No. 2, 2007

News & Issues

This issue covers regulatory and safety information on more than thirty medicines, both old and new products. Previous warnings have been reiterated, labels updated, products withdrawn or new adverse reaction reports have been recorded, as may be the case. The feature item includes recommendations from the fourth Meeting of the WHO Advisory Committee on Safety of Medicinal Products.

In the last issue we promised to include letters from you on items that we publish in our newsletters. We are happy to bring you one such letter on a feature article from 2006. By sharing this interesting exchange we hope that we can motivate you to take a more interactive interest. We look forward to receiving your comments on any items published in this newsletter.

Contents Regulatory matters Safety of medicines Feature

Letters

© World Health Organization 2007

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Printed by the WHO Document Production Services, Geneva, Switzerland TABLE OF CONTENTS

Regulatory Matters

Aprotinin -- Label updated for specific use, new safety information ...... 1 Attention deficit hyperactivity disorder (ADHD)-treatments -- Patients to be notified of cardiovascular and psychiatric events ...... 1 Drug-eluting stents -- To be used with utmost restraint ...... 1 Interferon-1b -- Not approved for idiopathic pulmonary fibrosis ...... 1 Isotretinoin -- Web page about dangers of online buying ...... 2 Metoclopramide -- Increasing reports of extrapyramidal symptoms in children; paediatric use tightened . 2 Miconazole -- Interaction with warfarin...... 2 Omalizumab -- Label update about anaphylaxis...... 3 Pentavalent rotavirus (W179-9) vaccine -- Label updated with information on intussusception and haematochezia ...... 3 Pergolide -- Risk of heart valve damage; to be removed from the market ...... 4 Pioglitazone -- Fractures in females...... 4 Sedative-hypnotic drugs -- Stronger warnings about allergic reactions and sleep-related complex behaviours...... 5 Tegaserod -- Withdrawn due to life-threatening cardiac effects...... 5 Telithromycin -- Updates on use, contraindications, adverse events ...... 5 Topical anaesthetics -- Professional advice needed before use in cosmetic procedures...... 6

Safety of Medicines

Angiotensin Converting Enzyme (ACE) inhibitors -- Reports of visual disturbances...... 7 Antiepileptic drugs -- Enzyme-inducing drugs may increase fracture risk ...... 7 Antipsychotics -- Reports of neuroleptic malignant syndrome ...... 7 Bupropion -- Reports of depression ...... 7 Carbasalate -- Reports of tinnitus ...... 7 Codeine -- Lowest dose recommended in nursing mothers...... 8 Deferasirox -- Reports of renal failure ...... 8 Domperidone -- Heart rate and rhythm disorders ...... 8 Entecavir -- Report of a resistant HIV-variant in HIV/HBV co-infected patient ...... 9 Erythropoiesis-stimulating agents -- New studies suggest serious and life threatening side effects ... 9 Estazolam -- Present in a dietary supplement ...... 10 Fluticasone -- Reports of behavioural changes ...... 10 Goserelin, buserelin -- Reports of psychiatric disorders ...... 10 Levofloxacin -- Reports of blood glucose, liver and biliary disorders: an update...... 10 Linezolid -- Risk of death when used in catheter-related blood stream infections ...... 11 Olanzapine -- Reports of amenorrhoea ...... 11 Oseltamivir -- Close monitoring of treated children and adolescents...... 11 Quetiapine -- Reports of alopecia...... 12 Selective serotonin reuptake inhibitors (SSSRIs), Venlafaxine -- Reports of bruxism ...... 12 Ranibizumab -- Intravitreal injections and incidence of stroke ...... 12 Rosiglitazone -- Increased risk of fractures in women receiving long-term treatment...... 12 Tacrolimus -- Reports of malignancies ...... 13 Zolpidem -- Reports of sleep walking ...... 13

Feature

Recommendations of the fourth meeting of the WHO Advisory Committee on Safety of Medicinal Products, 26 and 27 February 2007...... 14

Letters to the WHO Pharmaceuticals Newsletter

REGULATORY MATTERS

exposure during the last 12 Reference: months is contraindicated. FDA News. U.S. Food and Drug Aprotinin Administration, Label updated for In the US the product label for 21 February 2007 specific use, new safety aprotinin (Trasylol) has been (www.fda.gov). information revised to include a more focused indication for its use, Canada. Health Canada has and the above safety warnings Drug-eluting issued a Notice to Hospitals and a and contraindications (see WHO stents Public Communication with the Pharmaceuticals Newsletter following information: No. 1, 2007). To be used with utmost • Aprotinin injection is indicated restraint for prophylactic use to reduce References: Sweden. The Swedish Medical blood loss and the need for 1. Notice to Hospitals. Health Products Agency (MPA), in blood transfusion only in Canada, 27 March 2006 conjunction with the National those patients who have an (www.hc-sc.gc.ca). Board of Health and Welfare increased risk of blood loss 2. Public Communication. and the Swedish Society of and blood transfusion Health Canada, Cardiology, has recommended associated with 27 March 2006 utmost restraint in the use of cardiopulmonary bypass (www.hc-sc.gc.ca). drug-eluting stents. The during coronary artery bypass recommendation was based on grafting. the results of clinical studies, • Administration of aprotinin Attention deficit including the Swedish Coronary increases the risk of renal hyperactivity and Angioplasty Registry dysfunction, and may (SCAAR) study that showed increase the requirement for disorder increased risk of thrombosis dialysis peri-operatively. The associated with the use of drug- risk is particularly high in (ADHD)- eluting stents. The results of patients with pre-existing treatments the SCAAR study and four other renal impairment or those randomized studies showed who receive aminoglycoside Patients to be notified that drug-eluting stents have antibiotics or drugs that alter of cardiovascular and no advantages in terms of renal function. psychiatric events myocardial infarction or • Aprotinin administration may mortality, compared with bare- cause fatal and nonfatal USA. The United States Food metal stents; in addition, the anaphylactic or anaphylactoid and Drug Administration SCAAR study data indicated a reactions, both with an initial (US FDA) has issued a directive small, long-term increased risk (test) dose as well as with that patients receiving of these events. According to any of the components of the pharmacotherapies for the MPA, drug-eluting stents dose regimen. Fatal reactions attention-deficit hyperactivity must only be used in patients have also occurred in disorder (ADHD) must be for whom no other treatment situations where the initial informed of potential alternative exists or in patients (test) dose was tolerated. As cardiovascular and psychiatric who are at greatly increased a result, aprotinin should only adverse events by the risk of restenosis and for whom be administered in operative manufacturers of such drug the effect of restenosis is settings where products. Manufacturers of expected to be severe. cardiopulmonary bypass can ADHD therapies must develop

be rapidly initiated. Patient Medication Guides Reference: • The risk for anaphylactic or highlighting these possible risks Internet document. Swedish anaphylactoid reactions is and advise patients of Medical Products Agency, increased among patients precautions that can be taken. 13 February 2007 with prior aprotinin exposure, A US FDA review of ADHD (www.lakemedelesverket.se). and a history of any prior products found reports of aprotinin exposure must be sudden death in patients with verified before aprotinin existing heart problems and Interferon-1b reports of stroke and cardiac administration. The risk for a Not approved for fatal reaction appears to be arrest in adults with certain risk greater upon re-exposure factors. A second US FDA idiopathic pulmonary within 12 months of the most review identified a slight fibrosis recent prior aprotinin increase in the risk of ADHD USA. The US FDA has issued a exposure. As a result the drug-related psychiatric events Public Health Advisory about administration of aprotinin to such as auditory hallucinations, the early termination of the patients with a known or paranoid disorders and mania. INSPIRE clinical study suspected previous aprotinin

WHO Pharmaceuticals Newsletter No. 2, 2007 • 1

REGULATORY MATTERS

(International Study of Survival (Accutane, Amnesteem, are the drugs of first choice in Outcome in Idiopathic Pulmonary Claravis and Sotret). The web nausea due to strongly Fibrosis) of interferon-γ-1b (IFN- page warns that the drug emetogenic chemotherapy γ-1b) for idiopathic pulmonary should only be taken under the because of better efficacy and fibrosis (IPF); the Agency says close supervision of a physician fewer adverse events than with that IFN- γ-1b (Actimmune) is not or a pharmacist, and provides metoclopramide. approved for the treatment of links to helpful information. The IPF. An interim analysis of the new web page is in addition to Reference: INSPIRE study showed that IFN- special safeguards put in place News and Publications. The γ-1b recipients did not benefit by the US FDA and Medicines Evaluation Board, the from the drug compared with manufacturers of isotretinoin to Netherlands, 21 February 2007 12.7% deaths in the placebo reduce the risks of the drug, (www.cbg-meb.nl/uk/nieuws). group; 14.5% of patients died in including a risk management the IFN- γ-1b group. An programme called iPLEDGE. The independent data monitoring aim of iPLEDGE is to ensure 'First-in-man' clinical trials committee subsequently that women using isotretinoin guideline for Public recommended early termination do not become pregnant, and Consultation of the trial. IFN- γ-1b-related side that women who are pregnant effects reported in the INSPIRE do not use isotretinoin. The European Medicines trial included neutropenia, Agency's Committee for constitutional symptoms, and Reference: Medicinal Products for Human possibly pneumonia. The US FDA FDA Warning: Risks of buying Use (CHMP) has adapted a has advised patients who are Accutane (isotretinoin) over the draft guideline for first-in- receiving IFN- γ-1b to consult Internet. U.S Food and Drug man clinical trials for potential their doctors about whether they Administration, 28 March 2007 high-risk medicinal products. should continue the treatment. (www.fda.gov). This guideline has been The Agency has also advised prepared as one of the doctors to discuss the results of Metoclopramide measures for minimizing the the INSPIRE trial with their risk of serious adverse patients who are receiving IFN- Increasing reports of reactions of the nature that γ-1b for IPF, and to carefully extrapyramidal occurred during the first-in- consider whether the treatment symptoms in children; man clinical trials of should be continued in such paediatric use TGN1412. It gives guidance patients or not. on managing the transition tightened from non-clinical studies to Reference: The Netherlands. Following an first tests in humans for high- Public Health Advisory. U.S. Food increase in the number of risk medicinal products. and Drug Administration, registered cases of 9 March 2007 (www.fda.gov). extrapyramidal symptoms in The draft guideline has been

