Contents Regulatory Matters Safety of Medicines Features

No. 3, 2008

NEWS & ISSUES

This issue has been delayed considerably on account of some of our support staff leaving the unit, and due to teething difficulties with an all new global resource management system in WHO. But things are slowly getting back on track and we apologize for the inconvenience to our readers. Some of the information in this issue may be a bit old but we thought it would be useful to record them nevertheless, as a way of archiving the information for your future reference. Thank you for your continuing interest.

Contents Regulatory matters Safety of medicines Features

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TABLE OF CONTENTS

Regulatory Matters

Conventional antipsychotics...... 1 Becaplermin ...... 1 Epoetins ...... 1 Etanercept ...... 1 Etoricoxib ...... 2 Fluoroquinolones...... 2 Label changes for use in pregnancy ...... 2 Moxifloxacin ...... 2 Norfloxacin...... 3 Pegvisomant-somatostatin analogues ...... 3 Perflutren injectable suspension ...... 3 Rotavirus gastroenteritis vaccine ...... 4 ADR reporting in Finland ...... 4

Safety of Medicines

Abacavir and abacavir-containing medications...... 5 Abacavir and abacavir-containing medications...... 5 BCG vaccine...... 5 Clozapine...... 5 Fluorescein ...... 6 Fluticasone propionate...... 6 Nitrofurantoin...... 6 Pioglitazone ...... 7 Rimonabant ...... 7 Risperidone, pipamperone ...... 7 Salbutamol ...... 8 Statins ...... 8 Strontium ranelate ...... 8 TNF antagonists...... 8 Varencicline ...... 9 Risk evaluation and mitigation studies (REMS) ...... 9 FDA Sentinel Initiative ...... 9

Feature

Review of Oseltamivir Reports in Vigibase is reassuring but vigilance for hepatic and skin disorders recommended...... 10

REGULATORY MATTERS

mortality in patients who have venous thromboembolism and Conventional used three or more tubes of the shorter overall survival in product. Becaplermin is mainly cancer patients who received antipsychotics used to heal wounds in patients epoetins compared to patients Boxed warnings on with diabetes. This action who did not receive them. fatalities in elderly follows the Agency's review of patients safety data from a retrospective Reference: study showing a five-fold EMEA Press Release, increased risk of cancer 26 June 2008 USA. The United States Food mortality in patients exposed to (www.emea.europa.eu). and Drug Administration (US three or more tubes of FDA) is requiring manufacturers becaplermin (see WHO of conventional antipsychotics Pharmaceuticals Newsletter to add Boxed Warnings about Etanercept No. 2, 2008). The US FDA the increased risk of death in cautions health-care Label to indicate risk of elderly patients treated for professionals to carefully weigh infections in children dementia-related psychosis. the risks and benefits of The FDA based this requirement treating patients with USA. The US FDA's on recent studies together with becaplermin. Dermatologic and Ophthalmic earlier evidence for atypical Drugs Advisory Committee is antipsychotics, that both recommending that labelling for atypical and conventional Reports in WHO ICSR database: Amgen's etanercept (Enbrel) antipsychotics have an include warnings that use of the increased risk of death in Total 58 reports, 2004 – 2008 agent in paediatric patients elderly patients with dementia- all from USA: may lead to moderate to severe related psychosis. infections and can result in Melanoma malignant 1 death. Manufacturers of antipsychotics Adenocarcinoma NOS 1 are being asked to update Pulmonary carcinoma 1 The committee recommended labelling so that all drugs have Skin hypertrophy 55 the following labelling changes: the same warnings. • Under the 'Adverse Reference: Reactions in Patients with The FDA advises health-care Becaplermin Information, Juvenile Idiopathic professionals that: US FDA, 6 June 2008 Arthritis' section, the • antipsychotics are not (www.fda.gov). wording should be approved for treatment of changed to reflect that dementia-related use of etanercept therapy psychosis in the paediatric • physicians who prescribe population may lead to antipsychotics to elderly Epoetins moderate to severe patients with dementia- Warning for use in cancer infections and can result related psychosis should patients in serious outcomes, discuss the increased including death and mortality risk with their Europe. European Medicines hospitalisation. patients, patients' families Agency (EMEA) has • In the same section, the and caregivers. recommended updating the list of serious adverse

product information for epoetin- events reported in the Reference: containing medicines with a postmarketing period Media Release, FDA, new warning for their use in should be updated to 16 June 2008 (www.fda.gov). cancer patients stating that include macrophage blood transfusion should be the activation syndrome, preferred method of correcting malignancies, diabetes anaemia in patients suffering mellitus and systemic Becaplermin cancer. lupus erythematosus.

Boxed warning added Epoetin-containing medicines Reference: about increased cancer are indicated in patients with Media Release, US FDA, risk chronic renal failure and for the 18 June 2008, treatment of anaemia in (www.fda.gov). USA. The US FDA has added a symptomatic patients with non- boxed warning to the label of myeloid tumours receiving 0.01% becaplermin gel chemotherapy. New data from (Regranex) regarding the studies that show an increased increased risk of cancer risk of tumour progression, WHO Pharmaceuticals Newsletter No. 3, 2008 • 1

