio darone occurred in a patient who had had a previous urticarial reaction to an iodinated radiocontrast agent (134A). • A 55-year-old man developed facial urticaria after intra-arterial injection of iohexol during coronary angiography and was successfully treated with intravenous hydrocortisone and promethazine. Two subsequent episodes of
346 fast atrial fibrillation were treated with intravenous amiodarone, which was followed by oral therapy. Within 1 hour after the first oral dose of 400 mg, he developed lip swelling and tingling, which was treated with intravenous promethazine. Amiodarone was withdrawn. The Naranjo scale suggested a probable adverse reaction.
Death In a post-hoc analysis of the effects of amiodarone in 364 patients (155 of New York Heart Association [NHYA] class II and 209 of class III) from among 3029 patients with chronic heart failure who were randomized to carvedilol or metoprolol and followed for a median of 58 months, mortality was higher than in those who did not take amiodarone: 39% and 59% of those who used amiodarone in NYHA classes II and III þ IV died compared with 26% and 43% of those who did not use amiodarone (135c). This difference was maintained in a multivariate analysis (HR = 1.5; 95% CI = 1.2, 1.7). The difference was explained by an increased risk of death due to circula tory failure (HR = 2.4; CI = 1.9, 3.1). Sudden death was not different (HR = 1.07; CI = 0.8, 1.4). The authors concluded that amiodarone was associated with an increased risk of death from circulatory failure independent of functional class. However, analyses of this sort often prove to be wrong because of confounding factors. In another example of this type of posthoc analysis, an apparent association between the use of amiodarone and death has been reported in a study that was designed for a completely different purpose (136c). The study was a randomized com parison of valsartan, captopril, or both in patients with acute myocardial infarction with heart failure and/or left ventricular sys tolic dysfunction. In 825 patients who were taking amiodarone at randomization and 13 875 patients who were not, amiodarone was associated with a significant increase in mortality during three of the four study periods: HR = 1.5 (95% CI = 1.1, 2.0) for days 1–16; 2.1 (1.5, 2.9) for days 17–45; 1.1 (0.83, 1.46) for days 46–198; and 1.4 (1.2, 1.6) for days 199–1096. However, the patients who were treated with amiodarone were older, had higher Killip class, and were
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more likely to have a history of diabetes mellitus and hypertension. Although the analysis was adjusted for baseline predictors of mortality, it is highly likely that other confounders were not allowed for. Only proper prospective randomized stu dies can be relied upon to answer the ques tions posed by these post-hoc analyses. Fetotoxicity Amiodarone can cause transi ent congenital hypothyroidism after gesta tional exposure, as has again been reported in two cases (137Ar). The neonatal TSH concentrations were 78 and 134 mU/l (reference range <15 mU/l). Both were successfully treated with levothyroxine 50 micrograms/day, which was withdrawn at 16 and 10 months, respectively. They had normal growth and mental development. Drug–drug interactions Clozapine An interaction of amiodarone with clozapine has been described (138A). • A 75-year-old man with schizophrenia was well managed with clozapine 300 mg/day and divalproex sodium 1000 mg/day. When he later developed a ventricular tachycardia he was given intravenous magnesium and amiodarone 150 mg, and sinus rhythm was restored within 10 minutes. Amiodarone 400 mg/day was con tinued and a few weeks later his serum cloza pine concentration was 1580 ng/ml (combined clozapine plus norclozapine 1786 ng/ml), sig nificantly higher than the prehospital value of 242 ng/ml. The dosage of clozapine was halved to 150 mg/day, and the serum clozapine con centration fell to 355 ng/ml after 2 weeks. The dosage of divalproex was not changed during this time.
Clozapine is primarily metabolized by cyto chrome P450 1A2 (CYP1A2), of which desethylamiodarone is a potent inhibitor, and the authors proposed this as the mechanism of this interaction. Rosuvastatin An interaction of amiodarone with rosuvastatin has been proposed in a patient whose serum transaminases rose when amiodarone was added to rosuvastatin therapy and normalized when the rosuvastatin was withdrawn (139A). This effect could equally have been due to the rosuvastatin alone.
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Monitoring drug therapy The reasons for monitoring amiodarone therapy have again been reviewed, in the context of a case report (37Ar). In summary: • monitor liver function tests and thyroid and renal function at baseline and every 6 months in patients taking amiodarone if the values are within the population reference range: thyroid profile should include TSH, FT4, and FT3; liver enzymes (AsT); renal function (creatinine and electrolytes); • annual chest X-ray, electrocardiogram, and clinical assessment; • monitor the prothrombin ratio weekly during the first 7 weeks of warfarin treatment, after which the dose of warfarin should be adjusted depending on the response.
Managing adverse drug reactions Photothermolytic treatment using a Q-switched ruby laser has been used successfully to treat amiodarone-induced facial discolora tion (140A).
Cibenzoline
(SED-15, 740; SEDA-30, 217; SEDA-31, 330)
Neuromuscular function Myasthenia has been attributed to cibenzoline in a patient with chronic renal insufficiency (141A). • A woman in her late sixties with chronic kidney disease took cibenzoline 300 mg/day for 3 days and developed blepharoptosis. Anti-acetylcholine receptor antibody and edrophonium tests were negative. After another 4 days she developed pneumonia with a pleural effusion and had gradually worse blepharoptosis, dull headache, weakness, difficulty in chewing and dyspnea. Cibenzoline was withdrawn and she improved. The blood concentration of cibenzoline immediately after withdrawal was extremely high at 2448 µg/l.
Drug overdose A case of cibenzoline overdose has been reported in a patient with progressive renal insufficiency (142A). Combined hemoperfusion and hemodialysis was used and was associated with a rapid fall in plasma cibenzoline concentration and clinical improvement. However, only 29 mg of an estimated body load of ciben zoline (447–807 mg) was removed during
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the 8 hours of treatment. It is not clear to what extent hemoperfusion and hemodia lysis were beneficial in this case, since ciben zoline has a very large volume of distribution (about 4000 l). The plasma clearance of cibenzoline after intravenous administration in healthy subjects is about 700 ml/minute and the half-life is 7 hours (143C); in renal insufficiency the clearance falls to 224 ml/minute and the half-life increases to 22 hours and hemodialysis accounts for only 13% of drug clearance.
Disopyramide Neuromuscular function Worsening of pre-existing myasthenia gravis has been attributed to disopyramide (144A). • A 63-year-old woman with ocular myasthenia gravis and an anti-acetylcholine receptor antibody concentration of 16 nmol/l responded to a cholinesterase inhibitor and prednisolone 10 mg/day. When she developed atrial fibrillation and heart failure, she was given disopyramide 300 mg/day and furosemide 20 mg/day. Within 6 weeks she developed an aspiration pneumonia secondary to dysphagia with bulbar paralysis-like symptoms. A myasthenic crisis was excluded, since the antiacetylcholine receptor antibody concentration was 0.3 nmol/l. The electrocardiogram showed QTc interval prolongation (549 ms) and she developed torsade de pointes. Despite correction of hypokalemia, administration of magnesium and a continuous intravenous infusion of lidocaine, the tachydysrhythmia did not improve, but it was resolved by intravenous verapamil. All medications were withheld and after 4 days her spontaneous respiration and muscle weakness improved. She eventually died with sepsis and disseminated intravascular coagulation from acute enteritis.
Dofetilide
(SED-15, 1173; SEDA-27, 195; SEDA-29, 187; SEDA-30, 217)
Cardiovascular Cardiac dysrhythmias are common during treatment with dofetilide and can be life-threatening (145A, 146Ar). In a retrospective review of 34 patients with symptomatic paroxysmal atrial fibrilla tion, normal left ventricular function, and no
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significant valvular disease, who were given dofetilide, 9 had to withdraw because of cardiac dysrhythmias; 3 withdrew before discharge from hospital (2 with QT interval prolongation and 1 with supraventricular tachycardia); and 6 withdrew later (3 with ventricular tachycardias, 1 with QT interval prolongation, and 2 with supraventricular tachycardias) (147c). Treatment with dofeti lide was successful in less than 1 in 5 patients. Drug overdose A case of intentional over dose of dofetilide has been reported (148A). • A 33-year-old man with a history of cocaine abuse took about 5 mg of dofetilide in a suicide attempt and came to the emergency department about 45 minutes after ingestion. His QTc interval was about 570 ms. He was treated with activated charcoal and sorbitol by nasogastric tube and received aggressive supplementation with potassium and magnesium. He was monitored for several days and responded well.
Flecainide
(SED-15, 1370; SEDA-29, 188; SEDA-30, 217; SEDA-31, 330)
Cardiovascular Flecainide usually does not cause cardiac dysrhythmias in patients with no structural cardiac abnormality, but rare reports do appear, as in a case of a 77 year-old woman whose only cardiac struc tural abnormality was atrial dilatation and who developed bradydysrhythmias, prolon gation of the QT interval and torsade de pointes 10 days after starting treatment with flecainide 100 mg bd (149A). In another case, episodes of syncope asso ciated with marked QRS widening in a 63-year-old man taking flecainide 100 mg bd were precipitated by hypokalemia due to bendroflumethiazide (150A). • A 32-year-old man who was taking flecainide 200 mg/day and bisoprolol 5 mg/day for atrial fibrillation developed rapidly worsening nausea and dyspnea (151A). His systolic blood pressure was 70–85 mmHg and his pulse was irregular. Echocardiography showed no specific acute abnormalities, but the electrocardiogram showed broad complexes and 2:1 heart block. The flecainide concentration was very high at 8.4 µmol/l (usual target range 0.4–2.1).
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Nervous system Central nervous system adverse effects are commonly associated with flecainide, but are rarely severe. A patient with end-stage renal failure developed a paranoid psychosis and myoclonus, which resolved after withdrawal of flecainide (152A). Drug overdose Flecainide overdose can cause severe cardiovascular collapse and dysrhythmias, but responds to hypertonic sodium bicarbonate, as another report has emphasized (153A).
Pilsicainide Pilsicainide is a class IC antidysrhythmic drug, widely used in Japan. It inhibits the fast inward sodium current with slow kinetic properties (154R). It reduces intra-atrial con duction and prolongs the atrial effective refractory period. It increases heart rate and mean pulmonary arterial pressure and reduces stroke volume index (155R). It pro longs the PQ interval, QRS width, and QT interval; prolongation of the PQ interval correlates with plasma pilsicainide concentrations. The plasma concentration associated with suppression of supraventri cular tachycardia is about 0.5 mg/l. The pharmacokinetics of a single oral dose of pilsicainide 50 mg have been studied in 32 patients with varying degrees of renal impairment (156c). The apparent volume of distribution at steady state was 1.48 l/kg, clearance 5 ml/minute/kg and half-life 3.4 hours. Pilsicainide is about 90% eliminated unchanged by the kidneys, by glomerular fil tration and tubular secretion, and the half-life was prolonged to 24 hours in severe renal failure. Pilsicainide is bound in plasma to alpha1-acid glycoprotein (CRP), increased concentrations of which cause increased bind ing and therefore reduced clearance (157C). Observational studies Single oral doses of pilsicainide have been evaluated in 34 patients (aged 48–81, mean 66 years, 26 men) who had 42 episodes of supraventricular dysrhythmias after coronary artery bypass grafting, most within 2–4 days, classified as
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follows: paroxysmal atrial fibrillation (n = 34), paroxysmal atrial flutter (6), and sinus tachy cardia (2) (158c). Sinus rhythm was restored in 32 episodes by a single oral dose of pilsi cainide 50–100 mg, within 90 minutes in 44% and within 3 hours in 56% of episodes (mean conversion time 119 minutes). There were no significant changes in blood pressure and no significant adverse effects. The pharmacokinetics of pilsicainide have been studied in 16 healthy Korean men (mean age 25 years, weight 72 kg, height 177 cm) and 16 healthy Japanese men (age 25 years, weight 60 kg, height 172 cm) (159c). The AUC and Cmax of pilsicainide increased in proportion to dose. There were no differ ences in the kinetics between the two groups. There were nine adverse events in seven of the Korean subjects; all were mild and they included dizziness, a feeling of being hot, somnolence, and atrioventricular block. Two of the 16 Japanese subjects had a total of four adverse events; one had a reduced blood pressure, a sense of discomfort, and PR interval prolongation, and the other had extra ventricular beats. Placebo-controlled studies The effects of a single oral dose of pilsicainide have been evaluated in a double-blind, placebo-con trolled study in 75 patients (51 men) with recent-onset atrial fibrillation (160C). There was conversion to sinus rhythm within 90 minutes in 18 of the 40 patients who received pilsicainide and in 3 of the 35 who received placebo. The mean times to conversion were 37 minutes with pilsicainide and 50 minutes with placebo. In 30 patients whose pilsicai nide concentrations were determined, the mean plasma concentration was 1.05 ng/l at 90 minutes; there was no significant differ ence in the plasma concentrations between 15 responders and 15 non-responders (1.07 ver sus 1.03 ng/l). Pilsicainide increased the QRS duration at 40–90 minutes after administra tion. There was a sinus pause of 8 seconds after termination of atrial fibrillation in one patient with Wolff–Parkinson–White syn drome who received pilsicainide, and in one non-responder there was conversion to atrial flutter with 2:1 atrioventricular conduction but without hemodynamic deterioration.
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In a placebo-controlled study 62 patients with chronic atrial fibrillation were given oral placebo (n = 10) or pilsicainide 150 mg/day (n = 52) for 4 weeks before elec trical cardioversion (161C). Before cardio version, 11 of those who were given pilsicainide reverted to sinus rhythm com pared with none in the placebo group. Of 51 patients in whom direct current cardiover sion was performed, 8 were not converted to sinus rhythm (5 pilsicainide and 3 placebo) and 3 needed intracardiac cardioversion. There were asymptomatic bradydysrhythmias in 5 of those who were given pilsicainide. Cardiovascular Of 35 patients, 11 without ST segment depression were given pilsicai nide; 24 had ischemic ST segment depres sion, of whom 9 were given pilsicainide; they were compared with 16 age-matched controls (162C). The QRS duration was mea sured at rest and at heart rates of 80, 100, and 120/minute during exercise. There were no changes in the QRS duration as heart rates increased in the controls. However, ischemia independently caused a significant increase in QRS duration at a heart rate of 120/min ute. Pilsicainide produced a rate-dependent prolongation of the QRS duration in patients without ST segment depression as the heart rate increased to 100/minute. The combina tion of ischemia þ pilsicainide led to a much greater rate-dependent prolongation of the QRS duration. The authors concluded that the combination of a class IC drug and acute ischemia could lead to additive rate-depen dent ventricular conduction slowing, and that such an effect could have explained the increased mortality in the Cardiac Arrhyth mia Suppression Trial (CAST). In a study of the electrophysiological mechanisms of the adverse effects of class I antidysrhythmic drugs of different subtypes (cibenzoline, disopyramide, pilsicainide, and procainamide) in 14 patients (mean age 37 years, 10 men) who had inducible atrio ventricular re-entrant tachycardias, the drugs induced unidirectional conduction block in the accessory pathway (antegrade conduction block associated with preserved retrograde conduction) and enhanced the induction of the tachycardia with atrial extrastimulation
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in 4 of 6 patients with a manifest accessory pathway; in 8 patients with a concealed acces sory pathway, there was outward or inward expansion of the tachycardia induction zone in patients who had greater prolongation of the conduction time than the refractory period of the retrograde accessory pathway after class I drugs (163c). During ventricular extrastimulation, induction of bundle branch re-entry after class I drugs initiated the tachy cardia in patients with both types of accessory pathway. The authors concluded that the adverse effects of all class I drugs, regardless of subtype, are mainly due to induction of unidirectional retrograde conduction in the manifest accessory pathway and greater prolongation of the retrograde conduction time in the concealed accessory pathway than the refractory period. Delayed conduction has been attributed to pilsicainide (164A). • A 74-year-old man with atrial fibrillation was given pilsicainide 50 mg tds and 2 days later he suddenly lost consciousness. He was cyanotic, with an irregular pulse and a systolic blood pressure below 50 mmHg. An electrocardiogram showed a heart rate of less than 40/minute, with sinus pauses, ventricular escape beats, an extremely long PQ interval, and broad QRS complexes. He responded to intravenous dopamine 15 micrograms/kg/ minute), dobutamine 15 micrograms/kg/minute and atropine sulfate 1 mg and reverted to atrial fibrillation with a broad QRS complex and a systolic blood pressure of 100 mmHg. Pilsicainide was withdrawn and 2 days later the rhythm was atrial flutter/fibrillation and the QRS complex was normal.
In 89 patients (aged 62 years, 72 men) with episodes of atrial fibrillation (65 with parox ysmal, 11 with persistent, and 13 with perma nent atrial fibrillation) who were given oral pilsicainide for 4 weeks, the dose was increased in those who did not develop atrial flutter; those who did have atrial flutter underwent ablation (165c). Pilsicainide caused atrial flutter in 17 patients, in whom the pilsicainide plasma concentration was significantly higher than in those without atrial flutter (0.79 versus 0.51 mg/l). Like other class IC antiarrhythmic drugs with slow kinetics, pilsicainide can cause Brugada like changes on the electrocardiogram,
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mimicking acute inferior myocardial infarc tion (166A). • An 81-year-old woman with normal renal func tion developed pilsicainide intoxication asso ciated with dehydration after taking pilsicainide 100 mg/day for paroxysmal A atrial fibrillation (167 ). Electrocardiography showed atrioventricular dissociation, idioventri cular rhythm with marked QRS widening and QTc interval prolongation. The plasma concen tration of pilsicainide was 6.2 mg/l (usual target range 0.25–1.0). Rehydration with intravenous saline caused reversion to sinus rhythm after 2 hours and the QRS and JT intervals gradually normalized.
In a 17-year-old man with Brugada syn drome intravenous pilsicainide caused further ST segment elevation in the inferior leads, new ST segment depression in leads V2–V6 and two distinct forms of ventricular extra beats, which triggered short runs of poly morphous ventricular tachycardia; an infusion of isoprenaline suppressed the dysrhythmias and normalized the ST segment (168A). In another case a 65-year-old man with a Brugada-type electrocardiogram developed chest pain, palpitation, and faintness while taking pilsicainide; intravenous pilsicainide caused ST segment elevation in V1–V4 and vasospasm of the right coronary artery (169A). In a patient with a ventricular pacemaker, ventricular pacing failure occurred immediately after a single oral dose of pilsicainide (170A). Ventricular dysrhythmias have been attributed to pilsicainide, including ventricu lar tachycardia in an 88-year-old man taking pilsicainide 100 mg/day for atrial fibrillation (plasma pilsicainide concentration 2.42 mg/l) (171A), ventricular fibrillation in a 56-year old man with Brugada syndrome taking pil sicainide 150 mg/day for paroxysmal atrial fibrillation syndrome (172A), and ventricular tachycardia originating from the right ventri cular outflow tract (173A). Ventricular dysrhythmias due to pilsicai nide have been examined in 28 patients with Brugada-type electrocardiographic abnorm alities (174c). In all patients, pilsicainide increased the ST segment elevation and accentuated type 1 electrocardiographic changes. Ventricular tachycardia developed in three patients and ventricular extra beats
Positive inotropic drugs and drugs used in dysrhythmias
in two other patients. These 5 patients had higher ST segment elevation in lead V2 at baseline and after pilsicainide and a longer QTc interval after pilsicainide than the other 23 patients. However, there was no difference between the two groups in the incidence of prior cardiac events, the results of signalaveraged electrocardiography, HV interval, inducibility of ventricular fibrillation by pro grammed electrical stimulation or QRS duration. In one patient, ventricular extra beats originated from three sites, two of which triggered polymorphous ventricular tachycardia. The right ventricular outflow tract was the origin of two types of ventricu lar extra beats, and other sites were the ori gins of five other types. Breast feeding In a healthy nursing mother who took oral pilsicainide 50 mg, the pilsi cainide concentration in milk was higher than that in plasma at all times up to 12 hours, with an average ratio of 1.75:1; how ever, the estimated daily amount of drug that a baby who takes 150 ml/kg/day of breast milk would ingest would be very low (0.06 mg) (175A). Susceptibility factors Sex In a population pharmacokinetic study of intravenous pilsi cainide 10 mg in 91 patients with cardiac dysrhythmias, plasma concentrations were 50% lower in women than in men (176c). Drug overdose Fatal poisoning has been attributed to an overdose of the combination of pilsicainide and atenolol, with high plasma concentrations of both (177A). • A 34-year-old man took an overdose of pilsicainide hydrochloride (2500 mg) with suicidal intent (178A). His consciousness was impaired and there was circulatory failure. His systolic blood pressure was 74 mmHg. He had a ventricular tachycardia, and since cardioversion was ineffective, he was given intravenous magnesium sulfate, which resulted in immediate reversion to normal rhythm, although the PQ and QRS intervals remained prolonged, consistent with the effects of a class IC sodium channel blocker. The blood pressure rose to over 100 mmHg and his circulatory and respiratory functions improved immediately. The plasma concentration of pilsicainide was high (7.22 mg/l). Hemoperfusion was performed
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but the plasma pilsicainide concentration did not fall satisfactorily.
Drug–drug interactions Cetirizine An interaction of cetirizine with pilsicainide has been described in an anecdotal report, a small clinical study, and an in vitro study, (179AcE). A 72-year-old woman with renal insufficiency who was taking oral pilsicai nide 150 mg/day felt faint 3 days after starting to take oral cetirizine 20 mg/day. She had a wide QRS wave with bradycardia, and her symptoms were relieved by withholding pilsi cainide. The plasma cetirizine concentration fell when pilsicainide was withdrawn. In a pharmacokinetic study in six healthy men after a single dose of either cetirizine 20 mg, pilsicainide 50 mg, or both, the renal clearance of each drug was significantly reduced during co-administration (from 475 to 279 ml/minute for pilsicainide and from 189 to 118 ml/minute for cetirizine). In vitro studies using Xenopus oocytes with micro-injected human organic cation transporter 2 and renal cells transfected with human multidrug resistance protein 1 showed that transport of the substrates of these transporters was inhibited by both cetir izine and pilsicainide. Cimetidine In nine healthy men aged 21–38 years, oral cimetidine 800 mg increased the AUC of oral pilsicainide 50 mg by a mean of 33%, prolonged its half-life by a mean of 24% (from 5 to 6.2 hours), reduced its apparent oral clearance by a mean of 26% (from 245 to 180 ml/minute), and reduced its renal clearance by a mean of 28% (from 197 to 142 ml/minute); the net renal clearance by tubular secretion was significantly reduced by a mean of 38% (from 151 to 93 ml/min ute) (180c). In the same study, oral probene cid 1500 mg had no effect on cimetidine kinetics. The authors concluded that pilsicai nide is secreted by the active transport system for organic bases in the proximal renal tubule.
Propafenone (SED-15, 2939; SEDA-30, 218; SEDA-31, 331) Cardiovascular ‘Cardiac memory’ is the phenomenon whereby T wave changes
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persist after aberrant ventricular activation. Propafenone toxicity has been reported to cause cardiac memory after QRS widening and markedly abnormal ventricular activa tion in a 74-year-old woman (181A). Propafenone can cause Brugada-like changes on the electrocardiogram (182A), which can be mistaken for acute myocardial infarction (183A). Drug–drug interactions Citalopram Epi sodes of chest tightness and dizziness, which occurred when citalopram was added to the regimen of a woman, an inter mediate to the extensive cytochrome P450 2D6 (CYP2D6) metabolizer, who was tak ing a large number of other drugs, including propafenone, were unconvincingly attribu ted to the latter (184A). Lithium Electrocardiographic changes compatible with type 1 Brugada syn drome occurred when a patient with Wolff–Parkinson–White syndrome who was taking lithium, with serum concentrations within the usual target range, was given propafenone (185A). The authors suggested that the electrocardiographic changes had occurred because of synergistic blocking effects of the two drugs on sodium channels. Venlafaxine An interaction of propafenone with venlafaxine has been hypothesized (186A). • An 85-year-old woman who was taking propafenone 150 mg bd, ramipril, ticlopidine, torsemide, theophylline, paracetamol, and triazolam developed a mood disorder and was found to have cortical atrophy. She was given modified-release venlafaxine 75 mg/day and 4 weeks later the dosage was increased to
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150 mg/day. After 10 days she developed bouts of visual hallucinations lasting about 2 hours, especially at night, and psychomotor agitation. Venlafaxine was withdrawn and the hallucinations and psychomotor agitation resolved in about 4 days. She was given citalopram instead, without adverse effects.
As venlafaxine is metabolized primarily by CYP2D6 and is a substrate of P glycopro tein, both of which propafenone inhibits, the authors proposed that propafenone had increased venlafaxine plasma concen trations, causing the hallucinations.
Quinidine and derivatives (SED-15, 2997; SEDA-29, 189; SEDA-30, 219; SEDA-31, 332) Immunologic Antiphospholipid antibodies have been reported in patients taking quinidine (SEDA-20, 179). A 68-year-old woman with easy bruising and hematomas provoked by minimal trauma, who had been taking quinidine for 18 years, had antiphospholipid antibodies and antiprothrom bin antibodies (187A). Susceptibility factors Genetic In a doubleblind, crossover, randomized study of the pharmacokinetics and pharmacodynamics of quinidine-induced QT prolongation in 13 healthy Caucasians and 24 Koreans, there were no pharmacokinetic differences, but the QTc intervals in the Caucasians were longer than those in Koreans at the same quinidine concentrations, especially at higher quinidine concentrations, and in women; in an Emax model, E0 was related to sex, and DEmax was related to ethnicity (188C).
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VA, Cerri GG. Differentiation between the two types of amiodarone-associated thyro toxicosis using duplex and amplitude Dop pler sonography. Acta Radiol 2007;48 (4):412–21. Loy M, Perra E, Melis A, Cianchetti ME, Piga M, Serra A, Pinna G, Color-flow MS. Doppler sonography in the differential diagnosis and management of amiodarone induced thyrotoxicosis. Acta Radiol 2007;48 (6):628–34. Bogazzi F, Bartalena L, Dell’Unto E, Tomisti L, Rossi G, Pepe P, Tanda ML, Grasso L, Macchia E, Aghini-Lombardi F, Pinchera A, Martino E. Proportion of type 1 and type 2 amiodarone-induced thyrotoxicosis has changed over a 27-year period in Italy. Clin Endocrinol (Oxf) 2007;67(4):533–7. Batcher EL, Tang XC, Singh BN, Singh SN, Reda DJ, Hershman JM, Investigators. SAFE-T. Thyroid function abnormalities dur ing amiodarone therapy for persistent atrial fibrillation. Am J Med 2007;120(10):880–5. Nakazawa T, Murata S, Kondo T, Naka mura N, Yamane T, Iwasa S, Katoh R. His topathology of the thyroid in amiodarone induced hypothyroidism. Pathol Int 2008;58 (1):55–8. Tanda ML, Piantanida E, Lai A, Liparulo L, Sassi L, Bogazzi F, Wiersinga WM, Braverman LE, Martino E, Bartalena L. Diagnosis and management of amiodar one-induced thyrotoxicosis: similarities and differences between North American and European thyroidologists. Clin Endocrinol (Oxf) 2008;69(5):812–8. Bogazzi F, Bartalena L, Tomisti L, Dell’Unto E, Cosci C, Sardella C, Tanda ML, Lai A, Gasperi M, Aghini-Lombardi F, Martino E. Potassium perchlorate only tem porarily restores euthyroidism in patients with amiodarone-induced hypothyroidism who continue amiodarone therapy. J Endo crinol Invest 2008;31(6):515–9. Gursoy A, Tutuncu NB, Gencoglu A, Anil C, Demirer AN, Demirag NG. Radioactive iodine in the treatment of type-2 amiodar one-induced thyrotoxicosis. J Natl Med Assoc 2008;100(6):716–9. Shavit E, Sherer Y. Hyponatremia induced by amiodarone therapy. Isr Med Assoc J 2007;9(7):564–5.
Positive inotropic drugs and drugs used in dysrhythmias 124. Paydas S, Araz F, Balal M. SIADH induced by amiodarone in a patient with heart fail ure. Int J Clin Pract 2008;62(2):337. 125. Mohamed T, Sanjay R, Sycheva T, Aish L, Schneider D, Oo TH. Amiodarone-asso ciated bone marrow granulomas: a report of 2 cases and review of the literature. Int J Hematol 2007;85(2):101–4. 126. Rizzioli E, Incasa E, Gamberini S, Savelli S, Zangirolami A, Tampieri M, Manfredini R. Acute toxic hepatitis after amiodarone intravenous loading. Am J Emerg Med 2007;25(9):1082.e1–4 127. Chan AL, Hsieh HJ, Hsieh YA, Lin SJ. Fatal amiodarone-induced hepatotoxicity: a case report and literature review. Int J Clin Pharmacol Ther 2008;46(2):96–101. 128. Chen YY, Chen CY, Leung KK. Acute pancreatitis and amiodarone: a case report. World J Gastroenterol 2007;13(6):975–7. 129. Pintavorn P, Cook WJ. Progressive renal insufficiency associated with amiodarone induced phospholipidosis. Kidney Int 2008;74(10):1354–7. 130. Ammoury A, Michaud S, Paul C, ProstSquarcioni C, Alvarez F, Lamant L, Launay F, Bazex J, Chouini-Lalanne N, Marguery MC. Photodistribution of blue-gray hyper pigmentation after amiodarone treatment: molecular characterization of amiodarone in the skin. Arch Dermatol 2008;144 (1):92–6. 131. Aronson JK, Hauben M. Anecdotes that provide definitive evidence. BMJ 2006;333 (7581):1267–9. 132. Nikolaou M, Ikonomidis I, Lekakis I, Tsio dras S, Kremastinos D. Amiodarone induced epididymitis: a case report and review of the literature. Int J Cardiol 2007;121(1):e15–6. 133. Karth GD, Buberl A, Nikfardjam M, Meyer B, Wollenek G, Grimm M, Lassnigg A, Brannath W, Hiesmayr M, Heinz G. Role of amiodarone on the systemic inflamma tory response induced by cardiac surgery: proinflammatory actions. Can J Anaesth 2007;54(4):262–8. 134. Stafford L. Hypersensitivity reaction to amiodarone in a patient with a previous reaction to an iodinated radiocontrast agent. Ann Pharmacother 2007;41(7): 1310–4.
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135. Torp-Pedersen C, Metra M, Spark P, Lukas MA, Moullet C, Scherhag A, Komajda M, Cleland JG, Remme W, Di Lenarda A, Swedberg K, Poole-Wilson PA, Investiga tors. COMET. The safety of amiodarone in patients with heart failure. J Card Fail 2007;13(5):340–5. 136. Thomas KL, Al-Khatib SM, Lokhnygina Y, Solomon SD, Kober L, McMurray JJ, Califf RM, Velazquez EJ. Amiodarone use after acute myocardial infarction complicated by heart failure and/or left ventricular dysfunc tion may be associated with excess mortal ity. Am Heart J 2008;155(1):87–93. 137. Pavan-Senn CC, Nesi-França S, Pelaez J, Pereira RM, Boguszewski MC, Sandrini Neto R, Lacerda Filho L. Hipotireoidismo neonatal transitorio causado pelo uso de amiodarona durante a gestacao – relato de dois casos e revisao da literatura. [Transient neonatal hypothyroidism due to amiodar one administration during pregnancy – two case reports and review of literature.] Arq Bras Endocrinol Metabol 2008;52 (1):126–30. 138. Stevens JR, Freudenreich O, Stern TA. Ele vated clozapine serum level after treatment with amiodarone. Psychosomatics 2008;49 (3):255–7. 139. Torp-Pedersen C, Metra M, Spark P, Lukas MA, Moullet C, Scherhag A, Komajda M, Cleland JG, Remme W, Di Lenarda A, Swedberg K, Poole-Wilson PA, Investiga tors. COMET. The safety of amiodarone in patients with heart failure. J Card Fail 2007;13(5):340–5. 140. Wiper A, Roberts DH, Schmitt M. Amiodar one-induced skin pigmentation: Q-switched laser therapy, an effective treatment option. Heart 2007;93(1):15. 141. Kawasaki H, Yahata K, Okamoto C, Imamaki H, Seta K, Sugawara A. [Myasthe nia-like syndrome induced by cibenzoline overdose in a patient with chronic kidney disease.] Nippon Jinzo Gakkai Shi 2008;50 (7):942–7. 142. Meeus R, Verpooten GA, De Paep R, Pae linck BP, Neels H, Cooreman S, De Doncker M, Jorens PG. Cibenzoline intox ication: effect of combined hemoperfusion– hemodialysis on plasma clearance. Clin Toxicol (Phila) 2008;46(4):303–6.
360 143. Aronoff G, Brier M, Mayer ML, Barbalas M, Aogaichi K, Sloan R, Brazzell R, Mas sarella J. Bioavailability and kinetics of cibenzoline in patients with normal and impaired renal function. J Clin Pharmacol 1991;31(1):38–44. 144. Hirose K, Yamaguchi H, Oshima Y, Chor aku M, Hirono A, Takamori N, Tamura K. Severe respiratory failure and torsades de pointes induced by disopyramide in a patient with myasthenia gravis. Intern Med 2008;47(19):1703–8. 145. Kolb C, Ndrepepa G, Zrenner B. Late dofetilide-associated life-threatening proar rhythmia. Int J Cardiol 2008;127(2):e54–6. 146. Aktas MK, Shah AH, Akiyama T. Dofeti lide-induced long QT and torsades de pointes. Ann Noninvasive Electrocardiol 2007;12(3):197–202. 147. Mykytsey A, Bauman JL, Razminia M, Zheutlin T, Wang T, Saleem M, Leal S, Kehoe RF. Observations on the safety and effectiveness of dofetilide in patients with paroxysmal atrial fibrillation and normal left ventricular function. J Cardiovasc Phar macol Ther 2007;12(1):36–43. 148. Campbell KB, Mando JD, Gray AL, Robin son E. Management of dofetilide overdose in a patient with known cocaine abuse. Pharmacotherapy 2007;27(3):459–63. 149. Nogales Asensio JM, Moreno Sanchez N, Doncel Vecino LJ, Villar Mariscal C, López-Mínguez JR, Merchan Herrera A. Torsade-de-pointes in a patient under flecai nide treatment, an unusual case of proar rhythmicity. Int J Cardiol 2007;114(2):E65–7. 150. Khavandi A, Walker PR. Flecainide cardi otoxicity precipitated by electrolyte imbal ance. Caution with thiazide diuretics. Emerg Med J 2007;24(5):e26. 151. Airaksinen KE, Koistinen MJ. ECG find ings in fatal flecainide intoxication. Heart 2007;93(12):1499. 152. Ting SM, Lee D, Maclean D, Sheerin NS. Paranoid psychosis and myoclonus: flecai nide toxicity in renal failure. Cardiology 2008;111(2):83–6. 153. Devin R, Garrett P, Anstey C. Managing cardiovascular collapse in severe flecainide overdose without recourse to extracorpor eal therapy. Emerg Med Australas 2007;19 (2):155–9.
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154. Kumagai K, Nakashima H, Tojo H, Yasuda T, Noguchi H, Matsumoto N, Ogawa M, Saku K. Pilsicainide for atrial fibrillation. Drugs 2006;66(16):2067–73. 155. Ino T, Atarashi H, Kuruma A, Onodera T, Saitoh H, Hayakawa H. Electrophysiologic and hemodynamic effects of a single oral dose of pilsicainide hydrochloride, a new class 1c antiarrhythmic agent. J Cardiovasc Pharmacol 1998;31(1):157–64. 156. Takabatake T, Ohta H, Yamamoto Y, Ishida Y, Hara H, Ushiogi Y, Nakamura S, Hashi moto N, Sasaki T, Satoh S, Yamada Y, Ohta K, Ise T. Pharmacokinetics of SUN 1165, a new antiarrhythmic agent, in renal dysfunc tion. Eur J Clin Pharmacol 1991;40(4):411–4. 157. Fukumoto K, Tanemura M, Tsuchishita Y, Kusumoto M, Matsumoto K, Kamakura S, Ueno K. Effect of protein binding of pilsi cainide on the pharmacokinetics. Drug Metab Pharmacokinet 2005;20(3):183–6. 158. Kohno K, Takeuchi Y, Gomi A, Nakatani H, Suda Y, Shimabukuro T, Nagano N. Efficacy and safety of a single oral dose of pilsicainide in supraventricular arrhythmia after coronary artery bypass grafting. Jpn J Thorac Cardiovasc Surg 1998;46(4):361–7. 159. Kim BH, Kim JR, Lim KS, Kim JW, Kim KP, Hong JH, Jang IJ, Shin SG, Yu KS, Tanaka T. An open-label, single-dose, parallel-group, dose-increasing study compar ing the pharmacokinetics and tolerability of pilsicainide hydrochloride in healthy Korean and Japanese male subjects. Clin Ther 2009;31(3):609–18. 160. Atarashi H, Inoue H, Hiejima K, Hayakawa H. Conversion of recent-onset atrial fibrilla tion by a single oral dose of pilsicainide (Pilsicainide Suppression Trial on atrial fibrillation). The PSTAF Investigators. Am J Cardiol 1996;78(6):694–7. 161. Okishige K, Nishizaki M, Azegami K, Igawa M, Yamawaki N, Aonuma KKana gawa Arrhythmia Task Force investigators. Pilsicainide for conversion and maintenance of sinus rhythm in chronic atrial fibrillation: a placebo-controlled, multicenter study. Am Heart J 2000;140(3):e13. 162. Sadanaga T, Ogawa S. Ischemia enhances use-dependent sodium channel blockade by pilsicainide, a class IC antiarrhythmic agent. J Am Coll Cardiol 1994;23(6):1378–81.
Positive inotropic drugs and drugs used in dysrhythmias 163. Fujiki A, Tani M, Yoshida S, Inoue H. Electrophysiologic mechanisms of adverse effects of class I antiarrhythmic drugs (cibenzoline, pilsicainide, disopyramide, procainamide) in induction of atrioventricu lar re-entrant tachycardia. Cardiovasc Drugs Ther 1996;10(2):159–66. 164. Toeda T, Susa R, Saigawa T, Abe T, Yama guchi Y, Fuse K, Murooka H. A case of sinus pause due to the proarrhythmia of pilsicainide. Jpn Heart J 2000;41(3):405–10. 165. Hirao K, Okishige K, Yamamoto N, Otomo K, Azegami K, Isobe M. Long-term efficacy of hybrid pharmacologic and ablation ther apy in patients with pilsicainide-induced atrial flutter. Clin Cardiol 2005;28(7):338–42. 166. Nakamura W, Segawa K, Ito H, Tanaka S, Class YN. IC antiarrhythmic drugs, flecainide and pilsicainide, produce ST segment eleva tion simulating inferior myocardial ischemia. J Cardiovasc Electrophysiol 1998;9(8):855–58. 167. Ozeki S, Utsunomiya T, Matsuo S, Yano K. Pilsicainide intoxication in a patient with dehydration. Jpn Circ J 1999;63(3):219–22. 168. Chinushi M, Izumi D, Furushima H, Wata nabe H, Aizawa Y. Multiple premature beats triggered ventricular arrhythmias dur ing pilsicainide infusion in a patient with inferior ST-segment elevation. Pacing Clin Electrophysiol 2006;29(12):1445–8. 169. Goda A, Yamashita T, Kato T, Koike A, Sagara K, Kirigaya H, Itoh H, Aizawa T, Fu LT. Pilsicainide-induced coronary vasos pasm in a patient with Brugada-type elec trocardiogram. Circ J 2005;69(7):858–60. 170. Numata T, Abe H, Nagatomo T, Kohshi K, Nakashima Y. Ventricular pacing failure after a single oral dose of pilsicainide in a patient with a permanent pacemaker and paroxysmal atrial fibrillation. Pacing Clin Electrophysiol 2000;23(9):1436–8. 171. Horita Y, Kanaya H, Uno Y, Yamazaki T, Kaku B, Funada A, Kitajima S, Matsumura M, Satoh T. A case of the toxicity of pilsi cainide hydrochloride with comparison of the serial serum pilsicainide levels and elec trocardiographic findings. Jpn Heart J 2004;45(6):1049–56. 172. Matsumoto K, Sumita S, Ishikawa T, Mat sushita K, Kobayashi T, Ohkusu Y, Yama kawa Y, Nakagawa T, Nakazawa I, Mochida Y, Ebina T, Uchino K, Kimura
173.
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K, amura S. [Brugada syndrome associated with ventricular fibrillation induced by administration of pilsicainide: a case report.] J Cardiol 2003;42(5):227–34. Shinohara T, Takahashi N, Saikawa T, Yoshimatsu H. Pilsicainide-induced ventri cular tachycardia originating from right ventricular outflow tract. J Cardiovasc Elec trophysiol 2007;18(5):552. Wakaumi M, Tsuruoka S, Sakamoto K, Shiga T, Fujimura A. Pilsicainide in breast milk from a mother: comparison with diso pyramide and propafenone. Br J Clin Phar macol 2005;59(1):120–2. Wakaumi M, Tsuruoka S, Sakamoto K, Shiga T, Fujimura A. Pilsicainide in breast milk from a mother: comparison with diso pyramide and propafenone. Br J Clin Phar macol 2005;59(1):120–2. Ogawa R, Kishi R, Mihara K, Takahashi H, Takagi A, Matsumoto N, Masuhara K, Nakazawa K, Miyake F, Kobayashi S, Echi zen H. Population pharmacokinetic and pharmacodynamic analysis of a class IC antiarrhythmic, pilsicainide, in patients with cardiac arrhythmias. J Clin Pharmacol 2006;46(1):59–68. Hikiji W, Kudo K, Nishida N, Ishida T, Usumoto Y, Tsuji A, Ikeda N. Acute fatal poisoning with pilsicainide and atenolol. Int J Legal Med 2008;122(6):503–6. Nakata K, Moriwaki R, Yamaguchi A, Takenouchi S, Mato T, Tsutsumi H. [Case in which magnesium sulfate effectively trea ted ventricular tachycardia due to overdose of pilsicainide hydrochloride.] Chudoku Kenkyu 2006;19(1):49–53. Tsuruoka S, Ioka T, Wakaumi M, Saka moto K, Ookami H, Fujimura A. Severe arrhythmia as a result of the interaction of cetirizine and pilsicainide in a patient with renal insufficiency: first case presentation showing competition for excretion via renal multidrug resistance protein 1 and organic cation transporter 2. Clin Pharmacol Ther 2006;79(4):389–96. [erratum 80(6):645]. Shiga T, Hashiguchi M, Urae A, Kasanuki H, Rikihisa T. Effect of cimetidine and probene cid on pilsicainide renal clearance in humans. Clin Pharmacol Ther 2000;67(3):222–8. Wylie Jr JV, Zimetbaum P, Josephson ME, Shvilkin A. Cardiac memory induced by QRS
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183.
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widening due to propafenone toxicity. Pacing Clin Electrophysiol 2007;30(9):1161–4. Jastrzebski M. Migotanie komor i uniesie nia odcinka ST jak w zespole Brugadow podczas leczenia propafenonem. [Ventricu lar fibrillation and Brugada-like ECG pattern during propafenone treatment.] Kardiol Pol 2008;66(2):207–9. Chutani S, Imran N, Grubb B, Kanjwal Y. Propafenone-induced Brugada-like ECG changes mistaken as acute myocardial infarction. Emerg Med J 2008;25(2):117–8. Garcia A. Adverse effects of propafenone after long-term therapy with the addition of citalopram. Am J Geriatr Pharmacother 2008;6(2):96–9. Fragakis N, Iliadis I, Papanastasiou S, Lambrou A, Katsaris G. Brugada type electrocardiographic changes induced by concomitant use of lithium and propafenone
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in patient with Wolff–Parkinson–White syn drome. Pacing Clin Electrophysiol 2007;30 (6):823–5. 186. Gareri P, De Fazio P, Gallelli L, De Fazio S, Davoli A, Seminara G, Cotroneo A, De Sarro G. Venlafaxine–propafenone interac tion resulting in hallucinations and psycho motor agitation. Ann Pharmacother 2008;42(3):0434–8. 187. Clauser S, Fischer AM, Darnige L. Quinidine-induced lupus anticoagulant, hypoprothrombinemia, and antiprothrombin antibodies. Am J Hematol 2007;82(4):330. 188. Shin JG, Kang WK, Shon JH, Arefayene M, Yoon YR, Kim KA, Kim DI, Kim DS, Cho KH, Woosley RL, Flockhart DA. Possible interethnic differences in quinidine-induced QT prolongation between healthy Cauca sian and Korean subjects. Br J Clin Phar macol 2007;63(2):206–15.
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Beta-adrenoceptor antagonists and antianginal drugs
BETA-ADRENOCEPTOR ANTAGONISTS (SED-15, 452; SEDA-29, 194; SEDA-30, 223; SEDA-31, 339) Metabolism The GEMINI study compared the effects of antihypertensive therapy with carvedilol and metoprolol tartrate on glyce mic control in 1237 patients with diabetes and hypertension and an average baseline body weight of 97 kg already taking angio tensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (1C). After 5 months, weight gain from baseline was 1.19 kg with metoprolol and 0.17 kg with car vedilol. The greatest difference in weight gain between carvedilol and metoprolol occurred in the most overweight patients and in those not using insulin. Gain in body weight has previously been reported with other beta-blockers and may well be seen as a beneficial effect when applied to patie nts with heart failure, in which beta-blockers delay the development of cachexia. Skin Several case series have reported a possible association between beta-blockers and induction or exacerbation of psoriasis. A matched case-control analysis in the
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32018-6 2010 Elsevier B.V. All rights reserved.
General Practice Research Database (GPRD) was conducted on 36 702 cases of first-time diagnosis of psoriasis and an equal number of matched controls (2C). There was no association between the prescription of antihypertensive drugs, among them beta-blockers, and the risk of psoria sis. This is the largest study so far to have explored a possible association between beta-blockers and the risk of psoriasis.
Betaxolol Another case of beta-blocker poisoning has been reported (3A). � A 38-year-old woman took 5.32 g of betaxolol and developed severe shock, resistant to catecholamines. Cardiac support with per cutaneous cardiopulmonary bypass and oxyge nation was begun and acute renal insufficiency was treated by continuous hemodiafiltration over 5 days. She was extubated on day 14 and was discharged after 1 month.
Carvedilol (SED-15, 676; SEDA-28, 216) Cardiovascular Beta-blockers are life saving in adults with heart failure, but little is known about their value in children and adolescents. The effects of carvedilol, target dose 0.2 or 0.4 mg/kg, in children and adolescents with symptomatic systemic ventricular systolic dysfunction have been prospectively evaluated in a multi center,
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double-blind, randomized, placebo-controlled study in 161 children and adolescents (4C). There was no statistically significant differ ence between the groups in the composite primary end point based on the percentage of patients who improved, worsened or were unchanged. More than 90% of the pat ients reported at least one adverse event, the most common being upper respiratory tract infections, vomiting, and cough, without differences between placebo and carvedilol. There was worsening heart failure in 11% of the patients in both groups. At variance with results in adults, carvedilol did not sig nificantly improve heart failure outcomes in children and adolescents. Skin Cutaneous vasculitis has rarely been reported after administration of betablockers, but carvedilol has never pre viously been implicated (5 A ). � A 65-year-old man who had taken two doses of carvedilol 3.125 mg developed a generalized palpable purpuric eruption less than 24 hours after the first dose. He had long-standing type 2 diabetes mellitus, arterial hypertension, a chronic cardiomyopathy, diabetic nephropa thy, and recent renal insufficiency, and was taking many regular medications, including enalapril, diltiazem, metoprolol, methyldopa, folic acid, ranitidine, pentoxifylline, furose mide, epoetin, and insulin. Carvedilol was withdrawn and the eruption began to sub side. In less than 10 days the rash disap peared, leaving behind only hyperpigmented macules. Both his past medical history and available documents confirmed that he had not been exposed to the drug before.
Labetalol
(SED-15, 1985)
Drug overdose An accidental overdose of labetalol for paradoxical hypertension after surgical correction of coarctation of the aorta in a neonate has been reported (6A). � An 8-month-old girl born prematurely underwent surgical correction of an aortic coarctation. After surgery she was given labetalol, and on postoperative day 4 by mistake received an overdose of 17.2 mg/kg intravenously, about 17 times the usual dose. Her blood pressure fell from 70 to 38 mmHg,
M.G. Franzosi and R. Latini
but returned to baseline within the next 45 minutes. Echocardiography showed normal left ventricular size and contractility. The serum concentration of labetalol 1 hour after injection was 0.9 mg/l.
Despite a very large overdose of labetalol, the effects were mild and transient. Altered response of alpha-adrenoceptors down stream of the coarctation and the reported lack of toxicity of beta-blockers in children may have contributed. � A 44-year-old woman with depression and alcoholism was found dead. Drugs of abuse were not detected in her urine, but ethanol and labetalol 1.7 mg/l were found in post mortem blood.
This is the first report of fatal intoxication after overdose of labetalol, directly attribu table to this drug, in the absence of any other apparent cause of death (7A).
Metoprolol
(SED-15, 2321)
Drug overdose In 2004, among 2.4 million cases of toxic exposure, 5.6% of all cases of adult poisoning were by cardiovascular medications. Poisoning with a beta-blocker usually results in cardiovascular and central nervous system effects. Acute myocardial infarction after poisoning with metoprolol has been reported in the presence of pre existing coronary artery disease (8A). � A 56-year-old woman with history of coronary artery disease took 15 tablets of metoprolol 100 mg. After 2 hours her blood pressure was 66/44 mmHg, heart rate 46/minute; she was disoriented and confused and reported chest pain. There was ST segment elevation and increased markers of cardiac damage. She had a 45% global ejection fraction and coronary angiography showed a 90% occlusion in the ri ght coronary artery, an 80% occlusion in the left coronary artery, and a 40% occlusion in the circumferential artery.
Nadolol Respiratory Beta-blockers are contraindi cated in asthma, because they can cause
Beta-adrenoceptor antagonists and antianginal drugs
bronchospasm. However, their safety pro file during chronic administration has not been well evaluated. In an open, nonplacebo-controlled pilot study, 10 subjects with mild asthma took the non-selective longacting beta-blocker nadolol over 9 weeks (9c). Four subjects tolerated only 10 mg/day, four achieved a dose of 20 mg/day, and three tol erated 40 mg/day. All completed the study and there was a dose-related attenuation of airway responsiveness, as assessed by meta choline testing. Despite this result, care should still be taken when contemplating the use of beta-blockers in patients with a history of bronchospasm.
Oxprenolol Fetotoxicity The data set of the large population-based Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980–1996, has been analysed to evaluate possible associations between all kinds of drug given during pregnancy and isolated cleft lip with or without cleft palate and posterior cleft palate in the offspring. In a case-control study in 1374 children with cleft lip and 601 with posterior cleft palate, compared with 38 151 population controls (without birth defects) and 20 868 malformed controls with other defects, there was an increased risk of cleft lip in those born to mothers who had taken amoxicillin, phenytoin, oxprenolol, or thiethylperazine during the second and third months of pregnancy (10C). The risk of posterior cleft palate was increased in mothers who had taken oxytetracycline and carbamazepine during the third and fourth months of pregnancy. This study has confirmed the teratogenic effects of these drugs and has suggested a possible association between orofacial clefts and oxprenolol (OR = 4.2; 95% CI = 1.8, 10.0). However, these findings should be consid ered to be preliminary, because, as the authors pointed out, drugs may have only a limited role in the origin of isolated orofacial clefts.
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Timolol
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(SED-15, 3428)
Sensory systems Ophthalmic administrat ion of beta-adrenoceptor antagonists can result in rapid systemic absorption and significant effects, despite relatively low doses. The systemic availability of ophthal mic timolol in particular is comparable to that of intravenous timolol, while other beta adrenoceptor antagonists (e.g. betaxolol) are more variable in their systemic absorption and may be less well absorbed (11A). � An 85-year-old woman developed presyncopal episodes associated with visual symptoms, during which she described her vision ‘closing in like a tunnel’ and felt faint and unsteady. She had previously been using 0.25% timolol eyedrops for bilateral glaucoma after a right drainage procedure and left laser trabeculoplasty. She was switched, because of a wheeze, to betaxolol eyedrops. The presyn copal symptoms started soon after. She had atrial fibrillation with a ventricular rate of 120/minute, compared with her home monitor ing, which had showed a pulse rate of 80/minute.
Her symptoms were felt to be due to poorly controlled atrial fibrillation, with subopti mal rate control leading to presyncope. A regular oral beta-blocker was associated with complete resolution of symptoms. Sys temic absorption of ophthalmic timolol had successfully controlled this woman’s atrial fibrillation and the effect was lost with the substitution of betaxolol.
POTASSIUM CHANNEL ACTIVATORS Nicorandil
(SED-15, 2505; SEDA-31, 340)
Gastrointestinal Reports of intestinal ulceration induced by nicorandil are becoming more frequent (12A, 13A). The pathogenesis of this potentially lethal effect is not known. � A 76-year-old woman with angina developed an iron deficiency anemia, weight loss, and
366 diarrhea. Colonoscopy showed extensive ulceration of the colon and she recovered after withdrawal of nicorandil. � A 73-year-old man with severe ischemic heart disease, diabetes mellitus, hypertension, and hypercholesterolemia developed rectal bleed ing while taking aspirin, atenolol, amlodipine, simvastatin, allopurinol, gliclazide, and nicor andil 30 mg bd He had a posterior anal fissure and was given topical analgesics and laxatives. However, the fissure enlarged even after chemical sphincterotomy with diltiazem and glyceryl trinitrate ointment. Nicorandil was withdrawn, and in 2 months his symptoms improved and the ulcer reduced in size.
Nicorandil is an important cause of anal fissures and ulceration. Instead of perform ing unnecessary surgery, the treatment is to stop nicorandil while carefully monitoring for symptoms of ischemic heart disease. Four cases of peristomal ulceration caused by nicorandil have been reported after gastrointestinal surgery in patients with diverticular disease. Complete healing of the ulcers occurred in all cases within 2–10 months after withdrawal of nicorandil (14A). Leg ulcers have also been attributed to nicorandil (15A). � A 73-year-old woman developed progressive ulceration of the perianal area and right lower leg over 11 months. After possible causes had been excluded, and after progressive deterioration during treatment with systemic and topical corticosteroids, nicorandil was withdrawn. The ulcers gradually improved at both sites.
NITRATES, ORGANIC (SEDA-15, 2529; SEDA-29, 195; SEDA-30, 225)
Glyceryl trinitrate (nitroglycerin) Cardiovascular Glyceryl trinitrate can facilitate vasovagal syncope by enhancing venous pooling in the upright posture. In 29 otherwise healthy patients with a history of vasovagal syncope, sublingual glyceryl trinitrate during a tilt test caused a
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more gradual fall in blood pressure in older than in younger patients (16c).
CALCIUM CHANNEL BLOCKERS (SED-15, 598; SEDA-29, 195; SEDA-30, 225; SEDA-31, 340) Drug overdose Calcium channel blockers accounted for 16% of all cardiovascular drug exposures reported to the American Association of Poison Control Centers in 2002 (24 000 incidents), but accounted for 38–48% of deaths caused by cardiovascular drug overdosage. A review of the management of beta-adrenoceptor antago nists and calcium channel blockers toxicity that was first published in the 1994 Emer gency Medicine Clinics of North America has been updated (17R). The most signifi cant changes in the last 15 years in relation to beta-adrenoceptor antagonists and cal cium channel blocker toxicity have dealt with the search for improved treatments. New therapies have evolved and continue to evolve. The use of insulin-induced eugly cemia has yielded insights into the meta bolic abnormalities that occur during drug-induced shock and has now provided a valuable treatment; new formulations of stan dard antidotes, such as recombinant gluca gon, are now available; and there is additional experience with calcium supple ments. Emphasis on early and aggressive goal-directed therapy of shock has brought more critical care skills into the emergency department, including more rapid diagnosis of cardiogenic shock, with the advent of emergency department ultrasound. The clinical significance of hyperglyce mia after acute verapamil or diltiazem over dose has been described in a retrospective review of 40 adults at five universityaffiliated teaching hospitals. Serum glucose concentrations correlated with the severity of calcium channel blocker intoxication. The percentage increase in the peak glucose concentration was a better predictor of the
Beta-adrenoceptor antagonists and antianginal drugs
severity of the poisoning than hemodynamic changes (18R). Serum glucose concentration alone might be an indication for insulin ther apy (19c).
Amlodipine
(SED-15, 175; SEDA-29, 195; SEDA-30, 225; SEDA-31, 340)
Sensory systems Taste disturbance with the calcium channel blockers is rare adverse effect, but dysgeusia with amlodipine has been reported (20A). � A 59-year-old man took amlodipine 2.5 mg/day for 4 years for essential hypertension. The dose was increased to 5 mg and 2 years later he suddenly developed loss of taste sensation and numbness in the anterior two-thirds of the tongue. One week later he ran out of tablets and his taste sensation returned. After 10 days he started taking amlodipine again, after which he again had loss of taste sensation.
The causal relationship in this case was strengthened by inadvertent de-challenge and re-challenge. However, it is hard to explain the exceptionally long delay in the onset of dysgeusia. Fluid balance A common adverse effect associated with amlodipine commonly causes edema, most commonly pedal, followed by pretibial and facial edema. Va sodilatation and intracapillary hypertension are the underlying mechanisms. Bilateral edema of the arms has been attributed to amlodipine in a child (21A). � A previously well normotensive 6-year-old girl developed a generalized vasculitis of unknown origin and severe hypertension. Large vessels predominantly affecting the neck, chest, and abdomen were involved, resulting in abnormal arterial circulation and significant blood pres sure differences between the arms and legs. Multiple antihypertensive agents were initially required to control the blood pressure and she was eventually stabilized with amlodipine 10 mg/day, atenolol 50 mg/day and warfarin. Within 3 days she developed facial edema and bilateral pitting edema in the arms. Laboratory and radiological investigations of possible causes were negative. Withdrawal of amlodipine resulted in resolution.
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Nicardipine
(SEDA-15, 2502; SEDA-29, 197; SEDA-30, 227) Pregnancy and lactation The placental transfer and the appearance in breast milk of nicardipine after maternal intravenous administration has been evaluated in 10 women with pre-eclampsia (22c). The high est umbilical cord concentration after a maternal dosage of 4.5 mg/hour was 18 ng/ ml, which is subtherapeutic. Nicardipine con centrations were determined in 34 samples of breast milk from seven women, and were undetectable in 82% of the samples. In six samples of breast milk from four different women, nicardipine concentrations (5–19 ng/ml) were detectable after maternal nicardipine dosages of 1–6.5 mg/hour. The maximum possible exposure of a neonate to nicardipine was calculated to be less than 300 ng/day, which is insignificant.
Verapamil (SEDA-15, 3618; SEDA-29, 199; SEDA-30, 228; SEDA-31, 342) Cardiovascular Patients with cluster headache have increased sympathetic nervous system tone before an attack. This ‘sympathetic storm’ can cause short but hazardous periods of cardiac dysrhythmias. In contrast, during an attack there is parasym pathetic nervous system overactivity, with consequent bradycardia. Verapamil is widely used as a first-line prophylactic drug for cluster headache in doses starting at 360 mg/day, but it requires strict control of blood pressure and heart rate, because over lap between the effects of verapamil and the effects of parasympathetic overactivity during an attack could cause serious hypo tension and bradycardia (23A). � A 35-year-old man with a 10-year history of episodic cluster headaches (three to four attacks per day, previously treated with methy sergide, lithium and oxygen without significant benefit) took verapamil 240 mg/day, which reduced the frequency of attacks to two to three per day. After increasing the dose
368 of verapamil to 360 mg/day he developed hypotension (75/40 mmHg) and serious brady cardia (32/minute), which required implanta tion of a temporary ventricular non-sequential pacemaker. Cardiac examination and 24 hour
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M.G. Franzosi and R. Latini
electrocardiography had been normal before starting verapamil. Once the critical period had passed, the blood pressure normalized and the pacemaker was removed.
References 1. Messerli FH, Bell DSH, Fonseca V, Katholi RE, McGill JB, Phillips RA, Raskin P, Wright Jr. JT, Bangalore S, Holdbrook FK, Lukas MA, Anderson KM, Bakris GLGEMINI Investiga tors. Body weight changes with beta-bloc kers use: results from GEMINI, Am J Med 2007;120(7):610–5. 2. Brauchili YB, Jick SS, Curtin F, Meier CR. Association between beta-blockers, other antihypertensive drugs and psoriasis: popula tion-based case-control study. Br J Dermatol 2008;158(6):1299–307. 3. Bilbault P, Pynn S, Mathien C, Mazzucotelli JP, Schneider F, Jaeger A. Near-fatal betaxolol self-poisoning treated with percutaneous extracorporeal life support. Eur J Emerg Med 2007;14(2):120–2. 4. Shaddy RE, Boucek MM, Hsu DT, Boucek RJ, Canter CE, Mahony L, Ross RD, Pahl E, Blume ED, Dodd DA, Rosenthal DN, Burr J, LaSalle B, Holubkov R, Lukas MA, Tani LY, Pediatric Carvedilol Study Group. Carvedilol for children and adolescents with heart fail ure. A randomized controlled trial. J Am Med Assoc 2007;298(10):1171–9. 5. PavlovicMD, Dragojevic Simic V, Zolotarevski L, ZecevicRD, VesicS. Cuta neous vasculitis induced by carvedilol. J Eur Acad Dermatol Venereol 2007;21(7):1004–5. 6. Thorsteinsson A, Johannesdottir A, Eiriksson H, Helgason H. Severe labetalol overdose in an 8-month-old infant. Pediatr Anesth 2008;18 (5):435–8. 7. Delyle SG, Duverneuil-Mayer C, Abe E, Mathieu B, De La, Grandmaison GL, Charlier P, Alvarez JC. Fatal intoxication with labetalol (Trandate®). Forensic Sci Int 2008;178(2–3):e19–21. 8. Unverir P, Topacoglu H, Bozkurt S, Kaynak F. Cardiovascular toxicity due to metoprolol poi soning in a patient with coronary artery disease. Br J Clin Pharmacol 2007;64(5):694–7.
9. Hanania NA, Singh S, El-Wali R, Flashner M, Franklin AE, Garner WJ, Dickey BF, Parra S, Ruoss S, Shardonofsky F, O’Connor BJ, Page C, Bond RA. The safety and effects of the beta-blocker, nadolol, in mild asthma: an open-label pilot study. Pulm Pharmacol Ther 2008;21(1):134–41. 10. Puhó EH, Szunyogh M, Métneki J, Czeizel AE. Drug treatment during pregnancy and iso lated orofacial clefts in Hungary. Cleft Palate Craniofac J 2007;44(2):194–202. 11. Easton PJ. A cardiovascular benefit of ophthalmic beta-blockade. Age Ageing 2007;36(3):351. 12. Brown R, Lee A, Welfare M. Nicorandil induced colonic ulceration. Heart 2008;94 (5):678. 13. Akbar F, Maw A, Bhowmick A. Anal ulcera tion induced by nicorandil. Br Med J 2007;335(7626):936–7. 14. Ogden S, Mukasa Y, Lyon CC, Coulson IH. Nicorandil-induced peristomal ulcers: is nicor andil also associated with gastrointestinal fis tula formation? Br J Dermatol 2007;156 (3):575–612. 15. McJenna DJ, Donnelly J, Armstrong DKB. Nicorandil-induced leg ulceration. Br J Der matol 2007;156(2):378–410. 16. Verheyden B, Gisolf J, Beckers F, Karemaker JM, Wesseling KH, Aubert AE, Wieling W. Impact of age on the vasovagal response provoked by sublingual nitroglycer ine in routine tilt testing. Clin Sci 2007;113 (7):329–37. 17. Kerns II W. Management of b-adrenergic blocker and calcium channel antagonist toxi city. Emerg Med Clin N Am 2007;25(2):309–31. 18. Levine M, Boyer EW, Pozner CN, Geib AJ, Thomsen T, Mick N, Thomas SH. Assess ment of hyperglycemia after calcium channel blocker overdoses involving diltiazem or verapamil. Crit Care Med 2007;35(9):2071–5.
Beta-adrenoceptor antagonists and antianginal drugs 19. Verbrugge LB, van Wezel HB. Pathophy siology of verapamil overdose: new insights in the role on insulin. J Cardiothorac Vasc Anesth 2007;21(3):406–9. 20. Sadasivam B, Jhaj R. Dysgeusia with amlo dipine – a case report. Br J Clin Pharmacol 2007;63(2):253. 21. Ganeshalingham A, Wong W. Amlodipine induced bilateral upper extremity edema. Ann Pharmacother 2007;41(9):1536–8.
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22. Bartels PA, Hanff LM, Mathot RAA, Steegers EAP, Vulto AG, Visser W. Nicar dipine in pre-eclamptic patients: placental transfer and disposition in breast milk. BJOG 2007;114(2):230–3. 23. Perciaccante A, Fiorentini A, Mitrevski M, Tubani L, Granata M. Temporary pace maker in refractory cluster headache treated with verapamil. J Headache Pain 2007;8 (1):67–8.
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19
Drugs acting on the cerebral and peripheral circulations
DRUGS USED IN THE TREATMENT OF ARTERIAL DISORDERS OF THE BRAIN AND LIMBS Buflomedil
(SED-15, 566; SEDA-29, 202)
Placebo-controlled studies In an inter national placebo-controlled trial in 2078 patients with peripheral arterial disease there was a reduction in symptomatic cardiovascular events of 26% over a 3-year follow-up period in patients taking buflomedil (1C). The main contributor to benefit, however, was reduced deterioration in peripheral arterial disease, which was poorly documented. Systematic reviews The few available valid data on buflomedil in patients with inter mittent claudication have been evaluated in a Cochrane review (2M). The authors concluded that the benefit-to-harm balance is poor, mainly because of concern about the seriousness of overdose (SEDA-29, 202).
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32019-8 � 2010 Elsevier B.V. All rights reserved.
Cilostazol
(SED-15, 773; SEDA-29, 202; SEDA-30, 231)
Cardiovascular In 41 of 1639 patients who took cilostazol for intermittent claudication in a post-marketing study in many countries in 1999–2003, there were 61 events that the investigators considered to have been drugrelated (3C). Congestive heart failure was the most common. In the USA, the Food and Drug Administration (FDA) has issued a warning recommending that cilostazol should not be used in patients with congestive heart failure. Even so, an analysis of the entire cilostazol database has shown no difference from placebo in rates of myocardial infarction, stroke or cardiovascular deaths, and in two trials there was even a lower cardiovascular mortality and morbidity than with placebo (4R). The Cochrane Peripheral Vascular Diseases Group reached a similar conclusion, namely that there was no increase in major adverse events, including cardiovascular mortality, in patients who took cilostazol (5M). In a large US study there was no signal of cardiovascular mortality (6C). Hematologic A 90-year-old man developed a spinal epidural hematoma after removal of an epidural catheter on the third postoperative day after an arterial thrombectomy and needed decompression. He had been taking cilostazol from the first postoperative day. The authors suspected that
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the antiplatelet effects of cilostazol may have contributed (7A). In the large US study mentioned above, the rate of serious bleeding events was not increased (6C).
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causative role of triptans, because the serotonin receptor subtypes on which they act are not identical to those believed to be involved in the serotonin syndrome (13E).
Ginkgo biloba (Ginkgoacaeae) See Chapter 48, page 881.
OTHER PERIPHERAL VASODILATORS Inhibitors of phosphodiesterase type V (SED-15, 3133; SEDA-29, 203;
DRUGS USED IN THE TREATMENT OF MIGRAINE Triptans
(SED-15, 3525; SEDA-27, 210; SEDA-29, 203; SEDA-31, 346) Nervous system Pathological laughter has been attributed to sumatriptan (8A).
• A 38-year-old man with episodic cluster headaches used sumatriptan 6 mg subcutaneously to treat acute attacks. The injections provided relief but he reported that he experienced an attack of involuntary mirthless laughter about 5 minutes after each injection, each attack lasting 4–5 minutes.
Pathological laughter can occur with cen tral nervous system lesions or deep brain stimulation for Parkinson’s disease. Status gelasticus has also been reported after the use of levetiracetam (9A) and gelastic sei zures after the use of clobazam (10A) and anti-rabies vaccine (11A). Drug–drug interactions Monoamine reuptake inhibitors In 2006 the FDA issued an alert about the potentially lifethreatening serotonin syndrome with combined use of triptans with selective serotonin reuptake inhibitors or serotonin– noradrenaline reuptake inhibitors (SEDA 30, 232). However, this advice has been criticized, because the quality of the information in many of the case reports on which the alert was based was incomplete or anecdotal (12R). In addition, there is doubt about the biological plausibility of a
SEDA-30, 232; SEDA-31, 346) Cardiovascular Sildenafil has been associated with venous thrombosis (14A) and tadalafil with thrombophlebitis (15A). • A 57-year-old man had a deep vein thrombosis in a leg, severe thrombosis of the hemorrhoidal plexus and venous sinus thrombosis all within a single year. He took regular sildenafil, roughly twice a week, and two of the episodes occurred within 24 hours after treatment. • A 45-year-old man twice developed phlebitis of a superficial penile vein after taking tadalafil followed by sexual intercourse. Intercourse without tadalafil never caused that problem.
Apart from priapism, phosphodiesterase type 5 (PDE5) inhibitors have hitherto not been associated with venous thrombosis. In the second case, local anatomical factors, such as prolonged over-expansion of the corpora cavernosa, may have caused com pression of the superficial veins and contrib uted to the inflammation. In the first case, a causative link to thrombosis was not obvious for a drug with no known adverse effect on coagulation. Drug formulations Drug ordering by e-mail has given rise to an unauthorized pharmaceutical market worldwide, putting the various governmental authorities on an alert. Swissmedic has announced that the erectile stimulant PowerTabs, which is being advertised as being a purely herbal erectile stimulant and is being sold illegally, contains a potentially dangerous active substance related to sildenafil
Drugs acting on the cerebral and peripheral circulations
(16S–18S). Swissmedic has seized stocks of PowerTabs from illegal sources and instigated criminal proceedings. It has issued an urgent warning against taking this product. Similarly, Health Canada has warned the public not to use Eros Fire, a product that has been promoted to enhance sexual per formance, as this product may pose serious health risks (19S, 20S). It contains xantho anthrafil (also known as benzamidenafil),
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which is not indicated on the label. Little information is available about this com pound, including its safety when used in humans. It probably has similar properties to prescription drugs that are inhibitors of PDE5, used to treat erectile dysfunction, and may pose similar serious health risks, especially in patients with pre-existing car diac problems, those who are taking cardio active medications such as nitrates or those who are at risk of a stroke.
References 1. Limbs International Medicinal Buflomedil (LIMB) Study Group, Leizorovicz A, Becker F. Oral buflomedil in the prevention of cardi ovascular events in patients with peripheral arterial obstructive disease: a randomized, placebo-controlled, 4-year study. Circulation 2008;117(6):816–22. 2. de Backer TL, Bogaert M, Vander Stichele R. Buflomedil for intermittent claudication. Cochrane Database Syst Rev 2008;(1): CD000988. 3. Hiatt WR. The US experience with cilostazol in treating intermittent claudication. Atheros cler Suppl 2005;6(4):21–31. 4. Chi YW, Lavie CJ, Milani RV, White CJ. Safety and efficacy of cilostazol in the man agement of intermittent claudication. Vasc Health Risk Manag 2008;4(6):1197–203. 5. Robless P, Mikhailidis DP, Stansby GP. Cilos tazol for peripheral arterial disease. Cochrane Database Syst Rev 2007;(1):CD003748. Updated in: Cochrane Database Syst Rev 2008;23(1):CD003748. 6. Hiatt WR, Money SR, Brass EP. Long-term safety of cilostazol in patients with peripheral artery disease: the CASTLE study (Cilostazol: A Study in Long-Term Effects). J Vasc Surg 2008;47(2):330–6. 7. Kaneda T, Urimoto G, Suzuki T. Spinal epidural hematoma following epidural cathe ter removal during antiplatelet therapy with cilostazol. J Anesth 2008;22(3):290–3. 8. Barbanti P, Fabbrini G, Berardelli A. Acute pathological laughter induced by sumatriptan. Cephalalgia 2007;28:92–3.
9. Pustorino G, Spano M, Sgro DL, Di Rosa G, Tricomi G, Bellantone D, Tortorella G. Status gelasticus associated with levetiracetam as add-on treatment. Epileptic Disord 2007;9 (2):186–9. 10. Iwasaki T, Miura H, Sunaoshi W, Hosoda N, Takei K, Katayama F. [A case of intractable epilepsy showing frequent gelastic seizures by administration of clobazam.] No To Hat tatsu 2003;35(5):406–10. 11. Malhotra S, Malhotra S, Fernandes P, Ghosh D. Gelastic epilepsy possibly following antirabies vaccine. Indian J Med Sci 2000;54 (4):140–4. 12. Evans RW. The FDA alert on serotonin syn drome with combined use of SSRIs or SNRIs and triptans: an analysis of the 29 case reports. MedGenMed 2007;9(3):48. 13. Shapiro RE, Tepper SJ. The serotonin syndrome, triptans, and the potential for drug–drug interactions. Headache 2007;47 (2):266–9. 14. Rufa A, Cerase A, Monti L, Dotti MT, Giorgio A, Sicurelli F, Federico A. Recurrent venous thrombosis including cerebral venous sinus thrombosis in a patient taking sildenafil for erectile dysfunction. J Neuropsychiatry 2007;260 (1–2):293–5. 15. Guarneri C, Guarneri F. Mondor’s phlebitis after using tadalafil. Br J Dermatol 2007;157 (1):209–10. 16. Anonymous. Illegal medicines. Erectile sti mulant Powertabs ‘potentially dangerous’. WHO Newslett 2008;4:2.
374 17. Swissmedic. Swissmedic warnt vor Einnahme des gefälschten Erektionsfo¨ rderers ‘Power tabs’. http://www.swissmedic.ch/aktuell/00003/ 00342/index.html?lang=de. 18. Swissmedic. Swissmedic issues a warning about the counterfeit erectile stimulant ‘Powertabs’. http://www.swissmedic.ch/ aktuell/00003/00342/index.html?lang=en.
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R. Verhaeghe and P. Verhamme
19. Anonymous. Xanthoanthrafil-containing sexual dysfunction products. WHO Newslett 2008;5&6:3. 20. Health Canada. Health Canada warns consumers not to use Eros Fire or any unauthor ized products promoted to enhance sexual performance. http://www.hc-sc.gc.ca/ahc-asc/ media/advisories-avis/_2008/2008_169-eng.php.
Jamie J. Coleman and Tehreem F. Butt
20
Antihypertensive drugs
Quality of life and adherence to antihypertensive drugs National surveys in the UK and USA have shown that a substantial number of patients with hypertension have poorly controlled blood pressures (1S–3S). Inadequate control of blood pressure can be attributed to both health-care provider-related and patientrelated factors. A major patient-related factor is poor or non-adherence to prescribed med ications. Here we aim to elucidate the reasons for this non-adherence, including the effects of adverse effects from antihypertensive drugs and the effects of treatment on quality of life. Adherence to antihypertensive medications Medication adherence has been defined as ‘the extent to which a patient acts in accor dance with the prescribed interval and dose of a dosing regimen’ (4R). To that should be added other aspects of the dosage regimen, such as timing, route of administration, and duration of therapy. During the first year of treatment, up to 50% of patients have poor long-term adherence to prescribed antihyper tensive drugs, although these numbers improve considerably once patients are established in treatment regimens (5c). How ever, as many of the previous studies have relied on self-reporting by patients, rates of poor adherence may in fact be an underesti mate of the severity of the problem, as patients may be reluctant to admit to non adherence. In addition, patients who agree to Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32020-4 � 2010 Elsevier B.V. All rights reserved.
participate in studies of adherence to medica tions may be generally more compliant than patients who do not (6c). Many patients experience adverse drug reactions (ADRs) while taking antihyperten sive drugs, and in one survey-based study that was specifically designed to investigate rea sons for stopping or altering antihypertensive drug treatment, 34% of patients reported unacceptable ADRs, highlighting the signifi cance of the problem (7c). ADRs secondary to antihypertensive drug treatment may con tribute significantly to poor adherence to ther apy, and thus inadequate blood pressure control. Non-adherence to antihypertensive drug therapy may be intentional or uninten tional, and both are related to perceived adverse effects (8c, 9R). Other factors that contribute to poor compliance, in addition to ADRs, include excessive reliance on monotherapy and patient-related factors, including perceptions of over-medication (10C), depres sive symptoms (11C), and ethnicity (12C). Many physicians consider common ADRs, such as ankle edema and constipa tion due to a calcium channel blocker, or a dry cough secondary to an angiotensinconverting enzyme (ACE) inhibitor, as minor. Patients, however, may find such effects debilitating, as they can significantly impair their quality of life. They may also be reluctant to discuss some ADRs, such as erectile dysfunction due to beta-adrenoceptor antagonists, for example, which, unsurpris ingly, can lead to non-adherence to therapy. Many antihypertensive drugs cause ADRs in the therapeutic range of doses (collateral adverse effects), and patients may find it dif ficult to justify continuing taking such medi cations, particularly if there is a lack of awareness of the consequences of poorly controlled hypertension.
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Better adherence to antihypertensive drug therapy is associated with better blood pres sure control, and consequently a reduced risk of cardiovascular disease and a reduc tion in the cost and utilization of health-care resources. It is therefore essential to have strategies to improve long-term adherence to antihypertensive drug therapy. These should include initiating therapy at the lowest dosage, in order to minimize the incidence of ADRs, improved patient education regard ing hypertension and the aims of therapy, warning patients about the potential adverse effects of medications, and actively inquiring about adverse effects, particularly during the first year of therapy, so that problems can be addressed and dealt with promptly. Although the effects of antihypertensive drugs on quality of life may affect adherence to therapy, this does not only encompass phy sical effects of therapy, but also effects on psychological, social, and mental functioning. Effect of hypertension and antihypertensive drugs on quality of life Definitions of qual ity of life Improved quality of life is prob ably the most desirable outcome of all health-care policies and interventions. Yet, a consensus remains to be achieved on what constitutes quality of life, and its definitions are as numerous and inconsistent as the methods of assessing it (13r). Health-related quality of life is clearly defined as a sense of total well-being, psy chosocial and physical, and not merely the absence of disease in infirmity. A taskforce from the National Heart, Lung, and Blood Institute issued guidelines to assess quality of life in hypertension and other disease states, and identified six important domains (14S): • physical capabilities, e.g. mobility and self-care; • emotional status, including mood changes and depression; • social interactions, including sexual function; • intellectual functioning; • economic status; • self-perceived health status, involving selfevaluation of disease severity and level of impairment.
It is clear that quality of life is an important consideration when beginning
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Jamie J. Coleman and Tehreem F. Butt
antihypertensive drug therapy, as patients with a relatively asymptomatic disease will be taking long-term therapy, with an asso ciated risk of ADRs. Therefore, despite the many definitions of quality of life, it is important to determine which outcomes mat ter most to patients, particularly when initiat ing treatment. The relative value to patients of physical, mental, and social health when making treatment decisions has been investi gated in a study of over 16 000 adults who visited primary-care providers (15C). Using the ‘standard gamble’ and ‘time trade off’ utility methods, along with the Medical Out comes Study 12-item Short Form (SF-12), the authors found that although physical health contributed substantially to patient preferences, patients also placed high value on their mental and social health. The contribution of mental health outcomes to preferences was stronger in those with chronic conditions. These findings are parti cularly pertinent to the management of hypertension. Methods used to assess quality of life There are different methods for assessing subjective symptoms and well-being in clinical practice and in clinical trials, including spontaneous reporting, active questioning, and psycho metric testing. Spontaneous reporting may underestimate the prevalence of symptoms and patients may only report those symp toms they believe to be related to treatment. Active questioning can be undertaken verb ally or by using questionnaires, whereas psy chometric tests are designed to measure global well-being, without reference to any particular disorder (16r). It has, however, been difficult to assess quality of life reliably in patients with hyper tension; a review of the literature from 1990 to 2000, focusing on health-related quality of life in patients with hypertension, showed that the results of studies were frequently inconsistent, possibly owing to the wide vari ety of domains studied, the variety of instru ments used to assess quality of life, and a number of methodological weaknesses, including small sample sizes and failure to account for missing data (17R).
Antihypertensive drugs
Chapter 20
Effects of hypertension on quality of life It is important to note that although antihyper tensive drug therapy can impair quality of life because of ADRs, hypertension itself may not be completely without effect. Simply labelling a patient as ‘hypertensive’ can have a negative effect on their quality of life, but those who are unaware that they are ‘hyper tensive’ may also have symptoms that affect their quality of life when compared with normotensive subjects. A review has highlighted many studies that have shown this phenomenon (18R). One such study involved the development of a validated scale, known as the Subjective Symptoms Assessment Profile (SSAP), con sisting of 39 questions evaluating different domains. The authors concluded that hyper tensive patients who were unaware of their blood pressure and not taking treatment performed less well than normotensive sub jects in three main areas: ‘emotional distress’, ‘cardiac symptoms’, and ‘sex life’ (19c). Another study used the ‘Nottingham Scale’ to assess quality of life, and showed that untreated hypertensive patients who were unaware of their blood pressure performed poorly with regards to emotions and sleep disturbance compared with normotensive subjects (20c). However, these findings are to a degree at odds with those of a more recent cross-sectional study of over 3000 participants representa tive of the Spanish population over the age of 60 years, assessing health-related quality of life using the 36-item Short Form (SF-36) questionnaire (21C). A multiple linear regression analysis, adjusted for predictors of quality of life, including age, education, body mass index, the number of chronic conditions and social support, was used to analyse the results. In the adjusted model, neither awareness of hypertension nor anti hypertensive treatment was associated with worse quality of life in men. In women, however, awareness of hypertension was associated with a statistically significant and clinically relevant reduction in all the quality of-life domains measured, which remained after an additional adjustment for other factors, including moderate alcohol con sumption. After further adjustment for
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prescription of antihypertensive drugs, the association between hypertension awareness and quality of life lost statistical significance. Effect of antihypertensive drugs on quality of life Given that hypertension is associated with a reduced quality of life, researchers have attempted to investigate whether drug treatment of hypertension can actually improve well-being. Several studies have been undertaken in an attempt to answer this question (usually by including quality of life as a secondary end point), and also to determine whether there are differences in the effect on quality of life between different antihypertensive drug classes. The Hypertension Optimal Treatment (HOT) study showed a correlation between the degree of blood pressure lowering and an improvement in well-being (22C). In this study, patients were given a calcium channel blocker (felodipine), and an ACE inhibitor or a beta-adrenoceptor antagonist was added as necessary to achieve the target blood pres sure. Quality of life was assessed using the SSAP. The SSAP domains of ‘cardiac symp toms’ and ‘dizziness’ improved in all groups. The study also showed that the lower the diastolic blood pressure, the greater the improvement in well-being. There has been a comprehensive review of comparative studies detailing the differences in the effects of different antihypertensive drug classes on quality of life (23R). Several studies of the effects of ACE inhibitors showed no differences between ACE inhibi tors and other antihypertensive drugs on quality of life. In many of these studies ate nolol was one of the comparator drugs, and in four of the studies calcium channel block ers were used. Compared with atenolol, there was no difference in measures of quality of life across ACE inhibitors (captopril, enala pril, cilazapril, and lisinopril). However, compared with propranolol both atenolol and enalapril were associated with positive changes in quality of life, whereas propran olol was associated with a reduced score on the mood subscale. Although a dry persistent cough is one of the commonest adverse effects of ACE inhibitors, many of the trials were unable to determine whether
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quality of life in individuals who had this ADR was poorer than in those who did not. The Treatment of Mild Hypertension Study (TOMHS) was a randomized, pla cebo-controlled study of over 900 patients who took one of five different antihyperten sive drug classes (acebutolol, amlodipine, chlortalidone, doxazosin, or enalapril) (24C). Changes in seven quality-of-life domains were assessed, based on a 35-item question naire, including ‘general health’, ‘energy or fatigue’, and ‘social functioning’. There were improvements in quality of life in all groups, including those who took placebo, but there were greater improvements with a beta adrenoceptor antagonist (acebutolol) and a thiazide diuretic (chlortalidone) than with placebo, during follow-up for 4 years. The Systolic Hypertension in the Elderly Program trial (SHEP) randomized over 4000 elderly patients to either active hyper tensive drug therapy (chlortalidone with the addition of atenolol if required to achieve a target blood pressure) or placebo (25C). Apart from measuring the effect of using these agents to treat hypertension on cardio vascular outcomes, the effects of treatment on quality of life were also assessed at base line (before the start of therapy) and then twice yearly in the follow-up period. There were no differences between the active and placebo groups at baseline in the areas of cognitive function, depressive symptoms, or mood disorder. During the follow-up period, the active treatment did not have a negative effect on quality of life compared with pla cebo, and in fact there was a small significant positive effect on mood. The relative effects on quality of life of cilazapril, atenolol, and a modified-release formulation of nifedipine have been studied in another multicenter, double-blind, rando mized study in 540 patients with mild to moderate hypertension (26C). The authors concluded that cilazapril and atenolol had equivalent effects on quality of life, but that the calcium channel blocker was associated with more symptomatic complaints (e.g. per ipheral edema and flushing) and a higher withdrawal rate. These findings suggest that despite the risk of ADRs, drug treatment may in fact lead to
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an improvement in quality of life in patients with hypertension, and that certain antihy pertensive drug classes may be better at doing this than others.
Conclusion Better adherence to antihypertensive drug therapy is associated with better blood pres sure control and consequently a reduced risk of morbidity and mortality from cardiovas cular disease. Quality of life is an important consideration when beginning antihyperten sive drug therapy, and patients place a high value not only on physical health but also on mental and social health. Despite the risk of ADRs, there is some evidence that treating hypertension can improve quality of life and sense of well-being. The benefits and adverse effects associated both with treatment and non-treatment of hypertension should there fore be carefully discussed with patients.
GENERAL The European Societies of Cardiology and Hypertension have produced guidelines on the management of arterial hypertension that reflect the most recent evidence base for using different classes of antihyperten sive agents (27R). The lower position of beta-adrenoceptor antagonists in the hierar chy of treatment in most recent guidelines not only reflects the evidence shift but also takes account of their undesirable effects in certain conditions. Further commentary on the place of beta-adrenoceptor antagonists in hypertension guidelines has reaffirmed concerns about their adverse metabolic effects (28r) and has also emphasized their effects on erectile dysfunction (29r). Skin The association between beta adrenoceptor antagonists and other anti hypertensive drugs and the risk of psoriasis has been investigated in a population-based, case–control study (30c). The use of any
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antihypertensive drug class did not materially alter the risk of psoriasis in an adjusted logistic regression model. Sexual function Evaluating sexual distur bances in middle-aged and elderly hyper tensive patients is difficult and is an important problem, as it remains unclear whether hypertension per se or antihyper tensive drug use in general causes erectile dysfunction. A questionnaire-based study has investigated the effects of various cardi ovascular diseases and the use of cardiovas cular medicines in Finnish men (31c). Evaluation of responses after 6 months of therapy in men who had no erectile dysfunc tion at baseline showed that treated hyper tension or heart disease is associated with a higher risk of erectile dysfunction. There was a non-significant increased risk of erectile dysfunction with calcium channel blockers, angiotensin II receptor antagonists, non selective beta-adrenoceptor antagonists, and diuretics, but not with organic nitrates, ACE inhibitors, selective beta-adrenoceptor antagonists, or lipid-lowering agents.
ANGIOTENSIN CONVERTING ENZYME INHIBITORS (SED-15, 226; SEDA 29, 207; SEDA-30, 234; SEDA-31, 350 ) Combination studies Several trials and reviews have examined the beneficial effects and adverse effects of combining angiotensin II receptor antagonists with ACE inhibitors. A large industry-sponsored randomized controlled trial, the ONTARGET trial (Ongoing Telmisartan Alone and in Combination with Ramipril Global End point Trial), examined the effects of telmisartan, ramipril, or the combination in patients with vascular disease or high-risk diabetes without heart failure (32C). Telmi sartan was equivalent to ramipril in terms of vascular-related death, the primary out come, and perhaps not surprisingly there
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were lower rates of angioedema and cough from the angiotensin II receptor antagonist compared to the ACE inhibitor. The rate of adverse events, especially hypotensive symptoms, syncope, and renal dysfunction, was higher in the combination group than in the monotherapy groups. In the absence of obvious clinical benefits in this type of patient population it is best not to combine these drug classes. A quantitative review of data from four randomized controlled trials of the adverse effects of this combination of drug classes in patients with symptomatic left ventricular dysfunction also found worsening renal func tion and symptomatic hypotension (33M). There was a significant increase in with drawal rates in the combined groups because of adverse effects. However, the meta-analy sis did not show a significantly increased risk of severe hyperkalemia in the pooled cohort, although there was a non-significant increase in the risk of hyperkalemia. In a smaller crossover study of the effect of angiotensin II receptor antagonists, ACE inhibitors, the combination, or neither in patients with dialysis-dependent chronic kidney disease, neither monotherapy (with either class) nor the combination was asso ciated with an additional risk of hyperkale mia in patients on hemodialysis (34c). However, the authors concluded that patients with anuria still warrant cautious monitoring of serum potassium concentra tions to prevent hyperkalemia. Respiratory Cough has been reported as a beneficial side effect of ACE inhibitors in a short report of two patients who were unable to continue smoking owing to exces sive coughing during smoking, which started only after they started to take therapy (35A). The authors pointed out that pre scribing ACE inhibitors for patients with hypertension or chronic heart failure who smoke may therefore serve two ends. The incidence of cough secondary to dif ferent ACE inhibitors has been evaluated in a randomized, double-blind study in the Philippines, which included dechallenge and rechallenge to assess the likelihood of
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adverse drug effects (36c). Using an inten tion-to-treat analysis, the overall incidence of ACE inhibitor-induced cough was 17% and there were statistically significant dif ferences in the incidences of cough among the ACE inhibitors studied: 23% for cilaza pril, 22% for enalapril, 13% for imidapril, and 11% for perindopril. Sensory systems The effects of statins and ACE inhibitors on the incidence of agerelated macular degeneration have been inves tigated in a case–control study (37c). There was a slightly higher but significant increased risk of macular degeneration in users of ACE inhibitors (RR = 1.19; 95% CI = 1.07, 1.33). Urinary tract The renal protective effects of ACE inhibitors and angiotensin II receptor antagonists, especially in diabetic kidney dis ease, are well recognized. However, worsen ing of renal function in chronic kidney disease patients when patients start to take these therapies is also well reported. As well as cases of renal artery stenosis, there are other susceptibility factors for deteriorating renal function, such as volume depletion or concomitant treatments (38R). The effects of withdrawing angiotensin blockade in 100 patients with chronic kidney disease who had a greater than 25% increase in baseline serum creatinine after the start of treatment have been elucidated in a prospective obser vational study (39c). About 75% had sus tained improvement in renal function after drug withdrawal, whereas 16 progressed to end-stage renal failure. The authors particu larly concentrated on the small proportion (in this study 5%) who develop worsening renal function 3 months or more after administration of a stable dose of an ACE inhibitor or angiotensin II receptor antago nist, despite normal renal arteries and no identifiable risk factors and have called this ‘late-onset renal failure from angiotensin blockade’ (LORFFAB). They recom mended further work on this problem, but their recommendation that renal function be monitored indefinitely in patients with chronic kidney disease taking inhibitors of angiotensin function seems prudent.
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ACE inhibitors and angioedema Several studies have reviewed the association of ACE inhibitors with angioedema (SEDA 29, 207; SEDA-31, 352).
EIDOS classification: Extrinsic moiety: ACE inhibitors
Intrinsic moiety: Tissues affected by
bradykinin
Distribution: Areas of production of
bradykinin
Outcome: Tissue swelling (lips and
tongue, larynx and pharynx)
Sequela: Angioedema from ACE
inhibitors
DoTS classification: Dose-relation: Hypersusceptibility reaction
Time-course: Intermediate
Susceptibility factors: Genetic (blacks;
dipeptidyl peptidase IV deficiency); sex (female); exogenous factors (drugs – NSAIDs, vaccines, immunosuppressants; surgery – dental and maxillofacial procedures; devices – polyacrylonitrile membranes in hemodialysis); diseases (a history of angioedema; acquired dipeptidyl peptidase IV deficiency)
Case reports Benazepril Visceral angio edema presenting as subacute intestinal obstruction has been reported in association with benazepril (40A). Orolingual angio edema has also been reported 12 years after the start of treatment with benazepril (41A). • An 86-year-old woman developed dysarthria and acute, painless, non-pruritic tongue swelling. There was no evidence of airway compromise or urticaria. She had been taking benazepril for hypertension for 12 years. The benazepril was withdrawn and she was given intravenous glucocorticoids and antihistamines. After an initial period with little improvement, her tongue returned to normal size and she was symptom free several months later on alternative antihypertensive drugs.
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Captopril A further case of angioedema associated with captopril has been reported (42A). Cilazapril In a case of angioedema asso ciated with cilazapril, there were repeated admissions with breathlessness and a sense of strangulation over 4 months before the diagnosis was made because of widespread urticaria and lingual edema (43A). Enalapril Enalapril-induced angioedema has again been described (44A) and a number of further life-threatening or fatal cases have been reviewed (45A). The fatal cases related to delay in diagnosis and failed airway manage ment leading to anoxic brain injury. Lisinopril Several more cases of angio edema associated with lisinopril have been reported. Surgical manipulation or local trauma can precipitate angioedema, presum ably because of bradykinin release, and upper lip angioedema in association with lisinopril has been reported in a 35-year-old African American woman following a ‘bitten lip’ (46A). Another case of angioedema in a patient reportedly allergic to both lisinopril and topi cal lidocaine spray resulted in life-threaten ing airway obstruction during nasendoscopy (47A). The authors suggested that the lido caine spray may have sustained the laryngeal edema. Angioedema in a 62-year-old man taking lisinopril fulfilled the criteria for type 1 he reditary angioedema on the basis of comple ment and C1 inhibitor concentrations (48A). The hereditary condition was presumably unmasked by treatment with lisinopril. Diagnosis Small bowel angioedema was endoscopically visualized using doubleballoon enteroscopy in a 40-year-old woman with episodic abdominal pain on three occasions before enalapril-induced angioedema was suspected (49A). Intestinal angioedema has been reported fairly often, but this presentation is the first to describe the direct visualization of macroscopic changes in the small intestine in such a case.
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Complications Complications of angio edema usually relate to the adverse effect directly, such as airway compromise or unnecessary abdominal surgery in cases of intestinal angioedema. Episodes of severe pneumonia have been reported in three patients with angioedema induced by an ACE inhibitor or angiotensin II receptor antagonist (50A). In all three cases the patients were on hemodialysis, and the authors surmised that underlying host fac tors, glucocorticoid use, and respiratory colonization with Gram-negative bacteria contributed to the complications in these patients. Incidence The incidence of ACE inhibitorinduced angioedema has been investigated in a large pharmacoepidemiological study in the Veterans Affairs Health Care System and its determinants explored (51C). Overall, 0.2% of patients developed angioedema, with an incidence rate of 1.97 (1.77–2.18) cases per 1000 person-years. Most of the cases were seen within 3 months of the start of therapy, but cases occurred beyond 1 year, in common with previous reports. Determi nants of angioedema include black ethnicity (a fourfold increase) and female sex (a 50% higher incidence). This large study provides a reliable estimate of the frequency of ACE inhibitor-induced angioedema confirming that the true incidence is low but there is substantial variation by race and sex. The recurrence rate of angioedema in patients with previous drug-induced angio edema is fairly high, as indicated by previous reports of rechallenge and descriptions of cases of recurrent angioedema when the drug-induced nature of the presentation was not at first recognized. Susceptibility factors for recurrent episodes of ACE inhibitorinduced angioedema have been investigated retrospectively by examining episodes of angioedema for etiology, co-morbidities and documentation of prior ‘allergy’ to ACE inhibitors (52c). The recurrence rate in this analysis was 6.2%, and various factors were implicated, including failure to document prior episodes in the medical records and failure to consider the risk of recurrence
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when prescribing for patients with prior epi sodes. This study has reaffirmed the position that recurrence of ACE inhibitor-induced angioedema is important and common, and that any episodes should prompt careful documentation and communication, as well as extremely careful consideration before re-exposure is considered. Epidemiology The epidemiology of patients who present to emergency departments with ACE inhibitor-induced angioedema has been described (53c). ACE inhibitors were presumed to account for 30% of the 586 cases of angioedema seen, and a number of the patients required hospitalization, mainly for the management of upper airway pro blems. A similar number of patients were identified in an emergency department retro spective review of cases, which concentrated on the management of airway compromise (54c). The lips and anterior tongue were the most common sites of upper airway angio edema, and laryngeal or hypopharyngeal edema was most often associated with a need for airway intubation within 12 hours of presentation. Drooling was a useful sign that demonstrated inability to handle secre tions and a subsequent need for intubation. The use of antihistamines (H1 receptor antagonists) was also associated with a shor tened duration of intubation. Cross-reactivity with angiotensin receptor antagonists In a systematic review (55M) three articles were identified that described 71 patients who developed angioedema while taking ACE inhibitors and who were subsequently exposed to angiotensin II receptor blockers. The risk of subsequent angioedema with angiotensin II receptor antagonists after an episode of ACE inhibitor-induced angioedema was 2–17%. Mechanisms ACE inhibitors increase the level of pharmacologically active des-Arginine9 bradykinin, which is thought to be part of the vasoactive cause of angioedema. Such metabolic anomalies may also be causative in acute hypotensive transfusion reactions. An acute hypotensive transfusion reaction
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occurred during liver transplantation in a patient who had taken lisinopril before sur gery (56A). The patient was also found to have a low ACE concentration and reduced aminopeptidase P activity, which presumably, whether congenital or acquired, would have contributed to the adverse reaction. Susceptibility factors Reports of susceptibil ity or predisposing factors for ACE inhibitorinduced angioedema have reaffirmed what is already known on the subject, namely that black ethnicity is a susceptibility factor (57c) and that upper airway manipulation can pro voke the adverse effect, especially in relation to dental or maxillofacial work (58A). The hypothesis that activity of dipeptidyl peptidase IV (DPPIV), a multifunctional enzyme that contributes to the degradation of kinins and substance P, and DPPIV antigen are reduced in patients with ACE inhibitor-induced angioedema has been stu died (59c). DPPIV activity and antigen were both reduced in individuals with a history of ACE inhibitor-induced angioedema. Thus, genetic or environmental factors that reduce the activity of this enzyme may predispose patients to the adverse effect. A laboratory study has also shown that acquired, genetic and pharmacological factors can influence the risk of ACE inhibitor-induced angio edema (60E). A study on polymorphism in the ACE gene has shown no effect (61E). One susceptibility factor for ACE inhibi tor-induced angioedema is the concurrent use of non-steroidal anti-inflammatory drugs, which may either precipitate or wor sen the condition. Imidapril-induced angio edema has been reported after concurrent use of diclofenac (62A). • A 59-year-old woman with recurrent angioedema of the tongue complicated by upper airway obstruction required endotracheal intubation. Laboratory tests, including complement concentrations, were normal. ACE inhibitor-associated angioedema precipitated by NSAIDs was suspected. She improved after withdrawal of imidapril and diclofenac, without other specific treatment.
Although one known susceptibility factor for hypersensitivity reactions in dialysis patients taking ACE inhibitors is the
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polyacrylonitrile AN69 dialysis membranes, a case series has reported non-IgE mediated anaphylactic (i.e. anaphylactoid) reactions from the modified surface-treated AN69 dia lysers (ST-AN69), which were invented to try to reduce such adverse effects (63A). The authors described four patients taking ACE inhibitors who presented with anaphylactoid reactions (manifesting as hypotension and/or abdominal symptoms) in association with the use of ST-AN69 dialysis membranes. A non-IgE-mediated anaphylactic reaction, with hypotension and abdominal symptoms, has been described in a patient taking lisino pril during temporary use of an ST-AN69 dialyser (64A). The polyethyleneimine saline solution used to surface treat the AN69 mem branes is intended to make them less electro negative and therefore reduce bradykinin production, which is thought to be responsible for the reaction. The authors suggested that caution is required, even with the ST-AN69 dialysers in patients taking ACE inhibitors and that other biocompatible synthetic mem brane dialysers should be used.
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exposure to ACE inhibitors there was evi dence of neonatal acute anuric renal failure, although all recovered normal renal function within 3 months. Over the years, however, two of the three children developed progres sive renal impairment, hypertension, and proteinuria. The authors suggested longterm follow-up of such patients. The finding of long-term renal adverse effects of fetal exposure to ACE inhibitors is particularly worrying, given the widespread use of these drugs for several indications, including hypertension, especially in young adults. The long-term adverse renal effects in patients with fetal exposure to ACE inhi bitors may not be that infrequent, despite appropriate warnings. One prospective study has identified continued exposure to fetuses over the period 1986–2003 during the second and third trimesters of pregnancy, despite appropriate black box warnings (68c).
Management The treatment of ACE inhibi tor-induced angioedema is usually supportive, although glucocorticoids and antihistamines are often used. Angioedema in a 73-year-old man with no atopic history taking an ACE inhibitor has been successfully treated with parenteral C1 inhibitor concentrate after it failed to respond to a glucocorticoid, anti histamines and adrenaline (65A). It is worth reiterating that this approach is usually reserved for the treatment of hereditary angioedema; evidence is not strong for its use in acquired or drug-induced disease. Effective airway management is important in cases of severe orofacial angioedema, and failure to manage the airway effectively in such cases can be disastrous. Lisinopril induced angioedema with difficult airway management has been described, in which successful management of the airway was achieved by retrograde intubation (66A).
Susceptibility factors Perioperative use The use of ACE inhibitors in the perioperative period is controversial; there are arguments that continuation may reduce adverse peaks in blood pressure during anesthesia, but there are also reports of dangerous hypo tension during operations. Observational or retrospective investigations have shown that ACE inhibitors and angiotensin II receptor antagonists are associated with more frequent hypotension, especially in association with chronic diuretic therapy, in patients undergoing non-cardiac surgery (69C); an increased risk of acute kidney injury in the context of cardiovascular sur gery (70c); and more instances of hypoten sion requiring treatment when given on the morning of elective ophthalmic or ENT sur gery with no evidence of better operative blood pressure control (71c). Furthermore, in a best-evidence review of the periopera tive use of these drugs before cardiac sur gery has shown that their use before surgery contributes to lowering of vascular resis tance postoperatively (72R).
Fetotoxicity The long-term outcomes of fetal exposure to ACE inhibitors have been reported (67A). In three patients with fetal
Drug–drug interactions Aldosterone recep tor antagonists ACE inhibitors are com monly used concurrently with aldosterone
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receptor antagonists, such as spironolac tone, in the treatment of congestive heart failure, and occasionally in cases of resistant hypertension, especially when associated with hyperaldosteronism. However, the combination of these drugs can be asso ciated with serious hyperkalemia. In an observational cohort study in 114 patients with heart failure, 25% developed acute renal insufficiency, 15% developed hyper kalemia and 3% developed severe hyper kalemia (73c). Susceptibility factors for acute renal insufficiency included the presence of class IV (NYHA) congestive heart failure, diabetes mellitus, and a blood pressure reduction of 25 mmHg or more from baseline. Epoetin ACE inhibitors and angiotensin receptor blockers may impair the response to recombinant human epoetin-induced ery throcyte production in chronic renal insuffi ciency (74c). There was a smaller increase in hematocrit in this study and the authors therefore cautioned against the simultaneous use of ACE inhibitors or ARBs with epo etin, although they did not suggest a clear alternative strategy for these patients, who need to take cardiovascular or antihyperten sive drugs with epoetin derivatives.
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Jamie J. Coleman and Tehreem F. Butt
• A 74-year-old woman developed a pruriginous, bullous, lichenoid eruption after starting to take captopril for hypertension. The histopathological and immunological features were consistent with lichen planus pemphigoides. Captopril was withdrawn and glucocorticoids given; 8 months later no relapse had occurred.
Delapril Drug–drug interactions Calcium channel blockers Adding an ACE inhibitor or angiotensin II receptor blocker to calcium channel blocker therapy can reduce the occurrence of peripheral edema. The bene fits of adding the ACE inhibitor delapril to the calcium channel blocker manidipine have been evaluated in patients with mild to moderate essential hypertension in a crossover study of the use of each agent individually or in combination (77c). The combination was associated with a signifi cantly lower blood pressure and the addi tion of delapril was associated with a significant reduction in ankle edema (objec tively measured as ankle/foot volume) com pared with manidipine alone.
Enalapril Captopril
(SED-15, 625; SEDA-29, 210; SEDA-31, 355) Hematologic Hemolytic anemia has been attributed to captopril (75A).
• A 91-year-old African American woman with hypertension, hypothyroidism, and osteoarthritis developed cardiac failure and uncontrolled atrial fibrillation. After initial heart rate control, anticoagulation, and diuresis, she was given captopril. Over the next 2 days, and in the absence of clinical and imaging evidence of bleeding, her hemoglobin concentration fell from 12.0 to 8.2 g/dl. Further laboratory tests showed evidence of hemolysis and she required three units of blood. Captopril was withdrawn and her hemoglobin concentration stabilized and increased over the next 5 days.
Skin Lichen planus pemphigoides associated with captopril has been described (76A).
(SED-15, 1210; SEDA-29, 210; SEDA-30, 235; SEDA-31, 355)
Skin An interstitial granulomatous drug eruption (IGDE), which presented initially as erythroderma, has been described in a hypertensive patient taking enalapril (78A). • A 66-year-old Chinese man with controlled hypertension and benign prostatic hyperplasia developed a mildly pruritic rash. His medications included enalapril maleate, tamsulosin hydro chloride, and terazosin hydrochloride. The rash persisted, despite withdrawal of tamsulosin and terazosin and progressed to diffuse erythema over the whole body. There was a peripheral blood eosinophilia and atypical lymphocytosis. Skin biopsies showed diffuse interstitial granulo matous infiltrates in the dermis, with lymphocyte involvement around partially degenerated col lagen, small histiocytes, numerous eosinophils, and scattered multinuclear giant cells. There was no evidence of vasculitis or subcutaneous tissue involvement. All drugs were withdrawn and the skin lesions resolved within 2 months.
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This reaction, which mechanistically may be akin to a type IV delayed-type hypersen sitivity reaction, shares features with DRESS (drug rash with eosinophilia, and systemic symptoms), but without the constitutional features or internal organ involvement.
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Drug overdose Data on lisinopril overdoses reported to the Texas poison control cen ters have been reported in children (84c) and adults (85c).
Perindopril Fosinopril
(SED-15, 1450)
Management of adverse drug reactions Plasma exchange has been used as an effec tive treatment in a case of severe fosinopril induced cholestatic jaundice (79A). The authors pointed out that although ortho topic liver transplantation is the standard method for treating drug-induced liver fail ure, plasma exchange therapy is an alterna tive or a bridge to transplantation.
Lisinopril (SED-15, 2071; SEDA-29, 210;
(SED-15, 2782; SEDA-30,
237) Placebo-controlled studies In a large trial of antihypertensive treatment in patients aged 80 years or older (the Hypertension in the Very Elderly Trial, HYVET), a randomized, pla cebo-controlled trial of indapamide with the addition of perindopril 2 or 4 mg or matching placebo as required, there were significantly fewer adverse effects in the active treatment group (86C). On the basis of this trial, the investigators concluded that treatment of the very elderly for hypertension is beneficial, without risk of frequent adverse effects.
SEDA-30, 237; SEDA-31, 357) Pancreas Two further cases of lisinopril induced pancreatitis have been reported (80A, 81A). The second case involved fatal necrotizing pancreatitis in a patient taking a combination of hydrochlorothiazide and lis inopril. Although it was likely that this was a drug-induced event, the authors did not try to implicate one drug over the other, as both have been reported to cause pancreatitis. Skin Erythroderma presumed to be second ary to lisinopril has been reported in an 85 year-old man with no previous history of skin disease (82A). Susceptibility factors In a retrospective chart review of 123 children who took lis inopril for 9 years, adverse effects caused treatment withdrawal in only six (83c). There were six deaths, but they were related to underlying diseases or procedures rather than to the lisinopril. There were no adverse effects on growth or laboratory measurements. Overall, adverse effects that were identified were similar to those reported in adults; hypotension and asso ciated symptoms were the most common.
Ramipril
(SED-15, 3022; SEDA-29, 211; SEDA-30, 237)
Urinary tract A patient taking ramipril 2.5 mg/day developed acute renal insufficiency and shock after 7 days (87A). There was no previous history of renal problems, but the patient had a high-output ileostomy, and dehydration is a susceptibility factor for severe renal impairment in the context of ACE inhibitor treatment. Skin Angioedema followed by histologically proven fasciitis with eosinophilia has been attributed to ramipril (88A). Fetotoxicity Severe retinopathy of prema turity has been reported in twins after block ade of the renin–angiotensin system during pregnancy (89A). Although the authors acknowledged no direct cause-and-effect relationship, they examine the possible role in this disabling condition of drugs that affect angiotensin. Drug overdose A patient developed severe lactic acidosis and rhabdomyolysis after
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taking an overdose of metformin 56 g and ramipril 35 mg (90A). The lactic acidosis related mainly to metformin toxicity, but the cause of the rhabdomyolysis was less certain and was likely to have been multifactorial. Hypotension from ACE inhibitor toxicity is likely to have been relevant, but as neither metformin nor ramipril have been associated with rhabdomyolysis, a direct toxic effect of either of these drugs is possible.
ANGIOTENSIN II RECEPTOR ANTAGONISTS (SED-15, 223; SEDA-29, 211; SEDA-30, 238; SEDA-31, 358) Combination studies For studies of the effects of combining angiotensin II receptor antagonists with ACE inhibitors, see above under ACE inhibitors. Psychiatric The implication that cardio vascular drugs may be causal in cases of depression or suicide has been investigated in a nested case–control study of 743 cases of suicide in a death registry in Denmark compared with 14 860 age- and sex-matched controls (91c). There was no significant association with current exposure to lipidlowering drugs, calcium channel blockers, beta-adrenoceptor antagonists, or ACE inhibitors. However, there was a significant risk related to current use of angiotensin II receptor antagonists (OR = 3.52; 95% CI = 1.33, 9.30), although it was based on only five of the cases exposed. This impre cise estimate of an association should be cautiously interpreted. Autacoids Angioedema EIDOS classification: Extrinsic moiety: Angiotensin II receptor antagonists Intrinsic moiety: Tissues affected by bradykinin
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Jamie J. Coleman and Tehreem F. Butt
Distribution: Areas of production of bradykinin Outcome: Tissue swelling (lips and tongue, larynx and pharynx) Sequela: Angioedema DoTS classification: Dose-relation: Collateral Time-course: Time independent Susceptibility factors: Previous angioedema with an ACE inhibitor
Reviews of angioedema associated with angiotensin II receptor antagonists continue to appear (92R, 93R, 94r).
Candesartan
(SED-15, 612; SEDA-29, 211; SEDA-30, 241; SEDA-31, 358) Skin A patient developed pemphigus folia ceus, diagnosed on clinical and immuno pathological criteria, 2 months after taking candesartan, and developed similar lesions 2 months after starting a different angio tensin II receptor antagonist, telmisartan (95A).
Teratogenicity A woman who took cande sartan cilexetil for diabetic nephropathy from 8 to 26 weeks of gestation developed severe oligohydramnios and there was severe pulmonary hypoplasia in the child at autopsy after the induced delivery of a non-viable fetus at 27 weeks (96A).
Irbesartan
(SED-15, 1908; SEDA-29, 212; SEDA-30, 241; SEDA-31, 359)
Hematologic A child developed severe treatment-resistant anemia, thought to be due to irbesartan, after receiving a cada veric renal transplant for kidney disease related to congenital nephrotic syndrome (97A). Dechallenge resulted in an increase in hemoglobin after 4 weeks, and the authors suggested that a ‘drug holiday’ might be used to test whether hemoglobin increases after withdrawal in such cases.
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Teratogenicity The teratogenic effects of angiotensin II receptor antagonists have been discussed in the light of a case report and review of the literature (98Ar). A hyper tensive woman took irbesartan during the preconceptual period and had a sponta neous abortion of a fetus with developmen tal delay of the limbs and karyotypic Turner’s syndrome. The authors confirmed that exposure to angiotensin II receptor antagonists for at least more than the first trimester is associated with a high risk of adverse fetal outcomes.
Losartan
(SED-15, 2168; SEDA-30, 242; SEDA-31, 359)
Respiratory Angiotensin II receptor antagonists are not usually associated with cough and are recommended as effective antihypertensive drugs to use in patients who develop a cough in response to an ACE inhibitor. An unusual case of losar tan-induced cough has been described, with resolution after substitution with ena lapril (99A). • A 23-year-old non-smoking white woman who had not taken an ACE inhibitor and had no prior respiratory illnesses developed hyper tension, proteinuria, and hyperlipidemia. She was treated with losartan, hydrochlorothiazide, furosemide, and simvastatin and after 3 days developed a dry irritating cough, which persisted for 2 weeks. The angiotensin II receptor antagonist was withdrawn and enalapril was substituted, after which the cough resolved within 1 week. The patient was not rechallenged with losartan.
It is difficult to understand this unusual pattern of adverse events, and although the authors defined the relationship between the losartan and cough as ‘probable’, it should be noted that although the symptom did not recur after 6 months of follow-up the patient was also found to have systemic lupus erythematosus during this time. Nervous system A probable association between losartan and worsening of symp toms in Parkinson’s disease has been
387
reported (100A). The description of worsen ing falls, freezing episodes, and bradykinesia, both during a challenge and rechallenge with losartan was fairly convincing. The authors also pointed to experimental evidence that suggests that angiotensin facilitates the stria tal release of dopamine, supporting a possi ble deleterious effects of angiotensin II receptor antagonists in Parkinson’s disease. Skin Biopsy-proven erythema multiforme and probable Stevens–Johnson syndrome has been described in an 86-year-old man 3 months after losartan had been substi tuted for ramipril (101A). Teratogenicity The teratogenic effect of losartan has been examined in the develop ing rat kidney (102E). There were histologi cal changes and changes in receptor localization in exposed animals, with severe renal abnormalities after birth. Fetotoxicity Adverse renal effects have pre viously been shown both during fetal organogenesis and in utero development. Another case of transient fetal renal insuffi ciency in the first month of life has been described in a child born to a hypertensive mother who took losartan before and throughout pregnancy (103A).
Olmesartan Autacoids Angioedema has been reported in an ACE inhibitor-naïve patient after treatment with olmesartan medoxomil for 10 days (104A). Fetotoxicity Fetal renal toxicity has been reported after maternal treatment with olmesartan medoxomil (105A). • A 54-year-old woman with chronic hypertension and type 2 diabetes mellitus took olmesartan medoxomil 10 mg/day for 2 years before conception. At 29 weeks’ gestation, oligo hydramnios was found, although the fetus had normal kidneys on ultrasound. Withdrawal of the olmesartan, maternal rehydration and a
388 single dose of furosemide reversed the renal impairment and a healthy baby boy was delivered with no apparent renal abnormalities.
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Jamie J. Coleman and Tehreem F. Butt
dermatosis on the legs (108A). Pemphigus foliaceous occurred in association with tel misartan after similar adverse skin effects from prior exposure to candesartan (see above under candesartan).
Telmisartan
(SED-15, 3311; SEDA-29, 212; SEDA-30, 242; SEDA-31, 360)
A large industry-sponsored placebo-controlled trial of telmisartan has been reported in highrisk cardiovascular patients (106C). The Telmi sartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) trial showed mod estly reduced risks of death, myocardial infarc tion, and stroke, but failed to find a significant effect on the primary outcome, which included hospitalization for heart failure. Treatment withdrawals were similar between the telmi sartan and placebo groups, although in the active group there were significantly more hypotensive symptoms and a trend towards more cases of diarrhea and renal problems.
Valsartan (SED-15, 3593; SEDA-29, 213; SEDA-30, 242; SEDA-31, 360) Fetotoxicity Transient fetal oliguria second ary to in utero exposure to valsartan at 19–21 weeks’ gestation has been reported (109Ar). The authors discussed the manage ment of pregnancies exposed to angiotensin II receptor antagonists. Drug–drug interactions Lithium Lithium toxicity occurred in a 60-year-old woman with bipolar affective disorder after the sub stitution of amlodipine for valsartan to treat her co-existing hypertension (110A).
Urinary tract The renal outcomes of the ONTARGET trial have been reported sepa rately (107C). The number of events for the composite primary outcome was similar for telmisartan (n = 1147) and ramipril (n = 1150) (HR = 1.00; 95% CI = 0.92, 1.09), but was increased by combination therapy (n = 1233) (HR = 1.09; 1.01, 1.18). The sec ondary renal outcome, dialysis, or doubling of serum creatinine, was similar with telmisar tan (n = 189) and ramipril (n = 174) (HR = 1.09; 0.89, 1.34) and more frequent with combination therapy (n = 212) (HR = 1.24; 1.01, 1.51). Estimated glomerular filtration rate (eGFR) fell least with ramipril compared with telmisartan (–2.82 versus – 4.12 ml/minute/1.73 m2) or combination ther apy (–6.11). The increase in urinary albumin excretion was less with telmisartan and with combination therapy than with ramipril.
Two more reviews of the clinical pharma cology of aliskiren (111R) and trials of its effects (112R) have been published. Its anti hypertensive efficacy and tolerability at doses of 150, 300, and 600 mg/day compared with placebo over 8 weeks have been eval uated in a dose-ranging study (113c). The most frequent adverse effects were head ache and nasopharyngitis, and diarrhea was increased in incidence at the highest dose. These effects, and the specific high-dose effect of diarrhea, are similar to those seen in previous studies of aliskiren.
Skin Two separate reports have described adverse dermatological manifestations attributed to telmisartan. A 42-year-old hypertensive woman who had taken telmi sartan and hydrochlorothiazide for 2 months developed pigmented purpuric
Drug overdose A 12-year old-boy had an exaggerated hypotensive response after acci dental ingestion of a 300 mg tablet of alis kiren belonging to his mother (114A). There were significant falls of 63 and 40 mmHg in systolic and diastolic blood pressures
DIRECT RENIN INHIBITORS (SEDA-30, 242; SEDA-31, 360)
Aliskiren
(SEDA-30, 242)
Antihypertensive drugs
Chapter 20
respectively, to a nadir of 77/47 mmHg about 7 hours after ingestion. The child remained asymptomatic throughout the episode.
ENDOTHELIN RECEPTOR ANTAGONISTS (SED-15, 1215; SEDA-29, 213; SEDA-30, 245; SEDA-31, 360) The literature surrounding the endothelin receptor antagonists has expanded in recent years, especially as the number of agents in this class has increased. Most of the studies have been in the treatment of idiopathic pulmonary hypertension and secondary pul monary hypertension (related primarily to connective tissue diseases). A few studies have focused on the management of treat ment-resistant essential hypertension and other cardiovascular indications. The use of endothelin receptor antagonists in the treatment of pulmonary arterial hyperten sion has been reviewed (115R).
Ambrisentan
(SEDA-30, 245; SEDA
31, 361) Ambrisentan is propionic acid-based selec tive antagonist at endothelin type A recep tors. It is licensed for the treatment of some types of pulmonary hypertension under spe cialist supervision. Animal studies and clin ical trials have been reviewed (116R), as has the role of ambrisentan in the treatment of pulmonary artery hypertension (117R). Both of these reviews discuss the safety implications of ambrisentan treatment, par ticularly with respect to potential liver injury, because of the finding of raised transaminase activities in clinical trials and the need for monitoring during therapy. Its common adverse effects include peripheral edema, nasal congestion, headache, dizziness, and a fall in hemoglobin concentration. Drug–drug interactions Sildenafil Some of the endothelin receptor antagonists interact
389
with other agents that are commonly used for pulmonary artery hypertension, such as sildenafil. In a pharmacokinetic study of the combination of sildenafil and ambrisentan in healthy volunteers, there was no clinically relevant interaction (118c).
Bosentan
(SED-15, 549; SEDA-29, 213; SEDA-30, 245; SEDA-31, 361)
Placebo-controlled studies Bosentan is the most widely studied of the endothelin recep tor antagonists. The BUILD-1 study (Bosen tan Use in Interstitial Lung Disease) was a randomized, placebo-controlled trial of bosentan in 154 patients with idiopathic pul monary fibrosis (119C). Exercise capacity was not increased by bosentan, although there was a trend towards delayed time to death or disease progression. Respiratory complaints made up the majority of adverse events, but were less frequent among those who took bosentan. There were rises in ala nine transaminase only in those who took bosentan; they affected 21% and led to with drawal in 12%. The profile and frequency of the adverse effects of bosentan are similar to those seen in trials for its other indications, such as pulmonary artery hypertension. Liver Owing to concerns from early clinical trials about the hepatotoxicity of bosentan, the European Medicines Agency (EMA) required a specific post-marketing surveil lance (PMS) study before marketing author ization. The observational results were reported in a comprehensive report of nearly 5000 patients taking bosentan (120C). Rises in transaminase activities were fairly common (crude incidence of 7.6%), especially during the first 6 months of treatment. After 1 year the probability of liver enzyme abnormalities was greatly reduced, reinforcing the need for monthly monitoring of transaminases for the duration of bosentan treatment. No new adverse reactions were identified. Fatal hepatotoxicity has been reported in a patient who took bosentan for digital ulceration due to mixed connective tissue disease (121A).
390 • A 70-year-old Japanese woman with mixed connective tissue disease developed worsening digital gangrene and was given bosentan 125 mg/day (initial 2 weeks 62.5 mg/day). After 8 weeks she developed raised transaminases. Over the next 4 days both transaminases increased to a peak of over 5000 IU/l before gradually decreasing. However, the patient developed a gastrointestinal hemorrhage and died from multiple organ failure 10 days after withdrawal of bosentan.
Drug–drug interactions Phosphodiesterase 5 inhibitors Bosentan induces CYP2C9 and CYP3A4, and interacts significantly with sildenafil, both increasing plasma bosentan concentrations and reducing sil denafil concentrations. The interaction of phosphodiesterase 5 inhibitors with bosen tan deserve investigation, because they have independent mechanisms in the treat ment of pulmonary artery hypertension and concomitant treatment is desirable. In a pharmacokinetic study of the inter action of tadalafil with bosentan in healthy volunteers, bosentan reduced tadalafil expo sure by 42% after 10 days of co-administra tion, with minimal and clinically irrelevant differences in bosentan exposure (122c). A possible solution to the interaction between sildenafil and bosentan has been suggested by a Japanese group, who described the consecutive use of sildenafil and then bosentan, each for 6 months, in two patients with acute exacerbations of pulmonary artery hypertension associated with collagen vascular disease (123A). They suggested that using sildenafil as a reliever to replace bosentan as a controller may be a beneficial regimen, given the immediate effects of sildenafil and the potential for interaction when the agents are used concurrently.
Sitaxsentan (SEDA-29, 213; SEDA-30, 245; SEDA-31, 362) Sitaxsentan is a highly selective antagonist at endothelin type A receptors. Various studies have reported its use in pulmonary artery
Chapter 20
Jamie J. Coleman and Tehreem F. Butt
hypertension in trials under the acronym STRIDE – Sitaxsentan to Relieve Impaired Exercise. STRIDE-6 has reported the safety and efficacy of sitaxsentan in 48 patients who stopped taking bosentan because of adverse effects or inadequate efficacy (124c). Bosen tan was withdrawn in 13 patients, owing to ‘safety concerns’ (not clearly defined), of whom 12 had hepatotoxicity. Only one of these 12 patients developed abnormal liver function tests during alternative treatment with sitaxsentan, after 13 weeks of treatment. Other non-serious adverse events were simi lar to those that had been observed in trials of other endothelin receptor antagonists, including peripheral edema, headache, and flushing. The authors suggested that there is no cross-reaction between the different agents in the risk of hepatic damage and that patients who stop taking bosentan because of acute hepatotoxicity may benefit from sitaxsentan. They did acknowledge that the trial was small, and cautious interpreta tion would be justified in the absence of a larger study.
Tezosentan Tezosentan is a short-acting dual antagonist of endothelin type A and type B receptors, which has been developed for intravenous use. The Value of Endothelin Receptor Inhibition with Tezosentan in Acute Heart Failure Studies (VERITAS) was designed to test the hypothesis that its potent vasodi latory action would reduce systemic vascu lar resistance and increase cardiac output in the treatment of acute heart failure. In VERITAS-1 and VERITAS-2 (two inde pendent, identical, concurrent studies) 1435 patients with acute heart failure within the previous 24 hours and with persistent dyspnea at rest were randomized to placebo or tezosentan by infusion (125C). Tezosen tan did not improve either symptoms or clinical outcomes. There were more with drawals with tezosentan than placebo and significantly more patients developed hypo tension as a reason for treatment withdra wal (8.3% versus 4.7%).
Antihypertensive drugs
Chapter 20
DRUGS THAT ACT ON THE SYMPATHETIC NERVOUS SYSTEM (SEDA-29, 214; SEDA-30, 245; SEDA-31, 362) PRESYNAPTIC ALPHA ADRENOCEPTOR AGONISTS
Clonidine
(SED-15, 817; SEDA-29, 214; SEDA-30, 245; SEDA-31, 362)
391 deficit hyperactivity disorder (129A). He developed frequent terrors during sleep while taking the therapy, and severe insomnia and depression after withdrawal. All his adverse symptoms eventually abated 3 weeks after withdrawal. • A 79-year-old man received a subarachnoid infusion of clonidine, together with fentanyl and bupivacaine, for treatment of neuropathic pain related to previous spinal cord injury (130A). He described ‘violent and brutal’ nightmares and night terrors that led to depression because of an inability to sleep.
Placebo-controlled studies Clonidine is used for several indications other than hypertension. Its effects in children with attention-deficit hyperactivity disorder have been reported in a 16-week placebocontrolled study in 122 children (126c). There was more bradycardia in those who took clonidine but no other significant cardiovascular findings. Early drowsiness was also common but generally resolved after 6–8 weeks.
Methyldopa
Cardiovascular Clonidine is used by some pediatricians for the treatment of restless ness. A child taking clonidine had a cardiac arrest during induction of anesthesia (127A).
POSTSYNAPTIC ALPHA ADRENOCEPTOR ANTAGONISTS (SEDA-29, 214;
• A 5-year-old girl with cerebral palsy and a seizure disorder and who was taking clonidine for restlessness, was scheduled for placement of a baclofen pump. Her mother gave her three doses of clonidine during the 12 hours before surgery, in order to reduce anxiety. During induction of anesthesia with oxygen, sevoflurane and nitrous oxide the child developed severe bradycardia and hypotension and was successfully resuscitated.
Nervous system New-onset seizures in the form of status epilepticus were witnessed in a 9-year-old child with cerebral palsy treated with clonidine for the treatment of attention deficit hyperactivity disorder (128A). Psychiatric Two separate case reports have documented insomnia, night terrors, and depression in relation to clonidine. • An 8½-year-old boy took oral clonidine and methylphenidate for 9 months for attention
(SED-15, 2291; SEDA-31,
363) Fetotoxicity A neonate born to a mother who took methyldopa for hypertension throughout pregnancy developed a positive direct antiglobulin test and jaundice in the absence of hemolysis (131A).
SEDA-30, 246; SEDA-31, 363) Sensory systems The literature on the sub ject of intra-operative floppy iris syndrome and the use of alpha-adrenoceptor antago nists has been reviewed (132R). Drug–drug interactions Phosphodiesterase type 5 inhibitors There is concern about the concurrent use of inhibitors of phospho diesterase type 5 and alpha-adrenoceptor antagonists, as the combination can lead to severe hypotension. The hemodynamic interaction of tadalafil with doxazosin or tamsulosin has been investigated in a phase 1 study in 45 healthy men (133c). There was one potentially clinically significant hypoten sive episode (standing blood pressure less than 85 mmHg) in a subject taking combina tion therapy and there were three moderate hypotensive events lasting less than 2 hours (but only one of these was in association with the combination therapy).
392
Alfuzosin (SED-15, 74; SEDA-29, 214; SEDA-30, 246; SEDA-31, 363) Liver Acute liver damage has been reported in association with alfuzosin for the treat ment of benign prostatic hyperplasia (134A). • A 56-year-old Korean man developed jaundice, itching, and epigastric pain over 1 week. He had taken alfuzosin 10 mg/day for 1 month for benign prostatic hyperplasia. He had biochemical evidence of acute liver injury. There were no other clues as to the cause of his symptoms, in either the history or investigations. The alfuzosin was withdrawn and his liver function tests began to improve initially, but relapsed when the drug was restarted 1 week later for recurrent dysuria. Alfuzosin was completely withdrawn and a biopsy showed evidence of cholestasis, fibrosis, and necrosis, consistent with druginduced hepatitis.
Sexual function The effects of alfuzosin on sexual function have been investigated in 372 men over the age of 50 years with lower urinary tract symptoms who were randomized to alfuzosin 10 mg/day or pla cebo (135C). After 1 month the treatment group had significantly improved erectile function and no adverse effects on ejacula tory function. The only other significant adverse effect was an increased rate of dizziness with alfuzosin.
Doxazosin
(SED-15, 1188; SEDA-29, 214; SEDA-30, 246; SEDA-31, 363) Sensory systems Intra-operative floppy iris syndrome has been reported in a patient taking doxazosin (136A).
Musculoskeletal The association in elderly patients between fractures and the use of doxazosin has been investigated in a case–control study of primary-care records in the UK (137c). There was no increased risk of fractures associated with current or previous use of doxazosin, and no increased risk of fractures with other alpha-adrenoceptor antagonists.
Chapter 20
Prazosin
Jamie J. Coleman and Tehreem F. Butt
(SED-15, 2915)
Psychiatric Prazosin is sometimes used to treat the symptoms of post-traumatic stress disorder (PTSD). A 42-year-old Gulf War veteran developed bizarre behavior and dissociative feelings after taking a small dose of prazosin each night for the treat ment of nightmares (138A).
Tamsulosin
(SED-15, 3303; SEDA-29, 214; SEDA-30, 246; SEDA-31, 364)
Sensory systems There have continued to be reports documenting the association of tamsu losin with intra-operative floppy iris syndrome and consequent complications of cataract sur gery. In a retrospective evaluation of cataract surgery in men exposed to either tamsulosin or alfuzosin, there was a significantly higher risk of intra-operative floppy iris syndrome with tamsulosin (139c). In a large nested case–con trol study of adverse events within 14 days of cataract surgery, there was a significant asso ciation between the use of tamsulosin and ser ious ophthalmic events that was not seen with other alpha-adrenoceptor antagonists (140C). In a prospective evaluation of cataract surgery in patients taking tamsulosin management strategies to reduce the harm included the use of topical atropine preoperatively, the use of iris retractors, the use of a pupil expansion ring or the use of a viscoadaptive ophthalmic device (141c). Intra-operative floppy iris syn drome occurred with varying severity in 90% of the 167 eyes treated, but there was only one case of posterior capsule rupture and vitreous loss. Thus, compensatory surgical techniques seem to reduce the complication rate from cataract surgery significantly in patients taking tamsulosin. In a case series, intracameral phe nylephrine was a simple and effective tool for preventing the effects of intra-operative floppy iris syndrome in patients undergoing cataract surgery after taking tamsulosin (142A). A patient with a previous uncomplicated cataract extraction had three separate episodes of choroidal detachment, each in association with treatment with tamsulosin (143A). This ophthalmic adverse event is apparently not known, and ‘floppy choroid’ may require further investigation.
Antihypertensive drugs
Terazosin
Chapter 20
(SED-15, 3315)
Skin A lichenoid eruption has been attribu ted to terazosin in an elderly Chinese man with benign prostatic hyperplasia (144A). Sexual function New-onset priapism has been described in an otherwise healthy man who took terazosin for lower urinary tract symptoms (145A). Drug overdose Acute intoxication with ter azosin has been reported (146A). • A 75-year-old man with hypertension and benign prostatic hyperplasia developed a headache and dizziness. After an argument with his family he had taken more than 300 mg of terazosin. He had a 2-year history of both conditions and the tablets were the patient’s own. He had a severe bradycardia and hypotension and was immediately treated with saline gastric lavage, oral activated charcoal, intravenous atropine, and intravenous fluids. He made a full recovery.
393
Diazoxide (SED-15, 1188; SEDA-29, 214) Cardiovascular Diazoxide is used to treat neonatal hyperinsulinism. In two cases infants aged 1 month and 4 months developed pul monary hypertension (148A, 149A). In the first case a lung biopsy was performed, which showed a probable toxic vascular drug reac tion; in the other case the infant also devel oped neutropenia. In both cases the infants improved after diazoxide was withdrawn.
Hydralazine
(SED-15, 1701; SEDA-31,
365) Immunologic In an experimental study of the effects of hydralazine on receptor edit ing the authors concluded that the drug causes impaired B lymphocyte tolerance and contributes to the autoreactivity that occurs in drug-induced lupus-like syndrome (150E).
Urapidil Skin Worsening psoriasis has been described in a 67-year-old man who took urapidil for benign prostatic hyperplasia (147A).
Minoxidil See Chapter 14.
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35.
36.
37.
38.
39.
40.
41. 42.
43.
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45.
haemodialysis patients. Nephrol Dial Transplant 2007;22(4):1150–55. Ebihara S, Ebihara T, Yamanda S, Asada M, Arai H. Angiotensin-converting enzyme inhibitors and smoking cessation. Respira tion 2007;74(4):478. Tumanan-Mendoza BA, Dans AL, Villacin LL, Mendoza VL, Rellama-Black S, Barto lome M, Ragual J, Flor B, Valdez J. Dechal lenge and rechallenge method showed different incidences of cough among four ACE-Is. J Clin Epidemiol 2007;60(6):547–53. Etminan M, Brophy JM, Maberley D. Use of statins and angiotensin converting enzyme inhibitors (ACE-Is) and the risk of agerelated macular degeneration: nested casecontrol study. Curr Drug Saf 2008;3(1):24–26. Smellie WS, Forth J, Coleman JJ, Irvine W, Dore PC, Handley G, Williams DG, Gallo way PJ, Kerr KG, Herriot R, Spickett GP, Reynolds TM. Best practice in primary care pathology: review 6. J Clin Pathol 2007;60 (3):225–34. Onuigbo MA, Onuigbo NT. Late-onset renal failure from angiotensin blockade (LORFFAB) in 100 CKD patients. Int Urol Nephrol 2008;40(1):233–39. Khan MU, Baig MA, Javed RA, Ali S, Qamar UR, Vasavada BC, Khan IA. Bena zepril induced isolated visceral angioedema: a rare and under diagnosed adverse effect of angiotensin converting enzyme inhibi tors. Int J Cardiol 2007;118(2):e68–9. Cuculi F, Suter Y, Erne P. Angioedema of the tongue. CMAJ 2008;178(9):1136. Nicolas Sanchez FJ, Moreno AG, Gort OA, Sarrat Nuevo RM, Nicolas Sanchez ME, Cabau RJ. Angioedema asociado a capto pril. An Med Interna 2007;24(11):562–3. Gulec M, Caliskaner Z, Kartal O, Erel F, Karaayvaz M. Not all ACE inhibitor related angioedema is always evident: a case which is misdiagnosed as panic attack and speech disorder. Allergol Immunopathol (Madr) 2007;35(6):278–9. Llinares TF, Hernandez PC, Sansano CA, Escriva MS. Angioedema asociado con enalapril. Farm Hosp 2007;31(3):193–4. Cupido C, Rayner B. Life-threatening angio-oedema and death associated with the ACE inhibitor enalapril. S Afr Med J 2007;97(4):244–5.
396 46. Simmons BB, Folsom MA, Bryden LA, Studdiford JS. Angioedema after local trauma in a patient on angiotensin-converting enzyme inhibitor therapy. J Am Board Fam Med 2008;21(6):577–79. 47. Roper AJ, Farragher A, Homer JJ, Helbert M. Angioedema of the airway: an unusual case. J Laryngol Otol 2007;121(8):e11. 48. Ricketti AJ, Cleri DJ, Ramos-Bonner LS, Vernaleo JR. Hereditary angioedema pre senting in late middle age after angiotensinconverting enzyme inhibitor treatment. Ann Allergy Asthma Immunol 2007;98 (4):397–401. 49. Spahn TW, Grosse-Thie W, Mueller MK. Endoscopic visualization of angiotensin-con verting enzyme inhibitor-induced small bowel angioedema as a cause of relapsing abdominal pain using double-balloon enter oscopy. Dig Dis Sci 2008;53(5):1257–60. 50. Sharma M, Johnson LB. Gram-negative pneumonia among patients undergoing dialysis who were admitted to the hospital with angioedema secondary to angiotensinconverting enzyme inhibitors and angioten sin II receptor antagonists. Clin Infect Dis 2008;47(11):1494–5. 51. Miller DR, Oliveria SA, Berlowitz DR, Fincke BG, Stang P, Lillienfeld DE. Angioedema incidence in US veterans initi ating angiotensin-converting enzyme inhibi tors. Hypertension 2008;51(6):1624–30. 52. Roberts DS, Mahoney EJ, Hutchinson CT, Aliphas A, Grundfast KM. Analysis of recurrent angiotensin converting enzyme inhibitor-induced angioedema. Laryngo scope 2008;118(12):2115–20. 53. Banerji A, Clark S, Blanda M, LoVecchio F, Snyder B, Camargo Jr. CA. Multicenter study of patients with angiotensin-convert ing enzyme inhibitor-induced angioedema who present to the emergency department. Ann Allergy Asthma Immunol 2008;100 (4):327–32. 54. Grant NN, Deeb ZE, Chia SH. Clinical experience with angiotensin-converting enzyme inhibitor-induced angioedema. Oto laryngol Head Neck Surg 2007;137(6):931–35. 55. Haymore BR, Yoon J, Mikita CP, Klote MM, DeZee KJ. Risk of angioedema with angiotensin receptor blockers in patients with prior angioedema associated with
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angiotensin-converting enzyme inhibitors: a meta-analysis. Ann Allergy Asthma Immunol 2008;101(5):495–99. 56. Doria C, Elia ES, Kang Y, Adam A, Deso rmeaux A, Ramirez C, Frank A, Di Fran cesco F, Herman JH. Acute hypotensive transfusion reaction during liver transplan tation in a patient on angiotensin converting enzyme inhibitors from low aminopeptidase P activity. Liver Transpl 2008;14(5):684–87. 57. Mahoney EJ, Devaiah AK. Angioedema and angiotensin-converting enzyme inhibi tors: are demographics a risk? Otolaryngol Head Neck Surg 2008;139(1):105–8. 58. Wakefield YS, Theaker ED, Pemberton MN. Angiotensin converting enzyme inhi bitors and delayed onset, recurrent angioe dema of the head and neck. Br Dent J 2008;205(10):553–56. 59. Byrd JB, Touzin K, Sile S, Gainer JV, Yu C, Nadeau J, Adam A, Brown NJ. Dipeptidyl peptidase IV in angiotensin-converting enzyme inhibitor associated angioedema. Hypertension 2008;51(1):141–47. 60. Adam A, Desormeaux A, Moreau ME. Physiopathologie des effets secondaires aigus des inhibiteurs de l’enzyme de conver sion de l’angiotensine. Bull Acad Natl Med 2007;191(7):1433–43. 61. Gulec M, Caliskaner Z, Tunca Y, Ozturk S, Bozoglu E, Gul D, Erel F, Kartal O, Kar aayvaz M. The role of ace gene polymorph ism in the development of angioedema secondary to angiotensin converting enzyme inhibitors and angiotensin II recep tor blockers. Allergol Immunopathol (Madr) 2008;36(3):134–40. 62. Kampitak T. Recurrent severe angioedema associated with imidapril and diclofenac. Allergol Int 2008;57(4):441–3. 63. Roux VD, Plaisance M. Une série de réac tions indésirables associées a l’utilisation concomitante d’une membrane AN69-ST et d’un IECA. Nephrol Ther 2008;4(5):335–8. 64. Roux VD, Plaisance M. Abdominal mani festations associated with use of a surfacetreated AN69 membrane and ACEI during haemodialysis. Nephrol Dial Transplant 2007;22(6):1792–3. 65. Gelee B, Michel P, Haas R, Boishardy F. Angio-oedème acquis induit par les IEC: trai tement aux urgences par concentré de C1
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397 75. Trimble MA, Sketch Jr. MH, Mehta RH. Hemolytic anemia: a rare but potentially serious adverse effect of captopril. Herz 2007;32(1):62–4. 76. Ben SC, Chenguel L, Ghariani N, Dengue zli M, Hmouda H, Bouraoui K. Captopril induced lichen planus pemphigoides. Pharmacoepidemiol Drug Saf 2008;17(7): 722–4. 77. Fogari R, Malamani G, Zoppi A, Mugellini A, Rinaldi A, Fogari E, Perrone T. Effect on the development of ankle edema of add ing delapril to manidipine in patients with mild to moderate essential hypertension: a three-way crossover study. Clin Ther 2007;29(3):413–8. 78. Chen YC, Hsiao CH, Tsai TF. Interstitial granulomatous drug reaction presenting as erythroderma: remission after discontinua tion of enalapril maleate. Br J Dermatol 2008;158(5):1143–5. 79. Chou JW, Yu CJ, Chuang PH, Lai HC, Hsu CH, Cheng KS, Peng CY, Chiang IP. Success ful treatment of fosinopril-induced severe cholestatic jaundice with plasma exchange. Ann Pharmacother 2008;42(12): 1887–92. 80. Brown KV, Khan AZ, Paterson IM. Lisino pril-induced acute pancreatitis. J R Army Med Corps 2007;153(3):191–2. 81. Bedrossian S, Vahid B. A case of fatal necrotizing pancreatitis: complication of hydrochlorothiazide and lisinopril therapy. Dig Dis Sci 2007;52(2):558–60. 82. Broski SE, Regan TD, Sturgill WH. Case reports: lisinopril-induced erythroderma in an 85-year-old male. J Drugs Dermatol 2008;7(2):163–6. 83. Raes A, Malfait F, Van AS, France A, Donck erwolcke R, Vande WJ. Lisinopril in paedia tric medicine: a retrospective chart review of long-term treatment in children. J Renin Angiotensin Aldosterone Syst 2007;8(1):3–12. 84. Forrester MB. Pediatric lisinopril ingestions reported to Texas poison control centers. Hum Exp Toxicol 2007;26(2):83–9. 85. Forrester MB. Adult lisinopril ingestions reported to Texas poison control centers, 1998 2005. Hum Exp Toxicol 2007;26(6): 483–9. 86. Beckett NS, Peters R, Fletcher AE, Staes sen JA, Liu L, Dumitrascu D, Stoyanovsky V, Antikainen RL, Nikitin Y, Anderson C,
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107. Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J, Wang X, Maggioni A, Budaj A, Chaithiraphan S, Dickstein K, Keltai M, Metsärinne K, Oto A, Parkhomenko A, Piegas LS, Svendsen TL, Teo KK, Yusuf S. ONTARGET inves tigators. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372(9638):547–53. 108. Palenzuela RG, Losada J, Del P. Púrpura pigmentaria crónica inducida por telmi sarta´n. Form Med Contin Aten Prim 2008;15:323–4. 109. Roger N, Popovic I, Madelenat P, MahieuCaputo D. Toxicité foetale des antagonistes des récepteurs de l’angiotensine II. À pro pos d’un cas [Fetal toxicity of angiotensinII-receptor inhibitors. Case report.] Gyne col Obstet Fertil 2007;35(6):556–60. 110. Su YP, Chang CJ, Hwang TJ. Lithium intoxication after valsartan treatment. Psy chiatry Clin Neurosci 2007;61(2):204. 111. Brown MJ. Aliskiren. Circulation 2008;118 (7):773–84. 112. Sealey JE, Laragh JH. Aliskiren, the first renin inhibitor for treating hypertension: reactive renin secretion may limit its effec tiveness. Am J Hypertens 2007;20(5):587–97. 113. Oh BH, Mitchell J, Herron JR, Chung J, Khan M, Keefe DL. Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24-hour blood pres sure control in patients with hypertension. J Am Coll Cardiol 2007;49(11):1157–63. 114. Spiller HA. Hypotension after ingestion of Aliskiren. Clin Toxicol (Phila) 2008;46 (9):916–7. 115. Langleben D. Endothelin receptor antagonists in the treatment of pulmonary arterial hyper tension. Clin Chest Med 2007;28(1):s117–25. 116. Vatter H, Seifert V.Ambrisentan a nonpeptide endothelin receptor antagonist. Cardiovasc Drug Rev 2006;24(1):63–76. 117. Hrometz SL, Shields KM. Role of ambri sentan in the management of pulmonary hypertension. Ann Pharmacother 2008;42 (11):1653–59. 118. Spence R, Mandagere A, Dufton C, Venitz J. Pharmacokinetics and safety of ambrisentan in combination with sildenafil in healthy volun teers. J Clin Pharmacol 2008;48(12):1451–9.
399 119. King TE Jr., Behr J, Brown KK, Du Bois RM, Lancaster L, De Andrade JA, Stähler G, Leconte I, Roux S, Raghu G. BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2008;177(1): 75–81. 120. Humbert M, Segal ES, Kiely DG, Carlsen J, Schwierin B, Hoeper MM. Results of Eur opean post-marketing surveillance of bosentan in pulmonary hypertension. Eur Respir J 2007;30(2):338–44. 121. Nagai Y, Okada E, Mihara S, Sato K, Ohi S, Ishikawa O. Severe liver dysfunction due to bosentan in a patient with mixed connective tissue disease. Eur J Dermatol 2008;18 (2):190–1. 122. Wrishko RE, Dingemanse J, Yu A, Darstein C, Phillips DL, Mitchell MI. Pharma cokinetic interaction between tadalafil and bosentan in healthy male subjects. J Clin Pharmacol 2008;48(5):610–8. 123. Kamata Y, Iwamoto M, Minota S. Conse cutive use of sildenafil and bosentan for the treatment of pulmonary arterial hyperten sion associated with collagen vascular dis ease: sildenafil as reliever and bosentan as controller. Lupus 2007;16(11):901–3. 124. Benza RL, Mehta S, Keogh A, Lawrence EC, Oudiz RJ, Barst RJ. Sitaxsentan treat ment for patients with pulmonary arterial hypertension discontinuing bosentan. J Heart Lung Transplant 2007;26(1):63–9. 125. McMurray JJ, Teerlink JR, Cotter G, Bourge RC, Cleland JG, Jondeau G, Krum H, Metra M, O’Connor CM, Parker JD, Torre-Amione G, van Veldhuisen DJ, Lewsey J, Frey A, Rainisio M, Kobrin I; VERITAS Investigators. Effects of tezo sentan on symptoms and clinical outcomes in patients with acute heart failure: the VERITAS randomized controlled trials. J Am Med Assoc 2007;298(17):2009–19. 126. Daviss WB, Patel NC, Robb AS, McDer mott MP, Bukstein OG, Pelham WE Jr, Palumbo D, Harris P, Sallee FR. Clonidine for attention-deficit/hyperactivity disorder: II. ECG changes and adverse events analy sis. J Am Acad Child Adolesc Psychiatry 2008;47(2):189–98. 127. Goldfinger MM, Tripi PA. Cardiac arrest in a child with cerebral palsy undergoing sevoflurane induction of anesthesia after
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21 Thiamine deficiency due to diuretics Thiamine, or vitamin B1, is a water-soluble B complex vitamin. It is not synthesized in humans and its availability for vital cellu lar functions therefore hinges on continuous ingestion. The amount of thiamine that must be ingested to maintain balance depends on both co-morbidities and medications. Severe chronic thiamine deficiency can result in sig nificant neurological and cardiac effects, the combination being reflected in a particular type of heart failure called wet beriberi. Clinical reports In a number of studies fur osemide dose-dependently caused thiamine deficiency, mainly because of increased urin ary excretion of thiamine (1c). For example, thiamine deficiency was detected in 21 of 23 patients (mean age 70 years) with congestive heart failure who took furosemide 80–240 mg/ day for 3–14 months compared with 2 of 16 age-matched controls without heart failure and not taking diuretics (2c). Mean urinary thia mine was inappropriately high in the furose mide-treated subjects and intravenous thiamine was associated with an improvement in left ventricular function. In 24 of 25 patients with heart failure who were taking at least 80 mg/ day of furosemide and in four of seven patients who were taking 40 mg/day, erythrocyte trans ketolase activity suggested severe thiamine Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32021-6 2010 Elsevier B.V. All rights reserved.
Diuretics
deficiency (odds ratio [OR] = 19; 95% confi dence interval [CI] = 1.1, 601) (3c). Thiamine status was not associated with any other clin ical variables. In a prospective study of 149 elderly sub jects, vitamin B1 status worsened during hos pitalization and the only significant predictor of the change was the use of diuretics (4c). The changes in erythrocyte transketolase activity in whole blood correlated with the cumulative dosage of furosemide adjusted for the duration of therapy. In 30 patients with idiopathic dilated car diomyopathy using diuretics and 30 healthy controls, thiamine deficiency was observed in 9 of the former and 3 of the latter (5c). In patients with congestive heart failure taking high doses of furosemide there is whole-blood thiamine phosphate deficiency, but no reduction in the storage form of thia mine, thiamine diphosphate (6c).
Mechanism Thiamine is eliminated by renal excretion. Its renal elimination is non linear and depends on glomerular filtration, flow-dependent tubular secretion, and saturable tubular reabsorption, as well as the prevailing thiamine plasma concentrations (7R). At very high plasma thiamine con centrations (>100 nmol/l), which can only be achieved experimentally, or after particularly high doses (50–200 mg/day), the renal clearance of thiamine can approximate renal plasma flow. Tubular reabsorption of thiamine is an important aspect of its renal handling, and at plasma concentrations of 20–50 nmol/l, 2–5 times higher than are seen in healthy volunteers not taking supplements, it is only half maximal.
401
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In 100 hospitalized patients with conges tive heart failure and 50 control subjects, the former had more thiamine deficiency (33 versus 6); 99 were taking furosemide, 28 spironolactone, and 15 metolazone (8c). Thiamine deficiency was related to urinary thiamine loss, non-use of thiamine-containing supplements, and preserved renal function. Increased urinary thiamine loss was the only significant positive predictor of thia mine status. The OR for furosemide use in thiamine depletion was 1.62, but the CI was wide (0.53, 4.91). Urinary thiamine losses with loop diure tics are not specific to their site of action. Urinary thiamine losses occur with virtually all diuretics (working at multiple nephron sites), including mannitol, acetazolamide, chlorothiazide, and amiloride (9E, 10c, 11c). Data on mannitol and amiloride in parti cular show that the major determinant of diuretic-related urinary thiamine loss is urine flow rate and not sodium excretion. These findings suggest that diuretic-induced thiamine depletion, when it occurs in the patients with heart failure, is not unique to loop diuretic therapy, but possibly occurs in patients who take long-term high-dose diure tic therapy for whatever indication. Patients with persistent polyuria, unrelated to diuretic therapy, are also candidates for thiamine deficiency. In addition to an effect on urinary excre tion, amiloride may also inhibit the absor ption of thiamine, because there is an amiloride-sensitive, pH-dependent, electro neutral, carrier-mediated mechanism for thiamine absorption in the jejunal brush-border membrane vesicles (12E, 13E). The effect of furosemide may be enhanced by an action on cardiac cells, because furo semide and digoxin reduce intracellular con centrations of thiamine pyrophosphate after in vitro exposure, with a half-life of 16–19 days; the effects of furosemide or digoxin are additive (14E). However, not all diuretics have this effect. In 11 patients with heart failure (New York Heart Association [NYHA] grades III or IV) taking furosemide, the addition of spir onolactone 25 mg/day significantly increased thiamine concentrations, determined by
Chapter 21
Domenic A. Sica
measuring erythrocyte transketolase activity, compared with 11 patients who were not given spironolactone and were taking the same daily dose of furosemide (15c). Susceptibility factors Some studies have not shown thiamine deficiency as a recognizable complication of furosemide therapy (16c). The absence of thiamine deficiency in certain patients taking diuretics may be coupled to the manner in which the body responds to diuretic therapy. The urine flow rate response to a diuretic is temporally linked to chronicity of dosing. A diuretic most reliably increases urine flow rate in the first few days of therapy; thereafter, a new steady state arises as a consequence of avid post-diuretic sodium and chloride absorption. Urine flow rate and sodium excretion therefore fall off, unless a high sodium intake is maintained; thus, if thiamine excretion were to follow urine flow rate faithfully, it would fall over time unless somehow a high urine flow rate were to persist with diuretic therapy. Nevertheless, patients who take diuretics and have a significant daily diuresis can become thiamine-depleted, particularly when intake or absorption is marginal. Age Elderly people may be more susceptible to thiamine deficiency if they take diuretics. In a random sample of 342 home-bound older adults, diuretic users were at increased risk of deficient dietary thiamine intake (17c). Surgery Prior gastrointestinal surgery can reduce thiamine intake and increase the risk of diuretic-induced deficiency (18A, 19A). • A 68-year-old Japanese man developed pretibial pitting edema, foot numbness, and a gait disturbance after taking furosemide 20 mg/day for 2 months. He had had a pancreaticoduodenectomy several years before for carcinoma of the ampulla of Vater. He had a polyneuropathy, peripheral edema, and a hyperkinetic heart. His plasma thiamine concentration was 14 µg/l (reference range 20–72). Oral thiamine supplementation (75 mg/day) was started for a presumed diagnosis of beriberi; he soon had a massive
Diuretics
Chapter 21
diuresis and his polyneuropathy began to improve. His plasma thiamine concentration rose to 78 µg/l. • A 66-year-old man, who had had a partial gastrectomy for cancer, developed severe pitting edema in the legs and was given loop diuretics, which relieved the edema at first, but did not resolve it completely. Levothyroxine for hypothyroidism produced further partial relief. However, he then developed an unsteady gait and worse edema. There was a stocking-and glove pattern of sensory disturbance and distal muscle weakness in the legs. The plasma thiamine concentration was low, and supplementation caused complete resolution of the edema in a few days, with improvement in the gait disturbance.
In these cases previous gastrointestinal sur gery with latent thiamine deficiency may have contributed to diuretic-induced deficiency. Patients with prior gastrointestinal surgery of a type that might interfere with nutrient absorption should be carefully observed for signs and symptoms of thiamine deficiency if loop diuretics are being considered. Management The effect of intravenous thiamine 200 mg/day has been studied in 30 patients with moderate to severe congestive heart failure who had taken long-term furosemide therapy in a 1-week, double-blind, placebo-controlled study, followed by oral thiamine 200 mg/day in all 30 patients for 6 weeks (20C). After intravenous thiamine, diuresis, sodium excretion, and left ventricular ejection fraction all increased.
CARBONIC ANHYDRASE INHIBITORS (SED-15, 643; SEDA-29, 220; SEDA-30, 254; SEDA-31, 371)
Brinzolamide Comparative studies Brinzolamide and brimonidine Brimonidine 0.15% (n = 79) and brinzolamide 1% (n = 84) added to travoprost have been compared in a 3-month, randomized, double-masked, parallel-group design (21C). The most
403
frequent adverse events were allergy, eye pain, headache, hyperemia, and taste disturbances. The incidences were not significantly different between the groups, but that does not mean that the two drugs are equivalent in terms of the incidences of adverse effects. Brinzolamide and levobetaxolol In chil dren aged under 6 with congenital glau coma, adverse events were evaluated in a randomized, double-masked study of brinzolamide (n = 32) and levobetaxolol (n = 46) with a follow-up of 12 weeks (22C). Reported adverse events judged to be related to the drugs were based on all 80 patients. They were hyperemia of the eyes, discharge, discomfort, tearing, foreign body sensations, hordeolum, pruritus of the eye, fatigue, and bradycardia. No concerns were identified with regard to visual acuity, the adnexae, anterior segment, posterior segment, vitreous, patient alertness, or cardiovascular parameters. Eight patients (five using brinzolamide and three using levobetaxolol) had an increase in corneal diameter of at least 1 mm in at least one eye. The adverse events in the overall population were predominately non-serious and were generally mild to moderate in intensity. No patient had a serious adverse event that was related to a study drug. There were no withdrawals because of adverse events. Sensory systems Tear film and the integrity of the ocular surface can be altered by long-term therapy with antiglaucoma agents, such as brinzolamide, dorzolamide, brimonidine, and timolol. In 21 patients who had used long-term antiglaucoma medications for a minimum of 8 months, there was significantly higher fluorescein and lisamine green staining and lower tear film break-up times, with marginal differences for ocular discomfort compared with age- and sexmatched controls not using ocular or systemic medications (23c). A finding in common with all of these medications was that the preservative benzalkonium
404
chloride was used; thus, the anti-glaucoma medications (or their preservatives) may cause a pro-inflammatory environment on the ocular surface. However, this process appears to be heterogeneous in its occurrence, not precisely related to duration of therapy, and in other studies was partially reversible with preservativefree eyedrops.
Dorzolamide Comparative studies Dorzolamide and latanoprost Dorzolamide 2% and timolol 0.5% alone (n = 70) or added to latanoprost (n = 280) have been compared in an open, non-randomized study (24c). There were 116 predominantly mild non-serious adverse events reported by 86 patients (25%). The most frequent were eye irritation (n = 42; 12%) and a bad taste in the mouth (n = 15; 4%). There were five treatment-related non-serious adverse events of severe intensity (eye irritation, diarrhea, nausea, gout, and headache). There were no serious adverse events. Sensory systems Eyes The integrity of the lacrimal drainage apparatus can be damaged by anti-glaucoma medications. In a prospective, controlled, blinded, observational case series, 130 eyes from 98 patients using topical anti-glaucoma medications were compared with 280 eyes from 178 patients matched with respect to age, sex, and associated systemic disorders (25c). The participants underwent external eye and slit lamp examinations, diagnostic probing, irrigation tests, and a dye disappearance test. There was significantly more lacrimal duct system obstruction in the cases than in the control, in both the upper and lower portions of the drainage system. The patients had typically been using various drug combinations for differing durations of time. Two drug combinations, in particular, timolol þ dorzolamide and timolol þ dorzolamide þ pilocarpine, were
Chapter 21
Domenic A. Sica
associated with lacrimal duct system obstruction. As the upper lacrimal drainage system is close to the conjunctiva and fornix, it would not be expected to be more affected than the lower lacrimal drainage system, as was the case in this series. Unlike the controls, in whom lacrimal duct system obstruction was related to age, in the cases there was no relationship to age, suggesting that the duct obstruction was related more to the antiglaucoma medications. The widespread use of anti-glaucoma medications necessitates awareness by physicians of such findings such that early recognition and treatment of this adverse effect might lessen the need for future advanced lacrimal drainage apparatus surgery. Topical dorzolamide has been associated with hypotony and choroidal detachment (26A). • A 60-year-old white woman underwent trabeculectomy on both eyes. Fluctuating intraocular pressures over several years resulted in the need for topical anti-glaucoma medication in the left but not the right eye. A subsequent increase in intraocular pressure to 32 mmHg in the right eye prompted treatment with timolol 5% þ dorzolamide 2%. She then gradually lost vision in the right eye over 3 months (20/60 versus a baseline of 20/30) and hypotony (an intraocular pressure less than 5 mmHg). Fundoscopy and a B-scan ultrasound confirmed a four-quadrant choroidal detachment. All intraocular medications were stopped and over 12 weeks the choroidal detachment resolved, with improvement in visual acuity to 20/40. Three months later the intraocular pressure had risen to 28 mmHg in the right eye and timolol þ dorzolamide was restarted. However, her visual acuity fell dramatically once again (to 20/200) and the hypotony recurred (intraocular pressure 2 mmHg). Once again, there was choroidal detachment in the right eye. All anti-glaucoma medications were withdrawn and within 2 months the choroidal detachment resolved.
Achieving very low intraocular pressures with any combination of anti-glaucoma medications can result in choroidal detach ment, which may be heralded by sudden reduction in visual acuity. In 13 patients with peri-orbital dermatitis, ectropion was presumed to have been due to one or more of the drugs that they were using – betaxolol, brimonidine,
Diuretics
Chapter 21
405
dorzolamide, latanoprost, timolol, or travo prost, or the preservatives in which they were formulated; the drugs were withdrawn and the patients were assessed again, with re-challenge after the last assessment (27c). The ectropion resolved partly or completely after the eyedrops had been withheld and there was recurrence after re-challenge. Dorzolamide (seven cases) was the most common offender, followed by brimonidine (three cases). Two patients successfully underwent surgical correction for ectropion after withdrawal of the eyedrops, but those who had a short course of a glucocorticoid did not need surgical correction. Smell Anosmia associated with dorzolamide resolved after withdrawal (28A). In a series of patient-blinded experiments with challenges and re-challenges with dor zolamide and latanoprost, the dysosmia only occurred with dorzolamide. In the nasal mucosa, the balanced ion concentra tion that is maintained by carbonic anhy drase is necessary for depolarization of the olfactory receptor neurons during olfactory transduction. This could have been influ enced by dorzolamide. Skin Topical dorzolamide associated with erythema (29A).
• An 80-year-old woman developed conjunctival inflammation and severe peri-orbital eczematous dermatitis of the right eye, which had been evolving for 6 months in association with a few round, patchy, eczematous lesions on the abdomen. For more than 2 years she had been using timolol þ dorzolamide (Cosopt®) exclusively in the right eye. The Cosopt® was withdrawn and within 1 month there was discrete improvement in the peri orbital skin findings. A repeated open application testing with Cosopt® and timolol maleate (Timoptol®), each applied to the volar surface of the forearm, was performed. The test was positive with Cosopt® only, and within 3 days there was an obvious recurrence of dermatitis in the right eye and reactivation of the fixed eczematous lesions on the abdomen. The test was repeated 1 month later with dorzolamide (Trusopt®) alone and once again right peri-ocular dermatitis and abdominal eczematous lesions developed rapidly.
Topical dorzolamide is associated with a number of local adverse effects of an irritant or allergic nature; however, its use is rarely associated with systemic symptoms. In this instance, topical dorzolamide clearly trig gered a systemic contact dermatitis when applied to the forearm in the course of allergy testing. This pattern mimicked what had occurred with dorzolamide eyedrops.
has been multiforme
• An 80-year-old Caucasian woman developed eruptions on her arms, lips and ears, with peri ocular and peri-oral hyperemia after taking timolol þ dorzolamide (Cosopt®) for primary open-angle glaucoma. The lesions were symmetrically distributed, with several classic target lesions on the forearms. She had previously been exposed to Cosopt® and had developed peri-ocular hyperemia and itching at that time. Prompt withdrawal of dorzolamide, together with topical glucocorticoids, led to rapid resolution of the skin lesions.
Erythema multiforme can rarely occur with topical sulfonamide derivatives, in par ticular dorzolamide. Patients should be monitored carefully for skin reactions when treated with topical dorzolamide. Topical dorzolamide has been associated with systemic contact dermatitis (30A).
THIAZIDE AND THIAZIDE LIKE DIURETICS (SED-15, 3375;
SEDA-29, 221; SEDA-30, 256;
SEDA-31, 372)
Tumorigenicity Diuretics are photo sensitizers. However, there is scant information about how they affect the risk of skin cancers. In a population-based casecontrol study in Denmark to determine whether the use of photosensitizing diuretics was associated with an increased risk of basal cell carcinoma, squamous cell carcinoma, or malignant melanoma, primary cases during 1989–2003 were identified from the Danish Cancer Registry (31C).
406
Four age- and sex-matched population controls for each case were selected from the Danish Civil Registration System. Prescriptions for photosensitizing diuretics before the diagnosis of cancer were ascertained from the country’s Prescription Database. Conditional logistic regression was used to compute an incidence rate ratio (IRR), controlling for chronic medical conditions and prior use of oral glucocorticoids. There was an increased risk of squamous cell carcinoma (IRR = 1.79; 95% CI = 1.45, 2.21) and malignant melanoma (IRR = 1.43; CI = 1.09, 1.88) in users of the combination of hydro chlorothiazide þ amiloride. There was also an increased risk of malignant melanoma (IRR = 3.30; CI = 1.34, 8.10) among users of indapamide. For each of these findings there was a trend of increasing risk with the amount of drug and length of time between prescriptions and diagnosis. Because of the low proportion of cases in the general population, the risk estimates had very limited statistical precision, which is a significant limitation of these studies. These data are probably most relevant to individuals with pre-existing squamous cell carcinoma or malignant melanoma, in whom starting or continuing therapy with photosensitizing diuretics should be given careful consideration.
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Domenic A. Sica
concentration of at least 7 mmol/l (126 mg/dl), or a random glucose of at least 11 mmol/l. The mediating variable was the change in serum potassium during year 1 of treatment. Of the 459 incident cases of diabetes during follow-up, 42% occurred during year 1. In year 1, the adjusted risk of diabetes (hazard ratio [HR]) with chlortalidone was 2.07 (95% CI = 1.51, 2.83). After adjustment for the change in serum potassium, the risk was significantly reduced (HR = 1.54; 95% CI = 1.09, 2.17). The extent of risk attenuation (41%; 95% CI = 34, 49) was consistent with an effect mediated by potassium. Each 0.5 mmol/l fall in serum potassium was independently associated with a 45% (95% CI = 24, 70) higher adjusted risk of diabetes. After year 1, use of chlortalidone was not associated with a noteworthy increased risk of diabetes. Those with a fasting glucose of 5.5 mmol/l or more, treatment with chlortalidone 12.5 mg/day or more and a fall in serum potassium of 0.5 mmol/l or more were at the greatest risk of developing diabetes. Potassium supplementation might prevent thiazideinduced diabetes, but this remains to be proved in a suitably designed randomized trial.
Hydrochlorothiazide
Chlortalidone
Sensory systems Hydrochlorothiazide has been associated with retinal phototoxicity after exposure to an ultraviolet tanning device (33A).
Endocrine Multiple mechanisms have been proposed for the association of thiazide-type diuretics with diabetes mellitus, including potassium depletion. To determine the strength of the relationship between thiazide-induced diabetes and changes in potassium, 3790 non-diabetic participants in the Systolic Hypertension in Elderly Program, a randomized clinical trial of isolated systolic hypertension in individuals aged 60 years and over taking chlortalidone or placebo, were evaluated in a post hoc analysis (32c). Incident diabetes was defined by self-report, the use of antidiabetic medications, a fasting glucose
• A 40-year-old woman with myopia complained of blurred vision and a superior central scotoma in her left eye. These symptoms appeared immediately after exposure to an ultraviolet (UV) light source from a tanning bed. During the tanning session she had always worn UV-protective eyewear, except for a few minutes when she took the protective goggles off to put her spectacles. She had taken a fixed-dose combination of lisinopril 21.8 mg and hydrochlorothiazide 12.5 mg once a day for 2 years. At baseline her visual acuity was 10/25 and 10/80 in her right and left eyes, respectively. Fundoscopy showed lesions in both retinae. More specific tests confirmed the presence of phototoxic macular damage. Hydrochlorothiazide was withdrawn and she was advised to wear UV
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filtering glasses. Over the next 12 months she slowly recovered visual acuity in both eyes.
The UV absorption peak for hydro chlorothiazide is in the wavelength range 277–294 nm, which is the range encountered during artificial tanning. Endocrine Among antihypertensive drugs, beta-blockers and thiazide diuretics have been reported to cause reduced insulin sensi tivity and increase the risk of diabetes mellitus. Conversely, angiotensin receptor antagonists and angiotensin-converting enzyme inhibitors are associated with a reduced risk. The diabe togenic effects of thiazide and thiazide-like diuretics have been attributed to increased hepatic glucose production, impaired periph eral glucose uptake and/or b-cell dysfunction mediated by potassium depletion. The effects of candesartan 16–32 mg/day, hydrochlor othiazide 25–50 mg/day and placebo on the actions and secretion of insulin and on body fat distribution have been explored in 22 non-diabetic, hypertensive patients with abdominal obesity in the Mechanisms for the Diabetes Preventing Effect of Candesartan Study (MEDICA), a three-way, 12-week, randomized, crossover trial (34C). Insulin sen sitivity was reduced by hydrochlorothiazide compared with both candesartan and placebo, liver fat content was higher, and the subcuta neous to visceral abdominal adipose tissue ratio was reduced. Glycated hemoglobin and high-sensitivity C-reactive protein concentra tions and alanine and aspartate transaminase activities were higher after hydrochlorothia zide. Visceral fat redistribution, liver fat accu mulation, and low-grade inflammation appear to be additional factors that may explain increased insulin resistance observed in patients taking thiazide diuretics. Redistribu tion of fat in these studies could have related to insulin resistance and not to a primary effect of hydrochlorothiazide on adipocyte production.
Indapamide Cardiovascular Indapamide has been associated with prolongation of the QT
407
interval and Brugada syndrome in the setting of severe hypokalemia and hyponatremia (35A). • A 64-year-old man developed generalized weakness and dizziness. He was taking indapamide 2.5 mg/day for hypertension. Electrocardiography showed coved ST segment elevation in V2 with deep T-wave inversion (type 1 Brugada pattern) and a prolonged QT interval of 508 ms. His serum potassium concentration was 1.7 mmol/l and serum sodium 111 mmol/l. He had a sudden cardiac arrest with a polymorphous ventricular tachycardia, which was successfully defibrillated. His QTc interval gradually normalized as his serum potassium returned to normal; however, his Brugada pattern did not correct until his serum sodium had normalized some 48 hours later.
Indapamide-induced acquired long QT syndrome has been previously reported. However, an association between indapa mide and Brugada syndrome has not been previously reported. The exact mechanism by which the indapamide-related electrolyte disturbances resulted in Brugada syndrome in this case was unclear. Indapamide, and for that matter any diuretic that produces significant hypokalemia and hyponatremia, should be used with caution in patients who are genetically predisposed to or at risk of developing acquired long QT or Brugada syndromes. Endocrine Indapamide has been associated with primary hyperparathyroidism (36A). • A 75-year-old man developed constipation and epigastric discomfort and had a raised serum calcium concentration of 2.84 mmol/l. He had been taking indapamide 2.5 mg/day for about 2 years and was also taking perindopril 2 mg/day and atenolol 100 mg/day. His serum calcium had been 2.38 mmol/l when indapamide was started. Indapamide was withdrawn and his serum calcium fell to 2.46 mmol/l and his parathyroid hormone concentration fell from 10.6 to 7.0 pmol/l (reference range 1.5–7.7). His serum calcium and parathormone concentrations remained normal for more than a year after indapamide withdrawal.
Various renal, endocrine, and bonerelated mechanisms have been proposed to account for the development of hyper calcemia during therapy with thiazide-like
408
diuretics, but primary hyperparathyroidism has rarely been reported. Measurement of parathormone concentrations should be an important consideration in the initial eva luation of patients with thiazide-like diure tic-related hypercalcemia. Electrolyte balance Hyponatremia and hypokalemia
EIDOS classification: Extrinsic moiety: Loop, thiazide, and
thiazide-like diuretics
Intrinsic moiety: Na/K/Cl co-transporters (loop diuretics) or Na/Cl co transporters (thiazides) Distribution: Nephrons: loop of Henle (loop diuretics) or distal convoluted tubule (thiazides) Outcome: Altered physiology (excess
natriuresis and kaliuresis)
Sequela: Hyponatremia and
hypokalemia
DoTS classification: Dose-relation: Collateral Time-course: Time independent, but
typically occurs within weeks of
starting therapy
Susceptibility factors: Age; sex (female); physiological factors (reduced solute intake)
Hyponatremia and hypokalemia have again been reported in a patient taking indapamide (37A). • An 83-year-old woman took indapamide 1 mg/ day for hypertension and 2 months later developed nausea, vomiting, and loss of appetite, and frequently fell down. She was hypotensive (90/54 mmHg) and somnolent and had severe hyponatremia (115 mmol/l) and hypokalemia (2.8 mmol/l). Indapamide was withdrawn and her level of consciousness and serum electrolytes rapidly normalized.
In another case concomitant acquired long QT syndrome and Brugada syndrome were associated with severe hypokalemia and hyponatremia after the use of indapa mide for hypertension (38A).
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Nails Indapamide has been associated with photo-onycholysis (39A). • A 75-year-old Caucasian woman with hypertension and osteoporosis developed yellowish-brown discoloration, onycholysis, and nail-fold erythema of all 10 fingernails; the toenails were not involved. She had taken indapamide, risedronate, vitamin D, atorvastatin, atenolol, aspirin, and famotidine for several years and had been using artificial acrylic nails that were removed and reapplied by her beautician about every 6 weeks without problems. She stopped taking indapamide and applied an opaque nail polish as a photoprotective agent. Her nails returned to normal within about 4 months.
There was delayed onset in this case, probably as the result of photoprotection afforded by the artificial nails. The photo sensitizing potential of indapamide was thought to arise from the chlorine substi tuents that it shares with thiazide diure tics, resulting in UV-induced dissociation of the chlorine substituent and free radi cal reactions with lipids, proteins, and DNA.
(SED-15, 567, 1454; SEDA-29, 222; SEDA-30, 258; SEDA-31, 375)
LOOP DIURETICS
Skin Papuloerythroderma has associated with furosemide (40A).
been
• A 79-year-old man with a 25-year history of mild eczema on the trunk and limbs developed heart failure and was given furosemide. After 4 months he developed an erythematous papular eruption, which quickly progressed. There was widespread erythroderma, with coalescent solid papules predominantly on the trunk and limbs; the face, axillae, and skin folds were spared. There was a normal leukocyte count but 13% eosinophils (678 106/l). A biopsy showed moderate perivascular infiltration with lymphocytes and eosinophils in the papillary dermis. A patch test with furosemide was negative, but a lymphocyte stimulation test was positive. Furosemide was withdrawn and he was treated with topical 0.05% betamethasone
Diuretics
Chapter 21
butyrate propionate once a day for 1 month, resulting in improvement. After oral challenge with furosemide the erythematous papular eruption recurred within 48 hours.
Prior sensitization to furosemide can lead to rapid development of such skin lesions on repeat exposure. Torasemide has been associated with the development of pseudoporphyria (41A). • A 64-year-old man with chronic renal insufficiency took torasemide for about 4 months followed by furosemide for about 2 months before developing blistering lesions, crusts, erosions, and hypopigmented scars on his scalp and the backs of his hands. Urinary porphyrin concentrations were normal.
Diuretic-induced pseudoporphyria has been described in relation to chlortalidone, bumetanide, and furosemide and to an interaction of hydrochlorothiazide with triamterene. The persistence of lesions after switching to furosemide and disap pearance of the cutaneous eruption after withdrawing it suggests cross-reactivity between torasemide and furosemide. Drug–drug interactions Warfarin Tora semide has been reported to potentiate the effects of warfarin (42A). • A 43-year-old Hispanic woman with heart failure, hypothyroidism, anemia, atrial fibrillation, and a mechanical mitral valve was anticoagulated with a target international normalized ratio (INR) of 2.5–3.5 on a warfarin regimen of 50–52.5 mg/week. One week after she started to take torasemide 40 mg in the morning and 20 mg in the afternoon, there was a marked increase in the INR to 6.2, requiring a reduction in the dose of warfarin. Subsequent titration of the dose of warfarin over 3 weeks was required to reach a target INR of 2.9–3.3, with a new weekly dose of 47.5 mg.
The basis of this interaction was probably competition for CYP2C9, by which both warfarin and torasemide are metabolized. Protein binding displacement of warfarin from albumin by torasemide is less likely, since that would have produced only a tran sient effect. Other potential causes of an increased INR, such as reduced absorption of vitamin K, were ruled out. Care should be taken when torasemide is added to
409
warfarin therapy. A similar interaction with furosemide and bumetanide has not been previously reported; neither of those loop diuretics is metabolized by CYP2C9.
ALDOSTERONE RECEPTOR ANTAGONISTS Spironolactone
(SED-15, 3176; SEDA 29, 222; SEDA-30, 259; SEDA-31, 375)
Gastrointestinal There have been two reports of an increased rate of gastrointestinal bleeding in patients taking spironolactone. In a population-based case-control study in Denmark in 3652 subjects with serious upper gastrointestinal bleeding and 36 502 age- and sex-matched controls, the adjusted OR for an effect of spironolactone was 2.7 (95% CI = 2.2, 3.2) (43C). The risk increased with higher doses of spironolactone (OR = 5.4; CI = 3.4, 8.6), but there was no trend with increasing cumulative doses. The strongest association was found among users aged 55–74 years (OR = 13; CI = 6.5, 26). Current use of loop diuretics was also associated with an increased risk of upper gastrointestinal bleeding (OR = 1.9; CI = 1.7, 2.1). In another study using pharmaceutical prescriptions from 2000 to 2006, a cohort of residents in Milan was identified with chronic exposure to spironolactone or other diuretics 44C. The main outcome was defined as hospital admissions for upper gastrointestinal bleeding or ulcers. To control for potential bias related to the use of spironolactone, propensity scores were estimated, and each patient taking spironolactone was randomly matched with one taking other diuretics and having the same propensity score using the caliper matching method. Proportional hazard models were fitted by computing HRs. Of 53 550 non-exposed subjects and 10 564 who had been exposed to spironolac tone, 174 (3.2%) and 51 (4.8%) respectively had been hospitalized for upper gastrointestinal bleeding (HR = 1.94; 95% CI = 1.42, 2.65). A sensitivity analysis
410
based on the matched design using the propensity score showed a statistically significant twofold increase in upper gastrointestinal bleeding only among sub jects who had been exposed to high doses of spironolactone (HR = 2.50; 95% CI = 1.08, 5.79). Both of these studies suggest that spiro nolactone increases the risk of upper
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gastrointestinal bleeding. This relationship has been hinted at in previous literature, but has not been shown with such clarity. These studies do not offer a mechanistic basis for this effect. Considering that many patients taking spironolactone are at high risk of upper gastrointestinal bleeding, confound ing by treatment indication may have played some part.
References 1. Rieck J, Halkin H, Almog S, Seligman H, Lubetsky A, Olchovsky D, Ezra D. Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers. J Lab Clin Med 1999;134:238–43. 2. Seligmann M, Halkin H, Rauchfleisch S, Kaufmann N, Tal R, Motro M, Vered Z, Ezra D. Thiamine deficiency in patients with congestive heart failure receiving long-term furosemide therapy: a pilot study. Am J Med 1991;91:151–5. 3. Zenuk C, Healey J, Donnelly J, Vaillancourt R, Almalki Y, Smith S. Thiamine deficiency in congestive heart failure patients receiving long term furosemide therapy. Can J Clin Pharmacol 2003;10:184–8. 4. Suter PM, Haller J, Hany A, Vetter W. Diure tic use: a risk for subclinical thiamine defi ciency in elderly patients. J Nutr Health Aging 2000;4(2):69–71. 5. da Cunha S, Albanesi Filho FM, da Cunha Bastos VL, Antelo DS, Souza MM. Thiamin, selenium, and copper levels in patients with idiopathic dilated cardiomyopathy taking diuretics. Arq Bras Cardiol 2002;79 (5):454–65. 6. Härdig L, Daae C, Dellborg M, Kontny F, Bohmer T. Reduced thiamine phosphate, but not thiamine diphosphate, in erythrocytes in elderly patients with congestive heart failure treated with furosemide. J Intern Med 2000;247(5):597–600. 7. Sica DA. Loop diuretic therapy, thiamine bal ance, and heart failure. Congest Heart Fail 2007;13:244–7. 8. Hanninen SA, Darling PB, Sole MJ, Barr A, Keith ME. The prevalence of thiamin
deficiency in hospitalized patients with con gestive heart failure. J Am Coll Cardiol 2006;47(2):354–61. 9. Lubetsky A, Winaver J, Seligmann H, Olchovsky D, Almog S, Halkin H, Ezra D. Urinary thiamine excretion in the rat: effects of furosemide, other diuretics, and volume load. J Lab Clin Med 1999;134(3):232–7. 10. Markkanen T. The effect of acetazolamide and mercaptomerin on the urinary excretion of thiamine, riboflavin and pantothenic acid. Z Vitam Horm Fermentforsch 1965;14 (1):72–6. 11. Kasper H, Der HI. Einfluss von Hydrochlor othiazid auf die Thiaminausscheidung im Urin. [Influence of hydrochlorothiazide on urine thiamine excretion.] Klin. Wochenschr. 1966;44(10):568–71. 12. Dudeja PK, Tyagi S, Kavilaveettil RJ, Gill R, Said HM. Mechanism of thiamine uptake by human jejunal brush-border membrane vesi cles. Am. J. Physiol Cell Physiol 2001;281(3): C786–92. 13. Dudeja PK, Tyagi S, Gill R, Said HM. Evi dence for a carrier-mediated mechanism for thiamine transport to human jejunal basolat eral membrane vesicles. Dig Dis Sci 2003;48 (1):109–15. 14. Zangen A, Botzer D, Zangen R, Shainberg A. Furosemide and digoxin inhibit thiamine uptake in cardiac cells. Eur J Pharmacol 1998;361(1):151–5. 15. Rocha RM, Silva GV, de Albuquerque DC, Tura BR, Albanesi Filho FM. Influence of spironolactone therapy on thiamine blood levels in patients with heart failure. Arq Bras Cardiol 2008;90(5):324–8.
Diuretics
Chapter 21
16. Yue QY, Beermann B, Lindstro¨ m B, Nyquist O. No difference in blood thiamine diphosphate levels between Swedish Caucasian patients with congestive heart failure treated with furosemide and patients without heart fail ure. J Intern Med 1997;242(6):491–5. 17. McCabe-Sellers BJ, Sharkey JR, Browne BA. Diuretic medication therapy use and low thia min intake in homebound older adults. J Nutr Elder 2005;24(4):57–71. 18. Tsujino T, Nakao S, Wakabayashi K, Lee M, Kimura T, Yoshikawa H, Sakoda T, Ohyanagi M, Masuyama T. Loop diuretic pre cipitated beriberi in a patient after pancreati coduodenectomy: a case report. Am J Med Sci 2007;334:407–9. 19. Akahori H, Tsujino T, Masutani M, Akagami T, Tanabe K, Masai M, Fujioka Y, Ohyanagi M, Masuyama T. [Postgastrect omy beriberi exaggerated by diuretic use: a case report.] J Cardiol 2007;49(1):49–53. 20. Shimon I, Almog S, Vered Z, Seligmann H, Shefi M, Peleg E, Rosenthal T, Motro M, Halkin H, Ezra D. Improved left ventricular function after thiamine supplementation in patients with congestive heart failure receiv ing long-term furosemide therapy. Am J Med 1995;98(5):485–90. 21. Feldman RM, Tanna AP, Gross RL, Chuang AZ, Baker L, Reynolds A, Prager TC. Com parison of the ocular hypotensive efficacy of adjunctive brimonidine 0.15% or brinzola mide 1% in combination with travoprost 0.004%. Ophthalmology 2007;114:1248.e2–54. 22. Whitson JT, Roarty JD, Vijaya L, Robin AL, Gross RD, Landry TA, Dickerson JE, Scheib SA, Scott H, Hua SY, Woodside AM, Bergamini MVW. Efficacy of brinzolamide and levobetaxolol in pediatric glaucomas: a randomized clinical trial. J AAPOS 2008;12:239.e3–46. 23. Baffa L, Ricardo JR, Dias AC, Modulo CM, Braz AM, de Paula JS, Rodriguez M, Rocha EM. Tear film and ocular surface alterations in chronic users of antiglaucoma medica tions. Arq Bras Oftalmol 2008;71:18–21. 24. Lesk MR, Koulis T, Sampalis F, Sampalis JS, Bastien NR. Effectiveness and safety of dor zolamide–timolol alone or combined with latanoprost in open-angle glaucoma or ocu lar hypertension. Ann Pharmacother 2008;42:498–504.
411 25. Sharma T, Salmon JF. Hypotony and choir oidal detachment as a complication of topical combined timolol and dorzolamde. J Ocul Pharmacol Ther 2007;23:202–4. 26. Kashkouli MB, Rezaee R, Nilforoushan N, Salimi S, Foroutan A, Naseripour M. Topical antiglaucoma medications and lacrimal drai nage system obstruction. Opht Plas Recons Surg 2008;24:172–5. 27. Hegde V, Robinson R, Dean F, Mulvihill HA, Ahluwalia H. Drug-induced ectropion. What is best practice? Ophthalmology 2007;114:362–6. 28. Turgut B, Turkcuoglu P, Guler M, Akyol N, Celiker U, Demir T. Anosmia as an adverse effect of dorzolamid. Acta OphthalmolScand 2007;85:228–9. 29. Munshi V, Ahluwalia H. Erythema multiforme after use of topical dorzolamide. J Ocul Pharmacol Ther 2008;24:91–3. 30. Kluger N, Guillot B, Raison-Peyron N. Sys temic contact dermatitis to dorzolamide eye drops. Contact Derm 2008;58:167–8. 31. Jensen AÃ, Thomsen HF, Engebjerg MC, Olesen AB, SÏrensen HT, Karagas MR. Use of photosensitising diuretics and risk of skin cancer: a population-based case-control study. Br J Cancer 2008;99:1522–8. 32. Shafi T, Appel LJ, Miller III ER, Klag MJ, Parekh RS. Changes in serum potassium mediate thiazide-induced diabetes. Hyper tension 2008;52:1022–9. 33. Costagliola C, Menzione M, Chiosi F, Romano MR, Della Corte M, Rinaldi M. Retinal phototoxicity induced by hydro chlorothiazide after exposure to a UV tanning device. Photochem Photobiol 2008;84:1294–7. 34. Eriksson JW, Jansson PA, Carlberg B, Hägg A, Kurland L, Svensson MK, Ahlstro¨ m H, Stro
¨ m C, Lo
¨ nn L, Ojbrandt K, Johansson L, Lind L. Hydrochlorothiazide, but not can desartan, aggravates insulin resistance and causes visceral and hepatic fat accumulation: The Mechanisms for the Diabetes Preventing Effect of Candesartan (MEDICA) study. Hypertension 2008;52(6):1030–7. 35. Mok NS, Tong CK, Yuen HC. Concomitantacquired long QT and Brugada syndromes associated with indapamide-induced hypo kalemia and hyponatremia. PACE 2008;31:772–5.
412 36. Debono M, Banerjee R. Indapamide induced hyperparathyroidism: a case report. Eur J Clin Pharmacol 2007;63:809–11. 37. Hamano T, Yamamoto T, Miyamori I, Kuriyama M. [Hyponatremia with somno lence due to indapamide.] Rinsho Shinkei gaku 2008;48(1):52–5. 38. Mok NS, Tong CK, Yuen HC. Concomitantacquired Long QT and Brugada syndromes associated with indapamide-induced hypo kalemia and hyponatremia. Pacing Clin Elec trophysiol 2008;31(6):772–5. 39. Rutherford T, Sinclair R. Photo-onycholysis due to indapamide. Australas J Dermatol 2007;48:35–6. 40. Sugita K, Kabashima K, Nakashima D, Tokura Y. Papuloerythroderma of Ofuji induced by furosemide. J Am Acad Derma tol 2008;58(2 Suppl):S54–5.
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Domenic A. Sica
41. Pérez-Bustillo A, Sa´nchez-Sambucety P, Sua´ rez-Amor O, Rodríiguez-Prieto MA. Torsemide-induced pseudoporphyria. Arch Dermatol 2008;144:812–3. 42. Bird J, Carmona C. Probable interaction between warfarin and torsemide. Ann Phar macother 2008;42:1893–8. 43. Gulmez SE, Lassen AT, Aalykke C, Dall M, Andries A, Andersen BS, Hansen JM, Andersen M, Hallas J. Spir onolactone use and the risk of upper gastrointestinal bleeding: a populationbased case-control study. Br J Clin Phar macol 2008;66:294–9. 44. Russo A, Autelitano M, Bisanti L. Spirono lactone and gastrointestinal bleeding: a population based study. Pharmacoepidemiol Drug Saf 2008;17:495–500.
Gijsbert B. van der Voet
22 Aluminium (SED-15, 97; SEDA-29, 225; SEDA-30, 262; SEDA-31, 383) The occupational, environmental and clini cal human health risks of aluminium, alumi nium oxide and aluminium hydroxide have been reviewed (1R). Nervous system There is epidemiological evidence of an association between alumi nium in drinking water and Alzheimer’s dis ease, and between aluminium in dialysate and dialysis dementia. The exact role of alu minium in the pathogenesis of these and other dementias is not clear. The acute effects of aluminium on cognitive function have been investigated in patients with Alzheimer’s disease and related dementias and in age-matched and younger volunteers with normal cognitive function (2M). Whether individuals with Alzheimer’s dis ease and/or the apolipoprotein E (ApoE) "4 genotype had enhanced gastrointestinal absorption of aluminium was determined, as was the relation between blood aluminium concentrations and acute cognitive effects. The subjects were randomized to a single dose of aluminium orally (Amphojel plus citrate) for 3 days, followed by washout for 3 weeks, and then 3 days of matched placebo, or vice versa. Serum aluminium concentra tions were measured and the daily dose of the drug was adjusted to a target aluminium concentration of 50–150 µg/l. There was large inter individual variation in serum aluminium
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32022-8 � 2010 Elsevier B.V. All rights reserved.
Metals
concentrations after the same initial dose. There were no significant differences in neu ropsychological test scores after aluminium in healthy volunteers or patients with cogni tive impairment. There was no association between the ApoE 4 genotype and alumi nium absorption. These results neither sup ported the hypothesis that aluminium in these doses has acute effects on cognition or adverse effects, nor did they show that patients with Alzheimer’s disease are more vulnerable to such outcomes. Sensory systems Ears Potential ototoxi city of aluminium on the specified neural organ of the inner ear and its relation to serum aluminium concentration has been investigated in 40 patients on hemodialysis and 40 age-matched healthy subjects without hearing complaints (3C). Highfrequency hearing impairment was the pre dominant auditory dysfunction in patients on hemodialysis, who had worse high-tone hearing on pure-tone audiometry and diminished amplitudes of distortion-product otoacoustic emissions compared with controls. Serum aluminium concentration correlated negatively with the amplitude of distortion-product otoacoustic emissions 2K, but not with emissions 3K or 4K, hear ing pure-tone audiometry or wave latencies on auditory brainstem responses. These results suggest that aluminium mainly affects cochlear rather than retrocochlear function. Drug–drug interactions Clozapine An interaction of aluminium hydroxide with clozapine has been described (4A). • A 26-year-old man with a non-specified psychotic disorder, violence, and alcohol
413
414 abuse was given clozapine 100 mg bd. The clozapine serum concentration was stable at 382 ng/ml. A few weeks later he became sleepier and was drooling more than before. The clozapine concentration was 739 ng/ml. There had been no changes in his other medications, except that he was taking less aluminium hydroxide. The dose of clozapine was adjusted and the signs of clozapine overdose disappeared.
Aluminium hydroxide can adsorb clozapine and reduce its gastrointestinal absorption.
Antimony
(SED-15, 316; SEDA-29, 226; SEDA-30, 263; SEDA-31, 384)
Drug resistance Pentavalent antimonial compounds, such as sodium stibogluconate and meglumine antimoniate, continue to be used in the first-line chemotherapy of leish maniasis (5R) and in oncology (6R). Atten tion has been paid to the molecular mechanisms of resistance to antimonials in leishmaniasis (7R).
Arsenic (SED-15, 339; SEDA-29, 227; SEDA-30, 263; SEDA-31, 385) Observational studies Organic arsenicals have been investigated for their potential as anticancer drugs (8R). The use of arsenic trioxide in acute promyelocytic anemia is gaining more attention, and its adverse effects have been reviewed (9R). During induction therapy, a leukocytosis can occa sionally occur, which can be associated with fluid accumulation, pulmonary infiltration, prolongation of the QT interval, and dysrhythmias. Skin Arsenic-induced hyperkeratosis has been reported (10A). • A 52-year-old black woman developed rough painful lesions of the palms of both hands and the legs; she had had the lesions for many years. She had grown up in an area where the only drinking water came from a well. There were thick, firm, punctuate, brown, keratotic papules on both palms, the soles, and the
Chapter 22
Gijsbert B. van der Voet
legs. A skin biopsy showed arsenic keratosis, with epidermal hyperplasia, hyperkeratosis, and a sparse, perivascular, predominantly lymphocytic infiltrate in the dermis. Topical keratolytics produced minimal relief of pain and slight improvement in the lesions.
Psychological The effects of arsenic expo sure on children’s intelligence and growth have been investigated in a study of 720, aged 8–12 years, in rural villages in China (11c). The children had been exposed to drinking water containing arsenic 142 µg/l (medium-dose group) or 190 µg/l (high dose group) and a control group had been exposed to low concentrations of arsenic (mean 2 µg/l). Mean IQ scores were 105 in the controls, 101 in the medium-dose group and 95 in the high-dose group.
Bismuth (SED-15, 518; SEDA-29, 227; SEDA-30, 264; SEDA-31, 385) Systematic reviews The safety of bismuth salts (ranitidine bismuth citrate, colloidal bis muth subcitrate, tripotassium dictratobis muthate, bismuth subsalicylate, and bismuth subnitrate) used in Helicobacter pylori eradi cation regimens has been investigated in a systematic review of 35 randomized con trolled trials in 4763 patients (12M). Abdom inal pain, diarrhea, dizziness, headache, metallic taste, nausea, and/or vomiting and dark stools were included as adverse events. There were no serious adverse events in patients taking bismuth. There was no statis tically significant difference in total adverse events (RR = 1.01; 95% CI = 0.87, 1.16), adverse events that led to withdrawal of therapy (RR = 0.86; CI = 0.54, 1.37), or specific individual adverse events, with the exception of dark stools (RR = 5.06; CI = 1.59, 16).
Chromium (SED-15, 737; SEDA-29, 228; SEDA-30, 264; SEDA-31, 386) Observational studies The potential human health effects of occupational exposure to
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415
cobalt and chromium contaminants with exposure from surgical devices such as ortho pedic joint replacements have been reviewed (13R). Both industrial and surgical exposure cause inflammatory and other immune reac tions in the directly exposed tissues. There is a well-established risk of lung cancer after longterm exposures to hexavalent chromium; however, sarcoma in the connective tissues adjacent to implants in response to metal particles is rare. Both types of exposure are associated with changes in the peripheral blood, including evidence of oxidative stress and altered numbers of circulating immune cells. There is dissemination of cobalt and chromium to sites distant to the orthopedic implant, but less is known about systemic dissemination of these metals away from the lung. There is increasing concern about the health effects (hypersensitivity, osteolysis, carcinogenicity) of metal-to-metal surgical implants. Long-term wear and dissolution of the material can lead to internal exposure. The blood concentrations of chromium and cobalt were followed at 3, 6, 12, and 24 months after a metal-on-metal surface replacement hip arthroplasty using a high-carbon-content chromium–cobalt alloy implant in 64 patients (14C). The blood concentrations of chromium and cobalt were significantly increased 3 months postoperatively but gradually fell. At 1 year, mean whole blood ion concentra tions were 1.61 µg/l (0.4–5.5) for chromium and 0.67 µg/l (0.23–2.09) for cobalt, both of which are above the reference ranges. The preoperative ion concentrations, compo nent size, female sex, and the inclination of the acetabular component were inversely pro portional to the chromium and/or cobalt ion concentrations at 1 year postoperatively. Other factors, such as age and activity, did not correlate with the metal ion concentra tions. The authors concluded that these concentrations may be specific to the hip resurfacing implant and have diagnostic value.
available evidence suggests that genotoxic effects are very unlikely to occur in humans exposed to nutritional or to moderate recommended supplementary concentra tions of chromium(III). Excessive supple mentation is not warranted. Thus, like other nutrients that have genotoxic effects at high concentrations in vitro, the nutri tional benefits appear to outweigh the theoretical risk of genotoxic effects in vivo at normal or modestly raised intakes. However, this observation has been con tradicted in another review (16R), in which it was stated that the same biochemical mechanism underlies the beneficial as well as the toxic effects of chromium(III). Chromium(III) is transformed into different chemical species, including (i) partial hydrolysis products and (ii) highly reactive chromium(VI/V/IV) species and organic radi cals. Low concentrations of these species are likely to cause alterations in cell signal ling (including enhancement of insulin sig nalling), through interactions with the active centers of regulatory enzymes in the cell membrane or in the cytoplasm, while higher concentrations are likely to produce genotoxic DNA lesions in the cell nucleus. These data suggest that the poten tial for genotoxic adverse effects of chro mium(III) complexes may outweigh their possible benefits as insulin enhancers, and that recommendations for their use as either nutritional supplements or antidiabetic drugs need to be reconsidered.
Genotoxicity The question of the geno toxic effects of chromium(III) nutritional supplements has been reviewed (15R). The
Uses Wilson’s disease (17R, 18R) and Menke’s disease (19R), including the role of copper, have again been reviewed.
Cobalt
(SED-15, 847; SEDA-30, 264; SEDA-31, 386) See ‘Chromium’ above.
Copper
(SED-15, 901; SEDA-29, 228; SEDA-30, 265; SEDA-31, 387)
416
Systematic reviews A meta-analysis of 35 randomized controlled studies of the effec tiveness and adverse effects of copper-con taining intra-uterine contraceptive devices (IUCDs) has been published (20M). There were 18 comparisons of 10 different IUCDs in about 48 000 women. TCu380A was more effective in preventing pregnancy than MLCu375 (RD = 1.70%; 95% CI = 0.07, 2.95%) after 4 years of use. TCu380A was also more effective than MLCu250, TCu220, and TCu200. There tended to be fewer pregnancies with TCu380S than with TCu380A after the first year of use, a difference that became statistically signifi cant in the fourth year (RD = �1.62%; 95% CI = �3.00, �0.24%). This occurred despite more expulsions with TCu380S (RD = 3.50%; 95% CI = 0.36, 6.63% at 4 years). MLCu375 was no more effective than TCu220 at 1 year of use or than MLCu250 and NovaT up to 3 years. Com pared with TCu380A or TCu380S, none of the IUCDs showed any benefits in terms of bleeding or pain, or any of the other reasons for early withdrawal. None of the trials that reported events at insertion found one IUCD easier to insert than another or less painful. There is no evidence that uterine perforation rates vary by type of device. The authors concluded that TCu380A or TCu380S is more effective than other IUCDs. No IUCD had consistently lower removal rates for bleeding and pain than any other. There is no evidence that any particular framed copper device is better suited to women who have not had children.
Gallium
(SED-15, 1477; SEDA-29, 228; SEDA-30, 265)
Drug resistance Resistance to gallium of different cancer cell types has been reviewed (21R). This is the trigger for specific research on resistance mechanisms and the develop ment of new antineoplastic agents. The cytotoxicity of gallium maltolate, a novel gallium compound, has been compared with gallium nitrate in lymphoma cell lines, including p53 variant and unique gallium
Chapter 22
Gijsbert B. van der Voet
nitrate-resistant cells (22E). Gallium malto late inhibited cell proliferation and induced apoptosis through the mitochondrial path way at lower concentrations and more rapidly than gallium nitrate did. Gallium mal tolate produced an increase in intracellular reactive oxygen species (ROS) within 2 hours of incubation; this effect was blocked by mitoquinone, a mitochondria-targeted antioxidant. The role of the transferrin recep tor in the action of gallium maltolate was examined using monoclonal antibody 42/6 to block transferrin receptor function. How ever, although it reduced gallium maltolate induced caspase-3 activity, it had only a minor effect on cell growth inhibition. Gal lium maltolate induced apoptosis in cells resistant to gallium nitrate, and, unlike gal lium nitrate, its cytotoxicity was not affected by cellular p53 status. Cellular gallium uptake was greater with gallium maltolate than with gallium nitrate. The authors con cluded that gallium maltolate inhibits cell proliferation and induces apoptosis more efficiently than gallium nitrate. Gallium mal tolate is incorporated into lymphoma cells to a greater extent than gallium nitrate via both transferrin receptor-independent and recep tor-dependent pathways. It has significant activity against gallium nitrate-resistant cells and acts independently of p53.
Gold and gold salts
(SED-15, 1520; SEDA-29, 228; SEDA-30, 265; SEDA-31, 387)
Uses The clinical pharmacology of gold compounds has been reviewed (23R). Aur anofin exhibits potential as an antimalarial agent (24R) and gold complexes are receiv ing attention as anticancer agents (25R). Skin Gold salts are used in the treatment of pemphigus, but have paradoxically been reported to cause paucilesional pemphigus vulgaris (26A). • A 44-year-old woman took an oral auranofin 3 mg bd for 6 months for seronegative rheumatoid arthritis. During the first 3 months
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Chapter 22
bullous lesions appeared in her left leg. Glucocorticoid treatment caused them to disappear, but 3 weeks later new bullous lesions appeared in her legs and ruptured leading to reddened erosions, which were large because of their tendency to spread at the periphery. The auranofin was withdrawn and she recovered.
Iron salts
(SED-15, 1911; SEDA-29, 229; SEDA-30, 265; SEDA-31, 387)
Comparative studies The adverse effects of two intravenous iron formulations, iron dextran and iron sucrose, have been studied in 60 patients with end-stage renal disease (27C) who were randomized to one of the two formulations. Standard test doses of 25 mg of low-molecular-weight iron dextran and iron sucrose were given over 15 minutes during the initial visit, monitoring very clo sely for adverse reactions. If this dose was well tolerated, 75 mg of iron diluted in 100 ml of isotonic saline was given over 30 minutes. The mean age of the patients was 52 (range 21–80) years. Of the 30 patients who received low-molecular-weight iron dextran, 11 had adverse reactions: pruritus, wheezing, chest pain, hypotension, swelling (n = 1 each), headache (n = 2), and nausea (n = 4). Of the 30 patients who received iron sucrose, 13 developed adverse effects: prur itus, wheezing, diarrhea, swelling (n = 1 each), hypotension (n = 2), headache (n = 3), and nausea (n = 4). Adverse events occurred with similar frequency in the two treatment groups. There were no serious reactions. The adverse effects of parenteral iron products have been reviewed (28R). The authors concluded that iron sucrose and ferric gluconate are safer than iron dextran, but this may be a premature conclusion. Tumorigenicity Intramuscular iron–car bohydrate is not very often required, but can cause calcification of the soft tissues. The suggestion that it can cause sarcoma formation has not been proven. Siderosis at the injection site has been described (29A).
417 • A 66-year-old woman who had received injections of iron polymaltose into her right buttock every month for 8 months for iron deficiency anemia developed a hard lump at the injection site, which eroded through the skin over the next few years. Imaging showed that the mass was limited to the subcutaneous tissues with no intramuscular extension. The area was excised and a vacuum-assisted closure dressing was applied and closed with a skin graft. Histology showed only siderosis and inflammatory change.
Lanthanum carbonate (SEDA-31, 389) Susceptibility factors Renal disease Lan thanum carbonate is an aluminium-free, calcium-free, phosphate-binding agent used to control phosphorus concentrations in patients with renal insufficiency (30R). However, there are concerns about lanthanum accumulation in tissues during long-term oral administration. Moreover, the rate of intestinal absorption of lanthanum is increased in chronic renal insufficiency. Drug–drug interactions Ciprofloxacin The effect of six doses of lanthanum 1 g tds on the systemic availability of a single oral dose of ciprofloxacin 750 mg has been inves tigated in a randomized crossover study in 12 patients (31C). Lanthanum reduced the mean ciprofloxacin AUC by 54% and the Cmax by 56%. The 24-hour urinary recovery of cipro floxacin was reduced by 52%. There were no significant changes in tmax, half-life or renal clearance. The authors concluded that lanthanum carbonate significantly reduces the systemic availability of oral ciprofloxacin and that concomitant administration should be avoided.
Magnesium salts
(SED-15, 2196; SEDA-30, 266; SEDA-31, 390)
Systematic reviews In a meta-analysis of the use of intravenous magnesium sulfate to treat atrial fibrillation in 515 patients in 10 studies, magnesium caused transient
418
minor symptoms (flushing, tingling, and dizziness) in 17% (32M). Although intra venous magnesium was less effective than either calcium channel blockers or amiodar one (21% versus 59%; OR = 0.19, 95% CI = 0.09, 0.44), it was also less likely to cause significant bradycardia or atrioventri cular block (0% versus 9.2%; OR = 0.13, 95% CI = 0.02, 0.76); there was significant hypotension in only six patients. Nervous system Hypermagnesemia causes impaired neuromuscular junction transmis sion, which has reportedly caused quadripar esis (33A). • A 32-year-old woman with end-stage renal disease developed progressively worse abdominal pain. She had chronic constipation and for 1 year had been taking magnesium oxide powder 3.0 g/day. She was alert and her vital signs were stable, but by day 8 she could not move her arms or legs and her muscle strength was symmetrically reduced to grade 1–2. Nerve conduction studies showed a severe polyneuropathy, with blocked nerve conduction. The magnesium-containing cath artics were withdrawn. Her serum magnesium concentration was 4.35 mmol/l (10.6 mg/dl). By day 28 the serum magnesium had fallen to 1.27 mmol/l and her weakness and quadriparesis had improved.
Musculoskeletal Hypermagnesemia can cause impaired normal bone mineralization and osteomalacia (34A). • A 42-year-old woman developed joint pains, spreading from the ankles, to the knees, hips, and shoulders, and had difficulty in walking. She had used magnesium hydroxide as a laxative for the previous 2 years (10–15 g/day). Her serum calcium, phosphorus, and vitamin D concentrations were all reduced, while magnesium, alkaline phosphatase, and para thormone were increased. The magnesium was withdrawn and the osteomalacia was treated with vitamin D and oral calcium. She improved within 2 months.
Manganese
(SED-15, 2200; SEDA-29, 230; SEDA-30, 267) Nervous system The literature on manga nese accumulation in the brain, as detected
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Gijsbert B. van der Voet
by symmetrical high-signal intensity in the globus pallidus on T1-weighted MR images without an abnormal signal on T2-weighted images, has been reviewed (35AR). Com mon causes of manganese accumulation in the brain are overload from total parenteral nutrition and manganese intoxication in welders. However, manganese accumula tion in the brain can be due to acquired or congenital liver disease, including hepatic cirrhosis with a portosystemic shunt, congenital biliary atresia, primary biliary cirrhosis, congenital intrahepatic portosys temic shunt without liver dysfunction, Rendu–Osler–Weber syndrome with diffuse intrahepatic portosystemic shunting, and patent ductus venosus. Metal metabolism Manganese is an essen tial trace element included in parenteral nutrition. However, long-term parenteral administration, which bypasses the normal alimentary tract regulatory mechanism, can cause hypermanganesemia. Manganese poi soning presents clinically with parkinsonian symptoms and psychological changes. Sei zures are rare but have been reported (36A). • A 10-year-old girl, who had received total parenteral nutrition for 3 months because of short bowel syndrome, had a tonic–clonic seizure with a reduced level of consciousness and a fever. Her serum electrolytes, glucose, and cerebrospinal fluid were normal. Blood cul tures grew Pantoea agglomerans. A magnetic resonance imaging (MRI) scan of the brain showed no evidence of infection, but there were symmetrical high-intensity signals on T1-weighted images in the basal ganglia, especially the globus pallidus. The whole blood manganese concentration was 37 µg/l (670 nmol/l), which was significantly higher than the reference range (4–14 µg/l, 70–250 nmol/l).
The presence of hypermanganesemia and the symptoms of manganese toxicity depend on dose, duration of use and the presence of significant liver disease, because manganese is predominantly eliminated by biliary excretion. In this case the presenta tion was probably multifactorial, since sep tic shock could have contributed. Unusual
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features included the fact that the patient was receiving a daily dose of manganese within the recommended range (about 8 micrograms/kg/day, 145 nmol/kg/day; recom mended dose 2–10 micrograms/kg/day) and was given parenteral nutrition for a relatively short time, as symptoms are not usually expected until after 1 year (37R). Because there was no evidence of hepatic dysfunction, the reasons for this reaction are unclear. However, the daily dose was close to the upper limit of the recommended adult range, which may have been excessive in this child. Daily recommended pediatric doses of parenteral managanese have a lower limit of 1 micrograms/kg/day (18 nmol) (38S).
Mercury and mercurial salts (SED-15, 2259; SEDA-29, 230; SEDA-30, 268; SEDA-31, 391) The Global Advisory Committee on Vac cine Safety (GACVS) has considered a pharmacokinetic study of mercury in premature and low-birth-weight infants who received a birth dose of hepatitis B vaccine containing thiomersal (39S). The results suggested that exposure to thio mersal-containing vaccines does not result in accumulation of mercury in blood and that the half-life of intramuscular ethyl mercury from thiomersal in vaccines in infants (2.9–4.1 days) is substantially shorter than that of oral methyl mercury in adults. The authors concluded that exposure guidelines based on oral methyl mercury may not be appropriate for use in assessing the risk of thiomersal in vac cines at dosages consistent with standard immunization regimens. Nervous system The relation between neurotoxicity and mercury in dental amal gams and between autism and mercury (thiomersal) in vaccines continues to be discussed, without definitive conclusions (40r, 41R). The GACVS has considered the results of an Italian study that examined
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neuropsychological performance 10 years after immunization in infancy with thiomersal containing vaccines (39S). Higher thiomersal exposure through vaccines administered in the first year of life was significantly associated with lower scores on two neuro psychological outcomes (motor function, measured using the finger-tapping test, and language, measured using the Boston naming test). The differences in mean scores were very small, detected only in girls, of doubtful clinical relevance, and not consistent with results from other studies of ethyl mercury. The observed associations may reflect the effect of chance. On the basis of these data, GACVS remains of the view that there is no evidence supporting any change in WHO’s recommendations for thiomersal containing vaccines and the immunization of low-birth-weight infants when indicated. Sensory systems Thiomersal (sodium ethylmercurithiosalicylate) has been com monly used as a preservative in eyedrops and contact lens disinfecting solutions. However, it is a known sensitizer (SEDA 21, 255) and cases of allergy have been reported after application to the eyes (SEDA-23, 248). Although thiomersal is increasingly being withdrawn from phar maceuticals because of toxicity, it is still used in some products. Unilateral total limbal stem failure and corneal opacifica tion, secondary to thiomersal exposure from a contact lens solution, has further confirmed the need for restrictions in the use of thiomersal in ophthalmic formula tions (42A).
Nickel
(SED-15, 2502; SEDA-29, 230; SEDA-30, 268; SEDA-31, 392) Immunologic Nickel is allergenic. The use of nickel in alloy-based implant materials combined with titanium is a new internal route of exposure to nickel, which is a con cern for patients undergoing orthopedic surgery (43S).
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Selenium
(SED-15, 3119; SEDA-29, 231; SEDA-30, 269; SEDA-31, 392)
Uses Selenium may be an effective chemo preventive and anticancer agent, with a broad spectrum against several human can cer cells (prostate, colon, bladder, lung, liver, ovarian, and leukemia cells). Apoptosis is one of the most plausible mechanisms for this activity and has been reviewed (44R). The use of selenium in intensive care medi cine as adjuvant therapy has also received attention (45r).
Silver salts and derivatives (SED-15, 3140; SEDA-29, 231; SEDA-30, 269; SEDA-31, 393) Skin Another case of argyria has been reported (46A). • A 23-year-old man with recessive dystrophic epidermolysis bullosa developed diffuse silvery-grey pigmentation over several months. Since birth he had had silver sulfadiazine (Silvadene®) cream applied to denuded areas regularly to prevent infections and had consistently used it on affected areas two or three times a day. The diffuse slate-grey pigmentation was particularly prominent on the face. The serum silver concentration was 130 µg/l (reference range below 5 µg/l). He was not bothered by his argyria. Despite being advised to stop using the silver-containing cream, he chose to continue using it, because he believed that it helped his skin heal faster and prevented infections.
Although silver can be removed from the bloodstream, it is very difficult to remove it from the skin. Sunscreens can prevent further darkening. They also will prevent further reduction by sunlight of the colorless silver compounds in the dermis to elemental silver in a process similar to film developing.
Strontium salts The UK Medicines and Healthcare products Regulatory Agency (MHRA) has advised that there is a risk of severe allergic reac tions, including drug rashes and eosinophilia
Gijsbert B. van der Voet
with systemic symptoms (DRESS), with strontium ranelate (47S). The liver, kidneys, and lungs can also be affected. The symp toms usually resolve when treatment is with drawn and with glucocorticoid therapy, but recovery is often slow and there is a risk of recurrence during recovery. Patients who develop a rash should stop taking strontium and should consult their physician immedi ately. Health-care professionals are advised not to restart strontium once treatment has been stopped.
Titanium
(SED-15, 3434; SEDA-29, 231; SEDA-30, 270; SEDA-31, 394) Immunologic Allergic reactions to tita nium alloy in artificial joints can interfere with the implant/restoration process (48A).
• A 64-year-old man underwent a total hip arthroplasty for severe osteoarthritis of his left hip following avascular osteonecrosis. An SEM3 type (Science et Médecine, Montrouge, France) cementless forged Ti-6Al-4V alloy, with femoral stem size 12, coated with hydroxyapatite on the proximal third, with a metallic head of a diameter 28 mm and an ultra-high-molecular-weight polyethylene (UHMWPE) insert (liner) with a metal acetabular cup (50 mm) was inserted. Four years after the operation, he developed severe pain in the left hip while walking, which showed an inability to bear weight. An X-ray showed a fracture of the femoral neck without bone loss in the proximal femur and he underwent a revision of the total hip arthroplasty. There was an extensive amount of bone adherent to the device, and the fractured implant was well fixed.
Zinc
(SED-15, 3717; SEDA-29, 232; SEDA-30, 270; SEDA-31, 394)
Respiratory Pulmonary embolism has been reported after the intravenous admin istration of talc and zinc oxide (49A). • A 74-year-old woman recovering from colonic surgery died immediately after receiving an intravenous infusion of about 1.5 ml of a
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white emulsion that was believed to contain 1% propofol. However, it was suspected that a zinc oxide shake lotion (containing 20% zinc oxide, 20% talc, 25% glycerol, and 35% water), intended for external treatment, had been mistaken for propofol. At autopsy, an anatomical cause of death could not be found. Propofol and other drugs that she had received were found in therapeutic or sub-therapeutic concentrations. However, the concentration of zinc in the lungs was about 200 times higher than that found in a control case, 10 times higher in cardiac blood and 3–4 times higher in kidney and liver tissues. There was no increase in venous blood. Histology showed a large pulmonary embolism containing birefingent sharp-edged crystals, which were identified as talc, and an amorphous component (zinc oxide). There were similar smaller emboli in the brain, heart, liver, pancreas, and kidneys.
chronically. The zinc concentration in the denture creams was investigated as a possible source of excess zinc ingestion; Fixodent and Poli-Grip denture creams contained zinc in concentrations ranging from about 17 000 to 34 000 µg/g. The patients were given copper supplements. Copper and zinc concentra tions were obtained after treatment at vary ing intervals. Serum zinc concentrations improved in three patients after they stopped using the denture cream and copper supple mentation resulted in mild neurological improvement in two. No alternative source of excess zinc ingestion or explanation for the hypocupremia was identified. Exacerbation of epileptic seizures has been attributed to oral zinc supplementation (51R).
Nervous system Denture adhesives are a source of zinc and can cause hyperzincemia and hypocupremia. In four patients with various neurological abnormalities, hypo cupremia and hyperzincemia were identified (50A). Each wore dentures and had used very large amounts of denture cream
• A 28-year-old man with seizures about twice a year, for which he took phenytoin 300 mg/day, took oral zinc gluconate 240 mg/day (elemental zinc 64 mg/day) and within 2 days had three complex partial seizures. After withdrawal of the zinc he had no further seizures. One month later he started taking zinc again in the same dosage and had another seven seizures over 3 days. Electroencephalography showed an epileptiform focus.
References 1. Krewski D, Yokel RA, Nieboer E, Borchelt D, Cohen J, Harry J, Kacew S, Lindsay J, Mah fouz AM, Rondeau V. Human health risk assessment for aluminium, aluminium oxide, and aluminium hydroxide. J Toxicol Environ Health B Crit Rev 2007;10(Suppl 1):1–269. 2. Molloy DW, Standish TI, Nieboer E, Turnbull JD, Smith SD, Dubois S. Effects of acute exposure to aluminum on cognition in humans. J Toxicol Environ Health A 2007;70(23):2011–9. 3. Chu P-L, Wu C-C, Hsu C-J, Wang Y-T, Wu K-D. Potential ototoxicity of aluminum in hemodialysis patients. Laryngoscope 2007;117(1):137–41. 4. Allard M, Légaré N, Millaud F. A possible case of clozapine interaction with aluminium hydroxide. Scizophren Res 2008;101(1–3):346.
5. Mishra J, Saxena A, Singh S. Chemotherapy of leishmaniasis: past, present and future. Curr Med Chem 2007;14(10):1153–69. 6. Sharma P, Perez D, Cabrera A, Rosas N, Arias JL. Perspectives of antimony com pounds in oncology. Acta Pharmacol Sin 2008;29(8):881–90. 7. Ashutos SS, Goyal N. Molecular mechan isms of antimony resistance in Leishmania. J Med Microbiol 2007;56(Pt 2):143–53. 8. Dilda PJ, Hogg PJ. Arsenical-based can cer drugs. Cancer Treat Rev 2007;33(6):542–64. 9. Au WY, Kwong YL. Arsenic trioxide: safety issues and their management. Acta Pharma col Sin 2008;29(3):296–304. 10. Spohr K, Guavara D, Glick BP, Kerdel FA. Arsenic keratosis. J Am Osteol Coll Derma tol 2007;8(2):6–8.
422 11. Wang SX, Wang ZH, Chen XT, Li J, Sang ZP, Zhang XD, Han LL, Qiao XY, Wu ZM, Wang ZH. Arsenic and fluoride expose in drinking water: children’s IQ and growth in Shanyin Country, Shanxi Province, China. Envirom Health Perspect 2007;115(4):643–7. 12. Ford AC, Malfertheiner P, Giguère M, Santana J, Khan M, Moayyedi P. Adverse events with bismuth salts for Helicobacter pylori eradication: systematic review and meta-analysis. World J Gastroenterol 2008;14 (28):7361–70. 13. Keegan GM, Learmonth ID, Case CP. A systematic comparison of the actual, potential, and theoretical health effects of cobalt and chromium exposures from indus try and surgical implants. Crit Rev Toxicol 2008;38(8):645–74. 14. Vendittoli PA, Mottard S, Roy AG, Dupont C, Lavigne M. Chromium and cobalt ion release following the Durom high carbon content, forged metal-on-metal surface replacement of the hip. J Bone Joint Surg Br 2007;89–B(4): 441–8. 15. Eastmond DA, Macgregor JT, Slesinski RS. Trivalent chromium: assessing the genotoxic risk of an essential trace element and widely used human and animal nutritional supple ment. Crit Rev Toxicol 2008;38(3):173–90. 16. Levina A, Lay PA. Chemical properties and toxicity of chromium(III) nutritional supplements. Chem Res Toxicol 2008;21 (3):563–71. 17. Medici V, Rossaro L, Stumiolo GC. Wilson disease – a practical approach to diagnosis, treatment and follow up. Dig Liver Dis 2007;39(7):601–09. 18. Pfeiffer RF. Wilson’s disease. Semin Neurol 2007;27(2):123–32. 19. Bertini I, Rosato A. Menkes disease. Cell Mol Life Sci 2008;65(1):89–91. 20. Kulier R, O’Brien PA, Helmerhorst FM, Usher-Patel M, D’Arcangues C. Copper containing, framed intra-uterine devices for contraception. Cochrane Database Syst Rev 2007;(4):CD005347. 21. Heffeter P, Jungwirth U, Jakupec M, Hartinger C, Galanski M, Elbling L, Micksche M, Keppler B, Berger W. Resistance against novel anticancer metal compounds: differences and similarities. Drug Resist Updat 2008;11(1–2):1–16.
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22. Chitambar CR, Purpi DP, Woodliff J, Yang M, Wereley JP. Development of gallium com pounds for treatment of lymphoma: gallium maltolate, a novel hydroxypyrone gallium compound, induces apoptosis and circum vents lymphoma cell resistance to gallium nitrate. J Pharmacol Exp Ther 2007;322 (3):1228–36. 23. Kean WF, Kean IR. Clinical pharmacology of gold. Inflammopharmacology 2008;16 (3):112–25. 24. Sannella AR, Casini A, Gabbiani C, Messori L, Bilia AR, Vincieri FF, Majori G, Severini C. New uses of old drugs. Auranofin, a clinically established antiarthritic metallodrug, exhi bits potent antimalarial effects in vitro: mechanistic and pharmacological implica tions. FEBS Lett 2008;582(6):844–7. 25. Tiekink ER. Anti-cancer potential of gold complexes. Inflammopharmacology 2008;16 (3):138–42. 26. Lo Schiavo A, Sangiuliano S, Puca RV, Brunetti G, Rocco E, Cozzi R. Pemphigus and chrysotherapy: all that glitters is not gold! Int J Dermatol 2008;47(6):645–7. 27. Sav T, Tokgoz B, Sipahioglu MH. Is there a difference between the allergic potencies of the iron sucrose and low molecular weight iron dextran? Renal Fail 2007;29(4):423–6. 28. Auerbach M, Al Talib K. Low-molecular weight iron dextran and iron sucrose have similar comparative safety profiles in chronic kidney disease. Kidney Int 2008;73(5):528–30. 29. Maher R, Blake W, Brown T. Differential diagnosis of a soft tissue mass following long term parenteral iron injection. J Plast Reconstr Aesthet Surg 2008;61(5):582. 30. Dr€ ueke TB. Lanthanum carbonate as firstline phosphate binder: the ‘cons’. Semin Dial 2007;20(4):329–32. 31. How PP, Fischer JH, Arruda JA, Lau AH. Effects of lanthanum carbonate on the absorp tion and oral bioavailability of ciprofloxacin. Clin J Am Soc Nephrol 2007;2(6):1235–40. 32. Ho KM, Sheridan DJ, Paterson T. Use of intravenous magnesium to treat acute onset atrial fibrillation: a meta-analysis. Heart 2007;93(11):1433–40. 33. Jung GJ, Gil HW, Yang JO, Lee EY, Hong SY. Severe hypermagnesemia causing quad riparesis in a CAPD patient. Perit Dial Int 2008;28(2):206.
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34. Sivas F, G€ unesen O, Ozoran K, Alemdaroglu E. Osteomalacia from Mg-containing antacid: a case report of bilateral hip fracture. Rheumatol Int 2007;27(7):679–81. 35. Uchino A, Noguchi T, Nomiyama K, Takase Y, Nakazono T, Nojiri J, Kudo S. Manganese accumulation in the brain: MR imaging. Neuroradiology 2007;49(9):715–20. 36. Hsieh C-T, Liang J-S, Peng SS-F, Lee W-T. Seizure associated with total parenteral nutrition-related hypermanganesemia. Pediatr Neurol 2007;36(3):181–3. 37. Dickerson RN. Manganese intoxication and parenteral nutrition. Nutrition 2001;17(7–8):689–93. 38. Committee on Nutrition, American Acad emy of Pediatrics. Pediatrics Nutrition Hand book. 4th ed. Elk Grove Village, IL: American Academy of Pediatrics, 1998. 39. Global Advisory Committee on Vaccine Safety. Thiomersal. Meeting of Global Advisory Committee on Vaccine Safety, 18–19 June 2008. Wkly Epidemiol Rec 2008;83(32):287–92. 40. Anonymous. Silencing debate over autism. Nat Neurosci 2007;10(5):531. 41. Geier DA, Sykes LK, Geier MR. A review of thimerosal (merthiolate) and its ethylmer cury breakdown product: specific historical considerations regarding safety and effec tiveness. J Toxicol Environ Health B Crit Rev 2007;10(8):575–96. 42. Nguyen DQ, Srinivasan S, Hiscott P, Kaye SB. Thiomersal-induced limbal cell failure: report of a case and review of the literature. Eye Contact Lens 2007;33(4):196–8. 43. Thomas P, Schuh A, Ring J, Thomsen M. Orthopedic surgical implants and allergies. Joint statement by the Implant Allergy Working Group (AK 20) of the DGOOC (German Asssociation of Orthopedics and
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Orthopedic Surgery), DKG (German Con tact Dermatitis Research Group) and DGAKI (German Society for Allergology and Clinical Immunology). Haurartzt 2008;59(3):220–9. Sanmartín C, Plano D, Palop JA. Selenium compounds and apoptotic modulation: a new perspective in cancer therapy. Mini Rev Med Chem 2008;8(10):1020–31. Berger MM, Shenkin A. Selenium in inten sive care: probably not a magic bullet but an important adjuvant therapy. Crit Care Med 2007;35(1):306–7. Browning JC, Levy ML. Argyria attributed to silvadene application in a patient with dystrophic epidermolysis bullosa. Dermatol Online J 2008;14(4):9. Anonymous. Strontium ranelate. Risk of severe allergic reactions. WHO Pharmaceu ticals Newsletter 2008;1:9–10. Grivas TB, Savvidou OD, Psarakis SA, Bernard PF, Triantafyllopoulos G, Kovanis I, Alexandropoulos P. Neck fracture of a cementless forged titanium alloy femoral stem following total hip arthroplasty: a case report and review of the literature. J Med Case Rep 2007;1:174. Pragst F, Correns A, Priem F, Herre S, Martin H. A sudden death with lung embolism after inadvertent infusion of zinc oxide shave lotion. Forensic Sci Int 2007;170(2):207–12. Nations SP, Boyer PJ, Love LA, Burritt MF, Butz JA, Wolfe GI, Hynan LS, Reisch J, Trivedi JR. Denture cream: an unusual source of excess zinc, leading to hypocupre mia and neurologic disease. Neurology 2008;71(9):639–43. Green AL, Weaver DF. Potential proconvul sant effects of oral zinc supplementation: a case report. Neurotoxicology 2008;29 (3):476–7.
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23
Metal antagonists
IRON CHELATORS At the 16th International Conference on Chelation in 2006, it was emphasized that around the world the current regulations and practices for the development, approval, post-introduction safety evalua tion and pricing of new medicines are inap propriate and may disadvantage patients (1R). Drastic reforms are deemed neces sary, in particular with regard to diseases that are common in less affluent countries, such as thalassemia major. In the past few decades, thanks to the introduction of effective, tolerable, and last ing iron chelation regimens, the life expec tancy, in both duration and quality, of patients with thalassemia major has improved tremendously. In a medical records study in the Mazandaran Province of Iran, where thalassemia major is the most common genetic disease, morbidity and mortality among 1010 patients with tha lassemia have been reviewed (2CR). The complexity and seriousness of the secondary pathology in these patients demonstrates the devastating nature of the disease, in particu lar when supplies of iron chelators are lim ited and non-adherence is common. In other countries, myelodysplastic syndromes, aplastic anemia, Diamond– Blackfan anemia and other transfusiondependent anemia are more frequent indications for transfusion and can cause iron overload. Novel tests for measuring iron accumulation in the heart and liver, Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32023-X 2010 Elsevier B.V. All rights reserved.
such as superconducting quantum inference devices (SQUIDs) and magnetic resonance imaging (MRI), and new oral chelators enable even more sophisticated, effective, and tolerable treatment of thalassemia. In order to ensure that these new technologies are used to their best advantage, the Italian Society of Hematology has developed struc tured consensus clinical treatment guide lines, covering critical matters such as the level of iron storage requiring chelation therapy, when to start chelation, how to monitor chelation and switching to an alter native treatment (3R). There have been reviews of current knowledge about iron overload in myelo dysplastic syndromes, describing the com plexity of intra- and extracellular iron homeostasis and metabolism and the impor tance of the peptide hormone hepcidine produced by the liver and emphasizing the crucial role of non-transferrin-bound iron in damaging organs and the rationale of chela tion treatment (4R–6R). Until recently the use of deferoxamine for transfusional iron overload in myelodysplastic syndromes has been sparse, but the literature on the use of iron chelators in these patients is expanding (7R, 8R). A retrospective study in Japan has also confirmed that in these patients iron storage is a major cause of morbidity and mortality, in particular cardiac and hepatic dysfunction, underlining the fact that iron chelators should be started in time in these patients when the iron burden increases (e.g. when the serum ferritin concentration exceeds 1000 µg/l) (9CR). While awaiting further trials, it seems appropriate to offer, of the five general subtypes of myelodys plastic syndromes, iron chelation to at least patients with refractory anemia and refrac tory anemia with ringed sideroblasts.
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In the treatment of iron storage disease, the use of chelators aims at detoxifying and excreting surplus iron. Reactive oxygen spe cies should be scavenged as far as possible. Chelators containing ‘hard’ oxygen donor atoms stabilize the ferric state, resulting in redox-inactive complexes, and are suitable for the treatment of iron storage disease. The careful choice of ‘soft’ donor atoms, such as nitrogen or sulfur, on the other hand, results in redox-active iron complexes with high redox affinity and may be effective in oncolytic chemotherapy. Several series of such compounds are in development (10R): 2-pyridylcarboxaldehyde isonicotinoyl hydra zone series di-2-pyridylketone isonicotinoyl hydrazone series di-2-pyridylketone thiosemicarbazone series 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
Their toxicological properties differ consider ably from the classical iron chelators and they should receive more attention in future. Combination studies Deferoxamine + deferiprone The advantage of combining deferoxamine with deferiprone is that deferoxamine can be given less often and for a shorter duration, which may improve adherence. In a randomized, double-blind, controlled comparison of clinically equivalent doses of deferoxamine with deferiprone (n = 32) and deferoxamine with placebo (n = 33) in adults with thalassemia major, combination treat ment was superior in reducing myocardial iron and improving ventricular and endothelial functions (11cr). Mild gastrointestinal symp toms (nausea, vomiting, or abdominal pain) were the most common adverse events, in 38% of patients who received the combination and in 24% of those who received deferoxa mine monotherapy. Such events were more often recurrent in the combination group (19% versus only 3%). Pain and/or swelling of joints occurred in 9% of patients taking the combination and were more frequent in patients who only received deferoxamine, which is unexpected, since arthropathy typi cally occurs in connection with deferiprone.
