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Home , Bicalutamide, Isotretinoin, Thalidomide

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 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ASTEMIZOLE -- Withdrawn due to ventricular arrhythmias ...... 1 -- Withdrawn due to accelerated deaths...... 1 -- Warning about reactions, increased mortality in cardiac transplant study ...... 1 -- Use restricted to second line therapy in endometriosis ...... 1 LEVACETYLMETHADOL -- Product to be withdrawn due to adverse cardiac events; safer alternatives to be adopted...... 2 MOROCTOCOG ALFA -- Reports of lack of effect in prophylaxis patients...... 2 NEFAZODONE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, , ...... 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to be added ...... 3 SOMATROPIN -- Refused approval for use in AIDS-related wasting syndrome ...... 3 TERFENADINE -- Withdrawn due to ventricular arrhythmias...... 3 VALSARTAN -- Reports of interstitial pneumonia...... 3 SAFETY OF MEDICINES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 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 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 . 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 , Drug and bicalutamide 50 mg/day for patients receiving daclizumab Medical Devices agency in metastatic 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 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 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 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 with aspiration. effect in prophylaxis of associated with patients nefazodone use. Since its Reference: introduction in 1994, nefazodone News & Updates, UKMi, 10 Sept Canada. Wyeth Canada is has been temporally associated 2003. Available from URL: informing physicians of changes with hepatic adverse events such http://www.druginfozone.nhs.uk to the Precautions and Adverse as , and Reactions sections of the product hepatocellular necrosis in monograph for moroctocog alfa LEVACETYL- patients receiving therapeutic (Refacto, Recombinant Anti- doses. As of December 2002 METHADOL haemophilic Factor). Moroctocog there were 51 Canadian reports alfa (Refacto, Antihaemophilic Product to be of hepatotoxicity ranging from no Factor Recombinant) has been withdrawn due to symptoms to transplantation, licensed in Canada since 2002 suspected to be associated with adverse cardiac events; and is indicated for the control nefazodone use. Cases of safer alternatives to be and prevention of haemorrhagic injury have occurred as early as adopted episodes and for routine and a few weeks after initiation of surgical prophylaxis in patients therapy or after continuous use USA. Roxane Laboratories is to with haemophilia A. Reports of for up to three years. Physicians discontinue the sale and lack of effect, mainly in are advised to arrange alternate distribution of levacetylmethadol prophylaxis patients, have been therapies before 27 November (Orlaam) Oral Solution 10 received during the clinical trials 2003 for their patients currently mg/mL in the US due to and in the post-marketing on nefazodone and to consult the increasing reports of severe setting with this product product monographs for both adverse cardiac events. Since (Refacto, Antihaemophilic Factor) nefazodone and the chosen the product (Orlaam) was in Canada. The lack of effect alternate antidepressant before introduced in 1995 for the and/or low factor VIII recovery making the switch. management of opioid has been reported in patients dependence, Roxane has with inhibitors and also in Reference: received 15 reports of QT patients who had no evidence of ‘Dear Healthcare Professional’ letter interval prolongation, eight of inhibitors. The lack of effect has from Bristol-Myers Squibb Canada, torsade de pointes and six of been described as bleeding into 2 Oct 2003. Available from URL: cardiac arrest, as well as reports target joints, bleeding into new http://www.hc-sc.gc.ca of arrhythmias, and joints, other bleeding or a angina. These reports led to the subjective feeling by the patient NIMESULIDE removal of levacetylmethadol of new onset bleeding. The (Orlaam) from the European product insert now reflects these Product under ‘special market in March 2001 and observations and advises that, in pharmacovigilance’ extensive changes to the US view of these reports of less than Argentina. The food, drug and package insert in April 2001. expected therapeutic effect, it is medical devices agency in With less toxic treatment important to individually titrate Argentina, ANMAT, has directed alternatives available, the and monitor each patient’s dose that nimesulide should be company now believes that the of moroctocog alfa (ReFacto), brought under the category of risks of levacetylmethadol particularly when initiating products under ‘special (Orlaam) use no longer outweigh treatment, to ensure an pharmacovigilance’. This its benefits. The product will be adequate therapeutic response. discontinued after the current category includes those drugs inventory is depleted, which is Reference: that are put under high alert and estimated to occur in early 2004. ‘Dear Healthcare Professional’ letter scrutiny for adverse reactions. from Wyeth Canada, 30 Sept 2003. Manufacturers are obliged to Reference: Available from URL: report all adverse effects ‘Dear Healthcare Professional’ letter http://www.hc-sc.gc.ca associated with nimesulide use. from Roxane Laboratories Inc, 23 (For other related information on Aug 2003. Available from URL: http://www.fda.gov NEFAZODONE nimesulide, see WHO Pharmaceuticals Newsletter No. Sale discontinued due 2, 3 & 4, 2002; 3 & 4, 2003). to adverse hepatic Reference: events Disposicion de ANMAT no 4087/03, Canada. On 27 November 2003 6 Aug 2003. Bristol-Myers Squibb Canada will