REGULATORY MATTERS

Etoricoxib Fluoroquinolones are used during pregnancy and breastfeeding. Drug labelling Risk of cardiovascular Boxed warning against would be required to outline the side effects increased risk of potential risks and benefits of tendinitis and tendon the medication for both the Europe. The European rupture mother and the foetus, and how Medicines Agency (EMEA) these risks may vary recommended that the product USA. US FDA notified health- throughout the course of the information for etoricoxib- care professionals that a pregnancy. containing products should be BOXED WARNING and updated concerning the risk of Medication Guide are to be Reference: cardiovascular side effects. added to the prescribing Media Release, US FDA, information to strengthen 28 May 2008 (www.fda.gov). Etoricoxib is a non-steroidal existing warnings about the anti-inflammatory drug increased risk of developing (NSAID). It is currently tendinitis and tendon rupture in indicated to relieve the patients taking fluoroquinolones symptoms of osteoarthritis, for systemic use. Moxifloxacin rheumatoid arthritis and pain and signs of inflammation Hepatic reactions - Fluoroquinolones are associated restriction in use in upper associated with acute gouty with an increased risk of respiratory infections arthritis. In addition, an tendinitis and tendon rupture. application is currently under This risk is further increased in evaluation to extend the those over age 60, in kidney, Europe. EMEA has concluded indication of the etoricoxib- heart, and lung transplant that moxifloxacin-containing containing medicine Arcoxia to recipients, and with use of medicines for oral use should treat ankylosing spondylitis. concomitant steroid therapy. only be prescribed in the Physicians should advise treatment of acute bacterial In the evaluation of etoricoxib patients, at the first sign of sinusitis, acute exacerbation of concerns were raised over the tendon pain, swelling, or chronic bronchitis and cardiovascular safety of inflammation, to stop taking the community acquired pneumonia etoricoxib-containing medicines fluoroquinolone, to avoid when other antibiotics cannot when used to treat ankylosing exercise and use of the affected be used or have failed. The spondylitis at a dose of 90 mg area, and to promptly contact Agency also recommended once a day. These concerns their doctor about changing to a strengthening the warnings for also extended to the treatment non-fluoroquinolone oral moxifloxacin medicines. of rheumatoid arthritis which is antimicrobial drug. Selection of The reason is increased risk of used at the same dose. a fluoroquinolone for the hepatic reactions. treatment or prevention of an The Committee for Medicinal infection should be limited to The EMEA’s Committee for Products for Human Use those conditions that are Medicinal Products for Human (CHMP) recommended updating proven or strongly suspected Use (CHMP) has reviewed all the existing contraindication in to be caused by bacteria. available information on the patients with hypertension that safety of moxifloxacin- is not adequately controlled to Reference: containing medicines for oral state that patients whose blood Information for Healthcare use, following concerns over pressure is persistently above Professionals, US FDA, their liver safety when used for 140/90 mmHg and has not 8 July 2008 (www.fda.gov). acute bacterial sinusitis, acute been adequately controlled exacerbation of chronic should not take etoricoxib. bronchitis and community-

acquired pneumonia. The CHMP Reference: concluded that the benefits of EMEA Press Release, Label changes for oral moxifloxacin medicines 26 June 2008 use in pregnancy continue to outweigh its risks. (www.emea.europa.eu). However, due to safety Risks and benefits concerns, mainly related to an highlighted increased risk of adverse

hepatic reactions, the CHMP

USA. The US FDA has proposed recommended restricting their

extensive changes to labelling use in these indications. for prescription medications, including biological products, to The CHMP also recommended better inform patients of the that the warnings of oral risks and benefits of drugs that moxifloxacin-containing WHO Pharmaceuticals Newsletter No. 3, 2008 • 2

REGULATORY MATTERS medicines should be use of oral norfloxacin- Perflutren injectable strengthened concerning the containing medicines in other risk of diarrhoea, heart failure types of infection. suspension in women and older patients, Warning section to be severe skin reactions and fatal Reference: revised liver injury. EMEA Press Release, 24 July 2008 Canada. Bristol-Myers Squibb Reports in WHO ICSR database: (www.emea.europa.eu). Medical Imaging has issued a Moxifloxacin (terms with ‘Dear Healthcare Professional’ more than 15 reports) Pegvisomant- letter, in consultation with somatostatin Health Canada (HC), advising of Hepatic enzymes increased 57 changes to the safety SGOT increased 26 analogues information for the contrast SGPT increased 25 Increased risk of hepatic medium perflutren injectable Hepatic failure 18 enzyme elevations suspension, (Definity). Hepatic function abnormal 35 There have been worldwide Hepatitis 32 Canada. Pfizer, in consultation reports of serious Hepatitis cholestatic 17 with Health Canada, has issued cardiopulmonary reactions, Hepatocellular damage 18 a 'Dear Healthcare Professional' including fatalities, occurring Bilirubinaemia 23 letter advising of an increased during, within 30 minutes of, Jaundice 54 risk of hepatic enzyme and up to several days after elevations in patients receiving administration. As of (See also WHO Pharmaceuticals the anti-growth hormone March 31 2008, there had been Newsletter No. 2, 2008, for pegvisomant (Somavert) in one case in Canada of a fatal reports of multifocal combination with a cardiopulmonary adverse leukoencephalopathy). somatostatin analogue, such as reaction. octreotide. Pfizer advises

Reference: health-care professionals that The product monograph for EMEA Press Release, baseline serum ALT, AST, total Definity is being updated. The 24 July 2008 bilirubin and ALP levels should warning section will be revised (www.emea.europa.eu). be obtained prior to to include guidelines for close pegvisomant initiation and monitoring of patients with routinely monitored during the pulmonary hypertension or course of treatment. If a unstable cardiopulmonary patient develops liver test conditions, during and for at Norfloxacin elevations of 3−5 times the least 30 minutes after Restricted use in urinary upper limit of normal (ULN), administration. pegvisomant may be continued, infections but liver tests should be The revised product monograph monitored weekly. If a patient EMEA. The CHMP has will include a statement about develops liver test elevations of concluded that the marketing adverse drug reactions > 5 times the ULN, authorisations for oral occurring during post marketing transaminase elevations of > 3 norfloxacin-containing use. times the ULN with any medicines, when used in the treatment of acute or chronic increase in total bilirubin, or Reports in WHO ICSR database: complicated pyelonephritis signs or symptoms of liver

