prepared in collaboration with the WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden

The aim of the Newsletter is to No. 6, 2009 & No. 1, 2010 disseminate information on the safety and efficacy of pharmaceutical products, This is a double edition, that combines volumes based on communications received No. 6, 2009 and No. 1, 2010. Some of the information from our network of "drug might therefore be a bit outdated but we wish to present information officers" and other them anyhow, for those of you who do not have ready sources such as specialized access to this information from other sources. Under bulletins and journals, as well as ‘Feature’ we include an article on the WHO programme partners in WHO. The information for the prequalification of quality control laboratories; is produced in the form of résumés and the recommendations from the thirty-second in English, full texts of which may meeting of representatives participating in the WHO be obtained on request from: Programme for International Drug Monitoring.

Quality Assurance and Safety: We wish you all a very good year in 2010. And thank Medicines, EMP-HSS, you for your interest in the newsletter

World Health Organization, 1211 Geneva 27, Switzerland,

E-mail address: [email protected]

This Newsletter is also available on our Internet website: http://www.who.int/medicines

Further information on adverse reactions may be obtained from the WHO Collaborationg Centre for International Drug Monitoring Box 1051 751 40 Uppsala Tel: +46-18-65.60.60 Fax: +46-18-65.60.80 E-mail: [email protected] Internet: http://www.who-umc.org

Contents Regulatory matters

Safety of medicines Features

© World Health Organization 2010

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Regulatory Matters Benfluorex...... 1 Ceftriaxone...... 1 Clopidogrel ...... 2 Cough and cold medicines ...... 2 Cyproterone acetate ...... 3 Desipramine hydrochloride...... 3 Diclofenac sodium...... 3 Etravirine...... 4 Exenatide...... 4 Fosamprenavir calcium ...... 5 Gadoversetamide...... 6 Iron dextran injection ...... 6 Local anesthetics...... 6 Natalizumab...... 7 Orciprenaline sulphate...... 7 Oseltamivir...... 8 Oseltamivir...... 8 Promethazine injection...... 8 Sibutramine ...... 9 Sitagliptin...... 10 Sleep-aid medicines ...... 10 Statins ...... 11 Valproate ...... 11 Vigabatrin...... 12 Warfarin...... 12

Safety of Medicines

Alendronate ...... 13 Antidepressants...... 13 Bisphosphonates...... 13 Colchicine ...... 14 Deferasirox...... 14 Finasteride...... 15 Gadolinium-containing contrast agents ...... 16 H1N1 pandemic vaccines...... 16 Human insulin and insulin analogues ...... 17 Immune globulin ...... 18 Lamotrigine...... 19 Metoclopramide...... 19 Phenytoin ...... 19

Rituximab...... 20 SSRIs/SNRIs and thiazide diuretics...... 20 Zanamivir...... 21

Feature

Prequalification of Quality Control Laboratories ...... 22 Thirty-second annual meeting of representatives of national centres participating in the WHO Programme for International Drug Monitoring...... 25

REGULATORY MATTERS

Benfluorex Benfluorex vial for intravenous Withdrawal recommended administration because a Reported reactions (number of precipitate can form. Ceftriaxone

events): must not be administered Europe. The European Aortic valve incompetence: 2 simultaneously with calcium- Medicines Agency (EMEA) has Heart valve disorders: 6 containing intravenous solutions, recommended the withdrawal of Mitral insufficiency: 8 including continuous calcium- all medicines containing containing infusions such as benfluorex in the European Reference: parenteral nutrition via a Y-site, Union, because their risks, Press Release, Questions and because precipitation of particularly the risk of heart Answers, EMEA ceftriaxone-calcium can occur. valve disease, are greater than 18 December 2009 their benefits. Benfluorex is (www.emea.europa.eu). The Notice states that there approved for use in overweight have been no reports of patients with diabetes, combined interactions between ceftriaxone with an appropriate diet. Ceftriaxone and oral calcium-containing

products or interactions between This recommendation follows a Incompatibility with intramuscular ceftriaxone and review by the EMEA’s Committee calcium-containing calcium-containing products for Medicinal Products for Human solutions (intravenous or oral). Use (CHMP) on the safety and efficacy of benfluorex. The CHMP Canada (1). Health Canada has Ceftriaxone is a long-acting considered that the data indicate issued a Notice to Hospitals broad spectrum cephalosporin a risk of heart valve diseases regarding updated prescribing antibiotic for parenteral use. It is associated with the use of information for ceftriaxone with indicated for the treatment of benfluorex, and that the efficacy the following new lower respiratory tract infections, of benfluorex in the treatment of recommendations, which are urinary tract infections, bacterial diabetes is limited. Therefore, based on the results of two septicaemia, skin and skin the Committee concluded that recent in vitro studies that structure infections, bone and the benefits of benfluorex no showed an increased risk of joint infections, intra-abdominal longer outweigh its risks, and ceftriaxone-calcium precipitates infections, and meningitis, when recommended the revocation of in neonatal plasma. caused by susceptible organisms. all marketing authorisations for Ceftriaxone is also indicated for medicines containing benfluorex • Contraindications: uncomplicated gonorrhoea and in the European Union. Ceftriaxone is contraindicated in for prophylaxis of patients

neonates if they require (or are undergoing certain surgical The EMEA advises that doctors expected to require) treatment procedures. should stop prescribing with calcium-containing benfluorex and consider intravenous solutions, including UK (2). The Medicines and alternative treatments. For continuous calcium-containing Healthcare products Regulatory patients currently treated with infusions such as parenteral Agency (MHRA) has emphasized benfluorex, the Agency nutrition, because of the risk of that ceftriaxone should not be recommends making an precipitation of ceftriaxone- given simultaneously with appointment with their doctor at calcium. calcium-containing solutions a convenient time, to change (other than total parenteral their prescription. In addition, • Warnings: In patients nutrition solutions) for patients who have taken other than neonates, ceftriaxone intravenous administration benfluorex in the past are and calcium-containing solutions because of a risk of calcium advised to mention this to their may be administered precipitation. Ceftriaxone is doctor so that they can be sequentially if the infusion lines contraindicated in newborns up checked for the signs and are thoroughly flushed between to age 28 days who need symptoms of heart valve disease, infusions with a compatible fluid. intravenous treatment with because heart valve disease can calcium-containing solution develop some years after • Warnings: Diluents including total parenteral treatment. containing calcium, such as nutrition solutions as well as

Ringer's solution or Hartmann's those who have jaundice or who Reports in WHO Global ICSR solution, are not to be used to are hypoalbuminaemic or database, Vigibase reconstitute ceftriaxone vials or acidotic, because these are

to further dilute a reconstituted conditions in which bilirubin

WHO Pharmaceuticals Newsletter No. 6, 2009 & No. 1, 2010 • 1

REGULATORY MATTERS binding is likely to be impaired. professionals and the public drug interactions between Health-care professionals are about an interaction between clopidogrel and PPIs other than also advised that calcium and clopidogrel (Plavix), an anti- omeprazole and esomeprazole to ceftriaxone may be infused clotting medicine, and make specific recommendations sequentially in patients aged 28 omeprazole (Prilosec and about their co-administration. days or older provided that Prilosec OTC), a proton pump Health-care professionals and either a) the infusion line is inhibitor (PPI). New data show patients are advised to consider rinsed or flushed between that when clopidogrel and all treatment options carefully solutions, or b) the infusions are omeprazole are taken together, before beginning therapy. given via different infusion lines the effectiveness of clopidogrel is at different sites. reduced. Separating the Health-care professionals are administration of clopidogrel and also advised that there is no The MHRA explains that a review omeprazole in time will not evidence that other drugs that of the available data suggests reduce this drug interaction. reduce stomach acid, such as that newborns (up to age 28 most H2 blockers ranitidine, days) are at greater risk of The US FDA explains that famotidine, nizatidine, except calcium–ceftriaxone precipitation omeprazole inhibits the drug cimetidine (a CYP2C19 inhibitor) than older patients, particularly metabolizing enzyme (CYP2C19) or antacids interfere with the if they are premature or have which is responsible for the anti-clotting activity of impaired bilirubin binding. The conversion of clopidogrel into its clopidogrel. The clopidogrel label risk of calcium–ceftriaxone active metabolite. The new has been updated with new precipitation in adults is likely to studies compared the amount of warnings on omeprazole and be low; however, as a clopidogrel's active metabolite in other medicines that inhibit the precaution, ceftriaxone and the blood and its effect on CYP2C19 enzyme that could calcium should not be platelets (anti-clotting effect) in interact with clopidogrel in the administered simultaneously by people who took clopidogrel plus same way. the intravenous route. The omeprazole versus those who Agency also warns that some took clopidogrel alone. A (See WHO Pharmaceuticals total parenteral nutrition reduction in active metabolite Newsletters No. 2, 3, 4 and 5, solutions contain similar levels of levels of about 45% was found 2009 for previous information calcium to that in saline in people who received from USA, Canada and New solutions such as Ringer’s or clopidogrel with omeprazole Zealand, Europe, and Ireland Hartmann’s, and may present a compared to those taking respectively). similar degree of risk. clopidogrel alone. The effect of clopidogrel on platelets was Reference: (See WHO Pharmaceuticals reduced by as much as 47% in Safety Information, US FDA, Newsletters No. 3, 2009 and people receiving clopidogrel and 17 November 2009 No. 4, 2008 for related omeprazole together. These (www.fda.gov). information in USA and Canada reductions were seen whether respectively). the drugs were given at the same time or 12 hours apart. Cough and cold References: medicines (1) Advisories, Warnings and With regard to other medicines Recalls, Health Canada, that are expected to have a Contraindication 15 October 2009 similar effect, the US FDA recommended (www.hc-sc.gc.ca). recommends avoiding the (2) Drug Safety Update, MHRA, concomitant use of the following New Zealand. New Zealand Volume 3, Issue 3, October 2009 medicines and clopidogrel: Medicines and Medical Devices (www.mhra.gov.uk). cimetidine, fluconazole, Safety Authority (Medsafe) has ketoconazole, voriconazole, announced that the Cough and etravirine, felbamate, fluoxetine, Cold Review Group (CCRG) Clopidogrel fluvoxamine, and ticlopidine. In concluded the risk-benefit addition, esomeprazole, which is balance of cough and cold Drug interaction with a component of omeprazole, medicines to be unfavourable in omeprazole inhibits CYP2C19 and should be children under six years of age. avoided in combination with The CCRG has therefore USA. The United States Food clopidogrel. The Agency states recommended that cough and and Drug Administration (US that at this time, it does not cold medicines containing the FDA) has warned health-care have sufficient information about following substances be

