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  • 1. No 2, 2009 In this issue, we report the suspension of efalizumab in Europe and elsewhere, and the withdrawal of fenfluramine in China. We bring you information on risks and restrictions with some group products (anticonvulsants, antipsychotics, bisphosphonates, SSRIs etc) and advice on some individual drugs in the section on Safety of Medicines. The Feature section includes a short report from the nineteenth meeting of the Global Advisory Committee on Vaccine Safety. Contents Regulatory matters Safety of medicines Feature
  • 2. © World Health Organization 2009 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int). Requests for permission to reproduce or translate WHO publications – whether for sale or for non- commercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: permissions@who.int). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. Printed by the WHO Document Production Services, Geneva, Switzerland
  • 3. I:UnitDataSAFETYADMIN2009Newsletter2009 issue 22009news2_version3 rev.doc TABLE OF CONTENTS Regulatory Matters Aliskiren ...................................................................................................... 1 Atomoxetine................................................................................................. 1 Cough and Cold Medicines .............................................................................. 1 Efalizumab ................................................................................................... 2 Exenatide..................................................................................................... 3 Fenfluramine ................................................................................................ 3 Fluoroquinolones ........................................................................................... 3 Metoclopramide ............................................................................................ 4 Mycophenolate mofetil ................................................................................... 4 Natalizumab ................................................................................................. 4 Phosphodiesterase type 5 inhibitors ................................................................. 4 Zonisamide .................................................................................................. 5 Safety of medicines Anticonvulsants ............................................................................................ 6 Antipsychotics .............................................................................................. 6 Black cohosh ................................................................................................ 6 Bisphosphonates ........................................................................................... 6 Botulinum toxin type A................................................................................... 6 Clopidogrel................................................................................................... 7 Dietary supplement containing undeclared drug................................................. 7 Drotrecogin alfa (activated) ............................................................................ 7 Ezetimibe..................................................................................................... 8 Methylphenidate ........................................................................................... 8 Non-steroidal anti-inflammatory drugs ............................................................. 8 Proton pump inhibitors................................................................................... 8 Selective serotonin re-uptake inhibitors ............................................................ 9 Tibolone....................................................................................................... 9 Topical anaesthetics ...................................................................................... 9 Unauthorized tanning product ....................................................................... 10 Feature 19th Meeting of the Global Advisory Committee on Vaccine Safety, 17-18 December 2008 ......................................................................................................... 11
  • 4. r REGULATORY MATTERS Aliskiren with treatment-emergent be available for children between psychotic or manic symptoms, ages 6 to 12 years, but only in New contraindication and including hallucinations, delusional pharmacies. warning thinking, mania and agitation, in children and adolescents without a The PPB notes that these Europe. The European Medicines history of psychotic illness or medicines provide only Agency (EMEA) has recommended mania. Health-care professionals symptomatic treatment and that adding a contraindication to the have been advised to consider a there is no information that they Product Information for aliskiren, possible causal role of are really effective. Serious and which states that it is not to be atomoxetine and discontinuation potentially life-threatening side used in patients who have of treatment, if such symptoms effects can occur, if these experienced angioedema when occur. Atomoxetine (Strattera) is