No. 5, 2003 EDITORIAL We are pleased to report that the first meeting of the newly established Advisory Committee on Safety of Medicinal Products was held in October. This meeting was very productive and a number of recommendations as published in this issue were made. A statement was made by this Committee recommending the need to incorporate pharmacovigilance in the WHO strategy to provide antiretrovirals to three million people by 2005. The feature article emphasizes the urgency in evolving a safety strategy for herbal issues as these remain largely un-addressed. Representatives from WHO attended the International Contents Conference on Harmonization (ICH) expert working group meetings in November, in Osaka, as observers. The document Regulatory matters Pharmacovigilance Planning, which describes the link between Safety of medicines pre- and post-marketing surveillance will now be circulated to Member States for comments. The 26th Annual Meeting of Drugs of interest the National Centres participating in the International Drug Feature Monitoring Programme will be held in December, in India. The meeting will focus on ADR reporting and how it can be Miscellany improved. A detailed report of this meeting will appear in one of the later issues. TABLE OF CONTENTS REGULATORY MATTERS ASTEMIZOLE -- Withdrawn due to ventricular arrhythmias ...................................................... 1 BICALUTAMIDE -- Withdrawn due to accelerated deaths.......................................................... 1 DACLIZUMAB -- Warning about hypersensitivity reactions, increased mortality in cardiac transplant study ................................................................................... 1 DANAZOL -- Use restricted to second line therapy in endometriosis .......................................... 1 LEVACETYLMETHADOL -- Product to be withdrawn due to adverse cardiac events; safer alternatives to be adopted.............................................................................. 2 MOROCTOCOG ALFA -- Reports of lack of effect in prophylaxis patients..................................... 2 NEFAZODONE -- Sale discontinued due to adverse hepatic events ............................................ 2 NIMESULIDE -- Product under ‘special pharmacovigilance’....................................................... 2 OSELTAMIVIR -- Adverse reactions section to include acute renal failure, thrombocytopenia, leukopenia ........................................................................................... 3 PHENYLPROPANOLAMINE -- New warnings on cardiovascular risks to be added .......................... 3 SOMATROPIN -- Refused approval for use in AIDS-related wasting syndrome ............................ 3 TERFENADINE -- Withdrawn due to ventricular arrhythmias..................................................... 3 VALSARTAN -- Reports of interstitial pneumonia..................................................................... 3 SAFETY OF MEDICINES ROFECOXIB/CELECOXIB: -- GI adverse effects ...................................................................... 4 HRT -- CPMP to re-evaluate risk-benefit ................................................................................ 4 LEVETIRACETAM & LOPINAVIR/RITONAVIR -- Potential for dispensing errors ............................. 4 MEFLOQUINE HYDROCHLORIDE -- Issuance of medication guide for travellers ........................... 4 REPAGLINIDE & GEMFIBROZIL -- Risk of hypoglycaemia with concomitant use .......................... 4 SALMETEROL -- New safety information for use in asthma....................................................... 5 SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) -- Adverse effects in neonates ............. 5 VENLAFAXINE -- Unfavourable risk/benefit ratio for use in children and adolescents ................... 5 DRUGS OF INTEREST HMG-CoA Reductase Inhibitors and Ocular Haemorrhage......................................................... 7 FEATURE Safety Issues Involving Herbal Medicines: Kava as a Case Study.............................................. 8 MISCELLANY Recommendations from 1st Meeting of the Advisory Committee on Safety of Medicinal Products,20-22 October 2003, Geneva ................................................................. 