WHO Pharmaceuticals Newsletter No. 5, 2003 S 2 REGULATORY MATTERS

OSELTAMIVIR aids compared with the more Reference: conservative maximum daily PharmaTimes News Online, 5 Sept Adverse reactions dose of 100 mg in the OTC 2003. Available from URL: section to include preparations in ; appetite http://www.pharmatimes.com acute renal failure, suppressants are not approved in thrombocytopenia, Japan. The PPA products in TERFENADINE Japan already carry warnings leucopenia about the potential risk in people Withdrawn due to Japan. The Pharmaceuticals and with a history of high blood ventricular Food Safety Bureau’s Safety pressure or other cardiovascular arrhythmias problems. Despite these, there Division has advised that acute Argentina. As of 19 August renal failure, leucopenia and have been several reports necessitating the 2003, the Food, Drug and thrombocytopenia should be Medical Devices agency in added as clinically significant current move by MHLW to include stricter warnings on Argentina, ANMAT, has adverse reactions to the product withdrawn the marketing insert of oseltamivir (Tamiflu) possible side effects, including cerebral haemorrhage. The authorization for all products indicated in the treatment of containing terfenadine. This influenza. These additions are MHLW has not restricted sales but is encouraging manu- measure follows associations of based on reports associating life-threatening ventricular oseltamivir (Tamiflu) use with facturers to develop non-PPA products. (Also see WHO arrhythmias with terfenadine. acute renal failure and acute (Also see WHO Pharmaceuticals hepatitis. It is recommended that Pharmaceuticals Newsletter No. 4, 1996). Newsletter No. 3&4, 5&6, 1998; patients be carefully observed 5&6, 9&12, 1999 for previous upon onset of acute renal failure Reference: withdrawals). and appropriate measures taken Scrip World Pharmaceutical News immediately if any abnormalities No. 2876, 15 Aug 2003. Reference: occur. In case of leukopenia and Communication from ANMAT, 19 thrombocytopenia, the drug Aug 2003. Available from URL: should be discontinued. SOMATROPIN http://www.anmat.gov.ar

Reference: Refused approval for Pharma Japan 1859, 8 Sept 2003. use in AIDS-related VALSARTAN wasting syndrome Reports of interstitial PHENYLPROPAN- Europe. The Committee for pneumonia OLAMINE Proprietary Medicinal Products Japan. The Pharmaceuticals and (CPMP) in Europe has once again Food Safety Bureau’s Safety New warnings on refused to approve the use of Division has advised that cardiovascular risks to Serono’s somatropin (Serostim) interstitial pneumonia should be be added in treating AIDS-related wasting added to the list of adverse syndrome (). The reactions associated with the use Japan. The Ministry of Health, company’s application was of the antihypertensive valsartan Labour and Welfare (MHLW) has similarly turned down earlier in (Diovan). The product insert will asked manufacturers of products the year. The CPMP said it was now warn that interstitial containing phenylpropanolamine unable to identify a target pneumonia-associated symptoms (PPA) to include new warnings population for somatropin such as fever, cough, dyspnoea on cardiovascular risks. The (Serostim) treatment because of and abnormalities in chest X- move follows several reports of the heterogeneity of the study rays may occur with the use of cerebral haemorrhage and other group in terms of body valsartan (Diovan). If such problems associated with the use composition and antiviral symptoms are observed of PPA containing products. options. A lack of long-term following treatment with Around 170 products, mostly efficacy data, concerns over the valsartan, the drug should be OTC cough and cold preparations safety profile following repeated discontinued and appropriate containing PPA, are available in administration in AIDS patients measures such as Japan. Although a US study and doubts about the clinical adrenocorticosteroid published in 2000 suggested a relevance of the primary administration should be link between PPA and endpoints are also cited as initiated. haemorrhagic stroke, the reasons for the refusal. The US Japanese government did not FDA has accorded full approval Reference: impose use restrictions at the for using somatropin (Serostim) Pharma Japan 1859, 8 Sept 2003. time since the US study in cachexia. observations were based on a much higher dose (150 mg) used in appetite suppressants and diet

