No. 3, 2003
EDITORIAL
In the previous newsletter we had appealed to the Member States for greater communication on drug safety and regulatory information. We are happy to record that Bangladesh and the Republic of Maldives have responded with some recent regulatory developments in their countries. We acknowledge the Regional Adviser’s pivotal role in facilitating this information exchange.
Counterfeit medicines continue to threaten the healthcare world. Cleverly designed fake holograms of product labels and Contents imperceptible changes to the label text make counterfeiting ever more hard to detect. In this issue, we have included an
Regulatory matters article on fake artesunate tablets, to alert readers to the level Safety of medicines of sophistication in the world of counterfeiting.
Current concerns The feature section presents an article on the workshop on Drugs of interest pharmacovigilance that was held in Zambia in March 2003. The workshop was the first of many initiatives being planned Feature to integrate pharmacovigilance into public health programmes.
TABLE OF CONTENTS
REGULATORY MATTERS
ACETYLSALICYLIC ACID -- MHRA confirms labelling change ...... 1 ACITRETIN -- Warnings of depression added to label ...... 1 ASTEMIZOLE -- Withdrawn due to life-threatening ventricular arrhythmias ...... 1 CAMELIA SINENSIS -- Ethanolic extract products withdrawn due to hepatotoxicity ...... 1 DIETARY SUPPLEMENTS -- Withdrawal of two products due to presence of sildenafil...... 1 HUA FO -- Presence of tadalafil ...... 2 IODINE – Some products contain more than the RDA ...... 2 LEVODOPA/CARBIDOPA -- New warning about somnolence and sudden onset sleep ...... 2 LINDANE -- Additional warnings and medication guide added to label ...... 2 NEFAZODONE -- Regulatory status update ...... 3 NIMESULIDE -- Paediatric preparations banned in Bangladesh ...... 3 PERGOLIDE MESYLATE -- Risk of cardiac valvulopathy ...... 3 REPAGLINIDE -- Contraindicated with gemfibrozil...... 3 RISPERIDONE -- Prescribing information updated to reflect cardiovascular adverse events ...... 4 TELITHROMYCIN -- Aggravation of myasthenia gravis...... 4 SAFETY OF MEDICINES
ANTIRETROVIRALS -- Benefit/Risk balance remains strongly positive for combination antiretroviral therapy ...... 5 CYPROTERONE ACETATE & ETHINYLESTRADIOL -- Update on risk of venous thromboembolism...... 5 DIETHYLSTILBESTROL -- Gynaecological and obstetric complications after in utero exposure...... 5 EPHEDRA -- Moves to reduce risks of ephedra-containing products...... 5 FLUTICASONE PROPIONATE -- Reports of adrenal crisis ...... 6 GRAPEFRUIT JUICE -- Revised advice from ADRAC ...... 6 HORMONE REPLACEMENT THERAPY (HRT) -- Risk of dementia ...... 6 OMEPRAZOLE, RABEPRAZOLE -- Reports of interstitial nephritis ...... 7 ROFECOXIB, CELECOXIB -- Case reports support causal association with liver toxicity ...... 7 ROSIGLITAZONE, PIOGLITAZONE -- Adverse reactions update...... 8 SOMATROPIN -- Not to be authorised for AIDS-related wasting syndrome ...... 8 CURRENT CONCERNS
Counterfeit Artesunate Antimalarial Tablets ...... 9 DRUGS OF INTEREST
Haematologic toxicity of two glycopeptides: vancomycin and teicoplanin ...... 10 FEATURE
WHO Training Workshop on Pharmacovigilance: Basic Introduction and Specifics for Malaria Programmes ...... 11
REGULATORY MATTERS
ACETYL- drug’s use in pregnancy have were women, 27 – 69 years of also been enhanced. Female age, with a time to onset varying SALICYLIC ACID patients are now required to from 9 days to 5 months. 5 of MHRA confirms have two negative pregnancy the patients did not receive any tests before start of therapy and other medications. Negative viral labelling change must also simultaneously take serologies were observed in 8 UK. In a follow-up of the two effective forms of birth cases. There were 8 positive de- Medicines Control Agency’s control. Additionally, they must challenges and one positive re- Statement on acetylsalicylic sign an agreement that they are challenge. The suspension order acid (Aspirin) use (WHO not pregnant at start of therapy, will be effective until the Pharmaceuticals Newsletter No. must not get pregnant during company provides toxicological 4, 2002), the United Kingdom’s therapy, or for three years after data and additional chemical Medicines and Healthcare discontinuing treatment. analysis of the product. products Regulatory Agency Reference: Reference: (MHRA) has posted, on its Pharma Times News Online, 1. Communication from the website, a notification that from 9 May 2003. Spanish Pharmacovigilance 1 Oct 2003 all acetylsalicylic Available from URL: System, 11 April 2003. acid-containing products will be http://www.pharmatimes.co.uk 2. Spanish Medicines Agency Press required to include the following Release, 7 Apr 2003. statutory label warning: "Do not ASTEMIZOLE Available from URL: give to children under 16 years, http://www.msc.es/agemed/cs mh/notas/exolise.asp unless on the advice of a Withdrawn due to life- doctor". This requirement follows threatening ventricular an 8-week consultation process arrhythmias DIETARY after which the Medicines Commission endorsed the advice Spain. The Spanish Medicines SUPPLEMENTS of the UK Committee on Safety Agency has withdrawn the Withdrawal of two of Medicines that the warning marketing authorization for 10 products due to medicinal products containing was required. Professor presence of sildenafil Breckenridge, chairman of the astemizole due to the potential Agency pointed out that there of these products to produce life- USA. Two dietary supplement are plenty of alternative threatening ventricular ar- products (Vinarol from Ultra analgesic products for this age rhythmias. Health Laboratories Inc and group not associated with Reye’s Reference: Bionate Inc and Viga from Best Syndrome and that "there is Communication from the Spanish Life International) are