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Because it is common in clinical practice to alternate treatment with deferiprone and deferoxamine, in a comparative study in Egypt alternating use of these drugs (n = 30) was compared with simultaneous use in combination (n = 30) (12cr). Alternat ing administration of deferiprone 75 mg/kg/ day orally for 4 days and deferoxamine 40 mg/kg/day by subcutaneous infusion for the next 2 days was safe and effective in patients with thalassemia major. Taste dis turbances (a metallic taste and inability to distinguish between bitter and sweet) occurred in two patients after the first month. Taste returned to normal sponta neously while treatment was continued. Oral deferiprone alone 75 mg/day (n = 12) has been compared with deferiprone þ defer oxamine 40–50 mg/kg twice weekly (n = 12) and with deferoxamine alone 40–50 mg/kg on 5 days/week (n = 12) (13cr). There was neutropenia in two patients taking deferi prone (one with deferiprone alone, one with the combination). In one patient two episodes of neutropenia (in weeks 4 and 10) were fol lowed by full-blown agranulocytosis (in week 11), which was treated with granulocyte sti mulating factor and recovered within 11 days. In no case was there progressive hepatic fibrosis, and only in the patients taking com bination therapy did the histology activity index and liver iron scores fall substantially. There was grade 2 arthralgia in one patient taking combination therapy. Aseptic meningi tis occurred in week 45 in one patient taking deferiprone alone, and in another taking deferiprone alone an acute and transient cer ebellar syndrome was observed, which was thought not to be drug-induced but to have followed an infection. A quality-of-life assess ment questionnaire showed improvement in 64% of those who took deferiprone and only in 20% of those who took deferoxamine.
Deferasirox (SEDA-29, 236; SEDA-30, 273; SEDA-31, 401) There is increasing knowledge of the pharma cology of deferasirox and interest in its ther apeutic use, in particular in non-hemolytic
Metal antagonists
Chapter 23
transfusion-dependent anemias (8CR, R R 14 –20 ). At the same time, post-marketing reports have raised concerns about the possi ble occurrence of serious adverse reactions, such as anaphylaxis, gastrointestinal ulceration and hemorrhage, neurosensory hearing loss, lenticular opacities, acute renal insufficiency, liver damage, agranulocytosis, and thrombo cytopenia (8R, 16r, 17r, 21R, 22S). However, detailed information is sparse, and there is an urgent need for clarification of the current uncertainty. It is possible that deferasirox can damage various organs, especially the kidneys, by increasing iron absorption and de-compartmentalizing chelated iron in these tissues (1R). Drug–drug interactions A large but incomplete list of drugs that are assumed to interact with deferasirox is available on the Internet (23S). Aluminium salts Deferasirox has affinity for aluminium and forms lipophilic complexes with it. It should not be combined with aluminium-containing antacids (22S). Theoretically, long-term use of deferasirox might increase the gastrointestinal absorption of aluminium and lead to accumulation in the brain and perhaps to dementia (1R). Cytochrome P450 (CYP) isoenzymes Deferasirox is involved in both enzyme inhi bition and enzyme induction and affects CYP3A4, CYP2C8, CYP1A2, CYP2A6, CYP2D6, and CYP2C19. In particular, its effects on CYP3A4 and CYP2C8 may be clinically important. Potentiation of ciclos porin, hormonal contraceptives, midazolam, paclitaxel, repaglinide, and simvastatin has been documented or is expected, and it may be necessary to adjust the dose of these drugs (22S). Midazolam In healthy volunteers co-administration of deferasirox with midazolam, a CYP3A4 substrate, resulted in a 23% reduction in the Cmax of midazolam and a 17% reduction in AUC (22S). This was presumably due to induction of CYP3A4 by deferasirox.
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Repaglinide In healthy volunteers con comitant administration of deferasirox 30 mg/kg/day for 4 days with the CYP2C8 probe substrate repaglinide in a single dose of 0.5 mg increased the AUC of repaglinide 2.3 times and the Cmax by 62% (22S). The manufacturers recommended reducing the dose of repaglinide and monitoring blood glucose concentrations if this combination is used. UDP glucuronyltransferase inducers Deferasirox is metabolized by uridine 50 diphospho- (UDP) glucuronyltransferase (UGT), and concomitant use of inducers of UGT, such as rifampicin, phenytoin, or phenobarbital, can therefore lead to lower concentrations of deferasirox; monitoring of serum ferritin is indicated.
Drug–food interactions The effect of a high-fat or standard breakfast on the phar macokinetics of deferasirox has been investigated in healthy volunteers and patients with transfusional hemosiderosis (24c). The type of food, its caloric content and the fat content of the meal affected the systemic availability of deferasirox, but not when it was taken at least 30 minutes before a meal, which is the preferred timing.
Deferiprone (SED-15, 1054; SEDA-29, 237; SEDA-30, 273; SEDA-31, 402) Observational studies In an open trial in 13 patients with Friedreich’s ataxia aged 14–23 years, deferiprone 20–30 mg/kg/day for 6 months removed accumulated iron from a specific brain area (detected using MRI scanning) and produced significant neurological improvement compared with age-matched controls (25cr). Four patients withdrew because of adverse events, two because of musculoskeletal pain, one because of Guillain–Barré syndrome, and one because of reversible agranulocytosis.
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Guillain–Barré syndrome is not an estab lished adverse effect of deferiprone. During the study there was a clear reduction in body iron, as shown by reductions in serum iron, ferritin, and hemoglobin con centrations. It is not clear for how long deferiprone can be continued safely in Friedreich’s ataxia and whether iron supple ments are beneficial. Hematologic An underlying susceptibility may have played a part in a case of fatal agranulocytosis that was probably caused by deferiprone (26AR). • A 10-year-old girl was given deferiprone 45 mg/kg/day for excess iron storage following erythrocyte transfusions for congenital Diamond–Blackfan anemia. A fall in white cell count during week 8 rapidly progressed to agranulocytosis in week 9 followed by Staphylococcus aureus sepsis and pneumonia. She was given antibiotics and filgrastim, followed by glucocorticoids and ciclosporin, because of persistent agranulocytosis. However, the neutrophil count remained low and she died.
While in Diamond–Blackfan anemia only red cell production is affected, bone marrow examination in this patient on day 23 showed variable cellularity, with lympho cytic infiltration and fibrosis. In areas of low cellularity, mainly macrophages and megakaryocytes were found. Granulopoi esis and erythropoiesis were scarce. The lymphoid infiltrates consisted mainly of a mixture of CD4þ and CD8þ9 cells (CD, cluster of differentiation). CD117 staining showed a diffuse increase in mast cells. Bone-marrow flow cytometry showed that 72% of the cells were in the lymphocyte region, of which 86% were T cells with signs of activation. This report also illus trates that, despite regular monitoring, agranulocytosis can occur unexpectedly and can progress rapidly. There is one more case on record of agranulocytosis (together with reversible thrombocytope nia) in a patient with Diamond–Blackfan anemia who received deferiprone (27A) and another of neutropenia that slowly
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progressed to aplastic anemia (28A). Patients with Diamond–Blackfan may be more susceptible to agranulocytosis from deferiprone than those with thalassemia. In vitro progenitor cell cultures, using venous blood samples from 16 patients with major thalassemia and normal blood counts, yielded unexpected findings (29CR). Nine patients (three with splenect omy) received subcutaneous deferoxamine 45 mg/kg/day on 5 days/week, 7 patients (four with splenectomy) took deferiprone 75 mg/kg/day and there were 10 healthy controls. Granulocyte–erythrocyte–monocyte– megakaryocyte colony-forming units were more common in those who received defer oxamine or deferiprone than in the controls. Granulocyte–macrophage colony-forming units were more common and macrophage colony-forming units less common with deferiprone than in the controls. Granulo cyte colony-forming units were more com mon with deferoxamine than in the controls. Addition of serum from patients taking deferiprone to cultures of cells from the controls resulted in maturation arrest of the granulocytic lineage. These findings sug gest that deferiprone can cause maturation arrest of granulocyte–macrophage colonyforming units, an effect that may play a role in the pathogenesis of deferiprone induced agranulocytosis. Immunologic Rare serious adverse drug reactions probably result often from a com bination of different susceptibility factors, both known and unknown. Henoch–Schönlein purpura, with renal and pulmonary involve ment and intestinal invagination, has been reported in temporal association with expo sure to deferiprone (30AR). • A 7-year-old splenectomized boy with b-thalassemia, who had been receiving erythrocyte transfusions and deferoxamine for most of his life for a Coombs-positive hemolytic anemia, was given low-dose prednisolone and cyclophosphamide. Because of non-adherence and a serum ferritin concentration of 11489 ng/ml, the deferoxamine was replaced by deferiprone 60 mg/kg/day. After 5 months he developed arthritis of the ankles and palpable purpuric
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lesions on the legs. There was no history of infection, and virus serology and bacterial cultures were negative. A renal biopsy showed diffuse Henoch–Scho¨ nlein nephritis with crescent formation and immunoglobulin A (IgA) deposition in the mesangium and glomerular basement membrane. Deferiprone was withdrawn. At follow-up 2 years later renal function was normal and there was no proteinuria. DNA analysis because of recurrent attacks of abdominal pain showed familial Mediterranean fever and a homozygous M694V mutation.
therapeutic index of less than 0.025 she remained asymptomatic, but whereas initi ally her fundi had been normal, she slowly developed a pigmentary retinopathy. At 33 years the dose of deferoxamine was increased to 49 mg/kg/day and the deficits in dark-adapted visual sensitivity and postreceptor retinal sensitivity relapsed. When the dose of deferoxamine was again reduced, the dark-adapted visual sensitivity recovered. Mild deficits in post-receptor sensitivity persisted, as did deficits in photo receptor sensitivity.
In this patient Henoch–Scho¨ nlein purpura was thought to have developed because of the co-occurrence of M694V homozyg osity (an established susceptibility factor), profound cellular and humoral immunolo gical disturbances secondary to thalasse mia, and perhaps treatment with deferiprone.
The recovery of post-receptor sensitivity suggests that ‘remodelling’ of the retina and its functional processes is the basis for recovery of visual sensitivity despite irreversible compromise of photoreceptor function, leaving the retina particularly vulnerable to new exposure to deferox amine. The relation between retinal injury resulting from iron storage and that secondary to chelation treatment with deferoxamine has been reviewed (32AR).
Deferoxamine (SED-15, 1058; SEDA-29, 237; SEDA-30, 274; SEDA-31, 402)
Special senses Eyes A detailed case study of a woman with major thalassemia, receiving long-term deferoxamine 50 mg/kg/ day, yielded valuable information on deferoxamine-related retinopathy (31AR). • A 28-year-old woman with previously nor mal visual and retinal responses found that her eyes did not adjust to the dark. Eight weeks before, heart failure and raised liver iron concentrations had prompted a dou bling of the dose of deferoxamine. Visual acuity was 20/200 in both eyes. There were dense central and paracentral scotomata, and dark-adapted visual sensitivity was 2 log units below normal. Scotopic electrore tinography showed deficits in rod photore ceptor and post-receptor sensitivity. Deferoxamine was withdrawn and her visual acuity and visual fields rapidly normalized, while her dark-adapted visual sensitivity gradually improved. Three weeks later deferoxamine was restarted in a dose of 12 mg/kg/day and gradually increased to 25 mg/kg/day. During follow-up dark-adapted visual sensitivity gradually became normal, as did post-receptor sensitivity, but deficits in rod photoreceptor sensitivity persisted (at less than half the baseline sensitivity). While receiving deferoxamine doses adjusted to a
Ears The physiological capacity for elimination of iron from intracranial spaces is limited. Chronic or recurrent subarachnoidal bleeding, a rare condition, can cause superficial hemosiderosis in the central nervous system (33CR). As the vestibulocochlear nerve runs through the pontine cistern and has a long glial segment, superficial hemosiderosis almost always has auditory effects and causes bilateral sensorineural hearing loss. MRI scanning is very sensitive to ironcontaining hemosiderin and typically shows a rim of hypointensity on T2-weighted images, predominantly affecting the surfaces of the brainstem and cerebellum, the cranial nerves and the spinal cord. Pure-tone audiometry is used in the early detection of deferoxamine ototoxi city but may be insufficiently sensitive. In 60 patients with thalassemia receiving sub cutaneous deferoxamine 40 mg/kg/day on 5 days/week, distortion-product otoacous tic emission was compared with pure-tone audiometry (34C). The former was more sensitive than the latter and as a screening
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tool has the advantage of being non invasive, objective, rapid, and easy to use. Urinary tract Deferoxamine is contraindi cated in patients with severe kidney disease, and in overdose acute renal failure can occur (SEDA-28, 256). However, deferoxamine is commonly used off-label to remove alumi nium and to prevent or treat aluminiumrelated bone disease in patients with chronic kidney disease stage 4 (GFR 15–30 ml/min ute). The clinical and pathological findings in deferoxamine-induced acute renal failure in a patient with a renal transplant have been described (35AR). • A 58-year-old man with a cadaveric kidney transplant for Goodpasture’s syndrome who was taking long-term oral ciclosporin (trough concentration 90 µg/l), prednisolone, candesar tan, carvedilol, furosemide, verapamil, panto prazole, benzbromarone, pravastatin, ezetimibe, and warfarin was given subcutaneous deferox amine 2 g/day for 3 weeks, and 1 day after the last infusion was found to have renal impair ment. The serum creatinine concentration had increased to 250 µmol/l, there was proteinuria 1.1 g/day and the creatinine clearance was 31 ml/minute. To exclude graft rejection, a renal biopsy was performed. There were no signs of acute humoural or cellular rejection. There was no isometric vacuolization or microcalcification, as signs of calcineurin inhibitor toxicity, although the arterioles had marked cuff-like hyalinosis, indicating chronic vascular ciclosporin toxicity. There was about 15% cor tical tubular atrophy, interstitial fibrosis in a non-striped pattern and a partially flattened epithelium with attenuated brush borders, indicating acute tubular damage in the remain ing cortical tubules. The acutely damaged cor tical tubular epithelial cells had degenerated mitochondria, with myelin-like figures and loss of cristae, but there was no swelling of mitochondria or endoplasmic reticulum.
The authors suggested that the underlying mechanism of renal tubular toxicity in this patient was removal of iron from the mito chondria and subsequent depletion of mito chondrial ATP. The mitochondrial changes in this patient were different from the pat tern commonly seen in acute tubular injury, and may be diagnostic of deferoxamine toxicity. It is advisable to monitor renal function in patients with renal disease who receive deferoxamine.
R.H.B. Meyboom
Infection risk Deferoxamine and changes in iron metabolism may increase the infec tivity of a variety of fungi and bacteria (SED-15, 1064; SEDA-29, 237). In a case of endocarditis due to Salmonella enterica subsp. arizonae, chelation therapy with deferoxamine was thought to have been a possible susceptibility factor (36Ar).
PENICILLAMINE AND RELATED DRUGS (SED-15, 2729; SEDA-29, 238; SEDA-30, 274; SEDA 31, 403)
Penicillamine Uses In children, penicillamine-stimulated urinary copper excretion is a reliable non invasive test for Wilson’s disease. In a liver biopsy-controlled study in 43 patients it was also reliable and safe in adults; patients with penicillamine-stimulated urinary copper excretion below 1057 µg/day are unlikely to have Wilson’s disease and are unlikely to benefit from liver biopsy (37cr). In patients with an acute Wilsonian crisis, prompt copper chelation plus plasmapher esis can be life-saving. In an 18-year-old girl with Wilson’s disease, acute hemolysis and impending liver failure, chelation with peni cillamine (dose unspecified) and plasma pheresis led to recovery (38A). Observational studies In a trial in 15 preterm neonates, daily enteral penicillamine (in a locally produced formulation, dose not specified) for 2 weeks after birth elimi nated stage I and II retinopathy of prema turity but not of laser surgery (39cr). There were no adverse effects in these babies. The finding that penicillamine in high doses, as used in Wilson’s disease, reduces total skin collagen has prompted a trial in diffuse cutaneous systemic sclerosis. In a retrospec tive analysis of 84 patients with recent onset progressive disease, penicillamine, median dose 750 mg/day for at least 3 months, caused
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significant reduction in skin disease and improvement of renal, cardiac and pulmon ary involvement (40cr). At the last followup, 20% of the patients were still taking penicillamine, 30% had stopped because of disease improvement and 21% had stopped because of adverse effects, showing the familiar pattern of proteinuria (n = 7), rash (n = 4), neutropenia (n = 3), and pemphigus (n = 2). In addition, 23% had died, mainly from complications of the disease. Four patients were lost to follow-up. Systematic reviews Penicillamine 600– 1200 mg/day has been compared with pla cebo or no intervention in primary biliary cirrhosis, another disorder in which peni cillamine has been tried because of its effects on collagen, in a meta-analysis of seven randomized trials in 706 patients (41M). Although the treatment group had significantly reduced serum AlT activity, there were differences neither in other liver tests nor in pruritus, fatigue, liver complications, progression of liver histolo gical stage, liver transplantation, or mortality. Skin An eruption resembling elastoma perforans serpiginosa, with the typical lumpy-bumpy histological appearance and pruritic lesions of 5–7 cm, is a late complica tion of the use of high doses of penicilla mine, and was originally described by Gephart and Bardach (42AR).
OTHER CHELATORS Edetic acid (ethylenediaminetetraacetic acid, EDTA) (SED-15, 1300; SEDA-30, 276; SEDA-31 405)
Uses A newly identified inherited disorder in a 12-year-old girl, characterized by
431
manganese storage, dystonia, polycythemia, and liver injury, was successfully treated with monthly infusions of calcium disodium eden tate 40 mg/kg/day for 5 consecutive days (43A). Penicillamine had previously been ineffective. Urinary tract Lead compounds are nephrotoxic. In a placebo-controlled trial, the protective effect of lead chelation was studied in a follow-up study of 4 years duration in 58 Chinese patients with a high normal lead burden and non-diabetic chronic kidney disease (serum creatinine concentrations 133–345 µmol/l) (44cr). Compared with placebo there was a sub stantial reduction in the progression of renal insufficiency. Interference with diagnostic tests The use of EDTA as an anticoagulant in blood samples can cause pseudothrombo cytopenia in automated cell counts (SED 15, 1202), usually because of clumping of neutrophil leukocytes and only rarely lym phocytes. In vitro EDTA caused artifactual agglutination of lymphocytes in a patient with a large B-cell non-Hodgkin’s lym phoma (45A).
Trientine
(SED-15, 3508; SEDA-29, 239)
Comparative studies In patients with Wilson’s disease initial worsening of neu rological symptoms is a notorious compli cation of chelation therapy. In an 8-week double-blind trial, initial treatment with trientine 1 g/day and zinc 100 mg/day (salt not specified) was compared with tetrathiomolybdate 60 mg/day and zinc 100 mg/day, with special reference to the worsening of neuropsychiatric symptoms (46A). The adverse events are shown in Table 1. Of the 23 patients who received trien tine, 6 fulfilled the criteria for neurological deterioration, while of the 25 patients
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Table 1. Adverse events in a comparison of trientine and tetrathiomolybdate Adverse event
Trientine (n = 23)
Tetrathiomolybdate (n = 25)
Rise in aminotransferases Anemia and/or leukopenia Neurological deterioration Death
0 1 6 4
4 3 1 2
who received tetrathiomolybdate, dete rioration occurred in only 1, suggesting that tetrathiomolybdate is superior to tri entine in the initial treatment of neurolo gical Wilson’s disease. Four patients in the trientine arm died and two in the tetra thiomolybdate arm. With one exception of a case of fatal leukemia, all the patients who died had severe neurological impair ment. As four of the seven patients with neurological deterioration died, this event may forecast poor survival. Drug dosage regimens Trientine and zinc have become major tools in the manage ment of Wilson’s disease. Zinc (usually zinc acetate dehydrate 75–150 mg/day in three divided doses) inhibits the enteric absorption of copper by stimulating intest inal and hepatic metallothioneins. As a cop per chelator, trientine when taken with meals also reduces enteric copper absorp tion and promotes urinary copper excretion; the usual daily dose is 500–1500 mg/day, in two to four divided doses. However, non-adherence is a common problem. In a retrospective review of the clinical records of 22 children with Wilson’s disease, new increases in serum aminotransferase activities during long-term treatment (mostly with trientine and/or zinc) were commonly found to be secondary to non adherence (47CR). In a retrospective study in five patients, trientine 500–1000 mg/day as a single dose was effective in controlling Wilson’s dis ease (48c). Larger prospective trials are needed to confirm the efficacy of oncedaily trientine and to determine the required dose.
POLYSTYRENE SULFONATES (SED-15, 2894; SEDA-29, 239; SEDA-30, 275)
Treatments for non-oliguric hyperkalemia in preterm neonates, including ion exchange resins, have been reviewed (49M). Comparative studies In a comparison of rectal sodium polystyrene sulfonate 1 g/kg every 4 hours (n = 15) and salbutamol infu sion 4 micrograms/kg every 4 hours (n = 30) for non-oliguric hyperkalemia in preterm infants, there were no important adverse events in those who received salbutamol, but two cases of severe ventricular tachycar dia and one of intestinal obstruction in those who received the polystyrene sulfonate (50c). Gastrointestinal Perforated necrotizing enterocolitis requiring resection has been reported in a 27-week, 850 g infant after rectal administration of sorbitol-free sodium polystyrene sulfonate for life-threatening hyperkalemia due to progressive anuria (51A). Although sorbitol has previously been blamed for gastrointestinal damage after the administration of Kayexalate (SED-15, 2896), this case suggests that sodium polystyrene sulfonate can also cause such damage. Rectal stenosis due to sodium polystyrene sulfonate crystals, requiring colonic resec tion, has been reported in a 46-year-old man who was given sorbitol-free Kayexa late by a nasogastric tube (52A). Histology showed fibrosis of the submucosa with numerous basophilic polygonal crystals sur rounded by macrophages.
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Pam Magee
24
ALDEHYDES
Antiseptic drugs
and disinfectants
(SED-15, 1439, 1513;
SEDA-31, 409)
Formaldehyde Many countries have revised their regula tions and lowered their occupational expo sure limits (OELs) for formaldehyde. After a request from the Canadian Commission for Occupational Health and Safety, the impact on irritating effects (irritation of the eyes, nose and throat) of lowering the OELs for formaldehyde from 2 to 1, 0.75 or 0.3 ppm has been studied (1c). A concen tration of 0.75 ppm was considered to be safe, and the additional health gain was estimated to be negligible below this. Respiratory At low concentrations for maldehyde irritates the respiratory tract by a chemosensory effect, i.e. an interaction with local nerve endings. High occupational concentrations of inhaled formaldehyde increase the risks of impaired lung function and asthma (SEDA-20, 225; SEDA-31, 409). However, whether non-occupational exposure to formaldehyde is related to asthma is still subject to discussion. The effect of formaldehyde on the asthmatic response to inhaled allergen challenge has been investigated in a double-blind, cross over study in 12 subjects with intermittent
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32024-1 � 2010 Elsevier B.V. All rights reserved.
asthma and allergy to pollen. After expo sure to formaldehyde 500 mircrograms/m3, the higher end of a realistic environmental indoor formaldehyde concentration, there was no significant adverse effect on airway allergen responsiveness (2c). Sensory systems At low concentrations formaldehyde irritates the eyes by a chemosensory effect, i.e. an interaction with local nerve endings. In an examination of the occurrence of sensory irritation and subjective symptoms in volunteers exposed to formaldehyde concentrations relevant to the workplace, eye irritation was the most sensi tive parameter. There was minimal objective eye irritation at a concentration of 0.5 ppm. Subjective complaints of ocular and nasal irritation at lower concentrations were strongly influenced by personality and smell (3c). Although breathing air containing low concentrations of formaldehyde causes sensory irritation, it is not known if the symptoms of burning of the nose and throat, coughing and difficulty in breathing that can occur at higher concentrations, are associated with formaldehyde-specific immunoglobulin E (IgE) production. During long-term exposure of mice to gaseous formaldehyde, the threshold limit of formaldehyde 0.08 ppm did not cause ovalbumin-specific IgE inflammatory immune responses (4E). However, higher than threshold concentrations resulted in both enhanced allergen-specific IgE responses and natural killer (NK) cell activity in peripheral blood cells. Formaldehyde may therefore be involved in promoting allergic inflammatory effects in subjects primed with specific
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allergens by NK cell activation. This suggests that even threshold concentrations of formaldehyde may play a regulatory role in systemic cell-mediated immune responses. Occupational asthma from formaldehyde exposure is well documented, although it occurs sporadically. There is a latent period, which extends from weeks to years before symptoms begin. Pneumonitis and asthma, different from the occupational exposure data, have been reported, suggesting direct and indirect effects of formaldehyde in healthy human airways (5A). • A 54-year-old man accidentally ingested 10% formaldehyde and inhaled while vomiting. He developed a cough, dyspnea and wheezing, and there were bilateral infiltrates on a chest X-ray. His pulmonary symptoms and forced expiratory volume in 1 second (FEV1) responded well to systemic glucocorticoids and nebulized salbutamol, and the infiltrates cleared. Two weeks later he had massive hemoptysis, fever, a leukocytosis, bronchospasm, auscultatory crackles, and new infiltrates on a chest X-ray. After antibiotics and glucocorticoid therapy, his symptoms and crackles resolved and the radiographic infiltrates regressed. Delayed hypersensitivity to a formaldehyde patch test concurred with his late-onset symptoms.
Gastrointestinal Formalin is a 40% solution of formaldehyde in water. It has been used for many years in concentrations of 2–4% to treat radiationinduced hemorrhagic proctitis. Only a few minor complications have been reported after treatment – acute proctitis, worsening of radiation-induced strictures, worsening of incontinence, and severe pain (6c, 7c). In a retrospective review of 49 patients who received formalin for hemorrhagic radiation-induced proctitis, two sub sequently developed anorectal cancer. As pelvic irradiation increases the risk of a sec ond malignancy, it is not known what role, if any, formalin played in the development of these new cancers. However, continued sur veillance of patients exposed to formalin should be recommended (8A). Tumorigenicity Since 2004 formaldehyde has been classified as a human carcinogen,
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based on evidence of nasopharyngeal cancer (SEDA-31, 409). However, this classification is still debated. In a review of cohort and case-control studies of the association between occupational exposure to formaldehyde and nasopharyngeal cancer, the evidence failed to reach a convincing conclusion on carcinogenicity and could not be used to establish a possible dose-response relationship (9R). In a case-control study of excess naso pharyngeal cancer mortality among formal dehyde-exposed workers in Wallingford, Connecticut, the results suggested that the mortality excess may not have been due to formaldehyde exposure, but rather reflected the effect of external employment in the ferrous and non-ferrous metal indus tries in the local area (10C). However, a method has been established to integrate benchmark dose estimates with genomic data, using gene expression changes in rat nasal epithelium after acute formaldehyde exposure. This suggested that in rats the carcinogenic activity of formalde hyde is associated with cytotoxic/prolifera tive mechanisms (11E).
Glutaral (glutaraldehyde) Observational studies Glutaral-based pro ducts are typically used in hospitals and clinics as cold sterilizers, to disinfect and clean heat-sensitive medical devices. Glu taral is a potent sensitizer and respiratory irritant, and it has been implicated as a cause of asthma in health-care workers. This has led to a search for alterative disin fectants for instrumental sterilization (SEDA-20, 225). However, glutaral continues to be used as a disinfectant and sterilizer, particularly in developing countries. This requires occupa tional health monitoring and establishment of safe practices for its use. In a Canadian study to assess the effect of work practices and general ventilation sys tems on employees’ exposure to glutaral, air samples were taken in five hospitals (12c). The presence of local or general ventilation,
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air changes per hour, the quantity of glu taral used and work practices were recorded. Work practices constituted the most important factor affecting the degree of exposure to glutaral. In locations where ‘poor’ or ‘unsafe’ practices were employed, glutaral concentrations were much higher and there was an increased prevalence of headache and itchy eyes among employees.
BISBIGUANIDES Chlorhexidine
(SED-15, 714; SEDA-29, 241; SEDA-30, 278; SEDA-31, 410)
Observational studies Chlorhexidine inter ventions have been shown to have the potential to reduce maternal and neonatal mortality and morbidity significantly in lowresource settings, although data on safety were incomplete (SEDA-31, 410). A further review of the research available has shown that despite positive results the use of chlor hexidine to prevent perinatal mortality and morbidity has not been widely adopted (13R). In the transition from chlorhexidine research to public health implementation in developing countries, the authors suggested that high priority be given to evaluate whether further evidence is needed to demonstrate safety and effectiveness, and to determine how evidence should be obtained. Sensory systems Chlorhexidine has been associated with occasional reports of ulcera tive keratitis, cataract, and iris atrophy when it is used in the treatment of Acantha meba keratitis (SEDA-29, 242). In a retro spective study of 81 patients looking for the characteristics that are associated with cat aract during the treatment of Acanthameba keratitis, 9 had developed a densely white ipsilateral cataract (14c). Chlorhexidine was part of the multidrug treatment in all of these cases. It is generally considered that compounds such as chlorhexidine can dis rupt the surface of the lens, provoke lenti cular oxidative or osmotic stress and
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contribute to cataract formation by altering lipid membranes, damaging lens fibers and inducing electrolyte imbalance. A cornea that has been damaged by amebic infection may allow increased penetration of topi cally applied drugs that have intra-ocular adverse effects, and improved therapeutic alternatives are needed. Immunologic Chlorhexidine-induced ana phylaxis is well documented, although still rare (SEDA-31, 411). More often anaphylaxis occurs when chlorhexidine is applied to mucous membranes, although it does occur after non-mucosal topical application. Anaphylaxis, toxic epidermal necrolysis, and Stevens–Johnson syndrome after nonmucosal topical drug application have been evaluated in a systematic review of the Ger man pharmacovigilance authority’s Adverse Drug Reactions Database (15R). The data base included reports of chlorhexidine ana phylaxis, but no reports of toxic epidermal necrolysis or Stevens–Johnson syndrome. Application to skin wounds or skin with impaired barrier function was identified as a major susceptibility factor.
BORATES
(SED-15, 548)
Boric acid Boric acid was first used as a topical antisep tic by Lister in 1873. It has subsequently been used in eye washes, mouthwashes, skin powders and ointments. Boric acid has also been as an irrigant for body cavities, including the pleural space, vagina, and rec tum. The medical use of these solutions and irrigants has now been abandoned, because of toxicity and potential lethality. However, boric acid is used as a household disinfectant, and deaths due to accidental poisoning are still reported (16A). Comparative studies Boric acid is being investigated in pessary/suppository form for the treatment of vulvovaginal candidiasis. In
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a randomized open comparison of boric acid vaginal suppositories and oral fluconazole for the treatment of vulvovaginal candidiasis in 112 patients with diabetes mellitus, boric acid produced a higher mycological cure rate (17c). However, two of the patients who were given boric acid withdrew because of vaginal burning, which improved after withdrawal. In a review of conventional and non-con ventional methods of managing recurrent vulvovaginal candidiasis, boric acid pro duced a good response but with some skin irritation and a caution concerning systemic toxicity (18c).
CATIONIC SURFACTANTS Benzalkonium compounds (SED-15, 421; SEDA-28, 261) Comparative studies Benzalkonium chlor ide is widely used as a preservative in eyedrops; in higher concentrations it is used as an antiseptic and disinfectant. In a rando mized crossover study two concentrations of benzalkonium chloride, 0.1% and 0.4%, used as a sanitary wipe were compared with a 62% ethyl alcohol emollient gel for safety and acceptability in male genital antisepsis (19c). Of the 39 participants one reported dry skin with 0.1% benzalkonium and a gen ital ulcer was reported in one patient assigned to 0.4% benzalkonium. No adverse effects were observed during use of the etha nol gel, which was preferred by most men.
(SEDA-15, 1896; SEDA-29, 242; SEDA-30, 279; SEDA-31, 411)
IODOPHORS
Polyvinylpyrrolidone (povidone) and povidone–iodine Povidone–iodine is a stable chemical com plex of polyvinylpyrrolidone (povidone)
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and elemental iodine, which contains 9–12% iodine. Observational studies Povidone–iodine solution has been used as an effective broadspectrum antiseptic and disinfectant since the 1950s. In the early 1980s, a tumoricidal effect was reported. In colorectal operations, povidone–iodine has generally been used for the purpose of minimizing postoperative septic complications and reducing cancer recurrence, although there is little evidence to support its use. In a review of the literature on the use of povidone–iodine in colorectal surgery, few prospective randomized controlled trials were identified (20R). The authors found no conclusive evidence of benefits but were able to comment on adverse effects. Serious adverse effects of povidone–iodine were not common; metabolic acidosis, acute renal failure, hyperthyroidism and toxic reactions to iodine or iodide had been reported. The authors recommended that in general povidone–iodine should be avoided in patients with a history of allergic reactions to iodine-containing compounds, thyroid disease, renal insufficiency and established systemic sepsis. Endocrine Povidone–iodine for pleuro desis is safe and effective (SEDA-31, 411). However, topical administration can cause thyroid dysfunction (SEDA-25, 277; SEDA 28, 263; SEDA-30, 279; SEDA-31, 411). In a retrospective study of 12 patients who underwent povidone–iodine pleurodesis, in which thyroid hormone concentrations were routinely monitored, there were no signs or symptoms of hyper- or hypothyroidism (21c). Povidone–iodine is a widely used gargling preparation in Japan, where iodine-induced hypothyroidism has been reported. Usually, the hypothyroidism is mild and resolves spontaneously on cessation of gargling. However, in the case of a 63-year-old patient who developed overt hypothyroid ism due to habitual gargling with povidone– iodine for more than 10 years, thyroid func tion did not improve on discontinuing the gargling (22A).
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Skin Povidone–iodine is a very effective anti-infective agent in the treatment of infected and potentially infected wounds of various types and is widely used in the treatment of burns. Unfortunately, povidone–iodine formulations dessicate the wound surface. While a moist environment promotes epithelialization of superficial wounds, dessication of the wound surface can have a detrimental effect on wound healing. Immunologic Immediate allergic reactions to povidone–iodine are rare and often overlooked, as it is difficult to diagnose. Polyvinylpyrrolidone is thought to play a mechanistic role. The usefulness of the histamine release test for diagnosing polyvinylpyrrolidone allergy has been studied in a single case (23A). • A 9-year-old boy with eosinophilia (1500 � 106/l) and rasied total IgE (1376 IU/ml) was sus pected of having polyvinylpyrrolidone allergy, as he had anaphylactic reactions twice when he was exposed to povidone–iodine for impetigo contagiosum. Skin prick tests were performed with povidone–iodine solution, polyvinylpyr rolidone, gentamicin sulfate, and two other medicines containing polyvinylpyrrolidone. The histamine release test was assessed using peripheral blood basophils. Skin prick tests with povidone–iodine, polyvinylpyrrolidone and the other medicines were all negative. Polyvinyl pyrrolidone caused histamine release in the pre sence of autologous serum, but not in its absence.
These observations accorded with the clinical findings that anaphylaxis had devel oped only when his skin had been exposed to povidone–iodine solution so that baso phils could contact polyvinylpyrrolidone in
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the presence of serum, probably because of broken skin and vessels. Drug formulations A liposomal hydrogel of povidone–iodine, developed to combine the antimicrobial effects of povidone–iodine with the moisturizing effects of liposomal hydrogels, has been compared with a conven tional silver sulfadiazine cream in 43 patients with partial thickness burns (24c). The lipo somal povidone–iodine hydrogel produced significantly faster complete healing of the burn wounds than silver sulfadiazine. The cosmetic result was excellent in 37% of the wounds treated with liposomal povidone– iodine hydrogel compared with 13% of those treated with silver sulfadiazine cream.
PHENOLIC COMPOUNDS (SED-15, 2800, SEDA-28, 263) Nervous system Phenol indiscriminately damages motor and sensory nerves and intrathecal administration is used to relive spasticity in those who do not have any functional movement in their legs. A single injection often lasts many months and before administration a long-acting local anesthetic drug is given. In a retrospective review of the case notes of 40 patients who had been treated with intrathecal phenol over 10 years all had improvement in spasticity, rated as substantial or excellent in 34 (25c). Seven patients required repeat injections with similar outcomes. Seven had temporary adverse effects.
References 1. Noisel N, Bouchard M, Carrier G. Evaluation of the health impact of lowering the formaldehyde occupational exposure limit for Quebec work ers. Reg Toxicol Pharmacol 2007;48:118–27.
2. Ezratty V, Bonay M, Neukirch C, OrsetGuillossou G, Dehoux M, Koscielny S, Cabanes PA, Lambrozo J, Aubier M. Effect of formaldehyde on asthmatic response to
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inhaled allergen challenge. Environ Health Perspect 2007;115:210–4. Lang I, Bruckner T, Triebig G. Formalde hyde and chemosensory irritation in humans: a controlled human exposure study. Reg Toxicol Pharmacol 2007;50:23–6. Gu YH, Fujimiya Y, Kunugita N. Long-term exposure to gaseous formaldehyde promotes allergen-specific IgE-mediated immune responses in a murine model. Hum Exp Tox icol 2008;27:37–43. Baccioglu A, Kalpaklioglu AF. An unusual form of formaldehyde induced lung disease. Allergol Immunopathol 2007;35:110–2. Raman RR. Two percent formalin retention enemas for haemorrhagic radiation proctitis: a preliminary report. Dis Colon Rectum 2007;50:1032–9. Lee SI, Park YA, Sohn SK. Formalin appli cation for the treatment of radiation-induced haemorrhagic proctitis. Yonsei Med J 2007;48:97–100. Stern DR, Steinhagen RM. Anorectal cancer following topical formalin application for haemorrhagic radiation proctitis. Colorectal Dis 2007;9:275–8. Duhayon S, Hoet P, van Maele-Fabry G, Lison D. Carconogenic potential of formal dehyde in occupational settings: a critical assessment and possible impact on occupa tional exposure levels. Int Arch Occup Environ Health 2008;81:695–710. Marsh GM, Youk AO, Buchanich JM, Erdal S, Esmen NA. Work in the metal industry and nasopharyngeal cancer mortality among for maldehyde-exposed workers. Reg Toxicol Pharmacol 2007;48:308–19. Thomas RS, Allen BC, Nong A, Yang L, Bermudez E, Clewell HJ, Andersen ME. A method to integrate benchmark dose esti mates with genomic data to assess the func tional effects of chemical exposure. Toxicol Sci 2007;98:240–8. Nayebzadeh A. The effect of work practices on personal exposure to glutaraldehyde among health care workers. Ind Health 2007;45:289–95. McCkure EM, Goldenberg RL, Brandes N, Darmstadt GL, Wright LL, for the CHX working group. The use of chlorhex idine to reduce maternal and neonatal mortality and morbidity in low-resource
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settings. Int J Gynaecol Obstet 2007; 97:89–94. Herz NL, Matoba AY, Wilhelmus KR. Rapidly progressive cataract and iris atrophy during treatment of Acanthamoeba keratitis. Ophthalmology 2008;115(5):866–9. Sachs B, Fischer-Barth W, Erdmann S, Merk HF, Seebeck J. Anaphylaxis and toxic epidermal necrolysis or Stevens–Johnson syndrome after nonmucosal topical drug application: fact or fiction? Allergy 2007; 62:877–83. Hamilton RA, Wolf BC. Accidental boric acid poisoning following the ingestion of household pesticide. J Forensic Sci 2007;52:706–8. Ray D, Goswami R, Banerjee U, Dadwhal V, Goswami D, Mandal P, Sreenivas V, Kochupillai N. Prevalence of Candida glab rata and its response to boric acid vaginal suppositories in comparison with oral flucona zole in patients with diabetes and vulvovagi nal candidiasis. Diabetes Care 2007;30:312–7. Watson C, Calabretto H. Comprehensive review of conventional and non-conven tional methods of management of recurrent vulvovaginal candidiasis. Aust N Z J Obstet Gynaecol 2007;47:262–72. Bukusi EA, Steele M, Cohen CR, Nguti R, Maingi CW, Thomas KK, Holmes KK. Safety, acceptibility, and tolerability of 3 topical microbiocides among heterosexual Kenyan men. J Acquir Immun Defic Syndr 2007;44:423–8. Pattana-arun J, Wolff BG. Benefits of povi done–iodine solution in colorectal opera tions: science or legend? Dis Colon Rectum 2008;51:966–71. Yeginsu A, Karamustafaoglu A, Ozugurlu F, Eitkan I. Iodopovidine pleurodesis does not affect thyroid function in normal adults. Interact Cardiovasc Thorac Surg 2007;6 (4):563–4. Sato K, Ohmori T, Shiratori K, Yamazaki K, Yamada E, Kimura H, Takano K. Povidone iodine-induced overt hypothyroidism in a patient with prolonged habitual gargling; urinary excretion of iodine after gargling in normal subjects. Int Med 2007;46:391–5. Yoshida K, Sakurai Y, Kawahara S, Takeda T, Ishikawa T, Murakami T, Yoshioka A. Anaphylaxis to polyvinylpyrrolidone in povi done–iodine for impetigo contagiosum in a
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boy with atopic dermatitis. Int Arch Allergy Immunol 2008;146(2):169–73. 24. Homann H-H, Rosbach O, Moll W, Vogt PM, Germann G, Hopp M, Langer-Brauburger B, Reimer K, Steinau H-U. A liposome hydrogel with polyvinyl-pyrrolidone iodine
443 in the local treatment of partial- thickness burn wounds. Ann Plast Surg 2007;59: 423–7. 25. Pinder C, Bhakta B, Kodavali K. Intrathecal phenol: an old treatment revisited. Disabil Rehab 2008;30(5):381–6.
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Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines
Resistance to antibacterial drugs Emerging and increasing resistance to anti biotics continues to be a serious threat to public health worldwide. Thus, 70 years since their introduction, we are now facing the possibility of a future without effective antibiotics for several types of micro-organ isms that cause serious diseases. In 2001, the European Commission pre sented their strategy for combating this threat. Later in the same year, EU Health Ministers adopted a Council Recommenda tion (1S). The key point was surveillance. Since then, many working groups have worked hard in nearly all European coun tries and we have excellent overviews of high degrees of resistance in Southern Europe and considerably less in Northern Europe. How ever, a general trend has been an increase in both places. Surveillance is of importance, for the microbes are on the move. In short, the field of beta-lactamases exemplify what is happening. Alexander Fleming discovered that some strains of staphylococci could destroy penicillin because they produced penicillinases. It is now well recognized that the most effective resistance mechanism against beta-lactams is expression of beta lactamases. These enzymes hydrolyse the Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32025-3 � 2010 Published by Elsevier B.V.
beta-lactam ring, using either a serine residue (as in class A, C, and D beta-lactamases) or a zinc molecule (as in class B, also called metallo-beta-lactamases, MBLs) (2R). The spreading of metallo-beta-lactamases consti tutes an ever-increasing serious threat for human health, due to (i) their broad activity profiles that encompass most beta-lactam antibiotics, including the carbapenems; (ii) the potential for horizontal gene transfer; and (iii) the absence of clinically useful inhi bitors. The last of these points contrasts with serine beta-lactamases (3R), although sidero phore-containing monobactams show pro mising results in vitro and may be of clinical importance (4R). If these enzymes are becoming widespread among pathogenic bacteria, the end of the beta-lactam antibiotics is coming closer. Metallo-beta-lactamases are also present intracellularly in plants and animals, and the possibilities for interactions beyond these kingdoms are completely unknown. Thus, there is an increasing concern that surveillance might not be able to cope with the problem. There should be a focus on better guidelines for registration and use of antibiotics. In Europe this view brings into focus the European Medicines Agency (EMA), which is responsible for registering new antibiotics and general guidelines for their proper use. Without going into detail, it can briefly be mentioned that protocols for the approval of new antibiotics lack proper demands regard ing their environmental fate. It should be recognized that most chemicals, including
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drugs, can act on the environment. This is of specific concern for antibiotics, as microbes are everywhere. However, that view is not recognized in the current rules. Another area for improvement is regular post-marketing follow-up of the develop ment of resistance and cross-resistance. For example, if it became evident that the use of carbapenems triggered the spread of metallo beta-lactamases, their use would have to be restricted. On these – and other points – EMA and other agencies should act. Then pharmaceu tical companies should be challenged. For years they have been very active in produ cing sophisticated groups of antibiotics. The numbers of cephalosporins and fluoroquino lones on the market are overwhelming, and new ones, with very limited improvements, continue to appear. The time has come to change this, and some companies are already doing so. In relation to beta-lactam antibio tics, one can be mentioned. It has been shown that endogenous nitric oxide protects bacteria against a long list of cephalosporins, penicillins and moxalactam (5R). Cefotaxime kills nitric oxide-deficient Staphylococcus aureus far more efficiently than it kills wildtype bacteria. Moreover, pre-treatment with exogenous nitric oxide temporarily protects bacteria against cefotaxime toxicity.
Intrapartum antibiotics for mothers with group B streptococcal colonization: to treat or not to treat? Asymptomatic vaginal carriage of group B streptococci was described as early as in 1935 (6E). However, the first report of group B streptococcal sepsis in a neonate did not appear until 1964 (7c); since then, group B streptococci have been recognized as a com mon cause of neonatal infectious morbidity and mortality, maternal morbidity, asympto matic bacteriuria in pregnancy, and urinary tract and other infections in adults (8R). Over the years, it has been well established that the gastrointestinal tract, vagina, and
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urethra serve as reservoirs for group B strep tococci without causing disease. A systematic review of the prevalence has shown that the rate of vaginal colonization was 6.5–36%, and 10 of 31 studies showed a carrier rate above 20% (9M). In 1976, chemoprophylaxis was pro posed for reducing maternal colonization with group B streptococci, in order to reduce neonatal disease (10C). Since then many reports have appeared, and penicil lin and ampicillin have been the two most commonly used drugs. It is generally accepted that beta-lactams given during labor significantly reduce colonization with group B streptococci. However, severe allergic reactions to antibiotics have been reported (11C, 12A, 13c), besides an increased incidence of post-natal mater nal and neonatal yeast infections. Intra partum antibiotic prophylaxis may also increase exposure of neonates to ampicil lin-resistant Enterobacteriaceae (14C). This was the background to a recent Cochrane analysis (15M), in which it was stated that it is important to know if intra partum antibiotics do more good than harm in trying to reduce mortality and morbidity from neonatal group B streptococcal infec tions. Since most women colonized with group B streptococci are asymptomatic, screening is necessary if they are to be iden tified. However, of women in labor who have group B streptococci, very few will give birth to babies who are infected. Hence, giving intravenous antibiotics to all these women in labor will put many women and babies at unnecessary risk of adverse effects, includ ing potentially fatal anaphylaxis, and occa sion the emergence of drug-resistant organisms. The authors concluded that there is no evidence from well-designed and wellconducted studies that intrapartum antibiotics should be recommended in order to reduce early-onset neonatal infection. Ideally, the effectiveness of intrapartum antibiotics to reduce infection should be studied in ade quately sized, double-blind, controlled trials. They also stated that there is no information about whether intrapartum ampicillin is preferable to penicillin or about possible
Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines
changes in neonatal flora and the develop ment of resistance. It is not easy to be a doctor in the labor room, left alone with the question of whether to treat or not. The time has come for the regulatory authorities to come up with new guidelines. Unnecessary use of antibiotics should be reduced.
BETA-LACTAM ANTIBIOTICS (SED-15, 478; SEDA-29, 267; SEDA-30, 280; SEDA-31, 420) Immunologic Penicillin is the most com mon cause of drug-induced anaphylaxis (16S). Ever since the beta-lactam anti biotics came on the market, the incidence of cross-reactivity between penicillin and other groups of antimicrobial drugs has been a matter of concern. There are a confusingly large number of studies on this question and the conclusions have sometimes been contradictory. As a result, owing to a fear of serious crossreactivity, other beta-lactams are often avoided in patients with known penicillin allergy. This might result in increased health-care costs, a risk of bacterial resis tance, the use of alternative antibiotics with other potentially dangerous adverse affects (17R) and the use of inferior anti biotics, such as vancomycin for the treat ment of meticillin-susceptible S. aureus infections (18R). As reviews of cross-reactivity between penicillins and cephalosporins are common (19R–21R), only comments are made here on the possible allergic cross-reactivity of penicillins with carbapenems and mono bactams (22R). Penicillins versus carbapenems There is no current consensus on what the crosssensitivity is between penicillins and carbapenems, or how much allergy can be attributed to a coincidental total allergic
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reaction to the carbapenem that is not related to the fact that the patient is also allergic to penicillin. When studies that have verified penicillin allergy by accepted standards (i.e. skin tests with the major and minor penicillin determinants) and have tested for carbapenem allergy by administering a full therapeutic dose to carbapenem skin test-negative patients were examined, cross-reactivity between skin tests appeared to be 1%, with all carbapenem skin test-negative patients tolerating the challenge (23C–25C). The authors recommended that if a carbapenem skin test is negative in patient with penicillin allergy, carbapenem can be used safely. Penicillins versus monobactams Aztreonam is the only monobactam widely available for clinical use. Of 3360 patients who received multiple doses of aztreonam, 7 (0.2%) had type 1 reactions (26c). Reviews of the immu nological studies and evidence from clinical trials have not shown cross-reactivity between aztreonam and penicillins, except for sensitization reactions in patients with cystic fibrosis. In addition, some immunolo gical and clinical data suggest that there may be a degree of cross-reactivity between ceftazidime and aztreonam because of a similarity in the side chain. The authors emphasized that choosing antibiotics in penicillin-allergic patients is difficult. However, the risk of inducing an immunoglobulin E (IgE)-mediated-type reaction in these patients by choosing either a carbapenem or a monobactam is lower than many believe.
Teratogenicity Penicillins and cephalo sporins are generally thought to be safe in pregnancy. However, in a recent Ser bian study of 6099 women, congenital malformations were found in 7 babies born to 112 women who had taken a beta-lactam antibiotic during the first tri mester (27c). All except one (hypospa dias) were minor malformations. The
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results thus suggested a possible terato genic potential, even with antibacterial drugs that are considered to be safe. However, as those that occur are usually minor, they often pass unnoticed.
(SED-15, 638; SEDA-29, 246; SEDA-30, 246; SEDA-31, 420)
CARBAPENEMS
Drug–drug interactions Valproic acid (SEDA-30, 421) Carbapenems can reduce serum concentrations of valproic acid to one-third. Meropeneum seems to have the most pronounced lowering effect but the mechanism is unclear (28c). In a Japanese study on human, monkey, and rat liver cells, carbapenems inhibited valproic acid glucuronidases (29E).
Doripenem Nervous system The seizure-inducing potential of doripenem (SEDA-30, 421) has been reviewed (30R). In patients with nosocomial pneumonia, the incidence of seizures was 1.2% in patients taking doripe nem (6/485) and 3.8% in patients taking imipenem (10/263). For patients with condi tions that predispose to seizures, seizures occurred in 3 of 193 patients taking doripe nem (1.5%) and 6 of 116 taking imipenem (5.2%). These data suggest that doripenem has a lower seizure-inducing potential than imipenem.
Ertapenem Nervous system Seizures have been reported infrequently in patients receiving ertapenem (31R), but this might not reflect the real incidence. Of 30 patients taking ertapenem, 3 had seizures (32c). All had moderate renal insufficiency
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(creatinine clearances 44, 54, and 56 ml/min) and all had received intra venous ertapenem 1 g/day. All three patients had some kind of nervous system disorders, but only one previously had had seizures. Two were given prophylactic anti-epileptic drugs. Using Naranjo’s cri teria, the events were classified as prob able in one case and possible in the other two. Thus, like other carbapenems, erta penem may lower the convulsive thresh old in some patients.
(SED-15, 688; SEDA-29, 246; SEDA-30, 284; SEDA-31, 422)
CEPHALOSPORINS
Nutrition Pivoxil is used as a component of prodrugs for its ability to increase drug absorption from the gastrointestinal tract. However, it can cause carnitine depletion, as illustrated in a report from Japan where three different pivoxil-containing cephalo sporins are marketed (33A). • A 1-year-old boy was given pivoxil-containing cephalosporins for recurrent otitis media and upper respiratory tract inflammation. He developed a tremor in his hands and feet, which led to a generalized convulsion. His blood carnitine concentration of was about 1/10 of normal.
Cefdinir Gastrointestinal Passage of red stools after the use of cefdinir (SEDA-31, 422) continues to be reported and has been reviewed (34R). The red color is believed to be due to the formation in the gastro intestinal tract of a non-absorbable com plex between cefdinir or its breakdown products and iron (commonly found in infant formulae). Whether or not this influences the amount of cefdinir that is absorbed was not evaluated.
Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines
Cefoperazone Gastrointestinal A 9-year-old boy with Meckel’s diverticulum who was taking cefo perazone had gastrointestinal bleeding on the fifth day after an operation (35A). This is a reminder that cefoperazone, like other cephalosporins that contain a methylthio tetrazole side chain, can cause hypopro thrombinemia and bleeding.
Cefotaxime Biliary tract Ceftriaxone can cause biliary sludge and cholelithiasis in children. Reports related to other cephalosporins, including cefotaxime, have been rare (36C). Cefotax ime has now been implicated (37A). • A 2-week-old girl developed fever, abdominal distension, jaundice, and pale stools. Electrolytes and aspartate transaminase and alkaline phosphatase activities were normal, but gamma glutamyltransferase activity and bilirubin were raised. Ultrasonography showed ascites, but the liver was normal and there was no intrahepatic or extrahepatic biliary ductal ectasia or biliary sludge. Blood cultures grew Aeromonas hydrophila and Klebsiella pneumoniae. She was given ampicillin and cefotaxime for 10 days and the jaundice disappeared. However, 1 week later, the jaundice and pale stools recurred. There was mild hepatomegaly, and bilirubin and gamma glutamyltransferase were raised. Ultrasonography showed cholestasis, dilatation of the intrahepatic and extrahepatic biliary ducts with a lot of sludge, and a large sludge ball in the gall bladder. She was given ursodeoxycholic acid and her stools became pigmented after 2 days. Subsequent ultrasonography showed reduced sludge in the biliary tree and gall bladder. By 6 months there was complete resolution.
Ceftobiprole The controversial classification of cephalo sporins into ‘generations’ is partly based upon when they arrived on the market and partly upon their spectrum of activity (38R). Continuing development of new cephalosporins may create ‘fifth-generation’
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cephalosporins. Ceftobiprole is the frontrun ner in this group. It is already on the market in Canada, Switzerland, and Ukraine and is currently under review by the FDA and EMA. It has been stated to be active against methicillin-resistant staphylococci as well as several Gram-negative organisms, including Pseudomonas aeruginosa (39R). However, it can be broken down by extended-spectrum beta-lactamases from Escherichia coli, Kleb siella spp., and others. Based on one report it has been claimed that its characteristics make significant drug–drug interactions less likely (40R). However, the mere fact that it has to be given as a carbamate prodrug, ceftobiprole medocaril, and depends on plasma esterases to activate it, makes such statements uncer tain. Its main adverse effects are similar to those of most other cephalosporins, with one exception – it causes more taste disturbances (41c, 42C); the mechanism is not known.
Ceftriaxone Liver The advantage of a long half-life, broad spectrum, and high tissue penetration make ceftriaxone a frequent choice in the treatment of childhood infections, in spite of its tendency to cause formation of biliary and urinary sludge. Hepatitis has also been reported (43A) • A 12-year-old boy developed weakness and fatigue after taking ceftriaxone 50 mg/day for 6 days for tonsillitis. Aspartate and alanine transaminases, gamma glutamyltransferase and alkaline phosphatase activities, and total bilirubin were all raised. Ultrasonography showed a minimally enlarged liver with a normal parenchyma. The gall bladder was normal. There was eosinophilia of 8%. Ceftriaxone was withdrawn and the boy was given pulse methylprednisolone. He recovered slowly over the next 10 weeks.
The first case of hepatitis associated with ceftriaxone was described in 1991 (44A). It has since been associated often with hemo lytic anemia, which can be fatal (45A). The underlying mechanisms are still not known.
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(SED-15, 2378; SEDA-29, 247; SEDA-30, 286; SEDA-31, 423)
reasonable to agree with the authors’ statement that early use of amoxicillin is one of the causative factors of molar inci sor hypomineralization.
Chemically modified monobactams and their non-antimicrobial properties
Co-amoxiclav and clavulanic acid
MONOBACTAMS
N-Methylated derivatives of the mono bactams can cause DNA damage, growth arrest, and apoptosis in mammalian cell cul tures (46E). Stereochemical modifications may produce more specifically targeted compounds (47E), leading to the develop ment of novel anticancer drugs. In a breast cancer xenograft mouse model using syn thetic N-thiolated monobactams, the com pound L-1 caused significant inhibition of tumor growth (48E).
PENICILLINS (SED-15, 2756; SEDA-30, 286; SEDA-31, 424) Amoxicillin Teeth The etiology of molar incisor hypomineralization is still unclear, but it has been suggested that use of antibiotics in early childhood may play a role (49c–51c). However, it is not clear whether the causative factor is the illness itself or the drugs used to treat it. The use of anti biotics in 141 schoolchildren and children under the age of 4 has been examined (52cE). Of 23 children with molar incisor hypomineralization, 12 had taken anti biotics during the first year, compared with 40 of the children without hypomineraliz ation. The number of courses of amoxicillin was significantly associated with hypomineralization. The authors also cultivated embryonic mouse teeth with and without amoxicillin, which increased enamel but not dentine formation. Thus, the use of amoxicillin gives an altered pattern of amelogenesis and interferes with the mineralization. Of course, amoxicillin may not be the sole cause, but it seems
The combination of amoxicillin þ clavulanic acid (co-amoxiclav) has been marketed in several formulations. In Europe, it is avail able in ratios of 2:1, 4:1, and 7:1; in the USA, a 14:1 ratio has been approved (53S). Liver Clavulanic acid can cause liver damage. The first case was described more than two decades ago (54A), since when more than 100 cases have been reported (55Ar). Reports of liver damage due to amoxicillin alone are considerably fewer. In two studies, amoxicillin alone was asso ciated with a sixfold lower incidence of liver injury than co-amoxiclav (56c) (57C). Among all antibiotics co-amoxiclav is the one most frequently associated with liver damage and the one that most often leads to hospitalization for drug-induced liver dis ease (58R). The onset liver damage due to co amoxiclav generally occurs at several days to weeks after starting therapy. A combination of advanced age and longterm therapy (more than 10 days) increases the risk (56c). Co-amoxiclav induced hepatitis is usually reversible after rapid drug withdrawal, but may per sist for weeks. However, in an analysis from a Spanish hepatotoxicity register, co-amoxiclav was the most common cause of chronic liver damage (59c). Moreover, in a prospective case series in 69 patients, there was an unfavorable out come (death, liver transplantation or per sistent liver damage) in 5 (60c). The mechanism underlying liver damage from co-amoxiclav is unclear. The com bined deficiency of alleles M1 and T1 in glutathione S-transferase genes plays a role in susceptibility (61C).
Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines
Flucloxacillin Liver Flucloxacillin was the second most common beta-lactam to be associated with liver damage (58R). In 51 patients with flu cloxacillin-induced liver damage, a specific genotype, HLA-B*5701, was a major deter minant for this adverse effect (62c). This is the same phenotype that is associated with an increased risk of abacavir-induced hypersensitivity reactions (SEDA-31, 483). However, the authors stated that the overall clinical usefulness of such genotyping can be assessed accurately only by a prospective study of the risk of liver damage in subjects who take flucloxacillin and are positive or negative for the HLA B*5701 phenotype. Urinary tract Acute interstitial nephritis has been attributed to flucloxacillin in a report that included discussion of the treat ment of drug-induced acute nephritis (63Ar). Drug–drug interactions Warfarin Over the years, there have been a handful of reports saying that the effect of warfarin can be a reduction in patients taking either nafcillin or dicloxacillin (64Ar, 65A). A recent report has suggested that flucloxacillin might have a similar effect (66A).
TETRACYCLINES AND GLYCYLCYCLINES (SED-15, 3330; SEDA-29, 248; SEDA-30, 288; SEDA-31, 419)
Tetracyclines and glycylcyclines and their non-antimicrobial properties The matrix metalloproteinases (MMPs) form a family of nearly 30 enzymes that are intimately involved in tissue remo delling. Put simply, pathophysiological
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processes associated with the MMPs are related to imbalances between activation and inhibition of various MMPs, resulting in degradation of extracellular matrix. There are now about 25 000 reports on MMPs in Medline, covering a very large variety of diseases and experimental condi tions. Of the many groups of drugs that affect MMPs, the tetracyclines, including the glycylcyclines, have been the most pro mising. However, so far, only one drug (doxycycline) has been marketed for the treatment of one condition, periodontal dis ease. So far, most articles end by indicating in some way that there is hope that synthetic and natural matrix proteinase inhibitors will be useful in the prevention of . . . (67R).
Doxycycline Placebo-controlled studies Doxycycline 100 mg/day alone or in combination with diethylcarbamazine þ albendazole has been used in a 6-week, double-blind, random ized, placebo-controlled field trial in patients with Brugia malayi infection (68C). After 4 months of treatment with doxycycline (n = 119) or placebo (n = 42), the patients were given diethylcarbamazine 6 mg/kg þ albendazole 400 mg or a match ing placebo. The adverse effects of doxy cycline were mild and included myalgia (n = 6), nausea (n = 4), dizziness (n = 5), headache (n = 3), insomnia (n = 2), abdom inal pain (n = 2), itching (n = 2), diarrhea (n = 1), rash (n = 1), malaise (n = 1), and drowsiness (n = 1); none of the patients had to stop taking doxycycline because of adverse reactions. There were no reports of photosensitivity reactions. Adverse events in the placebo group (n = 42) were myalgia (n = 2), nausea (n = 1), dizziness (n = 2), insomnia (n = 1), and itching (n = 1). Adverse reactions were least common in those who took doxycycline þ placebo and most common in those who took placebo and diethylcarbamazine þ albendazole. There were significantly fewer patients with high fever and severe adverse reactions in those who took doxycycline and diethyl carbamazine þ albendazole.
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In a randomized, placebo-controlled trial in Ghana, 67 patients with onchocerciasis took doxycycline 200 mg/day for 4 or 6 weeks, followed by ivermectin 0.15 mg/kg after 6 months (69C). After 6, 20, and 27 months, efficacy was evaluated by onchocercoma histology, polymerase chain reaction (PCR), and determination of microfilariae. Doxycycline resulted in endobacteria depletion and female worm sterilization; the 6-week regimen was macrofilaricidal, and over 60% of the female worms were found dead, despite the presence of new Wolbachia-containing worms acquired after the administration of doxycycline. Doxycycline could be devel oped as a second-line drug for onchocercia sis, to be administered in areas without transmission, in foci with ivermectin resistance, and in areas with Loa loa co infections. Treatment with doxycycline was associated with bloody diarrhea in one patient; it resolved after withdrawal and treatment with metronidazole, although day 3 may have been too early for anti biotic-associated colitis. Other adverse events were mild, did not last longer than 3 days, and did not occur more often after administration of doxycycline. No serious adverse events were observed. Nervous system Pseudotumor cerebri, or benign intracranial hypertension, is a diag nosis of exclusion made by the following criteria: • signs and symptoms of increased intracranial pressure such as papilledema; • normal cerebral anatomy as shown on imaging; • increased intracranial pressure demonstrated on lumbar puncture; • normal cerebrospinal fluid (CSF) composition.
It can occur either as a primary condition or secondary to medications, and minocycline has long been known to cause it (70A, 71A). Doxycycline has rarely been implicated (72A, 73A), but another case has been reported (74A). • A 23-year-old woman took oral doxycycline 100 mg bd for acne and after 5–8 weeks developed worsening headaches associated
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with occasional nausea and blurred vision. Physical examination was normal except for bilateral papilledema. A lumbar puncture showed a mildly raised pressure with no CSF abnormalities. She felt substantially better soon after the lumbar puncture. A magnetic resonance imaging (MRI) scan of the brain was unremarkable and ruled out dural sinus thrombosis. Pseudotumor cerebri was suspected and doxycycline was withdrawn. Her headache, nausea, and blurred vision resolved after 1 week and the papilledema after 3 months.
Minocycline The French National Pharmacovigilance Committee has reported on the adverse effects of minocycline (75S). When sales fig ures were taken into account, reports were more frequent with minocycline than with doxycycline, and the proportion of severe adverse effects, including life-threatening hypersensitivity reactions and autoimmune adverse effects, were more common with minocycline than with doxycycline. Respiratory Acute eosinophilic pneumo nia has been attributed to minocycline in a 55-year-old woman who had taken mino cycline, paracetamol, theophylline, and pro caterol; the association with minocycline was confirmed by re-challenge, although a preceding lymphocyte stimulation test had suggested that paracetamol was to blame; re-challenge with paracetamol was unevent ful (76A). In another case, a 55-year-old man taking minocycline developed an acute eosinophilic pneumonia, and although a drug-induced lymphocyte stimulation test for minocycline was negative, the previous case suggests that minocycline may never theless have been to blame (77A). Pneumonitis has been attributed to mino cycline in a 51-year-old man who had taken minocycline for 11 days for a urinary tract infection (78A). A lymphocyte stimulation test for minocycline in the peripheral blood and pleural effusion was negative, but pro vocation with minocycline reproduced the original effects (fever, dry cough, and bilateral ground-glass opacities on the chest
Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines
X-ray). He recovered rapidly after gluco corticoid therapy. Sensory systems Blue sclerae and diffuse bilateral slate-grey pigmentation, particu larly in the interpalpebral fissures, devel oped in a 50-year-old man who had taken minocycline 100 mg/day for 10 years for acne (79A). He also had multiple superficial conjunctival cysts. Metabolism Lactic acidosis has been attributed to minocycline in an 18-year-old woman contributed to by a mitochondrial myopathy, with heteroplasmy for the G8363A mutation in tRNA(Lys), which was present in about 80% of her mitochon drial DNA (80A). Liver Fulminant hepatic failure requiring liver transplantation occurred in a 33-year old woman who had taken minocycline for 6 weeks (81Ar). Skin In a retrospective medical records review of 121 patients with rheumatoid arthritis who had taken at least one course of minocycline for 30 days or more, 44 (36%) developed hyperpigmentation, including 33 during the initial course over a median duration of 9 (range 2.2–78) months (82c). Hyperpigmentation was most commonly seen on the arms and legs and in the head and neck. Increasing age was the only significant susceptibility factor (hazard ratio [HR] = 1.04; 95% confidence interval [CI] = 1.00, 1.07). Hyperpigmentation in an 86-year-old woman taking warfarin was mistaken for bruising but was due to minocycline (83A). The affected areas showed blue-grey dis coloration with fading borders in a sym metric distribution over both forearms and hands, more on the ventral than the dorsal surfaces. They were darker during the day and lighter at night. The histology of minocycline pigmenta tion in the legs has been described in four
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cases with subcutaneous involvement (84c). There were brown/black pigment granules in macrophages clustered around vessels and eccrine coils in the reticular dermis. Similar pigmented macrophages were visi ble in fat septae and between lipocytes. There were macrophages laden with green-grey, flocculent, non-refractile glo bules in the subcutis in all cases, and two had lipid deposition associated with pigment. Hyperpigmentation attributed to mino cycline in a 23-year-old Hispanic man resolved after treatment with oral isotreti noin for acne vulgaris (85A). Nails Nail discoloration developed in a 73-year-old man and a 33-year-old woman after 8 weeks of therapy with minocycline 100 mg bd, without pigmentation elsewhere (86A). Musculoskeletal In a retrospective cohort study of patients, 27 developed rheumatolo gical symptoms while taking minocycline between 1996 and 2006 (87c). The mean age at onset was 17 years and the mean duration of minocycline use before diagno sis was 13 months. All presented with con stitutional symptoms: 22 had polyarthralgia and 17 had polyarthritis, mostly affecting hands and feet. Three types of syndrome were identified: transient, intermediate, and chronic. Seven patients developed chronic autoimmune disease that was still active a mean of 32 (13–48) months after onset. Six had an intermediate course, with resolution of symptoms within 12 months, and 14 had symptoms that resolved rapidly on withdrawal of minocycline. Immunologic Autoimmune hepatitis and idiopathic thrombocytopenic purpura have been attributed to minocycline in a 15 year-old girl who took it for 1 month for acne (88A). Minocycline-induced drug rash with eosinophilia and systemic symptoms (DRESS) has been studied in nine patients,
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seven of whom had skin phototypes V or VI (89c). The authors suggested that melanin in pigmented skin could promote the forma tion of a melanin–minocycline complex, which could explain the severe and pro longed skin manifestations of DRESS that occur in patients with dark skin, and espe cially in African and African-American patients. Lung involvement, with bilateral radiological alveolar opacities, has also been reported in a 19-year-old man with DRESS who had acute respiratory distress with a fever (40°C), lymph node enlarge ment, hepatomegaly, splenomegaly, and eosinophilia (1640 106/l) (90A). In a cross-sectional study in 252 patients with acne, 69% of whom had taken mino cycline at some time, there was no differ ence in the prevalence of positive antinuclear antibody (ANA) tests between patients who had been exposed or not exposed to minocycline, but high titers of ANA (1/160 or higher) were more common in the former (45% versus 12%). Antineu trophil cytoplasmic antibody (ANCA) titers were positive in 7% of the former and in none of the latter (91c). In 58% of cases, the ANCA was of the perinuclear pattern (pANCA) with myeloperoxidase specificity, and this was associated with symptoms in most cases. Two p-ANCA-positive patients were thought in retrospect to have devel oped a lupus-like syndrome. There have been a few reports of poly arteritis nodosa in patients taking mino cycline (92A), and a case of p-ANCA positive cutaneous polyarteritis nodosa has been reported (93Ar). • A 30-year-old Afro-Caribbean took mino cycline 100 mg/day for acne and after 1 year developed increasingly tender nodules with overlying brown pigmentation on her legs. Minocycline was withdrawn and a skin biopsy showed no evidence of minocycline pigmenta tion but a mixed inflammatory perivascular infiltrate throughout the dermis, with scattered nuclear dust and vasculitis involving a med ium-sized artery in the border between the reticular dermis and subcutis. There was focal and segmental fibrinoid necrosis in the vessel wall associated with nuclear debris and intimal thickening, all consistent with polyarteritis nodosa. pANCA was detected in a titer of 1/
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20, but myeloperoxidase ANCA and protei nase-3 ANCA were both negative, as was the antinuclear antibody. Within 3 months of min ocycline withdrawal, the nodules resolved with residual macular hyperpigmentation.
A lupus-like syndrome with severe myal gia and arthralgia occurred in a 15-year-old boy who had taken minocycline for 14 days (94A). Hyperthyroidism and lupus-like syndrome have been reported in a patient who took minocycline for acne (95A). Tumorigenicity Papillary thyroid carci noma surrounded by sarcoid granulomas developed in a 35-year-old woman who had taken minocycline 200 mg/day for 2.5 years; there was also dark brown pigment deposition typical of ‘black thyroid syndrome’ (96Ar). Previous reports have suggested that this syndrome can predis pose to thyroid carcinoma.
Tetracycline Urinary tract Renal damage following the use of tetracycline in a patient with pre existing renal disease has again been reported (97A). • A 42-year-old woman with polycystic kidney disease took tetracycline 250 mg qds after undergoing tooth extractions. She developed nausea, vomiting and diarrhea within days, and end-stage renal disease within 2 weeks. The tetracycline was withdrawn, but hemolysis was required to stabilize her condition.
Tigecycline Gastrointestinal Phase III studies have identified gastrointestinal effects, especially nausea and vomiting (20–45%), as the most common adverse effects of tigecycline (98C– 100C). Antiemetics are needed in 30% of cases and withdrawal in 4% (101R). Pancreas Pancreatitis has been attributed to tigecycline (102A).
Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines • A 35-year-old man was given tigecycline 50 mg bd by intravenous infusion over 30–60 minutes for chronic osteomyelitis. Nausea and vomiting occurred from the start of therapy, and 13 days later he developed an acute abdominal ‘stab-like’ pain. His serum lipase activity was up 16 times the upper limit of the reference range and a computed tomography (CT) scan showed pancreatic edema without necrosis. Abdominal echotomography and biliary echoendoscopy excluded biliary stones. Tigecycline was withdrawn and he rapidly improved, including resolution of the abdominal pain and vomiting. The lipase
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activity gradually normalized 43 days after withdrawal.
An unpublished manufacturers’ Phase III study of tigecycline showed raised amylase activity in 9 of 292 patients (3%) (103S). The authors emphasized that the second Periodic Safety Update Report had pre sented a cumulative review of 24 cases of acute pancreatitis, including cases from pre clinical studies and spontaneous reports; two were fatal.
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47. Frezza M, Garay J, Chen D, Cui C, Turos E, Dou QP. Induction of tumor cell apop tosis by a novel class of N-thiolated beta lactam antibiotics with structural modifica tions at N1 and C3 of the lactam ring. Int J Mol Med 2008;6:689–95. 48. Chen D, Falsetti SC, Frezza M, Milacic V, Kazi A, Cui QC, Long TE, Turos E, Dou QP. Anti-tumor activity of N-thiolated beta-lactam antibiotics. Cancer Lett 2008;268:63–9. 49. Jälevik B, Norén JG. Enamel hypominera lization of permanent first molars: a mor phological study and survey of possible aetiological factors. Int J Paediatr Dent 2000;10(4):278–89. 50. Jälevik B, Norén JG, Klingberg G, Barregård L. Etiological factors influen cing the prevalence of demarcated opaci ties in permanent first molars in a group of Swedish children. Eur J Oral Sci 2001;109(4):230–4. 51. Beentjes VE, Weerheijm KL, Groen HJ. Factors involved in the aetiology of molar– incisor hypomineraliation (MIH). Eur J Paediatr Dent 2002;3(1):9–13. 52. Laisi S, Ess A, Sahlberg P, Arvio P, Lukin maa PL, Alaluusua S. Amoxicillin may cause molar incisor hypomineralization. J Dent Res 2009;88:132–6. 53. GlaxoSmithKline. Prescribing information for Augmentin http:www.augmentin.com2. 54. van den Broek JW, Buennemeyer BL, Stricker BH. Cholestatische hepatitis door de combinatie amoxicilline en clavulaan zuur (Augmentin). [Cholestatic hepatitis due to amoxicillin and clavulanic acid (Aug mentin).] Ned Tijdschr Geneeskd 1988;132 (32):1495–7. 55. Cundiff J, Joe S. Amoxicillin–clavulanic acid-induced hepatitis. Am J Otolaryngol 2007;28(1):28–30. 56. Garcia Rodriguez LA, Stricker BH, Zim merman H. Risk of acute liver injury asso ciated with the combination of amoxicillin and clavulanic acid. Arch Intern Med 1996;156(12):1327–32. 57. De Abajo F, Montero D, Madurga M, García Rodríguez LA. Acute and clinically rele vant drug-induced liver injury: a population based case-control study. Br J Clin Pharma col 2004;58(1):71–80.
458 58. Salvo F, De Sarro A, Caputi AP, Polimeni G. Amoxicillin and amoxicillin plus clavula nate: a safety review. Expert Opin Drug Saf 2009;8(1):111–8. 59. Andrade RJ, Lucena MI, Kaplowitz N, García-Mun¸oz B, Borraz Y, Pachkoria K, García-Cortés M, Fernández MC, Pelaez G, Rodrigo L, Durán JA, Costa J, Planas R, Barriocanal A, Guarner C, Romero-Gomez M, Mun¸oz-Yag€ ue T, Salmerón J, Hidalgo R. Outcome of acute idiosyncratic druginduced liver injury: long-term follow-up in a hepatotoxicity registry. Hepatology 2006;44:1581–8. 60. Lucena MI, Andrade RJ, Fernández MC, Pachkoria K, Pelaez G, Durán JA, Villar M, Rodrigo L, Romero-Gomez M, Planas R, Barriocanal A, Costa J, Guarner C, Blanco S, Navarro JM, Pons F, Castiella A, Avila S, Spanish Group for the Study of DrugInduced Liver Disease (Grupo de Estudio para las Hepatopatías Asociadas a Medica mentos (GEHAM)). Determinants of the clinical expression of amoxicillin– clavulanate hepatotoxicity: a prospective ser ies from Spain. Hepatology 2008;44(4):850–6. 61. Lucena MI, Andrade RJ, Martínez C, Ulzurrun E, García-Martín E, Borraz Y, Fernández MC, Romero-Gomez M, Cas tiella A, Planas R, Costa J, Anzola S, Agún dez JA, Spanish Group for the Study of Drug-Induced Liver Disease. Glutathione S-transferase mM1 and T1 null genotypes increase susceptibility to idiosyncratic druginduced liver injury. Hepatology 2008;48 (2):588–96. Erratum in: 2009;49(3):1058. 62. Daly AK, Donaldson PT, Bhatnagar P, Shen Y, Pe’er I, Floratos A, Daly MJ, Goldstein DB, John S, Nelson MR, Graham J, Park BK, Dillon JF, Bernal W, Cordell HJ, Pir mohamed M, Aithal GP, Day CP, DILIGEN Study, International SAE Consortium. HLA-B*5701 genotype is a major determi nant of drug-induced liver injury due to flucloxacillin. Nat Genet 2009;41(7):816–9. 63. Xu B, Murray M. Flucloxacillin induced acute renal failure. Aust Fam Physician 2008;37:1009–11. 64. Kim Ky, Frey RJ, Epplen K, Furuhari F. Interaction between warfarin and nafcillin: case report and review of the literature. Pharmacotherapy 2007;27:1467–70.
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65. Lacey CS. Interaction of dicloxacillin with warfarin. Am Pharmacother 2004;38:898. 66. Alka G, Decreased MM. INR response sec ondary to warfarin–flucloxacillin inter action. Ann Pharmacother 2009;43:1374–5. 67. Lia NG, Shib ZH, Tang YP, Duan JA. Selective matrix metalloproteinase inhibi tors for cancer. Curr Med Chem 2009;16 (29):3805–27. 68. Supali T, Djuardi Y, Pfarr KM, Wibowo H, Taylor MJ, Hoerauf A, Houwing-Duistermaat JJ, Yazdanbakhsh M, Sartono E. Doxycycline treatment of Brugia malayi-infected persons reduces microfilaremia and adverse reactions after diethylcarbamazine and albendazole treatment. Clin Infect Dis 2008;46:1385–93. 69. Hoerauf A, Specht S, Buttner M, Pfarr K, Mand S, Fimmers R, Marfo-Debrekyei Y, Konadu P, Debrah AY, Bandi C, Brattig N, Albers A, Larbi J, Batsa L, Taylor MJ, Adjei O, Buttner DW. Wolbachia endo bacteria depletion by doxycycline as antfi larial therapy has macrofilaricidal activity in onchocerciasis: a randomised placebocontrolled study. Med Microbiol Immunol 2008;197:295–311. 70. Monaco F, Agnetti V, Mutani R. Benign intracranial hypertension after minocycline therapy. Eur Neurol 1988;144:218–20. 71. Ang ERG, Zimmerman C, Malkin E. Pseudotumor cerebri secondary to mino cycline intake. J Am Board Fam Pract 2002;15:229–33. 72. Lockhead J, Elston JS. Doxycycline induced intracranial hypertension. BMJ 2003; 326:641–2. 73. Friedman DI, Gordon IK, Egan RA, Jacob son DM, Pomeranz H, Harrison AR, Goldhammer Y. Doxycycline and intra cranial hypertension. Neurology 2004; 42:2297–9. 74. Tabibian JH, Gutierrez MA. Doxycyclineinduced pseudotomor cerebri. South Med J 2009;102:310–1. 75. French National Pharmacovigilance Com mittee. Fewer adverse effects with doxy cycline than with minocycline. Prescrire Int 2009;18(103):213. 76. Ono E, Miyazaki E, Matsuno O, Nureki S, Okubo T, Ando M, Kumamoto T. Mino cycline-induced acute eosinophilic pneumo nia: controversial results of lymphocyte
Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines
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83.
84.
85.
86.
87.
88.
stimulation test and re-challenge test. Intern Med 2007;46(9):593–5. Shimizu T, Shimizu N, Kinebuchi S, Toyama J. [Case of acute eosinophilic pneu monia probably induced by minocycline.] Nihon Kokyuki Gakkai Zasshi 2008;46 (2):136–40. Arai S, Shinohara Y, Kato Y, Hirano S, Yoshizawa A, Hojyo M, Kobayashi N, Sugiyama H, Kudo K. [Case of mino cycline-induced pneumonitis with bilateral pleural effusion.] Arerugi 2007;56(10): 1293–7. McAllum P, Slomovic A. Scleral and con junctival pigmentation following minocy cline therapy. Can J Ophthalmol 2007;42 (4):626–7. Zoraster RM, Rison RA. Severe lactic acidosis secondary to minocycline in a teen ager with infectious mononucleosis and mitochondrial myopathy. Clin Neurol Neurosurg 2008;110(6):627–30. Losanoff JE, Holder-Murray JM, Ahmed EB, Cochrane AB, Testa G, Millis JM. Minocycline toxicity requiring liver trans plant. Dig Dis Sci 2007;52(11):3242–4. Fay BT, Whiddon AP, Puumala S, Black NA, O’Dell JR, Mikuls TR. Minocycline induced hyperpigmentation in rheumatoid arthritis. J Clin Rheumatol 2008;14(1):17–20. Huq F, Durso SC. Spurious bruising in a patient taking warfarin: minocycline induced skin hyperpigmentation. J Am Geriatr Soc 2008;56(6):1156–7. Bowen AR, McCalmont TH. The histo pathology of subcutaneous minocycline pig mentation. J Am Acad Dermatol 2007;57 (5):836–9. Soung J, Cohen J, Phelps R, Cohen SR. Case reports: minocycline-induced hyper pigmentation resolves during oral isotreti noin therapy. J Drugs Dermatol 2007;6(12): 1232–6. Ban M, Kitajima Y. Nail discoloration occurring after 8 weeks of minocycline ther apy. J Dermatol 2007;34(10):699–701. El-Hallak M, Giani T, Yeniay BS, Jacobs KE, Kim S, Sundel RP, Dedeoglu F. Chronic minocycline-induced autoimmunity in chil dren. J Pediatr 2008;153(3):314–9. Egiguren L, Minondo L, Zapata E, Castiella A. Paciente con hepatitis autoinmunitaria y
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94.
95.
96.
97.
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púrpura trombocitopénica idiopática tras un tratamiento con minociclina. [Patient with autoimmune hepatitis and idiopathic thrombocytopenic purpura after minocycline therapy.] Gastroenterol Hepatol 2007;30(9): 565–6. Maubec E, Wolkenstein P, Loriot MA, Wechsler J, Mulot C, Beaune P, Revuz J, Roujeau JC. Minocycline-induced DRESS: evidence for accumulation of the culprit drug. Dermatology 2008;216(3):200–4. Favrolt N, Bonniaud P, Collet E, Fayard M, Rabec C, Camus C, Bour JB, Camus P. Syndrome d’hypersensibilité médicamen teuse avec manifestations systémiques sévères après traitement par minocycline. [Severe drug rash with eosinophilia and sys temic symptoms after treatment with mino cycline.] Rev Mal Respir 2007;24(7):892–5. Marzo-Ortega H, Baxter K, Strauss RM, Drysdale S, Griffiths B, Misbah SA, Gough A, Cunliffe WJ, Emery P. Is mino cycline therapy in acne associated with antineutrophil cytoplasmic antibody positivity? A cross-sectional study. Br J Dermatol 2007;156(5):1005–9. Tehrani R, Nash-Goelitz A, Adams E, Dahiya M, Eilers D. Minocycline-induced cutaneous polyarteritis nodosa. J Clin Rheumatol 2007;13(3):146–9. Gait RC, Affleck AG, Leach IH, Varma S. Perinuclear antineutrophilic cytoplasmic antibody-positive polyarteritis nodosa sec ondary to minocycline treatment for acne vulgaris. J Am Acad Dermatol 2008; 58(5 Suppl 1):S123–4. Geddes R. Minocycline-induced lupus in adolescents: clinical implications for physi cal therapists. J Orthop Sports Phys Ther 2007;37(2):65–71. Benjamin RW, Calikoglu AS. Hyperthyroid ism and lupus-like syndrome in an adolescent treated with minocycline for acne vulgaris. Pediatr Dermatol 2007;24(3):246–9. Bruins NA, Oswald JE, Morreau H, Kievit J, Pavel S, Smelt AH. Papillary thyroid car cinoma in a patient with sarcoidosis treated with minocycline. Neth J Med 2007;65(5): 185–7. Miller CS, McGarity GJ. Tetracyclineinduced renal failure after dental treatment. J Am Dent Assoc 2009;140:56–60.
460 98. Sacchidanand S, Penn RL, Embil JM, Cam pos ME, Curcio D, Ellis-Grosse E, Loh E, Rose G. Efficacy and safety of tigecycline monotherapy compared with vancomycin plus aztreonam, in patients with compli cated skin and skin-structure infections: results from a Phase III randomized dou ble-blind trial. Int J Infect Dis 2005;9 (5):251–61. 99. Breedt J, Teras J, Gardovskis J, Maritz FJ, Vaasna T, Ross DP, Gioud-Paquet M, Dar tois N, Ellis-Grosse EJ, Loh E, Tigecycline 305 cSSSI Study Group. Safety and efficacy of tigecycline in treatment of skin and skin-structure infections: results of a double-blind Phase III comparison study with vancomycin–aztreonam. Antimicrob Agents Chemother 2005;49(11):4658–66. 100. Ellis-Grosse EJ, Babinchak T, Dartois N, Rose G, Loh E. The efficacy and safety of
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tigecycline in the treatment of skin and skin-structure infections: results of 2 dou ble-blind Phase III comparison studies with vancomycin–aztreonam. Clin Infect Dis 2005;4(Suppl 5):341–53. 101. Zhanel GG, Karlowsky JA, Rubinstein E, Hoban DJ. Tigecycline: a novel glycyl cycline antibiotic. Exp Rev Am Infect Dis 2006;4:9–25. 102. Gilson M, Moachon L, Jeanne L, Dumaine V, Eyrolle L, Morand P, Ben m’Rad MB, Salmon D. Acute pancreatitis related to tige cycline: case report and review of the litera ture. Scand J Infect Dis 2009;40(8):681–3. 103. Calvo G (rapporteur), Marcia MA, MartinSerrano G (pharmacovigilance assessors), Fenandez-Cortizo MJ (clinical assessor). Tygacyl. Second Periodic Safety Update Report – Preliminary Assessment Report, 15 Jan 2005 to 14 Dec 2006. 1 April 2007.
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26
Miscellaneous antibacterial drugs
AMINOGLYCOSIDE ANTIBIOTICS (SED-15, 118; SEDA-29, 253; SEDA-30, 297; SEDA-31, 427) Sensory systems The use of aminoglyco sides in Ménière’s disease and the inci dence, mechanism, susceptibility factors, and prevention of ototoxicity have been reviewed, based on published literature from 1966 to 2004 (1R). Streptomycin and gentamicin primarily cause vestibular toxi city, whereas amikacin, neomycin, and kana mycin primarily cause cochlear toxicity. In a review of studies published between 1975 and January 2008 there was no corre lation of serum aminoglycoside concentra tions with vestibular toxicity but there was an effect of duration of therapy (2R). Ototoxicity was evaluated in 64 patients with tuberculosis, of whom 34 received amikacin, 26 kanamycin, and 4 capreo mycin, with a mean treatment duration of 20 months; 19% developed irreversible hearing loss and 6.3% had involvement of speech frequencies (3c). Urinary tract In a case–control study of 24 patients with cystic fibrosis, aminoglycoside therapy was associated with an increased risk of renal insufficiency, and gentamicin was more nephrotoxic than tobramycin (4c).
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32026-5 � 2010 Elsevier B.V. All rights reserved.
Amikacin
(SED-15, 111; SED A-29, 253; SEDA-31, 427)
Sensory systems Vestibular function has been evaluated by caloric testing and vestibular-evoked myogenic potentials (VEMPs) in 28 infants before and after treatment with systemic amikacin 15 mg/ kg/day over 10–14 days for respiratory tract infections or sepsis (5c). There were abnormal results in both VEMP (n = 4) and caloric testing (n = 6), without signs of hearing loss. Drug dosage regimens There was no significant difference in nephrotoxicity when amikacin 15 mg/kg/day or 12.5 mg/kg bd was given to 40 adults with hematolo gical malignancies (6c). However, because of differences in susceptibility factors between the groups these results must be interpreted cautiously.
Gentamicin
(SED-15, 1500; SEDA-29, 253; SEDA-30, 297; SEDA-31, 427)
Sensory systems Eyes The retinal toxicity of intravitreal gentamicin has been briefly reviewed (7r). A 75-year-old diabetic man developed retinal toxicity after subconjunc tival gentamicin injection following vitrect omy. The authors suggest that gentamicin should be avoided for this indication (8A). Ears Vincristine neurotoxicity on the medial olivocochlear bundle (MOCB) was not increased by adding different cumulative
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doses of gentamicin in 12 children with acute lymphoblastic leukemia being treated with the BMF-95 protocol (vincristine, daunorubicin, asparaginase, cyclophosphamide þ mesna, cytarabine, mercaptopurine, prednisone, and methotrexate) (9c). Impaired evoked vestibulo-ocular reflexes (eVORs) in 12 patients with disequilibrium after gentamicin treatment compared with healthy volunteers suggested that vestibular hair cell function might act as a the marker of gentamicin vestibular toxicity (10c). In 40 patients receiving hemodialysis who were given either gentamicin alone or with N-acetylcysteine, significantly fewer of the latter had ototoxicity; the authors concluded that acetylcysteine might be oto protective, mainly in the high audiometric tone frequency range (11c). Mineral metabolism In a retrospective analysis of 1624 neonates, serum calcium concentrations were measured during genta micin therapy (12c). There was hypocalcemia (<2.0 mmol/l) in 15 and 23% were still hypo calcemic when a second measurement was made, although 30% were given oral cal cium. The authors suggested that calcium concentrations should be monitored when gentamicin is given for more than 4 days in neonates. Urinary tract The mechanisms of the adverse effects of aminoglycosides, mainly gentamicin-induced glomerular nephrotoxicity, have been reviewed in detail (13R). In a retrospective review of 24 patients with cystic fibrosis, an aminoglycoside had been prescribed at onset of acute renal insufficiency in 88%, and 76% of these had been given gentamicin (14c). A renal biopsy showed tubular necrosis in six of seven patients. There was complete recovery in 92%. Immunologic A 69-year-old man developed urticaria, hypotension and loss of consciousness within minutes of receiving intravenous genta micin; prick tests and patch tests with genta micin were positive (15A).
Natascia Corti, Alexander Imhof, and Christa Wenger
Fetotoxicity There were no signs of ototoxi city in 40 infants who were tested for audiolo gical impairment after their mothers had been given a mean cumulative gentamicin dose of 764 mg during pregnancy, with a mean treat ment duration of 2.7 days (16c). Susceptibility factors Genetic A new possible genetic association with ototoxicity has been described (17A). • A 44-year-old woman had acute bilateral hearing loss after receiving two intravenous doses of gentamicin 80 mg given before and during urological surgery. She had an A1438G mutation in the ribosomal 12 rRNA gene, which has not previously been associated with aminoglycoside toxicity but lies within the region of the 1555 position, where mutations may facilitate aminoglycoside induced cochlear dysfunction.
Children In a review of the safety of gent amicin in children, nephrotoxicity and oto toxicity were relatively uncommon, although most of the studies reviewed were relatively small (18R). The authors concluded that short-term administration of gentamicin at the recommended dose is appropriate even without serum gentamicin concentration monitoring. Drug dosage regimens Once-daily genta micin dosage adjustment for gestational age and birth weight yielded desirable peak gen tamicin plasma concentrations and trough concentrations under 2 mg/l in 49 Thai neo nates with normal renal function; there was no renal impairment (19c). Different gentamicin dosage regimens have been compared in 68 neonates; 21 received 2.5 mg/kg/12 hours and the other 47 receiving a dose that was based on gesta tional age, body weight and clinical condi tion; only 5 in the first group had serum concentrations in the usual target range compared with 32 of the others (20c).
Neomycin
(SEDA-30, 297)
Skin The incidences of contact allergy from topical drugs have been reported in
Miscellaneous antibacterial drugs
Chapter 26
an epidemiological study (21C). The denomi nator (the number of patients who were tested) was estimated using data on the sales of patch tests. The numerator was estimated from data collected by a network of dermatologists in Germany who recorded the test results of patch tests. The estimated incidences were 1–69 per 100 000 person-years in the general population. This figure depends on the drug, assumptions in the calculation and the period of use. Neomycin gave the highest rate (29 per 100 000 person-years) and polymyxin B sul fate the lowest (1 per 100 000 person-years). These rates do not reflect the risk of the drug, since the calculated incidence also depends on the number of patients who have received it. Topical eye-drops can also cause general ized allergic reactions. A patient with an allergy to neomycin developed increased facial erythema, swelling, and crusting around the eyelids and a generalized rash while using Maxitrol (dexamethasone þ neomycin) (22A).
Paromomycin Comparative studies Intramuscular paromo mycin 375 mg for 21 days has been compared with intravenous amphotericin 1 mg/kg every other day for 30 days in an open randomized trial in 667 patients with visceral leishmania sis (23c). Paromomycin was associated with transient rises in AsT activity (6%), transient reversible ototoxicity (2%), and injection site pain (55%) significantly more often than amphotericin.
Streptomycin Sensory systems Selective damage to the vestibular system has been reported in a patient who was given intramuscular strep tomycin for bronchopneumonia (24A). Skin In a retrospective evaluation of 820 patients with active tuberculosis strepto mycin was the second major drug (1.45%)
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after pyrazinamide (2.38%) to cause cuta neous adverse drug reactions (total 5.7%) (25c).
Tobramycin
(SED-15, 3437; SEDA-29, 254; SEDA-30, 297; SEDA-31, 428)
Uses The efficacy and safety of tobramycin solution for inhalation in patients with cystic fibrosis have been reviewed (26R). Cyclical treatment with inhaled tobramycin seems to improve pulmonary function and reduce hospitalization rates and the use of systemic antibiotics. Respiratory Severe persistent broncho spasm and recurrent eosinophilia were associated with inhaled tobramycin solution in a patient with cystic fibrosis (27A). In another case bronchospasm and eosino philia occurred after ocular administration of tobramycin 0.3% (28A). Liver Possible tobramycin-induced hepato toxicity has been reported in a 20-year-old woman with Pseudomonas aeruginosa bacter emia and osteomyelitis (29A). Drug formulations In a multinational, double-blind, multicenter study, 247 patients with cystic fibrosis and chronic P. aeruginosa infection were randomized to a highly con centrated solution of nebulized tobramycin 300 mg (75 mg/ml) or placebo over 24 weeks, with 4-week treatment periods followed by 4 weeks without treatment (30C). Tobramycin significantly improved lung function and nutritional status and reduced the frequency of hospitalization. There were no significant changes in serum creatinine or auditory function. In a similar study in 59 patients who were randomized to a highly concentrated solu tion of nebulized tobramycin or placebo for 4 weeks, those who were given tobramycin had fewer treatment-related adverse events and there were no signs of renal or auditory toxicity (31c). Tobramycin powder for inhalation has been compared with tobramycin solution
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for inhalation in 84 patients with cystic fibro sis (32c). Serum tobramycin profiles were similar in the two groups. Adverse events associated with the powder were doserelated cough (20%) and dysgeusia (17%). Drug dosage regimens Intravenous tobra mycin if given once a day may be associated with an increased risk of toxicity compared with three times a day dosage, because the AUC is higher, despite target trough con centrations under 1 mg/l. It has therefore been suggested that AUC should be mea sured rather than trough concentrations when once-daily tobramycin is used (33r). Drug administration route In 19 patients undergoing continuous venovenous hemo dialysis who took oral tobramycin for decon tamination of the digestive tract, tobramycin was detectable in the plasma in 12 and in one case the tobramycin concentration was in the toxic range (3 mg/ml) (34c). In a pilot study in 10 patients with venti lator-associated pneumonia treated with either inhaled tobramycin or intravenous tobramycin, inhaled tobramycin appeared to be safe and effective (35c).
CHLORAMPHENICOL AND RELATED DRUGS (SED-15, 706; SEDA-29, 254; SEDA-30, 298; SEDA-31, 429) Uses The use of chloramphenicol and other older antibiotics in critically ill patients has been reviewed, with discussion of the possi ble usefulness of chloramphenicol in the treatment of vancomycin-resistant entero cocci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) (36R). Immunologic Of allergens tested for con tact sensitivity in patients with venous leg ulcers, chloramphenicol was one of the most commonly implicated (37c).
Natascia Corti, Alexander Imhof, and Christa Wenger
FLUOROQUINOLONES (SED-15, 1396; SEDA-29, 254; SEDA-30, 298; SEDA-31, 429) In a review of the literature on fluoroquino lones published between 1966 and 2007, the authors concluded that the incidence of ser ious adverse events is hard to determine. Gatifloxacin increases the risk of hospitaliza tion for dysglycemia in patients with and without diabetes, but dysglycemia can occur with any fluoroquinolone. Fluoroquinolones should be avoided in patients with a risk of QT interval prolongation and/or tendinopathy and caution is advised in those with a history of seizures. Phototoxicity can occur (38R).
Systematic reviews Fluoroquinolones and beta-lactams have been compared in a meta-analysis of 11 randomized controlled trials (39M). Adverse events did not differ significantly between the groups; nausea and diarrhea were the major adverse events. Cardiovascular Dysrhythmias associated with fluoroquinolones therapy have been reviewed. Moxifloxacin was associated with the greatest risk of QT interval prolongation, with lower risks for gemifloxacin, levofloxa cin, and ofloxacin; the lowest risk was attrib uted to ciprofloxacin (40R). Two cases of QT interval prolongation with torsade de pointes have been reported. • A 16-year-old boy, who had received intravenous ciprofloxacin 400 mg bd and metronidazole 500 mg 6-hourly for acute Crohn’s disease, developed reversible QT interval prolongation to 486 ms and a bradycardia (41A). • A 66-year-old man with an implanted cardioverter-defibrillator had QT interval prolongation and multiple episodes of torsade de pointes when ciprofloxacin and azimilide were co-administrated (42A).
Nervous system In a review of druginduced mania, fluoroquinolones were listed among the drugs that are most frequently implicated (43r).
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Sensory systems The ocular toxicity of fluoroquinolones has been reviewed (44R). Fluoroquinolones are generally safe when used to treat ocular infections. Minor adverse effects include local irritation, stinging, chemosis, conjunctival hyperemia, and super ficial punctuate keratitis. Reversible corneal precipitation can lead to delayed corneal healing and perforation in 10% of cases. Gastrointestinal Based on a literature review it has been concluded that fluoroquinolones seem to predispose patients to diarrhea associated with Clostridium difficile (45M). Musculoskeletal Several cases of fluoro quinolone-induced tendinopathy have been reported. Two were caused by levofloxacin and five by ciprofloxacin (46A–49A). In four studies of arthropathy in children there was only a weak association with different fluoroquinolones (50R). Immunologic The incidence of allergic reactions in a retrospective cohort study of patients taking fluoroquinolones was 4.5–8.7 per 10 000; the incidence of anaphylaxis was 0.1–0.5 per 10 000 (51c). Susceptibility factors Age Adverse events in patients taking fluoroquinolones have been reviewed. In elderly people there was no increase in the incidence of significant adverse effects (52R). There was a small rise in transaminases in 2–3% and severe hepatic damage in rare cases with cipro floxacin, gatifloxacin, levofloxacin, and moxifloxacin. Renal damage is rare. Dysglycemia can occur especially in elderly patients. Torsade de pointes has been asso ciated with gatifloxacin in 27 per 10 million prescription, with levofloxacin in 5.4 and with ofloxacin in 2.1.
Ciprofloxacin
(SED-15, 783; SEDA-29, 255; SEDA-30, 298; SEDA-31, 429) Nervous system An 84-year-old woman was given ciprofloxacin 500 mg bd for a wound infection but took it four times a day by mistake. After 3 days she developed slurring of speech and a palatal tremor.
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Ciprofloxacin was withdrawn and valproate was started. The symptoms resolved within 2 days (53A). Sensory systems A toxic optic neuropathy has been attributed to ciprofloxacin (54A). • Because of multiple bone injuries and chronic osteomyelitis a 55-year-old man was treated repeatedly with oral ciprofloxacin, maximum dose 1500 mg/day, over a cumulative period of 6 years. He developed progressive dimming and blurring of vision. His vision improved progressively over the next few months after withdrawal of ciprofloxacin.
Psychiatric A 45-year-old woman developed a progressive acute polymorphic psychosis after taking ciprofloxacin 500 mg bd for 4 weeks (55A). Hematologic Coagulopathy has been attributed to ciprofloxacin in two patients with cystic fibrosis (56A). • In a 29-year-old woman the international normalized ratio (INR) rose from 1.0 to 3.4 within 2 days of treatment with intravenous ciprofloxacin 400 mg bd. The activated partial thromboplastin time (aPTT) rose from 22 seconds while she was receiving subcutaneous enoxaparin to 41 seconds. Ciprofloxacin was changed to ceftazidime and both values returned to baseline within 24 hours. • In an 18-year-old woman with a high serum creatinine and normal liver function, the INR was 2.6 and the aPTT 45 seconds after she had taken oral ciprofloxacin 1 g bd and rifampicin 300 mg bd for 5 days; the INR returned to baseline 1 week later and the serum creatinine 3 weeks later.
Liver Three cases of ciprofloxacin-induced liver damage have been reported. • A 65-year-old man with an ischemic cardiomyopathy developed acute cholestatic jaundice with liver failure and acute renal failure requiring hemodialysis after taking ciprofloxacin 500 mg bd for 6 days for cellulitis (57A). A liver biopsy was consistent with drug-induced liver damage. After withdrawal of ciprofloxacin his renal function improved and the liver tests normalized within 5 months. • A 26-year-old man developed jaundice, weakness and anorexia preceded by a rash after taking ciprofloxacin for 5 days for
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diarrhea; the liver enzymes gradually normalized over 6 months (58A). • A 39-year-old woman with a diverticular abscess was given oral ciprofloxacin 500 mg bd and metronidazole 500 mg bd for 14 days and developed nausea, icterus and raised liver enzymes (59A). A liver biopsy showed infiltration of the portal tracts by a mixed inflammatory infiltrate with prominent eosinophils. She was given tapering doses of prednisone and the liver enzymes normalized over 3 months.
had syncope, QTc interval prolongation from 422 to 456 ms, and a polymorphous ventricular tachycardia (65A). Methadone was changed to buprenorphine and the QTc interval shortened. He had no further episodes of dizziness or syncope.
Skin Ciprofloxacin has been associated with a generalized bullous fixed drug eruption in a 57-year-old woman (60A) and with pseudoporphyria in a 65-year-old woman with sunlight exposure during cipro floxacin therapy (61A).
Observational studies Oral gatifloxacin has been evaluated in 108 patients with neutropenia aged 3–21 years (66c). There were adverse events in 11, including electro cardiographic changes (5%), diarrhea (3.5%), increased liver enzymes (2%), vomiting, (1.5%) and arthralgia (0.5%).
Immunologic Vasculitis has been attribu ted to ciprofloxacin (62A). • A 50-year-old man developed a purpuric rash on his legs after taking ciprofloxacin for 10 days for urinary sepsis. His symptoms improved with oral glucocorticoids, but 2 months later his plasma creatinine rose and he had proteinuria and an increased blood pressure. A renal biopsy showed diffuse glomerular proliferation. Renal function improved over 6 months without further therapy with corticosteroids.
Drug-drug interactions Clozapine Inter actions of ciprofloxacin with clozapine have been reported. • A 47-year-old man had an increase in clozapine exposure by 4.6 times after taking ciprofloxacin for 4 days, despite a clozapine dosage reduction from 750 to 500 mg bd, which had been undertaken before starting ciprofloxacin (63A). • A 64-year-old woman taking ciprofloxacin had clozapine 125 mg bd added and developed somnolence and dizziness within a few days. Clozapine and norclozapine concentrations were 1043 and 432 ng/ml, respectively. Her symptoms resolved after withdrawal of clozapine (64A).
Methadone After self-medication with ciprofloxacin 400 mg bd while he was taking methadone 120 mg/day, a 56-year-old man
Gatifloxacin
(SED-15, 1482; SEDA-29, 256; SEDA-30, 299; SEDA-31, 431)
Nervous system Two elderly patients with histories of convulsions developed general ized status epilepticus during treatment with oral gatifloxacin (67A).
Sensory systems A 30-year-old man devel oped a corneal perforation after using gati floxacin for an inflamed pterygium (68A). The corneal perforation may have been caused by a combination of corneal thinning and dellen formation secondary to the inflamed pterygium, since fluoroquinolones affect keratocytes. Psychiatric Gatifloxacin-induced psychosis has been reported in 60- and 62-year-old men with pre-existing stable schizoaffective disorders (69A). Metabolism The rate of fluoroquinolone associated dysglycemia is highest with gati floxacin, and most patients who experience fluoroquinolone-associated dysglycemia have diabetes mellitus (70R). It has therefore been suggested that gatifloxacin should be avoided in patients with diabetes mellitus, especially those taking sulfonylureas and those with hepatic or renal insufficiency.
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In a retrospective nested case–control study in 69 patients and 69 controls, dia betes mellitus, concomitant use of gluco corticoids and higher doses of gatifloxacin were associated with gatifloxacin-induced hyperglycemia (71c). Hypoglycemia associated with gatifloxacin has been reported in 4 of 3838 individuals and compared with 19 published cases (72cr). The patients generally had diabetes, were taking glibenclamide and developed hypo glycemic symptoms within a few hours. In some cases renal insufficiency was present. The hypoglycemia resolved within a few hours after withdrawal of gatifloxacin. In a retrospective cohort study in 532 patients taking gatifloxacin and 405 elderly patients taking levofloxacin, hypoglycemia and hyperglycemia were more often asso ciated with gatifloxacin than with levo floxacin (adjusted OR = 25 and 2.4, respectively) (73c). Musculoskeletal A 50-year-old man took gatifloxacin 200 mg/day for a urinary tract infection with renal insufficiency and devel oped rhabdomyolysis, with a creatine kinase activity of 5915 U/l; his symptoms resolved after withdrawal of gatifloxacin (74A).
Levofloxacin
(SED-15, 2047; SEDA-29, 257; SEDA-30, 299; SEDA-31, 432)
467 • A previously healthy 42-year-old woman took levofloxacin, meclizine, and guaifenesin þ phenylpropanolamine for sinusitis and vertigo for 2 days and developed insomnia; by day 4 she had developed agitation, paranoia, and visual and auditory hallucinations. Her symptoms resolved after withdrawal of levofloxacin (77A). • A 50-year-old man developed a psychosis after taking levofloxacin for 3 days (78A).
Metabolism Hypoglycemia has again been attributed to levofloxacin. • A critically ill 63-year-old man had several episodes of hypoglycemia while receiving levofloxacin for post-operative peritonitis after resection of a large liposarcoma; he developed a quadriplegia and hypoglycemiainduced central pontine myelinolysis (79A). • An 86-year-old woman with chronic respira tory insufficiency and insulin-treated type 2 diabetes had episodes of severe hypoglycemia while taking levofloxacin 500 mg/day for a respiratory infection, despite interruption of insulin treatment (80A). The blood glucose concentrations gradually returned to normal 3 days after withdrawal of levofloxacin.
Hematologic Thrombocytopenia has been attributed to levofloxacin (81A). • A 71-year-old woman with chronic renal insuf ficiency developed severe thrombocytopenia (3 109/l) with hematomas and petechiae while taking levofloxacin for an upper respira tory tract infection; after withdrawal of levo floxacin the platelet count normalized within 7 days.
Nervous system In a post-marketing sur veillance of spontaneous reports in Japan patients with nephropathies, aged over 75 years, and patients with a history of convul sions were more likely to have convulsions during levofloxacin therapy (75c). A patient developed benign cranial hypertension after taking levofloxacin for 3 weeks following an orbital fracture after a fall from the horse; there was no trauma to the brain or sinus venous thrombosis; the symptoms resolved 1 week after withdrawal of levofloxacin (76A).
Urinary tract Tubulointerstitial nephritis has been attributed to levofloxacin (82A).
Psychiatric Acute psychoses have been attributed to levofloxacin.
Musculoskeletal Five cases of Achilles ten dinopathy and rupture were associated with
• A 67-year-old man developed renal insuffi ciency caused by tubulointerstitial nephritis with kidney enlargement after taking levoflox acin. After withdrawal of the drug and predni sone treatment his renal function improved and his kidney size reduced.
Skin A 50-year-old woman with breast cancer developed radiation-recall dermatitis while taking levofloxacin 500 mg bd 3 years after radiation therapy (83A).
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levofloxacin and additional glucocorticoid treatment in four cases in patients aged over 60 years (84A, 85A). Dosage regimens High-dose levofloxacin 750 mg/day for 5 days has been compared with 500 mg/day for 10 days in a pooled data analysis of 1141 and 3268 patients (86M). Treatment-related adverse events that occurred in more than 2% included nausea, headache, diarrhea, insomnia, constipation, abdominal pain, dizziness, dyspepsia, and vomiting. Only vomiting and abdominal pain were more common in the high-dose group (6.5% versus 3.1%). Drug-drug interactions Warfarin The INR rose to over 6.0 when warfarin and levo floxacin were combined in three patients, although the authors pointed out that several retrospective studies have not shown evidence of this interaction (87A). A 70-year-old woman and an 80-year-old woman developed hemopericardium and a 34-year-old woman had a retroperitoneal hematoma.
Moxifloxacin
(SED-15, 2392; SEDA-29, 257; SEDA-30, 300; SEDA-31, 434)
In elderly patients taking moxifloxacin 400 mg/day in clinical trials, the most common complaints were nausea (7.1%), diarrhea (5.2%), and dizziness (2.6%) (88R). Single cases of tendinitis, nephrotoxi city, and cholestasis have been described. Because of central nervous adverse events, elderly patients should be under close supervision when taking fluoroquinolones. Comparative studies In a comparison of patients taking moxifloxacin (n = 71) versus ampicillin þ sulbactam (n = 68), the overall incidence of adverse effects was similar in the two groups. Treatment-related adverse events were single cases of drug hypersensi tivity, fever, raised liver enzymes, and pro longation of the QT interval in a patient with multiple susceptibility factors (89c).
Natascia Corti, Alexander Imhof, and Christa Wenger
Cardiovascular Three cases of moxifloxa cin-induced QT interval prolongation with torsade de pointes have been reported (90A–92A). All three were elderly – two women aged 87 years and a man aged 74. There was pre-existing cardiovascular dis ease with congestive heart failure or atrial fibrillation in two patients and renal insuffi ciency in one. In two cases moxifloxacin was given intravenously and in one orally at a dose of 400 mg/day. Hematologic Moxifloxacin-induced revers ible neutropenia occurred in a 77-year-old patient with cirrhosis who took moxifloxacin for cellulitis of the leg (93A). Skin A 72-year-old man with throat cancer, benign prostatic hyperplasia, and hypertension developed a vesicobullous eruption on his trunk after taking moxiflox acin for 7 days for an upper respiratory tract infection (94A). Histology showed linear immunoglobulin A bullous dermatitis. Musculoskeletal Cases of arthritis have been attributed to moxifloxacin. • A previously healthy 12-year-old boy was given moxifloxacin 2 g/day by mistake for a mild upper respiratory infection (95A). Two days later he developed severe bilateral polyarthritis. Immunological and infective causes were excluded and the symptoms improved within the next week. • An 88-year-old Chinese man developed a painful monoarthritis of the right wrist joint after taking moxifloxacin 400 mg/day plus isoniazid, rifampicin, and pyrazinamide for pulmonary tuberculosis (96A). The symptoms subsided quickly when the moxifloxacin was withdrawn and a second episode affecting the left wrist developed after it was reintroduced.
Immunologic A hypersensitivity syndrome with a rash and drug-induced hypersensitiv ity pneumonitis has been attributed to moxifloxacin (97A). • After taking moxifloxacin for 7 days for respiratory tract infection, a 50-year-old man developed a generalized maculopapular rash, a high fever and slightly raised transaminases.
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A CT scan of the chest showed interlobular septal thickening and ground glass opacities. The symptoms and the CT changes resolved after withdrawal of moxifloxacin.
Drug administration route Moxifloxacin eye-drops are used to prevent post-opera tive endophthalmitis after cataract surgery and it can be given by intracameral injec tion. Its adverse effects have been summar ized (98R). They stated that in three studies in 1765 humans no deleterious effects of intracameral moxifloxacin after cataract surgery had been observed. Drug–drug interactions Warfarin In a 74 year-old man taking warfarin after a mitral valve replacement the INR increased to 12 after moxifloxacin was added (99A).
Ofloxacin (SED-15, 2597; SEDA-29, 258; SEDA-30, 300; SEDA-31, 434) Musculoskeletal An 8-year-old boy devel oped right hip arthropathy after taking oral ofloxacin 15 mg/kg/day for 7 days; the pain and functional disability subsided gradu ally on withdrawal of the drug (100A).
GLYCOPEPTIDES
(SEDA-29,
260; SEDA-30, 435) Systematic reviews Publications since 1980 on skin reactions caused by glyco peptides have been reviewed; of 50 articles, most were case reports (101M). ‘Red man syndrome’ was the most common reaction (> 1000 cases). There were more than 20 cases of IgA linear dermatosis and maculo papular rash and single case reports of vancomycin-induced anaphylaxis, erythroderma, toxic epidermal necrolysis, and vasculitis. Skin reactions were reported significantly less often with teicoplanin. Cross-reactivity with vancomycin was postulated for most of
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the skin reactions, apart from the ‘red man syndrome’ and IgA linear dermatosis. Hematologic Agranulocytosis occurred in a 57-year-old woman after 24 days of van comycin therapy (102A). It resolved within 4 days after switching to teicoplanin but recurred on day 11. Possible cross-reactivity with teicoplanin was postulated. Urinary tract Renal function has been monitored prospectively in two groups of 50 patients with neutropenia and persistent fever (103c). One group received teico planin combined with gentamicin and piper acillin þ tazobactam and the other received vancomycin combined with meropenem and levofloxacin. Vancomycin and con comitant treatment with amphotericin were independently associated with an increased risk of nephrotoxicity. Immunologic DRESS (Drug-induced rash with eosinophilia and systemic symptoms) occurred in a 52-year-old Japanese woman with a meticillin-resistant post-operative ear wound after treatment with teicoplanin for 2 weeks (104A). Vancomycin was substi tuted, and a few days later she developed a high fever with generalized lymphadeno pathy, facial edema, leukocytosis, eosino philia and hepatic and renal dysfunction. The reaction was associated with reactiva tion of human herpesvirus-6 (HHV-6). After withdrawal of the glycopeptides and treatment with glucocorticoids her symp toms improved.
Teicoplanin
(SED-15, 3305; SEDA-29, 260; SEDA-30, 301)
Skin A 54-year-old woman with a T-cell lymphoma developed a pruriginous maculopapular rash after taking teico planin and co-trimoxazole for 7 days (105A). Provocation tests were carried out: co-trimoxazole was negative but intra venous teicoplanin was positive. However, a controlled challenge with vancomycin was well tolerated.
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Natascia Corti, Alexander Imhof, and Christa Wenger
(SED-15, 3593; SEDA-29, 261; SEDA-30, 301)
an infected total knee arthroplasty with combined gentamicin- and vancomycinimpregnated cement (111A). Acute interstitial nephritis with a raised eosinophil count was associated with combined treatment with vancomycin and ceftriaxone in two cases (112A). Despite persistently normal serum creati nine concentrations and estimated glomer ular filtration rate (eGFR), inappropriate doses of vancomycin led to toxic concentra tions and initially unrecognized worsening of kidney function in an emaciated HIVinfected man (113A). The authors pointed out that serum creatinine and eGFR may be misleading when estimating renal function or nephrotoxicity in HIV-infected patients with low muscle mass. Nephrotoxicity has been investigated in five neonates receiving prolonged treat ment with aminoglycosides and vancomycin (114c). Although serum drug concentrations were maintained in the usual target ranges, there was renal tubular wasting of potas sium, phosphate, and calcium, along with hypokalemia in all five and a transient rise in serum creatinine in four. Nephrotoxicity from more aggressive vancomycin dosing has been evaluated in 94 patients with meticillin-resistant S. aureus pneumonia in a retrospective observational cohort study (115c). Vancomycin serum trough concentrations of over 15 mg/l were independently associated with renal toxicity (adjusted OR = 2.82) and with a larger change in creatinine clearance (–19 ml/minute) than vancomycin trough concentrations below 15 g/l (–7.6 ml/minute). In another study, increased vancomycin doses of more than 4 g/day in 26 patients were compared with doses of 4 g/day or less in 220 patients and with linezolid (116c). There was a significantly higher rate of nephrotoxicity in the high-dose group than in the low-dose group (35% versus 11%) and compared with linezolid (6.7%).
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Vancomycin
Respiratory Acute non-cardiogenic pul monary edema developed in a 57-year-old man 4 hours after a first intravenous dose of vancomycin 1 g for cellulitis (106A). The edema resolved within 12 hours after treatment with furosemide, diphenhydra mine, and famotidine. Sensory systems In a review of intravitreal injections of antibiotics and antiviral drugs, vancomycin was considered to be safe if injected at doses of 1 g and at intervals of 48 hours (107R). Retinal toxicity can occur if doses of 10 g and over are injected. Hematologic In a prospective study in Japanese patients with MRSA nosocomial pneumonia, complicated skin and softtissue infections and sepsis were treated with either linezolid or vancomycin. Rever sible anemia and thrombocytopenia were reported more often in those who received linezolid, but significantly lower platelet counts were more common in those who received vancomycin (108c). Vancomycin-dependent, platelet-reactive antibodies of the IgG class, IgM class, or both were detected in 20% of blood samples from 34 patients in whom vanco mycin-induced thrombocytopenia was sus pected, whereas no IgG antibodies and one sample with IgM antibodies were detected in blood from 451 healthy donors and no antibodies were detected in 25 patients who received vancomycin without evidence of thrombocytopenia (109c). The authors concluded that testing for drug-dependent antibodies can be helpful in identifying vancomycin as a cause of thrombocytopenia. Vancomycin had to be withdrawn in a patient with left-sided endocarditis on day 36 because of neutropenia; the leukocyte count normalized after daptomycin was given instead (110A). Urinary tract A 61-year-old patient with diabetes mellitus and hypertension devel oped acute renal failure after treatment of
Skin A 63-year-old woman developed local skin necrosis during intravenous administration of vancomycin into the dorsum of the left foot for postoperative peritoneal infection (117A).
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The authors postulated leakage of the intra venous line or capillary leakage with drug extravasation causing necrosis. Two patients with vancomycin-associated, histopathologically confirmed linear IgA bullous dermatosis presented with a morbilli form eruption without blisters (118A). Immunologic A 16-year-old girl receiving vancomycin for endocarditis caused by viridans group streptococci developed a maculopapular rash after 18 hours, with an intermittent fever and progressive reduc tions in leukocyte and platelet counts (119A). She developed hypotension on day 8. She improved after withdrawal of vanco mycin and the use of glucocorticoids. Vancomycin-induced DRESS (drug rash with eosinophilia and systemic symptoms) has been reported (120A). • A 60 year diabetic woman with a wound infec tion with meticillin-resistant S. aureus devel oped a fever, a progressive maculopapular rash, eosinophilia and acute renal insufficiency after receiving vancomycin for 2 days. The syndrome resolved after withdrawal of vanco mycin and treatment with glucocorticoids.
KETOLIDES (SED-15, 1976; SEDA-29, 262; SEDA-30, 301; SEDA-31, 436) The ketolides are a subclass of macrolides, which were designed specifically to over come macrolide-resistant respiratory patho gens. Ketolides lack the cladinose sugar, which is replaced with a 3-ketone group. They bind to a secondary region on domain II of the 23S rRNA subunit. Telithromycin was the first ketolide to be approved by the Food and Drug Administration (FDA) in 2004 for community-acquired pneumonia, acute exacerbations of chronic bronchitis and sinusitis. However, after reports of ser ious hepatotoxicity, the FDA issued a public health advisory followed by a warning. In 2007 the indications for treatment of acute exacerbations of chronic bronchitis and sinusitis were removed from the label.
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Cethromycin (ABT-773) is the only other ketolide currently being developed.
Cethromycin Cethromycin is a once-daily ketolide that originated from research by Abbott Laboratories. It is effective against Strepto coccus pneumoniae, including multidrug resistant isolates, Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila. There have been few studies of cethromycin so far. Data on adverse effects are limited and appear to be mainly gastrointestinal; there have been no reports of serious hepato toxicity (121R, 122r).
Telithromycin Cardiovascular Telithromycin can cause prolongation of the QT interval, and a warn ing has been issued against using it in patients who are already at increased risk, including those receiving class IA and class III antidysrhythmic agents (123r). Nervous system Telithromycin has been implicated in exacerbation or unmasking of myasthenia gravis (124r). Liver Telithromycin-related hepatotoxi city has been reported. In a case–control study of spontaneous reports of hepatotoxi city in telithromycin recipients using the FDA’s Adverse Event Reporting System, 2219 cases and 20 667 controls were identi fied (125C). The reporting odds ratio for hepatotoxicity associated with telithromycin compared with other agents was 1.82 (95% CI = 1.12, 2.96) after controlling for age and sex, approximating an 82% excess risk in users of telithromycin relative. A 25-year-old man taking telithromycin 400 mg/day developed acute hepatitis (126A). Skin Toxic epidermal necrolysis has been associated with telithromycin (127A).
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Immunologic A 54-year-old woman with hypertension developed an immediate hypersensitivity reaction to telithromycin shortly after a singe dose, with severe short ness of breath, wheezing, and angioedema (128A). Her allergic history included a maculopapular rash after sulfonamide anti biotics, but she had used erythromycin and azithromycin in the past without adverse effects. She was treated with adrenaline, diphenhydramine, and glucocorticoids and made a full recovery.
(SED-15, 2063; SEDA-29, 263; SEDA-30, 302; SEDA-31, 437)
LINCOSAMIDES
Clindamycin Observational studies In a retrospective review of the records of 50 consecutive patients with active toxoplasmic chorioreti nitis treated with clindamycin, five had gastrointestinal adverse events and six had rashes (129c) Nervous system A 14-year-old girl with autism developed hiccup-like movements after receiving clindamycin 300 mg bd and risperidone 5.5 mg/day for 1 day; 3 days after withdrawal of clindamycin the abnormal movements resolved (130A). Sensory systems Topical clindamycin has been associated with taste disorders. In the adverse drug reactions database of the Netherlands Pharmacovigilance Centre, seven patients were identified with taste disorders (131c). In five cases an oral for mulation was involved, in one intravenous administration and in one both formulations were used. Latency was less than 1 day after exposure and in one case taste disorders occurred repeatedly at 10 minutes after every intravenous dose. The adjusted report ing odds ratio was 7.0 (95% CI = 2.8, 17), supporting a causal relationship.
Natascia Corti, Alexander Imhof, and Christa Wenger
Liver Acute hepatotoxicity occurred in a 42-year-old woman after administration of clindamycin for a dental infection (132A). Skin Acute generalized exanthematous pustulosis (AGEP) is a rare skin eruption most commonly caused by medications. AGEP occurred in an 82-year-old Cauca sian woman after she had taken clindamycin for 2 days. She was treated with intravenous methylprednisolone, hydrocortisone cream 1%, hydroxyzine, doxepin, and paracetamol. The redness and pustulosis stopped spread ing in 1 day and resolved in 5 days (133A). Immunologic A 47-year-old woman devel oped acute febrile neutrophilic dermatosis (Sweet’s syndrome) after receiving oral and intravenous clindamycin for a tooth infection; after the clindamycin was withdrawn her symptoms resolved over several days (134A). Infection risk In 836 patients aged 65 years or older, clindamycin exposure was associated with the highest rate ratio of infection with C. difficile (RR = 32, 95% CI = 18, 58) (135r).
MACROLIDE ANTIBIOTICS (SED-15, 2183; SEDA-29, 263; SEDA-30, 302; SEDA-31, 437) Simvastatin A 78-year-old man taking simvastatin 80 mg/day developed rhabdo myolysis after completing a short course of macrolides (136A). The mechanism was probably inhibition of CYP3A4 and possi bly P glycoprotein.
Azithromycin
(SED-15, 389; SEDA-29, 264; SEDA-30, 302; SEDA-31, 437) Cardiovascular Significant prolongation of the QT interval leading to torsade de pointes has been reported within a few hours of a dose of azithromycin (137A).
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Nervous system A 55-year-old man took azithromycin 500 mg/day for pharyngitis and within 12 hours of the first dose he developed hiccups, which were persistent and very distressing (138A). They lasted for 3 days and resolved when azithromycin was withdrawn. Sensory systems Ears Azithromycin has been associated with mild-to-moderate, gra dual, reversible sensorineural hearing loss in the speech frequencies, as in a patient with otitis media who took low-dose oral azithro mycin (139A). Taste Dysgeusia after a course of azithro mycin has been described (140A). Gastrointestinal In a randomized investi gator-blinded, multicenter trial, azithro mycin 500 mg/day for 3 days was compared with moxifloxacin 400 mg/day for 5 days in out-patients with acute exacerbations of chronic bronchitis (141C). At least one treatment-related adverse event was asso ciated with azithromycin in 18.3%. The most common adverse events were diar rhea, nausea, and abdominal pain. In an open, non-comparative study in 52 teenagers taking oral azithromycin 500 mg thrice weekly for 8 weeks for acne vulgaris, only three had adverse events, including heartburn and nausea (142c). In a double-blind, randomized study 208 patients with cystic fibrosis were assigned to azithromycin either 250 mg/day (n = 103) or 1200 mg once a week (n = 105) for 6 months; gastrointestinal adverse effects were more common with weekly therapy (143C). Liver Azithromycin can cause cholestatic jaundice (144R). Skin Onychomadesis is total or partial loss of the nail plate as a result of separation starting in the proximal nail unit. A 10-year-old girl developed onychomadesis after taking azithromycin 500 mg/day for 6 days (145A). Her parents reported that peri ungual erythema and edema had developed
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in the index finger of right hand on day 5 and that loss of the nails had started after com pletion of the course of azithromycin.
Clarithromycin (SED-15, 799; SEDA-29, 265; SEDA-30, 302; SEDA-31, 438) Cardiovascular Torsade de pointes in asso ciation with prolongation of the QT interval after treatment with clarithromycin has been reported in two women aged 79 and 55 years (146A, 147A). Psychiatric Acute psychosis induced by clarithromycin is extremely uncommon, but delirium has been reported in a 63-year-old woman (148A) and an 87-year old man (149A). Hallucinations have also been described (150A). Gastrointestinal In a study of high-dose clarithromycin in 343 children over a period of 9 months, 78% received doses that exceeded the recommended dose of 15 mg/ kg/day and 26% received doses of at least 30 mg/kg/day (median 20 mg/kg/day); adverse reactions, mainly gastrointestinal in nature, were reported in 18% (151c). Liver Clarithromycin can cause cholestatic jaundice and cases of fatal acute hepatitis have also been described (144R). Skin Toxic epidermal necrolysis has been described in a 2-year-old girl who was given clarithromycin suspension (152A). Stevens–Johnson syndrome has been described in a 13-year-old boy after treat ment with clarithromycin (153A). Drug–drug interactions Carbamazepine Carbamazepine is extensively metabolized by cytochrome P450 enzymes, especially CYP34A, as is clarithromycin. In seven patients taking carbamazepine alone or in combination with other drugs, clarithro mycin led to transient toxicity (ataxia,
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dizziness, diplopia, nausea, vomiting, and drowsiness) (154c). Colchicine An interaction of clarithro mycin with colchicine resulted in an acute neuromyopathy in a 73-year-old man with chronic renal insufficiency (155A). Clari thromycin inhibits the metabolism of colchi cine via CYP3A4 and inhibition of P glycoprotein can alter its cellular transport. Pranlukast In an open, two-way crossover, randomized study in 16 healthy men, clari thromycin minimally affected the pharmaco kinetics of pranlukast (156A). Repaglinide An interaction of clarithro mycin 500 mg bd with repaglinide has been described in an 80-year-old man with endstage renal disease and well-controlled type 2 diabetes (157A). He had taken repaglinide 0.5 mg tds for 2 years, but within 48 hours of starting to take clarithromycin he developed severe hypoglycemia, which resolved with intravenous glucose. However, 48 hours later, he again had hypoglycemia and was unresponsive. Intravenous glucose was again effective. Repaglinide was withdrawn, and he had no further episodes of hypoglycemia. Sirolimus Concomitant administration of clarithromycin and sirolimus in a woman with a kidney transplant caused a large increase in sirolimus trough concentrations from 6.2 to 54 µg/l (158A). This increase was associated with acute impairment of renal function, which was almost completely resolved on withdrawal of both drugs. This interaction was probably due to inhibition of CYP3A4 and P glycoprotein.
Erythromycin (SED-15, 1237; SEDA-29, 265; SEDA-30, 302; SEDA-31, 438) Psychiatric A 64-year-old man developed hallucinations and tremors 24 hours after he started to take oral erythromycin 1 g bd and methylprednisolone 16 mg bd (159A).
Natascia Corti, Alexander Imhof, and Christa Wenger
Sensory systems Ears Loss of auditory acuity and tinnitus can occur during treat ment with erythromycin, even oral treat ment at standard doses (160r). Gastrointestinal In a review of studies of the use of erythromycin for gastrointestinal dysmotility in preterm infants, none of the randomized controlled trials reported any adverse effects, in particular hypertrophic pyloric stenosis (161c, 162C). However, hypertrophic pyloric stenosis has been described in monovular extremely preterm twins after the use of erythromycin (163A). Liver In a Spanish study, erythromycininduced hepatotoxicity has been estimated to occur in 3.6 per 100 000 users (144R). Mouth Black hairy tongue has been asso ciated with long-term oral erythromycin (164A). Immunologic An immediate IgE-depen dent hypersensitivity reaction has been reported in patients taking erythromycin; the mechanism is unknown and skin tests are negative in most cases (165r).
(SED-15, 2645; SEDA-29, 266; SEDA-30, 304; SEDA-31, 439)
OXAZOLIDINONES
Although only minor adverse effects were seen in phase III trials of linezolid, more serious effects were reported after its com mercial release, including cases of lactic acidosis, peripheral and optic neuropathy, and serotonin syndrome (166r). Peripheral and optic neuropathies usually occurred after several months of therapy (median 5 months), lactic acidosis after several weeks (median 6 weeks) and serotonin syndrome after several days (median 4 days). Death occurred in two of seven reported cases of lactic acidosis, and three of fifteen reported cases of serotonin syndrome. Improvement or complete recovery occurred in all cases
Miscellaneous antibacterial drugs
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of optic neuropathy, but no patient with peripheral neuropathy recovered. Linezolid should be withdrawn immediately in patients who have these adverse effects. Hematological toxicity due to inhibition of mitochondrial protein synthesis has also been reported (167c). Observational studies There were serious adverse events in 18 of 24 patients with mycobacterial infection treated with combi nations that included linezolid (168c). There was an optic and/or peripheral neuropathy in 11 cases and anemia in 10 cases. Nervous system Posterior reversible leuko encephalopathy has been described a 71-year-old woman after 5 days of intra venous linezolid therapy; she improved rapidly after withdrawal of linezolid (169A). Prolonged use of linezolid can cause a painful neuropathy (170A). • A 53-year-old woman developed a pure smallfiber painful neuropathy after taking linezolid for 6 months. Eight months after withdrawal of linezolid her skin became fully re-innervated, the neuropathic pain resolved and the warm threshold normalized.
This raises the possibility that small-dia meter sensory nerves in the skin, which are responsible for transmitting nociceptive information, might be affected by linezolid. Sensory systems Long-term use of linezo lid can be associated with severe peripheral and optic neuropathy (swollen or pale optic disc), symmetrical painless impairment of visual acuity and color vision, and bilateral visual field defects (171r). Of 51 consecutive adults taking linezolid, 1 developed a reversible optic and an irre versible peripheral neuropathy after 24 months (172c). Metabolism Lactic acidosis has been asso ciated with linezolid in an 80-year-old woman (173A) and in another patient after renal transplantation (174A). Hematologic Hematological disturbances are a major concern when linezolid is
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administered for prolonged periods of time. Thrombocytopenia and anemia occurred in 5 of 51 adults taking linezolid, necessitating withdrawal in 3 of them (172c). In contrast, in a retrospective chart review of the use of linezolid in 45 patients with marked baseline thrombocytopenia, although platelet counts fell in 35 patients during linezolid therapy, there was only one episode of non-life-threa tening bleeding, which could have been attri butable to coagulopathy from heparin therapy (175c). The effects of pyridoxine, rifampicin, and renal function on hematological adverse events induced by linezolid have been stu died in 52 patients (176c). Thrombocyto penia was defined as a reduction to less than 75% of the baseline platelet count and anaemia when the hemoglobin count fell by at least 0.2 g/dl from the baseline value. Linezolid alone was used in 24 patients and linezolid plus pyridoxine 200 mg/day in 28; pyridoxine did not prevent linezolid-related hematological adverse events (the cumu lative probabilities of thrombocytopenia and anemia). Hematological adverse events were less frequent in patients taking rifampi cin and were more frequent in patients with renal failure. Rifampicin was the only inde pendent predictor associated with a lower risk of thrombocytopenia (HR = 0.37; 95% CI = 0.14, 0.98). Sideroblastic anemia following prolonged linezolid therapy has been described in a patient with laryngeal cancer (177A). Pancytopenia has been reported in two organ-transplant patients after treatment with linezolid 600 mg bd for 3 and 5 weeks (178A). Urinary tract Linezolid-related acute renal insufficiency has been reported in a patient with a kidney transplant. • A 60-year-old man took linezolid for 8 days and developed acute renal failure (serum creatinine 221 µmol/l), associated with mild eosinophilia, anemia, and thrombocytopenia (179A). A biopsy of the transplanted kidney 7 days later showed interstitial nephritis and focal tubular atrophy. After withdrawal of linezolid and treatment with prednisolone 20 mg/day, the serum creatinine fell and was 166 and 159 µmol/l after 2 and 4 weeks respectively.
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Skin Black hairy tongue has been asso ciated with long-term oral linezolid (180A). Drug–drug interactions Pethidine Serotonin syndrome has been described in a 27-year-old man with acute leukemia who took linezolid and pethidine (181A). Selective serotonin re-uptake inhibitors Linezolid interacts with selective serotonin re-uptake inhibitors and other sympatho mimetic drugs, resulting in serotonin syndrome (182r). Drugs that have been impli cated include citalopram and escitalopram (183A), fluoxetine (184A), and venlafaxine (185A).
(SED-15, 2542; SEDA-29, 266; SEDA-30, 303; SEDA-31, 439)
NITROFURANTOIN
Nervous system A 16-year-old girl devel oped weakness and paresthesia after taking nitrofurantoin for several months for recur rent urinary tract infections; within 3 months of drug withdrawal the paresthesia improved and she partially recovered motor function (186A). Respiratory
Natascia Corti, Alexander Imhof, and Christa Wenger
Pulmonary fibrosis has been associated with prolonged use of nitrofurantoin for recurrent urinary tract infection in two patients, both of whom died because of respiratory failure (187A, 188A). In two patients nitrofurantoin-induced lung disease was reversible after withdrawal of the drug despite prolonged use (189A, 190A). Acute pneumonitis was presumed to have been caused by nitrofurantoin after 48 hours in a pregnant woman with a urinary tract infection; acute dyspnea, hemoptysis, and chest pain resolved completely 24 hours after withdrawal of the drug and treatment with glucocorticoids (191A). Nitrofurantoin-induced eosinophilic pneu monitis has been described in a 46-year-old patient with multiple sclerosis who devel oped fatigue a dry cough, and patchy pul monary infiltrates on a CT scan; her symptoms resolved after withdrawal of nitro furantoin (192A). Combined pulmonary symptoms with radiographic changes compatible with pneumonitis and concomitantly raised liver enzymes have been reported in two women who took nitrofurantoin for prevention of recurrent urinary tract infections; in both cases the symptoms resolved after with drawal of the drug (193A, 194A).
POLYMYXINS
(SED-15, 2891;
SEDA-31, 441) EIDOS classification: Extrinsic species: Nitrofurantoin Intrinsic species: Cells involved in
allergic reactions (lymphocytes,
eosinophils), fibroblasts,
pneumocytes
Distribution: Lungs Outcome: Fibrosis or inflammation Sequela: Nitrofurantoin-induced lung disease DoTS classification: Dose-relation: Hypersusceptibility reaction
Time-course: Late
Susceptibility factors: Female sex
Colistin Respiratory A 29-year-old woman with cys tic fibrosis developed fatal acute respiratory distress syndrome (ARDS) after treatment for chronic airway infection with P. aerugi nosa with inhaled colistimethate sodium, a pro-drug of colistin (195A). A 5-week-old pharmacy-compounded pre-mixed solution had been administered and excessive conver sion to biologically active colistin was postu lated to have caused airway or alveolar injury. The authors recommended reconsti tution of colistimethate sodium solution just before use, in order to avoid toxicity.
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Urinary tract Of 15 patients treated with colistin 3 millionIU 8-hourly for multidrug-resistant Acinetobacter bau manii ventilator-associated pneumonia, 5 developed nephrotoxicity compared with 2 of 13 patients treated with ampicillin þ sulbactam 9 g every 8 hours (196c). In a prospective open study in 78 patients treated with intravenous colistin 5 mg/kg/day divided into two doses com pared with 25 patients treated with other antibiotics for infections with A. baumanii or P. aeruginosa, there was reversible nephrotoxicity in 24 of the colistin-treated patients (197c). In a retrospective chart review of 14 chil dren treated with intravenous colistin mean dose 4.74 mg/kg/day in three or four divided doses over 3–42 days, two developed signif icant rises in serum creatinine. Neither required renal replacement therapy or developed neurological complications (198c). In another retrospective study in 120 patients with ventilator-associated pneumo nia who were given either intravenous colis tin 6 millionIU divided into three doses or imipenem 2 g/day, none developed renal insufficiency (199c). Musculoskeletal Severe rhabdomyolysis associated with intravenous colistin has been reported (200A).
SULFONAMIDES, TRIMETHOPRIM, AND CO-TRIMOXAZOLE (SED-15, 3216, 3510; SEDA-29, 270; SEDA-30, 308; SEDA-31, 442) Hematologic In two reviews of epidemio logical studies of drug-induced agranulocy tosis, co-trimoxazole and sulfasalazine were associated with a high risk of agranulocyto sis (OR > 5) (201R, 202R). In a combined analysis of three case–control studies the
477
highest risk ratios were observed for sulfa salazine (OR = 207; 95% CI = 61, 708), antithyroid drugs, procainamide, and dipyrone.
Sulfadiazine Urinary tract An HIV-positive patient with toxoplasmic encephalitis developed acute renal failure after treatment with sulfa diazine; renal ultrasound showed echogenic areas presumed to be sulfonamide crystals (203A). Crystalluria occurs in 45% of patients taking sulfonamides and acute renal insuffi ciency in 0.4–29% (204R). Hydration and urinary alkalinization can prevent and resolve crystal formation.
Trimethoprim and co-trimoxazole Sensory systems Sulfa-based drugs like co-trimoxazole can cause acute angleclosure glaucoma by ciliary body edema with anterior rotation of the iris–lens diaphragm (205R). A 41-year-old woman who had taken tri methoprim for 2 days developed bilateral acute anterior uveitis with bilateral painful red eyes, chills, itching, arthralgia, and myalgia; subsequent rechallenge was posi tive (206A). Hematologic Thrombocytopenia with a platelet count of 4 109/l occurred in a 29-year-old man who had taken co-trimox azole for 7 days for a urinary tract infection. Platelet transfusion had little effect and a strong sulfamethoxazole-dependent, plateletreactive antibody was detected that and was still present after 5 years (207A). A Jehovah’s witness developed throm botic thrombocytopenic purpura within 48 hours of co-trimoxazole therapy (208A). Hemolysis triggered by co-trimoxazole occurred in two HIV-positive patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency (209c).
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A 44-year-old woman developed granulo cytic maturation arrest and a histiocytoid Sweet’s-like reaction after a course of co trimoxazole for sinusitis. She had a fever, agranulocytosis, and a hemorrhagic nodule on the left flank. The fever and agranulo cytosis resolved 2 days after withdrawal, and the nodule regressed 1 week later (210A). Liver A 30-year-old man with a urinary tract infection developed acute cholestatic hepatitis with fever and rash after taking co-trimoxazole for 15-day treatment; he improved after supportive therapy and pre dnisolone and recovered fully within a few months (211A). Skin In a retrospective analysis of 200 Indian patients with cutaneous eruptions, co-trimoxazole was the most common cau sative drug (n = 26), followed by ibuprofen (n = 20) (212c). Psoriasis in a 50-year-old man worsened dramatically after he had taken co-trimo xazole for 3 days after an insect bite (213A). There was erythroderma, fever, generalized malaise and severe edema of the legs. The symptoms resolved after withdrawal and administration of methylprednisolone. A 40-year-old woman developed Sweet’s syndrome with a neutrophilia after taking co-trimoxazole for 6 days for vaginitis (214A). Immunologic After receiving intravenous co-trimoxazole for 10 days for Pneumocystis jiroveci pneumonia after kidney transplan tation, a 48-year-old woman developed purpura associated with IgG/IgA-mixed cryoglobulinemia (type II); a skin biopsy confirmed hypersensitivity vasculitis (215A). Cross-sensitivity to celecoxib, a sulfacontaining drug, could not be demonstrated in five patients with confirmed sulfamethoxa zole allergy (216c). A 61-year-old patient with scleroderma developed a drug-induced hypersensitivity syndrome with a concomitant increase in mumps virus and parainfluenza virus type 2 antibody titers after taking co-trimoxazole for 3 weeks (217A).
Natascia Corti, Alexander Imhof, and Christa Wenger
Drug–drug interactions Coumarin anti coagulants In a retrospective cohort study in 52 102 users of acenocoumarol and 7885 users of phenprocoumon, co trimoxazole and other antibiotics were associated with an increased relative risk of bleeding of 3–5 (218C). Preventive reduc tion of the doses of coumarin anticoagulants has been evaluated; it produced a risk reduction but a prolonged duration of undercoagulation and the authors recom mended avoiding this combination (219c). Pioglitazone Trimethoprim increased the AUC of pioglitazone by 42% in a random ized crossover study in healthy volunteers (220c). Management of adverse reactions In three small clinical trials desensitization resulted in fewer treatment withdrawals and overall adverse reactions than co-trimoxazole rechallenge for prophylaxis of opportunistic infections in HIV-infected patients with a previous history of mild or moderate hyper sensitivity to co-trimoxazole (221c). In a 85-year-old woman with a nonallergic fixed drug eruption to co-trimoxazole, desensitization was successful after 10 days (222A).
OTHER ANTIMICROBIAL DRUGS Daptomycin
(SED-15, 1053; SEDA-29, 271; SEDA-30, 309; SEDA-31, 446)
Respiratory Because of known cephalo sporin sensitivity, a 60-year-old man was given intravenous daptomycin for S. aureus endocarditis and 2 weeks later developed a fever, rigors, profound sweating and raised C-reactive protein (CRP) concentrations. A CT scan of the lung showed diffuse patchy areas (223A). A transbronchial lung biopsy showed alveolar and interstitial eosinophils. Daptomycin was stopped for 8 days, but within 4 hours of reintroduction he spiked a fever, sweated profusely, and required
Miscellaneous antibacterial drugs
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intubation for respiratory failure. Daptomy cin was withdrawn and he was given intra venous methylprednisolone. There was significant improvement within 24 hours. Liver A 35-year-old man developed raised transaminases 5 weeks after starting treat ment with daptomycin for osteomyelitis; fol lowing withdrawal renal and hepatic function improved (224A). Musculoskeletal After three doses of daptomycin 5 mg/kg/day, a 68-year-old woman with recurrent postoperative cholangitis and fever developed profound muscle weakness and rhabdomyolysis with creatine kinase activity of 25 234 U/l and raised liver enzymes; daptomycin was with drawn and the enzymes normalized 10 days later (225A). In a retrospective record review of 29 patients receiving parenteral antibiotics as outpatients, two developed reversible myo toxicity (creatine kinase activity 2369 and
479
5500 U/l) while receiving daptomycin 6 mg/ kg/day and one developed transient cuta neous and renal toxicity with concomitant clindamycin (226c). Interference with laboratory tests An interaction of daptomycin with recombinant thromboplastin reagents leads to false pro longation of the prothrombin time and INR (227E).
Fusidic acid (SED-15, 1460; SEDA-29, 259) Drug–drug interactions Statins Rhabdo myolysis occurred in two patients who took fusidic acid with atorvastatin or simvastatin (228A, 229A). The authors postulated inhibition of CYP3A4 by fusidic acid, with increased exposure to atorvastatin and simvastatin.
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S, Morita A, Ueda R. Drug-induced hyper sensitivity syndrome associated with a marked increase in anti-paramyxovirus antibody titers in a scleroderma patient. Allergol Int 2007;56(3):303–8. Penning-van Beest FJ, Koerselman J, Her ings M. Risk of major bleeding during con comitant use of antibiotic drugs and coumarin anticoagulants. J Thromb Hae most 2008;6(2):284–90. Schalekamp T, van Geest-Daalderop JH, Kramer MH, van Holten-Verzantvoort AT, de Boer A. Coumarin anticoagulants and co-trimoxazole: avoid the combination rather than manage the interaction. Eur J Clin Pharmacol 2007;63(4):335–43. Tornio A, Niemi M, Neuvonen PJ, Backman JT. Trimethoprim and the CYP2C8*3 allele have opposite effects on the pharma cokinetics of pioglitazone. Drug Metab Dis pos 2008;36(1):73–80. Lin D, Li WK, Rieder MJ. Cotrimoxazole for prophylaxis or treatment of opportunis tic infections of HIV/AIDS in patients with previous history of hypersensitivity to co trimoxazole. Cochrane Database Syst Rev 2007;(2):CD005646. Patriarca G, Schiavino D, Buonomo A, Aruanno A, Altomonte G, Nucera E. Desensitization to co-trimoxazole in a patient with fixed drug eruption. J Investig Allergol Clin Immunol 2008;18(4):309–11.
489 223. Hayes Jr. D, Anstead MI, Kuhn RJ. Eosinophilic pneumonia induced by dapto mycin. J Infect 2007;54(4):e211–3. 224. Abraham G, Finkelberg D, Spooner LM. Daptomycin-induced acute renal and hepa tic toxicity without rhabdomyolysis. Ann Pharmacother 2008;42(5):719–21. 225. Patel SJ, Samo TC, Suki WN. Early-onset rhabdomyolysis related to daptomycin use. Int J Antimicrob Agents 2007;30 (5):472–4. 226. Seaton RA, Macconnachie AA. Experience with daptomycin in an infectious diseases service over 1 year: utility in an outpatient parenteral antibiotic programme. Int J Antimicrob Agents 2008;31(5):492–7. 227. Webster PS, Oleson Jr. FB, Paterson DL, Arkin CF, Mangili A, Craven DE, Adcock DM, Lindfield KC, Knapp AG, Martone WJ. Interaction of daptomycin with two recombinant thromboplastin reagents leads to falsely prolonged patient prothrombin time/International Normalized Ratio results. Blood Coagul Fibrinolysis 2008;19 (1):32–8. 228. Burtenshaw AJ, Sellors G, Downing R. Presumed interaction of fusidic acid with simvastatin. Anaesthesia 2008;63(6):656–8. 229. O’Mahony C, Campbell VL, Al-Khayatt MS, Brull DJ. Rhabdomyolysis with ator vastatin and fusidic acid. Postgrad Med J 2008;84(992):325–7.
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27 (SEDA-29, 280; SEDA-30, 316; SEDA-31, 457)
ALLYLAMINES Terbinafine
(SED-15, 3316; SEDA-29, 280; SEDA-30, 316; SEDA-31, 457)
Liver Terbinafine can cause a wide range of types of liver damage, from mild hepato cellular or cholestatic effects to acute or subacute liver failure. Terbinafine-induced autoimmune hepatitis has been reported in a patient with chronic hepatitis B infection (1A). • A 57-year-old Taiwanese man with chronic hepatitis B virus (HBV) infection and normal liver enzymes took oral terbinafine 250 mg/day for toenail onychomycosis. After 12 weeks he developed malaise and anorexia followed by ascites and jaundice and abnormal liver function tests. He was taking no other medications or herbal supplements, did not drink alcohol, and did not have a flare of HBV infection. The diagnosis was supported by the presence of transient autoantibodies and a liver biopsy consistent with acute autoimmune drug injury. Terbinafine was withdrawn and after 3 weeks AsT (1282 IU/l), AlT (1044 IU/l), and bilirubin (100 µmol/l) peaked. He was treated with supportive care, including vitamin K, diuretics, and adefovir, to prevent hepatitis B exacerbation. The liver function tests began to normalize 6 weeks after terbinafine was withdrawn.
The pathogenesis of this drug-induced autoimmune hepatitis was speculative, but may have involved hapten–carrier com-
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32027-7 � 2010 Elsevier B.V. All rights reserved.
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plexes and CYP isoenzymes. Chronic HBV infection state may have predisposed to this autoimmune reaction. In one case terbinafine-induced liver dis ease resulted in liver transplantation (2A). • A 50-year-old African-American man with normal liver function took terbinafine for toenail onychomycosis and became progressively more jaundiced, with weight loss, anorexia, myalgia, and pruritus. After 3 months his AsT activity was 95 IU/l, AlT 149 IU/L, total bilirubin 496 µmol/l, and creatinine 124 µmol/l. Terbinafine was withdrawn. After 33 days his AsT was 228 IU/l, AlT 144 IU/l, alkaline phosphatase 497 IU/l, albumin 22 g/l, bilirubin 1173 µmol/l, blood urea nitrogen (BUN) 41 mmol/l, and creatinine 1251 µmol/l. Hepatitis A, B, and C were negative, as were antinuclear antibody, anti-smooth muscle antibody, antimitochondrial antibody, and human immunodeficiency virus (HIV). Paracetamol was not detected in plasma. The serum ceruloplasmin concentration was normal. Supportive care, including hemodialysis, was instituted, but his condition deteriorated with progressive subacute liver failure, and he underwent successful orthotopic liver transplantation. Histological examination of his explanted liver showed severe cholestasis, hepatocellular injury, and marked paucity of bile ducts.
Hematologic Of 12 patients with granulo cytopenia associated with terbinafine in Australia, mean age 64 (range 35–79) years, 10 were women (3c). The time to onset of was 4–5 weeks in most cases. Neutropenia was typically severe, with neutrophil counts below 300 106/l in eight patients. Terbinafine was with drawn in all cases. Five patients were hospitalized and one died of septic shock. Six received antibiotics and three were given granulocyte colony stimulating factor.
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Skin Cutaneous adverse effects reportedly occur in 1–3% of patients taking terbinafine. The overwhelming majority of these reactions consist of mild to moderate macular rashes. More serious skin disorders, such as erythema multiforme, toxic epidermal necrolysis, Stevens–Johnson syndrome, toxic erythema, cutaneous lupuslike syndrome, acrodermatitis continua of Hallopeau, and generalized pustular eruptions, continue to be reported but are rare (4A–7A). Of five patients with severe rashes during oral terbinafine therapy, four had been treated without mycological testing and two had cutaneous or fingernail candidiasis, for which terbinafine is not indicated (8c). Acute generalized exanthematous pustu losis (AGEP) can be caused by terbinafine. Characteristic features include suddenonset fever over 38°C, with a widespread erythematous eruption, rapidly progressing to a fine, non-follicular, micropustular rash. There is usually a leukocytosis, sometimes with eosinophilia. The illness usually resolves spontaneously within 15 days, sometimes followed by desquamation. Further cases of AGEP associated with oral terbinafine have been reported (9C, 10), including one with hepatic dysfunction (11A). Terbinafine can cause a systemic lupuslike syndrome (12c), and has also been asso ciated with the cutaneous variety. An ana lysis of in 27 cases cutaneous lupus was 6 times more common in women than in men. Skin lesions evolved on average after about 7 weeks of exposure. In 21 cases antinuclear antibody was detected, and there were Ro/SS-A antibodies in 23, La/SS-B anti bodies in 11 and anti-histone antibodies in only 8. In all cases terbinafine-induced lupus resolved after withdrawal. Systemic treatment with antimalarial drugs and/or glucocorticoids does not appear to be man datory (6A). Dermatomyositis, in which antibodies to the endothelium of the microvasculature of the skin, muscle, and lung are implicated, is characterized by photodistributed erythema, a heliotrope rash, Gottron’s
papules, muscle weakness, and interstitial pulmonary fibrosis. Endotheliotropic viruses and underlying neoplasia are among the inciting triggers, but drugs have also been implicated, including terbinafine (13Ar). • A 57-year-old man developed a photodistrib uted rash and muscle weakness after taking terbinafine. A skin biopsy confirmed the presence of endothelial cell injury with pro minent staining of C5b-9 along the dermal– epidermal junction and in the vasculature. Western blot studies showed strong seroreac tivity of the serum to an endothelial-based protein weighing 45 000kDa, a common target described in other forms of microvascular damage.
The mechanism of this reaction is unknown but may include enhanced endothelial cell apoptosis, with displacement of various cel lular antigens, resulting in a state of neo antigenicity and anti-endothelial cell antibody formation, or promotion of an interferon-rich T-helper-1-dominant cytokine milieu. Musculoskeletal Rhabdomyolysis has been reported in association with terbinafine 250 mg/day in an otherwise healthy 24-year-old man with a fungal skin infection (14A). During the second 14-day treatment cycle he developed general malaise, myalgia, and dark urine. Creatine kinase was 1120 U/l; renal function was normal. Withdrawal of terbinafine and hydration resulted in prompt resolution of all signs and symptoms within a few days.
Drug–drug interactions Carbamazepine Terbinafine is a potent competitive inhibitor of CYP2D6. An interaction of carbamazepine with terbinafine has been reported in a 50-year-old Caucasian man whose carbamazepine concentration rose after he started to take terbinafine 250 mg/ day for toenail onychomycosis, causing carbamazepine toxicity (gait ataxia, dizziness, and falls) (15A). Terbinafine and carbamazepine are both metabolized by
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CYP3A4, CYP2C9, CYP1A2, CYP2C19 and CYP2C8, and terbinafine probably inhibited the metabolism of carbamazepine.
(SED-15, 192; SEDA-29, 280; SEDA-30, 317; SEDA-31, 458)
AMPHOTERICIN
Comparative studies Amphotericin and itraconazole have been compared in empiri cal antifungal drug treatment of febrile neu tropenia in an open, randomized study in 162 patients who received either intrave nous itraconazole followed by oral itra conazole suspension or intravenous amphotericin for a maximum of 28 days (16c). Itraconazole was associated with significantly fewer withdrawals because of any adverse event (22% versus 57%). The main reason was a rise in serum creati nine (1.2% versus 24%). Renal toxicity was significantly worse and there were more drug-related adverse events with amphotericin. Liver Amphotericin lipid formulations have been associated with abnormal liver function tests, but as such abnormalities are multifactorial in severely immunocompro mised patients, there is uncertainty about their clinical significance. Hepatic histo pathology at autopsy has been studied in 64 patients who had hematological malignancies and fungal infections and had received lipo somal amphotericin B (L-AmB) or ampho tericin B lipid complex (ABLC) for at least 7 days within 30 days before death (17c). Based on data from animal studies and in view of the lack of studies in humans, multifocal necrosis, fatty infiltration, macrophage vacuolation, and/or ‘foamy macrophage’ accumulation were all considered to be abnormalities asso ciated with the use of lipid formulations. There were no significant between-group differences in demographic factors, in the cumulative dose (6 and 7 g), the median
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daily dose (5 mg/kg) or the median duration of treatment (20 and 19 days). There were abnormal results (a greater than fivefold change from baseline) in 12 and 10 patients who received ABLC and L-AmB, respec tively, but these findings were thought to be associated with concomitant use of other hepatotoxic drugs. There were non specific abnormalities in 94% of patients. Thus, although abnormal liver function test results and histopathological changes in the liver were found in 94% of these debilitated patients with hematologic malignancies, there was no direct evidence of toxicity associated with lipid formula tions of amphotericin. Urinary tract Lipid-based formulations (amphotericin B colloidal dispersion [ABCD], ABLC and L-AmB) are less nephrotoxic than conventional amphotericin B deoxycholate (DAMB) (18R). In a pro spective cohort study of 418 consecutive adults who were treated with amphotericin in hematology and oncology wards in 20 hospitals in Europe, the patients initially received DAMB (62%), L-AmB (27%), or other lipid formulations of amphotericin (11%) (19C). Of the patients who were initi ally treated with DAMB, 36% had therapy switched to lipid formulations, primarily because of increased serum creatinine con centrations (46%) or other amphotericinattributed adverse events (41%). There was nephrotoxicity, defined as a 50% or more increase in serum creatinine concentration, in 57% of the patients who had normal kid ney function at baseline. Compared with patients without nephrotoxicity, patients with nephrotoxicity had a higher mortality rate (24%) and their mean length of stay in the hospital was prolonged by 8.6 days. Increases in serum creatinine concentration were associated with a significantly longer stay in the hospital. Severe nephro toxicity (a more than 200% increase in serum creatinine) was a significant predic tor of death, as were severe underlying medical conditions and documented fungal infections.
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Drug-dosage regimens Combinations of two different doses of amphotericin and flucytosine have been used in 64 HIVpositive patients with a first episode of cryptococcal meningitis (20C). They were randomized to either amphotericin 0.7 mg/ kg/day plus flucytosine 25 mg/kg qds or amphotericin 1 mg/kg/day plus flucytosine 25 mg/kg qds for 2 weeks, followed by oral fluconazole. The incidence of renal impairment was the same in the two groups. Anemia was associated with female sex. Renal impairment and anemia resolved when fluconazole was used.
Amphotericin B colloidal dispersion (ABCD) Drug-dosage regimens In an open, randomized trial in Bihar, India, a 6-day course of ABCD was investigated at three different total doses, 7.5, 10, and 15 mg/kg, each in 135 patients (21c). Although infusion-related fever and chills occurred in 56–68% of the patients in the three different dose groups, 401 of 405 patients completed the course. All 135 patients who were given 7.5 mg/kg completed treatment, and the final cure rate was 97%. Of those who received 15 mg/kg, severe backache, an unusual adverse effect, was observed in eight (5.9%). Serious adverse effects led to withdrawal of two patients (1.5%) each from those who received 10 and 15 mg/kg. The authors concluded that the high efficacy associated with short-term lowdose ABCD provided another alternative for the treatment of visceral leishmaniasis, especially in regions where the disease is refractory to antimonials.
Amphotericin B deoxycholate (DAMB) Cardiovascular Raynaud’s phenomenon after intravenous administration or inhalation of DAMB is rare and has been linked to spasm of peripheral vessels mediated by thromboxane A2 (22A).
Another case of acrocyanosis has been reported in a patient receiving DAMB; re-challenge with ABLC was well tolerated (23A). Liver A 53-year-old woman with an intraabdominal infection secondary to Candida albicans developed hyperbilirubinemia after receiving DAMB and ABLC (24A). While amphotericin can cause abnormal liver function tests, there have been only a few reports of hyperbilirubinemia, each with different patterns of abnormalities in other liver function tests. The unpredictable nature of this adverse effect warrants monitoring of liver function tests during amphotericin therapy. Drug overdose The adverse effects of DAMB have led to increased preference for lipid formulations with more favorable safety profiles. However, many hospital formularies list both lipid and non-lipid formulations. Fatal dispensing and administration errors can occur (SEDA-30, 319) and an error has again been reported (25A). • A 41-year-old woman with a history of proliferative glomerulonephritis developed cryptococcal meningitis and was scheduled to receive liposomal amphotericin 5 mg/kg/day; however, DAMB 5 mg/kg was inadvertently administered. The patient developed cardiac dysrhythmias, acute renal insufficiency, and anemia. The medication error was noticed after she had received two doses of DAMB, which was then withdrawn. Despite treatment in the intensive care unit (ICU), she died on day 6.
In overdose DAMB can cause significant cardiotoxicity in adults with pre-existing cardiac disease, with ventricular dysrhyth mias and bradycardia, and even when admi nistered at conventional dosages and infusion rates. Given the fulminant course of overdosage and lack of effective therapy, stringent safeguards against its improper administration should be in place, as has been emphasized by two further, non-fatal cases of DAMB overdose in infants due to administration errors (26A).
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Amphotericin B lipid complex (ABLC) Observational studies ABLC has shown promise in lung transplant recipients as a convenient means of delivering protective drug to the upper airways, avoiding systemic adverse effects (27c). Aerosolized ABLC in 40 subjects undergoing allogeneic hemopoietic stem cell transplantation has been prospectively investigated in an open, non-comparative study. ABLC was given once daily for 4 days, then once weekly for 13 weeks in addition to systemic fluconazole. Cough, nausea, taste disturbances, or vomiting occurred in 2.2% of 458 administrations of inhaled ABLC; 5.2% of administrations were associated with at least a 20% reduction in pulmonary function FEV1 or FVC), but none required treatment with bronchodilators or withdrawal from the study. Four mild adverse events were considered possibly or probably related to treatment; no deaths or withdrawals were attributed to treatment. Of three proven invasive fungal infections that occurred during the study, only one, a catheterrelated case of disseminated fusariosis, occurred while the subject was taking the study medication. Comparative studies The use of glucocorticoids is an important susceptibility factor for invasive fungal infections after allogeneic hemopoietic stem cell transplantation. In an open pilot study in which all patients received oral fluconazole or itraconazole 200–400 mg/day, those who were also taking prednisone in doses of at least 30 mg/day from day 30 onwards were switched to twice-weekly ABLC 4 mg/kg (28c). Those who were taking lower doses of prednisone continued to take fluconazole or itraconazole prophylaxis. Between 1999 and 2002, 100 patients were enrolled and followed for 1 year. Seven were given daily ABLC before day 30, and 30 did not need prophylactic ABLC; only one developed candidemia. ABLC prophylaxis was used for a median of 52 days (range: 1–289) in 63 patients, and there were seven
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breakthrough infections; there were no drug-related withdrawals.
Liposomal amphotericin (L-AmB) Observational studies Response rates and the adverse effects of treatment with L-AmB have been assessed in a Phase IV cohort study in 406 patients aged 1 day to 77 years, of whom 83% had malignancies and 66% had fever of unknown origin (29c). The mean duration of treatment was 20 days and the mean daily dose 2.3 mg/kg. There was either a complete or partial response in 314 patients (77%). There were drug-related adverse events in 94 patients (23%). Among these, hypokalemia (6.2%) and abnormal liver function tests (5.2%) were the most common; there was nephrotoxicity in 17 patients (4.2%). Weekly prophylactic high-dose L-AmB 7.5 mg/kg has been investigated in 21 adults receiving high-dose prednisone 2 mg/kg/day for acute graft-versus-host disease after allogeneic hemopoietic stem cell transplan tation (30c). Patients received a median of four (range: one to eight) infusions of L-AmB. Seven withdrew because of drugrelated adverse events, consisting of raised serum creatinine (> 1.5 times from baseline; n = 5), hypotension and pain (n = 1), and severe chest pain and dysrhythmias (n = 1). The overall frequency of infusion-related reactions was 29% (n = 6), but these reac tions were always transient and relieved by stopping the infusion. In an open, prospective pilot study in adults receiving chemotherapy for acute leukemia (n = 21) or allogeneic hemopoi etic stem cell transplantation (n = 8), the former received weekly infusions of L-AmB 10 mg/kg for 4 weeks and the latter 10 mg/kg for 8 weeks (31c). The most fre quent drug-related adverse events were infusion-related reactions, 12 of which (of a total of 76 infusions) led to increased infu sion duration for better tolerance. No adverse events led to withdrawal of prophy lactic treatment in the patients with acute leukemia. In those with hemopoietic stem cell transplants, eight adverse events (in six
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patients) were reported to be related to the study treatment and led to withdrawal.
hypokalemia below 3 mmol/l occurred in five patients in all.
Comparative studies In a double-blind, randomized, non-inferiority study, micafungin 100 mg/day (n = 264) was compared with L-AmB 3 mg/kg/day (n = 267) as first-line treatment of candidemia and invasive candidiasis (32C). Treatment was successful in 181/202 patients (90%) treated with micafungin and 170/190 patients (90%) treated with L-AmB. There were fewer treatmentrelated adverse events, including those that were serious or led to treatment withdrawal, with micafungin than with L-AmB. Aerosolized liposomal amphotericin and amphotericin B deoxycholate have been retrospectively compared in 38 consecutive lung transplant recipients (33c). In all, 1206 doses of DAMB and 1149 doses of L-AmB were administered; 18 patients received DAMB only, 11 received L-AmB only and 9 received the two medications sequentially. The total numbers of complaints were 1.0% of doses of DAMB and 1.2% of doses of L-AmB. There were no differences between the groups on lung biopsy specimens. Plasma amphotericin concentrations were 0.2–0.9 mg/l with DAMB and under 0.2 mg/l with L-AmB.
Cardiovascular A reversible cardiomyo pathy has been reported after treatment with liposomal amphotericin (5 mg/kg/day for 5 days) and flucytosine (100 mg/kg/day for 2 days) for cryptococcal laryngitis; either agent could have been responsible (35A).
Combination studies In an open pilot study, a combination of L-AmB 3 mg/kg/day and caspofungin at the standard dose or monotherapy was compared with high-dose L-AmB 10 mg/kg/day in 30 patients with invasive aspergillosis (34c). The median durations of treatment were 18 and 17 days respectively. There were significantly more favorable overall responses in the combination group (10 of 15 patients versus 4 of 15 patients). Survival rates at 12 weeks were similar. There were infusion-related reactions in three patients in the highdose monotherapy group. There was a twofold increase in serum creatinine in 4 of 17 patients who received highdose monotherapy and 1 of 15 patients who received combination therapy;
Drug-dosage regimens In a double-blind trial, patients with proven or probable invasive mould infection were randomized to L-AmB 3 or 10 mg/kg/day for 14 days followed by 3 mg/kg/day (36C). Of 201 patients with confirmed invasive mould infections, 107 received 3 mg/kg/day and 94 received 10 mg/kg/day. Invasive aspergillosis accounted for 97% of cases. There were favorable responses in 50% and 46% of patients given 3 and 10 mg/kg/ day, respectively; the respective survival rates at 12 weeks were 72% and 59%. However, there were significantly higher rates of nephrotoxicity and hypokalemia in the high-dose group. Thus, a regimen of 10 mg/kg/day had no advantage and higher rates of nephrotoxicity. Susceptibility factors Children In a pilot study of prophylactic L-AmB in preventing invasive fungal infections in hemopoietic stem cell transplant recipients, 51 patients (median age 6 years) were given L-AmB 3 mg/kg/day intravenously for 100 days. There were no breakthrough infections (37c). When used as secondary prophylaxis in 11 adolescents (aged 11–18 years) with acute leukemia and a history of antecedent invasive pulmonary aspergillosis, L-AmB 1 mg/kg/day from the start of the condition ing regimen until engraftment (median duration 30 days) was well tolerated and withdrawn early in only one patient (38c). In a pharmacokinetic pilot study of once-weekly high-dose L-AmB, 14 children (median age 37 months) undergoing hemo poietic stem cell transplantation received once-weekly intravenous L-AmB prophylaxis
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(10 mg/kg as a 2-hour infusion) (39c). L-AmB was well tolerated at this dose and achieved measurable amphotericin plasma concentrations 7 days after infusion. Interference with laboratory tests Acute increases in serum inorganic phosphate in the absence of hypocalcemia and tissue deposition of calcium phosphate have been seen in patients receiving L-AmB (40A, 41A). However, hyperphosphatemia was found only when the samples were measured by one of two analysers. There was a direct linear relation between the concentration of L-AmB in spiked samples and the analyser results, indicating an increase of 0.9 mmol/l inorganic phosphate for every 100 mg/l increase in L-AmB. Ultrafiltration normalized the results. Thus, serum inorganic phosphate may be falsely increased because of interference by L-AmB.
FLUCYTOSINE Cardiovascular A reversible cardio myopathy has been reported after treat ment with liposomal amphotericin (5 mg/ kg/day for 5 days) and flucytosine (100 mg/ kg/day for 2 days) for cryptococcal laryngi tis; either agent could have been responsi ble (35A).
ANTIFUNGAL AZOLES (SED 15, 301; SEDA-29, 282; SEDA-30, 320; SEDA-31, 459) Drug–drug interactions with antifungal azoles Ciclosporin The effect of steady-state ciclo sporin (trough whole blood concentrations 200–400 ng/ml) on the single-dose pharma
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cokinetics of itraconazole 200 mg as a 1-hour intravenous infusion has been investi gated in 10 patients with a hematological malignancy and an allogeneic stem cell transplant (42c). The AUC0!24 h of itraconazole was not significantly altered, but the AUC0!24 h of hydroxyitraconazole was significantly increased (median increase 49%), with significant pro-longation of the tmax (37%) and half-life (176%). These differences may have resulted from variability in the affinity of itraconazole, hydroxyitraconazole, and ciclosporin for the CYP3A4 and the occurrence of P glyco protein polymorphisms. Co-administration of ketoconazole with ciclosporin in children with idiopathic gluco corticoid-dependent nephrotic syndrome caused a significant reduction in ciclosporin cost and net cost savings, which is important in developing countries (43C). It also appeared to result in a significant improve ment in the response to ciclosporin and more successful glucocorticoid withdrawal as well as a reduction in the frequency of renal impairment. Liver function tests remained normal up to and including the final followup at a mean of 34 months. The effect of oral posaconazole on the pharmacokinetics of ciclosporin has been assessed in a single-center, open pharmaco kinetic study in four adult heart transplant recipients (44C). The patients had taken an established dose of ciclosporin three times a day for 6 weeks or longer and were given posaconazole 200 mg/day for 10 days. Co administration of posaconazole increased ciclosporin exposure and necessitated dosage reductions of 14–29% in three subjects. These findings suggest that the dosage of ciclosporin should be reduced when posaco nazole is started and that plasma ciclosporin concentrations should be monitored during posaconazole therapy and after withdrawal, so that dosages are adjusted accordingly. Cinitapride The pharmacokinetic and electrocardiographic interactions of the prokinetic drug cinitapride with ketoconazole have been investigated in a double-blind, crossover, placebo-controlled study in healthy men and women (45c). Cinitapride
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is rapidly absorbed after oral administration and is metabolized by CYP3A4 and CYP2C8. At steady state, co-administration with ketoconazole 200 mg bd increased its mean Cmax and AUC during a dosage interval by 1.63 and 1.98 times, respectively. There were small increases in the mean QTc interval and baseline-corrected QT interval on day 7, due to the effects of ketoconazole alone. Cyclophosphamide Fluconazole inhibits CYP2C9, which is involved in the activation of cyclophosphamide and may provide protection from cyclophosphamide-related adverse effects. Cyclophosphamide and metabolite data have been compared in patients who took fluconazole (n = 56) or not (n = 17) (46c). Fluconazole increased the cyclophosphamide AUC and reduced the Cmax of 4-hydroxycyclophosphamide. In a separate study, outcomes were analysed in patients taking cyclophosphamide who were randomized to either fluconazole (n = 152) or placebo (n = 147). Those who took fluconazole had less hepatic and renal toxicity and lower mortality; there was no difference in relapsed malignancy. Efavirenz An interaction of itraconazole with efavirenz has been reported in a patient with disseminated histoplasmosis and AIDS. The combination resulted in persistently raised urinary Histoplasma antigen concentrations and subtherapeutic plasma itraconazole concentrations (47A). Changing treatment from efavirenz to a protease inhibitor resolved the problem. In a one-sequence, two-period pharmaco kinetic interaction study in 12 HIV-positive subjects, pre-treatment with efavirenz signifi cantly increased the clearance of ketocona zole by 201%. Cmax was significantly reduced by 44%, AUC0!24 h by 72% and half-life by 58% (48c). Thus, efavirenz is a strong inducer of the metabolism of ketoconazole. The interactions of voriconazole with anti retroviral drugs are complex (49R). The inter action of voriconazole with efavirenz has been evaluated in a two-period, multiple-dose, randomized, placebo-controlled study in
34 healthy men (50C). They took voriconazole 200 mg bd after two loading doses of 400 mg (n = 17) or placebo (n = 17) for 3 days; then they took efavirenz 400 mg/day for 10 days followed by efavirenz co-administered with voriconazole 200 mg bd or placebo for 9 days. Efavirenz reduced the mean steadystate voriconazole AUC by 80% and Cmax by 66%. This was probably mainly due to induc tion of CYP2C19 and CYP2C9 by efavirenz. Voriconazole increased the mean steady-state AUC of efavirenz by 43% and Cmax by 37%. This was probably due to inhibition of CYP3A4 by voriconazole. The authors sug gested that co-administration of voriconazole with efavirenz should be contraindicated. Different dosage combinations of efavirenz and voriconazole have been assessed in an open, four-treatment, multiple-dose, fixedsequence study in 16 healthy men, with the goal of finding a dosage combination that pro vides systemic exposures similar to standarddose monotherapy with each drug (51C). Steady-state pharmacokinetics were assessed after two test treatments (voriconazole 300 mg bd þ efavirenz 300 mg/day and voriconazole 400 mg bd þ efavirenz 300 mg/ day) and compared with standard-dose monotherapy (voriconazole 200 mg b.d. and efavirenz 600 mg/day). Voriconazole 300 mg bd þ efavirenz 300 mg/day reduced voricona zole steady-state AUC by 55% and Cmax by 36% compared with monotherapy. Vorico nazole 400 mg bd þ efavirenz 300 mg/day reduced voriconazole steady-state AUC by 7% and increased Cmax by 23%, and increased efavirenz AUC by 17% without a change in Cmax when compared with monotherapy. Thus, the authors recommended that when voriconazole and efavirenz are co administered, the dosage of voriconazole should be increased to 400 mg bd and the dosage of efavirenz reduced to 300 mg/day in order to provide systemic exposures similar to standard-dose monotherapy. Fentanyl The potential interactions of fentanyl with fluconazole and voriconazole have been investigated in a randomized crossover study in three phases in 12 healthy volunteers (52C). They were given intravenous fentanyl 5 micrograms/kg without pre
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treatment, after oral fluconazole (400 mg once on the first day and 200 mg once on the second day) or after oral voriconazole (400 mg twice on the first day and 200 mg twice on the second day). Plasma concentrations of fentanyl, norfentanyl, fluconazole, and voriconazole were determined up to 24 hours. The mean plasma clearance of intravenous fentanyl was reduced by 16% by fluconazole and 23% by voriconazole. Voriconazole increased the AUC by 40%. Caution should be exercised, especially in patients who are given voriconazole or fluconazole during long-lasting fentanyl treatment, because insidiously elevated fentanyl concentration can cause respiratory depression. Care should be taken in patients who are given fluconazole or voriconazole during long-lasting fentanyl treatment, because insi diously raised fentanyl concentration can cause respiratory depression. This has been emphasized by a report of a fatal outcome that was attributed to an interaction of fen tanyl with fluconazole (53A). • A 46-year-old man weighing 80 kg, with tonsillar cancer, was given a fentanyl transdermal patch 100 micrograms/hour (Durogesic), which was increased to 150 micrograms/hour over a period of 1.5 months. He also took oral morphine 10 mg/day, diclofenac 50 mg tds, paracetamol 1 g tds, oxazepam 15 mg bd, zolpidem 5 mg before bedtime, nystatin 100 000 IU/ml 3–4 ml qds, lactulose 670 mg/ml 20 ml tds, lidocaine oral spray, and rectal metoclopramide 20 mg tds. He was then given oral fluconazole 50 mg/day for an oral fungal infection and after 3 days he died in his sleep. Forensic analysis of femoral blood showed a toxic concentration of fentanyl (0.017 µg/g), high concentrations of fluconazole (2.4 µg/g), lidocaine (1.6 µg/g), and metoclopramide (0.15 µg/g), and a therapeutic concentration of zolpidem (0.07 µg/g). Ethanol and drugs of abuse were not identified. Autopsy showed no pathological findings other than pulmonary congestion and brain edema.
The coroner concluded that the cause of death was respiratory depression and circulatory failure due to fentanyl intoxication; there was no indication of intentional overdose. Haloperidol The combined effects of the CYP3A4 inhibitor itraconazole and the CYP2D6*10 genotype on the pharmacokinetics and pharmacodynamics of
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prolongation and haloperidol (QTc neurological adverse effects), a substrate of both CYP2D6 and CYP3A4, have been evaluated in 19 healthy volunteers in a randomized crossover study (54C). A single dose of haloperidol 5 mg was given after pre treatment with placebo or itraconazole 200 mg/ day for 10 days. Itraconazole increased the mean AUC of haloperidol by 55%; those with the CYP2D6*10/*10 genotype had 81% higher AUCs than those with the CYP2D6*1/ *1 genotype. The CYP2D6*10 genotype and itraconazole pre-treatment reduced the oral clearance of haloperidol by 24% and 25% respectively, but without statistical significance. Itraconazole in those with the CYP2D6*10 genotype significantly reduced the oral clearance of haloperidol to 42% of the value in subjects with the wild genotype after placebo pre-treatment. The Barnes Akathisia Rating Scale (BARS) after itraconazole pre-treatment in subjects with CYP2D6*10/*10 was significantly higher than in those with the CYP2D6*1/*1 genotype after placebo pre-treatment. No other pharmacodynamic measurements were significantly changed. Thus, the moderate effect of the CYP2D6*10 genotype on the pharmacokinetics and pharmacodynamics of haloperidol is augmented by itraconazole. Hormonal contraceptives The interaction of voriconazole with Ortho-Novum 1/35, an oral contraceptive containing norethindrone 1 mg and ethinylestradiol 35 micrograms, has been studied in 16 healthy women, who took voriconazole 400 mg bd on day 1 and 200 mg bd on days 2–4, Ortho-Novum on days 12–32, and the combination on days 40–60 in an open study (55c). OrthoNovum increased the steady-state AUC of voriconazole by 46% and the Cmax by 14%. Voriconazole increased the AUC of ethinylestradiol by 61% and the Cmax by 36% and the AUC of norethindrone by 53% and the Cmax by 15%. Adverse events were generally mild, although four subjects had severe adverse events. Ibuprofen The effects of fluconazole and voriconazole on the pharmacokinetics of S-(þ)- and R-(–)-ibuprofen have been
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investigated in 12 healthy men in a randomized study, in which they took a single oral dose of 400 mg racemic ibuprofen alone and after fluconazole or voriconazole 400 mg bd on day 1 and 200 mg bd on day 2 (56c). Fluconazole increased the AUC of S-(þ)-ibuprofen to 183% and the Cmax to 116% of the control values and prolonged the terminal half-life from 2.4 to 3.1 hours; this was probably due to inhibition of CYP2C9. Voriconazole had weak effects on the pharmacokinetics of R-(–)-ibuprofen. Similarly, voriconazole increased the AUC of S-(þ)-ibuprofen to 205% and the Cmax to 122% of the control values and prolonged the terminal half-life from 2.4 to 3.2 hours; this was probably due to inhibition of CYP2C9. Voriconazole had weak effects on the pharmacokinetics of R-(–)-ibuprofen. The authors recommended that the dosage of ibuprofen should be reduced when it is co-administered with fluconazole or voriconazole, especially when the initial ibuprofen dose is high. Imidafenacin The effect of itraconazole on the pharmacokinetics of imidafenacin, a muscarinic receptor antagonist, has been investigated in 12 healthy subjects in an open study (57c). After a single oral dose of imidafenacin 0.1 mg, they took oral itraconazole in ‘multiple doses’ of 200 mg for 9 days and a single oral dose of imidafenacin 0.1 mg on day 8. Itraconazole increased the Cmax of imidafenacin 1.32 times (90% CI = 1.12, 1.56) and the AUC 1.78 times(1.47, 2.16). The authors concluded that itraconazole or other potent CYP3A4 inhibitors should be used carefully in patients taking imidafenacin.
pharmacokinetics of maraviroc 100 mg bd, a chemokine receptor (CCR5) antagonist, ketoconazole 400 mg/day increased mara viroc steady-state AUC (59c). Nevirapine The interaction of itraconazole with nevirapine has been studied in 12 healthy volunteers, who were randomized to nevirapine 200 mg/day for 7 days or itraconazole 200 mg/day for 7 days, followed by the combination (60C). Itraconazole disposition was altered by nevirapine, with significant reductions in Cmax (38%), AUC0!96 h (61%) and half-life (31%). Itraconazole did not alter the pharmacokinetics of nevirapine, but the authors suggested that a higher dosage might have an inhibitory effect. Nevirapine concentrations, adverse events and 36-week efficacy have been compared retrospectively in patients, mean age 36 years, who did not take fluconazole (n = 81) or who took fluconazole 200 or 400 mg/day (n = 41) (61c). Baseline characteristics in the two groups were similar. Fluconazole signifi cantly increased mean nevirapine concentra tions from 6.5 to 11.4 mg/l but there were no differences in the 36-week antiviral efficacy between the groups.
Ixabepilone In patients with cancer, co administration of ketoconazole 400 mg/day to ixabepilone resulted in a 79% increase in AUC, with evidence of a direct relation between ixabepilone pharmacokinetics, neutrophil counts and microtubule bundle formation in peripheral mononuclear cells (58c).
Phenytoin The interaction of phenytoin with posaconazole has been assessed in a randomized, open, parallel-group, multipledose study in 36 healthy men, who were randomly assigned for 10 days to either posaconazole 200 mg/day, phenytoin 200 mg/ day or the combination (62c). On day 1 the Cmax and AUC0!24 h were unchanged, but at steady state posaconazole reduced phenytoin Cmax by 44% and AUC by 52%, although there was a lot of interindividual variability. There was also a 90% increase in the steady-state clearance of oral posaconazole. Because co-administration of phenytoin and posaconazole significantly reduces posaconazole exposure and increases phenytoin concentrations in some subjects, concomitant use of these agents should generally be avoided.
Maraviroc In a two-way crossover study of the effect of CYP3A4 inhibitors on the
Praziquantel The interaction of ketocona zole with praziquantel has been investigated
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in healthy adult Thai men in an open, twophase crossover, randomized study (63c). Concurrent administration of ketoconazole with praziquantel significantly increased the mean AUC of praziquantel by 93% and the Cmax by 102%; the mean oral clearance of praziquantel was significantly reduced by 58%. The mechanism was possibly inhibition of CYP3A4. Rifabutin In a open, parallel-group, multiple-dose, non-randomized study of the pharmacokinetics of rifabutin 300 mg/day for 17 days and posaconazole 200 mg/day for the last 10 days in 24 healthy men, 4 subjects withdrew because of adverse events (64c). Rifabutin reduced steady-state posaconazole Cmax by 43% and AUC by 49%. Conversely, posaconazole increased steady-state rifabutin Cmax by 31% and AUC by 72%. Concomitant use of rifabutin and posaconazole should generally be avoided. Sirolimus Concurrent use of voriconazole and sirolimus is contraindicated but still occurs. In a retrospective single-center review of medical records, 23 inpatients received at least one dose of voriconazole and sirolimus concomitantly within a 24 hour period (65c). Sirolimus concentrations were not raised above 20 mg/l in patients who had been stabilized on voriconazole before starting low-dose sirolimus 0.5–1 mg/ day, or in those who had been stabilized with sirolimus 0.5–2 mg/day, who had baseline sirolimus concentrations of 12 ng/ml or lower, and whose sirolimus dose was reduced by 50% before the addition of voriconazole. In contrast, sirolimus concentrations were raised in patients who took doses of 4 mg/day or higher, who had sirolimus concentrations of 12 ng/ml or higher and whose sirolimus dose was not reduced before the addition of voriconazole. Thus, sirolimus and voriconazole can be safely co-administered as long as consideration is given to which agent the patient receives first, the sirolimus dosage, sirolimus concentrations, concurrent disease states and CYP3A inhibitors. Sirolimus concentrations should be closely and routinely monitored before, during, and
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after co-administration of voriconazole and other CYP3A inhibitors. • Supratherapeutic trough concentrations of sirolimus occurred when itraconazole 200 mg bd was added in a 20-year-old recipient of a hemopoietic stem cell transplant (66A). Sirolimus was withheld and reintroduced at a lower dosage when the sirolimus trough concentration had normalized. Both the itraconazole and sirolimus were eventually withdrawn.
SPP301 SPP301 is a potent, highly selective endothelin A receptor antagonist. In a randomized, open, two-period crossover study in 12 healthy men, ketoconazole co-administration increased the systemic availability of SPP301 and its hydroxymethyl metabolite threefold and prolonged their half-lives twofold; individual exposures increased by up to 5.9 times (67c). Statins A patient with prostate cancer tak ing simvastatin developed rhabdomyolysis after co-administration with fluconazole (68A). The rhabdomyolysis promptly resolved after withdrawal of fluconazole, suggesting a possible interaction. Tacrolimus The effect of oral posaconazole 400 mg bd on the pharmacokinetics of tacrolimus 0.05 mg/kg/ day has been assessed in a single-center, open, crossover study in 36 healthy adults (44C). Posaconazole increased the tacrolimus Cmax by 121% and AUC by 358%. Posaconazole pharmacokinetics were not altered. These findings suggest that the dosage of tacrolimus should be reduced when posaconazole is started and that plasma tacrolimus concentrations should be monitored during posaconazole therapy and after withdrawal, so that dosages are adjusted accordingly. Vinca alkaloids Although itraconazole should not be used with vincristine, further cases of neurotoxicity have been reported in patients with lymphoma who were given the combination (69A). Four patients had severe myalgia resembling polymyalgia rheumatica, with or without arthralgia. Two had
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constipation due to sub-ileus and one had a severe paralytic ileus. Appropriate manage ment, including withdrawal of itraconazole, resulted in recovery in each case. Potentiation of neurotoxicity from vincris tine by concurrent use of posaconazole has been reported (70A). • A 21-year-old man with acute lymphocytic leukemia who was taking posaconazole 400 mg/day was given vincristine 2 mg/week. Soon after the third weekly dose he developed bilateral foot paresthesia and within 10 days had foot drop and could not walk without assistance. He had a mixed axonal and demyelinating sensorimotor neuropathy with acute denervation. There was no improvement 5 months after withdrawal of vinca alkaloids and posaconazole.
Enhanced vindesine neurotoxicity has been reported in an adult with acute lympho blastic leukemia (71A), and a combination of neurotoxicity and severe myelosuppression in a boy with Hodgkin’s lymphoma after con current administration of vinblastine, doxor ubicin, methotrexate, and prednisone (VAMP) with itraconazole (72A). Inhibition of CYP isoenzymes and P glycoprotein are thought to interfere with the disposition of several anticancer agents.
Fluconazole
(SED-15, 1377; SEDA-29, 286; SEDA-30, 325; SEDA-31, 462)
Comparative studies In a randomized, double-blind, Phase III comparison of anidulafungin 100 mg/day and fluconazole 400 mg/day, in 245 mostly non-neutropenic patients with invasive candidiasis, the adverse effect profiles of the two drugs were very similar; the types and frequencies of adverse events were comparable and fewer than 5% of the patients withdrew because of drug-related adverse events (73C). Cardiovascular Antifungal azoles, as a class, can cause QTc interval prolongation and potentially fatal cardiac dysrhythmias
by a direct blocking action on IKr channels. • A 68-year-old woman with cerebellar and pontine cryptococcosis was given amphotericin and flucytosine but developed hypokalemia, hypomagnesemia and atrial fibrillation (74A). She was given electrolyte replacement and metoprolol, and conventional amphotericin was changed to ABLC for 6 weeks, after which high-dose oral fluconazole was initiated. However, 6 days later, she had a generalized tonic–clonic seizure and cardiopulmonary arrest. Her QTc interval was 556 ms and she had recurrent episodes of torsade de pointes. Fluconazole was withdrawn and amphotericin was reintroduced, but she died 2 days later. Autopsy showed no coronary artery disease or hemorrhagic transformation of the pontine cryptococcoma.
In some cases cardiac dysrhythmias can be precipitated by the concomitant use of other prodysrhythmic compounds. • An 11-year-old critically ill child was given fluconazole 150 mg bd for Candida peritonitis after a perforated gastric volvulus and developed torsade de pointes after being given amiodarone (75A). • A 33-year-old woman with systemic lupus erythematosus and a C. albicans pneumonia was given intravenous fluconazole 200 mg/day and the dosage was then adjusted according to renal function; she was also given domperidone (76A). Prolongation of the QTc interval and torsade de pointes occurred. Fluconazole and domperidone were withdrawn. Torsade de pointes recurred several weeks later when she was given fluconazole and resolved on withdrawal. • A 23-year-old woman with acute promyelo cytic leukemia developed torsade de pointes after 4 weeks of concomitant treatment with arsenic trioxide and fluconazole (77A).
Arsenic trioxide can cause electrocardio graphic abnormalities, such as ventricular tachycardia and prolongation of the QT interval, and both arsenic trioxide and flu conazole are metabolized by CYP. Endocrine Adrenal insufficiency occurred in a 38-year-old man with obstructive sleep apnea and polycythemia, who received fluconazole plus broad-spectrum antibiotics for pulmonary infiltrates during ventilation;
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he recovered after fluconazole was stopped (78A). The authors concluded that adrenal suppression attributable to fluconazole may be under-recognized and that critically ill patients who are given fluconazole should be monitored. Urinary tract A patient developed recurrent episodes of membranous nephropathy after taking fluconazole repeatedly (79A). Teratogenicity Fluconazole can be teratogenic when it is used continuously in a dosage of 400–800 mg/day. Common features include multiple synostoses (including craniosynostosis and digital synostosis), congenital heart defects, skeletal anomalies, and dysmorphic facial features (SEDA-28, 306). The association between maternal use of fluconazole during pregnancy and the risk of congenital malformations has been assessed in a population-based cohort study in northern Denmark in 1079 women who had a live birth or a stillbirth after the 20th week of gestation and who had redeemed at least one prescription for fluconazole during the first trimester (80c). The reference cohort comprised 170 453 pregnant women who had not redeemed a prescription for fluconazole during pregnancy. The prevalence odds ratio (POR) for congenital malformations after fluconazole exposure was adjusted for maternal smoking, parity, maternal age and concurrent prescriptions for anti-epileptic or antidiabetic drugs. Of the 1079 women who filled a fluconazole prescription during the first trimester, 797 (74%) took 150 mg/day, 235 (22%) took 300 mg/day, 24 (2%) took 350 mg/day, and 23 (2%) took 600 mg/day. These women gave birth to 44 (4.1%) children with congenital malformations. The 170 453 controls gave birth to 6152 (3.6%) children with congenital malformations. For congenital malformations overall, the adjusted POR associated with first-trimester fluconazole use was 1.0 (95% CI = 0.8, 1.4).
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Genotoxicity The genotoxic effects of fluconazole have been assessed using the chromosome aberration (CA) test in mouse bone-marrow cells in vivo, and CA, sister chromatid exchange (SCE) and micronucleus (MN) tests in human lymphocytes (81E). Fluconazole was used in doses of 12.5, 25, and 50 mg/kg for the in vivo assay and in concentrations of 12.5, 25, and 50 mg/l in the in vitro assay. In both test systems, a negative and a positive control were also included. In the in vivo test, fluconazole did not significantly increase the frequency of CAs. In the in vitro assays, CAs, SCEs, and MN frequencies were significantly increased in a dose-related manner compared with the negative control. The mitotic index, replication index and cytokinesis-block proliferation index (CBPI) were not affected. Thus, fluconazole is clastogenic and aneugenic in human lymphocytes, but these effects were not be observed in mice. Susceptibility factors High-risk extremely low birth weight infants Extremely low birth weight infants are at increased risk of invasive candidiasis and are sometimes given prophylactic fluconazole. In a historical comparison, 9 of 137 low-birth weight infants (6.6%) developed invasive candidiasis during a pre-prophylaxis period (January 1998 to February 2002) compared with none of 140 who were given fluconazole after that time (82c). However, of the infants who were given fluconazole, 60 (43%) developed conjugated hyper bilirubinemia compared with 12 (8.8%) of the controls. Thus, fluconazole prophylaxis was effective in preventing invasive candidiasis, and although there was an increase in the incidence of conjugated hyperbilirubinemia, the benefit-to-harm balance may be favorable. HIV-infected subjects receiving tuberculo static drugs The incidence and suscepti bility factors for severe hepatotoxicity in 144 HIV-positive patients taking antituber culosis drugs have been assessed in a prospective, 12-year analysis (83c). There was severe hepatotoxicity in 15 (11%), and
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the median time to development of hepato toxicity was 14 days. Independent suscept ibility factors included abnormal baseline AlT activity and bilirubin concentration and the use of fluconazole. Caution should be advised when fluconazole and antituber culosis drugs are used concomitantly. Drug-dosage regimens Different doses of fluconazole (800–2000 mg/day) for 10 weeks alone or combined with flucytosine 100 mg/ kg/day for the first 4 weeks have been investigated in a Phase II dose escalation study (84c). Increasing doses of fluconazole were associated with increased survival and a reduced time to conversion of the cerebrospinal fluid (CSF) from culturepositive to culture-negative. The addition of flucytosine to fluconazole improved outcomes in each dosing cohort.
Itraconazole (SED-15, 1932; SEDA-29, 286; SEDA-30, 326; SEDA-31, 463) Cardiovascular An otherwise healthy 30-year-old man who took itraconazole for onychomycosis developed palpitation and frequent ventricular extra beats (85A). A 12-lead electrocardiogram was normal, but Holter recording showed 17 484 (18%) monomorphic extra beats and four runs among 96 930 beats/day. Another Holter recording after withdrawal of itraconazole showed 1032 atrial extra beats but no ventricular extra beats. The QTc interval was 0.39 seconds without itraconazole, 0.41 seconds with itraconazole and 0.43 seconds when multiple ventricular extra beats were documented. The underlying mechanism for this effect is obscure. Liver In 54 studies of the frequency of adverse effects of antifungal agents in 9228 patients, itraconazole was the most hepatotoxic (32%) (86M). However, lack of standard definitions, heterogeneous patient pools, and differing protocols make large-scale comparisons between studies and agents difficult.
Skin A fixed drug eruption has been attributed to itraconazole (87A). Susceptibility factors Children In a pro spective study of itraconazole prophylaxis, in which dosages were adjusted to target plasma trough concentrations of 0.5 mg/l or more in 44 prophylactic cycles in 39 chil dren with cancer, a median dosage of 8 (3.5–16.0) mg/kg/day was required to achieve the dosing target (88c). Adverse effects (gastrointestinal, raised transamina ses, and one case of hemolysis) that required drug withdrawal were reported in 11% of courses. There were no break through infections.
Posaconazole (SED-15, 2905; SEDA-29, 286; SEDA-30, 327; SEDA-31, 463) Observational studies In 428 patients with refractory invasive fungal infections (n = 362) or febrile neutropenia (n = 66) who received posaconazole in two Phase II/III open trials, 109 took posaconazole for at least 6 months (89c). Treatmentrelated adverse events were reported in 38%, the most common being nausea (8%) and vomiting (6%). There were serious adverse events in 8%. There were low rates of treatment-related QTc and/or QT interval prolongation (1%) and raised hepatic enzymes (2%). The rates of adverse events were similar in patients who took posaconazole for more or less than 6 months. Comparative studies Posaconazole has been compared with fluconazole and itraconazole in antifungal prophylaxis in a randomized, international, multicenter, evaluator-blind study in 602 patients with prolonged neutropenia (90C). They received prophylaxis with each cycle of chemotherapy until recovery from neutropenia and complete remission, or until occurrence of an invasive fungal infection or for up to 12 weeks, whichever came first. A total of 304 patients were
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randomly assigned to posaconazole, 240 to fluconazole and 58 to itraconazole. There were significantly fewer invasive fungal infections and fewer cases of invasive aspergillosis, and survival was significantly longer in those who were given posaconazole. Serious adverse events that were possibly or probably related to treatment were reported by 19 patients (6%) given posaconazole and 6 (2%) given fluconazole or itraconazole. The most common treatment-related adverse events were gastrointestinal tract disturbances. Oral posaconazole has been compared with oral fluconazole for prophylaxis against invasive fungal infections in an international, randomized, double-blind trial in 600 patients with graft-versus-host disease who were receiving immunosuppressive therapy; 301 were assigned to posaconazole and 299 to fluconazole (91C). At the end of the fixed 112-day treatment period, posaconazole was as effective as fluconazole in preventing all invasive fungal infections and was superior to fluconazole in preventing proven or probable invasive aspergillosis. Mortality was similar in the two groups, as was the incidence of treatment-related adverse events (36% with posaconazole and 38% with fluconazole); the rates of treatment-related serious adverse events were 13% and 10% respectively. In comparative trials in HIV-positive patients with azole-refractory oropharyn geal and esophageal candidiasis, posacona zole 400 mg bd for up to 12 months was well tolerated; the most frequently reported treatment-related adverse event was vomit ing (4/100) during the early follow-up per iod (on or before day 105) and raised hepatic enzymes (3/51) during long-term fol low-up (after day 105) (92c). Drug-dosage regimens In 199 subjects with oropharyngeal and esophageal candidiasis, oral posaconazole 400 mg bd for 3 days followed by oral posaconazole 400 mg/day for 25 days was compared with oral posaconazole 400 mg bd for 28 days; the most common treatment-related adverse events were diarrhea (11%), neutropenia (7%), flatulence (6%), and nausea (6%),
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and 8 subjects withdrew because treatment-related adverse events (93c).
of
Voriconazole (SED-15, 3688; SEDA-29, 287; SEDA-30, 328; SEDA-31, 463) Observational studies All adverse events in patients taking voriconazole reported to the French Pharmacovigilance Database between 2002 and 2005 have been analysed (94c). There were 227 adverse events in 178 adults and 9 children; 66% occurred in male patients. The median age was 50 (2–80) years. Adverse events included liver function test abnormalities (23%), visual disturbances (18%), rashes (17%), neurological disturbances (14%), cardiovascular events (10%), hematological disorders (8%), and renal disturbances (4%). Other less common events included headache, nausea, vomiting, and diarrhea. There were drug–drug interactions in seven cases. According to the Naranjo criteria, 84% of the events were classified as possible, 7% as probable, 5% as highly probable, and 4% as doubtful. Cardiovascular A 14-year-old Tahitian girl with acute myeloid leukemia and suspected mucormycosis was given intravenous voriconazole 300 mg bd and caspofungin (95A). Because of worsening infection, voriconazole was switched to posaconazole, but 4 hours after the first dose of posaconazole she developed QT interval prolongation, torsade de pointes and reversible cardiac arrest. The voriconazole plasma concentration 15 hours after the last dose was 7 mg/l. Genotyping suggested that the patient was an extensive metabolizer with respect to CYP2C9 and CYP2C19. Hypomagnesemia and the additional use of ondansetron were thought to have increased her susceptibility to torsade de pointes, and she was eventually found to have a congenital long QT syndrome. Respiratory A 71-year-old man with chronic necrotizing pulmonary aspergillosis
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and Mycobacterium intracellulare infection developed dyspnea and cough after taking voriconazole for 15 days (96A). A computed tomography (CT) scan showed a new dif fuse ground-glass opacity in the left lower lobe; arterial blood gas analysis showed severe hypoxemia. Voriconazole was with drawn and a glucocorticoid was given. His symptoms and left-sided lesions resolved. Although a lymphocyte stimulation test for voriconazole was negative, the authors thought that this lesion may have been an adverse reaction to voriconazole. Nervous system Painful peripheral neuropathy can occur in association with voriconazole (SEDA-30, 328) and further cases have been reported. Two patients with hematological malignancies who received voriconazole for invasive aspergillosis developed neuropathy after 2 and 4 weeks (97A). Electromyography showed a pattern of sensorimotor neuropathy compatible with axonal disease. Other causes of peripheral neuropathy were excluded. After withdrawal of voriconazole, the effects abated. Liver The relationship between CYP polymorphisms and hepatotoxicity from voriconazole has been explored in a retro spective study of 86 immunocompromised patients (98c). Median serum bilirubin and liver enzyme activities rose during voricona zole treatment. However, there were no statistically significant differences in the maximum values or the maximum increases in relation to CYP2C9, CYP2C19 or CYP3A5 polymorphisms. Lack of cross-reactivity between voricona zole and posaconazole has been suggested by the case of a 70-year-old man with chronic lymphocytic leukemia who had persistent increases in liver function test values while taking voriconazole 200 mg bd, which resolved when posaconazole 400 mg bd was given instead (99A). Skin Another case of pseudoporphyria has been attributed to voriconazole in a lung transplant patient; it was controlled
with a sunscreen during continued voricon azole exposure (100A). The association of voriconazole with blistering of the skin after allogeneic hemo poietic stem cell transplantation may be difficult to establish and the diagnosis delayed by a history of graft-versus-host disease (101A). The recognition of voricon azole-induced blistering as a separate and distinct entity in patients with a history of graft-versus-host disease is important, because delayed withdrawal of voricona zole can cause unnecessary and potentially dangerous increases in immunosuppressive drug therapy. Musculoskeletal Of 27 lung transplant patients receiving voriconazole, 9 developed painful neuromuscular disorders, leading to drug withdrawal (102c). All but one had cystic fibrosis. The delay before onset of the symp toms varied considerably, from 2 weeks to 1 year. The intensity of symptoms was also diverse: from mild muscle and joint pains to sharp pain mainly in the legs, with numbness of both feet, leading to severe disability. There was no edema, rash, or arthritis. Ten don reflexes were present in most cases. Five patients underwent needle electromyogra phy and nerve conduction studies and in four cases there was a demyelinating neuro pathy motor predominance. Some patients worsened rapidly and had intolerable pain, whereas others had progressive pain. All other medications except tacrolimus were stopped, without improvement. Trough concentrations of voriconazole were highly variable (0.2–4.5 mg/l), and after withdrawal of voriconazole there was complete recovery in all cases within about 1 week. Tumorigenicity Because of reports of squamous cell carcinoma with prolonged use of voriconazole in an HIV-infected patient (103A) and a 69-year-old renal transplant patient (104A), voriconazole has been suggested to be involved in the development of multifocal invasive squamous cell carcinoma when complicated by a phototoxic reaction, in
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which case an alternative antifungal prophylaxis regimen should be considered. Severe retinoid-like photosensitivity (cheilitis and erythema, desquamation, and ulceration of light-exposed skin) has previously been attributed to voriconazole. The mechanism is unknown, but inhibition of retinoid metabolism or a direct phototoxic effect of voriconazole or one of its metabolites has been implicated (SEDA-30, 328). Photoageing caused by voriconazole therapy has previously been reported in a 15-year-old patient with residual solar elastotic changes, multiple lentigines, and ephelides on sun-exposed areas after withdrawal (105A). Susceptibility factors Renal disease The effect of renal impairment on the pharmacokinetics of oral and intravenous voriconazole has been studied in two prospective, open, parallel-group studies in healthy volunteers (106c). In the first study, 24 men without renal impairment, or with mild, moderate, or severe impairment, took oral voriconazole 200 mg. In the second study 13 men with no renal impairment or moderate impairment received multiple doses of intravenous voriconazole (6 mg/kg bd on day 1 followed by 3 mg/kg bd on days 2–7); the drug was dissolved in sulfobutylether beta-cyclodextrin. The pharmacokinetics of voriconazole were unaffected by renal impairment in both studies, but in the second study the clearance of sulfobutylether-beta cyclodextrin was proportional to creatinine clearance. Monitoring therapy Monitoring therapy with voriconazole has been studied in 52 patients, in whom 181 measurements were performed during 2388 treatment-days (107c). There was large variability in voriconazole trough blood concentrations, ranging from below 1 mg/l, the minimum inhibitory concentration at which 90% of most fungal pathogens are susceptible, in 25% of cases, to over 5.5 mg/l, a concentration that can be associated with toxicity, in 31% of cases. Lack of response to therapy was more frequent in six patients
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with voriconazole concentrations below 1 mg/l; in those cases blood concentrations over 1 mg/l were reached after increasing the dosage, with complete resolution of infection in all six. Of 16 patients with voriconazole trough blood concentrations over 5.5 mg/l, 5 had an encephalopathy, including 4 who were given intravenous voriconazole in a median dosage of 8 mg/ kg/day; none of the patients with concentrations below 5.5 mg/l developed neurological toxicity. Co-medication with omeprazole possibly contributed to voriconazole accumulation in four cases. In all cases, withdrawal of therapy resulted in prompt and complete neurological recovery. The authors concluded that voriconazole therapeutic drug monitoring improves the efficacy and safety of therapy in patients with invasive mycoses.
(SED-15, 1197; SEDA-29, 288; SEDA-30, 329; SEDA-31, 464)
ECHINOCANDINS
Anidulafungin Comparative studies Anidulafungin 100 mg/ day has been compared with fluconazole 400 mg/day for invasive candidiasis in a rando mized, double-blind, Phase III study in 245 mostly non-neutropenic patients (73C). The safety profile of anidulafungin was similar to that of fluconazole, and less than 5% of patients withdrew because of drug-related adverse events. Infusionrelated reactions after anidulafungin included flushing (2.3%), pruritus (2.3%), rashes (1.5%), and urticaria (0.8%). Other treatment-related adverse reactions included increased hepatic enzyme activities (5.3%), hypokalemia (3.1%), diarrhea (3.1%), and increased bilirubin (1.5%). Susceptibility factors Children Anidula fungin has been investigated in a multi center study in children with neutropenia, who were divided into two cohorts (aged 2–11 and 12–17 years) and received 0.75 or 1.5 mg/kg/day
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(108c). Plasma concentrations after the first and fifth doses were similar across patients, and, in contrast to caspofungin and micafun gin, weight-adjusted clearance rates were consistent across age. The pharmacokinetic parameters were similar to those observed in adults. There were no serious drug-related adverse events. Hepatic or renal disease The effects of hepatic and renal impairment on anidulafungin pharmacokinetics have been assessed (109c). A single intravenous dose 50 mg was given to subjects with varying degrees of hepatic or renal insufficiency or with end-stage renal disease; all were matched to healthy controls. Anidulafungin was well tolerated in both populations. The pharmacokinetic parameters did not different significantly between subjects with renal impairment and controls, and the drug was not detectable in dialysate. The pharmacokinetic parameters were not affected by mild or moderate hepatic insufficiency and small but statistically significant changes in AUC and Cmax in severe hepatic impairment were not clinically relevant. Thus, dosage adjustment of anidulafungin is not needed in subjects with hepatic or renal impairment or in those undergoing hemodialysis. Drug–drug interactions Ciclosporin Clini cally relevant pharmacokinetic or pharma codynamic interactions have not been found in vitro and in vivo between anidulafungin and ciclosporin (110c).
Tacrolimus The interaction of anidulafun gin 200 mg with tacrolimus 5 mg has been investigated in a single-sequence, open study in healthy volunteers; there were no pharmacokinetic interaction and no drugrelated serious adverse events (111c).
Caspofungin Observational studies In 104 consecutive courses of caspofungin for invasive
candidiasis, cure rates were 83% (57/69) for bloodstream infections and 84% (22/ 26) for abdominal infections (112c), response rates similar to those obtained in controlled trials. There were no withdrawals because of adverse events. In 48 patients with non-fungemic invasive candidiasis who received caspofungin 50 mg/day with the option of dosage escala tion of up to 150 mg/day for endocarditis, osteomyelitis or septic arthritis, the overall success rate was 81%. None of the patients had a serious drug-related adverse event or withdrew because of adverse effects (113c). Comparative studies The clinical useful ness of caspofungin for patients with invasive candidiasis has been further sub stantiated by the results of a randomized, double-blind, Phase III comparison of micafungin 100 mg/day and micafungin 150 mg/day with a standard dosage of caspofungin in 595 adults. There were similar success rates. The types and fre quen-cies of adverse events were similar, and less than 5% of patients withdrew prematurely because of drug-related adverse events (114c). Caspofungin has been compared with liposomal amphotericin in the management of febrile neutropenia or invasive fungal infections in an open study of 73 episodes in patients with hematological malignancy (115c). There were fewer episodes of drug toxicity with caspofungin than liposomal amphotericin (58% versus 84%). Response rate for episodes of febrile neutropenia were similar but there were more breakthrough fungal infections with caspofungin (33% versus 0%). None of four episodes of can didemia or hepatosplenic candidiasis responded to caspofungin compared with three of four episodes treated with liposo mal amphotericin. Mortality was signifi cantly higher with caspofungin than with liposomal amphotericin (6/24 versus 2/49), mainly because of an excess of fungal infections. The effectiveness and tolerability of caspofungin 35–50 mg/day for up to 100 days as primary prophylaxis in 123 stem
Antifungal drugs
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cell transplant recipients (117 allogeneic) has been assessed retrospectively (116c). The median duration of caspofungin prophylaxis was 73 (range 10–100) days. Nine patients developed breakthrough invasive fungal infections; by day 100, there were five deaths, two of which were directly attributable to invasive fungal infec tions. There were no caspofungin-related adverse events. Combination studies In 53 adults with documented invasive aspergillosis who received caspofungin and one other mould-active antifungal agent as secondline therapy for an average of 31 days, success rates at the end of combination therapy and day 84 were 55% (29/53) and 49% (25/51) respectively (117c). There were two serious drug-related adverse events, both attributed to voriconazole. None of the patients stopped taking caspofungin because of adverse effects. In an open pilot study of a combination of liposomal amphotericin 3 mg/kg/day and caspofungin at the standard dose or monotherapy with high-dose amphotericin 10 mg/ kg/day for proven or probable invasive aspergillosis in 30 patients, the median durations of treatment were 18 and 17 days respectively (34c). There were signifi cantly more favorable overall responses in the combination group (10 of 15 patients versus 4 of 15 patients). Survival rates at 12 weeks were similar. Infusion-related reactions occurred in three patients in the high-dose monotherapy group. There was a twofold increase in serum creatinine in 4 of 17 patients who received high-dose monotherapy and 1 of 15 patients who received combination therapy; hypokalemia below 3 mmol/l occurred in three patients and two patients respectively. In 40 organ transplant recipients who received voriconazole and caspofungin as primary therapy for invasive aspergillosis compared with a historical control group of 47 consecutive transplant recipients who had received a lipid formulation of ampho tericin as primary therapy, combination
509
therapy was independently associated with an improved 90-day survival; there was no evidence of increased risk of adverse effects with the combination regimen (118c). Susceptibility factors Elderly patients In a retrospective analysis of the use of caspofungin in 159 elderly patients, median age 71 (range 65–84) years, who received caspofungin in studies performed by the manufacturers, the median duration of caspofungin therapy was 12–28 days, depending on indication (119c). Adverse events related to caspofungin occurred in generally similar proportions of elderly versus non-elderly patients with invasive candidiasis (clinical 33% versus 27%; laboratory 17% versus 29%), with invasive aspergillosis (clinical 7% versus 13%; laboratory 13% versus 14%) or receiving empirical therapy (clinical 47% versus 47%; laboratory 24% versus 22%). Nephrotoxicity and infusion-related adverse effects developed in comparable proportions of elderly and non-elderly caspofungin recipients. Children In a dose-ranging study in children (aged 2–11 years) and adolescents (aged 12–17 years), 50 mg/m2/day provided comparable exposure to that in adult patients given the standard dose of 50 mg/ day (120c). In a survey of 64 immunocompromised children who were given caspofungin for a median of 37 days (range 3–218) as single agent (n = 20) or in combination (n = 44) at a median daily maintenance dosage of 1.1 (range 0.4–2.9) mg/kg or 34 (range 16–58) mg/m2 (121c), none withdrew because of adverse events. There were mild to mod erate adverse events in 34 patients. Transa minase activities were increased at the end of treatment, but serum bilirubin, alkaline phosphatase, and creatinine were not differ ent from baseline. Of 20 children with proven (n = 12) or probable (n = 8) invasive fungal infections who received caspofungin as monotherapy (n = 5) or in combination (n = 15), 9 had 11
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drug-related adverse events, none of which was severe and none of which led to drug withdrawal (122c). Of 56 patients with febrile neutropenia aged 1–17 years who received 67 courses of caspofungin, 10 had an adverse event that was probably or possibly attributable to caspofungin (123c). Rash and hypokalemia were the most common adverse effects. One of 19 children who received caspofun gin and ciclosporin concurrently developed hepatotoxicity possibly related to caspofungin. Hepatic disease In single-dose and multipledose studies in patients with mild and moderate hepatic insufficiency who received either a single dose of caspofungin of 70 mg or a loading dose of 70 mg followed by 50 mg/day (mild insufficiency) or 35 mg/ day (moderate insufficiency) for 14 days, there were no withdrawals because of adverse events (124c). Dosage adjustment was not required in patients with mild hepa tic insufficiency, but a reduction to 35 mg/ day was needed in patients with moderate hepatic insufficiency. Solid organ transplant recipients Of 22 patients aged 34–67 years with solid organ transplants and invasive candidiasis (n = 6) or invasive aspergillosis (n = 16) who received at least one dose of caspofungin 50–100 mg/day, none had a serious drugrelated adverse event or withdrew because of adverse effects (125c). Critically ill patients In a retrospective study of 224 patients with documented inva sive candidiasis who received caspofungin 50 mg/day or conventional amphotericin 0.6–1.0 mg/kg/day for 10–14 days, 97 (43%) received their first dose in the ICU (126c). After accounting for differences in Acute Physiology and Chronic Health Evaluation II (APACHE II) score, neutropenia status and geographic region, the patients who had their first dose in ICU were more likely to die, but had fewer drug-related adverse events.
Drug–drug interactions Ciclosporin In a retrospective chart analysis of 54 patients who received caspofungin as salvage monotherapy for invasive aspergillosis, the con comitant use of caspofungin and ciclosporin for over 7 days was an independent suscept ibility factor for raised liver transaminases, but clinically relevant hepatotoxicity was rare (127c). In a retrospective study in 12 liver trans plant recipients who received caspofungin with either ciclosporin or tacrolimus, there was no rise in liver enzymes and no cases of hepatotoxicity (128c).
Micafungin (SEDA-29, 290; SEDA-30, 331; SEDA-31, 464) Observational studies In 23 patients aged 27–82 years with hematological malignan cies and febrile neutropenia, the rate of success with micafungin was 74% (129c). There were one or more adverse events in five patients, but all were below grade 2. Among 18 patients with acute leukemia who developed febrile neutropenia, treat ment was successful in 14 patients (130c). None required withdrawal or dose reduc tion because of adverse events, except for one patient with severe hypokalemia.
Comparative studies Micafungin 100 mg/ day has been compared with liposomal amphotericin 3 mg/kg/day in 531 adults (32C). Candidemia constituted approxi mately 85% and 88% were non-neutro penic. The overall success rate in both treatment arms was similar (in about 90%), as was survival. There were fewer treatment-related adverse events with mica fungin than with liposomal amphotericin, including those that were serious or led to treatment withdrawal. Micafungin 100 mg/day and micafungin 150 mg/day have been compared with a standard dosage of caspofungin (50 mg/ day) in 595 mostly (92%) non-neutropenic
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Chapter 27
adults with candidemia and other forms (15%) of invasive candidiasis (114c). At the end of blinded intravenous therapy, treatment was considered successful in 76% of the patients who received mica fungin 100 mg/day, in 71% of those who received micafungin 150 mg/day and in 72% of those who received caspofungin. There were no significant differences in time to culture negativity, mortality, or relapsing and emergent infections between treatments, and the patterns and types of adverse events were similar. Susceptibility factors Neonates In a Phase I, single-dose, multicenter, open study of three doses of intravenous micafungin (0.75, 1.5, and 3.0 mg/kg) in 18 premature infants weighing under 1000 g (6 in each dosage group) (131c). Another 5 infants (500–1000 g) were given 0.75 mg/kg only. The pharmacokinetics of micafungin in preterm infants were linear. However, the infants on average had a more rapid rate of clearance compared with published data in older children and
511
adults. There were no serious drug-related adverse events. Transplant recipients The maximum tol erated dose of intravenous micafungin in patients undergoing hemopoietic stem cell transplantation has been explored in an open study of increasing doses of 3, 4, 6 or 8 mg/kg/day from 7 days to a maximum of 28 days or until neutropenia resolved (132c). The maximum tolerated dose was defined as the highest dose did not cause the same grade 3 or 4 adverse event in three or more patients. All 36 participants received treatment for at least 8 (median 18, range 8–28) days. One withdrew consent and another 11 withdrew and received another systemic antifungal agent for a suspected infection. Adverse events were those expected for patients undergoing hemopoietic stem cell transplantation. No patient had a grade 3 or 4 adverse event that was considered causally related to micafungin. Thus, the maximum tolerated dose of micafungin can be inferred to be 8 mg/kg/day or higher.
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therapy and fluconazole. BMC Infect Dis 2007;7:14. Krishna G, Sansone-Parsons A, Kantesaria B. Drug interaction assessment following concomitant administration of posaconazole and phenytoin in healthy men. Curr Med Res Opin 2007;23(6):1415–22. Ridtitid W, Ratsamemonthon K, Mahattha natrakul W, Wongnawa M. Pharmaco kinetic interaction between ketoconazole and praziquantel in healthy volunteers. J Clin Pharm Ther 2007;32(6):585–93. Krishna G, Parsons A, Kantesaria B, Mant T. Evaluation of the pharmacoki netics of posaconazole and rifabutin follow ing co-administration to healthy men. Curr Med Res Opin 2007;23(3):545–52. Surowiec D, DePestel DD, Carver PL. Con current administration of sirolimus and vor iconazole: a pilot study assessing safety and approaches to appropriate management. Pharmacotherapy 2008;28(6):719–29. Said A, Garnick JJ, Dieterle N, Peres E, Abidi MH, Ibrahim RB. Sirolimus–itraco nazole interaction in a hematopoietic stem cell transplant recipient. Pharmacotherapy 2006;26(2):289–95. Dieterle W, Mann J. Pharmacokinetic inter action between ketoconazole and SPP301 in healthy volunteers. Int J Clin Pharmacol Ther 2006;44(7):326–30. Hazin R, Abuzetun JY, Suker M, Porter J. Rhabdomyolysis induced by simvastatin– fluconazole combination. J Natl Med Assoc 2008;100(4):444–6. Takahashi N, Kameoka Y, Yamanaka Y, Ubukawa K, Saito K, Fujishima M, Fujishima N, Saito H, Hirokawa M, Scott SA, Sawada K. Itraconazole oral solution enhanced vincristine neurotoxicity in five patients with malignant lymphoma. Intern Med 2008;47(7):651–3. Mantadakis E, Amoiridis G, Kondi A, Kalmanti M. Possible increase of the neuro toxicity of vincristine by the concurrent use of posaconazole in a young adult with leukemia. J Pediatr Hematol Oncol 2007;29(2):130. Chen S, Wu D, Sun A, Qiu H, Jin Z, Tang X, Miao M, Fu Z, Ma X, Han Y, Hu X. Itraconazole-enhanced vindesine neuro toxicity in adult acute lymphoblastic leukae mia. Am J Hematol 2007;82(10):942.
515 72. Bashir H, Motl S, Metzger ML, Howard SC, Kaste S, Krasin MP, Hudson MM. Itra conazole-enhanced chemotherapy toxicity in a patient with Hodgkin lymphoma. J Pediatr Hematol Oncol 2006;28(1):33–5. 73. Reboli AC, Rotstein C, Pappas PG, Chap man SW, Kett DH, Kumar D, Betts R, Wible M, Goldstein BP, Schranz J, Krause DS, Walsh TJ, Anidulafungin Study Group. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 2007;356(24):2472–82. 74. McMahon JH, Grayson ML. Torsades de pointes in a patient receiving fluconazole for cerebral cryptococcosis. Am J Health Syst Pharm 2008;65(7):619–23. 75. Esch JJ, Kantoch MJ. Torsades de pointes ventricular tachycardia in a pediatric patient treated with fluconazole. Pediatr Cardiol 2008;29(1):210–3. 76. Pham CP, de Feiter PW, van der Kuy PH, van Mook WN. Long QTc interval and tor sade de pointes caused by fluconazole. Ann Pharmacother 2006;40(7–8):1456–61. 77. Naito K, Kobayashi M, Sahara N, Shi geno K, Nakamura S, Shinjo K, Tobita T, Takeshita A, Ohno R, Ohnishi K. Two cases of acute promyelocytic leukemia complicated by torsade de pointes during arsenic trioxide therapy. Int J Hematol 2006;83(4):318–23. 78. Krishnan SG, Cobbs RK. Reversible acute adrenal insufficiency caused by fluconazole in a critically ill patient. Postgrad Med J 2006;82(971):e23. 79. Shin GT, Yim H, Park J, Kim H. Membra nous nephropathy associated with flucona zole treatment. Am J Kidney Dis 2007;49(2): 318–22. 80. Nørgaard M, Pedersen L, Gislum M, Erich sen R, Søgaard KK, Schønheyder HC, Sørensen HT. Maternal use of fluconazole and risk of congenital malformations: a Danish population-based cohort study. J Antimicrob Chemother 2008;62(1):172–6. € 81. Yuzbas ¸iog˘ lu D, Unal F, Yilmaz S, Aksoy H, Celik M. Genotoxicity testing of fluconazole in vivo and in vitro. Mutat Res 2008;649(1–2): 155–60. 82. Aghai ZH, Mudduluru M, Nakhla TA, Amendolia B, Longo D, Kemble N, Kaki S, Sutsko R, Saslow JG, Stahl GE.
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Fluconazole prophylaxis in extremely low birth weight infants: association with choles tasis. J Perinatol 2006;26(9):550–5. Pukenyte E, Lescure FX, Rey D, Rabaud C, Hoen B, Chavanet P, Laiskonis AP, Schmit JL, May T, Mouton Y, Yazdanpa nah Y. Incidence of and risk factors for severe liver toxicity in HIV-infected patients on anti-tuberculosis treatment. Int J Tuberc Lung Dis2007;11(1):78–84. Milefchik E, Leal MA, Haubrich R, Bozzette SA, Tilles JG, Leedom JM, McCutchan JA, Larsen RA. Fluconazole alone or combined with flucytosine for the treatment of AIDS-associated cryptococcal meningitis. Med Mycol 2008;46(4):393–5. Okamoto J, Fukunami M, Kioka H. Fre quent premature ventricular contractions induced by itraconazole. Circ J 2007;71(8): 1323–5. Girois SB, Chapuis F, Decullier E, Revol BG. Adverse effects of antifungal therapies in invasive fungal infections: review and meta-analysis. Eur J Clin Microbiol Infect Dis 2006;25(2):138–49. Gupta R, Thami GP. Fixed drug eruption caused by itraconazole: reactivity and cross reactivity. J Am Acad Dermatol 2008;58(3): 521–2. Simon A, Besuden M, Vezmar S, Hasan C, Lampe D, Kreutzberg S, Glasmacher A, Bode U, Fleischhack G. Itraconazole prophylaxis in pediatric cancer patients receiving conventional chemotherapy or autologous stem cell transplants. Support Care Cancer 2007;15(2):213–20. Raad II, Graybill JR, Bustamante AB, Cor nely OA, Gaona-Flores V, Afif C, Graham DR, Greenberg RN, Hadley S, Langston A, Negroni R, Perfect JR, Pitisuttithum P, Restrepo A, Schiller G, Pedicone L, Ull mann AJ. Safety of long-term oral posaco nazole use in the treatment of refractory invasive fungal infections. Clin Infect Dis 2006;42(12):1726–34. Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, Helfgott D, Holowiecki J, Stockelberg D, Goh YT, Petrini M, Hardalo C, Suresh R, AnguloGonzalez D. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with
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99. Foo H, Gottlieb T. Lack of cross-hepato toxicity between voriconazole and posa conazole. Clin Infect Dis 2007;45(6):803–5. 100. Kwong WT, Hsu S. Pseudoporphyria asso ciated with voriconazole. J Drugs Dermatol 2007;6(10):1042–4. 101. Conlon JD, Dauenhauer M, TonkovicCapin V, Talano J, Margolis D, Drolet BA, Fairley JA. Voriconazole-induced blis tering in the setting of graft versus host disease: a report of 2 patients. J Am Acad Dermatol 2008;58(3):484–7. 102. Boussaud V, Daudet N, Billaud EM, LilloLe Louet A, Chevalier P, Amrein C, Bergé MM, Guillemain R, Le Beller C. Neuro muscular painful disorders: a rare side effect of voriconazole in lung transplant patients under tacrolimus. J Heart Lung Transplant 2008;27(2):229–32. 103. Brunel AS, Fraisse T, Lechiche C, Pinzani V, Mauboussin JM, Sotto A. Multifocal squamous cell carcinomas in an HIVinfected patient with a long-term voricona zole therapy. AIDS 2008;22(7):905–6. 104. Vanacker A, Fabré G, Van Dorpe J, Pee termans WE, Maes B. Aggressive cuta neous squamous cell carcinoma associated with prolonged voriconazole therapy in a renal transplant patient. Am J Transplant 2008;8(4):877–80. 105. Racette AJ, Roenigk Jr. HH, Hansen R, Mendelson D, Park A. Photoaging and phototoxicity from long-term voriconazole treatment in a 15-year-old girl. J Am Acad Dermatol2005;52(5 Suppl 1):S81–5. 106. Abel S, Allan R, Gandelman K, Tomas zewski K, Webb DJ, Wood ND. Pharmaco kinetics, safety and tolerance of voriconazole in renally impaired subjects: two prospective, multicentre, open-label, parallel-group volunteer studies. Clin Drug Investig 2008;28(7):409–20. 107. Pascual A, Calandra T, Bolay S, Buclin T, Bille J, Marchetti O. Voriconazole therapeu tic drug monitoring in patients with invasive mycoses improves efficacy and safety out comes. Clin Infect Dis 2008;46(2):201–11. 108. Benjamin Jr. DK, Driscoll T, Seibel NL, Gonzalez CE, Roden MM, Kilaru R, Clark K, Dowell JA, Schranz J, Walsh TJ. Safety and pharmacokinetics of intravenous
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anidulafungin in children with neutropenia at high risk for invasive fungal infections. Antimicrob Agents Chemother 2006; 50(2):632–8. Dowell JA, Stogniew M, Krause D, Damle B. Anidulafungin does not require dosage adjustment in subjects with varying degrees of hepatic or renal impairment. J Clin Phar macol 2007;47(4):461–70. Dowell JA, Stogniew M, Krause D, Henkel T, Weston IE. Assessment of the safety and pharmacokinetics of anidulafungin when administered with cyclosporine. J Clin Pharmacol 2005;45(2):227–33. Dowell JA, Stogniew M, Krause D, Henkel T, Damle B. Lack of pharmacokinetic inter action between anidulafungin and tacroli mus. J Clin Pharmacol 2007;47(3):305–14. Zaas AK, Dodds Ashley ES, Alexander BD, Johnson MD, Perfect JR. Caspofungin for invasive candidiasis at a tertiary care medical center. Am J Med 2006; 119(11): 993.e1–6. Cornely OA, Lasso M, Betts R, Klimko N, Vazquez J, Dobb G, Velez J, Williams-Diaz A, Lipka J, Taylor A, Sable C, Kartsonis N. Caspofungin for the treatment of less com mon forms of invasive candidiasis. J Anti microb Chemother 2007;60(2):363–9. Pappas PG, Rotstein CM, Betts RF, Nucci M, Talwar D, De Waele JJ, Vazquez JA, Dupont BF, Horn DL, Ostrosky-Zeichner L, Reboli AC, Suh B, Digumarti R, Wu C, Kovanda LL, Arnold LJ, Buell DN. Mica fungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis 2007; 45(7): 883–93. Ellis M, Frampton C, Joseph J, Alizadeh H, Kristensen J, Hauggaard A, Shammas F. An open study of the comparative efficacy and safety of caspofungin and liposomal amphotericin B in treating invasive fungal infections or febrile neutropenia in patients with haematological malignancy. J Med Microbiol 2006;55(Pt 10):1357–65. Chou LS, Lewis RE, Ippoliti C, Champlin RE, Kontoyiannis DP. Caspofungin as pri mary antifungal prophylaxis in stem cell transplant recipients. Pharmacotherapy 2007;27(12):1644–50.