children receiving released for a two-month

metoclopramide, the Medicines public consultation. Isotretinoin Evaluation Board (MEB) in the Comments are invited by Web page about dangers Netherlands has restricted the 23 May 2007 (see of online buying use of metoclopramide in this www.emea.europa.eu for

population. The Board says details). USA. The US FDA notified metoclopramide should be used consumers and health-care only in the treatment of severe Reference: professionals of a special web nausea and vomiting of known Press Release. EMEA, page launched to warn about the origin, and only if treatment 26 March 2007. dangers of buying isotretinoin online. Isotretinoin is a drug with other products is approved for the treatment of ineffective or is not possible. severe acne that does not The MEB says there are better Miconazole respond to other forms of alternatives to metoclopramide. Interaction with For example, domperidone is a treatment. If the drug is warfarin improperly used, it can cause better choice in treating post- severe side effects, including birth operative nausea in children. Finland. The use of miconazole defects. Serious mental health Domperidone is also the drug of (Daktarin) oral gel in patients problems have also been reported choice in treating migraines in receiving warfarin may lead to with isotretinoin use. The new children because the risk of increased International web page, www.fda.gov/ extrapyramidal effects is lower Normalized Ratio (INR) for buyonline/accutane, will appear in than with metoclopramide. prothrombin time, warns online search results for one of Similarly, 5-HT3 receptor Finland's National Agency for the brand names of isotretinoin antagonists (e.g. ondansetron) Medicines (NAM). Two cases

WHO Pharmaceuticals Newsletter No. 2, 2007 • 2

REGULATORY MATTERS

reported to NAM's adverse about possible anaphylaxis W179-9 vaccine (RotaTeq). reaction database in 2005 were associated with the use of the Intussusception is a serious and associated with the use of drug. Anaphylaxis may include potentially life-threatening warfarin (Marevan) for auricular chest tightness, dizziness, condition that occurs when the fibrillation and miconazole pruritus, swelling of the mouth, intestine gets blocked or (Daktarin) oral gel. In the first, a syncope, trouble breathing and twisted. RotaTeq is indicated for 75-year-old woman receiving urticaria. The Agency has also the prevention of rotavirus warfarin (Marevan) started requested Genentech to provide gastroenteritis. It is not known treatment with miconazole a patients 'Medication Guide' to how many of the 28 cases are (Daktarin) for an intestinal strengthen the existing warning vaccine-related and how many mycosis and, six days later, her for anaphylaxis in the may have occurred by INR increased from a therapeutic omalizumab (Xolair) label. coincidence. The US Vaccine level to 15. In the second case, a According to the US FDA, the Adverse Event Reporting 62-year-old woman receiving frequency of anaphylaxis System (VAERS) received these warfarin (Marevan) had a high reported in the clinical trials of reports between (undetermined) INR level omalizumab (Xolair) was about 3 February 2006 (when approximately two weeks after 0.1%, but the life-threatening RotaTeq was licensed for use in starting the miconazole gel potential and frequency of the US) and 31 January 2007. (Daktarin) for candidiasis. In reports in the post-marketing Intussusception occurred after 2006, NAM received another experience of omalizumab dose 1, dose 2 and dose 3 of report in which an 84-year-old (Xolair), and the possibility for the vaccine, and approximately woman, who was receiving the delayed anaphylaxis onset, 50% of cases occurred warfarin (Marevan), developed have prompted the agency to 1−21 days postvaccination haematuria and an increase in recommend the boxed warning (range 0−73 days). Surgical INR to >7 after starting treatment and strengthen the existing repair was necessary in with the miconazole (Daktarin) warning. The warning includes 16 infants while the remaining oral gel. None of the patients the possibility of developing infants had reduction of the developed serious haemorrhage anaphylaxis after any dose of intussusception by contrast or and their INR levels normalized omalizumab (Xolair); the air enema. after miconazole gel was stopped anaphylaxis may be delayed up The US FDA noted that the and treatment was given (fresh to 24 hours after number of the rotavirus (W179- frozen plasma, vitamin K and administration. The US FDA has 9) vaccine (RotaTeq)- coagulation factor concentrate). advised health-care providers associated intussusception In addition to the above cases, to observe patients for at least cases reported to date does not the national adverse reactions two hours after an injection of exceed the expected number database has 10 non-fatal reports omalizumab (Xolair). based on annual background of interactions between warfarin rates of 8−43 cases per (Marevan) and the miconazole Reports in WHO database: 100 000 for an unvaccinated (Daktarin) oral gel; all involve the Omalizumab (Xolair) - population of infants aged potentiation of the effect of Anaphylactic reaction - 28 6−35 weeks. However, the warfarin (Marevan) and some are agency acknowledged that Reference: associated with haemorrhage. vaccine adverse events are not FDA News. U.S. Food and Drug NAM suggests that patients always reported and that there Administration, receiving warfarin should avoid may be additional unreported 21 February 2007 the use of miconazole oral gel cases of intussusception (www.fda.gov). (Daktarin), and if alternative following vaccination. Currently, treatments are unavailable, INR there are two large-scale levels should be checked Pentavalent postmarketing studies being frequently. conducted by Merck & Co. rotavirus (W179- (involving about 44 000 infants) Reference: and the US Centers for Disease TABU: Drug Information from the 9) vaccine Control and Prevention's National Agency for Medicines, Label updated with Vaccine Safety Data Link Finland, No. 6, 2006. information on (involving approximately intussusceptions and 90 000 infants). haematochezia The US prescribing information Omalizumab for rotavirus (W179-9) vaccine) Label update about USA. The US FDA is notifying (RotaTeq) has been updated to anaphylaxis health-care providers and the reflect the above information. public about 28 post-marketing USA. The US FDA has asked reports of intussusception Reference: Genentech to add a boxed following the administration of FDA Public Health Notification. warning to the labelling for live, oral, pentavalent rotavirus U.S. Food and Drug omalizumab (Xolair) to warn Administration (Center for

WHO Pharmaceuticals Newsletter No. 2, 2007 • 3

REGULATORY MATTERS

Biologics Research and an Investigational New Drug Evaluation), 13 February 2007 Pergolide (IND) application for those few (www.fda.gov). Risk of heart valve patients who are currently damage; to be removed receiving pergolide and who from the market cannot be successfully switched Methotrexate dosage to other available treatments. USA (1). Manufacturers have errors volunteered to remove Canada (2). Heath Canada has pergolide drug products from The Belgian Drug Monitoring informed that it is currently the market due to the risk of Centre has received evaluating the new data on the serious damage to the heart notification of two cases of risk of heart problems valves of patients treated with severe adverse events associated with pergolide these products. Pergolide is a resulting from dosage errors treatment. When completed, dopamine agonist and is used associated with methotrexate. results of the review will be with levodopa and carbidopa to In the first case, a patient communicated to the public and manage the symptoms of misunderstood the dosage to health-care providers. Heath Parkinson's disease. The and took six 2.5 mg tablets of Canada stresses that patients US FDA notes that new studies methotrexate a day for two should not stop taking their confirm old data associating weeks, instead of six tablets a medication without consulting pergolide with increased chance week, for rheumatoid their physician since sudden of regurgitation (back-flow of arthritis. In the second case, discontinuation of pergolide blood) of the mitral, tricuspid a patient took three 2.5 mg may have serious consequences and aortic valves of the heart. tablets of methotrexate a day for the patient. Valve regurgitation is a for one week, instead of one condition in which valves do not tablet a day, for psoriasis, on References: close tightly, allowing blood to a friend's advice. Both 1. FDA News. U.S. Food and flow backward across the valve. patients were hospitalized for Drug Administration, Symptoms include shortness of diarrhoea and mucositis, and 29 March 2007 (www.fda.gov). breath, fatigue and heart one developed pronounced 2. Information Update. Health palpitations. Valvular heart bone marrow depletion. Canada, 31 March 2007 disease was first described in (www.hc-sc.gc.ca). association with pergolide in The Belgian Drug Monitoring 2002. In 2003 the product label Centre says that confusion was updated to include Pioglitazone may arise when a drug does valvulopathy to the warnings not have to be taken every Fractures in females section. Then in 2006, the day. Such errors have been warning was upgraded to a USA. Takeda Pharmaceuticals reported with mefloquine for black box warning because of and the US FDA notified health- malaria prevention with, for new data concerning risks of care professionals of recent example, one dose being heart valve damage. The safety data concerning taken daily instead of weekly. Agency advises that the pioglitazone-containing Unusual dosages are also products being removed include products. The results of an seen with some two generic versions of analysis of the manufacturer's bisphosphonates: weekly for pergolide manufactured by Par clinical trial database of risedronic acid (Actonel and Teca and a proprietary pioglitazone showed more Hebdomadaire) and version (Permax) manufactured reports of fractures in female alendronic acid (Fosamax by Valeant Pharmaceuticals. patients taking pioglitazone Hebdomadaire), and monthly The removal of these products than those taking a comparator for ibandronic acid. is not expected to adversely (either placebo or active). The