a medicines are taken taking aliskiren in the past. The selective noradrenaline reuptake inappropriately: these include Agency has also recommended inhibitor, authorized for use in the death, convulsions, increased including a warning, stating that treatment of attention- heart rates and reduced levels of patients who develop signs of deficit/hyperactivity disorder consciousness. angioedema should stop treatment (ADHD) as part of a and seek medical attention. comprehensive treatment UK (2). The Medicines and Aliskiren is authorized for the regimen. Healthcare products Regulatory treatment of essential Agency (MHRA) has announced a hypertension. Product information for prescribers comprehensive package of has been updated to reflect the measures to promote the safer According to the EMEA, there were safety information. use of OTC cough and cold reports of cases of angioedema or medicines for children under 12 similar reactions in association Reference: years, based on the advice from with aliskiren-containing Drug Safety Update, MHRA, the Commission on Human medicines. The EMEA's Committee Volume 2, Issue 8, March 2009 Medicines. for Medicinal Products for Human (www.mhra.gov.uk). Use (CHMP) concluded that the The MHRA has recommended that parents and carers should no benefits of aliskiren-containing Cough and cold longer use OTC cough and cold medicines in the treatment of essential hypertension outweigh medicines medicines in children under the their risks, but that angioedema age of six, because there is no New advice on use of over- evidence that these medicines can occur as a rare and serious the-counter cough and cold adverse effect. work and due to the fact that they medicines for children can cause side effects such as Reports in WHO Global allergic reactions, effects on sleep Individual Case Safety Reports Kenya (1). The Kenya Pharmacy or hallucinations. For six to 12 (ICSR) database, VigiBase: and Poisons Board (PPB) stated year old children, the Agency says Aliskiren that the following over-the- that these medicines will continue counter (OTC) cough and cold to be available but only in A total of 54 reports of medicines are not recommended pharmacies, with clearer advice on angioedema in children under six years of age: the packaging and from the • Antitussives (dextromethorphan pharmacist. This is because the Reference: and pholcodine) risks of side effects is reduced in Press Release, EMEA, • Expectorants (guaifenesin and older children since they weigh 19 February 2009 ipecacuanha) more, get fewer colds and can say (www.emea.europa.eu). • Nasal decongestants (ephedrine, if the medicine is doing any good. oxymetazoline, phenylephrine, More research is being done by pseudoephedrine and industry on how well these Atomoxetine xylometazoline) medicines work in children aged Risk of psychotic or manic • Antihistamines six to 12 years. (brompheniramine, symptoms chlorpheniramine, Some combinations which are diphenhydramine, doxylamine, illogical (such as cough UK. The Medicines and Healthcare promethazine and tripolidine). suppressants and expectorants) products Regulatory Agency are being phased out, and all (MHRA) has alerted that Cough and cold medicines liquid cough and cold medicines atomoxetine can be associated containing these ingredients will WHO Pharmaceuticals Newsletter No. 2, 2009 • 1
  • 5. REGULATORY MATTERS will be packaged in child resistant review the treatment of patients The EMEA has advised prescribers containers. taking this medicine to assess the not to issue any new prescriptions most appropriate alternative. The for efalizumab (Raptiva) and to The products affected are the public are warned not to change or review the treatment of patients medicines containing the following stop their treatment without first currently receiving the medicine to active ingredients: consulting doctors because abrupt assess the most appropriate • Antitussives: dextromethorphan discontinuation of the medicine alternative. and pholcodine without alternative treatment may •Expectorants: guaifenesin and be followed by a return of (Also see WHO Information ipecacuanha psoriasis or onset of new psoriasis. Exchange System Alert No. 121, •Nasal decongestants: ephedrine, Drug Alert URL: oxymetazoline, phenylephrine, (See WHO Pharmaceuticals www.who.int/medicines) pseudoephedrine and xylometazoline Newsletter No. 1, 2009 for •Antihistamines: brompheniramine, warnings of progressive multifocal Switzerland (3). The Swiss chlorphenamine, diphenhydramine, leukoencephalopathy (PML) in Agency for Therapeutic Products doxylamine, promethazine and Canada and UK). (Swissmedic) has announced its tripolidine. intention to suspend authorization Europe (2). The EMEA has of efalizumab (Raptiva), following The labelling will be updated and recommended the suspension of EMEA's recommendation of the the legal status of medicines the marketing authorization for suspension of the marketing authorized for children aged six to efalizumab (Raptiva), which is authorization for the product. 