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117. Maertens J, Glasmacher A, Herbrecht R, Thiebaut A, Cordonnier C, Segal BH, Killar J, Taylor A, Kartsonis N, Patterson TF, Aoun M, Caillot D, Sable C, Caspofun gin Combination Therapy Study Group. Multicenter, noncomparative study of caspofungin in combination with other anti fungals as salvage therapy in adults with invasive aspergillosis. Cancer 2006;107(12): 2888–97. 118. Singh N, Limaye AP, Forrest G, Safdar N, Muñoz P, Pursell K, Houston S, Rosso F, Montoya JG, Patton P, Del Busto R, Aguado JM, Fisher RA, Klintmalm GB, Miller R, Wagener MM, Lewis RE, Kon toyiannis DP, Husain S. Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study. Trans plantation 2006;81(3):320–6. 119. Dinubile MJ, Strohmaier KM, Lupinacci RJ, Meibohm AR, Sable CA, Kartsonis NA. Efficacy and safety of caspofungin therapy in elderly patients with proven or suspected invasive fungal infections. Eur J Clin Microbiol Infect Dis 2008;27(8): 663–70. 120. Walsh TJ, Adamson PC, Seibel NL, Flynn PM, Neely MN, Schwartz C, Shad A, Kaplan SL, Roden MM, Stone JA, Miller A, Bradshaw SK, Li SX, Sable CA, Kart sonis NA. Pharmacokinetics, safety, and tolerability of caspofungin in children and adolescents. Antimicrob Agents Chemother 2005;49(11):4536–45. 121. Groll AH, Attarbaschi A, Schuster FR, Herzog N, Grigull L, Dworzak MN, Beutel K, Laws HJ, Lehrnbecher T. Treatment with caspofungin in immunocompromised paediatric patients: a multicentre survey. J Antimicrob Chemother 2006;57(3):527–35. 122. Merlin E, Galambrun C, Ribaud P, Blanc T, Michel G, Auvrignon A, Stéphan JL. Effi cacy and safety of caspofungin therapy in children with invasive fungal infections. Pediatr Infect Dis J 2006;25(12):1186–8. 123. Koo A, Sung L, Allen U, Naqvi A, DrynanArsenault J, Dekker A, Maloney AM, Dupuis LL. Efficacy and safety of caspofun gin for the empiric management of fever in
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neutropenic children. Pediatr Infect Dis J 2007;26(9):854–6. Mistry GC, Migoya E, Deutsch PJ, Winchell G, Hesney M, Li S, Bi S, Dilzer S, Lasseter KC, Stone JA. Single- and multiple-dose administration of caspofungin in patients with hepatic insufficiency: implications for safety and dosing recommendations. J Clin Pharmacol 2007;47(8):951–61. Petrovic J, Ngai A, Bradshaw S, WilliamsDiaz A, Taylor A, Sable C, Vuocolo S, Kartsonis N. Efficacy and safety of caspo fungin in solid organ transplant recipients. Transplant Proc 2007;39(10):3117–20. DiNubile MJ, Lupinacci RJ, Strohmaier KM, Sable CA, Kartsonis NA. Invasive candidiasis treated in the intensive care unit: observations from a randomized clin ical trial. J Crit Care 2007;22(3):237–44. Morrissey CO, Slavin MA, O’Reilly MA, Daffy JR, Seymour JF, Schwarer AP, Szer J. Caspofungin as salvage monotherapy for invasive aspergillosis in patients with hae matological malignancies or following allo geneic stem cell transplantation: efficacy and concomitant cyclosporin A. Mycoses 2007;50 (Suppl 1):24–37. Saner F, Gensicke J, Rath P, Fruhauf N, Gu Y, Paul A, Radtke A, Malagó M, Broelsch C. Safety profile of concomitant use of cas pofungin and cyclosporine or tacrolimus in liver transplant patients. Infection 2006;34(6):328–32. Toubai T, Tanaka J, Ota S, Shigematsu A, Shono Y, Ibata M, Hashino S, Kondo T, Kakinoki Y, Masauzi N, Kasai M, Iwasaki H, Kurosawa M, Asaka M, Imamura M. Efficacy and safety of micafungin in febrile neutropenic patients treated for hematolo gical malignancies. Intern Med 2007;46(1): 3–9. Yanada M, Kiyoi H, Murata M, Suzuki M, Iwai M, Yokozawa T, Baba H, Emi N, Naoe T. Micafungin, a novel antifungal agent, as empirical therapy in acute leukaemia patients with febrile neutropenia. Intern Med 2006;45(5):259–64. Heresi GP, Gerstmann DR, Reed MD, van den Anker JN, Blumer JL, Kovanda L, Keirns JJ, Buell DN, Kearns GL. The phar macokinetics and safety of micafungin, a
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novel echinocandin, in premature infants. Pediatr Infect Dis J 2006;25(12):1110–5. 132. Sirohi B, Powles RL, Chopra R, Russell N, Byrne JL, Prentice HG, Potter M, Koblinger S. A study to determine the
519 safety profile and maximum tolerated dose of micafungin (FK463) in patients undergoing haematopoietic stem cell transplantation. Bone Marrow Transplant 2006;38(1):47–51.
Oscar Ozmund Simooya
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Antiprotozoal drugs
ANTIMALARIAL DRUGS 4-AMINOQUINOLINES (CHLOROQUINE AND CONGENERS) (SEDA-29, 294; SEDA-30, 336; SEDA-31, 469)
Amodiaquine
(SED-15, 178; SEDA-28, 315; SEDA-31, 469)
Hematologic Amodiaquine þ artesunate and artesunate þ lumefantrine are currently the preferred regimens for the treatment of malaria in most of sub-Saharan Africa. How ever, there are limited data on their safety and efficacy in human immunodeficiency virus (HIV)-infected populations. In a study in 26 HIV-positive and 134 HIV-negative children with malaria (35 and 258 episodes respectively) in Uganda, 12 of the former were taking antiretroviral drugs (1C). They were all given amodiaquine þ artesunate and those with HIV infection were also given co-trimoxazole prophylaxis and antiretro viral therapy according to national guide lines. The study lasted 18 and 29 months in the HIV-positive and HIV-negative subjects, respectively. There was a greater risk of malaria recurrence in the HIV-negative subjects (2.9% versus 13%). The risk of neutropenia after 14 days was higher among the HIV-positive children (45% versus 6%) and 16% of the episodes of neutropenia in the HIV-positive children were classified as severe to life-threatening (neutrophil count <750 106/l). Furthermore, in the Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32028-9 � 2010 Elsevier B.V. All rights reserved.
HIV-positive children, the risk of neutropenia was higher in those taking antiretroviral drugs (75% versus 26%). The authors concluded that although artesunate þ amodiaquine was efficacious in the HIV-positive children, the high risk of neutropenia, especially in those receiving concurrent antiretroviral drugs, necessitates evaluation of alternative regimens. Susceptibility factors Genetic Amodia quine is metabolized to its primary metabo lite by cytochrome P450 2C8 (CYP2C8). The frequency of CYP2C8 variants in 275 malaria-infected patients, the effect of geno type on treatment outcomes, the metabolism of amodiaquine by CYP2C8 variants and the effect of other drugs on amodiaquine meta bolism have been studied in Burkina Faso (2C). The allele frequencies of CYP2C8*2 and CYP2C8*3 were 12% and 0.4% respec tively. There was no evidence of an effect of CYP2C8 genotype on amodiaquine efficacy or toxicity. The variant most common in Africans, CYP2C8*2, was associated with reduced metabolism of amodiaquine (a threefold higher Km and a sixfold lower intrinsic clearance), while CYP2C8*3 also had markedly reduced activity. The antiretro viral drugs efavirenz, saquinavir, lopinavir, and tipranavir were potent inhibitors of CYP2C8 at clinically relevant concentrations.
Chloroquine and hydroxychloroquine
(SED-15, 722; SEDA-29, 294; SEDA-30, 336; SEDA-31, 470) Cardiovascular Cardiomyopathy with longterm hydroxychloroquine is rare but poten tially life-threatening (3A).
521
522 • A 51-year-old woman with no history of cardiac disease developed congestive cardiac failure while taking hydroxychloroquine 100–200 mg bd and prednisone <10 mg/day for a long-standing polyarthropathy due to rheumatoid arthritis and systemic lupus erythematosus. Echocardiography showed increased left ventricular septal and posterior wall thickness, mild left ventricular systolic dysfunction, increased right ventricular wall thickness, mild bilateral atrial enlargement and mild valvular thickening. These findings were confirmed on magnetic resonance imaging (MRI) and the diagnosis of cardiomyopathy was confirmed by endomyocardial biopsy. The cardiomyopathy resolved after withdrawal of hydroxychloroquine.
Sensory systems Vortex keratopathy asso ciated with hydroxychloroquine has been reported (4A). • A 41-year-old woman who took hydroxychloroquine 200 mg bd for sarcoidosis developed a sensation of a foreign body in both eyes, with dryness and burning. Slit lamp examination showed a golden brown deposit throughout the left cornea. In vivo confocal microscopy showed highly reflective, dot-like, intracellular deposits concentrated in the basal epithelial layer and in the anterior and posterior stroma, but not in the endothelium. In the anterior stroma, several of these reflective cells were interconnected and formed an extended network, suggesting that they were keratocytes. Because the surrounding areas were free from granular deposits, phagocytosis appeared to have taken place.
The clinical picture described here closely resembles that found in chloroquine-induced keratopathy. Hematologic Secondary myelodysplastic syndrome has been attributed to hydroxychloroquine in two men and two women aged 65–76 years taking long-term hydroxychloroquine 400 mg/day for a median dura tion of 11 (range 6–16) years (5c). None had a history of exposure to myelosuppressive agents and none had vitamin B12 or folic acid deficiency. All presented with refrac tory anemia, two without ringed sidero blasts, one with excess blasts and the other with ringed sideroblasts, features consistent with the diagnosis of myelodysplastic syndrome. Liver Severe hepatitis has been associated with hydroxychloroquine (6A)
Chapter 28
Oscar Ozmund Simooya
• A 26-year-old woman with an intermittent fever, symmetrical arthritis in the legs, Raynaud’s phenomenon and a positive rheumatoid factor and highly positive DNA was given non steroidal anti-inflammatory drugs and then prednisone 40 mg/day and hydroxychloroquine 200 mg/day. She developed a fever of 39°C, nausea, and vomiting 8–10 hours after the first doses of hydroxychloroquine and prednisone. Liver function tests were as follows: AsT 399 IU/l, AlT 285 IU/l, and LDH 1478 IU/l. Hydroxychloroquine was withdrawn and she was given intravenous methylprednisolone 60 mg/ day and ceftriaxone 1 g/day. Liver computed tomography (CT) scan and ultrasonography were normal and serology for HIV and hepatitis A, B, and C was negative. The liver function tests gradually normalized over 5 days.
Skin Mucocutaneous hyperpigmentation has been associated with hydroxychloroquine (7A) • A 37-year-old woman developed asymptomatic bluish-grey macular pigmentation on her thighs after taking hydroxychloroquine 400 mg/day for 9 months for rheumatoid arthritis. A biopsy showed marked basal hyperpigmentation. After drug withdrawal, the pigmentation gradually abated.
Musculoskeletal A myopathy has been reported in a patient taking long-term hydroxychloroquine for rheumatoid arthritis (8A) • An 88-year-old woman with diabetes, hypertension and rheumatoid arthritis developed dyspnea while taking hydroxychloroquine 300 mg bd, prednisone 10 mg/day, enalapril, glibenclamide, and methotrexate. There was proximal muscle weakness in the limbs and diminished reflexes symmetrically. Sensory function and the cranial nerves were normal. Chest radiography showed small lung volumes. Pulmonary function tests showed a negative inspiratory force of 15 cm H2O, an FVC of 0.56 l (24% of predicted), and an FEV1 of 0.29 l (19% of predicted). Electromyography suggested a myositis and a skeletal muscle biopsy showed a necrotizing vacuolar myopathy with curvilinear bodies, a picture consistent with chloroquineinduced myopathy. Hydroxychloroquine was withdrawn and the dose of prednisone was reduced to 5 mg/day. Despite treatment of respiratory failure with non-invasive ventilation, the patient eventually died.
Diagnosis of adverse drug reactions Retinal toxicity caused by hydroxychloroquine has been reported but is rare. There are several tests to identify this adverse effect, but multi focal electroretinography (mfERG) has been
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proposed as a better and more objective test (9C). As the lesions and areas of depressed mfERG amplitude produced by hydroxychloro quine toxicity take the form of pericentral rings, the data can be averaged in rings to provide a measurement of the extent of the disorder. The ring ratios are defined as the ratio of the central ring amplitude to each of the other peripheral ring amplitudes. There are five rings (R1–R5), giving five measure ments in each eye: R1, R1/R2, R1/R3, R1/R4, and R1/R5. Because R1 has the highest ring amplitude, the normal eye will have higher ring ratios. In 62 patients referred for evaluation of hydroxychloroquine retinal toxicity and 67 referred for other problems, the incidence of abnormal mfERG results in patients with a cumulative hydroxychloroquine dose of more than 1250 g was nearly 50%, and was 2.8 times more than that in patients with a cumulative dose of less than 1250 g. There were significant changes at cumulative doses as low as 400 g. The most common abnormality was an increased R1/R2 ratio. Cumulative dose was more predictive of an abnormal result than daily dose or duration of treatment. There was locally reduced ret inal function in a large proportion of those who had taken high cumulative doses of hydroxychloroquine. High-speed ultra-high resolution optical coherence tomography (hsUHR-OCT) has been used in the diagnosis of hydroxy chloroquine-induced retinopathy (10C) in 15 patients. There were distinctive lesions in the perifoveal photoreceptor inner seg ment/outer segment junction and thinning of the outer nuclear layer in patients with mild retinopathy. In more severe cases, there were advanced retinal changes.
Mefloquine
(SED-15, 2232; SEDA-29, 295; SEDA-30, 337; SEDA-31, 471) Respiratory Mefloquine-induced eosinophilic pneumonia has been reported (11A)
• A 67-year-old woman took mefloquine 250 mg once a week for 7 weeks and developed a highgrade fever (39°C), malaise, a productive cough,
523 dyspnea, tachypnea, and a tachycardia. There were fine crackles in the middle and lower zones of the lungs. She had a normochromic normocytic anemia, a peripheral eosino philia (1.5 109/l) and an increased erythrocyte sedimentation rate (109 mm/ hour). Arterial blood gases showed moderate hypoxemia. Radiography and a CT scan of the chest showed diffuse airspace consolidation, ground glass attenuation and interlobular septal thickening in both lungs. Tests for Mycobacterium tuberculosis, Plasmodium species, and HIV were negative. The cells in the bronchoalveolar lavage fluid were 49% eosinophils (normal <1%), 32% alveolar macrophages (> 90%), 15% lymphocytes (<10%), and 4% neutrophils (<1%). Transbronchial biopsy of the right lower lobe showed alveolar spaces filled with eosinophils without granulomata or evidence of organized pneumonia, a picture consistent with eosinophilic pneumonia. Mefloquine was withdrawn and she improved gradually over a few weeks.
Sensory systems Retinopathy, typically described as bull’s-eye maculopathy, has been well documented with chloroquine and hydroxychloroquine, and a case has been associated with mefloquine (12A). • A 43-year-old man took mefloquine 250 mg/ week for about 18 months and developed bilateral macular changes. Corrected visual acuity was 20/20 bilaterally and slit-lamp examination was unremarkable. Fundoscopy showed retinal pigment epithelium changes and fluorescence angiography showed posterior pole transmission changes in several discreet patches, in the left more than in the right eye.
PYRIMETHAMINE AND CONGENERS (SED-15, 2984; SEDA-29, 296)
The use of pyrimethamine + sulfadoxine in intermittent preventive regimens in malaria The combination of pyrimethamine þ sulfa doxine has been recommended for the preven tion of malaria in pregnancy and young children, the two groups that are most at risk of severe malaria. Intermittent preventive
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treatment consists of antimalarial drugs given at defined times irrespective of whether the patient has parasites or symptoms. Intermit tent preventive treatment in pregnant women with pyrimethamine þ sulfadoxine is now standard practice in most malaria-endemic African countries. However, despite the promotion of inter mittent preventive treatment, widespread concerns about the safety and efficacy of malaria treatments in extended use in preg nancy and young children continue to affect implementation of the policy. In Gabon, 1189 infants were randomly allocated to either pyrimethamine þ sulfa doxine (50 and 250 mg, respectively) or pla cebo at 3, 9 and 15 months and were actively followed up until 18 months of age (13C). At 18 months there was a reduction in anemia with pyrimethamine þ sulfadoxine com pared with placebo but no significant differ ence in the number of malaria episodes between the two groups. There were no ser ious or life- threatening adverse events. In a double-blind, placebo-controlled study in Zambia, the standard preventive two-dose regimen of pyrimethamine þ sulfadoxine (n = 224) was compared with monthly admin istration (n = 232) in HIV-positive pregnant women (14C). There was no difference in pla cental malaria by histopathology or placental parasitemia and no difference in maternal anemia, stillbirths, preterm delivery, low birth weight, or all-cause mortality at 6 weeks. There were no significant adverse events in the infants or mothers in either group. In 1070 children who were randomly assigned to receive either pyrimethamine þ sulfadoxine or placebo in a trial in Ghana (15C), treatment was given at 3, 9 and 15 months and followed up for 21 months. The primary end point was the incidence of malaria. Other outcomes were anemia, out patient visits, hospital admission and mortal ity. Pyrimethamine þ sulfadoxine was protective after the first and second doses but not after the third. Two individuals who took pyrimethamine þ sulfadoxine group and one who took placebo developed Stevens–Johnson syndrome. Although these reports suggest a high degree of tolerability and safety for intermittent
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Oscar Ozmund Simooya
preventive regimens, continued monitoring of adverse events in these programs must be intensified, especially in countries where preventive treatments may be given in people who are taking antiretroviral drugs or treatments for opportunistic infections such as co-trimoxazole or isoniazid.
QUININE AND CONGENERS (SED-15, 3002; SEDA-29, 296; SEDA-31, 472) Skin Two cases of fixed skin eruptions due to quinine in tonic water have been reported (16c). • A 37-year-old man developed erythema on the same site after drinking a variety of cocktails on a number of occasions. Tonic water was suspected and oral challenge with tonic water was positive as was a patch test with quinine sulfate. • A 24-year-old woman developed recurrent erythematous lesions with a burning sensation on her lips, fingers and toes which regularly occurred at the same sites. The reactions always followed the ingestion of alcohol, especially cocktails. Oral challenge with tonic water and quinine sulfate was positive.
Fixed skin eruptions have been reported with therapeutic quinine but rarely with quinine in drinks. Drug administration route In a doubleblind comparison of the safety and efficacy of rectal versus intravenous quinine in 110 children (aged 6 months to 5 years) with cerebral malaria in Uganda, there was no difference in clinical and parasitological out comes between the two groups, and mortal ity was the same (17C). There were no major adverse events. In those who received rectal quinine there were no cases of rectal bleed ing or mucoid stools and the rectal quinine solution was not expelled. Vomiting occurred in 10 patients (7 of those given intravenous quinine and 3 of those given rectal quinine). Rectal quinine is efficacious and may be con sidered for the treatment of severe malaria when intravenous quinine is difficult to
Antiprotozoal drugs
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administer and when artemisinin compounds are unavailable or unaffordable.
ENDOPEROXIDES (SED-15, 342; SEDA-29, 297; SEDA-30, 338; SEDA-31, 473) There are five artemisinin derivatives that are active in malaria: arteether, artemether, arte misinin, artesunate, and dihydroartemisinin.
Artesunate Nervous system Although artemisinin deri vatives are relatively safe, neurotoxicity after artemisinin has been documented in animals and in a few humans. Chorea secondary to artesunate has been reported (18A). • A 29-year-old Nigerian man developed repetitive, jerky, involuntary movements of the body, which started gradually after a second dose of self-medicated artesunate for presumptive malaria. There was no history of head injury and he was fully conscious and oriented. There were no signs of meningeal irritation or photophobia. The cranial nerves were intact and muscle tone, power, and reflexes were normal. A blood smear was positive for malaria but all other tests were normal. Artesunate was withdrawn and he was given intramuscular diazepam 20 mg, repeated 1 hour later, and then oral diazepam 5 mg 6 hourly for 48 hours. The chorea subsided within 24 hours and he was given amodiaquine and pyrimethamine þ sulfadoxine and made an uneventful recovery.
Drug–drug interactions Efavirenz An interaction with potentially important clini cal implications has been reported between artesunate þ amodiaquine and efavirenz in healthy volunteers (19c). Amodiaquine þ artesunate was given on days 1–3 and then efavirenz on days 7–23 combined with amo diaquine þ artesunate on days 18–20. Five volunteers were recruited but the study was prematurely terminated because two devel oped significant increases in liver enzymes. Efavirenz markedly increased the AUC and
525
Cmax of amodiaquine and prolonged its halflife. The AUC of desethylamodiaquine fell. Amodiaquine has been reported to cause hepatic injury when used as a prophylaxis, but 3-day courses of amodiaquine þ artesu nate have not been reported to cause hepatotoxicity. Similarly, efavirenz-induced hepatitis is uncommon. These findings suggest that patients who take amodiaquine þ artesunate and concurrent efavirenz should be closely monitored for hepatotoxi city or that the combination should be avoided.
DRUGS USED IN THE TREATMENT OF PNEUMOCYSTIS JIROVECI INFECTIONS For sulfonamides and co-trimoxazole (trimethoprim þ sulfamethoxazole), see Chapter 26.
DRUGS USED IN THE TREATMENT OF OTHER PROTOZOAL INFECTIONS Metronidazole (SED-15, 2323; SEDA-30, 339; SEDA-31, 475) Cardiovascular QT interval prolongation after metronidazole has been described (20A). • A 90-year-old woman with Parkinson’s disease and osteoporosis was given intravenous ceftriaxone 1 g/day and metronidazole 500 mg tds for an aspiration pneumonia; her other medications included levodopa and calcium. An electro-cardiogram on admission showed a QTc interval of 324 ms, which rose to 703 ms the next day. Metronidazole was immediately withdrawn and over the next few days the QTc interval gradually returned to its initial value.
Nervous system Acute reversible cerebellar lesions associated with metronidazole have been reported (21A).
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• A 27-year-old man with acute lymphoblastic leukemia developed ataxia, dysarthria, and confusion after taking metronidazole for 2 weeks for Clostridium difficile colitis. A brain MRI scan showed cytotoxic edema without contrast enhancement in the cerebellar dentate nuclei, dorsal pons, and medulla. Metronidazole was withdrawn and the symptoms resolved over the next 3 weeks. A brain MRI scan 6 weeks later showed resolution of the previous changes.
raised serum and urine amylase activity. Liver biochemistry was normal and stool examination for bacteria, parasites and ova was negative. Abdominal ultrasonography and CT scan suggested acute pancreatitis and there were no gallstones or biliary sludge. Metronidazole and mesalazine were withdrawn. His symptoms resolved and the serum amylase normalized after 4 days. He was given prednisolone and then mesalazine. The pancreatitis did not recur.
Hematology Thrombotic thrombocyto penic purpura has been attributed to metro nidazole vaginal gel (22A).
Mesalazine was unlikely to have caused the acute pancreatitis because of the timing and negative re-challenge. Metronidazole was the more likely cause although an interaction with mesalazine could not be ruled out.
• A 58-year-old woman used metronidazole 0.75% vaginal gel and after 3 days developed chest pain and hematuria. Her hemoglobin concentration was 5.5 g/dl, the platelet count 11 109/l, a reticulocyte count 1.3% (reference range 0.5–1.5%), and lactate dehydrogenase 2392 U/ l (100–250); there was a raised D-dimer concentration of 3.89 µg/ml (0–0.58) but the fibrinogen concentration and coagulation tests were normal; there were numerous schistocytes in her peripheral smear. She was treated with plasmapheresis and glucocorticoids and gradually improved with the addition of vincristine and rituximab and continued plasmapheresis.
The time-course of the relationship between drug exposure and the adverse event in this case suggests that the throm botic thrombocytopenic purpura was prob ably due to the metronidazole gel. Pancreas Acute pancreatitis after metro nidazole has been described before but is infrequent in patients with inflammatory bowel disease. Acute pancreatitis as a possible consequence of metronidazole during relapse of ulcerative colitis has been reported (23A). • A 31-year-old man with ulcerative colitis who had taken mesalazine 1.2 g/day for 5 months and metronidazole 1.5 g/day for 5 days developed nausea and abdominal pain and tenderness. He had a mild leukocytosis and
MISCELLANEOUS DRUGS Eflornithine
(SED-15, 1207;
SEDA- 30, 341) Observational studies Eflornithine is the only alternative to melarsoprol in the treatment of second-stage African trypanosomiasis. The lat ter is associated with severe topical adverse effects and treatment failure, but eflornithine requires intravenous infusion every 6 hours for 14 days. In 1055 patients in Sudan with newly diagnosed second-stage human trypanosomia sis, who were given eflornithine 400 mg/kg/day for 14 days (adults) or 600 mg/kg/day (chil dren) (24C), there were 2824 drug reactions (2.7 per patient) during the stay in hospital, 1219 (43%) of which occurred after the first week. Severe reactions affected 138 patients (13%), mainly seizures, fever, diarrhea, and bacterial infections; there were 15 deaths. Of 924 patients (88%) who were followed up, 16 (1.7%) died during treatment, 70 (7.6%) relapsed, 15 (1.6%) died from the disease and 403 (44%) were cured.
References 1. Gasasira AF, Kamya MR, Achan J, Mebrahtu T, Kalyango JN, Ruel T, Charlebois E, Staedke SG, Kekitiinwa A, Rosenthal PJ,
Havlir D, Dorsey G. High risk of neutropenia in HIV infected children following treatment with artesunate plus amodiaquine for
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uncomplicated malaria. Clin Infect Dis 2007;46(7):985–91. 2. Parikh S, Ouedraogo J-B, Goldstein JA, Rosenthal PJ, Kroetz DL. Amodiaquine metabolism is impaired by common poly morphisms in CYP2C8: implications for malaria treatment in Africa. Clin Pharmacol Ther 2007;82(2):197–203. 3. Cotroneo J, Sleik KM, Rodriguez ER, Klein AL. Hydroxychloroquine-induced restrictive cardiomyopathy. Eur J Echocar diogr 2007;8: 247–51. 4. Dosso A, Rungger-Brändle E. In vivo con focal microscopy in hydroxychloroquine induded keratopathy. Graefes Arch Clin Exp Ophthalmol 2007;245:318–20. 5. Muslimani AA, Spiro TP, Chaudhry AA, Daw HA. Secondary myelodysplastic syn drome after hydroxychloroquine therapy. Ann Hematol 2007;86:531–4. 6. Galvañ VG, Oltra MR, Rueda D, Esteban MJ, Redón J. Severe acute hepatitis related to hydroxychloroquine in a woman with mixed connective tissue disease. Clin Rheumatol 2007;26:971–2. 7. Amichai B, Gat A, Grunwald MH. Cuta neous hyperpigmentation during therapy with hydroxychloroquine. J Clin Rheumatol 2007;13(2):113. 8. Siddiqui AK, Huberfield SI, Weidenheim KM, Einberg KR, Efferen LS. Hydroxychloroquine induced toxic myopathy causing respiratory failure. Chest 2007;131:588–90. 9. Lyons JS, Severns ML. Detection of early hydroxychloroquine retinal toxicity enhanced by ring ration analysis of multifocal electroreti nography. Am J Ophthalmol 2007;143(5):801–9. 10. Rodriguez-Padilla JA, Hedges IIITR, Monson B, Srinivasan V, Wojtkowski M, Reichel E, Duker JS, Schuman JS, Fujimoto JG. High-speed ultra-high resolution optical coherence tomography findings in hydroxychloroquine retinopathy. Arch Opthamol 2007;125:775–80. 11. Walker RA, Colleaux KM. Maculopathy associated with mefloquine (Lariam) therapy for malaria prophylaxis. Can J Ophthalmol 2007;42:125–6. 12. Katsenos S, Psathakis K, Nikolopoulou MI, Constantopoulos SH. Mefloquine-induced eosinophilic pneumonia. Pharmacotherapy 2007;27(12):1767–71.
527 13. Grobusch MP, Lell B, Schwarz NG, Gabor J, Dornemann J, Potschke M, Oyakhirome S, Kiessling GC, Necek M, Langin MU, Klein Klouwenberg P, Klopfer A, Naumann B, Altun H, Agnandji ST, Goesch J, Decker M, Salazar CL, Supan C, Kombila DU, Borchert L, Koster KB, Pongratz P, Adegnika AA, Glasenapp I, Issifou S, Kremsner PG. Intermittent preventive treatment against malaria in infants in Gabon – a randomized, double- blind placebo-controlled trial. J Infect Dis 2007;196(11):1595–602. 14. Hamer DH, Mwanakasale V, Macleod WB, Chalwe V, Mukwamataba D, Champo D, Mwananyanda L, Chilengi R, Mubikayi L, Mulele CK, Mulenga M, Thea DM, Gill CJ. Two-dose versus monthly intermittent pre ventive treatment of malaria with sulfadox ine–pyrimethamine in HIV-seropositive pregnant Zambian women. J Infect Dis 2007;196:1585–94. 15. Kobbe R, Kreuzberg C, Adjei S, Thompson B, Langefeld I, Thompson PA, Abruquah HH, Kreuels B, Ayim M, Busch W, Marks F, Amoah K, Opoku E, Meyer CG, Adjei O, May J. A randomized controlled trial of extended intermittent preventive antimalar ial treatment in infants. Clin Infect Dis 2007;45(1):16–25. 16. Muso Y, Kentarou O, Itami S, Yoshikawa K. Fixed eruption due to quinine: report of two cases. J Dermatol 2007;34:385–6. 17. Achan J, Byarugaba J, Barennes H, Tumwine JK. Rectal versus intravenous qui nine for the treatment of childhood cerebral malaria in Kampala, Uganda: a randomized, double-blind clinical trial. Clin Infect Dis 2007;45:1446–52. 18. Busari OA, Oligbu G. Chorea in a 29 yearold Nigerian following anti-malarial treat ment with artesunate. Int J Infect Dis 2007;12(2):221–3. 19. German P, Greenhouse B, Coates C, Dorsey G, Rosenthal PJ, Charlebois E, Lindegardh N, Havlir D, Aweeka FT. Hepatotoxicity due to a drug interaction between amodiaquine plus artesunate and efavirenz. Clin Infect Dis 2007;44:889–91. 20. Cohen O, Saar N, Swartzon M, KliukBenBasat O, Justo D. First report of metronida zole-induced QT interval prolongation. Int J Antimicrob Agents 2007;31(2):180–1.
528 21. Bonkowsky JL, Sondrup C, Benedict SL. Acute reversible cerebellar lesions associated with metronidazole therapy. Neurology 2007;68(3):180. 22. Rivkin A. Thrombotic thrombocytopenic purpura induced by metronidazole vaginal gel. Pharmacotherapy 2007;27 (7):1058–61. 23. Tsesmeli NE, Giannoulis KE, Savopoulos CG, Vretou EE, Ekonomou IA, Giannoulis EK.
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Acute pancreatitis as a possible consequence of metronidazole during a relapse of ulcera tive colitis. Eur J Gastroenterol Hepatol 2007;19(9):805–6. 24. Priotto G, Pinoges L, Fursa IB, Burke B, Nicolay N, Grillet G, Hewison C, Balasegaram M. Safety and effectiveness of first line eflor nithine for Trypanosoma brucei gambiense sleeping sickness in Sudan: cohort study. BMJ 2008;336:705–8.
Oliver Koch, Susanne Sheehy, Catherine Sargent, Jane Democratis, Sarah Abbas, Jurgen Schiefermueller, and Brian J. Angus
29
Editor’s note: Interferons are covered in Chapter 37.
DRUGS ACTIVE AGAINST CYTOMEGALOVIRUS Cidofovir
(SED-15, 771; SEDA-30, 343; SEDA-31, 477)
Respiratory Cidofovir has been used to treat adenovirus pneumonia in four pediatric lung transplant recipients (1c). Two developed bronchiolitis obliterans, one of whom underwent retransplantation with a good outcome. The other developed tracheomalacia and required continuous low-flow oxygen and positive pressure ventilation through a tracheostomy.
Urinary tract Of six hemopoietic stem cell transplant recipients, who were given cidofovir 5 mg/kg/week for 2 weeks, then on alternate weeks for a minimum of four (range 1–7) doses, three developed adenovirus hepatitis, two had colitis and one had nephritis (2c). All had CD34þ selected grafts and/or graft-versus-host disease and all had a CD4 count under 100 106/l. The patients were pre-hydrated
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32029-0 2010 Elsevier B.V. All rights reserved.
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and given probenecid and intravenous immunoglobulin 1–2 g/kg/week followed by 0.5 mg/kg on alternate weeks for a minimum of four doses. Two patients died of infection and four responded. None required withdrawal of treatment because of adverse effects. Baseline creatinine was slightly raised (167 µmol/l) in the patient with hepatitis and improved with cidofovir. Most of the patients had transient increases in creatinine as the number of doses increased. Cidofovir 5 mg/kg/week or 1 mg/kg on alternate days adjusted to creatinine clear ance was used to treat 11 hemopoietic stem cell transplant recipients with invasive ade noviral infection, including three with pneu monia, one with hepatitis, four with hemorrhagic colitis and three with hemor rhagic cystitis (3c). All had concomitant intravenous immunoglobulin, and those with colitis had in addition one or more of oral immunoglobulin, ribavirin, or donor lymphocyte infusion. They varied in their degree of immunocompromise and the pre sence of graft-versus-host disease and some had leukocyte-depleted allografts. Six died. There was nephrotoxicity in two cases. In a retrospective study of 19 recipients of hemopoietic stem cell transplants, mean age 42 years, who were given a mean of 4.5 (range 3–6) weekly doses of cidofovir 1 mg/ kg without probenecid for BK virus-asso ciated hemorrhagic cystitis, 84% had graft versus-host disease and were taking corti costeroids at the time of diagnosis (4c). There was no significant rise in creatinine in 14; 5 had renal insufficiency, but in all cases there were other potential causes. In
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only 3 cases could cidofovir have played a role. In those with normal renal function, 80–100% of the cidofovir was recovered from the urine, raising the possibility of therapeutic intravesicular administration.
DRUGS ACTIVE AGAINST HERPESVIRUSES (SEDA-29, 301; SEDA-30, 343; SEDA-31, 478)
Aciclovir
Oliver Koch et al.
and faintness within 5 minutes of taking valaciclovir 500 mg for genital herpes. Skin prick tests for aciclovir were positive.
Urinary tract As with aciclovir, renal insufficiency has been reported with valaciclovir (10A) • A 73-year-old Japanese man with cardio myopathy and chronic renal disease was admitted with anuria, systemic edema, and renal dysfunction after taking valaciclovir 1 g tds 5 days for Herpes zoster infection with a non-steroidal anti-inflammatory drug. He was briefly dialysis-dependent but made a full recovery.
Psychiatric Hemodialysis has been successfully used to treat an aciclovir induced psychosis (5A). • A 70-year-old man with rectal carcinoma and end-stage renal failure on hemodialysis was given intravenous aciclovir. He developed delirium, visual and auditory hallucinations, disorientation in place and time, and impaired recent memory. He recovered fully after 3 consecutive days of hemodialysis.
Urinary tract Reports of renal insuffi ciency associated with the use of intravenous aciclovir continue to appear (6A). In a retrospective review of 126 children there was no effect of dose per kilogram, age, or sex on nephrotoxicity (7c). The predictors of aciclovir nephrotoxicity were the concomitant use of nephrotoxic drugs and impaired glomerular filtration rate (GFR) at baseline. Fetotoxicity It has been suggested that maternal use of aciclovir may be associated with necrotizing enterocolitis in the neonate (8A).
Valaciclovir Immunologic An acute allergic reaction to valaciclovir has been described (9A). • A 50-year-old woman developed general malaise, diffuse pruritus, angioedema of the hands and feet, and reduced consciousness
DRUGS ACTIVE AGAINST HEPATITIS VIRUSES Adefovir
(SED-15, 35; SEDA-30, 344; SEDA-31, 480)
Observational studies In patients with lamivudine-resistant HBe antigen (HBeAg) negative disease, adefovir 10 mg alone (n = 14) or in combination with lamivudine (n = 28) caused a fall in creatinine clearance requiring a modification in adefovir dose in two patients on combined therapy; both had underlying liver cirrhosis (11c). One developed reduced liver function and biopsy showed steatohepatitis. One on adefovir monotherapy developed gastric cancer. Five on combined therapy with underlying cirrhosis developed hepatocellular carcinoma, but this was not statistically significant. Adefovir 10 mg/day in combination with lamivudine 300 mg/day has been used in 11 patients with recurrent hepatitis B virus infec tion after liver transplant (12c). All patients with chronic hepatitis B pre-transplant underwent a period of preoperative treat ment and peri-operative prophylaxis with lamivudine and hepatitis B immunoglobulin with or without adefovir if lamivudine-resis tant. No patient had adverse effects necessi tating drug withdrawal, but one required a dosage adjustment because of a rise in creati nine from 106 to 150 µmol/l. Three had a recurrence of hepatocellular carcinoma, two
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of whom died 12 and 14 months after starting adefovir therapy and one of whom continued to be positive for hepatitis B virus DNA. Drug–drug interactions Entacavir The interaction of entacavir 1 mg/day with adefovir 10 mg/day has been studied in a fixed-sequence crossover study in 26 heal thy adults (13c). The results suggested that combination therapy can be safely adminis tered without the need for dosage adjust ment of either drug. There was headache in nine subjects and dysmenorrhea in two when they took entecavir alone.
Amantadine See ‘Drugs active against influenza viruses: ion channel inhibitors’, below.
Entecavir Drug–drug interactions Adefovir The interaction of entacavir 1 mg/day with ade fovir 10 mg/day has been studied in a fixedsequence crossover study in 26 healthy adults (13c). The results suggested that com bination therapy can be safely administered without the need for dosage adjustment of either drug. There was headache in nine subjects and dysmenorrhea in two when they took entecavir alone.
Lamivudine
(SED-15, 1989, SEDA-30, 344; SEDA-31, 480)
Observational studies In 33 treatmentnaive HBeAg-positive children who took lamivudine and high-dose interferon alpha 2a combination therapy, flu-like symptoms and anorexia were the commonest adverse effects (90 and 76%); weight loss, nausea, vomiting, arthralgia, and loss of hair were also noted (14c). In an open study of the pharmacokinetics of lamivudine in 12 patients receiving peri toneal dialysis, eye redness (n = 2) and diar rhea (n = 2) were the commonest adverse events (15c).
531
Comparative studies In a double-blind, Phase III, randomized, controlled trial of lamivudine 100 mg/day (n = 687) versus tel bivudine 600 mg/day (n = 680), creatine kinase activity was raised in patients receiv ing lamivudine (3.1%) and telbivudine (7.5%) and fell spontaneously during drug treatment to grade 2 or lower in 74% of those taking lamivudine and 67% of those taking telbivudine (16C). Grade 3 or 4 rises in transaminases during treatment were more frequent with lamivudine than with telbivudine.
Ribavirin Observational studies High-dose ribavirin during an outbreak of severe acute respira tory syndrome in Toronto was associated with a high rate of adverse events: anemia (odds ratio [OR] = 3.0; 99% confidence interval [CI] = 1.5, 6.1), hypomagnesemia (OR = 21; 99% CI = 5.8, 73), and bradycar dia (OR = 2.3; 99% CI = 1.0, 5.1) (17c). The risks of anemia, hypomagnesemia, and bra dycardia attributable to ribavirin were 27%, 45%, and 17% respectively. The authors concluded that the use of high-dose ribavirin is appropriate only for the treatment of infectious diseases for which ribavirin has proven clinical efficacy, or in the context of a clinical trial. They further stated that ribavirin should not be used empirically for the treatment of viral syndromes of unknown origin. Skin Occasional rashes in areas of drug contact and conjunctival irritation occurred when aerosolized ribavirin was used for 10 months in an infant with immunodeficiency (18A).
Telbivudine Musculoskeletal In a double-blind, Phase III, randomized, controlled trial of lami vudine 100 mg/day (n = 687) versus telbivu dine 600 mg/day (n = 680), raised creatine kinase activity was more common in patients
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who took telbivudine and it fell sponta neously during drug treatment to grade 2 or lower in 67% of those who took telbivu dine and 74% of those who took lamivu dine. Myopathy (characterized by muscle pain, weakness, and moderately raised crea tine kinase activity before and during treat ment) was reported in one patient after telbivudine therapy for 11 months. When telbivudine was withdrawn, the creatine kinase activity normalized within 1 month and the symptoms resolved over 9–12 months (16C).
DRUGS ACTIVE AGAINST HIV: COMBINATIONS Cardiovascular Syncope occurred in a young man after he took tenofovir, emtricitabine and nevirapine for primary human immunodeficiency virus-1 (HIV-1) infection for 6 weeks and resolved after withdrawal of the antiretroviral drugs (19A). Metabolism The hemochromatosis gene polymorphism HFE 187C> G and possibly mitochondrial haplogroup J gave relative protection against lipoatrophy during antiretroviral drug therapy in a trial in which 96 patients were randomized to didanosine þ stavudine or zidovudine þ lamivudine, combined with efavirenz and/ or nelfinavir in AIDS Clinical Trials Group (ACTG) 384 sub-study A5005s (20C). Stavudine had a less favorable effect on lipid profile and caused more lipoatrophy than abacavir (38% versus 4.8%) in a ran domized, open trial, stratified by viral load and CD4 cell count, in which 237 adults with HIV infection were assigned to stavudine (n = 122) or abacavir (n = 115), both com bined with lamivudine and efavirenz (21C). There were dose-related increases in total cholesterol, LDL cholesterol, and triglycerides in an open study in 56 seronegative volun teers, with persistent increases 2 weeks after withdrawal (22c).
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In a randomized controlled trial of indina vir, saquinavir and lopinavir in combination with low-dose ritonavir in 656 patients, med ian total cholesterol increased by 0.5 mmol/l in the patients with the highest minimum drug plasma concentrations (23A). Gastrointestinal In a retrospective obser vational study of highly active antiretroviral therapy (HAART), 27 of 50 patients who took indinavir in combination with zidovudine and lamivudine developed nausea and were significantly more likely to stop taking the treatment than those who were taking zidovudine þ lamivudine þ tenofovir (24c). In a long-term follow-up study of 200 asymptomatic HIV-positive participants for 157 weeks taking a combination of indinavir, lamivudine, and zidovudine, 40 stopped treat ment because of adverse effects, of which nausea (69%), diarrhea (37%), and abdom inal pain (28%) were the most common (25c). The most common adverse events in 21 of 151 patients in a prospective study of once-daily saquinavir þ ritonavir and two nucleoside reverse transcriptase inhibitors (NRTIs) were abdominal discomfort, diar rhea, and vomiting (26c). Similar findings were seen by other investigators (27A). Liver In 199 HIV/hepatitis C co-infected patients, failure to achieve a sustained viral response, NRTI therapy, didanosine, and stavudine were significantly associated with worsening of hepatic fibrosis in 34 (17%) (28c). After multivariate analysis, didanosine (OR = 3.34; 95% CI = 1.39, 7.96) and failure to have a sustained viral response (OR = 9.05; 95% CI = 2.06, 40) remained significantly associated with worsening of fibrosis. In a retrospective study of 868 HIV-posi tive subjects (94% men), first-line therapy was efavirenz, lamivudine, and zidovudine; women of child-bearing potential were given nevirapine instead of efavirenz. An efavirenz-based regimen was used in 825 and 39 received a nevirapine-based regimen (29C). During the first year 48 subjects took isoniazid prophylaxis and 214 received
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antituberculosis therapy (2 months of rifam picin, isoniazid, pyrazinamide, and etham butol followed by 4 months of rifampicin and isoniazid). Of a random sample of 133 tested, 17% were hepatitis B surface anti gen (HBsAg)-positive. There was grade 2 or worse hepatotoxicity in 97 subjects (11%) and 40 had a first episode of grade 3 or 4 hepatotoxicity. Antituberculosis therapy (adjusted hazard ratio [HR] = 8.5; 95% CI = 2.7, 27) and HBsAg (adjusted HR = 3.0; 95% CI = 1.3, 7.0) were strongly associated with hepatotoxicity. However, hepatotoxicity had little impact on symp toms, the need for hospitalization and the need for a change in antiretroviral drug regimen. The use of isoniazid preven tive therapy during antiretroviral drug therapy did not increase the risk of hepatotoxicity. Three adults developed nodular regen eration of the liver while taking HAART regimens containing atazanavir, fosampre navir, and indinavir (30A). Pancreas In the large EuroSIDA study there was no association between an increased incidence of pancreatitis and cumulative exposure to antiretroviral drugs generally, or to didanosine and stavudine in particular (31C). There were 43 (9 presumptive) pancreatic events in 9678 individuals during 33 742 person-years (1.27 per 1000 person-years). The incidences among those with no, 2 or less, and over 2 years of exposure to antiretroviral drugs, including stavudine and didanosine, were 1.24, 1.73, and 0.78 per 1000 person-years, respectively. In multivariate analysis, higher baseline CD4 cell counts were associated with a reduced risk of pancreatitis. Urinary tract Of 445 HIV-positive patients who started to take tenofovir, 51 (11%) had reduced renal function (32C). Multivariate analysis showed a significant association between reduced renal function and concurrent use of amprenavir and di danosine, age over 50 years and lower baseline weight. There was an association
533
between concomitant use of tenofovir and amprenavir and reduced kidney function in 441 patients (OR = 3.5). Acute interstitial nephritis was seen on renal biopsy in three HIV-positive patients taking amprenavir þ tenofovir; it resolved after drug withdrawal (33A). In a randomized controlled trial of in dinavir, saquinavir, and lopinavir in combi nation with low-dose ritonavir in 656 patients, there was no apparent dose-related association with renal adverse events (23C). Immunologic An allergic reaction with possible cross-reactivity to didanosine and tenofovir has been reported (34A). • A 25-year-old woman tested positive for HIV-1 and was given a once-a-day regimen including tenofovir plus emtricitabine and efavirenz. After 10 days she developed a diffuse rash with fever and glossitis. Efavirenz was withdrawn but her conditions worsened over the next 3 days, so both tenofovir and emtrici tabine were withdrawn, with dramatic resolu tion of symptoms within 24 hours. After 10 days she was given zidovudine plus didanosine and ritonavir-boosted fosamprenavir. After 1 week she again developed a diffuse rash and the treatment was withdrawn. She restarted zidovudine and didanosine 7 days later and within a few days the rash appeared again. Under observation she was given zidovudine and atazanavir and after 8 days lamivudine and low-dose ritonavir. She remained well, except for mild hyperbilirubinemia, during the next 5 months.
Fetotoxicity There is equivocal evidence of a relation between in utero NRTI exposure and mitochondrial dysfunction in HIVnegative children born to HIV-infected women. In 1037 HIV-negative children, possible cases with unexplained signs of mitochondrial dysfunction according to the Enquête Perinatale Française criteria were identified in a retrospective review (35c). Associations between possible mitochondrial dysfunction and both overall in utero NRTI exposure and the trimester of first in utero NRTI exposure were estimated by exact logistic regression. Cases (n = 20) were significantly more likely to be boys and to be born in earlier years than non-cases
534
(n = 1017). There was no association between overall in utero NRTI exposure and mitochondrial dysfunction. In unadjusted models there were higher odds of first in utero exposure in the third trimester to lamivudine (OR = 3.76 versus unexposed; 95% CI = 1.09, 12) and to zidovudine þ lamivudine (OR = 3.29 versus unexposed; 95% CI = 0.96, 10) among cases than noncases. When adjusted for year of birth, the odds of first exposure in the third trimester to lamivudine (OR = 11; 95% CI = 1.9, 76) and zidovudine þ lamivudine (OR = 9.8; 95% CI = 1.7, 72) were significantly higher among cases than non-cases. Incomplete data precluded control of possible confounding by maternal viral load and psychoactive drug use. Drug–drug interactions Combinations of antiretroviral drugs Reports of renal toxicity with the combination of tenofovir and didanosine in children suggest that this combination should be avoided (36A). Combination of saquinavir with darunavir þ ritonavir is currently not recommended as plasma concentrations of darunavir are increased (37c). Buprenorphine Atazanavir and atazanavir þ ritonavir both resulted in increased metabolite concentrations of buprenorphine, and dosage reduction of buprenorphine is recommended; there was no change in the concentrations of the protease inhibitors (38c). Warfarin In two patients who were taking a non-nucleoside reverse transcriptase inhibitor (NNRTI), nevirapine, or a protease inhibitor, nelfinavir or lopinavir þ ritonavir, and two nucleoside analogues, high doses of warfarin were required to maintain therapeutic INRs (39A). Warfarin has two enantiomers, R-warfarin and S-warfarin, which are substrates of CYP3A4 (R-warfarin), CYP1A2 (R-warfarin), and CYP2C9 (S-warfarin). Protease inhibitors and NNRTIs have variable effects on CYPs: induction, inhibition, or mixed effects. The increased warfarin doses required in these two patients may have been caused by induction of CYP3A4 by nevirapine, of CYP2C9
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by nelfinavir, or of CYP2C9 by lopinavir þ ritonavir.
DRUGS ACTIVE AGAINST HIV: NUCLEOSIDE ANALOGUE REVERSE TRANSCRIPTASE INHIBITORS (NRTIS) (SED-15, 2586; SEDA-29, 304; SEDA-30, 349; SEDA-31, 482)
Abacavir (SED-15, 3; SEDA-29, 303; SEDA-30, 348; SEDA-31, 482) Gastrointestinal In patients with AIDSassociated dementia ADC taking optimal stable background antiretroviral therapy including either abacavir or placebo there was significantly more nausea in those who took abacavir (40c). Immunologic Three patients developed painful lymphadenopathy shortly after starting to take abacavir, mimicking immune reconstitution syndrome (41A). They also had a fever and a rash and all were HLA-B*5701-positive. They recovered after withdrawal of abacavir. Abacavir hypersensitivity occurred in a 36-year-old man after he switched from a twice-daily to a once-daily regimen (42A). In a 52-year-old woman, abacavir hyper sensitivity presented as acute fibrinous and organizing pneumonia, with dyspnea, hypoxia, and bilateral infiltrates (43A). Susceptibility factors Genetic A sequence variation in the HIV reverse transcriptase codon 245 has been associated with host HLA-B*5701 in 392 HIV-infected, antiretroviral drug-naive adults, and the relation between the codon 245 variation and premature abacavir withdrawal was investigated in 982 treated individuals (44C). Only one of 24 subjects with B*5701 harbored virus with the clade B ‘wild-type’ amino acid 245V, compared with 278 of 368
Antiviral drugs
Chapter 29
who did not have B*5701. The sensitivity and specificity of codon 245 substitutions for predicting HLA-B*5701 were 96% and 75% respectively, and the positive and negative predictive values were 20% and 99.6% respectively. The authors argued that the reverse transcriptase codon 245 could be adopted as a simple, low-cost screening method to identify individuals who could be safely treated with abacavir when detection of HLA-B*5701 is not rapidly and easily available. Drug–drug interactions Alcohol Three patients had possible reactions to alcohol while taking abacavir (45A). One had a disulfiram-like reaction (nausea, facial flushing, tachycardia) repeatedly on rechallenge with alcohol. Another described a feeling of being drunk after small amounts of alcohol. A third had malaise after increasing his alcohol intake. The authors suggested that abacavir might inhibit alcohol dehydrogenase.
Didanosine
(SED-15, 1113; SEDA-29, 303; SEDA-30, 348; SEDA-31, 483) Urinary tract Fanconi syndrome and nephrogenic diabetes insipidus associated with didanosine have been reported (46A).
• A 40-year-old man developed polydipsia, poly uria, fatigue, and weight loss after taking dida nosine, lamivudine and boosted atazanavir for 2 years. He had hypophosphatemia, hypouricemia, hyperchloremic metabolic acidosis with a normal anion gap, normoglycemic glycosuria, and low-molecular-weight protei nuria. The plasma antidiuretic hormone (ADH) concentration was high at 4.8 pg/ml (reference range 1.4–4.4 pmol/l). The didano sine was replaced with another protease inhi bitor and the other medications remained unchanged. He improved slowly.
Drug–drug interactions Ganciclovir It has been suggested that ganciclovir and its prodrug valganciclovir inhibit purine nucleoside phosphorylase (PNP) in a similar manner to tenofovir and increase didanosine concentrations, reducing its efficacy (47A).
535 • A 68-year-old woman with HIV and cyto megalovirus enteritis was given valganciclovir, lamivudine, didanosine, and lopinavir þ ritona vir. After 3 months, her viral load fell to less than 50 copies/ml and the CD4þ cell count was 317 106/l. Over the next 9 months her viral load remained suppressed, but the CD4þ cell count fell to 83 106/l and she had symptoms of didanosine toxicity. Didanosine was replaced with abacavir, leading to complete recovery of the CD4þ cell count and resolu tion of symptoms.
Reduction of the dosage of didanosine or substitution with an alternative antiretro viral drug may be necessary when ganciclo vir is used.
Stavudine Metabolism Lipodystrophy tended to occur more often in 58 HIV/hepatitis C co-infected patients who had severe weight loss than in 111 other patients (26% versus 18%), and patients who had persistent weight loss over 5% for 24 weeks after the completion of anti-hepatitis C virus (HCV) therapy were more likely to be taking a stavudine-based antiretroviral therapy (48c). In another study patients with lipoatrophy had higher drug exposure to stavudine than controls (49c). This was reflected in the higher geometric concentration ratios (0.978 and 0.741 respectively) and a higher percentage of ratios over 1.0, representing a drug concen tration above the normal population curve (46% versus 23%). In addition, the duration of stavudine therapy was independently asso ciated with lipoatrophy. In a multivariate ana lysis, both duration of stavudine therapy and a concentration ratio over 1.0 independently correlated with lipoatrophy. Changes in body habitus occur when sta vudine is withdrawn. In 574 HIV-positive women who stopped taking stavudine for over 2.25 years, there were significantly smaller reductions in hip and thigh circum ferences compared with the reductions that occurred at 1–2.25 years after stavudine withdrawal (50c). Stavudine reduces insulin sensitivity and causes mitochondrial toxicity in healthy sub jects. In 16 participants without a personal
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or family history of diabetes who were randomized to stavudine 30–40 mg bd or placebo for 1 month, insulin sensitivity was significantly reduced by stavudine (51c). In addition, muscle biopsies in those who took stavudine showed significant reductions in mtDNA/nuclear DNA, but there were no changes in placebo-treated subjects. P mag netic resonance spectroscopy studies of mito chondrial function correlated with measures of insulin sensitivity. In 125 patients in a retrospective study, symptomatic hyperlactatemia in 114 (91%) was associated with stavudine median dura tion 13 months (52C). Nine patients (7.2%) died; those who died had a higher mean lactate concentration (8.0 versus 5.1 mmol/l) and mean AlT activity (164 versus 48 U/l) at the time of diagnosis than those who sur vived. Those who died had a lower mean weight than those who survived (48 versus 59 kg). By logistic regression, mortality was associated with patients whose body weight was under 45 kg (OR = 9.1; 95% CI = 1.6, 53) and whose serum lactate was over 10 mmol/l (OR = 20; 95% CI = 2.6, 159). Dosage regimens A meta-analysis of clinical trials conducted before and after regulatory approval of stavudine has shown that a dosage of 30 mg bd has equivalent antiviral efficacy, with some evidence of lower rates of peripheral neuropathy and lipoatrophy, to the standard dosage of 40 mg bd (53M). It has been suggested that this is the most appropriate dose in resourcelimited settings (54M). Reducing the dosage of stavudine by one-half increased fat mtDNA and bone density and decreased lactate concentrations in a study of 24 patients already taking a standard dose (55c).
Zidovudine
(SED-15, 3713;
SEDA-31, 485) Hematologic Hemoglobin A2 can rise in HIV-infected patients, possibly because of therapy (56c). In cross-sectional and cohort studies, hemoglobin A2 was often raised in untreated patients, but a further rise during treatment was specifically
Oliver Koch et al.
attributable to zidovudine. The concentration of hemoglobin A2 may be high enough to lead to a misdiagnosis of beta-thalassemia. Genotoxicity Micronucleated reticulocyte frequencies have been measured as a mar ker of chromosomal damage in 16 HIVinfected mother–infant pairs, of whom 13 women had taken prenatal zidovudine and 3 antiretroviral drugs without zidovudine (57c). All the infants received zidovudine for 6 weeks. Venous blood was obtained from women at delivery and from infants at 1–3 days, 4–6 weeks, and 4–6 months of life; cord blood was collected immediately after delivery. Ten cord blood samples (controls) were obtained from infants of HIV-negative women who did not receive antiretroviral therapy. There were 10-fold increases in micronucleated reticulocytes in women and infants who received zidovudine-containing antiretroviral therapy prenatally and no increases in the other women and infants. Micronucleated reticulocytes in the zidovudine-exposed neonates fell over the first 6 months of life to values comparable to cord blood controls. The authors concluded that transplacental zidovudine exposure is genotoxic in humans and they recommended long-term monitoring of zidovudine-exposed infants. Teratogenicity A possible association between first trimester exposure to zidovudine and an increased risk of hypospadias based on one cohort study has been reported (58c). Among 2527 live births to 2353 women, defects were identified in 90 babies (3.56 defects per 100 live births). The rate of defects was 3.19 per 100 live births with first-trimester antiretroviral drug exposure, 3.54 per 100 live births with exposure later in pregnancy, and 4.05 of 100 live births with no antiretroviral drug use. Only genital abnormalities, specifically hypospadias, were significantly increased among babies born to women with firsttrimester exposure to antiretroviral drugs (7 of 382 male live births) compared with the two other groups (2 of 892 male live
Antiviral drugs
Chapter 29
births). Logistic regression suggested that use of zidovudine in the first trimester was associated with hypospadias (adjusted OR = 11; 95% CI = 2.1, 54).
Pregnancy In a pharmacokinetic study of three doses of zidovudine 300 mg 3-hourly in pregnancy in six subjects, plasma zidovudine concentrations were substantially lower than previously reported during continuous intravenous therapy (59A). In another study in four women who took an initial 600 mg dose followed by two 400 mg doses 3-hourly, the zidovudine AUC and concentrations increased approximately in proportion to the increase in dose but varied 6–7 times (60A). In both cohorts, the pharmacokinetic results suggested erratic absorption.
Drug–drug interactions Co-trimoxazole Combined exposure to zidovudine plus co-trimoxazole caused a clinically signifi cant suppression of humoral immune responses to influenza immunization in 23 HIV-positive patients with CD4 counts above 350 106/l (61c). Ribavirin Ribavirin did not inhibit the formation of zidovudine triphosphate in peripheral blood monocytes in 14 patients over 8 weeks (62c).
537
least two thymidine-associated resistance mutations were given tenofovir 600 mg/day for 4 weeks in addition to their current failing antiretroviral regimen (n = 10), one developed de Fanconi syndrome at week 2 and two developed grade one hypopho sphatemia (63c). In a multicenter, observational, retro spective study of 733 HIV-positive patients taking tenofovir, 85 patients (11.6%) stopped taking tenofovir because of adverse events, including nausea, vomiting, diarrhea, and headache. There was no association between any abnormal basal analytical parameter and a greater probability of stop ping treatment (64C). In a single-center, cross-sectional evalua tion of b2 microglobinuria as a marker of proximal renal tubule damage in 92 HIVinfected children, tenofovir was significantly associated with very high abnormal values (65C).
DRUGS ACTIVE AGAINST HIV: NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIS) (SED-15, 2553; SEDA-28, 334; SEDA-29, 305; SEDA-30, 349; SEDA-31, 486)
Efavirenz (SED-15, 1204; SEDA-29, 305; SEDA-30, 349; SEDA-31, 486)
DRUGS ACTIVE AGAINST HIV: NUCLEOTIDE ANALOGUE REVERSE TRANSCRIPTASE INHIBITORS Tenofovir
(SED-15, 3314; SEDA-29, 304; SEDA-30, 349; SEDA-31, 485) Urinary tract In a pilot, open, noncomparative add-on study, in which patients who had failed treatment with at
The efficacy, resistance profile, adverse effects, and drug interactions of efavirenz have been reviewed (66R). Psychiatric Neuropsychiatric symptoms provoked by efavirenz have been reviewed (67R). Of 103 patients who took didanosine, lamivudine, and efavirenz for 48 weeks, 19 had neuropsychiatric adverse effects related to efavirenz (68c). In an evaluation of the effectiveness and adverse effects of a simplification regimen
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with tenofovir, lamivudine, and efavirenz in 154 HAART-experienced HIV-1-infected subjects with sustained viral suppression, 9 had psychiatric adverse effects related to efavirenz, leading to drug withdrawal in most cases; the symptoms included nightmares, insomnia, nervousness, and anxiety (69c).
Metabolism ACTG study 5095 was a ran domized, placebo-controlled, double-blind study designed to compare three protease inhibitor-sparing antiretroviral drug regi mens (zidovudine þ lamivudine þ abacavir; zidovudine þ lamivudine þ efavirenz; zidovudine þ lamivudine þ abacavir þ efa virenz) in the initial treatment of HIV-1 infection in 1147 subjects (70C). There were modest rises in serum triglycerides, LDL cholesterol, and HDL cholesterol in the two efavirenz-containing arms com pared with the triple-nucleoside arm.
Urinary tract A renal calculus that occurred in a 47-year-old man taking efavirenz contained efavirenz metabolites (60%) and about 40% of unspecified proteins (71A). This was a between-the eyes adverse effect of type 1a, definitively implicating efavirenz (72H).
Breasts In cohort study from Cambodia, 2 of 343 patients developed gynecomastia while taking a regimen containing efavirenz (73c). Susceptibility factors Genetic Efavirenz is metabolized by CYP2B6. The pharmacokinetics of efavirenz have been studied in 71 children with a G-to-T polymorphism at position 516 of the CYP2B6 gene, which affected its oral clearance (74c). Children with the T/T genotype had a slower oral clearance rate than those with the G/T genotype and the G/G genotype. The fastest clearance was found in children under 5 years of age with the G/G genotype.
Oliver Koch et al.
The association between efavirenz-induced psychosis and a genetic polymorphism in CYP2B6 has been reported in a child (75A). • A 12-year-old HIV-positive girl taking lopinavir 400 mg bd, ritonavir 100 mg bd, stavudine 30 mg bd, didanosine 250 mg/day, and efavirenz 600 mg/day developed an overt psychosis. Her serum efavirenz concentration was 7–8 times higher than expected and she had a heterozygous gene polymorphism encoding for the CYP2B6 isoenzyme, which has previously been associated with reduced clearance of efavirenz. The psychotic symptoms resolved gradually after withdrawal of efavirenz.
Drug–drug interactions Antimalarial drugs Two healthy volunteers who took amodiaquine plus artesunate and efavirenz had significant asymptomatic rises in liver transaminases, which did not occur in the absence of efavirenz (76c). Voriconazole In a randomized, placebocontrolled, two-period, multiple-dose within-group, fixed-dose sequence study of the interaction of voriconazole 200 mg bd with efavirenz 400 mg/day in healthy men, repeated doses of efavirenz substantially reduced the steady-state mean AUC and Cmax of voriconazole by 80% and 66% respectively (77C). Repeated therapeutic doses of voriconazole moderately increased the steady-state mean AUC and Cmax of efavirenz by 43% and 37% respectively. When voriconazole was co-administered with efavirenz, the incidence of adverse events was similar to that with efavirenz alone.
Nevirapine Liver Hepatotoxicity is a major problem with nevirapine (78R). The frequency of large increases in liver enzymes in patients taking efavirenz is 1–8%, whereas in patients taking nevirapine it is 4–18%. A warning about the increased risk of hepatotoxicity in antiretroviral-naive patients who start to take nevirapine-containing combination antiretroviral therapy has
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Chapter 29
been issued based on CD4 cut-off values and sex. However, it is unclear whether this higher risk also applies to stable virolo gically suppressed patients. A meta-analysis of four published randomized studies in 410 patients, including virologically suppressed patients who switched to nevirapine-con taining regimens with a follow-up of at least 3 months, has shown that the risks of hepatotoxicity within the first 3 months were 2% and 4% in those with low and high CD4 counts, respectively, with a com bined OR of 1.5 (95% CI = 0.4, 5) (79M). The risk of hepatotoxicity at any time dur ing the study was similar in the groups, with a combined HR of 0.8 (95% CI = 0.3, 2.5). The authors concluded that virologically suppressed patients who switch to nevira pine do not have a significantly higher risk of hepatotoxicity or rash when stratified by sex and CD4 cell count. The aim of a retrospective study was to determine whether these recommendations are of use in preventing adverse effects (80c). Drug-naive patients (n = 142) who started treatment with nevirapine were divided into two groups: those with high or low CD4 counts (n = 61 and 81 respec tively). There were rashes in 4 patients in the high-CD4 group and in 12 of those in the low-CD4 group and hepatotoxicity in 3 and 5 patients respectively. The authors concluded that the advice not to use nevir apine in drug-naive patients at increased risk of toxicity on the basis of sex and CD4 cell count does not seem to be useful in preventing adverse effects. In a retrospective study, 582 patients (72% men) received 744 nevirapine-based HAART regimens (81c). During 10% of treatments, there were grade 3 or greater increases in transaminase activities, an overall incidence rate of 5.3 cases per 100 person-years. This led to treatment with drawal in 3.9% of cases. In a retrospective study of over 1000 pregnant women taking nevirapine-contain ing regimens, 93% started or continued nevirapine during the first and second trimesters (82cA). Concurrent chronic hepatobiliary disorders slightly increased the likelihood of hepatotoxicity. Of seven
539
patients who had liver dysfunction, six pre viously had had hepatitis C and gall blad der disease.
Skin Widespread vitiligo after erythroderma has been attributed to nevirapine (83A). • A 34-year-old man developed erythroderma, a high fever and hepatitis after taking nevirapine for 1 month. There was jaundice and a confluent macular rash on the arms, legs, trunk, and face. Histology showed a parakeratotic epidermis with focal spongiosis, necrotic keratinocytes and vacuolar degeneration of the basal layer, together with moderate edema and a perivascular mononuclear cell infiltrate, with some eosinophils in the upper dermis. The lesions faded on withdrawal of nevirapine and administration of oral glucocorticoids, but took around 6 months to finally subside.
Drug rash with eosinophilia and systemic symptoms (DRESS) has been associated with nevirapine in a child (84A) • A 12-year-old girl took a nevirapine containing regimen for 4 months and had recurrent episodes of fever, cough, sore throat, nausea, and vomiting 2–4 weeks apart. A chest X-ray showed mild bronchial wall thickening with left lower lobe atelectasis or a mild infiltrate. Her temperature was 40°C and she had a tachycardia of 145/minute. She had a generalized maculopapular confluent blanching rash, but no target lesions or blisters, conjunctival injection, nasal congestion, a hyperemic posterior pharynx, and several bilateral non-tender cervical lymph nodes. The liver was enlarged by 4 cm but the spleen was not palpable. The white blood cell count was 9.7 109/l, with a marked eosinophilia (31%). She was successfully treated with intravenous immunoglobulin and antiretroviral drug withdrawal.
Nevirapine-induced Stevens–Johnson syn drome has been reported as having been misdiagnosed as viral keratitis (85A). Immunologic In a retrospective study of trough plasma concentrations of nevirapine and five oxidative metabolites in 1357 patients with rashes or liver function abnormalities during the first 6 weeks of treatment and controls matched for glucocorticoid use, CD4 cell count, sex,
540
race, and hepatitis B/C status, 49 case– control pairs were studied (86c). Women had significantly greater exposure than men to nevirapine and four of the five metabolites at week 2, but the plasma concentrations were comparable by week 4. There were no strong relationships between plasma concentrations of nevirapine or any of its five metabolites and case-defining events. The authors commented that systemic exposure to 12-hydroxynevirapine and 4-carboxynevirapine, hypothesized to be reactive intermediates for immunemediated adverse reactions, were comparable between the cases and controls and were comparable in proportion to nevirapine exposure. Pregnancy In a retrospective, five-center comparison in HIV-1-infected women who took nevirapine as part of combination antiretroviral therapy during pregnancy, 15 of 235 eligible women (6.4%) developed a rash and 8 (3.4%) developed hepatotoxicity, including 4 with a co-existent rash, giving a combined incidence of 19 potential cases of nevirapine toxicity during pregnancy (8.1%) (87c). Alternative causes of rash or hepatotoxicity were suspected in 7 cases, and only 10 mothers (5.8%) stopped taking nevirapine. Of the 170 women who started taking nevirapine during pregnancy, 13 (7.6%) developed a rash and 8 (4.7%) hepatotoxicity. Only 2 of 65 women (3.1%) with nevirapine exposure before pregnancy had had a rash. Susceptibility factors Genetic HLA typing and demographic and immunological susceptibility factors for reactions to nevirapine and efavirenz have been studied in 21 HIV-positive patients with rashes (88c). Isolated rashes were significantly associated with HLA-DRB101. There were no cases of liver toxicity nor any association with the percentage of CD4 cells. In 326 HIV-1-positive individuals, 309 of whom were Japanese, 42% of those who had hypersensitivity reactions to nevirapine had HLA-Cw8, compared with only 10% of
Chapter 29
Oliver Koch et al.
the others and 9–14% of the general Japa nese population (89c). In the former group, four patients, including one who developed hepatotoxicity, had HLA-Cw*0801 and one had HLA-Cw*0803. Among the others, three patients had HLA-Cw*0801. There were no significant differences in the fre quencies of other HLA alleles between the two groups. Drug dosage regimens Nevirapine has a long half-life and could be given once a day, but the risk of rashes and concerns over liver toxicity preclude the routine use of once-daily dosing. However, tolerance to high concentrations of nevirapine can develop when doses are increased slowly during the start of therapy. It is therefore theoretically possible that the benefits of once-daily dosing could be achieved without excess toxicity by switching to once-daily nevirapine after several months of twice-daily administration (90R). However, in the DAUFIN study, a twicedaily regimen of zidovudine 300 mg þ lami vudine 150 mg þ nevirapine 200 mg was compared with a once-daily regimen of lamivudine 300 mg þ tenofovir 245 mg þ nevirapine 400 mg (91C). The study was stopped after early virological failure was observed in 8 of 36 once-daily patients. Resistance mutations accumulated during treatment, with high rates of K65R muta tions and severe NNRTI resistance profiles indicative of continuing viral replication caused by suboptimal nevirapine plasma trough concentrations, possibly due to non adherence. Non-B-subtype infection (sub types A and C not stated) was observed in 4 of 10 patients with virological failure. The authors suggested that once-daily dosing can be introduced after induction of viral suppression has been achieved with a twice-daily regimen. Drug–drug interactions Fluconazole Co-administration of nevirapine 200 mg/day with fluconazole 400 mg/day results in markedly increased trough plasma nevirapine concentrations compared with nevirapine
Antiviral drugs
Chapter 29
alone (92c). In a retrospective study in 112 patients who were given nevirapine-based therapy with or without fluconazole 200 or 400 mg/day, mean nevirapine concentrations were 6.5 mg/l without fluconazole and 11.4 with fluconazole. One patient taking fluco nazole developed hepatitis. Six of those who did not take fluconazole developed nevira pine-related rashes. There were no differ ences in 36-week antiviral efficacy between the two groups.
DRUGS ACTIVE AGAINST HIV: PROTEASE INHIBITORS (SED-15, 2586; SEDA-29, 306; SEDA-30, 351; SEDA-31, 487)
Atazanavir Liver Hyperbilirubinemia and jaundice occurred during administration of atazanavir in all 23 healthy volunteers taking part in a 30-day follow-up study; there was a 52% increased minimum plasma concentration with co-administration of darunavir (93c). Hair Alopecia has been reported with ritonavir-boosted atazanavir (94A). Drug–drug interactions Rifampicin Concomitant usage of rifampicin with regimens including atazanavir should be avoided, as they result in subtherapeutic concentrations of atazanavir (95A). Tenofovir Atazanavir increased tenofovir concentrations in an open, crossover study in 30 healthy volunteers (96c).
Fosamprenavir Placebo-controlled studies Rashes and gastrointestinal disturbances were the most
541
frequently reported adverse effects in a ran domized controlled trial of fosamprenavir þ ritonavir in treatment-naive HIV-infected patients (97C).
Indinavir Gastrointestinal Of 30 patients taking ritonavir þ indinavir 400/100 mg in an open pilot study in Mali, one reported nausea (98A). In a prospective study of 70 sub-Saharan African patients taking indinavir, 22 had severe vomiting (99A).
Liver Rises in serum unconjugated bilirubin concentrations were reported in the Pivotal Phase III Trial. The mechanism is thought to be direct inhibition of bilirubin conjugation by competitive inhibition of UDP glucuronosyltransferase. Patients with polymorphisms in the UGT 1A1 gene are more likely to develop hyperbilirubinemia (100R).
Urinary tract Indinavir causes nephro lithiasis and renal impairment as a result of crystallization in the urinary tract and resultant inflammation (101A). Continuation of the drug with some improvement in renal function is possible with drug concentration monitoring. Co-factors such as concomitant co-trimoxazole therapy and environmental temperature increase the risk (100R). Using indinavir þ ritonavir at the lower doses of 400 and 100 mg bd seems to reduce these adverse effects. Hematuria and flank pain each occurred in 38 patients in a study of asymptomatic HIV-infected individuals who took indina vir in a long-term follow-up study over 157 weeks (25c).
Hair and nails Paronychia, alopecia, curling of straight hair, and ingrowing toenails have all been attributed to indinavir (102R).
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Pregnancy In a study of 16 pregnant women taking indinavir, two women and eight infants developed hepatotoxicity and had increased concentrations of indinavir, suggesting increased intestinal/hepatic CYP3A activity during pregnancy (103A).
Nelfinavir Metabolism Of 111 pregnant women 15 taking nelfinavir developed gestational diabetes compared with none taking zidovudine monotherapy and two of 43 taking NRTIs and NNRTIs; the risk of gestational diabetes was increased in those with hepatitis C or who had begun HAART before pregnancy (104c). Nails Paronychia has been reported in a case report occurring during nelfinavir treatment (105A).
Ritonavir Drug–drug interactions Fluticasone Cush ing’s syndrome and adrenal suppression can be caused if protease inhibitors increase systemic glucocorticoid concentrations. Iatrogenic Cushing’s syndrome has been attributed to ritonavir by an interaction with fluticasone (106A). • A 16-year-old girl who had taken various antiretroviral drugs eventually took stavudine, lamivudine, and ritonavir and then used inhaled fluticasone þ salmeterol for bronchiectasis. After 3 months she had excessive weight gain, increased appetite, fatigue, facial edema, marked acne, stretch marks on her limbs and abdomen, hypercholesterolemia, hypertriglyceridemia and amenorrhea. Cushing’s syndrome was attributed to an interaction of fluticasone with ritonavir, which was changed to efavirenz. There was a gradual improvement within 30–60 days, with reduced edema and stretch marks and return of menstruation.
A similar case involved a 14-year-old girl (107A).
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Saquinavir Observational studies In the ASPIRE 1 study, 7 of 17 healthy volunteers who took saquinavir þ ritonavir for 3 months developed grade 3 gastrointestinal adverse effects and seven had hyperbilirubinemia (108c). In the ASPIRE 2 study there was hyperbilirubinemia in 8 of 16 healthy volunteers.
Tipranavir Tipranavir is a non-peptide protease inhibitor approved for use in patients with resistant strains of HIV (109R, 110M, 111R). Its pharmacokinetics, efficacy, and adverse effects in children and adolescents have been reviewed (112R). It can be used in combination with ritonavir. Observational studies In a 24-week multi-center, double-blind, randomized, dose-finding trial of ritonavir-boosted tipra navir in 216 patients, the most common adverse events were diarrhea, nausea, vomiting, fatigue, and headache (113C).
Hematologic Tipranavir boosted with ritonavir caused an increased risk of bleed ing in 3 of 30 HIV-infected patients with hemophilia (114c). Intracranial hemorrhage has been reported in a patient taking tipranavir (115A).
Liver Tipranavir is associated with an excess of grade 3/4 rises in liver enzyme compared with other ritonavir-boosted protease inhibitors (116R).
Pancreas Acute pancreatitis associated with hypertriglyceridemia has been reported in a patient taking tipranavir þ ritonavir (117A).
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• A 42-year-old man taking tenofovir 300 mg/day, trizivir (zidovudine, lamivudine, and abacavir) one tablet bd, and tipranavir 500 mg bd þ ritonavir 200 mg bd drank six standard alcoholic drinks 2 days before admission and developed marked tenderness in the epigastric region and a raised serum lipase at 113 IU/l (reference range below 65 IU/l). An abdominal computed tomography (CT) scan showed pancreatic edema with peripancreatic fluid consistent with acute pancreatitis. Ultrasonography showed a mildly dilated common bile duct with no evidence of cholelithiasis and CT cholangiography showed no evidence of gall-stone pancreatitis. The presumed diagnosis was alcohol-induced pancreatitis. He was managed conservatively by withdrawal of medications, intravenous fluids, and slow resumption of oral intake. However, within 12 days he again developed severe epigastric pain. He denied further alcohol use. The serum concentration of triglycerides was 99 mmol/l, and retrospective testing of blood samples taken during the earlier illness also showed marked hypertriglyceridemia. Tipranavir þ ritonavir was withdrawn, efavirenz given, and tenofovir and trizivir continued. His triglyceride concentrations fell to 10.3 mmol/l 3 weeks later and 4.8 mmol/l 12 months later without specific intervention.
Skin Porphyria cutanea tarda has been reported after the introduction of tipranavir þ ritonavir to a backbone of tenofovir and lamivudine (118A). • A 59-year-old heterosexual woman switched to tipranavir-containing therapy after virological failure. After 5 days she developed a rash accompanied by nausea, vomiting, malaise, and hyperamylasemia. All antiretroviral drugs were withdrawn, she improved, and treatment was restarted. Although the lesions were resolving, several blisters appeared on her hands, mainly on the fingers, along with itching and skin fragility on her arms. Aciclovir was ineffective and 1 month later the itch and blisters worsened. Urine concentrations of protoporphyrin and coproporphyrin were about 100 and 10 times higher than normal.
Drug resistance Virological response rates in tipranavir-treated individuals were reduced when isolates with substitutions at amino acid positions I13, V32, M36, I47, Q58, D60, V82, or I84 were present at baseline (119C). In addition, virological
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response rates to tipranavir were reduced when the number of baseline protease inhibitor mutations was five or more. Individuals who took tipranavir without concomitant enfuvirtide and had five or more baseline protease inhibitor mutations began to lose antiviral response at weeks 4–8. However, individuals taking enfuvirtide with tipranavir achieved more than 1.5 log10 reductions in viral load from baseline at 24 weeks, even if they had five or more baseline protease inhibitor mutations. Virological response rates to tipranavir were reduced when the baseline phenotype for tipranavir had a greater than threefold shift in the 50% effective concentration (EC50) from reference. The most common protease inhibitor mutations that were associated with virological failure were L10I/V/S, I13V, L33V/I/F, M36V/I/L V82T, V82L, and I84V.
Drug–drug interactions Interactions with tipranavir þ ritonavir have been reviewed (120R). Tipranavir is metabolized by CYP3A and tipranavir þ ritonavir in vitro inhibits CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A and induces glucuronidase and P glycoprotein. Protease inhibitors Ritonavir-boosted tipranavir, alone and in combination with comparator protease inhibitors, has been studied in 315 HIV-infected patients (121C). The addition of tipranavir þ ritonavir 2 weeks after single protease inhibitor therapy reduced plasma trough concentrations of lopinavir, saquinavir, and amprenavir by 52%, 80%, and 56% respectively. The efficacy of a dual protease inhibitor regimen depended on the presence of tipranavir, and additional recycled protease inhibitors had limited activity, even in drug-resistant patients with plasma trough concentrations regarded as likely to be adequate. However, there are no clear guidelines about adequate trough concentrations of antiretroviral drugs.
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DRUGS ACTIVE AGAINST INFLUENZA VIRUSES: NEURAMINIDASE INHIBITORS (SED-15, 2436; SEDA 29, 310; SEDA-30, 352; SEDA-31, 489)
Oseltamivir Psychiatric Oseltamivir-induced worsening of delirium has been reported in an 83-year old man, whose symptoms resolved 2 days after withdrawal (122A). Japanese authorities advised against using oseltamivir in adolescents aged 10–19 years after two suicides during 2007 and more than 100 reports of neuropsychiatric events identified during post-marketing sur veillance, including delirium, convulsions, and encephalitis (123r). However, it is not clear whether these events were due to the influenza or the drug; in Phase III trials, there were similar incidences of neurologi cal and psychiatric events in both treated and untreated patients (124R). Of 1113 patients enrolled in a Japanese neuramini dase inhibitor treatment study, 11 had neuropsychiatric symptoms, in 4 cases before the start of treatment (125C). The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have advised doctors to monitor patients for abnormal behavior throughout treat ment (123r). Gastrointestinal Acute hemorrhagic colitis has been associated with oral oseltamivir in a 61-year-old man, who developed abdominal pain, diarrhea and hematochezia after taking two doses of oseltamivir (126A). In a systematic review of three trials of neuraminidase inhibitors for preventing and treating influenza in 1500 children, 977 of whom had laboratory-confirmed influenza, those who took oseltamivir had vomiting more often than untreated children but withdrawal was rarely required (127M). Drug resistance Resistance occurs in under 1% of healthy adults but occurs
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more often in children, from 5.5% up to 18% in one study, although a lower dosage regimen was used in that study. Resistance is often seen among immunocompromised patients. It was reported in two of eight patients infected with H5N1 and was associated with a fatal outcome. Resistance is associated with loss of fitness (128R). In 2008 widespread resistance emerged in H1N1 influenza, but it remains to be seen whether its circulation is sustained after the emergence of oseltamivir-sensitive swine vH1N1. Susceptibility factors Genetic There was no evidence of a difference in AUC1!20 of oseltamivir or its active metabolite oseltamivir carboxylate between 14 Japanese subjects and 14 Caucasian subjects, or between children aged 1–2 years old and adults (129c).
Zanamivir Systematic reviews A meta-analysis of the adverse effects of zanamivir in children showed that it was no worse than placebo (127M).
DRUGS ACTIVE AGAINST INFLUENZA VIRUSES: ION CHANNEL INHIBITORS (SED-15, 105 3051; SEDA-31, 269) Comparative studies In a randomized controlled trial in patients with chronic hepatitis C treated with interferon-alfa 2a alone (n = 53), with amantadine 100 mg bd (n = 111), with ribavirin (n = 106) or with amantadine þ ribavirin (n = 108), there was a sustained virological response in 13%, 6%, 18%, and 22% respectively (130C). This was statistically different between interferon þ amantadine and triple therapy but not between interferon þ ribavirin and triple therapy. The spectra and frequencies of adverse effects were similar in all four treatment arms. However, six patients
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withdrew because of adverse effects, three of them in an arm containing amantadine. In two groups of non-responders with HCV genotype 1 chronic infection taking interferon and ribavirin, with or without amantadine 200 mg/day, viral load fell more markedly in the group taking triple therapy including amantadine, but the response rates at the end of treatment were not signifi cantly different (131c). Although analysis of the viral ion channel p7 showed selective pressure during therapy, no specific resi dues appeared to be linked to the effect of amantadine on the virus. The authors sug gested that this implied that the antiviral effect of amantadine is non-specific and related to reduced endosomal acidification and therefore reduced transport of hepatitis C by a pH-dependent pathway. In a multicenter study of 75 non-respon ders with chronic hepatitis C randomized to interferon monotherapy (n = 26), dual ther apy with ribavirin (n = 24) and triple therapy with additional amantadine 200 mg/day (n = 25), amantadine did not increase the frequency or severity of adverse effects (132C). In 22 patients with chronic hepatitis C genotype 1b, with high viral loads treated with interferon-beta for 4 weeks followed by interferon-alfa 2b, ribavirin, and amantadine 150 mg/day for 22 weeks, there was a sustained virological response in 7. Only one patient had to stop taking amantadine, because of the adverse effect of light-headedness (133c). In 15 renal transplant recipients with chronic hepatitis C, doses of ribavirin monotherapy (n = 7) or ribavirin þ amantadine (n = 8) were adjusted according to creatinine
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clearance (134c). There was no difference between treatment groups with respect to liver enzymes, hepatitis C viremia, liver his tology, or renal function. Anemia, the main adverse effect, was most notable in those with a creatinine clearance below 50 ml/ minute. Other adverse effects included leukopenia, mood disorders and profuse sweating. Only one of those who received combination therapy were still taking aman tadine after 12 months; two completed treatment but with ribavirin alone. Four of those taking monotherapy completed treat ment. Neither regimen was clearly superior to no treatment, but the study was small and probably underpowered. Sensory systems In a post-marketing surveillance study of patients with a new diagnosis of corneal disease and new prescriptions for amantadine over 2 years, 36 (0.27%) of 13 137 patients developed Fuchs dystrophy (corneal edema) (135C). The relative risk of corneal edema was 1.7 (95% CI = 1.1, 2.8); in 12 patients (0.09%) the diagnosis was made in the first month. Drug resistance Amantadine is unreliable in the management of influenza because of the emergence of widespread resistance. This is notable in the H3N2 subtype and most H5N1 subtypes, but some seasonal H1N1 remains sensitive to amantadine (128R). However, in 2009, a novel pandemic strain vH1N1 influenza emerged, resistant to amantadine.
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hyperlactatemia among HIV-infected patients receiving antiretroviral therapy in a resource-limited setting. Int J Infect Dis 2008;12(6):582–6. Hill A, Ruxrungtham K, Hanvanich M, Katlama C, Wolf E, Soriano V, Milinkovic A, Gatell J, Ribera E. Systematic review of clinical trials evaluating low doses of stavudine as part of antiretroviral treat ment. Expert Opin Pharmacother 2007; 8(5):679–88. Makinson A, Moing VL, Kouanfack C, Laurent C, Delaporte E. Safety of stavudine in the treatment of HIV infection with a special focus on resource-limited settings. Expert Opin Drug Saf 2008;7(3):283–93. McComsey GA, Lo Re 3rd V, O’Riordan M, Walker UA, Lebrecht D, Baron E, Mounzer K, Frank I. Effect of reducing the dose of stavudine on body composition, bone density, and markers of mitochondrial toxicity in HIV-infected subjects: a randomized, controlled study. Clin Infect Dis 2008;46(8):1290–6. Wilkinson MJ, Bain BJ, Phelan L, Benzie A. Increased haemoglobin A2 percentage in HIV infection: disease or treatment? AIDS 2007;21(9):1207–8. Witt KL, Cunningham CK, Patterson KB, Kissling GE, Dertinger SD, Livingston E, Bishop JB. Elevated frequencies of micronucleated erythrocytes in infants exposed to zidovudine in utero and postpartum to pre vent mother-to-child transmission of HIV. Environ Mol Mutagen 2007;48(3–4):322–9. Watts DH, Li D, Handelsman E, Tilson H, Paul M, Foca M, Vajaranant M, Diaz C, Tuomala R, Thompson B. Assessment of birth defects according to maternal therapy among infants in the Women and Infants Transmission Study. J Acquir Immune Defic Syndr 2007;44(3):299–305. Mirochnick M, Rodman JH, Robbins BL, Fridland A, Gandía J, Hitti J, Bardeguez A, Rathore MH, Gonzalez Garcia A, Cababa say M, Samson P, Mofenson L, Bryson YJ, Dorenbaum A. Pharmacokinetics of oral zidovudine administered during labour: a preliminary study. HIV Med 2007;8(7):451–6. Watts DH. Teratogenicity risk of antiretro viral therapy in pregnancy. Curr HIV/AIDS Rep 2007;4(3):135–40.
549 61. Feola DJ, Garvy BA, Rapp RP, Thornton AC. Blunted humoral response to influenza vaccination in patients exposed to zidovu dine plus trimethoprim–sulfamethoxazole. Pharmacotherapy 2007;27(7):937–47. 62. Aweeka FT, Kang M, Yu JY, Lizak P, Alston B, Chung RT, AIDS Clinical Trials Group 5092s Study Team. Pharmacokinetic evaluation of the effects of ribavirin on zidovudine triphosphate formation: ACTG 5092s Study Team. HIV Med 2007; 8(5):288–94. 63. Dominguez S, Ghosn J, Peytavin G, Izze dine H, Wirden M, Ktorza N, Miller M, Aubron-Olivier C, Trylesinski A, Calvez V, Deray G, Katlama C. Efficacy and safety of tenofovir double-dose in treatment-experi enced HIV-infected patients: the TENO PLUS study. J Med Virol 2007;79(2):105–10. 64. Morillo Verdugo R, Gil Navarro MV, Abdel-Kader Martín L, Castillo Muñoz A, Baños Rold´an U, Artacho Criado S. Analisis de las causas y factores predictivos de discon tinuacion del tratamiento con tenofovir en pacientes VIH pretratados. [Analysis of the causes and predictive factors for discontinu ing treatment with tenofovir in pretreated HIV patients.] Farm Hosp 2007;31(4):200–5. 65. Papaleo A, Warszawski J, Salomon R, Jul lien V, Veber F, Dechaux M, Blanche S. Increased beta-2 microglobulinuria in human immunodeficiency virus-1-infected children and adolescents treated with tenofovir. Pediatr Infect Dis J 2007;26(10):949–51. 66. Maggiolo F Efavirenz Expert Opin Phar macother 2007;8(8):1137–45. 67. Arendt G, de Nocker D, von Giesen HJ, Nolting T. Neuropsychiatric side effects of efavirenz therapy. Expert Opin Drug Saf 2007;6(2):147–54. 68. S´anchez-Conde M, Palacios R, Sanz J, Rodríguez-Novoa S, Rivas P, Santos J, Sola J, Asensi V, de Mendoza C, Estrada V, Barreiro P, Gonz´alez-Lahoz J, JiménezNacher I, Soriano V. Efficacy and safety of a once daily regimen with efavirenz, lami vudine, and didanosine, with and without food, as initial therapy for HIV Infection: the ELADI study. AIDS Res Hum Retro viruses 2007;23(10):1237–41. 69. Arrizabalaga J, Arazo P, Aguirrebengoa K, García-Palomo D, Chocarro A, Labarga P,
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Koita V, Diallo F, Sangare AT, Sidibé MK, Calvez V, Sylla A, Katlama C, Tubiana R. Experience of indinavir/ritonavir 400/ 100 mg twice-daily highly active antiretro viral therapy-containing regimen in HIV-1 infected patients in Bamako, Mali: the NOGOMA study. J Acquir Immune Defic Syndr 2007;45(4):477–9. Danel C, Moh R, Peytavin G, Anzian A, Minga A, Gomis OB, Seri B, Nzunettu G, Gabillard D, Salamon R, Bissagnene E, Anglaret X. Lack of indinavir-associated nephrological complications in HIVinfected adults (predominantly women) with high indinavir plasma concentration in Abidjan, Côte d’Ivoire. AIDS Res Hum Retroviruses 2007;23(1):62–6. Boyd M. Indinavir: the forgotten HIVprotease inhibitor. Does it still have a role? Expert Opin Pharmacother 2007;8 (7):957–64. Gagnon RF, Mehio A, Iqbal S, Tsoukas CM. Néphropathie tubulo-interstitielle associée a l’indinavir. [Indinavir-associated tubulointerstitial renal disease.] Nephrol Ther 2007;3(7):461–2. Luther J, Glesby MJ. Dermatologic adverse effects of antiretroviral therapy: recognition and management. Am J Clin Dermatol 2007;8(4):221–33. Unadkat JD, Wara DW, Hughes MD, Mathias AA, Holland DT, Paul ME, Con nor J, Huang S, Nguyen BY, Watts DH, Mofenson LM, Smith E, Deutsch P, Kaiser KA, Tuomala RE. Pharmacokinetics and safety of indinavir in human immunodefi ciency virus-infected pregnant women. Antimicrob Agents Chemother 2007;51 (2):783–6. Martí C, Peña JM, Bates I, Madero R, de José I, Pallardo LF, Arribas JR, GonzalezGarcia J, Gonzalez A, Vazquez JJ. Obste tric and perinatal complications in HIVinfected women. Analysis of a cohort of 167 pregnancies between 1997 and 2003. Acta Obstet Gynecol Scand 2007;86 (4):409–15. Domínguez MV, Ceballos VC, Costa RV, Lara TE, Florencio VD. Paronychia in an HIV-infected patient under nelfinavir ther apy. J Eur Acad Dermatol Venereol 2007;21(5):710–1.
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552 106. Pessanha TM, Campos JM, Barros AC, Pone MV, Garrido JR, Pone SM. Iatrogenic Cushing’s syndrome in a adolescent with AIDSs on ritonavir and inhaled fluticasone. Case report and literature review. AIDS 2007;21(4):529–32. 107. St Germain RM, Yigit S, Wells L, Girotto JE, Salazar JC. Cushing syndrome and severe adrenal suppression caused by fluti casone and protease inhibitor combination in an HIV-infected adolescent. AIDS Patient Care STDS 2007;21(6):373–7. 108. King JR, Kakuda TN, Paul S, Tse MM, Acosta EP, Becker SL. Pharmacokinetics of saquinavir with atazanavir or low-dose ritonavir administered once daily (ASPIRE I) or twice daily (ASPIRE II) in seronegative volunteers. J Clin Pharmacol 2007;47(2):201–8. 109. Temesgen Z, Feinberg J. Tipranavir: a new option for the treatment of drug-resistant HIV infection. Clin Infect Dis 2007; 45(6):761–9. 110. Luna B, Townsend MU. Tipranavir: the first nonpeptidic protease inhibitor for the treatment of protease resistance. Clin Ther 2007;29(11):2309–18. 111. Orman JS, Perry CM. Tipranavir: a review of its use in the management of HIV infec tion. Drugs 2008;68(10):1435–63. 112. Courter JD, Girotto JE, Salazar JC. Tipra navir: a new protease inhibitor for the pediatric population. Expert Rev Anti Infect Ther 2008;6(6):797–803. 113. Gathe Jr. JC, Pierone G, Piliero P, Arasteh K, Rubio R, Lalonde RG, Cooper D, Lazzarin A, Kohlbrenner VM, Dohnanyi C, Sabo J, Mayers D. Efficacy and safety of three doses of tipranavir boosted with ritonavir in treatment-experienced HIV type-1 infected patients. AIDS Res Hum Retroviruses 2007;23(2):216–23. 114. Arbuthnot C, Wilde JT. Increased risk of bleeding with the use of tipranavir boosted with ritonavir in haemophilic patients. Hae mophilia 2008;14(1):140–1. 115. Chrysos G, Gerakari S, Stasini F, Kokkoris S, Kourousis D, Velegraki A. Intracranial haemorrhage possibly related to tipranavir in an HIV-1 patient with cryptococcal meningitis. J Infect 2008;57(1):85–7. 116. de Mendoza C, Morelló J, Garcia-Gascó P, Rodríguez-Novoa S, Soriano V. Tipranavir:
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126. Matsushita M, Nishihara H, Nishiyama R, Kobayashi Y. Acute hemorrhagic colitis associated with oral administration of osel tamivir for the treatment of influenza A. J Infect Chemother 2007;13(4):267–9. 127. Matheson NJ, Harnden AR, Perera R, Sheikh A, Symmonds-Abrahams M. Neur aminidase inhibitors for preventing and treating influenza in children. Cochrane Database Syst Rev 2007;(1):CD002744. 128. Ong AK, Hayden FG, John F Enders Lec ture 2006. Antivirals for influenza. J Infect Dis 2007;196(2):181–90. 129. Schentag JJ, Hill G, Chu T, Rayner CR. Similarity in pharmacokinetics of oseltami vir and oseltamivir carboxylate in Japanese and Caucasian subjects. J Clin Pharmacol 2007;47(6):689–96. 130. Salmerón J, Diago M, Andrade R, Pérez R, Sola´ R, Romero M, de la Mata M, Granados R, Ruiz-Extremera A, Muñoz de Rueda P. Induction doses of interferon alpha-2a in combination with ribavirin and/ or amantadine for the treatment of chronic hepatitis C in non-responders to interferon monotherapy: a randomized trial. J Viral Hepat 2007;14(2):89–95. 131. Castelain S, Bonte D, Penin F, François C, Capron D, Dedeurwaerder S, Zawadzki P, Morel V, Wychowski C, Duverlie G. Hepatitis C virus p7 membrane protein
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quasispecies variability in chronically infected patients treated with interferon and ribavirin, with or without amantadine. J Med Virol 2007;79(2):144–54. Gramenzi A, Andreone P, Cursaro C, Ver ucchi G, Boccia S, Giacomoni PL, Galli S, Furlini G, Biselli M, Lorenzini S, Attard L, Bonvicini F, Bernardi M. A randomized trial of induction doses of interferon alone or in combination with ribavirin or ribavirin plus amantadine for treatment of nonresponder patients with chronic hepatitis C. J Gastroenterol 2007;42(5):362–7. Uyama H, Nakamura H, Hayashi E, Ogawa H, Enomoto H, Yoshida K, Okuda Y, Yamamoto M, Hada T, Hayashi N. Triple therapy of initial high-dose interferon with ribavirin and amantadine for patients with chronic hepatitis C. Hepatol Res 2007; 37(5):325–30. Calanca LN, Fehr T, Jochum W, FischerVetter J, M€ ullhaupt B, W€ uthrich RP, € Ambuhl PM. Combination therapy with ribavirin and amantadine in renal trans plant patients with chronic hepatitis C virus infection is not superior to ribavirin alone. J Clin Virol 2007;39(1):54–8. French DD, Margo CE. Postmarketing sur veillance of corneal edema, Fuchs dystrophy, and amantadine use in the Veterans Health Administration. Cornea 2007;26(9):1087–9.
Soumya Swaminathan and V.V. Banu Rekha
30
Drugs used in tuberculosis
and leprosy
Hepatotoxicity of antituberculosis drugs Continuation-phase regimens incorporating pyrazinamide, isoniazid and/or rifampicin have been compared with regimens containing isoniazid and rifampicin in a case–control study in 3007 Chinese patients with active tuberculosis (1C). The cases included all patients with probable hepatotoxicity from 12 or more weeks after starting treatment. Hepatotoxicity was considered probable when the serum alanine aminotransferase (AlT) activity exceeded three times the upper limit of the reference range. There was hepatotoxicity in 48 (1.6%) patients. The adjusted odds ratio (95% CI) for regi mens incorporating pyrazinamide along with isoniazid and/or rifampicin relative to standard regimens was 2.8 (1.4, 5.9). There was a significant association between hepa totoxicity and hepatitis B, previous hepato toxicity, and treatment regimens. The authors concluded that the addition of pyrazinamide to isoniazid and rifampicin during the con tinuation phase increases the risk of hepato toxicity appreciably. Treatment of latent tuberculosis in liver transplant candidates with compensated cir rhosis has been investigated in a prospective study in California in nine patients who took
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32030-7 2010 Elsevier B.V. All rights reserved.
isoniazid for 9 months and in five who took rifampicin for 4 months (2c). Four of those who took isoniazid had mild asymptomatic rises of asparate aminotransferase (AsT) or AlT activity compared with none of those who took rifampicin. In two cases the enzyme changes were attributed to isoniazid and in the other two to alcoholism or active chronic hepatitis B. There were no deaths and no cases of fulminant hepatic failure. Fulminant hepatic failure In a crosssectional study in 37 Sudanese patients with fulminant hepatic failure, the presentations were classified as hyperacute, acute, and subacute (3c). All sera were tested for hepatitis A, B, C, and E; negative samples were tested for antinuclear antibodies and anti-smooth muscle antibodies. The commonest causative factors included seronegative hepatitis (38%), hepatitis B virus infection (22%), severe Plasmodium falciparum malaria (8%), autoimmune hepatitis (8%), hepatitis E virus infection (5%), and lymphomatous infiltration of the liver (5%); antituberculosis drugs were implicated in 5%. The mortality rate was 84%. Grade 3/4 encephalopathy, evidence of bacterial infection and a prolonged prothrombin time of more than 25 seconds were poor prognostic factors. Susceptibility factors Genetic The frequency of N-acetyltransferase 2 (NAT2) polymorphisms, the NAT2 acetylation profile and its relation to the incidence of
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gastrointestinal adverse drug reactions, antituberculosis drug-induced hepatotoxicity, and the clinical risk factors for hepatotoxicity have been studied in Brazilian patients taking isoniazid, rifampicin, and pyrazinamide (4c). Of 254 patients, 69 (27%) were slow acetyl ators and 185 (73%) were fast acetylators; 65 (26%) were HIV-positive; 33 (13%) dev eloped gastrointestinal adverse effects and 14 (5.5%) developed hepatotoxicity. Of the latter, nine were slow acetylators and five were fast acetylators. Slow acetylator status and HIV infection were identified as susceptibility factors for hepatotoxicity, but not age, sex, hepatitis C virus (HCV) infection, alcohol abuse, or baseline transaminase activities. Polymorphisms of the NAT2 and/or CYP2E1 genes have been studied in 132 Kor ean patients, of whom 18 developed antituber culosis drug-induced hepatotoxicity (5c). Slow NAT2 acetylators had a higher inci dence of hepatotoxicity than rapid acetyla tors (37% versus 9.7%) and had a 3.8-fold greater risk of hepatotoxicity. There was no significant association between any CYP2E1 genotype and antituberculosis drug-induced hepatotoxicity. The authors concluded that NAT2 geno typing may be useful in predicting antituber culosis drug-induced hepatotoxicity. Children The incidence of pediatric referrals for isoniazid-related liver failure has been estimated in 20 patients over a 10-year period (6c). Four recovered spontaneously, ten underwent orthotopic liver transplantation, and six died awaiting transplantation. The mean age at presentation was 9.8 (range 1.3–17) years. The mean duration of isoniazid therapy was 3.3 (range 0.5–9) months. Out of 4679 cases of orthotopic liver transplantation in children during the 10-year period, drug toxicity was reported in 56 (1.2%). Isoniazid-associated liver failure accounted for 0.2% (8 of 4679) of all cases and for 14% (8/56) of transplants for drug hepatotoxicity. An estimated 216 776 children aged 0–14 years were given isoniazid for latent tuberculosis during this
Soumya Swaminathan and V.V. Banu Rekha
period, and the estimated incidence of liver failure was up to 3.2/100 000 for children on prophylactic isoniazid. The authors concluded that although isoniazidassociated liver failure in children is rare, drug withdrawal at the onset of symptoms does not assure recovery, which indicates a need for increased awareness of the risk of hepatotoxicity, biochemical monitoring, and prompt withdrawal in symptomatic patients. Hepatic disease In a case–control study of the clinical characteristics and treatment responses in 36 patients with tuberculosis and hepatic cirrhosis and 108 randomly selected controls with tuberculosis but no liver disease, matched for age and sex, extrapulmonary tuberculosis was more common in the cases than in the controls (31% versus 12%) (7c). The frequency of hepatotoxicity was higher in the cases than in the controls, who were treated with a regimen containing rifampicin and isoniazid. However, the clinical and radiographic manifestations and the response to treatment did not differ between the two groups. The findings suggested that patients with tuberculosis and hepatic cirrhosis have extrapulmonary involvement more often and respond well to antituberculosis drugs, although they appear to have treatmentrelated hepatotoxicity more often. Hepatitis C virus infection In a casecontrol study in 54 HCV-positive patients and 97 seronegative patients who were given standard short-course regimens, 22 of the former and 19 of the latter had raised liver enzyme activities, including transient rises in transaminases, during antituberculosis drug treatment (8c). Drug-induced hepatotoxicity, defined as transaminase activity over 120 IU/l, was more frequent in the HCV-positive patients (7/54, 13%) than in the controls (4/97, 4%). Isoniazid and rifampicin were reintroduced after the transaminases had returned to baseline in five patients, in all cases without recurrence. These findings suggest that antituberculosis drug treatment in HCV-positive patients can be pursued in the usual manner, using standard short
Drugs used in tuberculosis and leprosy
Chapter 30
course regimens, provided that monthly liver function tests are performed. HIV In a retrospective study of 868 HIVpositive subjects (94% men), first-line therapy was efavirenz, lamivudine, and zidovudine; women of child-bearing potential were given nevirapine instead of efavirenz. An efavirenz-based regimen was used in 825 and 39 received a nevirapine based regimen. During the first year 48 subjects took isoniazid prophylaxis and 214 received tuberculosis therapy (2 months of rifampicin, isoniazid, pyrazinamide, and ethambutol followed by 4 months of rifampicin and isoniazid). Of a random sample of 133 tested, 17% were hepatitis B surface antigen (HBsAg) positive. There was grade 2 or worse hepatotoxicity in 97 subjects (11%) and 40 had a first episode of grade 3 or 4 hepatotoxicity. Tuberculosis chemotherapy (adjusted hazard ratio [HR] = 8.5; 95% CI = 2.7, 27) and HBsAg (adjusted HR = 3.0; 95% CI = 1.3, 7.0) were strongly associated with hepatotoxicity. However, hepatotoxicity had little impact on symptoms, the need for hospitalization, and the need for a change in antiretroviral drug regimen. The use of isoniazid preventive therapy during antiretroviral drug therapy did not increase the risk of hepatotoxicity (9C). Drug dosage regimens The relation between standard pyrazinamide-containing antituberculosis treatment and hepatotoxi city has been investigated in a nested retro spective case–control study in China in 3007 patients (10c). There was hepatitis in 167 patients, of whom 96 qualified as cases. HBsAg was the only susceptibility factor (OR = 1.8; 95% CI = 1.1, 3.1). Sex was non-significant. The risk of hepatitis increased from 2.6% (1.9, 3.5%) to 4.1% (3.2, 5.3%) as age exceeded 49 years. The authors concluded that dosing schedules in the first 9 weeks have little effect on the hepatotoxicity of standard antituberculosis drug regimens.
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Dosages of antituberculosis drugs in children Dosages of antituberculosis drugs in children are usually based on weight and are largely extrapolated from pharmacokinetic studies in adults. Earlier studies showed evidence of good tuberculosis treatment outcomes in children based on such dosages (11C–13C). However, later data have pointed to the inadequacy of currently recommended dosages of rifampicin, isoniazid, ethambutol and pyrazinamide (14c–17c). Children experience growth-related changes in the relative sizes of their body compartments as well as in their ability to absorb, metabolize, and excrete drugs, leading to pharmaco kinetics that differ from those in adults (18R). Many of these differences are most marked in the first few years of life, but they continue to occur throughout child hood. Body weight doubles by 5 months and triples by 1 year, body length increases by 50% by 1 year, and body surface area increases by 2500% by 1 year. Total body water comprises 85% of body weight in a premature infant, 70% in a full-term infant, and 55% in an adult (19R). Factors such as gastric pH, gastric emptying, intestinal transit time, functional absorptive area, and carrier mechanisms or drug transporters in the gas trointestinal tract influence gastrointestinal drug absorption (20c, 21R). However, very little is known about the metabolic capacity or maturation of drug transporters in the gut wall in children and their influence on the quantity and time of absorption (21R). Chil dren need weight-corrected doses that are substantially higher than adult doses for drugs that are metabolically eliminated solely by the specific CYP isoenzymes CYP1A2, CYP2C9, and CYP3A4 (22R). In contrast, weight-corrected doses for drugs eliminated by renal excretion or metabolism involving CYP2C19, CYP2D6, N-acetyltransferase 2, or uridine diphosphate glucuronosyltransfer ase are similar in children and adults. In children, the systemic availability of drugs with high first-pass metabolism is reduced for drugs that are metabolized by CYP1A2, CYP2C9, and CYP3A4. The limited data
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available suggest that by age 5 years, the systemic availability in children of drugs that are affected by efflux transporters should be equivalent to that in adults (22R). There are reports of lower concentrations and delayed absorption of antituberculosis drugs in children compared to adults taking the same dose (14c, 23c, 24c). In a study of the pharmacokinetics of isoniazid determined 2– 5 hours after a 10 mg/kg dose in 64 children with respiratory tuberculosis under 13 years of age (median 3.8), younger children elimi nated isoniazid faster than older children and adults (14c). The finding that they required a higher weight-corrected dose to achieve serum concentrations comparable to adults led to the recommendation of a dosage of 10 mg/kg rather than 5 mg/kg. In an evaluation of the pharmacokinetics of rifampicin in HIV type 1-infected (n = 21) and HIV-uninfected (n = 33) children with severe forms of tuberculosis, at about 1 and 4 months after the start of antituberculosis treatment, rifampicin 8–12 (mean 9.6) mg/kg produced serum concentrations that were considerably lower than the suggested lower limit for 2 hour rifampicin concentrations in adults of 8.0 µg/ml and even lower than the very minimal limit of 4 µg/ml (15c). These findings suggested that a dose of 10–20 mg/kg would be more appropriate, but further studies are required to confirm this. There was no difference between HIVpositive and HIV-negative children. Rifampicin serum concentrations in chil dren of different age groups were determined in 27 children in Germany after a single oral dose of rifampicin 10 mg/kg alone as well as after combination with ethambutol 35 mg/kg (25c). The mean serum concentrations in children of different age groups were highly variable, with mean maximum serum concentrations of 6.5–7.1 µg/ml during monotherapy and 4.5–5.4 µg/ml during com bination therapy. Mean maximum serum concentrations in children aged under 6 years after single and after combined drug administration tended to be lower than those found in the older children. Compared with monotherapy, the mean maximum serum concentrations during combined therapy were lower in all age groups. It may be
Soumya Swaminathan and V.V. Banu Rekha
appropriate or advisable to calculate rifam picin doses on the basis of body surface area rather than body weight, which would lead to higher doses, especially in younger children. Hence, assuming that efficient serum concen trations should be achieved with a dose of rifampicin in children that corresponds to the adult value of 350 mg/m2, a dose of 15 mg/kg rifampicin in toddlers and young children, reducing to 10 mg/kg rifampicin in adoles cents, has been suggested, but needs to be validated (26c). Pharmacokinetic studies of ethambutol and pyrazinamide have shown lower plasma drug concentrations and shorter half-lives in children than in adults using the same dosages, and it has been suggested that doses per kilogram need to be higher for children than for adults (23c, 24c). Serum drug concentrations achieved using intermit tent treatment with pyrazinamide (n = 27) and ethambutol (n = 18) at recommended doses were reported to be very low in Mala wian children, irrespective of HIV or mal nutrition (17c). However, a study in Berlin in 34 children aged 1–14 years, in which pyra zinamide serum concentrations were mea sured after oral pyrazinamide alone (n = 21) 30 mg/kg or in combination with rifampicin 10–15 mg/kg and isoniazid 5–10 mg/kg (n = 13), showed that effective serum con centrations were reached. The peak serum concentrations of pyrazinamide in all age groups were 31–38 µg/ml. Regardless of whether pyrazinamide was administered alone or in combination, the serum concen trations stayed above the minimum inhibitory concentration (MIC) for Mycobacterium tuberculosis (16–32 µg/ml) for more than 6 hours in all age groups (27c). In addition, in 40 children aged 5–13 years, pyrazina mide 30 mg/kg/day produced much higher concentrations than its MIC, suggesting that lower doses should be used (28c). In a study of peak ethambutol concentra tions among 28 European children of differ ent ages who received 35 mg/kg there were lower concentrations, quite often subthera peutic, in younger children than in older children (29c). Calculating ethambutol doses on the basis of body surface area rather than body weight may be more
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reliable (30c). To date, the key pharmaco dynamic parameter for ethambutol has not been determined. Given the lack of efficacy of a daily dose under 12 mg/kg, it appears that a Cmax/MIC ratio greater than 1 is required for at least part of each dosing inter val. MICs of ethambutol against susceptible varieties of Mycobacterium tuberculosis are 1.0–2.5 mg/ml. A range of 2–6 mg/ml was considered the normal Cmax range for daily doses, and 4–12 mg/ml for twice-weekly doses. Very low values of Cmax (below 1 µg/ml) were common in children, as was delayed absorption (tmax over 3 hours) at a median dosage of 16 mg/kg/day and 31 mg/kg bi-weekly (23c). The main worry about ethambutol had been ocular toxicity (retro bulbar neuritis), which is especially difficult to detect in children. A review of several studies that carefully evaluated significant numbers of children of all ages taking etham butol in doses of 15–30 mg/kg/day did not reveal ocular toxicity; in only 2 of 3811 cases (0.05%) was ethambutol withdrawn because of fears of poorly documented ocular toxicity. The authors concluded that daily doses of 20 (range 15–25) mg/kg and thrice-weekly doses of 30 mg/kg are safe in children of all ages, while lower doses are ineffective (16R). Treatment of tuberculosis/HIV co-infec tion is complex, because of the possibility of combined toxicity from antiretroviral and antituberculosis agents, poor drug absorp tion, drug interactions, pill burden, and, in children, lack of appropriate drug formula tions. The absorption of antituberculosis drugs has been widely reported to be low in HIV-infected adults (31c, 32c). The intestinal absorptive capacity, as measured by the D-xylose absorption test, has been reported to be suboptimal in HIV-infected patients with or without tuberculosis (33c, 34c). There is lack of information on the effect of HIV infection on blood concentrations of antituberculosis drugs and the intestinal absorptive capacity in children. There is a significant association between severe malnutrition and severe forms of tuberculosis in children (35c). Malnutrition has been reported to reduce the protein-bind ing capacity of rifampicin, thereby increasing
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its renal clearance and causing reduced drug concentrations (36c). Blood concentrations of pyrazinamide have been reported to be lower in malnourished children with tuber culosis, compared with well-nourished chil dren (17c). The uncertainties about pediatric dosing reflect the lamentable paucity of pharmaco kinetic data for first-line drugs in children (18R). Optimal dosing of antituberculosis drugs is an essential prerequisite for com plete cure, and the potential consequences of suboptimal blood concentrations include treatment failure and drug resistance. With the advent of new compounds in the tuber culosis drug pipeline, all efforts should be made to undertake comprehensive pharma cokinetic studies in children over a range of ages and doses to establish the dose of the new agent that will lead to exposures that achieve an optimal mycobacteriological response (19R). Future studies should care fully examine the role of malnutrition, HIV infection and pharmacogenetics in observed differences in the disposition, toxicity and efficacy of antituberculosis drugs.
Antituberculosis drug treatment in transplant recipients In a retrospective analysis of 1947 renal transplant recipients and 85 liver transplant recipients in China, tuberculosis developed in 28 organ transplant recipients, with a pre valence of 1.38% (28/2032) (37c). The med ian interval between transplantation and the development of tuberculosis was 32 (range 1–142) months. Most renal transplant recipi ents (22/25) received isoniazid, rifampicin (or rifabutin), and ethambutol (or pyrazina mide) for a mean duration of 10 (range 6–14) months. Three liver transplant recipi ents received a different protocol: isoniazid, rifabutin, ethambutol, and ofloxacin for 3 months, then isoniazid and rifabutin for 6 months. During follow-up, eight subjects (29%) died; five of the deaths were related to tuberculosis. During antituberculosis ther apy, there was toxic hepatitis in 12 patients (43%), ciclosporin concentrations fell in 15
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patients (54%), and 6 had allograft rejection. The authors concluded that the peak incidence of tuberculosis occurs during the first year after liver transplantation and after the first year after kidney transplantation. While the use of fluoroquinolones was emphasized for liver transplant recipients, antituberculosis treatment protocols that included isoniazid and rifampi cin for about 10 months were effective and tolerable in non-liver transplant recipients. The effect of tuberculosis on the outcome of kidney transplantation has been studied in Iran (38C). Of 1350 living-donor kidney transplant recipients, 52 (3.9%) had tubercu losis diagnosed in various organs, of whom 7 had tuberculosis before transplantation. The interval between transplantation and the diag nosis of tuberculosis was 55 (range 4–140) months. In 34 patients tuberculosis was diag nosed after the first year after transplantation. Pleuropulmonary tuberculosis was the most common form (68%). Antituberculosis drugs were associated with hepatotoxicity in 16 patients, including 12 mild cases in which liver function normalized after temporary withdrawal of isoniazid and rifampicin, and 4 severe cases; 12 patients died, but mortality was not attributable to hepatocellular failure. Hepatotoxicity possibly occurred as a result of additive toxic effects of immunosuppressive drugs. There was chronic allograft dysfunc tion in 34 patients, 19 with graft loss. In a retrospective study in Turkey, tubercu losis occurred in 18 of 343 dialysis patients (39c). The mean time between the start of dialysis to the diagnosis of tuberculosis was 20 months. Extrapulmonary tuberculosis was more frequent (78%). Tuberculosis was treated with three or four drugs for 6–12 months; second-line treatment was given to one patient with multidrug-resistant bacilli. Adverse effects were hepatotoxicity in three, optic neuritis in one and neuro psychiatric manifestations in three. A clinical response to therapy was achieved in all of the 16 patients who completed treatment. The authors noted the predominance of extrapul monary tuberculosis in dialysis patients, who have to be carefully monitored, because of a higher risk of adverse effects of antituber culosis drugs.
Soumya Swaminathan and V.V. Banu Rekha
Dapsone
(SED-15, 1050; SEDA-29, 315; SEDA-30, 357; SEDA-31, 406)
Drug administration route The pharmaco kinetics of topical 5% dapsone gel have been studied in 548 patients with acne vulgaris in three open prospective studies (40C). In a crossover study (n = 18), topical dapsone gel applied twice daily for 14 days to 23% of the body surface area was compared with a single dose of oral dapsone 100 mg (the typical clinical dose). The mean steady-state AUC was 418 h. ng/ml after 2 weeks of dapsone gel compared with 52 641 h. ng/ml after a single oral dose of dapsone, a 126-fold lower systemic exposure for the gel, In a drug interaction study in 24 patients, oral co-trimoxazole, topical dapsone gel, and the two in combination were used twice daily for 7, 21, and 7 days respectively. The steadystate AUC for dapsone was 222 h. ng/ml after 3 weeks of dapsone gel monotherapy and 320 h. ng/ml after 1 week of co administration with co-trimoxazole. In a long-term study in 506 patients, topical dapsone gel was applied twice daily to acne-affected areas for up to 12 months. The mean plasma dapsone concentrations were 7.5–11 ng/ml. There were no reports of any hematological adverse events in these studies. The authors concluded that topical application of dapsone gel in various settings ranging from 2 weeks to 12 months resulted in systemic exposure to dapsone and its metabolites approximately 100-fold less than after oral dapsone even in the presence of a therapeutic dose of co-trimoxazole.
Cycloserine
(SED-15, 1033)
Nervous system Cycloserine-induced neuro toxicity confirmed by neuroimaging has been reported (41A). • A 69-year-old woman with tuberculous lymphadenopathy was given isoniazid 400 mg/ day, rifampicin 450 mg/day, ethambutol 800 mg/ day, and pyrazinamide 1500 mg/day. She
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developed serious hepatotoxicity and was switched to cycloserine 500 mg/day, isoniazid 400 mg/day, and pyrazinamide 1500 mg/day. However, she developed hypersomnia and asterixis within a few days and her symptoms continued for 1 year, after which she was investigated. There were no hepatic or renal function test abnormalities. A magnetic resonance imaging (MRI) brain scan showed bilateral symmetrical thalamic hyperintensities and evidence of a vasogenic process. Cycloserine was withdrawn and her symptoms resolved completely within 1 month. A follow-up MRI scan showed marked reduction in the high signal intensities in both thalami.
The hypersomnia in this case may have been caused by dysfunction of the thalamo cortical network in the cerebral hemi spheres, which is closely associated with the ascending reticular-activating system. Asterixis could have been related to dys function of the ventral intermediate nucleus of the thalamus.
Ethambutol (SED-15, 1282; SEDA-29, 316; SEDA-30, 358; SEDA-31, 407) Sensory systems Optic neuropathy EIDOS classification Extrinsic species: Ethambutol Intrinsic species: Optic nerve fibers and retinal ganglion cells Distribution: Optic nerve and retina Outcome: Altered physiology initially; later nerve cell degeneration
Sequela: Optic neuropathy and
retinopathy due to ethambutol
DoTS classification:
Dose-relation: Collateral
Time-course: Intermediate
Susceptibility factors: Diseases (renal
impairment, zinc deficiency A review of 101 patients with clinical and electrophysiological findings suggestive of ethambutol retinopathy has been reported (42c). The retinal findings included retinal pigment epithelial changes, macular edema,
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and flame-shaped hemorrhages. Electro retinography showed reduced wave ampli tude and an abnormal wave pattern electro oculography showed an abnormal Arden ratio. The degree of optic nerve damage in patients with ethambutol-induced optic neuropathy, when the optic disc typically looks normal, is hard to assess. In a retro spective study in eight patients with a history of ethambutol-induced optic neuropathy, changes in retinal nerve fiber layer thickness (RNFLT) were measured using optical coherence tomography within 3 months after withdrawal of ethambutol (43c). All had visual deficits characteristic of ethambu tol-induced optic neuropathy at their initial visit, and the follow-up examination was per formed within 12 months. Compared with the initial measurement, there was a statisti cally significant reduction in mean RNFLT in the temporal, superior, and nasal quad rants, the greatest reduction being in the temporal quadrant. During follow-up peri ods of 2–12 months, there was improved vision in both eyes in six patients, but either further impairment of RNFLT or no change. The authors concluded that impaired RNFLT in all quadrants of the optic disc was associated with ethambutol-induced optic neuropathy. Selective loss of fibers in the papillomacular bundle could explain the more prominent reduction on the temporal side. Recovery is often not complete, even in patients who report visual improvement after withdrawal of ethambutol. Optical coherence tomography has been used to document reversible changes in the nerve fiber layer secondary to ethambutolinduced optic neuropathy (44A). • A 70-year-old man with Mycobacterium avium-intracellulare complex pneumonia was given a combination of drugs that included ethambutol 2 g/day (29 mg/kg/day). He developed gradual painless loss of vision over 3 months after 7 months of treatment. There was marked thickening of the inferior quadrant nerve fibers corresponding to the visual field defects in the superior quadrant. As the thickness of the inferior quadrant nerve fiber layer abated, the visual fields improved in the superior quadrant.
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These changes were attributed to retinal ganglion cell axonal swelling that resolved over time after withdrawal of ethambutol. Psychiatric Ethambutol-induced psychosis has been reported (45A). • A 40-year-old man with advanced HIV infection with Mycobacterium avium complex infection was given clarithromycin 500 mg bd, ethambutol 1.2 g/day, rifabutin 300 mg/day (reduced after 3 days to 150 mg/day), co-trimoxazole, fluconazole, and antiretroviral drugs. After 2 weeks he developed severe insomnia, daytime somnolence, forgetfulness, distractability, impulsive spending, episodic obsessive behavior, and delusions of grandeur. He was agitated and had exaggerated physical movements and facial expressions. He had a mild anemia and mild liver function test abnormalities. An MRI scan of the brain was normal. He stopped taking ethambutol, and within 1 week his confusion, hallucinations and uncharacteristic behavior all resolved.
Isoniazid
(SED-15, 1923; SEDA-29, 317, SEDA-30, 359; SEDA-31, 498) Nervous system Seizures have been repor ted in a patient with isoniazid toxicity (46A).
• A 5-year-old girl with pulmonary tuberculosis was given rifampicin, pyrazinamide, ethambutol, and isoniazid þ pyridoxine. After 1 week she became somnolent, with a reduced appetite and vomiting, followed by two seizures lasting about 5 minutes and fluctuating consciousness. A CT scan showed swollen thalami and brainstem. An MRI scan showed symmetrically increased signals in the thalami and more subtle symmetrical involvement of the medulla, the dentate nuclei, and hippocampi. MR angiography, venography, and MR spectroscopy were normal. The serum isoniazid concentration 12 hours after the seizures was 147 µmol/l (20 mg/l). Owing to a dispensing error, she had received 750 mg/day (43 mg/kg/day) instead of 250 mg/day. Her medications were withheld and pyridoxine 25 mg/day was continued. She had no further seizures and regained consciousness within 48 hours. A repeat MRI scan 3 days later showed partial resolution of the lesions in the thalami, hippocampi, cerebellum, and brainstem; by 7 weeks, there was complete resolution and full recovery.
Soumya Swaminathan and V.V. Banu Rekha
The mechanism of isoniazid-induced ner vous system toxicity is believed to be a reduction in g-aminobutyric acid (GABA) concentrations by inhibition of pyridoxine (vitamin B6) metabolism. Liver See ‘Hepatotoxicity of antitubercu losis drugs’ above. Susceptibility factors HIV infection The effect of isoniazid prophylaxis on the incidence and mortality of tuberculosis in 263 HIV-positive children (median age 25 months) has been studied in a placebocontrolled trial in South Africa, in which 132 were randomized to isoniazid (47C). Isoniazid significantly reduced the incidence of tuberculosis from 9.9% to 3.8% (HR = 0.28; 95% CI = 0.10, 0.78) and mortality from 21% to 11% (HR = 0.46; 95% CI = 0.22, 0.95). All the cases of tuberculosis that were confirmed by culture were in children who were given placebo. Drug dosage regimens Shorter 3- and 4-month combination regimens of isoniazid þ rifampicin (n = 694) have been compared with a 9-month regimen of isoniazid monotherapy (n = 232) for latent tuberculosis in children in a prospective, randomized, controlled study conducted over 11 years (48C). Isoniazid monotherapy for 9 months was associated with poorer adherence to therapy than the short courses of combination therapy. No patients developed clinical disease during the follow-up period of over 3 years. New radiographic findings suggestive of possible active disease were more common in those who used isoniazid monotherapy (24% versus 12%). There were no serious drugrelated adverse effects. Drug–drug interactions Methotrexate Concerns have been raised regarding the appropriate management of patients with rheumatoid arthritis and latent tuberculosis or exposure to active tuberculosis, before giving tumor necrosis factor (TNF) antagonists. In a retrospective study of 44 patients who were taking both drugs (49c),
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there were transient increases in liver function tests in 11% of patients, but in no case was this more than twice the upper limit of the reference range and all the abnormal tests resolved spontaneously without intervention. No patients developed signs or symptoms of tuberculosis reactivation.
TNF-alpha inhibitors Isoniazid 300 mg/ day for 9 months has been studied prospec tively in 86 patients with latent tuberculosis who were also taking TNF-alpha inhibitors for rheumatological diseases (50c). Five patients had at least threefold increases in AsT and/or AlT activity attributed to iso niazid; after temporary withdrawal, the transaminase activities normalized. There was no hepatotoxicity in those who did not use isoniazid. None of the 86 patients devel oped active tuberculosis.
Pyrazinamide
(SED-15, 2979;
SEDA-28, 344) See ‘Hepatotoxicity of antituberculosis drugs’ above.
RIFAMYCINS Rifabutin Drug–drug interactions Antiretroviral drugs A reduction in the dosage of rifabutin is recommended when it is co-administered with CYP3A4 inhibitors, such as protease inhibitors. Fosamprenavir, the phosphate ester pro-drug of the HIV type 1 protease inhibitor amprenavir, can be given with or without ritonavir. Steady-state rifabutin pharmacokinetics have been studied in 22 healthy adult subjects during con comitant administration of fosamprenavir þ ritonavir (700/100 mg bd), with a 75% reduced dose of rifabutin (150 mg every other day) compared with the standard regimen (300 mg once per day) (51c). Fosamprenavir þ ritonavir did not affect the
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rifabutin steady-state AUC and reduced the Cmax by only 14%, whereas the steady-state AUC and Cmax of D-acetyl rifabutin increased by 11 and 6 times respectively, resulting in a 64% increase in the total steady-state antimycobacterial AUC. Relative to historical controls, after co-administration of rifabutin with fosamprenavir þ ritonavir, the steady-state plasma amprenavir AUC and Cmax increased by 35%, and the Cmin was unchanged. The safety profile of the combination of rifabutin and fosamprenavir þ ritonavir was consistent with previously described events with rifabutin or fosamprenavir þ ritonavir alone. Based on the results of this study, a reduction in the rifabutin dose by at least 75% (to 150 mg every other day or three times per week) is recommended when it is co-administered with fosamprenavir þ ritonavir (700/ 100 mg bd).
Rifampicin
(SED-15, 3040; SEDA-29, 317; SEDA-31, 498) Endocrine Hypothyroidism induced by rifampicin, which is associated with underlying Hashimoto’s thyroiditis, has been previously described. A case of rifampicin-induced hypothyroidism without underlying thyroid disease has also been reported (52A).
• A 34-year-old woman with miliary tuberculosis was given isoniazid 300 mg/day, rifampicin 450 mg/day, ethambutol 800 mg/day, and pyrazinamide 1200 mg/day. After 2 weeks she developed generalized weakness, myalgia, and periorbital edema. The thyrotropin (TSH) concentration was over 100 IU/ml, T3 367 ng/l and free T4 4.5 ng/l. Anti microsomal and antithyroglobulin antibodies were negative. She was given levothyroxine 100 micrograms/day; there was no improvement and the dose was increased to 200 micrograms/day. Rifampicin and levothyroxine were then both withdrawn and although her thyroid function improved, it did not return to normal. Levothyroxine was restarted and she became euthyroid. Rifampicin was reintroduced for worsening infection, and her hypothyroid got worse. The dosage of levothyroxine was increased to 200 micrograms/day until she had completed 9 months of antituberculosis drug
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treatment. Levothyroxine 100 micrograms/day was then continued for 2 months, after which she became euthyroid and levothyroxine was withdrawn.
Rifampicin induces hepatic oxidases and the metabolic clearance rate of T4 by increased iodothyronine conjugate biliary excretion. Hypothyroidism induced by rifampicin, although rare, has to be consid ered, and thyroid function should be checked if symptoms of hypothyroidism occur. It appears to be reversible, and levothyroxine can be withdrawn after treatment with rifampicin has been completed. Gastrointestinal The frequency of gastro intestinal adverse effects and hepatotoxicity in patients taking rifampicin for an osteoar ticular infection and the association between rifampicin plasma concentrations and adverse effects have been studied prospec tively in 46 adults after a median duration of 8 (range 1–179) days (53c). There were gas trointestinal adverse effects in 13 patients on at least one occasion. When they occurred, the trough and peak plasma rifampicin con centrations were similar to the concentra tions in those without gastrointestinal adverse effects. AlT activity was higher than normal in only three patients while they were taking rifampicin. Since there was no association between rifampicin plasma concentrations and gastrointestinal adverse effects, the authors concluded that plasma rifampicin concentration measure ment is irrelevant in the management of gas trointestinal toxicity. Immunologic A leukocytoclastic vasculitis has been attributed to rifampicin (54A). • A 76-year-old man with Mycobacterium kansasii pulmonary disease was given isoniazid 250 mg/day, rifampicin 600 mg/day, and pyrazinamide 1500 mg/day and after 2 months developed a fever, dry cough, dyspnea, oliguria, and bilateral edema. He had acute renal failure (serum creatinine 846 µmol/l) and thrombocytopenia (85 109/l). Renal ultrasound and Doppler studies were
Soumya Swaminathan and V.V. Banu Rekha
normal. The antituberculosis drugs were withheld and he recovered within 2 weeks. A week later rifampicin was reintroduced at increasing dosages, starting at 50 mg/day. After 3 days (dosage 200 mg/day) he developed palpable purpura, his platelet count fell, and his serum creatinine concentration rose to 167 µmol/l. A biopsy showed a leukocytoclastic vasculitis. Rifampicin was withdrawn on day 4 and he recovered within 4 days.
Rifampicin-induced renal insufficiency is mediated by mechanisms of type II hyper sensitivity or less often type III. It has been hypothesized that anti-rifampicin antibodies bind to antigen I present on the cellular surface of erythrocytes, platelets, and renal tubular epithelium, inducing cellular destruction.
Drug dosage regimens In a double-blind randomized phase II trial of the potential effect of a higher dose of rifampicin in shortening the duration of tuberculosis treatment, 50 adult Indonesians with tuberculosis were randomized to a standard dose of rifampicin (450 mg/day, 10 mg/kg) or a higher dose (600 mg/day) in addition to other antituberculosis drugs (55c). The geometric means of steady-state rifampicin AUC and Cmax were significantly increased by 65% and 49% in patients taking the higher dose. The pharmacokinetics of pyrazinamide and ethambutol were similar in the two groups. Mild hepatotoxicity (grade 1 or 2) was more common in the higher-dose group (46 versus 20%), but no patient had severe hepatotoxicity. These findings suggest that the higher dose of rifampicin caused a dispropotinate increase in the mean steady-state AUC and Cmax of rifampicin without a change in the incidence of serious adverse effects. As increasing the dose of rifampicin is feasible and effective from a pharmacokinetic point of view, followup phase II studies should be performed to evaluate an even higher dosage of rifampicin. A higher dosage of rifampicin (possibly in conjunction with newer antituberculosis drugs) may allow shortening of the duration of tuberculosis treatment.
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Drug–drug interactions Antiretroviral drugs Whether the inducing effect of rifampicin 600 mg/day on CYP3A4 can be overcome by the inhibitory effect of ritonavir has been evaluated in three HIVpositive patients with tuberculosis taking atazanavir 300 mg/day and ritonavir 100 mg/day (56c). In all three cases, more than 50% of the time the atazanavir concentration was below the minimum recommended trough plasma concentration (150 ng/ml) for inhibition of HIV wild-type replication. These findings suggested that ritonavir did not overcome the enzyme-inducing effect of rifampicin on atazanavir. The combined use of rifampicin and adjusted doses of lopinavir þ ritonavir soft-gel capsules has been studied in 40 healthy volunteers who were intended to take rifampicin 600 mg/day alone on days 1–5 and in combination with lopinavir þ ritonavir 600/150 or 800/200 mg bd on days 6–15 (57c). There were no major complaints during days 1–5 (rifampicin only). However, after the addition of lopinavir þ ritonavir, eight volunteers had nausea and vomiting, one nausea only, and one vomit ing only. On day 7, increases in AsT and AlT activities were reported in all volun teers. On day 8, the study was terminated prematurely. AsT and AlT activities con tinued to rise and peaked on days 9–10, but returned to normal within 6 weeks. The geometric mean (range) of the lopina vir and ritonavir trough concentrations on day 7 were respectively 7.9 (6.6–10) mg/l and 0.71 (0.35–1.61) mg/l after 600/150 mg/ day and 11 (8.3–14) mg/l and 1.20 (0.64– 1.85) mg/l after 800/200 mg/day. The high incidence of adverse events when a higher than standard dose of lopinavir þ ritonavir was combined with rifampicin was not clearly explained. The effect of additional ritonavir on plasma lopinavir concentrations in 30 HIV-infected children taking rifampicinbased treatment for tuberculosis has been evaluated (58c) in two parallel groups tak ing combination antiretroviral drug therapy that included lopinavir (230 mg/m2) þ ritonavir (57.5 mg/m2), with and without
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rifampicin-based antituberculosis drug treatment. Additional ritonavir (172.5 mg/ m2) was given (lopinavir/ritonavir ratio of 1:1) during antituberculosis drug treatment. The pharmacokinetic parameters of lopina vir measures in children with and without rifampicin respectively were (median and interquartile range) Cmax 11 (7.1–14) versus 14 (12–24); AUC0!12 81 (51–122) versus 118 (80–176) h.mg/l; Cmin 3.94 (2.26–7.66) versus 4.64 (2.32–10.4) mg/l. Of 15 children who took antituberculosis drug treatment, 13 had a lopinavir Cmin greater than the recommended minimum therapeutic con centration (1 mg/l). The authors concluded that the effect of rifampicin-based treat ment on lopinavir concentrations was atte nuated by adding additional ritonavir to lopinavir. Moxifloxacin Rifampicin induces the phase II metabolic enzymes involved in the biotransformation of moxifloxacin. This interaction has been investigated in 19 Indonesian patients with pulmonary tuberculosis who were in the last month of treatment (59c). In phase 1 of the study, they took moxifloxacin 400 mg/day for 5 days in addition to rifampicin 450 mg and isoniazid 600 mg 3 times per week. In phase 2, after a 1-month washout period, they took moxifloxacin alone for another 5 days. The geometric mean steady-state Cmax, AUC, and MIC for moxifloxacin in phase 2 approached the desired values for fast-growing bacilli, in contrast to values that were about 30% lower in phase 1. The median tmax of moxifloxacin was pro longed from 1 to 2.5 hours when it was combined with rifampicin and isoniazid. The authors concluded that co-administra tion of moxifloxacin with intermittent rifam picin and isoniazid reduced moxifloxacin plasma concentrations, probably by induc tion of glucuronidation or sulfatation. The mutant prevention concentration (MPC) for moxifloxacin in tuberculosis treatment was set at 2.5 mg/l. The median time during which the moxifloxacin concentration was greater than the MPC was 5.5 (range 2.5–7.5) hours when it was given alone and 2 (range 0–7.5) hours when it was combined
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with rifampicin and isoniazid. Daily dosing of rifampicin instead of intermittent dosing might amplify the extent of this
Soumya Swaminathan and V.V. Banu Rekha
interaction. A higher dose of moxifloxacin might overcome the effect of rifampicin on the pharmacokinetics of moxifloxacin.
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18. Burman WJ, Cotton MF, Gibb DM, Walker AS, Vernon AA, Donald PR. Ensuring the involvement of children in the evaluation of new tuberculosis treatment regimens. PLoS Med 2008; 5:1168–72. 19. Donald PR. The assessment of new anti tuberculosis drugs for a paediatric indication. Int J Tuberc Lung Dis 2007; 11(11):1162–5. 20. Pinheiro VG, Ramos LM, Monteiro HS, Barroso EC, Bushen OY, Fac?anha MC, Peloquin CA, Guerrant RL, Lima AA. Intestinal permeability and malabsorption of rifampin and isoniazid in active pulmon ary tuberculosis. Braz J Infect Dis 2006; 10(6):374–9. 21. Benedetti SM, Baltes EL. Drug metabolism and disposition in children. Fundam Clin Pharmacol 2003; 17:281–99. 22. Anderson GD, Lynn AM. Optimizing pediatric dosing: a developmental pharma cologic approach. Pharmacotherapy 2009; 29:680–90. 23. Zhu M, Burman WJ, Starke JR, Stambaugh JJ, Steiner P, Bulpitt AE, Ashkin D, Auclair B, Berning SE, Jelliffe RW, Jaresko GS, Peloquin CA. Pharmacokinetics of ethambu tol in children and adults with tuberculosis. Int J Tuberc Lung Dis 2004; 8(11):1360–7. 24. Zhu M, Starke JR, Burman WJ, Steiner P, Stambaugh JJ, Ashkin D, Bulpitt AE, Bern ing SE, Peloquin CA. Population pharmaco kinetic modeling of pyrazinamide in children and adults with tuberculosis. Pharmacother 2002; 22(6):686–95. 25. Thee S, Detjen A, Wahn U, Magdorf K. Rifampicin serum levels in childhood tuber culosis. Int J Tuberc Lung Dis 2009; 13(9):1106–11. 26. Otto H, Aktueller MK. Stand der antituber kulo¨ sen Chemotherapie im Kindesalter. Prax Klin Pneumol 1981; 35:588–95. 27. Thee S, Detjen A, Wahn U, Magdorf K. Pyrazinamide serum levels in childhood tuberculosis. Int J Tuberc Lung Dis 2008; 12:1099–101. 28. Arya DS, Ojha SK, Semwal OP, Nandave M. Pharmacokinetics of pyrazinamide in chil dren with primary progressive disease of lungs. Indian J Med Res 2008; 128:611–5. 29. Hussels H, Kroening U, Magdorf K. Etham butol and rifampicin serum levels in children: second report on the combined administration
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a single-center experience. Transplant Proc 2007; 39:1008–11. Sen N, Turunc T, Karatasli M, Sezer S, Demiroglu YZ, OnerEyuboglu F. Tubercu losis in patients with end-stage renal disease undergoing dialysis in an endemic region of Turkey. Transplant Proc 2008; 40:81–4. Thiboutot DM, Willmer J, Sharata H, Halder R, Garrett S. Pharmacokinetics of dap sone gel, 5% for the treatment of acne vul garis. Clin Pharmacokinet 2007; 46:697–712. Kwon HM, Kim HK, Cho J, Hong YH, Nam H. Cycloserine-induced encephalopathy: evi dence on brain MRI. Eur J Neurol 2008; 15(7):e60–1. Vistamehr S, Walsh TJ, Adelman RA. Ethambutol neuroretinopathy. Semin Ophthalmol 2007; 22:141–6. Chai SJ, Foroozan R. Decreased retinal nerve fibre layer thickness detected by opti cal coherence tomography in patients with ethambutol-induced optic neuropathy. Br J Ophthalmol 2007; 91:895–7. Zoumalan CI, Sadun AA. Optical coherence tomography can monitor reversible nervefibre layer changes in a patient with etham butol-induced optic neuropathy. Br J Ophthalmol 2007; 91:839–40. Martin SJ, Bowden FJ. Ethambutol toxicity manifesting as acute onset psychosis. Int J STD AIDS 2007; 18:287–8. Hawkes M, Kitai I, Blaser S, Cohen E, Bitnun A, Fluss J, Tran D. Neuroimaging find ings in isoniazid central nervous system toxicity, presumed intramyelinic edema. Eur J Paediatr Neurol 2008; 12:512–5. Zar HJ, Cotton MF, Strauss S, Karpakis J, Hussey G, Schaaf S, Rabie H, Lombard CJ. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised controlled trial. BMJ 2007; 334:136–9. Spyridis NP, Spyridis PG, Gelesme A, Sypsa V, Valianatou M, Metsou F, Gourgiotis D, Tsolia MN. The effectiveness of a 9-month regimen of isoniazid alone versus 3- and 4-month regimens of isoniazid plus rifampin for treatment of latent tuberculosis infection in children: results of an 11-year randomized study. Clin Infect Dis 2007; 45:715–22. Mor A, Bingham III CO, Kishimoto M, Izmirly PM, Greenberg JD, Reddy S,
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Rosenthal PB. Methotrexate combined with isoniazid treatment for latent tubercu losis is well tolerated in patients with rheu matoid arthritis: experience from an urban arthritis clinic. Ann Rheum Dis 2008; 67:462–5. Hanta I, Ozbek S, Kuleci S, Sert M, Kocabas A. Isoniazid intervention for latent tuberculosis among 86 patients with rheumatologic disease administered with anti-TNFalpha. Clin Rheumatol 2007; 26:1867–70. Ford SL, Chen YC, Lou Y, Borland J, Min SS, Yuen GJ, Shelton MJ. Pharmacokinetic interaction between fosamprenavir–ritonavir andrifabutin in healthy subjects. Antimicrob Agents Chemother 2008; 52:534–8. Kim DL, Song KH, Jung HL, Kye YL, Suk KK. Rifampin-induced hypothyroidism without underlying thyroid disease. Thyroid 2007; 17:793–5. Roblot F, Besnier JM, Giraudeau B, Simonnard N, Jonville-Bera AP, Coipeau P, Chou tet P, Autret-Leca E, Le Guellec C. Lack of association between rifampicin plasma con centration and treatment-related side effects in osteoarticular infections. Fundam Clin Pharmacol 2007; 21:363–9. Munoz ME, Ruiz P, Borobia AM, Pagan B, Pano-Pardo JR, Cerezo JG. Rifampin related acute renal failure, thrombocyto penia, and leukocytoclastic vasculitis. Ann Pharmacother 2008; 42:727–8. Ruslami R, Nijland HMJ, Alisjahbana B, Parwati I, Van Crevel R, Aarnoutse RE. Pharmacokinetics and tolerability of a higher rifampin dose versus the standard dose in pulmonary tuberculosis patients. Antimicrob Agents Chemother 2007; 51:2546–51. Mallolas J, Sarasa M, Nomdedeu M, Soriano A, Lopez-Pua Y, Blanco JL, Martinez E, Gatell JM. Pharmacokinetic interaction between rifampicin and ritonavir-boosted atazanavir in HIV-infected patients. HIV Med 2007; 8:131–4. Nijland HMJ, L’Homme RFA, Rongen GA, Van Uden P, Van Crevel R, Boeree MJ, Aarnoutse RE, Koopmans PP, Burger DM. High incidence of adverse events in healthy volunteers receiving rifampicin and adjusted doses of lopinavir/ritonavir tablets. AIDS 2008; 22:931–5.
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58. Ren Y, Nuttall JJC, Egbers C, Eley BS, Meyers TM, Smith PJ, Maartens G, McIlleron HM. Effect of rifampicin on lopinavir pharmacokinetics in HIV-infected children with tuberculosis. J Acquir Immune Defic Syndr 2008; 47(5):566–9.
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Antihelminthic drugs
Pharmacovigilance of antihelminthic drugs in developing countries After the thalidomide disaster in the 1960s, most Western countries developed national pharmacovigilance systems. These systems use spontaneous reporting or other pharmaco epidemiological methods to collect and analyse adverse events associated with the use of drugs systematically, to identify signals or emerging problems and to communicate how to minimize or prevent harms. How ever, these processes are not perfect. Fewer than 27% of lower-middle-income and lowincome economies have national pharma covigilance systems registered with the WHO programme in Uppsala, compared with 96% of high-income countries (1R). This is because of lack of resources, infra structure, and expertise. Thus, although access to medicines is increasing in develop ing countries, there is a danger that their benefit-to-harm balance profiles in indigen ous populations will not be fully monitored and acted on. To make better use of planned studies, the ability to detect an adverse drug reaction depends on its frequency and the total number of people exposed to the drug. We should encourage collaboration between academic investigators, drug companies, and governments who undertake clinical studies to develop common adverse reactions
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32031-9 � 2010 Elsevier B.V. All rights reserved.
reporting formats (2r, 3H) and to deposit the data into a single database. The opera tional advantages of this approach are that data can be obtained from a range of studies and that pre-existing manual and technical infrastructures can be used to acquire the data. The pooling of data on adverse drug reactions would add value to clinical studies. In the long term every country should develop its own national pharmacovigilance system and contribute to the global database held by the Uppsala Monitoring Centre (4S, 5S). There are many neglected tropical diseases, including infestations with round worms (ascariasis), whipworms (trichuria sis), guinea worms (dracunculiasis), bilharziasis (schistosomiasis), elephantiasis (lymphatic filariasis), and river blindness (onchocerciasis), which produce a disease burden almost as great as that associated with HIV–AIDS, malaria, or tuberculosis but are virtually unknown to health-care workers in developed countries, because they occur almost exclusively in the poorest regions of the world. Seven of the most pre valent diseases have oral drug treatments. Identifying treatments that are effective against more than one disease could facilitate efficient and inexpensive treatment. The observation that adverse events are generally inadequately reported has been highlighted by a systematic review of oral drug therapy for these neglected diseases (6M), in which 29 randomized controlled trials were identified, of which 3 targeted four diseases simulta neously, 20 targeted three diseases, and 6 targeted two diseases: • albendazole þ diethylcarbamazine significantly reduced the prevalence of elephantiasis (from
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572 17 to 5.3%), hookworm (from 10 to 1.9%), roundworm (from 35 to 2.3%), and whipworm (from 56 to 40%); • albendazole þ ivermectin significantly reduced the prevalence of elephantiasis (from 13 to 4.6%), hookworm (from 7.8 to 0%), roundworm (from 36 to 6.1%), and whipworm (from 43 to 8.9%); • levamisole plus mebendazole significantly reduced the prevalence of hookworm (from 94 to 72%), roundworm (from 62 to 1.4%), and whipworm (from 93 to 75%); • pyrantel þ oxantel significantly reduced the prevalence of hookworm (from 93 to 85%), roundworm (from 23 to 1.4%), and whipworm (from 87 to 60%); • albendazole alone significantly reduced the prevalence of hookworm (from 8.1 to 1.3%), roundworm (from 28 to 0.9%) and whipworm (from 52 to 32%).
There were no randomized trials in river blindness or trachoma as part of an interven tion to target two or more neglected tropical diseases. The following adverse events were reported: • diethylcarbamazine and albendazole þ diethyl carbamazine: fever, headache, mild myalgia; • albendazole, ivermectin, and albendazole þ ivermectin: systemic effects were reported more often; • praziquantel and praziquantel þ albendazole: nausea, abdominal pain, headaches, and bloody diarrhea.
Adverse events reporting in all of the trials in this analysis was poor. Ten of the 29 publications did not include information about whether adverse events had been assessed, and absence of reporting adverse events is not equivalent to the absence of such events. In the 14 trials in this systema tic review in which adverse events were reported, the frequency and intensity of the events were not specified. The poor quality of the reporting of adverse events is not unique to research in neglected tro pical diseases; the quality and quantity of drug safety reporting have been found largely inadequate across medical fields. Possible drug-drug interactions when drugs for neglected tropical diseases are used in combination also need to be con sidered. Neglected tropical diseases occur predominantly in vulnerable populations,
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which can be at risk of adverse drug effects, making adverse events reporting a priority. One challenge raised by the mass adminis tration of drugs for neglected tropical diseases is that the doses of several drugs require indi vidualization by weight or height, especially in children. Further efforts are required to determine optimal doses, durations of treat ment and dosing schedules in different set tings. Furthermore, some of these drugs should not be given to vulnerable groups, such as pregnant women, nursing mothers, or very young children. There are also concerns about drug effi cacy. Further research is needed to identify particular geographic regions in which spe cific drugs are most efficacious, to identify areas where drug resistance is emerging (a possible consequence of mass drug adminis tration) and to identify regions with high rates of re-infection. Combination therapy may be one method of delaying the emer gence of drug resistance.
(SED-15, 424; SEDA-29, 320; SEDA-30, 364; SEDA-31, 508)
BENZIMIDAZOLES
Albendazole and mebendazole Observational studies The effectiveness of preoperative albendazole has been studied in a randomized comparison with no treatment in 84 patients with isolated hydatid cysts of the liver (7c); 21 patients each received albendazole 10 mg/kg bd for 1, 2, or 3 months or no preoperative therapy. Scolices were alive after treatment in 19 of 63 patients compared with 17 of 21 controls. Treatment with albendazole should be continued at least for 3 months preopera tively, and if viable scolices are identified, albendazole should follow surgical interven tion for at least 1 month to reduce the pos sibility of residual cysts and recurrence. Adverse events related to albendazole were reported as follows in 63 patients:
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epigastric pain (n = 5), diarrhea (n = 4), nausea and vomiting (n = 3), constipation (n = 2), dry mouth (n = 1), and anorexia (n = 1). There were abnormal biochemical and hematological results in 13 of the 63 patients: increases in transaminases in 5, leukopenia in 4 and neutropenia in 1 and hypoproteinemia in 3. The usefulness of ultrasonography in the diagnosis and treatment of complicated hydatid cysts has been evaluated in 221 patients with 294 hydatid cysts (8c). In 20 patients there were 22 complicated cysts (7.4%): 9 with infections, 5 ruptured into the bile ducts, 2 bilomas, 2 cystopleural fis tulas, 2 allergic reactions, 1 rupture into the peritoneum, and 1 splenic hematoma. In all cases ultrasonography yielded a specific or suspected diagnosis, and demonstrated complications at non-hepatic sites, con firmed by computed tomography (CT), endoscopic papillotomy, or percutaneous ultrasound-guided sampling. All patients with complicated cystic echinococcosis were treated with albendazole 800 mg/day for at least 3 months. In addition to alben dazole, 12 underwent ultrasound-guided drainage, which was ineffective in 3, who subsequently underwent surgery. Five patients were treated with endoscopic sphincterotomy for obstruction of the bile ducts and three received only medical ther apy. Medical, echo-guided, and surgical treatment led to resolution of the complica tions and complete remission of the para sitic pathology in 19/20 patients and in 21/22 cysts. There was partial remission in one case only. Albendazole did not cause major complications and the results were confirmed during follow-up lasting from 5 months to 15 years (mean 3 years). Of 20 patients with complicated echinococcosis, 9 presented with fever, 7 with abdominal pain, of whom 2 had jaundice, and 2 with an allergic rash. Albendazole was asso ciated with increased transaminase activity in 10% and headache and hair loss in 5%. Placebo-controlled studies Angiostrongylus cantonensis is the most common cause of eosi nophilic meningitis in the north-east of Thai land. About 95% of cases are non-fatal, but
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patients may suffer from long-lasting severe headaches. Although albendazole is effective in many parasitic infestations, its role in eosinophilic meningitis is still controversial. Albendazole 15 mg/kg/day for 2 weeks (n = 34) has been studied in a randomized, double-blind, placebo-controlled study in 66 patients with severe headaches caused by eosinophilic meningitis related to A. canto nensis (9c). After 2 weeks, 7 of those who took albendazole had persistent headaches compared with 13 in the placebo group. The mean duration of headache was significantly shortened by albendazole (from 16.2 to 8.9 days). There were no serious drug events; serum transaminases rose in four patients who took albendazole and in seven controls. Systematic reviews The efficacy of single doses of albendazole, mebendazole, levami sole, and pyrantel pamoate against Ascaris lumbricoides, hookworm, and Trichuris tri chiura has been assessed in a large meta analysis of 20 randomized controlled trials (10M): • Single-dose oral albendazole, mebendazole, and pyrantel pamoate for infection with A. lumbricoides resulted in cure rates of 88% (95% CI = 79, 93; n = 557), 95% (91, 97; n = 309), and 88% (79, 93; n = 131) respectively; • Cure rates for infection with T. trichiura after treatment with single-dose oral albendazole and mebendazole were 28% (13, 39; n = 735) and 36% (16, 51; n = 685) respectively; • The efficacy of single-dose oral albendazole, mebendazole and pyrantel pamoate against hookworm infections was 72% (59, 81; n = 742), 15% (1, 27; n = 853), and 31% (19, 42; n = 152) respectively; • Pooled relative risks could not be calculated for pyrantel pamoate against T. trichiura and levamisole for any of the parasites investigated.
Single-dose oral albendazole, mebendazole, and pyrantel pamoate produced high cure rates in infections with A. lumbricoides. For hookworm infection, albendazole was more efficacious than mebendazole and pyrantel pamoate. Treatment of T. tri chiura with single oral doses of current antihelminthic drugs is unsatisfactory. In 11 studies adverse events were not attribu ted to albendazole. One trial in the
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Philippines reported nausea in two patients and diarrhea in one. In three trials of meben dazole there were no adverse events, but in one study there was abdominal discomfort in 6 of 45 children who took mebendazole 500 mg/day. Almost half of the patients who took pyrantel pamoate in a study in Nigeria had adverse events, mainly abdominal pain, nausea, and dizziness. Liver Patients with AIDS are more likely to have echinococcal disease that develops rapidly and manifests early. A 32-year-old man with AIDS was given albendazole 400 mg bd and prednisolone; he took the albendazole in three 4-week courses separated by 1-week intervals, in the hope of reducing the risk of liver damage (11A). No liver damage occurred. A subsequent CT scan of the chest and abdomen showed that the Echinococcus cysts had decreased in size and number. Highly active antiretro viral therapy (HAART) was not started while he was taking albendazole, because of possible drug–drug interactions, a risk of iatrogenic liver damage, and a risk of immune reconstitution syndrome. Immunologic Immediate hypersensitivity to mebendazole and albendazole has been reported (12A). • A 52-year-old woman with an acute parasitic infection took a first dose of mebendazole 100 mg and 2 hours later developed acute gen eralized urticaria. Skin prick and intradermal tests (0.1–0.01 mg/ml) were negative with both mebendazole and albendazole. However, 90 minutes after an oral challenge with mebenda zole 75 mg, she developed itching and wheals on her forearms. She was given intramuscular methylprednisolone and dexchlorpheniramine and improved within 1–2 hours. Seven hours after taking albendazole 400 mg, she developed identical lesions on her trunk, was treated as before, and recovered within 1 hour. Mebenda zole- and albendazole-specific immunoglobulin E (IgE) was not detected.
It is notable that skin tests were apparently not useful in making the diagnosis in this case. Cross-reactivity with other benzimidazole derivatives could not be excluded.
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Genotoxicity Albendazole may have geno toxic effects in human lymphocytes in vivo. The genotoxicity of albendazole has been studied in 14 children (8 boys and 6 girls) who had undergone surgery for hepatic hydatid disease (13c). Genotoxicity was evaluated as the frequency of sister chroma tid exchanges and micronucleated cells in the patients’ lymphocytes before and after exposure to albendazole. In all patients there was a significant rise in the number of sister chromatid exchanges after albenda zole and all had a significant rise in the number of micronucleated cells.
Diethylcarbamazine
(SED-15, 1115; SEDA-29, 322; SEDA-31, 365)
Placebo-controlled studies The efficacy of doxycycline in treating the causal agent of human lymphatic filariasis, Brugia malayi, is unknown. Standard treatment with diethylcarbamazine þ albendazole is associated with adverse reactions. Doxycy cline 100 mg/day alone or in combination with diethylcarbamazine þ albendazole has been used in a 6-week, double-blind, randomized, placebo-controlled field trial in patients with B. malayi infection (14C). After 4 months of treatment with doxycy cline (n = 119) or placebo (n = 42), the patients were given diethylcarbamazine 6 mg/kg þ albendazole 400 mg or a match ing placebo. The adverse effects of doxycy cline were mild and included myalgia (n = 6), nausea (n = 4), dizziness (n = 5), headache (n = 3), insomnia (n = 2), abdominal pain (n = 2), itching (n = 2), diarrhea (n = 1), rash (n = 1), malaise (n = 1), and drowsi ness (n = 1); none of the patients had to stop taking doxycycline because of adverse reactions. There were no reports of photo sensitivity reactions. Adverse events in the placebo group (n = 42) were myalgia (n = 2), nausea (n = 1), dizziness (n = 2), insomnia (n = 1), and itching (n = 1). The most common adverse reactions to diethylcarba mazine þ albendazole were fever, headache, arthralgia, dizziness, lymph node
Antihelminthic drugs
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enlargement, and myalgia. Altogether, 51 of 99 patients who took diethylcarbamazine þ albendazole and 8 of 62 who took placebo and diethylcarbamazine þ albendazole had moderate or severe adverse reactions. Adverse reactions were least common in those who took doxycycline þ placebo and most common in those who took pla cebo and diethylcarbamazine þ albenda zole. There were significantly fewer patients with high fever and severe adverse reactions in those who took doxycycline and diethylcarbamazine þ albendazole.
Ivermectin
(SED-15, 1946; SEDA-29, 323; SEDA-30, 365; SEDA-31, 509)
Observational studies In a randomized, open study, a 7-day course of oral albenda zole 800 mg/day was compared with a single oral dose of the parenteral veterinary for mulation of ivermectin 200 micrograms/kg in 42 Thai patients with chronic strongyloi diasis (15c). The primary end points were relief of symptoms (if present) and clear ance of Strongyloides larvae from the feces immediately after treatment and at follow-up 16 weeks later. Cure rates in the albendazole and ivermectin groups were 38 and 76% respectively in the intentionto-treat analysis, and 50 and 89% respec tively in the per-protocol analysis. One patient had acute generalized exanthema tous pustulosis (AGEP) 1 day after receiv ing ivermectin. Five patients who took albendazole and one patient who took iver mectin had transient changes in transami nases, a well-recognized and reversible effect. Placebo-controlled studies In a randomized, placebo-controlled trial in Ghana, 67 patients with onchocerciasis took doxy cycline 200 mg/day for 4 or 6 weeks, followed by ivermectin 0.15 mg/kg after 6 months (16C). After 6, 20, and 27 months, efficacy was evaluated by onchocercoma histology, polymerase chain reaction (PCR), and
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determination of microfilariae. Doxycycline resulted in endobacteria depletion and female worm sterilization; the 6-week regi men was macrofilaricidal and over 60% of the female worms were found dead, despite the presence of new Wolbachia-containing worms acquired after the administration of doxycycline. Doxycycline could be devel oped as a second-line drug for onchocercia sis, to be administered in areas without transmission, in foci with ivermectin resistance, and in areas with Loa loa co infections. Treatment with doxycycline was associated with bloody diarrhea in one patient; it resolved after withdrawal and treatment with metronidazole, although day 3 may have been too early for antibio tic-associated colitis. Other adverse events were mild, did not last longer than 3 days, and did not occur more often after adminis tration of doxycycline. No serious adverse events were observed.
Levamisole
(SED-15, 2028; SEDA-29, 324; SEDA-30, 366; SEDA-31, 510)
Observational studies Many children with steroid-dependent nephritis have signifi cant sequelae despite steroid-sparing thera pies. Levamisole may reduce short-term relapse frequency with minimal adverse effects. However, there is little information about its long-term effects. In 10 consecu tive children with steroid-dependent nephritis treated with levamisole, both the relapse frequency and annual steroid bur den fell compared with the period before levamisole treatment (17c). These effects lasted for 12 months after withdrawal of levamisole. None of the patients had any serious sequelae attributable to levamisole. Hematological measurements fell slightly but remained well within the reference ranges. Transaminases and renal function tests were unchanged. Serum albumin con centrations improved significantly. There were no rashes or signs or symptoms of vasculitis.
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References 1. Pirmohamed M, Atuah KN, Dodoo ANO, Winstanley P. Pharmacovigilance in devel oping countries. BMJ 2007;335:462. 2. Aronson JK. Anecdotes as evidence. BMJ 2003;326:1346. 3. Aronson JK. PHARMA: Publishing His tories of Adverse Reactions to Medicaments Anecdotally. Reporting suspected adverse drug reactions and interactions: proposed guidelines for authors. http://bmj.com/cgi/ content/full/326/7403/1346/DC1#p. 4. Uppsala Monitoring Centre. http://www. who-umc.org/ 5. Hugman B. From the Uppsala Monitoring Centre: a review of Viewpoint part 1 and part 2. Drug Saf 2005;28(7):645–6. 6. Reddy M, Gill SS, Kalkar SR, Wu W, Ander son PJ, Rochon PA. Oral drug therapy for multiple neglected tropical diseases: a systema tic review. J Am Med Assoc 2007;298:1911–24. 7. Bildik N, Cevik A, Altintas M, Ekinci H, Canberk M, Gulmen M. Efficacy of pre operative albendazole use according to months in hydatid cyst of the liver. Am J Gastroenterol 2007;41:312–6. 8. Caremani M, Lapini L, Tacconi D, Giorni P, Corradini S, Giaccherini R. Sonographic management of complicated cystic echino coccosis. J Ultrasound 2007;10:179–85. 9. Jitpimolmard S, Sawanyawisuth K, Morakote N, Vejjajiva A, Puntumetakul M, Sanchaisur iya K, Tassaneeyakul W, Tassaneeyakul W, Korwanich N. Albendazole therapy for eosi nophilic mengitis caused by Angiostrongylus cantonensis. Parasitol Res 2007;100:1293–6. 10. Keiser J, Utzinger J. Efficacy of current drugs against soil-transmitted helminth infec tions: systematic review and meta-analysis. J Am Med Assoc 2008;299:1937–48.
11. Chopdat N, Menezes CN, John MA, Mahomed N, Grobusch MP. A gardener who coughed up blood. Lancet 2007;370:1520. 12. Gonzalez-Mendiola R, Martinez Borque N, Palomeque Rodriguez T, Torrecillas Toro M, Martinez Bohigas D. Type I allergic reac tion to benzimidazole antihelmintics. Eur J Allergyn Clin Immunol 2007;62:713–4. 13. Oztas S, Salman AB, Tatar A, Yigiter M, Yazgi H, Ertek M, Yesilyurt A, Ocak Z, Kursad H. Genotoxic effect of albendazole in pediatric patients with hepatic hydatid dis ease. Int J Infect Dis 2007;11(5):446–9. 14. Supali T, Djuardi Y, Pfarr KM, Wibowo H, Taylor MJ, Hoerauf A, Houwing-Duistermaat JJ, Yazdanbakhsh M, Sartono E. Doxycycline treatment of Brugia malayi-infected persons reduces microfilaremia and adverse reactions after diethylcarbamazine and albendazole treatment. Clin Infect Dis 2008;46:1385–93. 15. Suputtamongkol Y, Kungpanichkul N, Silpa sakorn S, Beeching NJ. Efficacy and safety of a single-dose veterinary preparation of iver mectin versus 7-day high-dose albendazole for chronic strongyloidiasis. Int J Antimicrob Agents 2008;31:46–9. 16. Hoerauf A, Specht S, Buttner M, Pfarr K, Mand S, Fimmers R, Marfo-Debrekyei Y, Konadu P, Debrah AY, Bandi C, Brattig N, Albers A, Larbi J, Batsa L, Taylor MJ, Adjei O, Buttner DW. Wolbachia endobacteria depletion by doxycycline as antfilarial therapy has macrofilaricidal activity in onchocerciasis: a randomised placebo-controlled study. Med Microbiol Immunol 2008;197:295–311. 17. Boyer O, Moulder JK, Grandin L, Somers MJG. Short- and long-term efficacy of levami sole as adjunctive therapy in childhood nephro tic syndrome. Pediatr Nephrol 2008;23:575–80.
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Vaccines
Editor’s note: Abbreviations used in this and previous issues of SEDA:
Adverse effects of vaccine adjuvants
• aP: Acellular pertussis • BCG: Bacillus Calmette Guérin • DTP: Diphtheria þ tetanus toxoids þ pertussis vaccine • DTaP: Diphtheria þ tetanus toxoids þ acellular pertussis • DTaP-Hib-IPV-HB: Diphtheria þ tetanus toxoids þ acellular pertussis þ IPV þ Hib þ hepatitis B (hexavalent vaccine) • DTwP: Diphtheria þ tetanus toxoids þ whole cell pertussis • HAV: Hepatitis A virus • HbOC (also called PRPCRM): Conjugated Hib vaccine (Hib capsular antigen polyribosylphosphate covalently linked to the non-toxic diphtheria toxin variant CRM197) • HBV: Hepatitis B virus • Hib: Haemophilus influenzae type b • HPV: Human papilloma virus • HZV vaccine: Herpes zoster virus vaccine • IPV: Inactivated polio vaccine
Adjuvants, particularly aluminium hydro xide, aluminium phosphate, and calcium phosphate, have been used for decades to improve immune responses to vaccine anti gens. More recently, many clinical studies with newly developed adjuvants, including mineral salts/gels, oil-emulsions, surfactantbased particulates, microbial (natural and synthetic) derivatives, endogenous human immunomodulators (cytokines), and combi nations of these, have been used (1S). The European Medicines Agency (EMA) has licensed some vaccines with newly devel oped adjuvants, including antigens incorpo rated into immunostimulating reconstituted influenza virosomes (IRIVs), vaccines con taining oil-in-water emulsions or monophosphoryl lipid (MPL) A derivatives.
• JE vaccine: Japanese encephalitis vaccine • MCV4: Meningococcal conjugate vaccine, 4-valent • MMR: Measles þ mumps þ rubella • MMRV: Measles þ mumps þ rubella þ varicella • OPV: Oral polio vaccine • PRP-D-Hib: Conjugated Hib vaccine (Hib capsular antigen polyribosyl phosphate covalently linked to a mutant polypeptide of diphtheria toxin) • SV40: Simian virus 40 • Td: Diphtheria þ tetanus toxoids (adult formulation) • wP: Whole cell pertussis • YF vaccine: Yellow fever vaccine
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32032-0 � 2010 Elsevier B.V. All rights reserved.
Oil-in-water emulsions MF59C.1 is an oil-in-water emulsion, the oil being squalene, a natural component of cell membranes (SEDA-31, 529). Since 1997, a seasonal influenza vaccine with the MF59C.1 adjuvant, Fluad® (Novartis), has been licensed for use in elderly people in the European Union and used in some countries. More than 45 million doses have been distributed since then. Clinical trials with several MF59C.1 adjuvanted vaccines have been performed in different age groups, including children from 6 months onwards, without raising safety concerns while showing increased immunogenicity of the combination of the adjuvant with the antigen. According to the EMA, nonclinical experience with MF59C.1, either alone or combined with a variety of
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antigens, is also sufficient and has not raised concerns. The AS03 adjuvant (GlaxoSmithKline) is also an oil-in-water emulsion manufactured for use in pandemic influenza vaccines. The oil phase contains two oils, squalene and DL-�-tocopherol (vitamin E). Non-clinical data are mainly derived from rodent studies, and raise no concerns. The manufacturer has generated a large amount of clinical data in adults and elderly people and limited data in children aged 3–9 years with an H5N1 mockup pandemic influenza vaccine. Pandemic influenza vaccine based on the AS03 adju vanting system was associated with greater reactogenicity than corresponding doses of non-adjuvanted influenza vaccine, but the safety profile was still considered to be acceptable (2S). The EMA has licensed these vaccines with adjuvants that contain MPL, such as AS04 in the hepatitis B vaccine Fendrix® and in the HPV vaccine Cervarix®. So far no safety signals have been detected that indicate an increased risk of autoimmune disease after the use of these licensed adjuvanted vaccines. In the United States USA, use of adjuvants in licensed vaccines is limited to aluminiumderived adjuvants. Therefore, the FDA has also not licensed pandemic influenza vaccines containing newly developed adjuvants. How ever, on 16 October 2009, the FDA approved an application for the HPV vaccine Cervarix® containing the adjuvant AS04 (3S). Interest in vaccine adjuvants has been growing rapidly, for several reasons. Ambi tious goals for enhancing current vaccines and for developing new ones have been established, and new vaccine candidates against infectious, allergic, or autoimmune diseases, and also for cancer and fertility treatment, have been emerging. In many cases, because of their low immunogenicity, these vaccines will require adjuvants. New technologies in the fields of biochemistry and recombinant technology and better understanding of immunological mechanisms and disease pathogenesis have helped to improve the technical basis for the develop ment and application of adjuvants. Advan tages of adjuvants (immune potentiators or immunomodulators) include enhancement
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of the immunogenicity of weaker antigens, reduction of the amount of antigen needed for successful immunization, reduction of the frequency of booster immunization needed, and an improved immune response in elderly and immunocompromised vaccinees. How ever, the benefits of an adjuvant in a vaccine must be weighed against the risk of any adverse reaction that it may cause, e.g. acute toxicity and the possibility of delayed adverse effects. The current attitude regarding the balance of benefit to harm in immunization favors safety over efficacy when a vaccine is given to healthy people. In some high-risk groups, such as patients with cancer or AIDS, and for therapeutic vaccines, increased toxicity may be acceptable if the benefit of the vaccine is substantial. Even when no serious adverse effects are observed in extensive non-clinical toxicological and safety studies, there is no guarantee that the new vaccine/adjuvant formulation presents no risk. Final safety evaluation can only be conducted on the basis of carefully designed clinical trials and post-marketing surveillance (1S, 4S). Currently, in many European countries, there is heated discussion about the safety of adjuvanted pandemic influenza vaccines, particularly regarding their use in pregnant women and young children. However, con sidering the public health threat of pandemic H1N1 influenza, the aim of the EMA was to ensure that vaccines were made available as soon as possible, based on a robust assess ment of the data, before the beginning of the Northern Hemisphere influenza season 2009–2010. Based on the concept of conju gated mock-up influenza vaccines, two con jugated pandemic influenza vaccines, Pandemrix® (GSK) and Focetria® (Novartis), were licensed by the EMA for use in Eur opean countries. The EMA was aware that only limited data on safety and immunogeni city of pandemic influenza H1N1v vaccines would be available when Member States start to use the vaccines, but extensive amounts of safety and efficacy data would be received in a very short time after initial authorization of the pandemic influenza vaccines. Therefore, post-marketing surveillance has been required and outlined. In order to explain
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the background for the decision, the EMA published, together with information on the marketing authorization of pandemic influenza vaccines, an “Explanatory note on scientific considerations regarding the licensing of pandemic influenza vaccines” (2S).
GENERAL Cardiovascular Thanjan et al. reported the first case of acute myocarditis and pericarditis 2 days after immunization with DTaP, menin gococcal conjugate (MCV4) and hepatitis A vaccines in an adolescent (5A). He recovered within a few days with non-steroidal anti inflammatory drugs and remained clinically stable, with improvement in the MRI scan after 10 weeks. The authors also reviewed cases of myopericarditis related to immuniza tion as reported in the pediatric literature. Cardiac complications after routine immuni zations are extremely rare, especially in chil dren. Smallpox vaccine has received much attention recently, particularly after reinstate ment of vaccination for military personnel in 2002 and the reports of over 50 cases of prob able myocarditis temporally related to it. In a prospective Finnish study there were electro cardiographic changes suggestive of myocar ditis without other evidence of cardiac disease in 3% of military recruits after immunization against mumps, polio, tetanus, smallpox, diphtheria, and type A meningococcus. A few cases of myocarditis after smallpox vaccination have also been reported in the pediatric literature. Other vaccines have been implicated in children, albeit much more rarely. There has been one reported case of myocarditis that developed hours after DTaP immunization in a 3-month-old child and another case of myocarditis after tetanus immunization alone in a 14-year-old child. Respiratory Balicer et al. searched the major medical electronic databases (Medline, National Library of Medicine Gateway and Cochrane Library) for relevant birth-cohort studies and randomized, controlled trials
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from 1966 to March 2006 (6R). They included only studies that directly compared immunized and non-immunized children, validated immunization status by medical charts, and used preset criteria to define asthma. The data were abstracted using a standardized protocol and a computerized report form. The results were analysed by applying a fixed-effects or random-effects model, according to heterogeneity. Sensitivity analyses by scoring criteria were performed. Seven studies of pertussis immunization (in 186 663 patients) and five studies of BCG immunization (41 479 patients) met the inclu sion criteria. There was no statistically signifi cant association between either wP or BCG immunization and incidence rates of asthma during childhood and adolescence. This lack of a significant association proved to be robust on sensitivity analyses for BCG but not for pertussis vaccine. The authors con cluded that currently available data do not support an association, provocative or protec tive, between BCG or wP immunization and risk of asthma in childhood and adolescence.
Mitochondrial diseases and immunization (SEDA-31, 523) The controversy about a possible causal relation between immuniza tion and autism, particularly in the United States USA, continues. A new hypothesis ‘that vaccines cause or contribute to an underlying mitochondrial disorder, which in turn causes autism’ has been discussed (SEDA-31, 516). To answer frequently asked questions in this respect, the CDC (Centers for Disease Prevention and Con trol, Atlanta, GA) has provided answers to the following frequently asked questions (FAQs) on their website (7S): What are mitochondrial diseases or disorders? Mitochondria are tiny parts of almost every cell in your body. Mitochondria are like the power house of the cells. They turn sugar and oxygen into energy that the cells need to work. In mitochondrial diseases, the mito chondria cannot efficiently turn sugar and oxygen into energy, so the cells do not work correctly.
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Is there a relationship between mitochondrial disease and autism? A child with a mitochondrial disease may also have an autism spectrum disorder, may have some of the symptoms/signs of autism, or may not have any signs or symptoms related to autism. A child with autism may or may not have a mitochondrial disease. When a child has both autism and a mitochondrial disease, they sometimes have other problems as well, including epilepsy, problems with muscle tone and/or movement disorders. More research is needed to find out how common it is for people to have autism and a mitochondrial disorder. Right now, it seems rare. In general, more research about mitochondrial disease and autism is needed. Do vaccines cause or worsen mitochondrial diseases? As of now, there are no scientific studies that say vaccines cause or worsen mitochondrial diseases. We do know that certain illnesses that can be prevented by vaccines, such as the flu, can trigger the regression that is related to a mito chondrial disease. More research is needed to determine if there are rare cases where underlying mitochondrial disorders are triggered by anything related to vaccines. However, we know that for most children, vaccines are a safe and important way to prevent them from getting lifethreatening diseases. The United Mitochondrial Disease Foun dation considered the decision of medical eva luators at the Department of Health and Human Services that there was a connection between a child’s autistic symptoms and the vaccines she had received as an infant. The evaluators stated that the child had an under lying mitochondrial disease that was aggra vated by the vaccines, causing the autistic-like symptoms. It was recommended that her family be compensated for the injuries. The United Mitochondrial Disease Foundation, in collaboration with its Scientific and Medical Advisory Board, stated ‘There are no scientific studies documenting that childhood vaccina tions cause mitochondrial diseases or worsen mitochondrial disease symptoms. In the absence of scientific evidence, the Foundation cannot confirm any association between mito chondrial diseases and vaccines’ (8r).
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BACTERIAL VACCINES Meningococcal vaccine
(SED-15, 2250; SEDA-29, 331; SEDA-30, 372; SEDA-31, 519) Nervous system To assess the risk of Guillain–Barré syndrome following admin istration of meningococcal serogroup C-CRM197 conjugate vaccine, provincial immunization records have been linked with hospital discharge records and medical charts in 1.9 million individuals (aged 2 months to 20 years); the observed post-immunization frequencies of Guillain– Barré syndrome were no higher than expected (9c).
Pertussis vaccine (including diphtheria–tetanus–whole cell pertussis vaccine [DTWP]) (SED-15, 2780; SEDA-29, 331; SEDA-31, 520) Respiratory It has been suggested that there is a reduced risk of asthma when DTP immunization is delayed (10H). During its 18th meeting the Global Advisory Committee on Vaccine Safety (GACVS) reviewed this study and considered the approach to be reasonable and the findings a possible signal that require further inves tigation (11S). The committee will assemble all relevant information and discuss the matter in a further meeting.
Susceptibility factors Children During its 18th meeting the GACVS considered the non-specific effects of DTP vaccine on child mortality (12S). The committee was presented with a summary of the presenta tions and discussions from a workshop held in London in April 2008 to consider meth odological issues in the design and analysis of studies of the non-specific effects of immunization. One of the outcomes of the workshop was a consensus that conclusive evidence for or against non-specific effects of vaccines on mortality, including a potential
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deleterious effect of DTP immunization on children’s survival, as has been reported in some studies, was unlikely to be obtained from observational studies (13C, 14C). The committee will keep a watch on the evidence of non-specific effects of immunization.
VIRAL VACCINES Influenza vaccine
(SED-15, 1753; SEDA-29, 332; SEDA-30, 374)
Immunologic There is clear evidence that genetic predisposition is necessary for some autoimmune diseases. In genetically predis posed individuals an infection can induce or trigger an autoimmune disease. Of the many potential environmental factors, infections are the most likely cause. The causal linkage between some infections and autoimmune diseases has raised the question of whether autoimmune diseases might also be triggered by vaccines. The relevant publications have been reviewed (15R). The effects of influenza vaccine in juvenile idiopathic arthritis have been the most studied. There was no increase in disease activity or serious adverse effects.
MMR vaccine and rubella vaccine (SED-15, 2207; SEDA-29, 335; SEDA-30, 375; SEDA-31, 521)
MMR vaccine Nervous system The tired hypothesis that MMR can cause regressive autism has been tested in Japan, where the vaccine was used only between 1989 and 1993, affording a natural experiment. Data on 904 patients with autism spectrum disorders were analysed (16C). During the period of MMR usage there was no significant difference in the incidence of regression between MMRimmunized children and non-immunized children. Hematologic Children who developed purpura and a reduced platelet count below
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30 109/l within 1 month after immuniza tion were collected in a population-based study of 506 consecutive children with newly diagnosed idiopathic thrombocyto penic purpura (17c). Of the 35 such patients, 24 had thrombocytopenia after MMR immunization, giving an estimated risk of idiopathic thrombocytopenic purpura of about 1 in 30 000 MMR immunizations. Symptoms in the 35 patients were nearly always acute. The thrombocytopenia resolved within 1 month in 74% of the patients and lasted longer than 6 months in only 10%. Bleeding episodes were uncommon during the follow-up period. The authors concluded that the incidence of symptomatic thrombocytopenia after immunizations is much lower than after respective natural infections and that the outcome in most cases is excellent. Immunologic There is clear evidence that genetic predisposition is necessary for some autoimmune diseases. In genetically predis posed individuals an infection can induce or trigger an autoimmune disease. Of the many potential environmental factors, infections are the most likely cause. The causal linkage between some infections and autoimmune diseases has raised the question of whether autoimmune diseases might also be triggered by vaccines. The relevant publications have been reviewed (15R). There are no largescale studies on the use of the MMR booster in children with autoimmune diseases. From studies of health authority registries, idio pathic thrombocytopenic purpura was accepted as an adverse effect of MMR, and arthritis has been associated with rubella immunization in young women. As microbial exposure decreases, the role of immunization in educating our immune system increases. In this way, vaccines might prevent infec tions as well as autoimmune diseases.
Rubella vaccine Musculoskeletal An 11-year-old woman, whose systemic juvenile idiopathic arthritis had been in remission for the previous 4 years
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with only small doses of ibuprofen (18A), had an abrupt second relapse with congestive heart failure 5 days after receiving rubella vaccine as primary immunization. Her serum concentrations of anti-rubella immu noglobulin M (IgM) and immunoglobulin G (IgG) antibodies increased, and she had a leukocytosis and raised serum concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), and other inflammatory cytokine pro files, similar to the findings observed during her previous active disease. After administra tion of a steroid pulse, ibuprofen, methotrex ate, and a phosphodiesterase inhibitor, her symptoms, such as fever, heart failure, and arthralgia, gradually improved. However, her intermittent fever and increased serum con centrations of CRP and IL-6 were sustained for more than 2 years, and this prolonged active clinical course therefore differed from her previous active disease. This abrupt relapse only 5 days after immuniza tion was suggested not to have been directly related to rubella infection, but instead to molecular mimicry between rubella and juvenile idiopathic arthritis. Teratogenicity The GACVS has discussed a large amount of data available on pregnancy outcomes among women inadvertently immunized with rubella vaccine in several countries (Germany, the Islamic Republic of Iran, the UK, and the USA). These data arose from both retrospective and prospec tive cohorts, and from case–control studies done in the context of routine administra tion or mass immunization campaigns. The time of immunization in relation to the time of conception varied across the studies. No neonates had congenital rubella syndrome, despite evidence that a few had infection with the vaccine virus (defined as IgM posi tivity). The Committee also considered newly reported data from five Latin Amer ican countries (Brazil, Costa Rica, Ecuador, El Salvador, and Paraguay). A total of 29 663 women who had been inadvertently immunized were identified; 3264 of them were susceptible to rubella. Of those who were susceptible, 2236 were followed and IgM measured; 68 (3%) potential fetal
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infections were identified, none of which manifested as congenital rubella syndrome. There was no increased risk of additional abnormalities compared with the expected background rates of congenital malforma tions in the population. The committee con cluded that these data support World Health Organization (WHO’s) statement that inad vertent immunization of women just before conception or during pregnancy poses little, if any, risk to the developing fetus. However, fetal infections have been documented and, although they have not been associated with congenital rubella syn drome, rubella immunization should still be avoided in pregnancy as a precautionary measure (19S).
Rabies vaccine
(SED-15, 301)
Observational studies On 20 October 1997, the FDA licensed a purified chick embryo cell (PCEC, RabAvert®) vaccine against rabies in humans. From October 1997 to December 2005, the Vaccine Adverse Event Reporting System (VAERS) received 336 reports of adverse events after immunization with PCEC vaccine in the United States USA; there were no deaths (20c). Serious events, including 20 hospitalizations and 13 neurological events, were described in 24 reports (7%). There was no pattern among the 13 neurological adverse events to suggest a plausible relation to immunization. A total of 20 adverse events, 3 serious, were classified as possible anaphylaxis. There were 312 non-serious adverse events (93%). In 19 cases (6%) immunization was discontinued because of non-serious adverse events. Most reported adverse events are nonserious and consistent with pre-licensure safety data.
Smallpox vaccine
(SED-15, 3150)
Cardiovascular Among 37 901 smallpox vaccinees, 10 had ischemic cardiac events, with symptoms a median of 10 days after
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immunization (range 0–28 days) (21c). The 10 patients were aged 42–65 years, and 6 were men. Seven had at least three cardiac risk factors or probable coronary artery disease before immunization. Two women, aged 55 and 57 years, had acute myocardial infarctions and fatal cardiac arrests. The background rates of ischemic cardiac events during a 3-week period for age- and sex-matched controls were estimated. The observed number of myocardial infarctions exceeded estimated expectations (five versus two) but was within the 95% predictive interval (0.6–5.4). New-onset angina was significantly less common than estimated expectations (1 versus 10; 95% predictive interval = 3.5, 16). After those with at least three cardiac risk factors or known heart disease were deferred from immunization, no ischemic cardiac events were reported among an additional 6638 vaccinees. Of over 39 000 civilian public health responders immunized against smallpox in 2003, 203 reported cardiovascular adverse events. There is an association between the US vaccinia strain and myocarditis and/or pericarditis; other associations are inconclu sive (22c). The authors used surveillance and follow-up survey data of patients with adverse events to estimate the resources used during the 2003 smallpox immuniza tion programme and used a probabilistic model to estimate the potential costs of such cardiovascular adverse events in a mass immunization campaign. For every million adult vaccinees, 3001 cardiovascular events (including 351 cases of myocarditis or pericarditis) would occur, over 92% in revaccinees. In a mass immunization cam paign, the care of a sizable number of patients would be resource-intensive. Vaccinia virus is the live viral component of smallpox vaccine. The Advisory Commit tee on Immunization Practices (ACIP) has recommended smallpox vaccination for laboratory workers who handle non-highly attenuated vaccinia virus strains or other orthopoxviruses (e.g. monkeypox, cowpox, or variola). Inadvertent vaccinia virus infection has been reported after smallpox vaccination (23A).
583 • On 5 July 2008, a man in his twenties who worked in a laboratory at an academic institution in Virginia went to a local urgent care clinic. He reported swelling of the cervical lymph nodes and pain and inflammation of his right earlobe with a purulent discharge, a feverish feeling, and swelling of his left eye, without change in vision. One day later, he had noted pustular lesions at similar stages of development on his right ear and left eye, and on his chest, shoulder, left arm, and right leg. He had right auricular cellulitis and suspected periorbital cellulitis. Vaccinia virus infection was confirmed and he made a full recovery after antiviral medication.
As a result of this incident, the academic institution now offers counselling and educa tion to all personnel with occupational expo sure to vaccinia virus. Vaccination is then offered to laboratory workers without medi cal contraindications, and a form is com pleted by laboratory workers who decline. In addition, changes have been made to the academic institution’s laboratories to better reflect CDC’s biosafety recommendations. Since 2003, the US Department of Agri culture’s Wildlife Services has coordinated a multistate oral rabies immunization pro gramme for wildlife. The programme uses baits containing liquid vaccinia–rabies glycoprotein recombinant virus vaccine. Because contact with ruptured baits can produce human vaccinia virus infection, human and domestic animal contact with the baits is surveyed (24A). • In August 2009, a 35-year-old woman with inflammatory bowel disease was picking blackberries in a rural area where oral rabies baits had recently been distributed. Her dog picked up a bait in his mouth and punctured the bait with his teeth. After the dog had dropped the bait, the woman picked it up, and the vaccine dripped on to her right hand and wrist, including sites that had been abraded by blackberry thorns. Nine days later, she had 26 classic vaccinia virus lesions, including one on her right arm that might not have been in contact with the vaccine initially. She had myalgia and headache, pronounced redness and edema in her right hand, and right axillary adenopathy. The scrapings were positive for non-variola orthopoxvirus DNA, and vaccinia virus DNA and rabies virus G protein DNA were found in the papules. There was serological evidence of rabies virusneutralizing antibodies. In an attempt to reduce viral replication and prevent progressive
584 vaccinia, she was given two doses of vaccinia immunoglobulin 6000 IU/kg plus the investigational antiviral agent ST-246 (SIGA Technologies, Corvalis, Oregon) orally for 14 days. By day 28, all the scabs from her lesions had separated and her underlying inflammatory bowel disease condition was stable.
Varicella vaccine and herpes zoster vaccine (SED-15, 3606; SEDA-26, 360; SEDA-31, 522) The varicella zoster virus causes two distinct diseases: varicella (chicken pox) and herpes zoster (shingles). The vaccines that are used to prevent these two diseases are based on the same varicella zoster virus, but each has a different virus content. Varivax®, a live attenuated varicella vaccine, is indicated for immunization against varicella in indivi duals aged at least 12 months; it contains a minimum of 1350 (103.13) plaque-forming units per dose. ZostavaxTM, a live attenu ated varicella zoster virus vaccine, is indi cated for immunization against herpes zoster; it consists of the same Oka/Merck strain as Varivax®, but it contains a minimum of 19 400 (104.29) plaque-forming units per dose and is about 14 times more potent than Varivax® (25R). The former is known as varicella zoster vaccine (VZV), and the latter as herpes zoster vaccine (HZV).
Varicella vaccine Observational studies The 10-year safety profile for Varivax has been described using data submitted to the manufacturer (Merck) from routine global post-marketing surveil lance, combined with information from a varicella zoster virus identification pro gramme, which uses polymerase chain reac tion (PCR) analysis to identify the presence and strain of varicella zoster in selected specimens (26C). Worldwide, 16 683 reports were voluntarily submitted to Merck, an overall reporting rate of 3.4 reports per 10 000 doses of vaccine distributed. PCR analysis of the vesicular rashes that occurred within the first 2 weeks after immunization
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was more likely to identify wild-type vari cella zoster, whereas the presence of Oka varicella zoster was generally associated with vesicular rashes that occurred 15–42 days after immunization. Reports of break through varicella that occurred more than 42 days after immunization were associated with wild-type varicella zoster. Among 697 reports of herpes zoster infections, PCR analysis identified Oka varicella zoster in 57 and wild-type varicella zoster in 38 reports. There were no primary neurologi cal adverse events associated with Oka var icella zoster, but there was secondary transmission from vaccine recipients with post-immunization vesicular rashes in three susceptible household contacts. Dissemi nated Oka varicella zoster was identified in six immunocompromised patients and in one patient with Down’s syndrome. Susceptibility factors Children Exposure of immunocompromised children to varicella often requires post-exposure prophylaxis, but exposures that require this are often not recognized. Varicella can be a severe disease when it occurs in immunocompromised chil dren, in spite of antiviral therapy. Varicella exposure and varicella in these children can also disrupt scheduled therapy for the under lying illness. Both post-exposure prophylaxis and treatment of varicella are likely to be expensive and use significant medical re sources. Trials of varicella vaccine in immuno compromised children reported since 1975 have been analysed, separately for children with leukemia and other malignancies, HIVinfected children, children with hemopoietic stem cell transplantation and children with solid-organ transplantation (27R). Varicella developed in 36 leukemic vac cine recipients during a variable observation period that was as long as 9 years. Of the 27 who did not receive varicella zoster immuno globulin, 78% had mild disease, 18% had moderate disease, and 1 had severe disease, indicating that immunization attenuated subsequent wild-type infection. Only two children subsequently received aciclovir. There were 11 cases of varicella after 83 household exposures for which varicella
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zoster immunoglobulin was not adminis tered. Compared with historical attack rates, this represented 86% protection against any diseases; none of these break through cases was severe. The rate of leu kemia relapse was not altered by varicella immunization. Subsequent studies of vac cine recipients with leukemia showed that herpes zoster infection is at least 2.5-fold less likely in vaccine recipients than in matched control subjects who had prior nat ural varicella. There was fever in 40% of the children, but less than 5% of the fevers reached 39.4°C. Adverse events were similar to those seen in non-infected children and were less frequent after the second dose. CD4 cell counts and viral load were not altered by immunization. Varicella zosterspecific antibody was present in 59–72% of vaccine recipients (depending on immune status) after two doses and in 43–65% after 1 year. A similar percentage with detectable antibody was found in a comparator group of HIV-infected children who had had natural varicella (instead of vaccine) in the previous year. In children with hemopoietic stem cell transplants, the primary response to immuni zation is markedly depressed for a long time, but generally less long after autologous trans plantation, primarily because the amount and duration of immunosuppressive therapy are smaller. The clinical and immunological out comes of children with solid tumors were similar to those in acute leukemia. Cutaneous manifestations of immunization occurred in about 10% of the children, and there were no cases of severe disease. Seroconversion occurred in 90–95% of the children, except in those with malignant lymphoma, of whom four of eight vaccine recipients developed severe vaccine-related varicella. Giving two doses of varicella vaccine before transplanta tion is the optimal approach to the problem of varicella in renal transplant recipients. Immu nization before and selectively after liver transplantation appears to be an equally use ful approach. Teratogenicity Data from the Pregnancy Registry for Varivax (Merck) haved been
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analysed (28C). The registry was established to monitor congenital varicella syndrome or other birth defects in the offspring of women who were exposed to varicella vac cine while pregnant. The registry receives voluntary reports from health-care providers or consumers about women who have been given the vaccine 3 months before or during pregnancy. Follow-up is conducted to obtain and classify pregnancy outcomes. From 17 March 1995 to 16 March 2005, 981 women were enrolled and pregnancy outcomes were available for 629 of them. Among the 131 live births to varicella zoster seronegative women, there were no cases of congenital varicella syndrome (95% CI = 0, 6.7), and there were major birth defects in three infants (3.7%; 95% CI = 0.8, 11). Although the numbers of exposures were insufficient to rule out a very low risk, data collected in the pregnancy registry to date do not support a relation between congenital varicella syndrome or other birth defects and varicella vaccine exposure during pregnancy.
Herpes zoster vaccine Herpes zoster (shingles) and post-herpetic neuralgia cause significant morbidity in older adults. The incidence and severity increase with age in association with an age-related decline in varicella zoster virus-specific cell-mediated immunity. The hypothesis that herpes zoster vaccine would protect older adults against herpes zoster and post-herpetic neuralgia has been tested in a randomized, double-blind, placebo-controlled trial in 38 546 adults over 60 years of age, of whom 19 270 received herpes zoster vaccine and 19 276 received placebo; 6.6% of the vaccine reci pients and 6.9% of the placebo recipients were over 80 years of age (29C). The pri mary end point was the burden of illness due to herpes zoster, a composite measure of the incidence, severity and duration of pain and discomfort caused by herpes zos ter. The secondary end point was the inci dence of post-herpetic neuralgia. Herpes zoster vaccine reduced the burden of illness
586
due to herpes zoster by 61% and the inci dence of post-herpetic neuralgia by 67%. The incidence of herpes zoster was reduced by 51%. Death rates were comparable in the vaccine and placebo recipients (4.1%), and during the first 42 days after immuniza tion the proportions of vaccine and placebo subjects with at least one serious adverse event were also similar (1.4%). The most frequent injection-site events reported by vaccine recipients were erythema (36%), pain or tenderness (35%), swelling (26%), and pruritus (7%). Injection-site rashes were significantly more common with vaccine than placebo, but rashes at other locations occurred at similar rates.
Yellow fever vaccine
(SED-15, 3703; SEDA-28, 366; SEDA-30, 336; SEDA-31, 523)
Nervous system The Yellow Fever Working Group has reviewed neurological adverse events after yellow fever immunization that were reported to the national Vaccine Adverse Events Reporting System (VAERS) (30c). Based on defined criteria, five cases of encephalitis were classified as ‘definitely’ caused by the vaccine and one case of acute disseminated encephalomyelitis was defined as ‘probably’ caused by the vac cine. Six cases of Guillain–Barré syndrome, one of encephalitis, and two of acute dissemi nated encephalomyelitis were classified as ‘suspect’ vaccine-associated diseases. Labora tory and epidemiological evidence suggested that yellow fever vaccine caused encephalitis. Gastrointestinal The GACVS has considered an update of the evidence regarding the safety of 17D yellow fever vaccines, focusing on serious adverse events, including hypersensitivity reactions, vaccine-associated viscerotropic disease, and vaccine-associated neurotropic disease (31S). Globally there are data on 43 welldocumented cases of viscerotropic disease, since this rare but serious adverse reaction was first recognized in 2001. Based on
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genomic sequencing of retained samples from one patient, the earliest confirmed occurrence of viscerotropic disease dates back to 1975. Among these 43 cases, there were four fatal cases and one survivor among 63 174 people immunized in the Ica region of Peru after a yellow fever immunization campaign conducted in September–October 2007 after a major earthquake. All five cases in the Ica region received one particular lot of yellow fever vaccine and were among an estimated 42 742 individuals who received vaccine from the same lot during the campaign. No other cases occurred among the 20 432 people immunized in the Ica region with a second vaccine lot. The committee noted that this was the first time that multiple cases of viscerotropic disease had been detected in a short time and associated with a single lot of vaccine. In addition, the incidence of viscerotropic disease in this situation, which was estimated as 12 per 100 000 immunized (based on the number of people receiving the vaccine lot associated with the five cases) or 8 per 100 000 (based on all those immunized in the Ica region), was more than 20 times higher than the risk previously associated with 17D vaccines in general. The committee considered the clinical and virological findings from the investigation, the overall epidemiological evaluation of adverse events that occurred during the campaign, review of the vaccine quality and production at the manufacturing facility and the conclusions of an expert panel convened by the Pan American Health Organization and WHO to assist the investigation. A known susceptibility factor (age) was present in one case (a 79-year-old man), and a potential risk factor was identified in a 49-year-old woman (a past history of rheumatoid arthritis and systemic lupus erythematosus and treatment with methotrexate and dexamethasone starting 4 days after immunization). The other cases did not appear to have susceptibility factors or altered immune states that may have contributed to their illness or its outcome. The committee noted that these cases occurred among a population naive for yellow fever infection or immunization.
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However, this does not explain the higher incidence when compared with other naive populations in the USA and other nonendemic regions where yellow fever vaccine-associated viscerotropic disease has been reported. Furthermore, experience with approximately 3 million doses of vaccine (albeit different 17D vaccine products) in immunization campaigns during 2007–2008 among other naive populations in Latin America (Argentina and Paraguay) has not resulted in any reported cases of viscerotropic disease. The cause of the cluster of cases in Ica is not clear. Vaccine evaluation showed that the lot administered (as well as its sister lots) met all quality specifications, and the yellow fever virus isolated from three confirmed cases was consistent with the vaccine virus and did not appear to have mutated. About 72 000 doses of the vaccine lot common to the cases of viscerotropic disease were confirmed to have been used elsewhere in Latin America without additional cases. Also, about 2 million doses from sister lots were distributed for use elsewhere in Latin America, again without any reports of viscerotropic disease. In summary, the committee concluded that the high incidence of viscerotropic disease in Peru remains unexplained. The evidence suggests potential differences in the incidence of adverse events in regions where yellow fever is endemic (0–0.21 per 100 000 doses) and in naive populations (0.09–0.4 per 100 000 doses), which are probably related to population differences (for example, previous immunization or exposure to wild yellow fever virus). However, with the exception of the cases in Peru, data from other settings show that the estimated incidence of
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viscerotropic disease is up to 0.4 cases per 100 000 doses. The committee noted and supported initiatives by WHO and other global partners to obtain better estimates of rates and better prediction of risks, including efforts being undertaken to enhance surveillance and evaluation of serious adverse events in mass yellow fever immunization campaigns in endemic regions in Africa and Latin America. An international laboratory network has been established with a goal of ensuring systematic and coordinated laboratory evaluation of reported cases. This initiative may help in elucidating the cause and pathogenesis of yellow fever vaccine-associated viscerotropic disease and neurotropic disease and an understanding of the relative contributions of vaccine factors versus host factors. The committee reiterated that recommendations for the use of yellow fever vaccine should remain unchanged. The vaccine should be administered only to travellers who are truly at risk of exposure. Furthermore, in communicating the risks, it should be acknowledged that the balance of benefit to harm may differ for immunization of travellers and immunization of populations living in at-risk areas.
OTHER COMPONENTS OF VACCINES Thiomersal
(SED-15, 2259; SEDA-29, 230; SEDA-30, 268; SEDA-31, 391) See Chapter 22.
References 1. Kunder S Regulatory aspects of the nonclinical safety assessment of adjuvanted preventive vaccines. http://www.fda.gov 2. European Medicines Agency. Pandemic influenza A(H1N1)v vaccines authorised via
the core dossier procedure. Explanatory note on scientific considerations regarding the licensing of pandemic A(H1N1)v vaccines. http://www.emea.europa.eu/pdfs/human/ pandemicinfluenza/60825909en.pdf
588 3. US Food and Drug Administration. October 16, 2009 Approval Letter – Cervarix. http:// www.fda.gov/BiologicsBloodVaccines/%20 Vaccines/ApprovedProducts/ucm186959.htm 4. European Medicines Agency. Guideline on adjuvants in vaccines for human use. http://www.emea.europa.eu/pdfs/human/vwp/ 13471604en.pdf 5. Thanjan MT, Ramaswamy P, Lai WW, Lytrivi ID. Acute myopericarditis after mul tiple vaccinations in an adolescent: case report and review of the literature. Pediatrics 2007;119:e1400–3. 6. Balicer RD, Grotto I, Mimouni M, Mimouni D. Is childhood vaccination associated with asthma? A meta-analysis of observational studies. Pediatrics 2007;120:e1269–77. 7. Centers for Disease Control and Prevention (CDC). Mitochondrial disease. Frequently asked questions. http://www.cdc.gov/ncbddd/ autism/mitochondrial-faq.html 8. United Mitochondrial Disease Foundation. Statement. http://www.umdf.org 9. De Wals Ph, Deceuninck G, Boucher RM, Ouakki M. Brief report. Risk of Guillain– Barré syndrome following serogroup C meningococcal conjugate vaccine in Quebec, Canada. Clin Infect Dis 2008;46:e75–7. 10. McDonald KL, Huq SI, Lix LM, Becker AB, Kozyrskyj AL. Delay in diphtheria, pertussis, tetanus vaccination is associated with a reduced risk of childhood asthma. J Allergy Clin Immunol 2008;121:626–31. 11. Global Advisory Committee on Vaccine Safety. Diphtheria–tetanus–pertussis vaccine and asthma. Meeting of Global Advisory Committee on Vaccine Safety, 18–19 June 2008. Wkly Epidemiol Rec 2008;83:290. 12. Global Advisory Committee on Vaccine Safety. Non-specific effects of DTP vaccine on child mortality. Meeting of Global Advisory Committee on Vaccine Safety, 18–19 June 2008. Wkly Epidemiol Rec 2008;83:290. 13. Jensen H, Benn CS, Lisse IM, Rodrigues A, Andersen PK, Aaby P. Survival bias in observational studies of the impact of routine immunizations on childhood survival. Trop Med Int Health 2007;12:5–14. 14. Aaby P, Benn CS, Nielsen J, Lisse IM, Rodrigues A, Jensen H. DTP vaccination and child survival in observational studies
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with incomplete vaccination data. Trop Med Int Health 2007;12:15–24. 15. Heijstek MW, Wulffraat NM. Vaccination in autoimmune diseases: a blessing in disguise? Future Rheumatol 2007;2:153–62. 16. Uchiyama T, Kurosawa M, Inaba Y. MMRvaccine and regression in autism spectrum disorders: negative results presented from Japan. J Autism Dev Disord 2007;37:210–7. 17. Rajantie J, Zeller B, Treutiger I. Vaccination associated thrombocytopenic purpura in chil dren. Vaccine 2007;25:1838–40. 18. Korematsu S, Miyahara H, Kawano T. A relapse of systemic type juvenile idiopathic arthritis after a rubella vaccination in a patient during a long-term remission period. Vaccine 2009;27:5041–2. 19. Global Advisory Committee on Vaccine Safety. Pregnancy outcomes after inadver tent immunization with rubella vaccine. Meeting of Global Advisory Committee on Vaccine Safety, 18–19 June 2008. Wkly Epi demiol Rec 2008;83:290–1. 20. Dobardzic A, Izurieta H, Woo EJ, Iskander J, Shadomy S, Rupprecht C, Ball R, Braun MM. Safety review of the purified chick embryo cell rabies vaccine: Data from the Vaccine Adverse Event Reporting System (VAERS), 1997–2005. Vaccine 2007;25:4244–51. 21. Swerdlow DL, Roper MH, Morgan J, Schieber RA, Sperling LS, Sniadack MM, Neff L, Miller JW, Curtis CR, Marin ME, Iskander J, Moro P, Hightower P, Levine NH, McCauley M, Heffelfinger J, Damon I, To¨ ro¨ k TJ, Whar ton M, Mast EE, Mootrey GT Smallpox Vac cine Cardiac Adverse Events Working Group., Ischemic cardiac events during the Department of Health and Human Services Smallpox Vaccination Program, 2003. Clin Infect Dis 2008;46:S234-41. 22. Ortega-Sanchez IR, Sniadack MM, Mootrey GT. Economics of cardiac adverse events after smallpox vaccination: lessons from the 2003 US vaccination program. Clin Infect Dis 2008;46:S168–78. 23. Centers for Disease Control and Prevention (CDC). Laboratory-acquired vaccinia virus infection – Virginia, 2008. MMWR Morb Mortal Wkly Rep 2009;58:797–800. 24. Centers for Disease Control and Preven tion (CDC). Human vaccinia infection after contact with a raccoon rabies vaccine
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bait – Pennsylvania, 2009. MMWR Wkly Epidemiol Rep 2009;58:1204–7. 25. Harpaz R, Ortega-Sanchez IR, Seward JF. Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC). Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2008;57(RR-5):1–30. 26. Galea SA, Sweet A, Beninger P. The safety profile of Varicella vaccine: a 10-year review. J Infect Dis 2008;197:S165–9. 27. Levin MJ. Varicella vaccination of immuno compromised children. J Infect Dis 2008;197: S200–6. 28. Wilson E, Goss MA, Marin M, Shields KE, Seward JF, Rasmussen SA, Sharrar RG. Varicella vaccine exposure during pregnancy:
589 data from 10 years of the pregnancy registry. J Infect Dis 2008;197:S178–84. 29. Oxman MN, Levin MJ. Shingles Prevention Study Group., Vaccination against herpes zoster and postherpetic neuralgia. J Infect Dis 2008;197:S228–36. 30. McMahon AW, Eidex RB, Marfin AA, Russell M, Sejvar JJ, Markoff L, Hayes EB, Chen RT, Ball R, Braun MM, Cetron M. Yellow Fever Working Group., Neurologic disease associated with 17D-204 yellow fever vaccination: a report of 15 cases. Vaccine 2007;25:1727–34. 31. Global Advisory Committee on Vaccine Safety. Safety of yellow fever vaccine. Meeting of Global Advisory Committee on Vaccine Safety, 18–19 June 2008. Wkly Epidemiol Rec 2008;83:s287–9.
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33
Blood, blood components, plasma, and plasma products
(SED-15, 54; SEDA-29, 338; SEDA-30, 381; SEDA-31, 527)
ALBUMIN
Observational studies In a prescription monitoring study in three hospitals of 187 patients who received 426 prescriptions for a total of 21 094 g of albumin for hypoalbu minaemia, plasmapheresis, and ascites or hepatorenal syndrome, no adverse events were attributed to albumin (1C). Comparative studies In a randomized study in which 67 patients with hepatic cirrhosis and hepatorenal syndrome were given intravenous terlipressin 1–2 mg 4-hourly þ albumin 1 g/kg followed by 20–40 g/day was compared with albumin alone (2C). Adverse events in the two groups included myocardial ischemia, dys rhythmias, intestinal ischemia, circulatory overload, bacterial infections, hepatic en cephalopathy, and arterial hypertension, among others. There was no statistical difference in the incidences of adverse events, but the authors noted that this is a population that is susceptible to severe complications. Systematic reviews A systematic review of 25 randomized clinical trials of hyperoncotic Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32033-2 2010 Elsevier B.V. All rights reserved.
albumin in 1485 patients has suggested that it might increase the risk of pulmonary edema and capillary leak. However, it is uncertain whether this was a risk of albumin per se or of fluid overload (3M).
ANTICOAGULANT PROTEINS (SED-15, 266; SEDA-29, 338; SEDA-30, 381; SEDA-31, 527)
The benefit to harm balance of drotrecogin alfa (activated) Hemorrhage is a potentially serious adverse effect of drotrecogin. There has been a great deal of discussion about whether the benefits outweigh the risk of harm. Of 261 consecutive patients who received drotrecogin in a multicenter study there was serious bleeding in 10%, of whom one had a fatal intracranial bleed (4 c). Multiple organ system failure and relative contraindications to drotrecogin were predictors of bleeding events. In a retrospective analysis of patients who received drotrecogin, serious adverse events occurred in 7.5% compared with 6.3% in the placebo-treated group (OR = 1.41; 95% CI = 0.89, 2.25) (5c). Patients who received drotrecogin had a higher risk of serious bleeding events during the infusion period, but most were treated without fatal conse quences. [This is the corrected version of a paper that was discussed in SEDA-31, 527, reference 6.] Others have calculated the odds ratios for bleeding from the published data and have con cluded that bleeding among surgical patients
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during infusion occurred in 4.9% of those who were given drotrecogin and 0.5% of those given placebo, whereas among non-surgical patients, bleeding occurred in 2.6% versus 1.0% respec tively (6r). The odds ratio for bleeding among surgical patients was about 10 times higher in those given drotrecogin (OR = 11, 95% CI = 2.7, 45) whereas among non-surgical patients it was only 2.7 (95% CI = 1.3, 5.6). The data provided by the original authors, pub lished later, were broadly similar and the risks of bleeding (odds ratios) at 28 days were 3.94 (1.97, 7.87) and 2.24 (1.31, 3.84) in surgical and non-surgical patients respectively (7 r). In another study in patients with severe sepsis who received drotrecogin (n = 3228) or placebo (n = 1231), serious bleeding was more common during infusion of drotrecogin (3.5% versus 0.8%) (8C). In a subsequent interrogation of INDEPTH, an integrated database of five trials in patients with severe sepsis, detailing 3228 patients who received drotrecogin and 1231 who received placebo for 96 hours, 13% of the former had at least one serious adverse event compared with 14% of the latter (9 c). There were serious bleed ing events in 5.6% versus 2.0%, a highly signif icant difference, and non-bleeding-related serious adverse events in 8.6 and 13%, also sig nificant. Those who received drotrecogin had fewer thrombotic events. Deaths In a pharmacovigilance programme in intensive care units in Italy, 668 patients who had been treated with drotrecogin were revie wed (10 c). The control group consisted of pa tients who were eligible for treatment with drotrecogin but had not received it. There was bleeding during infusion in 73 patients (11%), and a higher mortality rate in those with bleed ing (58 versus 45). Crude mortality was lower in those who received drotrecogin, but multi variate analysis showed that drotrecogin was associated with higher mortality after surgery. However, in an international 1-year followup of 2640 low-risk patients with severe sepsis who participated in a placebo-controlled study of drotrecogin, the difference in mortality rate between drotrecogin and placebo was less at 1 year (34.2 and 34.0% respectively) than at 28 days (18.5 and 17.0%), although neither differ ence was significant (11c). In the subgroups
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defined by organ dysfunction class (single or multiple) and Acute Physiology and Chronic Health Evaluation II score (less than 25 or 25 or more), the differences in mortality rate between treatment groups at 1 year were con sistent with those observed at 28 days. No addi tional serious adverse events were reported during the time between hospital discharge and 1 year. Reviews In the light of all these results, the benefit to harm balance of drotrecogin has been assessed (12R). Bleeding is undoubtedly more common with drotrecogin than placebo recipi ents, although many of the additional episodes of bleeding are related to the procedure and are more likely in surgical patients. The authors felt that bleeding did not outweigh the benefits of drotrecogin, although they did caution, reason ably, that since those with more severe illnesses were at greater risk of bleeding careful selection of patients is important. The authors of a review of the main trials of drotrecogin–PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis), ENHANCE (Extended Evaluation of Recombinant Human Activated Protein C, drotrecogin alfa [activated]), ADDRESS (Efficacy and Safety of Drotrecogin alfa [activated] in Adult Severe Sepsis Patients at Low Risk of Death), and XPRESS (Xigris and Prophy lactic Heparin Evaluation in Severe Sepsis)— came to a very similar conclusion (13R). PROWESS included 850 patients who were given drotrecogin and 840 who were given placebo (14C). There was at least one serious adverse event in 12% of the former and 13% of the latter. The respective rates of at least one bleeding event were 25 and 18%. Most of the bleeding events were ecchymosis or gastroin testinal tract bleeding and were not thought to be serious. The difference in the incidence of serious bleeding events occurred primarily during drug administration. ADDRESS involved 1317 patients with dro trecogin and 1293 with placebo (15C). There was at least one bleeding event in 11 and 6.4% respectively. The numbers of serious bleeding events during infusion were 31 (2.4%) 15 (1.2%). The numbers of patients with central nervous system bleeding during infusion were 4
Blood, blood components, plasma, and plasma products
(0.3%) and 3 (0.2%) respectively. Recent sur gery (within 30 days before administration) was associated with a higher risk of serious bleeding during infusion in both groups, but the differ ence was not significant. ENHANCE was a single-arm, open trial in 2378 adults with severe sepsis (16c). The rate of serious bleeding events was highest during the post-infusion period, suggesting a higher baseline risk for bleeding in ENHANCE than in PRO WESS. These patients had more hematolo gical and hepatic dysfunction, both of which are associated with an increased risk of bleeding. XPRESS was an open study in which all patients received drotrecogin, and it included patients with severe sepsis and more severe disease than in previous studies (17 c). Ser ious bleeding rates were similar to those observed in previous studies and prophylac tic heparin compared with placebo did not increase the risk (2.3 and 2.5% respectively), including nervous system bleeding (0.3% in both arms). However, those who received prophylactic heparin had a significantly higher rate of non-serious bleeding (8.7% versus 5.7%). The authors of this review reiterated the advice that patients be carefully chosen, and they published detailed guidelines for interrupting treatment with drotrecogin infusion when carrying out invasive proce dures, such as inserting intra-arterial and intravenous lines, in order to reduce the risks of bleeding. They recommended with holding drotrecogin 2 hours before any of the following: insertion of an arterial line; insertion of an intravenous femoral line or central venous catheters via compressible or non-compressible sites; re-intubation (tube change); insertion of a chest drain; gastroscopy; lumbar puncture; insertion of an epidural catheter; nephrostomy; para centesis; percutaneous drainage; sinus puncture; tracheostomy, wound debride ment; or any major surgical procedure. In most cases they also recommended waiting a further 2 hours before restarting treatment after the procedure and 12 hours after a major surgical procedure.
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BLOOD TRANSFUSION (SED-15, 529; SEDA-29, 338; SEDA-30, 381; SEDA-31, 528) Blood component transfusion, including ery throcyte concentrates, platelet concentrates, and fresh frozen plasma, is associated with adverse effects, some of which are severe or even lethal. Recent reports of several national hemovigilance offices include febrile non-hemolytic transfusion reactions, acute hemolytic transfusion reactions, delayed hemolytic transfusion reactions, transfusionrelated acute lung injury (TRALI), posttransfusion purpura, transfusion-associated graft-versus-host disease, acute allergic and anaphylactic reactions, other allergic reactions, transfusion-associated circulatory overload (TACO), viral infections, bacterial contami nation, hemosiderosis, and new allo-antibody formation (18S–23S). Respiratory Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related mortality and is believed to be widely under-diagnosed (24c, 25c). TRALI is defined new acute lung damage that occurs during or within 6 hours after transfusion, as indicated by the presence of hypoxemia and bilateral infiltrates seen on frontal chest radiography, in the absence of circulatory overload. Transfusion of plasma from female donors rather than male donors, the number of pregnancies among donors, the number of donor units positive for antigranulocyte antibodies and anti-HLA class II antibodies, and the concentration of lyso phosphatidylcholine in the donor product are susceptibility factors for TRALI.
BLOOD SUBSTITUTES (SEDA-29, 340; SEDA-30, 383; SEDA-31, 531) The development and current status of blood substitutes, including hemoglobin-based oxygen carriers and perfluorocarbons, have been reviewed (26R).
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Hemoglobin-based oxygen carriers can provide potential benefits when erythrocytes are unavailable, although in developed coun tries blood is generally available. Universal compatibility with all blood types, freedom from disease transmission and prolonged sto rage must be offset against unexplained bio chemical actions and a lack of knowledge regarding the underlying mechanisms of the harms. Information on adverse events of new compounds has not yet reached the public domain or is debated for lack of consistency or scientific merit. Nevertheless, adverse events can include hypertension, dysrhyth mias, gastrointestinal problems, pancreatitis, and rises in liver enzyme (27R).
Perfluorocarbons Nervous system In 36 adults who under went cardiac surgery the perfluorocarbon emulsion, AF0144 (Perflubron, Alliance Phar maceutical Corp., San Diego, CA) 1.8 or 2.7 g/kg, was used in conjunction with acute normo volemic hemodilution (28c). Both doses of AF0144 increased cerebral blood flow but the numbers of cerebral emboli were greater in those who were given high-dose AF0144 compared with placebo during the time from aortic cannulation to aortic cross-clamp place ment and from aortic cross-clamp placement to cross-clamp removal. However, the pre sence of these emboli has been debated. It was pointed out that an automated transcranial Doppler ultrasound device was used, a technique that is directly affected by the presence of perfluorocarbon in the blood stream (29r). This interference was not correc ted for in the original study design, warranting caution about the original conclusion, since the emboli failed to have any clinical effect.
(SED-15, 2847; SEDA-29, 340; SEDA-30, 383; SEDA-31, 532)
PLASMA PRODUCTS
Antithrombin III Antithrombin III is promising in mild or severe veno-occlusive disease. In a
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retrospective series of 48 patients directed at early intervention rather than prophylactic therapy to correct the antithrombin deficiency associated with veno-occlusive disease, there was no treatment-related morbidity; specifi cally, there were no overt complications such as bleeding or thrombosis (30c). In critically ill patients, a systematic review of 20 clinical trials in 3458 patients who were given antithrombin III, placebo, or no treatment showed that antithrombin III was ineffective in reducing overall mortality, but increased the risk of bleeding events (31M, 32r).
C1 inhibitor concentrate Hereditary angioedema, which is effectively and safely treatable with C1 esterase inhibi tor concentrates, continues to constitute a significant burden of disease to those affected even in the industrialized world. Other therapeutic indications for C1 ester ase inhibitor concentrates relating to inflammatory disease other than are cur rently being studied, including post ischemic myocardial protection, capillary leak syndrome, and sepsis (33R, 34R). The main adverse effects of C1 esterase inhibi tor concentrate, although very rare, are allergic reactions. In a study of the beneficial effects of C1 esterase inhibitor concentrates in ST-elevation myocardial infarction in patients undergoing surgical reperfusion, no adverse events were reported (35C).
PLASMA SUBSTITUTES (SEDA-27, 353; SEDA-29, 340; SEDA-30, 384; SEDA-31, 533) Controversy over the use of colloids continues. Difficulties in assessment lie in comparing var ious patients groups and their clinical state (36R). However, there is evidence that early volume restoration can cause lead to acceler ated blood loss, hypothermia, and dilutional coagulopathy (37r, 38r). A Cochrane review comparing albumin, gelatine, dextran, and
Blood, blood components, plasma, and plasma products
hydroxyethyl starches has not provided clarity on one safety profile over another (39M).
Dextrans Urinary tract Acute renal failure has been described in many case reports directly attributable to use of dextran. Its precipita tion or hyperviscosity in the tubular filtrate may result in acute anuria, histologically characterized by hydropic swelling, tubular vacuolization and necrosis, narrowing and obstruction of the tubular lumina, and inter stitial eosinophilic inflammation (40R).
Etherified starches
(SED-15, 1237; SEDA-29, 340; SEDA-30, 384; SEDA-31, 533)
Urinary tract Renal impairment, in some cases presenting as acute renal failure, is a wellknown complication of hydroxyethyl starch, as documented in case reports and large reviews, regardless of molecular weight, molar substitu tions, and C2–C6 ratios. As its use is increasing, the safety profile of hydroxyethyl starch, including its potential for renal impairment, is a concern (40R). Higher molecular weight star ches have a more pronounced effect, resulting from prolonged exposure. In cardiac surgery, the deleterious effect of hydroxyethyl starch on kidney function occurs in both adults and children. Urine output during bypass is significantly lower in those treated with 6% hydroxyethyl starch 200/0.5 compared with albumin 20% given as an intraoperative volu me expander. Furthermore, kidney failure can also occur in the absence of pre-existing renal dysfunction (41A, 42A), in some cases with a fatal outcome (43A).
Polygelines
(SED-15, 2888; SEDA-29, 341; SEDA-30, 384; SEDA-31, 534) Immunologic Although hypotension and hypersensitivity reactions to succinylated gelatin have been reported, with an
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incidence of 0.066–0.146%, severe anaphy laxis is rare (44A). • A 48-year-old woman undergoing surgery had an increase in airway pressure and reduced oxygen saturation due to bronchospasm min utes after infusion with Gelofusine. Just before Gelofusine was withdrawn she had cardio vascular collapse with a fall in arterial blood pressure, tachycardia, ST-segment depression and T-wave inversion. She developed erythema and goose flesh skin on both arms. Skin prick testing to Gelofusine and Hemaccel confirmed the diagnosis of hypersensitivity.
GLOBULINS Immunoglobulins (SED-15, 1719; SEDA-28, 372; SEDA-29, 343; SEDA-30, 385; SEDA-31, 534) Observational studies In a retrospective review of 63 cases of intramuscular immuno globulin in suppurative skin diseases, pain at the injection site was the most frequent com plaint; three patients had hyperpigmentation, but this was not distinguishable from adjacent skin lesions (45c). Mild adverse reactions to intravenous immunoglobulins (fatigue, headache, chills, fever, hypotension, flushing, low back pain, nausea, and myalgia) are often associated with a fast infusion rate (i.e. immediate adverse effects) and respond rapidly on slow ing the infusion. Very rare serious and poten tially fatal adverse reactions are anaphylactic reactions, aseptic meningitis, acute renal failure, and thrombotic complications (46R). Many of these are seen in conjunction with significant risk factors, such as patient age, underlying condition, dose, concentration, IgA content, stabilizing agent, and rate of infusion. Cardiovascular Deep venous thrombosis and arterial thrombosis have been associated with intravenous immunoglobulin in many case reports. Putative mechanisms include increased viscosity, vasospasm, and platelet activation. Although there have been anec dotal reports of thromboembolic events in
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elderly patients, one report described an ado lescent girl with idiopathic thrombocytopenic purpura who developed fatal bilateral jugular vein thrombosis after a single dose of intra venous immunoglobulin; she had multiple prothrombotic susceptibility factors (47A). Nervous system A possible relation bet ween intravenous immunoglobulin for chronic inflammatory demyelinating polyneuropathy and Guillain–Barré syndrome has been des cribed in a single patient (48A). There have been reports of chronic inflammatory demye linating polyneuropathy that begin like acute Guillain–Barré syndrome, but without typical subsequent deterioration. The authors specu lated that the presence of soluble CD receptors and cytokines may have a pro-inflammatory effect, leading to polyneuroradiculitis. Acute stroke has been described as a result of an increase in serum viscosity after intra venous immunoglobulin, but it may also have been attributable to platelet activation, contamination with coagulation factor XI, or passive infusion of antiphospholipid anti bodies (49A). Urinary tract The addition of sucrose to immunoglobulin formulations has reduced the total number of adverse events, but leads to an increase in episodes of acute renal failure, although this may be a transi ent reaction. The most susceptible patients are those of advanced age, with pre-existing renal impairment or diabetes mellitus, or who are taking diuretics (50c). Furthermore, electrolyte disturbances, such as transloca tional hyponatremia and hyperkalemia, after intravenous immunoglobulin may be of significance in patients with severely compromised renal function, resulting in impaired sucrose excretion. Infection risk Although the risk is extre mely small, transmission of abnormal prion proteins in immunoglobulins cannot be ruled out completely. Techniques to minimize the risks are available for removing particles and can achieve at least a 5-log reduction. A woman received batches of intravenous immu noglobulin that contained plasma from a donor who later developed variant Creutzfeldt–Jakob
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disease; however, an abnormal prion protein was not detected in histological, immunocyto chemical, or Western blot analyses (51A). Drug formulations In an observational, open study there were fewer adverse events from a 10% ready-to-use intravenous immunoglobulin formulation than a 6% lyophilized intravenous immunoglobulin product (52c). All of 14 patients with humoral immune deficiency received both treatments and all adverse events were considered as non-serious.
COAGULATION PROTEINS (SED-15, 845; SEDA-29, 345; SEDA-30, 387; SEDA-31, 537)
Factor VIIa Hematologic Recombinant factor VIIa (rFVIIa) has been proposed as an alterna tive to prothrombin complex concentrates for reversing the effects of warfarin. How ever, its short half-life may result in a need for repeated doses, increasing the risk of thrombosis (53c). Given recent reports of its usefulness in warfarin reversal, trials asses sing safety are needed (54R).
Factor IX Immunologic Anaphylaxis and irreversible nephritic syndrome have been described in immune tolerance induction therapy with factor IX for hemophilia B complicated by inhibitor formation. The formation of inhibitors of factor IX is very rare, but two cases in an infant and a 28-month-old child have been reported (55A).
Prothrombin complex concentrate Hematologic In a review of 14 individual studies of the reversal of warfarin anticoagula tion, there were 5 thrombotic events in 308
Blood, blood components, plasma, and plasma products
patients who received 4-factor prothrombin complex concentrates and 2 in 161 patients who were given 3-factor prothrombin complex concentrates, although none of the adverse events was deemed clinically significant (54R). The risk is therefore low, but it ought to be acknowledged. One should also bear in mind that the characteristics of the patient population included prothrombotic risk factors, which determine the very need for anticoagulant therapy. Caution must be taken when attributing thrombotic events to prothrombin complex concentrates, since the evidence is ambiguous. • A 52-year-old man with a mechanical aortic valve had taken warfarin for 4 years when he developed abdominal sepsis requiring surgery. His International Normalized Ratio (INR) was 5.9 and he was given one vial of prothrom bin complex concentrate (500 IU) plus intra venous vitamin K 2 mg. His INR fell to 1.7. Perioperatively he had a fatal myocardial infarction. Low grade disseminated intravascu lar coagulation may have been present, as the preoperative D-dimer concentration was raised.
Whether this patient’s co-existing procoagulant state or administration of prothrom bin complex concentrates was responsible for the event could not be established (56A). In an open non-randomized study of the volume of prothrombin complex concentrate to be administered initially and the rapidity with which it can shorten the INR, 42 patients were given 200 IU (n = 6), 500 IU (n = 30), 1000 IU (n = 3) or 1500 IU (n = 3) (57c). Adverse events, including shock, allergy and thrombotic or embolic episodes, were not observed. Attenuation of the risk of thrombosis from prothrombin complex concentrate (Octaplex®, Octapharma, Vienna, Austria) can be achieved by individualizing dosage schemes. In a study designed to demonstrate efficient correction of INR by individual dosages, only 3 events in 60 patients were regarded as being possibly related to the pro duct, whereas there were 126 events as a result of underlying disease or clinical status (58c). These three events were aggravation of pre-existing arterial hypertension, burning at the injection site, and a positive parvovirus
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B19 PCR screen without clinical symptoms. The latter was unlikely to be related to treat ment, since the original plasma pool from which this prothrombin complex concentrate was manufactured had been tested. Further more, no other patients who received Octa plex® from the same batch were positive. The patient had also received two packed red blood cells, but they were unavailable for testing.
Von Willebrand factor/factor VIII concentrate Immunologic In an open study in 28 patients with types 1, 2A or 3 von Wille brand disease and one with type 2M, designed to determine the feasibility of giving von Willebrand factor/factor VIII based on individual pharmacokinetics, five adverse events were possibly related to the product (59c). Vomiting, rash, and increased AlT acti vity were reported, as were thrombophlebitis of the leg and pulmonary embolism, the two last being classified as serious and moderately severe. Inhibitor antibodies were not detec ted. The patient who had a pulmonary embo lism was at risk of a thromboembolic event because of thrombocytosis (769 109/l) and recent major surgery after which no antith rombotic prophylaxis was prescribed.
ERYTHROPOIETIN AND DERIVATIVES (SED-15, 1243; SEDA-29, 346; SEDA-30, 388; SEDA-31, 538) Erythropoietin is an endogenous hormone that stimulates erythropoiesis. Forms of recombinant human erythropoietin (rHuEpo) are also erythropoiesis-stimulating agents, and are mostly called epoetin; for example, epo etin alfa and beta are different isoforms of erythropoietin and the main differences in their actions arise from differences in glyc ation (60E). Epoetin delta, unlike existing
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agents, is produced in a human cell line (61R). Darbepoetin alfa is an erythropoiesisstimulating glycoprotein that contains 165 amino acids and differs from endogenous erythropoietin by having two extra N-linked oligosaccharide chains (62R). Observational studies In a prospective, multicenter, open, comparative study, patients with pre-dialysis chronic kidney disease were randomized to one of two regimens: either subcutaneous epoetin alfa 1000 U twice weekly was given at an early stage of anemia to maintain the hemoglobin at 11.0 g/dl (n = 65) or the hemoglobin was allowed to fall to 9.0 g/dl or less before starting subcuta neous epoetin alfa 2000 U three times weekly then maintaining the hemoglobin at 11.0 g/dl (n = 132) (63c). There was a large number of adverse events, reflecting the length of the study and co-morbidities. The drug-related adverse events were hypertension, aggravated hypertension, hematemesis, and pure red cell aplasia. In an open study in the same type of patients, 54 of 66 patients reported adverse events (64c). Only hypertension was consid ered to be related to darbepoetin alfa. Intraperitoneal darbepoetin has been used in 19 children (mean age 6.8 years) with renal anemia on peritoneal dialysis and in children who had received intra peritoneal erythropoietin (variety not specified) 6 months before conversion to darbepoetin in a single-arm, retrospective, two-center study (65c). Eight children were converted from erythropoietin 200 U/kg/week to dar bepoetin 1 microgram/kg/week and were treated for a median of 32 months. Median darbepoetin dose for adequate erythropoi esis was 0.79 micrograms/kg/week. Three children developed hypertension and one had headache, complications that were due to a rapid increase in hemoglobin concentration. In a retrospective study of 100 children with renal transplants and peripheral blood transcriptional analysis of four renovascular abnormalities of the transplanted vasculature temporally associated with erythropoietin, early use of recombinant human erythro poietin (in the first week after transplanta tion) was significantly associated with the combined findings of severe hypertension
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and renovascular abnormalities (66c). The authors warned against early use of recombi nant human erythropoietin after transplanta tion in immunosuppression regimens with glucocorticoid minimization or avoidance, which may be associated with an increased incidence of anemia. Comparative studies Intravenous epoetin delta (n = 560) and epoetin alfa (n = 192) have been compared in a 6-month, multi center, double-blind, randomized trial in hemodialysis patients who had previously received epoetin alfa (67C). The most com mon adverse events possibly related to epoetin delta and alfa were thrombosis (2.5 and 2.6%), hypertension (1.4 and 1.0%), headache (1.6 and 1.0%), and anemia (0.4 and 0.5%). Placebo-controlled studies In a random ized, placebo-controlled trial in 1460 sur gical or trauma patients epoetin alfa (40 000 U) or placebo was given weekly for a maximum of 3 weeks; the patients were followed for 140 days. Epoetin alfa did not reduce the need for erythrocyte transfusions and caused more thrombotic vascular events than placebo (17% versus 12%) (68C). Among the patients who did not receive heparin at baseline, the difference in inci dence was even greater (20% versus 13%). The increase in the incidence of thrombotic vascular events was most apparent among patients who received three doses of epoetin alfa compared with placebo (23% versus 16%). Systematic reviews In very low birth weight preterm infants, intravenous recombinant human erythropoietin in a variety of dosages up to 2100 U/kg/week, in several randomized trials in the prevention of anemia, reduced the volume of transfusions per infant but had no effect on neurological development and increased the rate of severe retinopathy of prematurity (69M). Cardiovascular The dose of a recombinant human erythropoietin, the dose frequency, rate of rise of hemoglobin, and target hemo globin concentration should be carefully
Blood, blood components, plasma, and plasma products
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monitored and controlled (70R). Recombi nant human erythropoietin may not be toler ated by all individuals, especially those with co-morbid conditions such as congestive heart failure, hypertension, and neoplasms. Recom binant human erythropoietin can contribute to vascular stenosis with intimal hyperplasia. There is an increased risk of thrombotic vas cular effects. Acute and long-term administra tion of recombinant human erythropoietin can cause significantly increased mean arterial pressure. The use of recombinant human erythropoietin in neurovascular disea ses could be limited or halted due to cere bral ischemia with increased metabolic rate and blood viscosity. The FDA has issued an advisory warning that epoetin and darbepoetin result in an increased number of deaths and non-fatal heart attacks, strokes, cases of heart failure, and blood clots when doses were adjusted to maintain hemoglobin concentrations above 12 g/l (71S).
the routine management of cancer treat ment-induced anemia (73r).
Drug resistance Hyporesponsiveness occurs in about 5–10% of patients (72R). Iron defi ciency/chronic blood loss, inflammation, poor adherence to therapy, inadequate dialysis, hyperparathyroidism, nutrient deficiencies, angiotensin converting enzyme inhibitors and angiotensin receptor blockers, alumi nium overload, malignancies, antibodymediated pure red cell aplasia, and other causes such as primary bone marrow disor ders, myelosuppressive agents, hemolysis, and hypersplenism influence responsive ness. Enhancing responsiveness is critically important to improve clinical outcomes.