affect patient care because majority of fractures observed The Centre suggests that alternative therapies are in female patients were in the patient reminders may be available. The US FDA cautions distal upper limb (forearm, useful in the case of drugs that it is dangerous to stop hand and wrist) or distal lower with an unusual dosage, by taking the medication abruptly limb (foot, ankle, fibula and providing a note and clearly and that patients should consult tibia). There were more than specifying the dose on the their physicians to discuss 8100 patients in the drug container. switching to appropriate pioglitazone-treated groups and

alternative medications. over 7400 patients in the Reference: The US FDA is working with comparator-treated groups. The Folia Pharmacotherapeutica duration of pioglitazone 33(12): 108, 2006. manufacturers of pergolide to determine if it might be treatment was up to 3.5 years. possible, once the drug is The US FDA advises that withdrawn from the market, to health-care professionals make the drug available under should consider the risk of

WHO Pharmaceuticals Newsletter No. 2, 2007 • 4

REGULATORY MATTERS

fracture when initiating or other treatment options are treating female type 2 diabetes Tegaserod available and in whom the mellitus patients with Withdrawn due to life- benefits outweigh the chance of pioglitazone-containing products. threatening cardiac serious adverse effects. effects Reference: Reference: 'Dear Health-care Provider' letter USA. Novartis Pharmaceuticals FDA Public Health Advisory. from Takeda Pharmaceuticals, Corporation in consultation with U.S. Food and Drug March 2007 (www.fda.gov). the US FDA has agreed to Administration, withdraw tegaserod from the 30 March 2007 (www.fda.gov). market. This measure follows a Sedative-hypnotic new safety analysis that has drugs found a higher chance of heart Telithromycin attack, stroke, and worsening Updates on use, Stronger warnings about of chest pain in patients treated contraindications, allergic reactions and with tegaserod maleate adverse events sleep-related complex (Zelnorm) compared to those behaviours. treated with a placebo. USA (1). The US FDA has Tegaserod is a prescription finalized revisions to the USA. The US FDA has requested medication approved for short- telithromycin (Ketek) label, a labelling change for all term treatment of women with which include removing two of sedative-hypnotic drug products irritable bowel syndrome with the three previously approved to include a stronger warning of constipation and for patients indications − acute bacterial potential risks such as severe under 65 years of age with sinusitis and acute bacterial allergic reactions and complex chronic constipation. The exacerbations of chronic sleep-related behaviours. The US FDA has analysed the bronchitis. The Agency manufacturers of sedative- results of 29 clinical studies of determined that the balance of hypnotic drugs must revise tegaserod (Zelnorm) for the benefits and risks no longer product labelling to include treatment of a variety of supported approval of warnings about anaphylaxis and gastrointestinal tract conditions. telithromycin (Ketek) in the two angioedema, which can occur as These 29 studies included 11 indications. The antibacterial early as first administration, and 614 patients treated with will remain on the market for complex sleep related behaviours tegaserod maleate and 7031 the treatment of community- such as sleep-driving, making treated with a sugar pill. The acquired pneumonia of mild-to- telephone calls and eating food average age of these patients moderate severity. Additional while asleep. They must also alert was 43 years and 88% were changes include a boxed health-care providers about these women. The number of patients warning that telithromycin is new warnings and develop Patient who suffered a heart attack, contraindicated in patients with Medication Guides to inform stroke or severe chest pain that myasthenia gravis and a patients about the risks and can turn into a heart attack was strengthened warning section potential precautions that can be small. However, patients regarding specific drug-related taken. Since there may be treated with tegaserod maleate adverse events including visual differences among the various had a higher chance of having disturbances and loss of sedative-hypnotic drugs, the any of these serious and life- consciousness. US FDA has recommended that threatening side effects than the manufacturers conduct clinical did those on the sugar pill. Europe (2). The European trials to assess the frequency of Thirteen patients (0.1%) Medicines Agency (EMEA) has sleep-related behaviours for treated with tegaserod maleate recommended restrictions on individual products. Zolpidem had serious and life-threatening the use of telithromycin (Ketek) (Ambien), flurazepam (Dalmane), cardiovascular side effects. in three of its four approved triazolam (Halcion), ethchlorvynol Among these, four had a heart indications: for the treatment of (Placidyl), secobarbital (Seconal), attack (one died), six had a bronchitis, sinusitis and zaleplon (Sonata) are some of the type of severe chest pain which tonsillitis/pharyngitis; medicines that are the focus of can quickly turn into a heart telithromycin should only be the revised labelling. attack and three had a stroke. used for infections caused by Among the patients taking the bacterial strains that are Reference: sugar pill, only one (or 0.01%) suspected or proven to be FDA News. U.S. Food and Drug had symptoms suggesting the resistant to or cannot be Administration, 14 March 2007 beginning of a stroke that treated with macrolide or beta- (www.fda.gov). resolved without complication. lactam antibiotics. The Agency The Agency will work with has recommended no Novartis to allow special access restrictions for the remaining to tegaserod maleate (Zelnorm) indication, the treatment of for those patients for whom no community-acquired

WHO Pharmaceuticals Newsletter No. 2, 2007 • 5

REGULATORY MATTERS

pneumonia. The Agency has also Reference: recommended the FDA Public Health Advisory. contraindication of the use of U.S. Food and Drug telithromycin in patients with Administration, myasthenia gravis and 6 February 2007 strengthened warnings on (www.fda.gov). transient loss of consciousness and effects on vision. These recommendations are based on Heparin: Medication Errors the conclusions of a comprehensive review that the There is a potential for life- Agency has been carrying out threatening medication errors since January 2006, following with two heparin reports of severe liver injuries in preparations, advise Baxter in patients taking telithromycin. a `Dear Health-care Provider' letter posted on the US FDA References: website. The two products 1. Press Release. U.S. Food and involved are heparin sodium Drug Administration, injection 10 000 units/mL and 12 February 2007 Hep-Lock U/P 10 units/mL, (www.fda.gov). which have similar colour 2. Press Release. European labelling. Baxter are aware of Medicines Agency, fatal medication errors 30 March 2007 occurring when one product (www.emea.europa.eu). has been mistaken for another, including three infant deaths following Topical inadvertent administration of anaesthetics heparin 10 000 units/mL instead of Hep-Lock Professional advice 10 units/mL. Baxter advise needed before use in that health-care professionals cosmetic procedures should carefully read the product label and should not USA. The US FDA has issued a rely solely on label colour to Public Health Advisory about life- distinguish between products. threatening adverse effects associated with topical Reference: anaesthetics for cosmetic 'Dear Health-care Provider' procedures. These products letter from Baxter Healthcare contain drugs such as benzocaine, Corporation, lidocaine, prilocaine and 6 February 2007 tetracaine. The Agency is aware (www.fda.gov). of two women who developed seizures and went into a coma and subsequently died after applying topical anaesthetics before laser hair removal; these creams, which were made in pharmacies, contained high amounts of lidocaine and tetracaine. The Agency has also received reports of serious and life-threatening adverse effects such as coma, irregular heart beat and seizures associated with these products. Those who are thinking about a cosmetic or medical procedure on the skin are advised to discuss with their doctor whether they need a topical anaesthetic and, if so, to use a product approved by the US FDA.

