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WHO Drug Information Vol 19, No. 1, 2005 World Health Organization WHO Drug Information Contents Current Topics Regulatory Action Pharmacogenetics: towards improving Northern hemisphere influenza vaccine treatment with medicines 3 composition 2005/2006 30 Abnormal drug response: opportunities for Valdecoxib: severe skin reactions and risk reduction through pharmacogenetics 3 cardiovascular risk 30 COX-2 inhibitors: review plans 30 Safety and Efficacy Issues Co-proxamol products withdrawn 31 The role of pharmacovigilance in medicines Cisapride licences voluntarily cancelled 31 safety 13 Tentative approval for generic co-packaged National Centres discuss new safety antiretrovirals 31 monitoring methods 16 Natalizumab approved for multiple sclerosis 32 Signalling and safety problems 16 Pegaptanib for age-related macular Third meeting of the Signal Review Panel 17 degeneration 32 COX-2 inhibitors: overview 19 Amphetamine salts suspended 32 Telithromycin and warfarin: suspected Tolcapone: return to market 33 interaction 21 Patient reporting and public access to Penicillin: information strengthened 21 safety data 33 Linezolid and neuropathy 22 Australia and Canada agree mutual Ceftriaxone and immune haemolytic recognition 34 anaemia in children 22 Didanosine-tenofovir interactions: safety Ethinylestradiol/cyproterone: increased risk recommendations 34 of thrombosis 23 Influenza virus vaccine: interactions 23 Prequalification of Medicines Rosiglitazone and pioglitazone: dangers of Improving medicines quality through off-label use 24 prequalification 35 Naproxen and celecoxib suspended in How to participate in prequalification 36 Alzheimer prevention trial 24 Heparin contraindicated in severe renal ATC/DDD Classification impairment 24 Flucloxacillin: serious hepatic disorders 25 Final list 40 Bevacizumab and arterial thromboembolic Temporary list 43 events 25 Amiodarone toxicity concerns 26 The International Pharmacopoeia Darbepoetin alfa: adverse outcomes 26 Monographs for antiretrovirals Didanosine (final) 45 Vaccines and Biomedicines Indinavir sulfate (final) 51 Latest developments in biological Nelfinavir mesilate (final) 55 standardization 27 Ritonavir (final) 59 International Reference Standards 27 Saquinavir (final) 62 Recommendations and guidelines 27 Saquinavir mesilate (final) 65 Consolidated list of WHO recommendations and guidelines 29 Recommended International Nonproprietary Names: List 53 69 1 World Health Organization WHO Drug Information Vol 19, No. 1, 2005 WHO Drug Information e-mail table of contents & subscriptions available at: http://www.who.int/druginformation 2 WHO Drug Information Vol 19, No. 1, 2005 Current Topics Pharmacogenetics: towards improving treatment with medicines Increasingly, sponsors of new drugs are integrating pharmacogenetics into their drug development programmes. The outcome of this integration will present challenges to the traditional paradigms for drug development, regulatory evaluation of safety and efficacy and clinical use of drugs. Pharmacoge- netics is still an evolving discipline and a very active area of research. It promises to revolutionize therapeutics through ‘individually targeted therapy’. In principle, genotype-based individually targeted prescribing ought to be more effective at improving response rates and decreasing the burden of adverse drug reactions. The extent to which this promise of pharmacogenetics is fulfilled remains to be seen. The experience to date is mixed with a few successes but many frustrations. Discovering highly predictive associa- tions during drug development and demonstrating their clinical validity and utility in clinical trials will no doubt better define the role of pharmacogenetics in future clinical practice. The Council for International Organizations of Medical Sciences (CIOMS) and its Working Group on Pharmacogenetics have recently published a report entitled Pharmacogenetics: towards improving treatment with medicines. This is the outcome of discussions among a number of senior scientists from drug regulatory authorities, pharmaceutical companies and academia. It reflects their current views and visions and expectations for the future. The article below is drawn from the report, which is available from CIOMS. Details can be found on http://www.cioms.ch Abnormal drug response: able data suggesting that some ADRs might have a opportunities for risk reduction monogeneic or polygeneic basis, the application of pharmacogenetics provides an opportunity for fur- through pharmacogenetics ther reductions in both the incidence and severity of ADRs. An adverse drug reaction (ADR) can result from a variety of risk factors including variability in The article below reviews some of the data on ab- pharmacokinetics