STEM CELLS
Tumorigenicity A significant concern with recombinant human erythropoietin is potential progression of cancer, because erythropoietin and its receptor have been demonstrated in tumor specimens and erythropoietin expression has been suggested to block tumor cell apoptosis, enhance tumor pro gression, stimulate chemotaxis, increase metastatic disease, and negate the effects of radiotherapy by assisting angiogenesis. The UK National Institute for Health and Clinical Excellence (NICE) has stated that erythro poietin analogues are not recommended for
Drug dosage regimens In order to deter mine whether targeting different hemoglo bin concentrations with different doses of recombinant human erythropoietin is asso ciated with altered all-cause mortality and cardiovascular events in patients with ane mia caused by chronic kidney disease, a meta-analysis of nine randomized control led clinical trials in 5143 patients was per formed (74M). With a higher hemoglobin target there was a significantly greater risk of all-cause mortality, arteriovenous access thrombosis, and poorly controlled blood pressure compared with a low target hemo globin. The incidence of myocardial infarc tion was much the same in the two groups.
(SEDA-29, 347; SEDA-30, 389; SEDA-31, 539)
Allogeneic stem cell transplantation has con tinued to evolve as a common procedure for the treatment of hematological malignancies and bone marrow failure. Donor bone marrow and mobilized peripheral stem cells are routinely used to reconstruct immune function in patients with leukemia and lym phoma after radiation and/or chemotherapy. Transplantation of umbilical cord blood is the most recent strategy for expanding the potential donor pool while maintaining an acceptable degree of treatment-related complications. Cardiovascular Autologous transplanta tion with cryopreserved bone marrow or peripheral blood stem cells has been accom panied by an array of usually mild to moderate symptoms, including nausea, vomiting, hemoglobinuria, hypertension, hypotension, bradycardia, and second- and third-degree heart block (75R, 76c–82c). In a prospective study of adverse events after 179 infusions of hemopoietic progeni tor cells in patients with hematological
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neoplasms after high-dose chemotherapy, there was one or more adverse events in 51 infusions (29%) (83c). The frequency was higher after infusion of cells obtained by apheresis than after bone marrow (31% versus 4.5%). Other susceptibility factors were age, the number of total nucleated cells infused per kilogram, the volume per kilogram infused, the volume of packed ery throcytes, the content of non-mononuclear cells and the duration of infusion. However, after multivariate analysis, only age and non-mononuclear cell content remained sig nificant. There were significant correlations between reduced cardiac frequency and both volume per kilogram infused and dura tion of infusion. The adverse effects of infusing peripheral blood progenitor cells have been studied in 194 autologous and 25 allogeneic trans plants (84c). After infusion of autologous cells there were 46 adverse events during infusion, including 15 cardiac effects, which required withdrawal of the infusion, and 31 non-cardiac effects, which did not. There was sinus bradycardia after a minimum of 45 minutes after the end of the infusion in three patients. The median volume, amount of dimethyl sulfoxide, and total nucleated cells infused were significantly higher in patients with adverse effects. The median volume and amount of dimethyl sulfoxide infused were significantly higher in patients with cardiac adverse effects than in those with non-cardiac effects. Cardiovascular toxicity has been prospec tively evaluated in 34 patients undergoing unrelated cord blood transfusion (85c). Sys tolic hypertension, diastolic hypertension, extra beats, and bradycardia were observed in 58, 64, 9, and 32% of infusions respec tively. Non-cardiovascular complications, such as desaturation, chest discomfort, nausea and vomiting, and headache occurred less often. These results suggest that infusionrelated cardiovascular adverse effects are more frequent after umbilical cord blood transplantation than bone marrow or periph eral blood stem cell transplantation. Hematologic Evans syndrome, auto immune thrombocytopenia and autoimmune
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hemolytic anemia, has been attributed to transplantation of unrelated cord blood (86A). Selective red cell aplasia has been repor ted after hemopoietic stem cell transplanta tion (87A). Independent susceptibility factors for autoimmune hemolytic anemia are chronic graft-versus-host disease and unrelated donors. HLA mismatch is also a prognostic factor, although not an independent one. The prevalence and outcomes of pure red cell aplasia in patients with major and bi directional ABO mismatch have been investigated retrospectively after allogeneic stem cell transplants given for malignant and non-malignant hematological disorders (88c). Major ABO mismatch can lead to delayed donor erythroid engraftment, result ing in long-term transfusion dependence. Immunologic Initiation or exacerbation of graft-versus-host disease can occur after stem cell transplantation, and various grades of severity have been described, even when com plete conditioning regimens are performed (89c, 90c). Of 13 children with both malignant and non-malignant diseases receiving umbilical cord blood transplants after reducedintensity conditioning, 4 developed acute graft-versus-host disease grades II–IV and one developed extensive chronic graft-ver sus-host disease (91c). Infection risk Infections with human herpesviruses can occur in immunocompromised patients after hemopoietic stem cell transplantations (90c). Human herpesvirus 6 (HHV-6) can cause pneumonia (92c), encephalitis (92c), bone marrow suppression (92c) in the form of delayed neutrophil engraftment (93c) and delayed platelet engraftment (94c), myelosuppression after initial engraftment (95c), graft failure (96A), fever (97c), rashes (92c), thrombotic microangiopathy (98A), pericarditis (92c), and gastroduodenitis and colitis (92c, 99c). Reactivation of HHV-6, leading to pleurisy after unrelated cord blood transplantation is previously undocumented (90c).
Blood, blood components, plasma, and plasma products • Two infants, a 5-year-old boy and a 10-year-old girl, with stage III T-cell lymphoblastic lymphoma both received unrelated cord blood transplants after conditioning regimens consisting of total body irradiation (12 Gy), high-dose cytarabine, and cyclophosphamide. Tacrolimus and prednisolone were given as prophylaxis against graft-versus-host disease. The boy, after transient grade I graft-versus host disease of the skin, developed interstitial pneumonia with a high fever, bilateral pleural effusions and hypoxia. HHV-6 variant B DNA was detected in the pleural effusion. Ganciclo vir was effective and remission was maintained for 41 months. The girl, who also developed transient cutaneous grade I graft-versus-host disease, had severe chest pain, a unilateral pleural effusion, positive for HHV-6 variant B DNA, without a fever, pneumonia, or intersti tial pneumonitis. Ganciclovir was effective but she died 2 months after transplantation from progression of leukemic disease.
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Morbidity and mortality associated with myeloablative umbilical cord blood trans plantation is significant (99c). Besides full conditioning, reduced-intensity transplan tation preparatory regimens are being per formed to reduce regimen-related toxicity, including a high risk of infections and organ dysfunction (100c). Although parvovirus B19 may cause self-limiting erythroid aplasia in otherwise healthy individuals, in an immunocompro mised patient chronic anemia was caused by transmission of B19 after allogeneic, HLA-matched, ABO-compatible, human stem cell transplantation from a sibling (101A). Immune-mediated hemolysis may have an autoimmune or alloimmune origin.
References 1. Pradel V, Tardieu S, Micallef J, Signoret A, Villano P, Gauthier L, Vanelle P, Blin O; Albumin Study Group. Use of albumin in three French university hospitals: is pre scription monitoring still useful in 2004? Pharmacoepidemiol Drug Saf 2007;16 (1):79–85. 2. Martin-Llahi M, Pepin MN, Guevara M, Diaz F, Torre A, Monescillo A, Soriano G, Terra C, Fa´ brega E, Arroyo V, Rodés J, Ginès P, TAHRS Investigators. Terlipressin and albumin vs albumin in patients with cir rhosis and hepatorenal syndrome: a rando mized study. Gastroenterology 2008;134 (5):1352–9. 3. Jacob M, Chappell D, Conzen P, Wilkes MM, Becker BF, Rehm M. Small-volume resuscitation with hyperoncotic albumin: a systematic review of randomized clinical trials. Crit Care 2008;12(2):R34. 4. Kanji S, Perreault MM, Chant C, Williamson D, Burry L. Evaluating the use of drotreco gin alfa (activated) in adult severe sepsis: a Canadian multicenter observational study. Intensive Care Med. 2007;33(3):517–23. 5. Payen D, Sablotzki A, Barie PS, Ramsay G, Lowry S, Williams M, Sarwat S, Northrup J, Toland P, Booth FV. International
integrated database for the evaluation of severe sepsis and drotrecogin alfa (activated) therapy: analysis of efficacy and safety data in a large surgical cohort. Surgery 2007; 141 (4):548–61. Corrected and republished from Surgery 2006;140(5):726–39. 6. de Pont AC, Bakx R, Boermeester MA, Schultz MJ. Analysis of efficacy and safety of drotrecogin alfa (activated) in surgical patients, using an international integrated database. Surgery 2007;141(6):828–9. 7. Payen D, Sundin DP, Nelson DR, Williams MD. Analysis of efficacy and safety of dro trecogin alfa (activated) in surgical patients, using an international integrated database. Surgery 2007;142(3):426–7. 8. Laterre PF, Nelson DR, Macias W, Abra ham E, Sashegyi A, Williams MD, Levy M, Levi M, Utterback B, Vincent JL. Interna tional integrated database for the evalua tion of severe sepsis and drotrecogin alfa (activated) therapy: 28-day survival and safety. J Crit Care 2007;22(2):142–52. 9. Dhainaut JF, INDEPTH Clinical Evalua tion Committee. International integrated database for the evaluation of severe sepsis (INDEPTH): clinical evaluation committee report on the safety of drotrecogin alfa
602 (activated) therapy. Curr Med Res Opin 2008;24(4):1187–97. 10. Bertolini G, Rossi C, Anghileri A, Livigni S, Addis A, Poole D. Use of Drotrecogin alfa (activated) in Italian intensive care units: the results of a nationwide survey. Intensive Care Med 2007;33(3):426–34. 11. Laterre PF, Abraham E, Janes JM, Trzas koma BL, Correll NL, Booth FV. ADDRESS ADministration of DRotrecogin alfa [acti vated] in Early stage Severe Sepsis long-term follow-up: one-year safety and efficacy eva luation. Crit Care Med 2007;35(6):1457–63. 12. De Backer D. Benefit–risk assessment of drotrecogin alfa (activated) in the treatment of sepsis. Drug Saf 2007;30(11):995–1010. 13. Fumagalli R, Mignini MA. The safety profile of drotrecogin alfa (activated). Crit Care 2007;11(Suppl 5):S6. 14. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher Jr. CJ. Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344(10):699–709. 15. Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, François B, Guy JS, Br€ uckmann M, Rea-Neto A, Rossaint R, Perrotin D, Sablotzki A, Arkins N, Utterback BG, Macias WL, Administration of Drotre cogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study Group. Drotreco gin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 2005;353(13):1332–41. 16. Vincent JL, Bernard GR, Beale R, Doig C, Putensen C, Dhainaut JF, Artigas A, Fumagalli R, Macias W, Wright T, Wong K, Sundin DP, Turlo MA, Janes J. Drotre cogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: further evidence for survival and safety and implications for early treat ment. Crit Care Med 2005;33(10):2266–77. 17. Levi M, Levy M, Williams MD, Douglas I, Artigas A, Antonelli M, Wyncoll D, Janes J, Booth FV, Wang D, Sundin DP, Macias WL, Xigris and Prophylactic HepaRin Evaluation in Severe Sepsis (XPRESS) Study Group.
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Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (acti vated). Am J Respir Crit Care Med 2007;176(5):483–90. 18. National Haemovigilance Office. Annual Report 2006. Dublin, Ireland, National Hae movigilance Office. http://www.giveblood.ie/ Clinical_Services/Haemovigilance/Publications/ NHO_Annual_Report_2006.pdf 19. National Haemovigilance Office. Annual Report 2007. Dublin, Ireland, National Hae movigilance Office. http://www.giveblood.ie/ Clinical_Services/Haemovigilance/Publications/ Annual_Report_2007.pdf 20. SHOT. Serious Hazards of Transfusion Annual Report 2006. Manchester, United Kingdom, SHOT Office. http://www.shotuk. org/shot-reports/reports-and-summaries-2006 21. SHOT. Serious Hazards of Transfusion Annual Report 2007. Manchester, United Kingdom, SHOT Office. http://www.shotuk. org/shot-reports/reports-and-summaries-2007 22. Bureau TRIP. Transfusie Reacties in Patiënten. TRIP Rapport 2006. The Hague, The Netherlands. http://www.tripnet.nl/pages/ en/documents/75089_Rapportdefinitief.pdf 23. Bureau TRIP. Transfusie Reacties in Patiënten. TRIP Rapport 2007. The Hague, The Netherlands. http://www.tripnet.nl/pages/ nl/documents/85344_wwwRapport.pdf 24. Gajic O, Rana R, Winters JL, Yilmaz M, Men dez JL, Rickman OB, O’Byrne MM, Evenson LK, Malinchoc M, DeGoey SR, Afessa B, Hubmayr RD, Moore SB. Transfusion-related acute lung injury in the critically ill. Am J Respir Crit Care Med 2007;176:886–91. 25. Sanchez R, Bacchetti P, Toy P. Transfusionrelated acute lung injury. A case-control pilot study of risk factors. Am J Clin Pathol 2007;128(1):128–34. 26. Jahr TS, Walker V, Manoochehri K. Blood substitutes as pharmacotherapies in clinical practice. Curr Opin Anesth 2007;20(4):325–30. 27. Traynor K. Experts weigh future of blood substitutes. Am J Health Syst Pharm 2008;65(12):1110–2. 28 Hill SE, Grocott HP, Leone BJ, White WD, Newman MF, Neurologic Outcome Research Group of the Duke Heart Center. Cerebral physiology of cardiac surgical patients treated with the perfluorocarbon emulsion, AF0144. Ann Thorac Surg 2005;80(4):1401–7.
Blood, blood components, plasma, and plasma products 29. Mattrey RF. Are cerebral emboli real when perfluorocarbon emulsion (AF0144) is used in cardiac surgery? Ann Thorac Surg 2007;83(5):1922–3. 30. Peres E, Kintzel P, Dansey R, Baynes R, Abidi M, Klein J, Ibrahim RB, Abella E. Early intervention with antithrombin III therapy to prevent progression of hepatic venoocclusive disease. Blood Coagul Fibri nolysis 2008;19(3):203–7. 31. Afshari A, Wetterslev J, Brok J, Moller A. Antithrombin III in critically ill patients: sys tematic review with meta-analysis and trial sequential analysis. BMJ 2007;335 (7632):1248–51. 32. Torossian A, Graf J, Bauhofer A. Anti thrombin III in critically ill patients. BMJ 2007;335(7632):1219–20. 33. Kirschfink M, Mollnes TE. C1-inhibitor: an anti-inflammatory reagent with therapeutic potential. Expert Opin Pharmacother 2001;2(7):1073–83. 34. Wouters D, Wagenaar-Bos I, van Ham M, Zeerleder S. C1inhibitor: just a serine pro tease inhibitor? New and old considerations on therapeutic applications of C1 inhibitor. Expert Opin Biol Ther 2008;8(8):1225–40. 35. Fattouch K, Bianco G, Speziale G, Sampog naro R, Lavalle C, Guccione F, Dioguardi P, Ruvolo G. Beneficial effects of C1 esterase inhibitor in ST-elevation myocardial infarction in patients who underwent surgical reperfu sion: a randomised double-blind study. Eur J Cardiothorac Surg 2007;32(2):326–32. 36. Mills GH. Hydroxyethyl starch: does our choice of colloid prevent or add to renal impairment? Br J Anaesth 2007;98(2):157–9. 37. Deakin CD. Early fluid resuscitation in hae morrhagic shock. Eur J Emerg Med 1994;1 (2):83–5. 38. Bickell WH. Are victims of injury sometimes victimized by attempts at fluid resuscitation? Ann Emerg Med 1993;22(2):225–6. 39. Bunn F, Alderson P, Hawkins V. Colloid solutions for fluid resuscitation. Cochrane Database Syst Rev 2003;(1):CD001319. 40. Davidson IJ. Renal impact of fluid manage ment with colloids: a comparative review. Eur J Anaesthesiol 2006;23(9):721–38. 41. Arzneimittelkommission der deutschen Ärz teschaft: Arzneimittel-Schnellinformationen. Akutes Nierenversagen nach Infusion von
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Hydroxyethylstärke im Rahmen einer Hämo dilutionstherapie. Dtsch Ärztebl 1992;89: B–2745 42. Peron S, Mouthon L, Guettier C, Brechignac S, Cohen P, Guillevin L. Hydroxyethyl starchinduced renal insufficiency after plasma exchange in a patient with polymyositis and liver cirrhosis. Clin Nephrol 2001;55 (5):408–11. 43. Haskell LP, Tannenberg AM. Elevated urinary specific gravity in acute oliguric renal failure due to hetastarch administra tion. N Y State J Med 1988;88(7):387–8. 44. Ghai B, Wig J, Gupta V. Intraoperative severe anaphylaxis due to gelofusine during a neurosurgical procedure. Anesth Analg 2007;104(1):238. 45. Goo B, Chung HJ, Chung WG, Chung KY. Intramuscular immunoglobulin for recalci trant suppurative diseases of the skin: a retro spective review of 63 cases. Br J Dermatol 2007;157:563–8. 46. Carbone J. Adverse reactions and pathogen safety of intravenous immunoglobulin. Curr Drug Saf 2007;2(1):9–18. 47. Tam PY, Richardson M, Grewal S. Fatal case of bilateral internal jugular vein throm bosis following IVIg infusion in an adoles cent girl treated for ITP. Am J Hematol 2008;83(4):323–5. 48. Krasenbrink I, Kaps M, Blaes F. IVIg induced acute polyneuroradiculitis in a patient with CIDP? Eur J Neurol 2007;14(5):e9. 49. White DA, Leonard MC. Acute stroke with high-dose intravenous immune globulin. Am J Health Syst Pharm 2007;64(15):1611–4. 50. Daphnis E, Stylianou K, Alexandrakis M, Xylouri I, Vardaki E, Stratigis S, Kyriazis J. Acute renal failure, translocational hypo natremia and hyperkalemia following intra venous immunoglobulin therapy. Nephron Clin Pract 2007;106(4):c143–8. 51. El Shanawany T, Jolles S, Unsworth DJ, Williams P. A recipient of immunoglobulin from a donor who developed vCJD. Vox Sang 2009;96(3):270. 52. Kallenberg CG.A 10% ready-to-use intrave nous human immunoglobulin offers poten tial economic advantages over a lyophilized product in the treatment of primary immuno deficiency. Clin Exp Immunol 2007;150 (3):437–41.
604 53. Aledort LM. Comparative thrombotic event incidence after infusion of recombinant fac tor VIIa versus factor VIII inhibitor bypass activity. J Thromb Haemost 2004;2(10): 1700–17. 54. Leissinger CA, Blatt PM, Hoots WK, Ewen stein B. Role of prothrombin complex concen trates in reversing warfarin anticoagulation: a review of the literature. Am J Hematol 2008;83(2):137–43. 55. Klarmann D, Martinez Saguer I, Funk MB, Knoefler R, von Hentig N, Heller C, Kreuz W. Immune tolerance induction with mycophenolate-mofetil in two children with haemophilia B and inhibitor. Haemo philia 2008;14(1):44–9. 56. Bagot CN, Cregg R, Patel RK, Shariff A, Arya R. Perioperative myocardial infarc tion in a patient receiving low-dose pro thrombin complex concentrates. Thromb Haemost 2007;98(5):1141–2. 57. Yasaka M, Sakata T, Naritomi H, Minematsu K. Optimal dose of prothrombin complex concentrate for acute reversal of oral antic oagulation. Thromb Res 2005;115(6):455–9. 58. Riess HB, Meier-Hellmann A, Motsch J, Elias M, Kursten FW, Dempfle CE. Pro thrombin complex concentrate (Octaplex) in patients requiring immediate reversal of oral anticoagulation. Thromb Res 2007;121 (1):9–16. 59. Lethagen S, Kyrle PA, Castaman G, Haer tel S, Mannucci PM. von Willebrand factor/ factor VIII concentrate (Haemate P) dosing based on pharmacokinetics: a prospective multicenter trial in elective surgery. J Thromb Haemost 2007;5(7):1420–30. 60. Storring PL, Tiplady RJ, Gaines Das REG, Stenning BE, Lamikanra A, Rafferty B, Lee J. Epoetin alfa and beta differ in their erythropoietin isoform compositions and biological properties. Br J Haematol 1998;100(1):79–89. 61. Locatelli F, Del Vecchio L. Optimizing the management of renal anemia: challenges and new opportunities. Kidney Int Suppl 2008;(111):S33–7. 62. Del Vecchio L, Locatelli F. New erythro poiesis-stimulating agents: how innovative are they? Contrib Nephrol 2008;161:255–60. 63. Macdougall IC, Temple RM, Kwan JTC. Is early treatment of anaemia with epoetin-a
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beneficial to pre-dialysis chronic kidney dis ease patients? Results of a multicentre, open-label, prospective, randomized, com parative study. Nephrol Dial Transplant 2007;22:784–93. 64. Disney A, Jersey PD, Kirkland G, Mantha M, Charlesworth JA, Gallagher M, Harris D, Gock H, Mangos GJ, Macmillan J, Liu W, Viswalingam A. Darbepoetin alfa admi nistered monthly maintains haemoglobin concentrations in patients with chronic kid ney disease not receiving dialysis: a multicentre, open-label, Australian study. Nephrol ogy (Carlton) 2007(1);12:95–101. 65. Rijk Y, Raaijmakers R, van de Kar N, Schro¨ der C. Intraperitoneal treatment with darbepoetin for children on peritoneal dialy sis. Pediatr Nephrol 2007;22:436–40. 66. Nagarajan S, Mansfield E, Hsieh S, Liu R, Hsieh F, Li L, Salvatierra O Jr, Sarwal MM. Transplant renovascular stenoses associated with early erythropoietin use. Clin Trans plant 2007;21:597–608. 67. Martin KJ. Epoetin delta in the management of renal anaemia: results of a 6-months study. Nephrol Dial Transplant 2007;22:3052–4. 68. Corwin HL, Gettinger A, Fabian TC, May A, Pearl RG, Heard S, An R, Bowers PJ, Burton P, Klausner MA, Corwin MJ. Effi cacy and safety of epoetin alfa in critically ill patients. N Engl J Med 2007;357:965–76. 69. Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2006;3:CD004863. 70. Maiese K, Chong ZZ, Shang YC. Raves and risks for erythropoietin. Cytokine Growth Factor Rev 2008;19(2):145–55. 71. USA Food and Drug Administration. Ery thropoiesis stimulating agents: Aranesp (darbepoetin alfa), Epogen (epoetin alfa), and Procrit (epoetin alfa) November 2007. http://www.fda.gov/Safety/MedWatch/Safe tyInformation/SafetyAlertsforHumanMedi calProducts/ucm152274.htm 72. Johnson DW, Pollock CA, MacDougall IC. Erythropoiesis-stimulating agent hypore sponsiveness. Nephrology 2007;12:321–30. 73. Mauer ME, Botttomley A, Collette L, Slotman BJ. Erythropoetin analogues: an unnecessary class of drugs. Lancet 2008;9:81–2.
Blood, blood components, plasma, and plasma products 74. Phrommintikul A, Haas SJ, Elsik M, Krum H. Mortality and target haemoglobin con centrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet 2007;369:381–8. 75. Sauer-Heilborn A, Kadidlo D, McCullough J. Patient care during infusion of hemato poietic progenitor cells. Transfusion 2004;44(6):907–16. 76. Davis JM, Rowley SD, Braine HG, Pianta dosi S, Santos GW. Clinical toxicity of cryo preserved bone marrow graft infusion. Blood 1990;75(3):781–6. 77. Zambelli A, Poggi G, Da Prada G, Pedrazzoli P, Cuomo A, Miotti D, Perotti C, Preti P. Robustelli della Cuna G. Clinical toxicity of cryopreserved circulating progenitor cells infusion. Anticancer Res 1998;18(6B):4705–8. 78. Stroncek DF, Fautsch SK, Lasky LC, Hurd DD, Ramsay NK, McCullough J. Adverse reactions in patients transfused with cryopre served marrow. Transfusion 1991;31(6):521–6. 79. Alessandrino P, Bernasconi P, Caldera D, Colombo A, Bonfichi M, Malcovati L, Klersy C, Martinelli G, Maiocchi M, Pagnucco G, Varettoni M, Perotti C, Bernasconi C. Adverse events occurring during bone mar row or peripheral blood progenitor cell infu sion: analysis of 126 cases. Bone Marrow Transplant 1999;23(6):533–7. 80. Styler MJ, Topolsky DL, Crilley PA, Cova lesky V, Bryan R, Bulova S, Brodsky I. Transient high grade heart block following autologous bone marrow infusion. Bone Marrow Transplant 1992;10(5):435–8. 81. Keung YK, Lau S, Elkayam U, Chen SC, Douer D. Cardiac arrhythmia after infusion of cryopreserved stem cells. Bone Marrow Transplant 1994;14(3):363–7. 82. López-Jiménez J, Cerveró C, Muñoz A, Herna´ndez-Madrid A, Ferna´ ndez Pineda J, Garci?a Laraña J, Moro C, Maldonado M, Pérez Oteyza J, Otheo E. Cardiovascular toxi cities related to the infusion of cryopreserved grafts: results of a controlled study. Bone Marrow Transplant 1994;13(6):789–93. 83. Milone G, Mercurio S, Strano A, Leotta S, Pinto V, Battiato K, Coppoletta S, Murgano P, Farsaci B, Privitera A, Giustolisi R. Adverse events after infusions of cryopre served hematopoietic stem cells depend on non-mononuclear cells in the infused
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transplantation. Br J Haematol 1999;105 (4):1041–3. Yoshikawa T, Ihira M, Suzuki K, Suga S, Iida K, Saito Y, Asonuma K, Tanaka K, Asano Y. Human herpesvirus 6 infection after living related liver transplantation. J Med Virol 2000;62(1):52–9. Matsuda Y, Hara J, Miyoshi H, Osugi Y, Fujisaki H, Takai K, Ohta H, Tanaka-Taya K, Yamanishi K, Okada S. Thrombotic microangiopathy associated with reactiva tion of human herpesvirus-6 following high-dose chemotherapy with autologous bone marrow transplantation in young chil dren. Bone Marrow Transplant 1999;24 (8):919–23. Amo K, Tanaka-Taya K, Inagi R, Miya gawa H, Miyoshi H, Okusu I, Sashihara J, Hara J, Nakayama M, Yamanishi K, Okada S. Human herpesvirus 6B infection of the large intestine of patients with diarrhea. Clin Infect Dis 2003;36(1):120–3. Komatsu T, Narimatsu H, Yoshimi A, Kurita N, Kusakabe M, Hori A, Murashige N, Matsumura T, Kobayashi K, Yuji K, Tanaka Y, Kami M. Successful engraftment of mismatched unrelated cord blood trans plantation following reduced intensity pre parative regimen using fludarabine and busulfan. Ann Hematol 2007;86(1):49–54. Sanz J, Arriaga F, Montesinos P, Orti G, Lorenzo I, Cantero S, Puig N, Moscardó F, de la Rubia J, Sanz G, Sanz MA. Auto immune hemolytic anemia following allogeneic hematopoietic stem cell transplantation in adult patients. Bone Marrow Transplant 2007;39(9):555–61.
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Vitamins, intravenous solutions, and drugs and formulations used in nutrition
VITAMIN A (CAROTENOIDS)
(SED-15, 3642; SEDA-28, 386; SEDA-31, 548) Musculoskeletal Vitamin A is necessary for the synthesis of visual pigments and required in appropriate amounts for membrane stability. Acute vitamin A intoxication can lead to increased intracranial pressure, vomiting, and lethargy. Chronic excessive intake of vitamin A can lead to pruritus, muscle and bone tenderness, and failure to thrive. Reported effects of vitamin A intoxication on bone include osteoporosis, fracture, cortical thickening, and metaphyseal irregularity. Excessive chronic intake of vitamin A has been reported to cause central physeal arrest in the distal femur, proximal tibia, and distal tibia (1A).
• A 5-year-old boy was given megadoses of vitamin A at 10–18 months of age, supposedly to boost his immune system. At 3½ years, he began to show deterioration in speech and motor function, and at one point lost the ability to sit. He had liver damage, splenomegaly and a profound coagulopathy. A magnetic resonance imaging (MRI) scan of the brain showed enlarged ventricles and corticomedullary parenchymal volume loss, consistent with vitamin A-induced hydrocephalus. With medical management, Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32034-4 � 2010 Elsevier B.V. All rights reserved.
liver function improved and the hydrocephalus resolved. At 5 years he developed knee and ankle pain and had an increasing number of falls. The fibular heads were prominent bilaterally and he had bilateral genu varum, but no joint effusions and full movements in the hips, knees, and ankles. Neurological function was normal apart from mild hyper-reflexia in the legs. Radiography showed bilateral flaring of the femoral and proximal and distal tibial metaphyses. There was central arrest in both distal femoral physes and in the proximal and distal physes of both tibiae. The fibulae were relatively longer than the tibiae. A radiographic skeletal survey showed additional abnormalities in both distal radial and ulnar physes. There were coned epiphyses in the third and fourth middle phalanges in the left foot.
Dietary vitamin A is obtained from two sources, preformed vitamin A, which is the artificial source used in multivitamin pre parations as added to food, and naturally occurring provitamin A. While the latter is only poorly absorbed, and is subject to metabolic regulation, preformed vitamin A is well absorbed (up to 90%) and is unregu lated by the liver. A daily dose of 25 000 IU for more than 6 years, or more than 100 000 IU for 6 months, can be considered toxic (2R). Children are more sensitive to vitamin A, and daily intakes exceeding 1550 IU/kg can lead to toxicity. Acute toxi city occurs when a child receives more than 20 times the recommended daily allowance of vitamin A during a period of hours or days. Chronic toxicity results from ingestion of high amounts for months or years, the latter resulting in permanent hepatic damage and even failure. Bone and joints are also affected, as in this case, which the
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authors suggested is the first reported case of central physeal arrest secondary to hypervitaminosis A.
VITAMINS OF THE B GROUP (SED-15, 2700; SEDA-29, 353; SEDA-31, 548)
Cobalamins Immunologic Allergy to cyanocobalamin, which is rare, has been reported, along with a procedure for successful desensitization (3A). • A non-atopic woman with pernicious anemia received quarterly injections of cyanocobalamin for more than 3 years and developed generalized urticaria 10 minutes after an injection of hydroxocobalamin 1 mg. Her symptoms abated within 20 minutes after treatment with intramuscular chlorphenamine 10 mg. Intradermal tests with cyanocobalamin and hydroxocobalamin were positive. • A non-atopic woman with pernicious anemia received quarterly injections of cyanocobalamin for more than 3 years and developed anaphylaxis 5 minutes after an injection of hydroxocobalamin 1 mg. Her symptoms included facial angioedema, a swollen tongue, generalized urticaria, hypotension, dizziness, and chest tightness. Treatment with methylprednisolone and chlorphenamine was successful. She also reported remembering burning, redness of eyes, and mild facial angio edema 30 minutes after previous injections. Intradermal tests with cyanocobalamin and hydroxocobalamin were positive.
Both patients were desensitized with incremental subcutaneous injections every 15 minutes in increasing concentrations/ volumes, starting at dilutions of 1/10 000, until neat injections were used. This was repeated at 7-day intervals for 3 weeks, and on day 49. Loss of skin sensitivity was shown to be a good predictor of tolerance. Both patients then continued to receive monthly injections of cyanocobalamin with out ill effect. In these cases cross-sensitivity between the two products was evident, so desensitization was necessary to continue treatment.
M.C. Allwood
A rare case of a type I immediate hyper sensitivity reaction to cyanocobalamin but not to hydroxocobalamin has been reported (4A). • A 42-year-old woman with a background of autoimmune polyglandular syndrome developed an intense pruritic generalized urticarial rash about 1 hour after a monthly intramuscular injection of cyanocobalamin 1000 µg. She retrospectively commented that she had had itching of both hands after previous injections, which had started 18 months earlier. The urticaria persisted over the next 4 weeks and was beginning to fade, but flared dramatically with associated angio oedema within minutes of a further injection. Intradermal testing showed a positive reaction to cyanocobalamin, although a negative reaction to hydroxocobalamin. She was subsequently treated successfully with intra muscular hydroxocobalamin.
As both injections contained identical exci pients, it was concluded that this was a true immediate type 1 hypersensitivity reaction to cyanocobalamin, without cross-reactivity to hydroxocobalamin, which therefore provided a safe alternative source of the vitamin.
Folic acid Immunologic Presumed anaphylactic reac tions to oral folic acid have occasionally been reported without confirmation by controlled challenge. There has been a report, which may be the first, of the confirmation of the role of folic acid in such a reaction (5A). • A 44-year-old Caucasian woman had had anaphylactic reactions on a number of occasions 10–20 minutes after taking multivitamin products over 5 years. Skin prick tests were positive to only one of the products (which contained vitamin B6, cyanocobalamin, and folic acid). The formulation excipients tested negative on oral challenge. After oral provocation with the product, the patient developed a generalized urticarial eruption and mild laryngeal dyspnea. Her symptoms resolved gradually after treatment with an intravenous histamine H1 receptor antagonist and prednisolone and fenoterol by aerosol. After a repeated challenge 4 weeks later with an oral formulation of folic acid 500 µg, she had a similar anaphylactic reaction. Challenges with vitamin B6 and cyanocobalamin were negative.
Vitamins, intravenous solutions, and drugs and formulations used in nutrition
Naturally occurring folates (pteroylpoly glutamates) are composed of folic acid and polyglutamate moieties, which are cleaved in the gastrointestinal tract before absorption of the reduced form of folic acid. The patient was therefore advised to avoid synthetically produced folic acid and to take a diet rich in natural folates.
Tetrahydrobiopterin and sapropterin Tetrahydrobiopterin is a naturally occurring nutrient and an essential cofactor of enzymes involved in the biosynthesis of 5-hydroxy tryptamine (5-HT, serotonin), dopamine, noradrenaline (norepinephrine), adrenaline (epinephrine), melatonin, and nitric oxide (6R). The enzymes for which it is a cofactor include tryptophan hydroxylase, phenylala nine hydroxylase, tyrosine hydroxylase, nitric oxide synthase, and glyceryl ether monooxygenase. Sapropterin is a synthetic form of tetrahydrobiopterin prepared from the dihydrochloride salt (7R). Both tetra hydrobiopterin and sapropterin lower blood phenylalanine concentration not, as it is thought, by changing the synthesis or regen eration of the cofactor, but rather by an effect on the mutant enzyme phenylalanine hydro xylase, either by accommodating the higher Km of the mutant enzyme or by acting as a chaperone for it (8R). They have been used to treat phenylketonuria (9R, 10R, 11M), which affects about 50 000 people in devel oped countries, as it was shown that tetra hydrobiopterin reduced serum phenylalanine concentrations in a 6-month-old girl with atypical phenylketonuria due to defective dihydrobiopterin synthesis, with normal activities of phenylalanine hydroxylase and dihydropteridine reductase in a liver biopsy, but markedly reduced phenylalanine hydro xylase activity in serum (12A). However, not all patients with phenylketo nuria respond to these compounds (13c), and a fall in blood phenylalanine concentration of at least 30% is the benchmark for success. An initial challenge with 20 mg/kg/day and blood phenylalanine concentration measurements
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on days 0, 1, 7, 14, and 28 can identify respon ders; algorithms for doing this are shown in Figure 1. The algorithm shown in the upper panel of Figure 1 involves measurements over 4 weeks (14H). After measuring the blood phenylalanine concentration, give an initial dose of sapropterin of 20 mg/kg and re-measure on day 1, since some are very sensitive to its effects. Then re-measure at weekly intervals. If there is a satisfactory response continue the treatment and pay attention to dietary phenylalanine intake. If there is not, consider possible factors that may be interfering with treatment (e.g. poor adherence); if those are ruled out and there is still no response consider withdrawing the sapropterin, as the patient is a non-responder. A simpler algorithm, involving measurements over 3 days (15H), is shown in the lower panel of Figure 1. Another possible approach to predicting responders to sapropterin is to use a pharma cogenetic test, as specific mutations in the phe nylalanine hydroxylase gene are associated with partial responsiveness (16C–19C). How ever, factors other than the phenylalanine hydroxylase genotype, such as variations in the pharmacokinetics of sapropterin, contri bute to responsiveness (20C), and most patients are compound heterozygotes. More than 60 mutant alleles have been described, and in one study of 39 patients responsiveness to sapropterin was predicted by genotype in only 36% overall; the most responsive geno types were p.E390G/p.R408W and p.P281L/ p.E390G, and the p.E390G mutation was associated with 100% responsiveness (21C). The main adverse effects of sapropterin are headache, rhinorrhea, pharyngolaryngeal pain, nasal congestion, cough, diarrhea, vomiting, abdominal pain, and hypophenyl alaninemia (22R). Observational studies An 8-day course of sapropterin dihydrochloride 10 mg/kg/ day has been studied in 485 patients with phenylketonuria aged at least 8 years; 96 had at least a 30% reduction in blood phe nylalanine concentration after 8 days and were classed as responders, although there was wide variability and phenylalanine
Day 1
Day 7
Day 14
Measure Give sapropterin 20 mg/kg/day
Measure
Measure
Measure
610
Day 0
Day 28 Very low concentration
Y Consider adding phenylalanine to diet Give sapropterin 5–20 mg/kg/day
> 30% fall in concentration
N
Y
Continue sapropterin 20 mg/kg/day
>30% fall in concentration
N
Continue sapropterin 5–20 mg/kg/day
Y
Continue sapropterin 20 mg/kg/day
Measure
N
Continue sapropterin 5–20 mg/kg/day
Factors that could interfere with response (e.g. poor adherence)
N
Y
Continue sapropterin 20 mg/kg/day
Consider withdrawing sapropterin
Day 0
Y Continue sapropterin 5–20 mg/kg/day
N If no factors that could interfere with response (e.g. poor adherence), consider withdrawing sapropterin
Day 2
Measure × 3
Measure × 3
N > 30% fall in concentration
Figure 1 Algorithms for determining dosage regimens of sapropterin.
Continue sapropterin 5–20 mg/kg/day
N
Stop
Y
Continue sapropterin 5–20 mg/kg/day
> 30% fall in concentration
M.C. Allwood
Y
Continue sapropterin 20 mg/kg/day
Chapter 34
Measure × 3 Give sapropterin 20 mg/kg/day
Day 1
>30% fall in concentration
Vitamins, intravenous solutions, and drugs and formulations used in nutrition
concentration fell in all subgroups; the response was greater in those with lower baseline concentrations (23c). Most of the reported adverse events were mild and all resolved without complications. Adverse events that were reported by at least 2% of the patients were headache (n = 50, 10%), diarrhea (24, 5%), abdominal pain (23, 5%), nausea (16, 3%), upper respiratory tract infections (17, 3%), fatigue (14, 3%), flatulence (11, 2%), vomiting (9, 2%), reduced appetite (8, 2%), pharyngolaryngeal pain (9, 2%), hyper-reflexia (10, 2%) and tremor (9, 2%). The authors commented that the response to sapropterin dihy drochloride could not be predicted from the baseline phenylalanine concentration. Placebo-controlled studies The efficacy of sapropterin 10 mg/kg/day has been studied in 89 patients with phenylketonuria, mean age 20 years, in a Phase III, multicenter, randomized, double-blind, placebocontrolled trial for 6 weeks (24C). The blood concentration of phenylalanine fell from 843 to 236 µmol/l in those who were given sapropterin and rose by 3 µmol/l with placebo. There were adverse events that might have been drug-related in 11 of the 47 patients who took sapropterin and 8 of the 41 who took placebo; upper respiratory tract infections were the most common. In a 22-week, multicenter, randomized, placebo-controlled study in 80 patients aged at least 8 years, sapropterin reduced plasma phenylalanine concentrations dose-depen dently from 844 to 645 µmol/l (25c). There were adverse events in 68 patients; all but one were mild or moderate in intensity, but neither the severe nor any of the three serious adverse events was considered to have been related to sapropterin and none led to withdrawal. In an international, double-blind, rando mized, placebo-controlled study in 90 patients with phenylketonuria, sapropterin 20 mg/kg/ day caused the following adverse effects in more than 5% of subjects and more often than placebo: rhinorrhea (n = 7, 21%), headache (7, 21%), cough (5, 15%), pharyn golaryngeal pain, diarrhea, and vomiting (4 each, 12%), nasal congestion (3, 9%) and reduced appetite, erythema, excoriation,
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lymphadenopathy, and toothache (2 each, 6%); none was severe or serious (26C). Cardiovascular Sapropterin significantly increased endothelium-dependent vasodil atation in smokers but not in non-smokers (27c).
VITAMIN C (Ascorbic acid) (SED-15, 351; SEDA-30, 394; SEDA-31, 548) Metabolism Renal vitamin C is a precur sor of oxalate and promotes its absorption, potentially causing hyperoxaluria, the com monest cause being related to enzymic defi ciency. Less well recognized is subacute insidious nephropathy from secondary causes, for example excessive vitamin C intake and malabsorption, which causes cal cium chelation with fatty acids, producing enteric hyperoxaluria. This can be accentu ated by dehydration and hypocitraturia from diarrhea-induced metabolic acidosis (28A). • A 73-year-old man took an oxalate-rich diet plus vitamin C 680 mg/day and furosemide and developed chronic diarrhea and a serum creatinine of 740 µmol/l (compared with 106 µmol/l 4 months before; reference range 50–120). The cause was postulated as calcium oxalate-induced nephropathy, which was confirmed by hyperoxaluria and diffuse intraluminal crystals and extensive interstitial fibrosis on biopsy. He was haemodialysed six times to remove excess oxalate. Within 2 weeks of stopping vitamin C, his creatinine fell to 273 µmol/l, and 3 months later, on a low-oxalate diet and vitamin B6 100 mg/day, his urine oxalate-to-creatinine ratio fell from 0.084 to 0.02 (normal less than 0.035), while the creatinine fell and stabilized at 158 µmol/l.
High-dose vitamin C can cause hyperoxaluric nephropathy and progressive renal insufficiency, especially if aggravated by diarrhea, an oxalate-rich diet, metabolic acidosis, and dehydration. The authors
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conclude that the diagnosis should be sus pected in patients with unexplained renal insufficiency when associated with these susceptibility factors and recommend mon itoring urinary oxalate in patients taking high-dose vitamin C and renal biopsy if necessary.
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have been aggravated by the nephropathic adverse effects of tenofovir. However, after recovery of renal function, the tenofovir was restarted without further deterioration.
VITAMIN E (SED-15, 3677; SEDA-29, 355; SEDA-30, 395; SEDA-31, 549)
VITAMIN D ANALOGUES (SED-15, 3669; SEDA-29, 354; SEDA-30, 394; SEDA-31, 549) Mineral metabolism Hypercalcemia in patients with human immunodeficiency virus (HIV) infection is usually associated with conditions such as lymphoma and granulomatous diseases. Severe hypercal cemia secondary to vitamin D intoxication and secondary renal insufficiency in an HIV-positive patient has been described (29A). • A 38-year-old man developed acute symptoms of nausea, constipation, apathy, drowsiness, weakness, and polyuria. He had AIDS and had taken efavirenz, lamivudine, and tenofovir for 2 years. Physical examination was normal and there were no pulmonary, cardiac, or abdominal abnormalities. However, he had hypercalcemia (total serum calcium total 3.9 mmol/l; ionized plasma calcium 2.0 mmol/l) and renal insufficiency (creatinine 405 µmol/l); phosphate was normal. There were calcium oxalate crystals in the urine, and renal ultrasound showed normal-sized kidneys with a mild parenchymatous nephropathy reflecting acute renal insufficiency. There was ST segment elevation in leads V1 and V3 and diffuse T wave flattening. He had taken excess hormones and vitamins over 5 years, including multivitamin preparations, intramuscular testosterone and, for the last 4 months, a daily intramuscular veterinary injection of vitamins A (2 500 000 IU), D (700 000 IU), and E (700 IU). All medications were withdrawn and he was rehydrated and given furosemide. His condition slowly improved and his renal function returned to near normal after 7 days.
The authors suggested that the acute renal failure secondary to vitamin D abuse could
Infection risk In an analysis of the AlphaTocopherol, Beta-Carotene Cancer Preven tion (ATBC) study, a randomized con trolled trial of the effects of vitamin E 50 mg/day and beta-carotene 20 mg/day in 29 023 men aged 50–69 years with lung can cer in Finland in 1985–1993, neither vitamin E nor beta-carotene had any overall effect on the incidence of tuberculosis, but there was an effect of dietary vitamin C on the risk of tuberculosis associated with vitamin E (30c). Among participants who obtained 90 mg/day or more of vitamin C in foods (n = 13 502), vitamin E supplementation increased the risk of tuberculosis by 72% (95% confidence interval [CI] = 4, 185). This effect was restricted to those who smoked heavily. In those who were not given vitamin E supplements, dietary vita min C was negatively associated with the risk of tuberculosis. Death A meta-analysis of 11 randomized placebo-controlled trials of high-dose vita min E (over 400 IU/day) showed increased mortality (SEDA-29, 355). Its use has been studied in patients with cardiovascular disease (31c). After adjust ment for age and sex there was no associa tion between the use of vitamin E and mortality (adjusted hazard ratio [HR] = 0.93; 95% CI = 0.74, 1.15). Deaths were more frequent in those with a history of diabetes, stroke, coronary artery bypass graft surgery, or myocardial infarction, and were associated with the use of warfarin, nitrates, and diuretics. Mortality was increased in vitamin E users who had a
Vitamins, intravenous solutions, and drugs and formulations used in nutrition
history of stroke (adjusted HR = 3.64; CI = 1.73, 7.68), coronary bypass graft surgery (adjusted HR = 4.40; CI = 2.83, 6.83) or myo cardial infarction (adjusted HR = 1.95; CI = 1.29, 2.95), and independently in those taking nitrates (adjusted HR = 3.95; CI = 2.04, 7.65), warfarin (adjusted HR = 3.71; CI = 2.22, 6.21), and diuretics (adjusted HR = 1.83; CI = 1.35, 2.49).
PARENTERAL NUTRITION (SED-15, 2700; SEDA-29, 353; SEDA-31, 549) Liver A surgical patient with short bowel syndrome developed parenteral nutritionassociated liver disease and was successfully treated with fish oil-based lipids (32A). • A full-term neonate weighing 3.45 kg was referred at 60 days of age for surgery for short bowel secondary to a mid-gut volvulus. He was given parenteral nutrition and after 4 months developed conjugated hyper bilirubinemia. He was unable to tolerate enteral feeding, so parenteral nutrition was continued, despite jaundice. Infection and biliary obstruction were ruled out, and a range of treatments for jaundice were initiated without success. He continued to deteriorate despite cholecystectomy and irrigation of the biliary tree. After 80 days of parenteral nutrition, the lipid was changed from omega-6 lipids (Lipofundin®, B. Braun) and replaced by an omega-3 based emulsion (Omegaven®, Fresenius–Kabi), in an initial dose of 0.2 g/kg/day, increasing by 0.2 g/kg increments to 1.5 g/kg/day. His hepatic function improved rapidly over the following months, and was completely normal after 8 months, despite continuing cyclic parenteral nutrition with 50% enteral feeding.
This carefully investigated case provides further evidence for the potential value of fish oil-based fat emulsions to prevent and overcome parenteral nutrition-associated liver disease in neonates and small children. Biliary tract Cholestasis is a major complication of total parenteral nutrition,
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and is difficult to treat. It can progress to eventual cirrhosis and liver failure. The benefits of ursodeoxycholic acid (ursodiol) in the treatment of cholestasis can be explained by its effects on bile composition and flow and its cytoprotective, membranestabilizing, and immunomodulatory effects. The evidence for a role of ursodeoxycholic acid in parenteral nutrition-associated cholestasis has been reviewed (33R). In the short term it improves the biochemical and clinical signs and symptoms. However, this may not necessarily predict the outcome and it may not be effective in patients with short bowel syndrome or in those with resected terminal ileum because of reduced absorption of ursodeoxycholic acid. However, as optimal dosing, timing, duration of therapy, and long-term effects on the out come and prognosis in parenteral nutritionassociated cholestasis require further studies, its clinical effectiveness remains uncertain. Drug administration route Percutaneous central venous catheters are commonly inserted in neonatal intensive care nurseries. Placement of the catheter tip in a large central vein is desirable. Occasionally, owing to difficult venous access, catheter tips are left in places that are less than ideal (34A). • A female infant with complicated gastroschisis developed signs of short bowel syndrome after surgery. She was treated with a combination of enteral and parenteral nutrition. A central venous line was inserted through a scalp vein and the tip was in a vessel at the level of the mandible. About 2 weeks later she became unwell, with episodes of bradycardia and large milky pharyngeal aspirates, confirmed to contain parenteral nutrition fluid. Chest radiography showed aspiration. After withdrawal of parenteral nutrition, there was a dramatic reduction in oral secretions. The central venous line was removed because of presumed extravasation.
The authors recommended that when cathe ters are in unusual positions it may be helpful to obtain a second radiograph from a differ ent angle or an ultrasound scan to confirm the position of the catheter tip.
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References 1. Saltzman MD, King EC. Central physeal arrests as a manifestation of hypervitamino sis A. J Pediatr Orthop 2007;27(3):351–3. 2. Penniston KL, Tanumihardjo SA. The acute and chronic affects of vitamin A. Am J Clin Nutr 2006;83:191–201. 3. Caballero MR, Lukawska J, Lee TH, Dugue P. Allergy to vitamin B12: two cases of suc cessful desensitization with cyanocobalamin. Eur J Allergy Clin Immunol 2007;62:1341–2. 4. Moloney FJ, Hughes R, O’Shea D, Kirby B. Type I immediate hypersensitivity reaction to cyanocobalamin but not hydroxycobala min. Clin Exp Dermatol 2008;33:412–4. 5. Pfab F, Willi R, Albert A, Huss-Marp J, Athanasiadis GI, Jakob T, Ollert M, Ring J, Darsow U. Anaphylactic reaction to folic acid verified by provocational testing. Eur J Allergy Clin Immunol 2007;62(7):823–4. 6. Thöny B, Auerbach G, Blau N. Tetrahydro biopterin biosynthesis, regeneration and functions. Biochem J 2000;347(Pt 1):1–16. 7. Burton BK, Kar S, Kirkpatrick P. Fresh from the pipeline: sapropterin. Nat Rev Drug Dis cov 2008;7:199–200. 8. Michals-Matalon K. Sapropterin dihydrochlor ide, 6-R-L-erythro-5,6,7,8-tetrahydrobiopterin, in the treatment of phenylketonuria. Expert Opin Investig Drugs 2008;17(2):245–51. 9. Burnett JR. Sapropterin dihydrochloride (Kuvan/phenoptin), an orally active syn thetic form of BH4 for the treatment of phenylketonuria. Drugs 2007;10(11):805–13. 10. Sanford M, Keating GM. Spotlight on sapropterin in primary hyperphenylalanine mia. BioDrugs 2009;23(3):201–2. 11. Hegge KA, Horning KK, Peitz GJ, Hegge K. Sapropterin: a new therapeutic agent for phenylketonuria. Ann Pharmacother 2009; 43(9):1466–73. 12. Schaub J, Däumling S, Curtius HC, Nieder wieser A, Bartholomé K, Viscontini M, Schircks B, Bieri JH. Tetrahydrobiopterin therapy of atypical phenylketonuria due to defective dihydrobiopterin biosynthesis. Arch Dis Child 1978;53(8):674–6. 13. Doggrell SA. Is sapropterin treatment suita ble for all subjects with phenylketonuria? Expert Opin Pharmacother 2008;9(1):145–7.
14. Levy H, Burton B, Cederbaum S, Scriver C. Recommendations for evaluation of respon siveness to tetrahydrobiopterin (BH(4)) in phenylketonuria and its use in treatment. Mol Genet Metab 2007;92(4):287–91. 15. Blau N, Bélanger-Quintana A, Demirkol M, Feillet F, Giovannini M, MacDonald A, Trefz FK, van Spronsen FJ. Optimizing the use of sapropterin (BH(4)) in the manage ment of phenylketonuria. Mol Genet Metab 2009;96(4):158–63. 16. Trefz FK, Scheible D, Götz H, FrauendienstEgger G. Significance of genotype in tetrahydrobiopterin-responsive phenylketo nuria. J Inherit Metab Dis 2009;32(1):22–6. 17. Muntau AC, Röschinger W, Habich M, Demmelmair H, Hoffmann B, Sommerhoff CP, Roscher AA. Tetrahydrobiopterin as an alternative treatment for mild phenylketo nuria. N Engl J Med 2002;347(26):2122–32. 18. Zurfl€ uh MR, Zschocke J, Lindner M, Feillet F, Chery C, Burlina A, Stevens RC, Thöny B, Blau N. Molecular genetics of tetrahydrobiop terin-responsive phenylalanine hydroxylase deficiency. Hum Mutat 2008; 29(1):167–75. 19. Desviat LR, Pérez B, Bèlanger-Quintana A, Castro M, Aguado C, Sa´ nchez A, García MJ, Martínez-Pardo M, Ugarte M. Tetrahydro biopterin responsiveness: results of the BH4 loading test in 31 Spanish PKU patients and correlation with their genotype. Mol Genet Metab 2004;83(1–2):157–62. 20. Feillet F, Clarke L, Meli C, Lipson M, Morris AA, Harmatz P, Mould DR, Green B, Dor enbaum A, Giovannini M, Foehr E, Saprop terin Research Group. Pharmacokinetics of sapropterin in patients with phenylketonuria. Clin Pharmacokinet 2008;47(12):817–25. 21. Karacic I, Meili D, Sarnavka V, Heintz C, Thöny B, Ramadza DP, Fumic K, Mardesic D, Baric I, Blau N. Genotype-predicted tet rahydrobiopterin (BH4)-responsiveness and molecular genetics in Croatian patients with phenylalanine hydroxylase (PAH) defi ciency. Mol Genet Metab 2009;97(3):165–71. 22. Sanford M, Keating GM. Sapropterin: a review of its use in the treatment of primary hyperphenylalaninaemia. Drugs 2009;69(4): 461–76.
Vitamins, intravenous solutions, and drugs and formulations used in nutrition 23. Burton BK, Grange DK, Milanowski A, Vock ley G, Feillet F, Crombez EA, Abadie V, Hard ing CO, Cederbaum S, Dobbelaere D, Smith A, Dorenbaum A. The response of patients with phenylketonuria and elevated serum phe nylalanine to treatment with oral sapropterin dihydrochloride (6R-tetrahydrobiopterin): a phase II, multicentre, open-label, screening study. J Inherit Metab Dis 2007;30(5):700–7. 24. Levy HL, Milanowski A, Chakrapani A, Cleary M, Lee P, Trefz FK, Whitley CB, Feillet F, Feigenbaum AS, Bebchuk JD, Christ-Schmidt H, Dorenbaum A, Saprop terin Research Group. Efficacy of saprop terin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine con centration in patients with phenylketonuria: a phase III randomised placebo-controlled study. Lancet 2007;370(9586):504–10. 25. Lee P, Treacy EP, Crombez E, Wasserstein M, Waber L, Wolff J, Wendel U, Doren baum A, Bebchuk J, Christ-Schmidt H, Sea shore M, Giovannini M, Burton BK, Morris AA. Sapropterin Research Group. Safety and efficacy of 22 weeks of treatment with sapropterin dihydrochloride in patients with phenylketonuria. Am J Med Genet A 2008;146A(22):2851–9. 26. Trefz FK, Burton BK, Longo N, Casanova MM, Gruskin DJ, Dorenbaum A, Kakkis ED, Crombez EA, Grange DK, Harmatz P, Lipson MH, Milanowski A, Randolph LM, Vockley J, Whitley CB, Wolff JA, Bebchuk J, Christ-Schmidt H, Hennermann JB, Saprop terin Study Group. Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind,
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placebo-controlled study. J Pediatr 2009;154 (5):700–7. 27. Ueda S, Matsuoka H, Miyazaki H, Usui M, Okuda S, Imaizumi T. Tetrahydrobiopterin restores endothelial function in long-term smokers. J Am Coll Cardiol 2000;35(1):71–5. 28. Rathi S, Kern W, Vitamin LK. C-induced hyperoxaluria causing reversible tubulointersti tial nephritis and chronic renal failure: a case report. J Med Case Reports 2007;1:155–60. 29. Tuon FF, Nihei CH, Gryschek RC, Seguro AC. Vitamin D intoxication: a cause of hypo calcaemia and acute renal failure in a HIV patient. Int J STD AIDS 2008;19:137–8. 30. Hemilä H, Vitamin KJ. E supplementation may transiently increase tuberculosis risk in males who smoke heavily and have high dietary vita min C intake. Br J Nutr 2008;100(4):896–902. 31. Hayden KM, Welsh-Bohmer KA, Wengreen HJ, Zandi PP, Lyketsos CG, Breitner JC. Cache County Investigators. Risk of morta lity with vitamin E supplements: the Cache County study. Am J Med 2007;120(2):180–4. 32. Ekema G, Falchetti D, Boroni G, Tanca AR, Altana C, Righetti L, Ridella M, Gambarotti M, Berchich L. Reversal of severe parenteral nutrition-associated liver disease in an infant with short bowel syndrome using parenteral fish oil (omega-3 fatty acids). J Pediatr Surg 2008;43:1191–5. 33. San Luis VA, Btaiche IF. Ursodiol in patients with parenteral nutrition-associated cholesta sis. Ann Pharmacother 2007;41:1867–72. 34. Jardine LA, Inglis GDT, Davies MW. Aspiration of parenteral nutrition – a pre viously unreported complication of central venous access in an infant: a case report. J Med Case Reports 2008;2:63–5.
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35
Drugs that affect blood coagulation, fibrinolysis, and hemostasis
Editor’s note: The clotting factors, such as factor VIII, and anticoagulant proteins, such as activated factor C, are included in Chapter 33.
COUMARIN ANTICOAGULANTS
(SED-15, 983; SEDA-29, 358; SEDA-30, 399; SEDA-31, 553)
Cardiovascular Matrix g-carboxyglutamic acid protein, a vitamin K-dependent pro tein, is a potent in vivo inhibitor of arterial calcification (1E) and Growth Arrest Spe cific Gene 6 (Gas-6), which is also vitamin K-dependent, protects the vasculature by effects on vascular smooth muscle cell apoptosis and movement (2R). Unlike the coagulant factors, which are carboxylated in the liver, these two proteins are carboxy lated in blood vessels, but both are inhibited by warfarin. Furthermore, poly morphisms of the VKORC1 gene (the CC and CT genotypes) confer nearly twice the risk of vascular events (stroke, coronary artery disease, aortic dissection) and are associated with lower levels of osteocalcin and Protein Induced in Vitamin K Absence or Antagonism II (PIVKA-II, a des-gSide Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32035-6 2010 Elsevier B.V. All rights reserved.
carboxyprothrombin) than those with the TT genotype (3c). In this context it has therefore been suggested that three factors may influence arterial calcification: (a) the level of expression of matrix g-carboxyglu tamic acid protein; (b) vitamin K status; and (c) mutations or polymorphisms that affect the activities of either g-glutamyl carboxylase or vitamin K epoxide reduc tase complex (4Hr). One might therefore expect long-term warfarin treatment to be associated with an increased risk of vascu lar disease. Calciphylaxis (vascular calcification, thrombosis, and skin necrosis) has been attributed to warfarin in a patient with diabetes mellitus (5A). However, in 116 patients with diabetes and hypertension, half of whom were taking warfarin, there was no effect on systolic blood pressure or pulse pressure (6c). Arterial thrombosis has been attributed to the prothrombotic effect of warfarin in a patient with protein S deficiency (7A). Sensory systems The incidence of ocular bleeding has been studied in 210 patients taking warfarin and in 210 sex-matched and age-matched controls (8c). The inci dences of ocular bleeding were 11% in the patients and 3.8% in the controls; the risk was higher in older than in younger patients and was five times higher in patients with hypertension. A large subconjunctival hemorrhage occurred in a 76-year-old woman with an international normalized ratio (INR) of 10;
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the authors suggested that such abnormal ities could herald more serious risks (9A). Hematologic Thrombocytopenia with antibodies similar to those found in heparin-induced thrombocytopenia (HIT) has been reported in patients in whom there had been no previous exposure to heparin. In three cases the thrombocyto penia was preceded by an infectious or inflammatory episode (10A). In another case it was associated with warfarin (11A). • A 69-year-old woman with no previous known heparin exposure was given warfarin after a total knee replacement. After 7 days she developed thrombocytopenia and died after a complex postoperative course, which included multiple thrombotic events (adrenal necrosis presumably caused by adrenal vein thrombosis, digital infarcts, deep vein thrombosis), and disseminated intravascular coagulation. The presurgery serum was negative for HIT antibodies but three postoperative sera were strongly positive in three different assays. Her serum contained anti-PF4–heparin antibodies of the IgG class with strong platelet-activating properties, which is a feature of some HIT sera, especially those from patients with the delayed-onset type, the type that begins several days after stopping heparin.
The authors of these reports have called this syndrome ‘spontaneous HIT’, a potentially scatological nomenclature, which ought to be replaced, since it is also misleading, as it has nothing to do with heparin administration. Acquired hemophilia with antibodies to factor VIII has been reportedly masked by concurrent warfarin therapy, to which the prolonged activated partial thromboplastin time was falsely attributed (12A). Liver It has been hypothesized that the hepatotoxicity that has been attributed to warfarin in experimental animals is due to the formation of a toxic metabolite, o-hydroxyphenylacetylacetaldehyde, which is formed when warfarin is metabolized to 3-hydroxycoumarin, rather than 7-hydroxy coumarin; the former is more likely to be formed in patients with reduced CYP2A6 activity (13H).
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Skin Warfarin-induced skin necrosis (14A) can occur early in therapy because of local coagulation, since the anticoagulant factors protein C and protein S are vitamin Kdependent; it is more likely to occur in those who have deficiencies of these pro teins, as further reports have highlighted (15A), one in association with a leukocyto clastic vasculitis (16A). In one case there was also a mutation in the methylene tetrahydro folate reductase (MTFR) gene (17A), but this may have been coincidental. The necro sis usually affects areas with abundant sub cutaneous tissues and can start with painful plaques (18A); in one case painful prenecro tic lesions occurred in a patient with hetero zygous protein C deficiency (19A). A rare case affecting the eyelids has been reported (20A). In two other cases skin necrosis attrib uted to warfarin was accompanied by HIT (21A, 22A); it was not clear whether the two events were coincidental or mechanistically linked. However, skin and mucosal ulcera tion can occur in HIT in patients who have not received warfarin (23A); in one case skin necrosis was associated with deficiency of both protein C and protein S (24A). Musculoskeletal The effects of warfarin on bone mineral density have been assessed in 5533 men aged 65 years and older (25C). Warfarin users and 5212 non-users had similar baseline bone mineral density at the hip and spine and similar annualized bone loss at the total hip as 2683 non-users during a mean follow-up of 5.1 years; the risk of non-spinal fractures was similar in the two groups (adjusted HR = 1.06; 95% CI = 0.68, 1.65). Immunologic Coumarins can rarely cause hypersensitivity reactions. Leukocytoclastic vasculitis has been reported (26A, 27A). • A 48-year-old man who had taken warfarin sodium for 2 months developed acute renal failure and reddish purplish macules on his hypogastric regions and legs. Kidney biopsy showed allergic interstitial nephritis and a punch skin biopsy showed a leukocytoclastic vasculitis. Both biopsies also contained large numbers of eosinophils, highly suggestive of a drug-induced reaction.
Drugs that affect blood coagulation, fibrinolysis, and hemostasis • A leukocytoclastic vasculitis has been attributed to acenocoumarol in a 62-year-old woman because of the close temporal relation between exposure to the drug and the onset of the symptoms, and spontaneous resolution of the lesions after acenocoumarol was withdrawn.
Teratogenicity The teratogenic effects of warfarin (‘warfarin embryopathy’) include chondrodysplasia punctata, frontal bossing, a short neck, low birth weight, short limbs, polydactyly, and respiratory difficulty sec ondary to choanal atresia (28R, 29c). Neurological effects include optic atrophy and microcephaly (30c, 31A), the Dandy– Walker malformation and agenesis of the corpus callosum (32Ar), and cerebral hemi spheric atrophy and porencephaly (33A). Neurodevelopmental delay has also been described (34Ar). • A 27-year-old man, whose mother had taken warfarin throughout her pregnancy, had nasal and digital hypoplasia and thoracic kyphosis, delayed developmental milestones, bilateral deafness, and mild intellectual impairment. An MRI brain scan was normal but an MRI scan of the spinal cord showed cord thinning at mid-C2 and compression at C6 secondary to a posterior disc bulge; there was spinal cord compression at T4–T6 with focal thoracic kyphosis and posterior disc bulging.
In a study based on observational data collected by a Teratology Information Ser vice on 1186 pregnant women, of whom 173 had taken a coumarin anticoagulant (almost all phenprocoumon) and 1013 had not been exposed to potential teratogens, the crude rate for live births was higher in the controls (0.91 versus 0.53) and there were lower crude rates for induced abortion (0.02 ver sus 0.22) and spontaneous abortion (0.07 versus 0.25) (35c). When correction was introduced for potential biases, the rates for spontaneous abortion increased to 0.16 and 0.42 respectively. When adjustment was made for delayed entry, the rates of induced abortion were 0.04 (controls) and 0.29 (war farin) and for spontaneous abortion 0.05 and 0.36 respectively. Susceptibility factors Genetic In patients who were genotyped
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polymorphisms in 29 genes related to warfarin pharmacodynamics and pharmaco kinetics, polymorphisms in or flanking the genes VKORC1, CYP2C9, CYP2C18, CYP2C19, PROC, APOE, EPHX1, CALU, GGCX, and ORM1-ORM2, and haplotypes of VKORC1, CYP2C9, CYP2C8, CYP2C19, PROC, F7, GGCX, PROZ, F9, NR1I2, and ORM1-ORM2 were significantly associated with dose (36c). The associations with VKORC1, CYP2C9, CYP2C18, and CYP2C19 remained significant after correction for multiple testing, but the associations with CYP2C18 and CYP2C19 were explained by linkage disequilibrium with CYP2C9*2 and/ or CYP2C9*3. PROC and APOE were both significantly associated with dose after cor rection within each gene. A multiple regres sion model with VKORC1, CYP2C9, PROC, and the non-genetic predictors age, body weight, drug–drug interactions, and indication for treatment jointly accounted for 62% of the variance in warfarin dose. The authors of this chapter were perhaps unduly optimistic about the potential contri bution of these findings to the clinical use of warfarin, as others have been (37R). Some have been less impressed (38r, 39r). It has been commented that while there is evidence of clinical validity of both VKORC1 and CYP2C9 genes in predicting stable warfarin doses (an intermediate outcome), there is little or no evidence that VKORC1 and CYP2C9 testing will reduce the risk of severe bleeding events (40R). The American College of Medical Genetics has concluded (February 2008) that ‘there is insufficient evidence, at this time, to recommend for or against routine CYP2C9 and VKORC1 test ing in warfarin-naive patients’ (41S). A pharmacogenetic algorithm has been developed based on a study in 1015 patients, in whom the independent predic tors of therapeutic dose were VKORC1 polymorphism 1639/3673 G> A (–28% per allele); body surface area (þ11% per 0.25 m2); CYP2C9*3 (–33% per allele); CYP2C9*2 (–19% per allele); age (–7% per decade); target INR (þ11% per 0.5 unit increase); amiodarone use (–22%); smoker status (þ10%); race (–9%); and cur rent thrombosis (þ7%) (42C). The algorithm
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explained just over 50% of the variability in the warfarin dose in a sample of 292 indivi duals in the cohorts. A clinical equation explained only about 20% of the variability. In a prospective study of the use of the algo rithm in patients initiating warfarin therapy, two had a major hemorrhage. The algorithm is available on the web (43H). African-Americans have slightly higher warfarin dosage requirements. Polymorph isms in the gene encoding apolipoprotein E (APOE) may partly explain this variability by altering transport of vitamin K to the liver, as has been shown in a prospective study of 232 individuals (52% Caucasian and 48% African-American) (44c). In multi variate analyses, the presence of the 4 allele was associated with a statistically signifi cantly higher dose of warfarin among Afri can-Americans (45 mg versus 35 mg) but not in Caucasians (38 mg versus 35 mg). In addi tion, the warfarin maintenance dose increased in African-Americans according to the genotypes that have previously asso ciated with differential hepatic chylomicron clearance (2/2 or 2/3, 30 mg; 3/3, 35 mg; 3/4 or 4/4, 45 mg), although the 4/4 genotype was rare and not clearly associated with higher doses. The association of APOE with warfarin dosing was independent of CYP2C9 and VKORC1 polymorphisms. In a prospective study in 362 patients with INRs of 2–3 the maintenance dose of warfarin was significantly related to CYP2C9 genotype in Caucasians but not in African-Americans; among the former, variant carriers (CYP2C9*2 and CYP2C9*3) needed 31 mg/week while wild-type carriers required 38 mg/week, even after adjustment for possible con founding factors (45c). Among the AfricanAmericans there was no difference based on CYP2C9 genotype. In another comparison of CYP2C9 and VKORC1 1173C/T genotypes and the risk of hemorrhage among African-Americans and European-Americans there were 44 major and 203 minor episodes of hemor rhage during 555 person-years in 446 patients (mean age 61 years, 50% men, 227 African-Americans) (46c). The variant CYP2C9 genotype conferred an increased
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risk of major hemorrhage (HR = 3.0; 95% CI = 1.1, 8.0) but not minor hemorrhage (HR = 1.3; 95% CI = 0.8, 2.1). The risk of major hemorrhage was 5.3 times higher (95% CI = 0.4, 64) before stabilization of therapy, 2.2 times higher (95% CI = 0.7, 6.5) after stabilization and 2.4 times higher (95% CI = 0.8, 7.4) during all periods when anticoagulation was not stable. The variant VKORC1 1173C/T genotype did not confer a significant increase in the risk of major hemorrhage (HR = 1.7; 95% CI = 0.7, 4.4) or minor hemorrhage (HR = 0.8; 95% CI = 0.5, 1.3). The distribution of genotypes of CYP2C9*2, CYP2C9*3, and VKORC1 Asp36Tyr genotypes in Ethiopians has been reported: 13/150 were heterozygous for CYP2C9*2; 7/150 were heterozygous for CYP2C9*3; and 39/154 were hetero zygous and 3/154 were homozygous for the Asp36Tyr polymorphism in VKORC1, which confers warfarin resistance (47c). In contrast to African-Americans, Asian patients require a much lower maintenance dose than Caucasians. In a study of five single nucleotide polymorphisms of the vita min K epoxide reductase complex subunit 1 gene (VKORC1) and the CYP2C9*3 var iant 108 Korean patients with atrial fibrilla tion, the genotypic frequencies of VKORC1 þ1173CT and CYP2C9*1/*3 were 18 and 10% respectively; VKORC1 þ1173CC and CYP2C9*3/*4 were found in one patient each (48c). Patients with at least one copy of the VKORC1 þ1173C allele or the H7 (group B) haplotype required a significantly higher dose of warfarin (n = 20; 5.5 mg/day) than those who were homozygous for the þ1173T allele or the H1 (group A) haplo type (3.8 mg/day). There were also statisti cally significant differences in warfarin dose between those with the CYP2C9*1/*1 var iant (4.3 mg/day) and those with the geno types CYP2C9*1/*3 and CYP2C9*3/*4 (2.7 mg/day). Of 66 Korean patients in whom CYP2C19 polymorphisms were evaluated, 25 were homozygous for the wild type, 4 had hetero zygous mutations at both loci and others had mutations on either the CYP2C19*2 or *3 locus (49c). There was a higher incidence of
Drugs that affect blood coagulation, fibrinolysis, and hemostasis
bleeding complications in those with a higher allele frequency of CYP2C19. However, the distribution of polymorphisms was similar to that in a Caucasian population. In 191 patients taking warfarin, half of whom were Malays and half Chinese, two CYP2C9 genotypes were detected; 93% had CYP2C9 1/1 and 7% CYP2C9 1/3 (50c). Warfarin doses were higher in patients with the former genotype but patients with the latter genotype had a higher rate of serious and life-threatening episodes of bleeding (15 versus 6.2 per 100 patients per 6 months). Renal disease In a systematic review of case series, cohort studies and randomized controlled trials in patients undergoing dia lysis, the risk of bleeding associated with warfarin compared with no warfarin or subcutaneous heparin was reported as the number of bleeding episodes per number of patient-years of warfarin exposure or fol low-up (51M). Eight studies were eligible for analysis, seven of which evaluated the use of warfarin for the prevention of hemo dialysis access thrombosis. Formal meta analysis was not possible because of hetero geneity. Major bleeding episodes occurred at a rate of 0.1–0.54 events per patient-year of warfarin exposure, about twice as high as in patients who received either no warfarin or subcutaneous heparin. These results may have been confounded by co-morbidities. Dental extraction In 58 women and 92 men, mean age 66 years, the mean INR was 2.5 (range 0.9–4.2), and 49 (33%) had an INR over 2.5; 10 bled after dental extrac tion, 5 of whom had an INR over 2.5; they were all managed conservatively and none was admitted to hospital (52c). Drug administration route The successful use of intravenous warfarin has been reported in a 27-year-old woman with endstage Crohn’s disease, who was resistant to oral warfarin and unable to receive sub cutaneous low-molecular-weight heparin because of adverse effects (53A).
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In two patients who required long-term anticoagulation but had gastrointestinal dysmotility, sublingual warfarin was effec tive; the target INR was achieved within 6 days (54A). Drug overdose The anticoagulants in modern rodenticides, so-called ‘superwar farins’, have very long durations of action. In cases of overdose with such agents, prolonged therapy may be required before coagulation returns to normal, as another case has demonstrated (55A). Drug–drug interactions The frequency, severity, and preventability of cases of cerebral hemorrhage due to drug–drug interactions involving warfarin have been evaluated retrospectively in 593 patients; 59 were thought to have been related to warfarin, implying an incidence of 1.7/100 000 treatment-years (56c). Of the 59 cases, 26 (44%) had a fatal outcome, compared with 136 (25%) among the non warfarin-treated patients. A drug–drug interaction with warfarin could have con tributed in 24 patients, and in 7 of these the bleeding complication was thought to have been possibly avoidable. Antibacterial drugs Different antibacterial drugs can enhance the actions of coumarin anticoagulants in different ways. The risk of bleeding in patients taking acenocoumarol or phenprocoumon and a range of antibac terial drugs has been retrospectively assessed in a cohort study of 52 102 users of aceno coumarol and 7885 users of phenprocoumon, with 139 159 person-years of follow-up, dur ing which 838 patients (1.4%) were hospita lized for bleeding while taking coumarins (57c). Of the 62 different antibiotics they had taken, 19 were associated with a bleed ing episode and 10 were associated with a statistically significant increased risk. The relative risks of bleeding were 3–5 for amoxicillin, azithromycin, ciprofloxacin, co-amoxiclav, co-trimoxazole, doxycycline, and pheneticillin, 9 for tetracycline, and 43 for cefradine and neomycin.
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Antifungal azoles Azoles when given sys temically inhibit the metabolism of warfarin, potentiating its effects. Such an effect has also been described in six patients after topi cal use of the azoles econazole (n = 5) and bifonazole (n = 1), as lotions, powders, or creams (58A). Three were heterozygous for a CYP2C9 variant allele, all with INR values greater than 11. In most cases the azole had been applied to the vulva and/or groin. Benzethonium chloride A woman who took grapefruit seed extract for 3 days had a minor subcutaneous hematoma 3 days later, and her INR was 7.9 (59AE). The inhibitory effects of three constituents of the extract were tested in an in vitro baculosome assay. All three contained the synthetic preserva tive benzethonium chloride and no authentic grapefruit seed extract was found. Benzetho nium chloride was a potent inhibitor of CYP3A4 and CYP2C9 activity in vitro. Chitosan The use of chitosan on two sepa rate occasions prolonged the INR markedly in an 83-year-old man taking warfarin 2.5 mg/day (60A). Chitosan is a positively charged polymer that binds to negatively charged lipids and bile acids in the gastro intestinal tract and can reduce the absorption of vitamins A, D, E, and K. Reduced avail ability of vitamin K may have been respon sible for this proposed interaction; it is unlikely that chitosan altered (i.e. increased) the absorption of warfarin, as suggested by the authors of this report. Cinacalcet In a phase 1, randomized, dou ble-blind, placebo-controlled, two-treat ment, two-period, crossover study in 21 healthy subjects, oral cinacalcet 30 mg bd for 7 days and once on day 8 had no effect on the pharmacokinetics or pharmaco dynamics of a single dose of warfarin 25 mg on day 5, the R- and S-enantiomers being measured separately (61C). Coenzyme Q The risk of bleeding and supratherapeutic INRs associated with the
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use of complementary and alternative med icines (CAM) in patients receiving warfarin has been studied prospectively in an acute care, academic, and research hospital in Canada (62c). Of 171 patients, 87 (51%) reported at least one bleeding event and 36 (21%) had a supratherapeutic INR; 73 (43%) had used at least one CAM product previously reported to interact with war farin. Coenzyme Q was associated with an increased risk of self-reported bleeding (OR = 3.69; 95% CI = 1.88, 7.24). Doxycycline A patient who took oral doxycycline and warfarin developed promi nent ecchymoses on the arms associated with a marked rise in INR to 6.5; on withdrawal of the doxycycline the INR fell to 2.3 (63A). The authors attributed the interaction to dis placement of warfarin from albumin and possibly inhibition of the CYP isoenzymes; they did not discuss the possibility of a phar macodynamic interaction. Duloxetine Possible potentiation of aceno coumarol by duloxetine has been reported in a 44-year-old woman (64A). This would be consistent with inhibition of CYP2C9 by duloxetine. However, the opposite effect has been reported in a 63-year-old woman with Alzheimer’s disease (65A). Efavirenz Efavirenz has been reported to increase the INR in a patient taking war farin, an interaction that was attributed to inhibition of CYP2C9 (66A). Fluoroquinolones The possible inter actions of warfarin with the fluoroquino lones ciprofloxacin, levofloxacin, and moxifloxacin have been systematically reviewed (67M). There were 22 publications suitable for evaluation, including 16 case reports or case series, 2 retrospective cohort studies, and 4 prospective studies, which included 2 placebo-controlled studies. The six structured reports showed mean increases in prothrombin time and INR, but they were clinically insignificant.
Drugs that affect blood coagulation, fibrinolysis, and hemostasis
However, some patients had significant increases above the target range. Increased anticoagulation was typically observed dur ing the first week of fluoroquinolone ther apy. Two patients died because of bleeding complications. This analysis suggests that, as often is the case with drug interactions, fluoroquinolones may potentiate the effects of warfarin only in susceptible individuals, the effect not being demonstrable in relatively small clinical trials. Case–control studies may be the best way of eliciting such effects. Glucocorticoids Of 29 children with can cer, those who were taking glucocorticoids had significantly lower warfarin require ments (68c). Glucosamine There is evidence of an inter action of warfarin with glucosamine (69AM). • A 71-year-old man, who had taken warfarin 7.5 mg/day for 5 years for atrial fibrillation and had had an INR of 2.5–3.2, had also taken glucosamine hydrochloride 500 mg þ chondroitin sulfate 400 mg bd for arthritis. He then trebled the dosage of glucosamine þ chondroitin and about 3 weeks later his INR rose to 3.9. The dosage of glucosamine þ chondroitin was halved, but his INR 16 days later was 4.7. The supplement was then withdrawn and his warfarin dosage was changed to 7.5/3.75 mg on alternate days; 16 days later his INR was 2.6.
A subsequent pharmacovigilance survey of spontaneously reported adverse events in warfarin-treated patients who had concomi tantly taken glucosamine, glucosamine þ chondroitin sulfate, or chondroitin sulfate, using the US MedWatch database, yielded 20 reports of increased INR, bleeding, or bruising in patients taking warfarin with glucosamine or glucosamine þ chondroitin sulfate; in some cases, when the dosage of glucosamine was reduced the INR returned to the previous target range. In one case there was an intraventricular hemorrhage and a subdural hematoma. The database of the Uppsala Monitoring Centre contained 21 spontaneous reports of increased INR asso ciated with glucosamine, 17 of which resolved when glucosamine was stopped. The mechan ism is not known.
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Influenza vaccine In a prospective audit of 106 patients taking long-term warfarin, influ enza immunization had no effect on anti coagulant control and no bleeding or thrombotic complications were reported (70c). Lopinavir + ritonavir A complicated inter action involved warfarin, co-trimoxazole and lopinavir þ ritonavir has been reported (71A). The main details were as follows: • A 42-year-old man, who was taking warfarin 5.5 mg/day (INR 2–3), was given high-dose co trimoxazole for Pneumocystis jiroveci pneumonia. His INR rose to 4.4. The dose of warfarin was reduced to 3.0 and 3.5 mg/day on alternate days and his INR fell to 2.1. Two weeks later the dosage of co-trimoxazole was reduced (INR not stated) and 2 weeks after that he was given zidovudine, lamivudine and lopinavir þ ritonavir. The INR fell to 1.1–1.3. When the dosage of warfarin was increased to 13 mg/day the INR rose to 2–3.
The possible mechanisms for this scenario are as follows: • poor adherence to therapy – the authors said that this was ruled out; • a change to a warfarin formulation with poor availability – this was not mentioned but seems unlikely; • an interaction with a change in diet – the authors said that this was ruled out; • a drug–drug interaction.
If this was a drug–drug interaction it could have been due to reduced absorption of warfarin (unlikely), displacement of war farin from plasma albumin causing increased clearance (unlikely, since such an effect would produce only a transient change in INR), induction of warfarin meta bolism by lopinavir þ ritonavir, or induction of co-trimoxazole metabolism, resulting in reduced inhibition by co-trimoxazole of warfarin metabolism. Of these, induction by lopinavir þ ritonavir of warfarin metabo lism by CYP2C9 seems the most likely, as such induction has been reported (72c). Another clearer report has also implicated lopinavir þ ritonavir (66A) and similar inter actions have been described with nelfinavir and nevirapine (73A, 74R). When combina tions of these drugs are used in HAART
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such interactions can be very complex (75A). Lycium barbarum (Chinese wolfberry) A rise in the INR in an 80-year-old Chinese woman has been attributed to a herbal tea containing Lycium barbarum (76A). Metronidazole Metronidazole inhibits the metabolism of S-warfarin, enhancing its anticoagulant effect, as another report, a case of intracerebral hemorrhage in a 78 year-old woman, has shown (77A). Nafcillin In a 39-year-old man warfarin dosage requirements increased from 32 to 88 mg/week 1 week after the introduction of nafcillin; when nafcillin was withdrawn the warfarin requirements slowly fell over sev eral weeks to 42–48 mg/week (78Ar). The authors attributed this to enzyme induction by nafcillin. Noscapine The Swedish adverse drug interactions register (SWEDIS) received eight reports of suspected interaction between noscapine and warfarin up to December 2006; there was bleeding in one case and an increased INR in the others; the effect occurred within 3 days to 3 weeks of the introduction of noscapine (79AcE). Stan dard pharmacovigilance methods for asses sing the strength of this putative signal suggested that it was real. In vitro, nosca pine inhibited CYP2C9 and CYP3A4, the former providing a possible mechanism for this interaction. NSAIDs Of 100 patients undergoing total hip replacement surgery who were screened for mutations in the CYP2C9 gene, 52 were using NSAIDs (80c). Patients with a CYP2C9 mutation had a mean INR curve similar to those without the mutation when NSAIDs were not co-administered. How ever, among the 30 patients who were het erozygous for a CYP2C9 mutation only concomitant use of an NSAID resulted in an INR over 4.9 (0% versus 39%).
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Paracetamol The interaction of paraceta mol with warfarin, in which long-term paracetamol prolongs the INR markedly (SEDA-23, 377; SEDA-29, 358), has again been reported anecdotally (81A). Rifampicin Since rifampicin is a power ful enzyme inducer, doses of coumarin anticoagulants may need to be increased markedly during co-administration, as has been reported again, in a 79-year-old man, in whom a 5- to 6-fold increase in warfarin dose was required to maintain an INR in the target range; after rifampi cin was withdrawn the dose of warfarin was gradually reduced over the next 2 months (82A). A similar course of events occurred in a 73-year-old woman taking acenocoumarol who needed a sixfold increase in dose after the introduction of rifampicin (83A). Selective serotonin reuptake inhibitors (SSRIs) The risk of bleeding associated with the concurrent use of SSRIs and the coumarins acenocoumarol or phenprocou mon has been compared in a case–control study with the risk in users of non-steroidal anti-inflammatory drugs, using a Dutch linkage system, including pharmacy and linked hospitalization records for about 2 million subjects (84c). There were 1848 patients with abnormal bleeding. Users of SSRIs were at significantly increased risk of hospitalization because of non-gastro intestinal tract bleeding (adjusted OR = 1.7; 95% CI = 1.1, 2.5) but not because of gastrointestinal tract bleeding (adjusted OR = 0.8; 95% CI = 0.4, 1.5). Users of non-steroidal anti-inflammatory drugs had a similar increased risk of nongastrointestinal bleeding (adjusted OR = 1.7; 95% CI = 1.3, 2.2), and a higher risk of gastrointestinal bleeding (adjusted OR = 4.6; 95% CI = 3.3, 6.5). Statins In a case–control study of 79 207 warfarin users with atrial fibrillation there were 1518 cases of upper gastrointestinal or intracranial bleed and 15 100 matched
Drugs that affect blood coagulation, fibrinolysis, and hemostasis
controls without bleeding (85c). Long-term statin use (1 year or more) was associated with a lower risk of any bleeding (OR = 0.80; 95% CI = 0.66, 0.97). How ever, there was no association between bleeding and recent statin use (<6 months) (OR = 1.04; 95% CI = 0.74, 1.48) or statin use of any duration (OR = 0.91; 95% CI = 0.77, 1.07), which the authors thought suggested confounding. Nevertheless, there has been an anecdo tal report of an interaction of warfarin with simvastatin (86A). • In an 82-year-old woman the INR rose to over 8 when her lipid-lowering therapy was switched from atorvastatin 10 mg/day to simvastatin 10 mg/day after she had taken warfarin 2.5 mg/day for almost 30 years with a stable INR within the range 2.0–3.5 for more than 2 years.
Tamoxifen Enhanced anticoagulation has again been reported when tamoxifen and warfarin were co-administered (87A). Tibolone In a double-blind, randomized, placebo-controlled, two-way, crossover study in postmenopausal women the INR was stabilized and the subjects were then randomized to either tibolone 2.5 mg/day or placebo for 21 days; the treatments were then crossed over after a 7-day wash out period (88C). Tibolone caused a signifi cant increase in INR and a significant reduc tion in coagulation factors. Vildagliptin The effects of vildagliptin 100 mg/day on the pharmacokinetics and pharmacodynamics of a single oral dose of warfarin sodium 25 mg have been studied in an open, randomized, two-period, twotreatment, crossover study in 16 healthy subjects (89c). The pharmacokinetics and pharmacodynamics of R- and S-warfarin were not altered by vildagliptin and the pharmacokinetics of vildagliptin were not altered by warfarin. Zingiber officinale (ginger) The risk of bleeding and supratherapeutic INRs
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associated with the use of CAM in patients receiving warfarin has been studied pro spectively in an acute care, academic and research hospital in Canada (62c). Of 171 patients, 87 (51%) reported at least one bleeding event and 36 (21%) had a supratherapeutic INR; 73 (43%) had used at least one CAM product previously reported to interact with warfarin. Ginger was associated with an increased risk of selfreported bleeding (OR = 3.20; 95% CI = 2.42, 4.24).
Food–drug interactions Cranberry juice The potential interaction of warfarin with cranberry juice is well known, but it is based on only a handful of anecdotal reports (90R). Furthermore, two prospec tive, randomized, placebo-controlled clini cal trials have shown no evidence of an interaction involving CYP2C9 or CYP3A. Since small randomized trials may fail to show an effect that is limited to a subset of susceptible individuals, the trial evidence does not rule out the possibility of such an interaction, as another case suggests (91A), but more information is clearly needed.
Protein A high-protein diet has been reported to have reduced the INR in a 55-year-old man taking warfarin, with a 16% increase in dosage requirement (92Ar). After he stopped taking the diet, his INR increased, and several dosage reductions were required until the INR stabilized at the original dosage of 95 mg/ week. The report cites two other similar reports. The mechanism is not known. It is unlikely to be due to increased serum albumin concentrations, since warfarin is highly bound and has a relatively low clearance rate, so that a reduced effect would be associated with reduced protein binding and then only transiently. Reduced absorption of warfarin is also unlikely. Increased activity of CYP iso zymes is a possible mechanism.
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(SED-15, 1590; SEDA 29, 361; SEDA-30, 404; SEDA-31, 556)
HEPARINS
HIT type II in different populations of patients Various aspects of HIT have been repeatedly reviewed (93R–110R). There are two types. Type I is a non-immunological response and type II is immunologically mediated. Type I is not associated with an increased risk of thrombosis and is characterized by reversible thrombocyto penia. Type II occurs in up to 5% of patients who receive heparin and is the more severe form, because of an increased risk of thrombo tic events. HIT type II is caused by IgG anti bodies that bind to epitopes on platelet factor 4 (PF4) released from activated platelets that develop when it forms complexes with heparin. These antibodies occur more often than throm bocytopenia does. Bovine heparin may pose a greater risk than porcine heparin (111R). The risk of HIT is thought to be lower with low-molecular-weight heparin than with unfractionated heparin. However, the evi dence that that is so has been challenged in a meta-analysis of 13 randomized comparisons in 5275 patients; there were no statistically significant differences in the rates of heparinassociated thrombocytopenia between the two treatments (1.2% versus 1.5%) (112M). The incidences of HIT with and without thrombo sis were too low to make an adequate com parison between the groups. Incidence In a retrospective analysis of 1017 consecutive samples tested for anti bodies by enzyme-linked immunosorbent assay and for platelet function by 5HT release, most of the samples showed no ser ological evidence of HIT, but 4–5% of sam ples showed both antigenic and functional serological evidence of HIT; 12–18% of sam ples showed immunological evidence of PF4/ heparin antibodies but without functional evidence of 5HT release in vitro (113c). A small minority of samples (0.7%) caused 5HT release but were negative for antibodies. A polymorphism of platelet GPIIIa (PlA2, also called HPA1b) has been asso ciated with a higher risk of thrombosis. In 66
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consecutive patients with a laboratory diag nosis of HIT, thrombotic complications developed in 27 (41%) and were more likely in patients with PlA2 (69% versus 32%; OR = 4.7; 95% CI = 1.4, 16) (114c). Burns The incidence and complications of HIT have been studied in 625 patients with burns, of whom 43 (6.9%) underwent testing for HIT, 10 being positive; thus, the inci dence among all heparinized patients was 1.6% (115c). Thrombotic complications of HIT included arterial thrombosis requiring limb amputation (n = 2), deep venous thrombosis (n = 3), and pulmonary embo lism (n = 2, of whom one died). Cardiac surgery Anti-PF4/heparin anti bodies are often found during mechanical circulatory support, but only a few patients develop HIT. In 113 patients three types of sera were identified: platelet-activating anti PF4/heparin antibodies (n = 10), non-plate let-activating anti-PF4/heparin antibodies (n = 53) and anti-PF4/heparin antibody negative (n = 50) (116cE). The patients with platelet-activating antibodies had the highest risk of thromboembolic events, whereas those with non-platelet-activating antibodies did not differ from the antibody-negative patients. When all antibody-positive patients were further classified by an IgG-specific anti-PF4/heparin enzyme-immunoassay, the specificity for platelet-activating antibodies increased, as did the risk of HIT. In a prospective investigation of the use of PF4/heparin antibodies to predict clinical thrombosis in 299 patients scheduled for car diac surgery the prevalence of the antibodies was 4.3% (13 of 299) before surgery and increased more than fivefold to 22% (62 of 277) postoperatively (117C). There were thromboembolic events in 8.8% of patients with negative antibodies and in 6.3% of patients with positive antibodies. Of the 62 patients with positive antibodies postopera tively, 22 (36%) were treated with a nonheparin anticoagulant. There was a trend towards higher rates of thromboembolic events in subjects with thrombocytopenia compared with those without (17% versus
Drugs that affect blood coagulation, fibrinolysis, and hemostasis
6.7%), regardless of antibody status. Two of eight patients with both thrombocytopenia and positive antibodies had a thrombo embolic event, compared with 17 of 222 (7.7%) without clinical HIT. The authors concluded that the high prevalence of PF4/ heparin antibodies after cardiac surgery and the low rate of thromboembolic complica tions suggested that the antibodies alone do not confer an increased risk of thrombotic complications. Of 487 patients with thrombocytopenia (a 50% fall in platelet count or an absolute count below 100 109/l) after cardiac sur gery 113 (23%) had HIT. Multivariate pre dictors included previous percutaneous coronary interventions (OR = 1.76), class IV NYHA heart failure (OR = 1.80) and infectious endocarditis (OR = 3.66) (118c). Postoperative infections occurred more fre quently in patients with HIT, including sepsis (17% versus 9.9%) and pneumonia (47% versus 23%). The patients with HIT also had a higher rate of renal failure requiring hemodialysis (23% versus 9.1%) and acute limb ischemia (16% versus 4.3%). Mortality at 30 days was significantly higher in those with HIT (25% versus 15%). Postoperative HIT was an independent predictor of renal failure (OR = 1.73) and thromboembolic complications (OR = 2.39). Platelet counts have been measured in 329 patients who required ICU treatment beyond 7 days after cardiac surgery; although 70 patients (21%) developed thrombocyto penia, the overall incidence of HIT was only 1.8% (6/329; 95% CI = 0.7, 3.9) (119c). In a retrospective analysis of 358 consecu tive patients who were given heparin during the insertion of a ventricular assist device, 28 had HIT either before (n = 15) or after (n = 13) insertion (120c). In a review of 92 consecutive adult patients who had a ventricular assist device inserted as a bridge to cardiac transplantation, those in whom thrombocytopenia developed after heparin exposure were tested for PF4/ heparin antibodies (121c). Heparin was avoided in the 24 who were positive, but all were re-exposed to heparin during transplan tation. Survival to transplantation did not differ between the groups. Compared with
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the controls, HIT-positive patients who were re-exposed to heparin had a greater fall in platelet counts immediately after trans plantation, but there was no difference in mortality after transplantation or thrombo embolism. The authors concluded that anti body-positive were not at a higher risk of thromboembolism or death after heparin reexposure. In a retrospective study of 3465 patients who were given postoperative heparin, 20 developed HIT within an average of 7 days (122c). They required more platelet trans fusions perioperatively than controls and thromboembolic complications occurred in 14 patients with HIT but in none of 20 matched controls. Nine patients with HIT died and all the controls survived. Mortality was related to thrombotic complications in seven patients with HIT. In a study of the incidence of preoperative PF4/heparin antibodies and the associated risk of postoperative adverse outcomes in 1114 patients, 60 (5.4%) had positive anti bodies preoperatively (123c). These patients had longer mean postoperative lengths of stay (14 days versus 9.8 days), and higher incidences of prolonged mechanical venti lation (20% versus 9.2%), acute limb ischemia (5.1% versus 0.9%), renal complications including dialysis (20% versus 11%) and gastrointestinal complica tions (15% versus 5.9%). In Turkish patients undergoing cardiac surgery the incidences of heparin antibodies were 16% before surgery (n = 44), 34% on day 5 (n = 44), and 65% on day 10 (n = 115); however, platelet function (5HT release) was abnormal in only 4.4% on day 0 and 7.0% on day 10 (124c). The prevalence of heparin-dependent platelet antibodies has been determined pros pectively in 30 children after 5–10 days of postoperative exposure to heparin after cardio pulmonary bypass surgery; 15 were under 30 days old and 15 were aged between 30 days and 12 years (125c). None had antibodies, but six had symptomatic thromboses. Hemodialysis In 419 patients on hemo dialysis, 107 of whom had access
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thrombosis, antibodies to PF4/heparin were positive in 54 (13%); 9 (2.1%) had IgG specific antibodies (126c). There was no rela tion between hemodialysis access thrombosis and PF4/heparin antibodies. In a survey of 50 out of 81 renal units in the UK the combined population was 13 682 patients on dialysis, of whom 10 564 were on maintenance hemodialysis. The prevalence and incidence of HIT type II were 0.26 and 0.32 per 100 patients respectively. The mean age of the patients with HIT type II was 62 (range 22–86) years, 52% were women, and 92% were Caucasians. Only 17% of patients had complications of HIT. In a review of the medical records of 122 patients with suspected HIT on dialysis, 17 met the criteria of > 30% thrombocytopenia, clots in the extracorporeal circulation, posi tive for PF4/heparin antibodies, and improvement from HIT with the use of an alternative anticoagulant or another strategy for HIT (127c). HIV infection In a retrospective compari son of HIV-infected patients and uninfected patients, there was a higher incidence of HIT in the former (15/53 versus 0/106) after treat ment with unfractionated heparin and/or low-molecular-weight heparin (128c). Myeloproliferative disorders HIT is rarely reported in patients with myeloproliferative disorders; the authors of a report of three cases (two with essential thrombocythemia and one with polycythemia rubra vera) have suggested that this may be because of underdiagnosis, since these patients have high platelet counts (129A). Vascular surgery In a prospective study of the development and function of PF4/ heparin antibodies after infrainguinal bypass procedures blood samples were obtained from 79 patients before surgery and at 7, 14 and 28 days after; 67 reported previous expo sure to heparin (130c). There were PF4/ heparin antibodies before surgery in six, four of whom also had a positive result on an aggregation assay. After 28 days, 22
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subjects developed PF4/heparin antibodies and 5 of these also tested positive for plate let-activating antibodies. There were no cases of thrombocytopenia. There was early graft occlusion in three patients, but all were nega tive for antibodies and had normal platelet function. The authors concluded that patients who undergo vascular surgery often develop PF4/heparin antibodies, plate let-activating antibodies being detected in up to 11%, but that thrombocytopenia and vas cular graft thrombosis are uncommon.
Management HIT should be suspected whenever the platelet count falls by more than 50% from baseline or to below 150 109/l, 5–14 days after starting heparin (or sooner if there was prior heparin exposure), or if new thrombosis occurs during or soon after heparin treatment, other causes having been excluded. When HIT is suspected, heparin should be immediately withdrawn and an alternative anticoagulant used; alternatives have included danaparoid, fondaparinux, sulodexide (131A), and direct thrombin inhibitors such as argatroban, lepirudin, and bivalirudin. The American College of Chest Physi cians has issued guidelines on the recogni tion, treatment and prevention of HIT (132S). The key recommendations include the following: • for patients in whom the clinician considers the risk to be over 1.0%, the platelet count should be monitored during heparin therapy; • for those who are receiving heparin or have received heparin within the previous 2 weeks, HIT should be investigated if the platelet count falls by at least 50% and/or a thrombotic event occurs between days 5 and 14 inclusive after the start of heparin therapy, even if the patient is no longer receiving heparin when the thrombosis or thrombocytopenia occurs; • for those with strongly suspected or confirmed HIT, whether or not complicated by thrombosis, an alternative non-heparin anticoagulant should be used; • for those with strongly suspected or confirmed HIT, a coumarin should not be used until after the platelet count has substantially recovered (usually to at least 150 109/l); and when it is used it should be started in a low maintenance dose (maximum 5 mg of warfarin or 6 mg of
Drugs that affect blood coagulation, fibrinolysis, and hemostasis phenprocoumon); and the non-heparin anticoagulant should be continued until the platelet count has reached a stable plateau, the INR has reached the intended target range, and after a minimum overlap of at least 5 days between non-heparin anticoagulation and coumarin therapy; • for those who are taking a coumarin when HIT is diagnosed, vitamin K 10 mg orally or 5–10 mg intravenously should be given.
Metabolism Extreme hypertriglyceridemia in a 32-year-old man followed intravenous infusion of heparin for 5 days and was attrib uted to temporary depletion of lipoprotein lipase caused by heparin (133A). However, it is difficult to explain why this is the first reported case of this effect if lipoprotein lipase inhibition is the mechanism, since this is a well-known effect of heparin; severe lipoprotein lipase deficiency may have been partly due to other factors in this patient. Electrolyte balance Long-term use of heparin can cause hyperkalemia by inhibit ing aldosterone production. Heparin reduces the number and affinity of angio tensin-2 (AT2) receptors in the adrenal zona glomerulosa and reversibly suppresses aldosterone production within a few days. Hyperkalemia is more common in elderly patients and in those with renal insufficient and, as illustrated by another case report, diabetes mellitus (134A). Skin Delayed-type (class IV) hypersensitiv ity skin reactions to a low-molecular-weight heparin can be accompanied by cross-reac tivity to other heparins and heparinoids. When test doses of the low-molecular weight heparin bemiparin and several other heparins and heparinoids were given to eight patients with a history of local ecze matous reactions after subcutaneous enox aparin, seven had cross-reactivity to subcutaneous bemiparin, and nearly all the other substances that were tested caused local eczematous reactions in at least some patients, with the exception of fondapari nux, which was well tolerated by all (135c). Bemiparin had the highest cross-reactivity
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with enoxaparin. Substances with a lower molecular weight did not cross-react less often. The authors concluded that there was no relation between cross-reactivity and molecular weight. Delayed hypersensitivity skin reactions to enoxaparin and nadroparin did not show cross-reactivity to fondaparinux in a 30-year-old pregnant woman (136A). For reports of skin necrosis attributed to heparin, see warfarin above. Musculoskeletal The mechanism whereby heparin causes osteoporosis during longterm treatment is unknown. In animals, heparin reduces the number of osteoblasts and increases the number of osteoclasts, and these effects are accompanied by changes in biochemical markers of bone turnover, including a dose-related reduction in alkaline phosphatase and an increase in urinary type I collagen cross-linked-pyridi noline, a marker of bone resorption; in pregnant women taking long-term heparin there are subclinical reductions in bone density (137R). Osteoprotegerin, a glycoprotein that binds heparin, is a decoy receptor for RANKL, which is responsible for osteoclast development. Plasma concentrations of osteoprotegerin have been measured in 22 male students, who were given one of five regimens: • 5000 IU of unfractionated heparin intravenously followed by an infusion of 450 IU/kg/day for 3 days and then unfractionated heparin 5000 IU 4 and 24 hours later (n = 7); • subcutaneous low-molecular-weight heparin 200 IU/kg on 3 days and then unfractionated heparin 5000 IU 4 and 24 hours later (n = 8); • subcutaneous low-molecular-weight heparin 100 IU/kg once (n = 8); • subcutaneous unfractionated heparin 250 IU/kg once (n = 7); • a control infusion of saline for 12 hours (n = 7).
Bolus intravenous unfractionated heparin caused a prompt increase in plasma osteo protegerin from 0.68 to 1.13 µg/l, followed by a fall during continuous infusion, reaching baseline after 8 hours (138C). There were similar increases when repeated boluses of
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unfractionated heparin were given after the end of treatment. Subcutaneous low-molecu lar-weight heparin 200 IU/kg caused a modest but significant increase in plasma osteoprotegerin, similar to subcutaneous unfractionated heparin, but a threefold higher anti-Xa activity. Immunologic In a patient who had had a type I hypersensitivity reaction to heparin 2 years before, and no desensitization, bivalirudin did not elicit a reaction (139A). Drug resistance Resistance to heparin has been reviewed (140R). It is said to occur in up to 22% of patients who require cardio pulmonary bypass during cardiac surgery and is associated with reduced antithrombin concentrations. Treatment options include antithrombin or fresh frozen plasma. How ever, there have been no direct comparisons of these two treatments. Susceptibility factors Renal disease Low molecular-weight heparins can accumulate in renal insufficiency and cause bleeding, and the risk is greatest in patients with a creatinine clearance under 30 ml/minute (141R). There is some evidence that tinza parin does not accumulate to the same extent as enoxaparin (142R). Drug contamination Bacterial contamina tion Bacterial contamination is a risk asso ciated with the use of multiple-dose vials. In a 4-month study, multi-dose vials, singledose vials and vials containing locally pre pared mixtures were collected from various hospital wards for analysis, including 68 multi-dose vials containing sodium chloride 0.9% or heparin with added preservative, 17 single-dose vials containing water for injection or sodium chloride 0.9% and 11 vials containing preservative-free mixtures of heparin and sodium chloride 0.9% (143E). Four of the 96 vials were not sterile: two were contaminated with spore-forming bacteria and two with coagulase negative staphylococci. Three were multi-dose vials
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containing a preservative. The date of first use was not marked on 27 of the vials. In 15 of 68 multi-dose vials, the time limit after first use had been exceeded. In a systematic review of outbreaks of infection due to bacterial or viral contami nation, 2250 patients described in 128 arti cles were analysed; they were mostly from intensive care units or hematology depart ments (144M). Septicemia was the most frequent hospital-acquired infection. The most common source of infection was from contamination of blood products and heparin/sodium chloride solutions. The most frequent pathogens were hepatitis A virus, Yersinia enterocolitica, and Serratia spp. for blood products and Burkholderia cepacia and Enterobacter spp. for sub stances other than blood products. Morta lity was highest if erythrocytes or total parenteral nutrition formulas were contami nated. In 64 of the outbreaks multi-dose vials had been used against the manufac turers’ recommendations. The authors con cluded that drug-related outbreaks of infection are particularly likely when basic hygiene is not observed. They issued a cau tion about the use of multiple-dose vials. An outbreak of Burkholderia cepacia infection in 15 patients, which lasted for 3 months, was finally traced to contamination of a heparin vial (145c). An outbreak of infection due to Pseudo monas putida and Stenotrophomonas malto philia has also been reported in association with a contaminated heparin catheter-lock solution (146c). Of 154 patients who had had a catheter lock infused with solution from the lots that were suspected of being contaminated, 48 had central venous cathe ters, and by day 7 of the outbreak 18 of them had become symptomatic; of the 30 asymptomatic patients, 26 provided blood samples for culture, 10 of whom developed a fever soon after. There was P. putida bac teremia in 32 cases; 9 also had infection due to S. maltophilia. Oversulfated chondroitin sulfate After four deaths and 350 adverse events, 40% of which were serious, that were attributed
Drugs that affect blood coagulation, fibrinolysis, and hemostasis
to a particular formulation of heparin of Chinese origin, the formulation was recalled (147r). It was subsequently discovered that it was contaminated by an oversulfated chondroitin sulfate that contained a disac charide repeat unit of glucuronic acid linked to a b-N-acetylgalactosamine; the disacchar ide unit had an unusual sulfation pattern, being sulfated at the 2-O and 3-O positions of the glucuronic acid as well as at the 4-O and 6-O positions of the galactosamine, and the traditional screening tests could not dif ferentiate between affected and unaffected batches (148E). The oversulfated chondroi tin sulfate was responsible for severe non IgE-mediated anaphylactic (anaphylactoid) reactions, directly activating the kinin– kallikrein pathway in human plasma, lead ing to generation of bradykinin and C3a and C5a, potent anaphylotoxins derived from complement proteins (149E). Activation of these two pathways was unexpectedly linked to and depended on fluid-phase acti vation of factor XII. However, it has been suggested that the recalled heparin formulations may also have contained several other heparin-like and non-heparin substances, many of which have not been fully investigated, and whose association with the reported adverse events has not been established (150R). In a Brazilian study, four different heparin solutions were evaluated by mag netic nuclear resonance, and significant differences were found, including contami nation with other dermatan sulfates (151E). Whatever the cause of the adverse effects of the Chinese product, various procedures have been initiated in an attempt to harmo nize international controls for quality assur ance of heparin formulations. Drug dosage regimens In a systematic review of twice-daily and thrice-daily administration of heparin 12 studies were identified involving 7978 patients; 1664 were given thrice-daily and 6314 twicedaily heparin (152M). After adjustment for baseline risks, there was no difference in the overall rate of venous thromboembolism. However, the risk of major bleeding was
Chapter 35
significantly greater with heparin (0.96 versus 0.35).
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thrice-daily
Drug administration route Inhalation Inha lation of the low-molecular-weight heparin the certoparin has been compared with sub cutaneous injection in healthy subjects in a crossover study (153c). Certoparin had a longer duration of action after inhalation than after injection. There were no changes in lung function or other adverse effects. Subcutaneous Local bruising is almost inevitable after subcutaneous injection of heparin. Three different injection techniques have been studied in 36 patients, each of whom received three injections by the same investigator (154c). There were significantly smaller and fewer bruises when the injection was given over 30 seconds and when a 10 second injection was followed by a delay of 10 seconds before withdrawing the needle. In a similar study in 50 patients, heparin was injected over 10 seconds on the right of the abdomen and over 30 seconds on the left (155c). Bruising occurred in 64% with injec tions of 10 seconds duration and 42% with those of 30 seconds; the size of the bruising was smaller after the latter and pain intensity and duration were also reduced.
Danaparoid sodium Danaparoid is a low-molecular-weight hepar inoid, consisting of a mixture of sulfated glycosaminoglycans – heparan sulfate (84%), dermatan sulfate (12%), and chondroitin sul fate (4%). It inhibits factors Xa and IIa in a ratio greater than heparin (over 20), with a minimal effect on platelet function (156R, 157R). It has little effect on activated partial thromboplastin time, prothrombin time, and thrombin time. It is as effective as heparins in inhibiting the formation of thrombi. Hematologic Severe bleeding is uncommon with danaparoid but was 3.1% in one series (158c).
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The major advantage of danaparoid over low-molecular-weight heparins is its low rate of cross-reactivity with heparin-associated anti bodies from patients with HIT (159R). It has therefore been used in patients with heparinassociated thrombocytopenia who require further anticoagulation after withdrawal of heparin (160A, 161c, 162R). However, crossreactivity has been described (163A–165A, 166c) and danaparoid is not always effective (167c). It should not be used if there is in vitro cross-reactivity between heparin and danapar oid, the risk of which is quite high: of 281 patients who underwent cardiovascular surgery 81 developed HIT and 23 (28%) had in vitro cross-reactivity to danaparoid sodium (168c). In a review of 51 pregnancies in 49 patients, all of whom had had heparin intol erance (32 due to HIT and 19 mainly due to heparin-induced skin rashes) and had a cur rent and/or past history of thromboembolic complications, danaparoid cross-reactivity was suspected in four patients with HIT and five with skin reactions; it was confirmed serologically in one of the two patients with HIT who were tested (169M). Of 1418 patients, 1291 had HIT, in 39% of whom there was thromboembolism (170c). Danaparoid was given instead, for 1 day to 3.5 years and follow-up was for a further 3 months; 84% of the patients survived; 64% had no or minor adverse events and 20% had serious non-fatal adverse events. Major bleed ing was reported in 8.1% of treatment epi sodes. Clinical cross-reactivity of danaparoid (new or persistent platelet count reduction and/or new or extended thrombosis) was con firmed serologically in 23 of 36 patients with positive pretreatment serological danaparoid cross-reactivity and in 22 of 32 additional patients tested at the time of the new event, that is, a total of 45 patients (3.2%). In one study of antibodies to PF4/heparin complexes in 63 patients, two types of anti bodies were identified: • antibodies that only or mainly bound to PF4/ heparin complexes (type 1 antibodies); most of the epitopes recognized probably involved both heparin and PF4; • antibodies that had similar reactivity to r-PF4 and PF4/heparin (type 2 antibodies); the antigens recognized were possibly neoepitopes
J.K. Aronson
mainly expressed by modified PF4 and by PF4/ heparin complexes.
Most of the samples (n = 59) contained IgG antibodies, often associated with IgA antibodies, which were more frequently type 2 antibodies, and/or IgM antibodies. With unfractionated heparin thrombocytopenia was associated with both types of antibodies, whereas only type 1 antibodies were detected after low-molecular-weight heparin. Further more, cross-reactivity with danaparoid sodium was present only in those with type 1 antibodies and mainly involved patients who had received low-molecular-weight heparin. Cross-reactivity between heparins and danaparoid is uncommon but can result in thrombotic complications, which can be fatal (171A). Skin Delayed hypersensitivity reactions have been reported in patients given dana paroid (172A–174A). They usually present as pruritic, eczematous lesions at the injection sites, but generalized eczema can also occur. There may be cross-reactivity with heparin (175A–177A). Susceptibility factors Renal disease Dana paroid sodium is excreted by the kidneys, and its action is prolonged in patients with renal failure (178C). Its half-life in hemo dialysis patients was 31 hours compared with 18 hours in healthy volunteers (179C).
DIRECT THROMBIN INHIBITORS (SED-15, 1142; SEDA-29, 362; SEDA-30, 409; SEDA-31, 559)
Argatroban Hematologic Argatroban has been suc cessfully used in patients with HIT (180A–182A, 183c–190c). Susceptibility factors Renal disease Since argatroban is predominantly metabolized
Drugs that affect blood coagulation, fibrinolysis, and hemostasis
in the liver, in contrast to heparins and danaparoid, it is believed that no dosage adjustment is required in patients with renal insufficiency (191C). However, pro longed duration of action of argatroban has been described in patients with normal liver function but impaired renal function (192A); one had antiphospholipid antibo dies and end-stage renal disease maintained on peritoneal dialysis (193A).
Bivalirudin Hematologic Bivalirudin has been suc cessfully used in patients with HIT (194A, 195A, 196c, 197C).
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(n = 1162), starting the evening before sur gery (201C). There were episodes of venous thromboembolism in 60 (6.7%) of the 897 patients who were given enoxaparin, 53 (6.0%) of the 880 who were given dabigatran etexilate 220 mg, and 75 (8.6%) of the 874 who were given 150 mg. There were no sig nificant differences in major bleeding rates, increases in liver enzymes, or acute coronary events. In a double-blind, randomized study, 1896 patients undergoing unilateral total knee arthroplasty were randomized to oral dabigatran etexilate 220 or 150 mg/ day or subcutaneous enoxaparin 30 mg bd for 12–15 days after surgery (202C). Dabigatran was less efficacious than enox aparin, but bleeding rates were similar and no drug-related hepatic damage was recorded.
Dabigatran Dabigatran etexilate, a prodrug of dabiga tran, can be given orally. Its pharmacology has been reviewed (198R, 199R). Comparative studies Dabigatran versus enoxaparin In a double-blind, randomi zed, non-inferiority study in 2076 patients undergoing total knee replacement, oral dabigatran etexilate 150 or 220 mg/day was compared with subcutaneous enoxa parin 40 mg/day for 6–10 days; the patients were followed for 3 months (200C). Venous thromboembolism occurred in 193 of the 512 patients who were given enoxaparin, in 183 of the 503 who were given dabigatran etexilate 220 mg and in 213 of the 526 who were given 150 mg. The incidences of major bleeding did not differ significantly across the three groups (1.3, 1.5, and 1.3% respectively). There were no significant differences in the inci dences of liver enzyme rises or acute cor onary events. In a double-blind, non-inferiority study 3494 patients undergoing total hip replace ment were randomized to treatment for 28–35 days with dabigatran etexilate 220 mg/ day (n = 1157) or 150 mg/day (n = 1174) or subcutaneous enoxaparin 40 mg/day
Lepirudin Hematologic Lepirudin has been success fully used in patients with HIT (203A–206A, 207cr). Immunologic An anaphylactic reaction has been reported in a 57-year-old woman who had received five courses of lepirudin therapy uneventfully (208A).
Ximelagatran Liver In a systematic review of 13 randomi zed controlled trials in which ximelagatran and melagatran have been compared with conventional anticoagulants, 22 639 patients were included (209M). The indications for treatment were perioperative prophylaxis of deep vein thrombosis, management of deep vein thrombosis, and stroke prevention in atrial fibrillation. The risks of major adverse events (OR = 0.98; 95% CI = 0.83, 1.17) and major bleeding (OR = 1.01; 95% CI = 0.69, 1.47) did not differ significantly. However, there was a trend towards an increased risk of hepatotoxicity, with incidences of 5.8%
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versus 2.3% (OR = 1.74; 95% CI = 0.50, 6.01). The frequency of hepatotoxicity was markedly increased in patients with deep vein thrombosis (OR = 5.16; 95% CI = 3.38, 7.89), for treatment durations of at least 3 months (OR = 6.73; 85% CI = 5.01, 9.05), and in patients with atrial fibrillation (OR = 8.31; 95% CI = 5.65, 12). There were two fatal cases of liver damage with ximela gatran or melagatran. During follow-up after the EXTEND study, liver enzymes were assessed at post operative days 56 and 180 (210C). Rando mization and administration of the study drugs was stopped after a report of serious liver injury 3 weeks after completion of ximelagatran treatment. When the study was terminated, 1158 patients had been ran domized and 641 had completed the 35-day treatment; 303 patients took ximelagatran and 265 took enoxaparin up to day 56. Ala nine transaminase (AIT) activity increased to over twice the upper limit of the reference range in 58 of those who took enoxaparin and 27 of those who took ximelagatran; 3 of the latter also had symptoms of hepatotoxi city. Alanine transaminase activity increased after the end of the study in 11 patients taking ximelagatran. The mechanisms underlying rises in liver enzymes that occur during long-term therapy with ximelagatran (> 35 days) have been investigated in in vitro studies in fresh and cryopreserved hepatocytes, human hepa toma cell lines (HepG2 and HuH-7) and subcellular human liver fractions (211E). There was loss of cell viability only in HepG2 cells at ximelagatran concentrations of 100 µmol/l and in cryopreserved human hepatocytes at 300 µmol/l; HuH-7 cells were not affected by exposure for 24 hours up to 300 µmol/l. Calcium homeostasis was not affected in HepG2 cells. There was no evi dence of formation of reactive metabolites when cell systems were exposed to ximelaga tran. Expression of aspartate and alanine transaminases in human hepatoma cell lines was also unaffected, as were mitochondrial functions such as respiration, opening of the transition pore, mitochondrial membrane depolarization and b-oxidation. The authors suggested that these negative results may
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have occurred because the experimental systems did not reflect the characteristics of the human hepatocyte, because the expo sure time was too short, or because the pri mary mechanism of the liver damage due to ximelagatran is not on the parenchymal liver cell.
DIRECT FACTOR IXa INHIBITORS (SEDA-31, 561) Placebo-controlled studies In a multi center, double-blind, randomized study, 212 patients received oral TTP889 300 mg/ day) or placebo starting 6–10 days after hip fracture surgery and standard thromboprophylaxis for 5–9 days (212C). There was venous thromboembolism in 35 of the 109 who had been allocated to TTP889 and 29 of the 103 of who had been allocated to placebo. There were no major bleeding events and only two clini cally relevant non-major bleeding events with TTP889. REG1 consists of the drug RB006, an injectable RNA aptamer that specifically binds and inhibits factor IXa, and the anti dote RB007, the complementary oligo nucleotide that neutralizes its anti-IXa activity. REG1 has been evaluated in a dou ble-blind, randomized, placebo-controlled study in 50 subjects with coronary artery disease taking aspirin and/or clopidogrel, using four doses of RB006 (15, 30, 50, and 75 mg) and RB007 (30, 60, 100, and 150 mg) (213C). RB006 increased the activated partial thromboplastin time dose-depen dently; the median activated partial throm boplastin times at 10 minutes after a single intravenous boluses of 15, 30, 50, and 75 mg were 29, 35, 47, and 52 seconds. RB007 reversed the activated partial thrombo plastin time to baseline values within a med ian of 1 minute and there was no rebound increase over 7 days. There were no epi sodes of major bleeding or other serious adverse events.
Drugs that affect blood coagulation, fibrinolysis, and hemostasis
DIRECT FACTOR Xa INHIBITORS (SEDA-30, 411; SEDA-31, 561)
Apixaban Comparative studies Apixaban versus enoxaparin Apixaban has been evaluated in a double-blind study in 1238 patients after total knee replacement (214C). They were randomized to 5, 10, or 20 mg/day given as a single dose or twice-daily divided doses, enoxaparin 30 mg bd, or warfarin (titrated to an INR of 1.8–3.0). Treatment lasted for 10–14 days and started 12–24 hours after surgery. Adverse effects were assessed in 1217 patients and efficacy in 856. Apixaban was less effective than the comparators, but there were significant and similar dose-related increases in the incidence of total bleeding events with once- and twice-daily apixaban. In a dose-ranging study 520 patients with deep vein thrombosis were randomized to apixaban 5 mg bd, 10 mg bd, or 20 mg/day, or to low-molecular-weight heparin for 84–91 days followed by a coumarin (215C). The four regimens had equal efficacy. There was major bleeding or non-major clinically relevant bleeding in 28 (7.3%) of the 385 patients who received apixaban and in 10 (7.9%) of the 126 who received conventional anticoagulants.
Otamixaban Otamixaban has been studied in a placebocontrolled study in 947 patients, who were randomized before percutaneous coronary intervention to unfractionated heparin 50–70 U/kg or one of five otamixaban regimens consisting of an intravenous bolus followed by a 3-hour infusion: • • • • •
0.025 mg/kg 0.045 mg/kg 0.080 mg/kg 0.120 mg/kg 0.140 mg/kg
followed by 0.035 mg/kg/hour; followed by 0.065 mg/kg/hour; followed by 0.120 mg/kg/hour; followed by 0.160 mg/kg/hour; followed by 0.200 mg/kg/hour.
The highest dose of otamixaban reduced the concentrations of prothrombin fragments
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1þ2 significantly more than unfractionated heparin, but there was no significant difference in the incidence of bleeding (216C). Antifactor Xa concentrations were 65, 155, 393, 571, and 691 µg/l with the five regimens of otamixaban. There was significant bleeding (major or minor) in 2.0, 1.9, 3.8, 3.9, and 2.6% of patients respectively and in 3.8% of those who received unfractionated heparin. Ischemic events occurred in 5.8, 7.1, 3.8, 2.5, and 5.1% of those who received otamixaban and in 5.6% of those who received unfractio nated heparin.
Rivaroxaban The pharmacology of rivaroxaban has been reviewed (217R–220R). Comparative studies Rivaroxaban versus enoxaparin Several comparisons of rivar oxaban and enoxaparin have suggested equal efficacy in preventing venous thromboembolism after orthopedic surgery and similar rates of adverse effects. In an analysis of pooled results from two phase 2, double-blind, randomized compar isons of rivaroxaban and enoxaparin after major orthopedic surgery in 1343 patients, episodes of major bleeding with rivaroxa ban occurred in 0.9, 1.3, 2.1, 3.9, and 7.0% of patients who received total daily doses of 5, 10, 20, 40, and 60 mg respectively, com pared with 1.7% of those who received enoxaparin (221M). In a double-blind, randomized, phase 3 com parison, 4541 patients undergoing total hip arthroplasty received rivaroxaban 10 mg/day or enoxaparin 40 mg/day (222C). There were episodes of major bleeding in 6 (0.3%) of 2209 who received rivaroxaban and in 2 (0.1%) of 2224 who received enoxaparin. In a double-blind, randomized compari son of oral rivaroxaban 10 mg/day and enoxaparin 40 mg/day in 2531 patients undergoing total knee arthroplasty, sympto matic events occurred less often with rivar oxaban (223C). Major bleeding occurred in 0.6% of those who received rivaroxaban
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and 0.5% of those who received enoxa parin. The incidences of drug-related adverse events, mainly gastrointestinal, were 12 and 13% respectively. In a double-dummy, placebo-controlled comparison, 2509 patients undergoing total hip arthroplasty were randomized to oral riv aroxaban 10 mg/day for 31–39 days (with pla cebo injection for 10–14 days; n = 1252) or subcutaneous enoxaparin 40 mg/day for 10–14 days (with a placebo tablet for 31–39 days; n = 1257) (224C). The incidence of any bleeding during treatment was similar in the two groups: 81 events (6.6%) in 1228 patients who received rivaroxaban versus 68 (5.5%) of 1229 patients who received enoxaparin.
INDIRECT FACTOR Xa INHIBITORS (SEDA-29, 362; SEDA-30, 412; SEDA-31, 563)
Fondaparinux Hematologic Fondaparinux has been successfully used in patients with HIT (225A, 226c, 227c, 228R). However, crossreactivity has been reported (229A). Bleeding with fondaparinux is uncom mon but can be serious when it occurs, as has been illustrated by a case of sponta neous retroperitoneal bleeding from a rup tured lumbar artery in a 78-year-old man with only one kidney (230A). Susceptibility factors Renal disease In a subgroup analysis of a randomized, controlled trial of fondaparinux in 19 979 patients in whom serum creatinine was mea sured at baseline, the absolute differences in favor of fondaparinux (efficacy and adverse effects) were most marked in patients with a GFR less than 58 ml/minute/1.73 m2; the lar gest differences being in major bleeding, which occurred in 2.8 and 6.4% (HR = 0.42; 95% CI = 0.32, 0.56) (231c). Fondaparinux has been studied in 12 patients treated with hemodialysis and
J.K. Aronson
compared with unfractionated heparin (232c). Mean peak anti-Xa activity increased from 0.61 µg/l after the first dose to 0.89 µg/l after dose 9, whereas predialysis anti-Xa activity rose steadily to 0.32 µg/l. Fondaparinux produced suffi cient anticoagulation but was slightly less effective than heparin. The digital com pression time necessary to achieve hemo stasis at the puncture site increased slightly but significantly with fondaparinux from 23.7 to 24.8 minutes and six of the patients reported minor bleeding problems between dialyses. The authors concluded that accumulation of fondaparinux increases anti-Xa activity between dialyses and should be reserved for patients who require systemic anticoagulation on nondialysis days.
Idraparinux The pharmacology of idraparinux has been reviewed (233R). Comparative studies In two randomized, open, non-inferiority comparisons of idra parinux and heparin followed by a cou marin for either 3 or 6 months bleeding rates at 6 months were similar (234c). In patients with deep venous thrombosis effi cacy was similar, but in patients with pul monary embolism, idraparinux was less efficacious than standard therapy. In an extension study in 1215 patients, major bleeding occurred in 11 (1.9%) of those who were given idraparinux and in none in the placebo group; of the 11 episodes, 3 were fatal intracranial hemorrhages (235c). A randomized comparison of subcuta neous idraparinux 2.5 mg/week and a cou marin (target INR 2–3) was stopped after 4576 patients had been randomized at a mean follow-up period of 11 months because of excess clinically relevant bleed ing with idraparinux (346 cases versus 226 cases; 20 versus 11 per 100 patient-years) (236C). There were 21 instances of intra cranial bleeding with idraparinux and 9 with coumarins (1.1 versus 0.4 per 100 patient
Drugs that affect blood coagulation, fibrinolysis, and hemostasis
years); elderly patients and those with renal impairment were at greater risk.
THROMBOLYTIC AGENTS (SED-15, 3402; SEDA-29, 361; SEDA-30, 412; SEDA-31, 564)
Alteplase Observational studies Intrapleural instilla tion of alteplase 10–100 mg/day in 120 patients with complicated pleural effusions or empyemas who had failed simple chest tube placement and conventional medical treatment (52 with empyema, 41 with compli cated pleural effusions, 10 with hemothorax, and 17 with complicated malignant pleural effusions), there was complete resolution in 102 and partial resolution in 10; the 8 patients who failed to respond had either chronic empyemas or empyemas associated with lung abscesses (237c). Adverse effects were chest pain in seven patients and bleeding at the chest tube site in two. Systematic reviews In a review of four pro spective observational studies of 1966 patients with acute ischemic stroke treated within 3 hours with alteplase, the risk of sympto matic intracerebral hemorrhage was 4.7% (95% CI = 3.8, 5.8) and the risk was similar among patients with and without each of five selected characteristics (age over 70 years, baseline National Institute of Health Stroke Scale score over 20, diabetes mellitus, conges tive heart failure, and Hispanic origin) (238M).
Reteplase The pharmacology of reteplase has been reviewed (239R).
Streptokinase Urinary tract A patient with a mutation in the MTFR gene associated with deep vein
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thrombosis and massive pulmonary embo lism was given streptokinase and developed acute anuric renal failure without evidence of bleeding or an immunological reaction (240Ar). The authors reviewed all the possi ble causes of this association and could find no explanation.
Urokinase Hematologic In 114 patients with ischemic middle cerebral artery strokes, who presented within 6 hours of onset and who were randomized to intra-arterial urokinase or no extra treatment, there was an excess of episodes of cerebral hemorrhage in the treated group (9% ver sus 2%) (241c). The trial was stopped prematurely. The predictors of intracerebral hemor rhage after intra-arterial administration of urokinase have been assessed in 294 patients with strokes, 14 (4.8%) of whom had a subsequent hemorrhage (242c). Poor collaterals, early signs of ischemia on com puted tomography, a higher dose of urokinase, a lower recanalization rate, and a higher diastolic blood pressure on admission correlated with the risk of hemor rhage on univariate analysis; on multivari ate analysis, poor collaterals, urokinase dose, and early signs on computed tomogra phy remained predictors.
DRUGS THAT ALTER PLATELET FUNCTION (SEDA-29, 363; SEDA-30, 413; SEDA 31. 564)
Anagrelide Cardiovascular A cardiomyopathy has been attributed to anagrelide in a 50-year old Chinese man who took 2.5 mg bd for about 1 year; it resolved after withdrawal and did not recur when anagrelide was reintroduced in a lower dose (243A).
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Skin Painful leg ulcers on the lateral aspects of both ankles in a 38-year-old man occurred for the first time 6 weeks after starting treatment with anagrelide for thrombocythemia; no other causes could be found (244A).
Respiratory Pulmonary hemorrhage asso ciated with GP IIb/IIIa inhibitors is rare, but has been reported to be associated with abci ximab, eptifibatide, and tirofiban, with respective incidences of 0.7, 0.5, and 0.9% and an overall incidence of 0.68% (249c). Other cases have been reported (250A, 251A).
Dipyridamole (SED-15, 1140; SEDA-29, 365; SEDA-30, 413; SEDA-31, 564)
Hematologic In a series of 606 aneurysms treated by endovascular coil embolization, an intra-arterial thrombus developed in 32 (5.3%) (252c). Intra-arterial abciximab was administered at a concentration of 0.2 mg/ ml as a bolus of 4–15 mg over 15–30 min utes. Three patients had postprocedural rebleeding; one had severe thrombocyto penia and the other two showed a greater than 25% reduction in platelet count after abciximab. Abciximab-induced thrombocytopenia has been reported in a patient with a coro nary stent (253A). Thrombocytopenia that occurred 10 days after the use of tirofiban in a 57-year-old man was associated with tirofiban-depen dent anti-glycoprotein IIb/IIIa antibodies and responded to intravenous immuno globulin, suggesting a delayed hypersensitivity reaction (254A). In 305 patients given eptifibatide before percutaneous coronary intervention, the frequency of thrombocytopenia was 1.3% within 6 hours (255c). Another case has been reported (256A).
Cardiovascular Broadening of the P wave, which implies abnormal atrial depolariza tion, is associated with myocardial ischemia during treadmill exercise tolerance testing, but has also been reported during dipyrida mole stress imaging in five patients, without evidence of myocardial ischemia on subse quent myocardial perfusion imaging (245c). The mechanism is not clear. Coronary steal with ST segment elevation has also been described during dipyrida mole stress testing (246A).
Glycoprotein IIb–IIIa inhibitors (SED-15, 4; SEDA-29, 363; SEDA-30, 414; SEDA-31, 565) Comparative studies In a systematic review of comparisons of eptifibatide (n = 2812) and abciximab (n = 729), there were no dif ferences in the incidences of in-hospital death (4.1% with abciximab versus 3.5% with eptifibatide), recurrent myocardial infarction (0.8% versus 1.2%), or strokes/ transient ischemic attacks (0.7% versus 0.6%) (247M). There was no difference in the need for blood transfusion (12.4% ver sus 11.7%), but there was a higher incidence of gastrointestinal bleeding with abciximab (4.8% versus 2.8%). Cardiovascular Rupture of the ventricular septum has been reported after treatment with abciximab after myocardial infarction in a 55-year-old man, in the absence of thrombolysis, with which previous reports have all been associated (248A).
Susceptibility factors Renal disease In 2159 patients with coronary artery disease who underwent elective percutaneous cor onary intervention, the 30-day incidence of major adverse cardiac events in patients with moderate-to-severe renal insufficiency, mild renal insufficiency, and no renal insuf ficiency occurred in 5.2, 5.0, and 2.9% respectively in those who were given abcix imab and in 4.2, 3.8, and 4.0% respectively in those who were given placebo (257c). The corresponding figures for bleeding compli cations with abciximab were 8.9, 2.0, and 2.1%. Multivariate analysis identified GFR as an independent correlate of major adverse cardiac events and bleeding.
Drugs that affect blood coagulation, fibrinolysis, and hemostasis
Drug overdose Reports of 17 cases of over dose of eptifibatide have been reviewed (258M). The adverse effects included chest pain, bradycardia, angioedema, hypotension, and alveolar hemorrhage. Management of overdose requires withdrawal of eptifibatide and monitoring for bleeding. Eptifibatide clearance is delayed in renal insufficiency, and in one case hemodialysis was benefi cial. Platelet transfusion is indicated when there is acute thrombocytopenia, but not otherwise.
(SED-15, 821; SEDA-29, 365; SEDA-30, 415; SEDA-31, 566)
THIENOPYRIDINES
Clopidogrel
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taste for 2 weeks followed by complete loss of taste; his sense of smell was pre served (260A). After withdrawal of clopido grel, his taste sensation started to improve, but it took 4 months before he had near complete recovery. Psychiatric Hallucinations have attributed to clopidogrel (261A).
been
• A 58-year-old-man who underwent coronary angiography was treated with a stent and was given a loading dose of clopidogrel 600 mg followed by 75 mg/day. His other medications included atorvastatin, bisoprolol, furosemide, gabapentin, insulin, isosorbide mononitrate, metformin, and ramipril. Within 48 hours of the start of clopidogrel therapy he reported visual hallucinations, described as visions of ghostly apparitions walking past him. He stopped taking the clopidogrel and within 24 hours the hallucinations resolved. Ticlopidine was given instead and the hallucinations did not recur.
Combination studies The use of the com bination of aspirin plus, a thienopyridine and warfarin has been subjected to systema tic review (259M). One randomized clinical trial has evaluated the safety and efficacy of adding warfarin to dual antiplatelet ther apy; other published data are from case series, observational studies, and case– control studies, primarily of patients under going percutaneous coronary intervention with intracoronary stenting. Four of 12 stu dies reported no increased risk of major bleeding events. In the other eight studies, there was a 3- to 6-fold increase in bleeding events with triple antithrombotic therapy. Ischemic events were reported in only six of the studies. In only two studies was there additional benefit from a reduced incidence of ischemic events; in one study there were worse ischemic outcomes with the triple regimen compared with dual therapy. The authors concluded that there is little evidence to support the combined use of aspirin, a thienopyridine, and warfarin.
Gastrointestinal Of 11 patients who had undergone gastric bypass operations and were taking clopidogrel, 4 had significant upper gastrointestinal bleeding after 25–234 days (266c). All stopped bleeding after drug withdrawal and treatment with an intra venous proton pump inhibitor. The authors suggested that patients who have had gas tric bypass operations may be at high risk of bleeding complications when taking clopidogrel.
Sensory systems Taste After taking clopido grel bisulfate 75 mg/day for about 3 weeks, a 71-year-old man developed diminished
Liver Clopidogrel-induced hepatotoxicity is very rare, but two new cases have been reported.
Hematologic The adverse effects of clopidogrel have been reviewed (262M), and it has been suggested that the risks of aplastic anemia, thrombocytopenia, and neutropenia have been underestimated (263R). Anecdotal reports of these adverse effects continue to appear (264A). Thrombotic thrombocytopenic purpura has been attributed to clopidogrel in an 80 year-old woman who had taken clopidogrel for 4 days (265A).
640 • Following elective percutaneous coronary intervention a 56-year-old man received clopidogrel 75 mg/day and 2 months later was found to have abnormal liver function tests (267A). Clopidogrel was withdrawn. Serology for acute viral hepatitis, antimitochondrial antibodies, and anti-smooth muscle antibodies were all negative and abdominal ultrasound was normal. His liver function tests improved. Clopidogrel was reintroduced but the liver function tests again became abnormal. Clopidogrel was withdrawn indefinitely. • Acute hepatitis occurred in a 63-year-old man after he had taken clopidogrel 75 mg/day for 2 weeks (268A).
Skin Two hypersensitivity reactions to clopi dogrel have been reported (269A). In one case there was immediate type I hypersensitivity with erythematous prurigo on both elbows and arms, which persisted for 15 days despite medication with glucocorticoids and antihist amines but resolved when clopidogrel was withdrawn; skin prick-testing was positive. In the other case there was delayed type IV hypersensitivity, with generalized pruritus, erythema, and desquamation; a prick test and an intradermal test were negative but oral rechallenge was positive within 24 hours. Immunologic Acute severe non-cardio genic pulmonary edema occurred in a 71-year-old man who had taken clopidogrel 75 mg/day for 2 days; it was attributed to a type III hypersensitivity reaction (270A). In another case a type III reaction caused fever and an urticarial rash in a 34-year-old woman after she had taken clopidogrel for 10 days (271A). Drug resistance Resistance to clopidogrel has been thoroughly reviewed (272R, 273R). Treatment failure is not synonymous with drug resistance, since thrombosis is multi factorial. Clopidogrel resistance is best defined by evidence of residual post-treat ment activity of its platelet receptor P2Y12, by measuring ADP-induced platelet aggre gation before and after treatment. Clopido grel non-responsiveness occurs in 5–44% of patients. It is more common in patients with diabetes mellitus and after a loading dose of 300 mg than 600 mg.
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The mechanisms underlying variability in responsiveness to clopidogrel are not well understood. Differences in pharmaco kinetics (intestinal absorption and hepatic conversion to the active metabolite) and pharmacodynamics (platelet receptor poly morphisms) have been suggested. Resistance to clopidogrel varies with time. In one study, 53–63% of patients were resistant to clopidogrel at 2 hours after stenting, 30% on days 1 and 5; and 13–21% on day 30 (274c). This may be because the 300 mg loading dose was inade quate to generate a sufficient concentration of the active metabolite to affect platelets in some patients. Clopidogrel non-responsiveness may be linked to an increase risk of thrombotic events, including stent thrombosis, reports of which continue to appear (275A–278A). Of 50 patients scheduled for neuro-inter ventional stent placement and 50 healthy blood donors, 14 of the former were clopi dogrel non-responders and 5 had adverse effects (279c). Two developed transient intrainterventional thrombosis and three had transient ischemic attacks or infarc tion, one with a permanent neurological deficit. All five were clopidogrel nonresponders. Dual antiplatelet drug resistance (to acetylsalicylic acid and clopidogrel) has also been reported (280A). Clopidogrel resistance can be managed by the use of higher doses. The value of adjusting the loading dose of clopidogrel according to the vasodilator-stimulated phosphoprotein index has been studied in a prospective, randomized, multicenter study in 162 patients with clopidogrel resis tance undergoing percutaneous coronary intervention; there were 84 controls and 78 patients in whom the dose was guided by the in vitro measurement (281C). Among the latter, dose adjustment was effective in 67 patients (86%). There were eight major adverse cardiac events during follow-up for 1 month but no difference in the rate of major or minor bleeding (5% versus 4%). An alternative strategy is to use combina tions of two or even three antiplatelet drugs (aspirin, clopidogrel, and cilostazol) (282c).
Drugs that affect blood coagulation, fibrinolysis, and hemostasis
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Newer P2Y12 receptor antagonists, such as cangrelor and prasugrel may be helpful in future.
exposure to the active metabolite of clopi dogrel, SR62334, but tended to impair pla telet aggregation.
Susceptibility factors Genetic Conversion of clopidogrel to its active metabolite depends in part on the activity of CYP2C19, whose polymorphism CYP2C19 681G> A*2 has been associated with high residual platelet aggregation. Of 797 patients undergoing percutaneous coronary intervention, who were followed for 1 year while taking clopi dogrel 75 mg/day, 552 (69%) were homozy gous for wild-type CYP2C19 (*1/*1) and 245 (31%) carried at least one *2 allele (283c). Residual platelet aggregation at baseline did not differ significantly between the genotypes. However, during treatment with clopidogrel, residual platelet aggrega tion was significantly higher in CYP2C19 681G> A*2 carriers, who had a threefold increase (95% CI = 1.4, 6.8) in the 1-year incidence of death and myocardial infarction.
Statins Rhabdomyolysis has been attribu ted to an interaction of clopidogrel with ciclosporin and atorvastatin, which the patient had taken for more than 3 years without adverse effects or laboratory evi dence of muscle damage (286A). The symp toms and laboratory abnormalities resolved when all the drug were withdrawn and did not recur when ciclosporin and atorvastatin were restarted. The authors attributed this effect to competition for CYP3A4, causing increased atorvastatin concentrations. Conversely, it has been suggested that inhibition by some statins of CYP-mediated conversion of clopidogrel to its active meta bolite may reduce the action of clopidogrel (SEDA-28, 397). In 73 patients, 23 of whom had had a previous coronary stent thrombo sis and 50 of whom had not, platelet aggre gation was not affected by the addition of either atorvastatin 20 mg/day or pravastatin 40 mg/day to dual antiplatelet therapy with aspirin plus clopidogrel 75 mg/day (287c). However, this study does not solve the question of the clinical relevance of this putative interaction, since clopidogrel alone was not studied, since pravastatin is not a substrate of CYP3A4, and since the dose of atorvastatin may have been too low for it to have had an effect. In another study clopidogrel 75 mg/day had no effect on the pharmacokinetics of fluvastatin in healthy volunteers and fluva statin 80 mg/day did not alter the effect of clopidogrel on platelet function (288c). In a randomized placebo-controlled study of long-term clopidogrel 75 mg/day in patients with cardiovascular disease or multiple risk factors taking aspirin, a sec ondary analysis of the interaction of clopi dogrel with statins was performed (289c). The statins were categorized as those that are predominantly metabolized by CYP3A4 (atorvastatin, lovastatin, simvastatin) and those that are not (pravastatin, fluvastatin). Of 15 603 patients, 10 078 were taking a statin at baseline (8245 CYP3A4
Drug overdose Overdose with clopidogrel in 582 cases has been reviewed (284c). The majority (84%) involved a dose of no more than 150 mg and in 73% there were no adverse effects. The most common adverse clinical effects were vomiting (2.4%) and dizziness (2.4%). Drug–drug interactions Lansoprazole Clopidogrel and prasugrel are both prodrugs that are metabolized to active meta bolites, which inhibit platelet P2Y12 ADP receptors. The effects of the proton pump inhibitor lansoprazole on the pharmaco kinetics and pharmacodynamics of prasugrel and clopidogrel have been assessed in an open, four-period, crossover study in healthy subjects given single doses of clopi dogrel 300 mg and prasugrel 60 mg with and without concurrent lansoprazole 30 mg/day (285C). Lansoprazole reduced the AUC and Cmax of the active metabolite of prasugrel, R-138727, by 13 and 29% respectively, but did not affect platelet aggregation. In con trast, lansoprazole had no effect on
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metabolized and 1748 non-CYP3A4 meta bolized) and 5496 were not. For the overall population, the primary end-point (a com posite of myocardial infarction, stroke, or cardiovascular death at median follow-up of 28 months) was 6.8% with clopidogrel and 7.3% with placebo; it was similar among patients taking the two different types of statin. The authors therefore con cluded that there was no evidence of an adverse interaction of clopidogrel with statins. The interaction of statins, especially those that are metabolized by CYP3A4 (atorvastatin and simvastatin), with the antiplatelet effects of a 600-mg loading dose of clopidogrel has been investigated in 1395 patients scheduled for coronary angiography (290c). Atorvastatin and sim vastatin had no effect on the antiplatelet activity of a loading dose of clopidogrel 600 mg and did not affect clinical outcomes after percutaneous coronary intervention.
Susceptibility factors Genetic The genetic risk factors for ticlopidine-induced hepato toxicity have been studied in 22 Japanese patients with ticlopidine-induced hepato toxicity and 85 who tolerated ticlopidine without adverse reactions (294c). There was a significant correlation between ti clopidine-induced hepatotoxicity and five human leukocyte antigen (HLA) alleles: HLA-A*3303, HLA-B*4403, HLA Cw*1403, HLA-DRB1*1302, and HLA DQB1*0604. In particular, HLA-A*3303 was present in 15 of the 22 patients with ticlopidine-induced hepatotoxicity and in 12 of the 85 controls (OR = 13; 95% CI = 4.4, 39). HLA-A*3303 was present in 12 of the 14 patients with ticlopidine induced cholestatic hepatotoxicity (OR = 37; 95% CI = 7.3, 184).
Management of adverse reactions A pre viously described desensitization protocol (SEDA-30, 416) has been used successfully in 24 patients (291c). Allergic reactions occurred in four and two required repeat desensitization; 6 months later 23 remained asymptomatic and 1 had persistent but improved pruritus controlled with oral anti histamines.
HEMOSTATIC AGENTS
Ticlopidine Observational studies Adverse effects of ticlopidine occurred in 41 (9.3%) of 440 patients who had a sirolimus-eluting stent implanted, including liver dysfunction (4.5% with one death), rashes (3.6%), and neutropenia (0.7%); 28% of the adverse effects occurred later than 8 weeks after the start of therapy (292c). Hematologic Neutropenia presented with necrotizing gingivitis in a 54-year-old Malaysian Chinese woman who had taken ticlopidine 250 mg bd for 3 weeks (293A).
Aprotinin
(SED-15, 331; SEDA-29, 367; SEDA-31, 566)
Withdrawal of aprotinin Aprotinin was temporarily withdrawn worldwide in 2007, after consultation with the German Federal Institute for Drugs and Medical Devices (BfArM), the US Food and Drug Administration (FDA), Health Canada, and other health authorities, pend ing the final results from the Canadian BART trial; it was permanently withdrawn in May 2008 (295S, 296R). The results of various studies have sug gested that aprotinin increases mortality when it is used in patients undergoing car diac surgery. Not all studies have shown such an effect, but mortality has not always been an end-point and some studies have concen trated on the effect of aprotinin on renal function. Studies that have been published since 2007 are briefly reviewed here in chronological order of publication.
Drugs that affect blood coagulation, fibrinolysis, and hemostasis
Studies of mortality Long-term all-cause mortality has been studied in 3876 patients undergoing coronary artery bypass graft sur gery in an observational study conducted between November 1996 and December 2006 (297c). Aprotinin was associated with significantly increased mortality compared with controls. There were 223 deaths among 1072 patients (21% 5-year mortality) com pared with 128 deaths among 1009 control patients (13%) (co-variate adjusted hazard ratio for death = 1.48; 95% CI = 1.19, 1.85). Neither aminocaproic acid (132 deaths among 834 patients; 16%; adjusted hazard ratio for death = 1.03; 95% CI = 0.80, 1.33) nor tranexamic acid (65 deaths among 442 patients; 15%; adjusted hazard ratio for death = 1.07; 95% CI = 0.80, 1.45) was asso ciated with increased mortality. The effects of aprotinin on outcomes (mortality, cardiac events, renal failure, and cerebrovascular events) have been studied in 2064 patients undergoing cardiac surgery with cardiopulmonary bypass (298c). Post operative mortality and morbidity were higher in those who were given aprotinin, and this was related to an increased incidence of perioperative risk factors. Complex sur gery was the only independent variable asso ciated with postoperative cardiac events. Preoperative heart failure, a raised preopera tive creatinine concentration, and urgent and repeat surgery were the independent vari ables associated with postoperative hemodia lysis. Age over 70 years was the only independent variable associated with neuro logical dysfunction. In 2481 children, of whom 1251 received high-dose aprotinin compared with a histor ical cohort of 1230 who did not, univariate and multivariate analyses showed no signifi cant difference in operative mortality, acute renal failure, the need for temporary dialysis or neurologic complications; aprotinin had no effect on late mortality (299c). In 33 517 patients who received aprotinin and 44 682 who received aminocaproic acid on the day of coronary artery bypass graft ing, electronic administrative records showed that mortality was higher among the former (1512, 4.5%) than in the latter (1101, 2.5%) (300c). After adjustment for 41
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characteristics of patients and hospitals, the estimated risk of death was 64% higher with aprotinin (RR = 1.64; 95% CI = 1.50, 1.78). In the first 7 days after surgery, the adjusted relative risk of in-hospital death in the apro tinin group was 1.78 (95% CI = 1.56, 2.02). The relative risk in a propensity score-matched analysis was 1.32 (95% CI = 1.08, 1.63). In an instrumental-variable analysis, aprotinin was associated with an excess risk of death of 1.59 per 100 patients (95% CI = 0.14, 3.04). Postoperative revas cularization and dialysis were more frequent among recipients of aprotinin than among recipients of aminocaproic acid. In a retrospective analysis 1343 patients (13%) received aprotinin, 6776 (67%) received aminocaproic acid, and 2029 (20%) received no antifibrinolytic therapy (301c). All underwent coronary artery bypass grafting, and 1181 underwent com bined coronary artery bypass grafting and valve surgery. In a risk-adjusted model, sur vival was worse among patients treated with aprotinin, with a main-effects hazard ratio for death of 1.32 (95% CI = 1.12, 1.55) for the comparison with patients who received no antifibrinolytic therapy and 1.27 (95% CI = 1.10, 1.46) for the comparison with patients who received aminocaproic acid. Compared with aminocaproic acid or no antifibrinolytic agent, aprotinin was also associated with a higher risk-adjusted increase in the serum creatinine concentra tion, but not with a greater risk-adjusted inci dence of dialysis. In a multicenter, blinded trial, 2331 highrisk cardiac surgical patients were randomly assigned to one of three groups: 781 received aprotinin, 770 received tranexamic acid, and 780 received aminocaproic acid (302C). The trial was terminated early because of a higher rate of death in those who received aprotinin. Of those given aprotinin 74 (9.5%) had mas sive bleeding compared with 93 (12%) of those who were given tranexamic acid and 94 (12%) of those given aminocaproic acid (RR for both comparisons = 0.79; 95% CI = 0.59, 1.05). However, at 30 days, the rate of death from any cause was 6.0% in those who received aprotinin compared with 3.9% of those given tranexamic acid
644
(RR = 1.55; 95% CI = 0.99, 2.42) and 4.0% of those given aminocaproic acid (RR = 1.52; 95% CI = 0.98, 2.36). The rela tive risk of death with aprotinin compared with that in the other two groups was 1.53 (95% CI = 1.06, 2.22). The authors con cluded that despite the modest reduction in the risk of massive bleeding, the strong and consistent increase in mortality associated with aprotinin compared with the lysine ana logues precludes its use in high-risk cardiac surgery. In a meta-analysis of nine prospective ran domized head-to-head trials of aprotinin ver sus tranexamic acid in patients undergoing cardiac surgery, there was a statistically sig nificant 45% increase in mortality with apro tinin (RR = 1.45; 95% CI = 1.0002, 2.11) (303M). Studies of renal dysfunction In a cohort study of 3348 patients undergoing cardio thoracic surgery in a single tertiary care medical center those who received aprotinin were less likely to experience a cerebro vascular event compared with controls and they did not have an increased risk of myo cardial infarction; however, they were more likely to experience postoperative renal dys function (304c). In a prospective study in 11 198 patients, of whom 2757 received aprotinin, the overall incidence of acute renal insufficiency was 1.6% (180/11 198) and it was significantly higher in the aprotinin subset (2.6%, 72/2757 versus 1.3%, 108/8441) (305c). The incidence of acute renal insufficiency directly and significantly increased with increasing transfusions of packed erythrocytes. The authors concluded that the increased risk of renal insufficiency in patients who were given aprotinin was directly related to the increased number of erythrocyte transfusions in that high-risk patient population and that aprotinin does not independently increase the risk. In a retrospective analysis of 674 patients who underwent cardiac surgery 550 received aprotinin either in a low-dose regimen (load ing dose 1 million units, 1 million units in the pump, and 1 million units after bypass or a
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continuous infusion of 0.25 million units/ hour) or a high-dose regimen (loading dose 2 million units, 2 million units in the pump, and 2 million units after bypass or a conti nuous infusion of 0.5 million units/hour) (306c). In multivariate regression analyses, the likelihood of renal complications was not significantly increased. In a prospective study of 657 children who underwent cardiac surgery with cardiopul monary bypass, the incidences of dialysis (9.6% versus 4.1%) and renal dysfunction (26% versus 16%) were higher in those who received aprotinin; however, propensity adjusted risk ratios were not significant (307c). The authors concluded that their study had not shown an independent role of aprotinin in renal dysfunction or dialysis. In an observational study of 8548 patients there was no significant association between aprotinin dosage and renal outcome (308c). The most relevant predictor was a preopera tively raised creatinine concentration (OR = 11; 95% CI = 9, 14). Patients with postoperative renal impairment or failure were at higher preoperative risk and/or underwent more complex procedures. In a retrospective analysis of 123 unran domized patients undergoing cardiac sur gery who had increased preoperative serum creatinine concentrations 82 received aminocaproic acid and 41 aprotinin (309c). Only the duration of the aortic cross-clamp and bypass were significantly associated with acute perioperative renal dysfunction. Although the patients who were given apro tinin had higher renal risk scores, aprotinin did not adversely affect renal outcomes. In a retrospective analysis of 9106 patients who underwent on-pump or off-pump car diac surgery the combination of aprotinin with ACE inhibitors during off-pump car diac surgery was associated with a significant risk of postoperative renal dysfunction (310c). In a prospective observational study in 369 patients undergoing cardiac surgery, of whom 205 received aprotinin and 164 received aminocaproic acid intraoperatively, 51 of the former (25%) developed acute renal injury compared with 19 of the latter (12%) (311c). Aprotinin was associated with
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a twofold higher risk of acute renal damage when adjusted for potential confounders (age, Parsonnet score, preoperative serum creatinine, cardiopulmonary bypass, and cross-clamp times). Conclusions Most of the studies described above have been either retro spective or, if prospective, unrandomized. However, analyses of the prospective studies show that aprotinin increases mor tality in patients undergoing cardiac surgery. It also increases the risk of renal impairment, even if it is not an indepen dent risk factor.
Hematologic A hemolytic thrombotic microangiopathy has been attributed to aprotinin in a patient with acute myelogen ous leukemia (312A). • A 69-year-old man with acute monocytic leukemia received an intravenous bolus of aprotinin 1.5 million units followed by a continuous infusion of 200 000 units/hour, in addition to human fibrinogen 4 g. Within 48 hours the patient developed anuria, progressive thrombocytopenia, and livedo reticularis of both feet, with bluish discoloration of the left toes, suggesting cutaneous microvascular thrombosis. There was laboratory evidence of intravascular hemolysis and disseminated intravascular coagulation.
Immunologic Previous studies have sug gested that the risk of an allergic reaction to aprotinin is less than 0.1% on first sys temic exposure, but rises to 2.7% after reexposure; if re-exposure occurs within 6 months, the risk of a reaction is 5%, but if there is a delay of more than 6 months the risk is only 0.9% (313S). The risk of a severe allergic reaction after a second injection is 2.6% (314c). The incidence of hypersensitivity reac tions to aprotinin has been studied prospectively in 12 403 cases, with 801 re exposures in 697 patients (315c). There were 11 reactions to aprotinin (0.09%) after primary exposure; none was severe. There were 12 reactions (1.5%) after
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re-exposure, of which 5 were severe. All the severe reactions occurred in patients who had been re-exposed to aprotinin within 6 months. There were no reactions in 42 patients who were re-exposed within 3 days. The incidences of hypersensitivity reactions were 4.1, 1.9, and 0.4% in those who were re-exposed within less than 6 months, within 6–12 months, and after more than 12 months respectively. When aprotinin was still on the market for sys temic administration it was recommended that it should be avoided within 12 months of previous exposure. Although a test dose may predict an allergic reaction, reactions can occur despite a negative test dose, as a report illustrates (316A). • A 66-year-old man who was being prepared for cardiac surgery was given an intravenous bolus dose of aprotinin 20 000 units via a central venous catheter without adverse effects for 10 minutes thereafter. He was therefore given an intravenous loading dose of 2 million units but developed profound hypotension (systolic pressure 30–40 mmHg) within 3 minutes after the infusion had been started when only 200 000 units had been infused. The infusion was immediately stopped and he recovered after cardiopulmonary resuscitation.
The authors pointed out that a negative test dose is not a reliable predictor of anaphy laxis, but they also suggested that a test dose might act as a sensitizer, thus causing a reac tion rather than predicting one. Allergic reactions can certainly occur in response to test doses (317A, 318A). An anaphylactic reaction has been reported after primary exposure to a test dose of aprotinin in a child with a history of severe milk allergy; tests for aprotinin-specific IgG4 antibodies were positive but tests for aprotinin-specific IgE antibodies were negative (319A). The authors suggested that aprotinin should not be given to any one with a history of milk allergy. Systemic allergic reactions have been described in two women who had injections of aprotinin into their Achilles’ tendons for tendinopathy (320A). The risk is probably rare and would not warrant the use of a test dose. It has been suggested that a delay of 6
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weeks reduces the risk of systemic allergic reactions to local aprotinin, based on the results of a study in 223 patients with tendi nopathy who were usually treated with a rapid series of aprotinin injections spaced at intervals of 1–2 weeks and 158 who were given a single injection or had a delay of over 6 weeks between injections (321c). The risks of systemic allergic reac tions were 7% in the former and 2% in the latter. Injections given 2–4 weeks after a previous injection were significantly more likely to lead to allergic reactions (6%) than initial injections (0.3%) and injections given more than 6 weeks after a previous injection (0.9%).
Protamine
(SED-15, 2964; SEDA-30,
417) Comparative studies The concern that heparin reversal by protamine after carotid endarterectomy might increase the risk of thrombotic strokes has been studied in an unrandomized observational analysis of data derived from a randomized controlled study of anesthetic technique for carotid endarterectomy in 2107 patients, of whom 1513 received heparin alone and 594 had reversal with protamine (322A). The respec tive frequencies of the outcome events were
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stroke – 67/1513 (4.4%) versus 17/594 (2.9%); non-stroke or myocardial infarction death – 10/1513 (0.7%) versus 5/594 (0.8%); myocardial infarction – 6/1513 (0.4%) versus 3/594 (0.5%); hematoma – 157/1513 (10%) versus 44/594 (7.4%); re-operation – 51/1380 (3.7%) versus 18/565 (3.2%). Of these, only postoperative hematoma was more frequent when protamine was not used to reverse heparin. Cardiovascular Severe pulmonary vaso constriction occurred in a 62-year-old man within a few minutes of protamine adminis tration to reverse the effects of heparin after coronary bypass surgery; the systolic pressure fell to 50 mmHg, the central venous pressure rose rapidly to 15 mmHg, and there was mitral regurgitation and tricuspid regurgita tion with a gradient of 64 mmHg (323A). There was no evidence of anaphylaxis or myocardial ischemia, and the authors postu lated a direct myocardial depressant effect with secondary vasoconstriction. Hematologic A risk of using protamine to reverse anticoagulation with heparin after the insertion of a stent, in order to arrest bleeding, is thrombosis in the stent, as a report of two cases has underlined (324A).
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R. Ramnarace and H.R. Dalton
36
Gastrointestinal drugs
(SED-15, 243; SEDA-30, 423; SEDA-31, 573)
ANTACIDS Hydrotalcite
Comparative studies Hydrotalcite and famotidine have been compared in an open, randomized, parallel-group study in 53 patients with endoscopically proven gastro esophageal reflux disease, of whom 26 received a single dose of hydrotalcite 1 g and 27 a single dose of famotidine 10 mg for episodes of symptomatic reflux (1c). Hydrotalcite was significantly superior to famotidine in increasing the proportion of responders within the first 45 minutes, starting 10 minutes after drug administration. At 60–120 minutes, both compounds were equally efficacious. There were no adverse events in either group.
ANTIEMETICS AND DRUGS THAT AFFECT GASTROINTESTINAL MOTILITY (SEDA-29, 371; SEDA-30, 423; SEDA-31, 573)
Domperidone (SED-15, 1178; SEDA 30, 423) The pharmacology and uses of domperi done have been reviewed (2R). Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32036-8 � 2010 Elsevier B.V. All rights reserved.
Cardiovascular Cardiac dysrhythmias were reported after intravenous administration of high doses of domperidone, and this route of administration has therefore been discontin ued. Domperidone has electrophysiological properties similar to class III antidysrhythmic agents and can prolong the QT interval and predispose to ventricular dysrhythmias. This effect is more pronounced in the presence of hypokalemia. As with other class III antidysrhythmic agents, a QT interval of over 450 ms in men and 470 ms in women on the baseline electrocardiogram or sustained hypokalemia would be contraindications to domperidone. Nervous system Unlike metoclopramide, domperidone does not pass the blood–brain barrier well and therefore rarely causes nervous system symptoms. Extrapyramidal adverse effects have not been reported during controlled trials, although there have been a few anecdotal reports of such effects. Adverse effects with oral administration occur in less than 7% of patients and include headaches, dry mouth, diarrhea, anxiety, and changes in prolactin. Endocrine Like metoclopramide, domperi done can increase serum prolactin concentra tions and can therefore cause breast tenderness and enlargement, galactorrhea (uncommonly), and menstrual irregularities, including amenor rhea. Gynecomastia in men is infrequent. Domperidone stimulates thyroid-stimulating hormone, but this does not seem to have any clinical ramifications. Plasma concentrations of 18-hydroxycorticosterone, cortisol and plasma renin and angiotensin are not altered by domperidone. Domperidone does not stimulate aldosterone secretion.
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Drug–drug interactions Monoamine oxidase inhibitors Dopamine receptor antagonists should not be given in conjunction with monoamine oxidase (MAO) inhibitors. Stimulation of dopamine DA2 receptors causes inhibition of noradrenaline release from presynaptic nerve terminals. Antagonists of dopamine DA2 receptors would be expected to cause reduced inhibitory control, facilitating the release of noradrenaline, and concomitant administration of a monoamine oxidase (MAO) inhibitor would therefore impair the body’s ability to metabolize it. Because dopamine is broken down by MAO, it is possible that during long-term treatment with MAO inhibitors, dopamine could accumulate in sympathetic nerve terminals, leading to exaggerated end-organ response.
5-HT3 RECEPTOR ANTAGONISTS (SED-15, 1365; SEDA-29, 372; SEDA-30, 423; SEDA-31, 575)
Comparative studies In 50 patients with malignant tumors undergoing their first course of chemotherapy, who were randomized to ramosetron 0.3 mg/day or ondansetron 16 mg/day in a prospective crossover comparison, the two drugs had similar effects on chemotherapy-induced gastrointestinal adverse effects, emesis, and loss of appetite on day 1; however, by day 5, ramosetron was significantly better than ondansetron in controlling appetite loss (3c). From days 3 to 5, ramosetron tended to be more effective than ondansetron in its anti-emetic action. The incidences of headache, fatigue, and constipation were the same for the two drugs.
Alosetron (SEDA-29, 372; SEDA-30, 423; SEDA-31, 575) Placebo-controlled studies In a 12-week placebo-controlled study of alosetron 0.5 mg/ day, 1 mg/day, or 1 mg bd in 705 women with
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severe diarrhea-predominant irritable bowel syndrome, all doses of alosetron were effective (4C). Constipation was the most common adverse event in the three dosage groups (9%, 16%, and 19%, respectively). There was one case of intestinal obstruction and one of ischemic colitis with 0.5 mg/day and one case of fecal impaction with 1 mg bd All were self-limited and resolved without sequelae. Systematic reviews The efficacy of alosetron in diarrhea-predominant irritable bowel syndrome has been confirmed in a meta-analysis of eight placebo-controlled studies in 4170 patients (5M). The adverse events of statistical significance were constipation and abdominal pain and discomfort. Alosetron was associated with four cases of ischemic colitis (0.16%) and two cases of serious complications of constipation (0.08%); neither of these was reported in the placebo group. Alosetron was not associated with any deaths.
Dolasetron Drug overdose An overdose of dolasetron 20 � 100 mg in a 21-year-old woman was associated with prolongation of the QT interval and hypotension (6A). She was given intravenous fluids, inotropes, and sodium bicarbonate 400 mmol and the electrocardiogram normalized after 12 hours. The mechanism for the effects of overdose was postulated to be related to sodium channel blockade, and the authors suggested that more aggressive use of bicarbonate would lead to faster resolution of the widened QRS complex in sodium channel blockade. Dolasetron should be used with caution in patients who have or may develop prolongation of cardiac conduction intervals, particularly the QT interval. These include patients with hypokalemia or hypomagnesemia, patients taking diuretics with potential for inducing electrolyte abnormalities, patients with congenital long QT syndrome, and patients
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taking antidysrhythmic drugs or other drugs that lead to QT interval prolongation.
NK1 RECEPTOR ANTAGONISTS Aprepitant Substance P, a regulatory peptide that is the preferred endogenous ligand at neurokinin-1 (NK1) receptors, is found in the gastrointest inal tract (vagal afferents) and areas of the central nervous system thought to be involved in the vomiting reflex (including the nucleus tractus solitarius and area post rema). Aprepitant is the first NK1 receptor antagonist available for use as an anti emetic. It is a highly selective NK1 antagonist with a long half-life (9–12 hours) and is efficacious against opioid-induced emesis in animals. Comparative studies Aprepitant 40 mg and 125 mg have been compared with ondansetron 4 mg in 805 patients receiving general anesthesia for open abdominal surgery (7C). Aprepitant was not superior for complete response, control of nausea and rescue antiemesis, but it was better at preventing vomiting than ondansetron at both 24 and 48 hours. There were 69 adverse events in both the aprepitant arms of the study and 75 in the ondansetron arm. Nausea, constipation, and pruritus were the most common adverse events but there was no significant difference between the groups. There was slight prolongation of the QT interval, but usually not by more than 30 ms, and there were no adverse cardiovascular events. Special attention was given to the possibility of an interaction of aprepitant, which is an inhibitor of CYP3A4, and other drugs that are metabolized by CYP3A4 and that are commonly used peri operatively, such as fentanyl or midazolam. Aprepitant did not differ from ondansetron in terms of its effects on the pharmacodynamics of fentanyl or midazolam.
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HISTAMINE H2 RECEPTOR ANTAGONISTS (SED-15, 1629; SEDA-29, 373; SEDA-30, 423; SEDA-31, 576)
Systematic reviews In a review of the addition of bedtime histamine H2 receptor antagonists for the control of nocturnal gastric acid breakthrough, eight small randomized controlled studies were identified, involving 137 participants in the intervention group and 137 in the control group (8M). In the short term (under 4 weeks), the addition of a histamine H2 receptor antagonist was beneficial in controlling nocturnal symptoms, but the effect was not significant during long-term use. There were no adverse events.
Nizatidine Gastrointestinal In a crossover, doubleblind, placebo-controlled trial, 16 patients were randomized either to nizatidine 150 bd for the first 2 months, followed by a 1-month washout period and a 2-month placebo period, or to placebo for 2 months, followed by a 1-month washout period and 2 months of nizatidine (9c). Gastric emptying was measured by scintigraphy, and dyspeptic symptoms and quality of life were evaluated at the end of both treatment periods. Nizatidine caused prolonged gastric emptying of solids.
PROTON PUMP INHIBITORS (SED-15, 2973; SEDA-29, 373; SEDA-30, 424; SEDA-31)
Lansoprazole (SEDA-31, 578) Gastrointestinal Two cases of collagenous colitis associated with lansoprazole have been reported, both in older women (10A). Each developed profuse watery diarrhea within weeks of starting lansoprazole for
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upper digestive disorders. Colonoscopy was normal and biopsies showed the typical features of collagenous colitis. There was rapid clinical improvement when lansoprazole was switched to rabeprazole, and the histology was normal in follow-up biopsies. Tumorigenicity In three large populationbased studies from the Netherlands (11c), Denmark (12c) and the United Kingdom (13c), there was no evidence of an increased incidence of colorectal cancer in users of proton pump inhibitors.
Omeprazole and esomeprazole (SED-15, 1252, 2615; SEDA-29, 373; SEDA 30, 424; SEDA-31, 578) Immunologic A drug reaction with eosino philia and systemic symptoms (DRESS) has been attributed to esome-prazole (14A). • A 41-year-old woman who had undergone surgery for a glioblastoma had recurrent episodes of DRESS 20 days later. All drugs were withdrawn and she was given topical glucocorticoids and then high-dose oral prednisolone 120 mg/day, gradually tapering. Her symptoms gradually improved over 4 months. Neither the doses of medications nor renal or immunological test results were reported. Skin patch tests were performed with valproate sodium, clobazam, esomeprazole, zopiclone, paracetamol, and co-trimoxazole as 1–10% solutions. Esomeprazole gave a positive reaction at 48 and 72 hours and all the other drugs were negative.
The clinical significance of this report is dubious, as there was insufficient evidence to exclude an alternative diagnosis. Drug–drug interactions Antiplatelet drugs In a double-blind, placebo-controlled study, 140 consecutive patients undergoing coronary artery stent implantation received aspirin 75 mg/day and clopidogrel 75 mg/day and were randomized to either omeprazole 20 mg/day or placebo for 7
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days (15c). Platelet reactivity was tested on days 1 and 7. Platelet reactivity on day 7 was reduced by omeprazole from 43% to 33%. There was one episode of stent thrombosis in each group. There were no deaths. This result is of clinical importance. Clopidogrel and aspirin are used in combination in patients undergoing coronary artery re-vascularization for optimal inhibition of platelet activity and proton pump inhibitors are also commonly used. The authors pointed out that proton pump inhibitors inhibit CYP2C19, which metabolizes clopidogrel to its active metabolite, and so reduce its antiplatelet activity. Further evaluation to ascertain whether this results in increase of adverse coronary events is required; at present, no immediate change in practice can be recommended.
LAXATIVES AND ORAL BOWEL PREPARATIONS (SED-15, 2008; SEDA-29, 374; SEDA-30, 426; SEDA-31, 581)
Phosphates
(SED-15, 2820; SEDA-29, 375; SEDA-30, 427, SEDA-31, 581)
Electrolyte balance In 82 studies poly ethylene glycol and sodium phosphate were the most frequently used formulations for bowel cleansing. Case series have shown that sodium phosphate is associated with the highest risk of clinically significant electrolyte disturbances (16M). Urinary tract The US Food and Drug Administration (FDA) has issued an alert notifying health-care professionals and consumers of the risk of acute phosphate nephropathy associated with the use of oral sodium phosphate products for bowel cleansing before colonoscopy or other procedures (17S). The FDA has required the manufacturers of two products that are
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available by prescription only (Visicol and OsmoPrep) to add a boxed warning to the labels of these products and to develop and implement a risk evaluation and mitigation strategy, including a medication guide. The agency has recommended that in light of the risk, over-the-counter laxatives containing sodium phosphate should not be used for bowel cleansing.
AMINOSALICYLATES (SED-15, 138; SEDA-29, 377; SEDA-30, 428; SEDA-31, 583)
Balsalazide
(SEDA 29, 377; SEDA-31,
583) Balsalazide 2.25 g/day on 10 days per month in combination with a high-potency probio tic mixture (VSL#3) 450 billion/day for 15 days has been compared with VSL#3 alone for 15 days in maintaining remission after an attack of acute uncomplicated diverticu litis (18c). There was no significant differ ence in response between the groups and no adverse effects during the 12-month followup in both groups.
Mesalazine (5-aminosalicylic acid, mesalamine) (SEDA-29, 378; SEDA-30, 428; SEDA-31, 583) Cardiovascular Pericarditis occurred in a 44-year-old man with a 4-year history of Crohn’s disease taking mesalazine 3 g/day (19A). There were also electrocardiographic changes that mimicked Brugada syndrome. Drug formulations MMX mesalazine, which is marketed as Lialda in the USA, as Mezavant XL in the United Kingdom and Ireland, and as Mezavant elsewhere, uses the MMX Multi Matrix System technology, which delivers mesalazine throughout the colon. Combined data from two 8-week, doubleblind, placebo-controlled trials in 517
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patients have been analysed (20C, 21C, 22M). The patients were randomized to MMX mesalazine 2.4 g/day (either once daily or as 1.2 g bd), 4.8 g/day (once daily), or placebo. The 8-week remission rates were 37% and 35% with MMX mesalazine 2.4 g/ day and 4.8 g/day respectively, and 18% with placebo. The 8-week complete mucosal heal ing rates were 32% in both mesalazine groups and 16% with placebo. Most of the adverse events were mild or moderate. Gas trointestinal disorders (including abdominal pain, worsening ulcerative colitis, diarrhea, flatulence, and nausea) were the most com mon adverse events in all treatment groups, and occurred in 18%, 12%, and 24% with mesalazine 2.4, 4.8 g/day, and placebo respectively. The most common individual adverse events reported with mesalazine 2.4 and 4.8 g/day were headache (in 5.6% and 3.4% of patients respectively, versus 0.6% with placebo) and flatulence (4.0%, 2.8%, and 2.8%). The most frequently reported severe adverse events (10 out of a total of 13 individual events) were gastrointestinal disorders, and 7 were described by the inves tigator as colitis or ulcerative colitis. There were two cases of pancreatitis (one in each of the mesalazine 2.4 and 4.8 g/day groups); both were attributed to mesalazine hypersen sitivity reactions (in patients who had not taken mesalazine for at least 6 weeks before entering the study) and followed a benign course before completely resolving without sequelae after withdrawal from the study.
Drug dosage regimens Oral mesalazine 1.6 g/day has been compared with mesalazine 1.6 g/day for 10 days per month in patients with recurrent symptomatic uncomplicated diverticular disease; daily dosing was more effective than cyclic dosing in maintaining remission (23c).
Sulfasalazine Respiratory A 68-year-old woman who had taken sulfasalazine for rheumatoid
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arthritis for 6 months developed bronchiolitis obliterans organizing pneumonia (BOOP) associated with an eosinophilia of 970 � 106/l (24A). Pancreas In a survey of 1590 cases of acute pancreatitis in Denmark from 1991 to 2002 and 15 913 age- and sex-matched controls, there was an increased risk of acute pancreatitis in patients with Crohn’s disease (odds ratio [OR] = 3.7; 95% confidence interval [CI] = 1.9, 7.6) and a non-significant 1.5-fold increased risk of ulcerative colitis (25c). The use of 5-aminosalicylic acid or sulfasalazine was not associated with an increased risk of acute pancreatitis. In all patients taking 5-aminosalicylic acid and sulfasalazine, the adjusted ORs for acute pancreatitis were 0.7 (95% CI = 0.4, 2.2) and 1.5 (95% CI = 0.4, 5.2) respectively. Restricted to patients with inflammatory bowel diseases only, the respective adjusted ORs for acute pancreatitis were 0.7 (95% CI = 0.1, 3.8) and 0.6 (95% CI = 0.1, 6.7). Immunologic Sulfonamide hypersensitivity reaction has been attributed to sulfasalazine (26A). • A 34-year-old man with a history of occasional mild episodes of presumed Crohn’s disease developed a perirectal abscess and was given sulfasalazine 1 g qds. After withdrawal of sulfasalazine for a few weeks, the dose was started again and a day later he developed a macular rash over his arms, which later spread to his trunk and legs. He subsequently developed recurrent fevers of 103–104°F, moderate diarrhea and diffuse abdominal pain. His liver function tests were abnormal and his white cell count was raised at 15.4 � 109/l. The sulfasalazine was withdrawn and he was given broad-spectrum antibiotics. Hepatitis serologies, a monospot test and blood cultures were all negative, but Epstein– Barr virus serology showed a positive viral capsid immunoglobulin G (IgG) and negative immunoglobulin M (IgM). An abdominal CT scan showed enlarged mesenteric and inguinal lymph nodes and a slightly enlarged spleen. Over the next 4 days he developed progressively worse liver function tests, a leukocytosis and a prolonged prothrombin time. He developed bloody diarrhea and
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needed transfusions. He became confused and had episodes of hallucinations. He improved rapidly with methylprednisolone 40 mg bd
The authors proposed that this illness was due to a sulfonamide hypersensitivity reac tion exacerbated by Epstein–Barr virus infection.
ANTIDIARRHEAL AGENTS Hyoscine hydrochloride (scopolamine) Drug formulations Transdermal hyoscine (scopolamine, TDS) patches 1.5 mg have been compared with intravenous ondan setron 4 mg and droperidol 1.25 mg for antiemetic prophylaxis in 150 at-risk surgical patients (27c). There were no significant differences in any of the emetic outcomes or the need for rescue antiemetics in any of the groups in the first 72 hours after surgery. The complete response rates varied from 41 to 51% and did not differ significantly among the groups. The overall incidence of dry mouth was significantly more frequent in those who used the patches than in those who received droperidol or ondansetron (21% versus 3%).
Loperamide Immunologic Death has been reported in a patient who had an anaphylactic reaction to loperamide (28A). • A 37-year-old man took two loperamide tablets and, despite shortness of breath soon afterwards, took a further two tablets (4 mg) 8 hours later, which resulted in acute breathlessness. An ambulance was called and he was given adrenaline at the scene, without improvement. He later died on ITU despite treatment for suspected sepsis. A post-mortem showed evidence of a systemic allergic reaction, with raised mast cell tryptase and a large number of
Gastrointestinal drugs intra-alveolar eosinophils.
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inflammatory
671 cells
with
The cause of death was given as an ana phylactic reaction due to loperamide, with coronary artery atherosclerosis as a con tributing factor. However, the activity of mast cell tryptase was not diagnostic of anaphylaxis. There has been a previous report of anaphylaxis with loperamide in a 10-year-old who survived with treatment for anaphylaxis, but this is the first report of death associated with loperamide.
LAXATIVES Bisacodyl Comparative studies In a comparison of sodium picosulfate and bisacodyl in 144 patients with chronic constipation, there were similar responses to the two drugs with regards to stool frequency, consistency, and straining (29c). There were 7 adverse events with bisacodyl and 14 with sodium picosulfate. Neither treatment had any effect on serum electrolytes. Sodium phosphate 48 g has been com pared with polyethylene glycol 2 l plus bis acodyl 20 mg in 411 patients (30C). All four gastrointestinal adverse effects listed on the patient questionnaire (nausea, vomiting, bloating, and abdominal pain) were reported significantly less often by those who took sodium phosphate. Most of the adverse effects were mild or moderate in intensity. In another report, electrolyte dis turbances were more frequent and of greater severity in those who took sodium phosphate (31C). Drug-dosage regimens Bisacodyl 10 mg and 20 mg have been compared in 445 patients before colonoscopy (32c). There were 17 adverse events in each group. However the 10 mg dose was tolerated significantly better
with regards to abdominal cramping (14 versus 31) and nausea (28 versus 47). The other adverse effects reported included vomiting and stomach bloating. There were no deaths and no clinically significant changes in physical examination, weight, temperature, pulse, or blood pressure.
Sodium picosulfate Placebo-controlled studies In a randomized study in 57 patients with chronic constipation, sodium picosulfate 7 mg nightly for 3 days was compared with placebo (33c). Sodium picosulfate resulted in a treatment response in 86% of patients. There were no serious adverse events. In each treatment group one patient had diarrhea and one had abdominal pain. There were no cardiovascular effects or changes in hematocrit, creatinine, or electrolytes in either group.
CHLORIDE CHANNEL ACTIVATORS Lubiprostone Lubiprostone, a member of a new class of compounds called prostones, activates type 2 chloride channels (ClC-2) without affect ing the cystic fibrosis transmembrane con ductance regulator. By activating ClC-2, lubiprostone increases the chloride concen tration in intestinal fluid, causing an increase in intestinal fluid secretion without disturbing serum electrolyte balance. This increase in chloride-rich intestinal fluid may facilitate intestinal transit, thereby increasing the passage of stool and alleviat ing symptoms associated with chronic constipation. Placebo-controlled studies There was a significant increase in the incidence of nausea associated with lubiprostone in a 4-week double-blind, placebo-controlled
672
study (34C) in 244 patients who were randomized to lubiprostone of 24 µg bd or placebo. There were no other significant adverse events, no deaths and no serum electrolyte disturbances. Drug-dosage regimens Of 127 patients who were randomized and took at least one dose of the study drug, 78 had at least one adverse event: 13 in the placebo arm (39%), and 18 (62%), 24 (75%), and 23 (70%) of those who took lubiprostone 24, 48 and 72 micrograms respectively (35c). Nausea was the most commonly reported adverse event, in 31 of those who took lubiprostone (33%); 12 had at least one adverse event that was reported to be severe in intensity. Diarrhea and headache (in four patients on placebo and two patients on lubipro-stone 72 micrograms) were the only severe adverse events reported by more than one patient in either arm. Abdominal pain (one with placebo and one with lubiprostone 48 micrograms) and nausea (one each with lubiprostone 48 and 72 micrograms) were the only other severe adverse events with more than one patient overall. One patient stopped taking the study drug because of severe diarrhea (lubiprostone 72 micrograms). No patients required hospitalization or fluid replacement for diarrhea. Four patients withdrew because of nausea, one taking lubiprostone 24 micrograms (moderate intensity), two taking lubiprostone 48 micrograms (one moderate and one severe) and one taking lubiprostone 72 micrograms (severe).
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ANTISPASMODIC AGENTS Hyoscine butylbromide Systematic reviews The use of rectal hyoscine bromide in the management of cramping abdominal pain has been reviewed in a systematic review of 10 placebo-controlled studies (36M). Hyoscine butylbromide was beneficial in all of the trials, which included 3699 patients, of whom 911 received oral (n = 868) or rectal (n = 43) hyoscine butylbromide. Because the drug is hardly absorbed, it is generally well tolerated. Two large studies compared hyoscine butylbromide 30 mg/day with placebo (and paracetamol); 597 patients took hyoscine butylbromide and 592 took placebo. There were 75 adverse events with hyoscine butylbromide and 51 with placebo, which was not a significant difference. Anticholinergic adverse effects, such as nausea, constipation, dry mouth, blurred vision, tachycardia, and urinary retention, were infrequent (under 1.5%) and were mild and self-limiting.
CHOLELITHOLYTIC AGENTS Systematic reviews In a systematic review of 27 randomized studies of the use of bile salts in hepatitis B and hepatitis C, there was improvement in serum transaminase activities with bile salts compared with placebo but no effect on viral load or fibrosis; there were no adverse events (37M).
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673 inhibitors and the risk of colorectal cancer. Am J Gastroenterol 2008;103(4):966–73. 12. Robertson DJ, Larsson H, Friis S, Pedersen L, Baron JA, Sorensen HT. Proton pump inhibitor use and risk of colorectal cancer: a population-based, case-control study. Gas troenterology 2007;133(3):755–60. 13. Yang Y, Hennessy S, Propert K, Hwang W, Sedarat A, Lewis J. Chronic proton pump inhibitor therapy and the risk of colorectal cancer. Gastroenterology 2007;133(3):748–54. 14. Caboni S, Gunera-Saad N, Ktiouet-Abassi S, Berard F, Nicolas JF. Esomeprazole-induced DRESS syndrome. Studies of cross-reactivity among proton-pump inhibitor drugs. Eur J Allergy Clin Immunol 2007;62(11):1342–3. 15. Gilard M, Arnaud B, Cornily JC, LeGal G, Lacut K, LeCalvez G, Mansourati J, Mottier D, Abgrall JF, Boschat J. Influence of ome prazole on the antiplatelet action of clopido grel associated with aspirin: the randomized, double-blind OCLA (Omeprazole Clopido grel Aspirin) study. J Am Coll Cardiol 2008;51(3):256–60. 16. Belsey J, Epstein O, Heresbach D. Systema tic review: oral bowel preparation for colo noscopy. Aliment Pharmacol Ther 2007;25 (4):373–84. 17. Anonymous. Oral sodium phosphate pro ducts. New alert on acute phosphate nephro pathy. WHO Newslett 2009;1:1. 18. Tursi A, Brandimarte G, Giorgetti GM, Elisei W, Aiello F. Balsalazide and/or highpotency probiotic mixture (VSL#3) in main taining remission after attack of acute, uncomplicated diverticulitis of the colon. Int J Colorectal Dis 2007;22(9):1103–8. 19. Hermida JS, Six I, Jarry G. Drug-induced pericarditis mimicking Brugada syndrome. Europace 2007;9(1):66–8. 20. Lichtenstein GR, Kamm MA, Boddu P, Gubergrits N, Lyne A, Butler T, Lees K, Joseph RE, Sandborn WJ. Effect of onceor twice-daily MMX mesalamine (SPD476) for the induction of remission of mild to moderately active ulcerative colitis. Clin Gastroenterol Hepatol 2007;5:95–102. 21. Kamm MA, Sandborn WJ, Gassull M, Schreiber S, Jackowski L, Butler T, Lyne A, Stephenson D, Palmen M, Joseph RE.
674 Once-daily high concentration MMX mesa lamine in active ulcerative colitis. Gastroen terology 2007;132:66–75. 22. Sandborn WJ, Kamm MA, Lichtenstein GR, Lyne A, Butler T, Joseph RE. MMX multi matrix system mesalazine for the induction of remission in patients with mild-to-moder ate ulcerative colitis: a combined analysis of two randomized, double-blind, placebocontrolled trials. Aliment Pharmacol Ther 2007;26(2):205–15. 23. Tursi A, Brandimarte G, Giorgetti GM, Elisei W. Continuous versus cyclic mesalazine therapy for patients affected by recurrent symptomatic uncomplicated diverticular disease of the colon. Dig Dis Sci 2007;52 (3):671–4. 24. Ulubaş B, Sahin G, Ozer C, Aydin O, Ozg€ ur E, Apaydin D. Bronchiolitis obliterans orga nizing pneumonia associated with sulfasala zine in a patient with rheumatoid arthritis. Clin Rheumatol 2004;23(3):249–51. 25. Munk EM, Pedersen L, Floyd A, Nørgård B, Rasmussen HH, Sørensen HT. Inflammatory bowel diseases, 5-aminosalicylic acid and sul fasalazine treatment and risk of acute pan creatitis: a population-based case-control study. Am J Gastroenterol 2004;99(5):884–8. 26. Halmos B, Anastopoulos HT, Schnipper LE, Ballesteros E. Extreme lymphoplasmacytosis and hepatic failure associated with sulfasala zine hypersensitivity reaction and a concur rent EBV infection – case report and review of the literature. Ann Hematol 2004;83 (4):242–6. 27. White PF, Tang J, Song D, Coleman JE, Wender RH, Ogunnaike B, Sloninsky A, Kapu R, Shah M, Webb T. Transdermal sco polamine: an alternative to ondansetron and droperidol for the prevention of postopera tive and postdischarge emetic symptoms. Anesth Analg 2007;104(1):92–6. 28. Srinivasa MR, Phelan C. Death due to ana phylactic shock after ingestion of Imodium Instants (loperamide). Eur J Allergy Clin Immunol 2007;62(8):965–6. 29. Kienzle-Horn S, Vix JM, Schuijt C, Peil H, Jordan CC, Kamm MA. Comparison of bisa codyl and sodium picosulphate in the
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treatment of chronic constipation. Curr Med Res Opin 2007;23(4):691–9. 30. Lichtenstein GR,Grandhi N, Schmalz M, Lottes SR, Forbes WP, Walker K, Zhang B. Sodium phosphate tablets are preferred and better tolerated by patients compared to polyethylene glycol solution plus bisacodyl tablets for bowel preparation. Aliment Phar macol Ther 2007;26(10):1361–70. 31. Johanson JF, Popp JW, Cohen LB, Lottes SR, Forbes WP, Walker K, Carter E, Zhang B, Rose M. A randomized, multicen ter study comparing the safety and efficacy of sodium phosphate tablets with 2L poly ethylene glycol solution plus bisacodyl tablets for colon cleansing. Am J Gastroen terol 2007;102(10):2238–46. 32. DiPalma JA, McGowan J, Cleveland MV. Clinical trial: an efficacy evaluation of reduced bisacodyl given as part of a poly ethylene glycol electrolyte solution prepara tion prior to colonoscopy. Aliment Pharmacol Ther 2007;26(8):1113–9. 33. Wulkow R, Vix JM, Schuijt C, Peil H, Kamm MA, Jordan C. Randomised, placebo-con trolled, double-blind study to investigate the efficacy and safety of the acute use of sodium picosulphate in patients with chronic constipation. Int J Clin Pract 2007;61 (6):944–50. 34. Johanson JF, Morton D, Geenen J, Ueno R. Multicenter, 4-week, double-blind, random ized, placebo-controlled trial of lubipros tone, a locally-acting type-2 chloride channel activator, in patients with chronic constipation. Am J Gastroenterol 2008;103 (1):170–7. 35. Johanson JF, Ueno R. Lubiprostone, a locally acting chloride channel activator, in adult patients with chronic constipation: a doubleblind, placebo-controlled, dose-ranging study to evaluate efficacy and safety. Aliment Phar macol Ther 2007;25(11):1351–61. 36. Tytgat GN. Hyoscine butylbromide: a review of its use in the treatment of abdominal cramping and pain. Drugs 2007;67(9):1343–57. 37. Chen W, Liu J, Gluud C. Bile acids for viral hepatitis. Cochrane Database Syst Rev 2007; (4):CD003181.
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COLONY-STIMULATING FACTORS (SEDA-29, 383; SEDA-30, 435; SEDA-31, 589)
Granulocyte colony-stimulating factor (G-CSF) and granulocytemacrophage colony-stimulating factor (GM-CSF) (SED-15, 1542; SEDA-29, 383; SEDA-30, 435; SEDA-31, 589) Hematologic In a survey by the European group for Blood and Marrow Transplanta tion 840 patients received immuno-suppres sive therapy for severe aplastic anemia and 43% also received G-CSF. The incidence of myelodysplastic syndrome or acute myeloid leukemia was 11% in those who were treated with G-CSF as opposed to 5.8% in those who only received immunosuppres sion. Thus, G-CSF is associated with a significantly higher hazard (1.9) of myelo dysplastic syndrome or acute myeloid leukemia (227C). A 57-year-old man with refractory cardiac ischemia who received a course of G-CSF 10 micrograms/kg/day during an angiogen esis trial developed severe thrombocytope nia (nadir 5 109/l) (1A). Investigations suggested an immune-mediated mechanism. Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32037-X 2010 Elsevier B.V. All rights reserved.
A 53-year-old man with plasma cell mye loma received chemotherapy and then after 11 days of treatment GM-CSF 5 mg/kg/day and G-CSF 10 mg/kg/day; 1 week later he presented with a ruptured spleen (2A). Musculoskeletal A boy was treated with long-term daily injections of G-CSF 25–50 micrograms/kg from the age of 1 month for severe congenital neutropenia (3A). At the age of 9 years he developed recurrent headaches. Skull radiography showed thickening of the skull with the hair on-end sign that is usually associated with thalassemia. He also had generalized osteo penia with reduced vertebral height, ‘bone in bone’ appearance of some vertebrae, and thickened but decalcified ribs. The authors attributed the severe thickening of the skull to expansion of white blood cell precursors in the marrow and thought that it was the probable cause of the recurrent headaches.
Filgrastim Sensory systems One week after starting therapy with intravenous filgrastim 300 micrograms/day for 3 consecutive days, a 66-year-old woman developed bilateral kera titis, with epithelial defects and peripheral cor neal infiltrates (4A). Since her symptoms resolved 3 days after withdrawal of filgrastim, it is likely that the drug caused keratitis. Hematologic A 71-year-old man with mye lodysplasia was given pegfilgrastim 6 mg for
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persistent neutropenia and developed florid histiocytic hemophagocytosis (5A).
Insulin-like growth factor (SED-15, 1792; SEDA-26, 466) Immunologic Mecasermin (rDNA; Incre lex; Tercica, Inc.) is a recombinant insulinlike growth factor-I (IGF-I), which has been approved to treat growth failure in children with severe primary IGF-I deficiency. A 13-year-old boy developed life-threatening anaphylaxis early in the course of Increlex therapy (6A).
INTERFERONS (SED-15, 1841; SEDA-29, 384; SEDA-30, 436; SEDA-31, 591) Interferon alfa (SED-15, 1793; SEDA-29, 386; SEDA-30, 436; SEDA-31, 591) Sensory systems A 40-year-old man with multiple sclerosis taking interferon beta-1a developed cotton wool spots in the optic fundi, which seem to have been related to interferon (7A). Psychiatric The well-known psychiatric adverse effects of pegylated interferons have again been reported. Of 56 patients with hemophilia infected with hepatitis C who were treated with peginterferon alfa 2b 1.5 micrograms/kg/week and ribavirin 800–1200 mg/day, 22% developed depression that warranted the use of antidepressants; one developed a psychosis; 11% discontinued therapy owing to adverse effects (8c). Of 375 patients with renal cell carcinoma who were treated with subcutaneous inter feron alfa 9 MU three times a week, 12% developed grade 3 or 4 fatigue (9c). Endocrine Among 100 patients with chronic hepatitis C who were treated with
subcutaneous interferon alfa-2b (3 million units three times a week) and oral ribavirin (1000–1200 mg/day), overt thyroid disease (hyper- and hypothyroidism) developed in 13% and subclinical thyroid disease in 5% (10c). Hematologic In 91 patients with HCV/ HIV co-infection mean hemoglobin fell by 5.0 g/dl within 1 week of the start of interferon þ ribavirin combination therapy; increases in erythropoietin and reticulocyte counts were blunted in response to anemia compared with controls (11c). Immunologic Of 44 patients who under went liver transplantation and were treated with peginterferon alfa-2b and ribavirin for HCV infection for at least 6 months, nine developed graft dysfunction despite clear ance of HCV RNA in all but one case; his tological evaluation suggested probable autoimmune hepatitis (12c). Three other developed the following definite auto immune disorders: overlap antimitochondrial antibody-positive cholangitis, autoimmune thyroiditis, and systemic lupus erythematosus. Infection risk A 48-year-old man received a living donor liver transplant and was subsequently given peginterferon alfa-2a and ribavirin for recurrent hepatitis C. He developed cryptosporidial enterocolitis and recovered after withdrawal of interferon and ribavirin and intermittent lowering of the dose of immunosuppressant (13A).
(SED-15, 1842; SEDA-29, 394; SEDA-30, 438; SEDA-31, 592)
INTERLEUKINS
Aldesleukin (interleukin2, IL-2) (SED-15, 58; SEDA-29, 394; SEDA-30, 438) Skin Thickening of the skin has been attributed to aldesleukin (14A).
Drugs that act on the immune system: cytokines and monoclonal antibodies • A 49-year-old woman with relapsed renal cell carcinoma was given subcutaneous aldesleukin 11 106 U/m2 three times a week for 1 month and 3 weeks later developed rapidly progres sive thickening of the skin involving her legs and arms.
Respiratory Inhaled aldesleukin in three cycles of 36 MIU/day for 5 days/week or for 3 out of 4 weeks for 12 weeks has been investigated in 51 patients with pulmonary metastases from renal cell carcinoma (15c). In 40% of the cycles, inhalation of aldes leukin was associated with cough and 7% had fatigue.
Interleukin-4 (IL-4) (SED-15, 1845) Observational studies In 41 patients with relapsed or refractory indolent or aggressive non-Hodgkin’s lymphoma who received 2.5 or 5.0 µg/kg of interleukin-4 subcutaneously for 28 days of a 42-day cycle, repeated 2–6 times, adverse effects included edema (66%), malaise (56%), and abnormal liver function tests (56%) (16c).
Anakinra (interleukin-1 receptor antagonist) (SED-15, 215; SEDA-29, 394; SEDA-31, 592) Cardiovascular A 29-year-old woman with adult-onset Still’s disease was given anakinra 100 mg/day and 3 months later died of what seems to have been a dilated cardiomyopathy; she had had some cardiac dysfunction before the incident (17A). Infection risk The risk of serious infections and systemic inflammatory response syn drome (SIRS) during treatment with ana kinra is still diversely discussed. In a meta-analysis it was suggested that the risk needs to be taken seriously only during high-dose therapy in patients with signifi cant co-morbidities (18M). However, in con trast to this suggestion is the case of a man with Still’s disease who was treated with
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anakinra and had SIRS and ARDS and required 10 days of intensive care (19A). Of 35 patients with Still’s disease or sys temic juvenile onset rheumatoid arthritis enrolled in a trial of anakinra, two stopped taking the drug because of severe skin re actions, and two because of infections, one visceral leishmaniasis and one varicella (20c). Another patient with rheumatoid arthri tis who was given anakinra for 23 months developed reactivation of pulmonary tuber culosis (21A). In a 2-year observational study of the efficacy of anakinra in 60 patients with rheumatoid arthritis there were four cases of pneumonitis, of which two were hospita lized, and one of tuberculosis (previously treated with infliximab); the patients were given subcutaneous anakinra 100 mg/day in combination with intramuscular methotrex ate 7.5–10 mg/week or leflunomide 20 mg/ day (22c).
TUMOR NECROSIS FACTOR ALFA (TNF-a) ANTAGONISTS (SEDA-29, 395; SEDA-30, 439; SEDA-31, 592) Cardiovascular The risk of hospitaliza tion for heart failure has been studied in 1002 users of TNF-a antagonists and 5593 users of methotrexate aged at least 65 years with rheumatoid arthritis (23C). The adjusted hazard ratio for hospitaliza tion for heart failure comparing TNF-a antagonists and methotrexate was 1.70 (95% CI = 1.07, 2.69). Sensory systems TNF-a antagonists can cause uveitis, and etanercept seems to be associated with significantly more reports than infliximab and adalimumab (24c). Gastrointestinal There have been a few reports of new-onset or exacerbation of ulcerative colitis associated with TNF-a antagonists (25A).
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Skin There have been over 130 reports of the development of psoriasis during treat ment with TNF-a antagonists (26A–28A). This is a paradoxical adverse effect, as TNF-a antagonists have also been success fully used in the treatment of psoriasis (29H). Immunologic Of 440 patients who received unspecified TNF-a antagonists for rheumatoid arthritis, two had vasculitis that was attributed to the treatment (30c). Of 53 reported cases of drug-induced lupus-like syndrome due to TNF-a antago nists, 17 had cutaneous manifestations alone and three had overlap syndromes and mixed connective tissue disease (31c). Criteria for systemic drug-induced lupus erythematosus were fulfilled in 33 cases; 21 were due to infliximab, 10 due to eta nercept and only 2 were related to adalimumab. Few cases of properly reported hypersen sitivity reactions to TNF-a antagonists have been reported, but they may not be as rare as has been assumed. Whether these reac tions are immunoglobulin-mediated hyper sensitivity reactions or immune balance syndromes is a matter of debate (32H). Infection risk The risk of serious infec tions attributable to TNF-a antagonists is still controversial. When comparing patients with rheuma toid arthritis receiving TNF-a antagonists as opposed to methotrexate and glucocorti coids, serious infections are significantly more likely to occur during the first 3–6 months of treatment; the apparent differ ences in opinions and reports of serious infections attributable to TNF-a antagonists could be explained by the timing of the surveys (33R, 34c, 35c). In a meta-analysis of 21 studies of 5356 patients with Crohn’s disease, TNF-a antagonists did not increase the risks of death, malignancy, or serious infections (36M). Similarly, in a large cohort study of patients aged at least 65 years with rheumatoid arthritis there was no signifi cant increase in serious infections (37C).
In 200 patients with various rheumatoid diseases, severe infections occurred in 2% of patients receiving TNF-a antagonists (38c). Bacterial infections The mechanisms whereby TNF-a keeps Mycobacterium tuberculosis at bay are numerous and diffi cult to dissect. However, as it is a primary signal of granuloma formation antagonizing TNF-a alters control of initial and chronic infection. When comparing different studies and their incidences of reactivation of or increased susceptibility to tuberculosis, geographical factors must be kept in mind. The risk of TNF-a antagonist treatment in a country with a low incidence is likely to be less than in areas of moderate to high incidence. It should also not be forgotten that it is not just pulmonary tuberculosis that can develop: two women received adalimumab and developed peritoneal tuberculosis (39A, 40A). Comparing the different TNF-a antago nists the risk of tuberculosis reactivation by infliximab was 12 times higher than by etanercept (41c). In a survey of mycobacterial infections in 49 North American patients receiving TNFa antagonists, non-tuberculosis mycobacter ial infections were twice as common as tuberculosis; 16% of the patients died dur ing treatment for the infection (42c). Fungal infections In a meta-analysis of 281 cases of invasive fungal infections associated with TNF-a antagonists, 226 (80%) were associated with infliximab, 44 (16%) with etanercept and 11 (4%) with adalimumab (43R). The most common cau sative fungi were histoplasmosis (n = 84, 30%), candidiasis (n = 64, 23%), and asper gillosis (n = 64, 23%). Pneumonia was the most common pattern of infection. • A 63-year-old man taking prednisone and methotrexate for rheumatoid arthritis also received etanercept for 3 months and then adalimumab for 4 months; he subsequently developed systemic nocardiosis (44A). • Nocardiosis occurred in a 75-year-old man taking adalimumab (dosage not reported) for rheumatoid arthritis (45A).
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Adalimumab
(SED-15, 2380; SEDA-29, 397; SEDA-30, 439; SEDA-31, 597) Respiratory A 48-year-old man with rheu matoid arthritis was treated with infliximab and etanercept without any serious adverse events; however, when he received ada limumab for the second time he developed severe bronchospasm (46A).
Ear, nose, throat Within a few weeks of starting adalimumab four patients with chronic rheumatoid arthritis developed newly diagnosed recurring sinusitis refrac tory to standard treatment, which resolved after adalimumab was withdrawn (47c). Sensory systems A 60-year-old woman received subcutaneous adalimumab 40 mg every 2 weeks for 2 months and developed optic neuropathy in one eye (48A). Metabolism In two cases patients with rheumatoid arthritis, a 66-year-old man and a 40-year-old woman, there was a marked reduction in fructosamine concen trations after 1 month, suggesting that ada limumab might have improved insulin resistance (49A). Hematologic A 42-year-old woman with Crohn’s disease was given adalimumab 5 mg/kg at 0, 2, and 6 weeks and subse quently every 8 weeks (50A). She developed thrombocytopenia after 8 months and had platelet-associated IgG. Adalimumab was withdrawn and 5 months later reintroduced at a dose of 80 mg. One week after the first dose she again developed thrombocyto penia. The platelet count recovered after withdrawal of adalimumab. Skin Alopecia totalis has been described in two patients (51A, 52A). • A 38-year-old woman with rheumatoid arthri tis was treated with adalimumab for 2 years and then rapidly developed alopecia totalis. • A 48-year-old man received adalimumab 40 mg fortnightly for 6 months and developed alopecia totalis.
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Other dermatological effects possibly related to adalimumab have included pityr iasis rosea (53A), acute generalized skin eruptions (54A), cutaneous lupus (55A), and lichenoid reactions (56A). • A 51-year-old woman developed a pustular drug eruption on the flexural areas of her limbs while being treated with adalimumab (57A). • A 32-year-old man was given adalimumab 40 mg fortnightly for ankylosing spondylitis and developed urticaria (58A).
Musculoskeletal A 44-year-old woman with Crohn’s disease was treated with ada limumab in an initial dose of 160 mg fol lowed by 80 mg in week 2, when she developed severe myalgia; other causes were excluded (59A). Reproductive system A 32-year-old mor bidly obese white woman received adalimu mab 40 mg every other week for 4 months for psoriatic disease and developed menor rhagia and severe menstrual pain, which resolved when adalimumab was withdrawn (60A). Immunologic Adalimumab seems to have immunogenic effects, despite its fully human sequence, since 13 of 15 patients in a trial developed antibodies (61c). Such antibodies could lead to treatment failure. Other immunological reactions to adali mumab have been reported. • A 60-year-old woman with rheumatoid arthritis and a history of hypersensitivity to infliximab was given adalimumab 40 mg fortnightly (62A). After the seventh dose she developed edema of the hands and lips, erythema of the face and urticaria-like skin reactions on the trunk. She also had a husky voice, dyspnea, and hypotension. • A 82-year-old woman with rheumatoid arthritis developed giant cell arteritis after taking adalimumab for 2 years (63A). • A 63 year-old woman was treated with adalimumab for rheumatoid arthritis and developed ANCA-positive renal vasculitis (64A). • A 57-year-old woman, a heavy smoker, devel oped symmetrical synovitis affecting the meta carpophalangeal joints and the feet, without joint deformities or radiological erosions. She
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complained of Raynaud’s phenomenon and pain in the shoulders and knees without fever. She as given pulse methylprednisolone followed by prednisone 20 mg/day and sub cutaneous methotrexate 15 mg/week. After 6 months she was given subcutaneous adalimu mab 40 mg every other week because pred nisolone and methotrexate were insufficient. Adalimumab resulted in rapid clinical improvement, prednisone was withdrawn within 3 months, and adalimumab and metho trexate were continued. However, 8 months later her condition gradually worsened, with fatigue, weight loss, pruritus, proximal muscle pain, and progressive symmetrical proximal muscle weakness, without a rheumatic flare. She developed a rash over the thighs and abdomen. Skin biopsy showed non-specific inflammatory changes in the dermis. Both drugs were withdrawn, but her condition dete riorated further. Her erythrocyte sedimenta tion rate was 13 mm/hour, C-reactive protein 3 mg/l, creatine kinase 3223 U/l (reference range up to 190 U/l), and aldolase 147 U/l (up to 8 U/l). She had positive antinuclear anti bodies, anti-dsDNA, rheumatoid factor, anticyclic citrullinated peptide antibodies (anti-CCP) and anti-polymyositis–scleroderma antibodies (anti-PM-Scl). Deltoid muscle biopsy showed severe muscle necrosis with dense mono nuclear cell infiltrates, but no vasculitis. The diagnosis was an undifferentiated overlap syn drome, with features of polyarthritis, myositis and scleroderma, possibly caused or exacerbated by adalimumab. Prednisone 50 mg/day improved her muscle strength, normalized the muscle enzyme activities and normalized the titers of autoantibodies, except for the anti-PM-Scl antibodies, although her CK activity rose progressively over the next 8 months. She later had a serious relapse of the myositis accompanied by a flare of auto immunity similar to that seen initially. Treat ment with prednisone and methotrexate improved the symptoms.
In the last case it was uncertain whether the patient had initially true rheumatoid arthri tis or an overlap syndrome with prominent rheumatic symptoms. However, polymyo sitis/dermatomyositis can occasionally develop in patients with rheumatoid arthri tis. Also, she developed a definite polymyo sitis along with a flare in autoimmunity, which might have reflected active systemic lupus erythematosus. There has been a report of 12 patients who developed defi nite systemic lupus erythematosus while taking a TNF-a antagonist (infliximab in nine, etanercept in three) for various
rheumatic diseases (65A). However, the precise role of adalimumab in the occur rence of myositis is unclear (66Ar). Infection risk There have been further reports of infections in association with adalimumab. • A 69-year-old woman with rheumatoid arthritis had been treated with subcutaneous adalimumab 40 mg every 2 weeks for 1 year when she developed invasive cryptococcosis of one finger (67A). • A woman developed Pneumocystis jiroveci pneumonia when treated with adalimumab for rheumatoid arthritis (68A). • A 42-year-old woman with rheumatoid arthritis received subcutaneous adalimumab 40 mg/week for 70 weeks and developed recurrent varicella (69A).
Alefacept Alefacept is a bioengineered fusion protein of soluble lymphocyte function antigen (LFA-3) with Fc fragments of IgG1. It blocks the LFA-3/CD2 interaction neces sary for activation and proliferation of memory effector T cells by binding to CD2 expressed on the surface of T cells. It has been used in the treatment of psoriasis and psoriatic arthritis. There has also been a small pilot study of its use in rheumatoid arthritis (70c). Its uses and efficacy have been reviewed (71R, 72R). The reported adverse effects of alefacept are generally minor and include headache, nasopharyngitis, rhinitis, influenza, upper respiratory tract infections, pruritus, arth ralgias, fatigue, nausea, accidental injury, and increases in liver enzymes (73R). A few patients develop antibodies against alefacept. Observational studies In an open study in 11 patients with active psoriatic arthritis who were given alefacept for 12 weeks the most common adverse effects that were probably or definitely associated with the drug were a flu-like syndrome (54%) and infections (18%) (74c). There were two severe adverse events, which were both judged to be unrelated to alefacept.
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Placebo-controlled studies In a random ized, double-blind, placebo-controlled trial in 185 patients with psoriatic arthritis aged 18–70 years, alefacept 15 mg or placebo was given intramuscularly once a week for 12 weeks in combination with methotrexate, followed by 12 weeks of observation during which only methotrexate was continued (75C). Back pain and a raised alanine trans aminase activity were more common than in those given placebo. Adverse events led to withdrawal of treatment in two patients tak ing alefacept, one because of worsening and one because of increased transaminase activ ities to 3–5 times the upper limit of normal; in the latter the transaminases returned to normal after withdrawal of alefacept. There were serious adverse events in two patients who received alefacept (metrorrhagia, recto cele, and emphysema) and in three who received placebo (intervertebral disc protru sion, non-infectious gastroenteritis and breast cancer). Most of the recorded adverse events were mild to moderate in intensity and none of the serious events was attributed to the drug. There were no opportunistic infections or malignancies. Systematic reviews In a systematic review of double-blind, randomized, controlled trials of alefacept (n = 3), efalizumab (n = 5), etanercept (n = 4), and infliximab (n = 4); in patients with psoriasis the rela tive risks of one or more adverse events were significantly increased compared with placebo:
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Tumorigenicity Lymphoproliferative dis orders are more common in individuals taking immunosuppressive drugs, and mycosis fungoides has been reported in a 72-year-old patient with a psoriasiform dermatitis taking alefacept (79A). The authors suggested that alefacept should be used with caution in patients with known mycosis fungoides or an unclassified atypical lymphocytic infiltrate of the skin. Drug administration route In two open studies in healthy men a single dose of alefacept 0.15 mg/kg was given in one of three ways: a 30-second intravenous bolus (n = 12); 0.04 mg/kg intramuscularly (n = 8); or 0.04 mg/kg as a 30-minute intravenous infusion (n = 8) (80c). The intramuscular availability was about 60%. The half-life was about 12 days. In a randomized, open, crossover com parison of subcutaneous and intramuscular alefacept 15 mg in 50 healthy volunteers, the systemic availabilities were similar (81c).
Etanercept
(SED-15, 1279; SEDA-29, 397; SEDA-30, 440; SEDA-31, 600) Respiratory Another case of pulmonary nodulosis in a patient taking etanercept has been reported (82A).
• alefacept: RR = 1.09; NNTH = 15; • efalizumab: RR = 1.15; NNTH = 9; • infliximab: RR = 1.18; NNTH = 9.
• A 50-year-old woman with rheumatoid arthri tis was given etanercept 25 mg twice weekly and after 9 months developed pulmonary nodulosis. The etanercept was continued and there was no further progression of the nodu losis. Her symptoms resolved over time.
Serious adverse events were increased in a sensitivity analysis of four efalizumab trials (n = 2443; RR = 1.92; NNTH = 60) (76M).
In three cases interstitial lung disease was exacerbated during standard dosage treat ment regimens with etanercept (83A, 84A).
Hematologic Because of its pharmacologi cal action, the CD4þ count is reduced by alefacept. It has therefore been suggested that the CD4þ count should be monitored regularly to ensure that it does not fall below 250 106/l (77R); however, the usefulness of doing this has not been demonstrated (78R).
Nervous system There have been further reports of demyelinating disorders in patients taking etanercept. • A 37-year-old woman with rheumatoid arthri tis was given subcutaneous etanercept 25 mg twice a week and developed demyelinating
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disease, which resolved after withdrawal of etanercept (85A). • After 24 months of treatment with etanercept 50 mg a week for rheumatoid arthritis a 66-year-old woman developed demyelination in the spinal cord and cerebral cortex (86A). • After 3 months treatment for rheumatoid arthritis with etanercept 25 mg twice weekly a 60-year-old patient developed reversible posterior leukoencephalopathy syndrome (87A). • A 36-year-old woman received etanercept 25 mg twice weekly for psoriasis arthritis and developed multiple sclerosis after 4 months; even though the etanercept was withdrawn relapsing remitting multiple sclerosis persisted (88A). • A 74-year-old woman developed progressive multifocal leukoencephalopathy after receiving a standard dosage of etanercept for rheumatoid arthritis for 7 months (89A). • A 46-year-old woman with rheumatoid arthritis was given etanercept and after 22 months developed ophthalmic manifestations of demyelination of the central nervous system (90A). Etanercept was withdrawn. Her symptoms abated but progressed about 2 months later. She was reported to have sequelae of the demyelination, despite some improvement 1 year after diagnosis.
Metabolism A 54-year-old white woman with long-standing rheumatoid arthritis and type 2 diabetes mellitus developed episodes of hypoglycemia after starting to take subcutaneous etanercept 25 mg twice weekly (91A). Hypoglycemia occurred only on the day after each etanercept injection. The investigators suggested that the hypo glycemia was due to increased lipogenesis in the liver and adipose tissue. However, the exact mechanism is unclear. Marked hypoglycemia in female mice has been reported 2 hours after the administration of TNF-a (92E). Gastrointestinal There have been a few cases of Crohn’s disease after treatment with etanercept for 11–26 months (93A–95A). The diagnosis was confirmed histologically and responded to standard treatment and withdrawal of etanercept. Those who were not re-exposed to etanercept remained free of further flares. Liver Hepatitis has been suggested to have been aggravated by etanercept (96A, 97A).
• A 50-year-old woman with rheumatoid arthri tis received etanercept 25 mg twice weekly after non-steroidal anti-inflammatory drugs and methotrexate were not effective. Mild rises in AlT and AsT activity were thought to be due to NSAID-induced liver damage. How ever, 2 weeks after the first dose of etanercept, she developed progressive rises in AsT and AlT and had right upper quadrant tenderness and hepatomegaly. Etanercept was withdrawn. Liver biopsy showed lymphoplasmacytic inflammatory cell infiltration mainly in the portal tracts, consistent with autoimmune hepatitis. Glucocorticoids normalized liver function and produced stable joint symptoms. • A 17-year-old Caucasian woman developed pauciarticular erosive arthritis, which became polyarticular. Therapy included intra-articular and systemic glucocorticoids, non-steroidal anti-inflammatory drugs, sulfasalazine, metho trexate, gold, and ciclosporin, but active syno vitis and joint damage continued. She was therefore given subcutaneous etanercept 25 mg twice weekly, and the arthritis improved. The methotrexate was withdrawn and the dosage of prednisone was reduced to 3 mg/day. Later the etanercept was withdrawn but her arthritis flared and it was reintroduced in a dosage of 25 mg weekly. After 4 months, her liver function tests rose over 4 months and etanercept was again withdrawn. A liver biopsy showed granulomatous hepatitis with out fibrosing steatosis, as expected in metho trexate-associated hepatotoxicity.
Urinary tract A 67-year-old woman with rheumatoid arthritis developed minimal change nephrotic syndrome while under treatment with etanercept (98A). Acute interstitial nephritis occurred in a 58-year-old woman with rheumatoid arthri tis after therapy with etanercept 25 mg/ week for 3 months (99A). Skin There have been reports of tinea versicolor (100A), interstitial granulomatous dermatitis (101A), and lichen planopilaris (102A) in patients receiving etanercept. • A 71-year-old man with widespread psoriasis was given etanercept 25 mg twice a week and rapidly developed squamous cell carcinoma on the penis (103A). • A 55-year-old woman with rheumatoid arthri tis was given etanercept monotherapy 50 mg/ week and 1 year later developed a cutaneous pseudolymphoma (104A).
Immunologic A 52-year-old woman with rheumatoid arthritis was given etanercept
Drugs that act on the immune system: cytokines and monoclonal antibodies
25 mg twice a week and after 40 weeks the drug was withdrawn because of cold agglu tinin disease (105A). Sarcoidosis has been associated with etanercept. • Three women aged 46–65 with rheumatoid arthritis received etanercept 25 mg twice weekly and developed sarcoidosis 6 months to 2 years later; their symptoms abated when etanercept was withdrawn (106A, 107A). • A 35-year-old woman with sarcoidosis in remission relapsed after taking etanercept 50 mg/week for 3 weeks (108A). • A 40-year-old man’s pulmonary sarcoidosis was associated with etanercept; it did not resolve completely after withdrawal (109A). • A 52-year-old woman with rheumatoid arthritis took etanercept for 18 months and developed sarcoid-like granulomata with respiratory and parotid involvement (110A).
Infection risk Various infections have been associated with etanercept. • A 71-year-old woman with rheumatoid arthritis received methotrexate for 11 years and etanercept for 2 years and developed spontaneous purulent pericarditis (111A). • A 58-year-old woman who received etanercept and methotrexate for rheumatoid arthritis developed tuberculous uveitis (112A). • A 58-year-old man with severe chronic plaque psoriasis was given subcutaneous etanercept 50 mg twice a week. After 1 month he developed recurrent varicella. It was treated and etanercept was re-introduced. The varicella did not recur (113A). • A 41-year-old man who received etanercept 25 mg twice weekly developed Pneumocystis jiroveci pneumonia 3 years after the introduction of etanercept for psoriatic arthritis (114A).
Occult hepatitis B and etanercept-induced hepatitis B virus (HBV) reactivation have been reported (115A). • A 73-year-old white man with ankylosing spondylitis developed secondary amyloidosis. He was given subcutaneous etanercept 25 mg twice weekly and prednisone 5 mg/day. He was anti-HBs positive but HBsAg negative. AntiHBc and HBe antibodies and liver tests were normal. After 14 months therapy with etanercept and prednisone he developed malaise, right upper quadrant abdominal discomfort and increased activities of serum AsT 141 IU/l, AlT 65 IU/l, and gamma glutamyl transferase 121 IU/l; total bilirubin
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was 34 mmol/l. There was progressive disappearance of anti-HBs and seroreversion, with reappearance of HBsAg and HBV DNA. Withdrawal of etanercept and therapy with lamivudine 100 mg/day resulted in negative HBV DNA and seroconversion from HBsAg positive to anti-HBs-positive. Etanercept was restarted 4 months later, lamivudine was maintained and there was no flare-up of HBV infection during follow-up.
Hepatitis B virus reactivation is well known in HBsAg-positive patients undergoing immunosuppressive therapy. HBV serology should be monitored closely in such patients and nucleoside or nucleotide analogues should be given in case of HBV reactivation. Visceral leishmaniasis has been reported in a patient after etanercept treatment (116A).
Infliximab (SED-15, 1747; SEDA-29, 398; SEDA-30, 440; SEDA-31, 601) Observational studies In an analysis of the FDA’s AERS database, infliximab was identified as the suspect medication in 18 220 reports (117M). There were signals for lymphoma (EB05, the lower bound of the 90% confidence interval around the Empirical Bayes Geometric Mean = 6.9), neuropathy (EB05 = 3.8), infection (EB05 = 2.9), and bowel obstruction (EB05 = 2.8). The signal for granulomatous infections was stronger than the signal for non-granulomatous infections (EB05 = 13 and 2.4 respectively). The signals for bowel obstruction and infusion reaction were spe cific to patients with inflammatory bowel disease; this suggests potential confounding by indication, especially for bowel obstruction. During post-marketing surveillance for 6 months of 5000 patients treated with inflix imab for rheumatoid arthritis, 28% had adverse drug reactions, of which 6.2% were severe (118C). Bacterial pneumonia occurred in 2.2%, tuberculosis in 0.3%, Pneumocystis jiroveci pneumonia in 0.4%, and interstitial pneumonitis in 0.5%. There were serious infusion reactions in 0.5%.
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In 147 patients with inflammatory bowel disease who received 1924 infusions of infliximab, 21 were hospitalized because of serious infections that were considered to have been at least possibly related to inflix imab (119c). Nine patients (6%) developed malignancies during follow-up: four had colorectal carcinoma, one had a carcinoid tumor with another primary signet-ring cell carcinoma of the small bowel, one had a breast cancer, two had skin cancers, and one had a superficial melanoma. Of 165 patients who were treated with infliximab 3 mg/kg every 8 weeks, serious infections occurred in 8.5% (120c). In 78 patients with juvenile idiopathic arthritis reactions during infusion, such as dyspnea, flushing, chills, headache, hypoten sion, anxiety, and throat edema, occurred in 29 (35%) (121c). Anti-DNA antibodies were present in seven, but none developed a lupus-like syndrome. Cardiovascular A 78-year-old woman with rheumatoid arthritis and first-degree heart block was given infliximab 3 mg/kg fortnightly and after the third dose pro gressed to complete heart block (122A). Sensory systems A 65-year-old woman was given intravenous infliximab 3 mg/kg for rheumatoid arthritis, in addition to pre dnisolone 2.5 mg/day, methotrexate 2.5 mg/ week, folic acid, disodium etidronate, ome prazole, and thyroxine, and developed endophthalmitis (123A). Metabolism Infliximab was associated with very high concentrations of triglycerides in 32 patients with rheumatoid arthritis (124c). Hematologic The FDA’s Adverse Event Reporting System has received 8 reports of hepatosplenic T cell lymphoma in young patients receiving infliximab in combination with other immunosuppressants (125S). A 63-year-old woman with rheumatoid arthritis, who received methotrexate, predni solone and infliximab developed an EBVassociated lymphoproliferative disorder after 30 months; on withdrawal of infliximab the disorder resolved rapidly (126A).
Skin There is a multitude of reports of the adverse effects of infliximab on the skin, including palmoplantar pustulosis (127A), alopecia areata (128A), halo nevi (129A), cutaneous mucormycosis (130A), sub erythrodermic psoriasis (131A), dermatitis herpetiformis (132A), pustular psoriasis (133A, 134A), atopic dermatitis (135A), acne (136A, 137A), an overlap of exanthematous pustulosis and toxic epidermal necrolysis (138A), and an oral lichenoid reaction (139A). Immunologic Antinuclear antibodies at low titers occurred after 6 months in 13 of 20 patients with Behçet’s disease who received infliximab 5 mg/kg at weeks 0, 4, and 8 and every 6–8 weeks thereafter. Another patient developed anti-beta2 gly coprotein-I IgM antibodies (anti-beta(2) GPI). None had manifest disease due to the antibodies (140c). Autoimmune hepatitis has been reported in patients receiving infliximab (141A, 142Ar). • A 56-year-old woman with ankylosing spondylitis developed autoimmune hepatitis within 3 months of infliximab therapy; the effects of withdrawal were not reported. • A 39-year-old woman receiving infliximab developed autoimmune hepatitis; she devel oped liver failure and needed transplantation.
Lupus-like syndrome has been attributed to infliximab (143A, 144A). • A 34-year-old woman with ulcerative colitis was given infliximab 5 mg/kg at weeks 0, 2, and 6 and then every 8 weeks; after 5 months she developed a lupus-like syndrome with autoimmune hepatitis. • A 39-year-old man with Crohn’s disease was given infliximab 5 mg/kg at 0, 2, and 6 weeks and then bimonthly; co-medications included azathioprine 75 mg/day and mesalazine 2 g/day. He developed pleuritic chest pain associated with nausea and weakness; he was afebrile but had a tachycardia. An electrocardiogram showed mild inferolateral ST segment eleva tion; troponin I and CK-MB activities were normal. There was cardiomegaly on a chest X-ray and echocardiography showed a pericar dial effusion with normal left ventricular func tion. Coronary angiography was normal. He was given analgesics and prednisolone for pericarditis secondary to infliximab, which was nevertheless continued. Seven weeks
Drugs that act on the immune system: cytokines and monoclonal antibodies after the next infusion of infliximab he devel oped severe arthralgia in all small joints. Anti nuclear antibodies and anti-dsDNA antibodies were strongly positive, histone antibodies were weakly positive, and C3 and C4 were normal. A high-resolution CT scan showed pleural thickening. The infliximab was withdrawn and there was no recurrence of the lupus-like symptoms.
In Crohn’s disease, 6% of patients have a serious adverse event, and 8.2% have an infectious event related to infliximab with an overall mortality of 1%. Positive anti nuclear antibodies associated with TNF-a antagonists in Crohn’s disease have been reported to occur in 57% of patients after 1 year. However, drug-induced lupus has only been associated with infliximab in 0.6–1.6% of cases and pericarditis has not previously been reported. Vasculitis has been attributed to inflixi mab (145A). • A 31-year-old Caucasian man with active sero positive rheumatoid arthritis, despite treat ment with sulfasalazine, hydroxychloroquine, leflunomide, methotrexate, and ciclosporin, was given intravenous infliximab 3 mg/kg every 8 weeks. This was later increased to 5 mg/kg and after 12 weeks he developed wor sening joint pain and a tachycardia. He had pustular purpuric lesions and hemorrhagic papules over the elbows, hands and feet, and synovitis in the metacarpophalangeal and proximal interphalangeal joints, wrists, elbows, ankles and feet. Blood urea was 18 mmol/l (reference range 2.1–7.6) and serum creatinine 349 µmol/l (51–107). The urine contained blood and a trace of protein. Methotrexate, ciclosporin, and infliximab were withdrawn. Klebsiella infection was treated with trimetho prim. Antinuclear antibodies and c-ANCA were positive. Renal biopsy showed pauci immune crescentic glomerulonephritis.
Several hypotheses have been postulated for autoantibody induction during treatment with infliximab. The presence of nuclear or cytoplasmic debris as a result of cell apopto sis may be a trigger, and reduced TNF concentrations could induce autoreactivity. However, the precise mechanism involved in the development of vasculitis after treat ment with TNF-a antagonists is elusive. Other immunological adverse effects have been attributed to infliximab.
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• A 41-year-old woman with rheumatoid arthritis was given infliximab 3 mg/kg at intervals of 6–8 weeks combined with methotrexate; after 5 years she developed sarcoidosis, mainly involving the eyes and the central nervous system (146A). • A 67-year-old woman received infliximab 5 mg/kg in weeks 0, 2 and 6 and then every 8 weeks for psoriasis (147A). After eight infusions she developed acute ischemia in both legs due to arterial thrombosis. She was found to have antiphospholipid antibodies.
Infection risk The risk of mycobacterial infections, such as tuberculosis, is discussed above. There are many case reports of odd or opportunistic infections possibly asso ciated with the use of infliximab, such as Listeria meningoencephalitis (148A) and other Listeria infections (149A), Pneumo cystis jiroveci pneumonia (150A, 151A), pul monary actinomycosis (152A), visceral leishmaniasis (153A), coccidioidomycosis pneumonia (154A), severe malaria (155A), invasive trichophyton rubrum infection (156A), cryptococcal meningitis (157A), and severe adenovirus pneumonia (158A). In 11 patients with chronic hepatitis B infection, who were treated with infliximab for rheumatoid arthritis, hepatitis was reac tivated, but the two patients who were trea ted with etanercept did not have such a reaction (159A). An HBV mutant has been reported in patient who was given lamivudine for hepa titis B and infliximab for Crohn’s disease (160A). • A 29-year-old man with Crohn’s disease devel oped chronic hepatitis B (HBeAg and HBV DNA positive), which responded to lamivu dine 100 mg/day. However, his Crohn’s disease relapsed and did not respond to azathioprine 2.5 mg/kg/day. He was given three doses of infliximab followed by 8-weekly maintenance treatment, with a complete sustained response. About 2 years later his transaminase activities increased and 2 months later he developed weakness, malaise and nausea. IgM anti-HBc antibodies and high serum HBV DNA poly merase activities were detected. The pre viously positive HbeAg was negative at this time, suggesting lamivudine resistance with reactivation of a mutant B virus. Infliximab was withdrawn and adefovir dipivoxil was added. He became totally asymptomatic over the next few months.
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The authors suggested that caution should be taken when giving TNF-a antagonists to HBV-infected patients. In another report a 43-year-old woman who received lamivu dine prophylaxis did not develop an HBV mutant (161A). • A 25-year-old man with neurological Behçet’s disease was given infliximab 5 mg/kg in addi tion to monthly cyclophosphamide, interferon, and a combination of ciclosporin and azathioprine; he developed cytomegalovirus colitis 52 days after the first infusion of inflix imab (162A).
In 523 patients with ulcerative colitis, complications were 3.54 times more com mon in the 85 who were receiving inflix imab; the odds of sepsis were 14:1 and the odds of late complications 2.2 times greater (163c).
MONOCLONAL ANTIBODIES (SED-15, 2380; SEDA-29, 404; SEDA-30, 442; SEDA-31, 602)
Abciximab See Chapter 35 (Glycoprotein IIb–IIIa inhibitors).
Adalimumab See TNF-a antagonists above.
Alemtuzumab (Campath-1H®)
neutropenia (77%), anemia (76%), thrombo cytopenia (71%), pyrexia (69%), chills (53%), cytomegalovirus viremia (56%), and cytomegalovirus infection (16%) (164S). Other infections were reported in 90% of subjects. Skin manifestations included urti caria (16%), other rashes (13%), and erythema (4%). There was also hypotension (16%), hypertension (14%), headache (14%), tremor (3%), dyspnea (14%), diar rhea (10%), insomnia (10%), anxiety (8%), and tachycardia (10%). Respiratory A 26-year-old man with Alport’s syndrome underwent retransplantation with a renal allograft and was subsequently treated with a single intravenous dose of alemtuzumab 30 mg; on the second post-operative day he developed diffuse alveolar hemorrhage (165A). A patient with chronic lymphocytic leukemia received alemtuzumab for 3 weeks as salvage therapy and developed interstitial pneumonitis, which was not associated with either infection or the neoplasm (166A). Hematologic Of 357 pancreas transplant recipients, 20 developed red cell aplasia, autoimmune hemolytic anemia, and/or idio pathic thrombocytopenic purpura during therapy with alemtuzumab, daclizumab, and mycophenolate mofetil (167c). Alemtuzumab was used as induction therapy immediately before surgery in a man who received a living donor real trans plant; during surgery he developed a severe coagulopathy, which improved after 24 hours but recurred within 3 hours after a second dose of alemtuzumab, given exactly 24 hours after the first (168A).
(SED-15, 71; SEDA-29, 404; SEDA-30, 442; SEDA-31, 602)
Immunologic Immune reconstitution syn drome has been reported in two cases after the use of alemtuzumab (169A, 170A).
Observational studies On 19 September 2007 alemtuzumab was approved by the FDA as a single agent for the treatment of B-cell chronic lymphocytic leukemia. The common reported adverse effects in the CAM 307 trial include lymphopenia (99%),
• A 53-year-old man with Sézary syndrome received alemtuzumab 30 mg thrice weekly for 3 months. The disease responded, but 3 months later he developed sarcoidosis, which was thought to have resulted from T-cell reconstitution. • A 55-year-old man received alemtuzumab thrice weekly for T-cell prolymphocytic
Drugs that act on the immune system: cytokines and monoclonal antibodies leukemia and went into remission after 26 doses. A few weeks later, while he still had profound cellular immunodeficiency, he had a cryptococcal infection. After 10 months in remission he developed what was thought to be an immune reconstitution inflammatory response specific to Cryptococcus neoformans.