(kidney infection), should be injury, pegvisomant should be Perflutren withdrawn because the benefits immediately discontinued. If of these medicines do not liver injury is confirmed, Circulatory failure 1 (USA) outweigh their risks in this pegvisomant should be Fibrillation cardiac 1 (USA) indication. This is based on the permanently discontinued. The fact that the efficacy has not Canadian product monograph Reference: been adequately demonstrated will be updated to include this Bristol-Myers Squibb Medical for this type of infection. new information. Imaging. Updated safety

information on DEFINITY (Rm) In current practice, this disease is usually treated using either (Perflutren Injectable Suspension) and serious injectable antibiotics, or other adverse cardiopulmonary fluoroquinolones taken by reactions. Internet Document, mouth or given byinjection. The 23 May 2008 recommendation of the CHMP (www.hc-sc.gc.ca). does not have an impact on the

WHO Pharmaceuticals Newsletter No. 3, 2008 • 3

REGULATORY MATTERS

Rotavirus ADR reporting in gastroenteritis Finland vaccine 2007 Overview Additional safety studies required Finland. The Finnish National Agency for Medicines received

1174 reports of suspected USA. Approving adverse drug reactions (ADRs) GlaxoSmithKline's (GSK's) oral, in 2007. They included a total live attenuated, human of 2568 ADR symptoms. rotavirus vaccine (Rotarix) the

US FDA exercised its new • Reports were received for authority (Food & Drug 348 medical substances Administration Amendments Act (excluding vaccines) (FDAAA), 27 September 2007) • 753 reports (64%) were to require a postmarketing classified as serious. safety study (1). On • Iomeprol, with 47 reports, 3 April 2008, the Agency was at the top of the list of approved Rotarix for the most frequently reported prevention of rotavirus drugs (≥ 10 reports). gastroenteritis in infants (2). • Most of the drugs on the The approval was based on most frequently reported clinical data from nearly 75 000 list had also appeared on infants participating in trials the 2006 list, but conducted in North and South varenicline (23 reports), America, Europe, Asia and aripiprazole (18), Africa. buprenorphine/naloxone

(11), rimonabant (10) and The US FDA considers analyses escitalopram (10) were of spontaneous postmarketing newcomers to the list. adverse events insufficient to assess potential serious risks. Iodine-containing contrast Consequently, GSK is required media generated 59 reports in to conduct a US-based total, with urticaria (24) and postmarketing observational vomiting and/or nausea (25) study of Rotarix to assess the the most frequent ADRs. potential serious risk of Varenicline, which was granted intussusception and other marketing authorisation for serious adverse effects (start smoking cessation in June 2009; final report by September 2006, generated March 2012). reports of nausea and other

gastrointestinal symptoms (10), Reports in WHO ICSR database: dermatological symptoms (8), muscle cramps or myalgia (5) Intestinal obstruction and oedema or tiredness (4 (2001-2007) each). 122 reports: Australia 3 Overall, the individual ADR France 1 reported most often was rash USA 118 (88), followed by urticaria (74),

hepatic function test abnormalities (66), References: anaphylactic or allergic reaction 1. Rotarix Product Approval (63) and decreased white cell Information, US FDA, blood count. 3 April 2008 (www.fda.gov). 2. Media Release, US FDA, Reference: 3 April 2008 (www.gsk.com). TABU, Drug Information from the National Agency for Medicines, Finland 2: 53-56, 2008, (www.nam.fi).