WHO Pharmaceuticals Newsletter No. 6, 2009 & No. 1, 2010 • 2

REGULATORY MATTERS contraindicated for use in High-dose cyproterone acetate is Update to prescribing children under six years of age; indicated for use in the information brompheniramine, treatment of prostate cancer chlorphenamine, (dose 50–300 mg per day) and USA. Health-care professionals dextromethorphan, for the control of libido in men were notified of changes to the diphenhydramine, doxylamine, with severe hypersexuality or Warnings and Overdosage guaifenesin, ipecacuanha, sexual deviation. Lower-dose sections of the prescribing phenylephrine, pholcodine, cyproterone acetate (2 mg) is information for desipramine promethazine, pseudoephedrine, available for use in women as hydrochloride (Norpramin). The and triprolidine. The CCRG co-cyprindiol (Dianette) in medicine is indicated for the considered that cough and cold combination with 35 micrograms treatment of depression. The medicines containing ethinylestradiol for the treatment new safety information warn that bromhexine alone, or intra-nasal of severe acne that is refractory extreme caution should be used decongestants (such as to prolonged antibiotic therapy, when this medicine is given to oxymetazoline and and for moderately severe patients who have a family xylometazoline) should remain hirsutism. history of sudden death, cardiac available to adults and children dysrhythmias or cardiac over two years of age. Medsafe The MHRA says that conduction disturbances; and states that it will work closely meningiomas are the most that seizures precede cardiac with the pharmaceutical industry common intracranial tumours, dysrhythmias and death in some to implement the with an annual incidence of 6 per patients. recommendations as soon as 100 000 in the general possible. population. Multiple Reference: meningiomas account for Safety Information, US FDA (See WHO Pharmaceuticals approximately 1 to 10% of all 2 December 2009 Newsletters No. 2 and 3, 2009 cases. Though histologically (www.fda.gov). for new advice on the use of benign, they can have serious cough and cold medicines in consequences. The occurrence of children in Kenya and the UK, (multiple) meningiomas has Diclofenac sodium Canada and New Zealand, been reported in association with respectively). longer-term use (years) of Revisions to the cyproterone acetate at doses of prescribing information to Reference: 25 mg/day or higher. According warn of hepatic reactions Prescriber Update Vol. 30, No.4, to the Agency, until September November 2009 2009, 36 cases of meningioma, USA. Health-care professionals (www.medsafe.govt.nz). of which 19 described multiple were notified of revisions to the meningioma, have been reported prescribing information to add worldwide in association with new warnings and precautions Cyproterone acetate high-dose cyproterone acetate. about the potential for adverse Of the 36 cases, 32 occurred in Risk of meningiomas liver effects with all products women and four in men. containing diclofenac sodium. Duration of treatment with UK. The MHRA has advised cyproterone acetate ranged from According to Dear Healthcare health-care professionals that 4 years to 27 years, and in all Professional Letter for diclofenac patients with existing but one case it was prescribed at sodium topical gel (Voltaren® meningioma or a history of doses higher than 25 mg per Gel) 1% (non-steroidal anti- meningioma must not be day. None of the reported cases inflammatory medicine), in post- prescribed cyproterone acetate had a fatal outcome. marketing reports, cases of at doses of 25 mg per day or drug-induced hepatotoxicity higher (Cyprostat-50, Cyprostat- Reference: have been reported in the first 100, or Androcur-50). The Drug Safety Update, MHRA, month but can occur at any time Agency states that this advice Volume 3, Issue 3, October 2009 during treatment with diclofenac. does not apply to medicines that (www.mhra.gov.uk). Post-marketing surveillance has contain low-dose cyproterone reported cases of severe hepatic acetate such as co-cyprindiol reactions, including liver (Dianette). Product information Desipramine necrosis, jaundice, fulminant for all products that contain hydrochloride hepatitis with and without high-dose cyproterone acetate jaundice, and liver failure. Some will be updated accordingly. of these reported cases resulted

WHO Pharmaceuticals Newsletter No. 6, 2009 & No. 1, 2010 • 3

REGULATORY MATTERS in fatalities or liver (www.fda.gov). due to rash. Rash occurred most transplantation. commonly during the first six weeks of therapy. The most Physicians are advised to Etravirine frequently reported adverse drug measure transaminases reaction (ADR) of at least Grade Risk of severe skin and periodically in patients receiving 2 in severity in the Phase 3 long-term therapy with hypersensitivity reactions studies was rash (9.0%). diclofenac, because severe Stevens-Johnson syndrome, hepatotoxicity may develop Canada. Health-care severe hypersensitivity reaction, without a prodrome of professionals have been and erythema multiforme were distinguishing symptoms. It is informed that severe, potentially reported in < 0.1% of subjects also stated that transaminases life-threatening, and fatal skin during clinical development with should be monitored within 4 to reactions have been reported in etravirine (INTELENCE). In 8 weeks after initiating patients receiving combination general, rash was mild to treatment with diclofenac; therapy that included etravirine moderate, occurred primarily in however, severe hepatic (INTELENCE) tablets. These the second week of therapy and reactions can occur at any time include cases of Stevens- was infrequent after Week 4. during treatment with diclofenac. Johnson syndrome, toxic Rash generally resolved within epidermal necrolysis and one to two weeks on continued Reports in WHO Global ICSR erythema multiforme. therapy. database, Vigibase: Hypersensitivity reactions have also been reported and were (See WHO Pharmaceuticals Diclofenac sodium characterized by rash, Newsletter No. 5, 2009 for constitutional findings, and revisions to the prescribing Number of reports with liver and sometimes organ dysfunction, information for etravirine in USA biliary system disorders: 1855 including hepatic failure. The and the number of reports in the advise emphasizes the WHO Global Individual Case Most reported reactions (number importance of immediate Safety Reports (ICSR) database, of events): discontinuation of etravirine Vigibase). Hepatic enzymes increased: 159 (INTELENCE) in cases where SGOT increased: 269 signs or symptoms of severe Reference: SGPT increased: 280 skin reactions or hypersensitivity Advisories, Warnings and Gamma-GT increased: 133 reactions develop, including Recalls, Health Canada Hepatic function abnormal: 580 severe rash or rash accompanied 15 October 2009 Hepatitis: 507 by fever, general malaise, (www.hc-sc.gc.ca). Hepatitis cholestatic: 167 fatigue, muscle or joint aches, Bilirubinaemia: 214 blisters, oral lesions, Jaundice: 279 conjunctivitis, facial edema, Exenatide hepatitis, eosinophilia. Health- Reports of renal failure Diclofenac care professionals are also

advised that clinical status USA. The US FDA has notified Number of reports with liver and including liver transaminases health-care professionals of biliary system disorders: 2235 should be monitored and revisions to the prescribing appropriate therapy should be information for exenatide Most reported reactions (number initiated. This safety information (Byetta) to include information of events): will be incorporated in the on post-marketing reports of Hepatic enzymes increased: 227 Canadian Product Monograph. altered kidney function, including SGOT increased: 302 acute renal failure and SGPT increased: 313 According to the letter sent to insufficiency. Exenatide (Byetta) Gamma-GT increased: 160 health-care professionals, in is an incretin-mimetic that is Hepatic function abnormal: 677 Phase 3 clinical trials, Grade 3 approved as an adjunct to diet Hepatitis: 601 and 4 rashes were reported in and exercise to improve Hepatitis cholestatic: 193 1.3% of subjects receiving glycemic control in adults with Bilirubinaemia: 236 etravirine (INTELENCE) type 2 diabetes mellitus. Jaundice: 350 compared to 0.2% of placebo

subjects. A total of 2% of HIV-1- According to the US FDA, from Reference: infected patients receiving April 2005 through October Safety Information, US FDA etravirine (INTELENCE) 2008, the Agency received 78 4 December 2009 discontinued from Phase 3 trials

WHO Pharmaceuticals Newsletter No. 6, 2009 & No. 1, 2010 • 4

REGULATORY MATTERS cases of altered kidney function Most reported reactions (number be checked prior to with 62 cases of acute renal of events): initiating therapy with failure and 16 cases of renal Face oedema: 72 LEXIVA Tablets and Oral insufficiency, in patients using Renal calculus: 65 Suspension and at exenatide (Byetta). Some cases Micturition frequency: 96 periodic intervals during occurred in patients with pre- Azotaemia: 76 therapy. Appropriate existing kidney disease or in Renal failure acute: 65 clinical management of patients with one or more risk Renal failure chronic: 68 lipid disorders should be factors for developing kidney Renal function abnormal: 76 initiated as required. problems. Cystitis: 75 • Other modifiable risk Labeling changes include: Reference: factors for cardiovascular Safety Information, US FDA disease (such as • information regarding 2 November 2009 hypertension, diabetes post-market reports of acute (www.fda.gov). and smoking) should be renal failure and insufficiency, monitored in HIV- highlighting that exenatide Fosamprenavir infected subjects and (Byetta) should not be used in managed as clinically patients with severe renal calcium appropriate. impairment (creatinine clearance <30 ml/min) or end-stage renal Potential association with Reports in WHO Global ICSR disease; myocardial infarction and database, Vigibase: dyslipidemia • recommendations to Fosamprenavir calcium health-care professionals that USA. Health-care professionals caution should be applied when Number of reports with were notified of a potential initiating or increasing doses of metabolic and nutritional association between exenatide (Byetta) from 5 mcg disorders as well as myocardial fosamprenavir calcium (Lexiva) to 10 mcg in patients with endocardial pericardial and valve and myocardial infarction and moderate renal impairment disorders: 55 dyslipidemia in HIV infected (creatinine clearance 30 to 50 adults. The product is indicated ml/min); Most reported reactions (number in combination with other of events): antiretroviral agents for the • recommendations that Lipodystrophy: 9 treatment of HIV infection. The health-care professionals Weight decrease: 5 prescribing information for monitor patients carefully for the Acidosis lactic: 7 fosamprenavir calcium (LEXIVA) development of kidney Diabetes mellitus: 4 was revised to add myocardial dysfunction, and evaluate the Hyperglycaemia: 9 infarction and continued need for exenatide Hypokalaemia:5 hypercholesterolemia and to (Byetta) if kidney dysfunction is Hypercholesterolaemia:4 highlight that increases in suspected while using the Hypertriglyceridaemial:4 cholesterol have occurred with product; treatment. The Dear Healthcare Fosamprenavir Professional letter recommends • information about kidney the following actions: dysfunction in the Medication Number of reports with