Infection risk Of 547 organ transplant recipients 65% of whom received induction therapy with alemtuzumab only, 56 devel oped subsequent opportunistic infections, including infections with cytomegalovirus (n = 16), BK virus (12), Candida (12), invasive molds (4), Nocardia (4), mycobacteria (3), Cryptococcus neoformans (2), and HHV 6, parvovirus, Balamuthia mandrillaris, and Toxoplasma (one each) (171c). Patients who received alemtuzumab for allograft rejection were significantly more likely to develop an opportunistic infection than patients who received alemtuzumab for induction therapy only (4.5% versus 21%). Of 113 patients with chronic lympho proliferative disorders who received alem tuzumab-based therapy, 25 had reactivation of cytomegalovirus; the only significant difference between the groups was a low serum albumin concentration in those in whom reactivation occurred (172c). In a study of 67 patients with chronic lymphocytic leukemia, 33% of those who received salvage therapy developed an infection while none of those who received consolidation therapy had a similar response (173c). Of 67 patients who were Toxoplasma IgG-positive when they were given alemtu zumab at the time of hemopoietic stem cell transplantation, and were therefore classi fied as being at high risk of Toxoplasma reactivation, and were covered with co-tri moxazole prophylaxis after transplantation, two developed Toxoplasma invasive disease with cerebral involvement at 2 and 4 months after transplantation (174A). Comparing these results with those of stu dies of other T-cell replete cohorts receiving hemopoietic stem cell transplantation, there was no significant difference in the incidence of Toxoplasma reactivation. In 477 patients who received induction with alemtuzumab for renal transplantation
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the incidences of subsequent fungal and tuberculous infections were 0.6 and 0.4% respectively (175c).
Basiliximab
(SED-15, 418;
SEDA-29, 407; SEDA-30, 443; SEDA-31,
603)
Immunologic Of 18 renal transplant recipi ents who received basiliximab, two devel oped anaphylactic reactions on initial exposure to basiliximab; both had a history of allergies (bronchial asthma and drug allergy) (176A).
Bevacizumab See Chapter 47.
Daclizumab
(SED-15, 1047; SEDA-29, 408; SEDA-30, 444; SEDA-31, 605) Cardiovascular Three patients who were given intravenous daclizumab 1 mg/kg after liver transplantation developed sinus bradycardia for 6–9 days starting after 12–40 hours (177A).
Musculoskeletal Of 15 children who were treated with daclizumab for acute graft versus-host disease, one developed a reactive arthritis that was thought to be linked to the drug (178c). Infection risk Of 57 patients with acute graft-versus-host disease after allogeneic hemopoietic stem cell transplantation treated with daclizumab, 54 developed opportunistic infections; 33% of the deaths were due to graft-versus-host disease with infection (179c). Of 58 patients who underwent renal allo transplantation and induction with a single dose of daclizumab 1 mg/kg 2 hours before the operation, 10 developed an infection; how ever, the incidence was the same in those who did not receive daclizumab at all (180c).
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Of five patients with active non-infectious uveitis treated with daclizumab 8 mg/kg on day 0 and 4 mg/kg on day 14, one developed a left lower lobe pneumonia (181A).
Efalizumab (SEDA-29, 409; SEDA-30, 445; SEDA-31, 605) On 8 April 2009 the FDA recalled efalizu mab because of the risk of progressive multifocal leukoencephalopathy and lifethreatening infections (182S). Observational studies Among 49 patients with psoriasis who received subcutaneous efalizumab 1 mg/kg once a week for 12 weeks, the reported adverse effects were headache (35%), arthralgia/arthritis (29%), psoriasis (de novo or exacerbated; 27%), and pruritus (22%) (183c). Nervous system Aseptic meningitis has been reported in a 32-year-old woman receiving efalizumab for severe psoriasis (184A). Drug-induced aseptic meningitis is mainly caused by non-steroidal anti-inflam matory drugs, antibiotics, intravenous immunoglobulin and monoclonal antibo dies such as muromonab, intrathecal agents, and vaccines. Patients with autoimmune dis eases seem to be more susceptible, but the pathogenic mechanisms are not known. Efalizumab might cause aseptic meningitis by blocking LFA-1 and ICAM-5 interac tions or by binding to a cross-reacting neural antigen, thereby inciting local inflammation, as has been suggested by some authors for muromonab. Hematologic Of 39 patients who under went renal transplantation and were kept on a regimen with ciclosporin, mycopheno late mofetil, glucocorticoids, and subcuta neous efalizumab 0.5 or 2 mg/kg/week for 12 weeks, 8% developed lymphoprolifera tive disorders; all had received the higher dose of efalizumab (185C). Other cases have been reported (186A). The risk of thrombocytopenia associated with efalizumab is well established and has
been reported again (187A–189A). The guidelines suggest monthly monitoring platelet counts for 3 months after the start of treatment and every 3 months thereafter, but there seems to be an increased risk within at least the first 6 months (190cr) (i.e. an intermediate time-course). This is also applicable to autoimmune hemolysis, which can also develop beyond the first 6 months of treatment (191A). Skin Inflammatory papules developed in 15 patients who were receiving efalizumab (192A). As there was no increase in eosinophils in the papules, these lesions were thought not to be allergic. Immunohistochemistry showed an increase in CD11bþ, CD11cþ, and iNOSþ cells in the papules, with relatively few CD3þ T cells. Other reports of dermatological adverse events in patients receiving efalizumab have included hypertrichosis (193A), plantar ex foliation and desquamation (194A), severe exacerbation of chronic plaque psoriasis (195A), and guttate psoriasis (196A). • A 44-year-old Caucasian woman with recalcitrant psoriasis was given efalizumab 1 mg/kg/week and after 8 months developed multiple eruptive dermatofibromata, which resolved 6 months after withdrawal of efalizumab (197A). • A 60-year-old woman with psoriasis was given weekly efalizumab and 9 weeks later developed pityriasis rubra pilaris; the lesions responded to standard treatment and withdrawal of efalizumab (198A).
Musculoskeletal In a multicenter study newonset psoriatic arthritis occurred in 16 patients who were receiving efalizumab for psoriasis; one responded to withdrawal alone, eight required further treatment and two relapsed on reintroduction of efalizu mab (199c). Immunologic Immunological reactions to efalizumab have been reported. • A 58-year-old woman with psoriasis and a history of autoimmune hepatitis was given efalizumab 0.8 ml/week, and after a few
Drugs that act on the immune system: cytokines and monoclonal antibodies months developed a lupus-like syndrome, with a combination of polyarthralgia, hepatitis, pericarditis and immunological disorders; she improved shortly after drug withdrawal (200A). • A 52-year-old man developed a drug reaction with eosinophilia and systemic symptoms (DRESS) after receiving efalizumab 1.0 mg/ kg/week for 4 weeks for psoriasis; the symp toms persisted for 4 months after the drug was withdrawn (201A).
Infection risk Various infections have been reported in patients receiving efalizumab. • A 45-year-old woman with recalcitrant psoria sis had a flare-up and developed skin papules after re-treatment with efalizumab. There was complete remission after she had received efa lizumab for 12 weeks. Efalizumab was with drawn 3 months later. When the psoriasis relapsed she was again given efalizumab. After 3 weeks she developed eruptive whitish papules on the face and neck, resistant to topi cal glucocorticoids and vitamin D analogues, and her psoriasis flared up. The papules were due to disseminated giant molluscum contagio sum. Efalizumab was withdrawn and the papules resolved with methotrexate 15 mg/ week and narrow-band UVB.
This report suggests that under certain con ditions efalizumab might encourage the development of viral infections and defeat the immune system (202A). Disseminated cryptococcosis occurred in a patient with severe psoriasis who received efalizumab, ciclosporin, and methotrexate (203A). • A 34-year-old woman received subcutaneous efalizumab 1 mg/kg/week in addition to metho trexate 20 mg/week and ciclosporin 150 mg bd for severe pustular psoriasis. After 1 year she developed a progressive bilateral retro-orbital headache, which lasted 6 months. She also had weight loss of 2 kg and a solitary 0.5 cm umbi licated erythematous lesion on her right cheek resembling a nodular basal cell carcinoma. Histologically, the lesion showed encapsulated yeasts with occasional budding, consistent with Cryptococcus infection. The titer of serum cryptococcal antigen was 1:128. The cerebro spinal fluid contained fungal spores, encapsu lated yeasts, and there was a lymphocytic pleocytosis (35 106/l), raised protein (0.83 g/l) and a low glucose (1.4 mmol/l). Cere brospinal fluid cryptococcal antigen was positive (titer 1:128) and culture yielded Cryptococcus neoformans var. neoformans sensitive to amphotericin, flucytosine and fluconazole.
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The authors suggested that efalizumab had contributed to disseminated cryptococcal infection, because the patient had no oppor tunistic infections while taking metho trexate and ciclosporin for many years. However, triple drug immunosuppressive therapy is a risk factor for opportunistic infections such as cryptococcosis. Leishmaniasis has been associated with efalizumab (204A). • A 42-year-old man with generalized plaque psoriasis was given subcutaneous efalizumab 1 mg/kg/week and reported that his dog had died of leishmaniasis 10 weeks after the start of treatment; 2 weeks later he developed visceral leishmaniasis (205A).
Body temperature Efalizumab has been associated with fever of unknown origin (206A).
Gemtuzumab ozogamicin Liver The form of hepatotoxicity called sinusoidal obstructive syndrome in adults with acute myeloblastic leukemia who received gemtuzumab ozogamicin in clinical trials has been reviewed in the Research on Adverse Drug Events and Reports (RADAR) project (207M). The incidence was 3% at doses of 6 mg/m2 or more if used as monotherapy or in combination with nonhepatotoxic agents versus 28% if used with thioguanine and 15% when used as monotherapy in a dosage of 9 mg/m2. In observa tional studies the frequency of the syndrome was 15–40% if a stem cell transplantation was performed within 3 months of therapy with gemtuzumab ozogamicin. The FDAmandated Prospective Observational Regis try of patients who have received care at 60 medical centers has identified the sinusoidal obstructive syndrome associated with gem tuzumab ozogamicin in 14% of patients in whom stem cell transplantation is performed and 9% otherwise. Urinary tract Hemorrhagic cystitis has been associated with gemtuzumab ozogamicin (208A).
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• A 52-year-old man with acute promyelocytic leukemia received gemtuzumab ozogamicin after cord blood transplantation and 20 days later developed hemorrhagic cystitis with detection of adenovirus and BK virus. On days 218 and 232 he received gemtuzumab ozogamicin 9 mg/m2 again as part of a consolidation regimen, and on day 233 again developed a hemorrhagic cystitis, but without detection of microbial agents.
Immunologic A fatal hypersensitivity reac tion was reported in a 75-year-old man with acute myelogenous leukemia who received gemtuzumab ozogamicin 9 mg/m2 and a con comitant platelet transfusion; he had been given gemtuzumab ozogamicin and platelet transfusions before without adverse effects, but never on the same day (209A).
Infliximab See TNF-a antagonists above.
Natalizumab
(SEDA-30, 447)
Nervous system Natalizumab was with drawn from the market 3 months after its approval in February 2005 and was sus pended from all clinical trials because of reports of a rare neurological disease, pro gressive multifocal leukoencephalopathy, associated with the JC virus, a human poly omavirus, in patients with multiple sclerosis being treated with natalizumab (210A–212A, 213C). The Food and Drug Administration asked that all clinical trials involving drugs that target a4b1/VLA-4 be suspended until the full results of the TysabriTM safety data were completed (214R). Of three cases that occurred during clinical trials of natalizu mab in patients with multiple sclerosis, two were fatal (estimated incidence of 1 per 1000; 95% CI 0.2–2.8; mean treatment per iod 18 months). The risk of this viral infec tion, which is usually symptomatic only in severely immunosuppressed patients, was estimated at about 1 case per 1000 patients on natalizumab. During 2 years of treat ment, 6% of patients developed persistent
anti-natalizumab antibodies, leading to reduced efficacy and a higher incidence of reactions during infusion, as well as hyper sensitivity reactions (215R, 216R). Immunologic Hypersensitivity reactions have been associated with natalizumab. In one survey of 625 patients with multiple sclerosis, anti-natalizumab antibodies were detected in 57 (9%); 20 (3%) were transi ently positive and 37 (6%) were persistently positive (217c). In the latter there was loss of efficacy of natalizumab. The incidence of infusion-related adverse events was signifi cantly higher in persistently positive patients. Type III hypersensitivity reactions occurred in 4 of 40 patients with relapsing– remitting multiple sclerosis after infusion of natalizumab in one center (218A). Tumorigenicity Melanoma occurred in two women with multiple sclerosis who were treated with natalizumab (219A). In an experimental mouse model of melanoma, expression of the a4b1 integrin on melanoma cells promoted homotypic intercellular adhesion and a reduced ability to invade extracellular matrix gels, thus inhibiting the metastasis of melanoma at the earliest, invasive stage of the metastatic cascade (220E). Melanoma inhibitory activity protein is secreted by melanoma cells, promotes invasion and migration and binds to a4b1 integrin and down-regulates its activity (221E). Anti– a4 integrin antibodies potentially downregulate the immune system, both at the primary tumor site and in the regional nodal basin, thereby promoting spread of melanoma. Natalizumab should therefore not be given to patients with a personal or family history of melanoma or to those with atypical moles or ocular nevi.
Omalizumab
(SED-15, 2614;
SEDA-30, 447) Immunologic Of 39 510 patients with asthma, 35 had 41 episodes of anaphylaxis
Drugs that act on the immune system: cytokines and monoclonal antibodies
(0.09% of patients) associated with omalizumab; 22 (61%) reactions occurred in the first 2 hours after one of the first 3 doses and five (14%) of the events after the fourth or later doses occurred within 30 minutes (222C). In a review of reports of anaphylaxis to omalizumab submitted to the FDA, there were 124 cases of anaphylaxis in patients with asthma (223S). Many had a delayed onset of symptoms beyond 2 hours after administration and a number of cases were characterized by protracted progression. Non-IgE-mediated anaphylactic (i.e. ana phylactoid) reactions have been reported in two patients after successful long-term treat ment for asthma with omalizumab (224A).
Ranibizumab See Chapter 47.
TGN1412 TGN1412 is an agonistic anti-CD28 mono clonal antibody. CD28 is a co-stimulatory receptor on CD4 and many CD8 T lympho cytes. TGN1412 was genetically engineered, by a company called TeGenero, by transfer of the complementarity determining regions (CDRs) from heavy and light chain variable region sequences of a monoclonal mouse anti-human CD28 antibody into human heavy and light chain variable region frame works. Humanized variable regions were subsequently recombined with two human genes, one coding for the IgG4 � chain and one coding for a � chain. The intention was that TGN1412 would activate and expand regulatory T lymphocytes and induce anti-inflammatory cytokines. The proposed indications were B-cell chronic lymphocytic leukemia and rheumatoid arthritis. At a research unit in Northwick Park Hos pital in North London on 13 March 2006, six healthy volunteers received TGN1412 and two received placebo in a first-in-human study run by a company called Parexel. Within
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hours all six who had been given TGN1412 were in intensive care with severe inflamma tory reactions that progressed to multiorgan failure (225S). Their symptoms were as fol lows: headache within 50–90 minutes; lum bar myalgia, rigors within 58–120 minutes and a fever over 38°C within 2.5–6.5 hours. They subsequently developed hypotension, tachycardia, dyspnea and tachypnea, respiratory failure, radiological pulmonary infiltrates, and evidence of disseminated intravascular coagulation; two had periph eral limb ischemia; one developed dry gang rene of the fingers and toes. All developed lymphopenia, with significant falls in CD3, CD4þ and CD8þ counts. All recovered, but had prolonged memory problems, head aches, and inability to concentrate. This syndrome was due to a massive cyto kine storm. Serum concentrations of TNF-� rose markedly within 1 hour, and TNF-�, IL-2, IL-4, IL-6, and IL-10 all increased over days 1 and 2; there were very large increases in interferon gamma at 4 hours and on day 2. T lymphocytes normally require both anti gen receptor stimulation and co-stimulation of the CD28 receptors to become fully acti vated. However, TGN1412 was a superagonist that stimulated T (and B) lymphocyte activity without the need for con current antigen receptor stimulation. In vitro experiments had not predicted this effect. Following an enquiry by an independent expert scientific group, chaired by Sir Gor don Duff, Chairman of the Commission on Human Medicines (CHM, which was formed in February 2005 by conjoining the former Medicines Commission and the Committee on Safety of Medicines, CSM), the following 22 recommendations were made (226S): 1. The strategy for preclinical development of a new medicine and the experimental approaches used to assemble information rele vant to the safety of phase I trials must be regarded as science-based decisions, made and justified case by case by investigators with appropriate training. 2. Developers of medicines, research funding bodies, and regulatory authorities should expedite the collection of information on unpublished preclinical studies and phase I
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trials, and explore the feasibility of open access to this database. 3. Regulatory authorities should consider ways to expedite the sharing between regulators world wide of information on Suspected Unexpected Serious Adverse Reactions (SUSARs) in phase I trials, and explore the feasibility of open access to these data. 4. A broader approach to dose calculation, beyond reliance on the “No Effect Level ” or “No Adverse Effect Level” in animal studies, should be taken. The calculation of starting dose should use all relevant information. Factors to be taken into account include the novelty of the agent and its mechanism of action, the degree of species specificity of the agent, the dose-response curves of biological effects in human and animal cells, dose-response data from in vivo animal studies where relevance to human has been validated, the calculation of receptor occupancy versus concentration, and the calculated exposure of targets or target cells in humans in vivo. The “MABEL” approach is a good option for achieving this. 5. If different methods give different estimates of a safe dose in humans, the lowest value should be taken as the starting point in first-in-human trials and a margin of safety should be introduced. 6. When it is likely that preclinical information, for any reason, may be a poor guide to human responses in vivo, the starting dose in first-in human trials should be calculated to err on the side of caution. 7. Careful consideration should be given to the route and the rate of administration of the first dose in first-in-human trials, with careful monitoring for an exaggerated response. 8. Decisions on the starting dose and dose escalation should be made on a case-by-case basis, and should be scientifically justifiable, taking account of all relevant information. 9. The decision whether to conduct a first-in man trial in healthy volunteers or in volunteer patients should be carefully considered and fully justified, taking into account all factors relevant to the safety of the subjects and the value of the scientific information that is likely to be obtained. 10. Principal Investigators in first-in-human trials should always be appropriately qualified and satisfy themselves that they know enough about the agent, its target, and its mechanism of action to be in a position to make informed clinical judgements. 11. In first-in-man studies in which there is a predictable risk of certain types of severe adverse reaction, a treatment strategy should be considered beforehand. This should include the availability of specific antidotes, when they exist, and a clear plan of supportive treatment, including the pre-arranged contingency availability of ITU facilities.
12. First-in-human studies of higher-risk medicines should always be conducted in an appropriate clinical environment, supervised by staff with appropriate levels of training and expertise, with immediate access to facilities for the treatment and stabilization of individuals in an acute emergency and with pre-arranged contingency availability of ITU facilities. 13. New agents in first-in-human trials should be administered sequentially to subjects with an appropriate period of observation between dosing. 14. The interval of observation between sequential dosing of the subjects should be related to the kind of adverse reactions that might be anticipated based on the nature of the agent, its target, and the recipient. 15. A similar period of monitoring should occur between sequential doses during dose escalation. 16. More communication should be encouraged between developers and the regulator at an ear lier stage before an application is filed, espe cially for higher-risk agents, to ensure that there is time for appropriate consideration of any safety concerns, without introducing undue delay in product development. Ways to increase communication between the regulator and research ethics committees should also be considered. 17. For appraisal of applications for trials of higher-risk agents, as defined by the nature of the agent, its degree of novelty, its intended pharmacological target, and its intended recipient, the regulator should have access to additional opinions from independent, specialist experts with research knowledge of their fields. 18. An Expert Advisory Group (EAG) of the Commission on Human Medicines, or a similar body, might undertake this role, with a core membership of appropriate experts and the ability to co-opt additional experts as the need dictates. 19. Consideration should be given to introducing some flexibility in the time-scale of clinical trial appraisal in exceptional cases of unusual complexity. 20. The availability of ‘hands-on’ experience in the planning and conduct of clinical trials should be widened, for example by secondment periods to commercial organizations within postgraduate training programmes, or the development of specialist centres within the [UK’s] NHS and Universities (see next recommendation). 21. The feasibility of developing specialist centres for phase I clinical trials of higher-risk agents and advanced medicinal products should be explored. 22. The regulatory process for first-in-human trials of higher-risk agents and advanced medicinal products based on innovative technologies should be subject to frequent review.
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recommendations for patient selection and monitoring. Lancet Neurol 2007;6(5): 431–41. Calabresi PA, Giovannoni G, Confavreux C, Galetta SL, Havrdova E, Hutchinson M, Kappos L, Miller DH, O’Connor PW, Phil lips JT, Polman CH, Radue EW, Rudick RA, Stuart WH, Lublin FD, Wajgt A, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA. AFFIRM and SENTINEL Investigators. The incidence and signifi cance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL. Neurology 2007;69(14):1391–403. Hellwig K, Schimrigk S, Fischer M, Haghi kia A, Muller T, Chan A, Gold R. Allergic and nonallergic delayed infusion reactions during natalizumab therapy. Arch Neurol 2008;65(5):656–8. Mullen JT, Vartanian TK, Atkins MB. Mel anoma complicating treatment with nata lizumab for multiple sclerosis. N Engl J Med 2008;358(6):647–8. Qian F, Vaux DL, Weissman IL. Expres sion of the integrin alpha 4 beta 1 on mela noma cells can inhibit the invasive stage of metastasis formation. Cell 1994;77:335–47. Bauer R, Humphries M, Fässler R, Winkl meier A, Craig SE, Bosserhoff AK. Regula tion of integrin activity by MIA. J Biol Chem 2006;281:11669–77. Cox L, Platts-Mills TA, Finegold I, Schwartz LB, Simons FE, Wallace DV. American Academy of Allergy, Asthma &
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Immunology/American College of Allergy, Asthma and Immunology Joint Task Force report on omalizumab-associated anaphy laxis. J Allergy Clin Immunol 2007;120 (6):1373–7. Limb SL, Starke PR, Lee CE, Chowd hury BA. Delayed onset and protracted progression of anaphylaxis after omalizu mab administration in patients with asthma. J Allergy Clin Immunol 2007;120(6): 1378–81. Price KS, Hamilton RG. Anaphylactoid reactions in two patients after omalizumab administration after successful long-term therapy. Allergy Asthma Proc 2007;28(3): 313–9. Medicines and Healthcare products Regu latory Agency. Investigations into adverse incidents during clinical trials of TGN1412. 25 May 2006. http://www.mhra.gov.uk/ News Centre/Pressreleases/CON2023822. Department of Health. Expert Group on Phase One Clinical Trials. Final report. http://www.dh.gov.uk/en/Publicationsand statistics/Publications/PublicationsPolicyAnd Guidance/DH_063117. Socie G, Mary JY, Schrezenmeier H, Marsh J, Bacigalupo A, Locasciulli A, Fuehrer M, Bekassy A, Tichelli A, Passweg J. Granulocyte-stimulating factor and severe aplastic anemia: a survey by the European Group for Blood and Mar row Transplantation (EBMT). Blood 2007; 109(7):2794–6.
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38
Drugs that act on the immune system: immunosuppressive and immunostimulatory drugs
Ciclosporin
(SED-15, 743; SEDA-29, 426; SEDA-30, 452; SEDA-31, 619)
Cardiovascular Hypertension is a wellknown adverse effect of calcineurin inhibitor therapy. The mechanisms have not been elucidated and are still controversial. In a patient undergoing hemodialysis, cardio thoracic bioimpedance showed evidence of raised systemic vascular resistance with nor mal blood volume (1A). She stopped taking ciclosporin and her blood pressure fell. Ciclosporin was restarted in a dosage of 25 mg/day and her systemic vascular resis tance was 1275 dyne/s5. When the dosage was increased to 100 mg/day, her blood pressure rose to 200/80 mmHg and her sys temic vascular resistance to 1874 dyne/s5, with normal cardiac output and a low-normal intrathoracic fluid volume.
Nervous system Ciclosporin can cause pseudotumor cerebri (2A). • A 15-year-old girl with hypodiploid acute lym phoblastic leukemia took methotrexate and ciclosporin 1.5 mg/kg after bone marrow
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32038-1 � 2010 Elsevier B.V. All rights reserved.
transplantation and 30 days later developed a continuous frontal headache with bilateral papilledema. Her blood ciclosporin concentra tion was 85 µg/l. A CT scan showed mild pro minence of the lateral and third ventricles with no intracranial masses or obstructing lesions. The cerebrospinal fluid (CSF) was normal. Ciclosporin was withdrawn and replaced by tacrolimus. After a few days her headache resolved and fundoscopy showed less disc edema. • A 12-year-old boy with myelodysplastic syndrome took methotrexate and ciclosporin 1.5 mg/kg after stem cell transplantation and the blood ciclosporin concentration was kept at 150–200 µg/l. After 45 days he developed persistent unexplained nausea and vomiting with no headache, unresponsiveness to antiemetics and bilateral papilledema. A CT scan showed no evidence of intracranial masses and the CSF was normal. He was given acetazola mide and ciclosporin was replaced by myco phenolate mofetil. His symptoms resolved after a short course of methylprednisolone and the papilledema improved.
In 20–40% of liver transplant recipients taking calcineurin inhibitors, central nervous system toxicity presents a wide spectrum of mild to severe neurological and psychiatric disorders, for which intravenous lipid may be beneficial. Of 45 Japanese patients who received living-donor transplants, 10 devel oped neurological complications, such as changes in mental status, confusion, seizures, altered level of consciousness, neuralgia, headache, and tremor; 3 were taking ciclosporin and 7 tacrolimus (3c). If the
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blood–brain barrier is impaired, unbound calcineurin inhibitors might be able to enter the brain more readily. Based on this hypothesis, five patients (two of whom were taking ciclosporin and three tacrolimus) received an intravenous lipid supplement of 20% soybean oil 0.1–0.2 ml/kg/hour for 2–3 days, after which, and without a change in the dosage of the calcineurin inhibitor, their neurological symptoms improved remarkably. Metabolism In an international multicenter study of the incidence of diabetes mellitus after renal transplantation, the primary safety end point was a composite of new-onset diabetes or impaired fasting glucose within the first 6 months (4C). The primary efficacy end point was a composite of biopsy-proven acute rejection, graft loss or death at 6 months after transplantation. The patients were randomized to ciclosporin microemul sion (n = 336) or tacrolimus (n = 346) with mycophenolic acid, a glucocorticoid and basiliximab. Diabetes susceptibility factors, glucocorticoid doses and demographics were similar between the groups. There was new-onset diabetes or impaired fasting glucose at 6 months in 26% of those who were given ciclosporin and 34% of those who were given tacrolimus. The primary efficacy end points occurred in 13% of those who were given ciclosporin and 9.8% of those who were given tacrolimus. Mean glomerular filtration rate (GFR), mean serum creatinine and mean blood pressure were similar in the two groups at 6 months, but median total cholesterol, LDL cholesterol and triglycerides were significantly higher at 6 months with ciclosporin. The possible adverse effects of ciclosporin (mean dose 233 mg/day) on first- and second-phase insulin secretion have been investigated using a 3-hour hyperglycemic glucose clamp technique in nine non-diabetic patients on hemodialysis, seven men and two women, mean age 61 years, before and after 2 weeks of treatment with ciclosporin (5c). The average fasting concentration of C-peptide rose significantly from 1.65 to
1.93 nmol/l after 2 weeks of treatment with ciclosporin. First-phase insulin secretion did not change significantly, but second-phase secretion was significantly inhibited by ciclosporin and second-phase C-peptide secretion also fell in eight patients. Mouth Ciclosporin can cause oral nongingival inflammatory fibrovascular hyper plasia (6A). • A 14-year-old boy had a hemopoietic cell transplantation for acute lymphocytic leuke mia and was given ciclosporin. He had exophy tic, polypoid, multinodular masses on the tongue, measuring 2 1 and 0.5 0.5 cm. • An 8-year-old boy had a hemopoietic cell transplantation for acute leukemia followed by ciclosporin therapy. He later developed a 2 1 cm, ulcerated, slightly tender, exophytic, polypoid, multinodular mass on the right side of the tongue. • A 3-year-old boy had a hemopoietic cell transplantation for purine nucleoside phos phorylase deficiency and was later given first ciclosporin and then tacrolimus for graft versus-host disease involving the buccal mucosa and the tongue. He subsequently developed two polypoid, multinodular masses on the right and left dorsum and lateral bor ders of the tongue. • A 58-year-old woman underwent right lung transplantation for severe chronic obstructive pulmonary disease followed by immunosup pression with tacrolimus and prednisone. She later developed two linear, exophytic, slightly tender, sessile, polypoid soft-tissue masses in her lip.
In all cases the lesions were excised and histology showed granulation and fibrous tissue with collagenization and edema, overlying ulceration, and acute and chronic inflammation. Urinary tract Treatment with calcineurin inhibitors is often associated with chronic renal insufficiency and conversion to myco phenolate may improve renal function (7c). In a single-center study, 49 patients who underwent liver transplantation between 1986 and 2002 were given a combination of calcineurin inhibitors and glucocorti coids; azathioprine was used as adjuvant therapy in 71%, but was withdrawn before the introduction of mycophenolate, starting at 500 mg bd during the first week,
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followed by an increase every week up to 1 g bd. The daily dose of calcineurin inhibi tor was reduced by 10–20% stepwise every 4 weeks after the optimal dose of mycophe nolate was reached; the calcineurin inhibi tors were withdrawn if possible within 6 months. Mean creatinine clearance was 43 ml/minute when mycophenolate was introduced and in 45 patients it was less than 60 ml/minute. Of 39 patients who responded to a reduced dose of calcineurin inhibitor, 18 recovered completely and 21 had partial recovery of renal function; 10 were non-responders; 14 patients in whom the calcineurin inhibitor was completely withdrawn at 1 year after mycophenolate introduction tended to have a higher increase in creatinine clearance (22 ml/min ute). Patients with alcoholic cirrhosis had the worst deterioration in renal function and a smaller improvement after dosage reduction. In one patient, mycophenolate was withdrawn because of severe diarrhea. In 32 patients other adverse effects were easily controlled with symptomatic treat ment or a reduction in dosage. In 40 patients with renal dysfunction (creatinine clearance 40–80 ml/minute) who randomized to continue calcineurin inhibi tor therapy or switch to sirolimus, renal function improved in the latter within 3 months (75 versus 56 ml/minute) (8C). At 12 months this difference persisted (72 ver sus 58 ml/minute) but was not significant. Two patients developed steroid-sensitive rejection, one in each arm. Other adverse effects were mild, and included mouth sores (25%), hyperlipidemia requiring treatment (15%), and pruritus (5%). Infection risk Fungal infection Fungal infections are common in organ transplant recipients. In a prospective, multicenter, international study of the variables that affect the risk of dissemination and out comes, 111 transplant recipients with Cryp tococcus neoformans infection were studied (9C). Cryptococcus neoformans infection was defined as follows: positive cultures in specimens, including blood cultures; or histopathological or cytopathological exam ination of specimens from needle aspiration
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or biopsies showing encapsulated yeast cells; or positive cryptococcal antigen in the blood or CSF in a patient with a compatible clin ical presentation. Cryptococcosis occurred a median of 21 months after transplantation; 54% of the patients had pulmonary infec tions, 52% had nervous system infections, and 8.1% had skin, soft-tissue, or osteoarti cular infections. There was disseminated cryptococcosis in 61%, and in 32% the infection was limited to the lungs. Patients who were taking ciclosporin or tacrolimus were significantly less likely to have nervous system infections and were more likely to have cryptococcosis limited to the lungs. There were nervous system infections in 50% of the patients who took ciclosporin, 47% of those taking tacrolimus, and 80% of those taking azathioprine or mycophenolate mofetil. The risk of disseminated infection was significantly higher after liver transplan tation. The mortality rate at 90 days was 14%. The mortality rate was 20% in patients taking ciclosporin, 7.9% in those taking tacrolimus, and 40% in those taking azathioprine or mycophenolate mofetil. The mortality rate was significantly higher in patients with abnormal mental status, renal insufficiency at baseline, fungemia, and dis seminated infection, and was lower in patients taking a calcineurin inhibitor. Tumorigenicity In a single-center study, 10 patients who developed de novo neoplasms or had a recurrence of hepatocellular carci noma were switched from ciclosporin or tacrolimus to everolimus (10c). The median time from transplantation to diagnosis of the neoplasm was 38 (range 82–142) months. The median time from diagnosis to the start of everolimus therapy was 4 (range 2–32) months. Target everolimus trough concen trations were 3–8 ng/ml. At the end of fol low-up, seven patients were alive; five were in complete remission, and two had tumor stability without significant growth or distant metastases. Three patients died, one because of disease progression and the other two because of hepatic lymphoma and laryngeal cancer. Median survival from tumor diagno sis was 21 (range 7.5–41) months. In the control group of 14 patients, who took
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ciclosporin, prednisone, and azathioprine or mycophenolate mofetil, median survival was 5.3 (range 0–70) months. The probability of survival was significantly greater with everolimus. Drug–drug interactions Antiepileptic drugs In a 14-year-old girl levetiracetam did not affect the ciclosporin plasma concentra tion, but oxcarbazepine reduced it from 170 ng/l to 70 ng/l, despite an increase in ciclosporin dosage from 310 to 600 mg/ day (11A). When levetiracetam was used in stead of oxcarbazepine 750mg bd, the dose of ciclosporin was reduced to 340 mg/day, with satisfactory plasma concentrations. Itraconazole Co-medication with itra conazole causes a flattening of the ciclos porin blood concentration profile in lung transplant recipients (12c). The pharmaco kinetic profiles before and after itracona zole 200–400 mg/day in 13 lung transplant recipients were comparable. Food–drug interactions Tangerine juice did not alter the AUC0!12 h of whole-blood ciclosporin in children with renal transplants (13C). Management of adverse effects In patients taking ciclosporin there are increased con centrations of specific cytokines, particu larly transforming growth factor (TGF) beta, in hyperplastic gingival tissue, suggest ing that this growth factor plays a role in accumulation of extracellular matrix. Roxithromycin inhibits the production of TGF-beta by inflammatory cells and may reduce ciclosporin-induced gingival over growth (14c).
Everolimus (SDA-RAD) (SED-15, 1306; SEDA-29, 433; SEDA-30, 453; SEDA-31, 622) Respiratory There have been several reports of bronchiolitis obliterans organizing
pneumonia in patients taking everolimus (15A, 16A). • A 56-year-old woman took ciclosporin, azathioprine, and a glucocorticoid after renal transplantation. After excision of a lip malig nancy she was given everolimus instead, and 2 months later developed a cough, dyspnea, and a low-grade fever. A chest X-ray showed a lesion at the base of the left lung compati ble with pneumonitis. Bronchoscopy showed bronchiolitis obliterans organizing pneumo nia, which responded to a corticosteroid within 3 days. • A 45-year-old man took ciclosporin, azathio prine, and prednisone after heart transplanta tion, but developed worsening renal function and was given everolimus instead of ciclos porin; 4 months later he developed a fever, dry cough, dyspnea, and pleuritic chest pain. A chest X-ray and CT scan showed bilateral lesions predominantly in the superior lobes and on the left side. Bronchoscopy and alveo lar lavage showed no evidence of infection and he was given ciclosporin again. A transbron chial biopsy showed intra-alveolar fibrinous exudates with fibroblastic foci and scanty lym phoid interstitial infiltration. After withdrawal of everolimus he improved and the CT scan became normal. • A 66-year-old man took ciclosporin and azathioprine after heart transplantation but converted to everolimus because of progres sive renal dysfunction and 2 months later developed a fever, dry cough and pleuritic chest pain. A chest X-ray showed basal lesions on the right side. Transbronchial biopsy showed intra-alveolar fibrinous exudates with fibroblastic foci in the alveolar and bronchial lumens and a scanty lymphoid interstitial infil trate. Everolimus was withdrawn and ciclo sporin restarted. He improved rapidly and became asymptomatic within 6 months.
Infection risk In a short-term study in eight kidney transplant recipients who were switched from a calcineurin inhibitor to everolimus, renal biopsies were per formed in six and showed chronic allograft nephropathy grades 1A–2. In six cases the calcineurin inhibitor was withdrawn and in two the dosage was reduced by 30% (17c). Everolimus was started on the day after; the initial dose was 0.75 mg bd. Three patients had infections (pneumonia, ocular viral infection, and herpes zoster), which responded to antibiotics and everolimus dosage reduction.
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Leflunomide
(SED-15, 2015; SEDA-29, 435; SEDA-30, 454; SEDA-31, 625)
Observational studies BK virus, which is closely related to the JC virus, is the most frequent polyomavirus. It was first isolated in 1971 from the urine of a kidney transplant patient. Polyomavirus-associated nephropa thy affects 1–10% of kidney transplant reci pients, and there is graft failure/loss in about 90%. Treatment with leflunomide, besides reducing immunosuppression, improves graft function in such cases. In a single-center study, leflunomide was used to treat poly omavirus-associated nephropathy in 11 of 346 kidney transplant recipients (18c). The initial dose was 100 mg/day for 5 days, fol lowed by 40 mg/day, maintaining serum con centrations at 40–80 mg/l. The median follow-up time was 16 months, after which median serum creatinine concentration was 150 (90–378) µmol/l versus 189 (92–265) µmol/l at baseline and estimated creatinine clearance was 45 (19–95) versus 36 ml/min ute. There were no significant increases in liver enzymes. Platelet counts were reduced below 100 109/l in only three patients and there were no bleeding events. Four patients developed fungal pneumonia 2 weeks after leflunomide treatment, and were successfully treated with voriconazole. Respiratory In a prospective study of 136 patients with active rheumatoid or psoriatic arthritis taking leflunomide 20 mg/ day, 5 developed cavitating pneumonia after the start of leflunomide treatment (19c). Of 1010 patients who took leflunomide for rheumatoid arthritis for at least 1 month, 10 developed interstitial lung dis ease; the risk was greater in those with pre existing lung diseases (20c). Pulmonary nodulosis has been associated with leflunomide (21A). Thoracoscopic biopsy showed fibrinoid necrosis with palli sading macrophages and a few giant cells, suggestive of a rheumatoid nodule; Ziehl– Nielsen staining for mycobacteria was nega tive. Leflunomide was withdrawn and the pulmonary nodules regressed within 6 months.
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Nervous system In 32 patients with rheu matoid arthritis taking leflunomide or other disease-modifying antirheumatic drugs, leflu nomide was associated with an apparent increase in the symptoms of peripheral neuropathy after 6 months; however, the symptoms did not correlate with neuro physiological studies (22c). In 16 patients with rheumatoid arthritis taking leflunomide and 16 who were taking disease-modifying antirheumatic drugs, 54% of the former and 8% of the controls had increased neuropathy symptom scores 6 months into the study (23c). However, there was no significant difference between the two groups in upper and lower limb sensory and motor amplitudes. One developed both clinical and neurophysiological evidence of a peripheral neuropathy 5 months into the study and improved after withdrawal of leflunomide. Acid base balance Renal tubular acidosis has been associated with leflunomide (24A). • A 35-year-old woman with seronegative arthritis developed renal tubular acidosis after taking leflunomide 20 mg/day for 9 months; she had a metabolic acidosis with a normal anion gap; the urine pH was 6.9. Leflu nomide was withdrawn and she was given colestyramine to accelerate the clearance of leflunomide. The serum bicarbonate normal ized within 3 weeks and was still normal 8 months later.
Hematologic Reports of suspected adverse reactions associated with the use of leflunomide have been evaluated in Australia (25c). Pancytopenia was defined by the following diagnostic criteria: severe anemia (hemoglobin concentration below 10 g/dl), neutropenia (polymorphonuclear leukocyte count below 1.5 109/l), and thrombocytopenia (platelet count below 100 109/l). There were 11 cases from January 2000 to September 2002 that met these criteria. Three had fatal outcomes, in two cases due to sepsis. Five patients had recovered at the time of reporting and three had not. Nine were also taking methotrexate; of these, six had been taking doses of 7.5–20 mg/week when they started taking leflunomide. The other three
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patients had taken leflunomide and devel oped pancytopenia after methotrexate was taken in addition. In two cases, when methotrexate was added, pancytopenia occurred after 19 and 32 weeks of combina tion therapy.
RNA synthesis. Unlike other cell types that can recycle nucleotides via the salvage pathway, B and T lymphocytes depend on de novo synthesis and the action of myco phenolate is therefore directed against this specific cell group.
Skin Leflunomide-induced subacute cuta neous lupus erythematosus with erythema multiforme-like lesions (26A), leflunomide induced skin necrosis (27A) and progressive generalized blistering and a widespread pru nosus skin rash (28A) have been described.
Observational studies In a retrospective analysis 70 patients were identified who had received mycophenolate for inflamma tory bowel disease; 19 had ulcerative colitis and 51 had Crohn’s disease (31c). There were 40 women and 30 men; the mean age was 42 years. The average dose was 1.5 g/day. The mean duration of therapy was 3.9 months. Adverse effects were attrib uted to mycophenolate in 19 patients, 2 of whom continued taking it; one had a rash that resolved and the other had deranged liver function tests, which resolved after withdrawal of mycophenolate; on restarting treatment, the liver function tests remained normal. The other patients had to stop taking mycophenolate because of severe adverse effects, such as non-specific malaise, beha vioral changes (including depression), joint pains, rashes, pancreatitis, diarrhea, abnor mal liver function tests, and alopecia. Of six patients with myositis refractory to conventional immunosuppressive therapy, two had dermatomyositis, three had poly myositis, and one fulfilled the clinical cri teria for SLE and developed myositis (32c). They took mycophenolate for a mean of 22 months in a mean dosage of 1.6 g/day þ prednisolone. Two patients developed mild adverse effects, nausea and headaches, which did not require the with drawal of mycophenolate. In a retrospective analysis of the use of mycophenolate in uveitis in 17 children (10 boys, 7 girls, aged 2–13 years), there was a steroid-sparing effect in 88% (33c). There were mild adverse effects, such as headache, rash, or gastrointestinal discom fort, in seven patients, and withdrawal was required in one child. In a single-center study of mycopheno late in moderate to severe atopic dermatitis in 20 patients aged 54–79 years, all of whom had failed or developed dependence on systemic corticosteroids, and had failed
Infection risk Cytomegalovirus antigen emia rapidly increased following lefluno mide administration in a 46-year-old man with a diffuse large B-cell lymphoma, wor sening renal function and incompletely con trolled multidrug-resistant cytomegalovirus infection after an autologous stem cell transplantation (29A). Teratogenicity Congenital malformations have been described after maternal expo sure to leflunomide during the first tri mester of pregnancy (30A). • A 43-year-old woman with rheumatoid arthri tis became pregnant while taking leflunomide, which was withdrawn after 16 weeks of gesta tion. She gave birth 9 weeks prematurely to a boy who was blind in the right eye and had cerebral palsy with left-sided spasticity.
Leflunomide reversibly binds dihydro orotate dehydrogenase, the rate-limiting mitochondrial enzyme in the synthesis of pyrimidine ribonucleotide uridine mono phosphate. This leads to reduced DNA synthesis, inhibiting T cell clonal expansion.
Mycophenolate mofetil
(SED-15, 2402; SEDA-29, 445; SEDA-30, 455; SEDA-31, 627) Mycophenolate acid is a non-competitive, reversible inhibitor of inositol monophos phate dehydrogenase, an enzyme required for de novo guanosine nucleotide biosynth esis, and it subsequently affects DNA and
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or experienced adverse effects from other systemic therapies and/or phototherapy, mycophenolate produced improvement in 18 cases (34c). One patient withdrew at 4 weeks because of persistent severe pruritus. Another improved, but mycophenolate was withdrawn because of nausea; however, the patient later responded to and tolerated a second course. There were few adverse effects, the commonest ones being nausea, constipation, diarrhea, stomach pains, fati gue, anorexia, and headache. Four patients developed herpes zoster at 8–56 weeks after the start of mycophenolate therapy, and all responded promptly to standard antiviral therapy. In one patient, the white blood cell count fell but normalized on a lower dose. In a retrospective analysis of the use of mycophenolate in 14 children with atopic dermatitis (9 boys, 5 girls) aged 2–16 years, all of whom had failed to respond to con ventional topical treatment and/or oral glucocorticoids and ciclosporin, 4 responded completely, 4 had an excellent response, 5 had a good response and 1 had an inade quate response (35c). Two patients devel oped mild gastrointestinal upsets during the first week of treatment. One patient had a history of recurrent simplex viral infections and two requiring systemic antimicrobial therapy for episodes of extensive impetigi nization and folliculitis and recurrent sta phylococcal furunculosis. Metabolism Immunosuppressive drug ther apy causes hyperlipidemia. During com bined therapy for 12 months with a glucocorticoid þ mycophenolate or azathio prine, there were no significant differences between the groups in total cholesterol, high-density lipoprotein (HDL), LDL or very-low-density lipoprotein (VLDL) (36c). Mouth Mycophenolate can cause mouth ulcers (37A). • A 60-year-old woman with liver cirrhosis, taking ciclosporin and methylprednisolone, started taking mycophenolate when she had an acute episode of rejection and 5 days later developed ulcers on her tongue and hard palate. She was given aciclovir and
711 mycophenolate was withdrawn; 5 days later, the ulcers disappeared. • A 31-year-old woman who regularly took paracetamol and piroxicam olamine for polyarthralgia developed subacute liver failure and hepatic encephalopathy and underwent liver transplantation. Her immunosuppression con sisted of ciclosporin and methylprednisolone. One week later she developed biliary stenosis from choledochal kinking and required retro grade cholangiopancreatography and stent instillation. She was then given mycophenolate and developed oral ulcers. The mycophenolate was withdrawn and 1 week later the ulcers had completely disappeared.
Gastrointestinal Mycophenolate in induc tion and maintenance therapy of severe lupus nephritis has been compared with cyclophosphamide and azathioprine in a meta-analysis of randomized controlled trials (38M). Compared with cyclophospha mide, mycophenolate significantly reduced the risk of infection but there was no differ ence in the risk of end-stage renal disease. Mycophenolate increased the risk of gastro intestinal symptoms, but the results were not statistically significant. Compared with azathioprine, mycophenolate did not reduce the incidence of death, end-stage renal dis ease, relapse or doubling of serum creati nine. Gastrointestinal symptoms such as diarrhoea or nausea and vomiting occurred more often with mycophenolate than azathioprine. Teratogenicity Experimental studies and clinical observations have shown terato genic effects after in utero exposure to mycophenolate (39A). • A 25-year-old Spanish woman underwent renal transplantation. She took tacrolimus 12 mg/day and mycophenolate 500 mg/day and 2 years later became pregnant. Myco phenolate was discontinued at 10 weeks of gestation. At 20 weeks ultrasonography showed fetal cleft lip and palate. Amniocentesis was performed and a normal female karyotype was diagnosed. At 41 weeks a girl was delivered with bilateral upper cleft lip and complete cleft palate, bilateral microtia, hypertelorism, micro gnathia and mild left ptosis. A CT scan of the temporal bone showed bilateral absence of the external ear canals and small tympanic cavities. A CT scan of the brain and cerebellum was normal. At the age of 9 months the girl needed
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hearing aids, but her physical and neuro development were normal for her age.
Pimecrolimus (SED-15, 2833; SEDA-29, 449;SEDA-30, 456; SEDA-31, 628) Skin Pimecrolimus ointment can cause allergic contact dermatitis (40A). • A 9-year-old boy with atopic dermatitis devel oped allergic contact dermatitis after using tacrolimus ointment 0.1% for 8 months. A provocative test in the preauricular area resulted in a few isolated papules and a double-blind, vehicle-controlled test on the arms resulted in non-confluent erythematous papules on the side treated with pimecrolimus.
Sirolimus (rapamycin) (SED-15, 3148; SEDA-29, 449; SEDA-30, 457; SEDA-31, 628) Observational studies In a single-center study of drug-eluting stents in 64 patients, sirolimus-eluting stents were used in 57 and paclitaxel-eluting stents in 7 (41c). There was procedural success in 63 patients. One 87-year-old patient died in hospital due to papillary muscle rupture and refractory heart failure. There were no 30-day cases of stent thrombosis, re-infarction or target vessel re-intervention. During follow-up, one patient died in a rehabilitation facility 52 days after intervention due to nosoco mial pneumonia and sepsis. There were no late cases of stent thrombosis, re-infarction, or target vessel re-intervention. Systematic reviews Sirolimus-eluting stents and bare-metal stents have been compared in a meta-analysis of 14 trials in 4958 patients (42M). There was no significant effect on overall long-term survival and sur vival free from myocardial infarction. Siro limus-eluting stents were associated with a sustained reduction in the need for re-inter vention but with an overall risk of stent thrombosis that was at least as high as that seen with bare-metal stents.
Respiratory Sirolimus can cause alveolar hemorrhage (43A). • A 55-year-old man, who had undergone heart transplantation 8 years before for ischemic cardiomyopathy, and who was taking ciclo sporin and mycophenolate, was given siro limus. After 2 months he developed an intermittent low-grade fever with occasional spikes to 39°C, accompanied by chills, for about 4 weeks; he also had shortness of breath, a dry cough, a few episodes of diar rhea, weight loss of about 9 kg and worsen ing fatigue. There were bilateral basal coarse crackles in the lungs. The oxygen saturation was 93%, the PaO2 7.9 kPa, PaCO2 3.5 kPa, pH 7.48 and hemoglobin 8.4 g/dl. The serum creatinine rose from 159 to 283 µmol/l on day 4. A chest X-ray showed bilateral interstitial infiltrates, predominantly in the lower lobe, and a CT scan showed ground-glass parench ymal opacities. Opportunistic pulmonary infections were ruled out by serological tests and blood cultures. Bronchoscopy showed diffuse bloody secretions and bronchoalveo lar lavage showed diffuse alveolar hemor rhage; there were no malignant cells or organisms. Sirolimus was withdrawn and he was given prednisone 40 mg bd. He improved and 6 days later was asymptomatic.
Sirolimus can cause interstitial pneumonitis (44A–46A). • A 61-year-old man took azathioprine and methylprednisolone after kidney transplanta tion for chronic glomerulonephritis but later developed allograft nephropathy and multiple precancerous skin lesions. Azathioprine was withdrawn and sirolimus 2 mg/day introduced. After 1 month the dose was increased to 3 mg/ day and 2 weeks later he developed a fever and dyspnea on exertion and at rest. A CT scan showed bilateral interstitial infiltrates in the lower lobes. Sirolimus was withdrawn and he recovered rapidly. • A 67-year-old man took ciclosporin, myco phenolate, and methylprednisolone after renal transplantation for secondary focal seg mental glomerulosclerosis. After 2 years he was switched to sirolimus 4 mg/day þ methyl prednisolone because of a skin tumor and 2 weeks later developed stomatitis, progressive shortness of breath on exertion, and a non-pro ductive cough. A chest X-ray showed bilateral lower lobe infiltrates and a CT scan showed extensive interstitial changes. Transbronchial biopsy showed lymphocytic alveolitis with no evidence of infection. Sirolimus was withdrawn and methylprednisolone given. His symptoms improved immediately.
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• A 62-year-old man took ciclosporin þ methyl prednisolone after renal transplantation but developed borderline rejection and calcineurin inhibitor toxicity. His immunosuppression was switched to sirolimus 2 mg/day þ methylpred nisolone and 2 weeks later he developed shortness of breath on exertion, subfebrile temperatures, a non-productive cough, weight loss and fatigue. A chest X-ray and CT scan showed bilateral interstitial infiltrates in both lower lobes. Sirolimus was withdrawn and methylprednisolone given; he recovered immediately. • A 42-year-old woman was given thymoglobulin, high-dose methylprednisolone, tacrolimus, and mycophenolate for acute vascular rejection after kidney transplantation for systemic lupus erythematosus. Later, mycophenolate was switched to sirolimus 2–3 mg/day and she was subsequently given diltiazem 270 mg/day. After 3 weeks she developed leg edema and progressive dyspnea on exertion and at rest. The sirolimus trough concentration was 21 µg/l. Despite withdrawal of diltiazem and normaliza tion of sirolimus concentrations, the symptoms did not resolve. An X-ray and a CT scan showed interstitial pneumonitis. Sirolimus was with drawn and the dose of methylprednisolone was increased. Her symptoms improved and the infil trates vanished. • A 62-year-old man was given ciclosporin and glucocorticoids after liver transplantation for alcoholic liver cirrhosis but developed progres sive graft dysfunction. Ciclosporin was switched to tacrolimus þ mycophenolate. Later, siro limus 3 mg/day was introduced and tacrolimus withdrawn because of worsening renal func tion. Despite progressive dosage reduction the sirolimus concentration remained high (at around 20 µg/l) and after 3 months he devel oped progressive dyspnea, a low-grade fever, chills, a dry cough, and fatigue. He improved slightly with antibiotic therapy but relapsed 1 week later. Withdrawal of sirolimus led to rapid clinical improvement. • A 1-year-old girl was given tacrolimus, pred nisolone and mycophenolate after heart transplantation but developed intractable diarrhea. The dosage of mycophenolate was reduced and subsequently replaced by siro limus 1 mg/m2. After 3 days she developed dyspnea, hypoxemia and respiratory acidosis. A chest X-ray showed bilateral infiltrates. The sirolimus trough concentration was 23 µg/l. Despite broad-spectrum antimicrobial drug therapy, intubation and mechanical ventilation were required. Echocardiography showed nor mal allograft function and microbiological stu dies were all negative. After withdrawal of sirolimus and intravenous administration of hydrocortisone, there was pronounced clinical improvement.
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All these patients were given a loading dose at the start of therapy and/or had an increase in the dose of sirolimus or trough con centration before the onset of symptoms. Additional potential susceptibility factors included allograft dysfunction and male sex. Metabolism The effects of sirolimus and everolimus on serum triglycerides have been analysed retrospectively in 55 heart transplant patients (47c). In 28 patients taking sirolimus, median triglyceride con centrations increased significantly by up to 65% and were clearly above the upper limit of the reference range. Total cholesterol concentrations increased by 25%. The use of statins increased significantly from 48% at baseline to 93% at 12 months. LDL con centrations were higher in those taking sirolimus. Sirolimus inhibits the growth of tumor cell lines in vitro and in vivo. In 25 patients who were converted from a calcineurin inhi bitor-based immunosuppressive regimen to sirolimus (concentrations over 6 µg/l) after detection of a tumor (11 lymphomas, 10 skin cancers, 1 thyroid, 1 lung, 1 native kid ney, and 1 laryngeal carcinoma), serum cho lesterol rose significantly from 4.58 mmol/l at baseline to 5.60 mmol/l after 1 year; LDL rose from 2.65 to 3.30 mmol/l at 1 year and triglycerides from 1.66 to 2.05 mmol/l at 3 months; creatinine clearance increased from 60 to 66 ml/minute at 1 year (48c). Urinary tract Sirolimus can cause protein uria. In a single-center study in 78 patients (43 men, 35 women; mean age 37 years) after transplantation, 63 were converted from calcineurin inhibitors þ mycopheno late þ glucocorticoids to sirolimus; 16 devel oped proteinuria (49c). In addition, 2 of 15 patients who had received sirolimus de novo developed proteinuria. The protei nuria occurred at a mean of 11 months after the start of sirolimus therapy. The mean value was 2.6 g/day. In 5 patients it reached nephritic levels, and there was edema in 13. In five patients an angiotensinconverting enzyme (ACE) inhibitor or
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angiotensin II receptor antagonist was used. Sirolimus was withdrawn in six patients. At the time of proteinuria, sirolimus trough concentrations were 4.4–15.3 µg/l, but there was no correlation between proteinuria and trough concentrations. Withdrawal of siro limus was associated with resolution. Fertility Oligospermia has been attributed to sirolimus (50A). • A 26-year-old man was given sirolimus, tacro limus, and a glucocorticoid after heart–lung transplantation for severe pulmonary hyper tension. The glucocorticoid was withdrawn after 6 months. About 3 years later he devel oped a benign Leydig-cell tumor of the left testicle with widespread testicular atrophy and severely reduced spermatogenesis. Siroli mus was withdrawn and replaced by mycophe nolate and 1 year later spermatogenesis had improved.
Tacrolimus
(SED-15, 3279;
SEDA-29, 453; SEDA-30, 458; SEDA-31,
630)
Observational studies Tacrolimus prolongs graft survival and may be considered after high-risk keratoplasty. In a comparison of the effect of systemic tacrolimus on the survival of corneal grafts, high-risk patients (n = 47) were defined as having at least two quadrants of stromal vascularization and/or a history of previous graft failure (51c). Oral tacrolimus was begun at a dose of 2 mg/day on the day of surgery and was adjusted to achieve a whole blood tacrolimus trough concentration of 1–12 µg/l. The mean dosage was 2.5 mg/day. All the patients also used topical steroids. Tacrolimus was continued for 18 months postoperatively or until the sutures were removed; in patients who had episodes of rejection it was contin ued for 1 year after the last episode. Four patients stopped taking tacrolimus because of adverse effects and were excluded from the analysis; four died at various stages of follow-up. In the 43 patients who were analysed, the graft was clear in 28 at the time of the last follow-up or death. Eight patients had episodes of rejection while taking
tacrolimus, of whom three had multiple epi sodes that were controlled by intravenous steroids. Five had irreversible rejection resulting in graft failure. Four had episodes of rejection after discontinuing tacrolimus. Graft failure occurred in one patient because of rejection and in nine because of non-immune causes, including raised intra ocular pressure, stem cell failure, and bac terial keratitis. In 30 of 39 patients who were included in the 2-year survival analy sis, eligible grafts were clear at 2 years; 6 failed grafts were not related to rejection and 3 were due to rejection. Increased blood pressure attributed to tacrolimus was con trolled with low-dose ACE inhibitors. Other adverse effects were headaches, malaise (n = 4), paresthesia (n = 3), and insomnia, pancreatitis, folliculitis, diabetes, lymphopenia, and a reversible increase in serum creatinine (1 each). Nervous system Tacrolimus can cause sei zures. In a single-center study of 132 liver transplant patients, 12 had tacrolimus-related seizures during the early postoperative per iod (52c). In 5 patients with posterior leukoencephalopathy syndrome, MRI scans showed the characteristic findings of hyperintensity of the white matter on T2 weighted images; there were no abnormalities in the other 7 patients. Ciclosporin was substituted in 11 patients and sirolimus in 1, and all received antiepileptic drug therapy. After 3 months the MRI findings resolved. Antiepileptic drug therapy was withheld in 5 patients at an average follow-up of 20 months. Tacrolimus can cause cerebellar ataxia (53A). • A 58-year-old woman took tacrolimus þ prednisone after living-donor liver transplan tation for hepatic cirrhosis. After 7 days she developed slurred speech, an intention tremor and a swaying gait. Tacrolimus was withdrawn and she was given ciclosporin instead. An MRI scan showed no abnormal intensities. The dose of ciclosporin was reduced from 200 to 100 mg/day and mycophenolate 1 g/day was added. Her blood ciclosporin concentration fell below the usual target range. The next day, the cerebellar ataxia improved and she was able to walk for at least 20 minutes.
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Tacrolimus can cause cerebellar atrophy (54A). • A 31-year-old man developed cerebellar ataxia 9 years after heart transplantation while taking tacrolimus þ mycophenolate. An MRI scan showed dilated sulci in the cerebellar region and an atrophic cerebellum. Tacrolimus was switched to sirolimus and although the symptoms improved they did not resolve com pletely. He also had hyperthyroidism and underwent thyroidectomy.
Chronic sensorimotor polyneuropathy may be an adverse effect of tacrolimus (55A). • A 44-year-old woman took tacrolimus 3 mg bd after living-donor kidney transplantation for focal glomerular sclerosis. After 10 months she complained of ‘twitching’ of the right side of the face followed by that of the left side, associated with facial numbness. She had difficulty in chewing and drinking through a straw and complained of gait imbalance. There was bilateral, symmetrical, moderately severe peripheral facial weakness, and severe weakness of bilateral intrinsic hand muscles, hip flexors, hamstrings, extensor hallucis longus, and extensor digitorum brevis muscles. The serum tacrolimus concentration was 9.3 µg/l. Electromyography and nerve conduc tion studies showed typical findings of a demyelinating motor neuropathy involving limb and cranial nerves. She was given intra venous immunoglobulin for 5 days, and 3 months later her symptoms had completely resolved. • A 53-year-old man took tacrolimus 7 mg bd (trough concentration 7.3 µg/l) after a cada veric kidney transplant for hypertensive end-stage renal disease. Immediately post operatively he complained numbness of the medial three fingers of the right hand and 5 days later developed stiffness and pain in that region. Cranial nerve examination was normal but he had severe weakness of toe dorsiflexion bilaterally. Vibration sensation was reduced at both ankles and in the med ial three fingers of the right hand. Gait and coordination were unremarkable. The ankle jerks were absent bilaterally. Nerve conduc tion studies showed diffuse low-amplitude evoked responses in both arms and absent motor-evoked response in the legs, suggestive of diffuse, predominantly axonal neuropathy, except for partial conduction block in the left ulnar nerve. The dose of tacrolimus was reduced to 2 mg bd and 6 weeks later his sen sory symptoms resolved and the neurological examination returned to normal.
Tacrolimus binds to plasma proteins and accumulates in erythrocytes. In an unusual
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case, a woman with a trough tacrolimus concentration of 75 µg/l developed tacroli mus toxicity, with disorientation in space, time and person, somnolence and dys arthria; she recovered when her serum concentration fell to 75 µg/l after a gastro intestinal hemorrhage (56A). Tumorigenicity A kidney transplant recipient with unrecognized Muir–Torre syndrome used a tacrolimus-based mainte nance regimen and developed 33 sebaceous gland tumors over 2 years (57A). • A 51-year-old man underwent renal transplan tation and was given tacrolimus. At 39 years of age, he had had a sigmoid cancer treated by resection and 5 years later a transitional cell carcinoma of the renal pelvis treated by nephrectomy, after which his renal function deteriorated and hemodialysis was eventually necessary. Five months after transplantation he developed a rapid eruption of wart-like lesions on his face and chest wall, and during the next 2 years numerous lesions were removed. There was one sebaceous carcinoma, one basal cell carcinoma, one kerato acanthoma, and several sebaceous adenomas. Altogether he developed 33 sebaceous neo plasms and was found to have six adenomatous polyps in the colon. Muir–Torre syndrome was confirmed by genetic analysis. Therapy was switched to sirolimus, and during the next 5 weeks he developed no new sebaceous adeno mata. Owing to persistent severe weakness, muscle cramps and impaired concentration, he was switched back to tacrolimus and within 2 months developed numerous new sebaceous lesions. Sirolimus was again used and no new skin lesions occurred.
Muir–Torre syndrome is a rare autosomal dominant condition in which multiple pri mary tumors and sebaceous gland tumors co-occur. This report suggests that the risk of the latter may be enhanced by tacrolimus. Drug route of administration Topical application Tacrolimus ointment applied to the external auditory canal is being used in the treatment of chronic non-infectious external otitis refractory to other therapy. In an evaluation of tacrolimus for this indication in 53 patients (92 ears; 27 men and 26 women, aged 5–83 years), an ear wick containing Protopic 0.1% was inserted
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into the external auditory canal every sec ond or third day and continued until the symptoms resolved (58c). In the short term (days 9–12), there was improvement in 45 patients (77 ears). There were mild adverse effects, including a feeling of heat, occa sional skin burning or stinging, and tempora rily increased pruritus. There was bacterial superinfection in two cases, treated suc cessfully with local antibiotics. During longterm treatment (10–22 months), the number of episodes was reduced and only 15 patients complained of recurrence. There was com plete healing in 24 patients at the end of follow-up. In an open study in 466 children, aged 2–15 years, a thin coat of tacrolimus oint ment was applied twice daily to affected areas during episodes of active atopic der matitis (59c). Initially 0.03% tacrolimus ointment was used either for 2 weeks or until the lesions cleared, whichever was first. Then 0.1% ointment was used. There were 138 withdrawals during the study (30%), about half being for admin istrative reasons; 38 (8.2%) were because of lack of efficacy and 16 (3.4%) because of an adverse effect. The most common adverse effects were pruritus and a burning sensation in the skin. There was no increase in the incidence of viral infections. Topical tacrolimus is an alternative treatment for lichen sclerosus, a chronic relapsing disease. In 11 patients, all of whom had been unresponsive or poorly responsive to super-potent topical cortico steroids, tacrolimus 0.1% ointment was applied twice daily for 6 weeks and then tapered over a further 6 weeks (60c). The adverse effects were pruritus and burning, but these effects were always mild and transient and disappeared after a few applications. Drug–drug interactions Cinacalcet Co administration of tacrolimus 2 mg bd with cinacalcet 30 mg/day caused a fall in tacro limus concentrations from 4–8 µg/l to 2.6 µg/ l after 1 week (61A). The dosage of tacro limus was adjusted and after 19 days cina calcet was withdrawn, after which the tacrolimus concentration rose. During the
interaction renal function worsened and did not recover. Cinacalcet is mostly meta bolized by CYP3A4, CYP2D6, and CYP1A2 and it inhibits CYP2D6; tacrolimus is meta bolized by CYP3A4. Both are also highly protein-bound, and displacement of tacro limus by cinacalcet may have contributed to this interaction.
Temsirolimus Temsirolimus is a specific inhibitor of rapa mycin (mTOR) kinase, a component of intracellular signaling pathways involved in the growth and proliferation of cells and the response of such cells to hypoxic stress. Compared with the interferons, temsirolimus improves overall survival among patients with metastatic renal cell carcinoma and a poor prognosis. Observational studies The effect of temsiro limus on survival in renal cell carcinoma has been studied in a multicenter phase III trial in 626 patients (62c). The patients had advanced renal cell carcinoma, stage IV or recurrent disease, and a Karnofsky index 60, and had not received previous systemic therapy. They were divided into three groups, who were given interferon alfa-2a 3 million units three times a week (to a maximum of 18 million units if tolerated) (n = 207), temsiro limus 25 mg/week as a 30-minute intra venous infusion (n = 209) or the combination (n = 210) (temsirolimus 15 mg/week and interferon 3–6 million units three times a week). Treatment was continued as long as there was no disease progression, sympto matic deterioration or intolerable adverse events. Those who received temsirolimus alone had longer overall survival and progression-free survival times than those who received interferon alone (respective median overall survival times 10.9 and 7.3 months) The most common adverse effects of temsiro limus were rash, peripheral edema, hyper glycemia, and hyperlipidemia. Weakness was more common with interferon. Temsirolimus was associated with fewer serious adverse effects than interferon.
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THIOPURINES Liver Treatment with thiopurines can cause three types of hepatotoxicity: hypersensitivity, idiosyncratic cholestatic reactions, and endothelial cell injury (which can cause raised portal pressure, veno-occlusive disease or peliosis hepatis) (63M).
Azathioprine
(SED-15, 377; SEDA-29, 424; SEDA-30, 459; SEDA-31, 635) Cardiovascular Azathioprine has been associated with atrial fibrillation (64A).
• A 52-year-old man with steroid-dependent ulcerative colitis relapsed and was given azathioprine, which was withdrawn some months later because of episodes of lipo thymia, with bouts of palpitation, nausea, and vomiting. During an exacerbation 2 years later he was given azathioprine 50 mg and 2 hours later developed nausea, vomiting, and general malaise. He had an irregular heart beat, and an electrocardiogram showed atrial fibrillation with a ventricular rate of 120/minute. Azathioprine was withdrawn and propafenone given. Repeated electrocar diography showed sinus rhythm and there were no further episodes of atrial fibrillation.
Respiratory Bronchiolitis obliterans and non-infective pneumonia have been attribu ted to azathioprine (65A) • For a 71-year-old man with Crohn’s colitis, in whom prednisone 20 mg/day and mesalazine had been incompletely effective, the mesala zine was withdrawn and azathioprine 100 mg/ day was started. After 2 weeks he developed a fever, worsening diarrhea and abdominal pain. Intravenous glucocorticoids and then intravenous infliximab and ciclosporin were ineffective. He then developed shortness of breath and a non-productive cough, and required oxygen. There was a leukocytosis (> 20 109/l) and a CT scan showed ground glass opacities predominantly in the upper lobes of the lungs bilaterally. A biopsy sug gested bronchiolitis obliterans. Azathioprine was withdrawn and within 3 days the white cell count normalized and his clinical status improved. • A 43-year-old woman taking prednisone for ulcerative colitis was given azathioprine 100 mg/day for 3 weeks. She developed increasing cough and shortness of breath, and
717 continued to deteriorate despite oral anti biotics. She was cyanotic and hypoxic, and required intubation and ventilation. A CT scan showed a right middle lobe pneumonia with bibasal consolidation. Microbiology was negative. Azathioprine was withdrawn and she was given intravenous hydrocortisone. She improved and was weaned off the ventila tor 5 days later. Her respiratory function normalized.
Liver Azathioprine can cause nodular regenerative hyperplasia, a rare hepatic lesion defined by diffuse nodularity of the hepatic parenchyma, without annular fibro sis, with alternating areas of atrophy and hyperplasia. In a multicenter study of patients taking azathioprine between 1994 and 2005, 37 cases were identified (66c). The median dose of azathioprine was 2 mg/ kg/day. The median time to diagnosis was 48 months after the start of therapy. Portal hypertension was the presenting feature in 31 patients with complications in 14, includ ing 9 with acute variceal bleeding and 5 with ascites; 15 underwent primary or secondary treatment for portal hypertension, including beta-blockers and nitrates (n = 11), endo scopic therapy (n = 9), embolization (n = 2), and transjugular intrahepatic portosystemic shunting (n = 2). One patient underwent liver transplantation for hepatic encephalo pathy following TIPS insertion. There were no deaths or cases of hepatocellular carcinoma. Skin Acute generalized exanthematous pustulosis has been associated with azathioprine (67A). • A 54-year-old woman with diabetes was given prednisolone and azathioprine 50 mg/day for pemphigus foliaceus and after 20 days devel oped disabling arthralgia, a fever (40.7°C), hypotension (85/45 mmHg), and a generalized, non-follicular pustular eruption with back ground erythema over 24 hours. Initially she was treated for septic shock with intravenous fluids and cefuroxime. However, later her symptoms were thought to be consistent with hypersensitivity to azathioprine, which was withdrawn. She improved over the next 48 hours and the pustular eruption and systemic symptoms resolved, with mild desquamation. Patch and prick tests with azathioprine were negative.
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Susceptibility factors Genetic Homo zygous polymorphisms associated with absence of thiopurine methyltransferase (TPMT) can cause life-threatening azathiopr ine-induced myelotoxicity (68A).
pelvis and the mid and lower poles, with infil tration into surrounding structures. A large renal tumor engulfing the hilar vessels and infiltrating the duodenum and the inferior caval vein was excised. It was a well-differentiated squamous cell carcinoma. Postoperatively, azathioprine was withdrawn, and 1 year later the patient was asymptomatic.
• An 85-year-old man with idiopathic pulmonary fibrosis was given azathioprine 100 mg/day and prednisone 40 mg/day and after 6 weeks devel oped fatigue, increasing dyspnea and respira tory failure and required ventilation. There was leukopenia (0.4 109/l), anemia (hemo globin 65 g/l), and thrombocytopenia (17 109/l). Fibre-optic bronchoscopy showed diffuse bleeding and cultures of the bronchoal veolar lavage fluid grew Staphylococcus aureus. He was homozygous for the TPMT*3A muta tion and was therefore likely to have little or no TPMT activity. He died with respiratory failure.
Teratogenicity The effects of azathioprine have been studied in pregnancy in 419 women, 189 taking azathioprine and 230 controls (70c). Azathioprine 50–100 mg/day was associated with lower birth weight (2995 versus 3252 g) and gestational age (37.8 versus 39.1 weeks) and more cases of prematurity (21% versus 5.2%).
Tumorigenicity Long-term use of azathioprine can cause squamous cell carci noma of the kidney (69A).
6-Thioguanine
• A 43-year-old man took azathioprine for more than 2 years for a demyelinating neuropathy and developed vague right-sided abdominal pain with no urinary or bowel symptoms. Ultrasonography, unremarkable 2 years before, showed a large right renal mass and a CT scan showed a large contrast-enhancing mass in the right kidney involving the renal
Treatment with 6-thioguanine can cause hepatic nodular regenerative hyperplasia in patients with inflammatory bowel dis ease, resulting in an increased hepatic venous pressure gradient and clinically sig nificant portal hypertension (71c).
References 1. Wahba IM, Bennett WM. Increased vascular resistance and not salt retention charac terizes cyclosporine A-induced hypertension: report in an anuric patient. Am J Transplant 2007;7(8):2042–6. 2. Somech R, Doyle J. Pseudotumor cerebri after allogeneic bone marrow transplant associated with cyclosporine a use for graft versus-host disease prophylaxis. J Pediatr Hematol Oncol 2007;29(1):66–8. 3. Ide K, Ohdan H, Tahara H, Ishiyama K, Shishida M, Irei T, Ohira M, Tashiro H, Itamoto T, Asahara T. Possible therapeutic effect of lipid supplementation on neurologi cal complications in liver transplant recipi ents. Transpl Int 2007;20(7):632–5. 4. Vincenti F, Friman S, Scheuermann E, Rostaing L, Jenssen T, Campistol JM,
Uchida K, Pescovitz MD, Marchetti P, Tun cer M, Citterio F, Wiecek A, Chadban S, El Shahawy M, Budde K, Goto N. Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus. Am J Transplant 2007;7(6):1506–14. 5. Hjelmesaeth J, Hagen LT, Asberg A, Midtvedt K, Storset O, Halvorsen CE, Morkrid L, Hartmann A, Jenssen T. The impact of shortterm ciclosporin A treatment on insulin secre tion and insulin sensitivity in man. Nephrol Dial Transplant 2007;22(6):1743–9. 6. Al Mohaya M, Treister N, Al Khadra O, Lehmann L, Padwa B, Woo SB. Calcineurin inhibitor-associated oral inflammatory polyps after transplantation. J Oral Pathol Med 2007;36(9):570–4.
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7. Creput C, Blandin F, Deroure B, Roche B, Saliba F, Charpentier B, Samuel D, Durr bach A. Long-term effects of calcineurin inhibitor conversion to mycophenolate mofe til on renal function after liver transplanta tion. Liver Transpl 2007;13(7):1004–10. 8. Shenoy S, Hardinger KL, Crippin J, Desai N, Korenblat K, Lisker-Melman M, Lowell JA, Chapman W. Sirolimus conversion in liver transplant recipients with renal dysfunction: a prospective, randomized, single-center trial. Transplantation 2007;83(10):1389–92. 9. Singh N, Alexander BD, Lortholary O, Dromer F, Gupta KL, John GT, Del Busto R, Klintmalm GB, Somani J, Lyon GM, Pursell K, Stosor V, Munoz P, Limaye AP, Kalil AC, Pruett TL, Garcia-Diaz J, Humar A, Hous ton S, House AA, Wray D, Orloff S, Dowdy LA, Fisher RA, Hitman J, Wagener MM, Husain S. Cryptococcus neoformans in organ transplant recipients: impact of calci neurin-inhibitor agents on mortality. J Infect Dis 2007;195(5):756–64. 10. Gomez-Camarero J, Salcedo M, Rincon D, Lo IO, Ripoll C, Hernando A, Sanz C, Clem ente G, Banares R. Use of everolimus as a rescue immunosuppressive therapy in liver transplant patients with neoplasms. Trans plantation 2007;84(6):786–91. 11. Franzoni E, Sarajlija J, Garone C, Malaspina E, Marchiani V. No kinetic interaction between levetiracetam and cyclosporine: a case report. J Child Neurol 2007;22(4):440–2. 12. Irani S, Fattinger K, Schmid-Mahler C, Achermann E, Speich R, Boehler A. Blood concentration curve of cyclosporine: impact of itraconazole in lung transplant recipients. Transplantation 2007;83(8):1130–3. 13. Sorkhi H, Moghadamnia AA, Oaliaee F, Pouramir M, Firoozjahi AR, Pasha AA, Goodarzi MR. Effect of tangerine juice on cyclosporine levels in renal transplant chil dren. Pediatr Nephrol 2008;23(3):499–501. 14. Condé SA, Aarestrup FM, Vieira BJ, Bastos MG. Roxithromycin reduces cyclosporine induced gingival hyperplasia in renal trans plant patients. Transplant Proc 2008;40(5): 1435–8. 15. Carreno CA, Gadea M. Case report of a kidney transplant recipient converted to everolimus due to malignancy: resolution of bronchiolitis obliterans organizing
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pneumonia without everolimus discontinua tion. Transplant Proc 2007;39(3):594–5. Exposito V, de Prada JA, Gomez-Roman JJ, Gonzalez-Vilchez F, Llano-Cardenal M, Garcia-Camarero T, Fernandez-Valls M, Ruano J, Martin-Duran R. Everolimus related pulmonary toxicity in heart trans plant recipients. J Heart Lung Transplant 2008;27(7):797–800. Morales J, Fierro A, Benavente D, Zehnder C, Ferrario M, Contreras L, Herzog C, Buckel E. Conversion from a calcineurin inhibitor-based immunosuppressive regimen to everolimus in renal transplant recipients: effect on renal function and proteinuria. Transplant Proc 2007;39(3):591–3. Faguer S, Hirsch HH, Kamar N, GuilbeauFrugier C, Ribes D, Guitard J, Esposito L, Cointault O, Modesto A, Lavit M, Mengelle C, Rostaing L. Leflunomide treatment for polyomavirus BK-associated nephropathy after kidney transplantation. Transpl Int 2007;20(11):962–9. Bruyn GA, Jansen TL, Ten Brinke A, De Vries M, Houtman PM, van Roon EN. Cavi tating pneumonia, a severe complication of leflunomide therapy in chronic polyarthritis. Rheumatology (Oxford) 2007;46(3):553–4. Ju JH, Kim SI, Lee JH, Lee SI, Yoo WH, Choe JY, Chung SH, Lee J, Lee YH, Lee SS, Yoon HJ, Yoon CH, Kim HY, Park SH. Risk of interstitial lung disease associated with leflunomide treatment in Korean patients with rheumatoid arthritis. Arthritis Rheum 2007;56(6):2094–6. Arul Rajamurugan PS, Panchapakesa Rajen dran C, Rukmangatharajan S, Rajeswari S, Ravichandran R. Leflunomide-induced nodulosis in a case of rheumatoid arthritis. APLAR J Rheumatol 2007;10(3):246–7. Richards BL, Spies J, McGill N, Richards GW, Vaile J, Bleasel JF, Youssef PP. Effect of leflunomide on the peripheral nerves in rheumatoid arthritis. Intern Med J 2007;37(2): 101–7. Richards BL, Spies J, McGill N, Richards GW, Vaile J, Bleasel JF, Youssef PP. Effect of leflunomide on the peripheral nerves in rheumatoid arthritis. Intern Med J 2007;37 (2):101–7. Evans SJ, Webb D, Lawson TM, Siebert S. Renal tubular acidosis associated with
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leflunomide. Rheumatology (Oxford) 2007; 46(6):1040. McEwen J, Purcell PM, Hill RL, Calcino LJ, Riley CG. The incidence of pancytopenia in patients taking leflunomide alone or with methotrexate. Pharmacoepidemiol Drug Saf 2007;16(1):65–73. Marzano AV, Ramoni S, Del Papa N, Barbareschi M, Alessi E. Leflunomide induced subacute cutaneous lupus erythema tosus with erythema multiforme-like lesions. Lupus 2008;17(4):329–31. Gros C, Delesalle F, Gautier S, Delaporte E. Leflunomide-induced skin necrosis. Ann Dermatol Venereol. 2008;135(3):205–8. Jian X, Guo G, Ruan Y, Lin D, Li X. Severe cutaneous adverse drug reaction to lefluno mide: a report of two cases. Cutan Ocul Tox icol 2008;27(1):5–9. Battiwalla M, Paplham P, Almyroudis NG, McCarthy A, Abdelhalim A, Elefante A, Smith P, Becker J, McCarthy PL, Segal BH. Leflunomide failure to control recurrent cyto megalovirus infection in the setting of renal failure after allogeneic stem cell transplanta tion. Transpl Infect Dis 2007;9(1):28–32. Neville CE, McNally J. Maternal exposure to leflunomide associated with blindness and cerebral palsy. Rheumatology (Oxford) 2007;46(9):1506. Palaniappan S, Ford AC, Greer D, Everett SM, Chalmers DM, Axon AT, Hamlin PJ. Mycophenolate mofetil therapy for refrac tory inflammatory bowel disease. Inflamm Bowel Dis 2007;13(12):1488–92. Pisoni CN, Cuadrado MJ, Khamashta MA, Hughes GR, D’Cruz DP. Mycophenolate mofetil treatment in resistant myositis. Rheu matology (Oxford) 2007;46(3):516–8. Doycheva D, Deuter C, Stuebiger N, Biester S, Zierhut M. Mycophenolate mofetil in the treatment of uveitis in children. Br J Ophthalmol 2007;91(2):180–4. Murray ML, Cohen JB. Mycophenolate mofetil therapy for moderate to severe ato pic dermatitis. Clin Exp Dermatol 2007;32(1): 23–7. Heller M, Shin HT, Orlow SJ, Schaffer JV. Mycophenolate mofetil for severe childhood atopic dermatitis: experience in 14 patients. Br J Dermatol 2007;157(1):127–32.
36. Akman B, Uyar M, Afsar B, Sezer S, Ozdemir FN, Haberal M. Lipid profile during azathioprine or mycophenolate mofetil combi nations with cyclosporine and steroids. Trans plant Proc 2007;39(1):135–7. 37. Naranjo J, Poniachik J, Cisco D, Contreras J, Oksenberg D, Valera JM, Diaz JC, Rojas J, Cardemil G, Mena S, Castillo J, Rencoret G, Godoy J, Escobar J, Rodriguez J, Leyton P, Fica A, Toledo C. Oral ulcers produced by mycophenolate mofetil in two liver trans plant patients. Transplant Proc 2007;39(3): 612–4. 38. Zhu B, Chen N, Lin Y, Ren H, Zhang W, Wang W, Pan X, Yu H. Mycophenolate mofetil in induction and maintenance ther apy of severe lupus nephritis: a meta-analysis of randomized controlled trials. Nephrol Dial Transplant 2007;22(7):1933–42. 39. Perez-Aytes A, Ledo A, Boso V, Saenz P, Roma E, Poveda JL, Vento M. In utero exposure to mycophenolate mofetil: a char acteristic phenotype? Am J Med Genet A 2008;146A(1):1–7. 40. Shaw DW, Maibach HI, Eichenfield LF. Allergic contact dermatitis from pimecro limus in a patient with tacrolimus allergy. J Am Acad Dermatol 2007;56(2):342–5. 41. Novaro GM, Cherla A, Fromkin KR, Bush HS. Drug-eluting stent implantation in STelevation acute myocardial infarction: ‘real world’ 30-day and mid-term results. Cardio vasc Revasc Med 2007;8(1):5–8. 42. Kastrati A, Mehilli J, Pache J, Kaiser C, Valgimigli M, Kelbaek H, Menichelli M, Sabaté M, Suttorp MJ, Baumgart D, Seyfarth M, Pfisterer ME, Scho¨ mig A. Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med 2007;356(10): 1030–9. 43. Khalife WI, Kogoj P, Kar B. Sirolimus induced alveolar hemorrhage. J Heart Lung Transplant 2007;26(6):652–7. 44. Morath C, Schwenger V, Ksoll-Rudek D, Sommerer C, Beimler J, Schmidt J, Zeier M. Four cases of sirolimus-associated inter stitial pneumonitis: identification of risk fac tors. Transplant Proc 2007;39(1):99–102. 45. Perez MJ, Martin RO, Garcia DM, Rey JM, de la Cruz LJ, Rodrigo Lopez JM. Interstitial pneumonitis associated with sirolimus in
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liver transplantation: a case report. Trans plant Proc 2007;39(10):3498–9. 46. Das BB, Shoemaker L, Subramanian S, Johnsrude C, Recto M, Austin EH. Acute sirolimus pulmonary toxicity in an infant heart transplant recipient: case report and literature review. J Heart Lung Transplant 2007;26(3):296–8. 47. Tenderich G, Fuchs U, Zittermann A, Muckelbauer R, Berthold HK, Koerfer R. Comparison of sirolimus and everolimus in their effects on blood lipid profiles and haematological parameters in heart trans plant recipients. Clin Transplant 2007;21(4): 536–43. 48. Lopez V, Gutierrez C, Cabello M, Burgos D, Sola E, Gonzalez-Molina M. Conversion to sirolimus in posttransplant renal neoplasms. Transplant Proc 2007;39(7):2264–6. 49. Franco AF, Martini D, Abensur H, Noronha IL. Proteinuria in transplant patients asso ciated with sirolimus. Transplant Proc 2007; 39(2):449–52. 50. Deutsch MA, Kaczmarek I, Huber S, Schmauss D, Beiras-Fernandez A, Schmoeckel M, Ochsenkuehn R, Meiser B, Mueller-Hoecker J, Reichart B. Sirolimus associated infertility: case report and litera ture review of possible mechanisms. Am J Transplant 2007;7(10):2414–21. 51. Joseph A, Raj D, Shanmuganathan V, Powell RJ, Dua HS. Tacrolimus immunosup pression in high-risk corneal grafts. Br J Ophthalmol 2007;91(1):51–5. 52. Sevmis S, Karakayali H, Emiroglu R, Akkoc H, Haberal M. Tacrolimus-related seizure in the early postoperative period after liver transplantation. Transplant Proc 2007;39 (4):1211–3. 53. Yamaguchi I, Ichikawa T, Nakao K, Hamasaki K, Hirano K, Eguchi S, Takatsuki M, Kawasita Y, Kanematsu T, Eguchi K. Cere bellar ataxia in a patient receiving calci neurin inhibitors after living donor liver transplantation: a case report. Transplant Proc 2007;39(10):3495–7. 54. Kaczmarek I, Schmauss D, Sodian R, BeirasFernandez A, Oberhoffer M, Daebritz S, Schoenberg SO, Reichart B. Late-onset tacrolimus-associated cerebellar atrophia in a heart transplant recipient. J Heart Lung Transplant 2007;26(1):89–92.
721 55. Bhagavati S, Maccabee P, Muntean E, Sumrani NB. Chronic sensorimotor poly neuropathy associated with tacrolimus immunosuppression in renal transplant patients: case reports. Transplant Proc 2007; 39(10):3465–7. 56. Renner FC, Staak A, Bur Am OL, Walmrath HD, Weimer R. Tacrolimus intoxication resolved by gastrointestinal bleeding: case report. Transplant Proc 2007;39(2):522–5. 57. Levi Z, Hazazi R, Kedar-Barnes I, Hodak E, Gal E, Mor E, Niv Y, Winkler J. Switching from tacrolimus to sirolimus halts the appearance of new sebaceous neoplasms in Muir–Torre syndrome. Am J Transplant 2007;7(2):476–9. 58. Caffier PP, Harth W, Mayelzadeh B, Haupt H, Sedlmaier B. Tacrolimus: a new option in therapy-resistant chronic external otitis. Laryngoscope 2007;117(6):1046–52. 59. Remitz A, Harper J, Rustin M, Goldschmidt WF, Palatsi R, van der Valk PG, Sharpe G, Smith CH, Dobozy A, Turjanmaa K. Longterm safety and efficacy of tacrolimus ointment for the treatment of atopic dermatitis in chil dren. Acta Derm Venereol 2007;87(1):54–61. 60. Virgili A, Lauriola MM, Mantovani L, Cor azza M. Vulvar lichen sclerosus: 11 women treated with tacrolimus 0.1% ointment. Acta Derm Venereol 2007;87(1):69–72. 61. Maass E, Mueller GA, Heller T, Koziolek MJ. Decrease in serum tacrolimus level and rise in serum creatinine under late addition of cinacalcet in a renal transplant recipient with hyperparathyroidism: a case report. Transplant Proc 2007;39(10):3468–70. 62. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O’Toole T, Lustgarten S, Moore L, Motzer RJ. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356(22):2271–81. 63. Gisbert JP, Gonza´ lez-Lama Y, Maté J. Thio purine-induced liver injury in patients with inflammatory bowel disease: a systematic review. Am J Gastroenterol 2007;102(7): 1518–27. 64. Cassinotti A, Massari A, Ferrara E, Greco S, Bosani M, Ardizzone S, Bianchi PG. New onset of atrial fibrillation after introduction
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of azathioprine in ulcerative colitis: case report and review of the literature. Eur J Clin Pharmacol 2007;63(9):875–8. Ananthakrishnan AN, Attila T, Otterson MF, Lipchik RJ, Massey BT, Komorowski RA, Binion DG. Severe pulmonary toxicity after azathioprine/6-mercaptopurine initiation for the treatment of inflammatory bowel disease. J Clin Gastroenterol 2007;41(7):682–8. Vernier-Massouille G, Cosnes J, Lemann M, Marteau P, Reinisch W, Laharie D, Cadiot G, Bouhnik Y, De Vos M, Boureille A, Duclos B, Seksik P, Mary JY, Colombel JF. Nodular regenerative hyperplasia in patients with inflammatory bowel disease treated with azathioprine. Gut 2007;56(10):1404–9. Elston GE, Johnston GA, Mortimer NJ, Harman KE. Acute generalized exanthema tous pustulosis associated with azathioprine hypersensitivity. Clin Exp Dermatol 2007; 32(1):52–3. Perri D, Cole DE, Friedman O, Piliotis E, Mintz S, Adhikari NK. Azathioprine and
diffuse alveolar haemorrhage: the pharmaco genetics of thiopurine methyltransferase. Eur Respir J 2007;30(5):1014–7. 69. Nair B, Sukumar S, Poolari GK, Appu T. Azathioprine-induced squamous cell carci noma of the kidney. Scand J Urol Nephrol 2007;41(2):173–5. 70. Goldstein LH, Dolinsky G, Greenberg R, Schaefer C, Cohen-Kerem R, Diav-Citrin O, Malm H, Reuvers-Lodewijks ME. Rost van Tonningen-van Driel MM, Arnon J, Ornoy A, Clementi M, Di Gianantonio E, Koren G, Braunstein R, Berkovitch M. Pregnancy outcome of women exposed to azathioprine during pregnancy. Birth Defects Res A Clin Mol Teratol 2007;79(10):696–701. 71. Ferlitsch A, Teml A, Reinisch W, Ulbrich G, Wrba F, Homoncik M, Gangl A, Peck-Rado savljevic M, Vogelsang H. 6-Thioguanine associated nodular regenerative hyperplasia in patients with inflammatory bowel disease may induce portal hypertension. Am J Gastroenterol 2007;102(11):2495–503.
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Corticotrophins, corticosteroids, and prostaglandins
Editor’s notes: In this chapter adverse effects arising from the oral or intravenous administration of corticosteroids (glucocorti coids and mineralocorticoids) are covered in the section on systemic administration. Other routes of administration are dealt in the sec tions after that; inhalation and nasal adminis tration are dealt in Chapter 16, topical administration to the skin in Chapter 14, and ocular administration in Chapter 47. All the uses of prostaglandins are covered in this chapter, apart from topical administration to the eyes, which is covered in Chapter 47.
SYSTEMIC GLUCOCORTICOIDS (SED-15, 906; SEDA-29, 480; SEDA 30, 463; SEDA-31, 651) Observational studies All consecutive pat ients (n = 88) starting long-term ( � 3 months), high-dosage prednisone therapy ( � 20 mg/day) were enrolled in a study of the frequency of adverse events, susceptibil ity factors and patients’ opinions in two French centers (1c). Lipodystrophy was the most frequent adverse event (63%, range 51–73); it was considered the most distres sing by the patients and was most frequent in Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32039-3 � 2010 Elsevier B.V. All rights reserved.
women and young patients. Neuropsychiatric disorders occurred in 42 patients (53%, 41– 64), and needed hospitalization in five cases. There were skin disorders in 37 patients (46%, 35–58), more often in women. Muscle cramps and proximal muscle weakness were reported by 32% (22–44) and 15% (8–25) respectively. New hypertension occurred in 8.7% (2.9–20). Lastly, 39% (20–61) of the premenopausal women reported menstrual disorders. Long-term adverse effects of glucocorti coids are well characterized, but there are few data on the incidence and likelihood of short-term adverse effects. The records of all eligible kidney or pancreas–kidney transplant recipients have been examined, to determine the incidence of adverse effects potentially related to early administration of glucocorti coids and to determine the probability that the adverse effect was due to the glucocorti coid (2c). Adverse reactions were identified in all 103 patients by an average of 8 days. The mean number of adverse reactions per patient was 3.26. There was weight gain in 80%, hypertension in 72%, diabetes mellitus in 52%, hyperglycemia in 48, leukocytosis in 31%, insomnia in 27%, anxiety in 11%, and psychosis in 1.9%. According to the Naranjo algorithm, leukocytosis was judged as ‘prob able’ and weight gain and psychosis were ‘possible to probable’. Diabetes, hyperglyce mia, hypertension, and insomnia were ‘possi ble’, and anxiety was ‘possible to doubtful’. Systematic reviews The effects of systemic glucocorticoids in chronic obstructive
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pulmonary disease (COPD) have been sum marized in two Cochrane systematic reviews assessing chronic stable and acute exacerba tions of the disease (3M). In stable COPD, compared with placebo, oral glucocorticoid treatment increased mean FEV1 by 53 ml and mean 12-minute walking distance by 29 m, but at an increased risk of any drugrelated adverse event (OR = 7.7; 95% CI = 2.3, 25.7). In acute exacerbations, oral glucocorticoids reduced the risk of treat ment failure (OR = 0.48; 95% CI = 0.34, 0.68), improved mean FEV1 at 72 hours by 140 ml, and improved arterial blood gases, but increased the risk of drug-related adverse events (OR = 2.3; 95% CI = 1.6, 3.3). The authors commented that treatment of stable and acute exacerbations of COPD with systemic glucocorticoids results in sta tistically significant average benefits, but at an increased risk of adverse effects. In stable COPD, there is little support for the use of systemic glucocorticoid treatment, as data on long-term outcomes are lacking. For acute exacerbations, the evidence in support of the use of systemic glucocorticoids is stronger, but further research is required to define the optimum dose, route, and duration. Cardiovascular Andersen’s syndrome is a form of long QT syndrome. It is a rare genetic disorder, inherited in an autosomal dominant pattern and caused by muta tions in the KCNJ2 gene that encodes for Kir2.1, an inward rectifier potassium chan nel. Periodic paralysis, cardiac arrhyth mias, and bone features are the hallmarks of this syndrome. Rest following strenuous physical activity, carbohydrate ingestion, emotional stress, and exposure to cold are precipitating triggers. Two families with this disorder have been identified (4c). They had periodic paralysis and cardiac abnormalities, but only discrete develop mental features. One patient reported hav ing had symptoms twice during the day after glucocorticoids treatment and alle viated after withdrawal. Cardiac rhythm disturbances, both tachy dysrhythmias and bradydysrhythmias, have been reported in adults after high-dose
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intravenous pulse methylprednisolone, but much less often in children. Five children with rheumatic diseases developed sinus bradycardia during daily therapy with intra venous pulse methylprednisolone (5A). There were reductions in resting heart rate of 35–50% of baseline in each case. All the patients were asymptomatic and all recov ered spontaneously over a variable period of time after the end of pulse therapy. In a nested case–control study of the risk of acute myocardial infarction associated with oral glucocorticoids in 404 183 patients, aged 50–84 years, without cancer from the general UK population 4795 deaths from acute myocardial infarction or coronary heart disease were included (6c). A sample of 20 000 controls was randomly selected, frequency matched by age, sex, and calendar year. Relative risks were estimated using unconditional logistic regression. The adjus ted odds ratio for acute myocardial infarc tion in current users of oral glucocorticoids compared with non-users was 1.42 (95% CI = 1.17, 1.72). The risk during the first 30 days of use (OR = 2.24; 95% CI = 1.56, 3.20) was greater than with longer duration (OR = 1.22; 95% CI = 0.98, 1.52). The risk was more pronounced (OR = 2.15; 95% CI = 1.45, 3.14) among users of prednisolone equivalent doses over 10 mg/day. The dose effect was observed among patients with and without coronary heart disease or COPD/ asthma. These results suggest a small increased risk of acute myocardial infarction with oral glucocorticoids, with a greater risk in users of high doses. Oral glucocorticoids reduce the risk of re-stenosis after percutaneous coronary intervention. Of 220 patients, 28 had adverse effects that were probably related to prednisone: gastric pain (4%), increased arterial pressure needing increased anti hypertensive treatment (4%), edema (1.8%), and concomitant infections (1.4%) (7A). In three asymptomatic patients (1.4%), who were also taking a thienopyridine, there was neutropenia, detected during routine blood cell count 4 weeks after the interven tion. It resolved completely after withdra wal of prednisone and thienopyridine in all cases. Neutropenia after prednisone had
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never been reported before. However, a direct cause-and-effect relation between thienopyridines or prednisone (alone or in combination) and neutropenia cannot be proved because of lack of rechallenge. The authors hypothesized that prednisone, by increasing CYP3A4 activity, may enhance the formation of an active thienopyridine metabolite, possibly amplifying the risk of adverse effects. Nervous system A rare but reversible com plication of glucocorticoids therapy, poste rior reversible encephalopathy syndrome, has been reported in patients with renal diseases or hematological malignancies and in patients with bone marrow and solid organ trans plants. However, the patients were either acutely ill or had been exposed to other agents implicated in causing the syndrome (i.e. immunosuppressive agents or cytotoxic drugs). It has now been reported with highdose dexamethasone in a patient who was not taking concomitant medications (8A). Sensory systems Triamcinolone has been used to visualize the vitreous during ocular surgery, including pars plana vitrectomy and anterior vitrectomy. Few studies have repor ted complications. Post-operative infectious endophthalmitis has been reported after triamcinolone-assisted anterior vitrectomy in complicated cataract surgery (9A). The symptoms were mild and the absence of ocu lar pain kept the patient from returning earlier for care. The authors remarked that adequate patient instructions are necessary to detect the early signs and symptoms of endophthalmitis. Glucocorticoids can increase intraocular pressure, which can cause interlamellar stromal edema after laser in situ kerato mileusis (LASIK) (10A). Metabolism The authors of a prospective study in two French tertiary centers have described corticosteroid-induced lipodys trophy (11c). They enrolled 88 consecutive patients who started long-term ( � 3 months), high dosage ( � 20 mg/day) systemic gluco corticoid therapy and assessed the develop ment of lipodystrophy from standardized
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head and neck photographs. Arterial blood pressure and fasting blood glucose concentra tions were assessed at baseline and then every 3 months until month 12. Total choles terol, HDL-cholesterol, LDL-cholesterol, and triglycerides were recorded at baseline, month 3 and month 12. The mean age of the patients was 57 years and the mean baseline dosage of prednisolone was 56 mg/day; 64 patients were still taking glucocorticoids at month 12 (mean dosage 11 mg/day). The cumulative incidences of lipodystrophy at months 3 and 12 were 61 and 69% respec tively. Baseline characteristics were similar in those who developed lipodystrophy and those who did not, except with regard to baseline body mass index, which was higher in the former (24 kg/m2 versus 21 kg/m2). Blood pressure was significantly higher in patients with lipodystrophy at month 9 (135/78 mmHg versus 127/73 mmHg) and month 12 (141/81 mmHg versus 128/ 72 mmHg). Those with lipodystrophy had significantly higher plasma concentrations of fasting blood glucose, triglycerides, and total cholesterol and lower HDL-choles terol concentrations during follow-up. The prevalence of glucocorticoid-induced diabetes mellitus and susceptibility factors have been determined in patients with primary renal diseases (12c). During gluco corticoid therapy (initial dose of predniso lone 0.75 mg/kg/day), diabetes mellitus was newly diagnosed in 17 of 42 patients by hyperglycemia 2 hours after lunch, although they had normal fasting blood glucose con centrations. Age (OR = 1.40, 95% CI = 1.06, 1.84) and body mass index (OR = 1.87, 95% CI = 1.03, 3.38) were independent suscept ibility factors for glucocorticoid-induced diabetes mellitus. Liver Acute severe liver damage has been reported sporadically in patients who have received intravenous methylprednisolone pulse therapy for Graves’ ophthalmopathy, with fatal acute liver failure in four patients so far. In a prospective observational study in 13 patients with dysthyroid optic neuropathy (group A) and in 14 patients with moderately severe Graves’ ophthalmopathy (group B), who were given high-dose (group A) or
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low-dose (group B) intravenous methylpred nisolone pulse therapy; cumulative gluco corticoid doses were 8.45 g in group A and 4.5 g in group B, and the follow-up time was 24 weeks (13c). There were slight increases in serum transaminases (AlT more than AsT) in seven patients, exceeding the upper refer ence limit of 40 U/l. These changes were more prominent in group A than in group B, as was also evident from a reduced AsT/ AlT ratio in group A but not in group B. Changes in serum transaminases occurred especially during the first 6 weeks of therapy and became smaller thereafter with reduc tions in methylprednisolone dosage. Pre treatment liver steatosis or diabetes were not related to liver damage, but pre-existent viral hepatitis was. Intravenous methylpred nisolone pulse therapy in patients with Graves’ ophthalmopathy causes dose-related liver damage by a direct toxic effect on hepa tocytes. Nevertheless, it seems to be safe if cumulative doses exceeding 8 g are avoided and liver function is checked before and at regular intervals during therapy. • A 34-year-old man with multiple sclerosis devel oped acute central hepatic necrosis while receiv ing high-dose intravenous methylprednisolone (14A). He was initially given intravenous methylprednisolone 1 g/day for 5 days, and was then maintained on intravenous methylpred nisolone 1 g/month. AsT, AlT, and bilirubin were normal before the start of treatment, but rose 5 months later. AsT and AlT continued to worsen and peaked 8 months after the start of treatment. Tests for hepatitis A, B, and C, anti nuclear antibody, antimitochondrial antibody, and double-stranded DNA were negative. A liver biopsy showed striking centrilobular hepatic cell necrosis. His liver disease remitted after methylprednisolone was withdrawn.
The temporal relation between central hepa tic necrosis and the use of high-dose intrave nous methylprednisolone suggested that methylprednisolone was the cause. Exposure to a high total dosage of gluco corticoids has been associate with non alcoholic steatohepatitis (15A). Non-alcoholic steatohepatitis involves histological changes similar to those in alcoholic liver disease in patients without alcohol abuse; it occasionally progresses to hepatic cirrhosis, which is com mon in those with obesity, diabetes mellitus or hyperlipidemias. The association between
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glucocorticoids and non-alcoholic steatohepa titis has been studied in two groups of 48 patients with systemic lupus erythematosus (31 autopsy cases and 17 liver biopsy cases), a low total dose group (14 cases; total dose of prednisolone <3 g, duration of therapy 2 months to 1 year), and a high total dose group (34 cases; total dose > 10 g, duration of therapy 2–20 years) (16c). They had no major susceptibility factors for non alcoholic steatohepatitis, which was found in two patients in the high total dosage group. Skin Perioral dermatitis has been associated with topical glucocorticoids but rarely with sys temic administration. A 37-year-old woman with myasthenia gravis was given oral predni sone 100 mg/day and pyridostigmine, and after 3 weeks developed perioral dermatitis, with asymptomatic 1–2-mm erythematous papules distributed circumferentially around her mouth and over her chin (17A). Dermatofibromata are common, benign, dermal tumors, often occurring as single lesions on the legs of young adults. Multiple eruptive dermatofibromata are rare and are usually associated with autoimmune dis eases, immunosuppressant therapy or both. A 28-year-old woman with dermatomyositis developed multiple eruptive dermatofibro mata after undergoing methotrexate and cor ticosteroid treatment (18A). Musculoskeletal EIDOS classification: Extrinsic species: Glucocorticoids Intrinsic species: Osteoblasts and osteoclasts Distribution: Bone Outcome: Atrophy Sequela: Osteoporosis from glucocorticoids DoTS classification: Dose-relation: Collateral reaction Time-course: Late Susceptibility factors: Age (elderly patients); sex (female sex, post menopausal) The current evidence on susceptibility factors for glucocorticoid-induced osteoporosis, the
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prevention and treatment of consequent frac tures, and guidelines for management pub lished since 2000 have been summarized (19R). There is significant bone loss and an increased risk of fracture is seen with pred nisone doses as low as 5 mg/day. Alternate-day glucocorticoid therapy can lead to similar bone loss. There is no conclusive evidence for a safe minimum dose or duration of gluco corticoid exposure. Physicians should consider susceptibility factors for involutional osteo porosis, such as older age, post-menopausal status and baseline bone density measure ments, as they assess patients for prevention or treatment. Bisphosphonates reduce gluco corticoid-related vertebral fractures, but the data on hip fractures are inconclusive. Hor mone replacement therapy and parathyroid hormone analogues are effective in preser ving bone density. The risk of osteoporosis and fractures should be routinely assessed in patients receiving glucocorticoid therapy. Effective prevention and treatment options are available and can result in reduced mor bidity and mortality. Current guidelines for management recommend bisphosphonates, especially alendronate and risedronate, as first-line agents, and the preventive use of bisphosphonates early in glucocorticoid ther apy in high-risk patients. The risk of fractures has been evaluated in 191 752 patients over 40 years old taking inter mittent high-dose oral glucocorticoids using the UK General Practice Database (20c). Relative risks were estimated using Cox pro portional hazards models, adjusted for age, sex, body mass index, smoking, disease his tory, and drug history. Fractures of the radius/ ulna, humerus, rib, femur/hip, pelvis, or ver tebrae were evaluated. Patients who took intermittent high-dose glucocorticoids (at least 15 mg/day) and had no or little previous exposure to glucocorticoids (cumulative expo sure under 1 g) had a small increase in the risk of osteoporotic (but not hip/femur) fracture; this risk increased substantially with increas ing cumulative exposure. Among patients who took at least 30 mg/day and whose cumu lative exposure was over 5 g, the relative risk (RR) of an osteoporotic fracture was 3.63 (95% CI = 2.54, 5.20), of fracture of the hip/ femur 3.13 (95% CI = 1.49, 6.59) and of ver tebral fracture 14 (95% CI = 8.3, 25).
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The prevalence of asymptomatic verteb ral fractures has been assessed in 551 post menopausal women taking long-term gluco corticoids in a multicenter, cross-sectional out-patient study (21c). Inclusion criteria inclu ded age over 45 years, glucocorticoid therapy for at least 6 months with a cumulative dose of at least 1.35 g of a prednisone equivalent, and a diagnosis of rheumatoid arthritis, systemic lupus erythematosus, polymyalgia rheumatica, other vasculitides or connective tissue diseases, asthma, or COPD. There were one or more asymptomatic vertebral fractures in 37%, and 14% had two or more fractures. The distribu tion was bimodal, with peak incidences at thor acic vertebrae T7 and T11. The prevalence of asymptomatic vertebral fractures increased with age; 48% of participants aged over 70 years had at least one fracture. There was no correlation between fracture prevalence and cumulative glucocorticoid dose or duration of therapy. Lumbar spine and hip-bone mineral density, calcaneal bone stiffness, and healthrelated quality of life were not associated with the number of vertebral fractures or their severity. Time since menopause and a history of non-vertebral fractures were both signifi cantly associated with asymptomatic vertebral fractures. The disparity between bone quantity and quality in glucocorticoid-induced osteo porosis makes bone mineral density or ultra sonography inadequate for identifying patients at risk of glucocorticoid-associated fractures. Sexual function The persistent sexual arou sal syndrome is a newly described entity in which a woman becomes involuntarily geni tally aroused for extended periods of time in the absence of sexual desire and is distressed by this. The cause of this sexual problem is not well understood. A case in which the subjective feelings were confirmed by observing genital engorgement has been published (22A). The syndrome arose after the use of the mineralocorticoid fludrocorti sone for hypotension and bradycardia asso ciated with an atrial septal defect. The authors argued that the combined effect of the atrial septal defect and fludrocortisone may have increased the concentrations of atrial natriuretic peptide, causing profound vasodilatation and vascular leakage.
728
Infection risk The incidence of recurrence of hepatitis B after liver transplantation has been reduced by prophylaxis with hepatitis B immunoglobulin and lamivudine. The fac tors associated with recurrence of hepatitis B have been analysed in 203 recipients who underwent liver transplantation for hepatitis B in three major centers in Korea over 4 years (23c). There was a far higher incidence of recurrence of hepatitis B in patients who received glucocorticoid pulse therapy (21% versus 7.9%), in those who had a recurrence of hepatocellular carcinoma (31% versus 8.6%) and in patients who received chemotherapy to prevent recur rence of hepatocellular carcinoma (25% ver sus 4.4%). The cumulative glucocorticoid dose was higher in patients who had recur rence of hepatitis B. Community-acquired pneumonia with splenomegaly related to Q fever has been reported in a 49-year-old man with Crohn’s disease who was taking glucocorticoids (24A). Patients with limited small cell lung cancers can be cured with an aggressive approach (chest irradiation plus chemo therapy) followed by prophylactic cranial irradiation, during which dexamethasone is usually prescribed prophylactically to mini mize acute radiation-induced brain edema. This approach may cause immunosup pression, as in a case of reactivation of endogenous latent Herpes simplex virus infection and fatal acute encephalitis (25A). Infantile hemangiomas are common, benign and self-limited tumors. There are no approved treatments by the US FDA, but current practice includes the use of high-dose glucocorticoids. Pneumocystis jiroveci pneu monia occurred in an infant who was given oral glucocorticoids for hemangioma (26A). • A girl with a large facial infantile hemangi oma was given oral prednisolone 15 mg/day beginning at age 2 months. At 7 months, she developed severe respiratory distress with a fever, an increased respiratory rate, intercostal retraction, grunting, and bilateral lung infil trates on chest radiography. Pneumocystis jir oveci was isolated from endotracheal tube aspirates. There was no underlying primary immunodeficiency, and her infection was attributed to immunosuppression secondary to prednisolone.
Chapter 39
J. Costa and M. Farré
Tumorigenicity Glucocorticoid-induced im munosuppression may play a role in skin carcinogenesis. In a population-based study of non-melanoma skin cancers oral gluco corticoids are associated with a nearly six fold increased risk of squamous cell carcinoma among individuals with a common genetic variant in the glucocorticoid receptor (NR3C1) gene (27c). Teratogenicity The relation between the use of glucocorticoids during pregnancy and orofacial clefts in the offspring has been assessed by telephone interviews of the mothers of 1141 babies with cleft lip with or without cleft palate, 628 with cleft palate, and 4143 controls (28c). The mothers of 33 infants with cleft lip and palate (2.9%), the mothers of 6 infants with cleft palate (1.0%), and 72 controls (1.7%) reported glucocorti coid use from 4 weeks before conception to 12 weeks after. The results suggest a moder ately increased risk of cleft lip and cleft palate among women who use glucocorti coids during early pregnancy. Susceptibility factors Diseases Netherton’s syndrome is a rare autosomal recessive con dition characterized by ichthyosiform ery throderma, trichorrhexis invaginata, atopy, and increased percutaneous absorption. An 11-year-old boy with Netherton’s syndrome developed Cushing’s syndrome after appli cation of 1% hydrocortisone ointment to his entire body for more than 1 year (29A). Even low-potency steroid ointments should be used with caution in Netherton’s syndrome. Drug dosage regimens Most established topical glucocorticoids, such as betametha sone valerate and hydrocortisone, are applied at least twice daily, but three newer drugs (mometasone, fluticasone, and methylprednisolone) can be used once daily. It has been suggested that topical glucocorticoids can be applied only once daily without loss of efficacy and that that might reduce the risk of local adverse effects (30rH).
Corticotrophins, corticosteroids, and prostaglandins
PROSTAGLANDINS AND ANALOGUES (SED-15, 2955; SEDA-29, 487; SEDA-30, 465; SEDA-31, 651)
Alprostadil (prostaglandin E1) (SED-15, 94; SEDA-29, 487)
Observational studies Prostaglandin E1 (PGE1) is a routine palliative therapy for maintaining ductal patency in ductus arterio sus. It is usually given as an infusion of short duration. At the start of the treatment, sev eral adverse effects, usually reversible, can occur. However, in some neonates, therapy longer than 2 weeks may be needed. There has been a retrospective analysis of nine patients who received alprostadil for more than 14 days (31c). The leukocyte count remained high throughout the treatment period, and the proportion of neutrophils was over 50%. There were transient feeding difficulties, abdominal distension, and possi ble signs of gastric-outlet obstruction in two cases. In three patients, cortical hyperostosis developed after different cumulative doses (1584, 3384, and 4320 micrograms/kg). There were significant correlations between the doses of alprostadil and serum potassium concentrations and bicarbonate concentra tions. The three patients who received the largest cumulative doses developed pseudo Bartter’s syndrome. Musculoskeletal Hyperostosis occurred after a 4-day-old girl was given alprostadil for 38 days (32A).
Bimatoprost
(SED-15, 517;
SEDA-31, 655) Skin Periocular pigmentation has been stu died retrospectively in 400 consecutive patients treated with latanoprost (n = 263) or bimatoprost (n = 137) for 12 months (33c). There was periocular pigmentation in 0.8% of those treated with latanoprost and 5.8% of those treated with bimatoprost within 12 months of beginning treatment.
Chapter 39
Iloprost
729
(SED-15, 1716)
Sensory systems A 22-year-old man devel oped sudden bilateral hearing loss, tinnitus, and dizziness during the second of a series of five planned daily intravenous infusions of iloprost (0.5–2 nanograms/kg/minute) for Raynaud’s syndrome. The infusion was immediately interrupted and the dizziness subsided quickly. The tinnitus persisted for another 2 days and the hearing loss for 4 days. Audiography returned to normal within 8 days. The authors suspected endolymphatic hydrops as the cause of these symptoms, sec ondary to dysregulation of inner-ear pressure with iloprost, which leads to either increased production or reduced absorption of endolymph (34A).
Latanoprost
(SED-15, 2002; SEDA-29, 489; SEDA-30, 465; SEDA-31, 655) Sensory systems Choroidal detachment is a well-recognized early complication of trabec ulectomy, if the eye is hypotonic in the early post-operative period. Delayed choroidal detachment and hypotony have been reported in association with the use of topical prostaglandin analogues. Late-onset choroidal detachment after combined cata ract and glaucoma surgery (phacoemuls ification and trabeculectomy) has been associated with the use of topical latanoprost in the fellow eye (35A).
• An 89-year-old white woman developed gra dual reduction of vision in her left eye after combined phacoemulsification and trabeculect omy 11 months before. She was using topical latanoprost 0.005% once daily in her right eye only. Examination of the left eye showed visual acuity of hand movements, an intraocular pres sure of 0 mmHg, a deep anterior chamber and a non-leaking trabeculectomy bleb. Gonioscopy showed an open anterior chamber angle, Schaeffer grade III. There was no cyclodialysis. Left fundoscopy showed extensive choroidal detachment in all quadrants, confirmed by B-scan ultrasonography. Intraocular pressure in the right eye was 10 mmHg. Latanoprost was withdrawn. Over the next 6 weeks, the choroidal detachment in the left eye resolved
730 completely, the intraocular pressure rose to 12 mmHg, and Snellen visual acuity improved to 6/9. The intraocular pressure in the right eye remained within the reference range without treatment. The Naranjo causality scale sugges ted that the adverse reaction was possibly due to latanoprost. The choroidal detachment had not recurred at 1-year follow-up after with drawal of latanoprost.
Late choroidal detachment after trabeculect omy is rare in the absence of a leaking bleb. It has been reported up to 5 years after trabecu lectomy in association with topical latanoprost in the involved eye. In this patient, latanoprost 0.005% was being used once daily in only the fellow eye. The eye absorbs about 1% of topical latanoprost, and the remainder is absorbed into the systemic circulation. In stu dies in which patients have been treated with latanoprost in one eye only, intraocular pres sure in the fellow eye was reduced by only 0.4–1.2 mmHg. However, previous glaucoma surgery is likely to alter dose-responsiveness to intraocular pressure-lowering agents. In addition, individual patient sensitivity is likely to vary. The authors suggested that the patient’s sensitivity to systemically absorbed latanoprost, combined with the altered intraocular milieu after previous surgery, had been sufficient to cause chronic hypotony and choroidal detachment. In a prospective observer-masked study of the effect of patient age on the incidence of latanoprost-induced increases in iris pig mentation in 36 patients under 60 years and 36 patients older than 75 years with primary open-angle glaucoma has shown that age is an important susceptibility factor for latano prost-induced iris color change, because 28 of the older patients developed an increase in iris pigmentation compared with eight of the younger (36c). The morphological and melanin granule changes in irises have been studied after exposure to latanoprost for variable times (37c). Melanin granules in the anterior bor der melanocytes of the latanoprost-induced iris darkening eyes were significantly larger than those in the controls. There was a trend towards bigger melanin granules in the deep stroma, but this difference did not reach significance.
Chapter 39
J. Costa and M. Farré
Misoprostol (SED-15, 2357; SEDA-29, 490; SEDA-30, 466; SEDA-31, 655) Hematologic Acute hemolytic anemia has been attributed to high-dose misoprostol (4 mg) for medical abortion in a 21-year-old Nigerian woman (38A). The major causes of inherited and immune hemolytic anemias were excluded. Her peripheral blood smear showed acanthocytosis and anisopoikilocyto sis, which progressively disappeared in the days after ingestion. The intracellular erythrocyte sodium and potassium concen trations were reduced and there were abnormalities in membrane cation transport pathways and in calcium-activated potassium (Gardos) channels, suggesting possible direct effects of misoprostol on erythrocytes. Reproductive system Misoprostol should be used with caution in women with a pre viously scarred uterus, even in the first tri mester. Uterine rupture occurred at 8 weeks of gestation after the use of oral misoprostol 600 mg for management of delayed miscar riage (39A). Teratogenicity Poland syndrome is a rare abnormality characterized by the presence of unilateral symbrachydactyly and ipsilat eral aplasia of the sternocostal head of the pectoralis major muscle. Variable defects of other pectoral, chest wall, and upper limb components can occur. Other anomalies have also been described. Although most published cases have been sporadic, familial reports also have been published, suggest ing different patterns of inheritance. Some authors have also considered a possible vas cular origin for Poland syndrome, involving interruption of the subclavian artery proxi mal to the origin of the internal thoracic artery and distal to the origin of the verteb ral artery, during weeks 6–7 of gestation. Misoprostol is a well-known vascular teratogen associated with several congenital abnormalities, but never with Poland syn drome. There has been a report of a patient with Poland syndrome associated with an aberrant subclavian artery and vascular
Corticotrophins, corticosteroids, and prostaglandins
Chapter 39
abnormalities of the retina, whose mother had used misoprostol during pregnancy (40A).
eye. She had used timolol and dorzolamide combination therapy for 1 year, and then travoprost was added to the left eye. Her symptoms began after only two doses. She stopped using travoprost and 10 days later the discomfort resolved. Latanoprost was then added without adverse effects.
Drug overdose A death related to miso prostol overdose has been published (41A). • An adolescent developed upper gastrointest inal bleeding after self-medication with oral misoprostol 12 mg to cause abortion. She developed multiorgan failure, acute abdominal signs and hemodynamic instability. Emergency laparotomy showed gastric and esophageal necrosis. After several episodes of cardiac arrest, and despite efforts at resuscitation, she died.
The mechanism implicating misoprostol in gastrointestinal ischemia and necrosis was unknown.
Travoprost
(SED-15, 3481; SEDA-30, 466; SEDA-31, 655)
Sensory systems Acute iritis and corneal edema developed after only two doses of travoprost (42A). • A 70-year-old Caucasian woman with primary open-angle glaucoma developed redness, discomfort and blurring of vision in her left
731
Hair Prostaglandins cause growth of lashes and ancillary hairs around the eyelids. Mani festations include greater thickness and length of lashes, additional lash rows and conversion of vellus to terminal hairs in canthal areas as well as in regions adjacent to rows of eyelashes. Vellus hairs of the lower eyelids also undergo increased growth and pigmentation. Eyelash hypertrichosis has been reported in 75% of patients in clin ical trials evaluating efficacy of the PGF2a analogue travoprost in the treatment of ocu lar hypertension. Prostaglandin analogues are believed to prolong the anagen phase of eyelashes. Travoprost has therefore been proposed as a possible treatment for alope cia areata involving the eyelashes. Periocular skin pigmentation developed in three patients during treatment with topical travo prost for alopecia areata involving the eye lashes (43A).
References 1. Fardet L, Flahault A, Kettaneh A, Tiev KP, Genereau T, Toledano C, Lebbe C, Cabane J. Corticosteroid-induced clinical adverse events: frequency, risk factors and patient’s opinion. Br J Dermatol 2007;157(1):142–8. 2. Mathis AS, Liu MT, Adamson RT, Nambi SS, Patel AM. Retrospective analysis of early steroid-induced adverse reactions in kidney and kidney–pancreas transplant recipients. Transplant Proc 2007;39(1):199–201. 3. Wood-Baker R, Walters J, HaydnWalters E. Systemic corticosteroids in chronic obstruc tive pulmonary disease: an overview of Cochrane systematic reviews. Respir Med 2007;101(3):371–7. 4. Bendahhou S, Fournier E, Gallet S, Menard D, Larroque M-M, Barhanin J.
Corticosteroid-exacerbated symptoms in an Andersen’s syndrome kindred. Hum Mol Genet 2007;16(8):900–6. 5. Akikusa JD, Feldman BM, Gross GJ, Silverman ED, Schneider R. Sinus brady cardia after intravenous pulse methylpred nisolone. Pediatrics 2007;119(3): e778–82. 6. Varas-Lorenzo C, Rodriguez LAG, Maguire A, Castellsague J, Perez-Gutthann S. Use of oral corticosteroids and the risk of acute myocardial infarction. Atherosclerosis 2007;192(2):376–83. 7. Ribichini F, Ferrero V, Feola M, Rognoni A, Brunelleschi S, Vacca G, Vassanelli C. Neutropenia in patients treated with thieno pyridines and high-dose oral prednisone after percutaneous coronary interventions. J Interv Cardiol 2007;20(3):209–13.
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732 8. Irvin W, MacDonald G, Smith JK, Kim WY. Dexamethasone-induced posterior reversi ble encephalopathy syndrome. J Clin Oncol 2007;25(17):2484–6. 9. Lee SM, Shin YJ, Park KH. Postoperative infectious endophthalmitis after triamcino lone-assisted anterior vitrectomy. J Cataract Refract Surg 2007;33(4):731–2. 10. Miyai T, Yonemura T, Nejima R, Otani S, Miyata K, Amano S. Interlamellar flap edema due to steroid-induced ocular hyper tension after laser in situ keratomileusis. Jpn J Ophthalmol 2007;51:228–30. 11. Fardet L, Cabane J, Kettaneh A, Lebbé C, Flahault A. Corticosteroid-induced lipodystro phy is associated with features of the metabolic syndrome. Rheumatology 2007;46(7):1102–6. 12. Uzu T, Harada T, Sakaguchi M, Kanasaki M, Isshiki K, Araki S, Sugiomoto T, Koya D, Haneda M, Kashiwagi A, Yamauchi A. Glu cocorticoid-induced diabetes mellitus: preva lence and risk factors in primary renal diseases. Nephron Clin Pract 2007;105(2): c54–7. 13. Le Moli R, Baldeschi L, Saeed P, Regensburg N, Mourits MP, Wiersinga WM. Determi nants of liver damage associated with intravenous methylprednisolone pulse ther apy in Graves’ ophthalmopathy. Thyroid 2007;17(4):357–62. 14. Lee HM, Ditelberg JS, Kaplan MM. Pericen tral liver cell necrosis associated with the use of high-dose intravenous methylpredniso lone. Dig Dis Sci 2007;52(6):1533–4. 15. Matsumoto T, Yamasaki S, Arakawa A, Abe K, Abe H, Kon K, Kobayashi S, Takasaki Y. Exposure to a high total dosage of glucocor ticoids produces non-alcoholic steatohepati tis. Pathol Int 2007;57(6):388–9. 16. Toshiharu M, Shigetaka Y, Atsushi A, Keiko A, Hiroshi A, Kazuyoshi K, Shigeto K, Yoshi nari T. Exposure to a high total dosage of glucocorticoids produces non-alcoholic stea tohepatitis. Pathol Int 2007;57:388–9. 17. Goss JM, Nord KM, Olarte MR, Grossman ME. Perioral dermatitis in a patient with myasthenia gravis following sys temic corticosteroid treatment. Br J Derma tol 2007;156(3):582. 18. Huang P-Y, Chu C-Y, Hsiao C-H. Multiple eruptive dermatofibromas in a patient with dermatomyositis taking prednisolone and
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methotrexate. J Am Acad Dermatol 2007;57 (5 Suppl):S81–4. Gourlay M, Franceschini N, Sheyn Y. Pre vention and treatment strategies for gluco corticoid-induced osteoporotic fractures. Clin Rheumatol 2007;26(2):144–53. De Vries F, Bracke M, Leufkens HGM, Lammers J-W J, Cooper C, Van Staa TP. Fracture risk with intermittent high-dose oral glucocorticoid therapy. Arthritis Rheum 2007;56(1):208–14. Weinstein RS. Is long-term glucocorticoid therapy associated with a high prevalence of asymptomatic vertebral fractures? Nat Clin Pract Endocrinol Metab 2007;3(2):86–7. Bell C, Richardson D, Goldmeier D, Crow ley T, Kocsis A, Hill S. Persistent sexual arousal in a woman with associated cardiac defects and raised atrial natriuretic peptide. Int J STD AIDS 2007;18(2):130–1. Yi NJ, Suh KS, Cho JY, Kwon CH, Lee KW, Joh JW, Lee SK, Kim SI, Lee KU. Recur rence of hepatitis B is associated with cumu lative corticosteroid dose and chemotherapy against hepatocellular carcinoma recurrence after liver transplantation. Liver Transplant 2007;13(3):451–8. Nausheen S, Cunha BA. Q fever communityacquired pneumonia in a patient with Crohn’s disease on immunosuppressive therapy. Heart Lung 2007;36(4):300–3. Silvano G, Lazzari G, Resta F, Buccoliero G, Pezzella G, Pisconti S. Herpes simplex virus-1 fatal encephalitis following chemo-radiother apy, steroids and prophylactic cranial irradia tion in a small cell lung cancer patient. Lung Cancer 2007;57(2):243–6. Maronn ML, Corden T, Drolet BA. Pneu mocystis carinii pneumonia in infant treated with oral steroids for hemangioma. Arch Dermatol 2007;143(9):1224–5. Patel AS, Karagas MR, Perry AE, Spencer SK, Nelson HH. Gene–drug interac tion at the glucocorticoid receptor increases risk of squamous cell skin cancer. J Invest Dermatol 2007;127(8):1868–70. Carmichael SL, Shaw GM, Ma C, Werler MM, Rasmussen SA, Lammer EJ. Maternal corticosteroid use and orofacial clefts. Am J Obs Gynecol 2007;197(6):585.e 1–7. Halverstam CP, Vachharajani A, Mallory SB. Cushing syndrome from percutaneous
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31.
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33.
34.
35.
36.
37.
absorption of 1% hydrocortisone ointment in Netherton syndrome. Pediatr Dermatol 2007;24(1):42–5. Williams HC. Established corticosteroid creams should be applied only once daily in patients with atopic eczema. BMJ 2007;334 (7606):1272. Talosi G, Katona M, Turi S. Side-effects of long-term prostaglandin E1 treatment in neonates. Pediatr Int 2007;49(3):335–40. Estes K, Nowicki M, Bishop P. Cortical hyperostosis secondary to prostaglandin E1 therapy. J Pediatr 2007;151(4):441. Sharpe ED, Reynolds AC, Skuta GL, Jen kins JN, Stewart WC. The clinical impact and incidence of periocular pigmentation asso ciated with either latanoprost or bimatoprost therapy. Curr Eye Res 2007;32(12):1037–43. Dursun E, Dogru S, Cincik H, Cekin E, Gungor A, Poyrazoglu E. Iloprost-induced sudden hearing loss. J Laryngol Otol 2007;121:609–10. Horgan N,Kirwan RP, O’Brien CJ. Choroi dal detachment associated with latanoprost use in the fellow eye. Ann Pharmacother 2007;41(1):161–2. Arranz-Marquez E, Teus MA. Effect of age on the development of a latanoprost-induced increase in iris pigmentation. Ophthalmology 2007;114(7):1255–8. Kathryn PB, Cracknell KP, Grierson I, Hogg P. Morphometric effects of long-term
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exposure to latanoprost. Ophthalmology 2007;114(5):938–48. 38. Filippini A, Villa G, Corrocher R, De Fran ceschi L. Acute hemolytic anemia with acanthocytosis associated with high-dose misoprostol for medical abortion. Ann Emerg Med 2007;50(3):289–91. 39. Khan S, Alison G. Uterine rupture at 8 weeks’ gestation following 600 µg of oral misoprostol for management of delayed miscarriage. J Obstet Gynaecol 2007;27 (8):869–70. 40. Rosa RFM, Travi GM, Valiatti F, Zen PRG, Pinto LL, Kiss A, Graziadio C, Paskulin GA. Poland syndrome associated with an aber rant subclavian artery and vascular abnorm alities of the retina in a child exposed to misoprostol during pregnancy. Birth Defects Res A Clin Mol Teratol 2007;79(6):507–11. 41. Henriques A, Lourenço AV, Ribeirinho A, Ferreira H, Graça LM. Maternal death related to misoprostol overdose. Obstet Gynecol 2007;109(2 Pt 2):489–90. 42. Aydin S, Ozcura F. Corneal oedema and acute anterior uveitis after two doses of travoprost. Acta Ophthalmol Scand 2007;85 (6):693–4. 43. Feletti F, Vincenzi C, Pazzaglia M, Tosti A. Periocular pigmentation associated with use of travoprost for the treatment of alopecia areata of the eyelashes. J Eur Acad Derma tol Venereol 2007;21(3):421–3.
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40
Sex hormones and related compounds, including hormonal contraceptives
Author’s note: Sex hormones, particularly estrogens and progestogens, can be used separately or in combination, and for var ious purposes. It is often not possible to determine to which compound or combina tion a particular adverse reaction can be attributed; information on particular types of adverse effects may therefore need to be sought under a series of differing headings.
GONADOTROPHINS (SED-15, 1536; SEDA-29, 493; SEDA-30, 468; SEDA-31, 656) Reproductive system It is increasingly necessary to avoid ovarian hyperstimulation in view of growing evidence of its serious consequences. In one patient (1A) hyper stimulation led to a catastrophic antiphospho lipid syndrome, which in turn led to thrombotic complications in the heart and brain and apparently also to cardiac ischemia. Unfortunately, apart from the general principle that when inducing ovulation it is sensible to use moderate doses of gonado trophins, there seem to be few concrete principles that can usefully be observed to
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32040-X 2010 Elsevier B.V. All rights reserved.
reduce the risk of ovarian hyperstimulation syndrome (OHSS). In a study of the rele vant risk factors in Thailand (where the average body weight of women is relatively low), 13 of 117 patients enrolled for in vitro fertilization and treated with gonadotro phins had moderate OHSS and 1 had severe OHSS; all recovered (2c). Patients with OHSS were significantly younger, had sig nificantly lower body mass index and had significantly higher estradiol concentrations before injection of human chorionic gona dotrophin (hCG), and had a higher total number of follicles, a greater number of oocytes retrieved and higher total white cell and neutrophil counts after injection of hCG. Patients with the polycystic ovary syn drome were significantly more likely to develop OHSS. C-reactive protein (CRP) concentrations were higher in patients with OHSS, but the difference was not signifi cant. Multiple logistic regression showed that the combination of serum estradiol peak concentration of 4500 ng/l or more and a total number of oocytes retrieved of at least 15 predicted the occurrence of mod erate to severe OHSS; 12 of 14 patients who met these criteria had OHSS. Tumorigenicity In a case-cohort study of 54 362 women among whom 112 malignant melanomas were identified, there was no significantly increased risk with clomiphene, gonadotrophins, hCG or gonadorelin; how ever, the use of gonadotrophins (RR = 2.29; 95% CI = 1.16, 4.52) or gonadorelin
735
736
(RR = 3.26; 95% CI = 1.50, 7.09) was associated with a significant increased risk among parous women (3c). In 2768 women the risk of invasive ovarian cancer in those who had received gonadotro phins for non-ovulatory disorders was raised (standardized incidence ratio [SIR] = 5.89; 95% CI = 1.91, 14); however, there were only five cases and four reported hCG treat ment only, making the association biologically implausible. Multivariate analysis showed that treatment with gonadotrophins only was associated with an increased risk of invasive cancer (RR = 5.28; 95% CI = 1.70, 16). For borderline tumors, there was a more than threefold overall increase (SIR = 3.61; 95% CI = 1.45, 7.44), mostly attributable to clomiphene (4c). Pregnancy Some of the adverse effects of infertility treatment are in fact a troublesome consequence of its success rather than adverse effects of the drugs used. Pregnancies resulting from infertility treatments have, for example, a higher incidence of gestational hypertension and pre-eclampsia than spontaneous conceptions do. This increased risk is largely explained by a higher frequency of multiple gestations (5A).
(SED-15, 1253; SEDA-29, 494; SEDA-30, 469; SEDA-31, 657)
ESTROGENS
Comparative studies The originally ambi tious long-term international general practice trial of estrogens in the menopause (WIS DOM), which had been intended to continue for 10 years (6C), was suspended after 12 months when the results of the Women’s Health Initiative cast doubt on the acceptabi lity of this treatment. The abbreviated trial, as published in 2007, nevertheless accumulated data on 6498 women-years, and has provided a helpful picture of adverse events in 2196 trea ted women compared with 2198 untreated controls. The number of women who took estrogens alone was almost the same as the
Chapter 40
M.N.G. Dukes
number who took combined estrogen þ pro gestogen treatment. Compared with placebo, the treated group had significantly more major cardiovascular events (7 versus 0) and episodes of venous thromboembolism (22 versus 3). However, there was no statistically significant difference in the numbers of breast or other cancers, cerebrovascular events, fractures or overall deaths. The findings in those who took estrogens alone were very similar to those in women who took combined treat ment. It should be borne in mind that these women were recruited for treatment at a rela tively advanced age (50–69 years at randomi zation) and that the findings might be different from those in women in whom treatment was begun shortly after the menopause. Various writers have advanced other rea sons for regarding the findings of this study with a degree of caution. Ellen Grant has pointed out that of the women randomized to take part, 55% had already used hor mone replacement therapy (HRT) for a median of 5.3 years (7r); in addition, many of the women must previously have used estrogens and progestogens for contracep tion. Women who had developed serious conditions or had died because of past hor mone use would not be willing or available for randomization to take more of HRT. What is more, many of the women must have entered the study in their early fifties and could not truly be regarded as late starters. Nervous system Estrogens can precipitate attacks of migraine (SED-15, 1255) and the problem has been reviewed, both as regards post-menopausal treatment (8R) and the use of estrogens in male-to-female transsexuals (9R). The problem cannot be avoided in susceptible subjects, but it currently appears to be treatable in the same way as menstruation-related migraine, e.g. using sumatriptan 50–100 mg as required. Gastrointestinal At various times it has been suggested that HRT or oral contracep tives increase the risk of symptoms of gastro esophageal reflux by a relaxing effect on the
Sex hormones and related compounds, including hormonal contraceptives
lower esophageal sphincter. A Swedish group has examined this possible link using telephone interviews with individuals listed in the national register of twins (10C). His tories of estrogen use were compared in 4365 twins with reflux problems and 17 321 twins without such symptoms. In everusers of estrogens, the risk of reflux symp toms was increased by 32% (OR = 1.32; 95% CI = 1.18, 1.47). This association per sisted in the nested case–control analyses and increased slightly with higher body mass index. There was a similar pattern with the use of progestogens in the crosssectional design, but the association did not persist in the nested case–control analysis. The use of oral contraceptives was not asso ciated with an increased risk of reflux symptoms. Pancreas In view of scattered impressions that some instances of acute pancreatitis might have been triggered by HRT, a Danish group carried out a population-based case–control study in 1054 patients with a hospital discharge diagnosis of acute pancreatitis and a control group of healthy women, individuals in both groups being checked for a history of past or current HRT (11C). There was only a minimal difference in the treatment histories in the two groups and the authors concluded that the data did not support a substantial association. Immunologic Estrogens can have various adverse immunologic effects (SED-15, 1258). They are also believed to play a role in the etiology of both human and murine systemic lupus erythematosus (SLE), presumably through the agency of their cellular receptor proteins; indeed, SLE and other immune disorders are generally more common in women. Work on mice at the University of Arizona is throwing progressively more light on this problem (12E). From the therapeutic point of view the cardinal question is whether it is safe for patients with SLE to take estrogens. In an authoritative editorial, Bermas concluded, in the light of studies then becoming available, that it was
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defensible to prescribe estrogen-containing oral contraceptives for women with mild or moderate SLE, especially in view of their ability to counter the adverse effects of glucocorticoids on bone metabolism (13r). However, the question of using estrogens in patients with severe active SLE remains unsolved; they are probably better avoided (14R). Tumorigenicity Breast cancer In earlier volumes in this series, attention has been devoted to various factors that might explain the different incidences of breast cancer in different races and ethnic groups; relevant factors include body weight and differences in the frequency of use of hormonal treatment (SEDA-31, 471). A little additional light has been thrown on the matter by a study in Los Angeles County in 1277 women, all of Chinese, Japanese or Filipino origin (15C). In postmenopausal women the risk of breast cancer increased with increasing recent body weight. However, hormone treatment was also a significant and independent susceptibility factor; the risk increased by 26% for every 5 years of current use of estrogen and progestogen therapy. Both of these influences may explain the rapid increase in the rate of breast cancer among Asian-American women. To this must now be added evidence from France (16C). The prospective ‘MISSION’ study was published in 2007, data having been collected prospectively from 4949 patients over 30 months between 2004 and 2006. The patients were divided into two groups: an ‘exposed group’ of women taking HRT regimens that are commonly prescribed in France or who had stopped at least 5 years before, and an ‘unexposed group’ of women who had never taken HRT or who had stopped more than 5 years before. The two groups were of similar size; however, the women in the exposed group were younger and less overweight, and fewer had a firstdegree family history of breast cancer. The incidence of new cases of breast cancer was 0.64% in the exposed group and 0.70% in the unexposed group (relative risk exposed/
738
unexposed = 0.914, 95% CI = 0.45, 1.86; not modified when adjusted for age). The mean age at time of diagnosis was similar in the two groups. The incidence of breast cancer in the exposed group was not significantly affected by the route of estradiol administration (cuta neous 0.69%; oral 0.52%) or the type of HRT (estradiol alone 0.28%; estradiol þ progester one 0.40%; estradiol þ synthetic progestin 0.94%). The authors concluded that there was no evidence for an increased risk of breast cancer in women exposed to HRT. A positive conclusion such as this has to be accepted cautiously, in view of the fact that the risk of developing breast cancer during HRT has been documented by many authors and that the risk almost cer tainly varies with the patient population (see above) and with the treatment regi men. The same variation probably applies as regards the degree of malignancy of any breast cancer that results, which is sufficient reason to regard with some reservations even a well-documented study from Sweden, from which the authors concluded that HRT-induced breast cancers are relatively benign (17C). An epidemiological study in Norway has also shown, not unex pectedly, that the risk of breast cancer in users of HRT is relatively higher in those women who have used oral contraceptives in the past (18C). A thoughtful article has raised the ques tion why different studies of menopausal hormone therapy give different results for the same outcome (19r). Colorectal cancer A novel but still puzzling and incomplete finding relates to the effect of estrogens on the incidence of colorectal cancer. The most recent work on this was inspired by the fact that in several large prospective studies calcium and vitamin D intake were consistently inversely associated with the risk of colorectal cancer, whereas in the Women’s Health Initiative no such effect was found. However, in the main reports from the latter, the possible interaction with estrogens was not examined. In 2008, therefore, Ding et al. returned to the database of the Women’s Health Initiative to examine precisely this
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M.N.G. Dukes
point (20R). Their re-analysis showed that concurrent oestrogen therapy was a strong effect modifier of calcium and vitamin D supplementation on the risk of colorectal cancer. While calcium plus vitamin D supplements among women concurrently assigned to estrogens suggested an increase in risk (HR = 1.50, 95% CI = 0.96, 2.33), among women concurrently assigned to placebo arms in estrogen trials, calcium plus vitamin D appeared to confer benefit. One can only agree with the authors that this confusing picture demands further study. Hemangiomas Very occasional instances of hemangiomas have been reported in oral contraceptive users ever since these formulations were introduced 50 years ago, and some instances have concerned estrogens alone. An unusual case reported was that of a 42-year-old woman who had taken estrogens for many years; she had a giant splenic hemangioma and multiple hepatic hemangiomas (21A). Pancreatic cancer In a Japanese woman a mucinous cystadenocarcinoma of the pancreas developed during HRT (22A). Although this is the first report of its type, this is a disorder that is most prevalent in women who express estrogen receptors and is in some way associated with pregnancy; furthermore, the ability of HRT to induce other neoplasms is recognized. Susceptibility factors Adolescence The use of estrogens in girls to prevent excessive growth in height has often been questioned on grounds of safety, with concerns about thromboembolism dominating the discus sion. Looking back on their experience with this treatment over 15 years, Rask et al. concluded that their routine is effec tive and safe, at least as regards the risk of adverse effects on coagulation (23A). The 63 girls treated in their series received a median initial dose of ethinylestradiol of 300 micrograms/day. In some subjects, there were genetic susceptibility factors for thrombosis. After a year of treatment, concentrations of antithrombin and von
Sex hormones and related compounds, including hormonal contraceptives
Willebrand factor were significantly reduced, but there was no change in the concentra tions of plasminogen inhibitor type 1. There were no cases of venous thromboembolism or major adverse effects.
Diethylstilbestrol
(SED-15, 1119;
SEDA-31, 657) Cardiovascular The effect of stilbestrol in prostate cancer has been studied in 29 patients, who were given diethylstilbestrol 1 mg/day and 5 mg on the day before docetaxel, then docetaxel 36 mg/m2 intravenously weekly for 3 weeks of a 4-week cycle (24c). The median number of cycles was 6. Prophylactic anticoagulation was used in all cases. The combination of diethylstilbestrol and docetaxel produced a significant fall in prostate-specific antigen (PSA) and a measurable disease response rate. However, 15 patients had grade 3/4 adverse effects, 2 died of causes unrelated to therapy and another died from a glucocorticoid-induced ulcer; 6 patients developed thrombosis, and of those tested 75% had factor V mutations. The adverse effects pattern was similar to that seen without stilbestrol, except for venous thrombosis. Second-generation effects Evidence of the effects of stilbestrol on the fetus still accumulates, more than a generation after its use in pregnancy was abandoned (SEDA-31, 657). There is, for example, a higher incidence of pre-eclampsia when women who have themselves been exposed in utero to stilbestrol become pregnant (25c). The theory that exposure to estrogens could induce various abnormalities in the male reproductive system, including hypo spadias, cryptorchidism, and testicular can cer (thought to represent together a ‘testicular dysgenesis syndrome’), often linked with impaired spermatogenesis, has been studied in a meta-analysis of 12 stu dies that had not appeared in earlier sys tematic reviews (26M). Stilbestrol exposure doubled the risk of the syndrome, although
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the reviewers stressed that other factors could in many cases have been involved. A further case of primary vaginal clear cell carcinoma has been described in a 43-year-old woman who had been exposed to stilbestrol in utero (27A). The tumor metastasized to the right frontal lobe of the brain. The authors stressed the continu ing need to monitor patients with a history of vaginal carcinoma after stilbestrol expo sure. Epidemiological evidence now becom ing available also seems to show that the stilbestrol-associated increase in clear cell adenocarcinoma remains high throughout the reproductive years (28R). Third-generation effects There has long been a fear, backed by some evidence, that the effects of stilbestrol in pregnancy might extend not merely to the offspring but also to the third generation. In 2007 a group of authors in the Netherlands examined the transgenerational drug history of children with esophageal atresia and tracheo-esophageal fistulas (29C). Of 117 infants with these conditions, 4 (3.4%) had a mother who had been exposed to diethylstilbestrol in utero; in a much larger group of healthy children, only 0.37% had such a maternal history. It is very tempting to incriminate diethylstilbestrol on this score, but some caution is needed; in families with entirely healthy children there may be poor recall or even an understandable reluctance to admit to a history of maternal in utero exposure to stilbestrol.
Equine estrogens Drug formulations A Zurich group has noted that in the WISDOM study some of the women were treated with equine estrogens (30r). They have argued that a mixture of hormones derived from horse urine is not suitable and should not be regarded as replacement of natural human estrogens, such as 17-beta-estradiol, because equine hormones also contain androgens and several sex steroids of yet
740
unknown vascular activity. Regulation of estrogen targets, estrogen receptors alpha and beta and the novel membrane estrogen receptor G protein-coupled receptor 30 (GPR30), which is highly expressed in structurally intact human arteries, is sensitive to naturally occurring estrogens. The Zurich group has raised this point before in greater detail (31R), and it merits comment. Equine estrogens are indeed claimed to be derived from the urine of mares, but it was pointed out many years ago that the sales volume of products of this type much exceeded the supply that could possibly be derived from the existing mare population, and it appears that the equine material has long been supplemented during manufacturing by the addition of certain synthetic estrogens (SED-15, 1253). The ‘equine’ and ‘natural’ merits sometimes claimed for these products may therefore be poetic rather than scientific.
Hormone replacement therapy (HRT) (SED-15, 1684, 1686, 1692; SEDA-29, 496; SEDA-30, 469; SEDA-31, 659)
Hormone replacement therapy and ovarian cancer The possibility that HRT might increase the risk of subsequent ovarian malignancies was one of the reasons for the decline in this form of treatment after data from the Women’s Health Initiative were published from 1996 onwards. However, concerns regarding this particular risk subsequently faded into the background, when society became much more concerned about evi dence that HRT could increase the risk of malignancies in the breast and the endometrium. Since then, the evidence has progressively shifted towards the point where a causal link with ovarian cancer must be regarded as proven. Early in 2007, the Million Women
Chapter 40
M.N.G. Dukes
Study, a UK study of postmenopausal women, showed that those who took HRT were on average 20% more likely to develop and die from ovarian cancer than women who had never taken such therapy (32C). The authors estimated that in the 16 years to the time of their publication, HRT had resulted in some 1300 additional ovarian cancers and 1000 additional deaths from this malignancy in the UK alone. Similarly, in the United States USA, a prospective observational study in 82 905 postmenopausal women, including 389 women with ovarian cancer, in the Nurses’ Health Study from 1976 to 2002, showed that both current users (RR = 1.41, 95% CI = 1.07, 1.86) and past users for at least 5 years (RR = 1.52, 95% CI = 1.01, 2.27) had a significantly higher risk of ovarian cancer than never-users (33C). Examined by hor mone type in continuous years, use of unop posed estrogen was associated with a significant increase in the risk of epithelial ovarian cancer. In a study from Denmark of some 909 000 women over 10 years, there was a markedly increased rate of ovarian cancer in women who had used HRT (34C). The increase appeared to be independent of the nature of the drug used, and it was evident even in women who had been treated for as little as 6 months. The study included all Danish women aged 50–79 between 1995 and 2005, and data were obtained from the National Register of Medicinal Product Statistics and from cancer and pathology registers. During an average of 8 years of follow-up, 3068 ovarian cancers were detected. Of these, 2681 were epithelial tumors. Compared with never-users, current users of HRT had an overall 38% increased risk of ovarian cancer. When restricting the analyses to epithelial ovarian cancer, the relative risk among current HRT users was 44% higher, and previous users had a 15% increased risk compared with women who had never used HRT. The risks of ovarian cancer and epithelial ovarian cancer did not increase significantly with increasing duration of HRT. However, the risk of ovar ian cancer fell with longer time since last HRT
Sex hormones and related compounds, including hormonal contraceptives
use. The absolute risk is one extra ovarian cancer for every 8300 women taking hormone therapy each year. There have been other, less widely quoted, papers during the last decade that have pointed in the same direction (35C, 36C), and despite sporadic attempts to discredit these findings they must now be regarded as established and mutually supportive. A meta-analysis of the published evidence, con ducted in China in 2008, has provided further confirmation (37M). HRT thus significantly increases the risk of at least three types of female neoplasms and in the great majority of women does not offer any benefit that can possibly outweigh these dangers. HRT has declined very greatly since the Women’s Health Initiative was published and with it there has been a marked reduc tion in the incidence of endometrial and mammary malignancies. These new find ings with respect to ovarian cancer only add to one’s conviction that the massive commercial, medical, and propagandistic pressures that launched HRT more than a generation ago as a supposed elixir of health or fountain of everlasting youth for every postmenopausal woman (38R) was a seriously flawed step in the wrong direction.
HORMONAL CONTRACEPTIVES
(SED-15, 1642; SEDA-29, 499; SEDA-30, 473; SEDA-31, 663) Observational studies In the European Active Surveillance Study (EURAS), a multinational, prospective, non interventional cohort study of new users of drospirenone, levonorgestrel and other progestin-containing oral contraceptives, 58 674 women were followed for 142 475 women-years (39C). Loss to follow-up was 2.4%. Serious adverse and fatal
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events were rare, and rate ratios were close to unity. Cox regression analysis of cardiovascular outcomes yielded hazard ratios for drospirenone-containing versus levonorgestrel-containing and other oral contraceptives of 1.0 and 0.8 (upper 95% confidence limits = 1.8 and 1.3) for venous thromboembolism and 0.3 and 0.3 (1.2 and 1.5) for arterial thromboembolism. Similar results have been observed in a study of 22 429 women who took ethinyl estradiol þ drospirenone initiators and 44 858 other oral contraceptive users, who were followed for an average of 7.6 months (40C). Although those who used the latter had a slightly higher risk of thromboembo lism it was not significant (RR = 0.9; 95% CI = 0.5, 1.6), and more than 9000 women would have to be studied to observe a dif ference of one case.
Cardiovascular In a prospective Swedish cohort study over 11 years there was no evidence of increased risk of myocardial infarction in those taking oral contraceptives, either in the population as a whole or in particular subgroups (41C). Retinal central artery occlusion occurred in a young woman after she had taken a drospirenone-containing oral contraceptive for 10 days (42A).
Electrolyte balance Yasmin-28 contains ethinylestradiol 30 micrograms þ drospire none 3 mg. The latter is a progestin with anti-mineralocorticoid activity and has a potassium-sparing diuretic effect similar to that of spironolactone. However, in 32 healthy postmenopausal women who took indometacin alone for 5 days, estradiol þ drospirenone alone for 12 days and the combination for 5 days, there was no increased risk of hyperkalemia (43c).
Skin During the last decade there has been an increase in the incidence of lichen sclerosus among young women, and the hypothesis that this might be due to the
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use of oral contraceptives has been examined (44c). Of 40 premenopausal women with lichen sclerosus, all had been using oral contraceptives, compared with 66% of healthy women in a similar control group. The women with lichen sclerosus also appeared to have been more likely to have been exposed to oral contraceptives that have antiandrogenic activity (chlormadinone acetate, cyproterone acetate, dienogest, and drospirenone). These limited data suggest, but by no means prove, a link between lichen sclerosus and this form of contraception.
M.N.G. Dukes
medications for about 8 000 000 members of a large nationally dispersed health plan, showed that among women aged 10–59 years old who took Yasmin-28 or other oral contraceptives, although potassium monitoring was generally more frequent among those taking concomitant hyper kalemic drugs only 40% of 466 Yasmin users had serum potassium measured (47C).
Emergency contraception (SEDA-29, 501)
Reproductive system Vulvar vestibulitis syndrome, a distressing condition of unknown etiology, has generally not been regarded as being related to drug treatment, but a study in Israel has suggested that this possibility merits attention, at least where hormonal contraception is concerned (45c). Whereas in Israel the use of lowdose estrogen oral contraceptives is approximately equal to that of high-dose estrogen products, the bulk of the women with vulvar vestibulitis syndrome seen at the authors’ clinic, insofar as they were using hormonal contraception, were making use of the low-dose products. Pregnancy A single report has appeared of false pregnancy (pseudocyesis) in a teenage girl who over a long period had made use of oral contraceptives (46A). Monitoring drug therapy Potassium mon itoring is recommended during the first month of use in women concurrently taking Yasmin-28 (ethinylestradiol þ drospire none) plus medications that can increase serum potassium, because of the anti-miner alocorticoid action of drosperinone. However, a study of compliance with this recommendation using data from the Ingenix Research Datamart, which includes insurance claims for reimbursement for medical services and prescription
Cardiovascular Apart from nausea and vomiting, which are common after the use of ‘morning-after pill’, emergency contraception is reasonably well tolerated. However, it remains a technique that should probably be used only in exceptional circumstances, and one might expect its repeated or routine use to have certain ill effects, especially in patients predisposed to thrombotic or other complications. Such a case has been described, in which repeated use of this method was followed by cerebral venous thrombosis (48A). • A 45-year-old woman developed progressive headache, blurred vision and vomiting over 2 weeks and had papilledema. Eight months before, after unprotected coitus, she had taken the Yuzpe regimen, involving two doses of ethinylestradiol 0.1 mg combined with levonorgestrel 0.5 mg, the doses being taken 12 hours apart. She took the same course at least three times more during the months that followed. Magnetic resonance imaging (MRI) showed thrombosis of the superior sagittal, right transverse and right sigmoid sinuses. She was successfully treated with heparin followed by oral anticoagulation. She had low concentrations of antithrombin III and persistently high concentrations of factor VIII.
The high concentrations of factor VIII could have increased the risk of thrombosis in this case. A single report of retinal vein thrombosis after emergency contracep tion is to be found in the older literature (49A).
Sex hormones and related compounds, including hormonal contraceptives
ANTI-ESTROGENS AND SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMS) (SEDA-29, 502; SEDA-30, 474; SEDA-31, 664) Management of adverse drug reactions Aromatase inhibitors can cause bone loss, and the bisphosphonate zoledronic acid appears to be effective in countering this effect and hence reducing the risk of fractures. Of 602 patients who took letrozole for early-stage breast cancer, half were given zoledronic acid 4 mg intravenously every 6 months from the start of therapy, while in the remainder the use of zoledronic acid was delayed until the T score for the lumbar spine or the total hip assessment fell to less than –2.0, or until a non-traumatic fracture occurred (50C). Follow-up at 1 year suggested that early zoledronic acid prevented bone loss, whereas delayed treatment did not. An Austrian study has shown similarly favorable results with the same zoledronic acid regimen in patients taking anastrozole þ goserelin regimen (51c), and these find ings have been further confirmed in a 12-month analysis (52c).
Anastrozole Liver Various liver complications have been reported with selective estrogen receptor modulators, including tamoxifen, and it is not surprising to encounter a very short report of severe acute hepatitis in a patient taking anastrozole (53A). At present, the data are too limited to determine whether these complications occur more readily with one member of the series than another.
Clomifene (SED-15, 812; SEDA-30, 474; SEDA-31, 665) Cardiovascular A 33-year-old woman who had used clomiphene citrate had an anterolateral myocardial infarction when
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pregnant at 5 weeks; a subsequent exercise stress test and coronary angiography were normal (54A). Central retinal vein occlusion occurred in a 36-year-old woman who took eight courses of clomiphene citrate (55A). Sensory systems Bilateral anterior uveitis occurred during the use of clomiphene citrate in a 30-year-old woman with polycystic ovary syndrome; re-challenge with clomiphene 3 months later resulted in recurrence (56A). Psychiatric Acute mania has been associated with clomiphene (57A). • A 35-year-old woman with a history of bipolar disorder, successfully treated with lithium and lamotrigine, took clomiphene for 20 days before artificial insemination. After 6 days she felt ‘a little revved up’ and 9 days after completing the course of clomiphene suddenly began to have mood swings, increased energy, rapid thinking, crying spells, sleeplessness, and episodes of persecutory delusions. She was dishevelled and confused. She was evasive and unable to answer many questions coherently. Her speech ranged from soft and mumbled to pressured, loud outbursts filled with foul language. She was not oriented in time or place and was easily distracted. Her thoughts were extremely rapid, illogical and full of loose associations. She was given lithium, without much benefit, and then five courses of ECT, after which she recovered.
Clomiphene can occasionally cause psy choses, and another case has been reported (58Ar). • A 35-year-old woman with a history of depression took clomiphene 25 mg/day and after 1 day noticed a ‘vanishing of background noise’. She had the impression that colleagues talked only to her, and that no other conversations took place. After 3 days she started to have paranoid ideas and after 1 week had the idea that the whole working environment was nothing more than a test of her capabilities and that she was being evaluated by a hidden team. Her husband became the center of a complex conspiracy. She was given olanzapine 10 mg/day, and neurological examination, electroencephalography, an MRI scan of the brain and laboratory tests were normal. She gradually improved after withdrawal of clomiphene.
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The authors suggested that clomipheneinduced psychotic states might be caused by a similar mechanism to estrogen with drawal psychosis. Liver After the use of clomiphene citrate in two consecutive cycles, a 30-year-old woman each time developed intense right upper quadrant pain and on the second occasion had raised serum transaminases, which resolved over 2 months and did not recur; no other causes were discovered (59A). Pancreas Acute pancreatitis without hypertriglyceridemia on two occasions has been attributed to clomiphene (60A). Reproductive system A ruptured ovarian cyst in an ovary that had been hyperstimulated by clomiphene caused hemoperitoneum and was initially misinterpreted as OHSS in a 22-year-old woman (61A). Massive ovarian edema has been reported during pregnancy after induction of ovulation using clomiphene citrate (62A). Three men with oligospermia developed azoospermia after taking clomiphene citrate (63c). It was not clear that this was not merely due to the natural history of the condition; however, 3 months after with drawal of clomiphene, the sperm counts recovered to their previous oligospermic levels. Tumorigenicity In a case–control study of 42 women with borderline ovarian tumors and 257 controls with benign ovarian pathology, there were no differences between the groups (14% versus 27% respectively) in terms of infertility history, nor in the type of drug used, whether clomiphene citrate (9.5% versus 6.2%) or gonadotrophins (7.1% versus 10%); analysis in terms of the number of cycles also failed to reveal any differences (64C). However, in 2768 women the risk of borderline ovarian tumors was increased
M.N.G. Dukes
more than threefold (SIR = 3.61; 95% CI = 1.45, 7.44) in women taking clomi phene or gonadotrophins; women exposed to clomiphene because of ovulatory disor ders had the highest risk (SIR = 7.47; 95% CI = 1.54, 22) (4c). In a case-cohort study of 54 362 women among whom 29 thyroid cancers were iden tified, the use of clomiphene (RR = 2.28; 95% CI = 1.08, 4.82) or progesterone (RR = 10; 95% CI = 1.93, 53) was asso ciated with an increased risk of thyroid can cer, although the latter estimate was based on very few cases (65c). When stratifying for parity status, the risk was primarily asso ciated with clomiphene (RR = 3.09; 95% CI = 1.21, 7.88) in parous women. There was no significantly increased risk with gonadotrophins, hCG or gonadorelin. In the same cohort 112 malignant mela nomas were identified, but there was no association with the use of clomiphene (3c).
Exemestane
(SEDA-31, 665)
Musculoskeletal Fractures New data from the multinational Intergroup Exemestane Study (IES) have shown that 2–3 years after the end of treatment, 2362 postmenopausal women with estrogensensitive early breast cancer who switched to exemestane after taking tamoxifen for 2–3 years were 15–17% more likely to be alive, compared with 2380 patients who continued to take tamoxifen for the full 5 years of therapy (66C). There was a reduced risk of recurrence of breast cancer or of its appearance in the other breast. The withdrawal rate due to adverse events was 6.3% in patients with early breast cancer receiving adjuvant treatment with exemestane. Most of the adverse effects were mild, reflecting estrogen deprivation (hot flushes 22%, arthralgia 17%, fatigue 17%). Fractures occurred in 162 exemestane-treated patients (7%) and 115 tamoxifen-treated patients (4.9%). The investigators suggested that during adjuvant treatment with exemestane women with osteoporosis or at risk of osteoporosis
Sex hormones and related compounds, including hormonal contraceptives
should have their bone mineral density formally assessed by bone densitometry at the start of treatment. Rheumatoid arthritis Several reports during the last few years, when taken together, have raised the possibility that aromatase inhibitors might cause rheumatoid arthritis. This suspicion was voiced from France in 2007 (67Ar) in the light of earlier papers reporting that these agents could induce benign arthralgia (68c, 69C) and a single observation. • A 64-year-old woman, who for some 3 years had taken tamoxifen 20 mg/day for advanced breast cancer without adverse effects, was switched to exemestane 25 mg/day. Within days she developed arthralgia affecting the hips, shoulders, knees, wrists, and hands associated with morning stiffness. Treatment with non-steroidal anti-inflammatory drugs was not helpful. About 4 weeks later she developed symmetrical active arthritis, with swelling of the joints of the wrist and hands. Erythrocyte sedimentation rate and CRP concentration were raised (30 mm/hour and 15 mg/l). After 4 months, exemestane was withdrawn and tamoxifen restarted. However, this switch did not produce regression of her joint symptoms. Full examination confirmed the picture of rheumatoid arthritis.
This case suggests a role of aromatase inhi bitors in the induction (or aggravation) of rheumatoid arthritis, a condition that is alle viated during pregnancy and aggravated post-partum, as well as being more common in the menopause. There was some evidence of erosions before the use of exemestane, and so she may already have had rheuma toid arthritis with low disease activity, which became worse when aromatase inhibitors were used. However, arthralgias in women receiving aromatase inhibitors should be better evaluated to estimate the incidence of rheumatoid arthritis in these patients.
Raloxifene
(SEDA-31, 666)
Nervous system Reports lodged with national adverse reaction monitoring systems can be valuable in characterizing the
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nature of adverse effects, although they do not provide absolute data on their incidence or prove cause-and-effect relations. In view of published reports of stroke among subjects in two large trials (70A, 71A), the US Food and Drug Administration (FDA) in 2007 examined the reports that it had received of stroke associated with raloxifene (72c). From 1997 to September 2006 the FDA had received 6200 reports of adverse effects attributed to raloxifene, including 155 reports of stroke, 9 of which were fatal. The type of stroke was specified in about half the reports, the most common being ischemic. The stroke tended to occur within 6 months of starting the drug; the mean reporting age at the time of stroke was 70 years. In 67 of the reported cases there was at least one other susceptibility factor present in addition to age (e.g. hypertension, atrial fibrillation); 8 reports explicitly stated that no other susceptibility factors were present. In the light of these findings the FDA recommended consideration of the benefit to-harm balance when using raloxifene in postmenopausal women in whom any predisposition for stroke may be present. Raloxifene is, it is stressed, not indicated for cardioprotection and should not be used for this purpose.
Tamoxifen
(SED-15, 3296; SEDA-29, 503; SEDA-30, 475; SEDA-31, 667)
Placebo-controlled studies Even today, after many years of experience in the use of tamoxifen to prevent breast cancer in susceptible subjects, it remains very difficult to weigh the benefits against the harms, since on both scores the reported data vary so greatly (SEDA-29, 503). The Italian Randomized Tamoxifen Prevention Trial, originally published in 2000, found on the one hand no reduction at all in the risk of breast cancer with tamoxifen, whereas, on the other hand, in the United States USA, the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial, which had enrolled patients from 1992 to 1997, concluded that tamoxifen
746
reduced the risk of estrogen receptorpositive breast cancer. A follow-up report on the Italian study was rather more encouraging than its predecessor (73C). After 11 years of follow-up, 136 women (74 taking placebo, 62 taking tamoxifen) developed breast cancer (RR = 0.84, 95% CI = 0.60, 1.17; annual rates 2.48 and 2.07 per 1000 women-years respectively). The rates of breast cancer in the two groups were similar among women who had had bilateral oophorectomy and among women at low risk of hormone receptor-positive disease but were much lower in the tamoxifen group among women at high risk (placebo, 6.26 per 1000 women-years; tamoxifen, 1.50 per 1000 women-years). Against these results one must set adverse effects. During the treatment period, women taking tamoxifen reported more hot flushes (RR = 1.78, 95% CI = 1.57, 2.00), vaginal discharge (RR = 3.44, 95% CI = 2.90, 4.09), and urinary disturbances (RR = 1.52, 95% CI = 1.23, 1.89); hypertriglyceridemia, thromboembolic events and cardiac dysrhy thmias were also significantly more frequent with tamoxifen than placebo, but headaches were less common. Important support for these positive con clusions comes from what is probably the longest follow-up of this type of prophylac tic treatment to date, namely the blinded 20-year follow-up of the Royal Marsden trial in Britain (74C). Of the 2471 eligible participants (1238 tamoxifen and 1233 pla cebo), 186 developed invasive breast cancer (82 tamoxifen, 104 placebo; HR = 0.78, 95% CI = 0.58, 1.04). Of these 186 cancers, 139 were estrogen receptor-positive (53 tamoxifen, 86 placebo; HR = 0.61, 95% CI = 0.43, 0.86). The risk of estrogen receptor-positive breast cancer was not sta tistically significantly lower in the tamoxifen arm than in the placebo arm during the 8-year treatment period, but was statistically significantly lower in the post-treatment period (23 tamoxifen, 47 placebo; HR = 0.48, 95% CI = 0.29, 0.79). The authors concluded that there was a statisti cally significant reduction in the incidence of estrogen receptor-positive breast cancer with tamoxifen arm that occurred
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predominantly during the post-treatment follow-up. Cardiovascular pointed to the possible role of tamoxifen can cause thrombosis and embolism (SED-15, 3298). In an unusual case reported since then, a 64-year-old man, who was taking tamoxifen for gynecomastia and also had atrial fibrillation, developed an acute anterior wall myocardial infarction due to embolism (75A). Sensory systems Tamoxifen is deposited in the cornea, but this does not appear to result in structural or functional changes (SEDA-31, 667). However, any resultant belief that the effects on the eye are not of practical importance may need to be modified in view of a study in which the effects of tamoxifen and anastrozole on optic cup size were studied using confocal scanning laser ophthalmoscopy (76C). After treatment for up to 2 years with tamoxifen or anastrozole for breast cancer in generally accepted doses, there were significantly smaller cup volumes in the tamoxifen users than the cup volumes in the anastrozole users, which were indistinguishable from normal. The effect was particularly marked in women over 50. The authors suggested that the optic nerve head should be assessed biomorphometrically in tamoxifen users who report any visual change that cannot be attributed to causes other than tamoxifen. They also suggested that the results of modern intraocular imaging techniques suggest that tamoxifen causes astrocyte swelling. Tamoxifen can also affect the eye in various other ways (77c).When the eyes of a group of 30 women who had taken tamox ifen for 2 years were compared with those of 17 other breast cancer patients who had not taken it and the eyes of 21 healthy women, 2 of those who had used tamoxifen had diffuse color vision loss despite normal fundi, 2 others had refractile retinal crystals and 1 had a keratopathy (78A). However, some slight defects were also found in the cohort. This suggests that multiparameter measurements of ocular structure and
Sex hormones and related compounds, including hormonal contraceptives
function, which are in any case advisable in middle age, should be carried out before and during treatment with tamoxifen. Hematologic A rare case of thrombo cytopenia has been reported in a patient taking tamoxifen for breast cancer (79A). Skin Purpuric vasculitis has attributed to tamoxifen (80A).
been
Susceptibility factors Genetic The evi dence that tamoxifen can increase the risk of endometrial cancer (and possibly ovarian cancer as well) is still disputed in some quarters, but evidence of a causal association continues to mount (SEDA-31, 668). In a large prospective study 857 women aged 45–70 carrying a breast cancer 1 (BRCA1) or breast cancer 2 (BRCA2) gene were followed prospectively looking for endometrial or ovarian cancers (81C). After an average follow-up period of 3.3 years, there were 6 cases of endometrial cancer, compared with 1.13 cancers expected on the basis of population statistics. Four of these six patients had used tamoxifen in the past. The risk among women who had never taken tamoxifen treatment was not significantly increased, but among the 226 participants who had used tamoxifen (220 for treatment and 6 for primary prevention of breast cancer) the relative risk for endometrial cancer was 12. It now also seems clear that various other genotypes may be important in determining the degree of risk. In a case–control study there was good evidence that a subgroup of breast cancer patients who carry the CYP3A4*1B allele may be at particular risk of endometrial cancer when they take tamoxifen (82C). Management of adverse effects The authors of the BRCA study above suggested that the benefits and harms of prophylactic hysterectomy should be discussed with women with a BRCA mutation who are considering tamoxifen therapy. However, there are alternatives to hysterectomy.
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The possibility that adding an aromatase inhibitor (primarily in order to complement the treatment of the breast condition) might actually counter the unwanted endometrial proliferation has been considered for some years (SEDA 26, 445). In 36 postmenopausal women who had used tamoxifen for an average of 36 months, among those who had simultaneously taken aromatase inhibitors (not specified in the paper) during the later months of tamoxifen treatment, endometrial thickness was generally reduced significantly, although in a minority of women there was no effect (83c). Giving aromatase inhibitors for a longer period seemed to enhance the favorable effect. This treatment of an adverse effect therefore seems promising, but there is room for further study using alternative doses and periods of administration.
PROGESTOGENS (SED-15, 2930; SEDA-29, 505; SEDA-30, 477; SEDA-31, 669) Psychological Little attention has been devoted to whatever mental effects the progestogens or their metabolites may have; they have at most been regarded as uncertain adverse effects when progestogens are used to affect physical functions. However, the authors of a review and a small study have pointed out that progesterone’s neuroactive metabolite allopregnanolone modulates amygdala activity and thereby influences anxiety; it also appears to have an effect on cognition and memory (84Rc). In their study, a single oral dose of progesterone was given to healthy young women in a double-blind, crossover, placebo-controlled design, and the participants were asked to memorize and recognize faces while undergoing functional MRI. Progesterone reduced recognition accuracy without affecting reaction times. The imaging results showed that the amygdala, hippocampus, and fusiform
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gyrus supported memory formation. Importantly, progesterone reduced responses to faces in the amygdala and fusiform gyrus during memory encoding, whereas it increased hippocampal responses. The progesterone-induced reduction in neural activity in the amygdala and fusiform gyrus predicted the reduction in memory performance across subjects. However, progesterone did not modulate the differential activation between subsequently remembered and subsequently forgotten faces in these areas. There was a similar pattern of results in the fusiform gyrus and prefrontal cortex during memory retrieval. Whether further work in this area might result in certain progestogens acquiring a role in the treatment of mental conditions (or conversely form the basis for warnings or contraindications) is not yet clear. Teratogenicity Nearly 50 years ago, much optimism was engendered by the development of a series of synthetic progestogens that were thought to offer a promising approach to the treatment of threatened and habitual abortion. Several of these have faded from view, but there is a persistent trail of evidence that at least some instances of abortion are attributable to an insufficient supply of progesterone and can be prevented by the administration of either progesterone itself or substances closely related to it. However, a major consideration is that the treatment should not bring with it any appreciable risk to the fetus: masculinization of female fetuses is for example a real possibility if progestogens with androgenic properties are used. The authors of a massive review of this issue, which can only be briefly alluded to here, looked in particular for evidence from clinical and animal studies, despite the dubious relevance of the latter (85R). Two of the largest clinical trials conducted to date provided a signal for some embryo–fetal toxicity attributable to 17a-hydroxyprogesterone caproate, the most widely used agent in this area, and work in monkeys and rodent may be
M.N.G. Dukes
interpreted as supporting this finding. However, studies of children born at the end of pregnancies during which 17a-progesterone caproate was adminis tered continue to show that they have suffered no effects. A US study in 194 such children, and including comparison with a control group, showed that 17a-hydroxyprogesterone caproate seems to be safe for the fetus when given in the second and third trimesters (86c). Drug administration route Intrauterine administration of progestogens is generally well tolerated (SEDA-31, 670). The same appears to apply when progesterone itself is used intravaginally for luteal support (e.g. after in vitro fertilization), irrespective of the form in which it is administered. However, a Croatian study in 285 women gave the impression that Crinone 8% vagi nal gel 90 mg/day is somewhat better toler ated than Utrogestan vaginal capsules 200 mg tds (87c). More detailed documenta tion would be welcome.
Lynestrenol Liver There has been some evidence in the past of a link between hepatic adeno matosis and female sex hormones (SED-15, 1660), although the condition does occur in men as well. In a woman who had been taking the androgenic pro gestogen lynestrenol for 10 years, andro gen receptors were detected in the adenomatous material; the condition regressed markedly within 6 months after lynestrenol was withdrawn and at that time the androgen receptors were no longer detectable (88A). The authors sug gested that in some cases of hepatic ade nomatosis the androgenic progestogens must be held responsible.
Drospirenone
(SEDA-31, 670)
See ‘Hormonal contraceptives’.
Sex hormones and related compounds, including hormonal contraceptives
Medroxyprogesterone
(SED-15,
2225) Musculoskeletal Medroxyprogesterone acetate can cause reversibly reduced bone density, but the effect has not been found to be constant and it may vary with age. Bone density, bone turnover, and hormones have been measured in individually matched case–control pairs of women, of whom 50 pairs were aged 18–25 years and 50 pairs 35–45 (89c). Use of depot medroxyprogesterone was associated with a 5% bone density deficit at the lumbar spine and hip in women who started using it before the age of 20 but not after the age of 34. Bone turnover was increased in users in both age groups: medroxyprogesterone users had lower estradiol and higher inuslin-like growth factor I (IGF-I) than controls, and younger users had higher dehydroepiandrosterone sulphate than controls. In a multiple regression model, estradiol and IGF-I were associated with bone turnover, but addition of medroxyprogesterone to the model rendered the association with estradiol non significant. It can be concluded that use of depot medroxyprogesterone acetate is associated with a bone density deficit at the spine and hip when used before peak bone mass, and that it acts on the skeleton mainly through estrogen deficiency. A complementary study of this in a Scottish city confirmed that women who had used medroxyprogesterone for at least 5 years (mean 12 years) had a lower bone density than controls, but no new evidence as to the reversibility of the effect was provided (90c). Drug–drug interactions Antiretroviral drugs In a pharmacokinetic study in human immunodeficiency virus (HIV)-infected women, interactions were examined between depot medroxyprogesterone acetate (used as a contraceptive) and nucleoside analogues alone (n = 16) or combined with nelfinavir (n = 21), efavirenz (n = 17) or nevirapine (n = 16) (91c). The kinetics of all the substances, assessed regularly over 12 weeks, were virtually unaffected; nor was there any evidence of an
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interaction in the reverse direction, contraceptive efficacy being maintained.
Megestrol acetate
(SED-15, 1679,
2932; SEDA-31, 670) Endocrine Three men who took meges trol acetate 400–800 mg/day for metastatic cancers developed adrenal insufficiency and hypogonadism (92A). Adrenal insuffi ciency also occurred in a 74-year-old woman with infiltrating ductal breast carci noma refractory to prolonged hormonal treatment with megestrol acetate (93A).
Death In a case–control cohort study of 17 328 nursing home residents who had lost either 5% of total body weight within 3 months or 10% within 6 months, megestrol acetate was associated with an increase in all-cause mortality and no increase in body weight (94c). Of 709 patients who took megestrol acetate, 281 (40%) were alive and in the nursing home at last follow-up, 149 (21%) were alive and discharged to another facility or to home, and 279 (39%) died in the nursing home. Among the controls, 651 (46%) were alive and in the nursing home, 308 (22%) were discharged to another facility or to home, and 459 (32%) died in the nursing home.
PROGESTERONE ANTAGONISTS (SEDA-29, 506; SEDA-30, 477; SEDA-31, 671)
Mifepristone
(SED-15, 2344; SEDA-29, 506; SEDA-30, 477; SEDA-31, 671) Hematologic Thrombotic thrombocyto penic purpura occurred in a case in which mifepristone was used to terminate early pregnancy (95A).
750
Teratogenicity Little information seems to be available on the adverse effects on the fetus if elective abortion is unsuccessful. A boy with Möbius syndrome was delivered at 33 weeks, after an unsuccessful attempt to abort a pregnancy using mifepristone and misoprostol (96A). Möbius syndrome is characterized by unilateral or bilateral palsy of the abducens and facial cranial nerves; other cranial nerves (e.g. the hypoglossal) can also be affected and there may be craniofacial or orofacial anomalies and limb malformations. The usual etiology remains largely unknown and probably involves multiple factors; the most likely hypothesis is disruption of the developing vascular system, with transient ischemia (particularly of the vertebral arteries) and fetal hypoxia. A teratogenic cause of Möbius syndrome has previously been suggested. The critical period for the development of Möbius syndrome after teratogen exposure appears to be 5–8 weeks of gestation.
SEX HORMONE AGONISTS Tibolone (SEDA-29, 514; SEDA-30, 485; SEDA-31, 671) Reproductive system In a comparison of tibolone (up to 2.5 mg/day for 1–2 years) and combined estrogen þ progestogen therapy in more than 3000 postmenopausal women, tibolone did not induce endometrial hyperplasia or carcinoma and was associated with a better vaginal bleeding profile than estrogen þ progestogen (97C). However, these apparently reassuring data do not remove all doubts regarding the adverse effects of tibolone. In a study of endometrial histology in 17 patients over the age of 60 who had taken tibolone for long periods, 7 patients had a thickened endometrium of more than 4 mm (98c). Three had an area of translucency in the subendometrial space. Of the 10 women with an endometrial thickness less than 4 mm, 4 had subendometrial fluid.
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Hysteroscopy was performed in five women; in all five the endometrial cavity was reported as atrophic and the histology showed an inactive basal type. In two of the five cases examined histologically, there were additional changes suggesting endometrial polyps. The investigators noted that similar find ings have been described in women using selective estrogen receptor modulators and they suggested that tibolone may perhaps be regarded as belonging to this class of agents.
SEX HORMONE ANTAGONISTS Danazol (SEDA-29, 514; SEDA-31, 672) Metabolism Hungarian investigators have reported that when danazol is used prophylactically in hereditary angio edema, it has adverse effects on the lipid profile (99c). Patients with hereditary angio-edema taking danazol have been compared with similar patients not taking danazol and healthy subjects. Serum concentrations of high-density lipoprotein (HDL) and apolipoprotein A-I were significantly lower, whereas low-density lipoprotein (LDL) and apolipoprotein B-100 were higher in those who took danazol. Those who took danazol had a 12 times higher risk of abnormally low HDL concentrations and a 4.4 times lower risk of high LDL concentrations. Monitoring of HDL and LDL concentrations at regular intervals is therefore recommended during treatment with danazol. Biochemical findings do not of course provide absolute proof of an increased risk of atherosclerosis and one should take note of a more recent paper from these same investigators who have reported that longterm danazol prophylaxis in such patients did not lead to thickening of the carotid intima (100c). It seems clear that further evidence must be awaited.
Sex hormones and related compounds, including hormonal contraceptives
ANDROGENS, ANABOLIC STEROIDS, AND RELATED COMPOUNDS (SED-15, 216; SEDA-29, 507; SEDA-30, 477; SEDA-31, 672)
Androgens Endocrine The possibility that the use of testosterone gel by a man may on occasion affect his partner is raised by a curious case (101A). • A 63-year-old woman developed both physical and biochemical signs of virilization. Her husband had been using a testosterone gel and the authors had reason to believe that transmission of the androgen had occurred not through direct skin contact but because the couple shared a washcloth on which the testosterone had been deposited when the man made use of it.
Metabolism In a multicenter randomized study (102c) of the effects of testosterone gel in 75 HIV-positive men with abdominal obesity and low testosterone compared with placebo, the gel was associated with a greater reduction in whole body, total and subcutaneous abdominal fat mass and a greater increase in lean mass. However, changes in visceral fat mass were not significantly different. Further studies were recommended to determine the effects of testosterone on insulin sensitivity and cardiovascular risk. Tumorigenicity The long-standing contro versy about whether androgen replacement in men increases the risk of prostatic neo plasms (SEDA-31, 672) is no closer to being settled. The original evidence of this supposed risk was based on a single case report and it has been argued that even in men with a history of prostate cancer the risk is negligible or absent (103R, 104r). Susceptibility factors Sex The debate about the use of androgens in women (SEDA-29, 510), largely to stimulate
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sexual interest and desire, continues, and papers tend to dwell on the moral and social aspects, rather than on adverse effects. Although some women have androgen insufficiency, the indications (if any) for treatment are still poorly defined and the quality of the literature leaves much to be desired (105R). Evidence on treatment for longer periods is still needed, as is assurance of the reversibility of some particular effects, for example on the endometrium. There are also insufficient long-term safety data regarding possible adverse effects on the breast, endometrium and heart. However, the data available to date on shorter periods of use are reassuring, and it has been suggested that in postmenopausal women testosterone administration that results in physiological to slightly supra-physiological serum-free testosterone concentrations is safe for at least 2 years (106R). One would feel rather more comfortable with this conclusion if the data were of better quality.
Long-term medical and social consequences of androgenic anabolic steroid abuse The fact that both the mental and physical consequences of anabolic steroid abuse are commonly overlooked is becoming particu larly serious, with the apparently continuing increase in the prevalence of such misuse. The fact that the generation that first acquired this habit is now approaching mid dle age makes it necessary to consider the long-term consequences for society of the presence of a drug-injured population group of significant size. As a major paper by a Harvard group (to which the present review is much indebted) has pointed out, the bulk of misusers have never been profes sional sportsmen; they are simply individuals who want to improve their bodily condition and mistakenly turn to anabolic steroids for this purpose (107R). This large population of ‘amateur’ abusers began to grow in the late 1970s and early 1980s, but has remained less visible than most other populations of
752
substance abusers, as they rarely seek treat ment, rarely come to the attention of physi cians in general and frequently distrust health-care professionals. Field studies show that they commonly take two or more sub stances simultaneously (a practice known as ‘stacking’), often ingesting a total anabolic steroid dose equivalent to testosterone 600–1000 mg/week, and sometimes even 3000–5000 mg/week, which is 50–100 times greater than the natural weekly production of testosterone by the normal male testes. Illicit users typically take these compounds in repeated courses, or ‘cycles’, each lasting several weeks to several months, sometimes adding up to several years of cumulative life time exposure. It has also been argued that there is evidence, in part from animal studies, that anabolic steroids can cause dependence (108r), which would exacerbate this. Further more, dysphoric feelings associated with hypogonadism may prompt some former users to resume taking the drugs again and yet again. Although many of these individuals no longer use anabolic steroids when they reach middle age, accumulating evidence suggests that they may still be vulnerable to long-term psychiatric and medical effects from their former drug use. Even using the conservative figures from the US health sta tistics for 1991, it would follow that about half a million American men with a history of anabolic steroid use will have passed the age of 45 by the year 2010. This estimate would be even higher – well over a million – if we were to extrapolate from the higher figures generated by anonymous surveys of American high-school students in the 1980s. Similar data are available from several other Western countries. Cardiovascular Supraphysiological doses of anabolic steroids appear to produce a range of adverse cardiovascular effects, including hypertension, cardiomyopathy and left ventricular hypertrophy, dyslipidemia (increased low-density lipoprotein and reduced high-density lipoprotein cholesterol), with potential acceleration of atherosclerosis and myocardial ischemia, adverse effects on
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coagulation and platelet aggregation, and a predisposition to dysrhythmias. Some of these effects remit after the anabolic steroids are discontinued, but effects such as atherosclerosis and cardiomyopathy are likely to be irreversible. These effects have been blamed for numerous premature deaths among athletes in their twenties and thirties known or believed to have used anabolic steroids – either from cardiac disease or strokes. In Finland mortality among 62 male powerlifters who had been placed first to fifth in Finnish championships during 1977–1982 (all being likely to have used ster oids) was compared with that among 1094 male controls (109c). Of the powerlifters 13% had died compared with only 3.1% of controls – a ratio of 4.16:1 (95% CI = 2.04, 10.45). Three of the eight deaths among powerlifters were ascribed to myocardial infarction, and the authors speculated that these deaths may have been attributable to use of anabolic steroids. Similarly, in a comparison of 20 anabolic steroid-using bodybuilders, mean age 33 years, with 25 age-matched non-anabolic steroid-using bodybuilders and 25 non-athletic controls, using Doppler echocardiography, Doppler myocardial imaging, strain rate imaging and an electrocardiographic treadmill test, the users, although studied a mean of several years after their last exposure to the drugs, still had impaired myocardial function (110c). The investigators found, for example, that middle intraventricular septum strain rates among users were strongly associated both with the mean reported number of weeks of drug use per year and indepen dently with the mean reported weekly dose of anabolic steroid. Two cases of sudden cardiac death have been reported in previously healthy body builders who were chronic users (111A). Autopsy in both cases pointed to cardiac fail ure, probably attributable to the combined effect of the anabolic steroids and the vigorous weight training in which they had engaged. Nervous system Although abuse of anabolic steroids can cause stimulation of
Sex hormones and related compounds, including hormonal contraceptives
the nervous system, the resulting symptoms generally amount only to euphoria or insomnia, and convulsions are not a recognized consequence. Nor has premature death as such been clearly recorded as an epidemic consequence of anabolic steroid abuse. However, these effects were observed, among others, in an analysis of official patient care records in Sweden (112C). Diagnoses, mortality and adverse events were examined in 248 patients who had been taking anabolic steroids and 1215 patients who had not. The proportions of patients who had received institutionalized care for substance abuse, psychiatric disorder or central thoracic pain were significantly higher in those who had taken anabolic steroids (RR = 2.2, 95% CI = 1.2, 4.2; RR = 2.1, 95% CI = 1.4, 3.2; RR = 3.5, 95% CI = 1.1, 11 respectively). Furthermore, unspecified convulsions occurred in 11 subjects using anabolic steroids (4.4%), one of whom died during a seizure, but in only one of the subjects without a history of anabolic steroid use. The effect was thus highly over-represented in the anabolic steroid users (RR = 54, 95% CI = 7, 416). The standardized mortality ratios in the anabolic steroid users and non-users were 20 (95% CI = 11, 36) and 6.02 (95% CI = 3.77, 9.12) respectively. Thus, use of anabolic steroids appeared to be an indicator of increased risk of premature death in several categories of patients. Speculation as to the mechanism that might underlie the occurrence of seizures in users of anabolic steroids continues (113H). A less common complication of anabolic steroid abuse is ischemic stroke, despite the fact that these compounds can increase vas cular tone, arterial tension and platelet aggre gation. A case of this type in a male amateur athlete aged 26 has been reported (114A). Psychological Finally, anabolic steroid users may suffer from prominent bodyimage disorders, such as muscle dysmorphia, a form of body dysmorphic disorder in which they become preoccupied that they do not appear sufficiently strong and muscular (115R). This syndrome, sometimes
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also called ‘reverse anorexia nervosa’, is associated with considerable psychiatric morbidity, and may be both a cause and a consequence of using anabolic steroids. Also, as a result of their concerns about body image, anabolic steroid abusers may abuse a wide range of additional substances, including street drugs, to gain muscle, lose fat or otherwise affect body appearance. Psychiatric The psychiatric effects of anabolic steroid abuse are all too often overlooked. They include hypomania, aggressiveness and other disorders that justify increasing social concern regarding the dangers posed by these agents (see below). A particularly severe case of psychiatric imbalance resulting from the use of anabolic steroids has been described (116A). They can also cause major depressive illness (117C). The various types of psychiatric disorders that anabolic steroids can cause have been demonstrated mainly in current users and not in former users; even if they are con firmed in the latter, some doubt is likely to persist as to whether one is dealing with a true adverse after-effect or with mental char acteristics likely to be relatively frequent in the type of individual who is particularly prone to abuse anabolic steroids. However, recent Scandinavian studies have offered some cause for concern on this score. In one study (118C), suicide was significantly more common among deceased former ana bolic steroid users than among other types of substance users. Also, in the study of older powerlifters noted above, three of the eight deaths were from suicides. Recently, another Swedish group mailed a structured question naire to 996 former Swedish elite male ath letes; former anabolic steroid users were much more likely than other individuals to have sought treatment for psychiatric symp toms: for example, 13% of users had sought treatment for depression, compared with 5.0% of non-users, a difference that was highly significant (119c). Endocrine There are also concerns about neuroendocrine function in long-term users
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of anabolic steroids, which suppress the hypothalamic–pituitary–testicular axis. When a ‘cycle’ of anabolic steroid use ends, male users will often become temporarily hypogonadal. Although function usually recovers spontaneously within a few weeks to a few months, there are reports of men in whom hypogonadism persisted for more than a year after discontinuation, and several reports have documented hypogonadism of similar duration after abuse of anabolic steroids. Persistent suppression of hypothalamic–pituitary–testicular function can have serious clinical consequences, including infertility (120r). Liver Over a long period, volumes in this series have reported adverse effects of current anabolic steroid use involving the liver, including peliosis hepatitis, intrahepatic cholestasis, hepatocellular adenomas or carcinomas, hepatic angiosarcomas, and spontaneous hepatic rupture. Such reports continue to appear (121C). However, there is no clear evidence that these complications are more frequent in the later life of anabolic steroid abusers than in the remainder of the population. Tumorigenicity As the anabolic steroids are androgens, there is obvious reason to suspect that in the long term their use might increase the incidence of prostatic hyperplasia or even cancer, but there is virtually no evidence about this; prostatic cancer has been incidentally described in former users of anabolic steroids, but the association could have been fortuitous. Conclusions There is a risk that, as some authors have suggested, political and moral forces have excessively demonized the use of anabolic steroids and that the risks are therefore being much exaggerated (122R, 123R). Certainly these arguments deserve consideration – but on the other hand, there are several reasons to suspect that we might be underestimating, rather than overestimating, the public health consequences of long-term
M.N.G. Dukes
use of anabolic steroids, if only because a large proportion of former users may not admit to their true history of drug abuse. To adopt almost literally the conclusion advanced by Kanayama et al. (107R), the frequency and severity of anabolic steroidinduced morbidity and mortality are still poorly understood, largely because these effects often do not declare themselves until users enter middle or old age – and investigators have examined at most small samples of ageing users. However, as they point out, this is poised to change, as hundreds of thousands of former (and sometimes still current) illicit users begin to pass the age of 45. As this wave of ageing users approaches, it is imperative to initiate larger and more systematic studies of the long-term effects of anabolic steroids, so that we can better inform both current and future generations.
Stanozolol Observational studies In some centers, anabolic steroids are still in use to control attacks of hereditary angio-edema. The safety of this treatment, which obviously needs to be maintained over very long periods, has been evaluated by a questionnaire in 21 patients who had taken stanozolol since 1987 (124c). The minimal initial effective dosage of stanozolol was 0.5–2.0 mg/day, although most patients achieved symptomatic control and reduced the dose and frequency of intake as the number of attacks decreased. Treatmentrelated symptoms developed in 10 patients. Interruption of stanozolol therapy was not required, because symptoms subsided with a reduction in the stanozolol dosage. Adverse events included hirsutism, weight gain, menstrual irregularities or postmenopausal bleeding, acne, and mood changes. Liver enzyme assays showed no persistent abnormalities, although liver ultrasonography in three of eight cases showed changes unrelated to therapy. Five patients had reduced HDL cholesterol concentrations, and two had raised triglycerides.
Sex hormones and related compounds, including hormonal contraceptives
Respiratory A single previously reported case of obstructive sleep apnea was attributed to testosterone but could have been coincidental (SED-15, 217). Since then, there have been other scattered reports of this possible complication, and the sparse literature has been reviewed (125r). The cases are very few compared with the large numbers of men treated with testosterone, sometimes in supraphysiological doses and generally beyond middle age. There has been one double-blind, placebo-controlled study of the matter and it did point to an association, but other work seems to have discounted it. Bearing in mind that obstructive sleep apnea is associated with ageing in men, and perhaps to some extent with an increase in body weight, there is every reason for confusion and the connection between testosterone and this adverse event must probably still be regarded as unproven.
(SEDA-29, 510; SEDA-30, 479; SEDA-31, 673)
ANTIANDROGENS Bicalutamide
Breasts Tamoxifen 20 mg/day might help in reducing the gynecomastia and breast pain that are often caused by bicalutamide (SEDA-30, 480). A little more case material tending to confirm this finding has appeared (126r), but longer-term experience was still awaited. In a review of the literature on the subject tamoxifen was found to be
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remarkably effective, both in preventing gynecomastia during bicalutamide treatment and in causing it to regress (often completely) when it was already present (127R).
Dutasteride
(SEDA-31, 675)
Breasts Gynecomastia has been reported in a 66-year-old man with chronic obstructive pulmonary disease who took dutasteride 0.5 mg/day (128A).
Finasteride (SED-15, 3132; SEDA-30, 480; SEDA-31, 675) Sensory systems Two men underwent bilateral cataract surgery having taken finasteride for benign prostatic hyperplasia and both developed the intraoperative floppy iris syndrome (IFIS) (129A). In patients scheduled for cataract surgery it is therefore essential to take a medication history to determine whether they are taking finasteride, since IFIS raises considerable problems for cataract removal.
Flutamide
(SED-15, 1427; SEDA-29, 513; SEDA-30, 484; SEDA-31, 675) Skin Photosensitive dermatitis attribut able to flutamide was followed in one case by the appearance of vitiliginous lesions (130A).
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Thyroid hormones, iodine, and antithyroid drugs
Thyrotropin-releasing hormone (TRH, protirelin) (SEDA-31, 683)
patients and a transient increase in thyroid volume and tenderness in the first week of treatment (2R). Most patients also have a short period (2–4 weeks) of hyperthyroidism.
Endocrine The TRH test is generally safe for evaluating pituitary function, but pituitary apoplexy has been reported (1A). • A 41-year-old woman with acromegaly due to a pituitary macroadenoma developed pituitary apoplexy after a TRH 200-micro gram intravenous stimulation test. There was no acute hemorrhage or infarction on com puted tomography (CT) or magnetic reso nance imaging (MRI) scans, but 2 days later, the pituitary gland, removed trans sphenoidally, showed ischemic necrosis and acute hemorrhage.
Thyrotropin (thyroid-stimulating hormone, TSH) (SEDA-31, 683) Endocrine Recombinant human TSH (rhTSH) has been used to increase 131I uptake in patients with toxic and non toxic multinodular goiter. This procedure changes the distribution of 131I in the thy roid, lowers the absorption dose and reduces the volume of the goitre to 50– 75% of the baseline volume. However, a major disadvantage is induction of hypothy roidism in a relatively large number of Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32041-1 � 2010 Elsevier B.V. All rights reserved.
THYROID HORMONES (SED-15, 3409; SEDA-29, 520; SEDA-30, 490; SEDA-31, 687) Uses Overt hypothyroidism is widely recognized as a susceptibility factor for atherosclerosis by its association with other factors, including lipid disturbances (3C). Much controversy continues to surround the management of patients with subclinical hypothyroidism (raised serum TSH concen trations with normal serum free T3 and free T4 concentrations). There have been two reports of improved atherogenic lipid con centrations in patients taking levothyroxine for subclinical hypothyroidism compared with patients taking placebo (4c, 5c). How ever, despite these findings, there is cur rently insufficient evidence that the use of levothyroxine in patients with subclinical hypothyroidism is associated with reduc tions in long-term morbidity and mortality. There is a well-recognized association between hypothyroidism and psychiatric ill ness. Two studies have shown augmentation of the effects of serotonergic antidepressants by levothyroxine (6c) and L-triiodothyro nine (7c). Both reports indicated significant
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improvements in depression rating scores in patients undergoing combination therapy with thyroid hormones and a number of selective serotonin uptake inhibitors (SSRIs), suggesting that thyroid hormones can be used to accelerate antidepressant response and improve overall outcome in patients with refractory depression. Sensory systems There has been a previous report of an increased risk of age-related macular degeneration in patients taking thy roid hormones (8C). However, in a large population-based matched case–control study of patients with age-related macular degeneration, there were no significant associations between treatment with thyroid hormones or antithyroid drugs and the risk of macular degeneration (9C). Susceptibility factors Diseases Treatment with high doses of levothyroxine reduces the risk of recurrence of thyroid cancer. A novel phenomenon of reduced serum free T4 and increased serum free T3 concentra tions resulting in T3 thyrotoxicosis in patients taking fixed doses of levothyroxine has been described. These effects were only observed in subjects with large metastases from follicular thyroid and are thought to be due to increased conversion of T4 to T3 in tumor cells expressing high activities of the deiodinase enzymes D1 and D2 (10C). Drug–drug interactions Sevelamer Many substances, including the phosphate binders aluminium hydroxide and calcium carbonate, interfere with absorption of levothyroxine. There has been a further report that the phosphate binder sevelamer increased serum TSH concentrations in a patient with chronic renal insufficiency and hypothyroidism (11A). The administration of sevelamer and levothyroxine separately with an interval of several hours reversed the situation, showing that this phosphate binder directly binds levothyroxine in the gastrointestinal tract.
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IODINE AND IODIDES (SED-15, 1896; SEDA-30, 490; SEDA-31, 688) Endocrine Iodine deficiency remains a problem in several areas, including the southern part of Poland, which was a region of moderate iodine deficiency at the end of the twentieth century. Following the implementation of iodine prophylaxis by mandatory household salt iodization in this region, there were significant increases in the prevalence of antithyroid microsomal anti bodies and in the prevalence of hyperthyroid ism (defined as serum TSH concentrations below the reference range) (12C). These early adverse effects appear to be transient and are acceptable, in view of the evident benefits of adequate iodine intake.
Radioactive iodine Radioactive iodine 131 I is used in the treat ment of patients with hyperthyroidism and in those with thyroid cancer. 131I-labelled compounds are also used in the treatment of other cancers. In a small study there was a high rate response and prolonged survival after intra-arterial injection of 131 I-iodine-labelled lipiodol in the treat ment of patients with advanced hepato cellular carcinoma not amenable to surgery or local treatment (13c). Respiratory Two cases of acute airways obstruction following the administration of 131 I for Graves’ disease have been reported (14A). In both instances rapid resolution of the respiratory symptoms was obtained with administration of histamine H1 receptor antagonists and hydrocortisone. Salivary glands Salivary glands accumu late 131I, and acute salivary gland pain, swelling and inflammation, and xerostomia have been described following administra tion of radioiodine. Patients who receive larger doses of 131I for thyroid cancer are
Thyroid hormones, iodine, and antithyroid drugs
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especially at risk. In 76 patients there was acute salivary gland toxicity in 26% and chronic toxicity typically manifesting as xerostomia in 21%; these complications were more likely to occur after repeated doses of radioiodine (15c).
markers, including classical antineutrophil cytoplasmic antibody (c-ANCA) and proto plasmic-staining antineutrophil cytoplasmic antibody (p-ANCA), and without histo pathological evidence of capillaritis has been described (19A). An eosinophilic pleural effusion after long-term treatment with propylthiouracil has been reported. After withdrawal of pro pylthiouracil and a short course of low-dose glucocorticoids, the pleural effusion rapidly resolved (20A).
Fetotoxicity Pregnancy is an absolute contraindication to 131I therapy, and women of child-bearing age should undergo routine pregnancy testing before the admin istration of radioactive iodine. There have been three reports of inadvertent radio iodine administration during pregnancy despite negative pregnancy tests in two cases. Doses of 400 MBq (16A) and 500 MBq (17A) were associated with neonatal hypothyroidism, which was successfully trea ted with levothyroxine. A dose of 3700 MBq, administered to a patient with differentiated thyroid cancer, resulted in fetal death. Drug–drug interactions Antithyroid drugs Patients with hyperthyroidism are commonly treated with antithyroid drugs (propylthiour acil or carbimazole) before radioiodine ther apy. There is continuing disagreement about their beneficial and detrimental effects and the optimal sequencing of these drugs before and after 131I administration. In 14 rando mized controlled trials in a total of 1306 participants, adjunctive antithyroid medica tion was associated with an increased risk of treatment failure (RR = 1.28; 95% CI = 1.07, 1.52) and a reduced risk of hypothyroidism (RR = 0.68; 0.53, 0.87). There were no dif ferences in summary estimates for the differ ent antithyroid drugs or when the drugs were given before or after radioiodine treatment (18M).
ANTITHYROID DRUGS (SED-15, 3387; SEDA-29 520; SEDA-30, 490; SEDA-31, 689) Respiratory An atypical presentation of propylthiouracil-induced diffuse alveolar hemorrhage with negative serological
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Hematologic Drug-induced agranulo cytosis is the most serious disorder asso ciated with thionamide therapy; it can be life-threatening, with a reported mortality of 5–15%.
EIDOS classification: Extrinsic species: Thionamides Intrinsic species: Whiteblood cells Distribution: Bone marrow Outcome: Not known Sequela: Agranulocytosis due to thionamides DoTS classification: Dose-relation: Collateral Time-course: Intermediate Susceptibility factors: Exogenous (other drugs that can cause agranulocytosis)
The incidences of idiosyncratic neutropenia and agranulocytosis in England and Wales have been estimated at 120 and 7 cases per million per year respectively. Current users of drugs classed as ‘thyroid inhibitors’ had the highest adjusted odds ratios for neutro penia (adjusted OR = 35; 95% CI = 12, 100) and for agranulocytosis (OR = 21; 95% CI = 3.3, 1) compared with other classes of drug associated with this complication (21C). In a multinational case–control study in Latin America there was a relatively low overall incidence rate of agranulocytosis (0.38 cases per 1 million inhabitant-years). Patients who developed this hematological
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complication more often took medications already associated with agranulocytosis than controls, mainly methimazole (OR = 44; 95% CI = 6.8, 1) (22C). There has been a report of a patient who developed agranulocytosis, plasmacytosis, and thrombocytosis due to methimazoleinduced bone marrow toxicity. After withdra wal of methimazole and administration of granulocyte colony-stimulating factor (G-CSF) and methylprednisolone, the hema tological abnormalities rapidly resolved (23A). Acute myeloid leukemia occurred in a patient who had taken propylthiouracil for 15 years (24Ar). It has been proposed that combined immunosuppression, partly from chronic use of propylthiouracil and partly from pregnancy and the puerperium, could have been causative in this case. Liver There has been a report of methim azole-induced cholestatic jaundice in an elderly patient with hyperthyroidism (25A). Serial changes in liver function tests have been reported in 23 patients with Graves’ disease taking thionamide drugs compared with 14 patients with subacute thyroiditis not undergoing active treatment (26C). It is therefore plausible that some of the observed increases in AsT and AlT activ ities after starting antithyroid drugs are caused by changes in thyroid function, rather than by the drug treatment. The efficacy and adverse effects of meth imazole 15 mg/day, methimazole 30 mg/day or propylthiouracil 300 mg/day have been stu died in 240 patients (27C). The results sug gested that larger doses of methimazole are advisable for patients with severe hyperthy roidism, whereas methimazole 15 mg/day is suitable for mild and moderate hyperthyroid ism. Adverse effects, mainly mild hepatotoxi city, were most common with propylthiouracil and significantly less so with methimazole 15mg/day versus 30 mg/day. Skin Juvenile dermatomyositis has been reported in a 10-year-old girl after treatment with carbimazole for 3 months; drug with drawal resulted in rapid resolution of the symptoms and signs (28A).
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Immunologic Antithyroid drugs, and especially propylthiouracil, can be asso ciated with ANCA-positive vasculitis, often manifesting as renal disease. In one study propylthiouracil inhibited the activity of myeloperoxidase and induced ANCA against myeloperoxidase in a dose-related manner, suggesting that these effects may be involved in propylthiouracil-induced vasculitis (29c). Teratogenicity During pregnancy, propyl thiouracil is preferred to methimazole or carbimazole, and a meta-analysis has con firmed previous anecdotal evidence that propylthiouracil crosses the placenta less well, is associated with a lower frequency of fetal hypothyroidism and causes fewer teratogenic effects than methimazole (30M). Propylthiouracil should therefore still be considered as the first-line agent for Graves’ disease during pregnancy. However, it should be noted that one of the major hazards of antithyroid drugs in pregnancy is over-treatment, and hence induction of fetal hypothyroidism and goiter. It is there fore important to monitor maternal thyroid status carefully and to use the lowest possi ble dose of antithyroid drug sufficient to maintain maternal euthyroidism. Aplasia cutis congenita and choanal atre sia have been reported in association with maternal carbimazole therapy, suggesting a causative link either with the drug or with underlying hyperthyroidism. A rare case of a monozygotic twin with aplasia cutis con genita and complex skull defects after meth imazole exposure in utero has been reported (31A). The second child did not have any skin or skull defects, and the exact mechanisms underlying this rare adverse effect of methimazole remain unclear. Drug–drug interactions Warfarin Concomi tant therapy with warfarin and drugs that alter thyroid hormone concentrations, such as methimazole, warrants frequent monitoring of both thyroid function and the international normalized ratio (INR) (32A).
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References 1. Wang HF, Huang CC, Chen YF, Ho DM, Lin HD. Pituitary apoplexy after thyrotropinreleasing hormone stimulation test in a patient with pituitary macroadenoma. J Chin Med Assoc 2007;70(9):392–5. 2. Medeiros-Neto G, Marui S, Knobel M. An outline concerning the potential use of recombinant human thyrotropin for improving radioiodine therapy of multinodular goiter. Endocrine 2008;33(2):109–17. 3. Franklyn JA, Sheppard MC, Maisonneuve P. Thyroid function and mortality in patients treated for hyperthyroidism. J Am Med Assoc 2005;294(1):71–80. 4. Teixeira PF, Reuters VS, Ferreira MM, Almeida CP, Reis FA, Melo BA, Buescu A, Costa AJ, Vaisman M. Treatment of sub clinical hypothyroidism reduces atherogenic lipid levels in a placebo-controlled doubleblind clinical trial. Horm Metab Res 2008; 40(1):50–5. 5. Teixeira P, Reuters VS, Ferreira MM, Almeida CP, Reis FA, Buescu A, Costa AJ, Vaisman M. Lipid profile in different degrees of hypothyroidism and effects of levothyroxine replacement in mild thyroid failure. Transl Res 2008;151(4):224–31. 6. Lojko D, Rybakowski JK. L-Thyroxine augmentation of serotonergic antidepressants in female patients with refractory depression. J Affect Disord 2007;103(1–3):253–6. 7. Posternak M, Novak S, Stern R, Hennessey J, Joffe R, Prange Jr. A, Zimmerman M. A pilot effectiveness study: placebo-controlled trial of adjunctive L-triiodothyronine (T3) used to accelerate and potentiate the anti depressant response. Int J Neuropsycho pharmacol 2008;11(1):15–25. 8. Age-Related Eye Disease Study Research Group. Risk factors associated with agerelated macular degeneration. A case-control study in the age-related eye disease study: Age-Related Eye Disease Study report num ber 3. Ophthalmology 2000;107(12):2224–32. 9. Douglas IJ, Cook C, Chakravarthy U, Hubbard R, Fletcher AE, Smeeth L. A case-control study of drug risk factors for age-related macular degeneration. Ophthal mology 2007;114(6):1164–9.
10. Miyauchi A, Takamura Y, Ito Y, Miya A, Kobayashi K, Matsuzuka F, Amino N, Toyoda N, Nomura E, Nishikawa M. 3,5,3’ Triiodothyronine thyrotoxicosis due to incre ased conversion of administered levothyroxine in patients with massive metastatic follicular thyroid carcinoma. J Clin Endocrinol Metab 2008;93(6):2239–42. 11. Arnadottir M, Johannesson AJ. Phosphate binders and timing of levothyroxine admin istration. Nephrol Dial Transplant 2008; 23(1):420. 12. Golkowski F, Buziak-Bereza M, Trofimiuk M, Baldys-Waligorska A, Szybinski Z, Huszno B. Increased prevalence of hyper thyroidism as an early and transient side-effect of implementing iodine prophylaxis. Public Health Nutr 2007;10(8):799–802. 13. Boucher E, Garin E, Guylligomarc’h A, Olivié D, Boudjema K, Raoul JL. Intra arterial injection of iodine-131-labeled lipiodol for treatment of hepatocellular carcinoma. Radiother Oncol 2007;82(1):76–82. 14. Kinuya S, Yoneyama T, Michigishi T. Airway complication occurring during radioiodine treatment for Graves’ disease. Ann Nucl Med 2007;21(6):367–9. 15. Hyer S, Kong A, Pratt B, Harmer C. Salivary gland toxicity after radioiodine therapy for thyroid cancer. Clin Oncol (R Coll Radiol) 2007;19(1):83–6. 16. Perry RJ, Ainine A, Butler S, Donaldson MD. Hypoechoic thyroid nodules on ultra sound 4 years after prenatal exposure to radio iodine: resolution with thyroxine therapy. Acta Paediatr 2008;97(4):509–12. 17. Berg G, Jacobsson L, Nystrom E, Gleisner KS, Tennvall J. Consequences of inadvertent radioiodine treatment of Graves’ disease and thyroid cancer in undiagnosed pregnancy. Can we rely on routine pregnancy testing? Acta Oncol 2008;47(1):145–9. 18. Walter MA, Briel M, Christ-Crain M, Bonnema SJ, Connell J, Cooper DS, Bucher HC, M€ uller-Brand J, M€ uller B. Effects of antithyroid drugs on radioiodine treatment: systematic review and meta-analysis of randomised controlled trials. BMJ 2007; 334(7592):514.
768 19. Hadjiangelis NP, Harkin TJ. Propylthioura cil-related diffuse alveolar hemorrhage with negative serologies and without capillaritis. Respir Med 2007;101(4):865–7. 20. Sen N, Ermis H, Karatasli M, Habesoglu MA, Eyuboglu FO. Propylthiouracil-associated eosinophilic pleural effusion: a case report. Respiration 2007;74(6):703–5. 21. van Staa TP, Boulton F, Cooper C, Hagenbeek A, Inskip H, Leufkens HG. Neutropenia and agranulocytosis in England and Wales: incidence and risk factors. Am J Hematol 2003;72(4):248–54. 22. Hamerschlak N, Maluf E, Biasi Cavalcanti A, Avezum Júnior A, Eluf-Neto J, Passeto Falcão R, Lorand-Metze IG, Goldenberg D, Leite Santana C, de Oliveira Werneck Rodrigues D, Nascimento da Motta Passos L, Oliveira de Miranda Coelho E, Tostes Pintão MC, Moraes de Souza H, Borbolla JR, Pasquini R. Incidence and risk factors for agranulocytosis in Latin American coun tries – the Latin Study: a multicenter study. Eur J Clin Pharmacol 2008;64(9):921–9. 23. Oh EJ, Chae HJ, Park YJ, Park JW, Han K. Agranulocytosis, plasmacytosis, and thrombo cytosis due to methimazole-induced bone mar row toxicity. Am J Hematol 2007;82(6):500. 24. Focosi D, Caracciolo F, Galimberti S, Papineschi F, Petrini M. Long-term pro pylthiouracil use and acute myeloid leukemia: a case report and review of the literature. Ann Hematol 2008;87(3):233–5. 25. Ramos-Bonner LS, Goldberg TH, Moyer S, Anastasopoulou C. Methimazole-induced cholestatic jaundice in an elderly hyperthyroid patient. Am J Geriatr Pharmacother 2007;5(3): 236–40.
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26. Matsumoto Y, Amino N, Kubota S, Ikeda N, Morita S, Nishihara E, Ohye H, Kudo T, Ito M, Fukata S, Miyauchi A. Serial changes in liver function tests in patients with thyr otoxicosis induced by Graves’ disease and painless thyroiditis. Thyroid 2008;18(3): 283–7. 27. Nakamura H, Noh JY, Itoh K, Fukata S, Miyauchi A, Hamada N. Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves’ disease. J Clin Endocrinol Metab 2007;92(6): 2157–62. 28. Alvarez F, Pagot C, Vabre-Latre CM, Uro-Coste E, Paul C, Chaix Y, MazereeuwHautier J. Carbimazole-induced juvenile der matomyositis. Br J Dermatol 2008;158(1): 196–7. 29. Zhang AH, Chen M, Gao Y, Zhao MH, Wang HY. Inhibition of oxidation activity of myeloperoxidase (MPO) by propylthiour acil (PTU) and anti-MPO antibodies from patients with PTU-induced vasculitis. Clin Immunol 2007;122(2):187–93. 30. Chattaway JM, Klepser TB. Propylthiouracil versus methimazole in treatment of Graves’ disease during pregnancy. Ann Pharmaco ther 2007;41(6):1018–22. 31. Iwayama H, Hosono H, Yamamoto H, Oshiro M, Ueda N. Aplasia cutis congenita with skull defect in a monozygotic twin after exposure to methimazole in utero. Birth Defects Res A Clin Mol Teratol 2007; 79(10):680–4. 32. Akin F, Yaylali GF, Bastemir M, Yapar B. Effect of methimazole on warfarin anticoa gulation in a case of Graves’ disease. Blood Coagul Fibrinolysis 2008;19(1):89–91.
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GLUCAGON
Insulin, other hypoglycemic drugs, and glucagon (SED-15, 1510;
SEDA-31, 689) Gastrointestinal Parenteral glucagon is used to treat hypoglycemia. In 10 men aged 18–47 years, body mass index (BMI) 22–24 kg/m2, without diabetes, who received rectal suppositories containing indometacin 100 mg and varying doses of glucagon (0.1, 0.5, and 1 mg), two had mild nausea and colicky abdominal pain after the 1 mg dose (1c). Peak concentrations of glucagon were 200 ng/l compared with peaks of 1800 ng/l found after intramuscular glucagon 1 mg. This dose of rectal glucagon did not aid recovery from hypoglycemia in six men with type 1 diabetes.
(SED-15, 1761; SEDA-29, 523; SEDA-30, 494; SEDA-31, 689)
INSULIN
Metabolism Hypoglycemia In a review of studies of tight blood glucose control in intensive care, there were increased risks of hypoglycemia in patients who received intensive insulin therapy (2R). The risk was greatest in those with sepsis. In those with conventional insulin therapy and sepsis, the Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32042-3 2010 Elsevier B.V. All rights reserved.
risk of hypoglycemia was 2.9% compared with 1.2% in those without sepsis. When septic patients received intensive insulin therapy, the risk of hypoglycemia was 20% compared with 6.8% in those without sepsis. The risk of hypoglycemia coincided with an increased death rate in all patients, regard less of whether they received intensive or conventional insulin therapy (odds ratio [OR] = 3.2 in the surgical intensive care unit [ICU] study and 2.9 in the medical ICU study). However, hypoglycemia was not thought to be directly responsible for the increased death rate, more a marker of those at increased risk. Larger studies appro priately designed to achieve normoglycemia are required to answer questions about the adverse effects and benefits of using inten sive insulin therapy in this setting. Insight into a possible mechanism of this increased mortality has come from a study of patients with subarachnoid hemorrhage who received continuous intravenous insulin if they had hyperglycemia. Although blood glucose concentrations remained within the reference range at above 4.4 mmol/l, 19 of 24 patients receiving insulin had a reduction in cerebral glucose concentration to less than 0.6 mmol/l, assessed using microdialysis sam ples. However three of seven patients who were not receiving insulin also had reduced cerebral glucose concentrations. This reduc tion occurred at about 4 days after the insulin infusion was started. This suggests that very low concentrations of cerebral glucose, which are harmful, can occur regardless of the blood glucose concentration. However, as patients did not become hypoglycemic, it is
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not known whether hypoglycemia would have lowered the cerebral glucose concentra tions further (3c). Insulin glargine (n = 76) has been com pared with neutral protamine of Hagedorn (NPH) insulin þ lente (n = 81) in a multidose regimen in adolescents (mean age 13 years, 45% girls) with type 1 diabetes. There were more episodes of blood glucose concentrations below 4 mmol/l in those who received glargine (116 events per patientyear compared with 94), but there were no differences in severe hypoglycemic events (4c). In a review in which insulin glargine was compared with NPH insulin in type 2 diabetes, although overall symptomatic hypoglycemia was not reduced in all studies, nocturnal hypoglycemia did appear to be reduced (5R). Body weight Of 12 981 patients with type 2 diabetes who took part in the PREDIC TIVE study, an open observational study of patients taking insulin detemir, 2377 required basal insulin (6C). Those with a BMI of more than 25 kg/m2 had a slight reduction in weight proportional to their baseline BMI, and those with a BMI of more than 31 kg/m2 had the greatest reduc tion in weight (1.5 kg). Patients with a BMI of less than 25 kg/m2 had a slight weight gain (0.55 kg). There are many possible explanations for this, including the fact that the study was not randomized. How ever, others have reported similar findings. Pooled data from two randomized studies of 900 people with type 2 diabetes, lasting 22 and 24 weeks, showed that patients with a BMI of more than 35 kg/m2 who used NPH insulin gained a mean of 2.4 kg and those who used insulin detemir lost a mean of 0.5 kg (7R). Patients with a BMI of less than 35 kg/m2 gained weight, but those who took detemir gained less than those who took NPH insulin. Skin Lispro insulin has been reported to cause lipoatrophy in a patient in whom other forms of insulin did not (8A). • A 4-year-old Saudi girl with a 1-year history of type 1 diabetes used Actrapid and Insulatard
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insulin. After 5 months the Actrapid was chan ged to lispro insulin to try to improve blood glucose concentrations, and 2 months later she developed lipoatrophy, which worsened despite instructions on site rotation. On returning to Actrapid no new areas appeared.
Lipoatrophy is a well-recognized but uncommon adverse effect of insulin. The exact pathogenesis remains uncertain, but it is more common in women and is asso ciated with insulin antibodies. This patient had high concentrations of immunoglobulin G (IgG) insulin antibodies. Immunologic A review of the immune response to exogenous insulin describes types 1, 3, and 4 hypersensitivity. Type 4, although the most common type, is still rare. The exact nature of a hypersensitivity response can be difficult to determine in an individual, and mixed reactions can occur (9R). Insulin autoantibodies can be present in individuals who have not received exo genous insulin. They occur more often in those using insulin, although they are less common with modern human and analogue insulins than with animal insulins. Although studies have suggested links between anti body development and various problems relating to diabetes management, there is no conclusive evidence. In a study of 582 insulin-naive patients with type 2 diabetes, mean age 59 years, who were randomized to insulin detemir or glargine once daily, 231 who used detemir completed the study (79%) compared with 252 (87%) who used glargine (10C). Of those who used insulin detemir, 13 (4.5%) had a reaction at the injection site compared with 4 (1.4%) of those who used insulin glargine. Three had allergic reactions from detemir and one from glargine. There were skin reactions, including pruritus and rash, in six patients who used detemir and in one who used glargine. Withdrawals because of adverse events during therapy with detemir included two possible cases of cutaneous allergy and five injection site reactions. Pregnancy In a case-control comparison of 32 pregnant women (10 with type 1
Insulin, other hypoglycemic drugs, and glucagon
diabetes and 22 with gestational diabetes) who used insulin glargine and 32 women who used isophane or insulin zinc suspension, there were no differences in fetal outcomes relating to macrosomia, hypoglycemia or mode of delivery (11c). This was a small study and it is unlikely that any differences would have been detected. Insulin aspart has been compared with Actrapid insulin þ NPH insulin in the man agement of type 1 diabetes before and during pregnancy in 322 women, mean age 29 years (12C). Outcomes, including congenital abnormality rates (4.3% insulin aspart, n = 6, and 6.6% Actrapid, n = 9), were not different. In a multicenter, retrospective compari son of 72 pregnancies in women with type 1 diabetes who used lispro and 298 pregnancies in women who used regular insulin, malfor mations occurred with similar frequencies; there were 12 babies with malformations (4.5%) in those who used regular insulin compared with 3 (4.3%) in those who used lispro (13C). Drug administration route Continuous subcutaneous insulin infusion (CSII) Methods of insulin delivery have been com pared in a retrospective study in which two patients with type 1 diabetes treated with multiple-dose insulin injections (n = 60; mean age 29 years) were compared with each patient treated with CSII (n = 30; mean age 30 years) (14c). There was an increased risk of neonatal hypoglycemia babies of those using CSII (11 versus 8; 36% versus 13%). The maternal risk of hypoglycemia was similar in the two groups, but keto acidosis was more frequent in those who used CSII (4 versus 1; 13% versus 1.6%). Ketoacidosis was mild and due to mechan ical failure of the pump. Thus there were potential problems with CSII in pregnancy, without apparent benefits. In 50 patients with type 1 diabetes, mean age 13 years (26 women), who had used CSII for at least 6 months, common findings were scars of less than 3 mm (n = 47), erythema tous subcutaneous nodules (21) and lipo hypertrophy (22) (15c). There was no difference between men and women. Two patients had required oral antibiotics for
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local infections and 13 patients had used topical antibiotics. Patients who used non metal catheters inserted at 90° had fewer problems than those who had inserted them at smaller angles. BMI was negatively corre lated with the severity of the skin changes. Skin infections were more common with CSII in earlier studies, and further studies looking at longitudinal changes and the effects of cannula insertion are required. CSII has mainly been used by people with type 1 diabetes. In 382 patients with newly diagnosed type 2 diabetes, mean age 51 years, BMI 25 kg/m2, who were random ized to CSII, multiple daily injections or oral hypoglycemic drugs to achieve rapid normoglycemia, therapy was stopped after 2 weeks of achieving fasting blood glucose concentrations of less than 6.1 mmol/l and 2 hour postprandial glucose concentrations of less than 8 mmol/l (16C). There were no episodes of severe hypoglycemia, but there was a non-significant increase in the number of episodes of minor hypoglycemia in those who used CSII (42 of 137; 31%) and multi ple injections (35 of 124; 28%) compared with oral hypoglycemic drugs (23 of 121; 19%). Target blood glucose concentrations were achieved at a mean of 4 days in 133 of 137 patients who used CSII, 5.6 days in 118 of 124 who used multiple injections and 9.3 days in 101 of 121 who used oral drugs. • A 45-year-old man with a family history of type 2 diabetes, who had had type 1 diabetes for 18 years, started using CSII, taking 85 units of insulin in a day, half of which was basal to control raised blood glucose concentrations (17A). The dosage of insulin was gradually reduced to 43 units/day. There was no weight gain at 3 months (BMI 20.8 kg/m2), when blood glucose control was good. At 15 months his BMI had increased to 27 kg/m2 and his blood glucose control had deter iorated. He had hepatic steatosis. Metformin was added and improved his blood glucose concentrations.
The authors suggested that ease of manage ment led to increased calorie intake, causing excessive weight gain, allowing him to develop features of type 2 diabetes. This is not specific to CSII and can be seen in those who use other insulin regimens.
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Inhaled insulin Exubera, a formulation of insulin for inhalation, was withdrawn in 2008 for commercial reasons (SEDA-31, 691). However, other products remain in develop ment, and inhaled insulin remains of interest. AIR® insulin is inhaled as dry powder parti cles of more than 2–5 µm. In 24 chronic smo kers without diabetes, mean age 25 years, euglycemic glucose clamps were used to study the effect of smoking cessation with or without nicotine replacement and acute re-exposure to smoke (18c). Smoking cessa tion for 4 weeks without nicotine reduced the maximum insulin concentration (Cmax) by 32%, but when nicotine was used the Cmax was reduced by 56%. The cause of this was unclear and requires further investigation. In two studies of Exubera before its with drawal there was a higher incidence of cough. In 189 non-smoking patients with type 1 dia betes, aged 25–65 years, who were rando mized to Exubera or pre-meal subcutaneous insulin for 24 weeks, cough was reported in 31% of those who used Exubera and in 8% of those who used subcutaneous insulin (19c). The cough was usually mild and non-produc tive and occurred shortly after dosing. Two withdrawals were due to cough, which resolved on stopping Exubera. In a compar ison of Exubera with oral therapy alone for 104 weeks in patients with type 2 diabetes the crude rates of coughs per patient-month were small, although greater in those taking Exu bera: 0.014 compared with 0.004 in those taking metformin alone and 0.002 in those taking a sulfonylurea (20c). In a review of inhaled insulin in patients with asthma and chronic obstructive pul monary disease (COPD) in a preliminary study of Exubera, 52-week data were avail able on 27 subjects with asthma, 10 using inhaled insulin and 17 others (21c). Cough and respiratory adverse events were more common in those who used inhaled insulin. There were three withdrawals in those who used inhaled insulin, due to respiratory pro blems, two of which were due to exacerba tions of asthma. Users of Exubera inhaled insulin without lung disease have a small but significant fall in forced expiratory volume in 1 second (FEV1), which occurs early and appears to stabilize (22R).
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Preliminary data in patients with asthma and COPD who used Exubera suggest that there may be a greater reduction in pulmon ary function than in those without lung disease. The Technosphere delivery system, an ordered lattice array of Technosphere and recombinant human insulin, produced no change in pulmonary function after use for 6 months in 306 patients with diabetes without lung disease (21R). Drug overdose Insulin overdose has been reported in 25 patients (14 women), mean age 46 years (23c). A delay of more than 6 hours and a requirement for more than 48 hours of mechanical ventilation were predictors of a poor outcome. There were two deaths. Insu lin toxicokinetics and toxicodynamics were studied, with attempts to quantify the need for glucose repletion. However, careful monitoring and appropriate individual adjust ments are needed in management, owing to the variability in response.
ALPHA-GLUCOSIDASE INHIBITORS (SED-15, 85; SEDA 29, 526; SEDA-30,496; SEDA-31, 691)
Acarbose Gastrointestinal In a non-randomized, prospective, post-marketing surveillance study in 2550 people of Asian or Oriental origin (88% type 2 diabetes, 12% with impaired glucose tolerance), the mean length of observation was 14 weeks (24c). Most of the participants (about 84%) were given acarbose 150 mg/day and 91% of them found that they tolerated it well or very well; however, 14 patients (12 with type 2 diabetes) had abdominal distention, which resolved by the end of the study. This rate of adverse events is low compared with other studies. Possible explanations include the low dose of acarbose or an effect of post-marketing surveillance, in which patients must report events spontaneously.
Insulin, other hypoglycemic drugs, and glucagon
AMYLIN ANALOGUES (SEDA-29, 526; SEDA-30,496; SEDA-31, 692)
Pramlintide Metabolism Body weight Studies suggest that pramlintide is associated with a small amount of weight loss. In 137 subjects who used subcutaneous pramlintide 60 micro grams tds initially, the dose was increased by 30 micrograms every 4 days up to a max imum tolerated dose of 240 micrograms before meals over 4 weeks (25c). They then continued for a further 12 weeks at one of the following maintenance doses: 120, 180 or 240 micrograms, depending on the previous maximum tolerated dose; 88% used 240 micrograms tds and 8% used 180 micrograms tds. At 16 weeks ther apy was stopped. They were compared with 67 subjects who used placebo with a similar non-forced increase in the dose of subcuta neous injection therapy. The adverse effects of pramlintide included nausea (52 versus 15) and mild hypoglycemia (11 ver sus 1). Those who used pramlintide lost weight, which appeared to be independent of nausea. Placebo-corrected weight loss was 3.6 kg. In an open study 166 insulin-treated patients with type 2 diabetes (51% men) had pramlintide 120 µg added before meals (26c). The dose of insulin was adjusted depending on blood glucose concentration. Mean weight at the start of the study was 112 kg. Body weight fell by 2.3 kg at 3 months and by 2.8 kg 6 months. Only 127 patients completed treatment for 6 months. Withdrawals were mainly due to adverse events, withdrawal of consent and investi gator decisions; information was not given about the reasons for the last two. Gastrointestinal Eight subjects with type 1 diabetes, mean age 17 years (6 men), received either a pre-meal bolus of pramlin tide or an infusion of pramlintide 4–6 weeks apart (27c). The dose of pramlintide was calculated based on the insulin bolus taken with the meal, 5 micrograms of pramlintide
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per unit of insulin. There were reduced glu cagon concentrations and impaired gastric emptying when a bolus of pramlintide was used compared with an infusion. There are still uncertainties about the most effective way of using pramlintide.
BIGUANIDES (SED-15, 506; SEDA-29, 526; SEDA-30,497; SEDA-31, 692) Metformin Metabolism In 48 HIV-positive people (27 men), mean age 42 years, with increased abdominal girth, who were randomized to placebo or metformin, gradually increased to a dose of 0.5 mg tds over 4 weeks, visceral adipose tissue, assessed using CT scanning, was not different at 24 weeks, but there was a trend towards a reduction in the appendicular fat mass, suggesting that metformin may worsen peripheral lipoa trophy in this patient group (28c). Nutrition The association of metformin with vitamin B12 deficiency has been well documented, and patients who also take histamine H2 receptor antagonists or proton pump inhibitors in combination with met formin are at particular risk (29r). Acid base balance Lactic acidosis is often reported anecdotally in patients taking met formin, especially in patients with renal impairment, and more reports have appeared (30A, 31Ar, 32A, 33A). • A 77-year-old Caucasian woman with type 2 diabetes took metformin 3 g/day, perindopril 8 mg/day, and simvastatin 20 mg/day after making a full recovery from a stroke. One month later she was admitted with abdominal pain and vomiting. The serum creatinine was 530 µmol/l, pH 6.87, and blood lactate 16 mmol/l. • A 69-year-old man with type 2 diabetes took metformin 4 g/day and developed a bradycardia due to complete atrioventricular block, with a pulse of 30/minute, and an undetectable blood pressure. His serum creatinine was 195 µmol/l, pH 6.7, and lactate 18 mmol/l.
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Both patients received continuous veno venous haemodiafiltration and recovered fully. The authors suggested that renal impair ment in these cases may have been due to metformin, although there were other possi ble reasons – in the first case the use of peri ndopril and in the second severe hypotension. In both cases the doses of metformin were high – 4 g/day is above the licensed dosage. • A 78-year-old woman taking metformin 1500 mg bd, glibenclamide, rofecoxib, furosemide, levothyroxine, prednisone, azathioprine, and propranolol developed abdominal pain, nausea, vomiting, and anorexia. She was hypothermic (34.4°C), her blood pressure was 115/51 mmHg and pulse 104/minute, and the arterial pH was 7.0, serum creatinine 784 µmol/l, estimated glomerular filtration rate (eGFR) 57 ml/minute/ 1.73 m2, serum lactate 1.1 mmol/l, and serum metformin 17 mg/l (usual target range 1–2 mg/l). • A 64-year-old woman taking metformin 500 mg bd, lisinopril and ibuprofen developed nausea and vomiting. She was hypothermic (34.5°C), hypotensive (blood pressure, 85/38 mmHg) and tachypneic (28/minute). The arterial pH was 6.78, serum creatinine 520 µmol/l, eGFR 59 ml/minute/1.73 m2, serum lactate 2.4 mmol/l, and serum metformin 31 mg/l. • A 58-year-old woman with type 2 diabetes, taking metformin 500 mg bd, developed lactic acidosis and died. • A 61-year-old man with type 2 diabetes took metformin 1 g bd and fosinopril 40 mg/day and developed diarrhea and vomiting. His serum creatinine was 973 µmol/l, pH 7.15, and blood lactate 26 mmol/l. He received urgent treatment including dialysis and recovered.