WHO Pharmaceuticals Newsletter No. 5, 2003 S 3 SAFETY OF MEDICINES

ROFECOXIB/ LEVETIRACETAM consumer language to summarize information in the CELECOXIB & LOPINAVIR/ professional package insert, GI adverse effects including the approved indication RITONAVIR and major adverse events. Australia. A significant number Potential for Healthcare professionals are of cases of GI adverse effects dispensing errors advised to provide this guide to associated with rofecoxib and anyone who is given mefloquine celecoxib have been reported to USA. UCB Pharma, in hydrochloride (Lariam) for the the Adverse Drug Reactions collaboration with the US FDA is prophylaxis of malaria. The guide Advisory Committee (ADRAC), warning healthcare professionals is intended only for travellers many involving elderly patients about the potential for who are taking mefloquine with known risk factors. dispensing errors with hydrochloride (Lariam) to However, 16 reports of levetiracetam (Kepra) and prevent malaria and may not celecoxib-associated peptic ulcer lopinavir/ritonavir (Kaletra) apply to patients who are sick and 16 of celecoxib- and 5 of products on account of their with malaria and who are taking rofecoxib - associated GI similar sounding trade names. the product to treat malaria. haemorrhage occurred in Levetiracetam (Kepra) is an Reference: patients aged less than 60 years antiepileptic, while lopinavir/ ritonavir is an antiretroviral. ‘Dear Healthcare Professional’ letter with no stated risk factors. The from Roche Laboratories, Sept Physicians are requested to spell Committee points out that ‘the 2003. Available from URL: serious events reported to the drug names correctly and to http://www.fda.gov/medwatch ADRAC suggest that selective write clearly as can be easily COX-2 inhibitors should be read and understood by the treated with similar caution to person filling the prescription. REPAGLINIDE & other NSAIDs’. And, where appropriate, the GEMFIBROZIL intended use should also be Reference: indicated; patients should be Risk of hypoglycaemia Australian Adverse Drug Reactions advised to carefully counter- with concomitant use Bulletin 22: 15, No. 4, Aug 2003. check all medications they receive at the pharmacy and to Canada. Novo Nordisk Canada HRT immediately contact the Inc. has informed healthcare pharmacist for any observed professionals that the CPMP to re-evaluate discrepancies. concomitant use of repaglinide risk-benefit and gemfibrozil is now Reference: contraindicated, following the France. The French Regulatory ‘Dear Healthcare Professional’ letter publication of a study in healthy Agency AFFSSAPS, in from UCB Pharma Inc, Sept 2003. volunteers demonstrating a collaboration with the European Available from URL: markedly enhanced blood http://www.fda.gov Medicines Evaluation Agency, will glucose-lowering response to re-evaluate the risk-benefit repaglinide (GlucoNorm) with profile of hormone replacement MEFLOQUINE concomitant gemfibrozil. The therapy (HRT) in order to see Company says that these how the results of the Million HYDRO- findings indicate a potential risk Women study might be CHLORIDE of severe and prolonged incorporated into the body of hypoglycaemia and it has knowledge for HRT. As reported Issuance of medication therefore contraindicated the earlier (WHO Pharmaceuticals guide for travellers concomitant use of these agents. Newsletter No. 4, 2003), the USA. Roche Laboratories has In addition, Novo Nordisk’s Million Women study has international safety database confirmed the risks produced a medication guide (MedGuide) for mefloquine contains five reports of serious associated with HRT products. hypoglycaemia in patients The current re-evaluation will hydrochloride (Lariam) anti- malarial tablets. This guide was receiving concomitant help decide whether any changes repaglinide and gemfibrozil. need to be made to the labelling developed in collaboration with of HRT products, particularly the the US FDA to help travellers Reference: indications or, whether new understand the risks of malaria, ‘Dear Healthcare Professional’ letter usage guidelines need to be the risks and benefits associated from Novo Nordisk Canada Inc, 17 Jul 2002. Available from URL: prepared. with taking mefloquine hydrochloride (Lariam) to http://www.hc-sc.gc.ca Reference: prevent malaria and the rare but Scrip World Pharmaceutical News No. potentially serious psychiatric 2875, 13 Aug 2003. adverse events associated with use of the drug. The guide uses