being simply no need to expose those Medicines Agency, 8 Apr 2003. voluntarily recalled by the under 16 to the risk, however Available from URL: respective companies due to the small". http://www.msc.es/agemed/csmh/ unlabeled presence of sildenafil, notas/astemizol.asp a prescription drug that could Reference: have serious health risks if used Medicines and Healthcare products Regulatory Agency. Internet CAMELIA without medical supervision. Document, 4 Apr 2003. Both products were being sold as Available from URL: SINENSIS dietary supplements, without a http://www.mhra.gov.uk Ethanolic extract prescription, for increasing desire, confidence and sexual products withdrawn performance. Consumers who ACITRETIN due to hepatotoxicity have purchased either of these Warnings of depression Spain, France. The French and products are urged to added to label Spanish Advisory Boards have discontinue their use. suspended the marketing US. Warnings of depression, Reference: authorization of a Green Tea aggressive feelings and thoughts 1. Medwatch Safety Alert, 4 Apr (Camelia Sinensis) product 2003. Available from URL: of self-harm have been added to (Exolise), prepared from the http://www.fda.gov/medwatch/ the label of acitretin (Soriatane), ethanolic extract of Green Tea, SAFETY/2003/vinarol.htm a product indicated in the due to several reports of hepatic 2. Medwatch Safety Alert, 23 May treatment of psoriasis. These disorders. Thirteen cases of 2003. Available from URL: additions follow reports linking http://www.fda.gov/medwatch/ hepatic disorders have been such observations with the use SAFETY/2003/vinarol.htm reported (9 in France and 4 in of the product. However, a Spain) with this latter product definite causality has not been (Exolise) that has been marketed established since other factors by Arkopharma Laboratories in may have contributed to some of France, Belgium, Spain and the these events. Warnings over the United Kingdom. All patients
WHO Pharmaceuticals Newsletter No. 3, 2003 S 1 REGULATORY MATTERS
HUA FO adults; this could lead to serious use machines’ and ‘Undesirable adverse health consequences. effects’ (sections 4.7 and 4.8) Presence of tadalafil The RDA for iodine ranges from have been modified to reflect 90 micrograms per day for these additions. Canada. Health Canada is children aged 1-8 years to 150 warning consumers not to use Reference: micrograms per day for adults. Hua Fo VIGOR-MAX Tablets, a Drug Info Zone, UK Medicines Excessive iodine intake could Chinese Herbal product that Information Service, 28 May 2003. lead to thyroid disorders and in contains tadalafil. Tadalafil is a Available from URL: turn to heart problems. Three prescription drug approved for http://www.druginfozone.nhs.uk reports of serious adverse events sale for male erectile dysfunction have been associated with the in the UK, Germany, Sweden, use of these products; one LINDANE Denmark, Finland, New Zealand, patient required hospitalisation. Australia and Singapore. It is not Additional warnings The excessive iodine can approved for sale in Canada. and medication guide manifest itself as an under- or Inappropriate use of tadalafil added to label over-active thyroid. Individuals could cause severe adverse especially sensitive to the toxic USA. The US FDA has issued a reactions. Tadalafil should not be effect of excess iodine include Public Health Advisory used by individuals who are children of all ages, pregnant concerning the use of topical taking any medication or other women, foetuses and newborns formulations of lindane lotion or products containing nitrates: of breast feeding women and shampoo for the treatment of concurrent use could result in those under previous or current scabies and lice, which the development of potentially supervision for thyroid disease. announces significant updates to life-threatening low blood Individuals taking amiodarone, a the product labelling. The pressure. Also, tadalafil should prescription drug for treating labelling changes include the not be used by patients with heart rhythm disorders may also addition of a new boxed warning severe renal or hepatic be at increased risk. Health which emphasises that lindane is insufficiency. Health Canada Canada warns that concerned only indicated as a second-line issued a previous warning in consumers should talk to their treatment for scabies and lice in February 15, 2002 (WHO healthcare provider. patients who are intolerant of, or Pharmaceuticals Newsletter No. unresponsive to, other therapies. 2, 2002) concerning Hua Fo Reference: It also provides updated safety when it was found to contain Health Canada information regarding the sildenafil. At the time, Health Warnings/Advisories, 8 May 2003. potential risks of adverse effects Canada required the importer to Available from URL: associated with use and misuse remove the product from the http://www.hc-sc-gc.ca of the products, and states that shelves. Health Canada is again lindane lotion or shampoo is directing the importer to remove LEVODOPA/ contraindicated in premature Hua Fo VIGOR-MAX from the infants, is not recommended for market and has issued a CARBIDOPA use in infants and should be Customs Alert to stop its further New warning about used with caution in patients importation. somnolence and who weigh less than 50kg (110 Reference: sudden onset sleep pounds). The new warning also Health Canada Warnings/ advises practitioners that, if UK. Bristol Myers Squibb has Advisories, 27 May 2003. itching continues after a single revised the Summary of Product Available from URL: treatment, reapplication of Characteristics (SPC) for their http://www.hc-sc.gc.ca lindane lotion or shampoo is not levodopa/carbidopa (Sinemet) appropriate. The advisory states preparation to include new that lindane packaging sizes will IODINE warnings about somnolence and be limited to 1 and 2 