WHO Pharmaceuticals Newsletter No. 2, 2007 • 6

SAFETY OF MEDICINES

investigated in appropriate Reports in WHO database: studies. ADRAC has received Amisulpride - 73 Angiotensin relatively few reports of Aripiprazole - 115 decreased bone mineral density Quetiapine - 33 Converting Risperidone - 684 associated with antiepileptic

drugs, but notes that this may Enzyme (ACE) Reference: reflect a low level of awareness Australian Adverse Drug inhibitors of this adverse effect and the Reactions Bulletin 26(2): 2, Reports of visual delayed nature of the events, 2007. disturbances which often manifest years after treatment initiation. The Netherlands. Until Bupropion 24 March 2006, the Reference: Reports of depression Netherlands Pharmacovigilance Australian Adverse Drug Centre, Lareb had received six Reactions Bulletin 26(1): 3, The Netherlands. Until reports of visual hallucinations 2007. 1 March 2006 Lareb had associated with the use of ACE received 37 reports of inhibitors. Lareb advises that depression associated with these included two reports with Antipsychotics bupropion (amfebutamone; lisinopril and one report each Reports of neuroleptic Zyban). Of these reports, with captopril, enalapril, malignant syndrome 15 were explicitly associated ramipril and trandolapril. with suicidality, including According to Lareb, there was Australia. Previously (1997 attempted suicide. The 15 complete recovery in all cases and 1999) ADRAC had noted patients ranged in age from once the suspect drug was that two of the oldest atypical 31−80 years and, following the discontinued. Lareb suggests antipsychotics, clozapine and start of bupropion treatment, that the successful olanzapine can cause 10 patients developed suicidal dechallenges support a causal neuroleptic malignant syndrome tendencies, two patients relationship between the ACE (NMS). It now appears that all developed thoughts of self- inhibitors and the development of the atypical antipsychotics harm, two patients developed of visual hallucinations. available in Australia can cause suicidal ideation and one this problem. In the Australian patient attempted suicide; Reference: database there are 16 reports there was a latency of three ACE inhibitors and of NMS with quetiapine (this days to 11 weeks. In eight hallucinations. Lareb, being 5.2 % of all reports patients there was a positive Netherlands Pharmacovigilance received for this medicine), 45 dechallenge and in four there Centre, January 2007 for risperidone (5.7%), 15 for was a negative dechallenge; (www.lareb.nl). amisulpride (6.7 %), 15 for information regarding aripiprazole (10.3 %). There dechallenge was unknown in Antiepileptic are in all 85 NMS reports for two patients. clozapine (2.3 %) and 49 for drugs olanzapine (4.1 %) in the Reports in WHO database: Australian database. Although Depression - 1345 Enzyme-inducing drugs with the Australian data it Suicide attempts - 1161 may increase fracture appears that, of the atypical risk antipsychotics, NMS occurs Reference: most with aripiprazole, this Bupropion and suicidality. Australia. According to the trend is not seen in the WHO Lareb, Netherlands Australian Adverse Drug global database. Pharmacovigilance Centre, Reactions Advisory Committee Clinical features of NMS include January 2007 (www.lareb.nl). (ADRAC), decreased bone autonomic instability, mineral density and a confusion, disorientation or subsequent increased fracture other cognitive function Carbasalate risk have been documented in changes, fever, muscle rigidity Reports of tinnitus users of enzyme-inducing and profuse sweating. The Netherlands. There are antiepileptic drugs such as Increased creatine kinase (CK) eight reports of tinnitus phenobarbital, phenytoin and is often noted. ADRAC advises associated with carbasalate primidone. ADRAC says this risk that NMS can be life- calcium at doses of 38 mg and increases with the duration of threatening and rapid 100 mg in the Lareb database. drug exposure and is higher in recognition and treatment are Carbasalate calcium is used in women; there is presently no important. the treatment of fever, information on the effect of headache and pain due to 'flu `new' antiepileptics on bone and in other conditions like health, but this has not been

WHO Pharmaceuticals Newsletter No. 2, 2007 • 7

SAFETY OF MEDICINES

myalgia. The drug was doses of morphine through (Exjade). Increases in administered once daily in all of breast milk. The mother was an creatinine levels occurred at a the reports involving the 38 mg ultra-rapid metabolizer greater frequency in deferasirox dose. Lareb also received two receiving analgesia with recipients, compared with reports of tinnitus associated codeine for pain resulting from deferoxamine (another iron- with carbasalate calcium the delivery. The Swedish MPA chelator) recipients. The 600 mg, one report of warns that breastfeeding company says that serum ototoxicity associated with mothers receiving codeine creatinine levels should be 38 mg, and one report of should use the lowest dose monitored twice before decreased hearing with possible and monitor their initiating deferasirox (Exjade), 300 mg. The range of the time infant for signs of overdose followed by weekly monitoring to reaction (onset) was broad, such as breathing difficulties, in the first month of treatment, and, at the time of reporting, difficulty breastfeeding, and monthly thereafter; two of the patients had not drowsiness or listlessness, proteinuria should be monitored recovered after withdrawal of flaccidity and small pupils; every month and patients the drug. should any of these signs be should be adequately hydrated. According to Lareb, although noted, medical care should Novartis has also received the mechanism of the immediately be sought. reports of cytopenia in patients treatment induced ototoxicity is receiving deferasirox (Exjade), not apparent, it "may involve Reference: most of whom had pre-existing biochemical and consequent Codeine in normal doses to haematological disorders. In electrophysiological changes in breastfeeding mothers can in line with standard clinical the inner ear and a dysfunction rare cases cause serious management of cytopenias, of the auditory nerve". Lareb adverse reactions in the infant. blood counts should be concludes that the association Internet Document. Swedish monitored regularly. between tinnitus and the lower Medical Products Agency, Interruption of treatment with doses (38 and 100 mg) is December 2006 deferasirox should be disproportionte in the Lareb (www.lakemedelsverket.se). considered in patients who database, and that their data develop unexplained cytopenia. suggest an association between tinnitus and low doses of Deferasirox References: carbasalate calcium. Reports of renal failure 1. 'Dear Health-care Professional' letter from Canada, Switzerland. Reports in WHO database: Novartis Pharmaceuticals Novartis Pharma has issued a Tinnitus - 7 Canada Inc., 9 March 2007 'Dear Health-care Professional' (www.hc-sc.gc.ca). letter advising of a possible Reference: 2. 'Dear Doctor' letter from association between the use of Low dose carbasalate calcium Novartis Pharma Schweiz AG, deferasirox (Exjade) and renal and tinnitus. Lareb, Netherlands 28 March 2007 failure and cytopenia. Pharmacovigilance Centre, (www.swissmedic.ch). January 2007 (www.lareb.nl). Deferasirox is an iron-chelator. According to Novartis, reports of renal failure have been Domperidone Codeine received following the post- Heart rate and rhythm marketing use of deferasirox Lowest dose disorders recommended in (Exjade). Some of these reports had a fatal outcome. The nursing mothers Canada. From 1 January 1985 fatalities could have been to 15 August 2006, Health Sweden. The Swedish Medical because of the underlying Canada received nine domestic Products Agency (MPA) has diseases. However, the reports of heart rate and warned that, in rare cases, company says that it is rhythm disorders suspected of codeine in normal doses given impossible to rule out a being linked with domperidone to breastfeeding mothers can contributory role of deferasirox use. Four of these reports lead to dangerously high (Exjade). Discontinuation of described torsades de pointes amounts of morphine being deferasirox (Exjade) in most of and two described QT interval delivered to the infant. Codeine the nonfatal cases was prolongation. The other three is converted to morphine in the associated with improvement in reports included the following body, and mothers who are patients' condition, which is adverse reactions: arrhythmia, ultra-rapid metabolizers of suggestive of a contributory atrial fibrillation, bradycardia, codeine should be aware of role of deferasirox (Exjade). palpitation and ventricular possible signs of morphine Clinical trials have revealed tachycardia. Five patients had overdose in their infants. In a dose-dependent increases in recovered at the time of case reported in Canada, an serum creatinine levels in reporting and the outcome was infant died after receiving high patients receiving deferasirox not known in the remaining four

WHO Pharmaceuticals Newsletter No. 2, 2007 • 8

SAFETY OF MEDICINES

cases. The reports involved References: advanced head and neck patients aged from two months 1. Advisory. Health Canada, cancer receiving radiation to 74 years. 21 February 2007 therapy and in patients with (www.hc-sc.gc.ca). metastatic breast cancer Reports in the WHO database: 2. 'Dear Doctor' letter from receiving chemotherapy, Heart rate and rhythm disorders - Bristol-Myers Squibb SA, March when ESAs were given to 62 2007 (www.swissmedic.ch). maintain haemoglobin 3. Public Statement. European levels of more than Reference: Medicines Agency, 12 g/dL. Canadian Adverse Reaction 5 March 2007 • A higher chance of death Newsletter, January 2007, (www.emea.eu.int). was reported and no fewer 17(1): 2. blood transfusions were received when ESAs were Entecavir Erythropoiesis- given to patients with Report of a resistant stimulating cancer and anaemia not receiving chemotherapy. HIV-variant in agents • A higher chance of death HIV/HBV co-infected New studies suggest was reported and an patient serious and life- increased number of blood clots, heart attacks, heart Canada, Europe. Bristol-Myers threatening side failure and strokes were Squibb in consultation with effects reported in patients with Health Canada (1) and chronic kidney failure when USA. The US FDA is warning Swissmedic (2) has written to ESAs were given to health-care professionals and health professionals with the maintain haemoglobin the public of new safety following warning about the use levels of more than information for erythropoiesis- of entecavir (Baraclude): 12 g/dL. stimulating agents (ESAs) • Entecavir (Baraclude) has • A higher chance of blood darbepoetin alfa (Aranesp) and not been assessed in clots was reported in epoetin alfa (Epogen and HIV/HBV (hepatitis B) co- patients who were Procrit). ESAs are genetically infected patients who are scheduled for major surgery engineered forms of the not simultaneously and given ESAs. naturally occurring human receiving effective HIV • ESAs are not approved for protein, erythropoietin. ESAs treatment. treatment of the symptoms stimulate the bone marrow to • When considering therapy of anaemia such as fatigue make more red blood cells and with entecavir (Baraclude) in patients with cancer, are the US FDA approved for in an HIV/HBV co-infected surgical patients and use in reducing the need for patient who is not receiving patients with HIV. blood transfusions in patients HAART, the risk of The US FDA believes these new with chronic kidney failure, developing HIV resistance concerns apply to all ESAs and cancer patients on cannot be excluded based is re-evaluating how to safely chemotherapy, patients on current information. use this product class. The scheduled for major surgery • Caution is advised if US FDA and Amgen, (the (except heart surgery) and entecavir (Baraclude) is manufacturer of Aranesp, patients with HIV who are using used in this setting. Epogen and Procrit), have AZT. Four new studies in changed the full prescribing patients with cancer found a The EMEA has also made a information for these drugs to higher chance of serious and Public Statement (3) with include a new boxed warning, life-threatening side effects or similar information. updated warnings, and a death with the use of ESAs. change to the dosage and These research studies were The above warning was issued administration sections for all either evaluating an because an HIV variant ESAs. The new boxed warning unapproved dosing regimen, a containing the M184 resistance advises physicians to monitor patient population for which substitution was documented red blood cell levels ESAs are not approved, or a during entecavir (Baraclude) (haemoglobin) and to adjust new unapproved ESA. treatment in an HIV/HBV co- the ESA dose to maintain the infected patient who was not lowest haemoglobin level The US FDA has issued a Public simultaneously receiving needed to avoid the need for Health Advisory with the HAART. blood transfusions. The US FDA following information: advises that physicians and • A higher chance of death Reports in WHO database: patients should carefully weigh Entecavir (Baraclude) HIV test and an increased rate of the risks of ESAs against positive - 1 tumour growth were transfusion risks. reported in patients with