WHO Pharmaceuticals Newsletter No. 5, 2003 S 4 SAFETY OF MEDICINES

SALMETEROL SELECTIVE VENLAFAXINE New safety information SEROTONIN Unfavourable risk/ for use in asthma REUPTAKE benefit ratio for use in children and Canada. Following discussions INHIBITORS with Health Canada, adolescents GlaxoSmithKline (GSK) has (SSRIs) UK, USA, Canada, Sweden. highlighted safety information Adverse effects in The Expert Working Group of the from the SMART study in a Committee on Safety of `Dear Healthcare Professional' neonates 1 2 Medicines (CSM) has advised letter and in a Public Advisory . Australia. It is warned that that venlafaxine should not be In the US, the Salmeterol Multi- taking SSRI antidepressants used in children under the age of center Asthma Research Trial during or after can 18 years for the treatment of (SMART) was halted due to an result in adverse effects such as depressive illness since the increase in asthma-related hypotonia and agitation in balance of risks and benefits of deaths in patients receiving newborn babies. The Adverse this drug venlafaxine is salmeterol (Serevent) compared Drug Reactions Advisory Com- unfavourable in this population. with those receiving placebo. mittee (ADRAC) has received 26 New results from clinical trials do GSK announced that in Canada, reports in which neonates not demonstrate the efficacy of salmeterol (Serevent) is not developed symptoms attributed venlafaxine in depressive illness approved as monotherapy for to withdrawal effects of maternal in children between the age of 6 asthma, should not be used ingestion of SSRIs (paroxetine, -17 years; the data show an alone for the maintenance sertraline, fluoxetine, citalopram) increase in the harmful outcomes treatment of asthma and is not a during the third trimester of including hostility, suicidal substitute for inhaled or oral pregnancy. Onset of symptoms ideation and self-harm in the corticosteroids. Salmeterol occurred within 0−4 days of life venlafaxine (Efexor, Efexor XL) (Serevent) is a long-acting and in most cases resolved in group compared with the placebo beta2- and a ‘controller’ 2−3 days. ADRAC has also group. The efficacy and safety of medication for preventing received 13 reports of neonatal venlafaxine for other indications asthma symptoms like wheezing, adverse effects probably arising in this age group have not yet and from SSRI-transfer. been established. However, coughing. It is to be used as an In Australia paroxetine, venlafaxine should not be add-on therapy in those patients sertraline and fluoxetine are stopped abruptly but the dose already managed with listed as ‘C’ drugs, that is, drugs gradually reduced over two appropriate maintenance doses that have caused or may be weeks to minimise the risk of of inhaled corticosteroids. suspected of causing harmful withdrawal reactions. Patients should not stop taking effects on the human foetus or salmeterol (Serevent) or neonate without causing mal- Wyeth Pharmaceuticals has salmeterol/fluticasone propionate formations. Citalopram is given a issued a ‘Dear Healthcare preparation (Advair) without B3 classification in being a drug Professional’ letter, both in the consulting a physician as that has been taken only by a US and in Canada for the above symptoms may recur after limited number of pregnant safety and prescribing discontinuation. In the US, the women and women of information. labelling for salmeterol childbearing age without an The Swedish Medical Products (Serevent) has been updated increase in the frequency of Agency notes that the risk accordingly (see WHO malformations or other direct or benefit ratio of venlafaxine in Pharmaceuticals Newsletter indirect harmful effects. adolescents is being evaluated No. 4, 2003). References: on the EU level and that the References: 1. Maternal SSRI use and neonatal agency will hold a workshop in 1. ‘Dear Healthcare Professional’ effects. Australian Adverse Drug 2004 to come up with letter from GlaxoSmithKline Inc, Reactions Bulletin 22: 14, No. 4, recommendations for the 15 Aug 2003. Available from Aug 2003. treatment of ; the URL: http://www.hc-sc.gc.ca 2. Scrip World Pharmaceutical agency requests those 2. Public Advisory from News No. 2876, 15 Aug 2003. prescribing venlafaxine to be GlaxoSmithKline Inc, 4 Sep alert to suicidal thoughts in 2003. Available from URL: http://www.hc-sc.gc.ca children and points out that venlafaxine is not approved for use in this age group.