ounces to sudden onset of sleep. The Some products contain minimise the potential for ‘Special Warnings and more than the RDA patients to apply the product in Precautions for Use’ section excess and to minimise Canada. Health Canada is (Section 4.4) has been changed reapplication, and that advising consumers against to include a warning that states pharmacists should only using some products containing that levodopa has been dispense sufficient lindane for a iodine (SEAVITE Premium associated with somnolence and single application (< 2 fluid Atlantic Kelp Blend and SEAVITE sudden onset of sleep. Patients ounces). A medication guide Premium Atlantic Kelp tablets) must be advised to exercise informing patients of the risks since these products, when caution and refrain from driving, associated with lindane products consumed according to the label if affected. A reduction in dose or and providing instructions for the instructions, can provide 25 discontinuation of treatment may appropriate use of the drug must times the recommended daily be considered. The sections on now be dispensed by the allowance (RDA) of iodine for ‘Effects on ability to drive and
WHO Pharmaceuticals Newsletter No. 3, 2003 S 2 REGULATORY MATTERS
pharmacist with each new Reference: Although a causal relationship prescription. 1. Communication from the has not been established, the Division of Pharmacovigilance, ‘Warnings’ section of the product Reference: Ministry of Health, Republic of monograph is to be updated FDA Talk Paper, 28 March 2003. Turkey, 21 March 2003 accordingly. The company has Available from URL: 2. Adverse Drug Reaction News sent out a similar letter to http://www.fda.gov (Singapore), 5:1, Feb 2003. healthcare professionals in the USA earlier in the year, in NEFAZODONE NIMESULIDE February 2003 (WHO Regulatory status Paediatric preparations Pharmaceuticals Newsletter No.2, 2003). update banned in Bangladesh Reports in WHO-file: Republic of Turkey1. The Bangladesh. The manufacture, Cardiomyopathy 4 Directorate General of distribution, sale and use of all Pharmaceuticals and Pharmacy dosage forms of nimesulide Reference: has decided to suspend the paediatric preparations were ‘Dear Healthcare Professional’ letter from Draxis Health Inc and Eli Lilly license for nefazodone recently officially banned in hydrochloride preparations Canada Inc, 14 Apr 2003. Available Bangladesh. The banning of from URL: (Serzone) held by Bristol Myers adult dosage forms of nimesulide http://www.hc-sc.gc.ca Squibb Drugs Inc in Turkey. This preparations is now under active decision has been taken in view consideration of the Directorate of the latest data received by the of Drugs Administration of REPAGLINIDE Turkish Ministry of Health as well Bangladesh. A nation wide Contraindicated with as worldwide developments that survey of reports of adverse gemfibrozil suggest acute hepatic failure effects with nimesulide is being associated with nefazodone use. conducted before taking a final Europe. The European Medicinal A variety of other antidepressant decision with the adult usage Products Evaluation Agency agents are available in the formulations. Importation of (EMEA) has issued a public market and can be used nimesulide raw material has statement about an interaction effectively in its place. already been discontinued in between repaglinide (Novonorm/ Procedures to stop further order to discourage further Prandin), a medicine used to prescription and withdrawal of manufacture of nimesulide lower blood sugar in diabetic nefazodone (Serzone) from the preparations in the country. patients, and gemfibrozil, a lipid- market have been initiated. lowering agent. The blood Reference: glucose lowering effect of Singapore2. Since nefazodone, Communication to WHO, Geneva, from Director, Directorate of Drugs repaglinide maybe markedly indicated for the treatment of Administration, Ministry of Health enhanced and prolonged when depression, was licensed in and Family Welfare, Bangladesh, 11 administered together with Singapore in 1997, the Jun 2003. gemfibrozil, with an increased Pharmacovigilance Unit has risk of severe hypoglycaemia. received one local adverse drug The Agency has received 5 reaction (ADR) report of mildly PERGOLIDE reports of serious adverse elevated ALT levels associated MESYLATE hypoglycaemic episodes in with nefazodone. Up to patients using repaglinide and December 2002, 28 reports of Risk of cardiac gemfibrozil at the same time. liver failure, including 15 which valvulopathy Therefore, the EMEA’s resulted in death, associated Canada. A ‘Dear Healthcare Committee for Proprietary with nefazodone had been Professional’ letter regarding Medicinal Products (CPMP) has received worldwide. In Singapore pergolide mesylate (Permax) and decided to contraindicate the the package insert for the risk of cardiac valvulopathy concomitant use of these two nefazodone (Serzone) has been has been issued by Eli Lilly drugs. Patients already receiving amended to include warnings Canada Inc and Draxis Health repaglinide and gemfibrozil relating to the risk of hepatic Inc. During post-marketing should be reviewed and put adverse events and a ‘Dear surveillance, a small number of under alternative combination Healthcare Professional’ letter individuals have been identified treatment with close monitoring was issued in February 2002 to as developing cardiac of diabetic status. The inform physicians of these valvulopathy involving one or repaglinide Summary of Product amendments. more valves during pergolide Characteristics (SPC) and the Reports in WHO-file: therapy. In some cases, product package leaflet have Liver and biliary system disorders symptoms of valvulopathy been appropriately modified to 474 resolved on discontinuation of reflect the above mentioned pergolide therapy; two patients contraindication. required valve replacement.