WHO Pharmaceuticals Newsletter No. 3, 2008 • 4

SAFETY OF MEDICINES

infarction (MI) in HIV patients However, concern remains Abacavir and treated with abacavir- regarding the seriousness of abacavir-containing containing products (Ziagen, the reported reactions. The Kivexa and Trizivir). GSK has majority of the cases reported medications provided Health Canada with in 2007 included severe local Serious hypersensitivity recent findings of a study (1) reactions including abscess reactions which suggested an increased formation, lymphadenopathy MI risk in HIV-infected patients and/or secondary infections. treated with abacavir- Some cases required antibiotic USA. The US FDA informed containing products. The letter treatment and/or surgical health-care professionals that says that available data does intervention. serious and sometimes fatal not allow a definite conclusion hypersensitivity reactions about the association between Although the overall rate of caused by abacavir therapy are abacavir use and an increased reported ADRs with BCG significantly more common in MI risk at this time. GSK vaccine SSI is consistent with patients with a particular recommends that physicians the expected incidence of human leukocyte antigen (HLA) discuss the potential risks and reactions for this product, the allele, HLA-B*5701. Abacavir is benefits of abacavir with their Irish Medicines Board (IMB) has an anti-HIV medicine and is a patients and that the overall highlighted the potential of nucleoside reverse transcriptase benefit-risk profiles of abacavir serious ADRs associated with inhibitor (NRTI). The US FDA should be considered, BCG vaccine SSI if the vaccine reviewed data from two studies particularly in patients with pre- is inadvertently given that support a recommendation existing serious cardiovascular subcutaneously or for pre-therapy screening for diseases. The letter states that intramuscularly rather than the presence of the HLA- "at this time, Health Canada intradermally. B*5701 allele and the selection has undertaken the review of of alternative therapy in this safety data and will advise positive subjects. Genetic tests Reference: Canadians if further risk for HLA-B*5701 are available Drug Safety Newsletter measures are deemed and all patients should be No. 27: 3 May 2008, Irish necessary". (See WHO screened for the HLA-B*5701 Medicines Board (www.imb.ie) Pharmaceuticals Newsletter allele before starting or No. 2, 2008 for related restarting treatment with information). abacavir or abacavir-containing Clozapine medications. Development of clinically suspected abacavir Reports in WHO ICSR database: Increased cardiovascular hypersensitivity reactions risks requires immediate and Myocardial infarction permanent discontinuation of (1999 – 2008) New Zealand. New Zealand's abacavir therapy in all patients, 46 Medsafe has issued a prescriber including patients negative for update regarding the HLA-B*5701. Reference: association of clozapine with 1. Lancet, 26 April increased risks of myocarditis Reference: 2008;371(9622):1417-26 and cardiomyopathy. Clozapine Information for Healthcare (Epub 2 April 2008). is an atypical antipsychotic Professionals, US FDA, 2. Health Canada, Advisories, used for the management of 24 July 2008 Warnings and Recalls, schizophrenia. 25 cases of (www.fda.gov/cder). 18 Jun 2008 (www.hc-c.gc.ca). clozapine-associated myocarditis and 17 cases of clozapine-associated BCG vaccine cardiomyopathy were reported Abacavir and between March 2000 and abacavir-containing Reducing incidence, but November 2007 in New medications seriousness of ADRs a Zealand. Two patients died. concern Clozapine has been associated Risk of myocardial with myocarditis and, to a infarction Ireland. The incidence of lesser extent, cardiomyopathy. adverse drug reactions (ADRs) Myocarditis generally occurs Canada. GlaxoSmithKline associated with BCG 1−2 months after the initiation (GSK), in consultation with vaccine SSI (Danish 1331 of clozapine. It is not a common Health Canada, has issued a strain), used for active adverse event, but affects `Dear Healthcare Professional' immunisation against relatively young people, is not letter, regarding the potential tuberculosis, has decreased in necessarily dose-related, and increased risk of myocardial recent years in Ireland. can be fatal. Cardiomyopathy

WHO Pharmaceuticals Newsletter No. 3, 2008 • 5

SAFETY OF MEDICINES usually has a later onset, after Reports in WHO ICSR database: Haematoma 8 about nine months of treatment.Of the patients with Fluorescein Fluticasone myocarditis, the median age Total 131 reports from 17 propionate/Salmeterol xinafoate was 30.5 years. In 80% of countries (1979 – 2008) Total 30 reports from 7 these cases, the duration of countries, 2000 – 2008 treatment to reaction onset was Anaphylactic reaction 13 one month. Anaphylactic shock 78 Purpura 17 Anaphylactoid reaction 40 Purpura allergic 1 To date, no clear risk factors Haematoma 12 have been identified for Reference: clozapine-associated Fluorescein and anaphylactic Reference: myocarditis and reactions, Lareb, May 2008 Inhaled and intransal cardiomyopathy. Pre-treatment (www.lareb.nl). fluticasone propionate and cardiovascular screening is haematoma, Lareb, May 2008 recommended. Medsafe says (www.lareb.nl). that, in patients where myocarditis is suspected, Fluticasone clozapine should be withheld propionate Nitrofurantoin and the patient urgently referred to a cardiologist. If Reports of haematoma Reports of hepatotoxicity myocarditis is confirmed, clozapine should be Netherlands. The Netherlands Australia. Following two discontinued. If myocarditis is Pharmacovigilance Centre reports of submassive hepatic ruled out, other possible (Lareb) has received 12 reports necrosis associated with diagnoses, such as of haematoma associated with nitrofurantoin to the Adverse cardiomyopathy, should be the use of medications Drug Reactions Advisory considered. containing fluticasone Committee (ADRAC), a review (See WHO Pharmaceuticals propionate up to 3 September of hepatic adverse events with Newsletter No. 3, 2007 for 2007. A further six cases of this drug was conducted. reports of clozapine-associated purpura associated with the use According to ADRAC, the myocarditis received in of inhaled fluticasone Australian Therapeutic Goods Australia). propionate were reported in this Administration (TGA) has period. received 637 reports of adverse Reference: events associated with Prescriber Update Nine cases involved inhaled nitrofurantoin up to April 2008, 29(1):10-12 May 2008 salmeterol/fluticasone which included 17 reports of (www.medsafe.govt.nz) propionate, three involved death. Of the 637 reports fluticasone propionate nasal received, 119 were reports of spray or nasal drops hepatobiliary reactions, (Flixonase), and one involved including 32 serious cases; Fluorescein inhaled fluticasone propionate seven cases were fatal. Other Reports of anaphylactic (Flixotide) . reports included jaundice (4), reactions hepatitis (13) or hepatic failure While haematoma, purpura and (2). In seventeen of the serious ecchymosis are listed in the Netherlands. The Netherlands cases, nitrofurantoin was the Summary of Product Pharmacovigilance Centre only suspected drug. The Characteristics (SPC) of nasally (Lareb) has received four majority of reports involved acting or inhalation reports, concerning two events women aged more corticosteroid preparations of anaphylactic reactions than 50 years, who were taking containing beclometasone or associated with fluorescein use nitrofurantoin 50−200 mg/day budesonide, these adverse up to 31 August 2007. for acute urinary tract infections reactions are not listed in the Fluorescein is a colouring agent (UTIs; 11), recurrent UTIs (11), SPC for fluticasone propionate used in diagnostic procedures. or as prophylaxis (10). preparations. (Nitrofurantoin is used to treat