WHO Pharmaceuticals Newsletter No. 5, 2003 S 5 SAFETY OF MEDICINES

References: 1. Message from Professor G Duff, Chairman, Committee on Safety of Medicines, 19 Sept 2003. Available from URL: http://medicines.mhra.gov.uk/

2. ‘Dear Healthcare Professional’ letter from Wyeth Pharmaceuticals, 10 Sept 2003. Available from URL: http://www.hc-sc.gc.ca 3. ‘Dear Healthcare Professional’ letter from Wyeth Pharmaceuticals, 22 Aug 2003. Available from URL: http://www.fda.gov 4. Scrip World Pharmaceutical

News No. 2887, 24 Sept 2003.

WHO Pharmaceuticals Newsletter No. 5, 2003 S 6 DRUGS OF INTEREST

HMG-CoA unspecified. There were 53 References: males and 42 females with an 1. Hardman JG, Limbird L, Gilman Reductase average age of 62 years. AG. The Pharmacological Basis Average duration of therapy was of Therapeutics. 10th edition ed. Inhibitors and 288 days on standard dosages of 2001, New York: McGraw-Hill. 2. Physicians' Desk Reference. Vol. medication. There were 11 Ocular 56. 2002, Montvale, NJ: Medical Haemorrhage positive dechallenge cases and 2 Economics, p. 2642. positive rechallenge cases. 3. Bate A, et al. A bayesian neural F.W. Fraunfelder M.D. Comment network method for adverse Casey Eye Institute, Portland, drug reaction signal generation. Oregon, U.S.A. Statins have been prescribed European Journal of Clinical since at least 1987 (FDA Pharmacology, 1998. 54: p. HMG-CoA reductase in- approval of lovastatin) and the 315-321. hibitors, also referred to as profile has been 4. Hussein O, et al., Reduced “statins”, act by blocking the platelet aggregation after addressed many times over the rate-limiting step in cholesterol fluvastatin therapy is associated last 15 years. The spontaneous and are therefore with altered platelet lipid reports of ocular haemorrhage effective in the lowering of blood composition and drug binding to probably represent coincidence plasma cholesterol levels. Statins the platelets. British Journal of for the following reasons: include lovastatin, simvastatin, Clinical Pharmacology, 1997(44): p. 77-84. pravastatin, pentostatin, 1. Patients, in whom ocular 5. Edwards R, Biriell C. fluvastatin, atorvastatin and haemorrhages are reported, are Harmonisation in cerivastatin; the last drug has at risk for this ocular event due Pharmacovigilance. Drug Safety, been removed from the world to the friability of blood vessels 1994. 10(2): p. 93-102. market due to . in this age group (average age of Clinical trials have documented 62 years). the efficacy and safety of statins 2. Haemorrhages in small blood in preventing coronary heart vessels elsewhere in the body disease, cerebrovascular are not associated with the use accidents and death from of statins; there is no reason hypercholesterolemia related why blood vessels in the eye disease(1). would be affected while the