WHO Pharmaceuticals Newsletter No. 3, 2003 S 3 REGULATORY MATTERS
Reference: respiratory failure has occurred EMEA Public Statement in patients with myasthenia (EMEA/11700/03), 21 May 2003. gravis; the mechanism for this Available from URL: exacerbation is unknown. The http://www.emea.eu.int EMEA points out that
telithromycin use is not
RISPERIDONE recommended in patients with myasthenia gravis unless no Prescribing information therapeutic alternative exists and updated to reflect that patients with myasthenia cardiovascular adverse gravis taking telithromycin events should be advised to immediately seek medical USA. Janssen Pharmaceutica Inc attention if their symptoms has issued a ‘Dear Healthcare worsen. The telithromycin Provider’ letter in the US (Ketek) Patient Leaflet and the advising of changes to the Summary of Product prescribing information for Characteristics have been risperidone (Risperdal). The amended to reflect this safety ‘Warnings’ section of the information. prescribing information for risperidone has been updated to Reference: include information regarding EMEA Public Statement cerebrovascular adverse events (EMEA/8837/03), 23 Apr 2003. Available from URL: following reports of stroke and http://www.emea.eu.int transient ischaemic attack, including fatalities, in trials of risperidone in elderly patients Pan Pharmaceuticals Limited, Australia: Manufacturing Licence with dementia-related psychosis. Suspended In four placebo-controlled trials there was a significantly higher The Australian Therapeutic Goods Administration has suspended Pan incidence of cerebrovascular Pharmaceuticals’ Licence to manufacture medicines, for a period of six adverse events in patients months, following several safety and quality violations by the company. treated with risperidone The WHO has issued a worldwide alert (Alert No. 108, available from (Risperdal) compared with URL: http://www.who.int/medicines/library/qsm/drugalert/alert108.pdf) patients treated with placebo. to notify member states about the Australian decision. Prescribers are reminded that risperidone is not indicated for The Republic of Maldives has responded to the WHO alert notification by the treatment of dementia. adding Pan Pharmaceuticals’ products to the list of drugs withdrawn in
Reference: the country.
‘Dear Healthcare Provider’ letter from Janssen Pharmaceutica Inc,
16 Apr 2003. Available from URL: http://www.fda.gov
TELITHROMYCIN
Aggravation of myasthenia gravis
Europe. The European Medicinal Products Evaluation Agency (EMEA) has issued a public statement regarding the use of telithromycin (Ketek) in patients with myasthenia gravis. Recent reports, including one fatal case, indicate an association between telithromycin and myasthenia gravis exacerbation with respiratory failure. Within a few hours of telithromycin intake, exacerbation of muscle weakness, dyspnoea, or severe
WHO Pharmaceuticals Newsletter No. 3, 2003 S 4 SAFETY OF MEDICINES
ANTIRETRO- estrogen/progestogen combi- and pregnancy-related bleeding. nation products, the combination The number of children born of VIRALS of cyproterone and ethinyl- these pregnancies, now aged Benefit/Risk balance estradiol (Diane-35) is associated 25−52 years, is estimated to be with an increased risk of venous around 160 000 and problems remains strongly thromboembolism. This product is related to in utero diethyl- positive for therefore contraindicated in stilbestrol exposure are therefore combination women with thrombophlebitis, expected to occur until around antiretroviral therapy thromboembolic disorders or a 2015. history of these conditions. Some Compared with the general Europe. The Committee for published studies suggest that population, men who were Proprietary Medicinal Products users of this combination product exposed to diethylstilbestrol in (CPMP) has issued a public (Diane-35) may have an elevated utero have an increased risk of statement that the benefit/risk risk of venous thromboembolic pathologies affecting the balance of combination anti- events compared to users of urogenital system, including retroviral treatment (CART) combination oral contraceptives. epididymal cysts, testicular remains strongly positive in HIV The combination of cyproterone abnormalities and abnormalities infected patients. The statement and ethinylestradiol (Diane-35) of the urinary meatus. The follows an analysis of the results should not be prescribed for the primary complications seen in of studies undertaken by various sole purpose of contraception. women exposed to diethyl- groups to address questions And, during treatment with this stilbestrol in utero are clear cell concerning the prevalence and combination, other oral adenocarcinoma of the vagina or especially, the incidence of long- contraceptives should not be cervix, and structural, term cardiovascular and used. This information has been morphological and functional metabolic complications asso- sent to all healthcare abnormalities involving the ciated with CART. The CPMP professionals by Berlex Canada vagina, cervix, uterus and holds that the long-term Inc, in consultation with Health fallopian tubes; some of these cardiovascular effect of CART has Canada. not been conclusively demon- pathologies can result in fertility strated and therefore concerns Reports in WHO-file: problems and obstetric Thromboembolism 3, thrombosis 43 about the risk of cardiovascular complications. disease should not lead to the Reference: The letter advises that if in withholding of CART when ‘Dear Healthcare Professional’ letter utero diethylstilbestrol exposure indicated for HIV-patients; from Berlex Canada Inc, is suspected the patient should 10 Apr 2003. ongoing studies of long-term be referred to a specialist and cardiovascular complications Available from URL: http://www.hc-sc.gc.ca should consult a gynaecologist should be continued for an annually. All pregnancies in extended follow-up time, at least women exposed to till January 2005 to provide more DIETHYL- diethylstilbestrol should be conclusive results. STILBESTROL treated as high risk, although the Reference: majority will have normal CPMP Public Statement, Gynaecological and outcomes. EMEA/CPMP/2383/03, 25 Apr 2003. obstetric complications Reference: Available from URL: after in utero exposure Important drug safety information http://www.emea.eu.int from Health Canada, 18 Mar 2003. Canada. The Marketed Health Available from URL: Products and Therapeutic http://www.hc-sc.gc.ca CYPROTERONE Products Directorates of Health ACETATE & Canada have drawn attention to a EPHEDRA ETHINYL- recent letter issued to prescribers in France by the French regulatory Moves to reduce risks ESTRADIOL agency (AFSSAPS), now posted of ephedra-containing on the Heath Canada website, Update on risk of regarding the risks of products venous gynaecological and obstetric USA. In the US, the Department thromboembolism complications in women exposed of Health and Human Services to diethylstilbestrol in utero. In Canada. The combination (HHS) has announced plans to France, between 1948 and 1976, take action regarding the product of cyproterone and approximately 200 000 pregnant ethinylestradiaol (Diane-35) is potentially serious risks women received diethylstilbestrol associated with ephedra- prescribed in the treatment of (Distilbène; Stilboestrol-Borne) androgen related conditions such containing dietary products. treatment, which at the time was Ephedra is a naturally occurring as severe acne or hirsutism in indicated to prevent miscarriage women. As with all substance derived from the