Guide to help patients metabolic and nutritional • Combination understand the benefits and disorders as well as myocardial antiretroviral therapy potential risks associated with endocardial pericardial and valve has been associated with exenatide (Byetta). disorders: 75 redistribution of body fat

(lipodystrophy) in HIV- Reports in WHO Global ICSR Most reported reactions (number infected patients. Clinical database, Vigibase: of events): examination should Cachexia: 4 include evaluation for Exenatide Lipodystrophy: 11 physical signs of fat Phosphatase alkaline redistribution. Number of reports with urinary increased: 5 system disorders: 907 Weight decrease: 7 • Triglyceride and Weight increase: 4 cholesterol levels should Acidosis lactic: 10

WHO Pharmaceuticals Newsletter No. 6, 2009 & No. 1, 2010 • 5

REGULATORY MATTERS

Diabetes mellitus: 5 5 134 252 vials of the medicinal Hyperglycaemia: 9 product were distributed Iron dextran Hypokalaemia:7 worldwide from 1 August 2006 Hypercholesterolaemia:4 to 31 October 2009. Number of events: Hypertriglyceridaemial:4 Anaphylactic reaction: 58 Reference: Anaphylactic shock: 139 Reference: Advisories, Warnings and Anaphylactoid reaction: 183 Safety Information, US FDA Recalls, Health Canada 3 December 2009 12 January 2010 Reference: (www.fda.gov). (www.hc-sc.gc.ca). Safety Information, US FDA 16 October 2009 (www.fda.gov). Gadoversetamide Iron dextran injection Risk of nephrogenic Change in Boxed Warning Local anesthetics systemic fibrosis in patients with renal USA. The US FDA and American Reports of chondrolysis impairment Regent have notified health-care professionals that anaphylactic- USA. The US FDA has notified type reactions, including Canada. Health-care health-care professionals of 35 fatalities, have followed the professionals have been advised reports of chondrolysis (necrosis parenteral administration of iron of product labeling changes of and destruction of cartilage) in dextran injection. The Boxed gadoversetamide (Optimark®) patients given continuous intra- Warning has been modified to due to the risk of nephrogenic articular infusions of local include the following new systemic fibrosis (NSF) in anesthetics (marketed as information: patients with renal impairment. bupivacaine, chlorprocaine,

Gadoversetamide (Optimark®) is lidocaine, mepivacaine, procaine, • to administer a test dose a gadolinium (Gd)-based ropivacaine) with elastomeric prior to the first therapeutic dose contrast agent (GBCA) that is infusion devices to control post- used to enhance the contrast of surgical pain. • to observe for signs or magnetic resonance images. symptoms of anaphylactic-type According to the Agency, the reactions during administration According to the advisory issued local anesthetics (with and of iron dextran injection by the company, without epinephrine) were (Dexferrum) Gadoversetamide (Optimark®) infused for extended periods of will be contraindicated in time (48 to 72 hours) directly • to make clear that fatal patients with 1) acute or chronic into the intra-articular space reactions have occurred severe renal insufficiency using an elastomeric pump. following the test dose and have (glomerular filtration rate <30 Chondrolysis was diagnosed also occurred when the test dose mL/min/1.73m2), or 2) acute within a median of 8.5 months was tolerated. renal insufficiency of any after the infusion. Almost all of severity due to the hepato-renal the reported cases of • to note that patients syndrome or in the perioperative chondrolysis (97%) occurred with a history of drug allergy or liver transplantation period. following shoulder surgeries. multiple drug allergies may be at Gadoversetamide (Optimark®) is Joint pain, stiffness, and loss of increased risk of anaphylactic- not recommended for use in motion were reported as early as type reactions children below the age of two the second month after receiving years because the safety and the infusion. In more than half of It is recommended that efficacy of gadoversetamide, as these reports, the patients resuscitation equipment and well as impact of use in patients required additional surgery, personnel trained in the with an immature kidney including arthroscopy or detection and treatment of function have not been studied. arthroplasty. It is not known anaphylactic-type reactions be which specific factor or readily available during iron From 15 August 2006 to combination of factors dextran injection (Dexferrum) 15 October 2009, a total of 93 contributed to the development administration. reports of NSF have been of chondrolysis in these cases. reported worldwide associated The Agency says that single Reports in WHO Global ICSR with the use of gadoversetamide intra-articular injections of local database, Vigibase: (Optimark®). It is estimated that anesthetics in orthopedic

WHO Pharmaceuticals Newsletter No. 6, 2009 & No. 1, 2010 • 6

REGULATORY MATTERS procedures have been used for disease is severe and inflammatory syndrome many years without any progressing rapidly. (IRIS), particularly if reported occurrence of they have plasma chondrolysis. The CHMP concluded that the exchange or risk of developing PML appears immunoadsorption. The US FDA emphasizes that to increase when a patient has Intensive care facilities local anesthetics are approved as been receiving natalizumab should be available in injections for the production of (Tysabri) for two years or more. case patients develop local or regional anesthesia or However, the benefits of the severe IRIS. analgesia, and that the approved medicine continue to outweigh drug labels for local anesthetics its risks for patients with highly The CHMP also confirmed the do not include an indication for active relapsing-remitting existing recommendations that continuous intra-articular post- multiple sclerosis, for whom patients, and their carers, operative infusions or use of there are few treatment options partners and families be made infusion devices, such as available. Therefore, the aware of the symptoms of PML. elastomeric pumps. Health-care Committee recommended that professionals are advised not to its marketing authorisation be The EMEA advises prescribers to use elastomeric infusion devices maintained. closely monitor patients before, or any other infusion devices for The following measures have during and after treatment with continuous intra-articular been recommended to make natalizumab (Tysabri) including infusion of local anesthetics after sure that patients and doctors regular magnetic resonance orthopedic surgery. are fully aware of the risk of imaging (MRI) scans, to discuss Based on the reported cases of PML. the risks of PML with their chondrolysis above, the US FDA • The prescribing patients before treatment, and is requiring the manufacturers of information for to consider whether treatment local anesthetics and of pumps natalizumab (Tysabri) should continue beyond two that may be used to infuse local should be updated to years. anesthetics to revise their reflect the fact that the product labels to warn health- risk of PML increases (See WHO Pharmaceuticals care professionals about this after two years of Newsletters No. 5, 2009 and risk. treatment. No. 4, 2006 for reports of PML • Patients should be fully and the risk management Reference: informed about the risk programme for natalizumab in Safety Information, US FDA of PML both by their the USA). 13 November 2009 doctor and in an updated (www.fda.gov). ‘patient alert card’. Reference: • Patients should discuss Press Release, Questions and Natalizumab the risks of natalizumab answers, EMEA, 21 January 2010 (Tysabri) with their (www.emea.europa.eu). Additional measures to doctor both when better manage risk of treatment starts and Orciprenaline progressive multifocal again after two years. sulphate leukoencephalopathy Forms should be available for patients to Planned withdrawal Europe. The EMEA sign at both time points following a risk-benefit recommended introducing new to show that they have analysis measures to minimize the risk of been informed of the progressive multifocal risks associated with the UK. The MHRA has announced leukoencephalopathy (PML) medicine. Completed that orciprenaline sulphate will associated with natalizumab forms will be stored in be withdrawn from the market (Tysabri), following a review by the patients’ medical over the next year because a the CHMP on the benefits and notes. review recently conducted by the risks of natalizumab (Tysabri). • Patients who develop Agency has concluded that the The medicine is used to treat signs of PML should have balance of its benefits and risks relapsing-remitting multiple their treatment stopped is no longer favourable. sclerosis in patients with high promptly. These patients Orciprenaline sulphate (Alupent disease activity who have failed should be closely Syrup) is a non-specific β- to respond to treatment with a monitored for signs of agonist indicated for reversible beta-interferon, or whose immune reconstitution