The major systemic adverse vasculature elsewhere is not. effects reported for statins are Nevertheless, the possibility hepatotoxicity and myopathy. that this effect is real cannot be Initial concern over did ruled out. For instance, there is not become a proven effect over evidence that statins reduce time(1). The Physicians Desk platelet aggregation and Reference in the USA mentions decrease thrombi formation and eye haemorrhage as a possible it is possible that this occurrence for some of the alone could lead to ocular statins(2). haemorrhages(4). In addition, The WHO Centre for small blood vessels are mainly International Drug Monitoring apparent in the eye and and the National Registry of haemorrhages in other small Drug-Induced Ocular Side Effects vessels, for example the , (Casey Eye Institute, Portland, would not be readily evident Oregon) received 95 because physicians cannot spontaneous reports of ocular examine the external appearance haemorrhage from 1988 to in clinic. present. The WHO-UMC database If clinicians suspect an recently generated positive adverse ocular reaction to statins information component values or any other medication, the (IC) for the statins and ocular national registry of drug-induced haemorrhage lending more ocular side effects is a good significance to this possible drug site to report data adverse reaction combination(3). (www.eyedrugregistry.com). The Included in the case reports are association between statins and 23 haemorrhages, ocular haemorrhage is most 9 conjunctival haemorrhages, likely categorized as “possible” 7 vitreous haemorrhages, but not “certain” or “probable”(5). 1 hyphema, and 55 ocular haemorrhages otherwise

WHO Pharmaceuticals Newsletter No. 5, 2003 S 7 FEAT URE

Safety Issues last ten years saw an expanding for the Development of global market for herbal Entreprise (CDE), based in Involving Herbal preparations containing kava Brussels, commissioned extracts in the western Phytopharm Consulting, Medicines: Kava countries. For the most part, Germany, to prepare a detailed as a Case Study western use of kava largely report of the scientific and evolved in Germany. Kava technical evidence that led to the Background extracts were sold in many kava restrictions. The CDE is an German herb shops in the 1890s institution established by the Traditional herbal preparations and, thirty years later, the first Group of ACP (Asian, Caribbean account for 30-50% of the total pharmaceutical preparation, a and Pacific) states and the medicinal consumption in China. kava tincture was made available European Union within the In Ghana, Mali, Nigeria and as a mild and to lower framework of the Cotonou Zambia herbal medicines blood pressure. Standardized Agreement. In its summary constitute the first-line of kava root tablets, capsules, analysis, Phytopharm Consulting treatment for 60% of children tinctures and dried root were has stated that, of the 76 with high fever resulting from later introduced in the American hepatotoxicity reports that were malaria. Recent years record a and European markets. In the studied, only 4 were possibly growing interest in the usage of UK, three licensed medicines and linked to kava-intake(2). herbal medicines also in the rest a large number of unlicensed The WHO Global Database for of the world. The increasing herbal remedies containing kava Adverse Drug Reactions has demand for medicinal plants and were available until before the altogether 23 case reports of the products derived from them ban on kava products. These liver injury in suspected has led to concerns over their products were marketed for the connection with the use of kava safety and efficacy. In general, treatment of , , (Piper methysticum) containing use of herbal medicines has not premenstrual syndrome and products, coming from Canada, evolved around scientific stress and sold over the counter Germany, Switzerland, UK and evidence. The evaluation of as complementary medicines or the US; majority of these reports herbal medicines to ensure their as dietary supplements and are from Germany. In addition, safety and efficacy presents nutraceuticals. important challenges. Recent the database contains 26 reports reports of fatalities and adverse The pharmacological of a variety of hypersensitivity reactions with products such as properties of kava have been reactions. attributed to a group of Ma Huang (Ephedra) and kava- The mechanism of kava- components collectively know as kava (Piper methysticum), with toxicity remains to be elucidated. kava pyrones or kava lactones. the resultant regulatory decisions Histological examinations show to ban the products in many portal with parts of the world, suggest that Hepatotoxicity with lymphocytes and eosinophils(3,4). there is an urgent need to assist kava An idiosyncratic immune countries in creating a stronger response to a reactive evidence-base on the safety, Since 1999, several cases of severe hepatic toxicity in people has been suggested as a possible efficacy and quality of herbal cause(4). Genetic differences in medicines. using kava-containing herbal products were reported in liver of kava lactones may also need to be examined(4). Kava–kava Europe and in the . By late 2002 there were 10 Kava or Awa (Piper reports of patients requiring liver The adverse reaction methysticum) is a plant growing transplants (8 in Europe and 2 in reports with kava need in the South Pacific Islands. Eight the US; one died post- to be examined against species of kava are identified by transplant) following hepatic the following the local cultivators on the basis failure associated with the use of considerations: of the plant’s growth habitat kava-containing products. This such as mountainous versus led to various worldwide 1. Very few kava-related lowland derived, shade grown regulatory measures against adverse reaction reports are versus full sun - derived etc. In kava-containing products, available from the Pacific Island the Pacific Island countries kava ranging from a total ban of such Countries where traditional has been widely consumed as a products to consumer advisories preparations of kava have been traditional ceremonial beverage warning about the adverse used for over two thousand and for its mood-altering and effects with kava(1). years. This could be due to stress relieving properties. Understandably, the bans, under-reporting or due to the Traditional preparations use restrictions, alerts and market lack of systematic studies aqueous emulsion of the crushed recalls have had a tremendous investigating the adverse effects fresh or dried roots or lower economic impact on the South of traditional kava preparations. stems of the kava shrub. The Pacific kava industry. The Centre