WHO Pharmaceuticals Newsletter No. 3, 2003 S 5 SAFETY OF MEDICINES
Chinese herbal Ma Huang. It is ignore warning labels and dosage that, although there have been an adrenaline-like stimulant that information, a complete ban is no reports of significant clinical can have potentially dangerous necessary to eliminate the risks problems occurring when effects on the nervous system grapefruit juice and medication Reference: and heart. On the basis of new ingestion are separated by more 1. Department of Health and Human evidence in the medical literature Services Media Release: 28 Feb than a few hours, grapefruit juice and in adverse event reports, 2003. Available from URL: has the potential to have an there are reasons for the http://www.fda.gov interacting effect for up to 3 days heightened concern that dietary 2. American Heart Association Media after ingestion. ADRAC now supplements containing ephedra Release, 3 Apr 2003. Available considers that "the safest course may present a significant and from URL: is to avoid grapefruit and its unreasonable risk of illness and http://www.americanheart.org juice altogether when taking injury. medicines that interact". Statins and calcium channel blockers are Under the Dietary FLUTICASONE some of the classes of drugs Supplement Health and PROPIONATE reported to interact with Education Act of 1994, FDA does grapefruit juice. not review dietary supplements Reports of adrenal crisis for safety and efficacy before Australia. Adverse Drug Reference: Australian Adverse Drug Reactions they are marketed but the law Reactions Advisory Committee Bulletin 22: 8, Apr 2003. allows the FDA to prohibit the (ADRAC) in Australia has received sale of a dietary supplement if it 10 reports of inhaled ‘presents a significant or corticosteroid-associated adrenal HORMONE unreasonable risk’. In order to crisis. Eight cases involved REPLACEMENT assess these risks, the HHS and children aged 3−10 years who FDA will had received fluticasone THERAPY (HRT) S seek rapid pubic comment propionate (Flixotide) 250−1500 Risk of dementia on the new evidence on µg/day; in six cases, the daily health risks associated with dose was > 500µg, the upper As part of the Women’s Health ephedra limit recommended by The initiative (WHI) study, the Thoracic Society of Australia and Women’s Health Initiative S seek rapid public comment New Zealand and by The National Memory Study (WHIMS) sought on whether the currently Asthma Council in Australia, to evaluate the effect of available evidence presents before referral to a respiratory oestrogen plus progestogen a ‘significant or unreasonable physician. The committee notes hormone replacement therapy risk of illness or injury’ that higher fluticasone propionate (HRT) on the risk for dementia S seek rapid public comment doses may not confer greater and mild cognitive impairment in on a strong new warning efficacy and prescribers are women. HRT appears to increase label for ephedra products reminded that "inhaled the risk of dementia and mild corticosteroids should be given at cognitive impairment, doubling S immediately execute a series the lowest effective dose and the risk of dementia in women of actions against ephedra reviewed regularly". over the age of 65. The effect on products making unsubstan- dementia became apparent after tiated claims. Reports in WHO-file: Adrenal insufficiency 100 one year of treatment and The American Heart continued throughout the 5-year Reference: Association has also called for a duration of the study. These Australian Adverse Drug Reactions findings have been published in ban on ephedra-containing Bulletin 22: 6, Apr 2003. products in comments submitted JAMA (Journal of the American to the US FDA. The Association Medical Association), 28 May 1 supports the FDA's proposal to GRAPEFRUIT 2003 . Earlier analyses have limit the manufacturing and JUICE shown increased risk of stroke marketing of ephedra-based and breast cancer with long-term 2 supplements, but believes these Revised advice from HRT use . Several countries have products should be completely ADRAC reacted with new or reinforced banned. The president of the regulations on HRT use. Australia. The Adverse Drug American Heart Association, Dr 3 Reactions Advisory Committee Australia . Australia’s expert Robert O. Bonow, says that there committee on HRT has reiterated is growing evidence that the (ADRAC) in Australia has revised its previous advice (WHO its advice that HRT should not be risks of ephedra-containing used for long-term disease supplements, which are primarily Pharmaceuticals Newsletters No.3, 2002 and No.1, 2003) prevention. The committee in cardiovascular, far outweigh any Australia continues to have potential benefit, and because relating to grapefruit juice interactions. The committee notes concerns about HRT and strongly patients have a tendency to recommends that women discuss
WHO Pharmaceuticals Newsletter No. 3, 2003 S 6 SAFETY OF MEDICINES