The two events involved a 49- urinary tract infections.) year-old man and a 56-year-old Reports in WHO ICSR database: woman who experienced Reports in WHO ICSR database: anaphylactic reactions after Fluticasone administration of fluorescein for Total 54 reports from 11 Nitrofurantoin – Liver disorders angiography; the woman countries (1994 – 2008) Totally 1683 reactions subsequently died. (1968 – 2008) Purpura 45 Purpura allergic 1 WHO Pharmaceuticals Newsletter No. 3, 2008 • 6

SAFETY OF MEDICINES

Death in connection with liver Myocardial infarction 74 contraindicated in patients with disorders 23 ongoing major depression or Hepatic function abnormal 319 Reference: who are being treated with Hepatic failure 47 Update on reports of antidepressants because of the Hepatic necrosis 25 pioglitazone, Lareb, May 2008 risk of psychiatric adverse Hepatocellular damage 54 (www.lareb.nl) effects; see WHO Coma hepatic 7 Pharmaceuticals Newsletter No.4, 2007.) Reference: Rimonabant Australian Adverse Drug References: Reactions Bulletin 27(3), Reports of serious ADRs 1. Drug Safety Update June 2008. 1(10): 2-4, May 2008 UK. Spontaneous reports of (www.mhra.gov.uk) Reports in WHO ICSR database: depression, psychiatric 2. Drug Analysis Print - Drug disorders, hypoglycaemic name: RIMONABANT. MHRA, Somavert – pegvisomant reactions, paranoia, rash, 15 May 2008 coreported with octreotide - tremor and headache (www.mhra.gov.uk) liver disorders associated with the anti-obesity drug rimonabant (Acomplia) Reports in WHO ICSR database: have been reported to the UK Cholelithiasis 1 MHRA, according to an article in Hepatic enzymes increased 2 Total 58 reports from ARG, Drug Safety Update (1). A total both reports from DEU CHE, DEU,FIN, NOR of five fatal ADR reports have

been received up to 9 May Reference: Headache 5 2008. According to the agency, Media Release Health Canada, Tremor 2 the total number of ADR reports 2 June 2008 Hypoglycaemia 3 with rimonabant during this (www.hc-sc.gc.ca). Paroniria 4 period in the UK was 720. The Depression 27 fatal ADR reports comprised Other psychiatric disorders 136 two cases of myocardial

Pioglitazone infarction, one case of sudden ADR update death, one case of infection (fungal pneumonia) and one Risperidone, Netherlands. Up to 9 October case of suicide (2). Up to the pipamperone end of January 2008, 673 ADR 2007, the Netherlands Reports of epistaxis Pharmacovigilance Centre reports (1971 individual

(Lareb) received 57 reports reactions) with rimonabant Netherlands. As at 30 August involving 77 ADRs associated were received in the UK. Of 2007, the Netherlands with the oral anti-diabetic drug these, 423 were serious and Pharmacovigilance Centre pioglitazone. Of these reports, four reports had a fatal (Lareb) had received 12 and 11 two concerning the same outcome. The most commonly reports of epistaxis patient were filed by two reported ADRs were psychiatric (nosebleeds) associated with marketing authorization disorders (44%), CNS the use of the antipsychotic holders. The reported ADRs disorders, gastrointestinal drugs risperidone and involved only one report of disorders, general disorders and pipamperone, respectively. The cardiac failure and no reports of skin and subcutaneous majority of reports involved myocardial infarction. disorders; these ADRs are children aged 5−14 years. (In 2000 the product labelling labelled in the Summary of Epistaxis is not listed in the for pioglitazone was revised in Product Characteristics. The Dutch Summary of Product Japan to include information on most common psychiatric Characteristics for either adverse cardiac events reactions were depression, risperidone or pipamperone. associated with pioglitazone; related mood disorders and However, the adverse reaction see WHO Pharmaceuticals associated symptoms. is listed in the American SPC for Newsletter No. 4, 2000) Hypoglycaemic reactions, risperidone (incidence paranoia, rash, tremor and headache, which are not in the 0.1%−1%). Reports in WHO ICSR database: product information, were Reports in WHO ICSR database: Pioglitazone identified as new safety signals

Total 4273 reports from 22 based on spontaneous cases Risperidone countries (2000 – 2008) reported. (1994 – 2008)

Epistaxis 79, from 11 countries Cardiac failure 405 (According to the European

Cardiac failure left 14 Medicines Agency (EMEA) rimonabant (Acomplia) is Pipamperone WHO Pharmaceuticals Newsletter No. 3, 2008 • 7

SAFETY OF MEDICINES

(1997-2008) Administration (TGA) had had risk factors for venous Epistaxis 13. received 5846 adverse reaction thromboembolism. reports that implicated a statin. Reference: Of these reports, almost one ADRAC has advised patients to Risperidone and pipamperon in third were of muscle disorders stop treatment and seek association with epistaxis. such as myopathy, myalgia, medical advice at the first Lareb, May 2008 myositis or rhabdomyolysis. appearance of rash during (www.lareb.nl). When severe, the muscle strontium ranelate treatment. disorders were associated with Once stopped, strontium myoglobinuria and, in extreme ranelate should not be Salbutamol cases, renal failure. restarted.