12 years will be changed from authorized to treat adult patients general sale to pharmacy. with moderate to severe chronic Swissmedic has recommended plaque psoriasis, following the that physicians should no longer (See WHO Pharmaceuticals opinion of the CHMP that the risks issue any new prescriptions for Newsletter No. 4, 2007 for a public of this medicine outweigh its efalizumab (Raptiva). The Agency health advisory regarding OTC benefits. The CHMP reviewed the has also warned that control by a cough and cold medicines for use reports of serious side effects, physician is necessary to change in children in the USA). including three confirmed cases of the treatment for patients PML in patients who had taken currently using the product, efalizumab (Raptiva) for more adding that stopping the product References: than three years. Two out of the abruptly on a patient's own (1) Statement on cough and cold three cases resulted in death. initiative can lead to an acute medicines, Frequently Asked There was also a suspected case worsening of psoriasis and Questions, PPB, 13 March 2009 of PML reported. symptoms of inflammation. (www.pharmacyboardkenya.org) (2) Safety information, MHRA, The CHMP concluded the USA (4). The United States Food 28 February 2009 following: and Drug Administration (US FDA) (www.mhra.gov.uk). • Efalizumab (Raptiva)’s benefits has issued a Public Health are modest. Advisory to notify health-care Efalizumab • In addition to PML, efalizumab professionals of three confirmed (Raptiva) is associated with other cases and one possible case of Suspension of marketing serious side effects, including PML in patients treated with authorization recommended Guillain-Barré and Miller-Fisher efalizumab (Raptiva), and to in Europe and other syndromes, encephalitis, provide recommendations for countries encephalopathy, meningitis, sepsis health-care providers and patients and opportunistic infections. when treatment with this product Canada (1). Health Canada has • There is not enough evidence to is considered. issued recommendation to identify a group of patients in suspend efalizumab (Raptiva) in which the benefits of efalizumab The US FDA says that it will take Canada, after the EMEA has (Raptiva) outweigh its risks, in appropriate steps to minimize the determined that the benefit/risk particular there is a lack of data risks from efalizumab, and ensure for the product has become on effectiveness and safety in that patients prescribed the unfavourable due to safety patients who have no other product are clearly informed of the concerns. treatment options and who may signs and symptoms of PML, and already have a weakened immune that health-care professionals Prescribers in Canada are advised system as a result of previous carefully monitor patients for the not to issue any new prescriptions treatments. possible development of PML. for efalizumab (Raptiva) and to WHO Pharmaceuticals Newsletter No. 2, 2009 • 2
  • 6. r REGULATORY MATTERS In October 2008, the product Exenatide Fenfluramine labelling was revised to highlight the risks of life-threatening Risk of severe pancreatitis Withdrawal of the drug infections including PML in a Boxed and renal failure approval Warning. The US FDA also directed the manufacturer to develop a UK. The MHRA has announced China. According to the State Risk Evaluation and Mitigation that suspected adverse reaction Food and Drug Administration Strategy (REMS) to include a reports of necrotising and (SFDA), fenfluramine Medication Guide to ensure that haemorrhagic pancreatitis, some hydrochloride (including raw patients receive risk information of which were fatal, have been materials) will be withdrawn from about the medicine. received in association with China's market because of the risk exenatide (Byetta). Health-care of causing heart valve damage (Argentina and Turkey have professionals have been advised and pulmonary arterial informed WHO that the that if pancreatitis is diagnosed, hypertension. The production, sale authorization/commercialization of exenatide should be permanently and use of fenfluramine efalizumab (Raptiva) has been discontinued. Exenatide is hydrochloride (including raw suspended in their countries). indicated for treatment of type 2 materials) will be suspended, and diabetes mellitus in combination the drug approval number has Reports in WHO Global ICSR with metformin. been revoked. database, VigiBase: Efalizumab According to the Agency, up to Reference: February 2009, six case reports of Media Release, SFDA, Central and peripheral nervous pancreatitis and a further three 12 January 2009 system disorders: 461 cases of acute pancreatitis were (eng.sfda.gov.cn/eng/) Encephalopathy (including reported in the UK. There have encephalitis) 4 been approximately 800 000 Meningitis 40 Fluoroquinolones patient-years of exposure Polyneuropathy 5 worldwide since licensing. Up to Boxed warning about Neuritis (Miller-Fisher syndrome) September 2008, 396 case reports tendon disorders 11 of pancreatitis have been received worldwide and 80% of these Kenya. The PPB has alerted that Resistance mechanism disorders: reports were considered to be fluoroquinolones are associated 166 possibly related to exenatide, and with an increased risk of tendinitis Sepsis 18 in several cases there was and tendon rupture in all ages. Infection (including bacterial, evidence of positive rechallenge. This risk is further increased in fungal, secondary, staphylococcal, Nine reports of necrotising or older patients usually over 60 susceptibility increased, and viral) haemorrhagic pancreatitis have years of