their particular circumstances slightly increases the risk of Reference: with their doctors as individual cardiovascular disorders and Australian Adverse Drug Reactions factors may affect the risks and certain cancers, it now Bulletin 22: 7, Apr 2003. benefits of treatment. recommends that women with specific indications (e.g. hot Germany4. The German ROFECOXIB, flashes or vaginal dryness) use Regulatory Agency BfArM intends HRT for the shortest possible time CELECOXIB to reduce the use of hormone and at the lowest possible dose. replacement therapies. It plans Case reports support Furthermore, HRT class labelling to change the product causal association with is being amended by the FDA to information of HRT products to reflect the increased risk of breast liver toxicity include the findings from the cancer and cardiovascular events WHI study. BfARM says that HRT New Zealand. The recently observed with the use of should only be used for published IMMP (Intensive conjugated estrogens/medroxy- ‘pronounced’ menopausal Medicines Monitoring progesterone (Prempro) in the problems and the duration of the Programme) Prescriber Update Women's Health Initiative study treatment should be as short as Article on COX-2 inhibitors warns conducted by the National possible. The product leaflet will that, as with other Cyclo- Institutes of Health. be modified to describe the side oxygenase (COX) – inhibitors, effects of HRT in greater detail. Reference: liver toxicity may occur with BfARM does not recommend the 1. JAMA Vol 289, No.20, 28 May celecoxib and rofecoxib. 17 use of HRT in the prevention of 2003. reports of hepatotoxicity were osteoporosis since the benefits 2. JAMA Vol 288, No.7, 21 Aug received by the IMMP as part of do not outweigh the risks of 2002. the monitoring of COX-2 3. Therapeutic Goods Administration stroke, thrombosis, breast inhibitors. In most reports, the Media Release, 27 May 2003. cancer and other complications. onset time was less than three Available from URL: months. Three were case reports 5 http://www.health.gov.au UK . The UK Medicines and (one woman aged 85 years and Healthcare Products Regulatory 4. Scrip No. 2827, Feb 2003 5. Medicines & Healthcare products two men aged 81 and 61 years Agency (MHRA) is currently Regulatory Agency Statement, 28 age) of significant liver injury updating all HRT product May 2003. occurring in association with information to include Available from URL: rofecoxib. The other case reports appropriate warnings on the risk http://www.mca.gov.uk included other known hepato- of stroke. The current advice in 6. Health News Daily, 7 Mar 2003. toxic medicines. While the UK is that, in women who Available from URL: clinical details concerning these typically use HRT for the short- http://www.healthnewsdaily.com case reports were not complete term treatment of menopausal and the clinical investigations symptoms, the benefits of OMEPRAZOLE, reported were not exhaustive, it treatment are considered to is probable that these hepatic outweigh the risks. HRT is also RABEPRAZOLE events were related to rofecoxib. used in the prevention of Reports of interstitial There were three other reports osteoporosis; women should be nephritis of similar toxicity involving made aware of the increased celecoxib where the causal incidence of adverse effects with Australia. Eighteen biopsy- relationship was less clear due to long-term HRT use. The decision confirmed reports of interstitial concomitant hepatotoxic to use HRT should be discussed nephritis associated with medicines including metho- with each woman on an omeprazole have been received trexate and leflunomide. In individual basis, taking into by the Adverse Drug Reactions addition, there were 8 reports of consideration her age, history, Advisory Committee (ADRAC) in mild liver function abnormalities risk factors and personal Australia, with a median patient with celecoxib and three with preferences. In addition, the age of 68 years and median time rofecoxib. Two of these patients individual’s risks and benefits to onset of 3 months. In most recovered following withdrawal should be regularly reappraised cases elevated plasma levels of of the COX-2 inhibitor but the with continued HRT use. Women urea and/or creatinine were outcome of the others is on HRT should discuss their own documented. ADRAC has also unknown. Dr David Coulter, balance of risks and benefits with received two reports of biopsy- Director IMMP writes that their doctor. proven interstitial nephritis hepatotoxicity is reported USA6. The US FDA’s hormone associated with rabeprazole. infrequently in literature; the IMMP reports suggest that this therapy outreach campaign will Reports in WHO-file: type of reaction is an uncommon concentrate on promoting short- Esomeprazole 2, lansoprazole 15, term, low-dose use of HRT, omeprazole 96, pantoprazole 10, class effect of COX-2 specific and according to the agency's rabeprazole 4 non specific non steroidal anti- commissioner. Because the FDA inflammatory agents. COX-2 believes that long-term HRT inhibitors should be discontinued
WHO Pharmaceuticals Newsletter No. 3, 2003 S 7 SAFETY OF MEDICINES
in patients with signs or CPMP believes that the quality, symptoms that suggest liver safety and efficacy data suggest dysfunction. an unfavourable benefit to risk balance for somatropin Reference: (Serostim). Prescriber Update Articles, Apr 2003. Available from URL: Reference: http://www.medsafe.govt.nz CPMP Summary of Opinion (CPMP/5330/02), 25 Apr 2003. Available from URL: ROSIGLITA- http://www.emea.eu.int ZONE,
PIOGLITAZONE
Adverse reactions update
Australia. The Adverse Drug Reactions Advisory Committee (ADRAC) in Australia has received 44 adverse event reports associated with rosiglitazone and 28 with pioglitazone. These include 12 reports of hepatic reactions with rosiglitazone and four with pioglitazone, and six reports of cardiac reactions with pioglitazone and 12 with rosiglitazone. The committee states that these drugs should not be used in patients with liver disease or in patients whose cardiac failure limits their physical activity, and that monitoring of liver and cardiac function is required.
Reference: Australian Adverse Drug Reactions Bulletin 22: 6-7, Apr 2003.
SOMATROPIN
Not to be authorized for AIDS-related wasting syndrome
Europe. The European Committee for Proprietary Medicinal Products (CPMP) has ruled out granting a marketing authorization for Serono’s orphan drug somatropin
(Serostim), a recombinant growth hormone for AIDS- related wasting syndrome. Doubts about the clinical relevance of the primary endpoints used in the study, the lack of long-term efficacy data under controlled conditions and concerns about the long-term safety profile are being stated as reasons for this decision. The
WHO Pharmaceuticals Newsletter No. 3, 2003 S 8 CURRENT CONCERNS
Counterfeiting of pharmaceuticals is a worldwide phenomenon. The problem has grown over the years; international trading conditions as well as the use of sophisticated technology to mask fraudulent products make it more and more difficult to control this criminal act. Sharing of available information, a strong political will and a commitment to institute effective regulations against the counterfeiters, are some of the urgent measures needed in fighting this global menace.