Dental caries associated ADRAC reminds prescribers that (See WHO Pharmaceuticals with use in children statin treatment should be Newsletter No. 1, 2008 for initiated at the lowest possible reports of severe allergic Netherlands. The Netherlands dose. The dose may then be reactions associated with Pharmacovigilance Centre titrated, if necessary, according strontium ranelate in the UK.) (Lareb) has received five to lipid levels. Patients receiving reports of dental caries statins should be monitored for Reference: associated with the use of adverse reactions, especially for Australian Adverse Drug salbutamol (Albuterol) up to any symptoms of muscle Reactions Bulletin 5 September 2007. The five disorders. 27(3): 10 June 2008 cases involved four boys and (www.tga.gov.au). one girl aged 5−9 years who Reference: developed dental caries while Australian Adverse Drug TNF antagonists receiving salbutamol, which is a Reactions Bulletin beta-2 agonist used to treat 27(3): 10-11, June 2008 Review of lymphoma and asthma. While well-described in (www.tga.gov.au). other cancer risks in the literature, dental caries are children not listed in the SPC for the antiasthmatic drug sodium Strontium ranelate USA. FDA has issued an early cromoglicate nasal spray. communication about its ADR update ongoing safety review of Reports in WHO ICSR database: tumour necrosis factor (TNF) Australia. To date, 47 reports antagonists. The agency is Salbutamol – dental caries in of suspected adverse drug investigating a possible children (1988 – 2008) reactions related to strontium relationship between the use of ranelate (Protos) have been these drugs and development Total 10 reports. reported in Australia, according of lymphoma and other cancers to ADRAC. Strontium ranelate is in children and young adults; Reference: a bone formation stimulant currently, infliximab Salbutamol inhalation and used in the treatment of (Remicade), etanercept dental caries, Lareb, postmenopausal osteoporosis. (Enbrel), adalimumab (Humira) May 2008 (www.lareb.nl). and certolizumab pego (Cimzia) Of these 47 reports, 16 reports are the four TNF antagonists involved rash, one accompanied available in the US. The FDA is by eosinophilia and one by Statins investigating about 30 reports fever. ADRAC has also received of cancer submitted between High-dose associated a report of severe cholestatic 1998 and April 2008. These with muscle disorders hepatitis associated with reports involved patients who eosinophilia, pruritus and rash received TNF antagonists along Australia. The Australian in a 62-year-old woman. with other immunosuppressants Adverse Drug Reactions According to ADRAC, clinical for Crohn's disease, juvenile Advisory Committee (ADRAC) trials have shown an increased rheumatoid arthritis or other continues to receive reports of incidence of venous diseases when they were myositis/rhabdomyolysis in thromboembolism in patients aged ≤ 18 years. The Agency situations where treatment with receiving strontium ranelate, has advised parents, caregivers HMG-CoA reductase inhibitors compared with those receiving and healthcare providers of (statins) has been initiated at placebo. Three cases of deep children receiving an inappropriately high dose. venous thrombosis and one of TNF antagonists to be aware of superficial vein thrombosis have the possible risk of lymphoma By late 2007, the Australian been reported after and other cancers. Therapeutic Goods 1−4 months of treatment; however, two of these patients WHO Pharmaceuticals Newsletter No. 3, 2008 • 8

SAFETY OF MEDICINES

Reports in WHO ICSR database: to monitor for FDA Sentinel neuropsychiatric Etanercept symptoms; Initiative Total 6 reports: • to instruct patients to stop taking varenicline The US FDA has proposed a Leukaemia granulocytic 1 and contact their Sentinel Initiative that will Eye neoplasm 1 healthcare provider improve patient safety and Lymphoma malignant 1 immediately if they quality of medical care by Ovarian cyst 1 develop depressed mood, increasing the Agency's Renal carcinoma 2 agitation, hostility, capacity to monitor the behavioural changes, postmarketing use of a Infliximab suicidal ideation or medicinal product. The initiative Total 7 reports suicidal behaviour; has been described as a move • to `diligently monitor' from "reactive dependence on Leukaemia granulocytic 1 varenicline recipients with voluntary reporting of safety Hepatic neoplasm malignant 1 concomitant or previous concerns to proactive Lymphoma malignant 3 psychiatric conditions. surveillance of medicinal Thrombocythaemia 2 Reference: products on the market". The Sentinel Initiative includes 'Dear Healthcare Professional' Reference: development of a new letter from Pfizer Canada Inc, Media Release, US FDA, electronic system that will 13 June 2008, 4 June 2008 (www.fda.gov). enable the US FDA to gather (www.hc-sc.gc.ca). information from various

sources to identify possible

postmarketing adverse events. Varencicline The system will use information Serious neuropsychiatric from existing electronic claims adverse events Risk evaluation and and medical records data mitigation studies sources maintained by Canada. Pfizer Canada has participating private and issued a Health Canada- (REMS) government entities. Federal endorsed Dear Healthcare agencies and academic Professional letter informing USA. Under the FDAAA (see researchers will be able to use health-care providers about rotavirus vaccine story on page claims data from the Medicare postmarketing reports of 8), the US FDA can now require prescription drug programme. serious neuropsychiatric risk evaluation and mitigation adverse events associated with strategies (REMS) for new Reference: use of varenicline (Champix) for products if it determines such Media Release, US Department smoking cessation. schemes are necessary to of Health and Human Services, ensure that the benefits of a 22 May 2008 (www.hhs.gov). From April 2007, when drug outweigh the risks. varenicline was introduced in Notably, the FDA can withhold the Canadian market, to product approval until REMS are 30 April 2008, Health Canada in place. has received 226 reports of neuropsychiatric adverse Reference: (www.fda.gov) events; a total of 708 534 prescriptions were filled for the drug during this time period. The reported adverse events included depression, agitation, behavioural changes, hostility, suicidal ideation, suicide and worsening of pre-existing psychiatric illness.