WHO Pharmaceuticals Newsletter No. 2, 2007 • 9

SAFETY OF MEDICINES

(See WHO Pharmaceuticals Dreaming abnormal - 19 reports of psychiatric disorders Newsletter No. 1, 2006 for Insomnia - 17 associated with leuprorelin. The earlier revision to the ESA time to reaction onset was product labelling). Reference: seven months for the buserelin Advisory. Health Canada, recipient and one week to five References: 23 February 2007 months for three of the 1. FDA News. U.S. FDA, (www.hc-sc.gc.ca). goserelin recipients; the time to 9 March 2007 (www.fda.gov). reaction onset was not reported 2. Public Health Advisory. Fluticasone for one of the goserelin U.S. FDA, 9 March 2007 recipients. Reported adverse (www.fda.gov). Reports of behavioural reactions included depression, changes emotional lability, insomnia, psychosis and sleep disorder. The Netherlands. Lareb has Estazolam Only one patient had a history received 17 reports of Present in a dietary of a psychiatric disorder. Two behavioural changes in children patients received treatment supplement associated with the use of with antipsychotics or inhaled fluticasone propionate Canada. Health Canada has antidepressants. The reported (n = 13) or advised against using Sleepees, outcome was `recovered' for salmeterol/fluticasone an herbal sleep aid, as it was two patients and `not propionate (4). found to contain undeclared recovered' for two patients; the According to Lareb, in 11 cases, estazolam. Estazolam can be patient outcome for the symptoms disappeared when habit-forming when used for as remaining patient was not fluticasone propionate was little as a few months. Health reported. withdrawn. A positive Canada has advised consumers, who still have Sleepees in their rechallenge was observed in Reports in WHO database: homes, to consult a health-care one case. Lareb states that Goserelin, Psychiatric disorder - professional before six patients who had received 222; Buserelin, Psychiatric disorder discontinuing the drug as it fluticasone propionate also - 84; Leuprorelin, Psychiatric may cause withdrawal received salbutamol; however, disorder - 799 symptoms. Estazolam should in all but one case, the reporter not be used by individuals who did not see a causal relationship Reference: are allergic to benzodiazepines, between the adverse drug Goserelin and psychiatric or those with myasthenia gravis reaction and salbutamol. These disorders in the treatment of or sleep-apnoea syndrome. results, say Lareb, support "our prostate cancer. Lareb, Pregnant women should receive theory that fluticasone is Netherlands Pharmacovigilance estazolam only when absolutely responsible for the behavioural Centre, January 2007 necessary and caution is changes in the children." Lareb (www.lareb.nl). needed when using the drug in says that psychiatric effects the elderly or in those with a have also been reported in Levofloxacin history of substance abuse, association with the use of oral says the Agency. The side corticosteroids and inhaled Reports of blood effects associated with budesonide, which raises the glucose, liver and estazolam use include amnesia, possibility of a group effect. biliary disorders: an confusion, depression, update dizziness, drowsiness and Reference: hallucinations. According to Fluticasone inhalation and Canada. Between Health Canada, Sleepees is not behavioural changes in 1 January 1997 and authorized for sale in Canada children. Lareb, Netherlands 30 June 2006, Health Canada and consumers who have Pharmacovigilance Centre, received 22 reports of purchased the product should January 2007 (www.lareb.nl). dysglycaemia and 44 reports of return it to the place of liver and biliary disorders purchase. Goserelin, suspected to be associated with levofloxacin. The reports of Reports associated with estazolam buserelin dysglycaemia included diabetes in WHO database: Reports of psychiatric mellitus (1 report), Tolerance increased - 11 hyperglycaemia (2), Therapeutic response disorders hypoglycaemia (16), and decreased - 14 combined hyper- and Death - 14 The Netherlands. Lareb has Nausea - 13 received five reports of hypoglycaemia; the median Confusion - 9 psychiatric disorders associated reported age was 71 years. The Hallucinations - 10 with use of goserelin (n = 4) or 44 reports of levofloxacin- Amnesia - 8 buserelin (1) in men (aged related liver and biliary Somnolence - 22 56−80 years). There were no disorders included 15 reports of

WHO Pharmaceuticals Newsletter No. 2, 2007 • 10

SAFETY OF MEDICINES

liver failure, hepatitis and Gram-positive and Gram- hepato-renal syndrome, of negative organisms, or who had Oseltamivir which five reports had fatal no infection when they entered Close monitoring of outcomes; the remaining the study. treated children and 29 reports included elevated The US FDA reminds health- adolescents. liver enzyme levels, jaundice care professionals that linezolid and cholestatic hepatitis. For all is not approved for the Japan (1). The Ministry of reports of liver and biliary treatment of catheter-related Health, Labour and Welfare in disorders, the median time to bloodstream infections, Japan has issued a general onset was five days. The catheter-site infections or warning for oseltamivir disturbances of blood glucose Gram-negative infections. If (Tamiflu) advising close levels along with liver and infection with Gram-negative monitoring (for at least two biliary disorders are included in bacteria is known or suspected, days after diagnosis) of children the product monograph of appropriate therapy should be and adolescents with 'flu who levofloxacin. started immediately. The are receiving the drug. The US FDA is currently evaluating warning follows the recent Reports associated with levofloxacin the new study along with other reports of two teenagers in WHO database: information about linezolid. receiving oseltamivir who fell Hepatic function abnormal - 111 from buildings and died. In Reports in WHO database: total, 16 deaths in oseltamivir Reference: Death - 12 recipients aged <16 years had Canadian Adverse Reaction been reported in Japan by Newsletter, January 2007, Reference: October 2006, several involving 17(1): 1-2. FDA News. U.S. Food and Drug falls from high places. Administration, 16 March 2007 Linezolid (www.fda.gov). Europe (2). In a Press Release the European Medicines Agency Risk of death when (EMEA) states that it is aware used in catheter- Olanzapine of the new reports of related blood stream Reports of neuropsychiatric adverse events infections amenorrhoea associated with the use of oseltamivir (Tamiflu) in Japan. USA. The US FDA has issued an The Netherlands. As recorded The Agency's Committee for alert advising that the use of on 27 April 2006, there are Medicinal Products for Human linezolid to treat seriously ill seven reports of amenorrhoea use (CHMP) has monitored patients with intravenous associated with the use of closely all adverse drug catheter-related bloodstream olanzapine in the Lareb reactions reported in connection infections may be associated database. The time to reaction with the use of oseltamivir with an increased risk of death. onset ranged from a few weeks since it was introduced in the This alert follows data from an to 10 months, and the patient European Union in 2003. In open-label, randomized trial outcome was reported in three February 2007 the CHMP that compared linezolid to cases; one patient recovered recommended an update of the vancomycin, oxacillin, or after the drug was product information to warn dicloxacillin (comparator discontinued, and two patients health professionals and antibiotics) in the treatment of did not recover. Furthermore, patients about neuropsychiatric seriously ill patients with four of the seven patients were side effects with oseltamivir. intravascular catheter-related concomitantly receiving a According to the CHMP bloodstream infections including benzodiazepine, and one 'Patients, especially children those with catheter-site patient also experienced and adolescents should be infections. Patients treated with hyperprolactinaemia. closely monitored and their linezolid had a higher chance of health-care professional should death than did patients treated Reports in WHO database: be contacted immediately if the Amenorrhoea - 54 with any comparator antibiotic, patient shows any sign of and the chance of death was unusual behaviour'. The EMEA Reference: related to the type of organism and the CHMP will continue to Olanzapine and amenorrhoea. causing the infection. Patients closely monitor any emerging Lareb, Netherlands with Gram-positive infections safety information on Pharmacovigilance Centre, had no difference in mortality oseltamivir (Tamiflu), including January 2007 (www.lareb.nl). according to their antibiotic neuropsychiatric disorders and treatment. In contrast, will take further action if mortality was higher in patients needed. treated with linezolid who were infected with Gram-negative (See WHO Pharmaceuticals organisms alone, with both Newsletter No. 6, 2006 for