Counterfeit Artesunate genuine hologram in the shape under recognised serious public Antimalarial Tablets of mountain outline and the lack health problem. of the microscopic legend 'Guilin Reference Dr Paul Newton, Centre for Pharma' printed below the 1. Rozendaal J. Fake antimalarials Clinical Vaccinology and 'waves'. The printing on the circulating in Cambodia. Bull Tropical Medicine, Churchill blisterpack is not clear. All have Mekong Malaria Forum 2000; 7: Hospital, Old Road, Oxford OX3 the same code, and manufacture 62- 68. 7LJ, England, UK and expiry dates (code ‘00902’ 2. Newton PN, Proux S, Green M,
Artesunate is a vital life-saving and manufacture and expiry Smithuis F, Rozendaal J, Prakongpan S, Chotivanich K, antimalarial drug, developed in dates of ‘09/00’ and ‘09/03’, respectively). Mayxay M, Looareesuwan S, China, and now used extensively Farrar J, Nosten F,White NJ. in South-East Asia for the The third generation Fake artesunate in southeast treatment of falciparum malaria. hologram has a mountain outline Asia. Lancet 2001; 357: 1948- It is also commonly available similar to the genuine Guilin 1950. from the private sector. In the product but lacks the microscopic 3. Newton PN, Rozendaal J, Green late 1990s counterfeit artesunate legend 'Guilin Pharma' printed M, White NJ. Murder by fake appeared in the region and has below the 'waves'. The printing drugs – time for international action. British Medical Journal been disseminated from Vietnam on the blisterpack is crisp and to Burma (Myanmar). In 1999- 2002; 324: 800 - 801. similar to that on the genuine 4. Green MD, Mount DL, Wirtz RA. 2000 up to 38 % of artesunate, product, bearing the code Authentication of artemether, labelled as manufactured by ‘010901’ with manufacture and artesunate and Guilin Pharma, People's Republic expiry dates of ‘09/01’ and dihydroartemisinin antimalarial of China, bought in pharmacies ‘09/04’, respectively. It is likely tablets using a simple and shops in Burma, Laos, however that artesunate with colorimetric method. Trop. Cambodia, Vietnam and on the these 2nd and 3rd ‘generation’ Med. Int. Health 2001; 6: 980 - Thai/Burma border contained no fake holograms have or will be 982. 1-2 detectable artesunate . This made with different dates and 5. Newton PN, Dondorp A, Green M, Mayxay M, White NJ (in has led to the deaths of an codes. All ‘artesunate’ unknown but substantial number press). Fake artesunate blisterpacks with the 2nd and 3rd antimalarials in southeast Asia. of people who would otherwise generation fake holograms were Lancet have survived their malaria negative for artesunate by the 3 infection . A simple, inexpensive Fast-Red Dye Test and contained Genuine artesunate hologram Fast-Red dye test allows one to no artesunate on HPLC analysis. reliably check the authenticity of It is feared that counterfeit 4 artesunate tablets . The first artesunate blisterpacks bearing ‘generation’ fakes, which bear a the new sophisticated fake grey sticker rather than a true holograms are widely distributed hologram, are relatively easy to in Asia, and perhaps Africa, but distinguish from the genuine because of their similarity to the product but remain in circulation genuine product they are in South-East Asia. unrecognised by pharmacists, health staff and patients. There However, two further sophisticated 'generations' of are also reports of fake counterfeit artesunate, labelled intramuscular artemether, used Counterfeit artesunate as produced by ‘Guilin Pharma’, to treat patients with severe hologram – 2nd generation have recently been found in Laos falciparum malaria, labelled as and Cambodia with new, produced by Kunming convincing and very well crafted Pharmaceuticals (Kunming, PRC) but fake holograms attached in Burma (Myanmar) (New Light to the blisterpacks (see of Myanmar, Rangoon, figures below. Also see Myanmar; electronic edition, 9th www.shoklo-unit.com)5. The November 2001). second ‘generation’ hologram is There is an urgent need for a true hologram and only action and we hope that this appears to differ from the information might prompt interventions to combat this
WHO Pharmaceuticals Newsletter No. 3, 2003 S 9 DRUGS OF INTEREST
Peter Jacobs (Emeritus Professor of Haematology, University of Cape Town), Lucille Wood (Haematology Co- ordinator, Constantiaberg Medi-Clinic, Cape Town, South Africa) and Arderne Forder (Consultant and lecturer, University of Stellenbosch) have analysed the vancomycin and teicoplanin-associated adverse haematologic reactions that were reported to the WHO International Drug Monitoring Programme in Uppsala, Sweden. The following is a summary of their analysis.
Haematologic toxicity leucocytosis (n=34) being less of two glycopeptides: common. vancomycin and There are unaccountable teicoplanin differences in prescribing practices between the various All reactions reported to the countries and the longer period World Health Organization of vancomycin availability and Monitoring Centre in Uppsala usage explains the relatively high through the end of 2001 were incidence in side effects when analysed for the two drugs. compared to teicoplanin.