age, in patients taking 69 been received worldwide, two of corticosteroid drugs, and in which had a fatal outcome. After a patients with kidney, heart or lung References: Europe-wide review, product transplants. The Agency has (1). Advisories, Warnings and information for exenatide is being informed prescribers and other Recalls, Health Canada, updated to include further stakeholders that the Committee 20 January 2009 information about this risk. on Drug Registration (Human) has (www.hc-sc.gc.ca). recommended that all (2). Press Release, EMEA, Up to 30 January 2009, there were fluoroquinolones should include a 19 February 2009 seven case reports of acute renal boxed warning on the package, (www.emea.europa.eu). failure in the UK in association patient information leaflet and (3). Announcements, Swissmedic, with exenatide. The Agency has prescriber information leaflet with 20 February 2009 emphasized that exenatide is not this information. (www.swissmedic.ch). recommended for use in patients (4). Media Release, US FDA, with end-stage renal disease or (See WHO Pharmaceuticals 19 February 2009 severe renal impairment. Newsletters No. 3, 2008 and (www.fda.gov). No. 1, 2003 for a boxed warning Reference: against increased risk of tendinitis Drug Safety Update, MHRA, and tendon rupture in the USA and Volume 2, Issue 8, March 2009 reports of tendon disorders in (www.mhra.gov.uk). Australia, respectively) WHO Pharmaceuticals Newsletter No. 2, 2009 • 3
  • 7. REGULATORY MATTERS Reference: Mycophenolate mofetil treatment of patients with Fluoroquinolones and tendon relapsing-remitting multiple disorders: letter from PPB, Introduction of Medication sclerosis. PML is a known risk of 3 March 2009. Guide this product. Combination therapy is contraindicated. Metoclopramide USA. The US FDA and Roche Laboratories Inc. notified health- Since the product became Warning against chronic care professionals of the available on the market use introduction of a Medication Guide worldwide, five confirmed cases of for mycophenolate mofetil PML have been reported in (CellCept) to provide important patients receiving natalizumab USA. The US FDA has required safety information in a language (Tysabri) monotherapy. One case manufacturers of metoclopramide that patients can easily had a fatal outcome. As of the end to add a boxed warning to the comprehend. Pharmacists are of December 2008, approximately labels about the risk of its long- required to distribute a copy of the 37 600 patients were receiving the term or high-dose use. Chronic Medication Guide to every patient medicine worldwide. use of metoclopramide has been linked to tardive dyskinesia. Those who fills a prescription of this product. The US FDA has also (See WHO Pharmaceuticals at greatest risk include the elderly, required the introduction of a Newsletter No. 4, 2006 for especially older women, and Medication Guide for mycophenolic elements of the risk management people who have been taking the acid (Myfortic) marketed by programme for natalizumab in drug for a long time. Novartis. USA.) Metoclopramide is used as a short- term treatment of The Medication Guide states that Reference: gastroesophageal reflux disease the product can cause serious side Advisories, Warnings and Recalls, and diabetic gastroparesis. It is effects including possible loss of Health Canada, 13 January 2009 recommended that treatment not pregnancy and higher risk of birth (www.hc-sc.gc.ca). exceed three months. The Agency has become aware of continued defects, and increased risk of spontaneous reports of tardive getting serious infections and Phosphodiesterase dyskinesia in patients who used certain cancers. type 5 inhibitors metoclopramide and the majority of them had taken the drug for (See WHO Pharmaceuticals Risk of sudden hearing loss more than three months. Newsletters No. 2, 2008 and No.6, 2007 for reports of PML in Europe New Zealand. The New Zealand Manufactures will be required to and USA, and risk of pregnancy Medicines and Medical Devices implement REMS for loss and congenital malformations Safety Authority (Medsafe) metoclopramide-containing drugs in USA, respectively.) advised prescribers of the risk of to ensure that patients are sudden hearing loss associated provided with a medication guide Reference: with phosphodiesterase type 5 that discusses this risk. Media Release, US FDA, (PDE-5) inhibitors (sildenafil, 12 February 2009 tadalafil, vardenafil). As of Reports in WHO Global ICSR (www.fda.gov). 30 April 2008, the Centre for database, VigiBase: Adverse Reactions Monitoring Metoclopramide Natalizumab received three reports of sudden decrease or loss of hearing with A total of 362 reports of Updated information on sildenafil (2) and tadalafil (1). The dyskinesia tardive PML data sheets for these medicines have been updated to provide Reference: Canada. Health-care professionals prescribers with information on FDA News, US FDA, have been notified that the the risk and steps to take in the 26 February 2009 occurrence of post-marketing event of sudden hearing loss. (www.fda.gov). reports of PML in patients receiving natalizumab (Tysabri) Reference: monotherapy, including the typical Prescriber Update Vol. 30, No.1, symptoms of PML, has been February 2009 included in the Canadian Product (www.medsafe.govt.nz). Monograph. The product is authorized as monotherapy for the WHO Pharmaceuticals Newsletter No. 2, 2009 • 4