WHO Pharmaceuticals Newsletter No. 6, 2009 & No. 1, 2010 • 7

REGULATORY MATTERS airways obstruction and in treatment and prophylaxis of suggested for maintenance influenza in pediatric patients USA. The US FDA issued a Public therapy. one year of age and older. The Health Alert to notify prescribers US FDA notified health-care and pharmacists about potential The MHRA explains that an providers that there are limited dosing errors with oseltamivir analysis of the available data on safety and dosing when (Tamiflu for Oral Suspension). In literature demonstrated that considering use of oseltamivir the USA, health-care providers orciprenaline sulphate is (Tamiflu) in seriously ill, young usually write prescriptions for significantly less efficacious than infants with confirmed 2009 liquid medicines in milliliters salbutamol in terms of both the H1N1 influenza, or in one that (mL) or teaspoons, while extent and duration of has been exposed to a confirmed oseltamivir (Tamiflu) is dosed in bronchodilation. Yellow Card 2009 H1N1 influenza case. milligrams (mg). The dosing reports and clinical trial data Infants should be carefully dispenser packaged with show a significantly increased monitored for adverse events oseltamivir (Tamiflu) has incidence of cardiac side effects, when oseltamivir (Tamiflu) is markings only in 30, 45 and 60 mainly palpitations and used. The Agency also warns mg. The Agency has received tachycardia because of its non- that oseltamivir (Tamiflu) should reports of errors where dosing selectivity. In addition, clinical not be routinely used for instructions for the patient do trial data show that cardiac side prophylaxis in infants less than not match the dosing dispenser. effects occur before maximum three months of age due to bronchodilation is achieved extremely limited The US FDA has alerted that because of its non-selectivity. pharmacokinetic data to guide health-care providers should The Commission on Human dosing in this age group. write doses in mg if the dosing Medicines (CHM) has concluded Prophylaxis with oseltamivir dispenser with the medicine is in that: (Tamiflu) in infants less than mg, and that pharmacists should • there should be a planned three months of age should be ensure that the units of measure withdrawal of orciprenaline reserved for cases in which the on the prescription instructions sulphate from the UK market; exposure is significant and the match the dosing device • there are no patient groups for risk of severe illness is provided with the medicine. If whom transfer to a more- considered high. prescription instructions specify selective β2-agonist would be administration using mL, the inappropriate. The Agency advises health-care dosing device accompanying the providers that the oral dosing product should be replaced with Health-care professionals are dispenser included in the product a measuring device (e.g., a advised that patients who package should always be syringe) calibrated in mL. The require a liquid oral formulation removed and replaced with an Agency also recommends that of a β-agonist should be appropriate measuring device, prescribers should avoid switched to a more-selective when dispensing oseltamivir prescribing oseltamivir (Tamiflu) short-acting β2-agonist such as (Tamiflu oral suspension) for oral suspension in teaspoons. salbutamol or terbutaline. infants younger than one year of This can lead to inaccurate age. The pharmacist or other dosing. If a prescription is Reference: health-care provider should written in teaspoons, the Drug Safety Update, MHRA, provide a 3 ml or 5 ml oral pharmacist should convert the Volume 3, Issue 4, syringe to correctly measure the volume to mL and ensure that November 2009 dose and counsel the caregiver an appropriate measuring (www.mhra.gov.uk). on how to administer the device, such as an oral syringe prescribed dose. calibrated in mL, is provided. Oseltamivir Reference: References: Emergency use in infants Safety Information, US FDA Safety Information, US FDA less than one year of age 25 September 2009 24 September 2009 (www.fda.gov). (www.fda.gov). USA. The US FDA has authorized the emergency use of oseltamivir (Tamiflu) in infants Oseltamivir Promethazine less than one year of age in Potential medication injection certain cases. The oseltamivir errors with product for product (Tamiflu for Oral Reports of serious tissue Oral Suspension Suspension) is approved for use injuries

WHO Pharmaceuticals Newsletter No. 6, 2009 & No. 1, 2010 • 8

REGULATORY MATTERS

information for promethazine sibutramine. The use of New Zealand. Medsafe has hydrochloride in USA). sibutramine was not in recommended that intravenous accordance with the prescribing promethazine should only be Reference: information for most of the used if the benefits clearly Prescriber Update Vol. 30, No.4, patients in the SCOUT study, as outweigh the risks in each November 2009 the medicine is contra-indicated patient. Medsafe warns that (www.medsafe.govt.nz) in patients with cardiovascular promethazine injection is highly disease. However, the caustic to the intima of blood Committee considered that an vessels and surrounding tissues. Sibutramine increased risk can also apply to Promethazine injection is patients for whom sibutramine Suspension of marketing approved for the treatment of can be prescribed because obese vomiting, allergic reactions authorizations and overweight patients are (including anaphylaxis) and to recommended in the likely to be at risk of induce sedation. European Union cardiovascular disease. The CHMP also noted that the data Medsafe provides the following Europe (1). The EMEA has from available studies show that advice. announced that the CHMP the weight loss achieved with concluded that the risks of sibutramine treatment is 1. Deep intramuscular injection sibutramine-containing modest, and that it is not clear if is the preferred route of medicines are greater than their the effect on weight loss can be administration of promethazine benefits and recommended the maintained when sibutramine injection. suspension of marketing treatment is stopped. Therefore, 2. Promethazine must not be authorizations for these the CHMP concluded that the administered subcutaneously or medicines throughout the benefits of sibutramine as a intra-arterially. European Union. Sibutramine is weight-loss aid do not outweigh 3. An alternative medicine a serotonin-noradrenaline re- the cardiovascular risks. should be considered if uptake inhibitor (SNRI). intravenous administration is Sibutramine-containing The EMEA advises that doctors required. medicines are used in the should stop prescribing 4. Promethazine should be management of obesity, in sibutramine-containing administered through large conjunction with diet and medicines and that pharmacist patent veins. Veins in the hand exercise, in obese patients with should no longer dispense and wrist should be avoided if a body mass index (BMI) ≥ 30 sibutramine-containing possible. kg/m2, and in overweight medicines. Patients currently 5. If intravenous administration patients with a BMI ≥ 27 kg/m2 taking sibutramine are is required, the maximum who also have other risk factors, recommended to make an recommended concentration is such as type 2 diabetes or appointment with their doctor to 25mg/mL and the maximum dyslipidaemia. discuss alternative measures to recommended rate of lose weight. administration is 25mg/minute. The review was conducted on Further dilution and data from the Sibutramine USA (2). The US FDA has administration over 10 to 15 Cardiovascular Outcome Trial notified health-care professionals minutes may reduce the risks (SCOUT) as well as other studies and patients that the review of even further. on the effectiveness of preliminary data from the 6. The injection should be sibutramine for weight loss. The SCOUT study suggests that stopped immediately if pain or a SCOUT study was designed to patients using sibutramine burning sensation occurs. determine the impact of weight (Meridia) experienced a higher 7. Patients should be advised to loss with sibutramine on number of cardiovascular events seek medical assistance if pain, cardiovascular problems in a (heart attack, stroke, a burning sensation, swelling or large group of overweight and resuscitated cardiac arrest, or blistering occurs at any time obese patients at high risk for death) than patients using a after the administration of cardiovascular disease. The placebo (sugar pill). In addition, intravenous promethazine. CHMP noted that the SCOUT the review of additional data study showed an increased risk indicates the increased risk for (See WHO Pharmaceuticals of serious cardiovascular events cardiovascular events with Newsletter No. 5, 2009 for (such as heart attack or stroke) sibutramine occurred only in revision to the prescribing in patients with known patients with a history of cardiovascular disease taking cardiovascular disease.

WHO Pharmaceuticals Newsletter No. 6, 2009 & No. 1, 2010 • 9

REGULATORY MATTERS

general, and heart rate and patients carefully for the Based on those findings, rhythm disorders: 1515 development of pancreatitis after sibutramine will be initiation or dose increases of contraindicated for use in Most reported reactions (number sitagliptin or patients with a history of of events): sitagliptin/metformin, and cardiovascular disease, Arrhythmia: 47 discontinue sitagliptin or including: Cardiac arrest: 33 sitagliptin/metformin if • history of coronary Cardiac failure: 28 pancreatitis is suspected. It is artery disease (e.g., heart Fibrillation atrial: 63 noted that sitagliptin has not attack, angina) Heart disorder: 25 been studied in patients with a • history of stroke or Hypertension: 641 history of pancreatitis. transient ischaemic attack Hypertension pulmonary: 21 Therefore, it is not known • history of heart Hypotension: 94 whether these patients are at an arrhythmias Palpitation: 388 increased risk for developing • history of congestive Tachycardia: 337 pancreatitis and these medicines heart failure Tachycardia supraventricular: 32 should be used with caution and • history of peripheral with appropriate monitoring in arterial disease References: patients with a history of • uncontrolled (1) Press Release, Questions and pancreatitis. hypertension (e.g., > 145/90 answers, EMEA, 21 January 2010 mmHg). (www.emea.europa.eu). Reference: (2) Safety Information, US FDA, Safety Information, US FDA Patients currently using 20 November 2009, 25 September 2009 sibutramine are advised to talk 21 January 2010 (www.fda.gov). with their health-care (www.fda.gov). professional to determine if continued use of sibutramine is Sleep-aid medicines appropriate. Health-care Sitagliptin Risk of complex sleep- professionals are advised to Revisions to prescribing regularly monitor the blood related behaviours pressure and heart rate of information to include patients using sibutramine. If acute pancreatitis Canada. Health Canada has sustained increases in blood informed consumers and health- pressure and/or heart rate are USA. The US FDA notified care professionals of changes to observed, sibutramine should be health-care professionals and the labelling information of sleep discontinued. The Agency also patients of revisions to the aid medicines (sedative-hypnotic says that sibutramine should be prescribing information for medications). Sleep aid discontinued in patients who do sitagliptin (Januvia) and medicines are used for short- not lose at least 5% of their sitagliptin/metformin (Janumet) term treatment of insomnia baseline body weight within the to include information on characterized by difficulty in first three to six months of reported cases of acute falling asleep, or waking up often treatment, as continued pancreatitis in patients using during the night or in the early treatment is unlikely to be these products. Sitagliptin morning hours. The new effective and exposes the patient (dipeptidyl peptidase-4 (DPP-4) labelling describes reports of to unnecessary risk. inhibitor) is approved as an complex sleep-related adjunct to diet and exercise to behaviours that have occurred (Saudi Arabia has informed WHO improve glycemic control in while patients were not fully that the marketing adults with type 2 diabetes awake, such as talking, walking, authorizations for sibutramine mellitus. The Agency says that cooking, eating, and driving. (Reductil, Sibutral) have been 88 post-marketing cases of Patients typically did not cancelled in the country.) acute pancreatitis, including two remember these events cases of hemorrhagic or afterwards. Reports in WHO Global ICSR necrotizing pancreatitis in database, Vigibase: patients using sitagliptin, were The new labelling also reported between October 2006 emphasizes the proper use of Sibutramine and February 2009. these medicines. In particular, sleep aid medications should not Number of reports with It is recommended that health- be taken with alcohol, and cardiovascular disorders, care professionals monitor patients should not take more