10 REGULATORY MATTERS ASTEMIZOLE progression in patients with prevention of allograft rejection, localised prostate cancer in which 434 cardiac transplant Withdrawn due to otherwise managed by watchful recipients received concomitant ventricular waiting, AstraZeneca has cyclosporin, mycophenolate arrhythmias recommended that bicalutamide mofetil and corticosteroids. In 150mg be discontinued in such the study, increased mortality Argentina. As of 19 August patients. Patients taking was seen at 6 and 12 months in 2003, the Food, Drug and bicalutamide 50 mg/day for patients receiving daclizumab Medical Devices agency in metastatic prostate cancer are (Zenapax) compared with those Argentina, ANMAT, has not affected by this new receiving placebo (7% vs 5% (1) withdrawn all medicinal products information . The Committee on and 10% vs 6%, respectively). containing astemizole since these Safety of Medicines in the UK has Some of the increased mortality products have the potential to advised that for patients with appeared to be related to a cause life-threatening ventricular localized prostate cancer, the higher incidence of severe arrhythmias. (See also WHO balanced risk benefit of infection. Other sections of the Pharmaceuticals Newsletter No bicalutamide is unfavourable and product (Zenapax) labelling 4, 1993; 7 & 8, 1999; 3, 2003). the product is no longer licensed affected by the addition of this for the treatment of this information have also been Reference: condition. Other approved uses updated. Current information Communication from ANMAT, 19 are not affected. Patients relating to the risk of Aug 2003. Available from URL: receiving bicalutamide for hypersensitivity reactions has http://www.anmat.gov.ar localized prostate cancer should also been added to the be reviewed at the earliest ‘Warnings’ section, which states BICALUTAMIDE opportunity and treatment that severe, acute (onset within discontinued(2). 24 hours) hypersensitivity Withdrawn due to reactions including anaphylaxis References: accelerated deaths have been observed both on 1. Health Canada Warnings and initial exposure and following re- Canada, UK. Following Advisories, 18 Aug 2003. exposure to the product. discussions with Health Canada, Available from URL: Permanent discontinuation of AstraZeneca has issued a `Dear http://www.hc-sc.gc.ca daclizumab is advised in the Health Care Professional' letter 2. Communication from the Committee on Safety of event of a severe hyper- recommending that, due to a Medicines, 28 Oct 2003. sensitivity reaction. trend towards accelerated Available from URL: deaths, clinicians discontinue use http://www.mhra.gov.uk Reports in WHO-file: Allergic of bicalutamide (Casodex) reaction 3, anaphylactoid reaction 2 150mg in patients with localised DACLIZUMAB Reference: prostate cancer otherwise ‘Dear Healthcare Professional’ letter managed by watchful waiting Warning about from Roche Pharmaceuticals, Aug (i.e., therapy initiated only if hypersensitivity 2003. Available from URL: signs or symptoms of disease http://www.fda.gov progression occur). Approval was reactions, increased granted in November 2002 for mortality in cardiac bicalutamide 150mg as transplant study DANAZOL immediate therapy in some Use restricted to USA. The US prescribing patients with localised prostate information for daclizumab second-line therapy in cancer for whom surgery or (Zenapax) has been updated to endometriosis radiation was inappropriate. include two new warning Health Canada has now UK. The use of danazol (Danol) statements regarding increased withdrawn this approval after has been restricted to second- mortality seen in a cardiac reviewing data from a planned line therapy in endometriosis and transplant study and second analysis of the Early benign fibrocystic breast disease, hypersensitivity reactions. Roche Prostate Cancer trial programme as a result of safety and risk- Pharmaceuticals has issued a that show a trend towards benefit assessments suggesting ‘Dear Healthcare Professional’ accelerated deaths in patients that it may increase the baseline letter informing prescribers of with localised prostate cancer risk of ovarian cancer in patients the updates. The addition of who received bicalutamide being treated for endometriosis. information to the ‘Warnings’ 150mg, compared with those The following indications have section of the product label who received placebo (196 been removed from the Danol regarding increased mortality [25.2%] deaths vs 174 [20.5%] Summary of Product Character- reflects the findings of a deaths; hazard ratio 1.23; 95% istics (SPC): gynaecomastia, randomised, double-blind, CI 1−1.5). Based on this data, pre-operative thinning of the placebo-controlled trial of along with the absence of factors endometrium prior to surgery, daclizumab (Zenapax) for the suggesting a high risk of disease dysfunctional uterine bleeding WHO Pharmaceuticals Newsletter No. 5, 2003 S 1 REGULATORY MATTERS presenting as menorrhagia to MOROCTOCOG discontinue the sale of control excessive blood loss and nefazodone (Serzone-5HT2), to control dysmenorrhoea, ALFA indicated for the symptomatic control of benign, multiple or Reports of lack of relief of depressive illness. This recurrent breast cysts in decision follows several reports conjunction