  • 8. r REGULATORY MATTERS Zonisamide Alert on metabolic acidosis USA. Following a review of updated clinical data, the US FDA has alerted that treatment with zonisamide can cause metabolic acidosis in some patients. Zonisamide is indicated as adjunctive therapy in the treatment of partial seizures in adults with epilepsy. Metabolic acidosis can result in hyperventilation, and non-specific symptoms such as fatigue and anorexia, or more severe symptoms including cardiac arrhythmias or stupor. Chronic metabolic acidosis can have adverse effects on kidneys and bones and retard growth in children. According to the Agency, patients with predisposing conditions or therapies may be at greater risk for developing metabolic acidosis following treatment with the medicine. The risk of zonisamide-induced metabolic acidosis appears to be more frequent and severe in younger patients. Health-care professionals have been advised to measure serum bicarbonate before starting treatment and periodically during the treatment with the drug. The US FDA is working with the manufactures to revise the product labelling to reflect this safety information. Reference: Information for Healthcare Professionals, US FDA, 19 February 2009 (www.fda.gov). WHO Pharmaceuticals Newsletter No. 2, 2009 • 5
  • 9. SAFETY OF MEDICINES Anticonvulsants risperidone (Risperdal) is licensed Bisphosphonates for short-term treatment of Risk of congenital persistent aggression in Risk of atypical stress malformations Alzheimer's dementia with certain fractures conditions. New Zealand. Medsafe has UK. Following a Europe-wide alerted prescribers of the risk of In addition, the Agency review of bisphosphonates and congenital malformations recommends that health-care atypical stress fractures, the MHRA associated with the use of professionals should carefully has warned that atypical stress anticonvulsants (anti-epileptics) assess the risks and benefits fractures of the proximal femoral during pregnancy, and associated with risperidone shaft have been reported in recommended that the most treatment for every patient, patients treated long-term with effective medicine should be taking into consideration the alendronic acid. Bisphosphonates used at its lowest effective dose. known increased mortality rate are used for prophylaxis and associated with antipsychotic treatment of osteoporosis, In addition, Medsafe says that it treatment in the elderly, and that treatment of Paget's disease, and is important that all women of they should consider the risk of as part of some cancer regimens. child-bearing age taking cerebrovascular events before Health-care professionals have also anticonvulsants receive treating patients with risperidone. been advised that patients who counselling on the risk of develop atypical stress fractures congenital malformations References: should discontinue alendronic acid associated with the use of (1). Prescriber Update Vol. 30, and receive no further anticonvulsants. No.1, February 2009 bisphosphonate treatment unless (www.medsafe.govt.nz). the benefits clearly outweigh the (2). Drug Safety Update, MHRA, risks. The possibility that other Reference: Volume 2, Issue 8, March 2009 bisphosphonates may be associated Prescriber Update Vol. 30, No.1 (www.mhra.gov.uk). with an increased risk of atypical February 2009 (www.medsafe.govt.nz). stress fractures cannot be Black cohosh excluded. Antipsychotics Reports of hepatotoxicity Product information for alendronic acid will be updated to include a Increased mortality risk New Zealand. Medsafe has warning about atypical stress issued information on reports of fractures. New Zealand (1). Medsafe has hepatotoxic reactions in warned that the risk of death is association with the use of the (See WHO Pharmaceuticals significantly increased in elderly herb black cohosh (Cimicifuga Newsletters No. 1, 2008, patients with dementia who are racemosa) that is used for the No.5, 2006 and No.6, 2004 for prescribed conventional relief of menopausal symptoms. alert on musculoskeletal pain in antipsychotics, compared with Reported reactions include USA, reports of osteonecrosis of non-users. The risk appears to abnormal or elevated liver the jaw in Australia, and reports be similar to, or possibly greater function test results, hepatitis, of osteonecrosis of the jaw in than, the risk with atypical and hepatic failure sometimes USA, respectively.) antipsychotics. requiring liver transplantation. Medsafe advised prescribers that Reference: The Authority advised prescribers the use of antipsychotics in Drug Safety Update, MHRA, to look for signs of liver toxicity in elderly dementia patients should Volume 2, Issue 8, March 2009 patients taking black cohosh. only be considered after a (www.mhra.gov.uk) careful assessment of the risks (See WHO Pharmaceuticals and benefits of treatment. Newsletter No. 4, 2006 for Botulinum toxin type A reports of hepatotoxicity in Adverse reactions such as UK (2). MHRA has advised that Europe.) there is a clear increased risk of muscle weakness stroke and a small increased risk Reference: of death when antipsychotics Australia. The Australian (typical or atypical) are used in Prescriber Update Vol. 30, No.1, Adverse Drug Reactions elderly people with dementia. February 2009 Advisory Committee (ADRAC) Only one antipsychotic, (www.medsafe.govt.nz). and the Therapeutic Goods WHO Pharmaceuticals Newsletter No. 2, 2009 • 6