WHO Pharmaceuticals Newsletter No. 6, 2009 & No. 1, 2010 • 10

REGULATORY MATTERS than the prescribed dose. fluvastatin, and rosuvastatin) epilepsy taking valproate Caution should be used when will be updated with warnings on (monotherapy) is almost 4 times taking sleep aid medications at adverse reactions. This follows a higher than the rate of major the same time as other drugs Europe-wide review of clinical malformations in babies born to that can cause drowsiness, such trial data, adverse drug reaction women with epilepsy taking a as other tranquilizers or sleeping reports and published literature different antiepileptic drug. The pills, antihistamines that cause on statins. The MHRA states NAAED Registry reported a drowsiness, anticonvulsants, that the balance of risks and major malformation rate of painkillers that contain narcotics, benefits of statins as a class 10.7% (95% CI 6.3% to 16.9%) and medicines used to treat remains positive. However, the in the offspring of women depression or anxiety. review concluded that there is exposed to an average of 1000 sufficient evidence to support a mg/day of valproic acid The sleep-aid medicines with possible causal relationship monotherapy during pregnancy potential risk of complex sleep- between statin use and the (dose range 500 to 2000 related behaviours include following adverse reactions: mg/day). The major flurazepam, nitrazepam, sleep disturbances, memory malformation rate among the temazepam, triazolam, loss, sexual dysfunction, internal comparison group of zopiclone, zolpidem, and depression and interstitial lung 1048 women with epilepsy who zaleplon. disease. received any other antiepileptic drug monotherapy during Health Canada advises that Reference: pregnancy was 2.9% (95% CI discontinuing sleep aid Drug Safety Update, MHRA, 2.0% to 4.1%). There were 16 medication should be considered Volume 3, Issue 4 major malformations in the for patients who report complex November 2009 offspring of 149 women who sleep-related behaviours, due to (www.mhra.gov.uk). used valproate during the risk of harm to the patient pregnancy, and these and to others. These medications malformations included neural should only be discontinued by Valproate tube defects, craniofacial an individual after consulting defects, cardiovascular Increased risk of neural with their health care malformations and professional, as abrupt tube defects and other malformations involving other discontinuation may cause major malformations body systems. symptoms of withdrawal. USA. The US FDA notified Health-care practitioners are (See WHO Pharmaceuticals health-care professionals and advised to inform women of Newsletter No. 2, 2008 an patients about the increased risk childbearing potential about No. 5, 2007 for warning about of neural tube defects and other these risks, and to consider sleep disorders with zolpidem in major birth defects, such as alternative therapies, especially Australia and Sigapore). craniofacial defects and if valproate is used to treat cardiovascular malformations, in migraines or other conditions not Reference: babies exposed to valproate usually considered life- Advisories, Warnings and sodium and related products threatening. The US FDA also Recalls, Health Canada (valproic acid and divalproex states that health-care 7 October 2009 sodium) during pregnancy. professionals should inform (www.hc-sc.gc.ca). patients that taking folic acid According to the Agency, the before and during the first rates for neural tube defects in trimester of pregnancy can Statins babies exposed to valproate decrease the risk for congenital during the first trimester (1 in 20 neural tube defects. Patients are Updates to product safety babies) are 30 to 80 times advised that women of information higher than the rate for neural childbearing potential should tube defects in the general only use valproate if it is UK. The MHRA has announced population in the United States essential to manage their that Summaries of Product (about 1 in 1500 babies). Data medical condition. Characteristics and Patient from the North American Information Leaflets for all Antiepileptic Drug (NAAED) The US FDA has required a statins (HMG-CoA reductase Pregnancy Registry show that patient Medication Guide for inhibitors: simvastatin, the rate of major malformations each antiepileptic drug, including atorvastatin, pravastatin, in babies born to women with valproate. The Agency says that

WHO Pharmaceuticals Newsletter No. 6, 2009 & No. 1, 2010 • 11

REGULATORY MATTERS the valproate Medication Guide particular in young infants The details are available in a will explain the benefits and risks treated with high doses (≥125 public assessment report on of valproate and encourage mg/kg/day). These MRI MHRA website. patients to discuss options with abnormalities were transient and their health-care professional. seemed to be dose dependent, (See WHO Pharmaceuticals and in most patients resolved Newsletters No.5, 2009, No.6, (See WHO Pharmaceuticals even if treatment with vigabatrin 2007, No.1, 2006, No.5, 2004 Newsletter No. 7, 1993 for continued. The review concluded and No1. 2004 for information advice on association of sodium that it is not possible to correlate from New Zealand, Sweden, valproate and carbamazepine the MRI findings with the Canada, Australia, and UK on with neural tube defects in the movement disorders based on potential interactions with UK). the current data. warfarin as well as No.4, 2007 for labeling update in the USA.) Reference: The MHRA says that movement Safety Information, US FDA disorders and brain MRI Reference: 3 December 2009 abnormalities will be Warfarin: changes to safety (www.fda.gov). independently described in the information, UK updated product information for 3 December 2009 vigabatrin to reflect those new (www.mhra.gov.uk) Vigabatrin data.

Risk of movement Reference: disorders and MRI Drug Safety Update, MHRA, abnormalities Volume 3, Issue 4 November 2009 UK. The MHRA has informed (www.mhra.gov.uk). health-care professionals that movement disorders including dystonia, dyskinesia, and Warfarin hypertonia have been reported in patients treated with Product information to be vigabatrin for infantile spasms. amended The Agency has advised that if new movement disorders occur UK. The Medicines and during treatment with vigabatrin, Healthcare products Regulatory consideration should be given to Agency (MHRA) has announced dose reduction or a gradual that the safety sections in the discontinuation of treatment in product information for warfarin, consultation with specialist an anticoagulant, will be advice. Vigabatrin (Sabril) is an amended to give clearer, up-to- antiepileptic indicated, in date advice, following a UK combination with other review of safety information for antiepileptic drugs, for the warfarin products. In particular, treatment of patients with advice is provided on the resistant partial epilepsy who following: have not responded to, or who are intolerant to, all other • timing of warfarin treatment appropriate drug combinations. after ischaemic stroke Vigabatrin is also indicated as • management of the patient monotherapy in the treatment of before surgical or dental infantile spasms (West’s procedures syndrome). • patients at particular risk of haemorrhage The MHRA also explains that a • interactions with herbal Europe-wide review was products, foods, and food conducted and clinical trial data supplements for vigabatrin in infantile spasms • management of patients with provide evidence of brain MRI significantly raised INR and/or abnormalities at all doses, but in haemorrhage

WHO Pharmaceuticals Newsletter No. 6, 2009 & No. 1, 2010 • 12

SAFETY OF MEDICNES

switching antidepressants and Bisphosphonates Alendronate their possible outcomes, including the development of Review on the risk of Risk of low-energy serotonin syndrome. osteonecrosis of the jaw femoral shaft fracture Antidepressants include selective serotonin reuptake inhibitors Europe. The European New Zealand. Medsafe has (SSRI), tricyclic antidepressants Medicines Agency (EMEA) has advised prescribers to consider (TCA), monoamine oxidase announced that the Agency’s the risk of atypical stress inhibitors (MAOI), noradrenergic Committee for Medicinal fractures in patients treated with and 5HT1-serotonergic receptor Products for Human Use (CHMP) alendronate who report pain of agonists, serotonin and concluded that there is an the subtrochanteric or proximal noradrenaline reuptake increased risk of osteonecrosis femoral shaft, based on a inhibitors (SNRI), noradrenaline of the jaw in patients using number of published case reuptake inhibitors and herbals. bisphosphonates (including reports. Medsafe recommends ADRAC says that serotonin alendronic acid, clodronic acid, that the contralateral femur syndrome is a potential adverse etidronic acid, ibandronic acid, should be examined if a fracture effect of all antidepressants and neridronic acid, pamidronic acid, is suspected, because the that it can occur when treatment risedronic acid, tiludronic acid reported fractures associated is not interrupted as well as and zoledronic acid). However, with alendronate were during switching, particularly in further studies should be carried frequently bilateral. Factors the elderly. The risk of serotonin out to better identify the factors which may increase the risk of syndrome increases if there is that increase the risk and the fractures include: vitamin D simultaneous exposure to more measures needed to minimise it. deficiency, malabsorption, than one drug that can cause glucocorticoid use, previous this syndrome. The CHMP has agreed on the stress fracture, lower extremity following four areas: arthritis or fracture, extreme or ADRAC advises that an • the criteria that define increased exercise, diabetes appropriate washout or tapering osteonecrosis of the jaw related mellitus, and chronic alcohol period is necessary when to bisphosphonates; abuse. Medsafe also advises that switching between • how bisphosphonates the interruption of antidepressants. ADRAC also may cause osteonecrosis of the bisphosphonate therapy in states that factors that should jaw; patients with atypical stress be considered will vary • whether the risk of fractures should only be depending on the properties of osteonecrosis of the jaw is considered following an the antidepressants and the greater with some individual risk-benefit patient's situation including the bisphosphonates or for some assessment. duration of time the patient has groups of patients; been on the first antidepressant, • the measures that could (See WHO Pharmaceuticals patient age, other medications be taken to minimise this risk. Newsletter No. 2, 2009 for risk and other health issues. If there of atypical stress fractures are concerns about possible With regard to the definition of associated with bisphosphonates withdrawal syndrome, it may be osteonecrosis of the jaw related in the UK). more appropriate to taper the to bisphosphonates, the CHMP first drug before slowly has defined it as an area of Reference: introducing the second medicine exposed or dead bone in the jaw Prescriber Update Vol. 30, No.4, to minimise the risk of that has lasted for more than November 2009 withdrawal to the first as well as eight weeks, in a patient who (www.medsafe.govt.nz). the risk of adverse reactions due has been exposed to a to interactions when the second bisphosphonate and has not had Antidepressants is introduced. radiation therapy on the jaw.