Erythropoiesis had the most Another shortcoming is the lack adverse reactions reported from of information from many parts the United States (n=28), France of the globe where there is either (n=14), United Kingdom (n=9) no reporting or follow-up of and Australia (n=8). Of those outcome in serious complications associated with vancomycin such as aplasia, agranulocytosis (n=60), various types of or thrombocytopenia. This limits anaemia accounted for 33 with the value of their data. 18 examples of pancytopenia but Additionally, without detailed in 10, myelosuppression was case records on such issues as demonstrated. For teicoplanin the level to which platelets fell (n=9) much less experience and the response after existed with almost all being withdrawing antibiotics, accounted for by pancytopenia recommendations are difficult. (n=7). Nevertheless, as information Platelet and haemostatic accumulates, it is prudent for disorders were once again most users of these products to be commonly reported from the aware of the very widespread, United States (n=139), France and increasing range of (n=54) and Australia (n-27). haematologic adverse drug Venous thrombosis was reactions. infrequent with bleeding accounting for most of the reports. For vancomycin the surprisingly common finding was thrombocytopenia (n=148) followed by purpura from other causes (n=30) and then ecchymotic haemorrhage (n=23). For teicoplanin (n=54), almost all were due to thrombocytopenia (n=49). Leucocyte associated adverse reactions were most frequent from the United States (n=214), Austria (n=57), Germany (n=42) and United Kingdom (n=23). For vancomycin (n=508), leucopenia
(n=229) was followed by granulocytopenia (n=81) and this progressed to agranulocytosis (n=78) with eosinophilia (n=75) and
WHO Pharmaceuticals Newsletter No. 3, 2003 S 10 FEATURE
WHO Training pharmacovigilance of anti- pharmacovigilance, based on the Workshop on malarial drugs in these countries. best accepted international Pharmacovigilance: While initially the monitoring standards as promoted by WHO activities will focus on (24-28 March 2003); and Basic Introduction and antimalarial drugs only, it is Specifics for Malaria expected that over time the Part II – Country-specific Programmes system will be strengthened with adaptation of the general WHO the support of WHO to include protocol of artemisinin-based 24 March – 2 April 2003, safety monitoring of all drugs. combination therapies, practical Lusaka, Zambia aspects and planning (29 March It was with this background in – 2 April 2003) Because of increasing levels of mind that WHO convened a resistance to antimalarial drugs workshop of malaria managers The training workshop was several endemic countries are in and officials responsible for designed by WHO/EDM and the process of introducing pharmacovigilance from five WHO/MAL (HQ& AFRO) in close combinations of artemisinin African countries introducing collaboration with the WHO derivatives as 1st-line or 2nd - artemisinin-based combination Collaborating Centre for line treatment of malaria. therapies, notably Burundi, International Drug Monitoring South Africa has introduced Democratic Republic of Congo, (Uppsala Monitoring Centre). The artemether/lumefantrine Mozambique, Zambia and following tutors were actively (Coartemâ) as 1st-line treatment Zanzibar. A total of 18 engaged in planning and of malaria in 2001 and Zambia participants were exposed to the teaching actvities: Mr S. Olsson, has started phased deployment basic methods and skills for drug Sweden, Dr Ushma Mehta, South of this drug at the end of 2002, safety monitoring, with the aim Africa, Dr David Coulter, New also as 1st-line treatment. of introducing a common system Zealand, Dr Alex Dodoo, Ghana. Zanzibar and Burundi have of pharmacovigilance of new The following WHO Secretariat adopted artesunate + antimalarial treatments, with provided facilitation: Dr A. amodiaquine as 1st-line access to the WHO database and Bosman, WHO/MAL, Dr M. treatment and the new international expertise, and to Couper, WHO/EDM, Dr T. Sukwa, treatment policy will be initiate plans for early AFRO/MAL and Dr F. Masaninga, implemented in 2003. implementation in the respective WHO Office in Zambia. Overall Mozambique has recently countries. support from the WHO’s adopted amodiaquine + Representative Office and the The curriculum of the sulfadoxine/pyrimethamine as National Malaria Malaria Control ‘International training course on 1st–line treatment and Centre of the Central Board of pharmacovigilance’ developed artemether/lumefantrine Health of Zambia helped to make and regularly conducted by the (Coartemâ) as 2nd-line the workshop successful. treatment and implementation Uppsala Monitoring Centre was may start in late 2003. Both the adapted to provide the core Each of the five participating Democratic Republic of Congo introductory course. Several countries developed draft and Rwanda are considering a skills-oriented sections of the guidelines and plans of action for policy change to artemisinin- ‘Adverse events following pharmacovigilance which will be based combinations in the near immunization training course’, presented to the Ministry of future. conducted by the University of Health of the respective Cape Town, were adapted to the countries. WHO will provide As with all newly registered malaria-specific section of the technical support to countries for products, there is still limited training course. The WHO draft early implementation, monitoring experience with large-scale protocol for pharmacovigilance of and evaluation. operational use and safety of artemisinin-based combination It is hoped that the workshop these drugs in special population therapies, with components on can be used as a prototype for groups, such as infants, monitoring safety in pregnancy other diseases of public health pregnant women, patients with and amodiaquine safety importance. malnutrition and HIV/AIDS. monitoring, and the WHO Unfortunately in most malaria booklet Safety of Medicines: A endemic countries, particularly in guide to detecting and reporting Africa, pharmacovigilance is not adverse drug reactions, was yet implemented by the public offered for country-specific sector, and post-marketing adaptation. surveillance by the pharmaceutical sector is not The programme of the functioning. The introduction of training workshop was divided in artemisinin combination two parts: therapies (ACTs) provides an Part I - Basic introduction to opportunity to establish the general principles of
WHO Pharmaceuticals Newsletter No. 3, 2003 S 11 EVENTS & ANNOUNC EMENTS
The third annual meeting of the International Society of Pharmacovigilance (ISoP) will be held in Marrakesh, Morocco, 8-11 October 2003. A wide range of scientific topics will be covered under the conference theme of ‘Pharmacovigilance in Clinical Practice’. Abstracts for both oral and poster presentations are invited. The closing date for submission of abstracts is 15 July 2003. All registrations will have to be made online, through the website: www.isop2003.org. This site provides full details of scientific and social programmes, registration fees, accommodation and other relevant information. Two parallel pre-conference courses will also be offered on ‘Compliance in Pharmacovigilance’ and on ‘How to write a paper for peer-reviewed journals’. Separate registration is required for attending the pre-conference courses.
WHO Pharmaceuticals Newsletter No. 3, 2003 S 12