  • 10. SAFETY OF MEDICINES Administration (TGA) have Reference: Dietary supplement emphasized the importance of Australian Adverse Drug adherence to the indications and Reactions Bulletin, Volume 28, containing dosing instructions for use of Number 1, February 2009 undeclared drug botulinum toxin-containing (www.tga.gov.au). products. Botulinum toxin type A Warning about health risk (Botox, 100 U/vial) is used for Clopidogrel the treatment of strabismus, USA. The US FDA has warned blepharospasm and facial nerve Effects of genetic factors consumers not to take a product disorders, spasmodic torticollis, and other drugs on the named Venom HYPERDRIVE 3.0, various spasticity disorders, effectiveness of which was sold as a dietary spasmodic dysphonia, axillary clopidogrel supplement and containing hyperhidrosis, and treatment of undeclared sibutramine. brow furrow lines. A haemag- Sibutramine is a controlled glutinin complexed form of USA. The US FDA has notified substance with risks for abuse or botulinum toxin type A (Dysport, health-care professionals that addiction and poses potential 500 U/vial) has similar but more the manufacturers of clopidogrel safety risks such as increase in limited indications. bisulfate (Plavix), which is an blood pressure and heart rate. antiplatelet drug, have agreed to The product was sold in the Since mid 1994, the TGA has work with the Agency to conduct United States of America as well received 45 reports in studies to obtain information as in Australia, Canada, France, connection with the use of about the effects of genetic Hungary, Poland, South Africa, botulinum toxin, none of which factors and other drugs, Sweden, the Netherlands have described a fatal outcome. especially proton pump and the United Kingdom, The reactions reported most inhibitors (PPIs) on the according to the Agency. commonly are of muscle effectiveness of clopidogrel. weakness (16 cases) at sites There are published reports that clopidogrel is less effective in Reference: adjacent to or distant from the injected area, including some patients than it is in FDA News, US FDA, dysphagia (8 reports), others. Differences in 27 January 2009 respiratory failure or dyspnoea effectiveness may be due to (www.fda.gov). (3) and generalized muscle genetic differences in the way weakness (7). Other reactions the body metabolizes the drug Drotrecogin alfa include rash or other allergic or due to the fact that certain (activated) reaction, diplopia and fatigue. other drugs taken concomitantly Seven reports cited off-label use with clopidogrel can interfere Increased risk of serious and 17 cited use for cosmetic with its metabolism. bleeding events and death reasons, but the others cited use according to approved Until further information is available, the US FDA USA. The US FDA has informed indications. recommends that health-care the public of its ongoing safety ADRAC and the TGA say that providers should continue to reviews of drotrecogin alfa most adverse effects with prescribe and patients should (activated) (Xigris), indicated for botulinum toxin appear to be continue to take clopidogrel as the reduction of mortality in non serious and transient, based directed, because the drug has adult patients with severe sepsis on Australian and other demonstrated benefits in who have a high risk of death. countries' experience. Serious preventing blood clots. The The Agency refers to a adverse reactions are rare and Agency also advises health-care retrospective study (Gentry et usually relate to spread of the providers to re-evaluate the al.: Adverse outcomes toxin to non-target areas, need for starting or continuing associated with the use of generally attributed to excessive treatment with a PPI, including drotrecogin alfa (activated) in volume of injection. over-the-counter drugs, in patients with severe sepsis and patients taking clopidogrel. baseline bleeding precaution, (See WHO Pharmaceuticals Critical Care Medicine, 2009), Newsletter No. 1, 2009 for Reference: which reported an increased risk warning about distant toxin Early Communication about an of serious bleeding events and spread in Canada.) Ongoing Safety Review, US FDA, of death in patients with sepsis 26 January 2009 and baseline bleeding risk (www.fda.gov). WHO Pharmaceuticals Newsletter No. 2, 2009 • 7
  • 11. SAFETY OF MEDICINES factors who received the Reference: Reference: product. Prescriber Update Vol. 30, No.1 Press Release, EMEA, February 2009 22 January 2009 The current prescribing (www.medsafe.govt.nz). (www.emea.europa.eu). information for the drug describes the increased risk of bleeding. The Agency says that Methylphenidate Non-steroidal anti- overall, the finding by the study Updated guidance inflammatory drugs is consistent with the information in the current Cardiovascular risk product label. Prescribers have Europe. The EMEA has been advised to refer to the concluded that methylphenidate- UK. MHRA has informed health- product label for the specific containing medicines remain care professionals of the results contraindications, warnings and suitable for the treatment of of two recent epidemiological precautions