Risk of interactions when Reference: With regard to possible switching antidepressants Australian Adverse Drug underlying mechanism, the Reactions Bulletin, Volume 28, CHMP considered that further Number 5, October 2009 studies are required and a Australia. The Adverse Drug (www.tga.gov.au) suitable experimental model Reactions Advisory Committee should be developed. (ADRAC) has warned about possible interactions when

WHO Pharmaceuticals Newsletter No. 6, 2009 & No. 1, 2010 • 13

SAFETY OF MEDICINES

With regard to risk stratification, go to their dentist for a check-up hypovolaemic shock. Features the Committee noted that: if their dental health is poor. after one to seven days include • During treatment with confusion, decreased cardiac • the risk of osteonecrosis bisphosphonates, patients output, cardiac arrhythmias, of the jaw is greater in cancer should maintain good oral renal and hepatic impairment, patients receiving intravenous hygiene, go for routine dental respiratory distress, bisphosphonates than in check-ups and report any hyperpyrexia, and bone-marrow patients being treated for non- symptoms in the mouth such as depression. This can progress in cancer indications, such as loose teeth, pain or swelling. severe cases to include multiple osteoporosis; • Dentists should be organ failure with accompanying • the risk appears to be aware of the risks in patients bone-marrow aplasia, low in patients taking taking bisphosphonates and convulsions, coma, bisphosphonates by mouth. should keep dental treatment as rhabdomyolysis, and The CHMP concluded that further conservative and preservative as disseminated intravascular research on risk factors is possible. coagulation. Colchicine is needed, though the most • It is essential that licensed for the treatment of important risk factors seem to prescribers, dentists and acute gout, but only in cases be the potency of the patients work together to where non-steroidal anti- bisphosphonate used, the dose manage the risk of osteonecrosis inflammatory drugs are not and how it is given. of the jaw. tolerated or ineffective. It is also • Patients who have any licensed for short-term With regard to risk minimization questions or concerns should prophylaxis during initial therapy measures, the CHMP concluded speak to their doctor or dentist. with other drug treatments. that further data are needed to determine the precise measures Reference: For the initial management of that could minimise the risk of Questions and answers on the colchicine overdose, health-care osteonecrosis of the jaw, review of bisphosphonates and professionals are advised to including looking at how the risk of osteonecrosis of the consider oral activated charcoal intravenous bisphosphonates jaw, CHMP opinion, EMEA as well as general symptomatic should be given, and looking 24 September 2009 and supportive measures as into the risk of osteonecrosis of (www.emea.europa.eu) indicated by the patient’s clinical the jaw in patients taking condition, including monitoring bisphosphonates by mouth for of vital signs, long periods. The CHMP also Colchicine electrocardiography, and noted that other possible risk haematological and biochemical Risk of serious and fatal factors for developing indices. osteonecrosis of the jaw should toxicity in overdose be considered, such as gender, (See WHO Pharmaceuticals genetic factors, smoking and UK. The MHRA reminded health- Newsletter Nos 1, 2006 and 4, other treatments or diseases care professionals that colchicine 2006 for related warnings in that the patient has, as well as has a narrow therapeutic New Zealand) the type of cancer a patient has window and is extremely toxic in and how long they have had it. overdose. Patients at particular Reference: risk of toxicity are those with Drug Safety Update, MHRA, The following are recommended. renal or hepatic impairment, Volume 3, Issue 4, • Before taking any gastrointestinal or cardiac November 2009 decisions concerning treatment disease, and patients at (www.mhra.gov.uk). with bisphosphonates, extremes of age. There is often prescribers should take the risks a delay of up to 6 hours before and benefits for each individual toxicity is apparent, and some Deferasirox features of toxicity may be patient into account. Potential revisions to the • Prescribers should delayed by one week or longer. product information ensure that patients with cancer Early features of toxicity (up to one day after ingestion) include go to their dentist for a check-up Canada (1). Health-care and find out if they need any nausea, vomiting, abdominal pain, and diarrhoea. Diarrhoea professionals have been advised dental treatment before they about renal events and start taking a bisphosphonate. may be profuse and bloody, and the patient may present with gastrointestinal haemorrhage They should also ensure that associated with deferasirox patients who do not have cancer electrolyte disturbances and

WHO Pharmaceuticals Newsletter No. 6, 2009 & No. 1, 2010 • 14

SAFETY OF MEDICNES

(Exjade) in patients diagnosed appropriate upper limit of particularly in older patients and with myelodysplastic syndrome normal. patients with MDS. (MDS) and in elderly patients. Deferasirox (Exjade) is indicated • Gastrointestinal (See WHO Pharmaceuticals in the management of chronic hemorrhage is a known adverse Newsletter No. 2, 2008 for iron overload in patients with reaction of deferasirox (Exjade). reports of hepatic failure in transfusion-dependent anaemias There have been rare reports of Canada and the USA, and aged 6 years or older as well as fatal gastrointestinal No. 2, 2007 for reports of renal those aged 2 to 5 who cannot be hemorrhage, especially in failure in Canada and adequately treated with elderly patients who had Switzerland.) deferoxamine. advanced haematologic malignancies and/or low platelet References: A letter issued by the company counts. (1) Advisories, Warnings and to health-care professionals Recalls, Health Canada highlights the following points. USA (2). The US FDA has 3 December 2009 notified health-care (www.hc-sc.gc.ca). • Review of adverse professionals of an ongoing events for patients treated with review of safety issues with (2) Safety Information, US FDA deferasirox (Exjade) suggests a deferasirox (Exjade). 25 September 2009 greater risk of kidney failure, Deferasirox (Exjade) is an iron (www.fda.gov). gastrointestinal hemorrhage chelating agent that is approved (potentially fatal) and deaths in for use in the treatment of patients with MDS and in elderly patients aged two and older with Finasteride patients compared to younger chronic anaemia and iron Potential risk of male patients with other chronic overload as a result of receiving anaemias such as β- blood transfusions. The Agency breast cancer thalassaemia and sickle cell is reviewing adverse event disease. information for deferasirox UK. The MHRA warned that • The company has (Exjade) from a database that cases of male breast cancer proposed changes to the tracks all patients who are have been reported in clinical Canadian Product Monograph, prescribed the medicine and a trials and during post-marketing including a contraindication in company-sponsored global use with finasteride treatment. high risk MDS patients and safety database. The Agency Finasteride is an inhibitor of type those with advanced explains that this information II 5α-reductase, which malignancies because these suggests there may be a greater metabolises testosterone into patients are not likely to benefit risk for adverse events such as the more potent androgen, from iron chelation therapy due kidney failure, gastrointestinal dihydrotestosterone (DHT). In to the expected rapid hemorrhage (potentially fatal the UK, 5 mg finasteride progression of their disease. bleeding) and deaths in patients (Proscar) is used for the • Risk factors for kidney with myelodysplastic syndrome treatment and control of benign failure include pre-existing (MDS) compared to patients prostatic hyperplasia, and 1 mg compromised renal function, and without these conditions. Many dose (Propecia) is indicated for it is therefore recommended of these patients are over sixty the treatment of men with that creatinine clearance (and/or years old. The number of deaths androgenetic alopecia. According serum creatinine) be assessed and serious adverse events to the Drug Safety Update, up to twice before initiating therapy. seem to be fewer in younger November 2009, 50 cases of Weekly monitoring of creatinine patients with other chronic male breast cancer have been clearance (and/or serum anemias such as β Thalassemia reported worldwide with 5 mg creatinine) is recommended in and Sickle Cell disease. finasteride and 3 cases with the the first month after initiation or 1 mg dose. A review of available modification of therapy, and The US FDA is working with the data suggests that an increased monthly thereafter. In addition company with regard to risk of breast cancer with to the existing creatinine potential revisions to the finasteride cannot be excluded. clearance contraindication of prescribing information to warn <60 mL/min, the company has health-care professionals about The MHRA advises patients to proposed to include a the possible risks in certain promptly report to their doctor contraindication of serum patients and to ensure that the any changes in their breast creatinine >2 times the age- benefits of the medicine tissue such as lumps, pain or outweigh the potential risks, nipple discharge.

WHO Pharmaceuticals Newsletter No. 6, 2009 & No. 1, 2010 • 15

SAFETY OF MEDICINES

for at least 24 hours after a H1N1 pandemic Reference: scan. Drug Safety Update, MHRA, vaccines Volume 3, Issue 5 For medium- (Vasovist, Reports of suspected December 2009 Primovist and MultiHance) and adverse reactions (www.mhra.gov.uk) low-risk agents (Dotarem,

ProHance and Gadovist), the Europe (1). The European CHMP recommended adding new Medicines Agency issues Gadolinium- warnings in the prescribing pandemic pharmacovigilance information concerning their use containing contrast weekly updates that include a in patients with severe kidney agents summary of the adverse drug problems and patients receiving reactions reported after the use a liver transplant. Screening Recommendations to of centrally authorised pandemic patients for kidney problems minimise risk of vaccines (Celvapan, Focetria and using laboratory tests is nephrogenic systemic Pandemrix) and antivirals generally recommended before fibrosis (Tamiflu). administration of these