It is important to provide information and education to people taking metformin about discontinuing therapy and seeking medical help when they are unwell. Gastrointestinal In a review of the use of metformin for weight management in patients without type 2 diabetes, there were similar adverse effects to those reported in patients with type 2 diabetes. Nausea, vomiting, and other gastrointestinal adverse effects were the most frequent (34R). Pregnancy Metformin crosses the pla centa, but it is not thought to increase the risk of congenital abnormalities (35R). In a randomized comparison of metformin and insulin in pregnancy in 733 women with
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gestational diabetes at 20–33 weeks, 195 women used metformin alone, 168 met formin þ insulin, and 370 insulin (36C). The initial dosage of metformin was 500 mg once or twice daily and it was titrated to a maximum of 2.5 g/day. Insulin was added if blood glucose targets were not met. Infor mation was not given about the insulin regi mens used. Severe hypoglycemia (blood glucose below 1.6 mmol/l) was less common in those who used metformin. Preterm birth (before 37 weeks) was more common in those who used metformin (44 versus 28; 12% versus 7.6%). Further follow-up is being undertaken to establish the longterm safety of metformin. Susceptibility factors Age In 30 obese Chinese children aged 10–16 years with metabolic syndrome who took metformin 500 mg bd and underwent lifestyle modifica tions, 20 completed 3 months of treatment (37c). Adverse effects were similar to those seen in adults taking metformin: seven had a reduced appetite, two had nausea, and two had increased bowel movements during the first week of treatment. Drug overdose An overdose of metformin reportedly caused rhabdomyolysis (38A). • A 46-year-old man with type 2 diabetes took metformin 56 g, ramipril 35 mg and alcohol 500 ml. He developed vomiting and abdominal pain. His serum creatinine was 368 µmol/l, pH 7.24, and blood lactate 11.6 mmol/l. The pH fell and the lactate increased further after admission. On day 2 he developed rhabdomyolysis with a creatine kinase activity of 12478 U/l. He required an above-knee amputation, but was discharged with normal renal function.
DIPEPTIDYL PEPTIDASE 4 INHIBITORS (SEDA-30, 498; SEDA-31, 693) The activity of dipeptidyl peptidase type 4 (DPP-4) correlates inversely with inflamma tion in bony tissues in patients with chronic sinusitis. The enzyme also attenuates the
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pro-inflammatory actions of substance P during sensory nerve activation (39r). DPP-4 is expressed on many cell types, including lymphocytes (40R). It also inacti vates the chemokine CXCL12, which is thought to be important in the homing of hemopoietic stem cells to bone marrow (41r). Thus, the use of DPP-4 inhibitors needs long-term follow-up to ensure safety.
Sitagliptin Gastrointestinal Although sitagliptin is mainly well tolerated, nausea and vomiting have been reported (42R). Immunologic Hypersensitivity reactions have been reported, including anaphylaxis, angioedema, and urticaria. There is insuffi cient information to assess the frequency (43c). Pregnancy Sitagliptin appears in the milk of lactating rats, but the extent of excretion in human milk is unknown (42R). It is not recommended, as there are alternative drugs known to be safe in breast-feeding mothers. Susceptibility factors Renal disease Sita gliptin is excreted mainly unchanged in the urine. Dosage adjustment is required in patients with moderate renal impairment (creatinine clearance 30–50 ml/minute) or severe renal impairment (<30 ml/minute). Although older people have an age-related reduction in renal function, no dosage adjustment is required for age alone (44R). Drug–drug interactions Ciclosporin Co administration of sitagliptin 100 mg with a single dose of ciclosporin 600 mg caused a slight shortening of the half-life of sitagliptin (11.6 hours without ciclosporin compared with 10.6 hours) (42R). Glibenclamide Glibenclamide is metabo lized by the liver mainly by CYP2C9, but also by CYP2C19 and CYP3A4. Sitagliptin is excreted via the kidney mainly unchanged. CYP3A4 and CYP2C8 are involved to a lim ited extent in its metabolism. The effect of
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glibenclamide (glyburide) on the pharmaco kinetics of sitagliptin has been investigated in an open study in eight people, aged 22–44 years, who took glibenclamide 1.25 mg alone and then again after having taken sitagliptin 200 mg/day for 5 days (twice the usual pre scribed dose); a further dose of sitagliptin was taken on day 6 (45c). The AUC of glibencla mide was 193 hours. ng/ml when taken with sitagliptin and 177 without; Cmax was 32 in both conditions. Thus, sitagliptin had little effect on the disposition of glibenclamide.
INCRETIN MIMETICS (SEDA 29, 528; SEDA-30, 49; SEDA-31, 695) Gastrointestinal A review has shown that about 5% of people withdraw from studies when exenatide is used for 30 weeks to 2 years because of problems with nausea, which can be reduced by a gradual increase in dosage (46R). The withdrawal rate for liraglutide was about 3%. Immunologic Antibodies to exenatide are found in about 40–60% of patients (46R). The significance is unknown. Anti-liraglu tide antibodies have not been reported.
Exenatide Gastrointestinal effects
Gastrointestinal
adverse
EIDOS classification: Extrinsic species: Exenatide Intrinsic species: Not known Distribution: ?Stomach ?Brain Outcome: Altered function Sequela: Nausea and vomiting due to exenatide DoTS classification: Dose-relation: Collateral Time-course: Intermediate Susceptibility factors: None known
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Exenatide in combination with insulin has been evaluated in 124 patients with type 2 diabetes mellitus over 1-year follow-up; 48 patients (36%) stopped taking exenatide, primarily because of gastrointestinal intol erance and 14 (10%) had hypoglycemia, mostly mild (47C). The mechanism of the gastrointestinal adverse effects of exenatide is not fully established, but possible mechanisms include delay in gastric emptying, activation of afferent nerves and/or central effects of glucagon-like peptide-1 (GLP-1) receptor activation (SEDA-30, 499). It is doserelated in the therapeutic range of doses and is more likely to occur in the first 8 weeks. Gradually increasing the dose of exenatide may be helpful. Pancreas The FDA has reviewed 30 postmarketing reports of acute pancreatitis and 6 reports of hemorrhagic or necrotizing pan creatitis (48S). All patients starting exena tide should be warned of the risk, and that they should report severe abdominal pain promptly. In such cases exenatide should be withdrawn and should not be restarted unless there is a clear alternative cause for the pancreatitis. Urinary tract The FDA has received 78 reports of altered renal function, including 62 cases of acute renal insufficiency (48S). During the same period 6.6 million prescrip tions for exenatide were dispensed. Exena tide should not be used in people with severe renal impairment or end-stage renal disease. All those who use exenatide should have their renal function monitored. Those with a creatinine clearance of 30–50 ml/min ute should be monitored particularly closely. Susceptibility factors Renal disease The pharmacokinetics of a single subcutaneous dose of exenatide 5 or 10 micrograms have been studied in 31 patients with renal impairment (49CM). The mean half-lives in subjects with normal renal function, mild and moderate impairment and end-stage renal disease were 1.5, 2.1, 3.2, and 6.0 hours respectively. After combining data
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from multiple studies, mean apparent clear ances were 8.1, 5.2, 7.1, and 1.3 l/h respec tively. In those with end-stage renal disease, exenatide caused nausea and vomiting.
MEGLITINIDES
(SED-15, 2238;
SEDA-31, 695)
Nateglinide Metabolism Persistent hypoglycemia has been attributed to nateglinide (50A) • A 73-year-old woman with type 2 diabetes and chronic renal insufficiency treated with hemodialysis was taking an unknown dose of nateglinide. An episode of hypoglycemia was treated with 50 ml of 50% dextrose. She continued to take nateglinide. The following day a further episode was treated with 50% dextrose and 1 hour later a further episode was treated with 50% dextrose and octreotide 100 micrograms subcutaneously.
Nateglinide binds to ATP-dependent potas sium channels. The binding is similar to that with sulfonylureas but is more rapidly reversed. Octreotide can be useful in the management of hypoglycemia due to sulfo nylureas (SEDA-30, 500) and appears to have been useful in this case. Gastrointestinal In a post-marketing study of nateglinide using data from prescriptions by general practitioners, 11 847 forms were sent, of which there were 4557 valid returns; 54% were men, with a median age of about 60 years (51c). Most prescriptions were for nateglinide in combination with metformin. The most common adverse effects in the first month of therapy were those pre viously known: nausea (n = 43), malaise (n = 33), diarrhea (n = 27), and hypoglyce mia (n = 21). Drug–drug interactions When using nate glinide with drugs that can potentially inter act with it, it is sensible to start at a low dose, with dose titration depending on blood glucose concentrations.
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Antifungal azoles Fluconazole inhibits CYP2C9 and CYP3A4 and increases the AUC of nateglinide by 48%, again without altering Cmax. Fluconazole could prolong the blood glucose-lowering effect of nateglinide. When itraconazole 100 mg bd and gemfi brozil 600 mg bd were prescribed for 3 days, the effect on the pharmacokinetics of a single dose of nateglinide 30 mg was mod est: AUC was 47% higher and half-life was unchanged (52R).
itraconazole com-bined with gemfibrozil, clarithromycin, telithromycin, trimethoprim, and ciclosporin (52R). The clinical effect is variable; gemfibrozil in particular prolongs the blood glucose-lowering effect of repa glinide. When these drugs are used with repaglinide, the possibility of increasing the risk of hypoglycemia should be consid ered. Rifampicin has the opposite effect.
Immunosuppressants When nateglinide 120 mg qds for 2 weeks was used in 14 renal transplant recipients with type 2 dia betes or impaired glucose tolerance, there was no effect on ciclosporin or tacrolimus concentrations (53c).
(SED-15, 3230; SEDA-29, 530; SEDA-30,500; SEDA-31, 695)
Rifampicin Nateglinide is metabolized by CYP3A4 (about 30%) and CYP2C9 (about 70%). Rifampicin induces both CYP2C9 and CYP3A4 and reduces the AUC of nate glinide, but the Cmax is unchanged. The effect of rifampicin is modest in most patients taking nateglinide, but in some there appears to be a reduction in its blood glucose-lowering effect. Food–drug interactions Nateglinide is absorbed within an hour of ingestion via a nateglinide/Hþ co-transport system, identi cal to the intestinal fluorescein/Hþ system. When taken preprandially, nateglinide results in more effective blood glucose con trol, owing to an earlier insulin response, compared with taking it 10 minutes after the start of eating (irrespective of the com position of the meal) or taking it in the fasting state (52R). Appropriate advice should be given.
Repaglinide Drug–drug interactions Drugs that increase the AUC of repaglinide include ketoconazole, itraconazole, gemfibrozil,
SULFONYLUREAS
Death The effect of sulfonylureas on mortality continues to be debated. In a ret rospective 5-year study of 282 women and 286 men with type 2 diabetes, 33 of 378 patients who were taking glibenclamide died and 11 of 190 taking gliclazide (54c). The adjusted odd ratio for all-cause mortal ity was 2.1 for glibenclamide compared with gliclazide. In a similar observational cohort study of 2002 people with type 2 diabetes, of whom 696 were taking combinations of insulin secretagogues and metformin at enrolment, 3-year mortality was assessed (55c). The yearly mortality was 8.7% in those taking glibenclamide þ metformin compared with 2.1% in those taking gliclazide þ metfor min. The authors speculated that this may have been related to the difference in bind ing to sulfonylurea receptors. A meta-analysis of nine observational studies showed an increased relative risk of a composite end point of cardiovascular hospitalization or mortality when patients took a sulfonylurea þ metformin compared with monotherapy of various sorts (56M). However, patients taking combination therapy were likely to have more years of disease exposure or more progressive disease. The continued use of sulfonylureas is appropriate but glibenclamide should be avoided (57r).
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Glibenclamide Pregnancy In nine comparisons of gliben clamide and insulin in the management of gestational diabetes in 745 women taking glibenclamide 5–10 mg/day and 637 using insulin, there did not appear to be an increased risk of macrosomia, high birth weight or neonatal hypoglycemia when glibenclamide was used (58M). However, as most of the studies were small and not randomized and four were retrospective, further data are needed to confirm safety. Drug–drug interactions Clarithromycin Glibenclamide is 99% bound to plasma pro teins and mainly metabolized by CYP2C9; clarithromycin does not significantly inhibit CYP2C9. In 12 volunteers, aged 20–27 years, weights 51–98 kg, who took clarithro mycin 250 mg bd for 2 days and a further dose on the morning of day 3 followed by glibenclamide 0.875 mg, mean glibencla mide concentrations were higher after clar ithromycin than after placebo (59c). AUC was 1.35 times and Cmax 1.25 times higher, but tmax and half-life were not changed. The possible mechanisms are inhibition of P-glycoprotein in the intestinal wall and inhibition of CYP3A4. People taking both drugs should be warned to monitor for an increased risk of hypoglycemia. Food–drug interactions Grapefruit Gra pefruit juice 200 ml tds for 3 days did not alter the pharmacokinetics of a single dose of glibenclamide 0.875 mg (59c). Management of adverse drug reactions Octreotide has been recommended for the management of hypoglycemia induced by sulfonylureas. In a randomized controlled trial of 50 ml of 50% dextrose intravenously, oral carbohydrate with 50 ml of 50% dex trose and oral carbohydrate plus subcuta neous octreotide 75 micrograms in 40 subjects, the mean baseline glucose was similar (about 2 mmol/l) (60c). Glucose con centrations were higher in those who received octreotide for the first 8 hours, but there was then no difference between
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the groups. Ten patients had a solitary epi sode of hypoglycemia after octreotide and six had 13 episodes of hypoglycemia after placebo. It is likely that this was not the optimal dose of octreotide for the manage ment of hypoglycemia, which is frequently prolonged when due to a sulfonylurea. The half-life of octreotide in healthy people is about 1.8 hours, and continuous infusion is to be preferred (SEDA-31, 696).
Gliclazide Susceptibility factors Genetic Previous studies have suggested that the pharmaco kinetics of modified-release gliclazide (gli clazide MR) are highly variable in Chinese subjects but not in white populations. The effects of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics of gliclazide have been investigated in 24 Chi nese men aged 20–30 years without dia betes. They took gliclazide MR 30 mg either once or for 6 days (61c). There were no differences in single-dose or steady-state pharmacokinetics in subjects with various CYP2C9 genotypes. In contrast CYP2C19 poor metabolizer subjects had a prolonged half-life (2–3 times) and AUC (about three fold) compared with CYP2C19*1 homo zygotes. Asian populations have a greater incidence of CYP2C19 poor metabolizer phenotypes, and these findings may explain the variable pharmacokinetics in Chinese subjects.
Glimepiride Skin Leukocyctoclastic vasculitis has been attributed to glimepiride (62A). • A 72-year-old woman developed a rash on her legs, arms and trunk after taking glimepiride 1 mg/day for 6 weeks. A skin biopsy showed a leukocytoclastic vasculitis. All the lesions resolved within 1 week of withdrawal of glimepiride and no further episodes occurred.
Insulin, other hypoglycemic drugs, and glucagon
This was probably a type III hypersensitiv ity reaction, of a type that has previously been reported with other sulfonylureas.
THIAZOLIDINEDIONES (GLITAZONES) (SED-15, 3380; SEDA-29, 531; SEDA-30, 501; SEDA-31, 697) Comparative studies In head-to-head comparisons of pioglitazone and rosiglita zone, reporting of adverse events has been limited. In 719 people with type 2 diabetes, who took either drug for 24 weeks, weight change, liver function tests, hematocrit, and edema were similar (63M). Withdrawals because of adverse events were 2.7% for each drug. Pioglitazone may have an advan tageous lipid profile, based on indirect comparison. Cardiovascular Reviews continue to high light the problem of edema and an increased risk of heart failure with thiazolidi nediones, which they all seem to share (64r). The PROactive trial, the only cardiovascular outcomes study using a thiazolidinedione (SEDA-31, 697), showed that pioglitazone has a relatively good cardiovascular profile (65R). However, concerns remain about rosi glitazone. In a retrospective study of the incidence of hospitalization for myocardial infarction in patients who had started treat ment with pioglitazone or rosiglitazone in 14807 patients who took pioglitazone and 15104 who took rosiglitazone, during a mean follow-up period of about 1.2 years, 161 of those who took pioglitazone (1.1%) were hospitalized for myocardial infarction compared with 214 (1.4%) of those who took rosiglitazone. These data support reviews suggesting that pioglitazone may have better cardiovascular safety (66C). Liver Of 103 patients with type 2 diabetes 96 completed a 12-month randomized study, of whom 48 took rosiglitazone 4 mg/ day and 48 took pioglitazone 15 mg/day; all
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also took metformin initially 1.5 g/day, increasing to a maximum of 3.0 g/day (67c). Two patients taking pioglitazone had increased transaminase activities to 1.5 times the upper limit of the reference range, which normalized after 15 days. Three patients taking rosiglitazone had transaminase activities twice the upper limit, again normalizing after 15 days. Significant problems with liver function are rare but have been reported.
Reduced bone density and risk of fracture due to thiazolidinediones EIDOS classification: Extrinsic species: Thiazolidinediones Intrinsic species: Osteoclasts Distribution: Bone Outcome: Atrophy Sequela: Reduced bone density and increased risk of fractures due to thiazolidinediones DoTS classification: Dose-relation: Collateral Time-course: Late Susceptibility factors: Age (elderly patients); sex (female sex, postmenopausal) Thiazolidinediones increase the risk of frac ture in women, particularly in the arms, hands and lower legs. The FDA has issued warnings about both pioglitazone and rosi glitazone (68r). Data from ADOPT (A Diabetes Outcome Prevention Trial), in which 4360 patients with type 2 diabetes were randomized to rosiglitazone, metformin, or glibenclamide, have shown an increased number of frac tures in women taking rosiglitazone (69C). Upper limb fractures were increased in the humerus and hand, and lower limb fractures in the foot. There were 2.74 fractures per 100 patient-years compared with 1.54 in those taking metformin and 1.29 in those taking glibenclamide. There was no difference in hip fractures between the groups. Men taking
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rosiglitazone did not have an increased frac ture rate. The UK-based General Practice Research Database (GPRD) was used to identify peo ple aged 30–79 years with type 2 diabetes (n = 66 696), of whom 16 648 had not used insulin or oral hypoglycemic drugs and 50048 had received at least one prescription for an oral agent (70c). There were lowtrauma fractures in 1020 patients, who were matched with 3728 people without a fracture. Of those with a fracture, 208 were not taking oral therapy and 65 had used thiazolidine diones in combination with other therapies. The odds ratio for a fracture among users of thiazolidinediones for about 1 year com pared with non-users was 2.4. This was not found for other oral agents. The risk of frac ture was independent of age and sex and increased with the dose of thiazolidinedione. Bone turnover has been analysed in a 14 week, double-blind, randomized study in 50 postmenopausal women taking rosiglitazone 8 mg/day or placebo (71c). Osteocalcin and serum procollagen type-1 N-terminal propeptide (PINP) concentrations, markers of osteoblast activity, fell in the rosiglitazone group within 4 weeks. In a similar study, 30 premenopausal women with polycystic ovary syndrome were randomized to pio glitazone 30 mg/day or placebo for 16 weeks. There were no significant changes in osteocalcin (72c). In both studies, there were small reductions in bone mineral density. The increased risk of fractures has been confirmed in the RECORD study, in which the cardiovascular safety of rosiglitazone was investigated in 2220 patients with type 2 dia betes, aged 40–75 years, who took rosiglita zone in combination with metformin or a sulfonylurea and were compared with 2227 patients who took metformin and a sulfonyl urea (73C). They were followed for 5–7 years. Those who took rosiglitazone had a relative risk of fracture of 1.57. The relative risk was higher in women than in men (1.82 compared with 1.23). As with previous reports the frac tures were mainly in the arms and distal legs. Pregnancy Thiazolidinediones cross the placenta. In rats delayed body growth and
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insulin resistance have been found, but data for humans are not available (35R).
Pioglitazone Hematologic In 50 patients with type 2 diabetes, mean age 53 years (17 women), of whom 17 took placebo (mean age 54 years) and 33 pioglitazone 45 mg/day (mean age 52 years), total body water, extracellular water, and fat-free mass 3 were assessed using H2O and c bioimpedance (74 ). At 4 months body weight had not changed in the placebo group but had increased by 3.8 kg in those taking pioglitazone. Most of the weight change was fat (3.6 kg). Hemoglobin fell by 0.9 g/dl and hematocrit by 2.4% in those taking pioglitazone and did not significantly change in those taking placebo (0.3 g/dl and 0.5%). Total body water and extracellular water did not change significantly in either group. Thus, the small fall in hemoglobin and hematocrit was not explained by changes in body water and weight gain was due to an increase in fat mass rather than fluid. Drug–drug interactions CYP inhibitors Pioglitazone is metabolized mainly by CYP2C8, CYP3A4 and CYP2C9. The con tribution of each isoenzyme is unknown and the data are conflicting. Rifampicin reduces pioglitazone concentrations and gemfibrozil increases them. However, montelukast, a selective inhibitor of CYP2C8 in vitro, had no effect on pioglitazone pharmacokinetics (75R). Trimethoprim Trimethoprim 160 mg bd for 6 days, an inhibitor of CYP2C8, increased plasma concentrations of a single dose of pioglitazone 15 mg in a randomized crossover study in 16 healthy people aged 19–25 years (eight men), who had been genotyped for CYP2C8 alleles (76c). The mean AUC of unchanged pioglitazone was 42% higher when trimethoprim was taken. Genes were found to influence pio glitazone metabolism. Those with the CYP2C8*3 variant allele had lower con centrations of pioglitazone and higher metabolite formation.
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Rosiglitazone Placebo-controlled studies In a 12-week, double-blind, randomized trial of rosiglit azone 4 mg bd (n = 52) compared with placebo (n = 53) in patients with mild or moderate ulcerative colitis, rosiglitazone improved gut symptoms but caused more edema (nine versus one) and myalgia (four versus zero) (77c). Cardiovascular In 78 patients with type 2 diabetes and end-stage renal failure receiv ing hemodialysis, mean age 57 years (36 men, 42 women), who took rosiglitazone 2–8 mg/day for a mean of 15 months, there was an increase in cardiothoracic ratio on the chest X-ray and an increase in ultra filtration measured as kg/session. Weight also increased. Rosiglitazone appears to have an effect on cardiovascular reserve, which needs careful follow-up (78c). Reports and reviews of the cardiovascular safety of rosiglitazone continue to appear (64r, 79r, 80r). The RECORD study was a multicenter, open study in patients with type 2 diabetes aged 40–75 years with a BMI of more than 25 kg/m2, of whom 2220 took rosi glitazone in combination with metformin or a sulfonylurea and 2227 took metformin and a sulfonylurea for a mean of 5.5 years (73C). Heart failure causing death or admission to hospital was more common with rosiglita zone group (HR = 2.1; 61 versus 29). The HR for myocardial infarction was 1.14. There was no increase in the primary out comes of cardiovascular death or hospitaliza tion (HR = 0.99). A study using the Taiwan National Health Insurance database showed that patients tak ing rosiglitazone monotherapy had increased risks of any cardiovascular event (HR = 1.89), myocardial infarction (2.09), angina pectoris (1.79), and transient ischemic attacks (2.57) compared with those taking metformin monotherapy (81C). Rosiglitazone as an addon therapy had a comparable cardiovascu lar risk. These data suggest that the effect of rosiglitazone on fluid retention and heart failure is clinically significant. The effect of rosiglitazone on myocardial infarction found in meta-analysis may be real.
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Fluid balance Eight patients with type 2 diabetes who took placebo for 2 months and then rosiglitazone 8 mg/day þ feno fibrate 160 mg/day for 2 months have been compared with five who took placebo and then rosiglitazone alone (82c). Some were also taking other hypoglycemic agents. Body water did not increase in those taking rosiglitazone þ fenofibrate compared with placebo but did in those taking rosiglitazone alone. The significance of this is uncertain; it may be related to the peroxisome prolifera tor-activated receptor alpha (PPAR) activity of fenofibrate in the kidney. Drug–drug interactions Fibrates In a study of the combination of rosiglitazone þ a fibrate, 3213 patients took rosiglitazone 4 mg/day alone and 649 took rosiglitazone þ a fibrate (83C). There was a transient reduc tion in high-density lipoprotein (HDL) cholesterol in two patients taking a fibrate alone but not in those taking rosiglitazone alone. In nine patients taking rosiglitazone þ a fibrate there was a marked reduction in HDL cholesterol. One patient took cipro fibrate 100 mg/day and eight took bezafibrate 400 mg/day. When rosiglitazone was with drawn in four patients and the fibrate was withdrawn in five patients, the HDL choles terol returned to pretreatment concentra tions. When these drugs are combined, lipid concentrations should be monitored. Liver Abnormalities of liver function did not progress during treatment with rosigli tazone up to 8 mg/day in 78 patients treated with hemodialysis, 12 of whom had chronic hepatitis B infection and 13 had chronic hepatitis C infection (78c). • A 52-year-old man with type 2 diabetes, who had used Mixtard 30/70 for 5 years, took addi tional rosiglitazone 4 mg/day (84A). Liver func tion was within the reference range, but 7 months later he developed a low-grade fever and fatigue followed by severe abdominal pain. His bilirubin was 79 µmol/l, alanine amino trans fesase (AlT) 488 U/l (reference range 10–45), alkaline phosphatase 832 U/l (40–115), g-gluta myltransferase 690 U/l (11–49), and serum lipase 2611 U/l. Pancreatitis was diagnosed and treated conservatively. The AlT activity improved but the bilirubin concentration increased to
782 251 µmol/l. Rosiglitazone was withdrawn. Further investigation showed evidence of Hodg kin’s lymphoma. Liver function deteriorated further and he died 3 months later.
This case was complex, but rosiglitazone was a possible factor in the occurrence of liver failure. Rosiglitazone can cause hepatotoxi city, but in previous cases withdrawal has usually resulted in improvement and normal ization of liver function. Musculoskeletal An association of rosigli tazone with myalgia and raised creatine kinase activity has been uncommonly reported; another case has appeared (85A). • A 42-year-old man with type 2 diabetes took rosiglitazone 8 mg/day for 5 months and developed myalgia. Creatine kinase activity was 555 U/l (0–160) and rosiglitazone was withdrawn. The muscle symptoms resolved and the creatine kinase activity fell but remained above the reference range; 3 years later it was 277 U/l. He was given rosiglitazone 4 mg/day and was also taking aspirin 325 mg/ day, ramipril 10 mg/day, ezetimibe 10 mg/day, rabeprazole 20 mg/day, metformin 2.5 g/day, and glibenclamide 20 mg/day. After 14 days he had muscle pain during exercise and the creatine kinase activity was 2195 U/l. Rosiglitazone was withdrawn and the creatine kinase activity fell, although it remained slightly raised at 429 U/l.
Drug–drug interactions Montelukast CYP2C8 is primarily responsible for the hydroxylation and N-demethylation of rosi glitazone. There is a minor contribution from CYP2C9. CYP2C8 inducers such as rifampicin reduce the concentration of rosi glitazone, and CYP2C8 inhibitors, such as trimethoprim and gemfibrozil, increase rosi glitazone concentrations (75R). However, montelukast 10 mg/day for 6 days, a CYP2C8 inhibitor, had no effect on the phar macokinetics of a single dose of rosiglitazone 4 mg in 10 healthy men aged 23–36 years in a crossover, placebo-controlled study, in which rosiglitazone and N-desmethyl rosiglitazone concentrations were measured (86c). Mycophenolate mofetil Mycophenolate mofetil has a negative effect on erythro poiesis and rosiglitazone has also been asso ciated with a small fall in hemoglobin.
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• A 47-year-old man who had had a renal trans plant took mycophenolate mofetil 500 mg bd, ciclosporin 275 mg/day, nifedipine 60 mg/day, fur osemide 25 mg/day, calcitriol 0.0025 mg/day, allo purinol 150 mg/day, sodium bicarbonate 1 g/day, and darbepoetin 20 micrograms/week. Rosiglita zone 4 mg/day was added and after 3 months the erythrocyte count had fallen to 3.3 1012 cells/l despite darbepoetin. Mycophenolic acid AUC was twice that at baseline. Rosiglitazone was withdrawn and 2 months later the mycophenolic acid AUC had fallen and the erythrocyte count had increased to about 4 1012 cells/l.
It is likely in this case that an interaction with rosiglitazone resulted in high concen trations of mycophenolate mofetil (87A).
Peroxisome proliferator-activated dual receptor agonists PPARs are ligand-activated transcription fac tors of a nuclear hormone receptor super family with subtypes , , and (88R). Activation of PPAR reduces triglycerides, activation of PPAR causes insulin sensitiza tion and increases glucose metabolism, and activation of PPAR enhances fatty acid meta bolism. There have been several studies of the effects of PPAR and PPAR ligands in preventing the adverse cardiovascular effects of diabetes. Many drugs have been developed with dual or triple agonist properties. PPARa/g dual agonists These drugs have been used to increase insulin sensitivity and simultaneously prevent diabetic cardiovascu lar complications. However, many of them have been withdrawn because of adverse effects, including the following: • Imiglitazar, withdrawn in 2004 because of hepatotoxicity (89R). • JTT-501 (90E), withdrawn in 2002 because of edema. • MK 767 (KRP-297, L-410198), withdrawn in 2004 because of an association with hemangiosarcoma in animals (91E). • Muraglitazar, withdrawn in 2006 because of adverse cardiovascular events, including edema and heart failure (92C–94C), myocardial infarction, stroke, heart failure, and transient ischemic attacks (95C); it also caused urothelial cytotoxicity in animals (96E–98E). • Ragaglitazar, withdrawn in 2004 because of edema and anemia (99c), weight gain and leukopenia (100c), and urothelial cancer.
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• Tesaglitazar, withdrawn in 2006 because of raised serum creatinine (101C), reduced GFR, weight gain (102C), anemia, and leukopenia.
in development, including dual PPAR/, PPAR/, and PPAR/ agonists.
Other dual PPAR/ agonists that have been withdrawn include compound 3q (103E), farglitazar (104C), and naveglitazar (105C, 106C). Several other compounds are
PPARa/g/d triple agonists The triple ago nist bezafibrate has been available for many years (see Chapter 44). Several other com pounds are in development.
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86. Kim KA, Park PW, Kim KR, Park JY. Effect of multiple doses of montelukast on the pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in humans. Br J Clin Pharmacol 2007;63(3):339–45. 87. Cattaneo D, Bitto A, Baldelli S, Cortinovis M. Pharmacokinetic/pharmacodynamic drug interaction between rosiglitazone and myco phenolate mofetil in kidney transplantation: a case report. Transplantation 2008;85: 921–2. 88. Balakumar P, Rose M, Ganti SS, Krishan P, Singh M. PPAR dual agonists. are they opening Pandora’s box? Pharmacol Res 2007;56(2):91–8. 89. Rubenstrunk A, Hanf R, Hum DW, Fruchart JC, Staels B. Safety issues and prospects for future generations of PPAR modulators. Biochim Biophys Acta 2007;1771(8):1065–81. 90. Shinkai H, Onogi S, Tanaka M, Shibata T, Iwao M, Wakitani K, Uchida I. Isoxazoli dine-3,5-dione and noncyclic 1,3-dicarbonyl compounds as hypoglycemic agents. J Med Chem 1998;41(11):1927–33. 91. Oleksiewicz MB, Thorup I, Nielsen HS, Andersen HV, Hegelund AC, Iversen L, Guldberg TS, Brinck PR, Sjogren I, Thing gaard UK, Jørgensen L, Jensen MB. Gen eralized cellular hypertrophy is induced by a dualacting PPAR agonist in rat urinary bladder urothelium in vivo. Toxicol Pathol 2005;33:552–60. 92. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. J Am Med Assoc 2005;294:2581–6. 93. Buse JB, Rubin CJ, Frederich R, Vira swami-Appanna K, Lin KC, Montoro R, Shockey G, Davidson JA. Muraglitazar, a dual (alpha/gamma) PPAR activator: a randomized, double-blind, placebo-con trolled, 24-week monotherapy trial in adult patients with type 2 diabetes. Clin Ther 2005;27(8):1181–95. 94. Kendall DM, Rubin CJ, Mohideen P, Ledeine JM, Belder R, Gross J, Norwood P, O’Mahony M, Sall K, Sloan G, Roberts A, Fiedorek FT, DeFronzo RA. Improve ment of glycemic control, triglycerides, and HDL cholesterol levels with muraglitazar, a
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dual (alpha/gamma) peroxisome prolifera tor-activated receptor activator, in patients with type 2 diabetes inadequately con trolled with metformin monotherapy: a double-blind, randomized, pioglitazone comparative study. Diabetes Care 2006; 29(5):1016–23. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. J Am Med Assoc 2005;294(20):2581–6. Van Vleet TR, White MR, Sanderson TP, Cohen SM, Cano M, Arnold LL, Waites CR, Schilling BE, Mitroka J, Dominick MA. Subchronic urinary bladder effects of muraglitazar in male rats. Toxicol Sci 2007;96(1):58–71. Dominick MA, White MR, Sanderson TP, Van Vleet T, Cohen SM, Arnold LE, Cano M, Tannehill-Gregg S, Moehlenkamp JD, Waites CR, Schilling BE. Urothelial carcinogenesis in the urinary bladder of male rats treated with muraglitazar, a PPAR alpha/gamma ago nist: evidence for urolithiasis as the inciting event in the mode of action. Toxicol Pathol 2006; 34(7):903–20. Tannehill-Gregg SH, Sanderson TP, Minnema D, Voelker R, Ulland B, Cohen SM, Arnold LL, Schilling BE, Waites CR, Dominick MA. Rodent carcinogenicity pro file of the antidiabetic dual PPAR alpha and gamma agonist muraglitazar. Toxicol Sci 2007;98(1):258–70. Skrumsager BK, Nielsen KK, M€ uller M, Pabst G, Drake PG, Edsberg B. Ragaglita zar: the pharmacokinetics, pharmacody namics, and tolerability of a novel dual PPAR alpha and gamma agonist in healthy subjects and patients with type 2 diabetes. J Clin Pharmacol 2003;43(11):1244–56. Saad MF, Greco S, Osei K, Lewin AJ, Edwards C, Nunez M, Reinhardt RR; Ragaglitazar Dose-Ranging Study Group. Ragaglitazar improves glycemic control
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and lipid profile in type 2 diabetic subjects: a 12-week, double-blind, placebo-controlled dose-ranging study with an open pioglitazone arm. Diabetes Care 2004; 27(6): 1324–9. Ratner RE, Parikh S, Tou C; GALLANT 9 Study Group. Efficacy, safety and tolerabil ity of tesaglitazar when added to the ther apeutic regimen of poorly controlled insulin-treated patients with type 2 dia betes. Diab Vasc Dis Res 2007;4(3):214–21. Go¨ ke B, Gause-Nilsson I, Persson A; GALLANT 8 Study Group. The effects of tesaglitazar as add-on treatment to metfor min in patients with poorly controlled type 2 diabetes. Diab Vasc Dis Res 2007; 4(3):204–13. Calkin AC, Allen TJ, Lassila M, Tikellis C, Jandeleit-Dahm KA, Thomas MC. Increased atherosclerosis following treatment with a dual PPAR agonist in the ApoE knockout mouse. Atherosclerosis 2007;195(1):17–22. Spraggs C, McCarthy A, McCarthy L, Hong G, Hughes A, Lin X, Sathe G, Smart D, Traini C, Van Horn S, Warren L, Mosteller M. Genetic variants in the epithelial sodium channel associate with oedema in type 2 diabetic patients receiving the peroxisome proliferator-activated receptor gamma ago nist farglitazar. Pharmacogenet Genomics 2007;17(12):1065–76. Long GG, Reynolds VL, Lopez-Martinez A, Ryan TE, White SL, Eldridge SR. Urothelial carcinogenesis in the urinary bladder of rats treated with naveglitazar, a gamma-dominant PPAR alpha/gamma ago nist: lack of evidence for urolithiasis as an inciting event. Toxicol Pathol 2008;36(2): 218–31. Long GG, Reynolds VL, Dochterman LW, Ryan TE. Neoplastic and non-neoplastic changes in F-344 rats treated with nave glitazar, a gamma-dominant PPAR alpha/ gamma agonist. Toxicol Pathol 2009; 37(6):741–53.
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43
Miscellaneous hormones
Calcitonin
(SED-15, 595; SEDA-29, 539; SEDA-30, 507; SEDA-31, 703) The authors of a review have suggested that salmon calcitonin by injection and nasal spray are safe, with transient and non-life threatening adverse effects (1R). Hypersen sitivity reactions are rare but have been reported. Oral calcitonin is associated with nausea and diarrhea.
Gonadotropins (gonadorelin, GnRH, and analogues) (SED-15, 1536; SEDA-29, 539; SEDA-30, 507; SEDA-31, 703) Cardiovascular The effect of androgen suppression therapy used for prostate cancer, prescribed as leuprolide acetate or goserelin, plus flutamide, on the time to fatal myocardial infarction has been studied using pooled trial data (2c). The data suggest that in men over the age of 65 years, 6 months of androgen suppression therapy reduces the time to fatal myocardial infarction compared with men who have not received therapy. Numbers and data were insufficient to reach further conclusions.
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32043-5 2010 Elsevier B.V. All rights reserved.
Gastrointestinal Chronic intestinal pseudoobstruction has been associated with buserelin (3A). • Fertility treatment using subcutaneous buserelin (total dose 37.5 mg) was successful in a 24-year-old woman, but 6 years later, when she again used subcutaneous buserelin (total dose 17 mg), treatment had to be stopped after 17 days because of nausea. Two weeks later she developed persistent symptoms of vomiting, bloating, and abdominal pain. Over a number of months she lost 14 kg in weight. Investigations suggested chronic intestinal pseudo-obstruction.
Investigation of this patient led the authors to suggest that she had developed antiGnRH antibodies, which had destroyed GnRH producing neurons within the myenteric plexus. The role of GnRH in the gastrointestinal system needs further inves tigation in humans. • A 45-year-old woman with intestinal endometriosis received 3.75 mg of leuprolide acetate subcutaneously and 15 days later developed abdominal pain, which worsened over the following days. A diagnosis of ileal perforation was made.
It is possible that the GnRH agonist preci pitated intestinal perforation, which is a known but rare complication of ileal endo metriosis (4A). • A 41-year-old woman, receiving treatment for infertility, was given subcutaneous leuprolide acetate 0.5 mg/day. On day 14 she developed abdominal pain, rapid weight gain, and shortness of breath. She had massive ascites and bilateral pleural effusions. The ovaries were not enlarged. Leuprolide acetate was withdrawn and she was given diuretics. Her symptoms rapidly resolved.
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The ascites may have been caused by the initial increase in estradiol concentrations, which occurs with GnRH agonists (5A). Skin A change in sex hormone concen trations induced by leuprorelin has been blamed for the occurrence of cutaneous lupus erythematosus (6A). • A 76-year-old man with prostate cancer who had been given leuprorelin 3-monthly for 2 years, developed subacute cutaneous lupus erythematosus, which required systemic therapy. New skin lesions arose 1–2 weeks after an injection of leuprorelin. After stopping leuprorelin the disease activity decreased.
A cutaneous vasculitis has been attribu ted to leuprolide (7A). • A 39-year-old woman with endometriosis was treated with monthly injections of leuprolide acetate 3.75 mg. After the second injection she developed a few petechiae, which then resolved. After the third injection she developed a vasculitic rash. A skin biopsy confirmed cutaneous vasculitis. The rash resolved and she received no further injections.
Granulomatous reactions to leuprolide have previously been reported. In a single center seven patients who were initially given goserelin acetate injections and chan ged to leuprorelin acetate developed gran ulomata at the injection site within 3–5 days (8A). The authors suggested that this type of reaction may be more common than reported and that there should be clear warnings to patients using leuprolide. Musculoskeletal Low testosterone concen trations contribute to the risk of osteoporosis and have been reported in patients with prostate cancer receiving GnRH agonists. Patients treated for sexually obsessive behavior are usually younger, but osteoporo sis can still occur, as a report has suggested (9A). • A 35-year-old man with a sexual obsession was given intramuscular triptorelin 3.75 mg monthly, and, to prevent bone loss, alendronate 70 mg
Chapter 43
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weekly and daily calcium carbonate. His testosterone concentrations fell from 23 to 1.3 nmol/l. At the start of therapy his T score for bone mineral density was 0.04 SD and after 37 months of therapy had deteriorated to –1.53.
Bone mineral density was measured in 21 patients with early puberty and short height, who were allocated to growth hormone and a GnRH analogue for 3 years or to no treat ment, including boys aged under 13 years and girls under 12 (10c). The lumbar spine bone mineral density at the end of the study was lower in the six treated boys compared with the two controls. There was no differ ence in the girls, but the numbers were too small for statistical significance. Reproductive system In 120 women with primary hypothalamic amenorrhea who received pulsatile GnRH 20 µm per pulse every 90 minutes subcutaneously over 90–140 days, testosterone concentrations at the start of treatment were below 0.4 µg/l and ultrasound scans showed no evidence of polycystic ovaries (11c). In six patients aged 25–35 years there was an increase in testosterone concentrations to a peak of 1.5 µg/l and ultrasonography showed a progressive change to polycystic ovaries. Therapy may have unmasked polycystic ovary syndrome in these women. At the end of the treatment they reverted to low testosterone concentrations. Goserelin has been associated with accel erated necrosis in uterine fibroids, due to what has been called a ‘flare’ effect (12A). • A 40-year-old woman with fibroids was treated with goserelin before hysterectomy and 2 weeks after the first injection developed acute right iliac fossa pain, a fever, vomiting, and vaginal bleeding. At laparotomy the uterus contained necrotic fibroids.
Cetrorelix, a GnRH analogue with antagonist activity, has been used in women before planned surgery for uterine fibroids. It should in theory avoid the flare effect seen with GnRH agonists. One of 109 patients (mean age 42 years) who had received two 10-mg injections developed severe hypermenorrhea 3 days after the
Miscellaneous hormones
Chapter 43
second injection (13c). She was treated in hospital for 5 days with oral methylergo metrine. She was not withdrawn from the study and received two further injections. The investigators did not think that this had been a drug effect, but there are simi larities with the case that involved goserelin.
Somatropin (human growth hormone, hGH) (SED-15, 3163; SEDA-29, 540; SEDA-30, 508; SEDA-31, 705) Cardiovascular In 20 Brazilian adults (mean age 46 years, 10 men) with adult growth hormone deficiency due to familial autosomal recessive idiopathic growth hormone deficiency who received growth hormone for 6 months, there was a progressive increase in carotid intima media thickness (14c). One patient had a plaque at the start of the study, five after receiving growth hormone, nine 6 months after stopping growth hormone and 14 after 12 months. This finding is different to that reported in adults with growth hormone deficiency treated with growth hormone. Nervous system Tourette’s syndrome has been attributed to growth hormone (15A). • A 10-year-old boy with idiopathic growth hormone deficiency was treated with growth hormone 0.03 mg/kg/day; after 6 months he developed tics, shoulder shrugs, and facial grimacing, and 8 months later throat-clearing sounds. A diagnosis of Tourette’s syndrome was made and growth hormone was withdrawn. The throat-clearing, shoulder shrugs, and facial grimacing improved within 2 months. Risperidone was used and the tics stopped after 3 months.
Creutzfeldt–Jakob disease from cadaveric growth hormone, a well-known complica tion of growth hormone therapy, continues to be reported (16A). Metabolism The adverse effects that can occur when growth hormone is used outside
791
of growth hormone deficiency have been reviewed (17R). In children who are born small for gestational age, mild transient hyperglycemia has been reported. Increased insulin resistance is a possible mechanism, which resolves after treatment is stopped. Diabetes mellitus has not been reported, but the long-term effects on glucose metabolism are unknown. Concerns have also been raised over the use of growth hormone in children with Turner’s syndrome, who have a defect in glucose-stimulated insulin secretion and are predisposed to type 2 diabetes. The use of growth hormone in patients taking glucocorticoids, which can also increase blood glucose concentrations, can impair glucose metabolism. Although long-term studies have suggested that the risk of diabetes is small, patients require careful monitoring and follow-up (18R). In a 10-year study of 87 adults with adultonset pituitary disease receiving growth hormone (mean age 44 years, 53 men), the mean dose of growth hormone at 10 years was 0.47 mg/day (19c). One patient had received insulin before the study. In four other patients a diagnosis of type 2 diabetes was made 1–7 years after the start of the study. Mean fasting blood glucose concen tration increased from 4.0 to 5.0 mmol/l at 10 years. HbA1c concentrations initially increased from 4.9% at baseline to 5.1% at 1 year but then fell to 4.6%. It is unclear whether this includes the concentrations in patients with newly diagnosed diabetes who were treated with oral drugs. In a 5-year follow-up study of patients with Prader–Willi syndrome who had pre viously participated in a study and received growth hormone for 12 months, blood glu cose concentrations were measured in those who had decided to continue with growth hormone and those who had not (20c). Of 10 patients with genetically proven Prader– Willi syndrome, 6 had continued to take growth hormone; their median fasting blood glucose was 5.0 mmol/l at 5 years compared with 4.2 mmol/l at baseline. One patient had impaired glucose tolerance, which was also present at the start of the study. Of the four who had not continued
792
with growth hormone, one had an increase in BMI from 38 to 64 kg/m2 and developed diabetes; the others had slightly increased fasting glucose concentrations. Growth hor mone therapy did not appear to have nega tive effect on blood glucose concentrations, but the numbers were small. Electrolyte balance Acute administration of growth hormone causes reduced urinary sodium excretion within the first day, with a return to baseline by the second day (21R). Chronic administration of growth hormone reduces urinary sodium excretion, which over a period of weeks normalizes, although extracellular expansion persists. Gastrointestinal Intestinal perforation, a rare complication of Crohn’s disease, has again been reported (22A). • A 22-year-old woman with a 3-year history of Crohn’s disease was treated with growth hormone (0.4 U/day; 0.13 mg/day) for a low BMI and low IGF-1 concentrations. The dose was increased weekly until the IGF-1 concentration was above the 50th centile for age-related healthy controls (201 ng/ml). A dose of 3.2 U/day (0.02 mg/kg/day) was reached. About 1 year later she had an ileal perforation, which was treated with surgery.
There is nothing to suggest that growth hor mone therapy was causal in this case. Musculoskeletal In 10 children with X-linked hypophosphatemic rickets taking oral phosphate and 1a-hydroxycole calciferol, growth hormone 0.03 mg/kg/day was used instead for 12 months after which the pre vious therapy was given (23c). Two of five patients with mild genu vara before the study and one patient with severe genu vara showed progression. No new deformi ties occurred. There was a median increase in Zscore for sitting height to total height ratio, suggesting that body disproportion increased. Immunologic The possible effects on the immune system of growth hormone
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in glucocorticoid-treated patients have been reviewed. In children with kidney trans plants, controlled studies have not shown a difference between those who use growth hormone and the controls in the incidence of rejection. However, a study has suggested that an episode of rejection before growth hormone therapy was a susceptibility factor for further episodes of rejection in patients taking growth hormone (18R). Thymus gland rebound, an increase in the volume of the thymus after chemotherapy, can occur up to 5 years after treatment (24A). • A 3-year-old girl developed a rhabdomyosar coma of the nasopharynx. At 7 years of age she was treated with growth hormone for reduced growth velocity because of growth hormone deficiency, starting with 0.3 mg/kg/week. After 3 months CT scan of the chest showed an 89% increase in thymus volume compared with pre-growth hormone measurements. Growth hormone was withdrawn and a biopsy showed hyperplasia without malignancy. Growth hormone was restarted. The thymus reduced in size and at 7 months was 48% larger than at baseline. The measurements were stable at 22 months.
In this patient growth hormone deficiency may have prevented rebound from occur ring, with subsequent rebound when growth hormone was replaced. Infection risk The possible increase in the incidence of otitis media in patients with Turner’s syndrome who are treated with growth hormone has been reviewed (17R). Earlier studies were not prospective and a prospective study has suggested that otitis media occurred in untreated controls with a similar frequency. Tumorigenicity The problems in determi ning the risk of leukemia in children taking growth hormone have been reviewed (25R). Other factors, such as Fanconi anemia, and treatments for other cancers, such as radiation and chemotherapy, may predispose individuals. In those without susceptibility factors, the risk of leukemia is approximately 3 per 100 000 patient-years,
Miscellaneous hormones
Chapter 43
similar to the general population. In children with previous leukemia treated with growth hormone there is no evidence of an increased risk of recurrence, but the studies have been small. Children with renal transplants are at increased risk of developing a malignancy in the transplanted kidney, and the added effect of growth hormone therapy is uncertain. The Kabi International Growth Study (KIGS) database has reported three children with graft malignancies and one with a native renal carcinoma, from a cohort of 938 children treated with growth hormone before renal transplantation and 314 children treated after transplantation. In contrast, two cases of renal cell carcinoma were reported among 43 000 patients in the National Cooperative Growth Study (NCGS) and 42 000 children in the KIGS registry without renal disease and treated with growth hormone in childhood. The long-term use of growth hormone is relatively recent. Surveillance, especially in those with previous malignancies, is essential in order to determine the risks. It has been recommended that when growth hormone is used to treat individuals with previous can cers, a significant period of time should elapse between starting growth hormone and completing cancer treatment (25R). In a study of non-functioning pituitary adenomas that had been treated with sur gery and growth hormone, 55 patients were identified from the German KIMS database and were compared with a matched control group of 55 patients with the same diagnosis who had been treated with surgery but had not received growth hormone, identified from the database of the University of Erlangen–Nuremberg (26c). Two investiga tors blinded to growth hormone use reviewed the MRI scans. The patients had been followed for at least 5 years. Those who received growth hormone were younger at the time of surgery (42 years compared with 55 years), and this may have influenced results, but there were no differences in recurrence and progression. Pregnancy Growth hormone is not licensed for use during pregnancy (27R).
793
Eight women with growth hormone deficiency took their usual dose of growth hormone during 12 pregnancies. The usual dose was gradually reduced after 3 months and withdrawn at 6 months. There were no major adverse events. However, long-term data are required to ensure safety. Susceptibility factors Genetic Growth hormone is being used increasingly in the management of Turner’s syndrome. The potential for increased adverse effects in this patient group has been highlighted. Patients with Turner’s syndrome are at increased risk of intracranial hypertension. This risk is exacerbated by the use of growth hormone, which is also associated with an increased risk of intracranial hypertension. From the NCGS database, which contains data from 54 996 patients (35% women), of whom 5220 have Turner’s syndrome, the risk of intracranial hypertension is twice that of patients with idiopathic growth hormone deficiency and eight times that of patients with idiopathic short stature. Patients with chronic renal insufficiency, who are also at increased risk of intracranial hypertension, also have an exaggerated risk when treated with growth hormone. Scoliosis, which is common in patients with Turner’s syndrome may have acceler ated progression in patients treated with growth hormone. The NCGS database also suggests that the risk of pancreatitis, although small, is higher in patients with Turner’s syndrome. There were three cases compared with six reports in the other patients (28C). Genetic defects of oxidative phosphoryla tion (OXPHOS) cause a variety of defects. The effects of growth hormone therapy have been documented in four children with growth retardation treated for 6 days a week at a dose of 0.2–0.3 mg/kg/week (29c). Two patients worsened rapidly. One developed hypotonia, loss of language and memory skills. Therapy was withdrawn and there was some general improvement, but her condition subsequently worsened. The second developed hypotonia, loss of speech,
794
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and cerebellar ataxia. Growth hormone was withdrawn at 4 months; her speech improved but her other symptoms did not change. The other two patients did not appear to have adverse effects, but neither did they benefit from growth hormone ther apy. The use of growth hormone therapy in this group of patients does not appear to be beneficial and may cause harm.
stopped therapy and their liver function normalized. The effect of pegvisomant on pituitary volume is hard to interpret. Review of the MRI scans by an independent neurosurgeon suggested that the increase in tumor volume occurred after the start of treatment in only four patients. Further long-term data are required.
Drug administration route Ten men and ten women received growth hormone as bolus doses of 0.033 and 0.083 mg/kg sub cutaneously and 0.033 mg/kg intramuscularly in random order over three study periods (30c). There was no difference in Cmax and AUC between the sexes when growth hormone was given subcutaneously. However, men had 44% higher concentrations than women when the same dose was given intramuscularly. This could have been due to the fact that the gluteal fat layer in women is deeper than in men, and injections that are intended to be intramuscular are more likely to be delivered into fat than muscle.
Pregnancy The use of pegvisomant during pregnancy has been reported (32A).
Growth hormone receptor antagonists (SEDA-28, 529; SEDA-30, 510; SEDA-31, 707) Observational studies In 229 patients with a 9-year history of acromegaly who were treated with pegvisomant in a mean dose of 16.5 mg/day for a median duration of 1 year, adverse events included injection site reactions, including erythema, swelling, and lipohypertrophy (n = 17, 7.4%), raised liver enzymes (21, 9.1%), increased pituitary volume (12, 5.2%), and headache (4, 1.7%) (31c). This was an observational study, and 94% of the patients had received previous medical therapy for acromegaly. Liver function abnormalities have previously been reported. In this study, 12 of the patients developed transaminase activities more than 3 times the upper limit of the reference range. In 7 of these 12 cases, the activities returned to normal while pegvisomant was continued. Four patients
• A 26-year-old woman with acromegaly taking pegvisomant 15 mg/day became pregnant after 13 months of therapy. The pregnancy was planned, and a decision had been made to continue therapy throughout the pregnancy. Her growth hormone concentrations increased during pregnancy and the dose of pegvisomant was gradually increased to 25 mg/day. The baby was born by cesarean section at 40 weeks and weighed 3.8 kg. Cord blood pegvisomant concentrations were low. Concentrations in breast milk were below the lower limit of quantification.
Melatonin (SED-15, 2245; SEDA-29, 542; SEDA-31, 708) Uses There are no studies of the longterm use of melatonin, which could be particularly important in patients with autoimmune disease, because of melatonin’s immunomodulatory properties (33R). The use of melatonin for sleep disorders in children also requires further studies, especially with regard to long-term use (34R). There could be effects on sexual maturation or reproductive function. Large doses of melatonin minimally delay puberty. Debate continues with regard to dose and timing of therapy. Vivid dreams have been reported, which may be dose related. Nervous system In 17 adults with developmental brain disorders, the data from 15 (aged 18–60 years, five women) were analysed, because of problems with the data from two patients (35c). They were given 1-month courses of treatment
Miscellaneous hormones
Chapter 43
over 6 months, three of which were placebo and three of which were melatonin 1, 3, or 6 mg/day. One patient reported extreme tiredness while taking 6 mg/day. In one of the two excluded patients, the seizure frequency increased from 3 per month to 10 per month while taking 6 mg/day. Seizure frequency returned to normal on withdrawal of melatonin. Of 24 critically ill patients 12 (mean age 70 years, four men) took oral melatonin 10 mg and 12 received placebo; one patient reporting a single headache (36c).
Oxytocin and analogues
(SED-15, 2657; SEDA-30, 511; SEDA-31, 708)
Cardiovascular The cardiovascular effects of oxytocin are usually transient, but it should be used with caution. Oxytocin 10 IU (n = 20) or methylergometrine 0.2 mg (n = 20) were given to healthy women in a double-blind study after cesarean section under spinal anesthesia (37c). Ten non pregnant healthy women were controls and received oxytocin 10 IU. Mean age was about 32 years. Transient hypotension, tachycardia, and ST segment/T wave depression occurred in those who received oxytocin, including the controls. Symptoms of flushing, chest pain, and dyspnea were related to the injection of oxytocin. Those who received methylergometrine had increased arterial pressure with no effect on heart rate.
Immunologic Anaphylaxis has been attributed to oxytocin. In one case an allergic reaction thought to have been due to oxytocin could have been related to sensitization to latex (38A). • A 28-year-old woman having her third cesarean section received an infusion of oxytocin 5 units. She rapidly developed dyspnea, pruritus, flushing, and hypotension. She was treated for anaphylaxis and recovered. Patch reaction tests showed a response to latex but no response to oxytocin.
795
The authors suggested that oxytocin makes up a part of the epitope of the latex antigen, and that this is the basis of antigenicity. They compared the pro tein sequences of the nonapeptides human oxytocin and vasopressin with sequences of allergenic proteins. Of the latex antigens in Havea brasiliensis (the Par´a rubber tree), two patatin latex anti gens were homologous in six (oxytocin) and seven (vasopressin) contiguous amino acids. They suggested that their patient could have been sensitized to patatin, as she had had recent contact with latex (gloves and catheter) and that subsequent administration of oxytocin could have facilitated antigen recognition, resulting in an anaphylactic response. Latex allergy was reviewed in SEDA-31 (p. 761). Pregnancy Oxytocin can cause hyperstimulation of the uterus. In a retrospective study, contractions in 56 women who had 102, 30-minute periods of labor, with five contractions in 10 minutes, and 56, 30-minute periods with six or more contractions in 10 minutes were compared with the preceding 30-minute period with under five contractions (39c). There was 20% less oxygen saturation when there were five contractions and 29% less when there were six or more contractions and more abnormalities of fetal heart rate. The doses of oxytocin were low but differed by uterine activity. While normal activity took place the mean dose was 6.1 mU/ minute, compared with 9.6 mU/minute when there were five contractions in 10 minutes and 12 mU/minute when there were six or more. Of 25 005 women in a retrospective cohort study with a history of cesarean delivery, 13706 elected to try for a subsequent vaginal birth; 5501 of these women (40%) were exposed to oxytocin (40C). The women who received oxytocin had slightly lower parity and had a significantly higher rate of labor induction. They had an unadjusted relative risk of 2.49 for uterine rupture compared with those who did not receive oxytocin.
Chapter 43
796
There was a dose response relation between uterine rupture and the maximum dose of oxytocin. At a maximum dose of 1–5 mU/ minute there was no significant increase in uterine rupture. The hazard ratio for doses of 6–20 mU/minute was 3.34 compared with 1–5 mU/minute, 3.92 for doses of 21–30 mU/ minute, and 4.57 for doses of 31–40 mU/ minute. These give an estimated attributable risk of uterine rupture of 2.9% for oxytocin doses above 20 mU/minute and 3.6% for doses above 30 mU/minute. The authors sug gested that the dose of oxytocin should be less than 20 mU/minute in women having a trial of labor after previous cesarean sec tion (41C). Drug administration route In a national survey of 365 women, rare adverse effects were reported more often when oxytocin was delivered by bolus than infusion: 73 (20%) reported nausea using a bolus compared with 26 (7%) using an infusion; tachycardia was reported by 128 (35%) compared with none; hypotension, vomiting, headache, and flushing were also more commonly reported as rare adverse effects after bolus injection (42c). Anaphylaxis was very rare and was not influenced by mode of delivery.
Thyrotropin-releasing hormone and thyrotropin See Chapter 41.
Parathyroid hormone
(SED-15, 2689;
SEDA-29, 542) Mineral balance Hypercalcemia has been studied in 119 post-menopausal women (mean age 69 years) who received PTH1-84 100 micrograms/day with a placebo tablet and 59 who received 100 micrograms/day with alendronate 10 mg (43C). All also took elemental calcium as calcium carbonate 500 mg/day. Hypercalcemia occurred in 25 women on at least one occasion; 13% of
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those who received parathormone alone compared with 16% of those who also used alendronate. On repeat testing 14 of the 25 had normal calcium concentrations, 3 had a serum calcium of more than 3.0 mmol/l during a study visit, and 1 had a concentration of 3.6 mmol/l between visits. There was hypercalciuria in 15 women (8% of those who received parathormone alone and 11% of those in the combined group). The risk of hypercalcemia was related to baseline serum calcium and baseline 1,25 dihydroxycolecalciferol concentrations. While hypercalcemia can occur at any time in most individuals it usually occurs within the first 3 months of therapy. Of 50 post menopausal women, mean age 58 years, 25 received subcutaneous injections of PTH1-84 100 micrograms/day for 1 month followed by weekly injections for 11 months (44c). All 50 also took cal cium 500 mg/day and vitamin D 400 IU/day. Five of those who received parathormone developed calcium concentrations of more than 2.6 mmol/l; four occurred within 1 month while they were receiving daily injections and one occurred after 12 months.
Somatostatin (growth hormone
release-inhibiting hormone) and
analogues (SED-15, 3160;
SEDA-29, 541; SEDA-30, 510;
SEDA-31, 709)
The frequency of adverse effects has been discussed in a review of somatostatin treat ment for acromegaly (45R). The most com mon are gastrointestinal and biliary tract abnormalities. Pain at the injection site and cardiovascular effects, including bradycar dia, are also common. Cardiovascular In a 12-month study patients with acromegaly (mean age 50 years) receiving lanreotide (n = 107) or octreotide (n = 118) were investigated for cardiac valve abnormalities (46C). There was no control group. However, the results suggested that although 80% had some
Miscellaneous hormones
Chapter 43
degree of cardiac valve abnormality, the use of either drug did not appear to worsen valve problems. There was first-degree heart block in two patients using lanreotide and three using octreotide.
Gastrointestinal In a 12-month, random ized, crossover comparison of octreotide and lanreotide every 28 days in 12 patients with acromegaly (median age 53 years, 7 men, 5 women) for up to 10 years, 11 had previously received octreotide and none had received lanreotide (47c). Octreotide was given intramuscularly and the dose was unchanged from that given previously. Lanreotide was given by deep subcutaneous injection and the dose was calculated on the basis of the known dose of octreotide. There were gastrointestinal effects, such as abdominal cramps and diarrhea, lasting 2–3 days after an injection, in three patients with lanreotide, in one with octreotide, and in three during both therapies. One patient withdrew from the study owing to abnormal liver function, which was thought to be drug-related after 1 month of lanreotide, having previously received octreotide. These results suggest that it may be worth changing therapies if a patient develops gastrointestinal adverse effects.
Skin Of 12 patients with acromegaly, four developed palpable nodules at injection sites, two with lanreotide and two with octreotide (47c).
Octreotide (SEDA-30, 510; SEDA-31, 709) Metabolism Severe hypoglycemia in patients with insulinomas treated with octreotide has been previously documented and has been reported again (48A). • A 34-year-old man with metastatic neuroendo crine tumors had a single intramuscular injection of long-acting octreotide 30 mg. He was found unresponsive with hypoglycemia 7 days later. An insulinoma was subsequently
797 diagnosed. He suffered damage and died.
significant
brain
Octreotide produces relatively greater inhi bition of the secretion of growth hormone and glucagon than of insulin. Patients should first be assessed with short-acting octreotide to determine their response to octreotide. Hyperglycemia has also been reported (49A). • A 3-month-child with congenital hyper insulinism was treated with subcutaneous octreotide 0.5 micrograms 6-hourly and maintained blood glucose concentrations of 2.2–2.7 mmol/l. During subtotal pancreatect omy, the blood glucose concentrations rose to 19 mmol/l within 15 minutes, requiring insulin treatment. Within 20 minutes after induction the child developed bradycardia (35/minute), requiring atropine.
Hypoglycemia is usually present until a significant amount of pancreatic tissue has been removed. The effects of octreotide on glucose metabolism are unpredictable and depend on relative inhibition of the hor mones that regulate blood glucose concen trations, which can vary significantly. Biliary tract Gallstones are a wellrecognized adverse effect of somatostatin analogues (50c). Of 21 patients with hypoglycemia due to endogenous hyperinsulinism, mean age 64 years, who were given octreotide 50–2000 micrograms/day, 11 continued ther apy for more than 6 months (51c). Eight of those 11 had a normal gall bladder on ultrasound scan before treatment. One of these eight developed asymptomatic gall stones; three had asymptomatic gallstones on ultrasound before treatment and one of them developed biliary colic 3 years after starting octreotide and required cholecystectomy. Of 98 patients with acromegaly who were given octreotide LAR 10–30 mg, 68 (median age 50 years, 28 men, 40 women) completed 12 injections; 38 patients had newly occur ring or worsening of gallstones on ultra sound (52C). Of the patients who
798
withdrew, six had abdominal problems with or without gallstones.
VASOPRESSIN AND ANALOGUES (SED-15, 3609; SEDA-29, 542; SEDA-30, 511; SEDA-31, 710)
Desmopressin (N-deamino-8-D arginine vasopressin, DDAVP) (SED-15, 1076; SEDA-29, 543; SEDA-30, 512; SEDA-31, 710) The authors of a review of the use of des mopressin in von Willebrand disease have reported that transient headache, facial flushing, and mild tachycardia are relatively common adverse effects but are not usually severe (53R). It is safe in pregnant women with von Willebrand disease. Care is needed in older patients with vascular dis ease, as there have been reports of myo cardial infarction and stroke. When desmopressin is given to young children with von Willebrand disease there is a greater risk of hyponatremia (54R). Observational studies Since desmopressin first had marketing approval over 30 years ago, 2158 adverse reactions have been listed on the manufacturer’s safety database. Hyponatremia, headache, and convulsions are the most commonly reported reactions. More adverse reactions are reported from intranasal desmopressin than oral desmopressin for an equivalent number of prescriptions (55R). Cardiovascular Desmopressin can cause hypertension (56A). • A 62-year-old woman had transcranial pituitary surgery and 6 hours post operatively was thought to have diabetes insipidus. She was given desmopressin in an unstated dose and urinary frequency and fluid balance were monitored. She developed hypertension,
Chapter 43
R.C.L. Page
which did not respond to captopril. On the third post-operative day she had a tonic– clonic seizure. The hypertension responded to esmolol and she recovered.
In a systematic review of 16 trials of des mopressin in patients undergoing cardiac surgery there was a 2.4-fold increased risk of perioperative myocardial infarction com pared with placebo (57M). Electrolyte balance In 21 trials of desmopressin in children with nocturnal enuresis there were no reports of hyponatremia (58M). In 21 publications that included 48 case reports of hyponatremia in children with nocturnal enuresis all were treated with intranasal desmopressin. Postmarketing safety data included 151 cases of hyponatremia in children with nocturnal enuresis, of whom 145 were treated with intranasal desmopressin and six with the tablet formulation. Prodromal symptoms of hyponatremia were headache, nausea, and vomiting. The authors concluded that the data suggest that there is a smaller risk of hyponatremia with oral desmopressin than intranasal desmopressin. Identifiable and preventable susceptibility factors for hyponatremia are an inappropriately high fluid intake, administration of a larger than recommended dose, age less than 6 years, and concomitant administration of another medication. When desmopressin is prescribed, patients should be instructed to avoid a high fluid intake, not to take a higher than recommended dose, and to stop taking the medication promptly and seek advice if headache, nausea, or vomiting occur.
Terlipressin (SEDA-29, 544; SEDA-30, 512; SEDA-31, 710) Skin Skin necrosis in patients given terlipressin is well documented and usually occurs in the hands and feet. Three fatal cases have been reported (59A). • A 47-year-old man was given terlipressin 0.5 mg qds, octreotide, and albumin for hepatorenal
Miscellaneous hormones
Chapter 43
syndrome and 2 days later developed epidermal necrosis over his legs, which was attributed to terlipressin. He died 3 days later. • A 53-year-old woman with cirrhosis developed renal insufficiency and was given terlipressin 0.5 mg qds, octreotide, and albumin. After 5 days she developed large blisters over the abdominal wall and thighs. Terlipressin was
799 withdrawn but the skin worsened. She died 2 days later. • A 36-year-old man with bleeding esophageal varices due to hepatic cirrhosis was given terlipressin 1 mg qds, octreotide, and antibiotics and 3 days later developed blisters and bruising in the groin. Terlipressin was withdrawn. He died of multiorgan failure.
References 1. Karsdal MA, Henriksen K, Arnold M, Chris tiansen C. Calcitonin – a drug of the past or for the future? Physiologic inhibition of bone resorption while sustaining osteoclast num bers improves bone quality. Biodrugs 2008;22:137–44. 2. D’Amico AV, Denham JW, Crook J, Chen M-H, Goldhaber SZ, Lamb DS, Joseph D, Tai K-H, Malone S, Ludgate C, Steigler A, Kantoff PW. Influence of androgen suppres sion therapy for prostate cancer on the fre quency and timing of fatal myocardial infarctions. J Clin Oncol 2007;25:2420–5. 3. Ohlsson B, Veress B, Janciauskiene S, Montgomery A, Haglund M, Wallmark A. Chronic intestinal pseudo-obstruction due to buserelin-induced formation of anti-GnRH antibodies. Gastroenterology 2007;132:45–51. 4. Saito S, Murakami T, Suzuki K, Terada Y, Fukushima K, Moriya T. Intestinal endo metriosis complicated by ileal perforation after initiation of gonadotropin-releasing hormone agonist therapy. Fertil Steril 2007;88:969e.7–9. 5. Ferrari B, Pezzuto A, Coppola F. Massive ascites and hydrothorax after leuprolide acetate administration in a down regulated woman undergoing assisted reproduction. Fertil Steril 2007;88(968):e9–11. 6. Wilchert A, Tuting T, Bieber T, Haidl G, Wenzel J. Subcutaneous lupus erythemato sus in a leuprorelin-treated patient with prostate carcinoma. Br J Dermatol 2008;159:231–3. 7. Turk BG, Dereli T, Dereli D, Akalin T. Leu prolide acetate-induced leukocytoclastic vascu litis. Acta Obstet Gynecol Scand 2007;86:892–3.
8. Dangle P, Palit V, Sundaram SK, Weston P. Noninfective cutaneous granuloma with leuprorelin acetate – reality or myth. Urology 2007;69(779):e5–6. 9. Hoogeveen J, Van der Veer E. Side effects of pharmacotherapy on bone with longacting gonadorelin agonist triptorelin for paraphilia. J Sexual Med 2008;5:626–30. 10. van Gool SA, Kamp GA, Visser-van Balen H, Mul D, Waelkens JJJ, Jansen M, Verhoe ven-Wind L, Delemarre-van de Waal HA, de Muinck Keizer-Schrama SMPF, Leusink G, Roos JC, Wit JM. Final height outcome after three years of growth hormone and gonado tropin-releasing hormone agonist treatment in short adolescents with relatively early pub erty. J Clin Endocrinol Metab 2007;92:1402–8. 11. Mattle V, Bilgyicildirim A, Hadziomerovic D, Ott HW, Zervomanolakis I, Leyendecker G, Wildt L. Polycystic ovarian disease unmasked by pulsatile GnRH therapy in a subgroup of women with hypothalamic amenorrhea. Fertil Steril 2008;89:404–9. 12. Basu M, Ahmed AIH. Goserelin administra tion causing an acute abdomen in a patient with a fibroid uterus. J Obstet Gynaecol 2007;27:90–1. 13. Engel JB, Audebert A, Frydman R, Zivny J, Diedrich K. Presurgical short term treat ment of uterine fibroids with different doses of cetrorelix acetate: a double-blind placebo-controlled multicenter study. Eur J Obstet Gynecol Reprod Biol 2007;134:225–32. 14. Oliveira JLM, Anguiar-Oliveira MH, D’Oliveira A, Pereira RMC, Oliveira CRP,
800 Farias CT, Barreto-Filho JA, Anjos-Andrade FD, Marques-Santos C, Nascimento-Junior AC, Alves EO, Oliveira FT, Campos VC, Ximenes R, Blackford A, Parmigiani G, Salvatori R. Congenital growth hormone (GH) deficiency and atherosclerosis: effects of GH replacement in GH-naïve adults. J Clin Endocrinol Metab 2007;92:4664–70. 15. Doneray H, Tan H, New-onset OZ. Tourette syndrome following human growth hormone therapy. Eur Neurol 2007;57:116–7. 16. Furtner M, Gelpi E, Kiechl S, Knoflach M, Zangerl A, Gotwald T, Willeit J, Maier H, Stro¨ bel T, Unterberger U, Budka H., Iatrogenic Creutzfeldt–Jakob disease 22 years after human growth hormone therapy: clinical and radiological features. J Neurol Neurosurg Psychiatry 2008;79:229–31. 17. Quigley CA. Growth hormone treatment of non-growth hormone-deficient growth disor ders. Endocrinol Metab Clin North Am 2007;36:131–86. 18. Simon D. rhGH treatment in corticosteroidtreated patients. Hormone Res 2007;68:38–45. 19. Gotherstrom G, Bengtsson B-A, Bosaeus I, Johannsson G, Svensson JA. 10-year pro spective study of the metabolic effects of growth hormone replacement in adults. J Clin Endocrinol Metab 2007;92:1442–5. 20. Hoybye C. Five-years growth hormone (GH) treatment in adults with Prader–Willi syn drome. Acta Paediatr 2007;96:410–3. 21. Dimke H, Flyvbjerg A, Frische S. Acute and chronic effects of growth hormone on renal regulation of electrolyte and water homeo stasis. Growth Horm IGF Res 2007;17:353–68. 22. Wolkersdorfer GW, Michlke S, Schneider R, Ehninger G, Schiefke I, Mossner J, Teich N. Ilieal perforation in a patient with Crohn’s disease while receiving recombinant human growth hormone therapy. Int J Colorectal Dis 2007;22:983–4. 23. Makitie O, Toivianen-Salo S, Marttinen E, Kaitila I, Sochett E, Sipila I. Metabolic control and growth during exclusive growth hormone treatment in X-linked hypophosphatemic rick ets. Hormone Res 2008;69:212–20. 24. Polgreen L, Steiner M, Dietz CA, Manivel JC, Petryk A. Thymic hyperplasia in a child treated with growth hormone. Growth Horm IGF Res 2007;17:41–6.
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25. Banerjee I, Clayton PE. Growth hormone treatment and cancer risk. Endocrinol Metab Clin North Am 2007;36:247–63. 26. Buchfelder M, Kann PH, Wuster C, Tuschy U, Saller B, Brabant G, Kleindienst A, Nomikos P; German KIMS Board. Influence of GH substitution therapy in deficient adults on the recurrence rate of hormonally inactive pituitary adenomas: a case-control study. Eur J Endocrinol 2007;157:149–56. 27. Johannsson G. Management of adult growth hormone deficiency. Endocrinol Metab Clin North Am 2007;36:203–20. 28. Bolar K, Hoffman AR, Maneatis T, Lippe B. Long-term safety of recombinant human growth hormone in Turner syndrome. J Clin Endocrinol Metab 2008;93:344–51. 29. Ramano S, Samara D, Crosmier H, Valayan nopoulos V, Polak M, Chretien D, Rotig A, Munnich A, Brauner R, de Lonlay P. Vari able outcome of growth hormone adminis tration in respiratory chain deficiency. Mol Genet Metab 2008;93:195–9. 30. Keller A, Wu Z, Kratzsch J, Keller E, Blum WF, Kniess A, Preiss R, Teichert J, Strasbur ger CJ, Bindlingmaier M. Pharmacokinetics and pharmacodynamics of GH: dependence on route and dosage of administration. Eur J Endocrinol 2007;156:647–53. 31. Schreiber I, Buchfelder M, Droste M, For ssmann K, Mann K, Saller B, Strasburger CJ. Treatment of acromegaly with the GH recep tor antagonist pegvisomant in clinical prac tice: safety and efficacy evaluation from the German Pegvisomant Observational Study. Eur J Endocrinol 2007;156:75–82. 32. Brian SR, Bidlingmaier M, Wajnrajch MP, Weinzimer SA, Inzucchi SE. Treatment of acromegaly with pegvisomant during preg nancy: maternal and fetal effects. J Clin Endocrinol Metab 2007;92:3374–7. 33. Pandi-Perumal SR, Srinivasan V, Spence DW, Cardinali DP. Role of the melatonin system in the control of sleep. CNS Drugs 2007;21:995–1018. 34. Jan JE, Wasdell MB, Reiter RJ, Weiss MD, Johnson KP, Ivanenko A, Freeman RD. Melatonin therapy of pediatric sleep disor ders: recent advances, why it works, who are the candidates and how to treat. Curr Pediatr Rev 2007;3:214–24.
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35. Laakso M-L, Lindblom N, Leinonen L, Kaski M. Endogenous melatonin predicts efficacy of exogenous melatonin in consilida tion of fragmented wrist-activity rhythm of adult patients with developmental brain dis orders: a double-blind placebo controlled crossover study. Sleep Med 2007; 8: 222–39. 36. Bourne RS, Mills GH, Minelli C. Melatonin therapy to improve nocturnal sleep in criti cally ill patients: encouraging results from a small randomised controlled trial. Crit Care 2008;12:R52. 37. Svanstrom MC, Biber B, Hanes M, Johansson G, Naslund U, Balfors EM. Signs of myocar dial ischaemia after injection of oxytocin: a randomized double blind comparison of oxy tocin and methylergometrine during Caesarean section. Br J Anaesth 2008; 100:683–9. 38. Ogata J, Minami K. Synthetic oxytocin and latex allergy. Br J Anaesth 2007;98:845–6. 39. Simpson KR, James DC. Effects of oxytocininduced uterine hyperstimulation during labor on fetal oxygen status and fetal heart rate patterns. Am J Obstet Gynecol 2008; 199(34):e1–5. 40. Cahill AG, Stamilio DM, Odibo AO, Peipert JF, Stevens EJ, Macones GA. Does maxi mum dose of oxytocin affect risk for uterine rupture in candidates for vaginal birth after caesarean delivery. Am J Obstet Gynecol 2007;197:495e1–5 41. Cahill AG, Waterman BM, Stamilio DM, Odibo AO, Allsworth JE, Evanoff B, Macones GA. Higher maximum doses of oxy tocin are associated with an unacceptable high risk for uterine rupture in patients attempting vaginal birth after caesarean delivery. Am J Obstet Gynecol 2008;199:32e1–5 42. Wedisinghe L, Macleod M, Murphy DJ. Use of oxytocin to prevent haemorrhage at cae sarean section – a survey of practice in the United Kingdom. Eur J Obstet Gynecol Reprod Biol 2008;137:27–30. 43. Antoniucci DM, Sellmeyer DE, Bilezikian JP, Palermo L, Ensrud KE, Greenspan SL, Black DM. Elevations in serum and urinary calcium with parathyroid hormone (1–84) with and without alendronate for osteoporo sis. J Clin Endocrinol Metab 2007;92:942–7. 44. Black DM, Bouxsein ML, Palermo L, McGo wan JA, Newitt DC, Rosen E, Majumdar S,
801 Rosen; CJ; for the PTH Once-Weekly Research (POWR) group. Randomized trial of once-weekly parathyroid hormone (1–84) on bone mineral density and re modelling. J Clin Endocrinol Metab 2008;93: 2166–72. 45. Ben-Shlomo A, Melmed S. Somatostatin agonists for treatment of acromegaly. Mol Cell Endocrinol 2008;286:192–8. 46. Colao A, Marek J, Goth MI, Caron P, Kuhn JM, Minuto FM, Weissman NJ. No greater incidence or worsening of cardiac valve regurgitation with somatostatin analog treat ment of acromegaly. J Clin Endocrinol Metab 2008;93:2243–8. 47. Andries M, Glintborg D, Kvistborg A, Hagen C, Andersen MA. 12-month randomised crossover study on the effect of lanreotide autogel and octreotide long-acting repeatable on GH and IGF-1 in patients with acromegaly. Clin Endocrinol 2008;68:473–80. 48. Healy ML, Dawson SJ, Murray RML, Zalc berg J, Jefford M. Severe hypoglycaemia after long-acting octreotide in a patient with an unrecognized malignant insulinoma. Intern Med J 2007;37:406–9. 49. Batra YK, Rajeev S, Samra T, Rao KLN. Octreotide-induced severe paradoxical hyperglycemia and bradycardia during sub total pancreatectomy for congenital hyper insulinsim in an infant. Paediatr Anaesth 2007;17:1117–9. 50. Colao A, Pivonello R, Auriemma RS, Galdiero M, Savastano S, Lombardi G. Beneficial effect of dose escalation of octreotide-LAR as first-line therapy in patients with acromegaly. Eur J Endocrinol 2007;157:579–87. 51. Vezzosi D, Bennet A, Courbon F, Caron P. Short and long-term somato statin analogue treatment in patients with hypoglycaemia related to endogenous hyperinsulinism. Clin Endocrinol 2008;68: 904–11. 52. Mercado M, Borges F, Bouterfa H, Chang T-C, Chervin A, Farrall AJ, Patocs A, Petersenn S, Podoba J, Safari M, Wardlaw J, on behalf of SMS995B2401 Study Group. A prospec tive multicentre study to investigate the efficacy safety and tolerability of octreotide LAR (long-acting repeatable octreotide) in the
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802
53.
54.
55.
56.
primary therapy of patients with acromegaly. Clin Endocrinol 2007;66:859–68. Federuci AB. The use of desmopressin in von Willebrand disease; the experience of the first 30 years (1977–2007). Haemophilia 2008;14(Suppl 1):5–14. Castaman G. Desmopressin for the treat ment of haemophilia. Haemophilia 2008;14 (Suppl 1):15–20. Walle JV, Stockner M, Raes A, Norgaard JP. Desmopressin 30 years in clinical use: a safety review. Curr Drug Saf 2007;2:232–8. Sun I, Sun A, Gercek A, Kilic T. Desmopres sin induced hypertension as a rare cause of
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hypertensive encephalopathy. J Neurosurg Aesthesiol 2007;19:289–90. 57. Cattaneo M. The use of desmopressin in open-heart surgery. Haemophilia 2008;14 (Suppl 1):40–7. 58. Robson WLM, Leung AKC, Norgaard JP. The comparative safety of oral versus intra nasal desmopressin for the treatment of chil dren with nocturnal enuresis. J Urol 2007; 178:24–30. 59. Donnellan F, Cullen G, Hegarty JE, McCormick PA. Ischaemic complications of glypressin in liver disease: a case series. Br J Clin Pharmacol 2007;64:550–2.
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44
Drugs that affect lipid metabolism
Ezetimibe
(SED-15, 1308; SEDA-29, 546; SEDA-30, 515; SEDA-31, 715)
Placebo-controlled studies Several studies of the use of ezetimibe, reported by the Ezetimibe Study Group, funded by the man ufacturers Schering–Plough, have shown few differences in the rates of adverse events in patients taking ezetimibe or placebo (1C–6C), as have later studies (7C, 8C), including trials of ezetimibe monotherapy (9C). Systematic reviews In a systematic review of 18 randomized controlled trials of combina tions of ezetimibe with a statin in 14 471 patients, there were no increased risks of myalgias, increased creatine kinase, rhabdo myolysis, increased transaminases, gastro intestinal adverse events, or withdrawal because of an adverse event compared with statin monotherapy (10M). Psychiatric The psychiatric adverse reac tions that have been associated with statins, including depression, memory loss, confu sion, and aggressive reactions, have been reviewed in the context of reports to the New Zealand Centre for Adverse Reactions Monitoring (11cr). Hematologic Immune thrombocytopenia has been associated with ezetimibe in a 72-year-old man who took ezetimibe 10 mg/
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32044-7 2010 Elsevier B.V. All rights reserved.
day þ simvastatin 20 mg/day for 4 weeks; the platelet count normalized after withdrawal and the thrombocytopenia did nor recur on rechal lenge (12A). Metabolism A paradoxical adverse effect of ezetimibe, namely hyperlipidemia, has been reported in a patient with statin intol erance and familial combined hyperlipide mia (13A). There was an asymptomatic 770% increase in triglycerides (from 3.5 to 27 mmol/l) and a 190% increase in total cholesterol (from 9.8 to 19 mmol/1) second ary to an increase in hepatic cholesterol (lathosterol) synthesis (from 4.6 to 26 µmol/l). This lipid profile resolved 9 months after withdrawal of ezetimibe. Liver Hepatotoxicity has been attributed to ezetimibe in a woman who took 10 mg/day for 6 months (14A). Severe isolated hyper bilirubinemia occurred in a patient with hepatic cirrhosis, probably owing to non alcoholic steatohepatitis, who took ezeti mibe; it resolved after withdrawal (15A). Pancreas Pancreatitis has been attributed to ezetimibe in a 64-year-old African–Ameri can woman who had taken ezetimibe 10 mg/ day for 2 weeks in addition to simvastatin 20 mg/day (16A). Musculoskeletal There have been reports of myopathy during ezetimibe monotherapy (17A, 18A), in some cases after myopathy due to a statin (19A). Drug–drug interactions Fibrates In a 7-day, randomized, open, three-way, crossover, multiple-dose study in 12 healthy men
803
Chapter 44
804
there was no pharmacokinetic interaction of ezetimibe 10 mg/day with gemfibrozil 600 mg bd, apart from small increases in exposure to ezetimibe and ezetimibe glu curonide, which were not considered to be clinically relevant (20c). In a randomized placebo-controlled study in 625 patients the addition of ezeti mibe 10 mg/day to fenofibrate 160 mg/day for 12 weeks further reduced LDL choles terol, non-HDL-cholesterol, triglycerides, and apolipoprotein B; HDL cholesterol rose (21C). Statins Combining ezetimibe with statins reduces LDL cholesterol more than either drug alone (22M, 23M). In a randomized, placebo-controlled study ezetimibe 5, 10, or 20 mg/day increased the lipid-modifying effects of lovastatin, with only a small reduc tion in exposure to lovastatin and beta hydroxy-lovastatin (24C). In other studies ezetimibe has been shown to increase the lipid-modifying effects of atorvastatin (25C, 26C), rosuvastatin (27C), and simvastatin (28c, 29C). In a comparative study in 788 patients, co-administration of ezetimibe and simvastatin produced a greater fall in LDL cholesterol and a greater rise in HDL cholesterol than co-administration of ezeti mibe and atorvastatin (30C). In a multicen ter, double-blind, 6-week parallel-group comparative study there was a similar result in 1902 patients; rises in transaminase activ ities occurred in significantly more of those who took atorvastatin than simvastatin, but there were no cases of myopathy or liverrelated adverse events that led to study dis continuation (31C). There is no evidence from randomized trials that ezetimibe increases the risk of
J.K. Aronson
myopathy in patients taking statins (32M). In a double-blinded, double-dummy study of a modified-release formulation of fluva statin 80 mg/day and ezetimibe 10 mg/day, alone or together for 12 weeks, in 199 patients with previous myopathic reactions to other statins, the incidences of musclerelated adverse events were 24% with eze timibe, 17% with fluvastatin, and 14% with the combination (33C). In no case did crea tine kinase activity increase by more than 10 times the upper limit of the reference range. However, such trials can miss uncommon adverse effects or interactions of this type, particularly if they occur in susceptible subtypes of patients who are not included in the trials or who are greatly outnumbered by those who are not susceptible, as case reports have suggested. In two patients serum creatine kinase activity rose after ezetimibe was added to statin therapy; one also developed myalgia and tendinopathy (34A). Other cases have been reported (35A, 36A) or mentioned (37r).
Fibrates
(SED-15, 1358; SEDA-29, 546; SEDA-30, 515)
Observational studies The rates of adverse events reported to the US Food and Drug Administration for various lipid-modifying drugs have been reviewed (38c) and are given in Table 1. Drug–drug interactions Statins Increasingly, fibrates and statins are being used in com bination (39C), particularly in the treatment of the so-called metabolic syndrome, according to the criteria of the Expert
Table 1 Rates of adverse events reported to the FDA in 2000–2004 per 1 million prescriptions for various lipid-modifying drugs Adverse event
Serious events Hepatotoxicity Rhabdomyolysis
Fibrates
HMG Co-A reductase inhibitors
Gemfibrozil
Fenofibrate
Simvastatin
Pravastatin
Atorvastatin
104 16 90
31 8 4
23 5 8
15 5 2
19 4 2
Niacin-ER
10 2 1
Drugs that affect lipid metabolism
Chapter 44
Panel on Detection, Evalution and Treat ment of High Blood Cholesterol in Adults (the Adult Treatment Panel III ATP III) (40S). However, plasma creatine kinase activity increases significantly in patients who take a statin and a fibrate compared with a statin only (41c) and there is an increased risk of myopathy, as further reports have exemplified (42A–44A). In a retrospective review of the charts of 80 patients who had prescriptions for gem fibrozil at any dose and simvastatin at doses of more than 10 mg/day, only 45 met ATP III guidelines for combination therapy (45c). One death secondary to rhabdomyo lysis occurred in a patient whose care did not meet ATP III guidelines. The relative risks of myopathy in patients taking statins with and without fibrates have been assessed in a cohort study (46c). Myo pathy was significantly associated with sta tin monotherapy (RR = 2.8; 95% CI = 1.3, 5.9), a statin þ a fibrate (RR = 9.1; 95% CI = 3.5, 23), co-morbid liver disease (RR =4.3; 95% CI = 1.5, 13), and/or renal dis ease (RR = 2.5; 95% CI = 1.3, 5.0). The mean time to the event was 1.7 years for statin þ fibrate use, 2.0 years for statins alone, and 2.1 years for unexposed individuals.
Bezafibrate Bezafibrate is the first agonist that affects all three peroxisome proliferator-activated receptors (PPARs) subtypes, PPARa, PPARg, and PPARd. Activation of PPARa reduces triglycerides, activation of PPARg causes insulin sensitization and increases glucose metabolism, and activation of PPARd enhances fatty acid metabolism. There have been several studies of the effects of PPARa and PPARg ligands in preventing the adverse cardiovascular effects of diabetes. In addition to its beneficial effects on HDL cholesterol and triglycerides, beza fibrate improves insulin sensitivity and reduces blood glucose concentration and significantly reduces the incidence of
805
cardiovascular events and new diabetes in patients with features of the metabolic syn drome (47R). Immunologic Angioedema occurred 10 hours after ingestion of a modified-release formulation of bezafibrate in a 68-year-old man with hypertriglyceridemia, hyperten sion, and gout, necessitating tracheostomy; he had been taking bezafibrate for 22 months and had had several episodes of tongue swelling, always within 10–15 hours of ingestion (48A). The authors thought that the reactions had probably been IgE mediated, despite the delay in appearance after ingestion, but they could not rule out autacoid release. Anaphylactic reactions to bezafibrate have rarely been reported before (49A, 50A).
Fenofibrate Placebo-controlled studies The Fenofibrate Intervention and Event Lowering in Dia betes (FIELD) study was a multinational, randomized, controlled trial in 9795 partici pants aged 50–75 years, with type 2 diabetes mellitus, not initially taking statins (51C). Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events but did reduce total cardiovascular events, mainly because of fewer non-fatal myocardial infarctions and revasculariza tions. Similar proportions in each group withdrew (10% placebo versus 11% feno fibrate) and more patients on placebo (17%) than fenofibrate (8%) started other lipid-modifying treatments, predominantly statins. There was a small increase in the risk of pancreatitis (0.8% versus 0.5%) and pulmonary embolism (1.1% versus 0.7%) with fenofibrate. In a multicenter, double-blind, rando mized, placebo-controlled, parallel-arm trial for 12 weeks in 611 patients with mixed hyperlipidemias a combination of fenofibrate 160 mg/day with ezetimibe 10 mg/day þ simvastatin 20 mg/day was more effective than the two treatments alone, although the patterns of efficacy
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differed depending on whether LDL cho lesterol, HDL cholesterol, apolipoprotein A-I, apolipoprotein B, or triglycerides was being considered; adverse events were similar with the different treatments (52C). Cardiovascular In a case–control study in 677 patients with confirmed venous thrombo embolism and no major acquired risk factors and 677 controls, fibrate exposure was asso ciated with an increased risk (OR = 1.88; 95% CI = 1.29, 2.74) (53c). Those who used fibrates had a significantly higher mean plasma concentration of homocysteine than non-users (23 µmol/l versus 18 µmol/l). However, homocysteine was not associated with the increased risk of venous thrombo embolism associated with fibrates. Urinary tract Renal impairment has been attributed to fenofibrate (54A). • A 60-year-old man took fenofibrate 48 mg/day for 2 weeks and developed renal impairment. His eGFR fell from 25 to 18 ml/minute/ 1.73 m2. Because of persistently high triglyceride concentrations the dosage of fenofibrate was increased to 145 mg/day; the eGFR fell to 13 ml/minute/1.73 m2. Fenofibrate was withdrawn, and within 4 days his serum creatinine fell; within 6 weeks his eGFR was 21 ml/minute/1.73 m2.
Musculoskeletal Rhabdomyolysis with acute renal failure has been reported in a young woman without predisposing factors taking fenofibrate alone (55A). In the context of a case of rhabdomyoly sis associated with fenofibrate it has been suggested that hypothyroidism is a predis posing factor (56A). Breasts Gynecomastia occurred on the left side in a 56-year-old man who took feno fibrate 160 mg/day for 1 year; it resolved after the drug was withdrawn, but 16 months later fenofibrate was reintroduced and he developed gynecomastia on the right side (57A). Infection risk It has been suggested that fibrates, which increase biliary cholesterol excretion and reduce the excretion of bile
J.K. Aronson
acids, may impair the encystment of Giardia lamblia and thus predispose to gut coloniza tion of its trophozoites (58A).
Gemfibrozil Drug overdose In 118 cases of self-poison ing (55% men) with gemfibrozil the mean maximum dose was 2407 (range 300– 18 000) mg or 3.3 (range 1–30) tablets/cap sules (59c). Exposure was due to attempted suicide (11%) or was unintentional (83%), often because of therapeutic errors (49%). The event was considered potentially toxic in 3% of cases, but there were no deaths. Specific adverse clinical effects, which were reported in 9% of cases, were gastrointest inal (5%), neurological (3%), or cardio vascular (1%).
Fish oils
(SED-15, 1364; SEDA-30, 515)
Pregnancy Some have suggested that pure fish oil supplements should be explored as a means of providing the docosahexa enoic acid that is required for optimal maternal and fetal outcomes in pregnancy (60R), while others have suggested that there is no good evidence on which to base a recommendation that omega-3 fatty acids should be used during preg nancy (61r). The use of omega-3 fatty acid supplements has been studied in 59 pregnant and postpartum women with major depressive disorder in an 8-week double-blind, placebo-controlled trial, using a formulation that provided 1.84 g/ day of eicosapentaenoic acid and docosa hexaenoic acid or matching placebo (corn oil with 1% fish oil) (62c). Of 59 women, 13 (22%; six taking omega-3 fatty acids and seven placebo) reported mainly transient adverse effects, includ ing dizziness, diarrhea, nausea, burping, difficulty in swallowing the capsules, feel ing tired, heartburn/reflux, or unpleasant breath/bad taste; the last two were the most common.
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Drug–drug interactions Anticoagulants Concerns that omega-3 fatty acid ethyl esters can cause clinically significant bleed ing have been said to be unfounded (63R). However, occasional cases are reported, and the risk may be increased in patients taking other drugs that affect hemostasis. A subdural hematoma in patient who had a minor fall was attributed to concomitant use of high-dose omega-3 fatty acids 6 g/day with both aspirin and warfarin (64A).
HMG-CoA reductase inhibitors (SED-15, 1632; SEDA-29, 547; SEDA-30, 516; SEDA-31, 715) The adverse effects of statins other than those affecting liver and muscle have been extensively reviewed (65R). Systematic reviews In a meta-analysis of four trials of statins in 27 548 patients, representing 108 049 patient-years, high-dose therapy with atorvastatin or simvastatin 80 mg/day was associated with a significant increase in the risk of any adverse event (OR = 1.44; 95% CI = 1.33, 1.55) and adverse events requir ing withdrawal of therapy (OR = 1.28; 95% CI = 1.18, 1.39) (66M). High-dose therapy was also associated with an increased risk of abnormalities of liver function testing (OR = 4.48; 95% Cl = 3.27, 6.16) and rises in creatine kinase activity (OR = 9.97; 95% CI = 1.28, 78). The authors concluded that moderate-dose statin therapy may be most appropriate for achieving cardiovascular risk reduction in most individuals, reserving high-dose statins for those at highest risk. Respiratory Interstitial pneumonitis has been attributed to statins in seven patients (67c). A 60-year-old man, a non-smoker, devel oped bilateral serosanguinous pleural effu sions after taking pravastatin 40 mg/day for about 1 year; the effusions resolved rapidly after withdrawal of pravastatin, although that could have been coincidental (68A). Ear, nose, throat Several statins inhibit T-helper 1 cell development and induce
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T-helper 2 cell polarization and production of T-helper 2 cytokines, which promote the activation and chemotaxis of eosinophils. This prompts the question of whether sta tins cause nasal polyps. Among 200 patients who were using statins and 200 who were not nasal polyps were detected in four of the former and five of the latter (69c). Nervous system Peripheral polyneuropa thies attributed to statins have been briefly reviewed (70r). They are rare (about one per 10 000 per year) and include sensory or sen sorimotor polyneuropathies with signs of sensory impairment, and reduced or some times suppressed tendon reflexes. There may be markedly reduced muscle strength. Renal failure and diabetes are susceptibility factors. In 42 patients (mean age 52 years; 23 men, 19 women) neurophysiological inves tigation of the peroneal, tibial, and sural nerves before and for 24 months after treat ment with simvastatin 20 mg/day was initiated, although none of the patients reported subjective symptoms typical of polyneuropathy; nevertheless, there was electrophysiological evidence of damage to the peripheral nerves (71c). In a case–control analysis using the UKbased General Practice Research Database (GPRD), 3637 patients with idiopathic Parkinson’s disease were identified; there was no association with the use of statins or fibrates (72c). Sensory systems In a nested case–control study involving 2867 cases and 11 468 con trols, current users of ACE inhibitors or statins were at a slightly higher risk of devel oping macular degeneration (RR = 1.19; 95% CI = 1.07, 1.33; and RR = 1.30; CI = 1.17, 1.44 respectively) (73c). Psychiatric Paranoia, anxiety, and beha vioral changes have been attributed to ator vastatin 10 mg/day in a 79-year-old woman after about 17 days (74A). Psychiatric adverse events during statin therapy have been evaluated using the Interregional Group of Pharmacovigilance database of reports of suspected adverse drug reactions submitted since 1988 from
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eight Italian regions (75c). There were 35 314 reports, in 60 of which 71 psychiatric preferred terms combined with statins were identified. Among them, 14 were asso ciated with positive rechallenge. The five most frequently reported psychiatric events were insomnia, somnolence, agitation, con fusion, and hallucinations, but only insom nia was reported with a higher frequency for statins than with all other drugs (ROR 3.3; 95% CI = 1.9, 5.7); while confusion was reported at a lower frequency (ROR = 0.4; 95% CI = 0.1, 0.9). Among statins available in Italy, only simvastatin (ROR = 0.5; 95% CI = 0.2, 0.9) showed a significantly lower rate of reports of psychiatric events than all other drugs together. Metabolism Statins inhibit the production of 2,3-dimethoxy-5-methyl-6-polyisoprene parabenzoquinone (ubiquinone or coenzyme Q10), which is required for mitochondrial electron transport. Idiopathic or primary deficiency of coenzyme Q10 can cause a mitochondrial encephalomyopathy. A patient developed a mitochondrial syndrome, con sisting of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), the symptoms being temporally related to statin therapy (76A). Mouth The adverse effects of statins on the oral cavity have been studied in 26 patients aged 50–70 years (77c). The statin was with drawn and the patients were reviewed after 7–15 days. Dry mouth in 23 patients improved in 17 after withdrawal; itchiness in 15 patients improved in 6 after withdrawal; a bitter taste in 14 improved in 13 after withdrawal. Liver In a retrospective review of a registry of 146 men with hepatitis C who took a statin there were no significant increases in alanine transaminase activity and only one patient discontinued therapy because of an increase in AlT to more than 3 times the upper limit of the reference range (78c). In one case a rise in alanine transaminase due to fluvastatin 80 mg/day for 6 weeks, confirmed by dechallenge and rechallenge, led to an incidental diagnosis of hepatitis C infection (79A).
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Urinary tract In 90 patients who were ran domly assigned to rosuvastatin 10 mg/day (n = 45) or 20 mg/day (n = 45) there was a dose-related increase in the urinary excretion of alpha1-microglobulin but no adverse effect on renal function as assessed by eGFR (80c). Skin Eosinophilic fasciitis has been attribu ted to simvastatin (81A). • A 71-year-old woman developed progressive induration of the skin on her arms and legs, with weakness and dyspnea on moderate exertion, after taking simvastatin for 3 weeks. The effects worsened progressively until the drug was withdrawn 1 month later, after which the symptoms stabilized but did not improve. There was erythema, induration, and dimpling of the skin on the arms and legs. There was a mild eosinophilia (650 106/l). A skin biopsy showed fibrosis in the reticular dermis, the septa of the superficial fascia, and striated muscle; there was also a perivascular and interstitial lymphocytic infiltrate.
Musculoskeletal Myopathies Rhabdomyo lysis continues to be reported in patients taking statins (82A–84A), including one with McArdle’s syndrome (85A). Rarely, focal myositis can occur (86A). EIDOS classification: Extrinsic species: HMG Coenzyme A
reductase inhibitors
Intrinsic species: Skeletal muscle
mitochondria Distribution: Skeletal muscle Outcome: Necrosis Sequela: Myopathy and rhabdomyolysis due to statins DoTS classification: Dose-relation: Collateral
Time-course: Intermediate
Susceptibility factors: Genetic (the
C-allele of the rs4149056 SNP in SLCO1B1 on chromosome 12; COQ2 mutations); age (over 65 years); drugs (fibrates; compounds that inhibit statin metabolism, e.g. grapefruit); diseases (hypothyroidism; trauma and physical exertion; nephrotic syndrome).
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In a case-crossover study in 93 831 patients using two independent primary care databases (1991–2006) the risk ratios associated with all classes of statins and fibrates for myopathy were 11 (95% CI = 9.8, 11) and 20 (18, 23) respectively (87c). At 26 weeks, the largest risks were with fluvastatin (RR = 33; 95% CI = 17, 66) and ciprofibrate with previous statin use (RR = 41; 95% CI = 13, 122). At 12 weeks there were significant differences between cerivastatin and atorvastatin (RR = 2.05; 95% CI = 1.2, 3.5), and between rosuvasta tin and fluvastatin (RR = 3.0; 95% CI = 1.6, 5.7). After 12 months, the relative risk for all statins and fibrates increased to 26 (95% CI = 22, 30). The authors estimated the annual incidence of statin-induced myopathy or myalgia at around 700 per million per year. The prevalence of myopathic events, par ticularly myalgia, myositis, and rhabdomyo lysis, has been assessed retrospectively in a community-based practice among 32 225 subjects with diabetes (n = 10 247) or with out diabetes (n = 21 978), some of whom took statins (88c). More statin users than non-users had myopathic events, both among those with diabetes (7.9% versus 5.5%) and those without (9.0% versus 3.7%). However, 95% of the events were myalgia or mild myositis. The prevalence of severe myositis was 0.4 per 1000 personyears (95% CI = 0.2, 0.7) and 0.8 per 1000 person-years (95% CI = 0.6, 1.1) among sta tin users with or without diabetes respec tively. By comparison, the rates were 0.3 (95% CI = 0.1,0.5) and 0.2 (95% CI = 0.1, 0.4) per 1000 person-years among non-users with and without diabetes respectively. Rates of rhabdomyolysis were 0.1 (95% CI = 0.1, 0.3) and 0.2 (95% CI = 0.1, 0.5) per 1000 person-years among statin and non-statin users with diabetes respectively, and 0.2 (95% CI = 0.1, 0.4) in both groups without diabetes. The authors concluded that statin use was associated with an approximate doubling of the risk of any myopathic event but was not associated with an increased risk of rhabdomyolysis. The mechanisms of the myopathic effects of statins have been reviewed, stressing pos sible actions on mitochondria, including
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actions on coenzyme Q10 and inhibition of mevalonate metabolism (89R). It has been suggested that mitochondrial impairment leads to a mitochondrial calcium leak that directly interferes with the regulation of sarcoplasmic reticulum calcium cycling although there may also be a direct effect of statins on the sarcoplasmic reticulum; these actions may result in apoptosis, oxida tive stress, and muscle remodelling and degeneration (90R). The susceptibility factors for rhabdomyo lysis in patients taking statin monotherapy or a statin plus a fibrate have been elicited in a nested case–control study in 252 460 new users of lipid-lowering medications across 11 geographically dispersed US health plans (91c). There were 21 cases of rhabdo myolysis (0.008% or about 1 in 12 000) and they were compared with 200 individually matched controls without rhabdomyolysis. Statin users aged 65 years of age and older had four times the risk of hospitalization for rhabdomyolysis than those under 65 (OR = 4.36; 95% CI = 1.5, 14). There was a joint effect of high statin dosage and renal disease; when these two variables were added to the model with age, the OR was 5.73 for dosage (95% CI = 0.63, 53) and 6.26 for renal disease (95% CI = 0.46, 63). Although not statistically significant, there was a greater than two-fold increase in the risk of rhabdomyolysis among women (OR = 2.53; 95% CI = 0.91, 7.32). There is an increased risk of rhabdomyo lysis in patients with hypothyroidism, which is a susceptibility factor for statin-induced rhabdomyolyisis (92A). However, an unusual interaction between a statin and hypothyroidism has been reported in a patient with rhabdomyolysis (93A). • An 85-year-old woman with renal impairment and hypothyroidism was given simvastatin 80 mg/day and soon after developed severe muscle weakness and laboratory evidence of rhabdomyolysis. Although her hypothyroidism had been well controlled for years with levothyroxine 100 micrograms/day, her bio chemistry now suggested hypothyroidism. On withdrawal of the simvastatin her serum TSH fell to within the reference range within 4 weeks without any change in the dosage of levothyroxine.
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There is an increased risk of rhabdomyo lysis when people taking statins exercise. In 79 subjects who were randomized to ator vastatin 10 mg/day (n = 42) or 80 mg/day (n = 37) for 5 weeks, a downhill walk increased plasma CK and CK-MB activities, but there were no differences between the high and low doses (94c). The authors con cluded that exercise increases the risk of rhabdomyolysis even at low doses of a statin. Early-onset rhabdomyolysis has been reported in a patient with nephrotic syn drome who was taking atorvastatin (95A). Atorvastatin is highly protein bound, and a reduction in serum albumin concentration because of the nephrotic syndrome could have caused an increase in the unbound fraction in the plasma and hence greater distribution to muscle. In some cases statin-induced myopathy can persist or even progress after the drug is withdrawn. In eight such cases there was muscle fiber necrosis, but only three had an inflammatory infiltrate. In all cases there was diffuse or multifocal up-regulation of myosin heavy chain, MHC-I, expression, even in non-necrotic fibers. There was pro gressive improvement in seven cases when prednisolone and methotrexate were intro duced; in one case recover occurred sponta neously (96c). In a retrospective study of 37 patients with chronic primary muscle disease and 185 matched controls, 21 had dermatomyo sitis or polymyositis, 12 had a genetic myo pathy, and four had an unclassified disease (97c). The prevalence of exposure to statins was 41% in the patients and 20% in controls (OR = 2.73; 95% CI = 1.21, 6.14). There was also a significant positive interaction between statins and proton pump inhibitors (OR = 3.3; 95% CI = 1.37, 7.54). Statins reduce circulating concentrations of coenzyme Q10, a co-factor for mitochon drial energy production, although in one study pitavastatin had no such effect, while atorvastatin did (98c). Furthermore, their effects on intramuscular coenzyme Q10 in patients symptomatic statin-associated myo pathy are not well described (99M). Supple mentation with coenzyme Q10 (100 mg/day, n = 18) has been studied in patients with
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J.K. Aronson
myopathic symptoms in a double-blind ran domized comparison with vitamin E (400 IU/day, n = 14) for 30 days (100c). Coenzyme Q10 reduced pain severity by 40% and interference by pain with daily activities by 38%; vitamin E had no effect. However, in contrast, coenzyme Q10 sup plementation in a placebo-controlled study in 44 patients had no effect on statin-related myalgia when the dose of simvastatin was titrated from 10 mg/day, doubling every 4 weeks, if tolerated, to a maximum of 40 mg/day (101c). An algorithm for monitoring statin ther apy and managing suspected statin-asso ciated myopathy has been published as part of a thorough review (102R). Tendinopathy In a retrospective study of 96 patients taking statins, median age 56 years, with either tendinitis (n = 63) or tendon rupture (n = 33), the effects were related to atorvastatin (n = 35), simvastatin (n = 30), pravastatin (n = 21), fluvastatin (n = 5), and rosuvastatin (n = 5) (103c). Tendinopathy occurred more often within the first year of treatment (59%). When the statin was restarted, in seven patients, the tendinopathy recurred in all cases. Arthropathy A 42-year-old man developed a painful left knee with a small effusion after taking simvastatin 40 mg/day for 4 weeks, having previously taken 10 mg/day (104A). Simvastatin was withdrawn and after 2 weeks the symptoms completely resolved. He then took pravastatin 20 mg/day and the pain returned, but resolved completely when the dosage was reduced to 10 mg/day. Reproductive system Testicular pain occurred on three occasions in a 54-year old man after he took three different statins – lovastatin, simvastatin and atorvastatin (105A). During each episode the pain increased when he was sitting, driving, or wearing tight clothing, and on each occasion the pain resolved after the drug was withdrawn. Immunologic A systematic review of 28 reports of statin-induced autoimmune
Drugs that affect lipid metabolism
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diseases has identified 10 cases of lupus-like syndrome (including two with autoimmune hepatitis), three of subacute cutaneous lupus, 14 of dermatomyositis and polymyo sitis, and one of lichen planus pemphigoides (106M). The mean time of exposure before the onset of the disease was 13 months (range 1 month to 6 years). Systemic immunosuppressive therapy was required in most cases, and in many cases antinuclear antibodies were still positive many months after clinical recovery. Two patients died despite aggressive immunosuppressive ther apy. Other reports have appeared (107A). Tumorigenicity In a cohort study, in which data from a large state drug benefit pro gram were linked with cancer registry data and Medicare health-care utilization data, all patients who started to take statins, antiglaucoma medications or another preven tive drug were identified (108c). The statin users (n = 24 439) were slightly younger and used some services more often than those with glaucoma (n = 7284). The mean fol low-up was 2.9 years and the longest fol low-up was 8.4 years. The incidence rates of colorectal, lung and breast cancers in both groups were very similar to the rates in the general population. Adjusted hazard ratios were 0.96 (95% CI = 0.70, 1.31) for colorectal cancer, 1.11 (95% CI = 0.77, 1.60) for lung cancer, and 0.99 (95% CI = 0.74, 1.33) for breast cancer. The authors con cluded that it is unlikely that statins alter the risk of colorectal, lung, or breast cancers over the durations studied. In a registry study of 361 859 statin users, most of whom were taking lovastatin, simva statin, or both, there was no strong evidence of either causation or prevention of cancer by statins (109c). In a case–control study using cancer registries in women aged 50 years or older women with breast cancer were not more likely than controls to have ever used statins (110c). Indeed, ever use of fluvastatin was associated with a reduced risk of breast can cer (OR = 0.5; 95% CI = 0.3, 0.8). Similarly, in a retrospective case–control study it has been suggested that statins may reduce the risk of lung cancers (111c). Of
811
483 733 patients from eight states in the south-central USA 163 662 (34%) were tak ing statins and 7280 (1.5%) had a primary diagnosis of lung cancer. Statin use for more than 6 months was associated with a risk reduction of lung cancer of 55% (adjusted OR = 0.45; 95% CI = 0.42, 0.48). The pro tective effect of statins was seen across dif ferent age and racial groups and was irrespective of the presence of diabetes, smoking, or alcohol use. Teratogenicity Statins are probably not ter atogenic (112M). In a study of 288 pregnant women based on a pregnancy registry, women for whom statins had been prescribed during the first trimester were compared with those who had been given a prescription for a fibrate/nicotinic acid in the first trimester and those for whom a statin had been prescribed at between 1 year and 1 month before con ception, but not during pregnancy (113c). Among women with a live birth, the rates of congenital anomalies were respectively 3/ 64 (4.7%; 95% CI = 1.00, 14), 3/14 (21%; 95% CI = 4.41, 63), and 7/67 (10%; 95% CI = 4.19, 22). The adjusted OR for congeni tal anomalies in the first and third groups was 0.36 (95% CI = 0.06, 2.18). The authors con cluded that there was no evidence of an increased risk of congenital abnormalities in the live-born infants of women for whom statins had been prescribed during the first trimester of pregnancy. Susceptibility factors Genetic In 50 patients taking statins there was no association between the risk of myopathy and any genotypes of the CYP isoenzymes that are involved in the metabolism of the statins (114c). In contrast, the poor metabolizer form of CYP2D6 was associated with increased efficacy of the statins that are metabolized by this isoenzyme. However, in a case–control study (263 samples, 388 SNPs), the CYP2D6*4 allele was signifi cantly associated with statin-induced myo pathy, although with a relatively low odds ratio of 2.7. The frequency of the CYP2D6*4 allele was about 50% in patients with atorvastatin-induced myopathy and only 28% in controls (115c).
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Mutations in the coenzyme Q gene COQ2 are associated with severe forms of inherited myopathy and have therefore been studied in 133 patients who developed a myopathy while taking a statin and in 158 matched controls who tolerated statins without adverse effects (116c). COQ2 geno types, based on two single nucleotide poly morphisms (SNP1 and SNP2) and a 2-SNP haplotype, were all significantly associated with statin intolerance. The odds ratios for an increased risk of statin intolerance among homozygotes for the rare alleles were 2.42 (95% CI = 0.99, 5.89), 2.33 (1.13, 4.81), and 2.58 (1.26, 5.28) for the SNP1 and SNP2 genotypes and the 2-SNP haplotype respectively. In 195 patients taking statins (atorvasta tin, simvastatin, or pravastatin), with vary ing degrees of myalgia, 14 single nucleotide polymorphisms (SNPs) were selected from candidates within the 5HT receptor gene family (HTR1D, HTR2A, HTR2C, HTR3A, HTR3B, HTR5A, HTR6, and HTR7) and the serotonin transporter gene (SLC6A4). SNPs in the HTR3B and HTR7 genes, rs2276307 and rs1935349 respec tively, were significantly associated with the degree of myalgia (117c). The authors concluded that individual differences in pain perception and nociception related to specific serotonergic gene variants may affect the development of myalgia in sta tin-treated patients. Drug dosage regimens In two patients symptoms of myalgia during daily statin therapy were relieved by giving rosuvasta tin, which has a long half-life, on Mondays, Wednesdays and Fridays (118A). In eight patients previously resistant to daily statin therapy, rosuvastatin given once weekly was effective (119c). Drug overdose Of 2331 exposures to statins reported to Texas poison control centers during 1998–2004, 55% were to statins alone; of these 57% of the patients were aged 5 years or under and 22% were aged 60 years or over (120c). Most of the patients were female (53%), 94% of the exposures were unintentional, and 91% occurred at
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J.K. Aronson
home. In 94% the outcome was classified as ‘no effect’. Children and adults differed with respect to sex (45% versus 66% female), the reason for exposure (100% ver sus 88% unintentional), the final medical outcome (4% versus 11% minor effects, none versus 4% moderate effects), and treatment (60% versus 24% decontamina tion by dilution, 13% versus 6% decontami nation by food). Drug–drug interactions Antacids The effect of simultaneous and separate administra tion of 20 ml of an antacid formulation con taining aluminium hydroxide 880 mg and magnesium hydroxide 780 mg (co-magal drox) on the pharmacokinetics of a single dose of rosuvastatin 40 mg have been stu died in a randomized, open, three-way, crossover trial in 14 healthy men volunteers (121c). Co-magaldrox given simultaneously reduced the rosuvastatin AUC0!t by 54% and Cmax by 50%. When the antacid was given 2 hours after rosuvastatin, it reduced the rosuvastatin AUC0!t by 22% and the Cmax by 16%. Antifungal azoles Rhabdomyolysis devel oped after co-administration of simvastatin with fluconazole and resolved after withdra wal of fluconazole; the interaction was attributed to inhibition of CYP3A4 (122A). Ciclosporin Rhabdomyolysis has been reported after the addition of ciclosporin in a patient taking simvastatin, attributed to inhibition of CYP3A4 (123A). Clopidogrel Rhabdomyolysis has been attributed to an interaction of clopidogrel with ciclosporin and atorvastatin, which the patient had taken for more than 3 years with out adverse effects or laboratory evidence of muscle damage (124A). The symptoms and laboratory abnormalities resolved when all the drug were withdrawn and did not recur when ciclosporin and atorvastatin were restarted. The authors attributed this effect to competition for CYP3A4, causing increased atorvastatin concentrations. Conversely, it has been suggested that inhibition by some statins of CYP-mediated
Drugs that affect lipid metabolism
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conversion of clopidogrel to its active meta bolite may reduce the action of clopidogrel (SEDA-28, 397). In 73 patients, 23 of whom had had a previous coronary stent thrombo sis and 50 of whom had not, platelet aggre gation was not affected by the addition of either atorvastatin 20 mg/day or pravastatin 40 mg/day to dual antiplatelet therapy with aspirin plus clopidogrel 75 mg/day (125c). However, this study does not solve the question of the clinical relevance of this putative interaction, since clopidogrel alone was not studied, since pravastatin is not a substrate of CYP3A4, and since the dose of atorvastatin may have been too low for it to have had an effect. In another study clopidogrel 75 mg/day had no effect on the pharmacokinetics of fluvastatin in healthy volunteers and fluva statin 80 mg/day did not alter the effect of clopidogrel on platelet function (126c). In a randomized, placebo-controlled study of long-term clopidogrel 75 mg/day in patients with cardiovascular disease or multiple risk factors taking aspirin, a sec ondary analysis of the interaction of clopi dogrel with statins was performed (127c). The statins were categorized as those that are predominantly metabolized by CYP3A4 (atorvastatin, lovastatin, and simvastatin) and those that are not (pravastatin and flu vastatin). Of 15 603 patients, 10 078 were taking a statin at baseline (8245 CYP3A4 metabolized and 1748 non-CYP3A4 meta bolized) and 5496 were not. For the overall population, the primary end-point (a com posite of myocardial infarction, stroke, or cardiovascular death at median follow-up of 28 months) was 6.8% with clopidogrel and 7.3% with placebo; it was similar among patients taking the two different types of statin. The authors therefore con cluded that there was no evidence of an adverse interaction of clopidogrel with statins. The interaction of statins, especially ator vastatin and simvastatin, with the antiplate let effects of a 600-mg loading dose of clopidogrel has been investigated in 1395 patients scheduled for coronary angiogra phy (128c). Atorvastatin and simvastatin had no effect on the antiplatelet activity of
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a loading dose of clopidogrel 600 mg and did not affect clinical outcomes after per cutaneous coronary intervention. Colchicine A patient with mild chronic renal insufficiency who had taken simva statin for over a year developed acute weakness within 3 weeks of starting to take colchicine (129A). He had raised muscle enzymes and electromyography was consistent with a myopathy, which rapidly resolved after withdrawal of both medications. Efalizumab Rhabdomyolysis occurred within 3 days of therapy with efalizumab in a 42-year-old man who was taking prava statin 20 mg/day (130A). Fusidic acid Rhabdomyolysis occurred in a 63-year-old man (131A) and a 74-year-old man (132A) who had taken simvastatin and fusidic acid; the interaction was attributed to inhibition of CYP3A4. Lopinavir þ ritonavir The systemic avail ability of rosuvastatin 20 mg/day and lopina vir þ ritonavir alone and in combination has been evaluated in an open, single-arm, pharmacokinetic study in 15 HIV-seronega tive volunteers (133c). Rosuvastatin AUC and Cmax increased 2.1 and 4.7 times when lopinavir þ ritonavir was added. When the combination was used one subject had an asymptomatic rise in creatine kinase activity to 17 times the upper limit of the reference range and another had rises in liver function tests of 1.1–2.5 times. The reduction in lowdensity lipoprotein cholesterol due to rosu vastatin was attenuated by lopinavir þ ritonavir. Macrolides In addition to interactions of statins with clarithromycin, an interaction with erythromycin has been reported in two men who developed myalgia, muscle weakness, inability to raise the arms and legs, and more than 60-fold increased serum creatine kinase activities (134A). In another case an 80-year-old man developed rhabdomyolysis while taking simvastatin
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after taking erythromycin for 3 weeks (135A). The mechanisms are presumed to be inhibition of CYP3A4 and perhaps also P glycoprotein. Risperidone A 76-year-old man taking sim vastatin 20 mg/day was given risperidone 1 mg/day for 12 days and developed gener alized muscle weakness and a markedly raised creatine kinase activity; the authors attributed this to inhibition by risperidone of CYP3A4 (136A). Silymarin The effect of silymarin on the pharmacokinetics of rosuvastatin has been studied in in vitro systems overexpressing OATP1B1 or BCRP transporters and in eight healthy men (137cE). In the in vivo study the subjects were randomized to pla cebo or silymarin 140 mg tds for 5 days and on day 4 all took a dose of rosuvastatin 10 mg. Silymarin inhibited both OATP1B1 and BCRP-mediated rosuvastatin transport in vitro (Ki 0.93 and 97 µmol/l respectively). However, there were no significant changes in AUC, half-life, V/F, or CL/F of rosuva statin in the in vivo study. Warfarin In a case–control study of 79 207 warfarin users with atrial fibrillation there were 1518 cases of upper gastrointestinal or intracranial bleed and 15 100 matched con trols without bleeding (138c). Long-term statin use (1 year or more) was associated with a lower risk of any bleeding (OR = 0.80; 95% CI = 0.66, 0.97). However, there was no association between bleeding and recent statin use (<6 months) (OR = 1.04; 95% CI = 0.74, 1.48) or statin use of any duration (OR = 0.91; 95% CI = 0.77, 1.07), which the authors thought suggested confounding. Nevertheless, there has been an anec dotal report of an interaction of warfarin with simvastatin (139A). • In an 82-year-old woman the INR rose to over 8 when her lipid-lowering therapy was switched from atorvastatin 10 mg/day to simvastatin 10 mg/day after she had taken warfarin 2.5 mg/day for almost 30 years with a stable INR within the range 2.0–3.5 for more than 2 years.
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Atorvastatin Urinary tract Hemorrhagic cystitis has been attributed to atorvastatin; the hema turia resolved spontaneously when the drug was withdrawn (140A). Drug–drug interactions Hypericum perfor atum (St John’s wort) In 16 patients taking atorvastatin 10–40 mg/day the addition of Hypericum perforatum extract (Movina) 300 mg bd significantly increased the serum concentration of LDL and total cholesterol compared with a multivitamin control; there was no statistically significant change in HDL cholesterol or in triglycerides (141c). Istradefylline The effects of steady-state istradefylline on the pharmacokinetics of a single dose of atorvastatin 40 mg and its metabolites have been evaluated in 20 healthy volunteers (142c). Istradefylline increased atorvastatin Cmax by 53% and AUC by 54%, and prolonged the half-life by 27%; the AUC of orthohydroxy atorva statin was increased by 18%, but the Cmax was not affected and there was minimal effect on parahydroxy atorvastatin AUC. The authors therefore suggested that the mechanism of the interaction was through inhibition of P glycoprotein by istradefylline.
Pravastatin Tumorigenicity In a meta-analysis and meta-regression analysis of 12 randomized controlled trials of pravastatin in 42 902 patients, although the overall association between the use of pravastatin and cancer was not statistically significant in a fixedeffects model (RR = 1.06; 95% CI = 0.99, 1.13) or a random-effects model (RR = 1.06; 95% CI = 0.97, 1.14), meta regression showed that the age of the study participants significantly modified the effect of pravastatin therapy on the risk of cancer, and that pravastatin was associated with an increasing risk of cancer as age increased (143M). However, a
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Bayesian analysis of the results yielded a low likelihood of a true association (144r).
Rosuvastatin Observational studies The adverse effects of rosuvastatin have been recorded in a post-marketing surveillance study, using prescription-event monitoring in 11 680 patients (median age 64 years) (145c). The median period of treatment was 9.8 months. In all, 2047 (18%) of the patients were reported to have stopped taking rosuvastatin. Myalgia was the most frequent reason for stopping and the most frequently reported clinical event. The rate of abnormal liver function tests was higher in those whose starting dose was 40 mg/day than in those who started with 10 mg/day (OR = 2.71; 95% CI = 1.53, 4.53). There were no cases of rhabdomyolysis. Systematic reviews The adverse effects of rosuvastatin have been assessed using data from 16 876 patients who took 5–40 mg/day in a multinational phase II/III/IIIb/IV pro gramme, representing 25 670 patient-years of continuous exposure (146M). In placebocontrolled trials, there were adverse events in 52% of patients taking rosuvastatin (n = 931) and 52% of those taking placebo (n = 483). In all controlled clinical trials with comparator statins, rosuvastatin was associated with an adverse events profile similar to the profiles for atorvastatin 10– 80 mg/day, simvastatin 10–80 mg/day, and pravastatin 10–40 mg/day. Clinically signifi cant rises in alanine transaminase were uncommon. Raised creatine kinase activity (to more than 10 times the upper limit of the reference range) occurred in up to 0.3% of patients taking rosuvastatin or other sta tins. Myopathy (a raised creatine kinase with muscle symptoms) possibly related to treat ment occurred in 0.03% of patients taking rosuvastatin at doses up to 40 mg/day. The frequency of dipstick-positive proteinuria at rosuvastatin doses up to 20 mg/day was comparable to that seen with other statins, and the development of proteinuria did not
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predict acute or progressive renal disease. Both short-term and long-term rosuvastatin treatment were associated with small increases in eGFR. No deaths were attribu ted to rosuvastatin. There was one case of rhabdomyolysis in a patient who took rosuvastatin 20 mg/day and concomitant gemfibrozil. Breasts Gynecomastia has been attributed to other statins and has been reported in a 57-year-old man who developed bilateral gynecomastia after taking rosuvastatin for 2 months; when he switched to atorvastatin the effect resolved within 1 month, suggest ing that the association with rosuvastain may have been coincidental (147A).
Simvastatin Hematologic Thrombocytopenia occurred over 8 weeks in a 63-year-old man taking simvastatin 10 mg/day (148A). Simvastatin was withdrawn and the platelet count rose over the next 4 weeks. Simvastatin was then reintroduced and the platelet count fell again. Platelet antibodies were negative. Musculoskeletal Bilateral leg compartment syndrome and myonecrosis, requiring fas ciotomy, has been attributed to simvastatin in two patients, one of whom had hypothyroid ism treated with levothyroxine (149A, 150A).
NICOTINIC ACID DERIVATIVES (SED-15, 2512; SEDA-28, 536)
Niacin The adverse effects of niacin have been reviewed (151R). Flushing is the most com mon adverse effect. Serious hepatotoxicity can occur but is largely confined to the use of modified-release formulations used as unregulated nutritional supplements.
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There have been a few reports of myopathy associated with combinations of niacin with statins, but there is no evidence that niacin itself is myopathic, either alone or in com bination with statins. Rare, less well-defined adverse effects include blurred vision due to cystoid macular edema, nausea and vomit ing, and exacerbation of peptic ulceration. Laboratory abnormalities are usually clini cally unimportant; they include increased prothrombin time, increased uric acid, and a reduced platelet count and serum phos phorus concentration. Drug abuse Niacin has been used in the hope of clearing drugs of abuse, such as cocaine and cannabis, rapidly from the body, in order to interfere with urine drug screening (152S). In four cases this led to severe adverse effects (153A). Two subjects had isolated skin effects, but the other two had life-threatening effects, including nausea, vomiting, dizziness, hepatotoxicity, metabolic acidosis, and hypoglycemia evol ving into hyperglycemia. One also had a profound neutrophilia and QT interval prolongation. All improved after drug withdrawal and supportive treatment. Drug formulations Among 1053 patients who took a modified-release formulation of niacin in a 6-month, prospective, obser vational, multicenter, open study, flushing (mostly mild or moderate) occurred in 430 (41%) (154c). Other adverse effects occurred in 125 patients (12.5%), most commonly pruritus (2.7%), gastrointestinal symptoms (3.8%), and nervous system-related com plaints (3.8%). Serious adverse effects were uncommon (0.6%). All patients recovered completely after withdrawal. In all, 11% of the patients withdrew because of flushing and 8.4% because of other adverse effects. Management of adverse reactions Flushing due to niacin can be reduced by the use of a modified-release formulation (niacin ER; SEDA-28, 536). In a double-blind, doubledummy, randomized, placebo-controlled, crossover study of flush provocation in 148 healthy men who took niacin ER 2000 mg, the incidence of flushing and its intensity
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and duration were significantly reduced by aspirin 650 mg orally (both 30 minutes before and at the same time as the niacin) (155C). Suppression of niacin-induced flush has also been achieved with the prostaglandin D2 receptor subtype 1 antagonist laro piprant (156c, 157c). Other preventive strategies include regu lar consistent dosing, the use of modifiedrelease formulations, patient education, dosing with meals or at bedtime, and avoid ance of alcohol, hot beverages, spicy foods, and hot baths or showers near the time of dosing (158R).
Torcetrapib Torcetrapib is an inhibitor of cholesteryl ester transfer protein (CETP), which trans fers cholesterol from HDL cholesterol to VLDL or LDL cholesterol (159R). Inhibi tion of this process increases HDL concen trations and reduces LDL concentrations (160C–162C). Torcetrapib was withdrawn in 2006 when phase III studies showed increased all-cause mortality in patients taking it in combination with atorvastatin (163r, 164r). Cardiovascular In clinical trials torcetrapib increased blood pressure (165R, 166R). For example, in a randomized double-blind trial at 64 centers in North America and Europe in 752 patients taking atorvastatin, 377 of whom were randomized to additional torce trapib 60 mg/day and 375 to placebo, systolic blood pressure increased by 6.6 mmHg in the combined-treatment group and 1.5 mmHg in the atorvastatin-only group (167C). In a double-blind randomized study 15 067 patients at high cardiovascular risk took torcetrapib þ atorvastatin or atorvasta tin alone (168C). After 12 months in patients who took torcetrapib there was a 72% increase in HDL cholesterol and a 25% reduction in LDL cholesterol. Systolic blood pressure increased by 5.4 mmHg. There was an increased risk of cardiovascu lar events (HR = 1.25; 95% CI = 1.09, 1.44) and death from any cause (HR = 1.58; 95% CI = 1.14, 2.19). Post-hoc analyses showed
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an increased risk of death in patients taking torcetrapib whose reduction in serum potas sium or increase in serum bicarbonate was greater than the median change. In animal experiments the increase in blood pressure associated with torceterapib was not associated with its effect on the cholesteryl ester transfer protein; another inhibitor, ana cetrapib, did not increase blood pressure (169E). The mechanism was not mediated by adrenoceptors, angiotensin II, or endothelin receptors, and there was no direct contractile effect on vascular smooth muscle. However, torcetrapib was associated with an increase in plasma concentrations of aldosterone and cor ticosterone; in vitro it released aldosterone from adrenocortical cells. Adrenalectomy prevented the increase in blood pressure. In adrenal cell lines in culture torcetrapib induced the synthesis of both aldosterone and cortisol associated with induction of the expression of CYP11B2 and CYP11B1, two enzymes involved in the biosynthesis of
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aldosterone and cortisol respectively (170E). There was an increase in intracellular cal cium, and L-type calcium channel blockers completely blocked the effects of torcetrapib. Dalcetrapib, a structurally different inhibitor of cholesteryl ester transfer protein, did not share these actions (171E). In a systematic review of data from the RADIANCE 1 and 2 studies, in which patients were randomized to atorvastatin or torcetrapib þ atorvastatin, those who took torcetrapib had higher systolic blood pres sures and plasma sodium and bicarbonate concentrations and lower potassium concen trations (172M). The reduction in potassium concentrations was associated with the increase in blood pressure, and the use of renin–angiotensin–aldosterone system inhi bitors tended to worsen the increase in blood pressure. These results support the proposed mechanism whereby torcetrapib increases blood pressure, by actions on aldosterone and cortisol.
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Ami Sabharwal and Mark Middleton
45
Cytostatic and cytotoxic drugs
Editor’s note: The wide range of cytostatic and cytotoxic drugs, the multitude of their adverse effects and the fact that they are gen erally used in combinations of several agents all make it impossible to provide as detailed a review of the adverse effects of all the drugs in this field as the Annual gives in others. This year this chapter is devoted to a special review of the monofunctional alkylating agents dacarbazine and temozolomide. Previous special reviews in the SEDA ser ies have been as follows: • Anthracyclines (SEDA-25, 533) • Antimetabolites (SEDA-29, 551): Purine antagonists, pyrimidine antagonists, antifolate drugs, phosphatidylcholine antagonists, adenosine deaminase inhibitors • DNA alkylating N-Lost derivatives (SEDA-31, 721) • Fluorouracil (SEDA-23, 476) • Inhibitors of topoisomerase I and topoisomerase II (SEDA-27, 477) • Paclitaxel (SEDA-21, 463) • Platinum compounds (SEDA-26, 490) • Tyrosine kinase inhibitors (SEDA-30, 520) • Vinca alkaloids (SEDA-28, 538)
Monofunctional alkylating agents Dacarbazine and temozolomide are mono functional alkylating agents. Although dacarba zine shares structural similarity with certain purines, its main mechanism of action is Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32045-9 2010 Elsevier B.V. All rights reserved.
through methylation of DNA via its active meta bolite methyltriazen-imidazole-carboxamide (MTIC) (1C). Temozolomide is a second-generation imi dazotetrazine prodrug that undergoes hydro lysis to form the active alkylating metabolite MTIC (2C). Unlike dacarbazine, however, this conversion is spontaneous and non enzymatic and occurs under physiological conditions in all tissues to which the drug is distributed. MTIC forms methyl adducts with DNA bases (3C), the most common of which occur at the N7 position of guanine and the N3 position of adenine, which are repaired by the base excision repair (BER) mechanism. However, the most important lesion formed, in terms of mutagenesis, carcinogenesis, and cytotoxicity, is O6-methylguanine (O6-MG). O6-MG adducts can be repaired by O6-MG-DNA-methyltrans ferase (MGMT). If unrepaired, these adducts trigger futile DNA mismatch repair, G2 arrest, and ultimately cell death by a combination of senescence and mitotic catastrophe. Dacarbazine is commonly used in the treat ment of metastatic malignant melanoma (4C, 5R, 6C). Combination therapy with doxorubi cin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) is used in the standard treatment of both early and advanced Hodg kin’s disease, with or without radiotherapy (7R). It is also used in the treatment of endocrine tumors, including malignant pheochromo cytoma, islet cell carcinoma, and medullary carcinoma of the thyroid, in combination with other chemotherapy agents in patients with soft tissue sarcomas, fibrosarcomas, and rhabdomyosarcomas, alone or in combination with other agents for the treatment of Kaposi’s sarcoma, in conditioning before
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bone-marrow/stem-cell transplantation and in the treatment of childhood tumors, including neuroblastoma. Temozolomide is used in the treatment of refractory anaplastic astrocytomas, glioblas toma multiforme, recurrent glioblastoma multi form, and advanced or metastatic melanoma.
of dacarbazine. They occur in more than 90% of patients, usually 1–3 hours after treatment (15R). However, with current antiemetic regimens, including high-dose glucocorticoids, 5-HT3 receptor antagonists, and metoclopramide, severe nausea and vomiting (grades 3/4) are seen in only 2–17% of patients (4C, 9C–11C). Symptoms usually improve after 1–2 days when dacar bazine is given over 5 days, indicating a probable central nervous system mechanism. High doses of dacarbazine can cause gastrointestinal bleeding (4%) possibly due to a combination of low platelet count and abnormal platelet function, as suggested by coagulation studies in vitro. Severe abdom inal pain can also occur (9%) (9C). Other gastrointestinal adverse effects include anorexia 1% (9C), a metallic taste and diarrhea, which more commonly occurs after high-dose bolus intravenous treatment.
Dacarbazine Cardiovascular Local pain during intra venous infusion is common (over 10%) and can be minimized by administration through a central line or by administration as a short infusion as opposed to a bolus injection. This has been attributed to a photodegradation product of dacarbazine, 5-diazoimidazole 4-carboxamide (Diazo-IC) (8E). Nervous system Although relatively rare, a variety of neurological symptoms have been reported in patients treated with dacarbazine, including headache in 1–4% (9C), weakness in under 1% (4C), paresthesia, blurred vision, confusion, seizures, dizziness, and peripheral neuropathy. Lethargy has been reported following dacarbazine treatment (18%) (6C). Hematologic Mild to moderate myelo suppression is common with dacarbazine, usually beginning on days 5–7, with a nadir on days 7–10 and reversal within 3–6 weeks. However, more severe episodes (grades 3/4) can occur, especially with higher single doses of dacarbazine, requiring hematological sup port: anemia 2–6%, leukopenia (especially neutropenia) 2–19% and thrombocytopenia 1–7% (4C, 9C–11C). Eosinophilia can also occur occasionally. Leukopenia and thrombocytopenia can be predicted by pretreatment MGMT concen trations in peripheral blood mononuclear cells, thereby identifying patients at greatest risk of toxicity or those suitable for dose intensification (12C). There have been two reports of aplastic anemia after dacarbazine (13A, 14A). Gastrointestinal Nausea and vomiting are very common and limit the therapeutic dose
Ami Sabharwal and Mark Middleton
Liver Hepatotoxicity, with raised liver enzymes, including AsT, AlT, alkaline phos phatase, and gamma glutamyl transpeptidase, has been seen after dacarbazine treatment (4C, 9C). Hepatic vein thrombosis leading to fatal hepatic necrosis has been reported (16cr, 17C). Patients typically develop symptoms of liver failure during their second course of therapy with dacarbazine. Fatalities have been reported (18A). Death is rapid and post-mortem studies have confirmed acute widespread hepatic vein thrombosis and massive hepatic necrosis. Budd–Chiari syn drome (veno-occlusive disease) caused by an allergic thrombophlebitis with secondary liver necrosis appears to be the mechanism (19A). Immune pathology is suspected; as this reaction almost always occurs during the second course of treatment rather than the first, there is extensive lymphocytic and eosinophilic infiltration in hepatic veins and occasionally a peripheral eosinophilia (20A). Urinary tract Hemorrhagic cystitis is commonly associated with oxazaphosphor ine alkylating agents but has also been reported after dacarbazine treatment (21A).
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• A 63-year-old man with asymptomatic metastatic malignant melanoma received three cycles of dacarbazine monotherapy (600–850 mg/m2 every 21 days), after which he developed gross hematuria and mild dysuria. Cystitis was con firmed after investigation, including urinalysis, repeated urine cultures, ultrasonography, and cystoscopy.
Skin Phototoxic dermatitis can result in a pruritic maculo-urticarial, erythematous rash on light-exposed areas including face, neck, hands, and arms. Phototoxic dermatitis occur red in 10 patients with malignant melanoma treated with dacarbazine, in most cases as part of a combined schedule with carmustine, hydro xycarbamide (hydroxyurea) and interferon alfa-2a; the dermatitis occurred after a few well-tolerated sessions of chemotherapy (22c). In general, patients are advised not to expose themselves to direct sunlight during days of chemotherapy sessions, and skin reactions are treated with sunscreens and topical glucocorti coids. Dacarbazine should be withdrawn if the reaction gets worse with continued treatment. Urticaria and radiation recall dermatitis have also been reported after dacarbazine (23A, 24A). Facial flushing occasionally occurs (25c). C
C
Hair Alopecia can occur (26 , 27 ). In one study it affected 12 of 24 patients (28C). Immunologic There has been a single case report of anaphylactic shock due to dacarba zine (29A). A flu-like syndrome with chills, malaise, and myalgia can occur, usually with succes sive, single large doses of dacarbazine (30C). The symptoms usually start after 7 days and generally resolve after 1–3 weeks.
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in a patient with melanoma (13A). Acute promyelocytic leukemia has been reported after ABVD chemotherapy þ radiotherapy in a patient with Hodgkin’s disease (31A). There have also been reports of Hodgkin’s disease and non-Hodgkin’s lymphoma after dacarbazine (32A). Teratogenicity Dacarbazine is teratogenic in animals and contraceptive precautions are recommended. In 43 children born to mothers with hematological malignancies (18 with non-Hodgkin’s lymphoma, 14 with Hodgkin’s disease, 7 with acute leukemia and 4 with chronic granulocytic leukemia) who received chemotherapy during some portion of their pregnancy, including 19 who received chemotherapy during the first trimester, there were no physical, neurological, psychologi cal, hematological or immunological abnormalities, and cytogenetics were normal (33c). However, this small study does not rule out the possibility of teratogenic effects. Lactation Although the excretion of dacar bazine into breast milk is not known, breast feeding is not recommended. Drug administration route Dacarbazine is administered intravenously as a bolus or an infusion. It is extremely light sensitive and undergoes rapid photodegradation after exposure to sunlight. It is therefore adminis tered in light-protected infusion bags. It is a vesicant, and subcutaneous extravasation can cause tissue damage and severe pain.
Body temperature Dacarbazine can be asso ciated with fever (4%) (4C).
Drug–drug interactions CYP inducers Dacarbazine is a substrate of CYP1A2 and CYP2E1. CYP1A2 inducers (e.g. insulin) may therefore increase the metabolism of dacarbazine, and inhibitors of CYP1A2 (e.g. ciprofloxacin) and CYP2E1 (e.g. cimetidine) can reduce it.
Tumorigenicity Dacarbazine has been asso ciated with leukemias in some reports. Acute non-lymphocytic leukemia after treatment with dacarbazine in combination with other cytotoxic drugs has been reported in a patient with breast cancer and after adjuvant treatment with single-agent dacarbazine
Interleukin 2 The effects of interleukin-2 on the pharmacokinetics of dacarbazine and its major metabolite, 5-amino-imidazole 4-carboxamide, have been studied. Plasma concentrations of dacarbazine were signifi cantly lower after co-administration of inter leukin 2, due to an increase in clearance, and
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there was an increase in the steady-state apparent volume of distribution (34c). The effect was related to the dose of inter leukin-2. There was no effect in half-life or urinary excretion of dacarbazine and 5-amino-imidazole 4-carboxamide. Dacar bazine is only 5% bound to plasma pro teins, so protein binding displacement cannot be evoked as a mechanism for these effects.
radiotherapy, despite the use of lower doses of temozolomide because of the fatigue that is commonly associated with radio therapy (35C).
Temozolomide Cardiovascular Thromboembolic events have been recorded in 2% of patients treated with concurrent temozolomide and radiotherapy followed by adjuvant temozolomide in the treatment of glioblastoma multiforme (35C). Cerebral hemorrhage in the absence of thrombocytopenia or coagulation disorders occurred in two patients (<1%) treated with concurrent temozolomide and radiotherapy for glioblastoma multiforme and in the absence of thrombocytopenia in one patient (<1%) treated with temozolomide alone for metastatic melanoma (6C, 35C). Respiratory A variety of respiratory symp toms can occur with temozolomide, includ ing pharyngitis (8%), upper respiratory tract infections (3–8%) (36C), cough (5–8%), sinusitis (6%), dyspnea (5–13%) (37C), and pneumonitis (38A, 39A). Nervous system Numerous neurological symptoms have been reported with temozolo mide (6C, 36C, 37C). They include headache (8–41%), seizures (6–23%), hemiparesis (18%), dizziness (2–12%), abnormalities of coordination (11%), amnesia (10%), insom nia (4–10%), somnolence (9–12%), ataxia (8%), paresis (2–8%), anxiety (7%), memory impairment (7%), depression (6%), confu sion (3–5%), paresthesia (9%), blurred vision (5–8%), diplopia (5%), changes in vision (5%), and agitation (<1%). Fatigue is seen in 14–20% of patients treated with temozolomide monotherapy and more frequently (33%) in patients receiving con comitant treatment with temozolomide and
Ami Sabharwal and Mark Middleton
Fluid balance Peripheral edema has been reported with temozolomide in up to 11% of patients. Hematological Myelosuppression is com mon with temozolomide monotherapy (cumulative dose 800–1200 mg/m2). It is usually mild to moderate, but more severe episodes (grades 3/4) can occur, including lymphopenia (grades 3/4: 55%), thrombo cytopenia (grades 3/4: 3–19%), neutropenia (grades 3/4: 2–14%), leukopenia (grades 3/4: 1–11%), and anemia (grades 3/4: 1–4%) (6C, 36C, 37C). Lesser degrees of myelosuppression are seen with continuous low-dose temozolomide (75 mg/m2/day 7 days a week) plus concurrent radiotherapy, as used in the treatment of glio blastoma multiforme. Grades 3/4 neutropenia occurred in 2–4% of patients and grades 3/4 thrombocytopenia in 2–5.2% (35C, 40C, 41C). Leukopenia and thrombocytopenia can be predicted by pre-treatment MGMT con centrations in peripheral blood mononuclear cells, thereby identifying patients at greatest risk of toxicity or those suitable for dose intensification (12C). Gastrointestinal Gastrointestinal adverse effects are common with temozolomide (6C, 36C, 37C). Nausea has been reported in 30– 52% of patients (grades 3/4, 4–6%) and vomiting in 28–34% (grades 3/4, 4–8%). Mild to moderate constipation is seen in up to one-third of patients (5–30%) but it is rarely severe (3%) (6C, 36C, 37C). There is a lower incidence of anorexia (13–15%) with only occasional severe episodes (1–3%). Infrequent episodes of other gastrointest inal symptoms have also been reported, including diarrhea (4%), stomatitis (2%), dyspepsia (2%), abdominal pain, dysphagia, taste disturbance, and weight gain. Urinary tract A variety of genitourinary symptoms can occur with temozolomide, including incontinence (8%), urinary tract
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infections (8%), and increased urinary fre quency (6%). Skin A number of dermatological adverse effects are associated with temozolomide: rashes (8–13%), including desquamation (42A), pruritus (5–8%), dry skin (5%), radiation injury (2% during maintenance temozolomide therapy after radiotherapy), and erythema (1%). Stevens–Johnson syn drome/toxic epidermal necrolysis (43A) and palmar-plantar erythrodysesthesia (44A) have also been reported in single cases. Hair Alopecia occurs in about 5% of patients (36C). Musculoskeletal A number of musculo skeletal adverse effects have been attributed to temozolomide therapy including: back pain (8%), abnormal gait (6%), arthralgia (6%), and myalgia (5%) (45C). Immunologic Anaphylaxis occurs rarely with temozolomide (<1%). Infection risk Continuous daily temozolo mide can cause lymphocytopenia (46M), with a possible increased risk of opportunis tic infection; therefore patients receiving radiation and temozolomide are given pro phylaxis against Pneumocystis jiroveci (car inii) pneumonia with oral co-trimoxazole. The risk of opportunistic infections may be increased further, as this group of patients are often also taking long-term glucocorti coids (47A). Despite these measures, severe infections occurred in 9 patients (3%) during concomi tant temozolomide and radiotherapy and in 12 patients (5%) during temozolomide treat ment alone (35C). Body temperature Fever has been reported in about 10% of patients (6C). Drug resistance Epigenetic silencing of MGMT repair gene by promoter methylation compromises DNA repair and has been asso ciated with longer survival in patients with glioblastoma who receive alkylating agents. Patients with glioblastoma multiforme
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containing a methylated MGMT promoter benefited from temozolomide treatment, whereas those who did not have a methylated MGMT promoter did not (48C, 49C). MGMT promoter methylation correlates with improved progression-free and overall survi val in patients treated with temozolomide. Strategies to overcome MGMT-mediated che moresistance are being investigated. These include treatment with non-toxic pseudosub strate inhibitors of MGMT, such as lomegua trib (50c–54c), or RNA interference-mediated gene silencing of MGMT (55R). However, systemic use of MGMT inhibitors is limited by an increase in hematological toxicity. Another strategy is to deplete MGMT activity in tumor tissue using a dose-dense temozolo mide schedule (56c–58c). These alternative schedules are well tolerated; however, it remains unclear whether they are more effec tive than the standard dosing regimen or whether they effectively deplete MGMT activ ity in tumor tissue (59R, 60R). Tumorigenicity Secondary myelodysplastic syndrome, acute myeloid leukemia and non Hodgkin’s lymphoma have been attributed to temozolomide in patients with glioma (61A). • A 20-year-old woman with glioblastoma multiforme was given temozolomide 75 mg/m2/day with radiotherapy 60 Gy in 30 fractions daily, and she developed a non-Hodgkin’s lymphoma 2 months later. She did not receive adjuvant temozolomide. Nodal biopsy showed densely packed, monomorphic, small, atypical lymphoid cells staining positively for CD20 and MIB-1, establishing a diagnosis of Burkitt’s lymphoma. Although she was treated with combination chemotherapy for lymphoma, she died of a progressive glioblastoma 3 months after the diagnosis of lymphoma.
Although the latency period in this case was short, longer latency periods between temo zolomide treatment and the development of myelodysplastic syndrome, acute myeloid leukemia, and non-Hodgkin’s lymphoma have been reported of between 8 months and 3 years (62A–64A). As these patients also receive radiation and other chemo therapeutic agents, determining the contribu tion of a single agent is difficult.
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In 2007 the FDA reported 18 cases of aplastic anemia associated with temozolo mide from August 1999 to November 2006. The average age of these patients was 48 years and there was a slight male predominance (55% men). Eight were receiving concurrent radiotherapy. The median time to the devel opment of aplastic anemia was 36 (range 5–578) days. None had prior pancytopenia or aplastic anemia. Six had been exposed to other medications that may have contributed to the condition, including other alkylating agents, antibiotics, and antiepileptic drugs, but the timings of these drugs were not pro vided. The marrow recovered in five patients within 1–4 months after temozolomide with drawal and five eventually died of complica tions from aplastic anemia or from the complications of a bone-marrow transplant (65S). Three further cases of aplastic anemia have since been reported (66A–68A). A single case of severe and potentially irreversible thrombocytopenia has also been reported (69A). Fetotoxicity Numerous birth defects and testicular toxicity occurred in animals that were given doses less than those used in humans. Men and women should be advised to avoid pregnancy while receiving temozolomide. Lactation The excretion of temozolomide into breast milk is not known, but because of the risk of serious adverse reactions in the nursing infant, breast feeding is not recommended. Drug–drug interactions Valproic acid Val proic acid can enhance the adverse effects of temozolomide by inhibition of CYP450 and increase serum temozolomide concentra tions; monitoring is recommended. A 48 year-old patient with a glioblastoma devel oped acute cholestatic hepatitis with hepatic failure when valproic acid was added to ther apy with temozolomide and the integrin inhi bitor cilengitide (70A). Drug–food interactions Food reduces the rate and extent of temozolomide absorption, and therefore capsules should be taken con sistently either with or without food.
Chapter 45
Ami Sabharwal and Mark Middleton
Photodynamic therapy in the treatment of cancers In photodynamic therapy a photosensitizing compound is administered systemically, locally, or topically to a patient with a can cer (71R–73R). After a latent period, the cancer is illuminated with visible light, which, in the presence of oxygen, leads to the generation of cytotoxic species and cell death (74R, 75R). The choice of a photosen sitizing compound that is concentrated specifically in the malignant tissue confers selectivity on the technique (76R), which has been used to treat skin cancers (74R, 77R, 78R), including mycosis fungoides (79Ar), esophageal carcinoma (80c), oral and laryngeal cancers (81R), bronchogenic carcinomas (82c), pleural mesothelioma (83R), adenocarcinoma of the stomach and colorectal carcinomas (84c), tumors of the bile ducts and pancreas (85r), transitional cell carcinoma of the urinary bladder (86c, 87c), prostate cancer (88R), brain tumors (89R), and local recurrent breast cancer and gynecological tumors (cervical intraepithelial neoplasia, vulvar intraepithelial neoplasia, and ovarian cancers) (90R). It can be com bined with anticancer drugs (91R) and immu nomodulators (92R). Other applications have included hidradenitis suppurativa (93R), psoriasis (94R), cutaneous leishmaniasis (95R), actinic keratosis (96R), actinic cheilitis, sebaceous gland hyperplasia (97R), lichen sclerosus, acne vulgaris (98M), Barrett’s esophagus (99M), genital warts (100A), and recurrent laryngeal papillomatosis (101c, 102C). Photodynamic therapy with verteporfin has been used in the treatment of age-related macular degeneration (SEDA-30, 545). The classes of photosensitizers include porphyrin derivatives (103R), chlorins and purpurins (104R), phthalocyanines (105cR), porphycenes (106R), and fullerenes (107R). All have different photochemical and photophysical properties in terms of mechanisms of action and light activation (78R). Porphy rins were the first to be used, and the wave lengths of light chosen were based on the absorption spectrum of porphyrins – blue
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because the largest peak is at 400 nm (the Soret band) and red because it has greater penetration but less absorption at 650 nm (a Q band) (76R). Green light at 514 nm has also been used. The molecular mechanisms have been reviewed (108R), as have the phy sics, biochemistry, pharmacology, and pathology of the process (73R). Observational studies Of 49 patients with advanced esophageal cancer, 22 were given 5-aminolevulinic acid 60 mg/kg orally 6–8 hours before light exposure and 27 were given a hematoporphyrin derivative 2 mg/kg intravenously 48 hours before light exposure (80c). There was odynophagia in 9 and 13 patients respectively, fever up to 39.0°C on the afternoon of the treatment day (n = 5 and 8), and chest pain for 1–2 days (n = 9 and 13). After oral administration of 5-aminolevulinic acid dissolved in 250 ml of orange juice all the patients complained of nausea, which was relieved by ondansetron. There were no cases of sunburn. In a phase II study of the effects of monoL-aspartyl chlorin e6 in 41 patients with early superficial squamous cell carcinomas of the lung, there were no serious adverse effects (109c). Photosensitivity was studied by expo sure to sunlight for 5 minutes and the results were classified as follows: 0 – no reaction; 1 – minimum visible erythema; 2 – deep clearly defined erythema; 3 – intense erythema or edema. Five of 31 patients who were tested at 13 or 14 days after treatment had photo sensitive reactions; three patients had minimal visible erythema, one had deep clearly defined erythema, and one had blister formation. Of nine patients who were tested at other times from 9 to 18 days after treatment, none had any reactions. Comparative studies In 218 patients with advanced esophageal cancer randomized to photodynamic therapy with porfimer sodium and argon-pumped dye laser or to neodymium:YAG laser therapy, there was equivalent improvement in dysphagia (110C). There were more mild to moderate complications after photodynamic therapy, including sunburn in 19%. Perforations from laser treatment or associated dilatation
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occurred in 1% after photodynamic therapy and in 7% after neodymium:YAG laser ther apy. Treatment had to be stopped because of adverse events in 3% of those who were given photodynamic therapy and in 19% after use of the neodymium:YAG laser. In a partially blinded study in 208 patients with Barrett’s esophagus, 138 were treated with porfimer sodium þ omeprazole and 70 with omeprazole only (111C). The most common adverse events related to porfi mer were photosensitivity reactions (69%), esophageal strictures (36%), vomiting (32%), non-cardiac chest pain (20%), pyr exia (20%), dysphagia (19%), constipation (13%), dehydration (12%), nausea (11%), and hiccups (10%). Photosensitivity reactions occurred within 90 days after treatment, typi cally with sunburn-like reactions especially affecting the face, hands and neck. Most of the reactions were mild (69%), 24% were moderate, and 7% were severe. Although all resolved, one patient was left with photosensi tivity-related keloid scars. Gastrointestinal Deterioration of esopha geal motility can occur after photodynamic therapy for esophageal carcinoma or Barrett’s esophagus. Of 23 patients, 13 with esophageal carcinoma and 10 with Barrett’s esophagus, 11 had normal motility, 6 had ineffective esophageal motility, and 6 had aperistalsis; 5 of those with aperistalsis had carcinomas (112c). Follow-up tracings after photodynamic therapy showed that 6 had normal motility, 7 had ineffective esophageal motility, and 10 had aperistalsis. The authors concluded that photodynamic therapy can worsen esophageal motility in some patients and that dysphagia after photodynamic therapy may be related to underlying esophageal dysmotility and may not always be caused by a stricture or underlying carcinoma. Of 47 patients with Barrett’s high-grade dysplasia or mucosal carcinoma who were referred for endoscopic ablation and were prospectively evaluated with esophageal manometry before and after porfimer sodium, six did not complete the study (113c). There was abnormal esophageal
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motility in 14 patients before photodynamic therapy (3 with diffuse esophageal spasm, 7 with ineffective esophageal motility, and 4 with aperistalsis). After photodynamic ther apy, motility improved in 3 and worsened in 7. None developed new aperistalsis. Thus, abnormal motility was present in 19 patients after photodynamic therapy. Worsened func tion was more likely in patients with longer segment disease.
In 59 Japanese patients with cancers, photosensitivity was studied by exposure to a slide projector lamp 3 weeks or more after treatment with porfimer sodium (119c). Women needed significantly longer recovery periods than men, and those with lighter skins were more sensitive. Newer sensitizers, such as the prophyrin precursor 5-aminolevulinic acid, may cause less phototoxicity. Of 18 patients with colo rectal, duodenal, or esophageal tumors who were given 5-aminolevulinic acid 30–60 mg/kg orally, followed in 10 cases by a second dose a few weeks later, only 2 had mild photosensi tivity reactions; 6 had transient rises in serum transaminases and 5 had mild nausea and vomiting (120c). Of 14 healthy men aged 20–26 years who were given a single dose of temoporfin 0.100–0.129 mg/kg as part of a pharmacoki netic study and were exposed to a test dose of sunlight 2 weeks later, 12 had no reactions and were told to avoid prolonged exposure to bright sunlight for 3 months (121c). Within 48 hours of discharge, 6 of those 12 had devel oped partial thickness burns on the left fore arm and more superficial burns on other body areas (about 1% of the total body surface area) after transient exposure to daylight. Healing was much slower than with conven tional thermal injury (28 versus 14 days), and there was prominent scarring in several cases. The manufacturers responded that 957 healthy volunteers and patients had been exposed to temoporfin, and many had been treated with photodynamic therapy on two or more occa sions in clinical studies for a range of different indications (122c). In all, 22 serious adverse drug reactions attributable to photosensitivity, including burns, had been reported (2.3% of all subjects), including the six cases described in the report. In clinical studies, there had been 15 serious adverse drug reactions involving burns or photosensitivity reactions in 931 patients (1.6%). They suggested that the reac tions had been caused by extravasation of the agent at the site of infusion.
Skin Urticaria and respiratory distress have been attributed to porfimer sodium (114A). The use of porphyrin derivatives is asso ciated with cutaneous photosensitivity, which can persist for up to 3 months (115c). Of 180 patients who were given 266 intravenous injections of Photofrin polyporphyrin 0.5–2.0 mg/kg for photodynamic therapy, 20–40% reported some type of phototoxic response. There was an even higher inci dence in another study, in which 23 patients received a systemic porphyrin derivative and 17 reported cutaneous phototoxicity, includ ing 3 who had blistering (116c). The symp toms lasted for a mean of 6 (range 5–23) weeks. Failure to use photoprotective mea sures was thought to be the major contribut ing factor. Other complications included skin hyperpigmentation, ocular discomfort, prur itus, pain at the injection site, and urticaria. Of 26 patients with recurrent laryngeal papillomatosis who received dihemato porphyrin ether 2.5 mg/kg intravenously before photodynamic therapy, all had some degree of photosensitivity (117c). The reac tions included mild erythema and inflamma tion (88%), swelling (58%), blistering (23%), ocular discomfort (61.5%), pruritus (38%), and hyperpigmentation (46%). The effects lasted for 9 (range 4–17) weeks. The severity of the reactions was mainly determined by how compliant the patient was in following instructions to take precautionary measures. In 58 patients (29 with lung cancers, 5 with esophageal cancers, 12 with gastric cancers, 8 with cervical cancers, and 4 with bladder cancers) who were given porfimer sodium as part of photodynamic therapy, there was complete remission in 48; there were no ser ious complications; skin photosensitivity occurred in 13 patients (118c).
Ami Sabharwal and Mark Middleton
• A 15-year-old girl had a recurrent parietal malignant ependymoma excised, followed by photodynamic therapy with porfimer 0.75 mg/kg intravenously and precautionary use
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of sunglasses and avoidance of direct sunlight (123A). After 48 hours she developed a seconddegree burn on a finger to which an oximeter had been attached. The lesion was located on the side of the finger adjacent to the light-emitting diodes.
Light from the pulse oximeter probably acti vated the photosensitizer in this case.
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rest; mitomycin 10 mg/m2 by intravenous bolus every 6 weeks for a total of four doses. Oral dipyridamole 75 mg tds was given during the administration of fluorouracil. The most common adverse effect was stomatitis. Three patients had reversible hemolytic–uremic syndrome. Five had grade 4 toxicity. There were no treatment-related deaths.
OTHER CYTOTOXIC DRUGS
Paclitaxel
Fluorouracil
Observational studies In a single-center study of drug-eluting stents in 64 patients, paclitaxel-eluting stents were used in 7 and sirolimus-eluting stents in 57 patients (125c). There was procedural success in 63 patients. One 87-year-old patient died in hospital due to papillary muscle rupture and refractory heart failure. There were no 30-day cases of stent thrombosis, reinfarction, or target vessel reintervention. During follow-up, one patient died in a rehabilitation facility 52 days after intervention due to nosocomial pneumonia and sepsis. There were no late cases of stent thrombosis, reinfarction, or target vessel reintervention.
(SED-15, 1407)
Urinary tract The hypothesis that dual biochemical modulation of fluorouracil in combination with mitomycin improves the survival of patients with pancreas cancer has been tested in 50 patients with II or III unresectable adenocarcinoma of the pancreas, a performance status of 0–2 and adequate organ function (124c). Treatment included fluorouracil 200 mg/m2/day by continuous intravenous infusion for 4 weeks, followed by 1 week of rest; leucovorin 30 mg/m2 by intravenous bolus on days 1, 8, 15, and 22, followed by 1 week
(SED-15, 2663)
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841 108. Ortel B, Shea CR, Calzavara-Pinton P. Molecular mechanisms of photodynamic therapy. Front Biosci 2009;14:4157–72. 109. Kato H, Furukawa K, Sato M, Okunaka T, Kusunoki Y, Kawahara M, Fukuoka M, Miyazawa T, Yana T, Kaoru M, Shiraishi T, Horinouchi H. Phase II clinical study of photodynamic therapy using mono-L-aspartyl chlorin e6 and diode laser for early superficial squamous cell carcinoma of the lung. Lung Cancer 2003;42(1):103–11. 110. Lightdale CJ, Heier SK, Marcon NE, McCaughan Jr. JS, Gerdes H, Overholt BF, Sivak Jr. MV, Stiegmann GV, Nava HR. Photodynamic therapy with porfimer sodium versus thermal ablation therapy with Nd:YAG laser for palliation of esopha geal cancer: a multicenter randomized trial. Gastrointest Endosc 1995;42(6):507–12. 111. Overholt BF, Lightdale CJ, Wang KK, Canto MI, Burdick S, Haggitt RC, Bronner MP, Taylor SL, Grace MG, Depot M; Inter national Photodynamic Group for HighGrade Dysplasia in Barrett’s Esophagus. Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett’s esophagus: international, par tially blinded, randomized phase III trial. Gastrointest Endosc 2005;62(4):488–98. Erratum in 2006;63(2):359. 112. Malhi-Chowla N, Wolfsen HC, DeVault KR. Esophageal dysmotility in patients undergoing photodynamic therapy. Mayo Clin Proc 2001;76(10):987–9. 113. Shah AK, Wolfsen HC, Hemminger LL, Shah AA, DeVault KR. Changes in esopha geal motility after porfimer sodium photo dynamic therapy for Barrett’s dysplasia and mucosal carcinoma. Dis Esophagus 2006;19 (5):335–9. 114. Karasic DS, Pearson VE. Urticaria and respiratory distress due to porfimer sodium. Ann Pharmacother 2000;34(10):1208–9. 115. Dougherty TJ, Cooper MT, Mang TS. Cutaneous phototoxic occurrences in patients receiving Photofrin. Lasers Med Surg 1990;10(5):485–8. 116. Wooten RS, Smith KC, Ahlquist DA, Muller SA, Balm RK. Prospective study of cutaneous phototoxicity after systemic hematoporphyrin derivative. Lasers Surg Med 1988;8(3):294–300.
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117. Mullooly VM, Abramson AL, Shikowitz MJ. Dihematoporphyrin ether-induced photo sensitivity in laryngeal papilloma patients. Lasers Surg Med 1990;10(4):349–56. 118. Kato H, Horai T, Furuse K, Fukuoka M, Suzuki S, Hiki Y, Ito Y, Mimura S, Tenjin Y, Hisazumi H et al. Photodynamic therapy for cancers: a clinical trial of porfimer sodium in Japan. Jpn J Cancer Res 1993;84(11):1209–14. 119. Moriwaki SI, Misawa J, Yoshinari Y, Yamada I, Takigawa M, Tokura Y. Analysis of photo sensitivity in Japanese cancer-bearing patients receiving photodynamic therapy with por fimer sodium (Photofrin). Photodermatol Photoimmunol Photomed 2001;17(5):241–3. 120. Regula J, MacRobert AJ, Gorchein A, Buonaccorsi GA, Thorpe SM, Spencer GM, Hatfield AR, Bown SG. Photosensitisation and photodynamic therapy of esophaeal, duodenal and colorectal tumors using 5 aminolaevulinic acid induced protoporphyrin IX – a pilot study. Gut 1995;36(1):67–75.
121. Hettiaratchy S, Clarke J. Burns after photo dynamic therapy. BMJ 2000;320(7244):1245. 122. Bryce R. Burns after photodynamic ther apy. Drug point gives misleading impres sion of incidence of burns with temoporfin (Foscan). BMJ 2000;320(7251):1731. 123. Farber NE, McNeely J, Rosner D. Skin burn associated with pulse oximetry during perioperative photodynamic therapy. Anesthesiology 1996;84(4):983–5. 124. Isacoff WH, Bendetti JK, Barstis JJ, Jazieh AR, Macdonald JS, Philip PA. Phase II trial of infusional fluorouracil, leucovorin, mitomycin and dipyridamol in locally advanced unresectable pancreatic adeno carcinoma. J Clin Oncol 2007;25(13): 1665–9. 125. Novaro GM, Cherla A, Fromkin KR, Bush HS. Drug-eluting stent implantation in STelevation acute myocardial infarction: ‘real world’ 30-day and mid-term results. Cardio vasc Revasc Med 2007;8(1):5–8.
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4 6 Radiological contrast agents
WATER-SOLUBLE INTRAVASCULAR IODINATED CONTRAST AGENTS (SED-15, 1848; SEDA-29, 573; SEDA-30, 533; SEDA-31, 731) There are four types of iodinated watersoluble contrast media, classified according to their physicochemical properties (Table 1). They are mainly used intravascularly, but can also be injected into body cavities, par ticularly the low-osmolar contrast agents. Some are also used for oral or rectal admin istration, and the high-osmolar water-solu ble contrast agent diatrizoate is suitable only for these purposes. Low osmolar and iso-osmolar iodinated contrast media have almost completely replaced high osmolar agents for intravascular use and administra tion into body cavities. Observational studies The incidences of early reactions (<24 hours) and late reac tions (1–7 days) to two non-ionic contrast agents iopamidol 340 and iomeprol 350 (Niopam and Iomeron, Bracco UK Ltd) have been evaluated in a double-blind, ran domized trial in 1985 patients undergoing cardiac catheterization (1c). There was no significant difference between the two groups in the incidence of heat sensation or other early reactions (2.7% of those who received iopamidol and 4% of those who received iomeprol). There were significant Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32046-0 � 2010 Elsevier B.V. All rights reserved.
electrocardiographic changes in 1.7 and 1.0% respectively; bradycardia occurred sig nificantly more often after iopamidol (0.8%) than iomeprol (0.1%). Late reactions occurred in 16 and 22% respectively. There was significantly more nausea with iomeprol – 39 patients (6.2%) versus 23 (3.7%). In a study of spontaneous reports of sus pected adverse reactions attributed to con trast media sent to the Sicilian Regional Centre for the Spontaneous Reporting of Adverse Drug Reactions during 1996–2006 there were 100 reports, 29 of which involved serious adverse effects, including one death (2c). Skin, the respiratory system, and the gastrointestinal tract were the most fre quently affected sites. Most of the reports described immediate hypersensitivity reac tions. Iopromide (53%), iopamidol (14%), and iomeprol (12%) were the most com monly implicated contrast media. The incidences of immediate and delayed adverse effects of contrast media have been evaluated in a prospective intensive moni toring questionnaire study in 1514 patients who were given iodinated contrast media in two hospitals in Tuscany (3c). There were immediate and delayed reactions in 34 (2.2%) and 144 (9.5%) respectively. Delayed allergy of mild severity was more common with the use of monomeric lowosmolar agents (iopromide, iomeprol, iobi tridol) and the dimeric iso-osmolar agent iodixanol. Only one immediate reaction was severe. Immediate reactions were more likely with the monomeric agents and delayed reactions with iodixanol. Comparative studies In a large compara tive study of iodixanol and iohexol, the inci dence of immediate and delayed adverse events was significantly higher with the
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Table 1 Some iodinated water-soluble contrast media Properties
Examples (INNs)
Brand names
High-osmolar ionic monomers
Diatrizoate
Angiografin, Hypaque, Gastrografin, Renografin, Urografin Conray Telebrix Isopaque, Triosil Hexabrix Xenetrix Omnipaque Iomeron Isovue, Niopam, Solutrast Imagopaque Ultravist Optiray Amipaque Visipaque Iosmin Isovist
Low-osmolar ionic dimers Low-osmolar non-ionic monomers
Iso-osmolar non-ionic dimers
Iotalamic acid Ioxitalamic acid Metrizoate Ioxaglic acid Iobitridol Iohexol Iomeprol Iopamidol Iopentol Iopromide Ioversol Metrizamide Iodixanol Iosimenol Iotrolan
former (4c). Iodixanol was used for CT scan ning in 15 142 patients and iohexol in 22 044 patients; there were adverse events in 116 patients (0.77%) and 54 patients (0.25%) respectively. There were immediate and delayed adverse events in 76 and 40 patients (0.50 and 0.26% respectively) who received iodixanol and in 52 and 2 patients (0.24 and 0.01% respectively) who received iohexol. Cardiovascular ST segment depression in a 77-year-old man with coronary artery stenosis after administration of contrast medium was attributed to coronary artery vasoconstriction (5A). Coronary artery vasoconstriction due to a contrast agent during coronary angiography can influence the size of stent chosen; in 15 patients the proximal reference vessel diameter was 2.95 mm with coronary angiography and 4.65 mm as measured by ultrasound (6c). Nervous system Encephalopathy and rhabdomyolysis has been associated with leakage of epidural iotrolan because of an epidural tear (7A). • A 76-year-old man was given epidural injections of iotrolan and mepivacaine and
developed motor weakness and hypesthesia in both legs, which lasted for 3 hours. He also became confused, agitated and disoriented, and developed neck stiffness and tremors of the head and legs. There was diffuse contrast enhancement in the intracranial cerebrospinal fluid spaces, indicating an intraoperative dural tear. He had marked increases in serum creatine kinase and myoglobin, indicated acute rhabdomyolysis. He recovered after crystalloid infusion and semi-recumbent positioning, which facilitated iotrolan absorption from the CSF.
In another case, a middle-aged woman developed an acute encephalopathy after coronary angioplasty with iohexol, asso ciated with slowing on the electroencephalo gram; she recovered spontaneously within 24 hours with only supportive measures (8A). Sensory systems Transient cortical blindness has been reported in a 52-year-old woman after administration of iomeprol (9A) and in a 70-year-old woman after iobitridol (10A). Salivary glands Of 52 patients who under went parotid and submandibular sialogra phy, 17 reported pain, 25 reported swelling and 8 complained of different taste distur bances (11c).
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Sialadenitis due to iodinated contrast media ‘Iodide mumps’ is the name given to swelling of the salivary glands due to compounds that contain iodine. The term was first introduced in 1956 in relation to a case involving an intravenous highosmolar ionic contrast medium (sodium diatrizoate þ meglumine diatrizoate) (12A). Since then numerous cases have been reported (13A–23A).
EIDOS classification: Extrinsic species: Iodinated contrast media Intrinsic species: (Non-specific) Distribution: Salivary glands Outcome: Edema Sequela: Salivary gland swelling (‘iodide mumps’) DoTS classification: Dose-relation: Hypersusceptibility and toxic Time-course: First-dose and intermediate Susceptibility factors: Renal impairment; iodine hypersensitivity
Epidemiology and mechanism In a systematic review of 31 published case reports the ratio of men to women was 2:1 (24AM); their mean ages were 62 (range 29–78; median 62) and 53 (range 8–76; median 63) years respectively; 11 had impaired renal function and 17 did not. The overall time to onset was 10 minutes to 5 days (median 1 day); in those with renal impairment the median time to onset was 1 day and in those without renal impairment it was 12 hours. However, there was a bimodal distribution of times to onset – most occurred either before 4 hours (n = 9) or at 1 day or later (n = 15) (Figure 1); this suggests that there may be two different types of reaction, immediate hypersensitivity and either delayed hypersensitivity or a toxic effect, and this is supported by the observation that in only one of the patients with renal impairment was the onset immediate. In one case bilateral parotid enlargement was followed by an anaphylactoid reaction (25A). In another, marked sialadenitis was associated with allergic vasculitis, fever, and conjunctivitis (26A). Susceptibility factors Iodide mumps, particularly the delayed form, may be more likely when there is impaired renal excretion of contrast material, since excess inorganic
Number 10 9 8 7 6 5 4 3 2 1 0 <4h
4h
8h
12 h
18 h
1 day 2–5 days
Time to onset Figure 1 The frequency distribution of times to onset in 29 cases of iodide mumps; the marbled areas denote patients with renal impairment.
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iodide liberated from the contrast medium is concentrated by the salivary glands (27A,28A). However, it often occurs in patients with normal renal function. Incidence Iodide mumps is rare. In one study of adverse reactions to intravenous contrast media in 337 647 patients there were no reports, which suggests that the maximum likely incidence is about 9 per million (29c). However, it can occur on a second occasion after re-exposure (30A–32A), suggesting that some individuals may be particularly susceptible. One patient developed iodide mumps after oral diatrizoate meglumine and on another occasion intravenous iopromide (33A). One had reactions on six separate occasions after the use of three different contrast media (iopamidol, iohexol, and iopentol) (34A). Presentation Iodide mumps has been reported to affect the parotid glands (28A), the submaxillary glands (35A), and the submandibular glands (36A). In one case asymptomatic parotid gland swelling after injection of iotalamate salts was accompanied by pancreatic swelling, to which the authors gave the name ‘pancreatic mumps’ (37A). In another case submandibular gland swelling was accompanied by thyroid swelling in a patient with renal insufficiency and a very high serum iodine concentration after administration of iodixanol; ultrasonography showed that both glands were edematous (38A). The authors recommended that patients on renal replacement therapy should undergo dialysis immediately after the use of iodine-containing contrast media.
Compounds involved All of the early reports involved high-osmolar ionic media, such as diatrizoate and iotalamate, which were the only agents available at that time, but later reports have implicated all varieties of media, including the low-osmolar ionic dimer ioxaglate (39A), the low-osmolar non-ionic monomers iopamidol (40A,41A), iohexol (42A,43A), iopromide (44A,45A),
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and ioversol (46A), and the iso-osmolar non-ionic dimer iodixanol (47A). Management In most cases resolution is spontaneous. Some patients have been treated with glucocorticoids. Liver Acute hepatitis has been attributed to iopromide in a 65-year-old man (48A).
Contrast medium-induced nephrotoxicity Contrast-induced nephrotoxicity has been reviewed in successive volumes of SEDA (SEDA-29, 575; SEDA-30, 535; SEDA-31, 731). EIDOS classification: Extrinsic moiety: Iodinated
water-soluble contrast media
Intrinsic moiety: Renal tubular
cells
Distribution: Kidney
Outcome: Apoptosis
Sequela: Contrast medium-induced
nephrotoxicity DoTS classification: Dose-relation: Collateral
Time-course: Intermediate
Susceptibility factors: Drugs
(nephrotoxic drugs, such as non steroidal anti-inflammatory drugs; metformin; mannitol and diuretics, particularly loop diuretics; multiple repeat exposures to contrast media within 72 hours); diseases (pre existing renal insufficiency, particularly if it is secondary to diabetes mellitus; congestive heart failure; dehydration). Incidence In a prospective study of 1224 patients undergoing CT angiography none developed renal failure, giving a maximum likely incidence of 0.25%; however, 44
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developed laboratory-defined contrast nephropathy, defined as an increase in creatinine of more than 44 µmol/l or more than 25% of baseline, within 7 days, an overall frequency of 4% (49c). The incidence of contrast-induced nephro pathy in intermediate-risk patients receiving iodixanol has been studied in 100 patients with a serum creatinine concentration of 97–177 µmol/l and/or a glomerular filtration rate of 30–90 ml/minute (50c). Iodixanol (320 mgI/ml) 60–140 ml was given at a rate of 2.5–3 ml/second. The patients were hydrated with intravenous saline 500 ml before and after contrast injection. Three patients, who received iodixanol 90–110 ml, developed contrast induced nephropathy on day 3 without persistence on day 7; no spe cific therapy was needed. One had a rash on days 3 and 7. Comparative studies In a multicenter, double-blind, randomized, parallel-group comparison of intravenous iomeprol-400 and iodixanol-320 in 148 patients with pre existing chronic kidney disease, the incidence of contrast nephropathy was significantly higher after the latter (51C). In a retrospective study of all contrast procedures with a pre- and post-exposure creatinine measurement in 794 patients, iodixanol and iohexol did not carry signifi cantly different risks of contrast nephropathy (OR = 0.92, 95% CI = 0.57, 1.46) or mortal ity (RR = 0.79, 95% CI = 0.59, 1.06) (52c). Iodixanol and iopromide have been com pared in 117 patients (83 men, 34 women; mean age, 64 years; range 18–86 years) with impaired renal function (53c). There were no major differences between the two agents, except that fewer patients in the iodixanol group (8.5% versus 28%) had an increase in serum creatinine of 44 µmol/l or more and a reduction in GFR of 5 ml/minute or more (42% versus 24%). Dose-relation In 185 patients with chronic renal insufficiency and creatinine clearances less than 60 ml/minute/1.73m2, the volume of contrast administered was directly associated
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with the incidence of contrast nephropathy – 45 ml in those who developed nephropathy compared with 31 ml in those who did not (54c). Those who received the lowest quartile of contrast volume were 7-fold less likely to develop nephropathy than those with the highest quartile of contrast volume (4.4% versus 30%). In multivariate analysis, the only significant factor associated with nephropathy was the volume of contrast administered; each incremental 20 ml was associated with an incremental odds ratio of 2.12 (95% CI = 1.4, 3.4). In another study the risk of postoperative acute renal insufficiency after cardiac sur gery in 423 adults was increased by the volume of contrast medium used and was more likely when there was a short interval between angiography and subsequent car diac surgery (55c). The authors suggested that cardiac surgery should be delayed beyond 24 hours of exposure to contrast agents when feasible and that the use of these agents should be minimized. Susceptibility factors The effects of dia betes and pre-diabetes on the development of contrast-induced nephropathy have been studied in 421 patients with chronic kidney disease undergoing coronary angiography; 137 had diabetes mellitus, 140 had pre-dia betes and 144 had a normal fasting glucose (56c). Contrast-induced nephropathy occurred in 20 (RR = 3.6), 11 (RR = 2.1), and 5.5% respectively. Hemodialysis was required in 3.6 and 0.7% of those with diabetes and pre-diabetes respectively. A serum glucose concentration above 6.8 mmol/l (124 mg/dl) was the best cut-off point for prediction of contrast-induced nephropathy. Diagnosis The low-osmolar contrast med ium iopamidol and the iso-osmolar medium iodixanol have been compared in 414 patients at high risk of contrast-induced nephropathy (eGFR 20–59 ml/minute) after intra-arterial administration (57c). There were no significant differences between the two agents in the whole population or in
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patients with diabetes. The serum creatinine increased by at least 44 µmol/l in 9 of 204 patients (4.4%) after iopamidol and in 14 of 210 patients (6.7%) after iodixanol; increases of at least 25% occurred in 9.8 and 12% respectively. Prevention The efficacy of trimetazidine in the prevention of contrast-induced nephro pathy has been studied in 82 patients with high serum creatinine concentrations under going coronary angiography/angioplasty (58c). Trimetazidine 20 mg tds was given orally for 72 hours starting 48 hours before the procedure and all the patients were given intravenous isotonic saline 1 ml/kg for 24 hours starting 12 hours beforehand. Con trast-induced nephropathy developed in one of 40 who were given trimetazidine (2.5%) and in seven of 42 control (17%). Three different methods for preventing contrast-induced nephropathy have been compared in 326 patients with chronic kid ney disease: 0.9% saline infusion þ N-acetyl cysteine (n = 111), sodium bicarbonate infusion þ N-acetylcysteine (n = 108), and 0.9% saline þ ascorbic acid þ N-acetyl cysteine (n = 107) (59c). The mean amounts of contrast medium (iodixanol) administered were 179, 169, and 169 respectively and risk scores (9.1, 9.5, and 9.3) were similar in the three groups. Contrast-induced nephropathy occurred in 11 of 111 patients (9.9%) after saline þ N-acetylcysteine, in 2 of 108 (1.9%) after bicarbonate þ N-acetylcysteine, and in 11 of 107 (10%) after saline þ ascorbic acid þ N-acetylcysteine. The authors concluded that sodium bicarbonate þ N-acetylcysteine was superior to the other two methods that they had studied. Of 87 adults with renal insufficiency who underwent emergency CT scanning, 43 were hydrated and given N-acetylcysteine 900 mg intravenously; the other 44 were hydrated only (60c). There was a 25% or greater increase in serum creatinine concentration in two of the former and in nine of the latter. However, there was a 25% or greater increase in serum cystatin C concentration in seven and nine respectively. This disjunc tion between the effects of acetylcysteine on
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creatinine and cystatin led the authors to suggest that acetylcysteine might prevent the rise in serum creatinine after contrast admin istration without actually preventing contrast nephropathy. It is not clear how effective acetylcysteine is in preventing contrast-induced nephropa thy (61R), but in vitro acetylcysteine and ascorbic acid but not sodium bicarbonate prevented contrast-induced apoptosis (62E). In a double-blind, placebo-controlled study patients with moderately impaired kidney function receiving low-osmolar, non-ionic contrast media were randomized to oral acetylcysteine 1.2 g/day for 2 days (n = 19), oral zinc 60 mg/day for 1 day (n = 18), or placebo (n = 17) (63C). All received 0.45% saline 1 ml/kg/hour for 24 hours at the time of the procedure. There was a significant fall in serum creatinine in all patients during volume expansion, and creatinine did not increase after contrast administration. How ever, 2 days after contrast there was a signif icant rise in cystatin C concentration in those who were given zinc and placebo, but not after acetylcysteine. There was no difference in the incidence of nephropathy. The authors suggested that kidney function should be assessed by cystatin C in studies of contrast nephropathy, since creatinine can be misleading. In 59 patients who were randomized to sodium bicarbonate 154 mmol/l (n = 30) or sodium chloride (n = 29) as an intravenous bolus of 3 ml/kg/hour for 1 hour before the administration of contrast, followed by an infusion of 1 ml/kg/hour for 6 hours during and after the procedure, serum creatinine concentration remained unchanged within 2 days of contrast administration in those given sodium bicarbonate but rose in those who were given sodium chloride (64c). The incidence of contrast-induced nephropathy was significantly less in the former (7% ver sus 35%). Intravenous isotonic saline and prophy lactic hemodialysis have been compared in 82 patients with chronic renal failure referred for coronary angiography (65c). Prophylac tic hemodialysis lessened the reduction in creatinine clearance within 72 hours. Tem porary renal replacement therapy was
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required in 35% of the control patients and in 2% of the dialysis group and five of the controls, and none of the dialysis patients required long-term dialysis after discharge. The removal of contrast from the coron ary sinus during coronary angiography has been studied as a method of preventing con trast nephropathy in seven patients with pre existing renal insufficiency and was feasible in three, in whom 12–16 ml of blood was aspirated after each injection; serum creati nine concentrations did not rise (66c). Continuous venovenous hemofiltration in 12 patients with severe chronic renal impairment and at least two severe co-mor bidities significantly improved eGFR and serum creatinine after the use of iodixanol (67c). In a double-blind, randomized, placebocontrolled, two-center study in 247 patients with chronic renal insufficiency undergoing coronary angiography, simvastatin 40 mg orally every 12 hours starting the evening before and ending the morning after the pro cedure (160 mg in all) had no effect on mean peak increases in serum creatinine or the incidence of contrast nephropathy (68C). Recombinant human erythropoietin 200 U/ ml has been used to protect renal tubular epithelial cells against contrast mediuminduced injury in vitro in LLC-PK1 renal tub ular epithelial cells, which were exposed to a non-ionic low-osmolar agent iohexol and the iso-osmolar agent iodixanol for 6 hours (69E). Erythropoietin improved the viability of the iohexol-treated cells by 27 and the viability of the iodixanol-treated cells by 26%. It also reduced apoptosis rates and attenuated acti vation of caspase-3, caspase-8, and caspase-9. Asialoerythropoietin, a non-hemopoietic derivative of erythropoietin, attenuated con trast-induced renal dysfunction and renal tubular damage in rats, an effect that was attributed to inhibition of apoptosis by acti vation of Janus kinase 2 (JAK2) and the phospho-JAK2/signal transducer and activa tor of transcription 5 (STAT5) (70E).
Skin A 61-year-old physician developed a fixed drug eruption after intravenous
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administration of iopromide (71A). The eruption consisted of a red macule about 2 cm in diameter in the right inguinal region, which grew to a size of 15 8 cm, accompanied by a burning sensation. He had had a similar reaction in the same place 1 year before. Patch testing 4 months later was positive with iomeprol and iohexol. An injection of iopamidol 23 months later was well tolerated. The baboon syndrome is a form of sys temic contact dermatitis that occurs after exposure to a contact allergen in individuals previously sensitized by topical exposure. It presents with erythema of the buttocks and upper inner thighs. The acronym SDRIFE (symmetrical drug-related intertriginous and flexural exanthema) has been proposed specifically for cases that are associated with systemically administered drugs. SDRIFE has been reported after administration of iomeprol and iopromide (72A). There were positive delayed skin tests with both drugs, suggesting that the mechanism is cellmediated (type IV) allergy. A skin test with potassium iodide was negative. Extensive exfoliative dermatitis has been attributed to iodixanol during primary per cutaneous coronary intervention (73A). Sweet’s syndrome has been described in a 77-year-old woman, with a possible history of allergy to iodinated agents and penicillin, 8 hours after a dose of ioxitalamate; she had had similar episodes on two previous occa sions (74A). Immunologic Of 96 patients with anaphy laxis after contrast media, four had skin tests and basophil activation tests that strongly suggested IgE-mediated allergy to iopromide (n = 2), iomeprol, and iopentol (75c). In two patients with allergic reactions to iopromide and iomeprol, alternative non ionic monomers were tolerated in con trolled challenge tests with iopamidol and iopromide respectively. Severe complications from the use of iodinated contrast media in arthrography are uncommon. In a study of 262 000 arthro grams, there was a total complication rate of 3.6%, of which 0.03% were severe (76c).
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Minor reactions (n = 9594) included chemi cal synovitis, vagal reactions, and urticaria. Severe reactions (n = 75) included 29 cases of septic arthritis, 16 cases of cellulitis, 8 cases of anaphylaxis, and 5 cases of vascular complications. There were also 10 cases of seizures and four of nerve palsies. A man who was given diatrizoate (Reno graffin-60), lidocaine, and gadolinium for hip arthrography developed nausea during and at the end of arthrography and later com plained of chest tightness and lightheaded ness and lost consciousness for 15–30 seconds; he responded to methylpredniso lone, diphenhydramine, and ranitidine (77A). A 27-year-old woman had an immediate hypersensitivity reaction to ioxaglate (78A) and fatal anaphylaxis to ioversol has been reported in a 60-year-old man (79A) and to ioxaglate in a 57-year-old man (80c) and a 49-year-old woman (81A). About 3% of patients exposed to iodi nated contrast media develop delayed hyper sensitivity reactions. In a study of 13 different contrast media and potassium iodide in two patients with delayed hypersensitivity reac tions to iohexol and iomeprol, there was broad cross-reactivity in skin tests (82cE). However, in in vitro tests of T-cell activation and proliferation, while there was cross-reac tivity with iohexol-specific and iomeprol-spe cific CD4 cell clones, an iomeprol-specific CD8 cell clone did not cross-react. Reactivities to equimolar concentrations of iohexol and its dimer iodixanol were very similar, suggesting that the dimer was not more stimulatory than its monomer. There was low reactivity to iobi tridol and iodide had no effect. The authors concluded that clinical cross-reactivity between different contrast media results from the presence of contrast media-specific T cells, and that iodide ions are not causative. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been attributed to ioxitalamate (83A). Fetotoxicity There are reports that the low-osmolar non-ionic monomers iohexol and iopromide can cross the placenta in humans, as two cases of fetal bowel opacifi cation after maternal administration of
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ioversol have shown (84A, 85A). In one the presentation mimicked that of pneumo peritoneum and in the second the placenta was small and congested with a large sub chorionic hematoma and focal necrotizing deciduitis of the free membranes. Management of adverse reactions A sim ple manoeuvre has been described for the management of extravasation of contrast media after intravenous administration in eight patients who had more than 50 ml of contrast medium extravasation resulting in vascular compromise of the fingers (86c). The manoeuvre involved the following steps: • remove the intravenous catheter; • clean the skin around the insertion site with povidone–iodine; • puncture five to eight openings near the catheter insertion site as deeply as possible using an 18-gauge needle; • squeeze from the periphery of the swelling toward the needle holes; • as the contrast medium drains, swab it away with iodine-soaked cotton swabs.
In all eight patients this produced immediate resolution of the vascular compromise.
BARIUM SULFATE (SED-15, 414) Comparative studies Milk and VoLumen, a 0.1% suspension of barium, have been compared in 215 patients undergoing abdominal and pelvic CT scanning (87c). There were no statistically significant differ ences in the degree of bowel distention and mural visualization for all segments of bowel studied. Significantly more patients ranked milk as pleasant in taste and more preferred it. Barium caused more abdom inal adverse effects, including abdominal discomfort, cramps, nausea, and diarrhea. Respiratory Aspiration of barium can cause lung damage. In one case the appearances on CT scan mimicked pulmonary diseases such
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as pulmonary alveolar proteinosis, non-speci fic interstitial pneumonia, and pulmonary alveolar microlithiasis (88A). Gastrointestinal Peritonitis due to rectal perforation has been described in a 69-year old woman after a barium enema (89A). Lung entrapment by barium has been described after esophageal perforation (90A). Cases of intestinal obstruction due to baro liths (22 reports describing 31 cases) have been reviewed (91M). About one-third were successfully treated with conservative measures, including the use of laxatives. Sur gery was performed in nearly one-half and endoscopic dissolution in only three cases, in all of which it was successful. Another case of a barium-containing bezoar has been reported, in this case prox imal to a jejunal anastomosis (92A). Biliary tract Obstructive cholangitis in a 65-year-old man was found to be due to barium that had leaked into the common bile duct during stent placement for obstruction due to pancreatic cancer (93A). It has been suggested that stents make biliary reflux of barium more likely (94A). Musculoskeletal A man developed osteitis at the site of a mandibular osteotomy when he had a barium swallow examination 2 weeks after oral surgery (95A). Barium was demonstrated in the lesion, and this was therefore a between-the-eyes adverse effect of type 1a (96H).
MRI CONTRAST MEDIA Gadolinium salts (SED-15, 1469; SEDA-29, 578; SEDA-30, 538; SEDA-31, 734) The gadolinium salts that are used as contrast media in magnetic resonance imaging (MRI) and have been assigned
851 Table 2 Gadolinium salts that are used as contrast media in magnetic resonance imaging Name (INN)
Brand name
Gadobenic acid Gadobutrol Gadocoletic acid Gadodenterate Gadodiamide Gadofosveset Gadomelitol Gadopenamide Gadopentetic acid Gadoteric acid Gadoteridol Gadoversetamide Gadoxetic acid
Multihance Gadovist
Omniscan Ablavar Vistarem Magnevist Dotarem Prohance OptiMARK Eovist, Primovist
International Non-proprietary Names (INNs) by the WHO are listed in Table 2. Nervous system Encephalopathy occurred in a 64-year-old man who was accidentally given an intrathecal injection of 20 ml (10 mmol) of gadolinium dimeglumine instead of an iodine-containing contrast medium during CT myelography (97A). Urinary tract A 1:1 mixture of gadolinium þ a non-ionic contrast medium has been studied in 26 patients with renal dysfunction, mean age 66 years; there were no cases of contrast-induced nephropathy (98c). In patients with a raised serum creatinine who were given either a gadolinium salt (gadoteridol or gadodiamide; n = 57), an iodinated contrast medium (iohexol or iodix anol; n = 68), or a combination (n = 38), the incidence of immediate contrast nephropa thy was lowest in those who received gado linium alone (3/57, 5.3%) compared with those who received an iodinated contrast alone (14/68, 21%) or the combination (4/38, 11%) (99c). However, although this was associated with a reduction in the need for renal replacement therapy at 30 days, renal function and all-cause mortality were not different at a mean follow-up of 40 months. Two of those who were given gado linium developed pathology-proven nephro genic fibrosing dermopathy.
852
However, a larger study gave different results. Patients with a creatinine clearance below 60 ml/minute/1.73m2 who received intravenous hydration and oral acetylcys teine prophylaxis have been compared with patients who were given a mixture of gadodiamide þ iodine (n = 90) or iodinated contrast alone (n = 79) (100c). Although less iodinated contrast was used in the gadolinium mixture group, there was no difference in the incidence of contrastinduced nephropathy between the two groups. However, dialysis (n = 7) and death (n = 8) occurred only in those who were given gadolinium. Acute renal failure occurred after the administration of gadolinium 90 micromol/ kg to a patient with pre-existing mild renal insufficiency (creatinine clearance 55 ml/minute) due to kappa light-chain disease (101A).
Systemic fibrosis due to gadolinium-based contrast agents Systemic fibrosis due to gadolinium-based contrast agents was reviewed in SEDA-31 (p. 735) and many other reviews have appeared (102R–116R), as have further reports (117A–124A).
EIDOS classification: Extrinsic species: Gadolinium-containing contrast media
Intrinsic species: Fibroblasts
Distribution: Skin, lungs, liver, serous
membranes, skeletal and cardiac muscle
Outcome: Fibrosis
Sequela: Systemic fibrosis
DoTS classification: Dose-relation: Collateral
Time-course: Late
Susceptibility factors: Diseases (renal
insufficiency, acidosis, inflammatory events, hyperphosphatemia); drugs (epoetin therapy, sevelamer)
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J.K. Aronson
First description So-called nephrogenic fibrosing dermopathy was first described in 2000 in 15 hemodialysis patients with thick ening and hardening of the skin and sclero derma-like features, with hyperpigmented patches and plaques (125c). Presentation The first signs of the disease, which usually occur within a few months, are skin discoloration, induration, warmth, itching, constant pain, and other neuropathic symptoms in the lower legs. Associated early symptoms include sleeplessness and transient diffuse hair loss. Later, papules and coalescing plaques develop, and there is symmetrical skin stiffness with or without restricted joint movement. In one series 10 of 22 patients were severely disabled because of contractures that occurred at an average of 29 months after exposure (126c). Pathology and pathogenesis Histological examination shows proliferation of dermal fibroblasts in early lesions and florid proliferation of fibroblasts and dendritic cells in fully developed cases, thick collagen bundles with surrounding clefts, and a variable increase in dermal mucin and elastic fiber; CD-34 positive dermal dendrocytes are abundant, with dendritic processes aligned with elastic fibers and around collagen bundles in a dense network (127c). Factor XIIIa- and CD-68-positive mononucleated and multinucleated cells are also present in increased numbers. Electron microscopy shows increased elastic fibers closely apposed to dendritic cell processes. The entire dermis is commonly involved, with increased spindle cells, collagen, mucin, and elastic fibers extending through the subcutis along the septa of fatty lobules. When systemic involvement was reported (e.g. in lungs, liver, serous membranes, and skeletal and cardiac muscle) the name ‘nephrogenic systemic fibrosis’ was sug gested instead (128A), and the condition was found to be associated with gadolinium (129c, 130c), although it is occasionally reported in individuals who have not received gadolinium salts (131A). However,
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since it is not always associated with renal impairment, it would be better to call it sim ply ‘systemic fibrosis’. Gadolinium promotes fibrosis by either binding directly to the collagen helix or, after it has been engulfed by macrophages, through the production of free oxygen radi cals, cytokines, and other profibrotic factors that attract circulating fibrocytes to tissues (132R). These fibrocytes differentiate into fibroblast-like spindle cells, which produce connective tissue matrix and other angio genic and growth factors, further enhancing tissue fibrosis. Direct activation of transglutaminases on tissue fibroblasts may also promote fibrosis. Gadolinium has consistently been found in the tissues of patients with systemic fibro sis, showing that this is a between-the-eyes adverse effect of type 1a [96H]. Gadolinium was detected in four of 13 tissue specimens from seven patients with documented nephrogenic systemic fibrosis who had been exposed to gadolinium-based radiographic contrast (133c, 134c). In a 68-year-old woman with dermopathy after the adminis tration of gadodiamide, gadolinium was detected in a skin biopsy, but only in areas of calcium phosphate deposition in blood vessels (135Ar). In one case high concentra tions of gadolinium associated with calcium and phosphorus in skin persisted for at least 3 years after the last exposure (136A). In 57 skin biopsies from patients with systemic fibrosis, gadolinium, detected by quantitative scanning electron microscopy and energy dispersive X-ray spectroscopy, was asso ciated with phosphorus, calcium, and usually sodium in tissue deposits (137A). In one case gadolinium was found in the blood, hair, and fingernails (138A). In 43 skin biopsies from 20 patients with gadodiamide-related systemic fibrosis, gadolinium was detected in all cases, always in deposits that also con tained phosphorus, calcium, and sodium; the ratio of gadolinium to calcium correlated with the dose of gadodiamide and with serum ionized calcium at the time of gadoli nium exposure (139c). The authors suggested that gadolinium may be stored in bone and mobilized over time, explaining the variable delay in the onset of systemic fibrosis.
853
The stability of the gadolinium salt used may be important in the pathogenesis of the condition (140R, 141R). Incidence In a post-marketing surveillance study of 24 308 patients no cases of systemic fibrosis were reported (142c). This suggests an overall incidence rate of no more than about 1 in 10 000, although the risks from gadodiamide and gadopentetate are considerably higher. In a retrospective review, three patients (five studies) developed systemic fibrosis out of a total of 87 (123 studies), giving a risk per study of 2.4%; however, the authors did not specify the agents used (143c). In a retrospective analysis of 849 patients on renal replacement therapy over 5 years, four of the 261 who had received a single gadolinium exposure (1.5%) developed sys temic fibrosis compared with none of the 588 who had not been exposed (OR = 6.67; 95% CI = 1.54, 54) (144c). In a retrospective survey 14 of 1826 patients (0.77%) had a diagnosis of systemic fibrosis, of whom 13 had undergone gado linium-enhanced MR imaging compared with 408 (23%) of 1812 unaffected patients (145c). Those with systemic fibrosis had received a higher median cumulative dose of gadodiamide (390 versus 230 micromol/ kg) and more gadolinium-enhanced MR imaging than the unaffected individuals. In a retrospective study of 190 patients who had gadodiamide-enhanced MRI scans, 18 (9.5%) developed systemic fibrosis within a mean follow-up period of 29 (range 16–43) months; each had an eGFR below 15 ml/min ute/1.73m2 or was undergoing dialysis at the time of exposure to gadodiamide (146c). In 141 patients with 198 exposures to gadoteridol there were no cases of systemic fibrosis (147c). In a systematic review of published reports of 190 biopsy-proven cases of systemic fibro sis, 157 were associated with gadodiamide, 8 with gadopentetate, and 3 with gadoverseta mide; 18 were unspecified and in 4 cases more than one gadolinium salt had been used; five cases were not associated with gadolinium salts (148M).
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854
Following the FDA’s advice (SEDA-31, 736) that gadolinium-containing contrast agents should not be used in patients with advanced kidney failure unless clearly necessary and that in such cases prompt dialysis be instituted, the European Society for Magnetic Resonance in Medicine and Biology (ESMRMB) issued a statement list ing estimated risks (Table 3) and giving advice about the use of high-risk agents (149S). The ESMRMB advised that salts that carry a high risk (Table 3) should not be used in patients with a glomerular filtration rate below 30 ml/minute, in patients on dia lysis, and in those who have had or are awaiting liver transplantation; because renal function is immature in neonates and infants up to 1 year of age, they should not be used except after careful consideration. Susceptibility factors In a systematic review of published reports, the susceptibility factors associated with a risk of systemic fibrosis or dermopathy included medications that could cause transmetallation of gadolinium, medications that can cause acidosis, high doses of erythropoietin, and medical conditions such as hyperphosphatemia, acidosis, recent surgery, hepatic disease, hypercoagulability, and proinflammatory processes (150M).
J.K. Aronson
That acidosis predisposes to systemic fibrosis has again been demonstrated in six patients, five of whom had a raised anion gap metabolic acidosis (151c). It has been speculated that sevelamer, by causing an acidosis, enhances the deposition of gadoli nium in the tissues (152A, 153r). In a case–control study, in which 33 patients with fibrosing dermopathy and renal disease were studied, the risk was increased, although not significantly so (OR = 2.95; 95% CI = 0.48, 18), in those who had received a high dose (> 18 000 U/ week) of erythropoietin at the time of detec tion (OR = 1.53; 95% CI = 0.36, 6.49) and a high maximum dose (> 30 000 U/week) of erythropoietin in the preceding 6 months (154c). There were similar non-significant trends to associations with beta-blockers (OR = 2.01; 95% CI = 0.60, 6.66) and ACE inhibitors or angiotensin receptor blockers (OR = 1.92; 95% CI = 0.50, 7.33). There were significant associations with some co-morbidities – venous thrombosis (OR = 5.05; 95% CI = 1.25, 20), dependent edema (OR = 7.11; 95% CI = 1.95, 26), and hypothyroidism (OR = 4.10; 95% CI = 1.14, 15) – but confounding was likely, since these associations did not hold up in a multivariate analysis. In a case–control study of 19 histologi cally verified cases and 19 sex- and age-matched controls, all of whom had
Table 3 Risks of systemic fibrosis from gadolinium-containing salts Name (INN)
Chelate
Charge
Structure
Risk
Gadodiamide Gadopentetic acid Gadoversetamide Gadobenic acid Gadofosveset Gadoxetic acid Gadobutrol Gadoteric acid Gadoteridol
DTPA–BMA DTPA DTPA–BMEA BOPTA DTPA–DPCP EOB-DTPA BT-DO3A DOTA HP-DO3A
Non-ionic Ionic Non-ionic Ionic Ionic Ionic Non-ionic Ionic Non-ionic
Linear Linear Linear Linear Linear Linear Cyclic Cyclic Cyclic
High (3–7%) High (0.1–1%) High Intermediate Intermediate Intermediate Low Low Low
DPTA = diethylene triamine penta-acetic acid. BMA = 5,8-bis(carboxymethyl)-11-[2-(methylamino)-2-oxoethyl]-3-oxo 2,5,8,11-tetra-azatridecan-13-oic acid. BMEA = N,N0 -bis(methoxyethylamide). BOPTA = benzyloxypropionic tetra-acetic acid. DPCP = N,N0 -bis(pyridoxal-5-phosphate)-trans-1,2-cyclohexyldiamine-N,N0 -diacetic acid. EOB-DTPA = ethoxy benzyldiethylene triamine penta-acetic acid. BT-DO3A = 10-(2,3-dihydroxy-1-hydroxymethylpropyl)-1,4,7,10-tetra-aza cyclododecane-1,4,7-triacetic acid. HP-DO3A = 10-(2-hydroxypropyl)-1,4,7-tetra-azacyclododecane-1,4,7-triacetic acid. DOTA = 1,4,7,10-tetra-azacyclododecane-N,N0 ,N0 0 ,N0 0 0 -tetra-acetic acid.
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chronic renal insufficiency when exposed to gadodiamide, there was no difference in mean doses between the affected and unaffected individuals, but cumulative exposure while in chronic kidney disease stage 5 was significantly higher in cases than controls (410 versus 310 micromol/ kg) and in nine severe cases compared with non-severe cases (490 versus 330 micromol/kg) (155c). Those affected had higher serum concentrations of ionized calcium and phosphate than controls and had tended to receive higher doses of epoe tin-beta than controls at the time of exposure. Management Dermopathy due to gadodiamide in a 26-year-old woman with end-stage renal disease responded to sodium thiosulfate 12.5 g after each of three dialyses per week. Sodium thiosulfate might act by preventing calcium from displacing gadolinium from its chelate (transmetallation) (156A). In five patients with systemic fibrosis extracorporeal photopheresis produced mild improvements in three cases in skin tightening, range of motion and/or func tional capacity after a mean number of 34 treatment sessions over a mean of 8.5 months (157c). In another patient, a 68-year-old man with renal insufficiency, oral glucocorticoids followed by extracorporeal photopheresis produced improvement after 12 cycles (158A). Immunologic Anaphylaxis has been attributed to gadobenate dimeglumine in a 32-year-old woman with multiple sclerosis, who developed bronchospasm and acute urticaria with diffuse giant pruritic plaques within 1 minute of infusion (159A). The serum tryptase concentration was raised 2 hours after the reaction (21 µg/l) compared with that at 48 hours (3 µg/l). Skin prick tests using 1:1000, 1:100, and 1:10 dilutions of gadobenate, gadodiamide, and gadoteric acid were all negative, but intradermal tests with 0.03 ml of 1:100 and 1:10 dilutions produced a wheal-and-flare reaction. Skin tests with the other agents were negative.
855
In 10 controls all these tests were negative. The authors suggested that degranulation of mast cells had been responsible. During a 5-year period when 78 353 gado linium-containing contrast injections were performed, eight patients had allergic reac tions to intravenous gadolinium-containing contrast media despite premedication with a glucocorticoid and an antihistamine; six were mild and three were moderate; they included urticaria (n = 5), dyspnea (n = 3), and periorbital edema (n = 1) (160A). Allergic rashes to gadodiamide have been reported in four patients, in one case accompanied by fevers and rigors (161A). Teratogenicity In 26 pregnant women who were exposed to gadolinium derivatives in the first trimester there were no adverse effects on pregnancy or neonatal outcomes (162c).
ULTRASOUND CONTRAST AGENTS (SED-15, 3543; SEDA-30, 540)
Perflutren In October 2007 the FDA issued an alert, prompted by identification of four deaths secondary to cardiopulmonary events within 30 minutes of perflutren administra tion and 11 deaths overall within 12 hours of administration. However, it updated the alert in July 2008, highlighting the risk of serious cardiopulmonary reactions during or within 30 minutes after administration and recommending that high-risk patients with pulmonary hypertension or unstable cardiopulmonary conditions should be clo sely monitored during and for at least 30 minutes after administration (163S). The FDA also required that manufacturers of microbubble contrast agents should conduct clinical studies to assess more thoroughly the risks of serious cardiopulmonary reactions.
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856
Several of the contraindications that were added to the label in October 2007 were removed, because the FDA determined that in some patients the benefits from the diagnostic information that could be obtained through the use of perflutren can outweigh the risk of serious cardiopulmon ary reactions, even among some patients at particularly high risk. The contraindications that were removed included worsening or clinically unstable congestive heart failure, acute myocardial infarction or acute coron ary syndromes, serious ventricular dys rhythmias or a high risk of dysrhythmias due to prolongation of the QT interval, respiratory failure, severe emphysema, and pulmonary embolism or other conditions that cause pulmonary hypertension.
J.K. Aronson
Observational studies In a database review of 112 776 echocardiographic stu dies, 16 025 patients received perflutren; 12 974 received Definity and 20 had adverse events, four of which were serious; 3051 received Optison and none had adverse events (164c). Adverse events included severe back pain, which typically lasted 5–10 minutes (n = 12); a transient vaso depressor episode (n = 1); pruritus (n = 2); a seizure (n = 1), and serious but non-fatal cardiopulmonary events (suggestive of ana phylactoid reactions) without sequelae (n = 4). There were no deaths. The inci dence of serious events was 0.031%. Of patients with adverse events, 13 (65%) had a history of allergy and 13 (65%) were women.
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J.S.A.G. Schouten
47
Drugs used in ocular treatment
DRUGS USED IN THE MANAGEMENT OF AGE-RELATED MACULAR DEGENERATION (SEDA-30, 545; SEDA-31, 739)
Bevacizumab (SEDA-30, 545) Sensory systems Bevacizumab eye-drops, 5 mg/ml, used five times a day for 0.5–6 months in five patients, mean age 42 years, to reduce corneal neovasculari zation, did not have any epithelial adverse effects (1c).
Pegaptanib
(SEDA-31, 739)
Systematic reviews The adverse events in two trials of pegaptanib have been summarized in a systematic review (2M). Adverse effects were common, but most were transient mild to moderate events, and serious events were rare. There was endophthalmitis in 1.3% of patients in the first year, but in none of those who continued to use pegaptanib for a second year. Significantly, more of the patients who received pegaptanib than those who received sham injections had vitreous floaters (33% versus 8%), vitreous opacities (18% versus 10%), and anterior Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32047-2 2010 Elsevier B.V. All rights reserved.
chamber inflammation (14% versus 6%) in the first year of the VISION study. Observational studies Pegaptanib has been investigated in a combined study, including open administration in 37 patients, who were given 3 mg in 0.09 ml, and a randomized, double-masked, uncontrolled, multi center study in 110 patients, who were given 1 or 3 mg in 0.09 ml (3C). The dose of pegaptanib was three or ten times higher than the normal dose and was given every 6 weeks for 54 weeks. The mean number of injections was 9.6. No patients were lost to follow-up. Although there were urine abnormalities (proteinuria, hematuria, or altered albumin-to-creatinine ratio), these normalized after 60 weeks, or had not changed after 60 weeks, or were attributed to a disease. There were no important changes in hematological parameters, liver function, renal function, or electrolytes. There were no important changes from mean or median baseline measurements in vital signs, including blood pressure, and no changes in electrocardiography. All but two patients had at least one adverse event and 28 of 147 (19%) had serious adverse events, most often cardiac disorders. No patient withdrew because of adverse events, and there were no differences between the groups in overall adverse event rates. Nonocular adverse events were uncommon and there was no evidence of systemic toxicity. Five patients died before week 60 and within 60 days of the previous dose, but no deaths were considered to be related to the study treatment. There were ocular adverse events in the study eye in 138 of 147 patients
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(94%); most were mild to moderate in intensity. Only one ocular adverse event was reported as serious (moderate retinal hemorrhage); it was reported on day 245 and was considered to be unrelated to the treatment. There were no cases of endophthalmitis, retinal detachment, or traumatic cataract. The most common ocular adverse events were eye pain (69/147; 47%), vitreous floaters (63/147; 43%), punctate keratitis (60/147; 41%), visual disturbances (37/147; 25%), eye irritation (33/147; 22%), and increased intraocular pressure (31/147; 21%); 11 patients (7%) had mild anterior chamber inflammation. Most events occurred with similar frequencies across the treatment groups, but the incidence of increased intraocular pressure was greater with pegaptanib 3 mg. Most of the ocular adverse events were attributed by the investigators to the injection procedure, and few were attributed to the study drug. As expected, the incidence of ocular adverse events in the fellow eye was much lower than that in the study eye (35% versus 94%). Fluorescein angiography showed no retinal vascular or choroidal abnormalities in the study eye that were not expected during the natural progression of neovascular agerelated macular degeneration. There were no notable delays in arteriovenous transit time, abnormalities in choroidal perfusion or arteriolar occlusions. Sensory systems Intravitreal injections of 0.09 ml pegaptanib cause increased intraocular pressure (4c). Of 75 patients 77% had received prophylactic pressurelowering medications 1 hour before treatment. Immediately after the injection, pressure was exerted on the globe to lower intraocular pressure. Vision was also evaluated immediately after injection. Four patients had no light perception after the injection and the initial pressure was over 55 mmHg; immediate anterior chamber paracentesis was conducted. The mean preinjection pressure for the first injection was 14 mmHg, at 1 minute after injection
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38 mmHg, at 3–10 minutes 34 mmHg, and at 11–20 minutes 26 mmHg. In most cases the pressure fell significantly by 30 minutes after injection. There was no difference between patients with and without glaucoma. The increase in intraocular pressure was related to the volume injected, which in the case of pegaptanib is 0.09 ml. The pressure even increases in patients who received pressure-lowering drugs before treatment, and anterior chamber paracentesis before injection or use of a smaller volume (with another anti-VEGF drug) could be the best way to prevent the pressure increase. Immunologic In two cases systemic allergic reactions were associated with intravitreous administration of pegaptanib (5A). Autacoids A patient with occult choroidal neovascularization had a prolonged anaphylactoid reaction 35 minutes after a first dose of intraocular pegaptanib sodium 0.3 mg. The reaction included oral angioedema and generalized urticaria. Later skin tests with several medications that the patient had been given, including pegaptanib, were negative, except for intradermal histamine. IgE antibodies for latex were also negative. Six weeks later the patient received an injection of bevacizumab uneventfully. Another patient received four injections of pegaptanib over 6 months, and 12 hours after each injection, he developed mild lip angioedema that lasted for hours and an urticarial rash that lasted for days. He had these adverse events after each of four injections, but reported them only after the fourth injection. No other changes in his medical regimen or environment explained his symptoms. Bevacizumab was used for subsequent injections without adverse events. The authors described this as an anaphylactoid reaction (i.e. a non-IgE mediated anaphylactic reaction), since it occurred after the first injection and skin tests were negative. They hypothesized that the reactions could have been related to the polyethylene glycol moieties in
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pegaptanib, since polyethylene glycol-con taining products have been associated with cutaneous contact sensitivity, urticarial reactions, angioedema, and anaphylactoid reactions. Drug–drug interactions Warfarin The safety of intravitreal injections in patients with age-related macular degeneration using warfarin has been investigated in 31 patients who received 102 injections of pegaptanib (6c). There were no intraoperative or immediate postoperative hemorrhagic complications. One patient had an acute submacular hemorrhage 35 days after the third injection. There were no other hemorrhagic events. Submacular bleeding can also occur in patients with macular degeneration without intravitreal injections. Patients with exudative disease (‘wet’ degeneration) are at risk of massive macular bleeding when using anticoagulants and in many patients this therapy should be withdrawn (7c).
Ranibizumab
(SEDA-30, 545;
SEDA-31, 739) Comparative studies Adverse events have been reported in the 2-year results of a randomized, single-masked, controlled trial of ranibizumab 0.5 mg þ verteporfin photo dynamic therapy (n = 106) versus verte porfin photodynamic therapy alone (n = 56) in neovascular age-related macular degen eration (FOCUS study) (8C). Serious ocular adverse events occurred more often in those who received ranibizumab þ photodynamic therapy (17% versus 14%). This was due to endophthalmitis (2.9%, 3/105, versus 0%) and ocular inflammation (12%, 13/105, ver sus 0%). Serious systemic vascular events occurred more often with ranibizu mab þ photodynamic therapy (14/105, 13% versus 6/56, 11%). The authors reported that the cumula tive rates of serious non-ocular adverse events were similar in the two groups at 2 years (17/56 versus 30/105). Of the serious
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non-ocular adverse vascular events, which might plausibly have been due to systemic VEGF inhibition, the cumulative rates were 6/56 (11%) versus 14/105 (13%). Hypertension among patients who were not hypertensive at study entry emerged as a serious adverse event in only one patient who received ranibizumab. The rates of non-ocular hemorrhage were balanced between the groups (4/56 versus 7/105), and none was reported as serious. Arterial thromboembolic events as defined using the Antiplatelet Trialists’ Collabora tion (APTC) criteria (i.e. vascular death or death from an unknown cause, non-fatal myocardial infarction, non-fatal ischemic or hemorrhagic stroke, or stroke of unknown cause) were slightly more com mon in those who received photodynamic therapy alone (4/56 versus 5/105). Placebo-controlled studies In a multi center, randomized, double-masked, sham injection-controlled trial in patients with predominantly or minimally classic or occult with no classic lesions due to age-related macular degeneration, 184 patients were randomized to ranibizumab 0.3 or 0.5 mg or to sham treatment (9C). Ranibizumab was given monthly for 3 months and then quarterly. Assessment of serious or non-ser ious non-ocular adverse events showed no overall difference between the groups. There were no deaths during the first year of treatment. Hypertension in subjects who were not hypertensive at baseline was reported as an adverse event in 8.1% of sham-treated subjects, 6.8% of those who received ranibizumab 0.3 mg and 8.2% of those who received 0.5 mg. Routinely mea sured systolic and diastolic blood pressures were very similar among groups at baseline and at 12 months. Proteinuria was not reported during the first year. The rates of non-ocular hemorrhage were 2.4 and 6.6% with ranibizumab 0.3 and 0.5 mg respec tively, and 4.8% in the sham group. There was only one case of serious non-ocular hemorrhage (hemorrhage at the site of an intravenous catheter in a subject who received ranibizumab 0.5 mg). There were
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no cases of gastrointestinal perforation. There were no arterial thromboembolic events. The only serious or non-serious arterial thromboembolic event during the first year was ischemic cardiomyopathy in a sham-treated subject. Immunoreactivity to ranibizumab was assessed at screening and at month 12 or at early termination. During screening, one subject randomized to sham treatment tested positive, possibly because of pre-existing anti-Fab anti bodies. None of those who received rani bizumab tested positive before study treatment, but two of those who received 0.5 mg group tested positive at month 12; neither of these two subjects had any severe or serious adverse events during the study. Systematic reviews The adverse events in three trials of ranibizumab have been summarized in a systematic review (2M) Endophthalmitis occurred in 1.4 and 1.9% of patients receiving 0.5 mg ranibizumab in the ANCHOR and FOCUS trials, respectively. The rate per injection was 0.05% in the MARINA trial. Sensory systems In a review of three large clinical trials of ranibizumab in the treatment of age-related macular degeneration, serious adverse ocular events occurred in association with <0.1% of intravitreal injections (10M). They included retinal detachment and endophthalmitis. Less serious adverse ocular reactions occurred in <2% of patients, including intraocular inflammation and increased intraocular pressure. Retinal pigment epithelial tears have been reported after intravitreal injection of rani bizumab. One patient already had a pigment epithelial detachment and the symptoms appeared only after the third injection, with no adverse events after the previous two dosages (11A). Six other patients with age-related macular degenera tion, four of whom had a pigment epithelial detachment, developed a retinal pigment epithelial tear after intravitreous injections of ranibizumab (12A, 13A). In other cases
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this adverse event occurred within 2–6 weeks after the injections (14A–16A). Ocular hypertension can complicate intra vitreal injections. Four patients without a history of glaucoma or ocular hypertension had sustained ocular hypertension after intravitreal injections of ranibizumab (17A). The intraocular pressure rose as high as 30, 34, 46, and 50 mmHg, but only in the injected eye. All four were treated with topical anti-glaucoma medications. The importance of this observation is that the ocular pressure can be high and remain high after intravitreal injections of ranibizumab. In a retrospective chart review study in 50 patients, there was a short-term increase in ocular hypertension after intravitreal injec tion of ranibizumab from a mean of 14 (range 9–22) mmHg to 21 (range 10–31) mmHg (18c). There was no increase 1–4 weeks after injection. Hematologic Arterial thromboses at distant sites, in particular strokes, have been reported with intravitreous ranibizumab, at a higher frequency with 0.5 mg per injection (about 1%) than with 0.3 mg per injection (19r).
Verteporfin and photodynamic therapy (SEDA-30, 545; SEDA-31, 739); see also chapter 45 Observational studies After 12 months of photodynamic therapy with verteporfin in 64 patients with neovascular age-related macular degeneration, 51 received treat ment for a further 12 months (20c). In all, 118 adverse events were reported during the 12-month extension, of which 14 were considered possibly or probably related to the treatment. This compares with 47 (26%) of 180 adverse events that were considered possibly or probably related to the treatment during the first 12 months of the study in the 51 patients who enrolled in the extension. Most of the adverse events were mild to moderate in
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intensity. Three patients withdrew because of an adverse event during the first 12 months, and three did so during the extension. The adverse events during the extension phase were similar to those during the first 12 months, but a further seven patients had reduced vision, none related to the drug. One patient had an injection-site hemorrhage during the extension. There were no photosensitivity reactions at any time. Comparative studies Photodynamic ther apy with verteporfin has been compared with anecortave 15 mg under Tenon’s capsule at baseline and at 6 months as a periocular posterior juxtascleral depot (21C). There were no differences between the groups. The most common adverse event was reduced visual acuity, but there was no differ ence between the groups. There were 15 deaths, which were assessed as being un related to the treatment. There were non fatal serious adverse events in 97 patients (18%) during 12 months, of whom 45 (17%) received verteporfin. These were thought to be unrelated to the therapy or the injection procedure. Treatment had to be withdrawn because of adverse events in 13 patients (5%) who received verteporfin. Sensory systems Profound choroidal hypoperfusion occurred after verteporfin photodynamic therapy and intravitreal triam cinolone acetonide for age-related macular degeneration in 15 out of 108 patients with 155 treatments (22C). No susceptibility factors were identified. It occurred after the first treatment in some cases (n = 7) and after retreatment in others. If profound hypoperfu sion had occurred after several treatments, mild hypoperfusion had occurred after earlier treatments. Three patients with profound hypoperfusion were re-treated because of recurrence of the neovascularization. In all three the severity of hypoperfusion increased. Five patients with profound choroidal hypoperfusion had a pretreatment visual acuity of 20/80. The visual acuity worsened to 20/100 in two patients and to counting fingers in two;
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it increased by one line in one patient. Chor oidal hypoperfusion has been reported in patients with age-related macular degenera tion who were treated with verteporfin photo dynamic therapy, but the rate in this study (15/108) was higher than previously reported. Intravitreal triamcinolone may have contrib uted to the risk by preventing the inflamma tory response to photodynamic therapy and re-perfusion of normal vessels afterwards. Dosage regimens When verteporfin photodynamic therapy is used for choroidal neovascularization in age-related macular degeneration, adverse events include atrophy of the retinal pigment epithelium, choroidal ischemia, secondary choroidal neovascularization and transiently reduced macular function. Because of these adverse events, and since patients with acute central serous chorioretinopathy generally have a fairly good vision and a good prognosis, the effect of half-dose verteporfin has been investigated. Verteporfin 3 mg/m2 was infused over 8 minutes and indocyanine green angiography guided photodynamic therapy with 50 J/cm2 light energy was used to treat 43 eyes in 43 patients with acute central serous chorioretinopathy (23c). There were no ocular or systemic adverse events.
ADRENOCEPTOR AGONISTS (SEDA-28, 569; SEDA-31, 740)
Apraclonidine Susceptibility factors Children In five infants suspected of having Horner’s syndrome, apraclonidine eye-drops were used diagnostically (24Ac). The main adverse event was drowsiness in three cases; two required emergency admission for unresponsiveness. In one case there was bradycardia, hypertension, and reduced oxygen saturation. Based on these observations, apraclonidine eye-drops should not be used in infants.
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Brimonidine Sensory systems Brimonidine was reported to have caused granulomatous anterior uveitis and granulomatous papillary conjunctivitis after 2 years of treatment in a 78-year-old man (25A). Extensive additional investiga tions did not reveal an underlying cause. Withdrawal of brimonidine led to improve ment in 2 days and complete resolution within 1 month. Skin In 13 patients with periorbital dermatitis, ectropion was presumed to have been due to one or more of the drugs that they were using: brimonidine, betaxolol, dorzolamide, latanoprost, preservatives, timolol, or travoprost; the drugs were withdrawn and the patients were assessed again, with rechallenge after the last assessment (26c). The ectropion resolved partly or completely after the eye-drops had been withheld, and there was recurrence after rechallenge. Dorzolamide (seven cases) was the most common offender, followed by brimonidine (three cases). In six cases more than one drug was implicated, and in five cases the preservative in which the drug was formulated was blamed.
BETA-ADRENOCEPTOR ANTAGONISTS (SEDA-26, 525; SEDA-27, 509; SEDA-31, 740)
Carteolol Observational studies Carteolol is a non selective beta-adrenoceptor antagonist used in the treatment of glaucoma and ocular hypertension. During trials of carteolol 1–2% two patients had serious cardiac events, including bradycardia, congestive heart failure, and myocardial infarction; one had hypotension, which required drug withdrawal. Withdrawal was also necessary in one patient who developed bronchoconstriction and in five who developed breathlessness;
J.S.A.G. Schouten
patients with pulmonary disease had been excluded. These reactions act as a reminder that beta-blocker eye-drops can cause systemic adverse effects. Cardiovascular There are few if any differences between carteolol and other beta-adrenoceptor antagonists in terms of their effects on heart rate, blood pressure, or FEV1 in patients with glaucoma or ocular hypertension. However, in one study there was a significantly lower incidence of cardiovascular adverse events overall and a significantly lower incidence of bradycardia with carteolol than with timolol; in particular, carteolol seemed less likely to induce nocturnal bradycardia. Standard carteolol and long-acting carteolol did not differ in their effects on blood pressure or heart rate. Sensory systems The effects of carteolol eye-drops 1 and 2% have been reviewed (27R). The most common ocular symptoms were burning/stinging at the time of instillation, tearing, ocular pain, blurred vision, itching, and conjunctival hyperemia. In general, there were no significant differences in the incidence of ocular symptoms between patients who used carteolol and those who used other beta-adrenoceptor antagonists, such as timolol, metipranolol, or levobunolol. However, several studies have shown better ocular tolerability of carteolol versus timolol for certain end-points (e.g. fewer ocular symptoms overall and less burning and eye pain). The long-acting formulation of carteolol was associated with blurred vision in under 2% of patients.
Timolol
(SED-15, 3428; SEDA-31, 741)
Sensory systems In a retrospective study of 209 eyes (178 patients) with primary acquired nasolacrimal duct obstruction and 183 control eyes in patients who underwent cataract surgery, the prevalence of primary openangle glaucoma was significantly higher in the former (48/209 versus 11/183) (28C).
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In those who had primary open-angle glaucoma, the duration was longer in the former (14 years versus 9.63 years) and the average number of topical anti-glaucoma drugs per treated eye was higher (1.58 versus 0.73). Significantly more patients with glaucoma and nasolacrimal duct obstruction (69% versus 18%) were using timolol. There were no statistically significant differences for other topical glaucoma drugs. The authors concluded that chronic use of timolol eyedrops in patients with glaucoma is associated with an increased risk of nasolacrimal duct obstruction. However, a causal effect of timolol can not be based on this study and the mechanism is speculative.
CARBONIC ANHYDRASE INHIBITORS See Chapter 21.
GLUCOCORTICOSTEROIDS (SED-15, 906; SEDA-30, 548; SEDA-31, 741) Observational studies Intralesional gluco corticoids are used to treat periocular capil lary hemangiomas. Adverse events in 13 infants were adrenal suppression, transient reductions in linear growth, and localized eyelid necrosis (29c).
PROSTAGLANDIN ANALOGUES (SEE ALSO CHAPTER 39) Comparative studies Bimatoprost and latanoprost Bimatoprost (0.03%) and latanoprost have been compared in 129 patients with exfoliative glaucoma in a 3-month crossover observer-masked study
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(30C). There were no serious adverse events. More patients reported at least one adverse event with bimatoprost than with latanoprost (58 patients versus 34 patients). Conjunctival hyperemia and hypertrichosis were more common with bimatoprost than with latanoprost (32 versus 9 and 14 versus 2, respectively). There were no significant differences in other adverse events (lid dermatitis, itching, stinging, ocular pain, foreign body sensation, blurred vision, headache, change in iris color, and periocular pigmentation). The number of adverse events at the end of the trial was independent of treatment order. The incidence of periocular pigmenta tion in patients using bimatoprost (0.03%) or latanoprost has been studied retrospectively (31c). The 12-month inci dence was 0.8% (2/263) in patients who used latanoprost and 5.8% (8/137) in those who used bimatoprost. The pig mentation disappeared without withdra wal of treatment in some patients. The pigmentation ranged from deep red to brown. Latanoprost and travoprost In an observer-masked, crossover comparison of latanoprost and travoprost in 40 patients with exfoliative glaucoma, travoprost more often led to conjunctival hyperemia than latanoprost (15 versus 6) (32c).
Latanoprost Observational studies The adverse events that occurred after at least 6 months (mean 2.2 years) during latanoprost monotherapy in 353 patients have been reported (33c). Ocular adverse event occurred in 24%, including conjunctival hyperemia (21%), burning and stinging (5.9%), a foreign body sensation (3.7%), and allergic reactions (0.8%). Systemic adverse events occurred in 3.7% and included fatigue (3.1%), headache (1.4%), and nausea (0.3%). It is difficult to assess whether some of these common systemic adverse events were due to the drug.
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Sensory systems An iris pigment epithelial cyst has been associated with topical prostaglandin F2a analogues in a 76-year-old woman (34A). The cyst disappeared after withdrawal of latanoprost and recurred after rechallenge with latanoprost or bimatoprost, supporting a causal effect. The cyst did not disappear completely after drug withdrawal. It is therefore uncertain whether the cyst itself was caused by the prostaglandin analogues or whether it caused an increase in its size due to accumulation of fluid in the cyst. Choroidal detachment is a well-recognized early complication of trabeculectomy, if the eye is hypotonic in the early postoperative period. Delayed choroidal detachment and hypotony have been reported in association with the use of topical prostaglandin analo gues. Late-onset choroidal detachment after combined cataract and glaucoma surgery (phacoemulsification and trabeculectomy) has been associated with the use of topical latanoprost in the fellow eye (35A). • An 89-year-old white woman developed gra dually reduced vision in her left eye after combined phacoemulsification and trabecu lectomy 11 months before. She was using topical latanoprost 0.005% once daily in her right eye only. Examination of the left eye showed visual acuity of hand movements, an intraocular pressure of 0 mmHg, a deep ante rior chamber and a non-leaking trabeculect omy bleb. Gonioscopy showed an open anterior chamber angle, Schaeffer grade III. There was no cyclodialysis. Left fundoscopy showed extensive choroidal detachment in all quadrants, confirmed by B-scan ultrasono graphy. Intraocular pressure in the right eye was 10 mmHg. Latanoprost was withdrawn. Over the next 6 weeks, the choroidal detach ment in the left eye resolved completely, the intraocular pressure rose to 12 mmHg and Snellen visual acuity improved to 6/9. The intraocular pressure in the right eye remained within the reference range without treatment. The Naranjo causality scale suggested that the adverse reaction was possibly due to lata noprost. The choroidal detachment had not recurred at 1 year follow-up after withdrawal of latanoprost.