Pfizer has advised health-care professionals:

• to alert families and caregivers of varenicline recipients about the need WHO Pharmaceuticals Newsletter No. 3, 2008 • 9

FEATURE

Review of Oseltamivir Reports in Vigibase is reassuring but vigilance for hepatic and skin disorders recommended Report from the WHO Collaborating Centre for International Drug Monitoring, Sweden.

Introduction

The antiviral agent oseltamivir is a selective inhibitor of influenza virus A and B neuraminidase. It is indicated for the treatment and prophylaxis of influenza virus infection types A and B although vaccination is preferred for prophylaxis. It should be commenced early in the course of illness to achieve maximum benefit. The WHO has recommended its use for treating Avian influenza A (H5N1) (1).

In 2007 the Uppsala Monitoring Centre (UMC) undertook a review of the international adverse reaction reports attributed to oseltamivir in the WHO Global Individual Case Safety Report Database, Vigibase, as well as the relevant literature and product information. This review did not identify any clearly defined signals of unsuspected serious adverse reactions not already in the product information or regulatory authority alerts, the latter concerning neuropsychiatric reactions.

Reports of serious skin disorders

Reports of Stevens Johnson Syndrome and toxic epidermal necrolysis had been reported in Vigibase. These disorders are listed under adverse reactions in product information for Tamiflu® (oseltamivir) but with causality not established (2). The Vigibase reports did not provide additional information on causality.

Oseltamivir and reports of hepatic disorders

Despite the lack of a clear signal, reports in Vigibase of serious hepatic disorders occurring in association with oseltamivir use were of concern. Reports of hepatic failure, hepatic necrosis, hepato-renal syndrome, jaundice and bilirubinaemia were statistically disproportionate to the background data. Product information for oseltamivir (Tamiflu®)indicated that hepatitis and abnormal liver function tests had been identified during post-marketing experience and that it was not possible to establish a causal relationship with oseltamivir exposure.

Patient Characteristics

At the time of the review Vigibase held 770 reports for oseltamivir. There were 46 non-duplicated reports of hepatic reactions including reports of hepatic failure and necrosis. Numbers of males and females affected were similar and the age range was 18 to 88 years apart from two infants aged 12 months.

Duration of oseltamivir use

Data provided in 25 reports showed patterns of use duration and reaction onset. Overall oseltamivir was used for one to five days in 17 patients. The longest periods of use were 8 days and 19 days. Onset of hepatic manifestations occurred up to one week after oseltamivir was discontinued in 16 patients.

Hepatic reactions to medicines usually become evident between five and ninety days after first exposure (3). For this reason eight patients with onset one to two days after first exposure and one patient for whom onset was 120 days after exposure were excluded from further analysis.

Dechallenge and Rechallenge

No reports had valid dechallenge or rechallenge data.

WHO Pharmaceuticals Newsletter No. 3, 2008 • 10

FEATURE

Hepatic failure, hepatic necrosis and serious hepatocellular reactions

Five reports of hepatic failure and/or hepatic necrosis were identified that contained information on time to onset from first exposure that was appropriate for drug-induced hepatotoxicity. Oseltamivir was the only medicine considered suspect in two of these reports.

There were no reports of cholestatic hepatitis occurring within five and ninety days of oseltamivir use. There were five reports of hepatocellular damage but these were poorly documented in terms of exposure duration and other medicines were often co-suspect. The originals of eight reports of jaundice and/or bilirubinaemia together with elevated hepatic enzymes or hepatitis were requested from the countries of origin in order to identify serious hepatocellular reactions that are likely to progress to hepatic failure (4). Three such reports were obtained. Two of these patients progressed to the hepatic failure group described above. The third patient had not taken other suspect medicines, only low dose paracetamol.

Thus oseltamivir appeared to be the most likely causal medicine in two reports of hepatic failure and one serious hepatocellular reaction.

It is of note that one patient with hepatic failure had pre-existing renal failure and was taking the maximum recommended daily dose of oseltamivir.

Causality

While oseltamivir appeared to be the most likely causal medicine in three reports of the most serious suspected hepatic reactions no details of investigations for other potential causes, eg viral studies, were provided. The other reports of serious hepatic disorders could not readily be assigned a causality classification.

There are difficulties in assigning causality to hepatic reports with oseltamivir for the following reasons:

1. Prodromal symptoms of hepatic disorders may mimic influenza symptoms. 2. Dechallenge data is largely unhelpful as oseltamivir has usually been discontinued before the reaction is evident. 3. If patients have influenza symptoms they are likely to take other medicines that can be hepatotoxic eg nonsteroidal anti-inflammatory medicines and paracetamol. 4. A number of patients were also taking antibiotics as well as oseltamivir and many of these were also potentially hepatotoxic.

Items (1) and (2) describe problems that make it almost impossible to assign a “probable” rather than “possible” causality to hepatic reactions attributed to oseltamivir. However, one advantage is that the usual short duration of oseltamivir treatment means that more serious injury may be avoided in many cases, if the association is causal.

Most of these difficulties also apply when assessing causality of serious skin disorders following exposure to oseltamivir.