WHO Pharmaceuticals Newsletter No. 5, 2003 S 8 FEATURE

2. Traditional kava preparations dealing with herbal preparations. used water-based beverages Towards this we need to: made from the roots and underground stump called S collect unbiased rootstock. The more ‘modern’ information on natural capsules and tablets contain a kava products and their concentrated extract of kava safety lactones and other compounds S re-evaluate all available from kava roots and peelings data on kava products dissolved by non-aqueous S compare and investigate like and safety effects due to . The observed hepatic extraction procedures reactions with these latter across preparations. preparations may have depended The above steps could help on the concentration of the kava establish clear safety guidelines lactones or on the plant parts for kava in particular and herbal used; extraction with non- preparations in general. aqueous solvents could have eluted less polar kava alkaloids References: such as pipermethystine that are 1. Pharmaceuticals: Restrictions in known to have toxic effects on Use and Availability, April 2003, WHO. liver cells. 2. Kava Report 2003. An In-Depth Investigation into the EU 3. Liver function abnormalities Member States Market have been reported in heavy Restrictions on Kava Products. kava drinkers. The abnormalities Available from URL: in liver function returned to www.phytopharm.org normal within 1-2 months of 3. Hepatic toxicity possibly stopping kava use; and the associated with kava-containing serum alanine aminotransferase products-United States, (ALT) levels were always within Germany, and Switzerland, 1999-2002. Morbidity and normal limits(5). This is Mortality Weekly Report inconsistent with changes (MMWR) 2002, 51:1065-1067. documented in the cases of 4. Russmann S, Lauterburg BH, hepatotoxicity with other herbal Helbling A. Kava hepatotoxicity. products (Germander, Black Annals of Internal Medicine cohosh, etc) where 2001, 135(1):68-69. aminotransferase levels are seen 5. Clough AR, Jacups SP, Wang Z, to be especially high(6,7). et al. Health effect of kava use in eastern Arnhem Land 4. In many of the reported cases Aboriginal community. Internal Medicine Journal 2003, 33: 336- the patients were using other 340. medications as well. 6. Laliberte L, Villeneuve JP. Furthermore, in several cases, Hepatitis after the use of detailed information on the Germander, a herbal remedy. patient’s history, alcohol habits Canadian Medical Association and other particulars were Journal 1996, 154(11): 1689- missing. 1692. 7. Whitting PW, Clouston A, Kerlin To summarize, the situation P. Medical Journal of Australia with kava is far from clear. There 2002, 177: 432-435. is much uncertainty about causation and extent of the problem. However, kava as a case study emphasizes the value in understanding the principles of traditional practices. An in-depth re-analysis of existing data and studies designed to compare traditional versus standardized preparations of kava could go a long way in understanding the special safety issues while

WHO Pharmaceuticals Newsletter No. 5, 2003 S 9 MISCEL LANY

Recommendations from the first Meeting of the Advisory Committee on Safety of Medicinal Products, 20-22 October 2003, WHO, Geneva