and carefully weigh children aged six years or older studies on the thrombotic the increased risk of bleeding and adolescents with attention cardiovascular risk associated against the benefits of the drug. deficit/hyperactivity disorder with use of non-steroidal anti- (ADHD). inflammatory drugs (NSAIDs) in (See WHO Pharmaceuticals the general population. These Newsletters No. 2 and No. 3, The EMEA's Committee for new studies have found an 2005 for the use of drotrecogin Medicinal Products for Human increased cardiovascular risk with alfa in Canada and USA, and in Use (CHMP) has reviewed the all users of NSAIDs, not only Europe.) benefits and risks of those with baseline risk factors methylphenidate after recent and not only chronic users. Reference: concerns about cardiovascular However, the greatest concern Early Communication about an risks, cerebrovascular risks, relates to chronic use of high Ongoing Safety Review, US FDA, psychiatric safety and its long- doses, especially for coxibs and 4 February 2009 term effects. Following the diclofenac. The Agency says that (www.fda.gov). reviews, the CHMP concluded the findings support current that there was no need for an advice that patients should use urgent restriction on the use of Ezetimibe methylphenidate-containing the lowest effective dose and for the shortest duration necessary to Emerging evidence of medicines, but that new control symptoms. association with recommendations on prescribing the medicines and on pre- In addition, MHRA has explained pancreatitis treatment screening and that naproxen is associated with a ongoing monitoring of patients lower thrombotic risk than coxibs, New Zealand. According to are needed to maximize the safe and for ibuprofen, no significant Medsafe, there is emerging use of these medicines. All risk has been identified for doses evidence that ezetimibe can patients should be screened for up to 1200 mg daily. cause pancreatitis. There are any problems with blood proportionately more reports of pressure or heart rate and pancreatitis with ezetimibe than Reference: psychiatric disorders before with statins, in the Centre for Drug Safety Update, MHRA, starting treatment and Adverse Reactions Monitoring Volume 2, Issue 7, monitored regularly during database. It is known that anti- February 2009 treatment. Treatment should be HIV agents, statins, interrupted at least once a year (www.mhra.gov.uk). tetracyclines and valproate are to determine whether associated with acute continuation is needed. In Proton pump pancreatitis. Prescribers have addition, the CHMP asked that been advised that if acute further studies be carried out, inhibitors pancreatitis is confirmed, the particularly into the long-term Possible risk of fracture suspect medicine should be effects of methylphenidate. discontinued and supportive treatment initiated. Australia. According to the (See WHO Pharmaceuticals Australian Adverse Drug Newsletter No. 4, 2006 for Reactions Bulletin, to date, three revision of labelling for ADHD large retrospective studies have drugs in Canada.) suggested an association WHO Pharmaceuticals Newsletter No. 2, 2009 • 8
  • 12. SAFETY OF MEDICINES between proton pump inhibitors considered in consultation with a with known or suspected breast (PPIs) and an increased psychiatrist or paediatrician, and cancer, or in those with a history incidence of fractures, although that particular care should be of breast cancer. further study is necessary to taken in the period shortly after verify the association. In initiating antidepressant Reference: Australia, there have been only treatment, after a change in Drug Safety Update, MHRA, two reports of cases where a PPI dosage, and after discontinuing Volume 2, Issue 7, has been associated with a treatment. February 2009 pathological fracture and/or (www.mhra.gov.uk). osteoporosis, and the PPI was (See WHO Pharmaceuticals the sole suspect in only one of Newsletters No.3, 2005 and Topical anaesthetics these cases. PPIs (omeprazole, No.6, 2004 about risk of suicidal pantoprazole, lansoprazole, behaviour in children and Association with serious rabeprazole and esomeprazole) adolescents in Europe and adverse events have been available in Australia Australia respectively.) since the mid 1990s. Canada. Important safety Reference: information has been issued ADRAC says that despite the Prescriber Update Vol. 30, No.1, about the association of limitations of the available data, February 2009 excessive application of topical it would be reasonable to (www.medsafe.govt.nz). anaesthetics with serious consider the potential for adverse events. increased fracture risk, and has advised clinicians to prescribe Tibolone Health-care professionals have the lowest effective dose for Increased risk of breast been informed the following. recognized indications and • Serious adverse reactions periodically re-evaluate cancer recurrence including methaemoglobinaemia, individual cases to determine central nervous system toxicity whether PPI therapy remains UK. Tibolone increases the risk and cardiovascular collapse have necessary. of breast cancer recurrence in been associated with application women with a history of breast of topical anesthetics to large Reference: cancer, according to Drug Safety surface areas of the body, often Australian Adverse Drug