Late choroidal detachment after trabecu lectomy is rare in the absence of a leaking bleb. It has been reported up to 5 years after trabeculectomy in association with topical latanoprost in the involved eye. In
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this patient, latanoprost 0.005% was being used once daily in only the fellow eye. The eye takes up about 1% of topical latanoprost and the remainder is absorbed into the sys temic circulation. In studies in which patients have been treated with latanoprost in one eye only, intraocular pressure in the fellow eye was reduced by only 0.4–1.2 mmHg. However, previous glaucoma surgery is likely to alter dose-responsiveness to intraocular pressure-lowering agents. In addition, indivi dual patient sensitivity is likely to vary. The authors suggested that the patient’s sensitiv ity to systemically absorbed latanoprost, combined with the altered intraocular milieu after previous surgery, had been sufficient to cause chronic hypotony and choroidal detachment. Sensory systems The histological and cytological changes in the irises of 15 patients who had used latanoprost and had photographically demonstrated darkening of the iris have been compared to the irises of 15 controls who had never been exposed to latanoprost (36c). The specimens of iris were taken during trabeculectomy. A masked observer conducted extensive histological, cytological, and electron microscopic examinations. The darkening effect of latanoprost was not associated with either proliferative or generative iris changes, nor with increases in the number of granules. Instead, it appeared to be due to small increases in the size of mature melanin granules, particularly in the anterior border region. In a prospective observer-masked study of the effect of patient age on the incidence of latanoprost-induced increases in iris pigmen tation in unilaterally treated eyes in 36 patients under 60 years and 36 patients older than 75 years with primary open-angle glaucoma, heterochromia was assessed by means of photographs of both eyes at base line and after 6 months of follow-up (37c). Age was an important susceptibility factor for latanoprost-induced iris color change, because 28 of the older patients developed an increase in iris pigmentation (78%) com pared with 8 of the younger (22%).
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Macular edema can occur during the use of latanoprost and has been reported in a phakic patient with idiopathic juxtafoveal retinal telangiectasis using latano prost (38A). Patients with idiopathic juxtafoveal retinal telangiectasis are at risk of macular edema. Skin Latanoprost can cause hyper pigmentation of the periocular skin and has also been reported to darken a facial skin graft (39A). The darkening abated after withdrawal.
Travoprost
(SED-15, 3481; SEDA-31, 742)
Sensory systems Acute iritis and corneal edema developed after only two doses of travoprost (40A). • A 70-year-old Caucasian woman with primary open-angle glaucoma developed redness, discomfort, and blurring of vision in her left eye. She had used timolol and dorzolamide combination therapy for 1 year, and then travoprost was added to the left eye. Her symptoms began after only two doses. She stopped using travoprost and 10 days later the discomfort resolved. Latanoprost was then added without adverse effects.
In a before-and-after study in 379 patients with glaucoma or ocular hyperten sion, central corneal thickness was reduced by a mean of 6.9 µm, but without a signifi cant effect on intraocular pressure (41c). A control group was not included in this study, limiting a causal interpretation. If the thin ning is causative, based on a presumed effect on extra matrix remodelling, the effect is small (about a 1% change in cor neal thickness). Uveitis is rare in patients who use latano prost or travoprost, but drug withdrawal should be considered in patients who develop uveitis while using these drugs. In one patient, corneal edema and anterior uveitis occurred after two doses of travo prost and resolved 10 days after withdrawal of travoprost (40A). The intraocular was
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controlled with latanoprost, which did not cause uveitis in this patient. Hair Prostaglandins cause growth of lashes and ancillary hairs around the eye lids. Manifestations include greater thick ness and length of lashes, additional rows, and conversion of vellus to terminal hairs in canthal areas as well as in regions adja cent to the rows. Vellus hairs of the lower eyelids also undergo increased growth and pigmentation. Eyelash hypertrichosis has been reported in 75% of patients in clinical trials of travoprost in ocular hypertension. Prostaglandin analogues are thought to prolong the anagen phase of eyelash growth. Travoprost has therefore been proposed as a possible treatment for alope cia areata involving the eyelashes. Periocular skin pigmentation developed in three patients during treatment with topical travoprost for alopecia areata involving the eyelashes (42A).
Combinations of anti-glaucoma drugs Observational studies In 3333 patients using anti-glaucoma drugs, satisfaction, ocular adverse events, and the probability of changing eye-drops because of adverse events have been studied (43C). Although there were differences between drugs, they were not statistically significant for tolerability or the chance of discontinuing a drug. There was a statistically significant difference for the sum scores of adverse ocular events, because of a lower rate in those who used timolol gellans and a higher rate in those who used other combination of three or more medications. Comparative studies Brimonidine and lata noprost In a meta-analysis of randomized controlled comparisons of brimonidine and latanoprost, fatigue was more common with brimonidine (RR = 3.7; 95% CI = 1.14, 13); the risks were 5% (11/211) in those who
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used brimonidine and 1% (3/247) in those who used latanoprost (44M). There were no differences in other adverse events between the two groups. Brimonidine and brinzolamide Brimoni dine 0.15% (n = 79) and brinzolamide 1% (n = 84) added to travoprost have been compared in a 3-month, randomized, double-masked, parallel-group design (45C). The most frequent adverse events were allergy, eye pain, headache, hyperemia, and taste disturbances. The incidences were not significantly different between the groups, but that does not mean that the two drugs are equivalent in terms of the incidences of adverse effects. Brinzolamide and levobetaxolol Adverse events in a randomized, double-masked study of brinzolamide (n = 32) and levobe taxolol (n = 46) have been evaluated in children aged under 6 years with congeni tal glaucoma, with a follow-up of 12 weeks (46C). Adverse events that were judged to be related to the drugs were hyperemia, discharge, discomfort, tearing, foreign body sensations, hordeolum, pruritus of the eye, fatigue, and bradycardia. No con cerns arose with regard to visual acuity, the adnexae, anterior segment, posterior seg ment, or vitreous, patient alertness, or car diovascular parameters. Eight patients (five using brinzolamide and three using levobetaxolol) had increased corneal dia meter of at least 1 mm in at least one eye. In two patients (using brinzolamide) this was considered to be clinically relevant, but these patients also had increased intraocular pressure. The adverse events in the overall population were predomi nately non-serious and were generally mild to moderate in intensity. No patient had a serious adverse event that was related to a study drug. There were no withdrawals because of adverse events. Dorzolamide and timolol Dorzolamide 2% and timolol 0.5% either alone (n = 70) or added to latanoprost (n = 280) have been compared in an open
J.S.A.G. Schouten
non-randomized study (47c). There were 116 predominantly mild non-serious adverse events reported by 86 patients (25%). The most frequent were eye irritation (n = 42; 12%) and a bad taste in the mouth (n = 15; 4%). There were five treatment-related non-serious adverse events of severe intensity (eye irritation, diarrhea, nausea, gout, and headache). There were no serious adverse events. Systematic reviews In a systematic review of seven randomized controlled trials, there were no differences in adverse events between fixed combinations compared with the non-fixed components administered concomitantly (48M). The rates were 8–43%, and there were more overall drug-related adverse events in the non-fixed group in five of the seven studies. More patients withdrew because of intolerance or adverse events in the non-fixed combination groups in one of the seven studies; the rates were 1–6% and 13% in one study. Three main ocular adverse effects were reported: hyperemia, ocular irritation, and keratitis. Hyperemia was reported in all of the studies, and in three studies of prostaglandins there were more cases in the fixed than in the nonfixed groups; this difference was significant in one study. The systemic effect with the highest rate was bitter taste with dorzolamide, with equal rates in the fixed and non-fixed therapies.
PROCEDURES Intravitreal injection (SEDA-29, 581) Sensory systems Endophthalmitis after intravitreal injection has been reviewed (49R). Infectious endophthalmitis is most probably related to the procedure, and sterile endophthalmitis (uveitis) can also be due to the drug used.
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References 1. Bock F, Konig Y, Kruse F, Baier M, Cursie fen C. Bevacizumab (Avastin) eye drops inhibit corneal neovascularization. Graefes Arch Clin Exp Ophthalmol 2008; 246:281–4. 2. Takeda AL, Colquitt J, Clegg AJ, Jones J. Pegaptanib and ranibizumab for neovascular age-related macular degeneration: a sys tematic review. Br J Ophthalmol 2007; 91:1177–82. 3. Macugen AMD, Group S, Apte RS, Modi M, Masonson H, Patel M, Whitfield L, Adamis AP. Pegaptanib 1-year systemic safety results from a safety-pharmacokinetic trial in patients with neovascular age-related macular degen eration. Opthalmology 2007; 114:1702–12. 4. Frenkel REP, Mani L, Toler AR, Frenkel MPC. Intraocular pressure effects of pegap tanib (macugen) injections in patients with and without glaucoma. Am J Ophthalmol 2007; 143:1034–5. 5. Steffensmeier ACG, Azar AE, Fuller JJ, Muller BA, Russell SR. Vitreous injections of pegaptanib sodium triggering allergic reactions. Am J Ophthalmol 2007; 143:512–3. 6. Dayani PN, Siddiqi OK, Holekamp NM. Safety of intravitreal injections in patients receiving warfarin anticoagulation. Am J Ophthalmol 2007; 144:452–3. 7. Tilanus MA, Vaandrager W, Cuypers MH, Verbeek AM, Hoyng CB. Relationship between anticoagulant medication and mas sive intraocular hemorrhage in age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2000; 238:482–5. 8. Antoszyk AN, Tuomi L, Chung CY, Singh A. Ranibizumab combined with verteporfin photodynamic therapy in neovascular agerelated macular degeneration (FOCUS): year 2 results. Am J Ophthalmol 2008; 145:862–74. 9. Regillo CD, Brown DM, Abraham P, Yue H, Ianchulev T, Schneider S, Shams N. Randomi zed, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol 2008; 145:239–48. 10. Kourlas H, Abrams P. Ranibizumab for the treatment of neovascular age-related macu lar degeneration: a review. Clin Ther 2007; 29(9):1850–61.
11. Lee GKY, Lai TYY, Chan W, Lam DSC. Retinal pigment epithelial tear following intravitreal ranibizumab injections for neo vascular age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2007; 45:1225–7. 12. Carvounis PE, Kopel AC, Benz MS. Retinal pigment epithelium tears following rani bizumab for exudative age-related macular degeneration. Am J Ophthalmol 2007; 143:504–5. 13. Bakri SJ, Kitzmann AS. Retinal pigment epithelial tear after intravitreal ranibizumab. Am J Ophthalmol 2007; 143:505–7. 14. Chan CK, Lin SG. Retinal pigment epithelial tear after ranibizumab therapy for subfoveal fibrovascular pigment epithelial detachment. Eur J Ophthalmol 2007; 17(4):674–6. 15. Apte RS. Retinal pigment epithelial tear after intravitreal ranibizumab for subfoveal CNV secondary to AMD. Int Ophthalmol 2007; 27(1):59–61. 16. Kiss C, Michels S, Prager F, Geitzenauer W, Schmidt-Erfurth U. Retinal pigment epithe lium tears following intravitreal ranibizumab therapy. Acta Ophthalmol Scand 2007; 85:902–3. 17. Bakri SJ, McCannel CA, Edwards AO, Moshfeghi DM. Persisent ocular hypertension following intravitreal ranibizumab. Graefes Arch Clin Exp Ophthalmol 2008; 246:955–8. 18. Mojica G, Hariprasad SM, Jager RD, Mieler WF. Short-term intraocular pressure trends following intravitreal injections of ranibizu mab (Lucentis) for the treatment of wet agerelated macular degeneration. Br J Ophthal mol 2008; 92:584. 19. Anonymous. Ranibizumab: new drug. Macu lar degeneration: second-line use due to risks. Prescrire Int 2008; 17(93):3–6. 20. Ohji M, Tano Y, Bressler NM, Ishibashi T, Shiraga F, Takahashi K, Weisberger A, Yuzawa M, Japanese Age-Related Macu lar Degeneration Trial (JAT) Study Group. Photodynamic therapy with verte porfin in Japanese patients with subfoveal choroidal neovascularization secondary to age-related macular. Jpn J Ophthalmol 2008; 52:1049–61.
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associated with either latanoprost or bimatoprost therapy. Curr Eye Res 2007; 32:1037–43. Konstas AG, Kozobolis VP, Katsimpris IE, Boboridis K, Koukoula S, Jenkins JN, Stew art WC. Efficacy and safety of latanoprost versus travoprost in exfoliative glaucoma patients. Ophthalmology 2007; 114:653–7. Thelen U, Christ T, Schnober D, Hofstetter H-J, Stewart WC. Midterm response with latanoprost therapy in German ocular hyper tension patients. Curr Eye Res 2007; 32:51–6. Krohn J, Hove VK. Recurring iris pigment epithelial cyst induced by topical prostaglan din F2a analogues. Arch Ophthalmol 2008; 126:867–8. Horgan N, Kirwan RP, O’Brien CJ. Choroi dal detachment associated with latanoprost use in the fellow eye. Ann Pharmacother 2007; 41(1):161–2. Cracknell KPB, Grierson I, Hogg P. Morphometric effects of long-term exposure to latanoprost. Ophthalmology 2007; 114: 938–48. Arranz-Marquez E, Teus MA. Effect of age on the development of a latanoprost-induced increase in iris pigmentation. Ophthalmology 2007; 114(7):1255–8. Baba T, Nagayama M, Ohtsuki H, Hirooka K, Shiraga F. Macular edema associated with latanoprost use in a patient with idiopathic juxtafoveal retinal telangiectasis. Jpn J Ophthalmol 2008; 52:68–70. Calladine D, Harrison RJ. Severe darkening of a facial skin graft from latanoprost. Arch Ophthalmol 2007; 125:1427–8. Aydin S, Ozcura F. Corneal oedema and acute anterior uveitis after two doses of tra voprost. Acta Ophthalmol Scand 2007; 85 (6):693–4. Harasymowycz PJ, Papamatheakis DG, Ennis M, Brady M, Gordon KD, Archam bault P, Bazin G, Boucher S, Brochu J, Char bonneau A, Chehade N, Cohen S, Deschenes C, Gelinas G, Gosselin M, Hase gawa N, Isabelle N, Kavalec C, Krauss D, Lalonde G, Lalonde L, Lapointe A, Mayer J, Noel F, Podtetenev M, Robrerge M, Simard M, Weldon C. Relationship between travoprost and central corneal thickness in ocular hypertension and open-angle glau coma. Cornea 2007; 26:34–41.
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42. Feletti F, Vincenzi C, Pazzaglia M, Tosti A. Periocular pigmentation associated with use of travoprost for the treatment of alopecia areata of the eyelashes. J Eur Acad Derma tol Venereol 2007; 21(3):421–3. 43. Beckers HJM, Schouten JSAG, Webers CAB, Valk R, Hendrikse F. Side effects of commonly used glaucoma medications: comparison of tolerability, chance of dis continuation, and patient satisfaction. Graefes Arch Clin Exp Ophthalmol 2008; 246:1485–90. 44. Fung AT, Reid SE, Jones MP, Healey PR, McCluskey PJ, Craig JC. Meta-analysis of randomised controlled trials comparing lata noprost with brimonidine in the treatment of open-angle glaucoma, ocular hypertension or normal-tension glaucoma. Br J Ophthalmol 2007; 91:62–8. 45. Feldman RM, Tanna AP, Gross RL, Chuang AZ, Baker L, Reynolds A, Prager TC. Comparison of the ocular hypotensive efficacy of adjunctive brimonidine 0.15% or
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brinzolamide 1% in combination with travo prost 0.004%. Ophthalmology 2007; 114: 1248–54. Whitson JT, Roarty JD, Vijaya L, Robin AL, Gross RD, Landry TA, Dickerson JE, Scheib SA, Scott H, Hua SY, Woodside AM, Berga mini MVW. Efficacy of brinzolamide and levobetaxolol in pediatric glaucomas: a rando mized clinical trial. J AAPOS 2008; 12:239–46. Lesk MR, Koulis T, Sampalis F, Sampalis JS, Bastien NR. Effectiveness and safety of dor zolamide–timolol alone or combined with latanoprost in open-angle glaucoma or ocu lar hypertension. Ann Pharmacother 2008; 42:498–504. Cox JA, Mollan SP, Bankart J, Robinson R. Efficacy of antiglaucoma fixed combination therapy versus unfixed components in redu cing intraocular pressure: a systematic review. Br J Ophthalmol 2008; 92:729–34. Ho J, Loewenstein JI. Endophthalmitis asso ciated with intravitreal injections. Int Ophthalmol Clin 2007; 47:199–208.
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ASIAN HERBAL MEDICINES (SED-15, 1609; SEDA-27, 512; SEDA-28, 573; SEDA-29, 583) Respiratory Huoxiang Zhengqi Oral Liquid (‘Agastache Oral Liquid to Rectify the Qi’), a compound Chinese medicine formula, consists of Herba Agastaches seu pogostemi (huo xiang), Cortex Magnoliae officinalis (hou po), Pericarpium Citri reticulatae (chen pi), Folium Perillae frutes centis (zi su ye), Radix Angelicae dahuricae (bai zhi), Tuber Pinelliae ternatae (ban xia), Pericarpium Arecae catechu (da fu pi), Rhi zoma Atractylodis macrocephalae (bai zhu), Sclerotium Poriae cocos (fu ling), Radix Platycodi grandiflori (jie geng), and Honeyfried Radix Glycyrrhizae uralensis (zhi gan cao). It is a very commonly used over-the counter product in China for household medication, especially for symptoms such as fever and chills, headache, heaviness of the head, abdominal pain, and distension, vomiting, and diarrhea during the summer months. This formula is generally consid ered to have few adverse effects; however, it has been associated with asthma (1A). • A 73-year-old woman became asthmatic, with a pale complexion and profuse sweating within 10 minutes of a dose of Huoxiang Zhengqi
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32048-4 2010 Elsevier B.V. All rights reserved.
Oral Liquid 10 ml for abdominal pain, disten sion, and diarrhea. There were moist crackles on auscultation and her heart rate was 140/ minute. The asthmatic symptoms and signs resolved within 10 minutes of administration of antiasthmatic and antianaphylactic medica tions and she made an uneventful recovery. • A 82-year-old man became asthmatic 10 minutes after taking 10 ml of Huoxiang Zhengqi Oral Liquid for abdominal pain, vomiting, and diarrhea. There were moist crackles on auscultation. The asthma was effectively managed with conventional antiasthmatic and antiallergic medications and he recovered fully within 2 days.
The cause of the asthmatic reaction caused by Huoxiang Zhengqi Oral Liquid was unknown; however, it was believed to be associated with the complex chemical com ponents present in the product, especially those in huo xiang, such as patchouli, alcohol, and patchoulenone. Liver In a 26-month prospective study at an Asian tertiary hospital to test whether druginduced liver injury in 31 patients caused by traditional complementary and alternative medicines was related to adulterants, 23 had hepatocelluar damage, 6 had cholestasis, and 2 had a mixed pattern of injury (2c). Chinese medicines were implicated in 17 cases, fol lowed by Malay medicines in 5. Adulterants were found in 9 of the 31 traditional medi cines that were available for chemical analy sis. The authors concluded that drug-induced liver injury in Asia has a different pattern of causes from that in the West. Chai-Ling-Tang (Sairei-to in Japanese), a compound herbal formula, consists of 11
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herbs: Radix Bupleuri (chai hu), Radix Scutellariae (huang qin), Tuber Pinelliae ternatae (ban xia), Rhizoma Zingiberis recens (sheng jiang), Radix Ginseng (ren shen), Radix Glycyrrhizae (gan cao), Fruc tus Jujubae (da zao), Rhizoma Alismatis (ze xie), Poria (fu ling), Polyporus (zhu ling), and Rhizoma Atractylodis macrocephalae (bai zhu). It has been reported to cause acute liver damage (3A).
Radix Isatidis, artificial Cattle bezoar, Bor neolum, and Bufonis venenum, has the claimed therapeutic effects of clearing heat, removing toxicity and reducing swel ling to relieve pain. This proprietary herbal medicine is widely used in China to treat laryngopharyngitis and tonsillitis. Although it is generally believed to be safe, Houzheng Wan has been reported to cause laryngeal edema (5A).
• A 37-year-old man developed fatiguability, jaundice and an enlarged liver after taking the oral Japanese herbal medicine Sairei-to for infertility for several weeks. He had mark edly raised aspartate transaminase and alanine transaminase activities, but tests for hepatitis virus markers did not suggest active viral infection. A liver biopsy strongly suggested an allergic reaction. Pinellia tuber (tuber of Pinellia ternate Breit), one of the 11 compo nents of Sairei-to, was later determined to be the most probable causative component, based on a lymphocyte migration inhibition test. He made a full recovery 1 month after withdrawal of the preparation.
• A 21-year-old student developed chest disten sion and dyspnea 30 minutes after taking oral Houzheng Wan for a flu-like illness with a sore throat. Inhalation of oxygen was ineffective but intravenous infusion of dexamethasone 10 mg relieved his symptoms within 2–3 minutes.
This case report reminds us of the need to monitor the possible hepatotoxic effects of herbal medicines, even though they are often regarded as ‘natural’, mild, and non-toxic. Immunologic Suxiao Jiuxin Wan (‘Swift Acting Cardiac Saving Pill’), a formulation that contains two Chinese medicines, Rhi zoma Chuanxiong and Borneolum, is com monly used to prevent and treat attacks of angina. It has been associated with anaphy lactic laryngeal edema (4A). • A 38-year-old woman took Suxiao Jiuxin Wan sublingually for suspected angina pectoris and about 10 hours later developed generalized pruritus and rash and a feeling of obstruction from foreign matter in the throat. Self-medica tion with chlorphenamine maleate 10 mg failed to ameliorate the symptoms and she gradually developed a hoarse voice, numbness in the lips and swelling of the eyelids. There were wheezes on lung auscultation. Dexamethasone 10 mg intravenously produced gradual relief of the feeling of obstruction in the throat and the rash disappeared. She made a complete recov ery within 2 days.
Houzheng Wan (Throat Disease Pill), a compound herbal formula consisting of
Drug–drug interactions Warfarin The risk of bleeding associated with the use of alter native medicines has been evaluated in 171 patients taking warfarin in a prospective study in an acute-care academic research hospital in Canada (6c). The patients com pleted a 16-week diary by recording bleed ing events; 87 (51%) reported at least one bleeding event and 73 (43%) indicated that they had used at least one alternative med icine previously reported to interact with warfarin. The therapies associated with an increased risk of self-reported bleeding included cayenne, ginger, willow bark, St John’s wort and coenzyme Q10. Use of more than one alternative medicine while taking warfarin was also a significant sus ceptibility factor. Coenzyme Q10 (OR = 3.69, 95% CI = 1.88, 7.24) and ginger (OR = 3.20, 95% CI = 2.42, 4.24) were independently associated with an increased risk of self-reported bleeding.
Injectable formulations of Chinese medicines In recent decades many Chinese herbal med icines have been manufactured as injectable formulations and are being used in a wide variety of medical conditions. However, these injectable formulations are not without adverse effects; in fact, many of them often
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cause serious adverse effects, some of them life-threatening or fatal. Ci wu jia injection Ci wu jia injection is a sterilized injection fluid made of Radix et Caulis Acanthopanacis senticosi (also known as Siberian ginseng). It is widely used in China to treat transient ischemic attacks, cerebral arteriosclerosis, cerebral thrombosis, cerebral embolism, angina pec toris, coronary heart disease, neurasthenia, and menopausal syndrome. Allergic reac tions are the most common form of adverse effect associated with Ci wu jia injection (7A, 8A). • A 45-year-old woman was given an intravenous infusion of Ci wu jia injection fluid 250 ml in 40 ml of 5% dextrose for chest pain and insom nia with abundant dreams, and 10 minutes into the infusion suddenly developed chest distress, dyspnea, profuse sweating, and cold limbs. Her blood pressure was 90/60 mmHg and her heart rate was 98/minute. The Ci wu jia injection was immediately terminated and she was given oxy gen. Her symptoms gradually disappeared after she was given adrenaline 0.5 mg subcutaneously plus intramuscular promethazine 50 mg and dexamethasone 5 mg. • A 48-year-old woman with cerebral arterio sclerosis was given an intravenous infusion of Ci wu jia injection 60 ml in 250 ml of 5% dextrose. A few minutes into the infusion she started to complain of numbness in the lips and the ton gue. The infusion was immediately stopped and she was given intravenous promethazine and calcium. She subsequently developed dyspnea, profuse sweating, generalized itching, irritabil ity, swelling of the lips, and a swollen tongue. Laryngeal edema was diagnosed. All of her symptoms gradually resolved after she had been treated with intravenous dexamethasone 20 mg and other symptomatic measures.
Ligustrazine injection Ligustrazine is purified from Radix Chuanxiong. Ligustra zine injection is widely used in China for coronary heart disease and stroke, but has been associated with attacks of angina (9A). • A 61-year-old woman with renal insufficiency was given ligustrazine injection 0.1 g in 200 ml of saline by intravenous infusion. After 100 ml had been given she suddenly developed chest distress, palpitation, and headache. The symp toms resolved after oxygen inhalation and sub lingual isosorbide dinitrate. She had a similar
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adverse reaction on a second occasion when she was given ligustrazine. • A 55-year-old woman was given ligustrazine injection 0.2 g by intravenous infusion for ver tigo and hypertension, and she suddenly devel oped chest distress and palpitation. The symptoms were relieved by reducing the speed of infusion. A similar phenomenon occurred on the next day, when ligustrazine was given intravenously.
The authors of the report believed that these adverse events were not allergic reactions but were due to the calcium channel-blocking property of ligustrazine, which could increase heart rate and oxygen consumption. However, the clinical descriptions suggested the possibility of non-IgE-mediated anaphy lactic reactions. Qing Kai Ling injection Qing Kai Ling (which literally means ‘Clearing and Opening with Miracles’) is a sterilized injectable formu lation that contains eight components: Radix Isatidis, Flos Lonicerae, Fructus Gardeniae, Cornu Bubali, Concha Margaritiferae usta, baicalin, cholic acid and porcine deoxycholic acid. It is widely used in China in the treatment of stroke, hepatitis, and cancers, and has been used as an antidote for many forms of acute toxicity. However, it has adverse effects, mostly allergic reactions. In a review of articles about the adverse effects of Qing Kai Ling injection published between 1995 and 2005, 105 papers were identified from the CNKI database (10M). Of 329 cases of adverse events reported in these publications, 194 cases were moderate allergic reactions, 56 were cases of anaphylactic shock and there were 2 cases of death from anaphylactic shock. There were skin reactions in 49 patients, respiratory disorders in 4, drug-induced fever in 13, and lingering fever in 11. The authors believed that Qing Kai Ling injection-induced allergic actions were attributable to (1) the complex chemical components presented in the formula; (2) impurities in the final product; (3) interactions with other drugs; and (4) individual patient susceptibility and psychological factors. Shen Mai injection Shen Mai injection is a sterilized injection fluid containing Radix
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Ginseng and Radix Ophiopogonis extracts. It is commonly used in China to treat a wide variety of conditions, such as shock, coronary heart disease, viral myocarditis, and chronic pulmonary heart disease. Although Radix Ginseng and Radix Ophiopogonis are very safe in decoctions, Shen Mai injection can cause allergic reactions (11A, 12A). • A 48-year-old woman with hypertension, cor onary heart disease, and angina was treated with Shen Mai injection 60 ml in 5% dextrose by intravenous infusion. About 2 minutes into the infusion, she suddenly developed palpita tion, chest distress, shortness of breath, nausea, and dizziness. Her heart rate was 116/minute, her blood pressure 90/50 mmHg, and her respiratory rate 32/minute. The infusion was stopped immediately and oxygen, dexametha sone and promethazine eventually led to total amelioration of the symptoms. • A 59-year-old man with hepatic cirrhosis devel oped chest distension, fever, dizziness, a dark complexion, tremors in the limbs, and mental confusion after intravenous infusion of Shen Mai injection for 10 seconds. The injection infusion was immediately stopped and he was given oxygen and promethazine. He regained consciousness after 2 minutes and his other symptoms gradually disappeared.
Shuang Huang Lian injection Shuang Huang Lian injection is a sterilized aqueous extract of Flos Lonicerae, Radix Scutellariae and Fructus Forsythiae. It is commonly used in China to treat viral or bacterial upper respiratory infections, pneumonia, tonsillitis and laryngitis. However, it has been associated with a plethora of adverse effects, mostly anaphylactic reactions (13A, 14A). • A 31-year-old man with bronchial asthma developed acute asthma after intravenous administration of Shuang Huang Lian injection for an acute upper respiratory infection. The injection was immediately discontinued, and his symptoms gradually resolved after she had been given dexamethasone and aminophylline. • A 56-year-old woman with a history of penicil lin allergy and bronchial asthma developed acute anaphylactic shock, apnea, and cardiac arrest within 1 minute of administration of Shuang Huang Lian injection by intravenous infusion. She was successfully treated by cardio pulmonary resuscitation and large doses of glucocorticoids. • A 13-year-old boy with no history of allergy suddenly developed acute laryngeal edema,
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generalized urticaria, swelling of the eyelids, and conjunctival congestion after an intra venous infusion of Shuang Huang Lian injec tion for an acute upper respiratory tract infection. The medication was stopped immedi ately, he was given methylprednisolone 500 mg, and he made an uneventful recovery. • A 28-year-old woman with a history of peni cillin allergy developed generalized urticaria, nausea and vomiting after an intravenous infusion of Shuang Huang Lian injection. The medication was stopped immediately and her symptoms gradually resolved after she had been given dexamethasone and aminophylline. • A 40-year-old man developed anaphylactic shock 10 minutes after an intravenous infusion of Shuang Huang Lian injection (0.6 g of freeze-dried Shuang Huang Lian powder dissolved in 250 ml 5% glucose–saline). The medication was immediately withheld and he was treated for shock. He made a full recovery.
Yan Hu Ning injection Yan Hu Ning injection contains andrographolide, the active ingredient of a medicinal herb Herba Andrographitis. It is commonly used in China to treat viral pneumonia and upper respiratory infections. Although associated adverse reactions are rare in adults, it has been associated with allergic reactions in children (15A, 16A). • A 2.5-year-old boy developed a red complex ion, profuse sweating and shortness of breath about 35 minutes into an intravenous infusion of Yan Hu Ning injection 80 mg in 150 ml of 5% glucose in isotonic saline for suppurative tonsillitis. The infusion was stopped immedi ately and intravenous dexamethasone resulted in amelioration of the allergic reaction. • A 10-year-old girl developed itching in the limbs, followed by a red complexion, red eyes, abdominal pain, a generalized rash with prur itus, chest distension, and shortness of breath about 24 minutes into an intravenous infusion of Yan Hu Ning injection 120 ml in 150 ml of 5% dextrose for an upper respiratory infection. The infusion was stopped immediately and she was given dexamethasone and promethazine, which led to complete resolution. • A 7-year-old boy developed anaphylactic shock with a pale complexion, shivering, and an erythematous rash on the forehead about 20 minutes into an intravenous infusion of Yan Hu Ning injection for suppurative tonsillitis. The infusion was immediately stopped and he was given dexamethasone and promethazine, which completely relieved the allergic reaction.
Treatments used in complementary and alternative medicine
The underlying mechanism of Yan Hu Ning-induced allergic reaction is unknown, but it is probably attributable to impurities in the product, allergic susceptibility of the patients and perhaps too rapid intravenous infusion. If the last mechanism is involved, this reaction could be a non-IgE-mediated anaphylactic reaction, due to histamine release, similar to the red man syndrome after vancomycin. Yu xing cao injection Yu xing cao injec tion is a sterilized fluid made from a Chinese herb, Herba Houttuniae. It is widely used to treat upper respiratory infections, pneumo nia and gynecological inflammatory condi tions. Anaphylactic shock is not uncommon when Yu xing cao is given intravenously (17A). • A 45-year-old man with an upper respiratory infection was given an intravenous infusion of Yu xing cao injection 50 ml, and he suddenly developed violent coughing, chest distress, dys pnea, a sore throat, dry lips, generalized prur itus, numbness of the limbs, and a profuse cold sweat. The symptoms resolved with immediate antishock treatment and he made an uneventful recovery.
Conclusion Frequent adverse effects invol ving Chinese medicine injections in the past few years have caused the State Food and Drug Administration of China to issue a number of mandates and guidelines to regu late the production, quality control, evalua tion of efficacy, information sheets and safe use of this category of Chinese medicine (18S–23S).
OTHER FOLK REMEDIES Drug adulteration Lead poisoning has been reported in a 3-year-old child who took a Hispanic folk remedy (24A). • A 3-year-old boy who had been eating leadcontaminated sweets started to complain of vague non-localizing abdominal pain asso ciated with vomiting, nausea, loss of appetite, constipation, extreme fatigue, multiple joint pains, intermittent headache, and irritability.
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His mother took him to a Hispanic folk healer who diagnosed empacho, a collective diagnosis used to describe abdominal symptoms in the Hispanic community; the healer advised the use of a Hispanic folk remedy called greta. However, repeated administration of greta resulted in worsening of the symptoms. There was a high blood lead concentration of 190 µg/l, well above the Centers for Disease Control and Prevention’s limit of concern (100 µg/l). The child’s symptoms were attributed to lead colic. The greta was subsequently tested for lead and was found to contain 140 000 mg/kg of lead monoxide. The child’s abdominal con dition began to resolve after he stopped taking imported sweets and greta.
This case highlights a greater need for sur veillance of products such as folk medicine used and consumed by children.
SPECIFIC PLANTS The UK Medicines and Healthcare pro ducts Regulatory Agency (MHRA) has announced that any approved herbal pro duct will have a Product Licence number or Traditional Herbal Registration number on its packaging. Products labelled this way are supposed to meet assured standards of safety, quality and patient information. The Agency has been made aware of sev eral cases of a product sold as ‘Goldenroot Complex’ (promoted as a herbal alternative to Viagra for erectile dysfunction) incorrectly advertised on the Internet as regulated and approved by the MHRA, which is not so (25S). The Therapeutic Goods Administration in Australia has issued a health alert about voluntary recall of two herbal cold and flu medicines, following reports of a number of allergic and anaphylactic reactions (26S). The Agency has advised consumers to stop using these products (Nyal Day and Night Cold and Flu Fighter tablets and Nyal Cold and Flu Fighter tablets) immediately and to consult their doctor if they have concerns. Health Canada has provided an update on adverse effects of Echinacea, Gingko, and St John’s wort, based on reports received from 2003 to 2008 (27S). In
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addition it has announced that it received 31 reports of adverse reactions suspected of being associated with valerian-containing products from 1990 to 2008. Of these 31 reports, 15 described psychiatric reactions such as visual hallucinations, nightmares, and abnormal thinking. Other reports included gastrointestinal disturbances, aller gic reactions, increased hepatic enzyme activity, and cardiac complications.
Allium sativum (Liliaceae, garlic bulb) Mouth Garlic has been associated with chemical burns in the oral mucosa (28A). • A 50-year-old man with toothache developed a burning pain in the gums in the same region as the painful teeth. He had extensive caries in the maxillary right second and third molars. Adjacent to these teeth, there was an area of slough and mucosal ulceration in the buccal vestibule, extending to the gum and mucosa; the lesion was painful on palpation. Detailed questioning revealed that he had kept crushed raw garlic in the buccal vestibule adjacent to the painful teeth overnight to relieve the dental pain. The garlic was removed in the morning and resulted in a dull burning pain. He was advised to avoid further use of garlic paste in that region. A topical anesthetic, topical antibacterial agents, and systemic analgesics were also prescribed.
This was a between-the-eyes adverse effect of type 2 (29H). The use of herbal medicines or home remedies should be considered in the differential diagnosis for chemical burns if the burn is not found to be associated with other common factors.
Artemisia vulgaris (Asteraceae, mugwort, moxa) Immunologic Artemisia vulgaris, used in moxibustion, contains thujones, which can be toxic. Moxibustion has been associated with two cases of allergic reactions (30A). • A 32-year-old woman developed allergic symp toms, including discomfort, swelling, itching and
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erythema in the face after exposure to moxibus tion smoke on three occasions, each time lasting 20 minutes, while she accompanied her son to sessions of moxibustion for nocturnal enuresis. The swelling was most pronounced in the ears, eyelids, and lips. She had no history of drug or food allergy, and moxa smoke allergy was con sidered. She made a complete recovery after 3 days of antiallergic medications. • A 22-year-old woman was twice treated with moxibustion on the Shenque point (at the center of the umbilicus) for abdominal pain, each treatment lasting 20 minutes. She later developed erythema, pruritus, and millia around the umbilicus. The moxibustion and all her symptoms resolved after 1 week.
In these cases the chemicals produced by burning moxa were believed to have caused allergic reactions.
Cimicifuga racemosa (Ranunculaceae, black cohosh) Liver Black cohosh has been associated with two cases of hepatotoxicity in post menopausal women (31A). • A 50-year-old woman developed a retro-orbital headache. There were slightly raised aspartate transaminase and g-glutamyltransferase activ ities, but a full blood count and other biochem ical tests were normal. Her symptoms were attributed to an unidentified viral illness, and she was discharged after a few days. However, she was readmitted because of persisting head ache 10 days later. Her liver function had dete riorated and serology for hepatitis A, B, and C, Epstein–Barr virus, and cytomegalovirus was negative. On questioning, she revealed that she had been taking black cohosh to relieve meno pausal symptoms. She was advised to stop taking it, and 1 week later she became asymptomatic and her liver function normalized. • A 51-year-old woman developed epigastric pain with abnormal liver function tests (a raised alkaline phosphatase, alanine trans aminase, and g-glutamyltransferase); tests for hepatitis A, B, and C and Epstein–Barr virus were negative. Further questioning revealed that she had self-medicated with black cohosh since her hysterectomy 2 months before. The medication was withdrawn and 1 week later her liver function had normalized.
Although these cases were relatively mild because of early detection, liver damage due to black cohosh can be very serious
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and even life-threatening (32A, 33A, 34C). The authors concluded that when a patient develops unexplained jaundice or abnormal liver function tests, particularly in the peri menopausal age group, it is important to include consumption of herbal remedies in the history-taking. They might have added that it is always important to ask patients about con sumption of non-prescribed medicines.
• A 51-year-old man developed dizziness, nau sea and vomiting, general lethargy, profuse sweating, unstable walking, tongue stiffness, and blurred vision, but without loss of con sciousness or spasm of the limbs, 3 hours after self-medicating with a 400 ml decoction made from Shan dou gen 100 g. He had slight dyslalia, impaired vision in both eyes (reduced from 0.5 to 0.1), horizontal nystagmus, bilat eral dysdiadokokinesia and synergic flexion. Apart from slight dizziness while walking, he recovered fully 15 days later, after intensive symptom management.
Ecbalium elaterium (Cucurbitaceae, squirting cucumber)
Shan dou gen is a well-known toxic herb in Chinese medicine and can only be pre scribed by qualified herbalist. The normal dosage (3–10 g) should be strictly observed to avoid possible adverse effects.
Ear, nose, and throat The juice of Ec balium elaterium fruit has commonly been used to treat sinusitis in the Mediterranean region because of its anti-inflammatory effects. However, the undiluted juice can cause irritation and inflammation in muco sal membranes (35A). It has been associated with severe uvular edema and nasal mucosal necrosis after nasal administration of an undiluted formulation (36A). • A 36-year-old man developed swelling of the uvula and shortness of breath 5–6 hours after he had used three nasal drops of undiluted juice of E. elaterium for chronic sinusitis. Standard antiallergic drugs and subcutaneous adrenaline had no effect. Anterior rhinoscopy showed multiple necrotic areas in the nasal mucosa and he recovered spontaneously after 5 days.
Ephedra See Chapter 13.
Menispermum dauricum (Menispermaceae) Nervous system Rhizoma Menispermi, or shan dou gen in Chinese, is a herb with the claimed therapeutic functions of clearing heat, removing toxicity and benefiting a painful throat. It is classified as a toxic herb in the Chinese Pharmacopoeia, and it has been associated with ataxia and impair ment of vision (37A).
Psoralea corylifolia (Fabaceae, psoralea fruit) Skin Psoralea fruit is commonly used, both externally and internally, to treat viti ligo in various traditional medical systems, such as Islamic medicine (38c), Indian Ayur vedic medicine (39c), and Chinese medicine (40A). Topical use has been associated with skin irritation (41A). • A 40-year-old woman used topical psoralea fruit tincture 30% (obtained by soaking 30 g of coarse powder of psoralea fruit in 100 ml of 60% alcohol for 3 days) for vitiligo. She also took a proprietary drug called Vitiligo Capsule (containing Fructus Psoralea, Radix Astragali, Radix Veratri nigri, Flos Carthami and Zaocys). She developed erythema, pruritus, swelling, and a vesicular rash on skin that had been so treated over 5 days. The topical appli cation was discontinued after 5 days and the inflamed skin was washed with 2% saline sev eral times a day for 4 days until all the allergic symptoms disappeared.
ANIMAL DRUGS Mylabris phalerata Pallas (Miloidae, Mylabris) Hematologic Topical application of for mulations that contain mylabris (or ban
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mao in Chinese) has been associated with an acute hemopoietic disorder characterized by a reduced complete blood count (pancyto penia) and abnormal bleeding (42A). • A 32-year-old man developed epistaxis, tarlike stools, and a pale complexion after apply ing a topical paste containing ban mao for psoriasis. Hematological investigations sug gested pancytopenia. He was instructed to stop using ban mao and the hematological values normalized 25 days later. • A 9-year-old boy developed epistaxis and a pale complexion after repeated topical appli cation of a vinegar extract of ban mao for alopecia areata for about 4 months. Hemato logical investigations suggested pancytopenia. Ban mao was stopped immediately and he made a full recovery about 50 days later. • A 24-year-old woman developed palpitation, shortness of breath, and hematuria after using suppositories containing ban mao for 10 days. Hematological investigations suggested pan cytopenia. She made a complete recovery 37 days later after having stopped using the product.
Ban mao is an insect-based toxic Chinese medicine that contains cantharidin, which is thought to inhibit DNA synthesis in blood cells, resulting in acute hemopoietic disorders.
ACUPUNCTURE Observational studies In a prospective study of the use of acupuncture in the framework of statutory health insurance in Germany, 454 920 patients with at least one of three chronic pain, conditions (headache, low back pain, and osteoarthritis) were trea ted by 8727 medical acupuncturists (43C). At least one of the predefined adverse reac tions or complications was seen in 7.9% of the patients. The most frequent reactions were ‘needling pain’ (4.0%), ‘hematoma’ (3.3%), and ‘bleeding’ at the point of inser tion (1.6%). In 0.4% of the patients, the acupuncturists reported ‘orthostatic pro blems’, in 0.3% ‘forgotten needles’, and in 0.7% ‘other events’ (including ‘local skin irritation’, ‘worsening of symptoms’, ‘symp tom aggravation’, ‘fatigue’, and a ‘sensation
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of warmth’). During the 2-year reporting period, serious adverse reactions due to acupuncture were reported in 13 patients: pneumothorax (n = 3), acute hypertensive or hypotensive crises (n = 6), erysipelas (n = 2), acute asthma (n = 1), and aggravation of suicidal thoughts (n = 1). This represents a ratio of 1 in 34 994 of the total patient population and 1 in 295 000 of the total number of acupuncture sessions. The authors concluded that acupuncture pro vided by qualified therapists is safe and that patients benefited. They also found that more acupuncture training did not correspond to better therapeutic effects. Respiratory Although the risk of serious adverse events after acupuncture is very low, some severe adverse effects do occur, especially in inexperienced hands, including pneumothorax (44R). • A 50-year-old Caucasian woman suddenly developed severe right-sided chest pain and breathlessness 8 hours after receiving acupunc ture to her scapulothoracic region (45A). She was hypoxic and tachycardic (oxygen satura tion 91% breathing room air). Her trachea was central, but there were reduced breath sounds, poor chest wall excursion and hyper-resonance of the right hemithorax. A chest radiograph confirmed a moderate-sized right-sided pneumothorax. An intercostals chest drain was inserted, with good effect. She required opiates for pain but otherwise made an uneventful recovery.
Although acupuncture is considered to be of low risk, all patients should be counselled about the possibility of pneumothorax when needling is performed in the thoracic region. The acupoints on the inner bladder lines should be needled obliquely towards the spine, in order to avoid needle-induced pneumothorax. Nervous system Xiaozhendao (which means ‘small-needle-knife’) is a modified form of acupuncture, in which needles with flat edges on the needle tips are used to perform minimal soft-tissue dissection. In recent decades this form of treatment has become increasingly popular for a variety of conditions, such as acute and chronic pain,
Treatments used in complementary and alternative medicine
bursitis, tenosynovitis, herniated interver tebral disks, arthritis, spinal stenosis, and congenital bony abnormalities. Reports of adverse effects associated with this modified form of acupuncture are rare. However, a broken needle was found in the cervical spine 3 years after Xiaozhendao treatment (46A). • A 29-year-old man gradually developed neck pain, bilateral shoulder pain and sensory distur bance of the left lateral arm. A cervical spine radiograph showed a 4-cm metallic needle that tilted toward the tracheal wall at the level of C2. A cervical spine CT scan confirmed that the needle had penetrated the epidural space from the left side into the lateral mass of the C2 vertebra. He had received Xiaozhendao treat ment in his posterior neck region for chronic dizziness and stiffness of the neck from a non medical practitioner about 3 years before. A 4.8 cm Xiaozhendao needle was removed surgi cally and he made an uneventful recovery.
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Infection risk In a case–control study of the possible susceptibility factors of hepatitis C virus infection in 80 adult blood donors in Ho Chi Minh City, the independent predic tors of anti virus antibody positivity, using stepwise logistic regression, were blood transfusion, intravenous drug abuse, acu puncture, ventoused scarification, and the practice of scarification. The respective adjusted ORs (95% CI) were 3.8 (1.1, 13.1), 3.5 (1.7, 7.3), 5.4 (2.3, 12.7), 5.4 (2.5, 11.7), and 6.6 (1.6, 26.4) (47c). The authors concluded that ventoused scarification and acupuncture are susceptibility factors for the transmission of hepatitis C virus in Viet nam and that a campaign on hygienic prac tice for the general public and practitioners of traditional medicine is needed to ensure safer health-care provision.
References 1. Liang YQ, Wang HD. [Two cases of ana phylactic asthma caused by oral adminis tration of Huoxiang Zhengqi Oral Liquid.] Heilongjiang Med J 2007;20(6):636. 2. Wai CT, Tan BH, Chan CL, Sutedja DS, Lee YM, Khor C, Lim SG. Drug-induced liver injury at an Asian Center: a prospective study. Liver Int 2007;27(4):465–74. 3. Aiba T, Takahashi T, Suzuki K, Okoshi S, Nomoto M, Uno K, Aoyagi Y. Liver injury induced by a Japanese herbal medicine, sairei-to (TJ-114, Bupleurum and Hoelen Combination, Chai-Ling-Tang) R1. J Gastro enterol Hepatol 2007;22:762–3. 4. Yang ZD. [A case of anaphylactic reaction caused by Suxiao Jiuxin Pill.] J Commun Med 2008;6(20):17. 5. Cheng L. [Report on 1 case of laryngeal edema induced by orally administered Houzheng Wan. Hubei.] J Chin Med 2007;29(10):34. 6. Shalansky S, Lynd L, Richardson K, Ingaszewski A, Kerr C. Risk of warfarinrelated bleeding events and supratherapeutic international normalized ratios associated with complementary and alternative medi cine: a longitudinal analysis. Pharmacother apy 2007;27(9):1237–47.
7. Zhao Y, Ma YJ, Sun SJ. [A case of anaphy lactic reaction caused by intravenous admin istration of Ci wu jia injection.] Shenyang Milit Med 2008;21(2):138. 8. Yuan YH. [A case of laryngeal edema caused by Ci wu jia injection.] Chin J Chin Med Info 2007;9(14):105. 9. Wang LF, Shao XZ, Sun LX, Tian CY, Chen YC. [Two cases of angina attack induced by ligustrazine injection.] Hebei Med J 2007; 29(6):568. 10. Gong MX, Wang LB. [Review and analysis of 329 cases of allergic reactions associated with Qing Kai Ling injection.] Lishizhen Med Materia Medica Res 2007;18(9):2175–6. 11. Zhang ZC, Tian LX. [A case of allergic reaction caused by intravenous dripping of Shen Mai injection.] Chin J Chin Med West Med Crit Care 2007;14(4):253. 12. Cao Q, Shi JH. [A case of adverse reaction associated with the use of Shen Mai injection.] Chin Nur Res 2008;22(9B):2432. 13. Chen JK. [A case of anaphylactic shock caused by Shuang Huang Lian injection.] J Dermatol Venereol 2007;29(4):56. 14. Xie H. [Report on 4 cases of adverse reactions caused by Shuang Huang Lian
888 injection.] J Emerg Trad Chin Med 2007; 16(11):1315. 15. Fan SX. [A case of adverse reaction caused by Yan Hu Ning injection.] Chin Hosp Pharm J 2008;28(4):330. 16. Kuang XF, Qin WY, Zhang F, Zeng K, Ji CR. [Two cases of Yan Hu Ning injectioninduced allergic reaction.] Qilu Med J 2007;22(6):529. 17. Kang RJ. [Report on a case of anaphylactic shock induced by Yu xing cao injection.] Inner Mongolian J Chin Med 2007;26(4):2. 18. State Food and Drug Administration. [Cir cular concerning the decision on seven injec tions including Yu xing cao injection fluid.] http: //www.sda.gov.cn; SFDA Office Circular no. [2006] 461, 5 September 2006. 19. State Food and Drug Administration. [Circular regarding the revision of the infor mation sheets of Yu xing cao injection (for intramuscular use).] http://www.sda.gov.cn; SFDA Office Circular no.[2006] 561,3 November 2006. 20. State Food and Drug Administration. [Cir cular on the publication of the basic technical requirements for the injections of Chinese medicines and natural products.] http:// www.sda.gov.cn; SFDA Office Circular no. [2007] 743, 6 December 2007. 21. State Food and Drug Administration. [Cir cular regarding the initiation of the adjust ment work on the pharmaceutical companies which manufacture Ci wu jia injection fluid.] http://www.sda.gov.cn; SFDA Office Circu lar no. [2008] 172, 19 November 2008. 22. State Food and Drug Administration. [Announcement on further consolidation of the production and clinical application man agement of injection form of Chinese medi cine.] http://www.sda.gov.cn; SFDA Office Circular no. [2008] 71, 24 December 2008. 23. State Food and Drug Administration. [Announcement on the initiation of re evaluation on the safety of injection form of Chinese medicine.] http://www.sda.gov. cn; SFDA Office Circular no. [2009] 28, 13 January 2009. 24. Cabb EE, Gorospe EC, Rothweiler AM, Gerstenberger SL. Toxic remedy: a case of a 3-year-old child with lead colic treated with lead monoxide (greta). Clin Pediatr 2008; 47(1):77–79.
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25. Anonymous. Herbal medicines. New packa ging to combat misinformation. WHO News lett. 2008;5&6:1. 26. Anonymous. Herbal cold and flu products. Voluntary recall. WHO Newslett 2009;4:1. 27. Anonymous. Natural health products. Update on adverse reactions. WHO News lett. 2009;1:5. 28. Bagga S, Thomas BS, Bhat M. Garlic burn as self-inflicted mucosal injury – a case report and review of the literature. Quintessen Int 2008;39(6):491–4. 29. Aronson JK, Hauben M. Anecdotes that provide definitive evidence. BMJ 2006; 333(7581):1267–9. 30. Li HX, Liu SW. [Analysis of two cases of moxibustion-induced allergy.] J Emerg Trad Chin Med 2008;17(6):859–60. 31. Joy D, Joy J, Duane P. Black cohosh: a cause of abnormal postmenopausal liver function tests. Climacteric 2008;11:84–8. 32. Lynch CR, Folkers ME, Hutson WR. Fulmi nant hepatic failure associated with the use of black cohosh: a case report. Liver Transpl 2006;12:989–92. 33. Lontos S, Jones RM, Angus PW, Gow PJ. Acute liver failure associated with the use of herbal preparations containing black cohosh. Med J Aust 2003;179:390–1. 34. Dog TL, Powell KL, Weisman SM. Critical evaluation of the safety of Cimicifuga racemosa in menopause symptoms relief. Menopause 2003;10:299–313. 35. Satar S, Gokel Y, Toprak N, Sebe A. Lifethreatening uvular angioedema caused by Ecbalium elaterium. Eur J Emerg Med 2001;8:337–9. 36. Eken C, Ozbek K, Yildirim C, Eray O. Severe uvular edema and nasal mucosal necrosis due to Ecbalium elaterium (squirting cucumber): an allergic reaction or direct toxic effect? Clin Toxicol 2008;46:257–8. 37. Zheng HB, Wang LC, Yang XH, Chen Q, Shang WF. [Ataxia and vision impairment resulting from Subprostrate sophora root intoxication: a case report and review of lit erature.] West Chin Med J 2007;22(3):590. 38. Ali MI, Khan MM, Ali B, Ali M. Treatment of bars (vitiligo) with Arab medicine. Bull Islam Med 1981;1:454–61. 39. Donata K, Austin M, Rajagopalan K. Clin ical trial of certain Ayurvedic medicines
Treatments used in complementary and alternative medicine indicated in vitiligo. Ancient Sci Life 1990;9:202–6. 40. Vitiligo ZG. In:Qin WZ, editor. Research in dermatology. Shanghai: Shanghai Science and Technology Press, 1988:525–53. 41. Liang QX, Cao Y. [Report on a case of allergic reaction caused by Psoralea fruit tincture.] J Pract Trad Chin Med 2008;24(9):602. 42. Liu YK, Chi Y. [Three cases of acute hematopoietic disorder caused by topical application of ban mao preparations.] J Clin Hematol 2008;21(1):50–1. 43. Weidenhammer W, Streng A, Linde K, Hoppe A, Melchart D. Acupuncture for chronic pain within the research program of 10 German health insurance funds – basic results from an observational study. Comple ment Ther Med 2007;15:238–46.
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44. White A. A cumulative review of the range and incidence of significant adverse events associated with acupuncture. Acupunct Med 2004;22(3):122–33. 45. Juss JK, Speed CA, Warrington J, Maha deva R. Acupuncture induced pneumo thorax – a case report. Acupunct Med 2008;26(3):193–6. 46. Liou JT, Liu FC, Hsin ST, Sum DCW, Lui PW. Broken needle in the cervical spine: a previously unreported complication of Xiaozendao acupuncture therapy. J Altern Complement Med 2007;13(1):129–32. 47. Ngo Y, Maugat S, Duong QT, Nguyen TNH, Astagneau P. Risk of hepatitis C related to traditional medicine: a case control study in Ho Chi Minh City, Vietnam. Rev Epidemiolog Sante Publ 2007;55(2):107–12.
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Alcohol
Miscellaneous drugs, materials, medical devices, and techniques
(SEDA-31, 757)
Cardiovascular It has been suggested that there are individual differences in subjective responses to alcohol, and an exaggerated cardiac response to alcohol has been suggested to be a marker of increased sensitivity to its stimulant properties. The relation between cardiac reactivity to alcohol measured on the ascending limb of the Blood Alcohol Concentration (BAC) curve and its subjective stimulant and sedative effects throughout the BAC curve has been examined in 39 male social drinkers (1A). Cardiac responses to ethanol correlated positively with stimulant effects at numerous times during the ascending and descending limbs of the BAC curve. There were no associations between the cardiac changes and alcohol-related sedative effects at any time. The effects of potentially lethal serum concentrations of ethanol on features of the electrocardiogram that may be asso ciated with cardiac dysrhythmias have been studied in 84 patients with assumed acute ethanol intoxication and 27 hospitalized controls (2C). In subjects with moderately increased to high serum osmolality, the PR and QTc intervals were prolonged
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32049-6 2010 Elsevier B.V. All rights reserved.
compared with sober subjects. The authors suggested that ethanol at high to very high concentrations in the blood causes several electrocardiographic changes that might be associated with an increased risk of dysrhythmias.
Nervous system Cerebellar degeneration has been attributed to alcoholism (3C). Alcoholic cerebellar degeneration (ACD) is one of the most common neurological complications in alcoholics. As far as it is known, however, only four Japanese autopsy cases have been reported, and only limited pathological data are now available in Japan. ACD has been studied in six Japanese autopsy cases, including three asymptomatic cases, in order to elucidate the pattern of progression of the cerebellar lesions. The findings suggested that in ACD, severe lesions develop successively in the anterior superior vermis, the anterior superior hemisphere, the anterior inferior hemisphere and the anterior inferior vermis. In addition, cerebellar symptoms can often occur if the anterior superior and anterior inferior hemispheres are involved, in addition to the anterior superior vermis. Liver The possible role of alcohol in hepatotoxicity associated with therapeutic doses of paracetamol has been studied in a report of two patients who were regular consumers of alcohol and who developed
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liver failure within 3–5 days after hospitalization and stopping alcohol consumption while being treated with paracetamol 4 g/day (4A). The serum paracetamol concentration in one of these patients was not in the toxic range. Possible susceptibility factors for hepatotoxicity in patients taking therapeutic doses of paracetamol were investigated. In patients with susceptibility factors, such as regular consumption of alcohol, liver failure is possi ble when therapeutic doses of paracetamol are taken. The authors therefore proposed that the dose of paracetamol should not exceed 2 g/day in such patients and that liver function should be monitored closely while they are taking paracetamol. Death Ethanol-related deaths occur at all ages, including children, as in the case of a 5-year-old boy who died after drinking ethanol at the party held by his parents (5A). Urine and blood concentrations were 4 and 5 g/l respectively, which might explain sudden death. In addition, analysis of his hair showed the presence of ethyl glucuronide, a marker of alcohol consumption, suggesting that he had probably drunk alcohol before death. There were pathological lesions in the liver consistent with this. Tumorigenicity Moderate alcohol intake has been associated with a modest (30–50%) increase in the risk of breast cancer, but it is unclear whether certain individuals have greater susceptibility to the harmful effects of alcohol (6r). Individuals differ in their ability to metabolize alcohol through genetic differences in alcohol dehydrogenase, the enzyme that catalyses the oxidation of about 80% of ethanol to acetaldehyde, a known carcinogen. Women with breast cancer have been studied to see whether they differ with respect to alcohol consumption and alcohol metabolism from their sisters without breast cancer, using data from the Breast Cancer Family Registry (n = 811 sister sets). Neither alcohol drinking nor alcohol metabolizing ADH1B and ADH1C genotypes were
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associated with breast cancer. However, only 19 and 42% of sisters were discordant for ADH1B and ADH1C respectively, and even fewer were discordant for both genotype and alcohol intake, making it difficult to detect differences if they existed.
Teratogenicity Alcohol consumption during pregnancy is another hazard, particularly for boys, as has been reported in a study of prenatal exposure to alcohol. The association between maternal alcohol consumption during pregnancy and cryptorchidism (undescended testis) among 2496 boys was examined in a prospective Danish–Finnish birth cohort study. There were 128 cases of cryptorchidism in 2368 boys and at 3 months of age 33 cases out of 2215 (7C). The odds for cryptorchidism increased with increasing weekly alcohol consumption. After adjustment for con founders (country, smoking, caffeine intake, binge episodes, social class, maternal age, parity, maturity, and birth weight), the odds remained significant for women who had a weekly consumption of five or more alcoholic drinks. The authors therefore concluded that regular alcohol intake during pregnancy increases the risk of congenital cryptorchidism. However, the mechanism for this association is unknown. Pregnant women should be advised to avoid alcohol.
Artificial sweeteners (SED-15, 348) Tumorigenicity Attempts have been made to determine the role of habitual use of the most common artificial sweeteners in the development of urinary tract tumors in 197 patients with histologically confirmed transitional tumors and 397 controls with acute, non-neoplastic, and non-urinary tract disease admitted to a hospital between 1999 and 2006 (8c). All were interviewed about their use of artificial sweeteners and exposure to other known or suspected risk factors for urinary tract tumors. Artificial sweeteners had been used by 51 patients with urinary tract tumors (26%) and 87
Miscellaneous drugs, materials, medical devices, and techniques
controls (22%). The risk of urinary tract tumors was significantly increased in those who had used artificial sweeteners for more than 10 years compared with non-users. The OR (95% CI) for long-term consumers was 2.18 (1.22, 3.89) and for short-term users 1.10 (0.61, 2.00) after adjustment for age, sex, BMI, social status, and years of tobacco use.
Bisphosphonates (SED-15, 523; SEDA-28, 590; SEDA-29, 602; SEDA-30, 561) Musculoskeletal Osteonecrosis of the jaw The range of adverse reactions to bisphos phonates has been reviewed, with particular emphasis on the association between longterm treatment and osteonecrosis of the jaw, a potentially serious adverse effect that occurs mostly in patients with multiple myeloma or breast cancer (9R). While the etiology is uncertain, there is a strong association with dental pathology and interventions, highlighting the need for close attention to dental health. The clinical features, predisposing factors, and treatment outcomes in patients with oral bisphosphonate-related osteonecrosis of the jaw have been studied retrospectively (10A). Of 98 patients with osteonecrosis of the jaw, 13 had used oral bisphosphonates and two were excluded because of previous adminis tration of intravenous bisphosphonates. In the other 11 patients the mean duration of alendronate use before osteonecrosis of the jaw was 4.1 years. It was triggered by dental surgery in nine patients and by ill-fitted den tures in two. Heavy smokers were particu larly at risk. Among the nine patients with at least 6 months of follow-up, the osteonecro sis healed completely in three, partially in four, and not at all in two. The authors con cluded that osteonecrosis of the jaw is a rare devastating adverse effect of oral bispho sphonates associated with a high financial burden. Osteonecrosis of the jaw associated with bisphosphonate therapy has been studied in 12 patients with multiple myeloma or bone
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metastases from solid tumors (11c). With drawal of the bisphosphonate was not asso ciated with resolution of the osteonecrosis, and surgical manipulation of the involved site worsened the underline bone pathology. Hyperbaric oxygen, which has proven effica cious in other forms of osteonecrosis by establishing an oxygen gradient, is of no defi nitive benefit to patients with bisphospho nate-induced exposed bone. Antibiotic therapy is useful in controlling pain and swel ling, but ineffective in preventing progression of the exposed bone. To date, prevention is the only possible therapeutic approach to the management of this complication. The frequency, clinical presentation, radiology, pathology, and treatment of osteonecrosis of the jaw due to bisphospho nates have been investigated in a prospec tive study of 80 patients, of whom 22 developed osteonecrosis (11 men and 11 women, median age 25 years) (12C). Ten of them had multiple myeloma, 5 had breast cancer and 7 had other malignancies; 14 had used zoledronate, 3 pamidronate, 4 pami dronate followed by zoledronate and 1 ibandronate followed by zoledronate. The median time of exposure was 32 months compared with 27 months in patients with out osteonecrosis. The mean induction time until bone exposure was 26 months for those who used zoledronate, 54 months for pamidronate, and 48 months for pamidro nate followed by zoledronate. There was exposure of the mandible in 13 cases, the maxilla in 6, and both jaws in 3. In 5 patients osteonecrosis occurred sponta neously and in 17 it occurred after tooth extraction. Nine had had previous extrac tions of molars, six of premolars, and two of front teeth. The cumulative hazard was 3.5 times higher in those using zoledronate than in the other groups. There was no association of osteonecrosis with age, sex, the use of high doses of conventional chemotherapy, or the use of glucocorticoids, thalidomide, or borte zomib. Patients with multiple myeloma and breast cancer were at higher risk. The prevalence of bisphosphonate associated osteonecrosis of the jaw has been studied in the catchment area of a university hospital maxillofacial unit in a
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retrospective study of all patients with osteonecrosis, osteomyelitis, and osteora dionecrosis treated for 5 years (13c). There was odontogenic or surgically induced osteomyelitis in 40%, osteoradio necrosis in 28%, osteonecrosis after treatment with bisphosphonates in 10%, osteomyelitis or sequestrum due to trauma in 8%, and osteomyelitis of unknown origin in 14%. All the patients with bisphosphonate-asso ciated osteonecrosis had had metastatic dis eases of the bone (plasmacytoma, breast carcinoma, and prostate cancer) for up to 5 years. All had been given a nitrogencontaining bisphosphonate (either pamidro nate or zoledronate). There had been a possible trigger, such as previous tooth extraction, pressure denture sore or period ontal disease in 13 of the 17 patients with bisphosphonate-associated osteonecrosis and in 14 of the 45 with osteoradionecrosis.
suggesting that fractures may indeed have an effect on mortality.
Osteoporosis On the other hand, osteoporosis is a silent disease, because skeletal deterioration proceeds with no outward symptoms until a symptomatic fracture occurs; the condition is therefore under-recognized and affected individuals are under-treated (14R, 15R). Vertebral fractures may not cause recognizable symptoms or the patient may present with an acute self-limiting episode of back pain. However, subclinical fractures are important predictors of future risks. People with vertebral fractures have an increased mortality rate, which extends beyond the first year. Reduced survival is difficult to attribute to direct effects of the fracture, and enhanced mortality appears to be a consequence of co-morbidities. All types of osteoporotic fractures are asso ciated with increased age-specific mortality; this effect lasts for at least 5 years after the fracture event and the impact is worse in men than in women (16R). In a randomized controlled trial of intravenous bisphospho nate in men and women with prior hip frac tures, there were reductions in subsequent fractures and mortality (17R). This study and others have shown increased mortality soon after a fracture and a subsequent return to the expected mortality rates,
Dimethylsulfoxide (DMSO)
Cyanoacrylates (SED-15, 1022) Tumorigenicity Cyanoacrylates are liquids that are used in the manufacture of polymers and adhesives. They have long been thought to be linked to malignancies. A 36-year-old man with pre-B cell acute lymphoblastic leukemia had used industrial strength glue to reattach a chipped tooth for about 1 year, and such use was associated with chronic exposure of his oral mucosa to the glue (18A). This case raises the possibility that chronic exposure to cyanoacrylates may be associated with acute lymphoblastic leukemia.
(SED-15, 1131) Nervous system Toxicity related to the infusion of dimethylsulfoxide (DMSO) cryopreserved peripheral blood stem cells mainly comprises cardiovascular events. Autologous stem cell transplantation complicated by cerebral infarction and myocardial damage has been reported (19A), and it has been postulated that DMSO may have been responsible. Of 51 patients who received DMSOpreserved peripheral blood stem cells, only one had neurotoxicity in the form of a gen eralized tonic seizure after the infusion (20A). However, there was no neurotoxicity in eight patients with pre-existing neurological dis ease, nor in patients who received particu larly large volumes of DMSO. In all patients, there were mild non-neurological adverse effects. • A 49-year-old man who received two infusions of DMSO-cryopreserved autologous peripheral blood progenitor cells after myeloablative chemotherapy for a relapsing lymphoma had a tonic–clonic seizure over a few minutes after the start of each infusion and developed a profound and sustained but reversible encephalopathy with coma after the second infusion (21A).
Miscellaneous drugs, materials, medical devices, and techniques His neurological condition correlated with the electrophysiological findings (electroencephalo graphy and multimodality evoked potentials) and to a lesser extent with MRI abnormalities. • A 50-year-old woman with nodular-sclerosing Hodgkin’s disease received stem cells cryo preserved in 10% DMSO, which were infused after high-dose conditioning with carmustine, etoposide, cytarabine, and melphalan, and pre medication with diphenhydramine 50 mg and hydrocortisone 200 mg (22A). After infusion of the second bag, she became pale, lost conscious ness, and developed mydriasis, trismus, and respiratory arrest. The stem cell infusion was immediately stopped. She was given phenytoin 15 mg/kg and assisted ventilation, and she recov ered consciousness in less than an hour. She was given intravenous phenytoin 4.5 mg/kg for 5 days and then switched to oral therapy. Later the remaining cryopreserved stem cells were reinfused and there were no adverse effects. A brain CT scan was normal but an electro encephalogram showed diffuse abnormalities in electrical activity with irregular slow-wave paroxysms. A brain MRI scan showed a small punctate area of hyperintensity in the right middle frontal lobe of unclear significance.
Disulfiram
(SED-15, 1148; SEDA-31, 760)
Cardiovascular A 27-year-old man took disulfiram and ethanol and developed significant hypotension and ischemic electrocardiographic changes (23A). He was treated with intravenous fluids and noradrenaline (norepinephrine), which has been advocated as the pressor agent of choice. Drug–drug interactions Dexamfetamine Disulfiram has also shown promise in several clinical trials for cocaine addiction, but its potential usefulness in the treatment of amphetamine addiction has not been examined. The effects of disulfiram, 250 mg/day for 4 days, on acute physiological and subjective responses to dexamfetamine have been studied in 10 healthy volunteers, 5 men and 5 women, in an outpatient crossover, double-blind, placebo-controlled study (24c). Disulfiram did not affect dexamfetamine-induced increases in heart rate, blood pressure, cortisol concentration, or prolactin, but it
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did enhance some of the subjective effects of dexamfetamine, including ratings of ‘high’, ‘anxious’, ‘bad drug effects’, ‘want more drug’, and ‘drug liking’, and was also associated with a reduced performance in the Sustained Attention to Response Test.
DYESTUFFS Fluorescein
(SEDA-29, 607)
Nervous system It is important to identify intraoperative leakage of cerebrospinal fluid (CSF) in successful closure after endoscopic cranial base surgery, for which intrathecal injection of fluorescein is useful. However, complications have been reported with various doses and the technique has fallen out of favor. Low-dose intrathecal fluorescein has been studied in a retrospective chart review and postoperative patient survey in 54 patients undergoing endoscopic cranial base surgery (25c). Intraoperative CSF leak was identified with fluorescein in 25 patients and helped determine the reconstruction technique. There was postoperative leakage of CSF in five patients and it resolved with lumbar drainage. There were no seizures. Most of the adverse events were non-specific, transient and probably not caused by fluorescein, including malaise (n = 31), headache (n = 30), dizziness (n = 17), or nausea and vomiting (n = 13). Three patients had persistent postoperative subjective leg weakness (n = 2) and numbness (n = 2); however, two of them had undergone lumbar drainage. The authors concluded that low-dose intrathecal fluorescein after premedication with a glucocorticoid and an antihistamine is generally safe. However, fluorescein should be administered with caution, because it can occasionally cause weakness and numbness in the legs. Immunologic The Netherlands Pharmaco vigilance Center has received reports of two anaphylactic reactions associated
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with fluorescein in a 49-year-old man and a 56-year-old woman; the woman subsequently died (26S).
Indocyanine green
(SED-15, 2595;
SEDA-31, 760) Sensory systems Visual field defects have been reported after macular hole surgery with indocyanine green-assisted internal limiting membrane peeling in a retrospective review of 140 eyes, in 96 of which indocyanine green 0.25% was used (27c). There were nasal visual field defects in 11 eyes, temporal visual field defects in 7 and concentric visual field defects in 1. In the group in whom indocyanine green was used, the visual field defects were far higher in the left eye than in the right. The authors speculated that the postoperative nasal visual field defects were caused by enhanced toxicity of indocyanine green, resulting from exposure to illumination. Changes in macular function and potential retinal toxicity have been studied using multifocal electroretinography after epiret inal membrane surgery in 13 eyes of 13 patients; internal limiting membrane peel ing was facilitated by staining with indocya nine green 0.5 or 1.25 mg/ml (28c). The median best corrected visual acuity improved from 20/70 at baseline to 20/30 at 6 months postoperatively. At 3 months those in whom indocyanine green 0.5 mg/ml had been used had no significant changes in multifocal electroretinographic N1 and P1 response amplitudes and peak latencies, whereas those in whom indocyanine green 1.25 mg/ml had been used had significant reductions in N1 and P1 response amplitudes compared with baseline. There were no sig nificant changes in either group at 6 months after surgery. These findings suggest that the use of a higher concentration of indocyanine green to stain the internal limiting membrane can result in transient retinal functional impairment postoperatively. The lowest pos sible concentration of indocyanine green should be used intraoperatively to minimize potential retinal toxicity.
N.H. Choulis
Tartrazine Tartrazine is a synthetic lemon yellow azo dye used as a food coloring; it can be com bined with Brilliant Blue FCF or Green S to produce various shades of green. Many foods contain tartrazine in varying propor tions, although nowadays the trend is to avoid it or to substitute a non-synthetic dyestuff, such as annatto, malt color, or b-carotene. Pharmaceutical products contain ing tartrazine include vitamins, antacids, med icinal capsules, and certain prescription drugs. In animals the acceptable daily intake was 7.5 mg/kg (29R). Extrapolating from these data, the estimated maximum theore tical intake of tartrazine in children is 37% of the acceptable daily intake at the 97.5th percentile. One can therefore conclude that toxic effects of tartrazine should not be expected in humans. Immunologic Of all the azo dyes, tartrazine is the most allergenic and particularly causes reactions among asthmatics and those with aspirin intolerance. Symptoms from tartrazine hypersensitivity can occur from either ingestion or cutaneous exposure, and the effects can include anxiety, migraine, depression, blurred vision, itching, general weakness, hot sensations, a feeling of suffocation, purple skin patches, and sleep disturbances. It has been suggested that children with hyperactivity can develop increased irritability, restlessness, and sleep disturbances after taking tartrazine (30C).
Methylthioninium chloride (methylene blue) (SED-15, 2314; SEDA-28, 595; SEDA-29, 610; SEDA-30, 569) Drug–drug interactions Serotonergic drugs The UK MHRA has received two reports of nervous system toxicity when intravenous methylthioninium was used as a visualizing agent for thyroid or parathyroid surgery (31Sr). This has previously been attributed to an interaction with selective serotonin
Miscellaneous drugs, materials, medical devices, and techniques
reuptake inhibitors (SSRIs) (SEDA-30, 569). The MHRA has advised health-care professionals to • assess carefully the need for intravenous methylthioninium chloride for visualization in surgical procedures; • avoid methylthioninium chloride in patients who have recently used serotonergic drugs; • use the smallest possible dose of intravenous methylthioninium chloride if it cannot be avoided; • observe patients closely for nervous system effects for up to 4 hours after administration.
Nicotine
(SED-15, 2508; SEDA-29, 610; SEDA-30, 571; SEDA-31, 571)
Death In 90 smokers who were admitted to an intensive care unit and were given nicotine replacement therapy to prevent withdrawal, and who were matched, based on the severity of illness and age, with one control smoker who did not receive nicotine replacement therapy, the mean mortality rate predicted by the Acute Physiology and Chronic Health Evaluation III was 9.2% in the cases and 10.3% in the controls (32c). However, the observed hospital mortality rate was 20% in the cases and 7% in the control group. When adjusted for the severity of illness and invasive mechanical ventilation, nicotine replacement therapy was independently associated with increased mortality. Fetotoxicity Maternal smoking during pregnancy causes significant fetal morbidity and is a public health problem, as 36% of women in the UK and 11% of those in the USA smoke during pregnancy (33R). Behavioral support for smoking cessation, provided outside of routine antenatal care, is effective in promoting smoking cessation by pregnant women, but relatively few pregnant women have access to such support. Effective pharmacological aids to smoking cessation, which have been studied in non-pregnant populations, include nicotine replacement therapy, bupropion (amfebutamone), and
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varenicline. However, there is very little evidence to justify the use of these drugs in pregnancy, and it is doubtful that definitive trials of the effectiveness of either bupropion or varenicline for smoking cessation will be conducted in pregnant women in the foreseeable future. In the short-to-medium term, research information relating to the use of these drugs in pregnancy is therefore likely to be derived from observational studies, which are more difficult to interpret than clinical trials. There is therefore not enough evidence that nicotine replacement therapy is effective for smoking cessation in pregnancy and bupropion and varenicline cannot be recommended.
Sevelamer The FDA approved the use of sevelamer in 1998. It is a phosphate binder that is used to reduce the amount of phosphorus in the blood of patients with chronic kidney dis ease who are on dialysis. Its common adverse effects include diarrhea, infection, pain, vomiting, indigestion, low blood pres sure, headache, blood clot formation, reduced absorption of vitamins D, E, and K and folic acid, and bowel obstruction. Ser ious adverse effects that require medical attention include severe abdominal pain, new or worsening constipation, and other severe intestinal symptoms.
Comparative studies Raised serum phosphorus and calcium are associated with arterial calcification and mortality in dialysis patients. Unlike calcium-based binders, sevelamer attenuates arterial calcification, but it is not known whether it affects mortality or morbidity. In a multicenter, randomized, open study of all-cause and cause-specific mortality, sevelamer was compared with calcium-based binders in 2103 patients on hemodialysis of whom 1068 completed the study (34c). All-cause mortality rates and cause-specific mortality rates were not significantly different. However, there was a significant effect of
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N.H. Choulis
age: the effect of sevelamer in reducing mortality was limited to patients over 65 years of age. There was a suggestion that sevelamer was associated with lower overall, but not cardiac, mortality in older patients.
However, inappropriate use can cause severe unwanted effects.
Acid–base balance Sevelamer hydrochlor ide contains multiple amines, which may cause a significant dietary acid load. To evaluate the effect of sevelamer on arterial blood gases, two groups of patients on stable hemodialysis were followed for 24 months (35c). Those who were given sevelamer (n = 7) did not achieve the goals of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) for phosphorus and Ca � P product; those who were given calcium salts (n = 7) achieved those goals. Sevelamer was associated with worsening of chronic metabolic acidosis, which lasted throughout the study, and there were no significant changes in acid–base balance in the controls. The authors concluded that sevelamer caused small but persistent acid–base disturbances, which did not outweigh its beneficial effects on mineral and lipid metabolism. In a retrospective study the effect of seve lamer on metabolic acidosis was studied in 36 patients on hemodialysis and 36 matched for sex, diabetes mellitus, age and duration of dialysis who were not taking sevelamer (36c). Sevelamer significantly reduced the mean concentrations of bicarbo nate, base excess, and pH, but mean chloride concentrations and the anion gap did not change; there were no changes in the control group. The concentrations of bicarbonate, base excess, and pH correlated significantly with the daily dose and cumulative dose of sevelamer.
• A 74-year-old woman recovering from colonic surgery died immediately after receiving an intravenous infusion of about 1.5 ml of a white emulsion that was believed to contain 1% propofol. However, it was suspected that a zinc oxide shake lotion (containing 20% zinc oxide, 20% talc, 25% glycerol, and 35% water), intended for external treatment, had been mistaken for propofol. At autopsy, an anatomical cause of death could not be found. Propofol and other drugs that she had received were found in therapeutic or subtherapeutic concentrations. However, the concentration of zinc in the lungs was about 200 times higher than that found in a control case, 10 times higher in cardiac blood, and 3–4 times higher in kidney and liver tissues. There was no increase in venous blood. Histology showed a large pulmonary embolism containing birefringent sharp-edged crystals, which were identified as talc, and an amorphous component (zinc oxide). There were similar smaller emboli in the brain, heart, liver, pancreas and kidneys.
Talc
(SED-15, 3592; SEDA-29, 612)
Talc powder is widely used as an inert excipient in the manufacture of tablets and as a drying ingredient in baby powders.
Respiratory Pulmonary embolism has been reported after the intravenous administration of talc and zinc oxide (37A).
Sensory systems Talc from surgical gloves can cause granulomas in the conjunctivae, with chronic inflammation (38A). Respiratory Chronic exposure to talc during carpet installation resulted in silicopneumoconiosis in a 30-year-old man who had worked as a carpet installer for 15 years (39Ar).
Tumorigenicity A 68-year-old woman with stage III ovarian papillary serous carcinoma had used talc daily for 30 years to powder her genital area. Examination of her pelvic lymph nodes under polarized light microscopy showed diffuse areas of birefringence compatible with talc, confirmed by scanning electron microscopy and X-ray spectroscopy (40A).
Miscellaneous drugs, materials, medical devices, and techniques
Toluene The effects of toxic chemicals are usually studied in experimental animals for the pur pose of understanding and predicting their effects in humans. For this purpose, it is often assumed, as proposed by Lehman and Fitzhugh, that rats are less sensitive to the adverse effects than humans (41H). However, there is little direct evidence that this is so, because sufficient data for making this cross-species comparison are not available for most chemicals (42R). Cross-species comparisons are possible for the effects of toluene, a neurotoxic chemi cal, whose acute effects have been well documented in many studies (43c, 44c, 45E). These studies have provided a data base sufficient for a quantitative compari son of the sensitivities of rats and humans to the acute effects of toluene. Meta-analyses of these data have been previously pre sented (46ME). For regulatory purposes, it is necessary to quantify effects as a function of the magni tude of a subject’s external exposure to a toxic chemical, e.g. the concentration of toluene in the inhaled air. Many acute effects depend on the duration of exposure because of increasing uptake of the chemi cal with time. In risk assessment, the potency of a toxic chemical is often quanti fied by measuring the exposure or internal dose needed to produce an effect that lies on some threshold of statistical detectabil ity, e.g. a lowest observable adverse effect level (LOAEL) or a benchmark dose. Alternatively, potency can be expressed as the dose or exposure needed to obtain a certain degree of effect, such as the dose that produces 50% of the maximum effect (ED50). It is difficult to convert information on the acute neurotoxicity of organic solvents into predictive relations between exposure and effects in humans, because (1) the data are usually derived from experimental ani mals, whose sensitivity to the chemical rela tive to humans is unknown; (2) the specific end-points measured in laboratory animals seldom translate into effects of concern in humans and (3) the mode of action of the
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chemical is rarely understood. Ways of esti mating the hazard and cost of exposure to organic solvents have therefore been sought, focusing on the acute behavioral effects of toluene in rats and humans (47H). Available published data include studies of shock avoidance behavior in rats and choice reaction time in humans. A meta-analysis of these data has suggested that there is a 10% change in rat avoidance behavior at a blood concentration of toluene that is 25 times higher than the concentration at which a 10% change in human choice reaction time occurs. By con trast, in vitro studies have suggested that nicotinic acetylcholine receptors in humans and rats do not differ in sensitivity to toluene. Analysis of other dose–response relations for visual and cognitive functions in rats suggests that the apparent difference between rats and humans may be driven by the specific end-points measured in the two species rather than by inherent differences in sensitivity to toluene. It has also been suggested that doseequivalent relations can be used to compare the societal costs of two chemicals. For example, ethanol-induced changes in choice reaction time, for which societal costs can be estimated, can be used as a benchmark for estimating the monetary benefits of con trolling exposure to organic solvents. This dose-equivalence method is applicable to solvents, because the data fulfil three important assumptions about an equiva lence relationship based on a single effect: (1) a common dose metric (the concentra tion of the chemical in the brain); (2) a common effect to provide a linking variable (the choice reaction time); and (3) a com mon mode of action (interference with neu ronal ion channel function).
TECHNIQUES Arterial embolization The role of hepatic arterial embolization and chemoembolization has been assessed
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in 60 patients with large-volume metastatic neuroendocrine tumors, melanomas, or gastrointestinal stromal tumors (GISTs) with over 75% liver involvement (48C). Radiological responses, progression-free survival, overall survival, and postprocedure complications were assessed. Of the 48 patients for whom follow-up imaging was available, there were partial responses in 12, minimal responses in 6, stable disease in 22 and progressive disease in 8. Median overall survival and progression-free survi val were 9.3 and 4.9 months respectively. Treatment resulted in radiological responses or disease stabilization in 82% and symptomatic responses in 65% of patients with neuroendocrine tumors. Patients with neuroendocrine tumors had higher response rates and longer survival than patients with melanoma and GISTs. There were major complications in 21
N.H. Choulis
Table 1. Major complications after hepatic arterial embolization (48C) Complication (n)
Deaths
Tumor lysis syndrome (4) Anasarca (4) Hepatic failure (3) Myocardial infarction (2) Sepsis (2) Hepatic and renal failure (2) Renal failure (2) Hypertension (1) Pancreatitis (1)
1 1 2 2 2 2 1 1 0
patients after 23 of 123 sessions (Table 1). Nine of the 12 who died after major compli cations had additional susceptibility factors, including carcinoid heart disease, sepsis, and rapidly worsening performance status.
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cell transplantation. Neurology 2007;68(11): 859–61. 20. Mueller LP, Theurich S, Christopeit M, Grothe W, Muetherig A, Weber T, Guenther S, Behre G. Neurotoxicity upon infusion of dimethylsulfoxide-cryopreserved peripheral blood stem cells in patients with and without pre-existing cerebral disease. Eur J Hematol 2007;78(6):527–31. 21. Bauwens D, Hantson P, Laterre PF, Michaux L, Latinne D, De Tourtchaninoff M, Cosnard G, Hernalsteen D. Recurrent seizure and sus tained encephalopathy associated with dimethylsulfoxide-preserved stem cell infu sion. Leuk Lymphoma 2005;46(11):1671–4. 22. Júnior AM, Arrais CA, Saboya R, Velasques RD, Junqueira PL, Dulley FL. Neurotoxicity associated with dimethylsulfoxide-preserved hematopoietic progenitor cell infusion. Bone Marrow Transplant 2008;41(1):95–6. 23. Milne HJ, Parke TRJ. Hypotension and ST depression as a result of disulfiram ethanol reaction. Eur J Emerg Med 2007;14(4):228–9. 24. Sofuoglu M, Poling J, Waters A, Sewell A, Hill K, Kosten T. Disulfiram enhances sub jective effects of dextroamphetamine in humans. Pharmacol Biochem Behav 2008; 90(3):394–8. 25. Placantonakis DG, Tabaee A, Anand VK, Hiltzik D, Schwartz TH. Safety of low-dose intrathecal fluorescein in endoscopic cranial base surgery. Neurosurgery 2007;61(3 Suppl): 161–5. 26. Anonymous. Fluorescein. Reports of ana phylactic reactions. WHO Newslett 2008;3:6. 27. Tsuiki E, Fujikawa A, Miyamura N, Yamada K, Mishina K, Kitaoka T. Visual field defects after macular hole surgery with indocyanine green-assisted internal limiting membrane peeling. J Ophthalmol 2007;143(4):704–5. 28. Lai TYY, Kwok AKH, Au AWH, Lam DSC. Assessment of macular function by multifo cal electroretinopathy following epiretinal membrane surgery with indocyanine greenassisted internal limiting membrane peeling. Graefes Arch Clin Exp Ophthalmol 2007; 245(1):148–54. 29. Elhkim MO, Heraud F, Bemrah N, Gauchard F, Lorino T, Lambre C, Fremy JM, Poul JM. New considerations regarding the risk assessment on tartrazine. An update tox icological assessment, intolerance reactions
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39. Szeinuk J, Wilk-Rivard EJ. Case report: sili catosis in a carpet installer. Environ Health Perspect 2007;115(6):932–5. 40. Cramer DW, Welch WR, Berkowitz RS, Godleski JJ. Presence of talc in pelvic lymph nodes of a woman with ovarian cancer and long-term genital exposure to cosmetic talc. Obstet Gynecol 2007;110(2):498–501. 41. Lehman AJ, Fitzhugh OG. 100-fold margin of safety. Assoc Food Drug Off US Quart Bull 1954;18:33–5. 42. Benignus VA, Boyer WK, Kenyon EM, Bushnen PJ. Quantitative comparisons of the acute neurotoxicity of toluene in rats and humans. Toxicol Sci 2007;100(1):146–55. 43. Echeverria D, Fine L, Langolf G, Schork A, Sampaio C. Acute neurobehavioral effects of toluene. Br J Indust Med 1989;46:483–95. 44. Rahill AA, Weiss B, Morrow PE, Frampton MW, Cox C, Gibb R, Gelein R, Speers D, Utell MJ. Human performance during expo sure to toluene. Aviat Space Environ Med 1996;67:640–7. 45. Shafer TJ, Bushnell PJ, Benignus VA, Woodward JJ. Perturbation of voltage-sensi tive Ca2+ channel function by volatile organic solvents. J Pharmacol Exp Ther 2005; 315:1109–8. 46. Benignus VA, Boyes WK, Bushnell PJ. A dosimetric analysis of behavioral effects of acute toluene exposure in rats and humans. Toxicol Sci 1998;43:186–95. 47. Bushnell PJ, Boyes WK, Shafer TJ, Bale AS, Benignus VA. Approches to extrapolating animal toxicity data on organic solvents to public health. Neurotoxicology 2007; 28(2):221–6. 48. Kamat PP, Gupta S, Ensor JE, Murthy R, Ahrar K, Madoff DC, Wallace MJ, Hicks ME. Hepatic arterial embolization and chemoem bolization in the management of patients with large-volume liver metastases. Cardiovasc Intervent Radiol 2008;31(2):299–307.
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Medication errors
DEFINING ERRORS The definitions used here are as follows (1RH, 2RH): Medication error A failure in the treatment process that leads to, or has the potential to lead to, harm to the patient. Prescribing fault A failure in the prescribing process that leads to, or has the potential to lead to, harm to the patient. Prescription error A failure in the prescription writing process that results in a wrong instruction about one or more of the normal features of a prescription. Together, prescribing faults (i.e. errors in the decision-making process) and prescrip tion errors (i.e. errors in producing the writ ten prescription) constitute prescribing errors. The words ‘prescribing’ and ‘pre scription’ are used separately in these two definitions, because the word ‘prescribing’ has two meanings: (a) the act of deciding what to prescribe and naming it (the pre scribing process) and (b) the act of writing the prescription (the outcome of the pro cess). Thus, the term ‘prescribing errors’ is ambiguous and could refer to either the process or the outcome. Distinguishing between prescribing faults and prescription errors overcomes this difficulty. However, it should be noted that sys tematic reviews of studies of medication Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32050-2 � 2010 Elsevier B.V. All rights reserved.
errors have repeatedly emphasized that the authors of different studies have used widely different definitions, and that there fore studies in this area are not directly comparable.
CLASSIFYING MEDICATION ERRORS There are several different methods of clas sifying medication errors; two are given here. The first is based on psychological theory and divides errors into four types: knowl edge-based errors, rule based errors, actionbased errors and memory-based errors (Figure 1) (1RH, 2RH). This classification gives insights into potential methods of prevention. The second is the classification proposed by the National Coordinating Council for Medication Error Reporting and Preven tion (NCC MERP, Table 1), according to the intensity of the resulting harm (3S, 4S). Inter-rater agreement when using the NCC MERP system has been determined in a study in which 550 users of the MED MARX system were asked to categorize 27 medication scenarios using the NCC MERP index and were randomly assigned to one of three tools (the index alone, a paper-based algorithm, or a computer-based algorithm) to assist in categorization (5c). Of 119 posi tive responses, 101 completed surveys were returned. Overall inter-rater agreement for the participants, regardless of group assign ment, was 0.61 and there was no difference among the kappa values of the three study groups and the tools used to aid in medica tion error classification.
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904
Error
Knowlegde based errors
Mistake: Plan is flawed
Rulebased errors Intention
Intended outcome
Plan
Error
J.K. Aronson
Good rules not applied
Unintended outcome
Slip/lapse: Error in implementing the plan
Actionbased errors
Bad rules
Technical errors
Memorybased errors
Figure 1. Classifying medication errors using a psychological approach.
Table 1 Classifying medication errors according to the intensity of the resulting harm Category
General description
Specific description
A B
No error Error, no harm
C
Error, no harm
D
Error, no harm
E
Error, harm
F
Error, harm
G
Error, harm
H I
Error, harm Error, death
Circumstances or events that have the capacity to cause error An error occurred but the error did not reach the patient (an error of omission does reach the patient) An error occurred that reached the patient but did not cause patient harm An error occurred that reached the patient and required monitoring to confirm that it resulted in no harm to the patient and/or required intervention An error occurred that may have contributed to or resulted in temporary harm to the patient and required intervention An error occurred that may have contributed to or resulted in temporary harm to the patient and required initial or prolonged hospitalization An error occurred that may have contributed to or resulted in permanent patient harm An error occurred that required intervention necessary to sustain life An error occurred that may have contributed to or resulted in the patient’s death
SOURCES OF MEDICATION ERRORS Although discomfort experienced by physi cians on duty has historically been endured and accepted as part of the profession (6R, 7C), research has suggested a link between physician fatigue and medical errors (8Cr, 9Cr). Methods to alleviate fatigue during night shifts are desirable, although the
potential long-term risks should not be overlooked. In a study of 6 years worth of records from the MEDMARX database, 19 differ ent causes of error in a post-anesthesia care unit were identified (10cR). They were grouped into three categories – problems with policies and procedures, dosing errors, and communication. The five leading causes of pediatric medication errors were poor
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performance, failure to follow a procedure or protocol, lack of knowledge, calculation errors, and lack of communication. The authors gave numerous recommendations for actions to prevent errors, including the following: • use of a pediatric formulary; • use of a uniform system of weight-related dosing (e.g. mg/kg); • inclusion in the prescription of the child’s weight, the dose, and the volume to be given; • provision of checks and balances; • avoidance of abbreviations; • use of leading zeros to the left of the decimal point (e.g. 0.1 mg rather than .1 mg); • avoidance of terminal zeros to the right of the decimal point (e.g. 5 mg rather than 5.0 mg); • watching for look-alike and sound-alike medications and storing such medicines apart; • knowing the antidote to each medication and ensuring that it is immediately available in the right dose;
905 • improved communication between physicians, pharmacists and nurses; • acknowledgement and reporting of medication errors in a blame-free environment.
Abbreviations In one study nearly 5% of 643 151 errors were attributable to the use of abbreviations (11c). Many of the problem abbreviations were on the Joint Commis sion’s ‘do not use’ list (Table 2). Automated dispensing cabinets Auto mated dispensing systems, such as the McLaughlin dispensing system, the Baxter ATC-212 dispensing system, and the Pyxis Medstation Rx, are intended to aid phar macy inventory, streamline distribution, and improve the security of dangerous drugs. However, their use does not reduce
Table 2 Abbreviations that should not be used in prescriptions Do not use
Potential problem
Mistaken for ‘0’ (zero), the number ‘4’ (four), or ‘cc’ IU (International Unit) Mistaken for IV (intravenous) or the number 10 (ten) QD, Q.D., qd, q.d. (every Unfamiliar abbreviations in some places. Period day) after the Q mistaken for ‘I’ (i.e. ‘qid’) QOD, Q.O.D., qod, q.o.d. Unfamiliar abbreviations in some places.‘O’ (every other day) mistaken for ‘I’ (i.e. ‘qid’) Trailing zero (e.g. Decimal point is missed (50 mg given) 5.0 mg) Lack of leading zero Decimal point is missed (5 mg given) (.5 mg) > (greater than) < (less Misinterpreted as the number ‘7’ (seven) or the than) letter ‘L’ or confused with one another Abbreviations for drug Misinterpreted because of similarities names Apothecary units Unfamiliar to many practitioners; confused with metric units @ Mistaken for the number ‘2’ (two) Cc Mistaken for U (units) when poorly written U (unit)
µg or ug or mcg (micrograms) ng (nanograms)
Mistaken for mg (milligrams), resulting in dosage error Mistaken for mg (milligrams) or µg (micrograms), resulting in dosage error
Adapted from the Joint Commission’s ‘do not use’ list (12S).
Use instead Write ‘units’ Write ‘International Units’ Write ‘once a day’ Write ‘every other day’ Write (e.g.) 5 mg Write (e.g.) 0.5 mg Write ‘greater than’ or ‘less than’ Write drug names in full Use metric units Write ‘at’ Write ‘mL’ or ‘ml’ or ‘millilitres’ (‘mL’ is preferred) Write ‘micrograms’ in full Write ‘nanograms’ in full
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the overall frequency of medication errors and can sometimes even increase the risks (13R). For example, errors can occur when the system is refilled with new medicines. The sources of errors in such systems have been reviewed, with recommendations for maximizing their usefulness (14R). Complex dosage regimens Complexity of dosage regimens contributes to medication errors. In 101 patients with lung transplants who took a median of 15 (13–17) different drugs and 31 (26–38) dosage forms daily, 2253 doses were analysed (15c). There were 152 errors, which resulted in 303 incorrect doses (13%). Failure to keep a diary card was the only factor that was significantly associated with a higher rate of incorrect doses, and there was a significant correlation between medication errors and clinical adverse events. Drug formulations The pharmaceutical form of a drug can contribute to adverse effects. In one case a 63-year-old woman with Crohn’s disease swallowed azathio prine in its original blister pack and devel oped abdominal pain and diarrhea due to obstruction between two proximal stenoses (16A). Working conditions In a questionnaire study of the working conditions that could lead to near-miss errors relating to intravenous medication by 88 nurses working for 525 person-days in four wards of a Japanese hospital in 2001, workload and lack of experience in the current ward were associated with errors (17c). The number of near-miss errors was 94 (18%). There was no significant difference in the occurrence of near-miss errors among the three shifts (day shift 19%; evening shift 19%; night shift 13%). During the day shift, there was a significantly higher frequency of errors when the nursing services were delayed because of workload. During the evening shift, errors were more common when the services were
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delayed because of workload and when years of experience in the current ward were shorter. Nurses whose perceived level of fatigue before work was lower during the day shift and nurses whose years of experience as a nurse were longer and who had more sleep during the evening shift made significantly fewer near-miss errors than other nurses.
DETECTING ERRORS In a systematic review of studies of medica tion errors three methods emerged that had been used to detect errors: spontaneous reporting (n = 10), medication order or chart review (n = 14) and direct observation (n = 8) (18M). There was great variation in the definitions of medication errors and the error rates reported. The most common type of error was dosing errors, involving up to 10 times the actual dose required. Antibiotics and sedatives were the most common classes of drugs involved. The authors concluded that interpretation of the literature was hindered by variation in definitions used by different researchers, variable research methods and settings, and a lack of theory-based research.
FREQUENCY OF ERRORS In a study of 1000 medical prescriptions in the Ribat University Hospital, Khartoum, the following defects were noted (19c): the patient’s full name was written on only 19% of prescriptions and that of the doctor on only 6.7%; in only 20% of prescriptions were drugs prescribed by their generic names; 60% lacked the quantity of the drug; 26% lacked the duration of treatment; 16% were difficult to read. In a study in 10 Norwegian pharmacies, 1884 (39%) of 4667 prescriptions collected during 2 days contained no information on
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the indication for therapy and there were 1696 other errors and omissions in 1359 (2%) of 69 315 prescriptions collected during 5 weeks (20c). The most common errors and omissions were incomplete instructions for use (26%) and missing information about the patient (17%); 294 (17%) were judged to have potential clinical significance. Of 140 755 prescriptions during 7 months in an academic tertiary-care hospital 5075 (3.6%) contained errors (21c). The hospital pharmacist detected only 79% of these errors during routine verification, and so 0.75% of wrong doses would have left the pharmacy undetected. Overall, 24% of undetected errors were associated with potential adverse drug effects, of which 28% were serious and 0.8% were life threa tening. The most common were incorrect medication (36%), incorrect strength (35%) and incorrect dosage form (21%). Using data from a voluntary medication error reporting system, MEDMARX, 816 harmful outcomes in children involving 242 medications were identified during a 5-year period, of which 11 medications accounted for 35% (n = 261) (22c). Wrong dosing and omission errors were common and were associated with therapeutic classes such as opioid analgesics (e.g. morphine and fenta nyl), antimicrobial agents (e.g. vancomycin and gentamicin) and hypoglycemic agents (e.g. insulin). In a retrospective study of adult in patients in Saudi Arabia, 2627 patient files were analysed and 3963 errors were found: 1559 files contained one error, 800 files two errors, and 268 three errors or more (23c). The most common type of error was the wrong strength (concentration) (n = 914, 35%); 807 patients (31%) had the wrong route of administration and 788 (30%) had the wrong dosage form. The most common causes were human error (1223 patients, 46%), miscommunication (920 patients, 35%); and name confusion (484, 18%). In a comparison of a public and a private hospital in Brazil the most frequent types of errors were omission and underdosing; there was a 2-fold higher rate of underdosing in the public hospital, but a 2-fold higher rate of wrong timing in the private hospital (24c).
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In a study of 78 patients with renal insuf ficiency (creatinine clearance below 60 ml/ minute) there were 1001 prescriptions, of which 142 (74%) were inappropriate (25c). The most common prescribing faults involved ranitidine, antibiotics, and digoxin. In a retrospective review of 1411 pre scriptions that were handwritten during 5 months in an internal medicine clinic, almost 28% contained one or more errors or potential errors, the latter comprising over 90% of the errors; only 0.2% of the errors caused patient harm (26c). Cancer chemotherapy In a review of the prescribing, dispensing, and parental administration of medications to children with acute lymphoblastic leukemia, the rate and types of medication errors during 2 months were logged (27c). There were 172 chemotherapeutic medications for 69 patients and there were one or more errors in 17 (9.9%), of which 12 (7.0%) were administration errors and 5 (2.9%) were prescription errors; there were no pharmacy dispensing errors. All the errors were due to incorrect dosing or failure to administer an indicated medication. In a 2-year retrospective study, 43 188 doses of parenteral cytostatic drugs were prepared for the treatment of 3959 patients (28c). A total of 135 errors were detected (3 per 1000 preparations). Errors were distrib uted as follows: incorrect dose (39%), drug omission (22%), incorrect drug (11%), fre quency error and incorrect treatment dura tion (9.6% each), incorrect patient (7.4%), incorrect administration rate (1.5%), and incorrect administration route (0.7%). At least 66 errors were capable of causing adverse events, and 11 cases of incorrect reductions in doses and 12 cases of omis sions of cytostatic drugs could have led to reduced efficacy. However, all of the errors were resolved in the pharmacy before the drugs were dispensed. HIV-positive patients In a retrospective study of HIV-infected patients there were 209 admissions during 1 year in which an
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HIV-infected patient received antiretroviral drug therapy (29c). In 77 cases with a potential error, 61 uncorrected errors from 54 admissions were identified (percentage of total admissions 26%). The most common types of error were related to the amount or frequency of dosage (34 admissions); 18 of these errors were attributable to failure to adjust the dosage appropriately in renal insufficiency. The next most common error was combining antiretroviral drugs with a contraindicated medication (12 admissions). Intensive care units In a prospective, direct observation study in a medical/ surgical intensive care unit, 185 incidents were identified during 17 days; 13 of 35 actual adverse drug events were thought to have been non-preventable (i.e. not medication errors) (30c). A further 40 of the other 172 medication errors were judged not to be clinically important. Of the 132 medication errors that were classified as clinically important, 110 (83%) were associated with potential adverse drug effects and 22 (17%) led to actual events. There was one error for every five doses. The potential adverse effects mostly occurred in administration and dispensing (34% in each); all of the actual events occurred in prescribing (77%) and administration (23%). Errors of omission accounted for most of the potential and actual adverse events (23%), followed by errors due to wrong dose (20%), wrong drug (16%), wrong administration technique (15%), and drug–drug interactions (10%). However, the equation of prevent ability with error is not a distinct one, and defining errors in this way is a dubious method (31M). Nursing homes In a study of 384 licensed nursing homes in North Carolina during 9 months, using a web-based reporting system, there were 9272 medication errors (32c). The specific medication involved was documented in 5986 of these. The medications most commonly involved were
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lorazepam (457 errors, 8%), warfarin (349, 6%), insulin (332, 6%), hydrocodone and hydrocodone combinations (233, 4%), furosemide (173, 3%), and fentanyl patches (150, 3%). The medication errors dispro portionately included central nervous system agents (16%) and analgesics (11%). Medications considered potentially inap propriate in elderly people were often involved (10% of all reported errors), and the greatest number of such errors were associated with lorazepam (457, 8%), alprazolam (130, 2%), and digoxin (74, 1%). Nursing homes that reported potentially inappropriate drugs among their 10 most common medication errors also reported a significantly greater mean number of errors than nursing homes that did not report such errors (27 versus 18), as well as a significantly greater number of errors that reached the patient (6148 versus 1393). Pediatrics In a prospective study in nine pediatric wards 75 questionnaires were analysed. Medical errors concerned prescription (n = 21) and administration (n = 45) (33c). Ten errors led to adverse effects and there was an attributable factor in 39 cases. Prescription errors were attributable to breaking rules (n = 11), lack of knowledge (n = 3), and communication failure (n = 3). Administration errors were attributable to human error (n = 8), unclear prescriptions (n = 6), and systems flaws (n = 6). In a prospective direct observation study in a 16-bed pediatric medical/surgical ICU at a tertiary care academic medical center, 357 written orders and 263 observed doses were reviewed (34c). There were 52 medi cation errors, six of which were thought to have been non-preventable adverse drug reactions and 42 (81%) of which were con sidered clinically important. Actual and potential adverse events occurred at rates of 3.6 and 9.8 per 100 orders respectively. Of 122 prescriptions in a neonatal unit, prospectively analysed, 35% contained pre scription errors; the most frequent were related to dosing (16%) (35c). Although
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62% of the drugs were prescribed by their generic name, only 4.1% specified the dose per kilogram. Errors were detected in 21% of transcriptions, the most frequent being absence of the route of administration (7.4%); the generic name was used in 57% of the transcriptions. In a systematic review of 31 studies of medication errors in children, the definition of a medication error was not uniform across the studies (36M). Dispensing and administration errors were the most poorly and non-uniformly evaluated. Prescribing errors occurred in 3–37%, dispensing errors in 5–58%, errors of administration in 72–75%, and documentation errors in 17–21%. Of 310 reports of pediatric chemotherapy errors, 85% reached the patient and 16% required additional patient monitoring or therapeutic intervention; 48% of the errors originated during administration and 30% during dispensing (37c). Of the 387 medica tions cited, 40% were antimetabolites, 14% were alkylating agents, 9.3% were anthra cyclines, and 9.3% were topoisomerase inhibitors. The most commonly involved agents were methotrexate (15%), cytara bine (12%), and etoposide (8.3%). The most common error types were improper dose/quantity (23% of 327 cited error types), wrong time (23%), omission error (14%), and wrong administration techni que/wrong route (12%). The most common error causes were poor performance (41% of 547 cited error causes), equipment and medication delivery devices (12%), commu nication (8.8%), lack of knowledge (6.8%), and written order errors (5.5%). In a systematic review of 11 studies in neonatal ICUs, medication error rates var ied widely between studies; the highest rate was 5.5 per 100 prescriptions (38M). The variations arose from differences in the definition of medication errors and the rigor of the method used to identify them. Computerized prescriber order entry and interventions by clinical pharmacists were the most common interventions suggested to improve medication safety, although very few data were available to evaluate the usefulness of such interventions in neonatal ICUs.
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Primary care In a study of 2282 pre scriptions for children in primary care, 2066 (91%) had major errors of omission, commission, or integration (39c). In 54% of prescriptions with errors of omission, in 28% the duration of therapy was not speci fied and in 13% the dosage form was not stated. In 44% of prescriptions with errors of commission, errors that related to dosing frequency (21%) and dose/strength (18%) were the most common. Errors of integra tion, such as potential drug–drug inter actions, comprised 2.4% of all prescribing errors. Prescribing that was categorized as irrational was divided into contraindicated medications (notably chlorphenamine, promethazine, and glucocorticoids, 16%); medications prescribed as required (13%); missing information regarding strength of formulations (2.8%); medications pre scribed over extended periods (2.7%); low dosing frequency (2.6%); suprathera peutic doses (2.3%); and excessive dosing frequency (0.8%). Psychiatry Prescribing errors have been studied in UK mental health units in a prospective, 1 week survey by pharmacists of 22 036 prescription items (40c). There were 523 errors (2.4%). Prescription writing errors (77%) were the most common, while decision-making errors accounted for 23%. In 280 cases (54%) the prescribed drug had been administered before the error was detected. Most of the errors were of doubtful or minor importance, but 22 (4.3%) were thought likely to result in serious adverse effects or death. In a study using direct observations, med ication chart review, and incident reports in two elderly long-stay psychiatric wards, 369 errors in 1423 opportunities for errors (26%) were detected by direct observation, compared with 148 detected by chart review and none reported (41c). Most of the errors were of doubtful relevance or minor. The commonest errors were unauthorized tablet crushing or capsule opening (111/369, 30%), omission without a valid reason (100/369, 27%), and failure to record administration (87/369, 24%).
910
Renal replacement units In a survey of 31 units, errors were made only in cases in which dialysate solutions were manually formulated in the units rather than when manufacturers’ formulations were used (42c). Transplant recipients Medication errors have been studied in 93 recipients of liver, kidney, and/or pancreas allografts who had prescriptions for a mean of 11 medications each (43c). There were 149 errors, and adverse events were associated with 48, including hospitalization (n = 17) or an invasive out-patient procedure (n = 3); there were nine episodes of rejection and six failed allografts. Patient errors were to blame in 83 cases (56%), prescription errors in 20 (13%), delivery errors in 20 (13%), availability errors in 15 (10%), and reporting errors in 12 (8%). Root cause analysis identified the patient as the cause in 101 errors (68%), while pharmacies and other sectors of the health-care team caused 41 errors (27%). Finances were linked to 7 errors (5%).
PREDICTING ERRORS Hierarchical task analysis has been described as a method of modelling drug administra tion, followed by use of the systematic human error reduction and prediction approach (SHERPA) in order to predict which errors are likely to occur (44R).
REPORTING ERRORS In a study of voluntary reporting of medica tion errors that affected 8837 in-patients and 820 out-patients using warfarin, the errors occurred most often during transcrip tion or documentation (35%) and adminis tration (30%) in hospitals and during prescribing (31%) and dispensing (39%)
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for out-patients (45c). Dosing errors were the most common type. In hospitals, more than 50% of reported errors were initiated by nurses and 50% were intercepted by nurses, whereas in out-patient settings about 50% of reported errors occurred in pharmacies and 50% were intercepted by pharmacists. About 17% of in-patient and 13% of out-patient warfarin errors resulted in changes in patient care, and 42% of in patient and 62% of out-patient errors resulted in procedural changes. The authors suggested that voluntary medical error reporting systems can, to some extent, pro vide information that helps guide improve ments in patient safety, but that their usefulness is limited, because of a lack of details, incomplete reporting, under-report ing, and various reporting biases. The accuracy and epidemiology of 1010 medication errors in 581 error reports at a large academic children’s institution have been retrospectively studied (46c). There were 298 (30%) prescription errors, 245 (24%) dispensing errors, and 410 (41%) administration errors; 57 (6%) involved medication administration records. Follow ing expert review, 208 errors (21%) were deleted, because they had been inappropri ately coded as errors, and 97 (10%) that had not been initially been coded were added. In addition, 352 reports had to have the subtype of error reclassified, but the overall distribution of error type categories did not change significantly. The most common medications were anti-infective drugs (17%), analgesics/sedatives (15%), nutri tional agents (11%), gastrointestinal agents (8%), and cardiovascular agents (7%). Barriers to reporting medication errors by nurses have been elucidated in a ques tionnaire study of 597 nurses in Taiwan (47c). The major perceived barrier was fear. The power hierarchy, a concern about saving face, and work environment factors (e.g. quality management and peer relations) accounted for 55% of the var iance in the barriers. Age, educational back ground, working experience, experience of having made errors, and failure to report errors were not associated with barriers to reporting.
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The effects of a pharmacist-led pediatrics medication safety team on the frequency and severity of medication errors reported have been studied in a pediatric critical care cen ter; reporting of medication errors increased 2-fold (48c). When a new reporting form and educational forums were added there was a further 3-fold increase. Error severity fell from 46 to 8% and then to zero. A web-based medication error reporting system has been evaluated in 23 nursing homes in North Carolina during 1 year (49c). The sites entered 631 error reports of 2731 discrete error instances, 52% of which were classified as having a serious effect, requiring monitoring, intervention, or worse. The most common errors were dose omission (n = 203, 32%), overdosing (n = 91, 14%), underdosing (n = 43, 7%), the wrong patient (n = 38, 6%), the wrong product (n = 38, 6%), and the wrong strength (n = 38, 6%). Errors most commonly occurred during administration (n = 296, 47%) and were attributed to human error (n = 402, 48%). Seven drugs were implicated in 175 cases (28% of all errors): lorazepam, oxycodone, warfarin, furosemide, hydro codone, insulin, and fentanyl. The implementation of a non-punitive reporting system in a US University Hospi tal, severing the link between reporting errors and performance evaluations, was associated with an increase in the number of reports received each month from an average of 19 to 102 (50c).
PREVENTING ERRORS The Institute of Medicine in the USA has issued a blueprint for the prevention of medication errors (51S): • the Food and Drug Administration (FDA) should work with manufacturers and consumer groups to redesign medication package inserts, making them simple to read, understandable, and useful to consumers; • drug names should be standardized; • the names of drugs that have different purposes should not sound alike;
911 • tablets should be designed so that no two medicines that have different purposes should look alike; • all doctors and pharmacies should rely on electronic prescribing systems that reduce transcription errors and can automatically detect potential drug–drug interactions; • consumers should take an active part in their medication.
The Broselow Tape is a tape measure that estimates a child’s weight and drug dosages from its length (52c). It has been described as a method of reducing medica tion dosing errors in pediatric emergency practice (53c). However, the tape has often been used inappropriately or incorrectly. A web-based education programme on proper use of the tape has therefore been devel oped and tested in a randomized, controlled trial in emergency providers (54C). After the educational intervention, dosing devia tions were much fewer in the education group (13% versus 25%). The Los Angeles County Emergency Medical Services Agency has instituted a programme to reduce the rate of adrenaline dosing errors in children during prehospital cardiopulmonary arrest, in which para medics were required to use Broselow tape and to report color zone categories to the base station after training (55c). Of 104 sub jects who received adrenaline before the introduction of the programme only 29 received the correct dose, while 46 received a first dose that was within 20% of the correct dose. After introduction of the pro gramme, 21 of 37 subjects received the cor rect dose, and 24 subjects received a dose within 20% (OR = 3.0 and 2.5 respectively compared with the previous results). The prevention of errors during intra venous administration in children has been reviewed (56r). Solutions include separating children’s facilities from those for adults, creating a child-friendly environment, and the use of syringe pumps equipped with features such as a drug library, dosing limits, and weight requirements.
Education A 30-minute tutorial that focused on appropriate methods for prescribing
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medications, followed by a written test, did not reduce the incidence of prescribing errors among 13 trainees in a prospective study in a pediatric emergency department (57c). In 899 orders given by trainees there were 66 (12%) errors in 533 orders given by those who attended the tutorial, and 46 (13%) in 363 orders given by those who did not attend (adjusted OR = 1.07; 95% CI = 0.66, 1.70). Two 30-minute computer modules focusing on medication safety produced a statistically significant change in knowledge regarding medication errors, but there was no change in safety scores, the use of behaviors advo cated in the medication safety education pro gramme to improve medication infusion safety, the number of infusion pump alerts, or the number of reported errors (58c). The authors concluded that strong administrative support and follow-up are needed to foster changes in behavior, if education is to lead to reduced harms caused by medication errors. When second-year nursing students were taught medication calculations using the tra ditional arithmetical method or using dimensional analysis, the latter produced more accurate calculations (59c). Standardized protocols When a standar dized protocol was used for sliding-scale insulin for 1 year, 86% of prescriptions fol lowed the guidelines (60c). The number of prescription errors fell from 10 to 1.2 per 100 patient-days. The number of episodes of hyperglycemia fell from 56 to 16 per 100 patient-days. Dosing charts The management of para cetamol overdose with acetylcysteine can be affected by failures in dosage calculation (61c). In a study of the ability of doctors and nurses to calculate correct doses using manual calcu lation skills and a weight-based dosing chart, errors were made in 26% of cases with man ual calculations but errors were not made when the dosing chart was used (62c).
Medication reports The use of a medication report at the time of discharge
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from hospital has been shown to reduce the frequency of medication errors in elderly patients; 79 of 248 patients (32%) had at least one medication error compared with 118 of 179 controls (66%) (63c). In the intervention group 15% of the patients had errors that were considered to have a moderate or high risk of clinical consequences compared with 32% in the controls. Electronic prescribing Computerized phy sician order entry (CPOE), which would be better called computerized prescriber order entry, is a method whereby instructions for treating of patients are entered into an electronic system by the prescriber and the orders are communicated over a com puter network to the relevant staff whose responsibility it is to carry out the orders (64c, 65R). Other terms that are sometimes used include computerized provider order entry and computerized prescription order entry. In a study in a neurosurgical intensive care unit there was a 5-fold increase in prescription errors after the introduction of computerized prescriber order entry, although the majority of medication errors did not result in harm to the patient (66c). Computerized prescriber order entry sys tems have been studied using a national voluntary medication error-reporting data base, MEDMARX, to compare facilities with CPOE and those without (67c). Facil ities with CPOE reported fewer in-patient medication errors but more out-patient medication errors than facilities without. Facilities with CPOE less often reported medication errors that reached or harmed patients. Of more than 7000 CPOE-related medication errors that were reported over 7 months in 2003, about 0.1% resulted in adverse events. The most common errors were dosing errors (wrong dose, wrong dosage form, or an extra dose). In a study of 16 938 medication orders for 678 admissions to the paediatric units of a large academic community hospital, there were 865 medication errors, a rate of 5.2
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per 100 medication orders (68c). The nearmiss rate was 0.96% and the rate of preven table adverse drug effects was 0.09%. In all, 78% of potentially harmful prescribing errors were intercepted; however, none of the potentially harmful errors that occurred at the time of administration was inter cepted (50% of preventable adverse drug effects). The authors concluded that the addition of a computerized prescriber order entry system to pharmacists is un likely to prevent errors of administration. Although computerized order entry sys tems can prevent some types of errors they can also introduce them. In a study of 352 randomly selected, in-patient, pediatric admissions, which were reviewed retrospec tively 3–12 months after implementation of computerized order entry, there were 6916 medication orders in 1930 patient-days (69c). Of 104 pediatric medication errors, 71 were serious (37 serious medication errors per 1000 patient-days). Of all errors detected, 19% (7 serious and 13 with little potential for harm) were computer related. The rate of computer-related errors was 10 errors per 1000 patient-days, and the rate of serious computer-related errors was 3.6 errors per 1000 patient-days. The following four types of computer-related errors were identified: duplicate medication orders, drop-down menu selection errors, keypad entry errors, and order set errors (orders selected from a set that were not appropri ate for the patient). In another study the total number of error reports increased after CPOE was introduced, but the level of patient harm related to those errors fell (70c). In a comparison of the effects of manual and computerized chemotherapy prescrip tion on medication errors, there was at least one error in all of the manual prescrip tions and in only 13% of the computerized prescriptions (71c). The median number of errors per computerized prescription was 0 (range 0–1), whereas in manual prescrip tions it was 5 (range 1–12). Errors of omis sion were predominant in manual prescriptions. Errors of commission were limited to one case of unjustified underdosage in a computerized prescription and
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three such cases in handwritten prescrip tions. Errors of interpretation of the date, use of abbreviations and illegible hand writing were frequent among manual prescriptions and were absent from compu terized prescriptions. In a prospective comparison of a paperbased unit and a computerized unit in a 22-bed ICU, three types of prescription error were described: minor (no potential to cause harm), intercepted (potential to cause harm but intercepted), and serious (adverse events with the potential to cause, or actually causing, harm) (72c). The inci dence of prescription errors was signifi cantly lower in the computerized unit (44/1286, 3.4% versus 331/1224, 27%). There were significantly fewer minor errors (9 ver sus 225), fewer intercepted errors (12 versus 46), and fewer serious errors (23 versus 60). There were no fatal errors. The most frequent drug classes involved were cardio vascular medications and antibiotics. In a systematic review of 22 papers on clinical decision support systems for compu terized prescriber order entry, 21 showed that such systems reduced the numbers of medication errors and that the effect was strongest for the second and third genera tions of systems (73M). In a retrospective survey of 4527 pre scriptions ordered in the out-patient clinics of a tertiary academic center, the use of computerized prescriber order entry rose from 1% in 1996 to 59% in 2002 (74c). During the same period, the number of intercepted prescription errors with compu terized prescriptions fell compared with handwritten prescriptions (4.9% versus 7.4%). The most common intercepted pre scription errors involved the dosage form, followed by the quantity dispensed, the dosage, and drug allergies. A computerized prescriber order entry system has been evaluated in a retrospec tive study in a community-based urban teaching hospital in Brooklyn, NY (75c). In all, 466 311 prescriptions were entered dur ing 1 year. There were 3513 errors (7.53 errors per 1000 prescriptions). More than half were made by the internal medicine specialty. Half of the errors were severe
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(overdosing medications with a narrow therapeutic index or over-riding allergies), 46% were moderate (overdosing, wrong dosing, duplicate orders, or prescribing mul tiple antibiotics), and 3.7% were not harm ful (wrong dosing or incomplete orders). Errors in antibiotic prescriptions accounted for 54% of all errors. In a study in an Emergency Department during two 10-day periods before and one 9 day period after implementing computer ized prescriber order entry, 2073 patients had 5950 orders (76c). Before and after implementation there were respectively 3.7 and 2.8 potential adverse events, 222 and 21 medication prescribing errors, and 5.1 and 0 rule violations per 100 orders. The effects on medication errors of a manual prescription system and a compu terized system have been compared in a sequential study of 1587 prescriptions with the former, followed by 1500 with a provi sional electronic system, and then 1034 with a modified electronic version (77c). Between the manual system and the provi sional electronic system there was a 17% increase in the number of incomplete pre scriptions for dose and a 49% increase in lack of completeness of prescription; after some modifications to the electronic system there were 39% and 24% reductions respectively. In a prospective comparison of a manual prescribing system and an electronic pre scribing system during the prescription and transcription in two in-patient units in a general hospital, 3908 treatment errors, and 129 patient identification errors were detected during both periods (78c). The rate of errors using the manual prescribing system was 14% compared with 1.3% after the electronic system was implemented. The effect of an electronic prescribing system on the incidence and type of pre scribing errors and the number of error-free visits has been evaluated in a before-and after study in a nephrology out-patients clinic at an acute tertiary care pediatric hos pital (79c). In all, 520 patients had 2242 items prescribed on 1141 prescriptions. The overall prescribing error rate was 77% for handwritten items and 4.8% with
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electronic prescribing. Before electronic prescribing, 1153 items (73%) were missing essential information, and 194 (12%) were judged illegible. After electronic prescrib ing, only 9 items (1.4%) were missing essen tial information, and illegibility errors were eliminated. The number of patient visits that were error-free increased from 21 to 90% after implementation of electronic prescribing. The effect of a closed-loop electronic pre scribing, automated dispensing, barcode patient identification and electronic medica tion administration record (EMAR) system on prescription and administration errors has been assessed in a surgical ward of a teaching hospital (80c). There were prescrip tion errors in 3.8% of 2450 medication orders before the intervention and in 2.0% of 2353 orders after. Errors in admini stration occurred in 7.0% of 1473 nonintravenous doses before intervention and in 4.3% of 1139 after. The patient’s identity was checked in only 17% of 1344 cases before the intervention and in 81% of 1291 cases after. Medical staff required 15 seconds to prescribe a regular in-patient drug before the intervention and 39 seconds after. The time spent providing a ward pharmacy service increased from 68 to 98 minutes each weekday. The time per drug adminis tration round fell from 50 to 40 minutes. Nursing time on medication tasks outside of drug rounds increased from 21 to 29%. The authors concluded that a closed-loop electronic prescribing, dispensing, and bar code patient identification system reduced prescription errors and administration errors and increased confirmation of patient identity before administration, but increased the time spent on medication-related tasks. Other forms of information technology Information technology can reduce the fre quency of medication errors, but there are major barriers to its adoption: cost, legal problems, time, fear, usefulness, complex ity, personnel, physical space, and Internet access. A medication error reporting system in rural hospitals has been assessed by com paring medication errors in eight rural
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hospitals, normalizing for bed size (81c). There was a direct correlation between increased error reporting and reduced num ber of adverse events resulting from medi cation errors. The major barrier to adoption of the system was cost. The barriers of time, fear, usefulness, and complexity were over come by involving and empowering the staff in design and decision-making processes. It is important that reporting systems be care fully implemented, with proper education of the staff who are intended to use them; they should be easy to learn and easy to use; they should save time in reporting medication errors and there should be feedback, parti cularly in the form of quality assurance reports. The implementation of technology may be different in rural and urban settings. A personal electronic medicine profile has been tested to establish whether it can contribute information about a patient’s medications on admission to hospital in a study in 48 patients admitted to an acute medical admissions ward (82c). There were 309 prescriptions registered and 85 errors. The medication history highlighted 73 of these, and the electronic system revealed a further 12. A bar code-assisted dispensing system has been studied in three configurations in a hospital pharmacy at a 735-bed tertiarycare academic medical center (83c). In two of the configurations, all doses were scanned once during the dispensing process. In the third configuration, only one dose was scanned if several doses of the same medication were being dispensed. Before and after implementation there were 115 164 and 253 984 dispensed doses respec tively. The rates of potential adverse effects due to errors fell by 63–74%. Of the three configurations of bar code technology stu died, the two that required staff to scan all doses produced a 93–96% relative reduc tion in the incidence of target dispensing errors and an 86–97% relative reduction in the incidence of potential adverse effects. However, the configuration that did not require scanning of every dose produced only a 60% relative reduction in the inci dence of target dispensing errors and an 2.4-fold increased incidence of potential
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adverse effects, of which several were potentially life-threatening. In a retrospective study of parenteral nutrition in a neonatal intensive care unit, the prescription error rate was 12% of 480 orders (84c). Use of an interactive compu terized worksheet reduced the prescribing error rate from 15 to 6.8% for all orders and from 29 to 9.6% for orders for peripheral parenteral nutrition. All 12 errors that occurred in the 177 prescriptions completed using the computerized worksheet were due to avoidable data entry or transcription mistakes.
TYPES OF MEDICATION ERRORS Pharmaceutical errors A Polish factory manufactured vials that contained suxa methonium instead of hydrocortisone; the clinical outcomes of this error were not clear, but 27 deaths were being inves tigated as a result (85 Cr ). Transcription errors Data on medication errors have been collected from 40 randomly selected Danish community pharmacies (86c). Cases that reached patients (n = 401) were analysed, and the most serious cases were selected for rootcause analysis. Most of the errors were made during the transcription stage; the most serious were errors in strength and dosage. There were four root causes: handwritten prescriptions; ‘traps’, such as similarities in packaging or names, or strengths and dosages stated in misleading ways; lack of effective control of the prescription label and medicine; and lack of concentration caused by interruptions. Drug administration route Blood trans fusion In the SHOT (Serious Hazards of Transfusion) database, including 485 reports, there were ‘wrong blood’ events, when a patient receives a blood component intended
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for a different patient or an incorrect group, in 18% of cases (87R). In 4.5% there were other pre-transfusion errors, including incorrect D groups, based on missed allo antibodies and missed serological incompat ibility. In 0.5% of cases blood of the incorrect group was given to recipients of ABO mis matched peripheral blood stem cell or bonemarrow transplants. Failures to provide blood of appropriate specification or that did not meet the patient’s special require ments occurred in 29%. Inappropriate or unnecessary transfusions were given in 14%. In 16% there was ‘unsafe’ transfusion, when there were handling or storage errors. In 18%, events were related to the administra tion of anti-D immunoglobulin. Hospital transfusion laboratory errors occurred in 180 cases (37%). In Ireland, of serious adverse events related to blood transfusion, incorrect blood component transfusion accounted for 65% of incidents reported, an increase of 37% from 2004 (88R). The site of the first error was in the prescription/request (45%), cross-matching or issuing (24%), storage or handling (8%), initial clerking in the hospi tal (8%), administration (7%), and sam pling (7%). Intravenous administration In a 5-year review of 73 769 medication errors related to intravenous administration, 3–5% of errors were harmful (89c). The most common type of error was omission and the most common cause involved poor clinician performance. Product shortage, calculation errors, and tubing interconnectivity were the main predisposing factors. Epidural administration In an unusual case an administration error occurred when a confused patient switched the tubing to intravenous and epidural infusions; dextrose 5% in saline 0.45% was infused into the epidural catheter at a rate of 100 ml/hour, and the increased resistance was detected by the infusion pump, activating the alarm (90A).
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SPECIFIC MEDICATIONS Amphotericin A 41-year-old woman with cryptococcal meningitis and no previous cardiac disease developed a fatal cardiac dysrhythmia, acute renal failure, and anemia after an acute overdose of amphotericin B deoxycholate (91A). The intention had been to give liposomal amphotericin 5 mg/kg/day; however, amphotericin B deoxycholate 5 mg/kg was inadvertently given instead, the usual dose of the deoxycholate formulation being 0.5–0.8 mg/kg/day.
Bismuth subsalicylate A 3-month-old in fant with colic developed salicylate toxicity as a result of continued administration of ‘Percy Medicine’, a gastrointestinal suspen sion containing bismuth subsalicylate 105 mg/ ml (92A). Bismuth subsalicylate contains about half the amount of salicylate in aspirin. For 3.5 weeks the infant’s parents gave the baby the equivalent of aspirin 57–84 mg/kg/ day, leading eventually to central nervous system depression, respiratory distress and a metabolic acidosis; his serum salicylate concentration was 5.4 mmol/l (747 mg/l). Digoxin Accidental intrathecal adminis tration of digoxin has been reported in three cases in which ampoules containing digoxin were thought to have been confused with ampoules containing lidocaine, because they looked alike (93A). In one case, paresthesia and paralysis of the lower limbs occurred up to the umbilical level; the patient, an 21-year-old man, was conscious but agitated, tachycardic, and hypertensive, with abdominal distension, urinary reten tion, and absent leg reflexes. He recovered spontaneously.
Glucocorticoids In an audit of prescribing faults in infants in 20 primary-care health centers in Bahrain, of 2282 prescriptions dispensed for infants, 296 (13%) involved glucocorticoids for topical application to the
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skin, eyes, and ears (94c). Based on potency the proportions of glucocorticoids pre scribed were mild (6.7%), moderately potent (2.6%), and potent (3.7%). Plain glu cocorticoids comprised 6.7% and glucocorti coids with anti-infective drugs 6.3%. The frequency of dosing and length of therapy were not stated in 22 and 44% of prescrip tions respectively. Base cream as a dilutional vehicle was prescribed in 11% (11/98) and 32% (12/37) of prescriptions containing hydrocortisone acetate 1% cream and betamethasone valerate 0.1% respectively. In a few instances two glucocorticoids were concomitantly prescribed. The authors concluded that prescription of moderate to-potent topical formulations in about half of the infants, co-prescription of multiple glucocorticoid formulations, omission of important components of the prescription and use of a controversial vehicle diluting technique suggest that topical glucocorti coid therapy is suboptimal. A 37-year-old woman underwent trabe culectomy for advanced glaucoma and was given topical prednisolone acetate 1% (Prednefrin Forte) and chloramphenicol (95A). The pharmacist dispensed fluoro metholone 0.1% instead (FML, Allergan, Bucks, UK), which was in its correct packa ging but mislabelled as Prednefrin Forte. As this error was discovered within 2 weeks, the patient did not suffer any adverse outcome. Gout medications In a study of data from a national Internet-accessible error-reporting program, MEDMARX, medication errors involving allopurinol and colchicine occurred in 39% (n = 273) of the facilities that participated in the program (96c). Reported errors predominantly affected in patients and related to the use of allopurinol (n = 524), colchicine (n = 315), probenecid (n = 50), and sulfinpyrazone (n = 2). Compared with errors involving other musculoskeletal treatments, allopurinol and colchicine errors were more often ascribed to problems with physician prescribing (23– 39% versus 7%) and less often to problems with drug administration or nursing errors (23–27% versus 50%).
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Opioids Harmful opioid errors on in-patient units that did not involve devices, such as patient-controlled analgesia, have been retro spectively analysed using the MEDMARX database (97c). There were 644 harmful errors from 222 facilities, of which 83% caused only temporary harm; 60% were errors of admin istration and 21% prescribing errors; 23% caused underdosing and 52% overdosing. Morphine and hydromorphone had a signifi cantly higher proportion of improper dose errors than other opioids (40 and 41% com pared with 22% with pethidine). Hydro morphone errors were significantly more likely to be overdoses (78% versus 47% with other opioids). Errors of omission were sig nificantly more common with fentanyl patches (36% versus 12% for other opioids). Wrong route errors were significantly more common with pethidine (given intravenously when pre scribed intramuscularly, 34% versus 3% for morphine). Oxycodone errors were signifi cantly more likely to be wrong drug errors (24% versus 11% for other opioids), often because of confusion between immediateand modified-release formulations. Phenytoin An unusual case of phenytoin underdosing occurred in a woman who was given intravenous phenytoin in a solution of erroneously low concentration, which resulted in trapping of the drug on a particle filter (98A).
Varicella vaccination An 18-month-old child was given Vaxigrip (flu vaccine) instead of Varilix or Varivax (Varicella vac cine) and had a febrile convulsion (99Ar).
COSTS OF ERRORS In a database survey covering 20 014 hospi tal admissions during a single year, the med ication errors that were analysed caused an additional 303 days of hospital stay and an overall annual cost of nearly €6000 (about £5000, $7500).
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91. Burke D, Lal R, Finkel KW, Samuels J, For inger JR. Acute amphotericin B overdose. Ann Pharmacother 2006;40(12):2254–9. 92. Lewis TV, Badillo R, Schaeffer S, Hagemann TM, McGoodwin L. Salicylate toxicity asso ciated with administration of Percy medicine in an infant. Pharmacotherapy 2006;26 (3):403–9. 93. Bagherpour A, Amri Maleh P, Saghebi R Accidental intrathecal administration of digoxin. Anesth Analg 2006;103(2):502–3. 94. Al Khaja KA, Damanhori AH, Al-Ansari TM, Sequeira RP. Topical corticosteroids in infants: prescribing pattern and prescribing errors in Bahrain. Pharm World Sci 2007;29 (4):395–9. 95. Mein E, Sii F, Shah P An ocular medication dispensing error. Br J Clin Pharmacol 2006;62(6):715–6. 96. Mikuls TR, Curtis JR, Allison JJ, Hicks RW, Saag KG. Medication errors with the use of allopurinol and colchicine: a retrospective study of a national, anonymous Internetaccessible error reporting system. J Rheuma tol 2006;33(3):562–6. 97. Dy SM, Shore AD, Hicks RW, Morlock LL. Medication errors with opioids: results from a national reporting system. J Opioid Manag 2007;3(4):189–94. 98. Burri E, R€ uegg S, Rutishauser J, Egger SS, Lampert ML. Subtherapeutische Phenytoin spiegel infolge eines Medikationsfehlers. [Subtherapeutic blood levels of phenytoin due to a medication error.] Praxis (Bern 1994) 2007;96(17):687–92. 99. Bird S. Medication errors: immunisation. Aust Fam Physician 2006;35(9):735–7.
Index of drugs
A abacavir acute fibrinous pneumonia,
534
AIDS-associated dementia,
534
alcohol, interaction, 535
hypersensitivity, 534
nausea, 534
painful lymphadenopathy, 534
acarbose abdominal distention, 772
glucose tolerance, impaired,
772
aciclovir necrotizing enterocolitis, 530
nephrotoxicity, 530
psychosis, 530
renal insufficiency, 530
acitretin capillary leak syndrome, 298
erythema/edema near eyes,
298
granulation tissue, excess of,
298
sixth nerve palsy, 298
watery eyes, 298
acupuncture acute asthma, 886
acute hypertensive or
hypotensive crises, 886
aggravation of suicidal
thoughts, 886
bleeding, 886
erysipelas, 886
hematoma, 886
hepatitis C virus infection,
887
hypoxia, 886
needling pain, 886
orthostatic problems, 886
pneumothorax, 886
tachycardia, 886
adalimumab, 682
acute generalized skin
eruptions, 679
alopecia totalis, 679
ANCA-positive renal
vasculitis, 679
bronchospasm, 679
chronic rheumatoid arthritis,
679
cryptococcosis, 680
cutaneous lupus, 679
dermis, inflammatory changes in, 680
edema, 679
fatigue, 680
fructosamine concentrations,
reduction, 679
giant cell arteritis, 679
lichenoid reactions, 679
menorrhagia, 679
menstrual pain, 679
muscle necrosis, 680
myalgia, 679
myositis, 680
optic neuropathy, 679
pityriasis rosea, 679
Pneumocystis jiroveci pneumonia, 680
polymyositis/
dermatomyositis, 680
progressive symmetrical
proximal muscle weakness,
680
proximal muscle pain, 680
pruritus, 680
pustular drug eruption on
flexural areas, 679
rash over thighs and
abdomen, 680
Raynaud’s phenomenon, 680
recurrent varicella, 680
sinusitis, 679
symmetrical synovitis, 679
systemic lupus
erythematosus, 680
thrombocytopenia, 679
urticaria, 679
weight loss, 680
Adderall (mixed amfetamine salts), 1–2 adefovir creatinine clearance, fall in, 530
dysmenorrhea, 531
entacavir, interaction, 531
HBe antigen (HBeAg) negative disease, 530
headache, 531
hepatitis B virus infection, 530
hepatocellular carcinoma, 530
steatohepatitis, 530
adenosine receptor agonists asthma, 337
blood pressure, reduced, 338
bronchospasm, 337
complete heart block, prolonged, 337
COPD, 337
coronary artery vasospasm,
337
dizziness, 339
dyspnea, 337, 338, 339
flushing, 338
gastrointestinal discomfort,
339
headache, 339
heart rate, increased, 338
monomorphic ventricular
tachycardia, 337
non-sustained polymorphous
ventricular tachycardia, 337
pre-excited atrial fibrillation,
337
rate–pressure product,
increased, 338
respiratory arrest, 337
second-degree
atrioventricular block,
sustained, 337
stress myocardial perfusion
imaging, 338
tachycardia, 339
throat, neck, or jaw pain,
338–339
Wolff–Parkinson–White
syndrome, 337
adrenaline (epinephrine) headache, 282
heart rate, increased, 281
hypotension, 281–282
mean arterial pressure,
reduced, 281
subarachnoid and
intraventricular
hemorrhages, 282
tonic–clonic seizure, 282
unconsciousness, 282
‘Agent Lemon’ technique, 188
albendazole and mebendazole
abdominal pain, 574
acute generalized urticaria,
574
allergic reactions, 573
Angiostrongylus cantonensis,
573
anorexia, 573
bile duct rupture, 573
bilomas, 573
constipation, 573
923
Index of drugs
924 cystic echinococcosis, 573
cystopleural fistulas, 573
diarrhea, 573, 574
dizziness, 574
dry mouth, 573
eosinophilic meningitis, 573
epigastric pain, 573
hair loss, 573
headache, 573
hepatic hydatid disease, 574
iatrogenic liver damage, 574
immediate hypersensitivity,
574
immune reconstitution
syndrome, 574
itching, 574
liver, hydatid cysts, 572, 573
nausea, 573
peritoneum rupture, 573
splenic hematoma, 573
transaminase activity,
increased, 573
vomiting, 573
wheals, 574
albumin arterial hypertension, 591
bacterial infections, 591
capillary leak, 591
circulatory overload, 591
dysrhythmias, 591
hepatic encephalopathy, 591
intestinal ischemia, 591
myocardial ischemia, 591
pulmonary edema, 591
alcohol cardiac dysrhythmias, 891
cerebellar degeneration, 891
cryptorchidism, 892
aldesleukin, 676
cough, 677
fatigue, 677
skin thickening, 676
alefacept accidental injury, 680
alanine transaminase activity,
raised, 681
arthralgias, 680
back pain, 681
CD4þ count, reduced, 681
fatigue, 680
flu-like syndrome, 680
headache, 680
influenza, 680
liver enzymes, increased,
680
lymphoproliferative
disorders, 681
nasopharyngitis, 680
nausea, 680
pruritus, 680
rhinitis, 680
upper respiratory tract
infections, 680
alemtuzumab anemia, 686
anxiety, 686
autoimmune hemolytic
anemia, 686
chills, 686
coagulopathy, 686
cytomegalovirus viremia,
686
diarrhea, 686
diffuse alveolar hemorrhage,
686
dyspnea, 686
erythema, 686
fungal and tuberculous
infections, 687
headache, 686
hypertension, 686
hypotension, 686
idiopathic thrombocytopenic
purpura, 686
immune reconstitution
syndrome, 686
insomnia, 686
interstitial pneumonitis,
686
lymphopenia, 686
neutropenia, 686
pyrexia, 686
rashes, 686
red cell aplasia, 686
sarcoidosis, 686
tachycardia, 686
thrombocytopenia, 686
Toxoplasma invasive disease,
687
tremor, 686
urticaria, 686
alfentanil, 187
propofol, interaction, 187
alfuzosin acute liver damage, 392
dizziness, 392
epigastric pain, 392
itching, 392
jaundice, 392
aliskiren diarrhea, 388
headache, 388
hypotension, 388
nasopharyngitis, 388
overdose, 388
Allium sativum (Liliaceae, garlic bulb) chemical burns, 884
gums, burning pain, 884
painful teeth, 884
alosetron abdominal pain and discomfort, 666
constipation, 666
intestinal obstruction, 666
ischemic colitis, 666
alprazolam impaired driving
performance, 75
traffic accidents, risk of, 75
alprostadil (prostaglandin E1) cortical hyperostosis, 729
pseudo-Bartter’s syndrome,
729
alteplase bleeding at chest tube site, 637
chest pain, 637
chronic empyemas, 637
congestive heart failure,
637
diabetes mellitus, 637
symptomatic intracerebral
hemorrhage, 637
aluminium Alzheimer’s disease, 413
dialysis dementia, 413
high frequency hearing
impairment, 413
amantadine abdominal discomfort, 532
abdominal pain, 532
acute interstitial nephritis,
533
allergic reaction, 533
anemia, 545
buprenorphine, interaction,
534
cholesterol, increased, 532
chronic hepatitis C, 544, 545
diarrhea, 532
Fuchs’ dystrophy (corneal
edema), 545
hepatotoxicity, 533
leukopenia, 545
light-headedness, 545
lipoatrophy, 532
mitochondrial dysfunction,
533–534
mood disorders, 545
nausea, 532
nodular regeneration of liver,
533
pancreatitis, 533
profuse sweating, 545
renal function, reduced, 533
renal toxicity, 534
syncope, 532
triglycerides, increased, 532
vomiting, 532
warfarin, interaction, 534
ambrisentan dizziness, 388
headache, 388
hemoglobin concentration,
fall in, 388
nasal congestion, 388
peripheral edema, 388
sildenafil, interaction, 388
Index of drugs amfetamine ADD/ADHD, 1–2
Adderall abuse, 1–2
apical ballooning syndrome, 1
cardiomyopathy, 1
amikacin nephrotoxicity, 461
vestibular function, 461
aminoglycoside antibiotics cochlear toxicity, 461
renal insufficiency, 461
vestibular toxicity, 461
aminolevulinic acid allergic contact dermatitis, 298
eczema, acute, 298
pain, 297–298
amiodarone acute hepatitis, 345
adverse reactions,
management of, 347
anosmia, 342
blue-grey skin pigmentation,
345
bone marrow granulomata, 345
cerebellar ataxia, 342
clozapine, interaction, 346
death, 346
Doppler scanning, 343
epididymitis, 345
epigastric pain, 345
eryptosis, 339
facial urticaria, 345
fatal case of lung damage, 342
Graves’ disease, 343
hypersensitivity reaction, 345
hyperthyroidism, 343, 344
hypothyroidism, 344
interstitial pneumonitis, 341
ischemic optic neuropathy,
342
isolated lung masses, 341
keratopathy, 342
non-arteritic anterior
ischemic optic neuropathy, 342
pancreatitis, 345
phlebitis, 340
pleural effusion, 341
pneumonitis, 340
potassium perchlorate,
effects of, 344
QT interval prolongation, 340
renal damage, 345
rosuvastatin, interaction, 346
sinus bradycardia, 340
syndrome of inappropriate
antidiuretic hormone secretion (SIADH), 345
thyroid dysfunction, 343
thyrotoxicosis, 343
torsade de pointes, 340
transient congenital
hypothyroidism, 346
925 amisulpride akathisia, 92
lassitude, 92
oligomenorrhea, 92
somnolence, 92
tardive dyskinesia, 92
tremor, 92
amitriptyline, 131, 134
amlodipine
dysgeusia, 367
edema, 367
pedal, 367
pretibial and facial edema, 367
amodiaquine malaria, 521
neutropenia, 521
amoxicillin illness, 450
molar incisor
hypomineralization, 450
amphotericin fungal infection, 493
hematologic malignancy, 493
hepatic histopathology, 493
nephrotoxicity, 493
renal impairment, 494
serum creatinine, rise in, 493
amphotericin B colloidal dispersion (ABCD) backache, 494
chills, 494
infusion-related fever, 494
amphotericin B deoxycholate (DAMB) acrocyanosis, 494
cardiotoxicity, 494
hyperbilirubinemia, 494
lipid formulation, 494
Raynaud’s phenomenon, 494
amphotericin B lipid complex
(ABLC), 493
cough, 495
invasive fungal infection, 495
nausea, 495
pulmonary function,
reduction, 495
taste disturbances (vomiting),
495
anagrelide cardiomyopathy, 637
painful leg ulcers, 638
anakinra (interleukin-1 receptor antagonist) dilated cardiomyopathy, 677
pneumonitis, 677
pulmonary tuberculosis, 677
varicella, 677
visceral leishmaniasis, 677
androgens, 750
angiotensin-converting enzyme
(ACE) inhibitors
abdominal surgery,
unnecessary, 381
acute/painless/non-pruritic
tongue swelling, 380
age related macular
degeneration, 380
airway compromise, 381
aldosterone receptor
antagonists, interaction, 383–384
angioedema, 380
cough, 379–380
diclofenac, 382
dysarthria, 380
epoetin, interaction, 384
hypotensive symptoms, 379
pneumonia, 381
renal dysfunction, 379
ST-AN69 dialysis
membranes, use of, 383
symptomatic hypotension, 379
syncope, 379
anidulafungin bilirubin, increased, 508
ciclosporin, interaction, 508
diarrhea, 508
flushing, 507
hepatic enzyme activities,
increased, 508
hepatic insufficiency, 508
hypokalemia, 508
pruritus, 507
rashes, 507
renal insufficiency, 508
tacrolimus, interaction, 508
urticaria, 507
anticholinergic drugs cardiovascular deaths, 318
dry mouth, 291
headache, 291
mild allergic reactions, 291
myocardial infarction, 318
nasopharyngitis, 291
overactive bladder, 290
QT interval prolongation,
291
redness of eye, 291
stroke, 318
urinary tract infection, 291
urinary urgency/
incontinence, 290–291
ventricular dysrhythmias, 291
anticoagulant proteins drotrecogin, action, 591–592
severe sepsis, 593
anticonvulsant hypersensitivity syndrome, See drug rash with eosinophilia and systemic symptoms (DRESS) antidepressants bupropion, 32
cardiovascular defects, 32
citalopram, 30
congenital malformations, 32
discontinuation syndrome, 31
Index of drugs
926 dose–response relationship, 30–31
dothiepin, 30
fluoxetine, 30
fracture, risk of, 30
hepatic damage, 30
hepatotoxicity, 30
hyperprolactinemia, 31
hypothermia, recurrent, 32
liver damage, 30
mirtazapine, 32
monoamine oxidase
inhibitors (MAOI), 30
nortriptyline, 30
paroxetine, 30
in pregnancy, 31
QT interval prolongation, 31
serotonin–noradrenaline re-
uptake inhibitor (SNRI), 30
SSRI, 31
suicidality, 29–30
venlafaxine, 30, 31
withdrawal symptoms, 31
antidysrhythmic drugs, 337
antifungal azoles
ciclosporin, interaction, 497
cinitapride, interaction,
497–498
cyclophosphamide,
interaction, 498
efavirenz, interaction, 498
fentanyl, interaction, 498–499
haloperidol, interaction, 499
hormonal contraceptives,
interaction, 499
ibuprofen, interaction, 499–
500
imidafenacin, interaction, 500
ixabepilone, interaction, 500
maraviroc, interaction, 500
nevirapine, interaction, 500
phenytoin, interaction, 500
praziquantel, interaction,
500–501
rifabutin, interaction, 501
sirolimus, interaction, 501
SPP301, interaction, 501
statins, interaction, 501
tacrolimus, interaction, 501
vinca alkaloids, interaction,
501–502 anti-glaucoma drugs, combinations of allergy, 874
bitter taste, 874
bradycardia, 874
diarrhea, 874
eye irritation, 874
eye pain, 874
fatigue, 873
gout, 874
headache, 874
hordeolum, 874
hyperemia, 874
keratitis, 874
nausea, 874
ocular irritation, 874
pruritus of the eye, 874
taste disturbances, 874
antihelminthic drugs abdominal pain, 572
bilharziasis (schistosomiasis),
571
bloody diarrhea, 572
elephantiasis (lymphatic
filariasis), 571
fever, 572
guinea worms
(dracunculiasis), 571
headache, 572
HIV–AIDS, 571
malaria, 571
myalgia, 572
nausea, 572
river blindness
(onchocerciasis), 571, 572
roundworms (ascariasis), 571
trachoma, 572
tuberculosis, 571
whipworms (trichuriasis), 571
anti-hepatitis C virus (HCV), 535 antimonial compounds leishmaniasis, 414
anti-estrogens and selective estrogen receptor modulators (SERMS) acute hepatitis, 743
aromatase, inhibition, 743
antithrombin III
bleeding events, 594
veno-occlusive disease, 594
antithyroid drugs acute myeloid leukemia, 766
agranulocytosis, 765
ANCA-positive vasculitis,
766
aplasia cutis congenita, 766
changes in liver function
tests, 766
choanal atresia, 766
cholestatic jaundice, 766
complex skull defects, 766
diffuse alveolar hemorrhage,
765
eosinophilic pleural effusion,
765
fetal hypothyroidism and
goiter, 766
Graves’ disease, 766
hepatotoxicity, 766
juvenile dermatomyositis,
766
plasmacytosis, 765
pleural effusion, 765
thrombocytosis, 765
warfarin, interaction, 766
antituberculosis drugs HIV co-infection, 559
malnutrition, 559
Mycobacterium tuberculosis,
558
antituberculosis drugs, hepatotoxicity active tuberculosis, 555, 556
alcohol abuse, 556
autoimmune hepatitis, 555
baseline transaminase
activities, 556
fulminant hepatic failure, 555
gastrointestinal adverse
effects, 556
HBsAg, 557
hepatic cirrhosis, 556
hepatitis B virus infection, 555
hepatitis C virus (HCV)
infection, 556–557
hepatitis E virus infection, 555
isoniazid-related liver failure,
556
lymphomatous infiltration of
liver, 555
seronegative hepatitis, 555
severe Plasmodium
falciparum malaria, 555
antituberculosis drugs in transplant recipients extrapulmonary tuberculosis, 560
hepatotoxicity, 560
neuropsychiatric
manifestations, 560
optic neuritis, 560
pleuropulmonary
tuberculosis, 560
toxic hepatitis, 559
tuberculosis, 559, 560
apixaban bleeding, increased, 635
appetite, drugs that suppress, 16
apraclonidine
bradycardia, 869
drowsiness, 869
hypertension, 869
oxygen saturation, reduced,
869
aprepitant constipation, 667
nausea, 667
pruritus, 667
QT interval prolongation, 667
aprotinin acute renal damage, 645
allergic reactions, 645
cardiac events, 643
cerebrovascular events, 643
hemolytic thrombotic
microangiopathy, 645
massive bleeding, 644
mortality, 643
Index of drugs postoperative hemodialysis,
643
renal failure, 643
argatroban impaired renal function, 633
aripiprazole akinetic hypertonic parkinsonian syndrome, 93
dry mouth, 94
galactorrhea, 94
haloperidol-induced
dyskinesias, 93
headache, 94
hyperglycemia, 94
insomnia, 94
lingual writhing movements,
93
lip smacking, 93
lisp, 93
menstrual disturbances, 93
olanzapine, 93
polydipsia, 94
polyphagia, 94
polyuria, 94
sedation, 94
tamoxifen, 93
‘tongue heaviness,’ 93
tongue protrusion, 93
weakness, 94
arsenicals dysrhythmias, 414
fluid accumulation, 414
hyperkeratosis, 414
IQ score, decrease, 414
leukocytosis, 414
pulmonary infiltration, 414
QT interval prolongation, 414
Artemisia vulgaris (Asteraceae, mugwort, moxa) abnormal liver function tests, 885
allergic reactions, 884
epigastric pain, 884
jaundice, 885
arterial embolization neuroendocrine tumors, 900
artesunate chorea, 525
efavirenz, interaction, 525
neurotoxicity, 525
articaine cardiovascular risk factors, 266
risk of neurotoxicity, 266
artificial sweeteners urinary tract tumors, 892
Asian herbal medicines, 879
acute liver damage, 880
anaphylactic laryngeal
edema, 880
asthma, 879
chest distension, 880
cholestasis, 879
dyspnea, 880
927 hepatocelluar damage, 879
hoarse voice, 880
laryngeal edema, 880
numbness in lips, 880
swelling of eyelids, 880
warfarin, interaction, 880
atazanavir alopecia, 541
hyperbilirubinemia, 541
jaundice, 541
rifampicin, interaction, 541
tenofovir, interaction, 541
atomoxetine, 8
abdominal pain, 8
aggression, 8
appetite, reduced, 8, 11
blood pressure, increased, 8, 11
CYP2D6, 9
dyspepsia, 8, 9
growth, effect on, 9
heart rate, increased, 11
hostility, 8
hyponatremia, 9
insomnia, 8
involuntary movements, 8
loose stools, 9
metabolizers, poor, 9
nausea, 9
overdose, pediatric cases, 10
psychosis, 8
salivary stones, 9
seizures, 8
somnolence, 8, 11
speech disturbance, 8
suicide-related events, 9
tics, 8
transaminase activities,
increased, 9
tremors, 8
vomiting, 8
atorvastatin hemorrhagic cystitis, 814
Hypericum perforatum extract, 814
istradefylline, interaction, 814
atracurium donepezil, interaction, 19
azathioprine abdominal pain, 717
acute variceal bleeding, 717
anemia, 718
ascites, 717
atrial fibrillation, 717
bronchiolitis obliterans, 717
diarrhea, 717
disabling arthralgia, 717
dyspnea, 718
exanthematous pustulosis, 717
fatigue, 718
fever, 717
general malaise, 717
hypotension, 717
leukopenia, 718
lower birth weight and gestational age, 718
myelotoxicity, 718
nausea, 717
non-follicular pustular
eruption, 717
non-infective pneumonia,
717
non-productive cough, 717
prematurity, 718
respiratory failure, 718
right-sided abdominal pain,
718
shortness of breath, 717
squamous cell carcinoma of
kidney, 718
thrombocytopenia, 718
vomiting, 717
azithromycin abdominal pain, 473
cholestatic jaundice, 473
diarrhea, 473
dysgeusia, 473
heartburn, 473
hiccups, 473
nausea, 473
onychomadesis, 473
QT interval prolongation, 472
sensorineural hearing loss, 473
B baclofen bradycardia and hypotension,
276
hot and cold temperature
perception, reduced, 276
overdose, 276
transient global amnesia, 276
barium sulfate abdominal discomfort, 850
cramps, 850
diarrhea, 850
esophageal perforation, 851
intestinal obstruction, 851
lung damage, 850
nausea, 850
non-specific interstitial
pneumonia, 851
obstructive cholangitis, 851
osteitis, 851
peritonitis, 851
pulmonary alveolar
microlithiasis, 851
pulmonary alveolar
proteinosis, 851
basiliximab bronchial asthma, 687
drug allergy, 687
benazepril, see angiotensin
converting enzyme inhibitors
benzalkonium compounds
dry skin, 440
genital ulcer, 440
Index of drugs
928 benzbromarone allergic reactions, 234
chronic active hepatitis, 234
coumarins, interaction,
234–235
diarrhea, 234
renal colic, 234
urate and oxalate stones, 234
urinary sand, 234
benzimidazoles, 572
benzocaine
methemoglobinemia, 266–267 benzylpiperazine, 55
amfetamine poisoning, 55
cardiotoxicity, 55
collapse, 55
convulsions, 55
pep pills, 55
piperazine poisoning, 55
seizures, 55
beta-lactam antibiotics anaphylaxis, 447
carbapenem allergy, 447
congenital malformations, 447
penicillin allergy, 447
S. aureus infection, 447
betaxolol, 363
bevacizumab, 865
bezafibrate
angioedema, 805
bicalutamide breast pain, 755
gynecomastia, 755
bimatoprost periocular pigmentation, 729
bisbiguanides, 439
bismuth
abdominal pain, 414
diarrhea, 414
dizziness, 414
headache, 414
Helicobacter pylori, 414
metallic taste, 414
nausea, 414
stool darkness, 414
bisphosphonates breast cancer, 893, 894
multiple myeloma, 893
osteonecrosis of jaw, 893
plasmacytoma, 894
prostate cancer, 894
bivalirudin, 633
blood substitutes
dysrhythmias, 594
gastrointestinal problems, 594
hypertension, 594
liver enzymes, rise in, 594
pancreatitis, 594
blood transfusion acute allergic and
anaphylactic reactions, 593
acute hemolytic transfusion
reactions, 593
alloantibody formation, 593
bacterial contamination, 593
febrile non-hemolytic
transfusion reactions, 593
hemolytic transfusion
reactions, delayed, 593
hemosiderosis, 593
post-transfusion purpura, 593
transfusion-associated
circulatory overload
(TACO), 593
transfusion-associated graft versus-host disease, 593
transfusion-related acute
lung injury (TRALI), 593
viral infections, 593
borates, 439
boric acid
potential lethality, 439
skin irritation, 440
toxicity, 439, 440
vaginal burning, 440
vulvovaginal candidiasis, 439
bosentan hepatotoxicity, 389
phosphodiesterase type 5
inhibitors, interaction, 390
pulmonary artery
hypertension, 389
respiratory complaints, 389
botulinum toxins chlorzoxazone, risk, 277
diplopia, 277
dysphagia, 277
fatigue, 277
Fournier’s gangrene, 277
hand weakness, 277
muscle weakness, 277
pain at the injection site, 277
rashes or other allergic
reactions, 277
respiratory failure or
dyspnea, 277
brachial plexus anesthesia Horner’s syndrome, 262
motor and sensory blockade,
262
brimonidine ectropion, 870
granulomatous anterior
uveitis, 870
granulomatous papillary
conjunctivitis, 870
brinzolamide allergy, 403
corneal diameter increment,
403
eye symptoms, 403
headache, 403
hordeolum, 403
hyperemia, 403
renal excretion, 401
taste disturbances, 403
brompheniramine hyperactivity, 305
sleepiness, 305
buflomedil, 371
bupivacaine
acute non-ST segment
elevation myocardial
infarction, 267
type IV hypersensitivity,
delayed, 267
buprenorphine, 209–210
abuse, 210
benzodiazepines, interaction,
210
cannabinoids, interaction,
210
cognitive deficits, 209–210
constipation, 209
dizziness, 209
dry mouth, 209
erythema, 209
fatigue and sweating, 210
headache, 209
HIV protease inhibitors,
interaction, 210
insomnia, 209
with methadone, 209
mild respiratory depression,
209
naloxone, interaction, 210
nausea and vomiting, 209
pruritus, 209
psychomotor functioning
deficits, 209–210
psychotic symptoms, 210
somnolence, 209
substance misuse, 210
weakness, 209
bupropion (amfebutamone) see also antidepressants
hepatocellular jaundice, 35
hepatotoxicity, 35
lopinavir, interaction, 35–36
ritonavir, interaction, 35–36
buspirone, 75
butorphanol, 210–211
agitation, 211
disorientation, 211
naltrexone, 210
tonic-clonic seizures, 211
C caffeine neonatal withdrawal syndrome, 14–15
regadenoson, interaction, 15
synephrine, interaction, 15
theanine, interaction, 15
zolpidem, interaction, 15
calcitonin hypersensitivity reactions,
789
nausea and diarrhea, 789
Index of drugs calcium channel blockers overdose, 366
candesartan pemphigus foliaceus, 386
pulmonary hypoplasia, 386
cannabinoids affective disorders, 57
blood oxygen level-
dependent (BOLD), 56
Brugada-like syndrome, 56
bullous lung disease, 56
cerebellar function, 56
cerebrovascular disease, 56
dronabinol-induced
gynecomastia, 57
eye-blink conditioning
(EBC), 56–57
gynecomastia or breast tissue
growth, 57
hypoactivity, 56
impaired memory and
learning, 56
lead intoxication, 58
psychosis, 57
revascularization, 55–56
captopril see also angiotensin
converting enzyme
inhibitors
hemolytic anemia, 384
lichen planus pemphigoides,
384
carbamazepine, 46, 126–129
abdominal pain, 131
ataxia, 131
atrioventricular block, 127
blurred vision, 127
bone density, lower, 130
conjunctival metaplasia, 128
dizziness, 131
double vision, 131
DRESS, 128, 129
drowsiness, 131
enthesitis, 130
headache, 127
hemolytic anemia, 128
Herpes simplex virus
encephalitis, 130
and levetiracetam, 127
monotherapy, 128
nausea, 127, 131
nystagmus, 131
overdose, 131
pneumonia, 130
pseudolymphoma, 128
psoriasiform eruption, 129
pure red cell aplasia, 128
and remacemide
hydrochloride, 127
somnolence, 127
Staphylococcus aureus tendon sheath abscess,
130
929 Stevens–Johnson syndrome (SJS), 129–130 thyroid hormones, affecting, 128
and topiramate, 126–127
toxic epidermal necrolysis
(TEN), 129–130
tremor, 127
unipolar depression, 127
urinary retention, 128–129
vomiting, 131
carbapenems valproic acid, interaction, 448
cardiac glycosides adverse reactions, management of, 336
atrial fibrillation, 333
calcium salts, interaction, 336
cardiac dysrhythmias, 335
digoxin toxicity, 333
hyperkalemia, 335
loss of balance, 336
lower body weight, 334
nausea, 336
non-fatal self-poisoning, 335
non-occlusive mesenteric
ischemia, 333
omeprazole, 335
overdose, 335
proton pump inhibitors,
interaction, 335–336
quinine, interaction, 336
rabeprazole, 336
second-degree heart block, 333
sinus bradycardia, 333
ventricular bigemini, 333
vildagliptin, interaction, 336
weakness, 336
xanthopsia, 336
carteolol blurred vision, 870
bradycardia, 870
bronchoconstriction, 870
congestive heart failure, 870
hypotension, 870
myocardial infarction, 870
carvedilol cough, 364
cutaneous vasculitis, 364
palpable purpuric eruption,
364
upper respiratory tract
infections, 364
vomiting, 364
caspofungin, 509
abdominal infection, 508
aspergillosis, invasive, 509, 510
bloodstream infection, 508
candidiasis, invasive, 508,
509, 510
ciclosporin, interaction, 510
endocarditis, 508
febrile neutropenia, 508, 510
fungal infections, invasive, 508, 509
hepatic insufficiency, 510
hypokalemia, 509, 510
osteomyelitis, 508
rash, 510
septic arthritis, 508
caudal anesthesia, 263
amplitude of
electrocardiographic T
wave, increased, 263
heart rate, increased, 263
cefdinir red stools, 448
cefoperazone gastrointestinal bleeding, 449
Meckel’s diverticulum, 449
cefotaxime abdominal distension, 449
Aeromonas hydrophila, 449
biliary sludge, 449
cholelithiasis, 449
fever, 449
jaundice, 449
Klebsiella pneumoniae, 449
pale stools, 449
ceftobiprole eosinophilia, 449
fatigue, 449
taste disturbances, 449
weakness, 449
celecoxib acute pancreatitis, 233
erectile dysfunction, 233
and etoricoxib, 233
renal/hepatic/combined
toxicity, 233
cephalosporins carnitine depletion, 448
tremor, 448
certoparin, see heparins
cethromycin
gastrointestinal disorders, 471
cetirizine fixed drug eruptions, 305
long QT syndrome, 305
urticarial reaction, 306
Chinese medicines, injectable formulations of acute anaphylactic shock, 882
acute asthma, 882
acute laryngeal edema, 882
allergic reactions, 881
anaphylactic shock, 882
angina, 881
apnea, 882
cardiac arrest, 882
chest distress, 881
chronic pulmonary heart
disease, 882
cold limbs, 881
coronary heart disease, 882
cough, 883
Index of drugs
930 dizziness, 882
dyspnea, 881
generalized itching, 881
headache, 881
laryngeal edema, 881
lips and tongue, numbness, 881
palpitation, 881
profuse sweating, 881, 882,
883
shock, 882
shortness of breath, 882
tremors in limbs and mental
confusion, 882
viral myocarditis, 882
chloral hydrate, 79
respiratory obstruction, 79
sedation, 79
chloramphenicol contact sensitivity, 464
chlorhexidine Acanthameba keratitis, 439
anaphylaxis, 439
ipsilateral cataract, 439
maternal morbidity, 439
maternal mortality, 439
neonatal morbidity, 439
neonatal mortality, 439
Stevens–Johnson syndrome,
439
toxic epidermal necrolysis, 439
chloroquine and hydroxychloroquine cardiomyopathy, 521
congestive cardiac failure, 522
depressed mfERG
amplitude, areas, 523
diabetes, 522
hepatitis, 522
hypertension, 522
intermittent fever, 522
lesions, 523
mucocutaneous
hyperpigmentation, 522
myelodysplastic syndrome,
522
myopathy, 522
proximal muscle weakness,
522
refractory anemia, 522
retinal toxicity, 522, 523
rheumatoid arthritis, 522
ringed sideroblasts, 522
symmetrical arthritis, 522
systemic lupus
erythematosus, 522
vortex keratopathy, 522
chlortalidone diabetes mellitus, 406
chromium cell signalling alterations, 415
DNA lesions, cell nucleus, 415
lung cancer, 415
sarcoma, 415
chromosome aberration, 503
cibenzoline
difficulty in chewing and dyspnea, 347
dull headache, 347
myasthenia, 347
overdose, 347
pneumonia, 347
weakness, 347
ciclosporin, 141
altered level of
consciousness, 705
changes in mental status, 705
cryptococcosis, 707
de novo neoplasms, 707
diabetes mellitus, 706
exophytic/polypoid/multi nodular masses on tongue, 706
fibrovascular hyperplasia, 706
headache, 705
hepatic lymphoma, 707
hyperlipidemia, 707
hypertension, 705
itraconazole, inhibition, 708
laryngeal cancer, 707
mouth sores, 707
nausea and vomiting, 705
neuralgia, 705
oxcarbazepine, inhibition, 708
pruritus, 707
pseudotumor cerebri, 705
roxithromycin, inhibition, 708
seizures, 705
tremor, 705
cidofovir adenovirus hepatitis, 529
adenovirus pneumonia, 529
bronchiolitis obliterans, 529
colitis, 529
graft-versus-host disease, 529
nephritis, 529
nephrotoxicity, 529
renal insufficiency, 529
tracheomalacia, 529
cilazapril, see angiotensin converting enzyme inhibitors
cilomilast, 321
cilostazol
congestive heart failure, 371
spinal epidural hematoma,
371–372
C1 inhibitor concentrate allergic reactions, 594
citalopram, see antidepressants
clarithromycin
acute hepatitis, 473
acute psychosis, 473
carbamazepine, interaction,
473
cholestatic jaundice, 473
colchicine, interaction, 474
pranlukast, interaction, 474
QT interval prolongation, 473
repaglinide, interaction, 474
sirolimus, interaction, 474
Stevens–Johnson syndrome,
473
toxic epidermal necrolysis,
473
clenbuterol
acute respiratory failure, 289
chest pain, 289
headache, 289
palpitation, 289
vomiting, 289
clindamycin
acute febrile neutrophilic
dermatosis, 472
acute generalized
exanthematous pustulosis
(AGEP), 472
acute hepatotoxicity, 472
autism, 472
taste disorders, 472
toxoplasmic chorioretinitis,
472
clomifene
acute mania, 743
acute pancreatitis, 744
anterolateral myocardial
infarction, 743
azoospermia, 744
bilateral anterior uveitis, 743
borderline ovarian tumors, 744
central retinal vein occlusion,
743
malignant melanomas, 744
massive ovarian edema, 744
psychoses, 743
right upper quadrant pain, 744
ruptured ovarian cyst, 744
serum transaminases, raised,
744
thyroid cancers, 744
clonidine
bradycardia, 391
cardiac arrest, 391
depression, 391
drowsiness, 391
insomnia, 391
methylphenidate,
comparison with, 11
new-onset seizures, 391
night terrors, 391
sedation, 11
clopidogrel
acute hepatitis, 640
aplastic anemia, 639
cardiovascular death, 642
desquamation, 640
dizziness, 641
dual antiplatelet drug
resistance, 640
erythema, 640
generalized pruritus, 640
Index of drugs hallucinations, 639
ischemic events, reduced
incidence, 639
lansoprazole, 641
loss of taste, 639
myocardial infarction, 641, 642
neutropenia, 639
non-cardiogenic pulmonary
edema, 640
permanent neurological
deficit, 640
stroke, 642
thrombocytopenia, 639
thrombotic
thrombocytopenic purpura,
639
transient intrainterventional
thrombosis, 640
transient ischemic attacks, 640
triple antithrombotic therapy,
639
type I hypersensitivity, 640
type III hypersensitivity, 640
type IV hypersensitivity, 640
upper gastrointestinal
bleeding, 639
vomiting, 641
worse ischemic outcomes, 639
clozapine, 134
agranulocytosis, 97
akathisia, 96
aluminium hydroxide,
interaction, 98
blepharospasm, 96
cardiomyopathy, 95
cataplexy, 96
chemotherapy, interaction, 98
ciprofloxacin, interaction, 98
CYP inhibitors, interaction,
98–99
delayed speech, 98
drug–smoking, interaction, 99
dystonia, 96
eating disorders, 96
effusoconstrictive
pericarditis, 96
extrapyramidal adverse
effects, 95
glycopyrrolate, 97
hypersalivation, 95
levomepromazine,
interaction, 99
microscopic colitis, 97–98
myocarditis, 95
overdose, 98
pericardial effusion, 95
pericarditis, 95
pleural effusion, 95
polyserositis, 96
priapism, 98
raised serum prolactin, 95
rapid eye movement (REM)
sleep, 96
931 restless legs syndrome, 96
rifampicin, interaction, 99
seizures, 96
sialorrhea, 95, 97
somnolence, 95
speech disorder, 95
stuttering, 96
tardive dyskinesia, 96
transient leukopenia, 95
weight gain, 95, 97
co-amoxiclav and clavulanic acid death, 450
hepatitis, 450
liver damage, 450
cobalamins (vitamin B12) allergy, 608
type I immediate
hypersensitivity, 608
cobalt, see chromium
cocaine
aortic dissection, 60
Brugada-like syndrome, 59
cardiac arrest, 58
cardiovascular toxicity, 58
chest pain, 59
depression, 60
dysrhythmias, 58
heroin, interaction, 61
hypernasal speech, reduced,
60
hypothermia, 58
myocardial infarction, 59
necrosis of hard palate, 60
necrosis of nasal septum, 60
oxycodone, interaction, 60
paracetamol, interaction,
60
pre-retinal hemorrhage, 60
QT interval prolongation,
58
quetiapine, interaction, 61
rhabdomyolysis, 59
speech intelligibility, 60
stent thrombosis, 59
toxic encephalopathy, 60
codeine, 187
Tylenol No. 3
(acetaminophen), 187
colistin fatal acute respiratory
distress syndrome
(ARDS), 477
nephrotoxicity, 476
neurological complications,
477
rhabdomyolysis, 477
complementary and alternative
medicines (CAM), 622
Alzheimer’s disease, 622
contrast agents, see water-
soluble intravascular
iodinated contrast agents
copper Menke’s disease, 415
Wilson’s disease, 415
coumarin anticoagulants acenocoumarol, intake, 624
acquired hemophilia, 618
anticoagulation, increased,
623
apolipoprotein E (APOE), 620
arterial calcification, 617
arterial thrombosis, 617
azoles econazole, 622
bifonazole, 622
bleeding, 621
bone mineral density, 618
calciphylaxis, 617
cerebral hemorrhage, 621
cerebral hemispheric
atrophy, 619
coagulation factors,
reduction, 625
corpus callosum, agenesis, 619
CYP2C9 and CYP3A4,
inhibition, 624
CYP2C9 mutation, 624
Dandy–Walker
malformation, 619
enhanced anticoagulation, 625
gastrointestinal dysmotility,
621
hemodialysis, 621
hepatotoxicity, 618
INR, increased, 622
intracerebral hemorrhage, 624
intraventricular hemorrhage,
623
leukocytoclastic vasculitis, 618
lower warfarin requirements,
623
mean INR, 621
microcephaly, 619
non-gastrointestinal tract
bleeding, 624
ocular bleeding, 617
optic atrophy, 619
pharmacogenetic algorithm,
619
polymorphisms, genetic, 619
porencephaly, 619
prolonged INR, 622
prominent ecchymoses, 622
prothrombin time, increased,
622
self-reported bleeding, 625
skin necrosis, 618
subconjunctival hemorrhage,
617
subdural hematoma, 623
superwarfarins, 621
supratherapeutic INRs with
CAM, 622
thrombocytopenia, 618
warfarin embryopathy, 619
Index of drugs
932 cyanoacrylates pre-B cell acute
lymphoblastic leukemia,
894
cycloserine asterixis, 561
hepatotoxicity, 561
hypersomnia, 561
neurotoxicity, 560
CYP2D6, 8, 9, 10, 16
D dabigatran venous thromboembolism,
633
dacarbazine acute non-lymphocytic
leukemia, 829
acute promyelocytic
leukemia, 829
alopecia, 829
anemia, 828
aplastic anemia, 828
blurred vision, 828
Budd–Chiari syndrome, 828
cimetidine, interaction, 829
ciprofloxacin, interaction, 829
confusion, 828
dizziness, 828
eosinophilia, 828
erythematous rash, 829
facial flushing, 829
fever, 829
flu-like syndrome, 829
gastrointestinal bleeding, 828
gross hematuria, 829
headache, 828
hemorrhagic cystitis, 828
hepatotoxicity, 828
lethargy, 828
leukopenia, 828
mild dysuria, 829
nausea and vomiting, 828
paresthesia, 828
peripheral neuropathy, 828
phototoxic dermatitis, 829
seizures, 828
thrombocytopenia, 828
weakness, 828
daclizumab left lower lobe pneumonia, 688
reactive arthritis, 687
sinus bradycardia, 687
danaparoid sodium bleeding, 632
delayed hypersensitivity
reactions, 632
eczema, 632
danazol HDL and apolipoprotein
A-I, lower, 750
LDL and apolipoprotein
B-100, higher, 750
dapsone acne vulgaris, 560
daptomycin
alveolar eosinophil, 478
INR prolongation, 479
interstitial eosinophil, 478
prothrombin time
prolongation, 479
raised transaminases, 479
rhabdomyolysis, 479
statins, interaction, 479
deferasirox
acute renal insufficiency, 427
agranulocytosis, 427
aluminium salt, interaction,
427
anaphylaxis, 427
cytochrome P450 (CYP)
isoenzymes, interaction, 427
dementia, 427
gastrointestinal ulceration,
427
hemorrhage, 427
lenticular opacities, 427
liver damage, 427
midazolam, interaction, 427
neurosensory hearing loss, 427
repaglinide, interaction, 427
thrombocytopenia, 427
UDP glucuronyltransferase
inducers, interaction, 427
deferiprone
agranulocytosis, 427, 428
Diamond–Blackfan anemia,
428
Guillain–Barré syndrome, 428
Henoch–Schönlein purpura,
428
musculoskeletal pain, 427
pneumonia, 428
Staphylococcus aureus
sepsis, 428
deferoxamine
acute renal failure, 430
bilateral sensorineural
hearing loss, 429
endocarditis, 430
Goodpasture’s syndrome, 430
renal tubular toxicity, 430
retinopathy, 429
delapril
calcium channel blockers,
interaction, 384
dental anesthesia
CK-MB activity, 264
lateral rectus nerve palsy, 264
ST segment depression, 264
desflurane
dark urine, 244
displacement of tympanic
membrane grafts, 244
hemotympanum, 244
hepatitis, 244
hepatotoxicity, 244
jaundice, 244
loss of hearing, 244
middle ear pressure,
increased, 244
Möbius syndrome, 244
pruritus, 244
tympanic rupture, 244
vomiting, 244
desloratadine, 306
desmopressin (N-deamino-8 Darginine vasopressin, DDAVP) convulsions, 798
facial flushing, 798
hypertension, 798
hyponatremia, 798
mild tachycardia, 798
myocardial infarction, 798
transient headache, 798
dexamfetamine lactation, 2
dexbrompheniramine dizziness, 306
dry mouth, 306
dexchlorpheniramine drowsines, 307
fatigue, 307
psychomotor disturbances, 307
dexibuprofen ankle joint and
dysmenorrhea, distortion,
229
ankylosing spondylitis, 229
aseptic meningoencephalitis,
230
and celecoxib, 229
and diclofenac, 229
fever, 229
gastrointestinal disorders, 229
and ibuprofen, 229
lumbar vertebral syndrome,
229
osteoarthritis, 229
phenytoin, interaction, 230
respiratory tract infections,
229
rheumatoid arthritis, 229
dexindoprofen, 230
dexketoprofen
abdominal pain, 231
co-magaldrox, interaction, 232
dermatitis, 232
diarrhea, 231
and diclofenac, 230–231
drowsiness, 231
erythematous rash, 231
feeling of hot/cold, 231
gastrointestinal bleeding, 230,
231
headache, 231
and ketorolac, 231
and metamizole, 231
Index of drugs myocardial infarction or death, 231
nausea, 231
neutropenia and
thrombocytopenia, 231–232
photosensitivity, 232
profuse bleeding, 231
and racemic ketoprofen, 231
renal pain, 231
and rofecoxib, 231
tiredness, 231
vomiting, 231
dextrans acute anuria, 595
acute renal failure, 595
dextromethorphan, 187–188
overdose, 188
phencyclidine (instant-view
multi-test), 188
psychosis, 187
diamorphine (heroin), 188–190
cardiomyopathy, 188
central nervous system
depression, 189
chronic heroin use
(neurotoxicity), 188
fentanyl, 190
illicit heroin, use of, 189
low Apgar scores, 189
and methadone, use of, 189
necrolytic migratory
erythema, 188–189
overdose, 190
protracted abstinence
syndrome, 189
respiratory depression, 189
resuscitation in neonates, 189
rhabdomyolysis, 189
sudden infant death
syndrome, risk of, 189
diazepam high dose, 76
hypotension, 76
refractory status epilepticus, 75
sleepiness, 76
diazoxide neonatal hyperinsulinism,
393
pulmonary hypertension, 393
didanosine cytomegalovirus enteritis, 535
Fanconi syndrome, 535
fatigue, 535
ganciclovir, interaction, 535
hyperchloremic metabolic
acidosis, 535
hypophosphatemia, 535
hypouricemia, 535
low-molecular-weight
proteinuria, 535
nephrogenic diabetes
insipidus, 535
normoglycemic glycosuria, 535
933 polydipsia, 535
polyuria, 535
weight loss, 535
diethylcarbamazine abdominal pain, 574
arthralgia, 574
diarrhea, 574
dizziness, 574
drowsiness, 574
fever, 574
headache, 574
human lymphatic filariasis, 574
insomnia, 574
itching, 574
lymph node enlargement, 574
malaise, 574
myalgia, 574
nausea, 574
rash, 574
diethylstilbestrol cryptorchidism, 739
esophageal atresia, 739
glucocorticoid-induced ulcer,
739
hypospadias, 739
impaired spermatogenesis,
739
pre-eclampsia, 739
testicular cancer, 739
thrombosis, 739
tracheo-esophageal fistulas,
739
vaginal clear cell carcinoma,
739
dihydrocodeine, 190–191
abuse, 191
hypogonadotrophic
hypogonadism, 191
and nabilone, 190–191
tiredness and nightmares, 191
dimethyl fumarate abdominal pain and cramps, 295
bloating, 295
bowel cancer, 295
contact dermatitis, 295
diarrhea, 295
flushing, 295
Fumaderm®, 295
malaise, 295
nausea, 295
partial bowel obstruction, 295
dimethylsulfoxide (DMSO) generalized tonic seizure, 894
mydriasis, 895
respiratory arrest, 895
trismus, 895
dipeptidyl peptidase type 4
inhibitors
chemokine CXCL12,
inactivated, 775
diphenhydramine overdose, 307
dipyridamole, 639
disopyramide
aspiration pneumonia, 347
dysphagia with bulbar
paralysis-like symptoms, 347
myasthenic crisis, 347
disulfiram dexamfetamine, 895
hypotension, 895
ischemic
electrocardiographic
changes, 895
methylphenidate, interaction,
13–14
diuretics wet beriberi, 401
dobutamine dysrhythmias, 285
dofetilide cardiac dysrhythmias, 347
overdose, 348
dolasetron hypotension, 666
QT interval prolongation, 666
domperidone amenorrhea, 665
anxiety, 665
breast tenderness/
enlargement, 665
cardiac dysrhythmias, 665
diarrhea, 665
dopamine DA2 receptors,
inhibition, 666
dry mouth, 665
galactorrhea, 665
gynecomastia, 665
headaches, 665
menstrual irregularities, 665
monoamine oxidase,
inhibition, 666
prolactin, changes in, 665
donepezil Alzheimer’s disease, use in, 19
atracurium, interaction, 19
intraoperative floppy-iris
syndrome (IFIS), 19
dopamine dry gangrene, 283
septicemia, 283
toxic shock, 283
doripenem nosocomial pneumonia, 448
dorzolamide bad taste, mouth, 404
choroidal detachment, 404
diarrhea, 404
dysosmia, 405
erythema multiforme, 404
eye irritation, 404
glucocorticoids, 405
gout, 404
headache, 404
Index of drugs
934 hypotony, 404
lacrimal duct system
obstruction, 404
nausea, 404
systemic contact dermatitis,
404
dothiepin, see antidepressants
doxazosin
intra-operative floppy iris
syndrome (IFIS), 392
doxycycline abdominal pain, 451
benign intracranial
hypertension, 452
bloody diarrhea, 452
blurred vision, 452
Brugia malayi infection, 451
diarrhea, 451
dizziness, 451
drowsiness, 451
headache, 451
insomnia, 451
itching, 451
Loa loa co-infections, 452
malaise, 451
myalgia, 451
nausea, 451
occasional nausea, 452
pseudotumor cerebri, 452
rash, 451
worsening headache, 452
doxylamine drowsiness, 307
giddiness, 307
rhabdomyolysis, 307
dutasteride gynecomastia, 755
E Ecbalium elaterium (Cucurbitaceae, squirting cucumber) nasal mucosal necrosis, 885
severe uvular edema, 885
echinocandins, 507
ecstasy and neurocognition,
63–67
amfetamine, 63
1-benzylpiperazine,
contamination, 68
cannabis, interaction, 67–68
cognitive function, 65
death, 68
depressive symptoms, 67
hyperthermia, 67
long-lasting neurotoxic
effects, 65
3,4-methylenedioxy-N,N dimethylamfetamine (MDDM), contamination, 68 neurocognitive deficits, 63
serotonin deficits, 63, 68
suicide, 67
edetic acid chronic kidney disease, 431
dystonia, 431
liver injury, 431
polycythemia, 431
pseudothrombocytopenia, 431
renal insufficiency, 431
efalizumab arthralgia/arthritis, 688
aseptic meningitis, 688
chronic plaque psoriasis, 688
DRESS, 689
eruptive whitish papules, 689
fever, 689
guttate psoriasis, 688
headache, 688
hypertrichosis, 688
lupus-like syndrome, 689
lymphoproliferative
disorders, 688
multiple eruptive
dermatofibromata, 688
pityriasis rubra pilaris, 688
plantar exfoliation and
desquamation, 688
pruritus, 688
psoriasis, 688
visceral leishmaniasis, 689
efavirenz antimalarial drugs, interaction, 538
anxiety, 538
between-the-eyes effects, 538
gynecomastia, 538
HIV-1 infection, 538
insomnia, 538
nervousness, 538
neuropsychiatric symptoms,
537
nightmares, 538
psychosis, 538
renal calculus, 538
viral suppression, 538
voriconazole, interaction, 538
eflornithine bacterial infections, 526
diarrhea, 526
fever, 526
seizures, 526
enalapril see also angiotensin
converting enzyme
inhibitors
DRESS, 385
interstitial granulomatous
drug eruption (IGDE), 384
endoperoxides, 525
enoxaparin, see heparins
entecavir
adefovir, interaction, 531
dysmenorrhea, 531
headache, 531
ephedra and ephedrine overdose, 282
epidural anesthesia Horner’s syndrome, 263
trigeminal nerve palsy, 263
epinephrine, see adrenaline
equine estrogens, 740
ertapenem
renal insufficiency, 448
seizures, 448
erythromycin auditory acuity, loss, 474
black hairy tongue, 474
hallucinations, 474
hepatotoxicity, 474
hypertrophic pyloric stenosis,
474
IgE-dependent
hypersensitivity, 474
tinnitus, 474
tremors, 474
erythropoietin and derivatives aggravated hypertension, 598
anemia, 598
arteriovenous access
thrombosis, 599
blood clots, 599
headache, 598
heart failure, 599
hematemesis, 598
hypertension, 598
hyporesponsiveness, 599
mean arterial pressure,
increased, 599
non-fatal heart attacks, 599
number of deaths, increased,
599
pure red cell aplasia, 598
renovascular abnormalities,
598
retinopathy of prematurity, 598
strokes, 599
thrombosis, 598
vascular stenosis with intimal
hyperplasia, 599
estrogens, 947
acute pancreatitis, 737
gastro-esophageal reflux, 736
giant splenic hemangioma, 738
migraine, 736
mucinous
cystadenocarcinoma of
pancreas, 738
multiple hepatic
hemangiomas, 738
systemic lupus
erythematosus, 737
venous thromboembolism, 736
etanercept acute interstitial nephritis, 682
AsT and AlT, rise in, 682
bowel obstruction, 683
cold agglutinin disease, 683
Index of drugs Crohn’s disease, 682
cutaneous pseudolymphoma,
682
demyelinating disorders, 681
hepatitis, aggravated, 682
hepatomegaly, 682
hypoglycemia, 682
interstitial granulomatous
dermatitis, 682
interstitial lung disease, 681
lichen planopilaris, 682
minimal change nephrotic
syndrome, 682
multiple sclerosis, 682
ophthalmic manifestations of
demyelination, 682
pericarditis, 683
Pneumocystis jiroveci pneumonia, 683
posterior
leukoencephalopathy
syndrome, 682
progressive multifocal leukoencephalopathy, 682
pulmonary nodulosis, 681
recurrent varicella, 683
right upper quadrant
tenderness, 682
sarcoid-like granulomata, 683
sarcoidosis, 683
spinal chord and cerebral
cortex, demyelination, 682
squamous cell carcinoma on
penis, 682
Tinea versicolor, 682
tuberculous uveitis, 683
visceral leishmaniasis, 683
ethambutol, 561
daytime somnolence, 562
delusions of grandeur, 562
distractability, 562
episodic obsessive behavior,
562
flame-shaped hemorrhages,
561
forgetfulness, 562
impulsive spending, 562
loss of vision, 561
macular edema, 561
Mycobacterium avium intracellulare complex pneumonia, 561, 562
optic neuropathy, 561
psychosis, 562
retinal ganglion cell axonal
swelling, 562
retinal pigment epithelial
changes, 561
retinopathy, 561
severe insomnia, 562
etherified starches acute renal failure, 595
kidney failure, 595
935 etomidate complete atrioventricular blockade, 248
hyperglycemia, 250
myoclonus, 248
schizoaffective disorder, 249
seizures, 248
transient myoclonus, 248
treatment refractory
depression, 248
etoricoxib, 233
everolimus
bronchiolitis obliterans, 708
cough, 708
dyspnea, 708
herpes zoster, 708
low-grade fever, 708
ocular viral infection, 708
pleuritic chest pain, 708
pneumonia, 708
exemestane arthralgia, 744
fatigue, 744
fractures, 744
hot flushes, 744
symmetrical active arthritis,
745
exenatide acute pancreatitis, 776
hypoglycemia, 776
nausea and vomiting, 776
type 2 diabetes mellitus, 776
ezetimibe aggressive reactions, 803
confusion, 803
depression, 803
hyperbilirubinemia, 803
hyperlipidemia, 803
memory loss, 803
myalgia, 804
myopathy, 803
pancreatitis, 803
tendinopathy, 804
thrombocytopenia, 803
F facial dimorphism, and
unilateral radius aplasia, 144
factor IX (coagulation proteins)
anaphylaxis, 596
irreversible nephritic
syndrome, 596
factor VIIa (coagulation proteins) thrombosis, 596
febuxostat abdominal pain, 235
cardiac disorders, 235
diarrhea, 235
dizziness, 235
headache, 235
liver function test
abnormalities, 235
nausea, 235
vomiting, 235
fenfluramines behavioral disturbances, 8
neurotoxicity, 7–8
pulmonary arterial
hypertension, 7, 17
valvular disease, 7, 17
fenofibrate encystment of Giardia lamblia, impairment, 806
gynecomastia, 806
pancreatitis, 805
pulmonary embolism, 805
renal impairment, 806
rhabdomyolysis, 806
venous thromboembolism, 806
fentanyl, 191–192
abuse, 192
apnea, 191–192
with bupivacaine, 191
constipation, 191
dizziness, 191
epidural analgesia, 191
hypertension and
hypotension, 191
low-dose intravenous
ketamine, 192
midazolam, 191
nausea, 191
osteoarthritis, 191
pruritus, 191
rashes, 191
reflex cough, 192
restlessness, 192
sedation, 191
serotonin syndrome, 192
somnolence, 191
vomiting, 191
fetotoxicity, 192–193 antifungal azoles, interaction, 192–193
Horner’s syndrome, 192
impaired infant feeding, 192
irritation/erythema/pain/oral
ulcers, 192
loss of consciousness, 192
midazolam, interaction, 193
nausea and dizziness, 192
overdose, 192
fibrates myopathy, 805
finasteride intraoperative floppy iris
syndrome (IFIS), 755
fish oils burping, 806
diarrhea, 806
difficulty in swallowing the
capsules, 806
dizziness, 806
heartburn/reflux, 806
nausea, 806
Index of drugs
936 omega-3 fatty acid ethyl esters, interaction, 807
tiredness, 806
unpleasant breath/bad taste,
806
flecainide cardiac dysrhythmias, 348
overdose, 348
paranoid psychosis and
myoclonus, 348
flucloxacillin acute interstitial nephritis, 451
hypersensitivity reaction, 451
liver damage, 451
warfarin, interaction, 451
fluconazole adrenal insufficiency, 502
aneugenic effect, 503
cardiac dysrhythmias, 502
clastogenic effect, 503
congenital heart defect, 503
conjugated
hyperbilirubinemia, 503
dysmorphic facial features, 503
electrocardiographic
abnormalities, 502
hepatotoxicity, 503–504
invasive candidiasis, 502
membranous nephropathy,
503
multiple synostoses, 503
QT interval prolongation, 502
skeletal anomalies, 503
flucytosine cardiomyopathy, 497
fluorescein dizziness, 895
headache, 895
malaise, 895
nausea and vomiting, 895
fluoroquinolones allergic reactions, 465
anaphylaxis, 465
arthropathy, 465
bullous fixed drug eruption,
466
chemosis, 465
clozapine, interaction, 466
coagulopathy, 465
conjunctival hyperemia, 465
diarrhea, 464, 465
dysglycemia, 464
dysrhythmias, 464
hepatic damage, 465
liver damage, 465–466
local irritation, 465
methadone, interaction, 466
nausea, 464
ocular toxicity, 465
palatal tremor, 465
phototoxicity, 464
progressive acute
polymorphic psychosis, 465
QT interval prolongation,
464
reversible corneal
precipitation, 465
slurring of speech, 465
superficial punctuate
keratitis, 465
tendinopathy, 464, 465
toxic optic neuropathy, 465
transaminases, 465
vasculitis, 466
fluorouracil hemolytic–uremic syndrome,
835
stomatitis, 835
fluoxetine, see antidepressants
flutamide
photosensitive dermatitis, 755
folic acid (vitamin B) anaphylactic reactions, 608
folk remedies lead poisoning, 883
fondaparinux anti-Xa activity, increased, 636
spontaneous retroperitoneal
bleeding, 636
formaldehyde acute proctitis, 438
anorectal cancer, 438
asthma, 437, 438
auscultatory crackles, 438
breathing difficulty, 437
bronchospasm, 438
chemosensory effect, 437
cough, 437, 438
dyspnea, 438
eye irritation, 437
fever, 438
hemorrhagic radiation-
induced proctitis, 438
impaired lung function, 437
incontinence, worsening,
438
irritating effect, 437
leukocytosis, 438
massive hemoptysis, 438
nasal irritation, 437
nose/throat, burning, 437
ocular irritation, 437
pneumonitis, 438
pollen allergy, 437
radiation-induced strictures,
worsening, 438
sensory irritation, 437
severe pain, 438
wheezing, 438
formoterol confusional states, 317
insomnia, 317
mean heart rate, rise in, 316
serum potassium, reduction
in, 316
tremor, 316, 317
fosamprenavir gastrointestinal disturbances,
541
rashes, 541
fosinopril adverse reactions,
management of, 385
cholestatic jaundice, 385
G gabapentin, 131–134
alcohol withdrawal, 133
and amitriptyline, 131
amnesia, 132
ataxia, 132
chorea, 133
chronic masticatory myalgia,
132
congenital nystagmus, 133
constipation, 131
cough, 132
diplopia, 132
dizziness, 131, 132, 133
drowsiness, 131, 132
dry mouth, 131, 132
dysarthria, 132
erythema, 132
fatigue, 131, 132
fibromyalgia, 132
forgetfulness and shaking,
133
headaches, 132, 133
high-altitude headache, 133
impairment of memory and
cognition, 132
lethargy, 133
leukopenia, 133
light-headedness, 132
malaise and tiredness, 132
myoclonic status, 133
myopathy, 133
myotonia and dystonia, 134
nausea, 131, 132, 133
neuropathic pain, 131–132
nystagmus, 131
post-operative pain and
morphine consumption, 132
pruritus, 132
sedation, 132
severe itching, 131
sexual dysfunction, 131
shortness of breath, 131
sleeplessness or light headedness, 133
somnolence, 132
spasticity and pain, increased,
131
tiredness, 133
transient ataxia, 131
vertigo, 132
vomiting, 132
weight gain, 132
withdrawal, 134
Index of drugs gadolinium salts acute renal failure, 852
contrast-induced
nephropathy, 851
encephalopathy, 851
nephrogenic fibrosing
dermopathy, 851
systemic fibrosis, 852–855
gallium, 415
gamma-hydroxybutyric acid
(GHB), 68–69
acute poisoning, 69
agitation, 68
alcoholism, 68
amnesia, 68
behavioral disturbances, 69
Cushing’s syndrome, 69
death, 68
delayed speech development,
69
depression, 68
dizziness, 68
epileptic seizures, 69
euphoria, 68, 69
insomnia, 68
intoxication, 68
libido, increased, 68
narcolepsy, 68
nausea, 68
pleasurable effects, 69
psychomotor retardation, 69
respiratory depressed, 68
sociability, 68
suicidal intent, 69
unconsciousness, 68
gatifloxacin arthralgia, 466
corneal perforation, 466
diarrhea, 466
dysglycemia, 466
electrocardiographic
changes, 466
generalized status
epilepticus, 466
hyperglycemia, 467
hypoglycemia, 467
liver enzymes, increased, 466
psychosis, 466
rhabdomyolysis, 467
schizoaffective disorders, 466
vomiting, 466
gemfibrozil, 806
gemtuzumab ozogamicin
fatal hypersensitivity reaction, 690
hemorrhagic cystitis, 689, 690
sinusoidal obstructive
syndrome, 689
gentamicin acute renal insufficiency, 462
glomerular nephrotoxicity,
462
hypocalcemia, 462
937 hypotension, 462
loss of consciousness, 462
nephrotoxicity, 462
neurotoxicity, 461
ototoxicity, 462
retinal toxicity, 461
tubular necrosis, 462
urticaria, 462
Ginkgo biloba
(Ginkgoacaeae), 372
glibenclamide clarithromycin, interaction, 778
grapefruit juice, interaction,
778
high birth weight, 778
macrosomia, 778
neonatal hypoglycemia, 778
octreotide, action, 778
gliclazide, 778
glimepiride
leucocyctoclastic vasculitis, 778
glomerular filtration rate
(GFR), 530
glucagon
colicky abdominal pain, 769
mild nausea, 769
glucocorticosteroids adrenal suppression, 871
localized eyelid necrosis, 871
transient reductions in linear
growth, 871
glutaral (glutaraldehyde) headache, 439
itchy eyes, 439
glyburide, see glibenclamide
glyceryl trinitrate
(nitroglycerin), 366
glycopeptides
agranulocytosis, 469
anaphylaxis, 469
DRESS, 469
erythroderma, 469
IgA linear dermatosis, 469
maculopapular rash, 469
nephrotoxicity, 469
red man syndrome, 469
renal function, 469
toxic epidermal necrolysis, 469
vasculitis, 469
glycoprotein IIb–IIIa inhibitors alveolar hemorrhage, 639
angioedema, 639
bradycardia, 639
chest pain, 639
gastrointestinal bleeding, 638
hypotension, 639
pulmonary hemorrhage, 638
thrombocytopenia, 638
ventricular septum, rupture,
638
gold salts paucilesional pemphigus
vulgaris, 416
gonadotrophins gestational hypertension, 735
invasive ovarian cancer, 736
malignant melanoma, 735
pre-eclampsia, 735
gonadotropins (gonadorelin, GnRH and analogues) abdominal pain, 789
acute right iliac fossa pain,
790
bloating, 789
chronic intestinal pseudo-
obstruction, 789
cutaneous lupus
erythematosus, 790
cutaneous vasculitis, 790
fatal myocardial infarction,
789
hypermenorrhea, 790
necrosis in uterine fibroids, 790
osteoporosis, 790
polycystic ovary syndrome,
790
rapid weight gain, 789
shortness of breath, 789
vaginal bleeding, 790
vomiting, 789
granulocyte colony-stimulating factor (G-CSF) acute myeloid leukemia, 675
anaphylaxis, 676
bilateral keratitis, 675
decalcified ribs, 675
epithelial defects, 675
florid histiocytic
hemophagocytosis, 676
myelodysplastic syndrome,
675
osteopenia, 675
peripheral corneal infiltrates,
675
ruptured spleen, 675
thrombocytopenia, 675
vertebral height, reduced,
675
growth hormone receptor antagonists erythema, 794
headache, 794
lipohypertrophy, 794
liver enzymes, raised, 794
liver function abnormalities,
794
pituitary volume, increased,
794
swelling, 794
H hair dyes non-Hodgkin’s lymphoma, 296
halogenated vapors postoperative nausea and
vomiting (PONV), 243
Index of drugs
938 henna hemolysis, 296
painful cutaneous
granulomata, 296
pallor and jaundice, 296
heparins anti-PF4/heparin antibodies,
626
antithrombin concentrations,
reduced, 630
arterial thrombosis, 626
bemiparin, 629
Burkholderia cepacia, contamination, 630
delayed-type
hypersensitivity, 629
Enterobacter spp,
contamination, 630
high platelet counts, 628
hyperkalemia, 629
hypertriglyceridemia, 629
lipoprotein lipase deficiency,
629
non-IgE-mediated
anaphylactic reactions, 631
non-immunological response,
type I, 626
osteoporosis, 629
osteoprotegerin, 629
platelet GPIIIa,
polymorphism, 626
postoperative infections, 627
renal failure, 627
renal insufficiency, 630
septicemia, 630
thrombin inhibitors, 628
thrombocytopenia, 618, 626
hepatitis B surface antigen
(HBsAg), 533, 557
herpes zoster vaccine
erythema, 586
injection-site rashes, 586
morbidity, 585
pain and discomfort, 585, 586
pruritus, 586
swelling, 586
tenderness, 586
herpes zoster vaccine (HZV),
584
high-density lipoprotein
(HDL), 750
highly active antiretroviral
therapy (HAART), 532, 533,
574
HMG-CoA reductase inhibitors agitation, 808
anxiety, 807
behavioral changes, 807
bitter taste, 808
ciclosporin, 812
clarithromycin, interaction, 813
clopidogrel, 812
colchicine, interaction, 813
confusion, 808
dermatomyositis/
polymyositis, 810, 811
dry mouth, 808
dyspnea, 808
efalizumab, 813
eosinophilic fasciitis, 808
erythromycin, interaction, 813
fluconazole, interaction, 812
focal myositis, 808
fusidic acid, interaction, 813
genetic myopathy, 810
hallucinations, 808
insomnia, 808
interstitial pneumonitis, 807
itchiness, 808
lopinavir, interaction, 813
lupus-like syndrome, 811
macular degeneration, 807
McArdle’s syndrome, 808
MELAS, 808
mitochondrial
encephalomyopathy, 808
muscle weakness, 809
myalgia, 813
nasal polyps, 807
painful left knee, 810
paranoia, 807
peripheral polyneuropathies,
807
pleural effusions, 807
polymyositis, 811
rhabdomyolysis, 808
risperidone, interaction, 814
ritonavir, interaction, 813
silymarin, interaction, 814
somnolence, 808
subacute cutaneous lupus,
811
tendinitis/tendon rupture, 810
tendinopathy, 810
testicular pain, 810
warfarin, interaction, 814
hormonal contraceptives arterial thromboembolism, 741
blurred vision, 742
cerebral venous thrombosis,
742
hyperkalemia, 741
lichen sclerosus, 741
myocardial infarction, 741
papilledema, 742
progressive headache, 742
pseudocyesis, 742
retinal central artery
occlusion, 741
retinal vein thrombosis, 742
venous thromboembolism, 741
vomiting, 742
vulvar vestibulitis syndrome,
742
5-HT3 receptor antagonists constipation, 666
fatigue, 666
headache, 666
human herpesvirus-6 (HHV-6),
469
hydralazine drug-induced lupus-like
syndrome, 393
impaired B lymphocyte
tolerance, 393
hydrochlorothiazide insulin sensitivity, reduced,
407
retinal phototoxicity, 406
hydromorphone constipation, 193
dizziness, 193
headache, 193
hypogonadotrophic
hypogonadism, 193
nausea, 193
pruritus, 193
somnolence, 193
vomiting, 193
hydrotalcite famotidine, comparison, 665
I
idraparinux intracranial hemorrhage, 636
iloprost bilateral hearing loss, 729
dizziness, 729
tinnitus, 729
immunoglobulins acute renal failure, 595, 596
acute stroke, 596
anaphylactic reactions, 595
arterial thrombosis, 595
aseptic meningitis, 595
chills, 595
Creutzfeldt-Jakob disease, 596
deep venous thrombosis, 595
fatigue, 595
fever, 595
flushing, 595
Guillain–Barré syndrome, 596
headache, 595
hyperpigmentation, 595
hypotension, 595
low back pain, 595
myalgia, 595
nausea, 595
pain at injection site, 595
thrombotic complications, 595
immunoglobulin G (IgG), 582
immunoglobulin M (IgM), 582
immunomodulators, topical, 297
interdigitating dendritic cell
tumor, 297
incretin mimetics nausea, 775
Index of drugs indacaterol anxiety, 318
cough, 318
erythema, 318
headache, 318
insomnia, 318
nasopharyngitis, 317
nausea, 318
palpitation, 318
respiratory/thoracic/
mediastinal disorders, 318
tachycardia, 318
vertigo, 318
indapamide Brugada syndrome, 407
hypokalemia, 408
hyponatremia, 408
photo-onycholysis, 407
primary
hyperparathyroidism, 407
QT interval prolongation, 407
indinavir alopecia, 541
flank pain, 541
hematuria, 541
hepatotoxicity, 542
hyperbilirubinemia, 541
ingrowing toenails, 541
nausea, 541
nephrolithiasis, 541
paronychia, 541
renal impairment, 541
straight hair, curling, 541
vomiting, 541
indocyanine green macular function, changes in, 896
potential retinal toxicity, 896
visual field defects, 896
infiltration anesthesia adverse reactions,
management of, 264
fatalities, 264
infliximab acne, 684
acute ischemia, 685
alopecia areata, 684
anxiety, 684
atopic dermatitis, 684
autoimmune hepatitis, 684
bacterial pneumonia, 683
chills, 684
cutaneous mucormycosis, 684
cytomegalovirus colitis, 686
dermatitis herpetiformis, 684
dyspnea, 684
endophthalmitis, 684
exanthematous pustulosis,
overlap, 684
flushing, 684
halo nevi, 684
headache, 684
heart block, complete, 684
939 hemorrhagic papules, 685
hepatitis, 684
hypotension, 684
interstitial pneumonitis, 683
joint pain, 685
liver failure, 684
lupus-like syndrome, 684
lymphoma, 683
lymphoproliferative disorder,
684
malaise, 685
nausea, 685
neuropathy, 683
oral lichenoid reaction, 684
palmoplantar pustulosis, 684
pleuritic chest pain, 684
Pneumocystis jiroveci pneumonia, 683
pustular psoriasis, 684
pustular purpuric lesions, 685
sarcoidosis, 685
suberythrodermic psoriasis,
684
tachycardia, 685
throat edema, 684
toxic epidermal necrolysis, 684
tuberculosis, 683
vasculitis, 685
weakness, 685
influenza vaccine autoimmune disease, 581
juvenile idiopathic arthritis,
581
insulin allergic reactions, 770
cough, 772
erythematous subcutaneous
nodules, 771
forced expiratory volume,
reduced 772
hepatic steatosis, 771
hypoglycemia, 769
ketoacidosis, 771
lipoatrophy, 770
lipohypertrophy, 771
neonatal hypoglycemia
babies, 771
pruritus and rash, 770
interferon alfa autoimmune hepatitis, 676
autoimmune thyroiditis, 676
cotton wool spots in optic
fundi, 676
cryptosporidial enterocolitis,
676
depression, 676
fall in hemoglobin, 676
fatigue, 676
psychosis, 676
systemic lupus
erythematosus, 676
thyroid disease, 676
interleukin-4 (IL-4)
abnormal liver, 677
edema, 677
liver function tests, abnormal,
677
malaise, 677
interleukin-6 (IL-6), 582
interpleural anesthesia
bradycardia and asystole, 264
symptomatic bradycardia, 265
transverse rectus abdominis
myocutaneous (TRAM),
264
intravenous regional anesthesia erythema and edema, 265
prilocaine, 265
intravitreal injection endophthalmitis, 874
iodine and iodides antithyroid microsomal
antibodies, increased, 764
hyperthyroidism, increased,
764
iodophors, 440
irbesartan
karyotypic Turner’s
syndrome, 387
treatment-resistant anemia,
386
iron chelators acute cerebellar syndrome, 426
agranulocytosis, 426
arthralgia, 426
aseptic meningitis, 426
gastrointestinal symptoms,
426
neutropenia, 426
pain and swelling of joints, 426
taste disturbances, 426
transient cerebellar
syndrome, 426
iron salts, 417
calcification, soft tissues, 417
chest pain, 417
diarrhea, 417
headache, 417
hypotension, 417
nausea, 417
pruritus, 417
swelling, 417
wheezing, 417
isoflurane withdrawal, 244
isoniazid latent tuberculosis, 562
methotrexate, interaction, 562
nervous system toxicity, 562
rheumatoid arthritis, 562
seizures, 562
TNF alpha inhibitors,
interaction, 563
tuberculosis, 562
Index of drugs
940 isotretinoin abnormal meibomian gland secretion, 299
agranulocytosis, 300
blepharoconjunctivitis, 299
blurred vision, 299
bouts of palpitation, 298
cardiac dysrhythmias, 298
cerebellar demyelination,
299
cerebral ischemia, 299
corneal opacities, 299
intracranial pressure, raised,
299
keratitis, 299
menstrual irregularities, 301
myopia, 299–300
night blindness, 299
night vision and glare,
reduced, 299
photophobia, 299
pleuritic chest pain, 300
pregnancy rate, 301
retinal function, reduced, 299
sacroiliitis, 300
sensorimotor demyelinating
polyneuropathy, 300
sensory polyneuropathy, 299
sicca syndrome, 299
tolerance to contact lenses,
reduced, 299
itraconazole fixed drug eruption, 504
gastrointestinal, 504
hemolysis, 504
palpitation, 504
raised transaminases, 504
ventricular extra beats, 504
ivermectin acute generalized
exanthematous pustulosis
(AGEP) 1, 575
antibiotic-associated colitis, 575
bloody diarrhea, 575
chronic strongyloidiasis, 575
endobacteria depletion, 575
female worm sterilization, 575
Loa loa co-infection, 575
onchocerciasis, 575
K ketamine airway malalignments, 250
apnea, 250, 251
atrial fibrillation, 250
chronic ulcerative cystitis, 252
dysuria, 252
emergence reactions, 250
hallucinations, 251
hypoxia, 250
nausea and vomiting, 251
neuropsychiatric effects, 251
painful hematuria, 252
post-micturition pain, 252
respiratory depression, 251
urgency, 252
ketolides chronic bronchitis, 471
chronic sinusitis, 471
community-acquired
pneumonia, 471
hepatotoxicity, 471
khat aggravation of psychotic disorders, 69
anorexia, 69
blood pressure and heart
rate, increased, 69
constipation, 69
depression, 69
gastroesophageal reflux, 69
insomnia, 69
liver toxicity, 69
mental illness, 69
mouth/esophagus carcinoma,
increased risk of, 69
stomatitis, 69
L labetalol depression and alcoholism,
364
overdose, 364
lamivudine anorexia, 531
arthralgia, 531
diarrhea, 531
eye redness, 531
flu-like symptoms, 531
loss of hair, 531
nausea, 531
vomiting, 531
weight loss, 531
lamotrigine, 134–137 adverse reactions, management, 137
and amitriptyline, 134
aripiprazole, interaction, 137
aseptic meningitis, 135
ataxia, 137
ballismus, 135
birth defects, 134
bone mineral densities, 136
clozapine, 134
disorientation, 137
dizziness, 137
headache, 137
hemophagocytic syndrome,
135
hepatitis, 136
lethargy, 137
or lithium, 134
mouth ulcers, 135–136
myoclonus, 135
overdose, 137
paranoid–hallucinatory
(schizophrenia-like)
symptoms, 135
seizures, 137
status epilepticus, 137
stupor, 137
sudden unexpected death in
epilepsy (SUDEP), 136
suicide attempt, 135
and sustained-release
carbamazepine, 134
tonic–clonic seizures, 136
torsade de pointes, 136
urticarial/maculopapular
eruptions, 135
lanthanum carbonate, 417
latanoprost
allergic reactions, 871
burning and stinging, 871
choroidal detachment, 729,
872
conjunctival hyperemia, 871
fatigue, 871
foreign body sensation, 871
headache, 871
iris pigmentation, increased,
730, 872
macular edema, 873
melanin granules size,
increased, 872
nausea, 871
periocular skin,
hyperpigmentation, 873
late-onset renal failure from
angiotensin blockade
(LORFFAB), 380
Lawsone (2-hydroxy-1,4 naphthoquinone), see henna leflunomide cavitating pneumonia, 709
cutaneous lupus
erythematosus, 710
Cytomegalovirus antigenemia, increased,
710
DNA synthesis, reduced,
710
interstitial lung disease, 709
pancytopenia, 709
peripheral neuropathy, 709
prunosus skin rash, 710
pulmonary nodulosis, 709
renal tubular acidosis, 709
skin necrosis, 710
lepirudin anaphylactic reaction, 633
levacetylmethadol (levo-a acetylmethadol, LAAM), 193–196 antiretroviral drugs, interaction, 196
CYP3A inhibitors, 195–196
heroin addicts, 195
Index of drugs human ether-a-go-go-related gene (HERG) channels, 194–195 ketoconazole, interaction, 196
methadone and
buprenorphine, 194
naloxone, 195
opioid addicts, 195
opioid withdrawal, 193
torsade de pointes, 194
levamisole steroid-dependent nephritis,
575
levetiracetam, 127, 137–141
add-on therapy, 137–138
aggression, 138
agitation/anxiety/
sleeplessness, 140
Alzheimer’s disease and newonset epileptic seizures, 138–139 anger/hostility and mood,
effects on, 140
antiepileptic drugs,
interaction, 141
anxiousness, 139
asymptomatic hyponatremia,
140
blurred vision, 140
ciclosporin, interaction, 141
cognitive disturbances, 138
depression, 138
diastolic blood pressure,
reduced, 140
dizziness, 137, 138, 140
drowsiness, 138
dysuria, 140
ear pain, 140
emotional lability, 138
encephalopathy, 138–139,
139–140
epilepsy, 139
fatigue, 137, 138, 139
gastrointestinal disorders, 138
hallucinations, 140
headache, 137–139
hyperactivity, 138
hyperkinesia, 139
hyponatremia, 140
idiopathic generalized
epilepsy, 139
imbalance, 141
insomnia, 139
interstitial pneumonitis, 140
irritability, 138–139, 141
light-headedness, 141
loss of appetite, 138
mood disorders, 138
myoclonic seizures, 139
nervousness, 138
non-convulsive status
epilepticus, 138
overdose, 141
941 phenytoin, 138
psychiatric disorders, 139
refractory epilepsies, 138
sadness, 139
school participation, reduced,
139
seizure remission, 138
sleep disturbances, 138
sleepiness, 138
somnolence, 137, 138, 139
status gelasticus, 140
thrombocytopenia, 140
tics, 139
tiredness, 138, 139, 141
tonic–clonic seizures, 139
treatment-resistant partial
seizures, 137–138
verbal aggression, 139
weight loss, 140
withdrawal, effects, 138
levocetirizine, 308
levodopa
abnormal involuntary eye movements, 285
compulsive singing, 288
daytime tiredness, 288
dizziness, 286
dopamine dysregulation
syndrome, 288
dyskinesia, 285
fatigue, 286
fibrotic heart valve disease,
286
hypersexuality, 288
hypotension, 287
nausea, 286
orthostatic hypotension, 286,
287
Parkinson’s disease, 286, 287,
288
peripheral edema, 286
pleuropulmonary fibrosis, 286
and pramipexole, 285, 288
ropinirole, 285
sleep attacks, 286
somnolence, 286
valvular regurgitation, 286
vomiting, 286
levofloxacin abdominal pain, 468
Achilles tendinopathy and
rupture, 467
benign cranial hypertension,
467
constipation, 468
convulsions, 467
diarrhea, 468
dizziness, 468
dyspepsia, 468
headache, 468
hemopericardium, 468
hypoglycemia, 467
insomnia, 468
nausea, 468
psychoses, 467
radiation-recall dermatitis, 467
retroperitoneal hematoma,
468
thrombocytopenia, 467
tubulointerstitial nephritis,
467
vomiting, 468
lidocaine
allergic contact dermatitis, 267
methemoglobinemia, 267
overdose, 268
seizures, 267
type I hypersensitivity, 267
lincosamides, 472
liposomal amphotericin B
(LAMB), 493
abnormal liver function tests,
495
acute leukemia, 496
candidemia, 495
cardiomyopathy, 496
chest pain, 495
dysrhythmias, 495
hypokalemia, 495, 496
hypotension, 495
invasive candidiasis, 495
nephrotoxicity, 495, 496
pain, 495
raised serum creatinine, 495
lisinopril
see also angiotensin
converting enzyme
inhibitors
erythroderma, 385
hypotension, 385
overdose, 385
pancreatitis, 385
lithium
acute mania, 41
amisulpride, interaction, 47
angiotensin-converting
enzyme (ACE) inhibitors,
47
angiotensin receptor
antagonists, 47
antioxidant effect, 42
antisuicidal effect, 43
basal ganglia glutamate/
glutamine, reduced, 42
bipolar disorder, 42, 43
bone fracture, 44
brain-derived neurotrophic
factor (BDNF), 42
Brugada-type
electrocardiographic
changes, 43
catatonic-like state, 43
cerebellar dysfunction, 44
cognitive dysfunction, 44
concentrations, 48
dementia, 42
Index of drugs
942 diabetes insipidus, 45
encephalopathy, 43
hippocampal volume,
increased, 41
hypernatremia, 45
hyperparathyroidism, 44
infants, serum
concentrations, 46
metrorrhagia, 46
microcysts, 45
mood disorders, 43
mood relapse, 42
multiglandular disease, 44
negative anion gap, 45
neuroplastic changes, 41
neutrophil leukocytosis, 45
non-convulsive status
epilepticus, 43
plasma antioxidant, reduced,
42
pseudotumor cerebri, 44
psoriasis, 45
renal damage, 45
and risperidone, 47
serotonin syndrome-like
state, 47
sexual dysfunction, 46
teratogens, 46
thyroid, 44
thyroid-stimulating hormone
(TSH), 42
toxicity, 42, 47
tumor necrosis factor-a
(TNF-a), 45–46
vascular endothelial growth
factor (VEGF), 41–42
verbal memory performance,
41
long-acting beta2-adrenoceptor
agonists (LABAs), 314
acute myocardial infarction,
risk of, 315
adrenoceptor agonists vs.
glucocorticoids, 314–315
age related adverse events,
316
arformoterol vs. salmeterol,
314
dizziness, 314
dry mouth, 314
formoterol Turbuhaler®,
effects of, 314
formoterol vs. salbutamol, 314
fracture, risk of, 315
genetic factors, 316
headache, 314, 315
heart rate and palpitation,
maximum, 314
lactic acidosis, 315
salbutamol Diskhaler®,
effects of, 314
tremor, 314
withdrawals, 315
loop diuretics, 408
papuloerythroderma, 408
pseudoporphyria, 409
loratadine dry mouth, 308
headache, 308
insomnia, 308
lorazepam deductive reasoning, 76
sibutramine, interaction, 19
lormetazepam sleepiness, 77
losartan cough, 387
erythema multiforme, 387
Parkinson’s disease, 387
renal insufficiency, 387
Stevens–Johnson syndrome,
387
lynestrenol hepatic adenomatosis, 748
M macrolide antibiotics rhabdomyolysis, 472
magnesium salts bradycardia/atrioventricular block, 418
dizziness, 418
flushing, 418
hypotension, 418
neuromuscular junction
impairment, 418
osteomalacia, 418
tingling, 418
manganese congenital biliary atresia,
418
congenital intrahepatic
portosystemic shunt, 418
hepatic cirrhosis, 418
hypermanganesemia, 418
intrahepatic portosystemic
shunting, 418
patent ductus venosus, 418
primary biliary cirrhosis, 418
mebendazole, see albendazole medroxyprogesterone bone density, reduced, 749
efavirenz, interaction, 749
nelfinavir, interaction, 749
mefloquine bull’s-eye maculopathy, 523
dyspnea, 523
eosinophilic pneumonia, 523
high-grade fever, 523
malaise, 523
normochromic normocytic
anemia, 523
peripheral eosinophilia, 523
productive cough, 523
tachycardia, 523
tachypnea, 523
megestrol acetate adrenal insufficiency, 749
hypogonadism, 749
mortality, 749
melatonin delay puberty, 794
headache, 795
seizure frequency increased,
795
tiredness, 795
vivid dreams, 794
meloxicam, 233–234 memantine Alzheimer’s disease, use in, 20
anorexia, 20
diarrhea, 20
insomnia, 20
nausea, 20
vascular dementia, 20
vomiting, 20
meningococcal vaccine Guillain–Barré syndrome,
580
Menispermum dauricum (Menispermaceae) ataxia, 885
bilateral dysdiadokokinesia,
885
blurred vision, 885
dizziness, 885
dyslalia, 885
general lethargy, 885
horizontal nystagmus, 885
impaired vision in both eyes,
885
impairment of vision, 885
nausea and vomiting, 885
profuse sweating, 885
tongue stiffness, 885
unstable walking, 885
meperidine, see pethidine
mepivacaine, 268
mercurial salts
corneal opacification, 419
unilateral total limbal stem
failure, 419
mercury, 419
metamfetamine, 3
ADHD, 6
arousal, reduced, 5
cardiomyopathy, 4
cardiovascular subjective
effects, 3
chemical burns, 6
cognitive performance
effects, 3
fetotoxicity, 3
frontal executive function,
impairment of, 4
injuries, risk, 6
lethargy, 5
motor neuron disease, 4
nervous system stress, 5
Index of drugs neural substrate dysfunctions, 5
neurobehavioral patterns, 5
overdose, 6
periventricular leukomalacia, 5
physiological stress, 5
PICK1 gene, 6
plasma concentrations, 3
poisoning, acute, 6
psychomotor/performance
effects, 3
sex differences, 6
smoking, 3
metformin abdominal pain, 773
actic acidosis, 774
appetite, reduced, 774
bradycardia, 773
hypoglycemia, severe, 774
lactic acidosis, 773
nausea, 774
rhabdomyolysis, 774
vitamin B12 deficiency, 773
vomiting, 773
methadone, 196–199
aspirin, interaction, 198
cerebellitis, 197
chronic back pain, 197
diazepam, interaction, 198
erectile dysfunction, 197
fatal posterior ischemic
cerebral/cerebellar
changes, 197
heat and pain perception,
abnormal, 197
HIV, 196
horizontal nystagmus, 198
long QT syndrome, 196
neonatal abstinence
syndrome, 198
nevirapine, interaction, 198
pulmonary edema, 197
QT interval prolongation, 196
quetiapine, interaction, 199
remifentanil infusion, 198
torsade de pointes, 196
voriconazole, interaction, 199
withdrawals, 198
methicillin-resistant Staphylococcus aureus (MRSA), 464
methoxyflurane
agitation, 245
blurred vision, 245
dizziness, 244, 245
euphoria, 244, 245
hallucinations, 244
headache, 244
lip paresthesia, 244
nausea, 244
Ramsay sedation scores,
244–245
sore throat, 244
943 methyldopa jaundice, 391
positive direct antiglobulin
test, 391
methylene blue, see methylthioninium chloride methylenedioxymetamfetamine
(MDMA), 61
alveolar rupture, 62
myelopathy, 62
overinflation, 62
pneumomediastinum, 62
psychobiological functions,
61
spontaneous
pneumomediastinum, 62
methylnaltrexone, 211
abdominal pain, 211
body temperature, increased,
211
dizziness, 211
flatulence, 211
nausea, 211
opioid-induced urinary
retention, 211
methylphenidate, 10
abuse, 13
ADHD, use in, 10
anemia, 13
appetite reduced, 11
blood pressure, increased, 11
bruisability, easy, 13
cardiac death, 12
disulfiram, interaction, 13–14
dyskinesia, 12
eosinophilia, 13
epistaxis, 13
genomic damage, 13
gingival bleeding, 13
hematological changes, 13
hepatitis, 13
hypersexuality, 12
immediate-release vs.
modified-release, 10
leukopenia, 13
masturbation, 12
modified-release vs.