Setting Priorities Health: emerging needs’ was be reviewed by a subgroup discussed and the Committee of the committee and later The Committee raised the proposed that the document discussed at the next following issues as key points in should clearly identify policy meeting of the Advisory promoting drug safety activities makers and public heath Committee. through the WHO International programme managers as target Drug Monitoring Programme. audiences. The introductory 5. Pharmacovigilance in parasitic 1. Advocacy: There is a real section should stress the vision disease programmes: need to convince the public and of the document by including the S Further data on praziqunatel politicians of the importance and following: use in pregnancy should be reviewed impact of adverse drug reaction S Medicines in public health S The initial surveillance of (ADR) reporting. An advocacy programmes should be used triclabendazole in fascioliasis document should be drafted to safely and effectively to (foot-borne trematode) outline a common vision for achieve the best possible should be followed by an on- excellence in pharmacovigilance health outcomes going monitoring. and the positive cost/benefit S All public health programmes value of ADR monitoring, with a should include a medicine 6. Pharmacovigilance in herbal link to rational drug use around risk management strategy, medicines: the world. defined prior to the S The Committee’s approval of implementation of a project 2. Development of risk the proposed WHO S All public health programmes management plans: A well- Guidelines on Safety should promote designed risk management Monitoring and Pharmaco- pharmacovigilance in the strategy should be in place, vigilance of Herbal Medicines countries in which they complementing the methods of is solicited operate. risk assessment. A workshop S Committee members will should be organized to develop provide written comments to 3. Progress in pharmaco- and implement such a strategy. WHO by mid-December prior vigilance for antimalarials: 3. Alternative approaches to to further revision and wider drug safety-monitoring: Methods S Following the initial launch of consultation in early 2004. such as cohort (prescription the programme to monitor event) monitoring should be artemisinin combination Pharmacovigilance for encouraged, in addition to the therapy (ACT) in the five antiretrovirals current spontaneous ADR countries of Burundi, DRC, 1. The Committee unanimously reporting system, to account for Mozambique, Tanzania and recommended that the issue of local situations and practices and Zambia, the initiative will be patient safety as an aspect of the thus providing a more complete rolled out to include other 3 by 5 initiative is of paramount and comprehensive picture. countries in Africa importance. 4. Traditional Systems of S The Committee acknow- 2. The Committee prepared a Medicine: There needs to be ledged the rapid progress document detailing the additional focus in special areas made with this initiative, challenges, specific safety such as traditional Chinese recognizing the significance concerns and proposals to medicine. of what has been achieved to date. The committee address these issues and recommended that this enhance the success of the Pharmacovigilance in important activity should be programme. Public Health endorsed by WHO, extended and used as a model for 1. Public health programmes other disease-driven projects could serve as important such as HIV and TB. gateways to introduce and implement pharmacovigilance in 4. Pharmacovigilance in lym- countries currently lacking safety phatic filariasis: monitoring programmes. S Experience from national 2. The draft document on programmes on filariasis will ‘Pharmacovigilance in Public

WHO Pharmaceuticals Newsletter No. 5, 2003 S 10 MISCELLANY

Current safety issues

1. Chlorproguanil/: use in African countries A statement was drafted and will be published at a later date.

2. : teratogenicity The committee agreed that a review of isotretinoin should be undertaken but limited to its inappropriate or illicit use, with a request for information circulated via vigimed; it may be necessary to consult with external agencies (e.g. police departments, enforcement groups etc) at the national level.

3. : current status of registration The current status of review of thalidomide at the EU level, availability of any evaluation reports and the proposal for monitoring thalidomide within the ‘Steps’ programme will be investigated. The outcome will determine future needs to commission an expert review of available evidence-base for concerns associated with thalidomide use, including the Cochrane database.

4. Kava-kava: traditional use S The Committee endorsed the recommendation to obtain data/assessments from countries from whom kava- use associated adverse re- action reports are available, including comprehensive literature reviews. S The WHO Collaborating Centre for International Drug Monitoring would help compile the available data on kava-products and their safety as well as re-evaluate all data thereafter. S The investigation, com- parison of extraction and analysis procedures across the various kava preparations could be undertaken possibly as a PhD project in a suitable location.

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