and pharmacodynamics of a normal drug response related to polymorphisms in drug due to the genetic make-up of an individual. drug metabolizing enzymes, pharmacological tar- Other important influences are external factors gets and drug transporters. It illustrates how, at least such as co-medications and co-morbidities, which in some areas, pharmacogenetics may offer the give rise to drug-drug or drug-disease interac- prospects of minimizing the risks of drug toxicity and tions. The net effect of these interactions is that therapeutic failures. the prescribed dose of a drug is an inappropriate one. Usually, clinically relevant drug interactions result when the plasma concentration of one of Pharmacogenetics and drug the interacting drugs increases to toxic levels. metabolizing enzymes A number of drug metabolizing enzymes displays With careful attention to prescribing information re- genetic polymorphisms. Candidate gene associa- garding dose, age-related adjustments and popu- tion studies, investigating the role of these lations at risk for drug-drug and drug-disease inter- polymorphic drug metabolizing enzymes such as actions, the impact of ADRs can be greatly mini- CYP2D6, CYP2C9, CYP2C19, N acetyltrans- mized. However, it is unlikely that any single ap- ferase (NAT2), thiopurine S-methyltransferase proach will completely eliminate all ADRs. With avail- (TPMT), UDP-glucuronosyltransferases (UGTs) 3 Current Topics WHO Drug Information Vol 19, No. 1, 2005 and dihydropyrimidine dehydrogenase (DPD) products of gene expression have been consid- have already shown that there is a genetic ered as markers for optimization of drug therapy, predisposition to a number of ADRs. most especially in the field of oncology. It is now generally assumed that because of this Polymorphic variation in CYP2D6 genetic predisposition, there may be a great Studies over the last two decades have shown potential for preventing ADRs and improving the that any given population may be divided into two safe and effective use of medicines through the phenotypes – extensive metabolizers (EMs) or increasing knowledge of genetic factors that poor metabolizers (PMs) – depending on their determine drug response. Polymorphic genes and ability to mediate CYP2D6-dependent Table 1. Clinical consequences for PM and ultrarapid EM phenotypes of CYP2D6 Clinical Consequences for the Poor Metabolizer Increased risk of toxicity Debrisoquine Postural hypotension and physical collapse Sparteine Oxytocic effects Perphenazine Extrapyramidal symptoms Flecainide Ventricular tachyarrhythmias Perhexiline Neuropathy and hepatotoxicity Phenformin Lactic acidosis Propafenone CNS toxicity and bronchoconstriction Metoprolol Loss of cardioselectivity Nortriptyline Hypotension and confusion Terikalant Excessive prolongation in QT interval Dexfenfluramine Nausea, vomiting and headache L-tryptophan Eosinophilia-myalgia syndrome Indoramin Sedation Thioridazine Excessive prolongation in QT interval Failure to respond Codeine Poor analgesic efficacy Tramadol Poor analgesic efficacy Opiates Protection from oral opiate dependence Clinical Consequences for the Ultrarapid Metabolizer Increased risk of toxicity Encainide Proarrhythmias Codeine Morphine toxicity Failure to respond Nortriptyline Poor efficacy at normal doses Propafenone Poor efficacy at normal doses Tropisetron Poor efficacy at normal doses Ondansetron Poor efficacy at normal doses 4 WHO Drug Information Vol 19, No. 1, 2005 Current Topics hydroxylation of the antihypertensive drug Polymorphic variation in CYP2C9 debrisoquine. Among the EM phenotype, there Retrospective case studies have shown that the are two subgroups of particular interest at either presence of mutant CYP2C9 allele (especially extreme of the EM population distribution. One CYP2C9*3 allele) confers a significantly in- subgroup, termed the ultrarapid metabolizers creased risk of bleeding following treatment with (UMs), is comprised of individuals possessing warfarin. Available data, however, indicate that multiple copies of the gene for normal metabolic although the CYP2C9*3/ CYP2C9*3 genotype is capacity and the other group, termed the interme- associated with dramatic over anticoagulation diate metabolizers (IMs), is comprised of a soon after the introduction of oral anticoagulants, heterozygous genotype (“gene-dose effect”). UMs overdose during the maintenance period is mostly metabolize drugs so avidly that they attain very related to environmental factors [2, 3]. It is also low concentrations of the parent drug and high recognised that inter-individual variability in concentrations of rapidly accumulating metabo- warfarin sensitivity also originates from environ- lites while IMs display a modest impairment in mental factors. In one study, age and CYP2C9 drug metabolizing