WHO Pharmaceuticals Newsletter No. 2, 2007 • 11

SAFETY OF MEDICINES

oseltamivir label updates in Reference: Venlafaxine - teeth grinding - 32 Canada and in the USA). McLean RM, Harrison- Reference: Woolrych M. Alopecia SSRIs and venlafaxine in Reports in WHO database: associated with quetiapine. association with bruxism. Oseltamivir (Tamiflu) - suicide International Clinical Lareb, Netherlands attempts - 3 Psychopharmacology No. 2, Pharmacovigilance Centre, 2007, 22: 117-119. January 2007 (www.lareb.nl). References: 1. Adis Reactions (Weekly) No. 1143: 2, 2007. Selective Ranibizumab 2. Press Release. European serotonin Intravitreal injections Medicines Agency (EMEA), and incidence of stroke 23 March 2007 reuptake (www.emea.europa.eu). USA. Genentech has issued a inhibitors `Dear Health-care Provider' letter advising of important Quetiapine (SSSRIs), safety information regarding Reports of alopecia venlafaxine ranibizumab injection (Lucentis). The letter refers to New Zealand. The Intensive Reports of bruxism interim data from the ongoing Medicines Monitoring study which show that patients Programme (IMMP) has The Netherlands. Lareb, the with neovascular (wet) age- received two reports of alopecia Pharmacovigilance Centre in related macular degeneration associated with quetiapine. The the Netherlands has received (AMD) who received intravitreal first case reported to the IMMP seven reports of bruxism (teeth ranibizumab in doses of 0.5 mg involved a 34-year-old woman grinding) associated with SSRIs had a significantly higher with psychotic depression. (two with citalopram, one with incidence of stroke compared Approximately six weeks after fluoxetine, one with with those patients in the starting therapy with citalopram fluvoxamine, three reports with 0.3 mg dose group (1.2% and quetiapine (initially paroxetine,) and three reports versus 0.3%). Patients with a 25 mg/day and titrated to associated with venlafaxine prior stroke history appeared to 100 mg/day), she noticed use, up until 5 April 2006. The be at greater risk for significant, continuing hair loss. SSRI cases were reported at subsequent stroke. There was Quetiapine was withdrawn dosages of 20 mg/day for no difference between the one week later and her alopecia paroxetine, citalopram and doses for the events of resolved; citalopram was fluoxetine, and 100 mg/day for myocardial infarction or continued throughout. fluvoxamine. The time to vascular death. The second patient was a 34- bruxism onset ranged from year-old woman with bipolar six hours to eight weeks, Reference: disorder who was receiving although the time to onset was 'Dear Health-care Provider' quetiapine 300 mg/day, not known in three SSRI cases. letter from Genentech, zopiclone and clonazepam; she Recovery occurred in three 24 January 2007 was also using a salbutamol cases following cessation of the (www.fda.gov). (Albuterol) inhaler as required. SSRI, although one patient had She developed increasing hair permanent enamel damage; loss 20 days after starting bruxism did not resolve in one Rosiglitazone patient and the outcome was quetiapine; her medical history Increased risk of recorded alopecia while unknown in three patients. The receiving valproic acid. venlafaxine cases were fractures in women Quetiapine was stopped and her reported at dosages of receiving long-term hair loss resolved. 75 mg/day. The time to treatment bruxism onset ranged from According to Dr McLean and days to weeks in two cases; the USA (1), Canada (2), Dr Harrison-Woolrych, the time to onset was unknown in Switzerland (3), UK (4). positive dechallenges and "the one case. According to Lareb, According to a 'Dear Health- temporal relationship with the bruxism was disproportionately Care Professional' letter from medicine in each case provides associated with the use of GlaxoSmithKline, the ADOPT evidence of a `probable' causal SSRIs and venlafaxine in both (A Diabetes Outcome and association". the WHO and Lareb databases. Progression Trial) safety data suggest an increased rate of Reports in WHO database: Reports in WHO database: fractures in women receiving Quetiapine - Alopecia - 22 Citalopram - teeth grinding - 16 rosiglitazone-containing Fluoxetine - teeth grinding - 14 products for type 2 diabetes. Fluvoxamine -teeth grinding - 1 The information applies to Paroxetine - teeth grinding - 46 rosiglitazone maleate

WHO Pharmaceuticals Newsletter No. 2, 2007 • 12

SAFETY OF MEDICINES

(Avandia), rosiglitazone 22 March 2007 16 reports of sleep walking maleate and metformin (www.mhra.gov.uk). associated with its use; the hydrochloride (Avandamet) reports detail inappropriate or and rosiglitazone maleate and strange autonomic behaviour glimepiride (Avandaryl). The Tacrolimus while the individuals were primary goal of the ADOPT Reports of `asleep'. Among the reports study was to compare the malignancies were two cases involving glycaemic control with uncontrollable eating binges rosiglitazone relative to The Netherlands. Lareb, the during sleep. In the first report metformin and to glibenclamide Pharmacovigilance Centre in the patient's weight increased monotherapies in 4360 the Netherlands has received by 23 kg over seven months randomised patients with three reports of malignant while receiving zolpidem. The type 2 diabetes mellitus. While adverse effects associated with problem of weight gain was a review of the ADOPT safety topical tacrolimus (Protopic) up resolved after the patient was data was generally consistent to 6 June 2006. In all three found eating while asleep. The with the known safety profile of cases, 0.03% tacrolimus second report involved a rosiglitazone, significantly more (Protopic) was used. In one patient who experienced women receiving rosiglitazone case, a child developed significant weight gain with experienced fractures (9.3%) T-cell leukaemia two years after zolpidem therapy; again, the than women receiving starting tacrolimus therapy and, patient was discovered eating metformin or glibenclamide at the time of notification, the while asleep. The 16 reports (5.1% and 3.5%, respectively). child had not recovered. In the also included one where a The incidence of fractures in second case, a man developed patient had been painting while men was similar for all three a squamous cell carcinoma on asleep, and two reports which drugs. At the company's the glans of his penis one year suggested the patients may request, an independent safety after starting tacrolimus have driven while asleep. committee conducted an therapy; the patient's outcome Patients, and in particular first- interim analysis of safety data was unknown. In the third case, time users, should be warned for another large, ongoing trial an elderly woman developed a about the possibility of of rosiglitazone; the results of malignant tumour of her tongue `distressing' neurological or the preliminary analysis were which required the surgical psychiatric reactions associated consistent with the ADOPT removal of a part of her tongue. with zolpidem, including those findings. The independent Topical tacrolimus is used in associated with sleeping, safety committee recommended atopic dermatitis. Lareb says according to ADRAC. that the second trial continue that, because topical tacrolimus without modification; final is often used for extended Reports in WHO database: results should be available in periods and off-label use is not Zolpidem - Somnambulism - 66 2009, according to uncommon, health GlaxoSmithKline. professionals should be aware Reference: of a potential risk for Australian Adverse Drug Reports in WHO database: malignancies. Reactions Bulletin 26 (1): 2-3, Rosiglitazone - Fracture - 6 2007. Fracture pathological - 1 Reports in WHO database: Fracture spontaneous - 1 Tacrolimus - Neoplasm - 206

References: Reference: 1. 'Dear Health-care Provider' Topical tacrolimus and letter from malignancies. Lareb, GlaxoSmithKline, Netherlands Pharmacovigilance February 2007 Centre, January 2007 (www.fda.gov). (www.lareb.nl). 2. ' Dear Health-care Professional' letter from Zolpidem GlaxoSmithKline, 23 February 2007 Reports of sleep (www.hc-sc.gc.ca). walking 3. 'Dear Health-care Provider' Australia. From the time when letter from zolpidem (Stilnox) was GlaxoSmithKline, marketed in Australia in late 8 March 2007 2000 to the time of this report, (www.swissmedic.ch). the Australian Adverse Drug 4. 'Dear Health-care Provider' letter from Reactions Advisory Committee GlaxoSmithKline, (ADRAC) had received

WHO Pharmaceuticals Newsletter No. 2, 2007 • 13 FEATURE

Recommendations of the fourth meeting of the WHO Advisory Committee on Safety of Medicinal Products 26 and 27 February 2007 Constituted to provide advice on pharmacovigilance policy, and issues related to the safety and effectiveness of medicinal products, the WHO Advisory Committee on Safety of Medicinal Products (ACSoMP) held its fourth meeting in February 2007. The following are the key recommendations from the meeting.

WHO Strategy for Medicine Safety A strategy for safety of medicines in WHO is under preparation. A plan is needed for capacity building in countries. The strategy outlines the initiatives which WHO Headquarters intends to undertake in the area of strengthening the safety of medicines during the next five years. It will be complementary to the 4-year plan of the Collaborating Centre for International Drug Monitoring and the strategic plans of the member countries participating in the Programme. It was agreed that a small group should be convened to take this forward.