Update. Tibolone is a synthetic in preparation for laser removal Reactions Bulletin, Volume 28, hormone therapy for first-line of body hair. Number 1, February 2009 treatment of menopausal • Patients are more likely to (www.tga.gov.au). symptoms and for second-line experience serious side effects prevention of osteoporosis in from a topical anesthetic if they women at high risk. MHRA use it on a large area of their Selective serotonin explains that the LIBERATE body, if they apply it to abraded re-uptake inhibitors (randomized controlled trial), or diseased skin or if they which was designed to occlude the treated area with Increased risk of investigate whether tibolone is plastic wrap or other dressing. suicidality effective and safe to use in • Children should be closely women with a history of breast observed during and after use of New Zealand. Medsafe has cancer, was stopped early topical anesthetics, as they may issued advice to prescribers because it identified a be at greater risk than adults for about the risks and benefits significantly increased frequency serious adverse events. associated with selective of breast cancer recurrence in serotonin re-uptake inhibitors the tibolone group compared Systemic toxicity from local (SSRIs) when used to teat major with the placebo group. anesthetics may include depressive disorder (MDD) in cyanosis, headache, drowsiness, children and adolescents. The Tibolone is contraindicated in respiratory depression, advice includes the finding that women with known or suspected confusion, convulsions, all SSRIs have consistently been breast cancer and those with a bradycardia, hypotension and associated with an increase in history of breast cancer. Health- cardiac arrhythmias. suicidality in meta-analyses of care professionals have been clinical trials of the use of SSRIs advised not to use tibolone (or (See WHO Pharmaceuticals to treat MDD in children and conventional hormone- Newsletter No. 1, 2009 for adolescents. It was advised that replacement therapy) in women antidepressant use should be WHO Pharmaceuticals Newsletter No. 2, 2009 • 9
  • 13. SAFETY OF MEDICINES information on a related public health advisory in USA.) Reference: Advisories, Warnings and Recalls, Health Canada, 13 January 2009 (www.hc-sc.gc.ca). Unauthorized tanning product Safety alert against purchase via the internet Ireland. The Irish Medicines Board (IMB) has issued a safety alert on Melanotan, which is an unauthorized medicine marketed through the internet as a drug that purports to assist tanning. The IMB warns that this product poses the risk of infection owing to microbial contamination found in the product as well as no evidence that it is safe or effective. The IMB advises consumers to stop using the product immediately and consult their pharmacist or doctor. The Agency also advises consumers not to purchase any medicinal product on the internet. Reference: Press Statement, IMB, 27 February 2009 (www.imb.ie) WHO Pharmaceuticals Newsletter No. 2, 2009 • 10
  • 14. SAFETY OF MEDICINES Nineteenth Meeting of the Global Advisory Committee on Vaccine Safety, 17-18 December 2008 The Global Advisory Committee on Vaccine Safety (GACVS), established by WHO in 1999 to respond promptly, efficiently, and with scientific rigour to vaccine safety issues of potential global importance, met on 17–18 December 2008. Among topics discussed were the safety profiles of rotavirus and human papillomavirus vaccines. Rotavirus vaccines The Committee was presented with post-marketing information on the Rotateq and Rotarix vaccines from Australia, Latin America and the United States. Given the data presented, members were reassured that a risk of intussusception of the order of that which had been associated with Rotashield could be ruled out with confidence. The Committee also indicated, however, that the available post-marketing surveillance data were still too few to rule out, with confidence, a risk of substantially lower magnitude. The Committee emphasized the importance of continuing to accumulate post-marketing surveillance data on intussusception and other possible adverse effects and stressed the importance of setting up surveillance systems for such effects as the vaccines were introduced into increasing numbers of developing countries. Human papillomavirus (HPV) vaccines The Committee reviewed the latest recommendations of the WHO Strategic Advisory Group of Experts on immunization on HPV vaccines as well as data related to their large-scale use and articles on early post-marketing surveillance. After careful methodological review of the evidence, GACVS concluded that none of the reports raised sufficient concern to change previous advice given by GACVS. Given that many countries have only recently introduced HPV vaccines at the national level, and as plans exist to introduce the vaccines in many countries with varying capabilities for monitoring of adverse events following immunization, the Committee called for increased attention to building capacity for post-marketing surveillance in those countries where introduction is planned. The Committee also agreed to comprehensively review the post- marketing safety profile of HPV vaccines during 2009. Full report - http://www.who.int/wer/2009/wer8405.pdf WHO Pharmaceuticals Newsletter No. 2, 2009 • 11