atomoxetine, 10–11
overdose, 14
pediatric cases, 14
psychosis, acute, 12
risperidone, interaction, 14
sleep difficulties, 11
thrombocytopenia, 13
weight loss, 11
methylthioninium chloride, 896–897 metoprolol coronary artery disease, 364
overdose, 364
metronidazole abdominal pain, 526
acute pancreatitis, 526
acute reversible cerebellar lesions, 525
ataxia, 526
chest pain, 526
confusion, 526
dysarthria, 526
hematuria, 526
nausea, 526
Parkinson’s disease, 525
QT interval prolongation, 525
tenderness, 526
thrombotic
thrombocytopenic purpura,
526
micafungin candidemia, 510, 511
febrile neutropenia, 510
hematological malignancy,
510
hypokalemia, 510
invasive candidiasis, 511
neutropenia, 511
midazolam agitation, 78
asthma, 78
cardiopulmonary
resuscitation, 78
chronic obstructive
pulmonary disease
(COPD), 78
clonidine, interaction, 77
desaturation, 77–78, 78
diazepam, interaction, 77
excessive secretions, 77–78
hiccups, 77–78
roflumilast, interaction, 78
sedation, 77
vomiting, 78
mifepristone fetal hypoxia, 750
Möbius syndrome, 750
thrombotic
thrombocytopenic purpura,
749
transient ischemia, 750
milrinone, 336–337
minocycline
acne vulgaris, 453
acute eosinophilic
pneumonia, 452
autoimmune adverse effects,
452
autoimmune hepatitis, 453
bilateral ground-glass
opacity, 452
black thyroid syndrome, 454
blue sclerae, 453
chronic autoimmune disease,
453
chronic syndrome, 453
diffuse bilateral slate-grey
pigmentation, 453
DRESS, 453, 454
Index of drugs
944 dry cough, 452
fever, 452
fulminant hepatic failure, 453
hyperpigmentation, 453
hypersensitivity reactions,
452
hyperthyroidism, 454
idiopathic thrombocytopenic
purpura, 453
lactic acidosis, 453
lupus-like syndrome, 454
nail discoloration, 453
papillary thyroid carcinoma,
454
pneumonitis, 452
polyarteritis nodosa, 454
polyarthralgia, 453
polyarthritis, 453
rheumatological symptoms,
453
superficial conjunctival cysts,
453
tender nodules, 454
minoxidil, 393
bouts of palpitation and
dizziness, 297
hypotension and tachycardia,
297
Stevens–Johnson syndrome,
297
mirtazapine agitated, 37
cardiovascular effects, 37
desmethylmirtazapine,
interaction, 37
drowsiness, 37
heart rate and blood
pressure, 37
hepatic enzymes, rise in, 37
hyponatremia, 37
manic phase, 36
obstructive sleep apnea, 36
pancreatitis, 37
pharmacodynamic,
interaction, 37
phenytoin, 36
seizures, 36
tachycardia, 37
mirtazapine, see antidepressants misoprostol acute hemolytic anemia, 730
cardiac arrest, during
pregnancy, 731
eyelash hypertrichosis, 731
gastric and esophageal
necrosis, 731
periocular skin pigmentation,
731
Poland syndrome, 730
redness/discomfort/blurring
of vision, 731
uterine rupture, 730
mitochondrial
encephalomyopathy, lactic
acidosis, and stroke-like
episodes (MELAS), 808
mivacurium cholinesterase activity,
reduced, 274
prolonged postoperative
paralysis, 274
MMR vaccine arthritis, 581
autism spectrum disorders,
581
autoimmune diseases, 581
bleeding, 581
idiopathic thrombocytopenic
purpura, 581
platelet count, reduced, 581
purpura, 581
regressive autism, 581
thrombocytopenia, 581
modafinil hallucinations, 14
monoamine oxidase
inhibitors, interaction, 14
tranylcypromine, interaction,
14
monoamine oxidase inhibitors see also antidepressants
amitriptyline, 32
clozapine, 32
cocaine, 32
myocarditis, 32
monobactams apoptosis, 450
DNA damage, 450
growth arrest, 450
tumor growth, inhibition, 450
montelukast abnormal behavior, 320
headache, 320
hepatitis, 320
lower respiratory tract
infection, 320
nasopharyngitis, 320
otitis media, 320
pharyngitis, 320
pyrexia, 320
sinusitis, 320
somnolence, 320
upper respiratory tract
infections, 320
morphine, 199–201
apnea, 199
bradycardia or tachycardia,
199
buspirone, interaction, 201
catechol O-methyltransferase
(COMT), 200
constipation, 200
downbeat nystagmus, 200
higher transcutaneous carbon
dioxide pressures, 199
hyperalgesia, 200
intramuscular morphine, 201
ketamine, 199
longer duration of
hypercapnia, 199
lower respiratory rates, 199
lumbar plexus blockade, 199
multidrug resistance-1
(MDR-1), 200
multiple myeloma, 201
nausea, 199, 200
opioid-induced respiratory
depression, 199
overdose, 201
oxygen saturation, 199
in preterm infants and elderly
people, 200–201
pruritus, 199
respiratory depression, 199
sedation, 199
sickle cell disease, 201
transdermal fentanyl patches,
200
unconsciousness and
respiratory depression, 199
urinary retention, 199
vomiting, 199, 200
moxifloxacin arthritis, 468
cholestasis, 468
congestive heart failure, 468
diarrhea, 468
dizziness, 468
fever, 468
hypersensitivity, 468
linear immunoglobulin A
bullous dermatitis, 468
mitral valve replacement, 469
nausea, 468
nephrotoxicity, 468
neutropenia, 468
pneumonitis, 468
post-operative
endophthalmitis, 469
QT interval prolongation, 468
raised liver enzyme, 468
tendinitis, 468
vesicobullous eruption, 468
mucolytics cardiac events, 326
gastrointestinal upsets, 326
mycophenolate mofetil alopecia, 710
anorexia, 710
behavioral changes, 710
bilateral microtia, 711
bilateral upper cleft lip, 711
complete cleft palate, 711
constipation, 710
diarrhea, 710, 711
fatigue, 710
gastrointestinal discomfort, 710
gastrointestinal upsets, 711
Index of drugs headaches, 710 hepatic encephalopathy, 711 hyperlipidemia, 711 hypertelorism, 711 joint pains, 710 left ptosis, mild, 711 liver function tests, abnormal, 710
malaise, 710
micrognathia, 711
mouth ulcers, 711
nausea, 710, 711
pancreatitis, 710
pruritus, 710
rashes, 710
recurrent simplex viral
infections, 711 stomach pains, 710 subacute liver failure, 711 vomiting, 711 Mylabris phalerata Pallas (Miloidae, Mylabris) abnormal bleeding, 886 acute hemopoietic disorder, 886
epistaxis, 886
hematuria, 886
palpitation, 886
pancytopenia, 886
shortness of breath, 886
tar-like stools, 886
N nadolol, 364–365 nadroparin, see heparins nalbuphine, 211 nalmefene agitation, 211 anxiety, 211 dizziness, 211 fatigue, 211 hangover, 211 impaired sense of taste, 211 insomnia, 211 malaise, 211 muscle tightness, 211 nausea, 211 nightmares, 211 pancreatitis, 211 psychotropic effects, 211 sweating, 211 vomiting, 211 naltrexone anxiety/irritability, 211 Crohn’s disease, 212 dizziness, 212 headache, 211 hepatomegaly, 212 hypotension, 212 nausea, 212 sedation, 212 self-injurious behavior, 212 sleep disturbances, 212
945 stereotyped movements, 212 vomiting, 212 natalizumab hypersensitivity reactions, 690
melanoma, 690
multiple sclerosis, 690
progressive multifocal
leukoencephalopathy, 690 type III hypersensitivity, 690 nateglinide blood glucose, reduced, 777 diarrhea, 776 fluconazole, interaction, 777 hypoglycemia, 776 malaise, 776 nausea, 776 rifampicin, interaction, 777 nefopam anaphylactic reactions, 212 confusion, 212 fatal convulsions, 212 hallucinations, 212 malaise, 212 nausea, 212 skin reactions, 212 sweating, 212 tachycardia, 212 vomiting, 212 nelfinavir gestational diabetes, 542
paronychia, 542
neomycin contact allergy, 462
crusting, 463
facial erythema, 463
generalized rash, 463
swelling, 463
nevirapine chronic hepatobiliary disorders, 539 cough, 539 DRESS, 539 erythroderma, 539 fever, 539 fluconazole, interaction, 540– 541 gall bladder disease, 539 hepatitis, 541 hepatitis C, 539 hepatotoxicity, 538, 539, 540 HLA-Cw*803, 540 HLA-Cw*805, 540 hypersensitivity, 540 jaundice, 539 liver dysfunction, 539 liver function abnormality, 539 macular rash, 539 nausea, 539 necrotic keratinocytes, 539 non-B-subtype infection, 540 parakeratotic epidermis, 539
perivascular mononuclear cell infiltrate, 539 rashes, 539, 540, 541 sore throat, 539 Stevens–Johnson syndrome, 539 vacuolar degeneration, 539 viral replication, 540 virological failure, 540 vitiligo, 539 vomiting, 539 niacin blurred vision, 816
dizziness, 816
exacerbation of peptic
ulceration, 816 flushing, 815 gastrointestinal symptoms, 816 hepatotoxicity, 816 hypoglycemia, 816 metabolic acidosis, 816 nausea and vomiting, 816 nervous system-related complaints, 816 platelet count and serum phosphorus concentration, reduced, 816 prothrombin time, increased, 816
pruritus, 816
uric acid, increased, 816
nicardipine, 367 nickel, 419 nicorandil anal fissures and ulceration, 366 intestinal ulceration, 365 leg ulcers, 366 peristomal ulceration, 366 nicotine, 897 nimesulide, 233 nitrofurantoin acute pneumonitis, 476 eosinophilic pneumonitis, 476 paresthesia, 476 pulmonary fibrosis, 476 weakness, 476 nitroglycerin, see glyceryl trinitrate nitrous oxide hyperhomocysteinemia,
247–248
myeloneuropathy, 247
non-nucleoside reverse transcriptase inhibitor (NNRTI), 534 non-prescription cough and cold medicines abdominal pain, 326
nausea, 326
urticaria, 326
Vicks Kingo, 326
vomiting, 326
Index of drugs
946 noradrenaline
(norepinephrine), 282
nortriptyline, see
antidepressants
nucleoside reverse transcriptase
inhibitors (NRTI), 532
O obstetric anesthesia hypotonia, 265
pupillary mydriasis, 265
octreotide bradycardia, 797
gallstones, 797
hyperglycemia, 797
hypoglycemia, 797
ocular anesthesia apneaic, 265
brainstem anesthesia, 265
death, 266
hypertension, 265
pain and nausea, 266
peribulbar or retrobulbar
local anesthesia, 265
retrobulbar hemorrhage, 266
seizures, 265
sub-Tenon’s block, 265
tachycardic, 265
unresponsive, 265
ofloxacin arthropathy, 469
olanzapine acute urinary retention, 103
arthralgia, 104
bipolar disorder, 102
cardiac and musculoskeletal
abnormalities, 103
constipation, 100
dysglycemia, 100
headache, 104
hyperglycemia and diabetic
ketoacidosis, 102
hyperprolactinemia and
amenorrhea, 102
hypersomnia, 100
insomnia, 100, 104
and lithium, 100
nasopharyngitis, 100
nausea, 100
orthostatic faintness, 100
overdose, 104
psychotic depression, 102
pulmonary
thromboembolism, 102
and quetiapine, 100
quetiapine and risperidone,
100
quetiapine, risperidone, and
haloperidol, 101
schizoaffective disorder, 102
sexual dysfunction, 100
smoking, interaction, 104
somnambulism, 102
somnolence, 100, 101
weight loss, 102
olmesartan angioedema, 387
renal toxicity, 387
omalizumab non-IgE-mediated anaphylactic reactions, 691
OROS, 13
oseltamivir
abdominal pain, 544
acute hemorrhagic colitis, 544
convulsions, 544
delirium, worsening, 544
diarrhea, 544
encephalitis, 544
hematochezia, 544
H5N1 infection, 544
loss of fitness, 544
neuropsychiatric events, 544
vomiting, 544
otamixaban ischemic events, 635
prothrombin fragments
concentrations, reduced,
635
oxazolidinones acute renal insufficiency, 475
anemia, 475
bilateral visual field defects,
475
black hairy tongue, 475
color vision, impairment, 475
hematological toxicity, 475
lactic acidosis, 474, 475
optic neuropathy, 474, 475
painful neuropathy, 475
pancytopenia, 475
peripheral neuropathy, 474,
475
pethidine, interaction, 476
posterior reversible
leukoencephalopathy, 475
selective serotonin re-uptake
inhibitor, interaction, 476
serotonin syndrome, 474
sideroblastic anemia, 475
thrombocytopenia, 475
visual acuity, impairment, 475
oxcarbazepine, 141–145
angioedema, 144
bipolar I and II disorders,
142
clomethiazole capsules, 142
diabetic neuropathy, use in,
141
dizziness, 141, 142
facial dimorphism, 144
fatigue, 142–143
giant hepatic adenoma, 144
headache, 143
hemolytic anemia, 144
hyponatremia, 141–143
idiopathic partial epilepsy,
143
leukopenia and
thrombocytopenia, 144
lupus-like syndrome, 143
malignant neuroleptic
syndrome, 143
micrognathia/low-set ears,
143
in migraine, effects, 142
naltrexone, 142
nausea, 141, 142
psychosis, 143
schizoaffective disorder, 144
somnolence, 141
status migrainosus, 143
unilateral radius aplasia, 144
vomiting, 141
withdrawal, 141
oxprenolol, 365
oxycodone
with alcohol and
phenylpropanolamine,
202
cholestatic hepatitis, 203
chronic neck pain, 202
constipation, 202
distension, 202
dizziness, 202
drowsiness, 202
dysuria, 202
nausea, 202
pruritus, 202
sedation, 202
somnolence, 202
tramadol, interaction, 203
vomiting, 202
oxymorphone anticholinergic drugs,
interaction, 205
central nervous system
depressants, 205
chronic osteoarthritis-related
pain, 203
cimetidine, interaction, 205
constipation, 203
dizziness, 203
immediate-release (IR)
oxymorphone, 203–204
intramuscular oxymorphone,
205
intrathecal route of
administration, 205
and morphine, 203
nausea, 203
oral oxymorphone, 204
postoperative respiratory
depression, delayed, 204
pruritus, 203
pyrexia, 203
rectal administration, 205
sedation, 203
somnolence, 203
Index of drugs oxymorphone insufficiency, 204
oxytocin and analogues
anaphylaxis, 795
chest pain, 795
dyspnea, 795
flushing, 795, 796
headache, 796
hyperstimulation of uterus,
795
hypotension, 795, 796
methylergometrine, action,
795
nausea, 796
pruritus, 795
ST segment/T wave
depression, 795
tachycardia, 795, 796
transient hypotension, 795
uterine rupture, 796
vomiting, 796
P paclitaxel papillary muscle rupture, 835
refractory heart failure, 835
papaverine dizziness and sleepiness, 205
non-steroidal anti inflammatory drugs
(NSAIDs), 205
paraphenylenediamine contact dermatitis, 296
parathyroid hormone hypercalcemia, 796
hypercalciuria, 796
parenteral nutrition cholestasis, 612
percutaneous central venous
catheters, 612
short bowel syndrome, 612
ursodeoxycholic acid, 612
paromomycin AsT activity, rise, 463
injection site pain, 463
ototoxicity, 463
paroxetine, see antidepressants pegaptanib anterior chamber inflammation, 865
endophthalmitis, 865
eye symptoms, 866
generalized urticaria, 866
hematuria, 865
intraocular pressure,
increased, 866
mild anterior chamber
inflammation, 866
oral angioedema, 866
proteinuria, 865
punctate keratitis, 866
submacular bleeding, 867
systemic allergic reactions, 866
visual disturbances, 866
947 vitreous floaters, 865, 866
vitreous opacities, 865
warfarin, interaction, 867
penicillamine acute hemolysis, 430
elastoma perforans
serpiginosa, 431
fatigue, 431
impending liver failure, 430
liver complication, 431
neutropenia, 431
pemphigus, 431
penicillamine chelation, 430
plasmapheresis, 430
primary biliary cirrhosis, 431
proteinuria, 431
pruritus, 431
rash, 431
Wilson’s disease, 430
penicillins, 450
penobarbital and primidone,
145
aplastic anemia, 145
chronic liver damage, 145
CYP2C9 and CYP2C19,
145
excessive restlessness and
hyperactivity, 145
HIV protease inhibitors,
interaction, 145
pentazocine calcific myofibrosis, 205
Phenergan®, 206
perfluorocarbons cerebral emboli, 594
perflutren acute coronary syndrome,
856
acute myocardial infarction,
856
allergy, 856
dysrhythmias, 856
severe back pain, 856
unstable congestive heart
failure, 856
Perindopril, 385
peripheral nerve block
femoral nerve block, 266
perphenazine midodrine, interaction, 104
pertussis vaccine asthma, 580
pethidine (meperidine) Alzheimer’s disease, 206
dexamethasone, 206
nausea and dizziness, 206
neonatal depression, 206
retrograde amnesia, 206
serotonin syndrome, 206
phentermine Fen–Phen, 17
pulmonary hypertension, 17
valvular regurgitation, 17
phenylephrine acute blepharoconjunctivitis, 284
blood pressure, rise in, 284
cardiac dysrhythmias, 283
phenylpropanolamine ABBA study, 284
hemorrhagic stroke, 284
phenytoin and fosphenytoin, 145–146 adverse reactions, management of, 146
Brugada pattern, 145
cerebellar atrophy, 145
efavirenz, interaction, 146
erlotinib, interaction, 146
erythema multiforme,
145–146
hypotension, 145
osteomalacia, 146
phenytoin-induced toxic
epidermal necrolysis, 146
respiratory depression, 145
salivary IgA hyposecretion,
146
pholcodine activated charcoal, interaction, 207
anaphylaxis, 207
facial angioedema, 207
hypersensitivity, 207
norpholcodine and
pholcodine-N-oxide, 206
phosphodiesterase type V,
inhibitors of
deep vein thrombosis, 372
phlebitis, 372
thrombophlebitis (tadalafil),
372
venous thrombosis
(sildenafil), 372
photodynamic therapy in
treatment of cancers, 832–835
aperistalsis, 833
Barrett’s high-grade
dysplasia, 833
Barrett’s esophagus, 833
blistering, 833
chest pain, 833
constipation, 833
dehydration, 833
dysphagia, 833
esophageal carcinoma, 833
esophageal strictures, 833
fever, 833
hiccups, 833
hyperpigmentation, 834
ineffective esophageal
motility, 833
mild erythema and
inflammation, 833
mucosal carcinoma, 833
nausea, 833
Index of drugs
948 non-cardiac chest pain, 833
ocular discomfort, 833, 834
odynophagia, 833
pain at the injection site, 834
pruritus, 833–834
pyrexia, 833
respiratory distress, 834
skin hyperpigmentation, 834
swelling, 833
urticaria, 834
vomiting, 833
pilsicainide antegrade conduction block, 349
atrial fibrillation, 349
Brugada syndrome, 350
cetirizine, interaction, 351
cimetidine, interaction, 351
overdose, 351
preserved retrograde
conduction, 349
pulse and blood pressure,
irregular, 350
unconsciousness, 350
pimecrolimus allergic contact dermatitis, 297, 712
cutaneous/viral infections, 297
erythematous papules, 712
molluscum contagiosum, 297
pioglitazone fall in hemoglobin, 780
gemfibrozil, interaction, 780
rifampicin, interaction, 780
trimethoprim, interaction,
780
piroxicam, 234
fixed drug eruption, 234
plasma substitutes accelerated blood loss, 594
dilutional coagulopathy, 594
hypothermia, 594
polygelines anaphylaxis, 595
erythema, 595
goose flesh skin, 595
polymyxins, 476
polystyrene sulfonates
intestinal obstruction, 432
non-oliguric hyperkalemia,
432
perforated necrotizing
enterocolitis, 432
rectal stenosis, 432
ventricular tachycardia, 432
polyvinylpyrrolidone (povidone) and povidone– iodine acute renal failure, 440
allergic reactions, 441
anaphylaxis, 441
burns, 441
histamine release, 441
hyperthyroidism, 440
hypothyroidism, 440
metabolic acidosis, 440
renal insufficiency, 440
systemic sepsis, 440
thyroid disease, 440
thyroid dysfunction, 440
posaconazole diarrhea, 505
flatulence, 505
gastrointestinal tract
disturbances, 505
graft-versus-host disease, 505
nausea, 504, 505
neutropenia, 505
raised hepatic enzymes, 505
vomiting, 504
postsynaptic alpha adrenoceptor antagonists intra-operative floppy iris
syndrome (IFIS), 391
phosphodiesterase type 5
inhibitors, interaction, 391
pramlintide glucagon concentrations,
reduced, 773
impaired gastric emptying,
773
mild hypoglycemia, 773
nausea, 773
weight loss, 773
pravastatin, 814–815 prazosin bizarre behavior, 392
dissociative feelings, 392
pregabalin, 147–148
adverse reactions,
management, 148
antiepileptic drugs,
interaction, 148
ataxia, 146, 147
blurred vision, 146
cholestasis, 148
confusion, 147
dizziness, 146, 147
exacerbation of heart failure,
147
fatigue, 146
fibromyalgia, 147
flexible-dose regimen, 146–147
flu, 147, 148
lower limb edema, 146
malaise, 147, 148
myoclonic jerks, 147
nausea, 147
neuropathic pain, 147
neutropenia, 148
peripheral edema, 147
postherpetic neuralgia, 147
somnolence, 147
weight gain, 146, 147
worsening cognitive
performance, 147
prilocaine and EMLA® barbiturates, interaction, 269
cardiovascular collapse, 268
leg ulcers, 268
methemoglobinemia, 268
progression of necrotic
ulcers, 268
progestogens anxiety, 747
masculinization of female
fetuses, 748
recognition accuracy,
reduced, 747
propafenone Brugada-like changes, 352
cardiac memory
phenomenon, 351–352
citalopram, interaction, 352
lithium, interaction, 352
venlafaxine, interaction, 352
propofol antimuscarinic syndrome, 253–254
aspiration pneumonitis, 253
hypotension, 252
hypoventilation, 253
hypoxemia, 253
impaired left ventricular
function, 252
impaired memory, 254
oculocardiac reflex, 252
palpitation, 252
propofol infusion syndrome,
254
respiratory depression, 253
seizures, 253
sleep disturbance, 254
wheezing, 253
prostaglandin analogues blurred vision, 871
conjunctival hyperemia, 871
dermatitis, 871
foreign body sensation, 871
headache, 871
hypertrichosis, 871
iris color and periocular
pigmentation, changes, 871
itching, 871
ocular pain, 871
stinging, 871
protamine hematoma, 646
mitral regurgitation, 646
myocardial infarction, 646
severe pulmonary
vasoconstriction, 646
tricuspid regurgitation, 646
prothrombin complex concentrate abdominal sepsis, 597
arterial hypertension, 597
burning at the injection site,
597
Index of drugs positive parvovirus B19 PCR
screen, 597
pseudoephedrine acute generalized
exanthematous pustulosis
(AGEP), 282
acute urinary retention, 282
death, 282–283
selegiline, interaction, 283
psilocybin acute coronary syndrome, 69–70 alterations of time perception, 70
depersonalization, 70
magic mushrooms, 70
Takotsubo cardiomyopathy,
70
Psoralea corylifolia (Fabaceae, psoralea fruit) erythema, 885
pruritus, 885
skin irritation, 885
swelling, 885
vesicular rash on skin, 885
pyrazinamide, 563
pyrimethamine and congeners
anemia, reduction, 524
malaria, 523, 524
Stevens–Johnson syndrome,
524
Q quazepam diazepam, interaction, 78
dosing, 78
food, interaction, 78
nitrazepam, interaction, 78
psychomotor performance, 78
quetiapine abuse, 107
akathisia, 106
alopecia, 107
Alzheimer’s disease, 106
appetite, 106
coma, 107
constipation, 105
diarrhea, 105
dizziness, 105
drowsiness, 107
fatigue, 105
galactorrhea, 106
hallucinations, 105
headache, 105, 106
hypotension, 105, 107
irritability, 106
lethargy, 106
leukopenia, 107
and lithium, 105
nasopharyngitis, 105
nausea, 105
orthostatic hypotension, 106
overdose, 107
949 polysubstance dependence, 107
refractory schizophrenia, 106
respiratory depression, 107
and risperidone, 105
sedation, 105, 106
seizures, 107
somnolence, 105, 106, 107
tachycardia, 105, 107
thigh fracture, 105
thrombocytopenia, 107
tonic–clonic seizures, 106
tremor, 106
vomiting, 105
weight gain and fatigue, 106
quinidine and derivatives antiphospholipid antibodies,
352
quinine and congeners erythema, 524
erythematous lesions, 524
fixed skin eruptions, 524
vomiting, 524
R rabies vaccine anaphylaxis, 582
radioactive iodine acute airways obstruction, 764
acute salivary gland pain, 764
carbimazole, interaction, 765
fetal death, 765
neonatal hypothyroidism, 765
propylthiouracil, interaction,
765
swelling and inflammation,
764
xerostomia, 764, 765
raloxifene atrial fibrillation, 745
hypertension, 745
stroke, 745
ramelteon circadian sleep–wake cycle rhythms, 79
clearance, 80
dizziness, 79
fatigue, 79
headache, 79
insomnia, 79
nausea, 79
prolactin concentrations,
raised, 79
sleep latency, 79–80
somnolence, 79
urinary tract infection, 80
ramipril acute renal insufficiency, 385
angioedema, 385
fasciitis with eosinophilia, 385
overdose, 385–386
retinopathy of prematurity,
385
ranibizumab arterial thromboembolic events, 867
arterial thromboses, 868
endophthalmitis, 867, 868
hypertension, 867
non-fatal ischemic/
hemorrhagic stroke, 867
non-fatal myocardial
infarction, 867
non-ocular hemorrhage, 867
ocular hypertension, 868
ocular inflammation, 867
retinal pigment epithelial
tears, 868
rasburicase dyspnea and cyanosis, 236
fatal respiratory arrest, 236
gingivitis, 236
methemoglobinemia and
hemolytic anemia, 236
renal disease, 236
reboxetine erectile dysfunction, 36
pseudopheochromocytoma,
36
seminal emission and
ejaculation, 36
Regadenoson, 339
caffeine, interaction, 15
remacemide hydrochloride, 127
remifentanil, 207–208
bradycardia, 207
elective cholecystectomy, 207
hypotension, 207
prolonged apnea, 208
propofol anesthesia, 207
sedation and lower
hemoglobin oxygen
saturations, 208
von Willebrand’s disease, 207
repaglinide, 777
blood glucose-lowering
effect, prolonged, 777
ciclosporin, interaction, 777
clarithromycin, interaction,
777
gemfibrozil, interaction, 777
itraconazole, interaction, 777
ketoconazole, interaction, 777
telithromycin, interaction, 777
trimethoprim, interaction, 777
ribavirin acute respiratory syndrome, 531
anemia, 531
bradycardia, 531
conjunctival irritation, 531
hypomagnesemia, 531
rashes, 531
rifabutin antiretroviral drug,
interaction, 563
Index of drugs
950 rifampicin acute renal failure, 564
antiretroviral drug,
interaction, 565 bilateral edema, 564 dry cough, 564 dyspnea, 564 fever, 564 gastrointestinal disorders, 564 generalized weakness, 563 Hashimoto’s thyroiditis, 563 hepatotoxicity, 564 hypothyroidism, 563, 564 leukocytoclastic vasculitis, 564 moxifloxacin, interaction, 565–566
myalgia, 563
mycobacterium kansasii pulmonary disease, 564 nausea, 565 oliguria, 564 osteoarticular infection, 564 palpable purpura, 564 periorbital edema, 563 renal insufficiency, 564 tuberculosis, 565 vomiting, 565 rifamycins, 563 rimonabant, 16 diarrhea, 19 dizziness, 19 insomnia, 19 nausea, 19 risperidone, 14 acquired long QT syndrome, 109 agitation, 108 anxiety, 108 depression, 108 diabetes mellitus, 108 dry mouth, 109 dyskinesia, 109 extrapyramidal disorder, 109 fever, 109 haloperidol, 108 headache, 108, 109 hyperkinesia, 109 hypokinesia, 109 impotence, 108 insomnia, 108 involuntary muscle contractions, 109 non-puerperal lactation, 108 and olanzapine, 108 psychosis, 108 rhinitis, 109 seizure frequency, 108 senile dementia and psychosis, 109
sialorrhea or hyper
salivation, 110
sleepiness, 109
somnolence, 108, 109
tardive dyskinesia, 109 tremor, 109 upper respiratory infections, 109 ritodrine, 318 maternal neutropenia, 289 pulmonary edema, 289 systolic and diastolic blood pressures, low, 289 ritonavir adrenal suppression, 542 amenorrhea, 542 appetite, increased, 542 Cushing’s syndrome, 542 excessive weight gain, 542 facial edema, 542 fatigue, 542 fluticasone, interaction, 542 hypercholesterolemia, 542 hypertriglyceridemia, 542 marked acne, 542 stretch marks, 542 rivaroxaban bleeding, 636 rivastigmine 11 C-nicotine binding, changes in, 21 cognitive function, 20 heart block, complete, 20–21 memantine, interaction, 21 NAP226-90, 21 nausea, 21 transdermal availability, 21 vomiting, 21 rocuronium prolonged paralysis, 274 vs. suxamethonium, 274 rofecoxib, 233 roflumilast diarrhea, 321
headache, 321
nausea, 321
vomiting, 322
weight loss, 321, 322
ropivacaine CYPD26 inhibitors, interaction, 269 death, 269 multiple myeloma, 269 nervous system toxicity, 269 Takayasu’s disease, 269 ventricular tachycardia, 269 rosiglitazone abdominal pain, 781 angina pectoris, 781 bezafibrate, interaction, 781 cardiothoracic ratio, increased, 781 ciprofibrate, interaction, 781 edema, 781 fatigue, 781 fibrates, interaction, 781 gemfibrozil, interaction, 782
heart failure, 781 Hodgkin’s lymphoma, 782 liver failure, 782 low-grade fever, 781 myalgia, 781, 782 mycophenolate mofetil, interaction, 782 myocardial infarction, 781 transient ischemic attacks, 781 trimethoprim, interaction, 782 rosuvastatin gynecomastia, 815 myalgia, 815 myopathy, 815 proteinuria, 815 rubella vaccine arthralgia, 582 congenital malformation, 582 congestive heart failure, 582 fever, 582 fetal infection, 582 heart failure, 582 juvenile idiopathic arthritis, 581, 582 rupatadine allergic rhinitis, 308 chronic idiopathic urticaria, 308 S saquinavir grade 3 gastrointestinal adverse effect, 542 hyperbilirubinemia, 542 selective serotonin re-uptake inhibitors (SSRI) see also antidepressants gastrointestinal bleeding, 33–34 hemorrhagic stroke, 33 mild skin reactions, 34 serotonin, 34 syndrome of inappropriate secretion of antidiuretic hormone (SIADH), 33 toxic epidermal necrolysis, 34 vascular injury, 34 selenium, 420 serotonin and noradrenaline re-uptake inhibitors (SNRI), 34–35 see also antidepressants sertindole cognitive deficits, 110 death, 110–111 sevelamer blood clot formation, 897 bowel obstruction, 897 chronic metabolic acidosis, 898 constipation, 897 diarrhea, 897 headache, 897
Index of drugs indigestion, 897
infection, 897
low blood pressure, 897
pain, 897
severe abdominal pain, 897
vomiting, 897
sevoflurane agitation, 245
Duchenne muscular
dystrophy, 246
epileptiform effects, 245
fatal hepatic failure, 245–246
malignant hyperthermia, 246
myasthenia gravis, 245
torsade de pointes, 245
sibutramine, 17
lorazepam, interaction, 19
psychosis, 19
sleep apnea, 18
silver salts and derivatives argyria, 420
simvastatin bilateral leg compartment syndrome, 815
myonecrosis, 815
thrombocytopenia, 815
sirolimus (rapamycin) allograft nephropathy, 712
alveolar hemorrhage, 712
benign Leydig-cell tumor,
714
diarrhea, 713
dry cough, 713
dyspnea, 712, 713
fatigue, 713
fever, 712
hypoxemia, 713
interstitial pneumonitis, 712
LDL concentrations, higher,
713
leg edema, 713
low-grade fever, 712, 713
multiple precancerous skin
lesions, 712
non-productive cough, 712
nosocomial pneumonia, 712
oligospermia, 714
papillary muscle rupture,
712
progressive graft dysfunction,
713
proteinuria, 713
refractory heart failure, 712
respiratory acidosis, 713
sepsis, 712
shortness of breath, 712
stomatitis, 712
weight loss, 713
sitagliptin anaphylaxis, 775
angioedema, 775
nausea and vomiting, 775
urticaria, 775
951 sitaxsentan flushing, 390
headache, 390
hepatotoxicity, 390
peripheral edema, 390
smallpox vaccine acute myocardial infarctions, 583
auricular cellulitis, 583
axillary adenopathy, 583
coronary artery disease, 583
edema, 583
fatal cardiac arrests, 583
headache, 583
inflammatory bowel disease,
583
ischemic cardiac event, 582
myalgia, 583
myocarditis, 583
pericarditis, 583
periorbital cellulitis, 583
redness, 583
vaccinia virus infection, 583
somatostatin (growth hormone release-inhibiting hormone) and analogues abdominal cramps, 797
bradycardia, 796
diarrhea, 797
first-degree heart block, 797
palpable nodules, 797
somatropin (human growth hormone, hGH) carotid intima media thickness, increased, 791
cerebellar ataxia, 794
Creutzfeldt–Jakob disease, 791
facial grimacing, 791
hyperglycemia, 791
hypotonia, 793
intestinal perforation, 792
intracranial hypertension, 793
leukemia, 792
loss of speech, 793
scoliosis, 793
shoulder shrugs, 791
throat-clearing sounds, 791
thymus gland rebound, 792
tics, 791
Tourette’s syndrome, 791
urinary sodium excretion,
reduced, 792
spinal (intrathecal) anesthesia bilateral myoclonus, 263–264
conjunctival injection, 263
Horner’s syndrome, 263
lacrimation, 263
permanent urinary
incontinence, 264
runny nose, 263
spinal myoclonus, 263
trigeminal nerve
involvement, 263
spironolactone gastrointestinal bleeding, 409
stavudine hyperlactatemia, 536
insulin sensitivity, reduction,
535
lipoatrophy, 535, 536
lipodystrophy, 535
mitochondrial toxicity, 535
peripheral neuropathy, 536
weight loss, 535
stem cells autoimmune hemolytic
anemia, 600
bone marrow suppression,
600
bradycardia, 599, 600
chest discomfort, 600
colitis, 600
desaturation, 600
diastolic hypertension, 600
encephalitis, 600
Evans syndrome, 600
extra beats, 600
fever, 600
gastroduodenitis, 600
graft-versus-host disease, 600
headache, 600
hemoglobinuria, 599
hypertension, 599
hypotension, 599
myelosuppression after initial
engraftment, 600
nausea, 599, 600
neutrophil engraftment,
delayed, 600
pericarditis, 600
platelet engraftment,
delayed, 600
pneumonia, 600
rashes, 600
second and third degree
heart block, 599
selective red cell aplasia, 600
sinus bradycardia, 600
systolic hypertension, 600
thrombotic microangiopathy,
600
vomiting, 599, 600
streptokinase acute anuric renal failure, 637
streptomycin cutaneous adverse drug
reactions, 463
vestibular system, 463
strontium salts DRESS, 420
sufentanil, 208
in fast-track cardiac
anesthesia, 208
nausea and vomiting, 208
pruritus, 208
respiratory depression, 208
Index of drugs
952 sugammadex nausea and shivering, 275
overdose, 276
sulfadiazine acute renal failure, 477
crystalluria, 477
toxoplasmic encephalitis, 477
sulfonamides agranulocytosis, 477
sulfonylureas mortality, 777
sulfuric acid burns, 6
suxamethonium butyrylcholinesterase, 273
hyperkalemia, 273
synephrine, 15
caffeine, interaction, 15
systemic glucocorticoids acute myocardial infarction,
724
acute severe liver damage,
725
Andersen’s syndrome, 724
anxiety, 723
arterial pressure, increased,
724
bilateral lung infiltrates, 728
bradydysrhythmias, 724
central hepatic necrosis, 726
centrilobular hepatic cell
necrosis, 726
concomitant infections, 724
Cushing’s syndrome, 728
dermatofibromata, 726
diabetes mellitus, 723
dysthyroid optic neuropathy,
725
edema, 724
fractures, 727
gastric pain, 724
Graves’ ophthalmopathy, 725
grunting, 728
hepatitis B, recurrence, 728
hyperglycemia, 723
hypertension, 723
infantile hemangiomas, 728
infectious endophthalmitis,
725
insomnia, 723
intercostal retraction, 728
interlamellar stromal edema,
725
leukocytosis, 723
lipodystrophy, 723, 725
menstrual disorders, 723
muscle cramps, 723
Netherton’s syndrome, 728
neuropsychiatric disorders,
723
non-alcoholic steatohepatitis,
726
orofacial clefts, 728
perioral dermatitis, 726
persistent sexual arousal
syndrome, 727
Pneumocystis jiroveci pneumonia, 728
posterior reversible
encephalopathy syndrome,
725
proximal muscle weakness, 723
psychosis, 723
Q fever, 728
respiratory distress with
fever, 728
respiratory rate, increased, 728
sinus bradycardia, 724
squamous cell carcinoma, 728
tachydysrhythmias, 724
T
tacalcitol, 301
abdominal pain and
vomiting, 301
hypercalcemia, 301
psoriasis, 301
tacrine interleukin-6 gene
polymorphisms, 21
MDR3, 21
tacrolimus, 714, 716
blood pressure, increased,
714
burning sensation in skin, 716
cerebellar ataxia, 714
cerebellar atrophy, 714, 715
chronic sensorimotor
polyneuropathy, 715
diabetes, 714
facial numbness, 715
folliculitis, 714
headaches, 714
hyperthyroidism, 715
insomnia, 714
intention tremor, 714
loss of vibration sensation, 715
lymphopenia, 714
malaise, 714
Muir–Torre syndrome, 715
muscle cramps, 715
pancreatitis, 714
paresthesia, 714
pruritus, 716
reversible increase in serum
creatinine, 714
sebaceous gland tumors, 715
sebaceous lesions, 715
seizures, 714
slurred speech, 714
swaying gait, 714
tacrolimus toxicity, 715
toe dorsiflexion, weakness,
715
weakness, 715
talc granulomas, 898
ovarian papillary serous
carcinoma, 898
pulmonary embolism, 898
silicopneumoconiosis, 898
tamoxifen acute anterior wall myocardial infarction, 746
atrial fibrillation, 746
breast cancer, 746
cardiac dysrhythmias, 746
color vision loss, 746
embolism, 746
endometrial cancer, 746
hot flushes, 746
hypertriglyceridemia, 746
keratopathy, 746
purpuric vasculitis, 746
refractile retinal crystals, 746
thrombocytopenia, 746
thromboembolic events, 746
thrombosis, 746
urinary disturbances, 746
vaginal discharge, 746
tamsulosin choroidal detachment, 392
intra-operative floppy iris
syndrome (IFIS), 392
tartrazine anxiety, 896
blurred vision, 896
depression, 896
feeling of suffocation, 896
general weakness, 896
hot sensations, 896
irritability, increased, 896
itching, 896
migraine, 896
purple skin patches, 896
restlessness, 896
sleep disturbances, 896
teicoplanin provocation test, 469
pruriginous maculopapular
rash, 469
telbivudine myopathy, 532
telithromycin angioedema, 472
hepatotoxicity, 471
myasthenia gravis, 471
QT interval prolongation, 471
shortness of breath, 472
toxic epidermal necrolysis,
471
wheezing, 472
telmisartan diarrhea and renal problems, 388
hypotensive symptoms, 388
pigmented purpuric
dermatosis, 388
Index of drugs temozolomide, 831 abdominal pain, 830 abnormal gait, 831 abnormalities of coordination, 830 acute cholestatic hepatitis, 832 acute myeloid leukemia, 831 agitation, 830 alopecia, 831 amnesia, 830 anaphylaxis, 831 anemia, 830 anorexia, 830 anxiety, 830 arthralgia, 831 ataxia, 830 back pain, 831 blurred vision, 830 cerebral hemorrhage, 830 changes in vision, 830 confusion, 830 constipation, 830 cough, 830 depression, 830 diarrhea, 830 diplopia, 830 dizziness, 830 dry skin, 831 dyspepsia, 830 dysphagia, 830 dyspnea, 830 fever, 831 headache, 830 hemiparesis, 830 incontinence, 830 insomnia, 830 leukopenia, 830 lymphopenia, 830 memory impairment, 830 myalgia, 831 myelosuppression, 830 neutropenia, 830 non-Hodgkin’s lymphoma, 831
palmar-plantar
erythrodysesthesia, 831 paresis, 830 paresthesia, 830 peripheral edema, 830 pharyngitis, 830 pneumonitis, 830 pruritus, 831 radiation injury, 831 rashes, 831 secondary myelodysplastic syndrome, 831
seizures, 830
sinusitis, 830
somnolence, 830
stomatitis, 830
taste disturbance, 830
testicular toxicity, 832
953 thrombocytopenia, 830
upper respiratory tract
infections, 830
weight gain, 830
temsirolimus hyperglycemia, 716 hyperlipidemia, 716 peripheral edema, 716 rash, 716 tenofovir de Fanconi syndrome, 537 diarrhea, 537 headache, 537 hypophosphatemia, 537 nausea, 537 proximal renal tubule damage, 537 vomiting, 537 terazosin headache and dizziness, 393 lichenoid eruption, 393 new-onset priapism, 393 overdose, 393 terbinafine acute generalized exanthematous pustulosis (AGEP), 492 autoimmune hepatitis, 491 carbamazepine, interaction, 492 cutaneous lupus-like syndrome, 492 dermatomyositis, 492 erythema multiforme, 492 generalized pustular eruptions, 492 granulocytopenia, 491 Hallopeau, acrodermatitis continua, 492 macular rash, 492 rhabdomyolysis, 492 Stevens–Johnson syndrome, 492 systemic lupus-like syndrome, 492 toxic epidermal necrolysis, 492 toxic erythema, 492 terlipressin blisters and bruising in groin, 799 skin necrosis, 798 tetrabenazine akathisia, 277 depression, 277 drowsiness, 277 parkinsonism, 277 tics, 278 tetracaine malignant hyperthermia, 269 tachycardia and fever, 269 tachypnea and muscle rigidity, 269
tetracyclines diarrhea, 454
and glycylcyclines, 451
nausea, 454
renal damage, 454
vomiting, 454
tezosentan hypotension, 390 TGN1414 dry gangrene, 691 dyspnea, 691 fever, 691 headache, 691 hypotension, 691 lumbar myalgia, 691 lymphopenia, 691 peripheral limb ischemia, 691
radiological pulmonary
infiltrates, 691
respiratory failure, 691
rigors, 691
tachycardia, 691
tachypnea, 691
theanine caffine, interaction, 15 theophylline Inje cocktail, 16 seizures, 15–16 thiazide, 404, 405 thiazide-like diuretics, 405 thiazolidinediones (glitazones) fractures, increased risk, 779
heart failure, 779
transaminase activities,
increased, 779 6-thioguanine hepatic nodular regenerative hyperplasia, 718 hepatic venous pressure gradient, increased, 718 portal hypertension, 718 thiopental sodium diffuse brain edema, 255
dysphagia, 255
imbalance in potassium
regulation, 255
sore throat, 255
subdural hematoma, 255
traumatic subarachnoid
hemorrhage, 255 thiopurine methyltransferase (TPMT), 718 thiopurines endothelial cell injury, 717 hypersensitivity, 717 idiosyncratic cholestatic reactions, 717 thyroid hormones age-related macular
degeneration, 764
T3 thyrotoxicosis, 764
Index of drugs
954 thyrotropin-releasing hormone (TRH, protirelin) acute hemorrhage, 763
ischemic necrosis, 763
pituitary apoplexy, 763
thyrotropin (thyroidstimulating hormone, TSH) hyperthyroidism, 763 thyroid volume and tenderness, transient increased, 763 tiagabine, 148–149 cocaine dependence, 148 dizziness, 148 fatigue, 148 headache, 148 influenza, 148 light-headedness, 148 myoclonic status epilepticus, 149 nausea, 148 overdose, 149 post-traumatic stress disorder, 148 social anxiety disorder, 148 somnolence, 148 tremor, 149 vomiting, 148 tibolone subendometrial space, translucency, 750 thickened endometrium, 750 ticlopidine cholestatic hepatotoxicity, 642 liver dysfunction, 642 neutropenia, 642 rashes, 642 tigecycline acute abdominal pain, 455 chronic osteomyelitis, 455 nausea, 454, 455 pancreatitis, 454, 455 vomiting, 454, 455 timolol presyncopal episodes, 365 primary acquired nasolacrimal duct obstruction, 870 visual symptoms, 365 tiotropium bromide, 319 acute angle-closure glaucoma, 319 dry mouth, 319 photosensitivity reactions, 319 urinary retention, 319 tipranavir acute pancreatitis, 542, 543 bleeding, increased risk, 542 diarrhea, 542 epigastric pain, 543 fatigue, 542 headache, 542 HIV, resistant strains, 542
hyperamylasemia, 543 hypertriglyceridemia, 542 intracranial hemorrhage, 542 itching, 543 liver enzyme, rise, 542 malaise, 543 nausea, 542, 543 porphyria cutanea tarda, 543 protease inhibitor, interaction, 543 ritonavir, interaction, 543 skin fragility, 543 vomiting, 542, 543 titanium, 420 tizanidine hypotension, 278
liver disease, 278
tobramycin AUC measurement, 464 auditory function, 463 bronchospasm, 463 eosinophilia, 463 hepatotoxicity, 463 osteomyelitis, 463 pulmonary function, 463 venovenous hemodialysis, 464 tolcapone diarrhea, 289 dizziness, 289 dyskinesias, 289 dystonia, 289 hallucinations, 290 liver damage, reversible, 290 nausea, 289 orthostatic hypotension, 289 sleep disorders, 289 toluene, 899 topiramate, 126–127, 149–153 adverse reactions, management, 153 aggression, 149 agitation, 149 alcohol dependence, 150–151 alkalosis, 153 angle closure glaucoma, 152 anorexia, 149, 150, 151 antipsychotic drugs, interaction, 153 appetite, reduced, 150 benign rolandic epilepsy, 149 binge eating disorder, 151 chronic migraine, 150 cognitive impairment, 149 delusional parasitosis, 152 dementia, 151 depression or apathy, 149 depressive symptoms, 149 diarrhea, 150 difficulty in concentration, 150 dizziness, 149, 150, 154 dry mouth, 149, 150 dysgeusia, 150 dysphasia, 149
ear pressure, 149 facial myoclonus, 151–152 factor XIII, 156 fatigue, 150, 151 gastrointestinal disturbances, 149, 150 hair loss, 154 headache, 150, 151 hirsutism, 155 hyperirritability, 149 hypocalcemic seizures, 153 hypomania, 152 impaired attention, 150, 151 impaired cognitive speed, 152 impaired concentration, 150, 151 impaired memory, 149, 150, 151 impaired platelet aggregation, 156 impotence, 154 insomnia, 150, 151 and lamotrigine, 150 leukopenia, 154 levetiracetam, 149 long-term weight changes, 152–153 loss of appetite, 149, 151 menstrual abnormalities, 155 mental slowing, 149 migraine, 150 monotherapy or adjunctive therapy, 149 nausea, 150, 151, 154 nervousness, 150, 151 neurovisual or neuroacustical effects, 154 panic attacks, 152 paresthesia, 149, 150, 151 polycystic ovarian syndrome, 155 poor memory, 149 prolonged bleeding time, 156 restless legs syndrome, 151 short-term memory, 152 and sibutramine, 149–150 skin complaints, 149 sleepiness, 149, 150 somnolence, 149, 150, 151, 154 suprachoroidal effusions, 152 taste disturbance, 150, 151 thrombocytopenia, 154, 156 tiredness, 149 tremor, 149, 154 verbal fluency, 152 visual problems, 149 von Willebrand factor, 156 weight gain, 155 weight loss, 149, 150 torcetrapib blood pressure, increased, 816 intracellular calcium, increased, 817
Index of drugs tramadol, 208–209
constipation, 209
dizziness, 208, 209
epidural tramadol, 209
flushing, 209
hypotension, 208
Munchausen syndrome, 209
nausea, 208, 209
pethidine and morphine,
208–209
respiratory reactions, 208
restless legs syndrome, 209
somnolence, 209
vomiting, 208
weakness, 208
travoprost acute iritis, 731, 873
blurring of vision, 873
central corneal thickness,
reduced, 873
corneal edema, 731, 873
eyelash hypertrichosis, 873
glaucoma, 873
growth of lashes and ancillary
hairs around eyelids, 873
ocular hypertension, 873
periocular skin pigmentation,
873
uveitis, 873
tretinoin (all-trans retinoic acid,
ATRA), 301
acne, 301
contact dermatitis, 301
desquamation, 301
hypersensitivity reactions, 301
sunburn, 301
triazolam amnestic effects, 79
dexamfetamine sulfate,
interaction, 79
sedative effects, 79
trichloroethylene chest/abdominal pain, 246
drowsiness, 246
overdose, 246–247
trientine aminotransferases, rise, 432
anemia and leukopenia, 432
death, 432
neurological deterioration,
432
Wilson’s disease, 431, 432
trimethoprim and co trimoxazole acute angle-closure
glaucoma, 477
acute cholestatic hepatitis, 478
anterior uveitis, 477
coumarin anticoagulant,
interaction, 478
cutaneous eruptions, 478
granulocytic maturation
arrest, 478
955 hemolysis, 477
hypersensitivity vasculitis, 478
pioglitazone, interaction, 478
psoriasis, 478
Sweet’s syndrome, 478
thrombocytopenia, 477
thrombotic
thrombocytopenic purpura,
477
triptans monoamine reuptake
inhibitors, interaction, 372
pathological laughter, 372
tumor necrosis factor alfa
(TNF-a) antagonists, 677
heart failure, 677
hypersensitivity reactions,
678
lupus-like syndrome, 678
mycobacterium tuberculosis,
678
pneumonia, 678
psoriasis, 678
systemic nocardiosis, 678
ulcerative colitis, 677
uveitis, 677
vasculitis, 678
U urapidil worsening psoriasis, 393
urokinase hemorrhage, 637
higher diastolic blood
pressure, 637
ischemia, early signs of, 637
lower recanalization rate,
637
poor collaterals, 637
V
vaccines acute myocarditis, 579
asthma, 579
autism, 579
autism spectrum disorder,
580
autistic-like symptoms, 580
diphtheria, 579
epilepsy, 580
mitochondrial disorder, 579
movement disorders, 580
mumps, 579
muscle tone problem, 580
pericarditis, 579
polio, 579
smallpox, 579
tetanus, 579
type A meningococcus, 579
valaciclovir acute allergic reaction, 530
Herpes zoster infection, 530
renal insufficiency, 530
valproate, 46
valproate sodium and
semisodium (divalproex),
153–157
acquired factor VII
deficiency, 156
acylcarnitine, 155
Alpers–Huttenlocher
disease, 156
bone marrow suppression, 156
cervical dystonia, 154
chronic migraine or chronic
tension-type headache, 154
confusion or disorientation,
154
encephalopathy, 155, 156
gingival enlargement, 157
hematological abnormalities,
156
hepatic failure, 156
hepatopathy, 156
histone acetyltransferase/
deacetylase, 154
hypospadias, 157
intravenous sodium valproate
or diazepam, 153
lamotrigine, interaction, 160
leukopenia and
thrombocytopenia, 154
levetiracetam, interaction, 160
long-term sodium valproate
therapy, 155
manic behavior, 155
megakaryocyte dysplasia, 156
meropenem, interaction, 160
mild pancreatitis, 156
monotherapy, effects, 155
nausea, 154
neurocognitive impairment,
154
neurovisual or neuroacustical
adverse effects, 154
overdose, 157–160
oxcarbazepine, interaction,
160
pancreatitis, 156
parkinsonism, 154
or phenytoin, 153
postoperative bleeding, 156
proliferation of immature
myeloid precursors, 156
pure red cell aplasia, 156
somnolence, 154
status epilepticus, 153–154
subclinical hypothyroidism,
155
subcutaneous histamine, 154
syndrome of inappropriate
secretion of antidiuretic
hormone (SIADH), 156
trigonocephaly, 157
visual field defect, 155
vomiting, 154
Index of drugs
956 valsartan fetal oliguria, 388
lithium, interaction, 388
vancomycin, 470
acute interstitial nephritis,
470
acute renal failure, 470
anemia, 470
local skin necrosis, 470
maculopapular rash, 471
neutropenia, 470
non-cardiogenic pulmonary
edema, 470
renal tubular wasting, 470
retinal toxicity, 470
S. aureus pneumonia, 470
thrombocytopenia, 470
varicella vaccine chicken pox, 584
congenital varicella
syndrome, 585
fever, 585
herpes zoster infection, 585
leukemia, 584, 585
malignant lymphoma, 585
post-immunization vesicular
rashes, 584
seroconversion, 585
varicella zoster vaccine (VZV),
584
venlafaxine, see antidepressants Venom Hyperdrive 3.0, 17 verapamil bradycardia, 367
episodic cluster headaches,
367
hypotension, 367
verteporfin and photodynamic therapy choroidal hypoperfusion,
869
visual acuity, reduced, 869
vigabatrin, 160–161
withdrawal, 161
vitamin A (carotenoids) cortical thickening, 607
distal femur/proximal tibia/
distal tibia, central physeal
arrest, 607
fractures, 607
metaphyseal irregularity, 607
muscle and bone tenderness,
607
osteoporosis, 607
pruritus, 607
vitamin B endothelium-dependent
vasodilatation, increased,
610
sapropterin dihydrochloride,
609
upper respiratory tract
infections, 610
vitamin C (ascorbic acid) hyperoxaluria, 610
hyperoxaluric nephropathy,
610
vitamin D analogues hypercalcemia, 611
tenofovir, 611
vitamin E mortality, 611–612
tuberculosis, 611
von Willebrand factor/factor VIII concentrate AlT activity, increased, 597
pulmonary embolism, 597
rash, 597
thrombophlebitis of leg, 597
vomiting, 597
voriconazole cardiovascular events, 505
cough, 506
diarrhea, 505
dyspnea, 506
headache, 505
hematological disorders, 505
liver function test
abnormalities, 505
nausea, 505
neurological disturbances,
505, 507
painful neuromuscular
disorders, 506
painful peripheral
neuropathy, 506
photoageing, 507
pseudoporphyria, 506
QT interval prolongation,
505
rashes, 505
renal disturbances, 505
renal impairment, 507
retinoid-like photosensitivity,
507
reversible cardiac arrest, 505
skin, blistering, 506
squamous cell carcinoma, 507
visual disturbances, 505
vomiting, 505
W water-soluble intravascular iodinated contrast agents acute encephalopathy, 844
acute hepatitis, 846
anaphylaxis, 849
baboon syndrome, 849
cellulitis, 850
chemical synovitis, 850
coronary angiography, 844
diabetes mellitus, 847
DRESS, 850
encephalopathy, 844
exfoliative dermatitis, 849
fixed drug eruption, 849
immediate hypersensitivity reaction, 850
iodide mumps, 846
motor weakness and
hypesthesia, 844
nausea, 843
neck stiffness, 844
nerve palsies, 850
pain, 844
pancreatic mumps, 846
rhabdomyolysis, 844
seizures, 850
septic arthritis, 850
Sweet’s syndrome, 849
swelling, 844
taste disturbances, 844
transient cortical blindness,
844
tremors, 844
urticaria, 850
vagal reactions, 850
X
xenon nausea and vomiting, 248
ximelagatran alanine transaminase activity,
increased, 634
hepatotoxicity, increased
risk, 634
liver damage, 634
Y yellow fever vaccine acute disseminated encephalomyelitis, 586
encephalitis, 586
Guillain–Barré syndrome,
586
hypersensitivity reaction, 586
rheumatoid arthritis, 586
systemic lupus
erythematosus, 586
vaccine-associated
neurotropic disease, 586
vaccine-associated
viscerotropic disease, 586,
587
Z zafirlukast asthma, 321
bronchopneumonia, 321
COPD, 321
headache, 321
nausea, 321
zanamivir, 544
Zhen de Shou Fat Loss
Capsules, 17
zidovudine
beta-thalassemia,
misdiagnosis, 536
chromosomal damage, 536
Index of drugs co-trimoxazole, interaction, 537 hemoglobin A2, 536 HIV-infection, 536 humoral immune suppression, 537 hypospadias, risk, 536 ribavirin, interaction, 537 zileuton accidental injury, 323 asthma, 323 back pain, 323, 324 bronchitis, 323 diarrhea, 323 dizziness, 323 dyspepsia, 322, 323, 324 exacerbation of asthma or eczema, 323 flu-like syndromes, 323, 324, 325 headaches, 323, 324, 325 infections, 323, 324, 325 insomnia, 324 liver enzymes, raised, 322 myalgia, 323, 324 nausea, 322, 323, 324, 325 pain, 323, 324, 325 pharyngitis, 323, 324, 325 propranolol, interaction, 325 rhinitis, 323, 324 sinusitis, 323, 324 terfenadine, interaction, 325 theophylline, interaction, 325 thrombotic adverse effects, 324 vomiting, 323 warfarin, interaction, 325 weakness, 323
957 zinc exacerbation of epileptic seizures, 421 hyperzincemia, 421 hypocupremia, 421 pulmonary embolism, 420 ziprasidone acute dystonic reaction, 111 agitation, 111 body stiffness, 111 conjugate eye deviation, 111 deaths, 111 depression, 111 dizziness, 111 dysphonia and dysphagia, 112 extrapyramidal symptoms, 111 galactorrhea and breast pain, 112 gastrointestinal syndromes, 111 generalized body stiffness, 111 hyperprolactinemia, 112 insomnia, 111 lockjaw, 111 oculogyric crisis, 111 overdose, 111 Pisa syndrome, 112 psychoses, 111 respiratory difficulty, 111 schizophrenic reactions, 111 tongue protrusion, 111 transient tongue dystonia, 111 urticaria, 111 zolpidem caffeine, interaction, 15, 81 drug abuse, 81 insomnia, 80
oxazepam, interaction, 81 sleep latency, 80 triazolam, interaction, 81 zonisamide, 161–164 antiepileptic drugs, interaction, 163 appetite, reduced, 161 binge eating disorders and obesity, 162 bipolar disorder, 161–162 childhood-onset epilepsy, 162 cognition and mood, 162–163 euthymic bipolar disorder, 163 hypohidrosis, 163 interstitial pneumonitis, 162 lamotrigine, interaction, 164 Lennox–Gastaut syndrome, 161 neuroleptic malignant syndrome, 162 Parkinson’s disease, 162 psychotic symptoms, 163 renal calculi, 163 restless legs syndrome, 162 somnolence, 161 topiramate, interaction, 164 toxic epidermal necrolysis, 163 tremor, 162 valproic acid, interaction, 164 weakness, 161 xerosis and pityriasis, 163 zuclopenthixol aggressive behavior, 112
diarrhea, 112
insomnia, 112
nausea, 112
Index of adverse effects
A abdominal cramps barium, 850
bisacodyl, 671
dimethyl fumarate þ
monoethyl fumarate, 295
lanreotide, 797
octreotide, 797
opioids, 186
abdominal discomfort alosetron, 666
barium, 850
etanercept, 683
mebendazole, 574
prednisone, 682
saquinavir þ ritonavir, 532
sugammadex, 275
abdominal distension acarbose, 772
alprostadil, 729
digoxin, 916
abdominal pain alosetron, 666
amiodarone, 345
atomoxetine, 8
azathioprine, 717–18, 906
azithromycin, 473
bisacodyl, 671
buserelin, 789
carbamazepine, 131
dacarbazine, 828
deferoxamine þ deferiprone,
426
dimethyl fumarate þ
monoethyl fumarate, 295
doxycycline, 451, 574
febuxostat, 235
fumaric acid esters, 295
glucagon, 769
lamivudine, 532
leuprolide acetate, 789
levofloxacin, 468
lubiprostone, 672
mesalazine, 669
metformin, 773, 774
methylnaltrexone, 211
metronidazole, 526
moguisteine, 326
moxifloxacin, 473
oseltamivir, 544
praziquantel þ albendazole, 572
pyrantel pamoate, 574
ranitidine bismuth citrate, 414
rosiglitazone, 781
sapropterin, 609–10
sevelamer, 897
simvastatin þ perindopril, 773
sodium phosphate, 671
sodium picosulfate, 671
sulfasalazine, 670
tacalcitol, 301
temozolomide, 830
Yan Hu Ning injection, 882
zidovudine, 532
zonisamide, 162
abstinence syndrome, protracted heroin, 189
accidental injury alefacept, 680
zileuton, 323
Achilles tendinopathy see tendinopathy acidosis see metabolic acidosis acne azithromycin, 473, 542
fluticasone þ salmeterol, 542
infliximab, 684
lamivudine þ ritonavir, 542
phosphate þ tretinoin, 301
ritonavir, 542
stanozolol, 754
acrodermatitis continua of Hallopeau terbinafine, 492
actinomycosis infliximab, 685
activated partial thromboplastin time, prolongation ciprofloxacin, 465
acute angle-closure glaucoma co-trimoxazole, 477
tiotropium, 319
acute asthma acupuncture, 886
Shuang Huang Lian
injection, 882
zileuton, 323
acute bilateral angle closure topiramate, 153
acute coronary syndrome psilocybin, magic mushrooms, 69–70 acute disseminated
encephalomyelitis
yellow fever vaccine, 586
acute febrile neutrophilic
dermatosis
clindamycin, 472
co-trimoxazole, 478
ioxitalamate, 849
acute generalized
exanthematous pustulosis
(AGEP)
azathioprine, 717
clindamycin, 472
ivermectin, 575
morphine
pseudoephedrine, 282
terbinafine, 492
acute generalized skin
eruptions
adalimumab, 679
acute hypertensive crisis acupuncture, 886
acute hypotensive crisis acupuncture, 886
acute intoxication terazosin, 393
acute leukemia linezolid, 476
pethidine, 476
acute lymphoblastic leukemia cyanoacrylates, 894
acute myeloid leukemia G-CSF, 675
temozolomide, 831
acute renal failure see renal failure acute renal insufficiency see renal insufficiency acute respiratory distress
syndrome (ARDS)
amiodarone, 340
anakinra, 677
colistimethate sodium, 477
acute tubular necrosis chromium picolinate tenofovir, 543
959
Index of adverse effects
960 adenovirus pneumonia infliximab, 685
adrenal insufficiency etomidate, 250
fluconazole, 502
megestrol acetate, 749
adrenal suppression etomidate, 249, 250
fluconazole, 503
glucocorticoids, 313, 871
ritonavir, 542
adult respiratory distress syndrome see acute respiratory distress syndrome AGEP see acute generalized exanthematous pustulosis age-related macular degeneration ACE inhibitors þ statins, 380
thyroid hormones, 764
aggression anabolic steroids, 753
atomoxetine, 8
levetiracetam, 138, 149
statins, 803
agitation butorphanol, 211
digoxin, 916
diphenhydramine, 307
fentanyl þ midazolam, 193
gamma-hydroxybutyric acid
(GHB), 68
guaifenesin þ
phenylpropanolamine, 467
iotrolan þ mepivacaine, 844
levetiracetam, 149
levetiracetam þ valproate, 140
levofloxacin, 467
mepivacaine þ prilocaine, 261
methoxyflurane, 245
methylphenidate, after
risperidone withdrawal, 13
nalmefene, 211
olanzapine, 108
prilocaine, 261
risperidone, 108
sevoflurane, 245
statins, 808
temozolomide, 830
valproate þ levetiracetam, 160
venlafaxine, 352
ziprasidone, 111
agranulocytosis see also granulocytopenia,
leukopenia, neutropenia
antithyroid drugs, 765
carbimazole, 766
clozapine, 97
co-trimoxazole þ
sulfasalazine, 477
deferasirox, 427
deferiprone, 427–8
deferoxamine þ deferiprone,
426
methimazole, 766
ritodrine, 289
thionamides, 765
vancomycin, 469
airway malalignment ketamine, 250
airway obstruction ACE inhibitors, 381, 382
adenosine, 337
131 I (radioiodine), 764
lidocaine, 381
airway pressure, increased gelofusine, 595
akathisia clozapine, 96
olanzapine, 100
risperidone, 472, 791, 814
tetrabenazine, 91, 277
alanine transaminase (AIT) see liver function tests albumin-to-creatinine ratio, altered pegaptanib, 865
alcoholic cerebellar degeneration alcohol, 891
alkalosis topiramate, 153
allergic rashes see rashes allergic reactions ACE inhibitors, 381
amoxicillin þ clavulanic
acid, 450
anesthesia, 265
aprotinin, 645
Artemisia vulgaris, 884
atropine, 291
benzbromarone, 234
beta-lactams, 445
botulinum toxin, 277
brimonidine, 874
brinzolamide, 403, 874
C1 esterase inhibitor, 594
carbapenem, 447
chlorhexidine, 439
Ci Wu Jia injection, 881
clavulanic acid, 450
co-trimoxazole, 477
coxibs, 232
cyanocobalamin, 608
detemir, 770
dimethyl fumarate, 296
eye-drops, 463
fluoroquinolones, 465
formaldehyde, 437
gadolinium-based contrast
agents, 855
glargine, 770
intralipid, 261
iobitridol, 843
iomeprol, 843
iopromide, 843
irbesartan, 386
latanoprost, 871
moxibustion, 884
neomycin, 462, 463
nickel, 419
pegaptanib, 866
penicillin, 447
pimecrolimus, 297
polyvinylpyrrolidone, 441
povidone–iodine, 441
prilocaine, 265
Qing Kai Ling injection, 881
Shen Mai injection, 882
sulfamethoxazole, 478
sulfonamides, 405
tenofovir þ didanosine, 533
thiomersal, 419
titanium, 420
valaciclovir, 530
valerian, 884
Yan Hu Ning injection, 882
alopecia
adalimumab, 679
albendazole, 573
atazanavir, 541
carbamazepine, 129
dacarbazine, 829
indinavir, 541
infliximab, 684
lamivudine, 531
mycophenolate, 710
quetiapine, 107
temozolomide, 831
valproate, 154
AlT activity see liver function tests alveolar fibrosis amiodarone, 341
alveolar hemorrhage eptifibatide, 639
pimecrolimus, 712
Alzheimer’s disease aluminium, 413
amenorrhea
dihydrocodeine, 191
domperidone, 665
metoclopramide, 665
olanzapine, 102
opioids, 186
penicillamine, 430
ritonavir, 542
Index of adverse effects aminotransferases see liver function tests amnesia see also memory
baclofen, 276
gabapentin, 132
gamma-hydroxybutyric acid
(GHB), 68
pethidine, 205, 206
silver compounds, 420
temozolomide, 830
triazolam, 79
anal fissures nicorandil, 365
anal ulceration nicorandil, 365
anaphylactic reactions aprotinin, 645
basiliximab, 687
Chinese medicines, 881
fluorescein, 895, 896
folic acid, 608
gelofusine, 595
loperamide, 670, 671
non-IgE-mediated, 881
Shuang Huang Lian
injection, 882
succinylated gelatin, 595
transfusion-related, 593
anaphylactic shock dacarbazine, 829
nefopam, 212
Qing Kai Ling injection, 881
Shuang Huang Lian
injection, 882
Yan Hu Ning injection, 882
Yu Xing Cao injection, 883
anaphylaxis antibiotics, intrapartum, 446
antibiotics, intravenous, 446
chlorhexidine, 439
clindamycin, 472
contrast media, 849
co-trimoxazole, 477
deferasirox, 426, 427
diamorphine, 263
factor IX, 596
fluoroquinolones, 446, 465,
559
gadobenate dimeglumine,
855
glycopeptides, 469
hydroxocobalamin, 608
increlex, 676
intralipid, 262
iodinated contrast media, 850
ioversol, 850
omalizumab, 691
oxytocin, 795, 796
penicillin, 447
961 rabies vaccine, 582
sitagliptin, 775
temozolomide, 831
TNF-a antagonists, 685
vancomycin, 469
yeast, 446
anasarca
hepatic arterial embolization,
900
ANCA see antineutrophil cytoplasmic antibodies (ANCA) ancillary hairs, around eyelids prostaglandins, 730, 873
anemia
see also aplastic anemia,
autoimmune hemolytic
anemia
ACE inhibitors, 375, 381
alemtuzumab, 686
amantadine þ ribavirin, 545
amphotericin, 494
anesthesia, 267
azathioprine þ prednisone,
718
ceftriaxone, 449
dacarbazine, 828
daptomycin, 478
deferiprone, 428
deferoxamine, 428
endothelin receptor
antagonists, 389
epoetin alfa, 598
epoetin delta, 598
erythropoietin, 598
ethambutol, 562
irbesartan, 386
leflunomide, 709
linezolid, 470, 475
mefloquine, 523
methylphenidate, 13
nicorandil, 365
ragaglitazar, 782
ranitidine, 364, 414
ribavirin, 531
temozolomide, 830
tesaglitazar, 783
tetrathiomolybdate, 432
trientine, 432
zinc, 445, 848
angina
see also myocardial infarction
ligustrazine, 881
angina pectoris rosiglitazone, 781
angioedema
ACE inhibitors, 381–3
angiotensin II receptor
antagonists, 386
benazepril, 380
bezafibrate, 805
captopril, 381
cilazapril, 381
diclofenac, 382
enalapril, 381
eptifibatide, 639
imidapril, 382
lisinopril, 381, 383
nefopam, 212
olmesartan medoxomil, 387
oxcarbazepine, 144
pegaptanib sodium, 866
ramipril, 385
sitagliptin, 775
telithromycin, 471, 472
valaciclovir, 530
angle closure glaucoma topiramate, 152
anion gap, negative lithium, 45
anorexia see appetite loss anosmia amiodarone, 342
dorzolamide, 405
anterior chamber inflammation pegaptanib, 865, 866
anterior uveitis clomiphene citrate, 743
methadone, 466
travoprost, 873
trimethoprim, 477
anterior uveitis, granulomatous brimonidine, 870
antibodies, development adalimumab, 679
anticholinergic effects olanzapine, 100
risperidone, 100
anticonvulsant hypersensitivity syndrome lamotrigine, 136
antimuscarinic syndrome propofol, 254
antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis adalimumab, 679
antithyroid drugs, 765
minocycline, 454
antiphospholipid syndrome gonadotrophins, 735
antithyroid microsomal antibodies salt iodization, 764
anuria aprotinin, 645
dextran, 595
streptokinase, 637
Index of adverse effects
962 anxiety atorvastatin, 807
clonidine, 391
domperidone, 665
efavirenz, 538
glucocorticoids, 723
infliximab, 684
levacetylmethadol, 195
levetiracetam, 139, 141, 372
levetiracetam þ valproate, 140
methylphenidate, 391
nalmefene, 211
naltrexone, 211
olanzapine, 108
progestogens, 747
psilocybin
risperidone, 108
tartrazine, 896
temozolomide, 830
valproate þ levetiracetam, 160
aortic dissection cocaine, 60
aortic valvular disease fenfluramines, 7
apathy levetiracetam, 149
zonisamide, 162
aplasia cutis congenita antithyroid drugs, 766
carbimazole therapy, 766
aplastic anemia see also anemia
carbamazepine, 473, 492
chloramphenicol, 464
clopidogrel, 639
dacarbazine, 828
phenobarbital, 145
temozolomide, 832
apnea ACE inhibitors, 377, 379
chloral hydrate, 79
colistin, 476
fentanyl þ midazolam, 191,
193
fluconazole, 502
ketamine, 251
midazolam, 78
mivacurium, 274
morphine, 199
obstetric anesthesia, 265
oxymorphone þ cimetidine,
205
polymyxins, 476
Shuang Huang Lian
injection, 882
suxamethonium, 274
tramadol, 208
apoptosis gallium maltolate, 416
selenium, 420
appetite loss albendazole, 573
cholinesterase inhibitors,
20
ciprofloxacin, 465
dacarbazine, 828
indapamide, 408
isoniazid, 562
lamivudine, 531
lead contamination, 883
levacetylmethadol, 195
levetiracetam, 138, 372
metformin, 774
methylphenidate, 391
mycophenolate, 711
ondansetron, 666
ramosetron, 666
temozolomide, 830
terbinafine, 491
topiramate, 149, 150, 151
tramadol, 208
zonisamide, 161, 162
appetite, reduced atomoxetine, 8
metformin, 774
methylphenidate, 10
sapropterin, 610
topiramate, 150
zonisamide, 161, 162
argyria silver salts, 420
argyria-like symptoms silver sulfadiazine, 393
arousal, reduced metamfetamine, 5
arrhythmias see dysrhythmias arsenic keratosis arsenic, 414
arterial hypertension see hypertension arterial pressure, increased human erythropoietin, 599
methylergometrine, 795
prednisone, 724
arterial thrombosis immunoglobulins,
intravenous, 595
ranibizumab, 868
warfarin, 617
arteritis adalimumab, 679
cannabis, 55
arthralgia alefacept, 680
azathioprine þ prednisolone,
717
co-trimoxazole, 477
deferoxamine þ deferiprone,
426
diethylcarbamazine þ
albendazole, 574
efalizumab, 688
exemestane, 744, 745
gatifloxacin, 466
infliximab, 685
lamivudine, 531
minocycline, 454
olanzapine, 104
temozolomide, 831
trimethoprim, 477
arthritis aromatase inhibitors, 745
arsenic trioxide, 414
auranofin, 416
deferiprone, 428
efalizumab, 688
methotrexate, 682
moxifloxacin, 468
rubella vaccine, 581
arthropathy deferoxamine, 426
fluoroquinolones, 465
ofloxacin, 469
aseptic meningitis deferoxamine þ deferiprone,
426
efalizumab, 688
immunoglobulins, 595
lamotrigine, 135
NSAIDs, 230
aspartate transaminase (AsT) see liver function tests aspiration pneumonitis propofol, 253
AsT activity see liver function tests asterixis cycloserine, 561
asthma acupuncture, 886
adenosine, 337
beta2- adrenoceptor agonists
(LABAs), 314
beta-blockers, 364
DTP immunization, 580
formaldehyde, 438
glutaral, 438
Huoxiang Zhengqi oral
liquid, 879
omalizumab, 690
Shuang Huang Lian
injection, 882
zileuton, 322
asystole interpleural anesthesia, 263
ataxia amiodarone, 342
carbamazepine, 131, 492
clarithromycin, 474
Index of adverse effects gabapentin, 132
lamotrigine, 124, 137
metronidazole, 526
pregabalin, 124, 146
propoxyphene, 187
Shan Dou Gen, 885
temozolomide, 830
atherosclerosis
anabolic steroids, 752
cocaine, 348
magnesium, 346, 347, 351
atopic dermatitis infliximab, 684
atrial fibrillation
adenosine, 337
amiodarone, 342
amphotericin þ flucytosine,
502
azathioprine, 717
captopril, 384
digoxin, 333, 334
disopyramide, 347
flecainide, 348
furosemide, 347
ketamine, 250
pilsicainide, 349, 350
atrioventricular block
adenosine, 337
carbamazepine, 127
etomidate, 248
magnesium salts, 418
pilsicainide, 349
attention, impaired topiramate, 150, 151
auditory acuity loss erythromycin, 474
auditory hallucinations
aciclovir, 530
guaifenesin þ
phenylpropanolamine, 467
levofloxacin, 467
meclizine, 467
nalmefene, 211
rofecoxib, 233
autism
clonidine, 391
mercury, 419
MMR vaccine, 581
autoantibodies insulin, 770
autoimmune disorders interferons, 676
autoimmune hemolytic
anemia
stem cells, 540
unrelated cord blood,
transplantation, 600
autoimmune hepatitis infliximab, 684
minocycline, 453
963 peginterferon alfa þ
ribavirin, 676
statins, 811
terbinafine, 491
autoimmune thrombocytopenia cord blood, unrelated,
transplantation, 600
autoimmune thyroid disease alemtuzumab, 686, 687
amiodarone, 344
ethambutol, 563
isoniazid, 563
pyrazinamide, 563
rifampicin, 563
autoimmune thyroiditis antipsychotic drugs, 87
interferons, 676
peginterferon alfa þ
ribavirin, 676
azoospermia clomiphene citrate, 744
B B lymphocyte tolerance, impaired hydralazine, 393
baboon syndrome contact allergen, 849
back pain alefacept, 681
amphotericin, 494
bupivacaine, 262
immunoglobulins,
intravenous, 595
lidocaine, 262
methylprednisolone acetate,
262
perflutren þ Definity, 856
temozolomide, 831
zileuton, 323, 324
bacterial infections eflornithine, 526
infliximab, 683
terlipressin þ albumin,
591
bad feeling nalbuphine, 211
bad taste dorzolamide, 404, 874
fish oil supplements, 806
timolol, 874
bad trip, psychotic reaction psilocybin, 70
balance, loss of digoxin, 336
opioids, 186
ballismus lamotrigine, 135
Bartter-like syndrome alprostadil, 729
B-cell depletion thiazides, 407
behavioral disturbances atorvastatin, 807
levetiracetam, 138, 141
montelukast, 320
prazosin, 392
zonisamide, 162
benign intracranial hypertension see intracranial hypertension, benign bezoar barium, 851
biliary disorders nevirapine, 539
biliary sludge ceftriaxone, 449
biliary tract abnormalities somatostatin, 796
bilirubin increase anidulafungin, 508
birth defects lamotrigine, 136
birth weight, low khat, 69
methadone, 198
warfarin, 619
bitter taste dorzolamide, 874
statins, 808
black hairy tongue erythromycin, 474
linezolid, 476
bleeding abciximab, 638
acenocoumarol, 624
acupuncture, 886
alteplase, 637
amoxicillin, 621
antithrombin III, 594
apixaban, 635
aspirin þ thienopyridine and
warfarin, 639
azithromycin, 621
ban mao, 886
captopril, 384
cefradine, 621
chondroitin sulfate þ
glucosamine, 623
ciprofloxacin, 621
clopidogrel, 639
co-amoxiclav, 621
co-trimoxazole, 621
coumarins, 621, 624, 636
dabigatran, 633
danaparoid, 631, 632
dexketoprofen, 231
doxycycline, 621
drotrecogin, 591–3
Index of adverse effects
964 enoxaparin, 633, 635
eptifibatide, 639
fondaparinux, 636
ginger, 625
heparin, 630, 631
idraparinux, 636
neomycin, 621
noscapine þ warfarin, 624
otamixaban, 635
pheneticillin, 621
phenprocoumon, 624
rivaroxaban, 635
SSRIs, 624
tetracycline, 621
tipranavir, 542
tranexamic acid, 643
valproate, 156
warfarin, 621, 814, 880
warfarin þ glucosamine, 623
bleeding time, prolonged valproate, 156
blepharoconjunctivitis isotretinoin, 299
phenylephrine, 284
blepharospasm clozapine, 96
blistering dihematoporphyrin ether, 833
terlipressin, 799
bloating bisacodyl, 671
buserelin, 789
dimethyl fumarate þ
monoethyl fumarate, 295
gonadorelin (GnRH), 789
opioids, 186
sodium phosphate, 671
blood clots darbepoetin, 599
epoetin, 599
sevelamer, 897
blood pressure, increased see also hypertension
ACE inhibitors, 383
aliskiren, 388
amphetamines, 895
antihypertensive
medications, 375
atomoxetine, 11
ciclosporin, 339, 430, 497
dobutamine, 350
erythropoietin, 599
felodipine, 377
indacaterol, 317
khat, 69
methylergometrine, 795
methylphenidate, 11
metoprolol, 364, 365
NSAIDs, 382, 682
phenylephrine, 284
pilsicainide hydrochloride,
351
prednisone, 724
sibutramine, 18
tacrolimus, 714
torcetrapib, 816
venlafaxine, 35
blood pressure, reduced adenosine receptor agonists,
338
ritodrine, 289
sevelamer, 897
bloody diarrhea doxycycline, 452
blue-grey skin pigmentation amiodarone, 345
blue sclerae minocycline, 453
blurred vision see vision, blurred body dysmorphic disorder anabolic steroids, 753
body image disorders anabolic steroids, 753
body temperature, increased methylnaltrexone, 211
body weight, low cardiac glycosides, 334
bone density, abnormal carbamazepine, 130
medroxyprogesterone
acetate, 749
oxcarbazepine, 143
phenytoin/phenobarbital, 126
bone loss aromatase inhibitors, 743
glucocorticoid therapy, 313
prednisone, 727
bone marrow granulomata amiodarone, 345
bone marrow suppression stem cells, 600
valproate, 156
bone tenderness vitamin A, 607
BOOP see bronchiolitis obliterans organizing pneumonia (BOOP) borderline ovarian tumors, higher risk clomiphene, 744
gonadotrophins, 744
bowel movements, increased metformin, 774
bowel obstruction infliximab, 683
sevelamer, 897
bradycardia adenosine, 338
alfentanil þ propofol, 187
amiodarone, 340
anesthesia, interpleural,
263
apraclonidine, 869
baclofen, 276
blood stem cells, 599
blood transfusion, 600
brinzolamide, 403, 874
brinzolamide þ
levobetaxolol, 403
bupivacaine þ adrenaline,
265
carteolol, 870
cetirizine, 351
clonidine, 11, 391
daclizumab, 687
digoxin, 333, 334, 335
eptifibatide, 639
iomeprol, 843
iopamidol, 843
levobetaxolol, 403, 874
lithium, 43
magnesium salts, 418
metformin, 773
methylprednisolone, 724
morphine, 199
ribavirin, 531
somatostatin, 796
terazosin, 393
timolol, 870
verapamil, 368
bradydysrhythmias methylprednisolone, 724
bradykinesia losartan, 387
brain-derived neurotrophic factor heroin, 188
brain hemorrhage buprenorphine þ cannabis,
210
brainstem anesthesia retrobulbar block, 265
breast cancer dacarbazine, 829
ethanol, 892
fluvastatin, 811
breast enlargement domperidone, 665
metoclopramide, 665
breast pain bicalutamide, 755
breast reduction tamoxifen, 746
breast tenderness domperidone, 665
metoclopramide, 665
breath, unpleasant fish oil supplements, 806
Index of adverse effects breath, shortness of azathioprine, 717
ban mao, 886
Ecbalium elaterium juice, 885
gabapentin, 131
Shen Mai injection, 882
sirolimus, 713
telithromycin, 472
Yan Hu Ning injection, 882
breathlessness acupuncture, 886
carteolol, 870
bronchiolitis obliterans amiodarone, 341
azathioprine, 717
cidofovir, 529
bronchiolitis obliterans organizing pneumonia (BOOP) carbamazepine, 130
everolimus, 708
sulfasalazine, 670
bronchitis zileuton, 323
bronchoconstriction carteolol, 870
bronchospasm see also asthma
adalimumab, 679
adenosine, 337, 338
blood transfusion, 534
bupivacaine, 262
formaldehyde, 438
gadobenate dimeglumine, 855
gelofusine, 595
isoflurane, 244
nadolol, 364
tobramycin, 463
tramadol, 208
zileuton, 322
brown staining of teeth chlorhexidine, 439
Brugada-like changes pilsicainide, 350
propafenone, 352
Brugada-like syndrome cannabis, 56
cocaine, 59
Brugada pattern phenytoin, 145
Brugada syndrome indapamide, 407, 408
lithium, 43
mesalazine, 669
pilsicainide, 350
bruisability, easy methylphenidate, 13
bruising chondroitin sulfate þ
glucosamine, 623
965 doxycycline þ warfarin, 622
drotrecogin, 592
glucocorticoids, inhaled, 312
heparin, 631
quinidine, 352
terlipressin, 799
warfarin, 453, 626
warfarin þ glucosamine,
623
bullous lesions captopril, 384
bullous fixed drug eruption ciprofloxacin, 466
bullous lung disease cannabis, 56
bull’s-eye maculopathy mefloquine, 523
burning sensation latanoprost, 871
quinine, 524
burning/stinging carteolol, 870
burping fish oil supplements, 806
C calcific myofibrosis pentazocine, 205
calciphylaxis warfarin, 617
calculi see gallstones, nephrolithiasis, salivary stones, urate and oxalate stones cancers see also individual names and
organs
epoetin, 599
infliximab, 684
candidiasis, invasive caspofungin, 509
capillary leak syndrome acitretin, 298
albumin, 591
carbon dioxide pressure, transcutaneous, raised morphine, 199
carcinoid tumor infliximab, 684
cardiac abnormalities olanzapine, 103
cardiac arrest alfentanil þ propofol, 187
anticholinergic drugs, 318
bupivacaine, 267
cardiac glycosides, 335
clonidine, 391
cocaine, 58
indapamide, 407
misoprostol, 731
posaconazole þ
voriconazole, 505
prothrombin complex, 597
ropivacaine, 269
Shuang Huang Lian
injection, 882
smallpox vaccine, 583
suxamethonium, 273
voriconazole, 505
cardiac complications valerian, 884
cardiac conduction abnormalities propofol, 252
cardiac dysrhythmias amiodarone, 339
amphotericin B deoxycholate
(DAMB), 494, 916
antifungal azoles, 502
dofetilide, 347, 348
domperidone, 665
ethanol, 891
flecainide, 348
isotretinoin, 298
phenylephrine, 283
pilsicainide, 351
pseudoephedrine, 283
tamoxifen, 746
verapamil, 367
cardiac failure captopril, 384
cardiac malformations paroxetine, 32
cardiac memory propafenone, 351–2 cardiac problems beta2-adrenoceptor agonists,
316
bupropion, 32
minoxidil, 297
mucolytics, 325–6
opioids, 183
cardiac rhythm disturbances methylprednisolone, 724
cardiac wall motion abnormalities opioids, 184
cardiac valve disease, fibrotic dopamine receptor agonists,
286
cardiomyopathy anabolic steroids, 752
anagrelide, 637
clozapine, 95
hydroxychloroquine, 521
liposomal amphotericin B
(L-AmB), 496
liposomal amphotericin B
(L-AmB) þ flucytosine, 497
metamfetamine, 4
Index of adverse effects
966 cardiothoracic ratio, increased rosiglitazone, 781
cardiovascular collapse flecainide, 348
gelofusine, 595
local anesthetics, topical,
268
cardiovascular deaths anticholinergic drugs,
inhaled, 318
cardiovascular depression anesthetics, local, 262
cardiovascular disease beta2-adrenoceptor agonists,
315
cardiovascular disorders sibutramine, 17–18 cardiovascular effects khat, 69
cardiovascular events voriconazole, 505
cardiovascular physiology cocaine, 58
cardiovascular risk coxibs, 225
carnitine depletion pivoxil, 448
carotid intima media thickness, increased growth hormone, 791
cataplexy clozapine, 96
cataract chlorhexidine, 439
caustic ingestion metamfetamine, 7
cavitating pneumonia leflunomide, 709
cellulitis ciprofloxacin, 465
iodinated contrast media, 850
isotretinoin, 300
moxifloxacin, 468
vaccinia virus infection, 583
central nervous system depression syndrome bismuth subsalicylate, 916
heroin, 189
olanzapine, 104
central physeal arrest vitamin A, 607
central retinal vein occlusion clomiphene citrate, 743
cerebellar ataxia amiodarone, 342
growth hormone, 794
tacrolimus, 714
cerebellar atrophy phenytoin, 145
tacrolimus, 715
cerebellar degeneration alcohol, 891
cerebellar demyelination isotretinoin, 299
cerebellar dysfunction cannabis, 56
lithium, 44
cerebellar lesions metronidazole, 525, 526
cerebellar symptoms phenytoin, 145
cerebral emboli perfluorocarbon emulsion, 594
cerebral hemorrhage temozolomide þ
radiotherapy, 830
cerebral ischemia isotretinoin, 299
cerebral vasospasm buprenorphine þ cannabis,
210
cerebral venous thrombosis emergency contraception,
742
cerebrovascular disease cannabis, 55
cerebrovascular dysfunction coxibs, 225
non-selective NSAIDs, 225
cervical dystonia quetiapine þ valproic acid,
154
chemical burns Allium sativum, 884
chemical synovitis iodinated contrast media, 850
chemosis fluoroquinolones, 465
chest discomfort blood transfusion, 600
chest distension Houzheng Wan, 880
Shen Mai injection, 882
Yan Hu Ning injection, 882
chest distress Ci Wu Jia injection, 881
ligustrazine, 881
Shen Mai injection, 882
Yu Xing Cao injection, 883
chest pain acupuncture, 886
Adderall, 2
adenosine, 338
alteplase, 637
azathioprine þ infliximab,
684
aminolevulinic acid, 833
ciclosporin, 708
clenbuterol, 289
cocaine, 59
eptifibatide, 639
everolimus, 708
hematoporphyrin derivative,
833
iron dextran, 417
iron salts, 417
isotretinoin, 300
liposomal amphotericin B
(L-AmB), 495
mesalazine þ infliximab, 684
metoprolol, 364
metronidazole, 526
nitrofurantoin, 476
oxytocin, 795
pilsicainide, 350
porfimer, 833
regadenoson, 338–339
chest tightness
cyanocobalamin, 608
diatrizoate þ lidocaine þ
gadolinium, 850
propafenone þ citalopram,
352
chills
alemtuzumab, 686
dacarbazine, 829
doxycycline, 420
immunoglobulins, 536, 595
infliximab, 684
sirolimus, 712
trimethoprim, 477
choanal atresia carbimazole therapy, 766
cholangitis, obstructive barium, 851
cholangitis, overlap
antimitochondrial antibody-
positive
peginterferon alfa þ
ribavirin, 676
cholelithiasis
abacavir, 543
cefotaxime, 449
ceftriaxone, 449
lamivudine, 543
tenofovir, 543
zidovudine, 543
cholestasis
alfuzosin, 392
anabolic steroids, 754
CAM þ adulterants, 879
cefotaxime, 449
moxifloxacin, 468
nutrition, parenteral, 612
pregabalin, 148
terbinafine, 491
cholestatic hepatitis
co-trimoxazole, 478
oxcarbazepine, 144
oxycodone, 203
Index of adverse effects cholestatic jaundice azithromycin, 473
clarithromycin, 473
fosinopril, 385
methimazole, 766
cholesterol and triglyceride concentrations, increased olanzapine, 101
cholesterol, increased indinavir þ saquinavir, 532
lopinavir þ stavudine, 532
chondrodysplasia punctata warfarin, 619
chorea artesunate, 525
gabapentin, 133
tetrabenazine, 91
choroidal detachment dorzolamide, 404
latanoprost, 729, 730, 872
tamsulosin, 392
choroidal hypoperfusion photodynamic therapy þ
verteporfin, 869
chronic intestinal pseudoobstruction buserelin, 789
chronic obstructive pulmonary disease (COPD) inhaled glucocorticoids, 311,
312
chronic plaque psoriasis, severe exacerbation efalizumab, 688
chronic ulcerative cystitis ketamine, 252
circulatory overload terlipressin þ albumin, 591
cirrhosis parenteral nutrition, 612
Clostridium botulinum heroin, 189
CNS bleeding drotrecogin, 592–3 coagulopathy alemtuzumab, 686
ciprofloxacin, 465
heparin, 475
plasma substitutes, 594
vitamin A, 607
coccidioidomycosis pneumonia infliximab, 685
cochlear toxicity amikacin, 461
kanamycin, 461
neomycin, 461
cognition, impaired see also thinking
gabapentin, 132
cognitive deficits
967 zonisamide, 163
cognitive disorder/problems
buprenorphine, 209
carbamazepine, 127
ecstasy, 64, 66
levetiracetam, 138, 141
lithium, 44
opioids, 183
pregabalin, 147
progestogens, 747
toluene, 899
topiramate, 123, 151
valerian, 884
cognitive impairment opioids, 186
topiramate, 124, 150
cold agglutinin disease etanercept, 683
cold limbs Ci Wu Jia injection, 881
colitis mesalazine, 669
colitis, collagenous lansoprazole, 667
colitis, microscopic clozapine, 97
collapse 1-benzylpiperazine, 55
colorectal cancer estrogens, 738
infliximab, 684
color vision impairment linezolid, 475
color vision loss tamoxifen, 746
coma
dimethylsulfoxide (DMSO),
894
diphenhydramine, 307
compartment syndrome simvastatin, 815
complexion, red Yan Hu Ning injection, 882
compulsive singing dopamine, 288
concentration, lack of
diazepam, 146
pregabalin, 146
topiramate, 150
confusion
calcineurin inhibitors, 705
chlorzoxazone, 277
colistin
dacarbazine, 828
ethambutol, 562
formoterol, 317
iotrolan and mepivacaine, 844
lithium, 352
metronidazole, 526
morphine, 201
nefopam, 212
opioids, 183
oxycodone, 202
oxymorphone þ cimetidine,
205
pregabalin, 147
Shen Mai injection, 882
statins, 803, 808
temozolomide, 830
valproate, 154
congenital abnormalities metformin, 774
congenital heart defects fluconazole, 503
congenital malformations
bupropion, 32
cephalosporins, 447
fluconazole, 503
leflunomide, 710
penicillins, 447
rubella vaccine, 582
congestive heart failure
cilostazol, 371
hydroxychloroquine, 522
pseudoephedrine, 283
conjunctival congestion
Shuang Huang Lian
injection, 882
conjunctival cysts minocycline, 453
conjunctival hyperemia
bimatoprost, 871
carteolol, 870
fluoroquinolones, 465
latanoprost, 871
travoprost, 871
conjunctival inflammation dorzolamide þ timolol, 405
conjunctival irritation ribavirin, 531
conjunctival metaplasia carbamazepine, 128
consciousness, altered level calcineurin inhibitors, 705
consciousness, loss of
fentanyl, 192
gentamicin, 462
valaciclovir, 530
constipation
albendazole, 573
alosetron, 666
amitriptyline, 131
antihypertensive
medications, 375
aprepitant, 667
bisacodyl, 671
buprenorphine, 209
calcium channel blockers, 375
fentanyl, 191
gabapentin, 131
Index of adverse effects
968 hydromorphone, 193
hyoscine butylbromide, 672
indapamide, 407
itraconazole, 502
itraconazole þ vincristine, 502
lead contamination, 883
levofloxacin, 468
lubiprostone, 671
magnesium oxide, 418
mebendazole, 573
methadone, 209
morphine, 200
mycophenolate, 711
olanzapine, 100
ondansetron, 666
opioids, 183, 186, 204, 205
oxycodone, 202
oxymorphone, 203, 204
porfimer, 833
quetiapine þ lithium, 105
ramosetron, 666
sevelamer, 897
sodium picosulfate, 671
temozolomide, 830
tramadol, 209
zonisamide, 162
contact dermatitis diclofenac, 382, 499
dimethyl fumarate, 295, 296
dorzolamide, 405
emla cream, 268
ethylenediamine, 298
lidocaine, 267, 268
paraphenylenediamine, 296
phosphate þ tretinoin, 301
photodynamic therapy,
topical, 298
pimecrolimus, 297, 712
tacrolimus, 297
contact lenses, reduced tolerance isotretinoin, 299
contact sensitivity chloramphenicol, 464
contrast induced nephropathy iodixanol, 847
convulsions anabolic steroids, 753
benzylpiperazine, 55
calcitonin
desmopressin, 798
gatifloxacin, 466
levofloxacin, 467
nefopam, 212
oseltamivir, 544
coordination abnormalities temozolomide, 830
COPD see chronic obstructive pulmonary disease (COPD)
corneal diameter, increased brinzolamide, 874
levobetaxolol, 874
corneal opacities isotretinoin, 299
corneal perforation gatifloxacin, 466
coronary artery atherosclerosis loperamide, 670
coronary artery vasospasm adenosine, 337
coronary atherosclerosis,
accelerated
cocaine, 58
coronary steal dipyridamole, 638
coronary syndrome, acute psilocybin, magic mushrooms, 69–70 coronary vasoconstriction cocaine, 58
cortical blindness, transient iobitridol, 844
iomeprol, 844
cortical hyperostosis alprostadil, 729
corticosteroids see glucocorticoids cotton wool spots, optic fundi interferon, 676
cough ACE inhibitors, 375, 377,
379, 380
aldesleukin, 677
amphotericin B lipid complex
þ fluconazole, 495
antihypertensive
medications, 375
arsenic, 414
azathioprine, 717
carvedilol, 364
everolimus, 708
Exubera, 772
fentanyl, 192
formaldehyde, 437, 438
indacaterol, 317, 318
isoniazid þ rifampicin þ
pyrazinamide, 564
losartan, 387
mefloquine, 523
methoxyflurane, 245
minocycline, 452
nevirapine, 539
nitrofurantoin, 476
sapropterin, 609, 610
sirolimus, 712, 713
temozolomide, 830
tobramycin, 464
voriconazole, 506
Yu Xing Cao injection, 883
creatine kinase activity, raised
ezetimibe þ statins, 804
lamivudine, 531
telbivudine, 531–2
creatinine clearance, fall in adefovir, 530
creatinine, increased
cidofovir, 529
itraconazole, 493
liposomal amphotericin B
(L-AmB), 495
tacrolimus, 714
tesaglitazar, 783
Creutzfeldt-Jakob disease growth hormone, 791
immunoglobulins, 596
Crohn’s disease etanercept, 682
CRP concentration, raised daptomycin, 478
crying spells clomiphene, 743
cryptococcal meningitis
amphotericin B deoxycholate
(DAMB), 494
infliximab, 685
cryptococcosis, disseminated
ciclosporin, 689
efalizumab, 689
methotrexate, 689
cryptococcosis, invasive adalimumab, 680
cryptogenic organizing
pneumonia
amiodarone, 341
cryptorchidism alcohol, 892
estrogens, 739
cryptosporidial enterocolitis
peginterferon alfa þ
ribavirin, 676
crystalluria sulfonamides, 477
Cushing’s syndrome gamma-hydroxybutyric acid (GHB), 69
hydrocortisone, 728
ritonavir, 542
cutaneous cross-reactivity
cetirizine, 306
hydroxyzine, 306
levocetirizine, 306
cutaneous eruptions
see also rashes
co-trimoxazole, 478
dexketoprofen, 232
oxcarbazepine, 144
cutaneous lupus erythematosus adalimumab, 679
leuprorelin, 790
Index of adverse effects cutaneous lupus-like syndrome terbinafine, 492
cutaneous mucormycosis infliximab, 684
cutaneous thinning inhaled glucocorticoids,
312
cutaneous vasculitis carvedilol, 364
leuprolide, 790
cyanosis amphotericin B
deoxycholate, 494
benzocaine, 267
local anesthetics, 265, 268
obstetric anesthesia, 265
prilocaine, 268
cystitis, chronic ulcerative ketamine, 252
cytomegalovirus antigenemia leflunomide, 710
cytomegalovirus infection alemtuzumab, 686
leflunomide, 710
D Dandy–Walker malformation warfarin, 619
darkening effect latanoprost, 872
dark stools bismuth salts, 414
death aminocaproic acid, 643, 644
amiodarone, 339, 346
anabolic steroids, 752, 753
antipsychotic drugs, 89
aprotinin, 643
beta2-adrenoceptor agonists,
316
boric acid, 439
bosentan, 389
botulinum toxin A, 276
brompheniramine, 282
carbinoxamine, 282
chlorphenamine, 282
chlorzoxazone, 277
co-amoxiclav, 450
dacarbazine, 828
darbepoetin, 599
dextromethorphan, 282
diethylstilbestrol þ
docetaxel, 739
digoxin, 333
doxylamine, 282
drotrecogin, 592
eflornithine, 526
epoetin, 599
ethanol, 282, 892
fentanyl, 499
969 gamma-hydroxybutyric acid
(GHB), 68
glucocorticoids, 311
hormone replacement
therapy (HRT), 740
insulin, 772
isoniazid, 555
labetalol, 364
linezolid, 474
loperamide, 670, 671
lubiprostone, 672
megestrol acetate, 749
misoprostol, 730, 731
paracetamol, 282
perflutren, 855
phenobarbital, 282
phenytoin, 282
propofol, 254, 421, 898
pseudoephedrine, 282
ramipril, 379
ropivacaine, 269
rosiglitazone, 781
salmeterol, 315
salmeterol þ fluticasone,
315
sub-Tenon’s block, 266
sulfonylureas, 777
tetrathiomolybdate, 432
tiotropium, 319
tolcapone, 290
torcetrapib, 816, 817
tranexamic acid, 643
trientine, 432
vitamin E, 611
zafirlukast, 321
deductive reasoning lorazepam, 76
deep bone pain opioids, 186
deep venous thrombosis immunoglobulins,
intravenous, 595
dehydration haloperidol, 100
porfimer, 833
delayed awakening sugammadex, 275
delayed conduction pilsicainide, 350
delayed hypersensitivity reactions danaparoid, 632
iodinated contrast media,
850
delayed postoperative respiratory depression oxymorphone, 204
delayed type IV
hypersensitivity
bupivacaine, 267
local anesthetics, 268
delayed type IV
hypersensitivity skin
reactions
heparin, 629
delayed wound healing inhaled glucocorticoids,
312
delayed puberty melatonin, 794
delirium aciclovir, 530
baclofen, 276
bupropion
clarithromycin, 473
diphenhydramine, 307
lamotrigine, 135
olanzapine, 104
opioids, 185
oseltamivir, 544
pethidine, 186
delusional parasitosis topiramate, 152
dementia antiepileptic drugs, 124
olanzapine
topiramate, 151
demyelinating disorders etanercept, 681
isotretinoin, 299
dendritic cell tumor, interdigitating tacrolimus, 297
depression adrenaline, 264
anabolic steroids, 753
anesthetics, local, 262
antidepressants, 31
antihypertensive drugs, 376
bupivacaine, 267
clonidine, 391
ecstasy, 67
fentanyl, 499
fluconazole, 499
interferon alfa, 676
khat, 69
levetiracetam, 138, 141, 149
mycophenolate, 710
olanzapine, 108
oxycodone, 202
peginterferon alfa þ
ribavirin, 676
risperidone, 108
statins, 803
tartrazine, 896
temozolomide, 830
tetrabenazine, 91, 277
voriconazole, 499
ziprasidone, 111, 112
zonisamide, 163
Index of adverse effects
970 depressive symptoms
barbiturates, 124
ecstasy, 67
lithium, 48
topiramate, 124, 149
vigabatrin, 124
derealization nalmefene, 211
dermatitis see also acrodermatitis, atopic dermatitis, contact dermatitis, eczematous dermatitis, exfoliative dermatitis, eyelid dermatitis, interstitial granulomatous dermatitis, perioral dermatitis, photoallergic contact dermatitis, photosensitive dermatitis, phototoxic dermatitis, radiation recall dermatitis, systemic contact dermatitis dorzolamide þ timolol, 405 moxifloxacin, 468 dermatitis herpetiformis infliximab, 684
dermatofibromata
glucocorticoid treatment, 726
methotrexate, 726
dermatomyositis
carbimazole, 766
statins, 811
terbinafine, 492
dermopathy, nephrogenic
fibrosing
gadolinium, 851
desaturation
blood transfusion, 600
fentanyl þ midazolam, 193
midazolam þ ketamine, 78
desensitization phenytoin, 146
desquamation
clopidogrel, 640
efalizumab, 688
phosphate þ tretinoin, 301
temozolomide, 831
diabetes insipidus didanosine, 535
lithium, 45
diabetes mellitus
antipsychotic drugs, 87–8
glucocorticoids, 723, 725
nelfinavir, 542
olanzapine, 108
quetiapine, 106–107
risperidone, 108
sibutramine, 17
tacrolimus, 714
thiazide-type diuretics, 406
diabetic ketoacidosis olanzapine, 102
Diamond–Blackfan anemia deferiprone, 428
diarrhea albendazole, 573, 574
alemtuzumab, 686
aliskiren, 388
allopurinol, 236
alosetron, 666
anidulafungin, 508
azathioprine, 717, 906
azithromycin, 473
barium, 850
benzbromarone, 234
bismuth subnitrate, 414
bismuth subsalicylate, 414
calcitonin, 789
cholinesterase inhibitors, 20
ciprofloxacin, 466
colloidal bismuth subcitrate,
414
dacarbazine, 828
dimethyl fumarate, 295
dimethyl fumarate þ
monoethyl fumarate, 295
domperidone, 665
dorzolamide, 404, 874
doxycycline, 451, 574, 575
eflornithine, 526
febuxostat, 235
fish oil supplements, 806
fluoroquinolones, 464, 465
furosemide, 610
gatifloxacin, 466
indinavir, 532
iron dextran, 417
lamivudine, 531, 532
lanreotide, 797
lansoprazole, 667
latanoprost, 404
levofloxacin, 468
lubiprostone, 672
mesalazine, 669
metformin, 774
moxifloxacin, 468
mycophenolate, 710, 711
nateglinide þ metformin, 776
nicorandil, 366
nucleoside reverse
transcriptase inhibitors, 532
octreotide, 797
oseltamivir, 544
oxymorphone, 204
posaconazole, 505
praziquantel, 572
praziquantel þ albendazole,
572
quetiapine þ lithium, 105
ranitidine bismuth citrate,
414
rimonabant, 19
risperidone, 105
roflumilast, 321, 322
sapropterin, 609, 610
sapropterin dihydrochloride,
610
saquinavir þ ritonavir, 532
sevelamer, 897
sodium picosulfate, 671
sugammadex, 275
sulfasalazine, 670
telmisartan, 388
temozolomide, 830
tenofovir, 537
tetracycline, 454
timolol, 874
tipranavir, 542
tolcapone, 289, 290
topiramate, 150
tripotassium
dicitratobismuthate, 414
vitamin C, 611
voriconazole, 505
zidovudine, 532
zileuton, 323
zonisamide, 162
zuclopenthixol, 112
diastolic blood pressure, reduced levetiracetam, 140
diastolic hypertension blood transfusion, 600
diffuse alveolar hemorrhage propylthiouracil, 765
digital hypoplasia warfarin, 619
Digitalis purpurea poisoning digitoxin, 334
dilated cardiomyopathy anakinra, 677
diplopia acitretin, 298
artemisinin
botulinum toxin, 277
clarithromycin, 474
dental anesthesia, 263
gabapentin, 132
ketamine, 251
lamotrigine, 124
discharge brinzolamide, 874
brinzolamide þ
levobetaxolol, 403
levobetaxolol, 874
discomfort brinzolamide, 874
brinzolamide þ
levobetaxolol, 403
Index of adverse effects levobetaxolol, 874
moxibustion, 884
discontinuation syndrome antidepressants withdrawal
symptoms, 31
disorientation butorphanol, 211
iotrolan and mepivacaine, 844
lamotrigine, 137
oxymorphone þ cimetidine,
205
valproate, 154
disseminated cryptococcosis ciclosporin, 689
efalizumab, 689
methotrexate, 689
dissociation nalmefene, 211
dissociative feelings prazosin, 392
distension oxycodone, 202
distractability ethambutol, 562
disulfiram-like reaction alcohol þ abacavir, 535
diuresis butorphanol þ naltrexone, 211
dizziness ACE inhibitors, 377
Adderall, 2
alfuzosin, 392
allopurinol, 236
ambrisentan, 389
bismuth salts, 414
buprenorphine, 209
carbamazepine, 131, 473, 492
ciprofloxacin þ clozapine,
466
citalopram, 352
clarithromycin, 473, 474
clopidogrel, 641
cyanocobalamin, 608
dacarbazine, 828
dexbrompheniramine þ
pseudephedrine, 306
diazepam, 146
diethylcarbamazine þ
albendazole, 451, 574
doxycycline, 451, 574
febuxostat, 235
felodipine, 377
fentanyl, 191, 192
fish oil supplements, 806
fluorescein, 895
formoterol, 314
gabapentin, 124, 131, 132, 133
gamma-hydroxybutyric acid
(GHB), 68
hydromorphone, 193
971 iloprost, 729
indapamide, 407
ketamine, 251
lamotrigine, 124, 137
levetiracetam, 137, 138, 140,
141
levofloxacin, 468
magnesium salts, 418
mebendazole, 574
mepivacaine þ prilocaine, 261
methoxyflurane, 244, 245
methylnaltrexone, 211
minoxidil, 297
moxifloxacin, 468
nalbuphine, 211
nalmefene, 211
naltrexone, 212
niacin, 816
oxcarbazepine, 141, 142
oxycodone, 202
oxymorphone, 203
papaverine, 205
pethidine, 205, 206
pilsicainide, 349
pramipexole, 286
pregabalin, 124, 146, 147
propafenone þ citalopram, 352
propoxyphene, 187
pyrantel pamoate, 574
quetiapine þ lithium, 105
ramelteon, 79
regadenoson, 339
rimonabant, 19
ropinirole, 286
salbutamol, 314
Shan Dou Gen, 885
Shen Mai injection, 882
temozolomide, 830
terazosin, 393
tiagabine, 148
tolcapone, 289
topiramate, 124, 149, 150
tramadol, 208, 209
valproate, 154
zileuton, 323
ziprasidone, 111
zonisamide, 124, 162
dopamine dysregulation syndrome dopamine, 288
double vision carbamazepine, 131
downbeat nystagmus morphine, 200
dreams vivid melatonin, 794
DRESS see drug rash with eosinophilia and systemic symptoms
driving performance, impaired alprazolam, 75
driving-related visual/cognitive
skills, compromised
topiramate, 152
drowsiness
amitriptyline, 131
apraclonidine, 869
carbamazepine, 131, 473
clarithromycin, 474
clonidine, 11, 391
clozapine, 91
dexchlorpheniramine, 307
doxycycline, 451, 574
doxylamine þ
dextromethorphan þ
ephedrine þ paracetamol,
307
gabapentin, 131, 132
levetiracetam, 138, 141
opioids, 183
oxcarbazepine, 141
oxycodone, 202
quetiapine, 104
tetrabenazine, 91, 277
Vicks Medinite Syrup, 307
drug dependence opioids, 183
drug rash with eosinophilia and
systemic symptoms
carbamazepine, 128, 129
esomeprazole, 668
ioxitalamate, 850
minocycline, 453, 454
nevirapine, 539
oxcarbazepine, 144
phenytoin, 146
vancomycin, 469, 471
dry gangrene dopamine, 283
dry lips Yu Xing Cao injection, 883
dry mouth
albendazole, 572
amitriptyline, 131
aripiprazole, 94
buprenorphine, 209
dexbrompheniramine þ
pseudoephedrine, 306
domperidone, 665
droperidol, 670
formoterol, 314
gabapentin, 131, 132
gabapentin þ
dexamethasone, 132
hyoscine butylbromide, 672
loratadine þ
pseudoephedrine, 308
mebendazole, 572
ondansetron, 670
Index of adverse effects
972 opioids, 183
salbutamol, 314
scopolamine, 670
statins, 808
tiotropium, 319
tolterodine, 291
topiramate, 150, 151
zonisamide, 162
dry skin
benzalkonium, 440
opioids, 183
temozolomide, 831
Duchenne muscular dystrophy sevoflurane, 246
dysarthria
benazepril, 380
gabapentin, 132
metronidazole, 526
dysgeusia
amlodipine, 367
azithromycin, 473
tobramycin, 464
topiramate, 150
dysglycemia
fluoroquinolone, 464, 465,
466
gatifloxacin, 464, 466
dyskinesias
levodopa, 285
methylphenidate, 12
tetrabenazine, 91
tolcapone, 289
dyslipidemia anabolic steroids, 752
antipsychotic drugs, 88
dysmenorrhea entacavir, 531
dysmorphic facial features fluconazole, 503
dyspepsia
atomoxetine, 9
levofloxacin, 468
temozolomide, 830
zileuton, 323, 324
dysphagia
antipsychotic drugs, 88
botulinum toxin, 277
fish oil supplements, 806
porfimer, 833
temozolomide, 830
thiopental, 255
dysphasia topiramate, 149
dysphoria ketamine, 251
levacetylmethadol, 195
dyspnea
adalimumab, 679
adenosine, 338
botulinum toxin, 277
Ci Wu Jia injection, 881
enalapril, 522
everolimus, 708
formaldehyde, 438
gadolinium-based contrast
agents, 855
glibenclamide, 522
Houzheng Wan, 880
hydroxychloroquine, 522
infliximab, 684
isoniazid þ rifampicin þ
pyrazinamide, 564
mefloquine, 523
methotrexate, 522
oxytocin, 795
prednisone, 522
regadenoson, 339
simvastatin, 808
sirolimus, 712, 713
temozolomide, 830
TGN1414, 691
tramadol, 208
voriconazole, 506
Yu xing cao injection, 883
dysrhythmias anesthetics, topical, 268
arsenic trioxide, 414
blood substitutes, 594
bupivacaine, 261
carbamazepine, 127
cocaine, 58
dobutamine, 285
flecainide, 348
fluoroquinolones, 464
lidocaine þ ropivacaine, 261
liposomal amphotericin B
(L-AmB), 495
terlipressin þ albumin, 591
dystonias clozapine, 96
gabapentin, 134
haloperidol, 84
tetrabenazine, 91
tolcapone, 289
dysuria dacarbazine, 829
ketamine, 252
levetiracetam, 140
oxycodone, 202
E ear pain levetiracetam, 140
ear pressure topiramate, 150
ears, low-set oxcarbazepine þ lamotrigine,
144
easy bruisability methylphenidate, 13
eating disorders clozapine, 96–7 ecchymosis see bruising ectropion betaxolol, 404, 870
brimonidine, 404
dorzolamide, 405, 870
latanoprost, 405, 870
timolol, 405, 870
travoprost, 405, 870
eczema phenylephrine, 284
photodynamic therapy,
topical, 298
zileuton, 323
eczematous dermatitis dorzolamide þ timolol, 405
eczematous lesions danaparoid, 632
eczematous reaction bupivacaine, 267
edema ACE inhibitors, 375
acitretin, 297
adalimumab, 679
ambrisentan, 389
amiodarone, 341, 342
amlodipine, 367
anesthesia, regional, 265
bupivacaine, 262
calcium channel blockers,
375
clenbuterol, 289
clomiphene citrate, 744
dental anesthesia, 262
dopamine receptor
agonists, 286
glucocorticoids, 725
interleukin-4, 677
isoniazid þ rifampicin þ
pyrazinamide, 564
JTT-501, 782
lidocaine, 262
methadone, 197
methylprednisolone acetate,
262
muraglitazar, 782
niacin þ statins, 816
olanzapine, 103
prednisone, 724
pregabalin, 146
ragaglitazar, 782
ritodrine, 289
rosiglitazone, 781
sitaxsentan, 390
sirolimus, 713
temozolomide, 830
temsirolimus, 716
thiazolidinediones, 779
Index of adverse effects travoprost, 730, 873
vaccinia virus infection,
583
vancomycin, 470
edema, acute laryngeal Shuang Huang Lian
injection, 882
ejaculation, abnormal risperidone, 109
elastoma perforans serpiginosa penicillamine, 431
electrocardiographic changes diphenhydramine, 307
gatifloxacin, 466
electrocardiographic T wave, increased amplitude caudal anesthesia, 263
electroencephalographic abnormalities clozapine, 96
electrolyte disturbances beta2-adrenoceptor agonists,
316
embolism tamoxifen, 746
emergence reactions ketamine, 250
emesis see vomiting emetogenic xenon, 248
emotional lability levetiracetam, 138
encephalitis NSAIDs, 230
oseltamivir, 544
yellow fever vaccine, 586
encephalomyelitis, acute disseminated yellow fever vaccine, 586
encephalopathy antituberculosis drugs, 555
cefepime
cocaine, 60
dimethylsulfoxide, 894
gadolinium dimeglumine,
851
iohexol, 844
iotrolan, 844
levetiracetam, 139–40
linezolid, 475
lithium, 43
terlipressin þ albumin, 591
valproate, 155, 156
endocarditis deferoxamine, 430
endometrial cancer tamoxifen, 747
endometrium, thickened tibolone, 750
973 endophthalmitis folic acid þ disodium
etidronate þ omeprazole þ
thyroxine, 684
infliximab þ prednisolone þ
methotrexate, 684
intravitreal injection, 874
pegaptanib, 865
ranibizumab, 868
ranibizumab þ
photodynamic therapy, 867
triamcinolone, 725
energy, increased clomiphene, 743
enterocolitis, perforated necrotizing polystyrene sulfonate, 432
enthesitis carbamazepine, 130
eosinophilia see also drug reaction with
eosinophilia and systemic
symptoms
dacarbazine, 828
dimethyl fumarate, 295
methylphenidate, 13
oxcarbazepine, 144
strontium salts, 420
tobramycin, 463
vancomycin, 471
eosinophilic fasciitis simvastatin, 808
eosinophilic pleural effusion propylthiouracil, 765
eosinophilic pneumonia mefloquine, 523
minocycline, 452
eosinophilic pneumonitis nitrofurantoin, 476
epididymitis amiodarone, 345
epigastric pain albendazole, 573
alfuzosin, 392
epileptiform effects sevoflurane, 245
epistaxis ban mao, 886
methylphenidate, 13
erectile dysfunction beta-adrenoceptor
antagonists, 375, 378
celecoxib, 233
etoricoxib, 233
methadone, 197
reboxetine, 36
eryptosis amiodarone, 339
erysipelas acupuncture, 886
erythema buprenorphine, 209
clopidogrel, 640
dihematoporphyrin ether,
833
fentanyl, 192
gabapentin, 132
gelofusine, 595
Herpes zoster vaccine,
586
indacaterol, 318
mepivacaine, 268
moxibustion, 884
nefopam, 212
pegvisomant, 794
Psoralea, 885
quinine, 524
sapropterin, 610
sugammadex, 275
temozolomide, 831
terbinafine, 492
erythema multiforme dorzolamide, 405
losartan, 387
phenytoin, 145
terbinafine, 492
erythema multiforme-like lesions leflunomide, 710
erythematous papular eruption furosemide, 408
erythematous subcutaneous nodules CSII, 771
erythrocyte see red cell erythrocyte count, fall in rosiglitazone, 782
erythroderma co-trimoxazole, 478
furosemide, 408
lisinopril, 385
nevirapine, 539
vancomycin, 469
esophageal strictures porfimer, 833
esophagus carcinoma, risk of khat, 69
euphoria anabolic steroids, 753
gamma-hydroxybutyric acid
(GHB), 68
methoxyflurane, 244, 245
Evans’ syndrome unrelated cord blood,
transplantation, 600
exanthematous pustulosis infliximab, 684
excessive activation amisulpride, 92
Index of adverse effects
974 excessive restlessness carbamazepine, 145
phenobarbital, 145
excessive secretions midazolam þ ketamine, 78
excoriation sapropterin, 610
exfoliative dermatitis iodixanol, 849
extra beats blood transfusion, 600
extrapyramidal adverse effects
antipsychotic drugs, 91
clozapine, 95
domperidone, 665
extrapyramidal symptoms
amisulpride, 92
antipsychotic drugs, 85–6
aripiprazole, 93
olanzapine, 108
quetiapine þ lithium, 105
risperidone, 108, 109
ziprasidone, 111
eye irritation
dorzolamide, 404, 874
pegaptanib, 866
timolol, 874
eyelash hypertrichosis travoprost, 730, 873
eyelid dermatitis bimatoprost, 871
latanoprost, 871
eyelid eczema phenylephrine, 284
eyelid necrosis glucocorticoids, 871
eyelid swelling
Shuang Huang Lian
injection, 882
eye movements, abnormal
involuntary
levodopa, 285
eye pain
brimonidine, 874
brinzolamide, 403, 874
pegaptanib, 866
eye redness
atropine, 291
lamivudine, 531
trimethoprim, 477
F facial dimorphism
oxcarbazepine þ lamotrigine,
144
facial discoloration amiodarone, 347
facial flushing dacarbazine, 829
facial myoclonus
topiramate, 151
facial sensation, altered sugammadex, 275
facial tics atomoxetine þ venlafaxine, 8
factor VII deficiency valproate, 156
faintness pilsicainide, 350
Fanconi syndrome didanosine, 535
tenofovir, 537
fatigue see also malaise, tiredness, weakness
acupuncture, 886
adalimumab, 680
aldesleukin, 677
alefacept, 680
amitriptyline, 131
azathioprine þ prednisone,
718
baclofen, 276
botulinum toxin, 277
brimonidine, 873, 874
brinzolamide, 403, 874
brinzolamide þ
levobetaxolol, 403
buprenorphine, 210
ceftriaxone, 449
Chai-Ling-Tang (Sairei-to),
880
didanosine, 535
didanosine þ lamivudine þ
boosted atazanavir, 535
exemestane, 744
gabapentin, 131, 132
immunoglobulins, 595
interferons, 676
latanoprost, 871, 874
lead contamination, 883
levetiracetam, 137, 138, 139
levobetaxolol, 403, 874
mycophenolate, 711
nalmefene, 211
nitrofurantoin, 476
ondansetron, 666
oxcarbazepine, 141, 142, 143
peginterferon alfa þ
ribavirin, 676
penicillamine, 431
pregabalin, 124, 146
quetiapine, 105
ramelteon, 79
ramosetron, 666
ritonavir, 542
ropinirole, 286
rosiglitazone, 781
sapropterin dihydrochloride,
610
sirolimus, 712
temozolomide, 830
tiagabine, 148
topiramate, 123, 124, 150, 151
valproate, 154
zonisamide, 162
febrile convulsion Vaxigrip, 917
feeding difficulties alprostadil, 729
feeling overmedicated levacetylmethadol, 195
female neoplasms HRT, 741
femoral nerve block anesthesia, local, 266
fetal death 131 I (radioiodine), 765
fetal heart rate variability pethidine, 206
fetal hypothyroidism antithyroid drugs, 766
fetal oliguria valsartan, 388
fever abacavir, 534
albendazole þ
diethylcarbamazine, 572,
574, 575
aminolevulinic acid, 833
amphotericin B colloidal
dispersion (ABCD), 494
azathioprine þ prednisolone,
717
ceftriaxone, 449
co-trimoxazole, 478
dacarbazine, 829
daptomycin, 478, 479
didanosine, 533
diethylcarbamazine, 572
diethylcarbamazine þ
albendazole, 451, 574
doxycycline, 575
ecstasy, 67
efalizumab, 689
efavirenz, 533
eflornithine, 526
emtricitabine, 533
everolimus, 708
formaldehyde, 438
gadodiamide, 855
goserelin, 790
hematoporphyrin derivative,
833
hydroxychloroquine þ
prednisone, 522
immunoglobulins, 595
isoniazid þ rifampicin þ
pyrazinamide, 564
isotretinoin, 300
Index of adverse effects ligustrazine, 881
liposomal amphotericin
(L-AmB), 495
manganese, 418
mefloquine, 523
minocycline, 453
montelukast, 320
moxifloxacin, 468
nevirapine, 539
olanzapine, 103
oxymorphone, 203
porfimer, 833
prednisolone, 728
prilocaine, 268
Qing Kai Ling injection,
881
rosiglitazone, 781
sirolimus, 712, 713
sulfasalazine, 670
teicoplanin, 469
temozolomide, 831
tenofovir, 533
tenofovir þ emtricitabine þ
efavirenz, 533
terbinafine, 492
tetracaine, 269
TGN1414, 691
trimoxazole, 478
vancomycin, 469, 471
varicella vaccine, 585
fever with lymphadenopathy oxcarbazepine, 144
fibrinogen concentration, reduced valproate, 156
fibrinogen formation, increased amiodarone, 345
fibrosing dermopathy, nephrogenic gadolinium, 851
fibrosis alfuzosin, 392
pramipexole, 286
ropinirole, 286
fibrosis, nephrogenic systemic gadolinium, 852
fibrotic heart valve disease dopamine receptor agonists,
286
fibrovascular hyperplasia ciclosporin, 706
fixed drug eruptions cetirizine, 305
iopromide, 849
itraconazole, 504
levocetirizine, 305
piroxicam, 234
flame-shaped retinal hemorrhages ethambutol, 561
975 flank pain indinavir, 541
flare effect goserelin, 790
flatulence mesalazine, 669
methylnaltrexone, 211
oxymorphone, 203
posaconazole, 505
sapropterin dihydrochloride,
610
floppy choroid tamsulosin, 393
flu/flu-like symptoms/flu-like syndromes see influenza fluid accumulation arsenic trioxide, 414
flushing alcohol þ abacavir, 535
anidulafungin, 507
desmopressin, 798
dimethyl fumarate, 295
immunoglobulins, 595
infliximab, 684
magnesium salts, 418
niacin, 815, 816
oxytocin, 795, 796
regadenoson, 338–9
sitaxsentan, 390
tramadol, 209
folic acid, reduced absorption sevelamer, 897
folliculitis tacrolimus, 714
foot numbness furosemide, 402
foot paresthesia posaconazole þ vincristine, 502
foreign body sensation bimatoprost, 871
hydroxychloroquine, 522
latanoprost, 871
foreign body sensations brinzolamide, 874
brinzolamide þ
levobetaxolol, 403
levobetaxolol, 874
forgetfulness ethambutol, 562
forgotten needles acupuncture, 886
Fournier’s gangrene botulinum toxin, 277
fractures antidepressants, 30
beta2-adrenoceptor agonists
(SABAs), 315
doxazosin, 392
glucocorticoids, 727
glucocorticoids, inhaled, 312,
313, 315
glucocorticoids, oral, 313, 315
opioids, 184
prednisone, 727
thiazolidinediones, 779, 780
frontal bossing warfarin, 619
frontal executive function impairment metamfetamine, 4
Fuchs dystrophy (corneal edema) amantadine, 545
fulminant hepatic failure minocycline, 453
fungal infections, invasive see also individual organisms
adalimumab, 678
caspofungin, 510
etanercept, 678
TNF-a antagonists, 678
G gait disturbance amiodarone, 342
carbamazepine, 492
furosemide, 402
tacrolimus, 715
tacrolimus þ prednisone, 714
temozolomide, 831
terbinafine, 492
thiamine, 402
galactorrhea domperidone, 665
metoclopramide, 665
quetiapine, 106
gallstones somatostatin analogues, 797
gambling, pathological dopaminergic therapies, 288
gangrene, dry dopamine, 283
gangrene, Fournier’s botulinum toxin, 277
gastric emptying, delayed exenatide, 776
nizatidine, 667
opioids, 186
pramlintide, 773
gastric-outlet obstruction alprostadil, 729
gastric pain prednisone, 724
gastroduodenal ulcers coxibs, 226
non-selective NSAIDs, 226
gastroenteritis montelukast
rabeprazole,
Index of adverse effects
976 gastrointestinal bleeding abciximab, 638
acetylsalicylic acid, 226
cefoperazone, 449
clopidogrel, 639
dacarbazine, 828
drotrecogin, 592
non-steroidal anti inflammatory drugs, 226
spironolactone, 409–10
SSRIs, 33–4
gastrointestinal discomfort adenosine receptor agonists,
338, 339
mycophenolate, 710
regadenoson, 338–9
gastrointestinal disorders dexindoprofen, 230
levetiracetam, 138
mesalazine, 669
topiramate, 149
gastrointestinal disturbances blood transfusion, 594
exenatide, 775
fosamprenavir þ ritonavir,
541
itraconazole, 504
mucolytics, 325–6
non-selective NSAIDs, 227
ondansetron, 666
posaconazole, 505
ramosetron, 666
rifampicin, 564
saquinavir þ ritonavir, 542
somatostatin, 796
topiramate, 150
valerian, 884
gastrointestinal intolerance exenatide, 776
gastrointestinal symptoms deferoxamine þ deferiprone,
426
niacin, 816
gastrointestinal syndromes ziprasidone, 111
gastrointestinal ulceration deferasirox, 427
gastroesophageal reflux hormone replacement
therapy (HRT), 736
khat, 69
oral contraceptives, 736
gelastic seizures see also laughing
anti-rabies vaccine, 372
clobazam, 372
genital ulceration benzalkonium, 440
gestational diabetes nelfinavir, 542
GFR, reduced tesaglitazar, 783
giant cell arteritis adalimumab, 679
giant hepatic adenoma oxcarbazepine, 144
giddiness Vicks Medinite Syrup, 307
gingival bleeding methylphenidate, 13
gingival enlargement valproate, 157
glare isotretinoin, 299
glaucoma see also ocular hypertension
acetazolamide
co-trimoxazole, 477
tiotropium, inhaled, 319
topiramate, 152
glomerular filtration rate, reduced tesaglitazar, 783
glomerular nephrotoxicity aminoglycosides, 462
glossitis tenofovir þ emtricitabine þ
efavirenz, 533
glucagon concentrations, reduced pramlintide, 773
glucocorticoid-induced ulceration diethylstilbestrol þ
docetaxel, 739
glutamate/glutamine concentrations, reduced buprenorphine, 209–10 glutamyl transferase activity, raised oxcarbazepine, 141
goiter antithyroid drugs, 766
gonadotrophin concentrations dihydrocodeine, 191
Gottron’s papules terbinafine, 492
gout dorzolamide, 404, 874
timolol, 874
graft failure tacrolimus, 714
graft-versus-host disease stem cell transplantation,
600
granulation tissue excess, on palbebral conjunctivae acitretin, 298
granulocytic maturation arrest co-trimoxazole, 478
granulocytopenia terbinafine, 491
granulomas talc, 898
granulomatous reactions leuprolide acetate, 790
growth atomoxetine, 9
Guillain–Barré syndrome deferiprone, 427–8
immunoglobulins,
intravenous, 596
meningococcal vaccine, 580
yellow fever vaccine, 586
guttate psoriasis efalizumab, 688
gynecomastia antipsychotic drugs, 94
bicalutamide, 755
cannabis, 57
domperidone, 665
dutasteride, 755
efavirenz, 538
fenofibrate, 806
metoclopramide, 665
rosuvastatin, 815
statins, 815
H hair color and structure, changes in valproate, 156–7 hair curling indinavir, 541
hair loss see alopecia hair texture, changes in valproate, 156
hallucinations aciclovir, 530
clarithromycin, 473
clopidogrel, 639
erythromycin, 474
ethambutol, 562
guaifenesin þ
phenylpropanolamine, 467
ketamine, 251, 252
lamotrigine, 135
levetiracetam, 140
levofloxacin, 467
meclizine, 467
methoxyflurane, 244
methylphenidate, 12
modafinil, 14
morphine, 201
nalmefene, 211
nefopam, 212
opioids, 183
paracetamol, 352
propafenone, 352
Index of adverse effects ramipril, 352
rofecoxib, 233–4
statins, 808
sulfonamides, 670
theophylline, 352
ticlopidine, 352
tolcapone, 290
triazolam, 352
valerian, 884
venlafaxine, 352
halo nevi infliximab, 684
hand weakness botulinum toxin, 277
hangover nalmefene, 211
hard palate necrosis cocaine, 60
hard stools opioids, 186
Hashimoto’s thyroiditis rifampicin, 563
HDL cholesterol efavirenz, 538
HDL cholesterol concentrations, reduced stanozolol, 754
headache acupuncture, 886
adrenaline, 282
albendazole, 573
albendazole þ
diethylcarbamazine, 572
alefacept, 680
alemtuzumab, 686
aliskiren, 388
ambrisentan, 389
aripiprazole, 94
beta2-adrenoceptor agonists,
316
bimatoprost, 871
bismuth salts, 414
black cohosh, 884
blood transfusion, 600
brimonidine, 874
brinzolamide, 403, 874
buprenorphine, 209
calcineurin inhibitors, 705
carbamazepine, 127
cibenzoline, 347
ciclosporin þ methotrexate,
705
clenbuterol, 289
dacarbazine, 828
desmopressin, 798
diazepam, 146
diethylcarbamazine, 572
diethylcarbamazine þ
albendazole, 574
domperidone, 665
977 dorzolamide, 404, 874
doxycycline, 451, 452, 574
efalizumab, 688, 689
entacavir, 531
epoetin alfa, 598
epoetin delta, 598
febuxostat, 235
fluorescein, 895
formoterol, 314
glucocorticoids, 315
glutaral-based products, 439
GM-CSF, 675
hemoglobin concentration,
increased, 598
hydromorphone, 193
immunoglobulins, 595
indacaterol, 318
infliximab, 684
iron dextran, 417
iron salts, 417
LABAs þ inhaled
glucocorticoids, 315
lamotrigine, 137
latanoprost, 404, 871
lead contamination, 883
levetiracetam, 137–9, 141
levofloxacin, 468
ligustrazine, 881
loratadine þ
pseudoephedrine, 308
lubiprostone, 672
mesalazine, 669
methoxyflurane, 244
methylphenidate, 10
metoclopramide, 665
montelukast, 320
mycophenolate, 710
naltrexone, 211
olanzapine, 104, 108
ondansetron, 666
oxcarbazepine, 142, 143
oxytocin, 795, 796
pegvisomant, 794
phenylephrine, 284
pregabalin, 146
quetiapine, 106
ramelteon, 79, 80
ramosetron, 666
regadenoson, 338–9
risperidone, 108
roflumilast, 322
salbutamol, 314
sapropterin, 609, 610
sevelamer, 897
sitaxsentan, 390
stem cells, 599
sumatriptan, 372
tacrolimus, 714
tamoxifen, 746
temozolomide, 830
tenofovir, 537
terazosin, 393
TGN1414, 691
tiagabine, 148
timolol, 874
tipranavir, 542
tolterodine, 291
topiramate, 150, 151
vaccinia virus infection, 583
verapamil, 367
voriconazole, 505
zafirlukast, 321
zileuton, 323–5
zonisamide, 162
hearing impairment, high
frequency
aluminium, 413
hearing loss
azithromycin, 473
deferoxamine, 429
iloprost, 729
heart attacks
darbepoetin, 599
epoetin, 599
lumiracoxib, 228
non-selective NSAIDs, 227,
228
rofecoxib, 228
heart block
adenosine, 337
digoxin, 333
infliximab, 684
lanreotide, 797
octreotide, 797
rivastigmine, 20
stem cells, 599
heart failure
carteolol, 870
darbepoetin, 599
epoetin, 599
muraglitazar, 782
pregabalin, 147
rosiglitazone, 781
thiazolidinediones, 779
TNF-a antagonists, 677
heart rate, increase
adenosine receptor agonist,
338
atomoxetine, 11
caudal anesthesia, 263
khat, 69
heart valve disease, fibrotic
dopamine receptor agonists,
286
heartburn azithromycin, 473
fish oil supplements, 806
heat perception, abnormal methadone, 197
tacrolimus, 716
Index of adverse effects
978 heavy metal contamination henna, 296
hemangiomas contraceptives, 738
hemangiosarcoma MK 769, 782
hematological disorders voriconazole, 505
hematological disturbances linezolid, 475
hematomas acupuncture, 886
cilostazol, 371
quinidine, 352
hematuria ban mao, 885
dacarbazine, 829
indinavir, 541
ketamine, 252
metronidazole, 526
pegaptanib, 865
hemoglobin concentration fall ambrisentan, 389
interferon þ ribavirin, 676
pioglitazone, 780
hemoglobin oxygen saturation, lowered remifentanil, 208
hemoglobinuria stem cells, 599
hemolysis co-trimoxazole, 477
henna, 296
itraconazole, 504
hemolytic anemia captopril, 384
carbamazepine, 128
cord blood, unrelated,
transplantation, 600
misoprostol, 730
oxcarbazepine, 144
rasburicase, 236
stem cells, 540
hemolytic thrombotic microangiopathy aprotinin, 645
hemolytic–uremic syndrome fluorouracil, 835
hemophagocytic syndrome lamotrigine, 135
hemorrhage deferasirox, 427
drotrecogin, 591
hemorrhages, retinal, flameshaped ethambutol, 561
hemorrhagic colitis oseltamivir, 544
hemorrhagic cystitis dacarbazine, 828
gemtuzumab ozogamicin,
689, 690
hemorrhagic stroke phenylpropanolamine, 284
SSRIs, 33
hemiparesis temozolomide, 830
Henoch-Schönlein purpura deferiprone, 428, 429
heparin-induced
thrombocytopenia (HIT)
type II
heparin, 626–9 hepatic see also liver hepatic adenoma/adenomatosis anabolic steroids, 754
female sex hormones, 748
oxcarbazepine, 144
hepatic angiosarcomas anabolic steroids, 754
hepatic carcinoma anabolic steroids, 754
hepatic damage antidepressants, 30
ciprofloxacin, 465
gatifloxacin, 465
levofloxacin, 465
moxifloxacin, 465
vitamin A, 607
hepatic encephalopathy terlipressin þ albumin, 591
hepatic failure hepatic arterial embolization,
900
sevoflurane, 245, 246
valproate, 156
hepatic fibrosis didanosine þ stavudine, 532
hepatic necrosis, central methylprednisolone, 726
hepatic portal inflammatory infiltrates phenobarbital, 145
hepatic rupture, spontaneous anabolic steroids, 754
hepatic toxicity celecoxib, 233
hepatitis alfuzosin, 392
amiodarone, 345
anastrozole, 743
antituberculosis drugs, 555,
559
ceftriaxone, 449
chlorzoxazone, 277
clarithromycin, 473
clopidogrel, 640
co-amoxiclav, 450
co-trimoxazole, 478
desflurane, 244
efavirenz, 525
etanercept, 682
hydroxychloroquine, 522
infliximab, 684
interferons, 676
iopromide, 846
lamotrigine, 136
methylphenidate, 13
methylprednisolone, 726
minocycline, 453
montelukast, 320
nevirapine, 539
NSAIDs, 682
peginterferon alfa þ
ribavirin, 676
statins, 811
tamoxifen, 743
telithromycin, 471
terbinafine, 491
valproic acid þ
temozolomide, 832
hepatitis B recurrence etanercept, 683
glucocorticoid pulse therapy,
728
hepatitis, chronic active benzbromarone, 234
hepatocelluar damage CAM þ adulterants, 879
hepatomegaly naltrexone, 212
hepatopathy valproate, 156
hepatosplenic T cell lymphoma infliximab, 684
hepatotoxicity antituberculosis drugs, 503,
555–7, 560
atorvastatin, 804
benzbromarone, 234
black cohosh, 884
bosentan, 389, 390
bupropion, 35
clindamycin, 472
desflurane, 244
erythromycin, 474
ezetimibe, 803
fenofibrate, 804
gemfibrozil, 804
imiglitazar, 782
indinavir, 542
isoniazid þ rifampicin þ
ethambutol þ
pyrazinamide, 560–1
ketolides, 471
methimazole, 766
monoamine oxidase
inhibitors (MAOIs), 30
nevirapine, 538, 540
Index of adverse effects niacin, 815, 816
pravastatin, 804
propylthiouracil, 766
simvastatin, 804
telithromycin, 471
tobramycin, 463
trichloroethylene, 247
tricyclic antidepressants, 30
tuberculosis chemotherapy,
532–3
warfarin, 618
hiccup-like movements clindamycin þ risperidone,
472
hiccups azithromycin, 473
midazolam þ ketamine, 78
porfimer, 833
hirsutism sodium valproate, 155
stanozolol, 754
histiocytic hemophagocytosis pegfilgrastim, 675, 676
Hodgkin’s disease dacarbazine, 829
hordeolum brinzolamide, 874
brinzolamide þ
levobetaxolol, 403
levobetaxolol, 874
horizontal nystagmus methadone, 198
Horner’s syndrome brachial plexus anesthesia,
262
epidural blockade, 263
fentanyl, 192
spinal (intrathecal)
anesthesia, 263
hostility atomoxetine, 8
hot and cold temperature perception, reduced baclofen, 276
hot flushes exemestane, 744
tamoxifen, 746
hot sensations tartrazine, 896
husky voice adalimumab, 679
hydropic swelling dextran, 595
hyperactivity antihistamines þ
decongestants, 305
carbamazepine, 145
levetiracetam, 138
methylphenidate, 13
phenobarbital, 145
979 hyperemia brimonidine, 874
brinzolamide, 403, 874
brinzolamide þ
levobetaxolol, 403
dorzolamide, 874
levobetaxolol, 874
timolol, 874
hyperalgesia morphine, 200
opioids, 183
remifentanil, 208
hyperammonemic encephalopathy valproate þ lamotrigine, 160
hyperamylasemia tipranavir, 543
hyperbilirubinemia amphotericin B deoxycholate
(DAMB), 494
amphotericin B lipid complex
(ABLC), 494
atazanavir, 541
ezetimibe, 803
fluconazole, 503
indinavir, 541
saquinavir þ ritonavir, 542
hypercalcemia parathyroid hormone, 796
tacalcitol, 301
vitamin D, 611
hypercapnia prolonged morphine, 199
hyperglycemia aripiprazole, 94
etomidate, 250
octreotide, 797
olanzapine, 102, 108
risperidone, 108
temsirolimus, 716
hyperhomocysteinemia nitrous oxide (N2O), 247
hyperirritability levetiracetam, 149
hyperkalemia cilazapril
drospirenone þ indometacin
þ estradiol, 741
heparin, 629
suxamethonium, 273
hyperkeratosis arsenic, 414
hyperkinesias levetiracetam, 139
tetrabenazine, 91
hyperlactatemia stavudine, 536
hyperlipidemia calcineurin inhibitors, 707
ezetimibe, 803
irbesartan, 387
temsirolimus, 716
hypernatremia lithium, 45
hyperosmolar, increased aniongap metabolic acidosis etomidate, 250
hyperostosis alprostadil, 729
hyperoxaluria vitamin C, 610
hyperoxaluric nephropathy vitamin C, 610
hyperparathyroidism indapamide, 407
lithium, 44
hyperphosphatemia liposomal amphotericin B
(L-AmB), 497
hyperpigmentation dihematoporphyrin ether,
833
immunoglobulins, 595
latanoprost, 873
minocycline, 453
hyperprolactinemia antipsychotic drugs, 31, 89
olanzapine, 102
ziprasidone, 112
hyper-reflexia sapropterin dihydrochloride,
610
hypersalivation antipsychotic drugs, 95
clozapine
hypersensitivity reactions abacavir, 534
albendazole, 574
amiodarone, 345
anesthesia, 243
anesthetics, local, 268
aprotinin, 645
bupivacaine, 267
calcitonin, 789
clopidogrel, 640
cyanocobalamin, 608
digoxin, 916
heparin, 629
lidocaine, 267
mebendazole, 574
mepivacaine, 268
mesalazine, 669
minocycline, 452
moxifloxacin, 468
natalizumab, 690
pholcodine, 207
phosphate þ tretinoin, 301
pseudoephedrine, 283
succinylated gelatin, 595
tartrazine, 896
Index of adverse effects
980 TNF-a antagonists, 678
yellow fever vaccine, 586
hypersensitivity syndrome, drug-induced see also drug rash with
eosinophilia and systemic
symptoms
co-trimoxazole, 478
moxifloxacin, 468
hypersensitivity vasculitis co-trimoxazole, 478
hypersexuality levodopa, 288
methylphenidate, 12
hypersomnia cycloserine, 561
olanzapine, 100
quetiapine, 100
risperidone, 100
hypertension see also blood pressure,
increased
ACE inhibitors, 375, 387
acupuncture, 886
Adderall, 2
albumin, 591
allopurinol, 366
amfetamine, 1
amlodipine, 366, 367
anabolic steroids, 752
apraclonidine, 869
aspirin, 366, 408
atenolol, 366, 408
atorvastatin, 408
benazepril, 380
blood substitutes, 594
ciclosporin, 705
darbepoetin, 598
desmopressin, 798
diazoxide, 393
epoetin alfa, 598
epoetin delta, 598
famotidine, 408
fentanyl þ midazolam, 191
gentamicin, 470
gliclazide, 366
glucocorticoids, 723
hemoglobin concentration,
increased, 598
hepatic arterial embolization,
900
irbesartan, 387
lithium, 388
losartan, 383, 387
MAS-XR, 2
methylphenidate, 391
nicorandil, 366
olmesartan, 387
prothrombin complex, 597
ranibizumab, 867
risedronate, 408
sibutramine, 17
simvastatin, 366
sirolimus, 714
stem cells, 599
tacrolimus, 714
telithromycin, 472
terlipressin þ albumin, 591
valsartan, 388
vancomycin, 470
vitamin D, 408
hyperthermia see fever hyperthyroidism amiodarone, 344
levothyroxine, 764
povidone–iodine, 440
salt iodization, 764
thyrotropin-releasing
hormone, 763
hypertrichosis bimatoprost, 871
efalizumab, 688
latanoprost, 871
hypertriglyceridemia heparin, 629
tamoxifen, 746
hypertrophic pyloric stenosis erythromycin, 474
hyperzincemia zinc, 421
hypesthesia iotrolan and mepivacaine,
844
hypocalcemia gentamicin, 462
hypocupremia zinc, 421
hypofibrinogenemia valproate sodium hypogammaglobulinemia carbamazepine, 130
hypoglycemia continuous subcutaneous
insulin infusion (CSII), 771
etanercept, 682
insulin therapy, 769
nateglinide, 776
nateglinide þ metformin, 776
niacin, 816
octreotide, 797
pramlintide, 773
hypoglycemia biguanides
gatifloxacin, 467
hypoglycemic coma sibutramine þ lorazepam, 19
hypogonadism megestrol acetate, 749
opioids, 183, 186
hypogonadotrophic hypogonadism dihydrocodeine, 191
hydromorphone, 193
hypokalemia amphotericin þ flucytosine,
502
anidulafungin, 508
caspofungin, 510
indapamide, 407, 408
liposomal amphotericin B
(L-AmB), 495, 496
liposomal amphotericin þ
caspofungin, 509
micafungin, 510
hypomagnesemia amphotericin þ flucytosine,
502
ribavirin, 531
hypomania anabolic steroids, 753
lamotrigine, 135
topiramate, 152
hyponatremia amiodarone, 345
atomoxetine, 9
desmopressin, 798
indapamide, 407, 408
levetiracetam, 140
mirtazapine, 37
oxcarbazepine, 141, 142,
143
hypophenylalaninemia sapropterin, 609
hypophosphatemia tenofovir, 537
hyporesponsiveness epoetin, 599
hypospadias estrogens, 739
valproate, 157
zidovudine, 536, 537
hypotension ACE inhibitors, 383
acupuncture, 886
adalimumab, 679
adrenaline, 281
aliskiren, 388
anesthetics, local, 264
aprotinin, 645
azathioprine þ prednisolone,
717
baclofen, 276
bupivacaine, 264, 267
carteolol, 870
clonidine, 391
cyanocobalamin, 608
diazepam, 76
disulfiram, 895
dolasetron, 666
Index of adverse effects eptifibatide, 639
fentanyl þ midazolam, 191
gentamicin, 462
immunoglobulins, 595
infliximab, 679, 684
iron dextran, 417
iron salts, 417
LAMB, 495
liposomal amphotericin B
(L-AmB), 495
magnesium salts, 418
minoxidil, 297
naltrexone, 212
oxytocin, 795, 796
phenytoin, 145, 153
remifentanil, 207
spinal anesthetic, 264
stem cells, 599
succinylated gelatin, 595
terazosin, 393
tezosentan, 390
TGN1414, 691
tizanidine, 278
tolcapone, 289
tramadol, 208
vancomycin, 471
venlafaxine, 35
verapamil, 368
hypotension, orthostatic
apomorphine, 287
dopamine receptor agonists,
286
quetiapine, 105, 106
tolcapone, 289
hypotensive symptoms
telmisartan, 388
telmisartan þ ramipril,
379
hypothalamic–pituitary–
testicular function
suppression
anabolic steroids, 754
hypothyroidism amiodarone, 343, 344, 345,
346
levothyroxine, 403
povidone-iodine, 441
ribavirin, 676
rifampicin, 563
valproate, 155
hypotonia
growth hormone, 793
obstetric anesthesia, 265
hypotony dorzolamide, 404
hypoxemia propofol, 253
sirolimus, 713
hypoxia ketamine, 251
981 I
IBCT see incorrect blood component transfusion (IBCT) icterus see jaundice idiopathic thrombocytopenic purpura (ITP) minocycline, 453
MMR immunization, 581
idioventricular rhythm, accelerated bupivacaine, 267
IFIS see intraoperative floppy iris syndrome (IFIS) IgA linear dermatosis glycopeptides, 469
IGDE see interstitial granulomatous drug eruption (IGDE) IgE-dependent hypersensitivity reaction erythromycin, 474
ileus morphine, 200
imbalance levetiracetam, 141
immature myeloid precursors, proliferation valproate, 156
immediate hypersensitivity reaction ioxaglate, 850
immune cells, altered numbers chromium, 415
immunological reactions local anesthetics, 262
immunosuppressive effects codeine, 186
fentanyl, 186
methadone, 186
morphine, 186
opioids, 183
remifentanil, 186
impotence olanzapine, 108
opioids, 186
risperidone, 108
valproate, 154
impulsive spending ethambutol, 562
incontinence see urinary incontinence incorrect blood component transfusion (IBCT) blood transfusion, 916
indigestion sevelamer, 897
infant feeding, after birth, impaired fentanyl, 192
infections alefacept, 680
anakinra, 677
etanercept, 683
everolimus, 708
glucocorticoids, 678
infliximab, 683
methotrexate, 678
prednisone, 724
sevelamer, 897
TNF-a antagonists, 678
infections, opportunistic alemtuzumab, 687
daclizumab, 687
temozolomide, 831
infectious endophthalmitis triamcinolone, 725
inflammation dihematoporphyrin ether,
833
inflammatory papules efalizumab, 688
inflammatory reactions TGN1414, 691
inflammatory reactions, in biliary ducts phenobarbital, 145
influenza/influenza-like symptoms/influenza-like syndromes alefacept, 680
dacarbazine, 829
lamivudine, 531
pregabalin, 147
tiagabine, 148
zileuton, 323–5
infusion-related fever and chills amphotericin, 494
infusion-related reactions liposomal amphotericin B
(L-AmB), 495
ingrowing toenails indinavir, 541
inhibitory control, impaired methadone, 197
injection-site burning prothrombin complex, 597
injection-site pain botulinum toxin, 277
paromomycin, 463
somatostatin, 796
injection-site rashes Herpes zoster vaccine, 586
injury, accidental alefacept, 680
zileuton, 323
Index of adverse effects
982 INR prolongation chondroitin sulfate þ glucosamine, 623 daptomycin, 479 glucosamine, 623 Lycium barbarum, 624 noscapine þ warfarin, 624 protein, 625 tibolone, 625 warfarin þ glucosamine, 623–4 insomnia alemtuzumab, 686 anabolic steroids, 753 antiretroviral drugs, 562 aripiprazole, 94 atomoxetine þ clonidine þ dexamfetamine, 8 buprenorphine, 209 cholinesterase inhibitors, 20 clarithromycin, 562 clonidine, 391 co-trimoxazole, 562 doxycycline, 451, 574 efavirenz, 538 fluconazole, 562 formoterol, 317 glucocorticoids, 723 guaifenesin þ phenylpropanolamine, 467 indacaterol, 318 khat, 69 levetiracetam, 139 levofloxacin, 467, 468 loratadine þ pseudoephedrine, 308 meclizine, 467 methylphenidate, 10 nalmefene, 211 olanzapine, 104, 108 rimonabant, 19 risperidone, 100, 108, 109 statins, 808 tacrolimus, 714 temozolomide, 830 theophylline, 324 topiramate, 150, 151 zileuton, 324 ziprasidone, 111 zuclopenthixol, 112 insulin autoantibodies insulin, 770 insulin sensitivity, reduced antihypertensive drugs, 407 beta-blockers, 407 hydrochlorothiazide, 407 stavudine, 535 thiazide diuretics, 407 intention tremor tacrolimus, 714
interstitial granulomatous dermatitis etanercept, 682 interstitial granulomatous drug eruption (IGDE) enalapril, 384, 522 interstitial lung disease amiodarone, 341
etanercept, 681
leflunomide, 709
interstitial nephritis etanercept, 682 flucloxacillin, 451 tenofovir þ amprenavir, 533 vancomycin þ ceftriaxone, 470
warfarin, 618
interstitial pneumonia barium, 851
oxcarbazepine, 144
interstitial pneumonitis alemtuzumab, 686 amiodarone, 341 infliximab, 683 levetiracetam, 140 sirolimus, 712, 713 statins, 807 zonisamide þ valproate, 162 interstitial pulmonary fibrosis terbinafine, 492 intestinal ischemia terlipressin þ albumin, 591 intestinal obstruction alosetron, 666 polystyrene sulfonate, 432 intestinal perforation GnRH agonists, 789
growth hormone, 792
intestinal ulceration nicorandil, 364 intoxication gamma-hydroxybutyric acid (GHB), 68 terazosin, 393 intracerebral hemorrhage metronidazole, 624
alteplase, 637
intracranial hemorrhage tipranavir, 542 intracranial hypertension growth hormone, 793
isotretinoin, 299
intracranial hypertension, benign ciclosporin, 705
levofloxacin, 467
lithium, 44
minocycline, 452
intrahepatic cholestasis see cholestasis
intraocular pressure, increase see also glaucoma pegaptanib, 866 intraoperative floppy-iris syndrome (IFIS) alpha-adrenoceptor antagonists, 391 donepezil, 19 doxazosin, 392 finasteride, 755 tamsulosin, 392 invasive candidiasis caspofungin, 509 invasive cryptococcosis adalimumab, 680 invasive fungal infections adalimumab, 678 aspergillosis, 678 candidiasis, 678 caspofungin, 510 etanercept, 678 histoplasmosis, 678 TNF-a antagonists, 678 invasive ovarian cancer gonadotrophins, 736 invasive Trichophyton rubrum infection infliximab, 685 involuntary movements artesunate, 525 atomoxetine þ clonidine þ dexamfetamine, 8 iodide mumps iopromide, 846 oral diatrizoate meglumine, 846 sodium diatrizoate þ meglumine diatrizoate, 845 iris atrophy chlorhexidine, 439 iris color change bimatoprost, 871 latanoprost, 871 iris pigmentation, increased latanoprost, 730, 872 iris pigment epithelial cyst prostaglandin F2a analogues, 872 iritis, acute travoprost, 730, 873 iron deficiency anemia nicorandil, 364 irritability Ci Wu Jia injection, 881 formaldehyde, 437 lead poisoning, 883 levetiracetam, 138, 139, 141 methylphenidate, after risperidone withdrawal, 13 naltrexone, 211
Index of adverse effects tartrazine, 896
irritation, local fentanyl, 192
fluoroquinolones, 465
ischemia cocaine, 58
dopamine, 283
otamixaban, 635
smallpox vaccine, 582
ischemic colitis alosetron, 666
ischemic electrocardiographic changes disulfiram, 895
ischemic optic neuropathy amiodarone, 342
ischemic stroke anabolic steroids, 753
itching see also pruritus
aciclovir, 543
alfuzosin, 392
Artemisia vulgaris, 884
bimatoprost, 871
carteolol, 870
Ci Wu Jia injection, 881
co-trimoxazole, 477
cyanocobalamin, 608
diethylcarbamazine, 574
doxycycline, 451, 574
gabapentin, 131
latanoprost, 871
mebendazole, 574
moxibustion, 884
statins, 808
tartrazine, 896
timolol þ dorzolamide, 405
tipranavir, 543
trimethoprim, 477
Yan Hu Ning injection, 882
J jaundice see also cholestatic jaundice,
liver
bupropion, 35
Chai-Ling-Tang (Sairei-to),
880
ciprofloxacin, 465
methyldopa, 391
metronidazole, 466
terbinafine, 491
jaw pain regadenoson, 338–9 joint pain benzocaine, 267
infliximab, 685
magnesium hydroxide, 418
mycophenolate, 710
voriconazole, 506
983 joints swelling deferoxamine þ deferiprone,
426
juvenile dermatomyositis carbimazole, 766
juvenile idiopathic arthritis rubella immunization, 581–2 K karyotypic Turner’s syndrome irbesartan, 387
keratitis chlorhexidine, 439
dorzolamide, 874
G-CSF, 675
isotretinoin, 299
timolol, 874
keratopathy amiodarone, 342
tamoxifen, 746
keratosis arsenic, 414
ketoacidosis continuous subcutaneous
insulin infusion (CSII), 771
kidney stones see nephrolithiasis L lacrimal duct system obstruction dorzolamide, 404
lactation, non-puerperal olanzapine, 108
risperidone, 108
lactic acidosis see also metabolic acidosis
beta2-adrenoceptor agonists,
315
linezolid, 474, 475
metformin, 386, 773, 774
minocycline, 453
statins, 808
language loss growth hormone, 793
laryngeal edema Ci Wu Jia injection, 881
Houzheng Wan, 880
Shuang Huang Lian
injection, 882
Suxiao Jiuxin Wan, 880
lashes, growth prostaglandins, 730, 873
lateral rectus nerve palsy dental anesthesia, 263
laughter, pathological see also gelastic seizures
cilostazol, 372
LDL cholesterol concentrations, increased
carbamazepine, 128
lead poisoning folk remedy, greta, 883
learning, impaired cannabis, 56
left ventricular apical
ballooning syndrome
amfetamine, 1
left ventricular ejection
fraction, reduced
opioids, 184
left ventricular function,
impaired
propofol, 252
leg ulcers anagrelide, 638
nicorandil, 365
Leishmaniasis efalizumab, 689
lenticular opacities deferasirox, 427
lethargy
dacarbazine, 828
gabapentin, 133
lamotrigine, 137
quetiapine, 106
Shan Dou Gen, 885
vitamin A, 607
leukemia
dacarbazine, 829
linezolid, 476
pethidine, 476
leukemia, acute lymphoblastic cyanoacrylates, 894
leukemia, acute myeloid G-CSF, 675
temozolomide, 831
leukocytoclastic vasculitis
acenocoumarol, 619
coumarins, 618, 619
glimepiride, 778
rifampicin, 564
warfarin, 618
leukocytosis
arsenic trioxide, 414
sulfasalazine, 670
terbinafine, 492
leukoencephalopathy
efalizumab, 688
etanercept, 682
linezolid, 475
natalizumab, 690
leukopenia
albendazole, 573
amantadine þ ribavirin,
545
amiodarone, 344, 345
azathioprine þ prednisone,
718
clozapine, 95, 97
Index of adverse effects
984 dacarbazine, 828
gabapentin, 133
levetiracetam, 141
mebendazole, 573
methylphenidate, 13
oxcarbazepine, 144
quetiapine, 107
ragaglitazar, 782
temozolomide, 830
tesaglitazar, 783
tetrathiomolybdate, 432
trientine, 432
valproate, 154
libido, increased
gamma-hydroxybutyric acid
(GHB), 68
libido, reduced opioids, 186
lichenoid eruption
captopril, 384
olanzapine, 103
terazosin, 393
lichenoid reactions adalimumab, 679
infliximab, 684
lichen planopilaris etanercept, 682
lichen planus pemphigoides captopril, 384
statins, 811
lichen sclerosus oral contraceptives, 741–2 light-headedness
amantadine, 545
diatrizoate þ lidocaine þ
gadolinium, 850
gabapentin, 132
levetiracetam, 141
tiagabine, 148
limbs, cold Ci Wu Jia injection, 881
limbs, short warfarin, 619
linear growth, reduced glucocorticoids, 871
lip blanching dental anesthesia, 263
lip dryness
Yu Xing Cao injection,
883
lip paresthesia methoxyflurane, 244
lipoatrophy
lispro insulin, 770
metformin, 773
stavudine, 532
lipodystrophy
glucocorticoids, 725
prednisone therapy, 723
stavudine, 535
lipohypertrophy continuous subcutaneous
insulin infusion (CSII), 771
pegvisomant, 794
Listeria meningoencephalitis infliximab, 685
livedo reticularis aprotinin, 645
liver see also hepat liver damage albendazole, 574
alfuzosin, 392
amoxicillin þ clavulanic acid,
450
amoxiclav, 450
Chai-Ling-Tang (Sairei-to),
879, 880
chlorzoxazone, 277
ciprofloxacin, 465
clavulanic acid, 450
co-amoxiclav, 450
deferasirox, 427
flucloxacillin, 451
melagatran, 634
methylprednisolone, 725, 726
NSAIDs, 682
terbinafine, 491
tolcapone, 290
vitamin A, 607
ximelagatran, 634
liver dysfunction amphotericin, 493, 494
black cohosh, 884, 885
bosentan, 390
clopidogrel, 640
interleukin-4, 677
lanreotide, 797
liposomal amphotericin B
(L-AmB), 495
mycophenolate, 710
octreotide, 797
rosuvastatin, 815
sitaxsentan, 390
terbinafine, 491
ticlopidine, 642
zileuton, 322, 323
liver, enlarged Chai-Ling-Tang (Sairei-to),
880
liver enzymes see liver function tests liver failure alcohol, 892
infliximab, 684
isoniazid, 556
nutrition, parenteral, 612
paracetamol, 892
rosiglitazone, 782
tolcapone, 290
liver function tests, abnormalities albendazole, 573
alefacept, 681
anidulafungin, 508
atomoxetine, 9
blood transfusion, 594
caspofungin, 509
clomiphene citrate, 744
daptomycin, 479
efavirenz, 538
febuxostat, 235
fluoroquinolones, 465
gatifloxacin, 466
itraconazole, 504
lamivudine, 531
methimazole, 766
mirtazapine, 37
moxifloxacin, 468
nevirapine, 539
paromomycin, 463
pegvisomant, 794
pioglitazone, 779
posaconazole, 505
quetiapine þ lithium, 105
telbivudine, 531
tipranavir, 542
tolcapone, 290
valerian, 884
von Willebrand factor/factor
VIII, 597
voriconazole, 505
ximelagatran, 634
zileuton, 323
liver necrosis chlorzoxazone, 277
liver toxicity khat, 69
long QT syndrome antihistamines, 305
risperidone, 109
loose stools atomoxetine, 9
lower respiratory tract infection montelukast, 320
low-set ears oxcarbazepine þ lamotrigine,
144
lung see also pulmonary,
respiratory
lung cancer chromium, 415
statin, 811
lung damage amiodarone, 342
barium sulfate, 850
transfusion, 593
lung masses, isolated amiodarone, 341
Index of adverse effects lupus erythematosus, cutaneous adalimumab, 679
leflunomide, 710
leuprorelin, 790
statins, 811
lupus-like syndrome efalizumab, 689
infliximab, 684
minocycline, 454
oxcarbazepine, 144
statins, 811
terbinafine, 492
TNF-a antagonists, 678
lupus-like syndrome, cutaneous terbinafine, 492
lymphadenopathy abacavir, 534
oxcarbazepine, 144
sapropterin, 610
lymph node enlargement diethylcarbamazine þ
albendazole, 574
vaccinia virus infection, 583
lymphoblastic leukemia, acute cyanoacrylates, 894
lymphocytes, artifactual agglutination EDTA, 431
lymphocytopenia temozolomide, 831
lymphoma infliximab, 683
lymphopenia tacrolimus, 714
lymphoproliferative disorders efalizumab, 688
infliximab, 684
M macular degeneration ACE inhibitors, 807
ACE inhibitors þ statins,
380
statins, 807
thyroid hormones, 764
macular edema ethambutol, 561
latanoprost, 873
macular function changes indocyanine green, 896
macular rashes sulfasalazine, 670
terbinafine, 492
maculopapular rashes fentanyl, 191
glycopeptides, 469
moxifloxacin, 468
vancomycin, 471
maculopathy, bull’s-eye mefloquine, 523
985 malaise alcohol, 535
azathioprine, 717
co-trimoxazole, 478
dacarbazine, 829
diethylcarbamazine þ
albendazole, 451
dimethyl fumarate, 295
doxycycline, 451, 574
etanercept, 683
fluorescein, 895
gabapentin, 132
infliximab, 685
interleukin-4, 677
mefloquine, 523
mycophenolate, 710
nalmefene, 211
nateglinide þ metformin, 776
nefopam, 212
pregabalin, 147
tacrolimus, 714
terbinafine, 491, 492
tipranavir, 543
valaciclovir, 530
malaria infliximab, 685
malformations see also congenital malformations
beta-lactam antibiotics, 447
fluconazole, 503
insulin, 771
leflunomide, 710
lispro insulin, 771
phenobarbital
malignancies growth hormone, 793
malignant hyperthermia sevoflurane, 246
tetracaine, 269
malignant neuroleptic syndrome oxcarbazepine, 143
mania clomiphene, 743
fluoroquinolones, 464
lamotrigine, 135
mirtazapine, 36
quetiapine, 105
valproate þ risperidone, 155
zonisamide, 162, 163
masturbation methylphenidate, 12
mediastinal disorders indacaterol, 318
megakaryocyte dysplasia valproate, 156
meibomian gland secretion, abnormal isotretinoin, 299
melanoma natalizumab, 690
membranous nephropathy fluconazole, 503
memory impairment
cannabis, 56
gabapentin, 132
progestogens, 747
propofol, 254
temozolomide, 830
topiramate, 149, 150, 152
memory loss statins, 803
memory skills, loss of growth hormone, 793
meningitis
see also aseptic meningitis
amphotericin B deoxycholate
(DAMB), 494
immunoglobulins, 688
infliximab, 685
lamotrigine, 135
Menke’s disease copper, 415
menorrhagia adalimumab, 679
menstrual abnormalities sodium valproate, 155
menstrual irregularities
domperidone, 665
glucocorticoids, 723
isotretinoin, 301
metoclopramide, 665
opioids, 186
stanozolol, 754
menstrual pain adalimumab, 679
mental clouding antipsychotic drugs, 85
mental illness khat, 69
mental retardation vigabatrin, 161
mental slowing topiramate, 149
mental status, changed calcineurin inhibitors, 705
mercury, cutaneous deposition henna, 296
metabolic acidosis
see also lactic acidosis
atazanavir, 535
bismuth subsalicylate, 916
didanosine, 535
etomidate, 250
heroin þ clenbuterol, 190
lamivudine, 535
linezolid, 475
niacin, 816
polyvinylpyrrolidone, 440
Index of adverse effects
986 povidone–iodine, 440
propofol, 254, 255
sevelamer hydrochloride, 898
topiramate, 153
metabolic effects, adverse beta-adrenoceptor
antagonists, 378
metabolic syndrome valproate, 124
metallic taste bismuth salts, 414
dacarbazine, 828
deferoxamine þ deferiprone,
426
methemoglobinemia benzocaine, 266, 267
prilocaine, 267, 268, 269
rasburicase, 236
metrorrhagia lithium, 46
microcephaly warfarin, 619
microcysts lithium, 45
micrognathia oxcarbazepine þ lamotrigine,
144
microscopic colitis clozapine, 97
middle ear pressure, increased desflurane, 243–4 migraine estrogen, 736
oxcarbazepine, 143
tartrazine, 896
miosis olanzapine, 104
mitochondrial dysfunction utero NRTI exposure, 533–4 mitochondrial encephalomyopathy statins, 808
mitochondrial neurotoxicity trichloroethylene, 246
mitochondrial syndrome statins, 808
mitochondrial toxicity stavudine, 535
mitral valvular disease fenfluramines, 7
Möbius syndrome mifepristone, 750
molar incisor hypomineralization amoxicillin, 450
molluscum contagiosum pimecrolimus, 297
monomorphic ventricular tachycardia adenosine, 337
mood disorders
amantadine þ ribavirin, 545
levetiracetam, 138
mood swings
clomiphene, 743
stanozolol, 754
zonisamide, 163
motor and sensory blockade brachial plexus anesthesia, 262
motor function deterioration vitamin A, 607
motor neuron disease metamfetamine, 4
motor weakness iotrolan and mepivacaine, 844
mouth carcinoma khat, 69
mouth, dry
albendazole, 572
amitriptyline, 131
aripiprazole, 94
buprenorphine, 209
dexbrompheniramine þ
pseudephedrine, 306
domperidone, 665
droperidol, 670
formoterol, 314
gabapentin, 131, 132
gabapentin þ
dexamethasone, 132
hyoscine butylbromide, 672
loratadine þ
pseudoephedrine, 308
mebendazole, 572
ondansetron, 670
opioids, 183
salbutamol, 314
scopolamine, 670
statins, 808
tiotropium, 319
tolterodine, 291
topiramate, 150, 151
zonisamide, 162
mouth sores calcineurin inhibitors, 707
mouth ulcers lamotrigine, 135
mycophenolate, 711
movement disorders risperidone, 110
movements, involuntary
artesunate, 525
atomoxetine þ clonidine þ
dexamfetamine, 8
mucinous cystadenocarcinoma
hormone replacement
therapy (HRT), 738
mucocutaneous
hyperpigmentation
hydroxychloroquine, 522
mucormycosis, cutaneous infliximab, 684
multifocal necrosis amphotericin, 493
multiorgan failure TGN1414, 691
multiple eruptive
dermatofibromata
efalizumab, 688
multiple sclerosis etanercept, 682
multiple synostoses fluconazole, 503
muscle aches opioids, 186
muscle cramps glucocorticoids, 723
muscle dysmorphia anabolic steroids, 753
muscle necrosis adalimumab, 680
muscle pain adalimumab, 680
muscle rigidity risperidone, 105
tetracaine, 269
muscle spasms vigabatrin, 161
muscle strength reduced statins, 807
muscle tightness nalmefene, 211
muscle weakness
botulinum toxin, 277
daptomycin, 479
glucocorticoids, 723
simvastatin, 809
terbinafine, 492
musculoskeletal abnormalities olanzapine, 103
musculoskeletal pain deferiprone, 427
myalgia adalimumab, 679
albendazole þ diethylcarbamazine, 572, 574
co-trimoxazole, 477
dacarbazine, 829
diethylcarbamazine, 572
diethylcarbamazine þ
albendazole, 572, 574
doxycycline, 451, 574
ezetimibe þ statins, 804
immunoglobulins, 595
itraconazole þ vincristine, 501
minocycline, 454
rifampicin, 563
rosiglitazone, 781, 782
rosuvastatin, 815
statins, 809, 810, 812, 813
Index of adverse effects temozolomide, 831
terbinafine, 491, 492
TGN1414, 691
trimethoprim, 477
vaccinia virus infection, 583
vincristine, 501
zileuton, 323, 324
myasthenia gravis cibenzoline, 347
disopyramide, 347
telithromycin, 471
mycosis fungoides alefacept, 681
myelodysplastic syndromes G-CSF, 675
hydroxychloroquine, 522
iron overload, 425
temozolomide, 831
myeloid leukemia, acute G-CSF, 675
temozolomide, 831
myeloneuropathy nitrous oxide (N2O), 247
myelosuppression temozolomide, 830
myelotoxicity azathioprine, 718
myocardial infarction anabolic steroids, 752
anticholinergic drugs, 318
aspirin þ methadone, 198
beta2-adrenoceptor agonists,
315
bupivacaine, 267
captopril, 346
carteolol, 870
celecoxib, 225, 226
clomiphene citrate, 743
cocaine, 59
desmopressin, 798
digoxin, 334
ephedrine, 282
glucocorticoids, 724
hepatic arterial embolization,
900
metoprolol, 364
muraglitazar, 782
noradrenaline, 283
oral contraceptives, 741
pilsicainide, 350
pioglitazone, 779
propafenone, 352
rofecoxib, 225, 226
rosiglitazone, 779, 781
sibutramine þ phentermine,
18 smallpox vaccine, 583
tamoxifen, 746
telmisartan, 388
vasopressin, 283
987 myocardial injury heroin þ clenbuterol, 190
myocardial ischemia
anabolic steroids, 752
terlipressin þ albumin, 591
myocarditis
amitriptyline, 32
clozapine, 32, 95
cocaine, 32
DTaP, meningococcal
conjugate (MCV4), 579
phenelzine overdose, 32
smallpox vaccine, 579, 583
myoclonic jerks pregabalin, 147
myoclonic status epilepticus gabapentin, 133
tiagabine, 149
myoclonus
etomidate, 248
flecainide, 348
lamotrigine, 135
tetrabenazine, 91
myofibrosis, calcific pentazocine, 205
myonecrosis simvastatin, 815
myopathy
ezetimibe, 803
gabapentin, 133
hydroxychloroquine, 522
niacin þ statins, 816
rosuvastatin, 815
statins, 803, 804, 809, 810
telbivudine, 531
myopia isotretinoin, 299, 300
myositis statins, 808
myotonia gabapentin, 134
N N-acetylaspartate, reduced
concentrations
buprenorphine, 209
naevi see nevi nail discoloration indapamide, 408
minocycline, 453
nail-fold erythema indapamide, 408
NAION see non-arteritic anterior ischemic optic neuropathy (NAION) nasal congestion ambrisentan, 389
sapropterin, 609, 610
nasal hypoplasia warfarin, 619
nasal mucosal necrosis Ecbalium elaterium juice, 885
nasal polyps statins, 807
nasal septum necrosis cocaine, 60
nasolacrimal duct obstruction timolol, 870, 871
nasopharyngeal cancer formaldehyde, 438
nasopharyngitis alefacept, 680
aliskiren, 388
indacaterol, 317
montelukast, 320
olanzapine þ lithium, 100
quetiapine þ lithium, 105
tolterodine, 291
nausea abacavir, 534
Adderall, 2
albendazole, 573
alcohol þ abacavir, 535
alefacept, 680
aminolevulinic acid, 833
amphotericin B lipid complex
þ fluconazole, 495
antiretroviral therapy, 534
aprepitant, 667
aspirin, 266
atomoxetine, 9
azathioprine, 684, 717
azithromycin, 473
barium, 850
beta-lactams, 464
bisacodyl, 671
bismuth salts, 414
blood transfusion, 600
brinzolamide, 874
buprenorphine, 209
buserelin, 789
calcitonin, 789
carbamazepine, 127, 131
ceftriaxone, 522
chlorzoxazone, 277
cholinesterase inhibitors, 20
ciclosporin þ methotrexate,
705
clarithromycin, 474
clopidogrel, 266
dacarbazine, 828
deferoxamine þ deferiprone,
426
desmopressin, 798
dexamethasone, 206
diatrizoate þ lidocaine þ
gadolinium, 850
dimethyl fumarate, 295
Index of adverse effects
988 dimethyl fumarate þ monoethyl fumarate, 295 dorzolamide, 404, 874 doxycycline, 451, 452, 574 Ecbalium elaterium, 885 exenatide, 775, 776 febuxostat, 235 fentanyl, 191, 192 fish oil supplements, 806 flecainide, 348 fluorescein, 895 fluoroquinolones, 464 gabapentin, 131, 132 gabapentin þ dexamethasone, 132 gamma-hydroxybutyric acid (GHB), 68 glucagon, 769 guaifenesin, 326 hydromorphone, 193 hydromorphone þ morphine, 193
hydroxychloroquine þ
prednisone, 522 hyoscine butylbromide, 672 immunoglobulins, 595 indacaterol, 318 indapamide, 408 infliximab, 684, 685 iomeprol, 843 iron salts, 417 lamivudine, 531, 532, 685 latanoprost, 871 lead poisoning, 883 levacetylmethadol, 195 levobetaxolol, 874 levofloxacin, 468 lopinavir þ ritonavir, 565 lubiprostone, 672 mebendazole, 574 mepivacaine, 268 mesalazine, 526, 669, 684 metformin, 774 methoxyflurane, 244 methylnaltrexone, 211 methylprednisolone, 522 metronidazole, 466, 526 moguisteine, 326 morning-after pill, 742 morphine, 199, 200, 201 moxifloxacin, 468 mycophenolate, 710, 711 nalmefene, 211 naltrexone, 211, 212 nateglinide þ metformin, 776 nefopam, 212 nevirapine, 539 niacin, 816 olanzapine, 100 opioids, 183, 204
oral contraceptive, morningafter, 742 oxcarbazepine, 141, 142 oxycodone, 202 oxymorphone, 203, 204 oxytocin, 796 pethidine, 205, 206 pethidine þ dexamethasone, 205 porfimer, 833 posaconazole, 504, 505 pramipexole, 286 pramlintide, 773 praziquantel, 572 praziquantel þ albendazole, 572 pregabalin, 147 pyrantel pamoate, 574 quetiapine þ lithium, 105 ramelteon, 79 rimonabant, 19 ritonavir þ indinavir, 541 rivastigmine, 20–1 roflumilast, 321, 322 ropinirole, 286 sapropterin, 609, 610 Shan Dou Gen, 885 Shen Mai injection, 882 Shuang Huang Lian injection, 882 sitagliptin, 775 sodium phosphate, 671 stem cells, 599 sub-Tenon’s anesthesia, 266 sugammadex, 275 tenofovir, 537 tetracycline, 454 tiagabine, 148 tigecycline, 454, 455 timolol, 874 tipranavir, 542, 543 tolcapone, 289 topiramate, 150, 151 tramadol, 208, 209 valproate, 154 voriconazole, 505 zafirlukast, 321 zidovudine þ lamivudine, 532 zileuton, 322–5 zonisamide, 161, 162 neck pain regadenoson, 338–9 neck, short warfarin, 619 necrolytic migratory erythema heroin, 188 necrosis see also individual organs alfuzosin, 392 dextran, 595
necrosis, multifocal amphotericin, 493 necrotizing enterocolitis aciclovir, 530 polystyrene sulfonate, 432 needling pain acupuncture, 886 negative anion gap lithium, 45 neonatal abstinence syndrome methadone, 198 neonatal depression pethidine, 206 neonatal hypoglycemia CSII, 771 neonatal hypothyroidism 131 I (radioiodine), 765 neoplasms, female hormone replacement
therapy (HRT), 741
nephritic syndrome, irreversible factor IX, 596 nephritis see interstitial nephritis, tubulointerstitial nephritis nephrogenic fibrosing dermopathy gadolinium, 851 nephrogenic systemic fibrosis gadolinium, 852 nephrolithiasis efavirenz, 538 indinavir, 541 ritonavir-boosted indinavir zonisamide, 163 nephropathic abnormalities tenofovir, 611 nephropathy, acute phosphate sodium phosphate products, 668 nephropathy, contrast-induced iodixanol, 847 nephrotic syndrome, minimal change etanercept, 682 nephrotoxicity aminoglycosides, 470 caspofungin, 509 cidofovir, 529 colistin, 476 lead, 431 liposomal amphotericin B (L-AmB), 495, 496
moxifloxacin, 468
vancomycin, 469, 470
nerve growth factor, reduced heroin, 188 nerve palsies iodinated contrast media, 850
Index of adverse effects nervousness efavirenz, 538
levetiracetam, 138
topiramate, 150, 151
zonisamide, 162
nervous system infections ciclosporin, 707
nervous system complaints niacin, 816
nervous system symptoms mepivacaine þ prilocaine,
261
nervous system toxicity dexindoprofen, 230
methylthioninium chloride,
896
ropivacaine, 269
nervous tension beta2-adrenoceptor agonists,
316
Netherton’s syndrome hydrocortisone, 728
neuralgia calcineurin inhibitors, 705
neural tube defects valproic acid, 126
neuroacoustical issues valproate, 154
neurocognitive deficits ecstasy, 63
neurocognitive impairment valproate, 154
neurodevelopmental delay warfarin, 619
neurodevelopmental disorders clozapine, 97
neuroleptic malignant syndrome antipsychotic drugs, 90
zonisamide, 162
neurological complications haloperidol, 499
ocular anesthesia, 265
neurological deterioration tetrathiomolybdate, 432
trientine, 432
neurological disturbances voriconazole, 505
neuromuscular disorders voriconazole, 506
neuropathy see also optic neuropathy
dacarbazine, 828
infliximab, 683
isotretinoin, 300
leflunomide, 709
linezolid, 474, 475
voriconazole, 506
statins, 807
tacrolimus, 715
989 neuropsychiatric disorders glucocorticoids, 723
ketamine, 251
neuropsychiatric manifestations
antituberculosis drugs,
560
neuropsychiatric symptoms efavirenz, 537
neurosensory hearing loss deferasirox, 427
neurotoxicity
articaine, 266
cycloserine, 560
dimethylsulfoxide (DMSO),
894
ecstasy, 63, 65
fenfluramines, 7
mercury, 419
neurotropic disease yellow fever vaccine, 586
neurovisual adverse effects valproate, 154
neutropenia
alemtuzumab, 686
anidulafungin, 508
artesunate þ amodiaquine,
521
clopidogrel, 639
clozapine, 91, 97
dacarbazine, 828
deferiprone, 426
dexketoprofen, 231
diazoxide, 393
gatifloxacin, 466
isotretinoin, 300
leflunomide, 709
micafungin, 510
moxifloxacin, 468
penicillamine, 431
posaconazole, 504, 505
prednisone þ
thienopyridines, 724
pregabalin, 148
ritodrine, 289
temozolomide, 830
terbinafine, 491
ticlopidine, 642
vancomycin, 470
neutrophil leukocytosis lithium, 45
nevi infliximab, 684
night blindness isotretinoin, 299
nightmares
dihydrocodeine, 191
efavirenz, 538
morphine, 201
nalmefene, 211
valerian, 884
night terrors clonidine, 391
night vision, reduced isotretinoin, 299
nocardiosis adalimumab, 678
nodular regeneration, liver atazanavir, 533
fosamprenavir, 533
indinavir, 533
non-alcoholic steatohepatitis methylprednisolone, 726
non-arteritic anterior ischemic optic neuropathy (NAION) amiodarone, 342
non-Hodgkin’s lymphoma dacarbazine, 829
hair dyes, 296
temozolomide, 831
non-infective pneumonia azathioprine, 717
non-occlusive mesenteric ischemia digoxin, 333
non-ocular hemorrhage ranibizumab, 867
non-pruritic tongue swelling benazepril, 380
non-puerperal lactation olanzapine, 108
risperidone, 108
non-sustained polymorphous ventricular tachycardia adenosine, 337
nose and throat, burning formaldehyde, 437
numbness Adderall, 2
Ci Wu Jia injection, 881
isotretinoin, 299
Yu xing Cao injection, 883
nystagmus carbamazepine, 131
morphine, 200
O obesity ethambutol, 562
topiramate
valproate, 124
obstruction, feeling of Suxiao Jiuxin Wan, 880
obstructive cholangitis barium, 851
obstructive sleep apnea testosterone, 754–5 ocular bleeding warfarin, 617
ocular discomfort dihematoporphyrin ether, 833
Index of adverse effects
990 ocular disturbances isotretinoin, 299
ocular hypertension see also glaucoma ranibizumab, 868
ocular inflammation
ranibizumab þ
photodynamic therapy,
867
ocular irritation dorzolamide, 874
timolol, 874
ocular pain
bimatoprost, 871
carteolol, 870
latanoprost, 871
oculocardiac reflex propofol, 252
odynophagia
aminolevulinic acid, 833
hematoporphyrin derivative,
833
isotretinoin, 300
oedema see edema oesophageal/oesophagus see esophageal/esophagus oligospermia sirolimus, 714
oliguria
isoniazid þ rifampicin þ
pyrazinamide, 564
onychomadesis azithromycin, 473
opportunistic infections
alemtuzumab, 687
daclizumab, 687
temozolomide, 831
optic atrophy warfarin, 619
optic neuritis antituberculosis drugs, 560
optic neuropathy
adalimumab, 679
ciprofloxacin, 465
ethambutol, 561
lithium transpose, 560
oral adverse effects isotretinoin, 300
oral ulcers fentanyl, 192
mycophenolate, 711
orofacial clefts glucocorticoids, 728
orolingual angioedema benazepril, 380
orthostatic faintness quetiapine, 100
orthostatic hypotension apomorphine, 287
dopamine receptor agonists,
286
quetiapine, 105, 106
tolcapone, 289
orthostatic problems acupuncture, 886
osteitis barium, 851
osteomalacia hypermagnesemia, 418
phenytoin, 146
osteonecrosis bisphosphonate, 893
osteopenia oxcarbazepine, 143
osteoporosis
beta2-adrenoceptor agonists,
316
bisphosphonates, 894
glucocorticoids, 727
heparin, 629
testosterone, 790
otitis media growth hormone, 792
montelukast, 320
ototoxicity paromomycin, 463
ovarian cancer, invasive gonadotrophins, 736
ovarian malignancies
hormone replacement
therapy (HRT), 740
ovarian papillary serous
carcinoma
talc, 898
overdose phenelzine, 32
ziprasidone, 111
overlap antimitochondrial
antibody-positive cholangitis
peginterferon alfa þ
ribavirin, 676
oxidative stress chromium, 415
oxygen desaturation alfentanil, 187
oxygen saturation, altered apraclonidine, 869
morphine, 199
P pain
deferoxamine þ deferiprone,
426
fentanyl, 192
formalin, 438
gabapentin, 131
Herpes zoster vaccine, 586
immunoglobulins, 595
iodinated contrast agents, 844
liposomal amphotericin B
(L-AmB), 495
methadone, 197
opioids, 186
photodynamic therapy, 297
sevelamer, 897
vitamin A, 607
zileuton, 323–5
painful gynecomastia see gynecomastia painful hematuria see hematuria palatal tremor ciprofloxacin, 465
pale complexion ban mao, 886
Yan Hu Ning injection,
882
pallor henna, 296
palmoplantar pustulosis infliximab, 684
palpable nodules lanreotide, 797
octreotide, 797
palpitation ban mao, 886
clenbuterol, 289
indacaterol, 318
itraconazole, 504
ligustrazine, 881
pilsicainide, 350
pregabalin, 147
quetiapine þ lithium, 105
Shen Mai injection, 882
pancreatic mumps iotalamate salts, 846
pancreatitis amiodarone, 345
antiretroviral drugs, 533
blood transfusion, 594
celecoxib, 233
clomiphene, 744
dithranol, 301
exenatide, 776
ezetimibe, 803
fenofibrate, 805
hepatic arterial embolization,
900
hormone replacement
therapy (HRT), 737
lisinopril, 385
mesalazine, 526, 669
metronidazole, 526
mirtazapine, 37
mycophenolate mofetil, 710
nalmefene, 211
rosiglitazone, 781
sulfasalazine, 670
tacalcitol, 301
Index of adverse effects tacrolimus, 714
tenofovir, 543
tigecycline, 454
tipranavir þ ritonavir, 542
valproate, 156
pancytopenia
ban mao, 886
leflunomide, 710
linezolid, 475
panic attacks topiramate, 152
papillary conjunctivitis,
granulomatous
brimonidine, 870
papillary thyroid carcinoma minocycline, 454
papilledema
ciclosporin þ methotrexate,
705
papuloerythroderma furosemide, 408
paresthesia dacarbazine, 828
temozolomide, 830
paralysis digoxin, 916
paralysis, prolonged rocuronium, 274
paranoia atorvastatin, 807
levofloxacin, 467
paranoid–hallucinatory
(schizophrenia-like)
symptoms
lamotrigine, 135
paranoid ideas clomiphene, 743
paranoid psychosis flecainide, 348
paresis temozolomide, 830
paresthesia
digoxin, 916
isotretinoin, 299
nitrofurantoin, 476
tacrolimus, 714
topiramate, 149, 150, 151
zonisamide, 162
parkinsonism
haloperidol, 83
losartan, 387
manganese, 418
tetrabenazine, 91, 277
trichloroethylene, 246
valproate, 154
paronychia indinavir, 541
nelfinavir, 542
parotid gland swelling iotalamate salts, 846
991 pauciarticular erosive arthritis methotrexate, 682
paucilesional pemphigus vulgaris gold salts, 416
peliosis hepatitis anabolic steroids, 754
pemphigus penicillamine, 431
pemphigus foliaceous candesartan, 386
telmisartan þ candesartan,
388
pemphigus vulgaris, paucilesional gold salts, 416
peptic ulceration niacin, 816
perforated necrotizing enterocolitis polystyrene sulfonate, 432
pericardial effusion clozapine, 95
pericarditis DTaP, meningococcal
conjugate (MCV4), 579
etanercept þ methotrexate,
683
smallpox vaccine, 583
periocular pigmentation, skin bimatoprost, 871
latanoprost, 871
latanoprost þ bimatoprost,
729
travoprost, 730, 873
perioral dermatitis glucocorticoids, 726
periorbital edema gadolinium-based contrast
agents, 855
rifampicin, 563
peripheral neuropathy dacarbazine, 828
leflunomide, 709
statins, 807
peristomal ulceration nicorandil, 365
peritoneal tuberculosis adalimumab, 678
peritonitis barium, 851
periventricular leukomalacia metamfetamine, 5
persecutory delusions clomiphene, 743
petechiae leuprolide, 790
pharyngitis montelukast, 320
olanzapine
temozolomide, 830
zileuton, 323–5
pharyngolaryngeal pain sapropterin, 609, 610
phenylalanine, reduced sapropterin, 609
phlebitis amiodarone, 340
phosphate nephropathy, acute sodium phosphate products,
668
photoageing voriconazole, 507
photoallergic contact dermatitis dexketoprofen, 232
photo distributed rash terbinafine, 492
photo-onycholysis indapamide, 408
olanzapine, 103
photophobia isotretinoin, 299
photosensitive dermatitis flutamide, 755
photosensitivity reactions dexketoprofen, 232
inhaled tiotropium, 319
porfimer, 833
phototoxic dermatitis dacarbazine, 829
phototoxicity fluoroquinolone, 464
pigmentation, skin amiodarone, 345
bimatoprost, 871
dihematoporphyrin ether,
833
hydroxychloroquine, 522
immunoglobulins, 595
latanoprost, 871
latanoprost þ bimatoprost,
729
minocycline, 453
silver salts, 420
travoprost, 730, 873
pigmented purpuric dermatosis telmisartan, 388
pituitary apoplexy thyrotropin-releasing
hormone, 763
pituitary tumors risperidone pituitary volume, increase pegvisomant, 794
pityriasis zonisamide, 163
pityriasis rosea adalimumab, 679
pityriasis rubra pilaris efalizumab, 688
Index of adverse effects
992 plantar exfoliation efalizumab, 688
plaques, with blisters cetirizine, 306
plasmacytosis methimazole, 766
plasma homocysteine concentrations carbamazepine, 125
platelet aggregation, impaired valproate, 156
platelet count, reduced abciximab, 638
pleural effusions amiodarone, 341
amiodarone þ
hypoalbuminemia, 341
pravastatin, 807
pleuropulmonary fibrosis dopamine receptor agonists,
286
Pneumocystis jiroveci pneumonia adalimumab, 680
etanercept, 683
glucocorticoids, 728
infliximab, 683, 685
pneumomediastinum, spontaneous ecstasy, 62
pneumonia see also specific types ACE inhibitors, 381
amiodarone, 341
fluticasone, 311
formoterol, 312
infliximab, 685
inhaled glucocorticoids, 311,
312
leflunomide, 709
salmeterol þ fluticasone, 311
pneumonitis alemtuzumab, 686
amiodarone, 340, 341
anakinra, 677
everolimus, 708
formaldehyde, 438
minocycline, 452
moxifloxacin, 468
nitrofurantoin, 476
sirolimus, 712, 713
temozolomide, 830
pneumothorax acupuncture, 886
Poland syndrome misoprostol, 730
polyarteritis nodosa minocycline, 454
polyarthralgia minocycline, 453
polyarthritis minocycline, 453
polycystic ovarian syndrome sodium valproate, 155
testosterone, 790
polycythemia fluconazole, 502
polydactyly warfarin, 619
polydipsia didanosine þ lamivudine þ
atazanavir, 535
polymyalgia rheumatica itraconazole þ vincristine, 501
polymyositis statins, 811
polyneuropathies, peripheral isotretinoin, 299
statins, 807
tacrolimus, 715
polyuria didanosine þ lamivudine þ
atazanavir, 535
PONV see postoperative nausea and vomiting (PONV) porphyria cutanea tarda tipranavir þ ritonavir, 543
posterior reversible encephalopathy syndrome glucocorticoids, 725
postmenopausal bleeding stanozolol, 754
post-micturition pain ketamine, 252
postoperative nausea pethidine þ dexamethasone,
205
sufentanil, 208
postoperative nausea and vomiting (PONV) anesthetic vapors, 243
sufentanil, 208
postoperative vomiting sufentanil, 208
postprocedural rebleeding abciximab, 638
potassium concentration, reduced formoterol, 316
potassium regulation, imbalance in thiopental, 255
pre-eclampsia stilbestrol, 739
pre-existing heart failure duloxetine, 34
venlafaxine, 35
pregnancy isotretinoin, 301
prematurity retinopathy human erythropoietin, 598
pre-retinal hemorrhage cocaine, 60
presyncopal episodes timolol, 364
preterm birth metformin, 774
priapism terazosin, 393
proctitis formalin, 438
progressive acute polymorphic
psychosis
ciprofloxacin, 465
progressive multifocal
leukoencephalopathy
natalizumab, 690
prolactin concentrations, raised
antipsychotic drugs, 91
clozapine, 95
domperidone, 665
ramelteon, 79
prolactin secretion, increased nalbuphine, 211
prolonged QT interval see QT interval prolongation propofol infusion syndrome propofol, 254, 255
prostatic neoplasms androgen replacement, 751
proteinuria
irbesartan, 387
losartan, 383
pegaptanib, 865
penicillamine, 431
rosuvastatin, 815
sirolimus, 713
prothrombin time, prolonged daptomycin, 479
sulfasalazine, 670
prothrombotic effects cocaine, 58
protracted abstinence
syndrome
heroin, 189
prurigo captopril, 384
pruriginous maculopapular
rash
teicoplanin þ co-trimoxazole,
469
pruritic lesions danaparoid, 632
pruritus
see also itching
adalimumab, 680
alefacept, 680
Allium sativum, 884
anidulafungin, 507
Index of adverse effects aprepitant, 667 brinzolamide, 403, 874 brinzolamide þ levobetaxolol, 403 buprenorphine, 209 calcineurin inhibitors, 707 clonidine, 193 detemir, 770 diazepam, 146 dihematoporphyrin ether, 833 efalizumab, 688 fentanyl, 191 glargine, 770 Herpes zoster vaccine, 586 hydromorphone, 193 hydromorphone þ morphine, 193 iron dextran, 417 iron sucrose, 417 levobetaxolol, 403, 874 lispro insulin, 770 mepivacaine, 268 morphine, 199, 201 moxibustion, 884 mycophenolate, 711 nefopam, 212 niacin, 816 opioids, 183 oxycodone, 202 oxymorphone, 203 oxytocin, 795 penicillamine, 431 perflutren þ Definity, 856 pregabalin, 146 Psoralea, 885 sirolimus, 707 sufentanil, 208 Suxiao Jiuxin Wan, 880 tacrolimus, 716 terbinafine, 491 valaciclovir, 530 vitamin A, 607 Yan Hu Ning injection, 882 Yu Xing Cao injection, 883 pseudo-Bartter’s syndrome alprostadil, 729 pseudocyesis oral contraceptives, 742 pseudolymphoma carbamazepine, 128
etanercept, 682
pseudopheochromocytoma reboxetine, 36 pseudoporphyria torasemide, 408
voriconazole, 506
pseudothrombocytopenia EDTA, 431 pseudotumor cerebri
993 see intracranial hypertension, benign psoriasiform eruption carbamazepine, 129 psoriasis beta-adrenoceptor
antagonists, 378
co-trimoxazole, 478
efalizumab, 688
infliximab, 684
lithium, 45
TNF-a antagonists, 678
urapidil, 393
psoriatic arthritis efalizumab, 688 psychiatric disorders anabolic steroids, 753 buprenorphine, 209 ecstasy, 64, 67 gamma-hydroxybutyric acid (GHB), 69 valerian, 884 psychiatric illness hypothyroidism, 763 psychiatric symptoms topiramate, 123 psychomotor performance gamma-hydroxybutyric acid (GHB), 69 psychomotor speed and working memory opioids, 185 psychosis aciclovir, 530 atomoxetine þ clonidine þ dexamfetamine, 8 cannabis, 57 ciprofloxacin, 465 clarithromycin, 473 clomiphene, 743, 744 dextromethorphan, 187 diphenhydramine, 307 efavirenz, 538 ethambutol, 562 flecainide, 348 gatifloxacin, 466 glucocorticoids, 723 interferon, 676 khat, 69 levofloxacin, 467 methylphenidate, 12 olanzapine, 108 oxcarbazepine, 143 peginterferon alfa þ ribavirin, 676 pregabalin, 146 psilocybin, 70 risperidone, 108 rofecoxib, 233–4 sibutramine, 19
ziprasidone, 111 psychosis, progressive acute polymorphic ciprofloxacin, 465 psychotic symptoms buprenorphine, 210 lamotrigine, 135 zonisamide, 163 puberty, delayed melatonin, 794 pulmonary alveolar microlithiasis barium, 851 pulmonary alveolar proteinosis barium, 851 pulmonary disease opioids, 185 pulmonary embolism fenofibrate, 805 talc and zinc oxide, 420, 898 von Willebrand factor/factor VIII, 597 zonisamide, 162 pulmonary fibrosis amiodarone, 341 nitrofurantoin, 476 pulmonary function, reduced amphotericin B lipid complex, 495 pulmonary hemorrhage abciximab, 638 eptifibatide, 638 tirofiban, 638 pulmonary hypertension diazoxide, 393 pulmonary hypoplasia candesartan, 386 pulmonary infiltration amiodarone, 341 arsenic trioxide, 414 pulmonary nodulosis etanercept, 681 leflunomide, 709 pulmonary edema albumin, 591 methadone, 197 ritodrine, 289 pulmonary thromboembolism olanzapine, 102 pulmonary tuberculosis anakinra, 677 pulmonary vasoconstriction protamine, 646 punctate keratitis pegaptanib, 866 pupillary mydriasis obstetric anesthesia, 265 pure red cell aplasia carbamazepine, 128 stem cell transplantation, 600
Index of adverse effects
994 valproate, 156
purple skin patches tartrazine, 896
purpuric dermatosis, pigmented telmisartan, 388
purpuric rash ciprofloxacin, 466
purpuric vasculitis tamoxifen, 747
pustular eruptions terbinafine, 492
pustular psoriasis infliximab, 684
pyrexia see fever Q Q fever glucocorticoid, 728
QT interval prolongation
amiodarone, 340
antifungal azoles, 502
antipsychotic drugs, 85
aprepitant, 667
arsenic trioxide, 414
cocaine, 58
desflurane, 243
dolasetron, 666
domperidone, 665
fluconazole þ domperidone,
502
fluoroquinolones, 464
haloperidol, 499
indacaterol, 317
indapamide, 407
levacetylmethadol, 194
methadone, 184, 196
metronidazole, 526
moxifloxacin, 468
opioids, 184
posaconazole þ
voriconazole, 505
quinidine, 352
sevoflurane, 245
telithromycin, 471
QT syndrome antihistamines, 305
risperidone, 109
quadriparesis hypermagnesemia, 418
R rabbit syndrome neuroleptic drugs, 86
radiation-induced strictures,
worsening
formalin, 438
radiation injury temozolomide, 831
radiation recall dermatitis
dacarbazine, 829
levofloxacin, 467
radius aplasia, unilateral oxcarbazepine þ lamotrigine,
144
rapid-cycling bipolar disorder quetiapine, 104
rashes adalimumab, 680
alemtuzumab, 686
anidulafungin, 507
botulinum toxin, 277
carbamazepine, 123, 125,
127
caspofungin, 510
clindamycin, 472
detemir, 770
doxycycline, 451, 574
felbamate, 125
fentanyl, 191
fentanyl þ midazolam, 193
fosamprenavir, 541
fosamprenavir þ ritonavir,
541
gabapentin, 125
gadodiamide, 855
glargine, 770
glimepiride, 778
heparin, 632
Herpes zoster vaccine, 586
iodixanol, 847
lamotrigine, 123, 125
levetiracetam, 125
mycophenolate mofetil, 710
nevirapine, 539–41
oxcarbazepine, 123, 125
penicillamine, 431
phenobarbital, 125
phenytoin, 125
Psoralea, 885
ribavirin, 531
strontium salts, 420
Suxiao Jiuxin Wan, 880
temozolomide, 831
temsirolimus, 716
tenofovir þ emtricitabine þ
efavirenz, 533
terbinafine, 492
ticlopidine, 642
tipranavir, 543
topiramate, 125
valproate, 125
varicella vaccine, 584
vigabatrin, 125
von Willebrand factor/factor
VIII, 597
voriconazole, 505
Yan Hu Ning injection, 882
rate–pressure product, increased
adenosine receptor agonist,
338
Raynaud’s phenomenon amphotericin B deoxycholate
(DAMB), 494
rectal stenosis polystyrene sulfonate, 432
reaction times, impaired opioids, 185
red cell aplasia carbamazepine, 128
stem cell transplantation, 600
valproate, 156
red complexion Yan Hu Ning injection, 882
red eyes trimethoprim, 477
red man syndrome glycopeptides, 469
red stools cefdinir, 448
reddish purplish macules warfarin, 618
redness vaccinia virus infection, 583
refractile retinal crystals tamoxifen, 746
regurgitation ergot derivatives, 287
rejection episode mycophenolate, 711
renal calculi see nephrolithiasis renal colic benzbromarone, 234
renal damage amiodarone, 345
lithium, 45
tetracycline, 454
renal disturbances voriconazole, 505
renal dysfunction ACE inhibitors, 383
telmisartan þ ramipril, 379
renal failure, acute amphotericin B deoxycholate, 916
aprotinin, 645
ciprofloxacin, 465
deferoxamine, 430
dextran, 595
fenofibrate, 806
gadolinium, 852
hepatic arterial embolization,
900
hydroxyethyl starch, 595
immunoglobulins, 595
isoniazid, 564
linezolid, 475
povidone–iodine, 440
Index of adverse effects rifampicin, 564
sucrose þ immunoglobulins,
596 sulfadiazine, 477 sulfasalazine, 477 vancomycin þ gentamicin, 470
warfarin, 618
renal function reduced tenofovir, 533 renal function worsening ACE inhibitors, 379
everolimus, 708
renal impairment ACE inhibitor, 383 amphotericin, 494 fenofibrate, 806 hydroxyethyl starch, 595 indinavir, 541 metformin, 774 opioids, 187 renal insufficiency abciximab, 638 acetylcysteine, 848 aciclovir, 530 aminoglycosides, 461–2 amphotericin, 494 aprotinin, 644 baclofen, 276 betaxolol, 363 calcineurin inhibitors, 706 cetirizine, 351 cidofovir, 529 colchicine, 474 deferasirox, 427 doxylamine, 307 furosemide, 409 gatifloxacin, 467 gentamicin, 461 imipenem, 477 iotalamate salts, 846 lanthanum, 417 levofloxacin, 467 linezolid, 475 losartan, 387 minoxidil, 297 ramipril, 385 rifampicin, 564 simvastatin, 849 sulfonamides, 477 torasemide, 409 valaciclovir, 530 vancomycin, 471 vitamin C, 610 renal pain, recurrences dexindoprofen, 231 renal problems telmisartan, 388 renal stones see nephrolithiasis
995 renal toxicity celecoxib, 233 olmesartan medoxomil, 387 renal tubular acidosis leflunomide, 709 renovascular abnormalities human erythropoietin, 598 reproductive function, effects on melatonin, 794 respiratory acidosis sirolimus, 713 respiratory arrest rasburicase, 236 respiratory compromise botulism, 276 respiratory depression buprenorphine, 209 gabapentin gamma-hydroxybutyric acid (GHB), 68 heroin, 189 ketamine, 251 levacetylmethadol, 195 morphine, 199, 201 opioids, 185 oxycodone, 202 oxymorphone þ cimetidine, 205
phenytoin, 145, 153
propofol, 253
sufentanil, 208
tramadol, 208
respiratory difficulty remifentanil, 207
warfarin, 619
respiratory disorders indacaterol, 318 Qing Kai Ling injection, 881 respiratory distress bismuth subsalicylate, 916 pethidine, 206 porfimer sodium, 833 prednisolone, 728 ritodrine, 289 respiratory failure botulinum toxin, 277
clenbuterol, 289
methadone, 197
TGN1414, 691
respiratory problems Exubera, 772 respiratory rate, reduced morphine, 199 restless legs syndrome clozapine, 96
pramipexole, 286
ropinirole, 286
topiramate, 151
tramadol, 209
zonisamide, 162 restlessness carbamazepine, 145
phenobarbital, 145
tartrazine, 896
retinal central artery occlusion drospirenone-containing oral contraceptive, 741 retinal function, reduced isotretinoin, 299 retinal hemorrhage pegaptanib, 866 retinal phototoxicity hydrochlorothiazide, 406 retinal pigment epithelial tears ranibizumab, 868 retinal toxicity gentamicin, 461 hydroxychloroquine, 522, 523 indocyanine green, 896 vancomycin, 470 retinal vein thrombosis emergency contraception, 742 retinoid-like photosensitivity voriconazole, 507 retinopathy deferoxamine, 429
ethambutol, 561
retrobulbar hemorrhage sub-Tenon’s block, 265 retrograde amnesia pethidine, 205, 206 reverse anorexia nervosa anabolic steroids, 753 reverse left ventricular apical ballooning syndrome amfetamine, 1 rhabdomyolysis atorvastatin, 804 clopidogrel þ ciclosporin þ atorvastatin, 641 clopidogrel þ ciclosporin þ atorvastatin, 812 cocaine, 59 colistin, 477 daptomycin, 479 doxylamine, 307 efalizumab, 813 fenofibrate, 804, 806 fusidic acid þ atorvastatin, 479 fusidic acid þ simvastatin, 479 gatifloxacin, 467 gemfibrozil, 804 heroin, 189 iotrolan, epidural, 844 metformin, 774 metformin þ ramipril, 385, 386
Index of adverse effects
996 olanzapine, 103
pravastatin, 804
propofol, 254
simvastatin, 804
simvastatin þ ciclosporin, 812
simvastatin þ fluconazole,
501, 812
simvastatin þ fusidic acid,
813
statins, 808, 809, 810
terbinafine, 492
rheumatoid arthritis see arthritis rhinitis alefacept, 680
levetiracetam
zileuton, 323, 325
rhinorrhea sapropterin, 609, 610
rigors daptomycin, 478
gadodiamide, 855
TGN1414, 691
ruptured ovarian cyst clomiphene, 744
ruptured spleen G-CSF, 675
S sacroiliitis isotretinoin, 300
sadness levetiracetam, 139
salicylate toxicity bismuth subsalicylate, 916
salivary gland swelling and inflammation 131 I (radioiodine), 764
salivary IgA hyposecretion phenytoin, 146
salivary stones atomoxetine, 9
salivation, increased (sialorrhea) clozapine, 95, 97
risperidone, 110
salivation, reduced (sicca syndrome) isotretinoin, 299
sarcoidosis etanercept, 683
infliximab þ methotrexate,
685
sarcoma chromium, 415
scars continuous subcutaneous
insulin infusion (CSII), 771
schizophrenia-like symptoms lamotrigine, 135
schizophrenic reactions ziprasidone, 111
school participation, reduced levetiracetam, 139
sclerae, blue minocycline, 453
scoliosis growth hormone, 793
SDRIFE see symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) sebaceous gland tumors tacrolimus, 715
secondary amenorrhea dihydrocodeine, 191
secondary myelodysplastic syndrome temozolomide, 831
second-degree atrioventricular block adenosine, 337
secretions, excessive midazolam þ ketamine, 78
sedation antipsychotic drugs, 85, 91
aripiprazole, 94
clonidine, 11
fentanyl, 191
gabapentin, 132
levacetylmethadol, 195
morphine, 199, 201
naltrexone, 212
opioids, 183, 186, 205
oxycodone, 202
oxymorphone, 203
quetiapine, 104, 105, 106
remifentanil, 208
zonisamide, 161
seizures anabolic steroids, 451
atomoxetine, 8
bupivacaine, 265
calcineurin inhibitors, 705
clonidine, 391
clozapine, 96
dacarbazine, 828
diphenhydramine, 307
doripenem, 448
eflornithine, 526
ertapenem, 448
etomidate, 248, 249
fluoroquinolones, 464
haloperidol þ promethazine,
84
intralipid, 261
iodinated contrast media, 850
isoniazid, 562
lamotrigine, 137
levetiracetam, 138, 372
lidocaine, 267
manganese, 418
melatonin, 795
mirtazapine þ phenytoin, 36
obstetric anesthesia, 265
oxcarbazepine, 142–3
oxymorphone þ cimetidine,
205
perflutren þ Definity, 856
propofol, 253
risperidone, 108
ropivacaine, 269
tacrolimus, 714
temozolomide, 830
theophylline, 15
topiramate, 153
valproic acid, 155
venlafaxine, 35
zinc, 421
selective myelopathy ecstasy and heroin, 62
self-injurious behavior naltrexone, 212
seminal emission and ejaculation, during defecation and micturition reboxetine, 36
sensorimotor demyelinating polyneuropathy isotretinoin, 300
sensorimotor polyneuropathy, chronic tacrolimus, 715
sensorineural hearing loss azithromycin, 473
deferoxamine, 429
sensory impairment statins, 807
sensory irritation formaldehyde, 437
sensory loss isotretinoin, 299
sensory polyneuropathy isotretinoin, 299
sepsis hepatic arterial embolization,
900
septicemia heparin vial, 630
septic arthritis iodinated contrast media,
850
serotonin syndrome fentanyl, 192
linezolid, 474
linezolid þ pethidine, 476
pethidine, 205, 206
triptans þ SSRIs, 372
sexual arousal syndrome fludrocortisone, 727
Index of adverse effects sexual disturbances clozapine, 97
sexual dysfunction carbamazepine, 131
lithium, 46
opioids, 186
sexual function, impairment risperidone, 110
sexual maturation, effects on melatonin, 794
shivering sugammadex, 275
Yan Hu Ning injection, 882
shock pseudoephedrine, 283
short bowel syndrome parenteral nutrition, 612
short limbs warfarin, 619
short neck warfarin, 619
short-term memory topiramate, 152
SIADH see syndrome of inappropriate secretion of antidiuretic hormone (SIADH) sialorrhea (hypersalivation) clozapine, 95, 97
risperidone, 110
sicca syndrome isotretinoin, 299
sick feeling nalbuphine, 211
sideroblastic anemia linezolid, 475
SIDS (sudden infant death syndrome) heroin, 189
silicopneumoconiosis talc, 898
silvery-grey pigmentation silver salts, 420
singing, compulsive dopamine, 288
sinus bradycardia amiodarone, 340
blood progenitor cells, 600
digoxin, 333
methylprednisolone, 724
sinusitis adalimumab, 679
montelukast, 320
temozolomide, 830
zileuton, 323, 324
sinusoidal obstructive syndrome gemtuzumab ozogamicin,
689
997 SIRS see systemic inflammatory response syndrome (SIRS) sixth nerve palsy acitretin, 298
SJS see Stevens–Johnson syndrome (SJS) skeletal anomalies fluconazole, 503
skin blistering voriconazole, 506
skin burning tacrolimus, 716
skin disorders glucocorticoids, 723
topiramate, 149
skin, dry
benzalkonium, 440
opioids, 183
temozolomide, 831
skin eruptions
see also rashes
adalimumab, 679
quinine, 524
skin induration simvastatin, 808
skin irritation
acupuncture, 886
boric acid, 440
Psoralea, 885
skin necrosis
heparin, 629
leflunomide, 710
terlipressin, 798
vancomycin, 470
warfarin, 618
skin papules efalizumab, 689
skin reactions
dexindoprofen, 230
etoricoxib, 233
Qing Kai Ling injection,
881
skin stinging tacrolimus, 716
skin thickening aldesleukin, 676, 677
skull defects methimazole, 766
skull thickening G-CSF, 675
slate-grey pigmentation, diffuse
bilateral
minocycline, 453
SLE see systemic lupus erythematosus (SLE) sleep apnea opioids, 185
sleep attacks dopamine receptor agonists,
286, 287
sleep/behavior disturbance beta2-adrenoceptor agonists,
316
sleep disturbances levetiracetam, 138
methylphenidate, 11
naltrexone, 212
propofol/remifentanil, 254
tartrazine, 896
tolcapone, 289
sleepiness antihistamines þ
decongestants, 305
diazepam, 76
levetiracetam, 138
papaverine, 205
topiramate, 149, 150
zonisamide, 162
sleeplessness clomiphene, 743
levetiracetam þ valproate,
140, 160
sleepwalking olanzapine, 102
slurred speech ciprofloxacin, 465
tacrolimus, 714
sociability gamma-hydroxybutyric acid
(GHB), 68
somatic hallucinations methylphenidate, 12
somnambulism olanzapine, 102
somnolence antiretroviral drugs, 562
aripiprazole
atomoxetine, 8, 11
atypical antipsychotic drugs,
84
buprenorphine, 209
carbamazepine, 127
ciprofloxacin þ clozapine,
466
clarithromycin, 562
co-trimoxazole, 562
dopamine receptor agonists,
286
ethambutol, 562
fentanyl, 191
fluconazole, 562
gabapentin, 123, 132
levetiracetam, 124, 137, 138,
139
levocetirizine, 320
montelukast, 320
norclozapine, 466
Index of adverse effects
998 olanzapine, 100
opioids, 204
oxcarbazepine, 141
oxycodone, 202
oxymorphone, 203
pilsicainide, 349
pregabalin, 124, 147
quetiapine, 106
ramelteon, 79
risperidone, 108, 109
ropinirole, 286
statins, 808
tacrolimus, 715
temozolomide, 830
tiagabine, 148
topiramate, 124, 149, 150,
151
tramadol, 209
valproate, 154
zonisamide, 124, 161, 162
sore throat methoxyflurane, 244
nevirapine, 539
thiopental, 255
Yu Xing Cao injection, 883
spasms vigabatrin, 161
spasticity, increased gabapentin, 131
speech deterioration vitamin A, 607
speech disorder atomoxetine þ venlafaxine, 8
clozapine, 95
speech, slurred ciprofloxacin, 465
tacrolimus, 714
spermatogenesis, impaired estrogens, 739
spinal myoclonus spinal (intrathecal)
anesthesia, 263
splenomegaly vitamin A, 607
spontaneous hepatic rupture anabolic steroids, 754
spontaneous pneumomediastinum ecstasy, 62
squamous cell carcinoma azathioprine, 718
etanercept, 682
glucocorticoids, 728
voriconazole, 507
Staphylococcus aureus tendon sheath abscess carbamazepine, 130
status epilepticus gatifloxacin, 466
lamotrigine, 137
status epilepticus, myoclonic gabapentin, 133
tiagabine, 149
status gelasticus levetiracetam, 140, 372
status migrainosus oxcarbazepine, 143
steatohepatitis adefovir, 530
stent thrombosis cocaine, 59
stereotyped movements naltrexone, 212
Stevens-Johnson syndrome
(SJS)
carbamazepine, 129–30
clarithromycin, 473
losartan, 387
metronidazole
minoxidil, 297
nevirapine, 539
temozolomide, 831
terbinafine, 492
stinging
bimatoprost, 871
fluoroquinolones, 465
latanoprost, 871
stomach pains mycophenolate, 711
stomatitis
fluorouracil, 835
khat, 69
sirolimus, 712
temozolomide, 830
stools, dark bismuth salts, 414
stools, hard opioids, 186
stools, loose atomoxetine, 9
stools, red cefdinir, 448
straight hair, curling indinavir, 541
stress amfetamine, 1
metamfetamine, 5
stroke
anabolic steroids, 753
coxibs, 226
darbepoetin, 599
epoetin, 599
intravenous
immunoglobulins, 596
muraglitazar, 782
non-selective NSAIDs, 226
phenylpropanolamine, 284
raloxifene, 745
SSRIs, 33
temozolomide, 830
ST segment depression bupivacaine, 267
contrast media, 844
dental anesthesia, 263
gelofusine, 595
oxytocin, 795
stones see gallstones, nephrolithiasis, salivary stones, urate and oxalate stones stupor lamotrigine, 137
stuttering clozapine, 96
subacute cutaneous lupus leflunomide, 710
statins, 811
subarachnoid hemorrhage phenylephrine, 284
subclinical hypothyroidism valproate, 155
subconjunctival hemorrhage warfarin, 617
subcutaneous hematoma benzethonium chloride, 622
suberythrodermic psoriasis infliximab, 684
sudden cardiac death anabolic steroids, 752
sudden death sertindole, 110
sudden infant death syndrome (SIDS) heroin, 189
sudden unexpected death in epilepsy (SUDEP) lamotrigine, 136
suffocation tartrazine, 896
suicidal thoughts acupuncture, 886
suicide anabolic steroids, 753
antidepressants, 29–30
ecstasy, 67
lidocaine, 268
oseltamivir, 544
suicide-related events atomoxetine, 9
sulfonamide hypersensitivity reaction sulfasalazine, 670
sunburn phosphate þ tretinoin, 301
superficial punctuate keratitis fluoroquinolones, 465
superficial rush oxcarbazepine, 142
suprachoroidal effusions topiramate, 152
Index of adverse effects swallowing difficulty see dysphagia sweating amantadine þ ribavirin, 545
buprenorphine, 210
Ci Wu Jia injection, 881
daptomycin, 478
nalmefene, 211
nefopam, 212
opioids, 183
Shan Dou Gen, 885
Yan Hu Ning injection, 882
Sweet’s syndrome see acute febrile neutrophilic dermatosis swelling cyanocobalamin, 608
dihematoporphyrin ether, 833
Herpes zoster vaccine, 586
iodinated contrast agents, 844
iron dextran, 417
iron salts, 417
iron sucrose, 417
moxibustion, 884
pegvisomant, 794
Psoralea, 885
symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) iomeprol, 849
iopromide, 849
sympathomimetic effects heroin þ clenbuterol, 190
syncope emtricitabine, 532
nevirapine, 532
telmisartan þ ramipril, 379
tenofovir, 532
syndrome of inappropriate secretion of antidiuretic hormone (SIADH) citalopram, 33
fluoxetine, 33
systemic fibrosis gadolinium, 852–3 systemic inflammatory response syndrome (SIRS) anakinra, 677
systemic lupus erythematosus (SLE) see also lupus
etanercept, 680
infliximab, 680
estrogens, 737
peginterferon alfa þ
ribavirin, 676
TNF-a antagonist, 680
systemic nocardiosis adalimumab, 678
etanercept, 678
999 methotrexate, 678
prednisone, 678
systemic toxicity boric acid, 440
systolic hypertension blood transfusion, 600
T T3 thyrotoxicosis levothyroxine, 764
tachycardia
acetazolamide, 92
Adderall, 2
adenosine, 337, 338
alcohol þ abacavir, 535
alemtuzumab, 686
amfetamine, 1
beta2-adrenoceptor agonists,
338
clozapine, 346
desmopressin, 798
digoxin, 916
dofetilide, 348
gelofusine, 595
hyoscine butylbromide, 672
indacaterol, 318
indapamide, 407
infliximab, 685
MAS-XR, 2
mefloquine, 523
methadone, 466
methylphenidate, 10
minoxidil, 297
morphine, 199
nefopam, 212
nevirapine, 539
olanzapine, 104
oxytocin, 795, 796
pilsicainide, 349
polygelines, 595
polystyrene sulfonate, 432
quetiapine, 105
regadenoson, 339
ropivacaine, 269
salbutamol, 432
sugammadex, 275
tetracaine, 269
TGN1414, 691
valproate
tachydysrhythmias methylprednisolone, 724
tachypnea
tetracaine, 269
mefloquine, 523
TGN1414, 691
tactile hallucinations methylphenidate, 12
TA-GVHD see transfusion-associated graft-versus-host disease
takotsubo cardiomyopathy amfetamine, 1
tardive dyskinesia amisulpride, 92
clozapine, 96
dopamine receptor
antagonists, 86
taste disturbances see also dysgeusia
amlodipine, 367
amphotericin B lipid complex
þ fluconazole, 495
brimonidine, 874
brinzolamide, 403, 874
ceftobiprole, 449
clindamycin, 472
clopidogrel, 639
deferoxamine þ deferiprone,
426
dorzolamide, 404, 874
fish oil supplements, 806
iodinated contrast agents,
844
nalmefene, 211
statins, 808
temozolomide, 830
timolol, 874
topiramate, 150, 151
tearing brinzolamide, 874
brinzolamide þ
levobetaxolol, 403
carteolol, 870
levobetaxolol, 874
teeth, brown staining chlorhexidine, 439
TEN see toxic epidermal necrolysis (TEN) tenderness Herpes zoster vaccine, 586
tendinitis moxifloxacin, 468
tendinopathy ezetimibe þ statins, 804
fluoroquinolones, 465
tendon rupture levofloxacin, 467–8 tendon sheath abscess carbamazepine, 130
testicular cancer estrogens, 739
testicular dysgenesis syndrome estrogens, 739
testicular pain atorvastatin, 810
lovastatin, 810
simvastatin, 810
thinking see cognition
Index of adverse effects
1000 thinking, rapid clomiphene, 743
thoracic disorders indacaterol, 318
thoracic kyphosis warfarin, 619
throat edema infliximab, 684
regadenoson, 338–9
throat, sore methoxyflurane, 244
nevirapine, 539
thiopental, 255
Yu Xing Cao injection, 883
thrombocytopenia abciximab, 638
adalimumab, 679
alemtuzumab, 686
amiodarone, 345
aprotinin, 645
azathioprine þ prednisone,
718
clopidogrel, 639
cord blood, unrelated,
transplantation, 600
co-trimoxazole, 477
dacarbazine, 828
deferasirox, 427
deferiprone, 428
dexketoprofen, 231
efalizumab, 688
ezetimibe, 803
G-CSF, 675
heparin, 618, 626–9
leflunomide, 709
levetiracetam, 140
levofloxacin, 467
linezolid, 470, 475
methylphenidate, 13
MMR immunization, 581
oxcarbazepine, 144
pyridoxine, 475
quetiapine, 107
rifampicin, 475
simvastatin, 815
tamoxifen, 747
temozolomide, 830, 832
trimethoprim, 477
valproate, 154, 156
vancomycin, 470
warfarin, 618
thrombocytosis methimazole, 766
thromboembolism hormonal contraceptives,
741
photodynamic therapy, 867
tamoxifen, 746
thrombophlebitis sildenafil, 372
von Willebrand factor/factor
VIII, 597
thrombosis diethylstilbestrol þ
docetaxel, 739
epoetin alfa, 598
epoetin delta, 598
factor VIIa, 596
immunoglobulins,
intravenous, 596
ranibizumab, 868
tamoxifen, 746
warfarin, 617
thrombotic complications heparin, 626
immunoglobulins, 595
thrombotic events 4-factor prothrombin
complex, 596–7
warfarin, 618
thrombotic risk zileuton, 324
thrombotic thrombocytopenic purpura (TTP) clopidogrel, 639
co-trimoxazole, 477
metronidazole, 526
mifepristone, 749
thrombotic vascular events epoetin alfa, 598
human erythropoietin, 599
thymus gland rebound growth hormone, 792
thyroid cancer clomiphene, 744
thyroid disease alemtuzumab, 686, 687
amiodarone, 344
ethambutol, 563
isoniazid, 563
peginterferon alfa þ
ribavirin, 676
pyrazinamide, 563
rifampicin, 563
thyroid dysfunction amiodarone, 343
thyroiditis, autoimmune antipsychotic drugs, 87
interferons, 676
peginterferon alfa þ
ribavirin, 676
thyrotoxicosis see also hyperthyroidism
amiodarone, 343–5
levothyroxine, 764
thyroxine circulating concentrations, reduced carbamazepine, 128
tics tetrabenazine, 91
tinea versicolor etanercept, 682
tingling magnesium salts, 418
tinnitus erythromycin, 474
iloprost, 729
tiredness dihydrocodeine, 191
fish oil supplements, 806
gabapentin, 132
levetiracetam, 138, 139, 141,
149
melatonin, 795
topiramate, 123
toenails, ingrowing indinavir, 541
tolerance beta2-adrenoceptor agonists,
316
tongue, black hairy erythromycin, 474
linezolid, 476
tongue, stiffness Shan Dou Gen, 885
tongue, swelling benazepril, 380
bezafibrate, 805
tonic/tonic-clonic seizures butorphanol, 211
dimethylsulfoxide (DMSO),
894
quetiapine, 106
toothache sapropterin, 610
torsade de pointes amiodarone, 340, 502
azithromycin, 472
clarithromycin, 473
digoxin þ quinine, 336
fluoroquinolones, 464
gatifloxacin, 465
lamotrigine, 136
levacetylmethadol, 194
levofloxacin, 465
moxifloxacin, 468
ofloxacin, 465
posaconazole þ
voriconazole, 505
sevoflurane, 245
Tourette’s syndrome growth hormone, 791
toxic encephalopathy cocaine, 60
toxic epidermal necrolysis (TEN) carbamazepine, 129–30
clarithromycin, 473
infliximab, 684
phenytoin, 129, 146
Index of adverse effects SSRIs, 34
telithromycin, 471
temozolomide, 831
terbinafine, 492
vancomycin, 469
toxic erythema terbinafine, 492
toxic optic neuropathy ciprofloxacin, 465
Toxoplasma invasive disease alemtuzumab, 687
TRALI see transfusion-related acute lung injury (TRALI) transaminases see liver function tests transfusion-associated graft versus-host disease blood transfusion, 593
transfusion-related acute lung injury (TRALI) blood transfusion, 593
transient congenital hypothyroidism amiodarone, 346
transient ischemic attacks muraglitazar, 782
rosiglitazone, 781
transient left ventricular apical ballooning syndrome amfetamine, 1
transient leukopenia clozapine, 95
transient myoclonus etomidate, 248
transient urinary incontinence spinal (intrathecal)
anesthesia, 263
tremor Adderall, 2
arformoterol, 314
atomoxetine þ venlafaxine, 8
beta2-adrenoceptor agonists,
316
calcineurin inhibitors, 705
carbamazepine, 127
erythromycin, 474
formoterol, 316, 317
indacaterol, 317
LABAs þ inhaled
glucocorticoids, 315
pivoxil, 448
salmeterol, 314
sapropterin dihydrochloride,
610
Shen Mai injection, 882
tacrolimus, 714
tiagabine, 149
topiramate, 150
valproate, 154
1001 Trichophyton rubrum infection,
invasive
infliximab, 685
trigeminal nerve involvement
spinal (intrathecal)
anesthesia, 263
trigeminal nerve palsy epidural anesthesia, 263
triglycerides, raised
efavirenz, 538
infliximab, 684
stanozolol, 754
trigonocephaly valproate, 157
TTP see thrombotic thrombocytopenic purpura (TTP) tuberculosis anakinra, 677
infliximab, 683
tuberculosis reactivation etanercept, 678
infliximab, 678
tuberculosis risk vitamin E, 611
tuberculous uveitis
etanercept þ methotrexate,
683
tubular necrosis aminoglycosides, 462
tubular vacuolization dextran, 595
tubulointerstitial nephritis levofloxacin, 467
tumor lysis syndrome
hepatic arterial embolization,
900
Turner’s syndrome, karyotypic irbesartan, 387
T-wave inversion gelofusine, 595
twitching tacrolimus, 715
type 2 diabetes mellitus sibutramine, 17
U ulcerative colitis mesalazine, 669
TNF-a antagonists, 677
ulcerative keratitis chlorhexidine, 439
unconsciousness
gamma-hydroxybutyric acid
(GHB), 68
morphine, 199
unpleasant breath
fish oil supplements,
806
upper gastrointestinal bleeding clopidogrel, 639
upper gastrointestinal complications lumiracoxib, 228
non-selective NSAIDs, 228
rofecoxib, 228
upper respiratory tract infections alefacept, 680
carvedilol, 364
montelukast, 320
sapropterin dihydrochloride,
610
temozolomide, 830
urate and oxalate stones benzbromarone, 234
urinary disturbances tamoxifen, 746
urinary N-acetyl glucosaminidase, increased sugammadex, 275
urinary incontinence formalin, 438
spinal (intrathecal)
anesthesia, 263
temozolomide, 830
urinary retention carbamazepine, 128
digoxin, 916
hyoscine butylbromide, 672
morphine, 199
olanzapine, 103
pseudoephedrine, 282
urinary sand benzbromarone, 234
urinary sodium excretion, reduced growth hormone, 792
urinary tract infections ramelteon, 80
temozolomide, 830, 831
tolterodine, 291
urinary tract tumors artificial sweeteners, 892
urinary urgency ketamine, 252
urine abnormalities pegaptanib, 865
temozolomide, 831
urothelial cancer ragaglitazar, 782
urothelial cytotoxicity muraglitazar, 782
urticaria adalimumab, 679
alemtuzumab, 686
amiodarone, 345
anidulafungin, 507
benazepril, 380
Index of adverse effects
1002 cetirizine, 306
cilazapril, 381
cyanocobalamin, 608
dacarbazine, 829
folic acid, 608
gadobenate dimeglumine, 855
gadolinium-based contrast
agents, 855
gentamicin, 462
guaifenesin, 326
hydroxyzine, 306
iodinated contrast media, 850
mebendazole, 574
nefopam, 212
pegaptanib, 866
photodynamic therapy, 838
porfimer sodium, 833
Shuang Huang Lian
injection, 882
sitagliptin, 775
zileuton, 322
ziprasidone, 111
urticarial/maculopapular
eruptions
lamotrigine, 136
urticarial rash cyanocobalamin, 608
urticarial reactions cetirizine, 306
coxibs, 232
uterine fibroids, necrosis goserelin, 790
uterine rupture misoprostol, 730
oxytocin, 796
uterus hyperstimulation oxytocin, 795
uveitis
brimonidine, 870
clomiphene citrate, 743
methadone, 466
TNF-a antagonists, 677
travoprost, 873
trimethoprim, 477
uvular edema Ecbalium elaterium juice, 885
V
vaccinia virus infection smallpox vaccine, 583
vagal reactions iodinated contrast media, 850
vaginal bleeding goserelin, 790
vaginal burning boric acid, 440
vaginal clear cell carcinoma stilbestrol, 739
vaginal discharge tamoxifen, 746
valvular disease, fibrotic
dopamine receptor agonists,
286
valvular disease, mitral fenfluramines, 7
valvular regurgitation
dopamine agonists, 287
fenfluramine þ phentermine
(Fen–Phen), 17
pulmonary hypertension, 17
varicella, recurrent adalimumab, 680
vascular complications
iodinated contrast media,
850
vascular stenosis, with intimal
hyperplasia
human erythropoietin, 599
vasculitic rash leuprolide, 790
vasculitis
acenocoumarol, 619
adalimumab, 679
amlodipine, 367
antithyroid drugs, 765
carvedilol, 364
ciprofloxacin, 466
co-trimoxazole, 478
coumarins, 618, 619
glimepiride, 778
infliximab, 685
leuprolide, 790
minocycline, 454
rifampicin, 564
sulfasalazine, 670
tamoxifen, 747
TNF-a antagonists, 678
vancomycin, 469
warfarin, 618
vasodepressor episode perflutren þ Definity, 856
venous thromboembolism
dabigatran etexilate, 633
enoxaparin, 633
fibrate exposure, 806
estrogen þ progestogen, 736
venous thrombosis sildenafil, 372
ventricular bigeminy digoxin, 333
phenylephrine, 284
ventricular dysrhythmias pilsicainide, 350
tolterodine, 291
ventricular extra beats itraconazole, 504
ventricular hypertrophy anabolic steroids, 752
ventricular septum rupture abciximab, 638
ventricular tachycardia adenosine, 337
ropivacaine, 269
salbutamol, 432
verbal aggression levetiracetam, 139
verbal commands, unresponsiveness to mepivacaine þ prilocaine,
261
verbal fluency topiramate, 152
vertebral fractures bisphosphonates, 894
glucocorticoids, 727
vertigo gabapentin, 132
indacaterol, 318
valproate, 154
vestibular system damage streptomycin, 463
vestibular toxicity gentamicin, 462
streptomycin, 461
virilization androgens, 751
visceral leishmaniasis etanercept, 683
infliximab, 685
viscerotropic disease yellow fever vaccine, 586,
587
vision, blurred bimatoprost, 871
carbamazepine, 127
carteolol, 870
dacarbazine, 828
diazepam, 146
doxycycline, 452
hyoscine butylbromide, 672
isotretinoin, 299
latanoprost, 871
levetiracetam, 140
methoxyflurane, 245
niacin, 816
pregabalin, 146
Shan Dou Gen, 885
tartrazine, 896
temozolomide, 830
travoprost, 730
vision loss ethambutol, 561
vision, reduced latanoprost, 872
visual acuity impairment linezolid, 475
photodynamic therapy þ
verteporfin, 869
temozolomide, 830
Shan Dou Gen, 885
Index of adverse effects visual disturbances pegaptanib, 866
voriconazole, 505
visual field defects indocyanine green, 896
linezolid, 475
valproate, 155
visual field loss vigabatrin, 160–1 visual hallucinations nalmefene, 211
rofecoxib, 233–4
valerian products, 884
visual problems topiramate, 150 vitamin B12 deficiency metformin, 773 vitamins (D/E/K), reduced absorption sevelamer, 897 vitiligo nevirapine, 539 vitreous floaters pegaptanib, 865, 866 vitreous opacities pegaptanib, 865 vomiting albendazole, 573 amphotericin B lipid complex þ fluconazole, 495 atomoxetine, 8, 9 azathioprine, 717 bisacodyl, 671 bismuth salts, 414 blood transfusion, 600 buprenorphine, 209 buserelin, 789 carbamazepine, 131 carvedilol, 364 celecoxib chlorzoxazone, 277 cholinesterase inhibitors, 20 ciclosporin þ methotrexate, 705 cilomilast, 322 clarithromycin, 474 clenbuterol, 289 clopidogrel, 641 dacarbazine, 828 deferoxamine þ deferiprone, 426 desmopressin, 798 dexamethasone, 206 exenatide, 776 febuxostat, 235 fentanyl, 191 fentanyl þ midazolam, 193 fluorescein, 895 formaldehyde, 438 gabapentin, 132
1003 gabapentin þ dexamethasone, 132 gatifloxacin, 466 goserelin, 790 hydromorphone, 193 hydromorphone þ morphine, 193 hydroxychloroquine þ prednisone, 522 indapamide, 408 indinavir, 541 isoniazid, 562 lamivudine, 531 levacetylmethadol, 195 levofloxacin, 468 lopinavir þ ritonavir, 565 metformin, 773, 774 midazolam, 78 moguisteine, 326 morning-after pill, 742 morphine, 199, 200, 201 mycophenolate, 711 nalmefene, 211 naltrexone, 212 nefopam, 212 nevirapine, 539 niacin, 816 ondansetron, 666 opioids, 183 oral contraceptive, morningafter, 742 oseltamivir, 544 oxcarbazepine, 141 oxycodone, 202 oxymorphone, 204 oxytocin, 796 pethidine þ dexamethasone, 205 porfimer, 833 posaconazole, 504, 505 pramipexole, 286 quetiapine þ lithium, 105 quinine, 524 ramosetron, 666 rivastigmine, 20–1 roflumilast, 322 ropinirole, 286 sapropterin, 609, 610 saquinavir þ ritonavir, 532 sevelamer, 897 Shan Dou Gen, 885 Shuang Huang Lian injection, 882 sitagliptin, 775 sodium phosphate, 671 stem cells, 599 tacalcitol, 301 temozolomide, 830 tenofovir, 537 tiagabine, 148
tigecycline, 454 tipranavir, 542, 543 tramadol, 208 valproate, 154 vitamin A, 607 von Willebrand factor/factor VIII, 597
voriconazole, 505
zileuton, 323
von Willebrand factor and factor XIII valproate, 156 vortex keratopathy hydroxychloroquine, 522 vulvar vestibulitis syndrome hormonal contraception, 742 W weakness see also fatigue, malaise, tiredness
aripiprazole, 94
buprenorphine, 209
ciprofloxacin, 465
colchicine, 813
dacarbazine, 828
digoxin, 336
indapamide, 407
infliximab, 684
methadone, 209
nitrofurantoin, 476
rifampicin, 563
simvastatin, 808
tartrazine, 896
tramadol, 208
zileuton, 323
zonisamide, 161
weight change zonisamide, 163 weight gain amisulpride, 92 antipsychotic drugs, 87–8, 91 atypical antipsychotic drugs, 84, 85 carbamazepine, 125 clozapine, 97 clozapine þ olanzapine, 95 gabapentin, 125, 132 glucocorticoids, 723 insulin therapy, 771 leuprolide acetate, 789 mirtazapine, 36 olanzapine, 83 pregabalin, 125, 146–7, 148 ragaglitazar, 782 sodium valproate, 155 stanozolol, 754 temozolomide, 830 tesaglitazar, 783
Index of adverse effects
1004 valproate, 123, 154
valproic acid, 125
vigabatrin, 125
weight loss adalimumab, 680 didanosine þ lamivudine þ atazanavir, 535 felbamate, 125 lamivudine, 531 levetiracetam, 140 methylphenidate, 11 nicorandil, 364 olanzapine, 102 pramlintide, 773 roflumilast, 321, 322 sibutramine, 17
terbinafine, 491 topiramate, 125, 149, 150 zonisamide, 125, 161, 162 wheals mebendazole, 574 wheezing formaldehyde, 438 iron dextran, 417 iron sucrose, 417 telithromycin, 471, 472 white cell count, reduced see agranulocytosis, granulocytopenia, leukopenia, neutropenia working memory, impairment oxycodone, 202
wound healing, delayed glucocorticoids, inhaled, 312 X xanthopsia digoxin, 336 xerosis zonisamide, 163 xerostomia 131 I (radioiodine), 764, 765 opioids, 183 Y yellowish-brown discoloration of nails indapamide, 408