Promoting Safety of Medicines in Children The manuscript on monitoring the safety of medicines in children was discussed. EMEA have recently published guidelines on the conduct of pharmacovigilance in paediatric populations. These guidelines should be considered in reviewing the text but the WHO manuscript is broader in its concept. However, the regulatory aspects of the text need to be improved and there is a need for a section on medication errors. It was agreed that several members of the Committee should provide input to the manuscript by the middle of April.

Social Marketing of Medicine Safety The manuscript on the Social Marketing of Medicine Safety was discussed. This script is intended to: • outline the strategic directions for medicine safety within the WHO Programme in the next decades; • to develop a strategy for the promotion of medicine safety around the world through a network of dedicated advocates, such as the WHO partners and national centres and • to provide suggestions on broad tactics, creative ideas and materials which can be used as the basis for promoting drug safety to a wide range of audiences. It was agreed that the text should be discussed and promoted during the annual meetings of national centres.

Global Networking A demonstration was made on the use of MedNet, the WHO site for linking partners and projects in WHO programmes. MedNet is hosting over 20 scientific communities. Documents can be shared and revised more easily than by using e-mail. Shared networks are available with security and collaborative e- workspaces. Different countries or subjects can be associated. Membership of communities is controlled by the community. A pharmacovigilance community could be created to exchange, share and communicate information. It was agreed that Vigimed could be elaborated using this system. A community for the Advisory Committee on Safety of Medicinal Products should be set up.

Vaccine collaboration Recommendations from a global consultation were presented. The aim is to get all adverse events following immunization (AEFIs) to the Uppsala Monitoring Centre (UMC), including from units outside the national pharmacovigilance centres. A person to act as a vaccine focal point is to be recruited to UMC. AEFI programmes should have access to Vigiflow, the online adverse drug reaction reporting system managed by the UMC. Improved advocacy and communication is necessary. The Anatomical Therapeutic Chemical classification system for vaccines needs to be revised. A pilot project in several countries for post-marketing surveillance to improve reporting and signalling is to be developed. There is a working group on safety monitoring needs in an emergency e.g. pandemic 'flu. A rapid alert system is needed for vaccines in a pandemic. Potential coordination with Quality Assurance and Safety: Medicines (QSM) for antivirals during a pandemic is to be discussed. It is planned that a new reporting chain will be set up for use in a pandemic aimed at getting timely information.

Causality assessment The discussion was introduced by outlining the history of development of the definitions. They were never meant to function as an algorithm. The system is used by over 70% of National Centres and needs to be refined for general use as such. There has been no validation of the system. The US FDA does not use a single system, but does use the principles at times. Different situations need different approaches. For example, drug-induced liver injury has special criteria prepared by an interest group. The hepatologists’

WHO Pharmaceuticals Newsletter No. 2, 2007 • 14 FEATURE

criteria were not designed for regulatory work, but to assist clinical understanding. There are situations where the WHO criteria do not fit well. The primary purpose is to get a clear understanding of the report. When looking at groups of reports, other means need to be considered to establish causality. Some points in the definitions are not exclusive requirements. Reporters often want to know if an event is drug-related. It was pointed out that the initial part of the assessment of a report is a relationship assessment and that this needs to be done using criteria that are as objective as possible. Causality is better established later on clusters of events and looking at other factors such as pharmacology and epidemiology. The general opinion was that the ‘WHO method’ was valuable and should be retained and improved. It was suggested that International Society of Pharmacovigilance would be a good forum for further discussion. Council for International Organizations of Medical Sciences (CIOMS) may also wish to discuss the issue.

Methodology for evidence of the need for pharmacovigilance A protocol for collection of data on incidence in selected hospital departments has been developed. This could be used as a baseline for comparisons over several years. It could be undertaken by interns. A pilot project in a few hospitals will be undertaken and the results published at the Annual Meeting of National Centres later this year.

Patient Safety pilot project This is a collaborative project between the World Alliance for Patient Safety and Medicine Safety and should build upon the success of the WHO Programme for International Drug Monitoring. The problem, the approach and techniques were outlined. An advocacy role is important. One objective is to determine whether National Centres can collect, identify and analyse reports with medication error. It is hoped that the UMC can analyse the pooled data. The future role of National Centres will be assessed. A tool kit needs to be developed. Early experience of the project in Morocco was described. The importance of assessing the preventability of adverse reactions was stressed. Cases already present in the WHO database will be analysed by the end of the year. It was suggested that ‘near misses’ may not be identified and that these could provide valuable information. Those involved in rational use should be linked to this programme.

Specific Medicines The Expert Committee on the Use and Selection of Essential Medicines have requested input from ACSoMP on questions on safety in relation to applications for listing in the Essential Medicines List (EML). These need to be of a standard that can be posted on the website and should not contain information that cannot be verified. It is desirable that the assessments should include: • Critical review of submissions with respect to safety information • Assessment of comparative safety • Less emphasis on Summaries of Product Characteristics (SPCs). • Data from the WHO database. In the future there will be an emphasis on safety of medicines in children. There is also a need to set up a mechanism for urgent additions and deletions to the EML on the grounds of safety.

Safety assessments and recommendations for the current applications for the EML were as follows:

Cefalexin It was agreed that cefalexin was acceptable in terms of safety.

Recommendation: Safe for inclusion in EML.

Cefazolin There are concerns over the number of reports of anaphylaxis associated with cefazolin.

Recommendation: Include in EML with the proviso that it should be used only where rapid resuscitation can be undertaken in cases of anaphylaxis.

Emtricitabine The recognized adverse reactions include lactic acidosis (usually associated with hepatic steatosis), fat redistribution, exacerbation of hepatitis B (HBV) in patients co-infected with HBV and HIV after emtricitabine withdrawal, immune reconstitution syndrome and osteonecrosis.

Recommendation: It is suggested that, should emtricitabine be included in the EML, the following points should be addressed: • Safety/efficacy concerns in patients with hepatitis B infection should be highlighted. • The risks of lactic acidosis/mitochondrial toxicity should be mentioned as a class effect. • The issue of osteonecrosis should be highlighted with specific advice to patients to seek medical advice if they experience joint stiffness, pain etc.

WHO Pharmaceuticals Newsletter No. 2, 2007 • 15 FEATURE

Emtricitabine + tenofovir The main safety concern for tenofovir DF is renal toxicity, including renal failure, proximal tubulopathy (including Fanconi Syndrome), nephritis (including acute interstitial nephritis) and nephrogenic diabetes insipidus.

Recommendation: It is suggested that should emtricitabine/tenofovir DF be included in the EML, the following points should be highlighted and addressed: • Recommendations for monitoring of renal function should be explicit and specified (including information in cases of patients at risk of, or with pre-existing renal disease, i.e. elderly patients) • Safety/efficacy concerns in patients with liver dysfunction, chronic hepatitis and in the context of concomitant use with other antiretrovirals should be highlighted.

Fluoxetine The adverse effect profile is well known and adequately described. Fluoxetine is better tolerated than tricyclic antidepressants (TCAs) considered as a group and is better tolerated in comparison with individual antidepressants, in particular amitriptyline. The relationship between SSRIs and suicide has been the focus of several investigations.

Recommendation: Safe for inclusion in the WHO EML.

Paromomycin More data including from different settings like AIDS, paediatric populations and elderly people users is very important. It is desirable to have Phase IV studies to identify new safety and effectiveness issues [e.g., drug-drug and drug-food interactions] in real world situations related with the new indication and new settings.

Recommendation: It is premature to include paromomycin in the EML. There is insufficient evidence of its safety in the treatment of visceral leishmaniasis.

Ribavarin This medicine has not been evaluated in children and the elderly. The drug has been shown to be teratogenic in animal at doses lower than therapeutic dose. The drug accumulates.

Recommendation: The application is for ribavirin for treatment. There should be some comments / statement on the use of ribavirin in post-exposure prophylaxis. The drug is likely to be used / misused for prophylaxis where the benefit / risk could be quite different from when used for treatment.

Simvastatin Increased risk of rhabdomyolysis with acute renal failure is associated with the use of simvastatin. As reversible increase in levels of serum aminotransferases may occur, liver function of the patient must be assessed before the start of the treatment with simvastatin.

Recommendation: Simvastatin may be added to the complementary list of the EML. There needs to be careful monitoring.

Sumatriptan Adverse reactions are common but the great majority are minor and evanescent. Although reactions are common, use of sumatriptan with the appropriate precautions is safe. There has been widespread use with few convincing serious reactions.

Recommendation: From the safety point of view, sumatriptan 50 mg tablets can be recommended for inclusion in the EML.

Tenofovir Recognized adverse reactions include lactic acidosis (usually associated with hepatic steatosis), fat redistribution, exacerbation of hepatitis B (HBV) in patients co-infected with HBV and HIV after tenofovir withdrawal, immune reconstitution syndrome and osteonecrosis.

Recommendation: Tenofovir should initially be placed on the “Complementary List” in view of concerns regarding the feasibility of renal monitoring in developing environments.