gadolinium-containing contrast According to the ninth weekly Europe. EMEA has adopted a agents. The decision to continue update, as of 1 February 2010, set of recommendations aimed or suspend breastfeeding for at at least 35.7 million people, at minimising the risk of least 24 hours after a scan including at least 261 000 nephrogenic systemic fibrosis should be taken by the doctor pregnant women, had been (NSF) with gadolinium- and the mother. vaccinated with one of the three containing contrast agents. centrally authorised vaccines, in Gadolinium-containing contrast The CHMP recommended that the European Economic Area. As agents are used in patients the prescribing information of all of 24 January 2010, a total of undergoing magnetic resonance gadolinium-containing contrast 12 705 case reports (432 imaging (MRI) or magnetic agents should include: reports for Celvapan, 2837 resonance angiography (MRA) reports for Focetria, 9449 scans. • a warning that the reports for Pandemrix) had been elderly may be at particular risk received by EudraVigilance since The CHMP conducted a review of NSF due to impaired ability of the authorisation of those three on gadolinium-containing their kidneys to clear gadolinium vaccines. With regard to contrast agents and NSF, and from the body; oseltamivir (Tamiflu), from 1 made recommendations • a statement that there is April 2009 to 24 January 2010, a according to their risk no evidence to support the total of 969 reports worldwide classification. initiation of haemodialysis to were received by prevent or treat NSF in patients EudraVigilance. For high-risk gadolinium- not already undergoing containing contrast agents haemodialysis; The vast majority of the adverse (Optimark, Omniscan, • a statement that the reactions that had been reported Magnevist, Magnegita and Gado- type and dose of contrast agent as of 24 January 2010 are MRT ratiopharm), the CHMP used should be recorded. considered to be non-serious. recommended contraindications The benefit-risk balance of the in patients with severe kidney (See WHO Pharmaceuticals pandemic vaccines and antivirals problems, in patients who are Newsletter No. 1, 2008 and being used for the current H1N1 scheduled for or have recently No.3, 2007 for warning about influenza pandemic continues to received a liver transplant and in risk of nephrogenic systemic be positive. newborn babies up to four fibrosis in Australia and USA weeks of age. To minimise the respectively). The safety profile of the three risk of using these high-risk pandemic vaccines have been agents in patients with unknown Reference: reassessed based on the kidney problems, the CHMP Press Release, EMEA periodic safety update reports advised that patients should 20 November 2009 submitted by the companies. always be screened for kidney (www.emea.europa.eu). Following evaluation, it was problems using laboratory tests before use. It is also concluded that the benefit-risk recommended that women balance remains positive. should discontinue breastfeeding According to the sixth update,

WHO Pharmaceuticals Newsletter No. 6, 2009 & No. 1, 2010 • 16

SAFETY OF MEDICNES regarding Celvapan, new safety paracetamol). EMEA has of Celtura® have been concerns, including convulsions, recommended that this delivered. It is not known how pain in extremity and influenza- information be included in the many doses have been like symptoms. are being prescribing information, and be administered. Up to 22 January, considered for addition to the taken into consideration when there have been 424 reports for product information. deciding whether to give a Pandemrix®, 54 reports for second dose to young children. Focetria®, and 29 reports for Details of the reported reactions Celtura®. The majority of are available on the EMEA Ireland (3). The Irish reports are self-limited reactions website. Medicines Board (IMB) provides at the injection site, as well as (www.emea.europa.eu). updates on national monitoring generalized reactions such as experience with Pandemic H1N1 headache, fever, muscle aches The EMEA has warned that vaccines (Pandemrix and and joint pain. young children may Celvapan) on a regular basis. Swissmedic states that the experience fever after their According to the 4 February reported adverse reactions second dose of the pandemic 2010 update, it is estimated that correspond with those described influenza vaccine Pandemrix approximately 1.6 million doses in clinical trials and with the (2). This follows the review by have been distributed and some profile from post-marketing the CHMP of new data on the 850 000 doses have been experience with seasonal use of a second dose of the administered in Ireland. Up to influenza vaccines. The reported pandemic vaccine Pandemrix in 2 February 2010, the IMB adverse reactions of the children aged from 6 months to received 1291 reports of pandemic influenza vaccines 3 years. The Agency also noted suspected adverse reactions to correspond to those observed in that the second dose increases the two Pandemic H1N1 other countries using the same the immune response against vaccines (840 reports for vaccine products. pandemic influenza. Pandemrix, 430 reports for Details of the reported reactions Celvapan, brand unknown in 21 are available on the Swissmedic According to the Agency, the cases). The reports remain website (www.swissmedic.ch). data showed a higher proportion consistent with the expected of children developing fever pattern of adverse effects for References: (temperature above 38°C, when the vaccines. The balance of (1) Pandemic pharmacovigilance measured under the armpit) risks and benefits for these weekly update, EMEA after the second dose of vaccines (Celvapan and (www.emea.europa.eu). Pandemrix, compared with after Pandemrix) remains positive. (2) Press Release, Questions the first. Moreover, there was The IMB advises health-care and Answers, EMEA more soreness at the site of professionals and parents to 4 December 2009 injection and more general monitor the temperature of the (www.emea.europa.eu). symptoms such as drowsiness, vaccinated child and to take (3) Update on National irritability and loss of appetite measures, if necessary, to lower Monitoring Experience with after the second dose. The study the fever (e.g. giving an Pandemic H1N1 Vaccines, IMB also indicated that a single dose antipyretic such as (www.imb.ie). of vaccine triggered a good paracetamol). (4) Latest information about immune response in young vigilance for H1N1 flu vaccines children, but that the second Details of the reported reactions in Switzerland, Swissmedic, dose further increased the are available on the IMB website (www.swissmedic.ch). immune response. (www.imb.ie).

EMEA advises that parents and Switzerland (4). The Swiss Human insulin and carers of young children (below Agency for Therapeutic Products insulin analogues 6 years of age) vaccinated with (Swissmedic) updates Pandemrix should be aware that information on reports of Review on a possible fever may occur, and that this suspected adverse events increased risk of cancer fever can be high (above 38ºC). following vaccination with Prescribers and parents/carers pandemic influenza Japan. The Ministry of Health, should monitor the temperature vaccines. According to the 28 Labour and Welfare (MHLW), of the vaccinated child and, if January 2010 update, as of 22 Japan published results of a necessary, take measures to January 2010, 286 250 doses of review on possible association of lower the fever (e.g. giving an Focetria®, 1 697 300 doses of human insulin and insulin antipyretic such as Pandemrix® and 985 330 doses analogues (insulin aspart, insulin

WHO Pharmaceuticals Newsletter No. 6, 2009 & No. 1, 2010 • 17

SAFETY OF MEDICINES glargine, insulin glulisine, insulin • Package inserts used in of cancer associated with insulin detemir and insulin lispro) with foreign countries do not glargine in Europe and the USA). an increased risk of cancer. The currently include any review was conducted by the information giving Reference: Pharmaceuticals and Medical precaution against an Pharmaceuticals and Medical Devices Agency (PMDA). PMDA increased risk of cancer. Devices Safety Information has concluded that, at this time, No.263, MHLW, November 2009 no additional safety measures Association between insulin (www.pmda.go.jp/english). are needed for those insulin glargine and risk of cancer preparations for the following • Regarding insulin reasons. glargine, some Immune globulin epidemiological studies Risk of hemolytic Association between insulin showed an increased preparations in general and risk risk of cancer associated reactions with of cancer with insulin glargine, intravenous immune • In the epidemiological compared with other globulin studies regarding an insulin preparations, increased risk of cancer whereas other studies Canada. Health Canada has in association with did not. Those results warned health-care insulin preparations, were found to be professionals to be aware of some studies showed an inconsistent. haemolysis associated with the increased risk of cancer, • Non-clinical studies use of intravenous immune whereas others did not. showed that cell globulin (IVIG). Haemolysis is a There were limitations in proliferation induced by rare but well-described adverse most of those studies, insulin glargine is of a reaction associated with IVIG for example, insufficient similar magnitude to therapy. IVIG products are adjustment for that induced by human indicated as replacement confounding factors such insulin. Furthermore, therapy in cases of primary and as family history. when compared with cell secondary immune deficiencies, Therefore, they can not proliferation induced by for idiopathic thrombocytopenic be considered to provide other insulin analogues, purpura and for the treatment of sufficient evidence that insulin glargine was not chronic inflammatory confirms a causal considered to be demyelinating polyneuropathy. relationship between associated with an insulin preparations and increased risk of cancer. According to the Canadian an increased risk of • Regarding an possible Adverse Reaction Newsletter, a cancer. increased risk of cancer standardized case definition of • The non-clinical data in association with IVIG-associated haemolysis has submitted at the time of insulin glargine, EMEA been proposed to assist in the application for approval does not consider it investigation and reporting of of insulin analogues necessary at present to suspected cases. Using this demonstrated that cell take any action, and definition, Health Canada proliferation induced by package inserts used in analyzed all reports of insulin analogues is of a foreign countries do not haemolysis (reported as similar magnitude to include any information hemolytic anemia, haemolysis, that induced by human giving precaution spherocytic anaemia, haemolytic insulin. Therefore, it was against an increased risk reaction, decreased haemoglobin concluded at the time of of cancer. and haemolytic transfusion approval review, that it reaction) suspected of being was not necessary to Based on the above, PMDA associated with the use of IVIG include any specific states that it is not necessary to that were received from 1 precaution in the alert about the risk of cancer, December 2006 to package insert. Also, a given that the association 31 March 2009. Of the 81 review of several reports between insulin preparations reports received, 20 involved published after the and cancer has not been cases that met the criteria for approval did not lead to suggested. IVIG-associated haemolysis, 23 a change in this had an alternate possible cause conclusion. (See WHO Pharmaceuticals for anaemia, and 38 lacked the Newsletter No. 4, 2009 for risk required laboratory work. Health