Summary and Recommendations

There are reports of hepatic reactions attributed to oseltamivir in Vigibase that are more serious than those described in the product information. Where identifiable the reports appeared to be predominantly of hepatocellular disorders. There is no clear evidence of causality because of difficulty in discriminating influenza and the early symptoms of hepatic disease, because of common concurrent use of other hepatotoxic medicines and because of the usual short duration of oseltamivir use.

There is a strong argument for the alternative explanations, listed under “causality”, for these reports particularly the likelihood that oseltamivir was used to treat prodromal symptoms of hepatic disease rather than influenza. However, given the potential widespread and unsupervised use of oseltamivir a cautious approach should be considered. This could involve

1. Alerting patients to the possibility of hepatic and serious skin reactions as well as other documented adverse effects, at the time of prescription, and 2. Discontinuation of oseltamivir with hepatic function testing where patients are slow to recover from presumed influenza, or relapse. Such testing would identify both those patients whose WHO Pharmaceuticals Newsletter No. 3, 2008 • 11

FEATURE

hepatic disorder had not been diagnosed earlier because they were presumed to have influenza and those who are developing an adverse reaction to oseltamivir. Oseltamivir will not provide any benefit at this stage and discontinuation may avoid more serious outcomes. 3. Prompt discontinuation of oseltamivir if a serious skin disorder occurs.

Patients prescribed or already holding oseltamivir should also be advised to consult their medical attendant prior to taking this medicine if they develop renal impairment as they may need to take a reduced dose.

References 1. World Health Organisation: Clinical management of human infection with avian influenza A (H5N1) virus. World Health Organisation, Geneva, Switzerland. 2007. Available from URL: http://www.who.int/csr/disease/avian_influenza/guidelines/Clinical Management07.pdf Accessed 11th July 2008. 2. Tamiflu capsules® (Roche). Physician’s Desk Reference. Revised January 2008. 3. Lee WM. Drug-induced hepatotoxicity. N Engl J Med 2003; 349(5): 474-485. 4. Reuben A. Landmarks in Hepatology. Hy`s Law. Hepatology 2004; 39(2): 574-578.

* Note from the Uppsala Monitoring Centre. There are now 918 reports for oseltamivir in Vigibase including three additional reports of hepatic reactions. These reports do not alter the conclusions and recommendations of this article.

Singapore reporting (2007)

Key features of the year’s reports

In 2007, the Pharmacovigilance Unit of Singapore's Health Sciences Authority received 13 475 local spontaneous adverse drug reaction (ADR) reports. Of these, 1740 ADR reports were reviewed and analysed. Of the reviewed reports, • 42% were classified as serious. • Most of the reviewed ADR reports were from healthcare professionals in public hospitals (50.6%) • More ADRs were reported in females (57.6%) than in males. • Chinese patients had the highest proportion of ADRs (61.6%), followed by Malays (12.5%) and then Indians (8.3%). • Most of the reported ADRs occurred in patients between the ages of 30 and 69 years (62.6%). • Most reports were associated with pharmaceutical medicines (96.9%). • The top four drugs suspected of causing an ADR were diclofenac (4.4%), naproxen (4.0%), cotrimoxazole [trimethoprim/sulfamethoxazole; 3.6%] and metoclopramide (3.6%). • Most of the reported ADRs were skin-related disorders (25.0%).

Reference: Health Sciences Authority. Analysis of ADR reports for year 2007. Adverse Drug Reaction News 10: 4-5, No. 1, Mar 2008 – Singapore (www.dh.gov.hk)

WHO Pharmaceuticals Newsletter No. 3, 2008 • 12

Substantial increase in number of reports in 2007: EMEA

EMEA received 381 990 ADR reports in 2007, recording a more than 25% increase on the previous year. • 40% of all 2007 ADR reports involved centrally authorised medicinal products. • 63 393 reports involved investigational medicines − an increase of 18% from 2006. • There were 762 suspected signals related to 139 intensively monitored medicines and 349 suspected signals related to 162 routinely monitored products. • After further analysis, follow-up was required for 22% and 10% of signals from intensively and routinely monitored products, respectively.

A greater number of periodic safety update reviews were conducted in 2007 than the previous year (313/273).

Reference: EMEA. Annual report of the European Medicines Agency 2007, 13 May 2008 (www.emea.europa.eu).

Valuing the patient's voice

Benefits of patients’ reports

Netherlands. ‘Patient reports contribute substantially to the reporting of ADRs, both in quantity and quality’ and can make a significant contribution to reliable pharmacovigilance, according to researchers in The Netherlands. Between April 2004 and April 2007, the Netherlands Pharmacovigilance Centre (Lareb) received 2522 reports directly from patients, concerning 5401 ADRs, and 10 635 reports from healthcare professionals, concerning 16 722 ADRs. Significant differences were noted in the categories of seriousness and outcomes reported by patients and by healthcare professionals. Patients reported a higher number of life-threatening ADRs (5.2% vs 2.7%) and disability (2.3% vs 0.4%), and reported non-recovery more frequently (35.4% vs 16.7%). ADRs such as weight gain, decreased libido and fatigue were among the most frequently reported ADRs by patients, probably reflecting the impact of these ADRs on quality of life.

Reference: de Langen J, Van Hunsel F, Passier A, de Jong-van den Berg L, van Grootheest K. Adverse drug reaction reporting by patients in the Netherlands: three years of experience. Drug Safety 31: 515-524, No. 6, 2008 (www.lareb.nl).

WHO Pharmaceuticals Newsletter No. 3, 2008 • 13