WHO Pharmaceuticals Newsletter No. 2, 2007 • 16 FEATURE

Amodiaquine/artesunate

There have been reports on adverse events associated with the use of artesunate amodiaquine in several African countries, most reliably reported in Ghana. The review of these reactions suggested that once daily exposure to artesunate 200 mg/amodiaquine 600 mg was common to all events, making it plausible that these effects are dose dependent.

Recommendation: It is premature to include amodaiquine-artesunate in the EML. An appropriate risk- management plan must be drawn up to address the dosage issues before contemplating inclusion of amodiaquine-artesunate in the EML.

Levamisole In 1994-2003, 632 cases of imidazoles-induced demyelinating encephalopathy were reported in the domestic literature in China, of which 543 cases were levamisole-induced. The causality of levamisole and demyelinating encephalopathy has been investigated and demonstrated by six pharmacoepidemiological studies. The WHO global database contains 81 case reports of central nervous system disorder.

Recommendation: Levamisole should be deleted from the EML because of the availability of safer products. However if resistance becomes a problem with the alternatives, it could be used as a second-line treatment.

Other specific medicines Thalidomide Foetal abnormalities with thalidomide are still being reported. The situation in Brazil is complicated by about 30 indications for use and the difficulty in controlling its use. Clear messages about risk management and minimization are needed. The Committee agreed that pressure should be put on governments to address this issue. If thalidomide is licensed, adequate control measures must be in place.

Generic reporting form A discussion took place on the pros and cons of developing a generic reporting form. The content and design need to be considered. Forms often need to be adapted to local situations. Another complication is the expanding nature of pharmacovigilance that requires new types of data e.g. medication error. Over the years all countries participating in the WHO Programme for International Drug Monitoring have developed their own forms to suit their own needs in spite of the existence of other models. Guidelines for designing a form should be developed.

Any other matters The methodology developed by the New Zealand Intensive Medicines Monitoring Programme (IMMP) is of great value in promoting medicine safety. Discontinuing the IMMP would be a real loss to worldwide pharmacovigilance.

WHO Pharmaceuticals Newsletter No. 2, 2007 • 17 LETTERS

Letters to the WHO Pharmaceuticals Newsletter

In WHO Pharmaceuticals Newsletter No. 2, 2006 we published an article by Professor Marcus Reidenberg with the title 'We should not say 'drug safety' when we mean 'drug toxicity''. Professor Reidenberg wrote that the term 'drug safety' could mislead the average person into assuming that a medicine is safe; when, in fact, drug toxicity or an adverse drug reaction is what is being discussed. Taking his cue from George Orwell's '1984', Professor Reidenberg argued that we must avoid 'newspeak' and must not promote a term which 'appears to be a euphemism for an adverse drug reaction programme'.

Below, we bring you Mr Ray Skinner's comments to the article, followed by Professor Reidenberg's response. ------Dear WHO Pharmaceuticals Newsletter,

I refer to the editorial and the article in the WHO Pharmaceuticals Newsletter No, 2, 2006, a copy of which I recently received at my office.

While I would hesitate to contradict Prof Reidenberg outright – he has raised a very valid question – I wonder if perhaps we are in danger of running counter to a necessary and humane cultural tradition of hopefulness that is almost universal in societies. Speaking of risk in terms of ‘safety’ may not be scientifically as accurate or coldly logical as one might favour, but I don’t think it is fundamentally dishonest or misleading. It certainly seems to me to express a more positive and hopeful viewpoint. To say “this is safe within limits, as far as we can test and tell”, will certainly encourage the recipients of medicines (i.e. the patients) to appropriate confidence in their treatment, while to tell them “This is frankly dangerous – watch out for this, and this”, would undoubtedly produce demonstrable negative effects in care. I’d be surprised if this had not already been verified by research. In the average mind, and with human cultures, languages, and thought conventions being what they are, I should think it very predictable to see a significant drop in public confidence in medicines if we suddenly change our tack from “We are here, in an honest scientific attempt to protect and promote your health and safety” to a more negative “We are here to monitor your drug disasters, and maybe we can help after the event, (or not, as the case may unhappily turn out)”. I agree the latter may be ruggedly honest, and ruthlessly scientific, but I am not sure that it is altogether kind or even very useful.

Scientifically we may not like it, but there it is. Like the good Professor, I too care very little for political doublespeak, but we do have to wrestle with the human element. It is probably true that no vocabulary anywhere is ideologically neutral, anyway. If the common understanding and convention of using positive terms to deal with what appear to be scientifically negative issues is in fact useful for human communication, why do we have to fight it?

Is the universal ideology of hopefulness - that medical things for sale or to be given on prescription are ‘safe’ and of ‘good quality’ - as unreal or as inappropriate as Professor Reidenberg might seem to hold? On his logic, and applying the argument to other relevant areas of life and thought, we would have to refuse to talk of quality management, and instead have only risk management – which is the same thing for all practical purposes. We might as well talk of Ministries of Illness instead of Department of Health. But it wouldn’t help public confidence, and the negative placebo effect on services and health outcomes would be quite awful. Would we have to then talk about medical wounding, instead of ‘surgery’? Because that’s what it is, with all its known risks, but we don’t speak like that to them, either, do we?

For me the key question is a practical one having regard to success in pharmacotherapy, not a merely scientific accuracy in drug regulatory activities. What people really want to know about medicines is normally expressed in positive terminology. I see no real reason to challenge that. Positive language always expresses an unspoken and corresponding negative aspect, does it not? We say good, and we know evil is there. We say right, and we know wrong is there. We say road safety, and we all know quite well that it is risks and hazards that we are talking about, and what we are seeking to minimize. But mostly, I think, people want and need the more positive lead in the presentation. It helps them focus better and move ahead more positively – in hope, rather than having to convince themselves every day to slog it out against the negative correspondent: despair.

Yours kindly,

RAY SKINNER Director, National Pharmacy Division Ministry of Health, Honiara, Solomon Islands ------

WHO Pharmaceuticals Newsletter No. 2, 2007 • 18 LETTERS

Professor Marcus Reidenberg's reply to Mr Ray Skinner:

Mr Skinner makes an important point of not abandoning patients by taking away their hope. I agree with this but think taking away hope is a very different issue from using euphemisms or even words that have different meanings to minimize or hide the idea that medications have adverse effects. As a society, we have acted with great surprise when confronted with a trial of rofecoxib vs placebo showing the NSAID caused some heart attacks (1). The possibility that COX-2 inhibitors could cause heart attacks was predicted based on the drug’s pharmacology (2) and was demonstrated in an early clinical trial (3,4). We are astonished at the possibility of antidepressant medications causing suicidal ideation in adolescents (5) even though we know that the risk of suicide increases during the early phase of effective drug therapy for depression. As a society, we have been led to believe that medicines are safe when, in truth, they are not free from the possibility of doing harm.

In addition, we often express the extent of benefit in a way that exaggerates its magnitude. For example, the antidepressant drugs are described as effective, yet in a representative randomized double- blind placebo-controlled study, 48% of all placebo recipients responded. The response rate of the two drug treatment groups was only 4% and 16% better than that of the placebo-treated patients. Because the patient groups were large enough, the difference between placebo and one of the study drugs was statistically significant. The authors concluded that this drug was “efficacious for the treatment of major depression” (6). Yet, because the better of the two study drugs was only a little bit better than the placebo, it was ineffective in the majority of the patients who needed it. Clearly stating that it is effective without qualification is misleading according to the dictionary definition of “effective”. My point is that there is nothing unusual about this study. It is really representative of how study results are interpreted. This interpretation leads to exaggerated expectations and disappointment when reality sets in. The “significant drop in public confidence in medicine” that Mr Skinner mentioned has already occurred in the United States. The reason is that some medicines previously promoted as safe are not. It is not because of Mr Skinner’s concern that if people would learn the complete truth at the outset, they would lose confidence. It was that people were not told the complete truth at the outset and do not know if they are being told the full truth now. Credibility lost is hard to regain.

What people really need to know about medicines is what they actually do. The words “safe” and “effective” have specific defined meanings. When we knowingly use these words to mean something different when describing a drug’s effects, we are deceiving the listener or reader. I think deception has no place in medicine.

Professor Marcus M. Reidenberg Weill Medical College of Cornell University New York USA

References:

1. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma prevention trial. The New England Journal of Medicine 2005; 352: 1092-1102.

2. Fitzgerald GA, Patrono C. The Coxibs, Selective Inhibitors of Cyclooxygenase-2. The New England Journal of Medicine 2001; 345:433-42.

3. Bombardier C, Laine L, Reicin A., et. al. Comparison of upper gastrointestinal toxicity of Rofecoxib and Naproxen in patients with Rheumatoid Arthritis. The New England Journal of Medicine 2000; 343:1520-8.

4. Mukherjee D, Nissen SE, Topol EJ. Risk of Cardiovascular Events Associated with selective COX-2 Inhibitors. The Journal of the American Medical Association 2001; 286:954-959.

5. Ryan ND. Treatment of depression in children and adolescents. Lancet 2005; 366:933-940.

6. Goldstein DJ, Mallinckrodt C, Lu Y, Demitrack MA. Duloxetine in the treatment of major depressive disorder: a double-blind clinical trial. The Journal of Clinical Psychiatry 2002; 63:225-31.

WHO Pharmaceuticals Newsletter No. 2, 2007 • 19