WHO Pharmaceuticals Newsletter No. 6, 2009 & No. 1, 2010 • 18

SAFETY OF MEDICNES

Canada states that risk factors 25 mg on alternate days) for 14 from a few months through for haemolysis included blood days, increased to 25 mg/day childhood to young adults, with group A (in 14 cases) or AB (in 6 for a further 14 days. The dose less than 10% in those over the cases) and a high total dose of of lamotrigine can thereafter be age of 40. IVIG (≥ 2 g/kg). Of the adverse increased by 25–50mg/day reaction reports that included every 7 to 14 days. ADRAC has received 11 reports the total dose in grams per of tardive dyskinesia in kilogram, 85% of the patients According to Medsafe, the association with (11 out of 13) received a total incidence of serious skin metoclopramide-containing dose of ≥ 2 g/kg. reactions (including TEN and medicines, of which 9 occurred SJS) in clinical trials using in women 68 years or older. (See WHO Pharmaceuticals recommended lamotrigine Where details of time to onset Newsletter No. 3, 2009 for dosing is approximately 1 in 500 from drug initiation were reports of severe adverse epilepsy patients and 1 in 1000 provided, it was generally more reactions with intravenous patients with bipolar disorder. than one year. The risk of immunoglobulin in Australia). The incidence of serious skin developing tardive dyskinesia reactions is greater in children with metoclopramide increases Reference: with estimates ranging from 1 in with age, female gender and Canadian Adverse Reaction 300 to 1 in 100 children. Serious duration of treatment/number of Newsletter Volume 19, Issue 4, skin reactions generally occur doses. Health Canada, October 2009 within 8 weeks of commencing (www.hc-sc.gc.ca). lamotrigine therapy. The risk is Prescribers are reminded of the increased by high initial doses of risk for development of tardive lamotrigine, exceeding dyskinesia in patients receiving Lamotrigine recommended doses, rapid dose long-term metoclopramide escalation and concomitant use treatment, particularly in the Risk of serious skin of sodium valproate. elderly. Prescribers are also reactions, including toxic advised that all patients taking epidermal necrolysis and Reference: metoclopramide should be Stevens Johnson’s Prescriber Update Vol. 30, No.4, regularly reviewed to determine syndrome November 2009 if continued treatment is (www.medsafe.govt.nz). necessary. New Zealand. Medsafe emphasizes the importance of (See WHO Pharmaceuticals adhering to the recommended Metoclopramide Newsletter No. 2, 2009 for dose guidelines when warning against chronic use in Risk for development of prescribing lamotrigine to USA and reports in WHO Global patients already taking sodium movement disorders ICSR database.) valproate, because of the risk of including tardive serious skin reactions. The dyskinesia Reference: CARM database contains reports Australian Adverse Drug of toxic epidermal necrolysis Australia. ADRAC warns about Reactions Bulletin, Volume 28, (TEN) and Stevens Johnson’s the risk of extrapyramidal acute Number 5, October 2009 syndrome (SJS) in patients dystonic reactions and tardive (www.tga.gov.au) taking concomitant lamotrigine dyskinesia associated with and sodium valproate. Medsafe metoclopramide. explains that risk factors Metoclopramide is a selective D2 Phenytoin included exceeding the dopamine receptor antagonist Risk of Stevens-Johnson recommended starting dose of that is a long-established lamotrigine or the rate of dose antiemetic and antinauseant. syndrome and presence of escalation. Lamotrigine is the HLA-B*1502 allele approved as adjunctive therapy Acute dystonic reactions in adults and children with generally occur within 72 hours UK. The MHRA has advised epilepsy, and for the prevention of exposure to metoclopramide health-care professionals that of mood disorders in adults with and affect younger population. the human leukocyte antigen bipolar disorder. In adult ADRAC has received 111 reports (HLA) allele HLA-B*1502 may be patients already taking sodium of acute dystonic reactions associated with an increased risk valproate, the starting dose of associated with metoclopramide. of developing Stevens-Johnson lamotrigine is 12.5 mg/day (or The age range is predominantly syndrome (SJS) in individuals of

WHO Pharmaceuticals Newsletter No. 6, 2009 & No. 1, 2010 • 19

SAFETY OF MEDICINES

Thai and Han Chinese ethnic Rituximab rituximab (RITUXAN) should be origin when treated with discontinued. phenytoin. The Agency A third case of recommends that if these progressive multifocal References: patients are known to be HLA- leukoencephalopathy Advisories, Warnings and B*1502-positive, phenytoin Recalls, Health Canada should be avoided when Canada and USA. Health 21 October 2009 alternative therapy can be Canada and the companies have (www.hc-sc.gc.ca). given. Phenytoin is an warned about association of Safety Information, US FDA antiepileptic drug, and is one of rituximab (RITUXAN) with 23 October 2009 the most common causes of progressive multifocal (www.fda.gov). antiepileptic-related cutaneous leukoencephalopathy (PML). adverse reactions, including SJS Rituximab (RITUXAN) is and toxic epidermal necrolysis authorized for the treatment of SSRIs/SNRIs and (TEN). B-cell non-Hodgkin's Lymphoma, thiazide diuretics According to the Drug Safety previously untreated B-cell Update, a recent study has chronic lymphocytic leukemia, Medicines most often shown a significant association stage B or C, and rheumatoid associated with between the HLA-B*1502 allele arthritis in combination with hyponatreamia and phenytoin-induced SJS in methotrexate to reduce signs patients of Thai or Han Chinese and symptoms in adult patients New Zealand. The November ethnic origin. However, available with moderately to severely 2009 issue of Prescriber Update data are too limited to active rheumatoid arthritis who describes the results of recommend screening of have had an inadequate examination of recent reports patients of Thai or Chinese response or intolerance to one with hyponatraemia in the ethnic origin for presence of the or more tumour necrosis factor database of the New Zealand HLA-B*1502 allele before (TNF) inhibitor therapies. Centre for Adverse Reactions starting phenytoin treatment. Monitoring (CARM). Medicines Health-care professionals have most often associated with MHRA states that in the been notified that a third case of hyponatraemia, which is defined Caucasian and Japanese PML has been reported in a as plasma sodium < population, the frequency of patient with rheumatoid arthritis 135mmol/L, were selective HLA-B*1502 is extremely low, treated with rituximab serotonin or noradrenaline and thus it is not possible at (RITUXAN). This is the first case reuptake inhibitors present to conclude on risk of PML in a patient with (SSRIs/SNRIs) and thiazide association between phenytoin- rheumatoid arthritis receiving diuretics. Other medicines induced SJS and the presence of rituximab (RITUXAN) who has reported more than once in this allele. Adequate information not been previously treated with 2007 and 2008 were anticancer about risk association in other other potent biologic immuno agents, proton pump inhibitors, patients of other ethnic origin is modulating therapies. While the sodium valproate and ACE currently not available. potential mechanism of inhibitor/diuretic combinations. rituximab (RITUXAN) in the Carbamazepine has also been (See WHO Pharmaceuticals development of PML is unclear, frequently associated in the Newsletter No. 5&6, 2008 for a contributory role is possible. database. Medicine-related caution against use in HLA- Available information to date hyponatraemia occurs most B*1502-positive patients in the suggests that patients with often in the elderly early in the USA). rheumatoid arthritis who receive course of treatment. The rituximab (RITUXAN) may have mechanism is most often Reference: an increased risk of PML. It is syndrome of inappropriate Drug Safety Update, MHRA, advised that physicians should antidiuretic hormone secretion Volume 3, Issue 6 consider PML in any patient (SIADH) or renal loss. January 2010 being treated with rituximab (www.mhra.gov.uk). (RITUXAN) who presents with In most of the serious new onset neurologic symptomatic reports that CARM manifestations (i.e. cognitive received, more than one impairment, motor deficit, hyponatraemic medicine was speech and vision impairment). associated. Reports for three In patients who develop PML, patients indicated that they each had persistent mild to

WHO Pharmaceuticals Newsletter No. 6, 2009 & No. 1, 2010 • 20

SAFETY OF MEDICNES moderately low plasma sodium Health-care providers are Serious skin disorders levels (128 to 133mmol/L) while alerted to the following associated with medicines taking two hyponatraemic information. medicines. Following addition of • Zanamivir (Relenza Dry Japan. MHLW issued a summary a third hyponatraemic agent, a Powder for Inhalation) is not of cases of Stevens- Johnson much more profound fall ranging intended to be reconstituted in syndrome (SJS) and toxic from 104 to 121mmol/L any liquid formulation and is not epidermal necrolysis (TEN) that occurred. recommended for use in any were reported to the Ministry nebulizer or mechanical between 1 October 2005 and 31 It is advised that plasma sodium ventilator. July 2009. There were 2370 cases should be measured shortly • Zanamivir (Relenza) for of adverse drug reactions after starting potentially nebulization has not been reported as SJS or TEN (2.2% out hyponatraemic medicines, approved by any regulatory of a total of 110 023 cases of especially SSRIs or diuretics. authority and the safety, adverse reactions reported for the Measurements should be effectiveness and stability of period). Of these, 146 cases repeated both before and after zanamivir use by nebulization (6.2%) were reported to be adding another hyponatraemic have not been established. possibly associated with over-the- medicine. If there is mild counter drugs. The outcomes in persistent hyponatraemia, the The letters sent to health-care the 2370 cases of SJS or TEN addition of further medicines professionals say that zanamivir were as follows: 1373 (57.9%) may lead to a more profound (Relenza Dry Powder for recovered or improved; 85 and symptomatic reaction. Inhalation) should only be used (3.6%) did not recover; 84 as directed in the prescribing (3.5%) had sequelae; 239 Reference: information by using the (10.1%) died; and outcome was Prescriber Update Vol. 30, No.4, Diskhaler inhalation device unknown in 589 (24.9%). November 2009 provided with the medicine. The (www.medsafe.govt.nz). product is a mixture of There were 400 active ingredients zanamivir active substance and associated with SJS or TEN. Most lactose drug carrier. There is frequently reported medicines Zanamivir risk that the lactose sugar in this were allopurinol, carbamazepine, formulation can obstruct proper Warning against loxoprofen sodium hydrate, functioning of mechanical acetaminophen, diclofenac reconstitution in liquid ventilator equipment. sodium, zonisamide, formation salicynamide/acetaminophen/anh References: ydrous caffeine/promethazine Canada and USA. Health Advisories, Warnings and methylenedisalicylate, Canada, the US FDA and Recalls, Health Canada clarithromycin, phenobarbital, and GlaxoSmithKline have notified 3 November 2009 levofloxacin hydrate. health-care professionals of a (www.hc-sc.gc.ca). report of the death of a patient Safety Information, US FDA MHLW warns that although SJS with influenza who received 9 October 2009 (www.fda.gov) and TEN are rare, these skin zanamivir (Relenza Dry Powder disorders may occur irrespective for Inhalation) which was of the medicine administered. The solubilized and administered by Ministry states that when rash mechanical ventilation. and accompanying hyperthermia Zanamivir (Relenza) is a develop after administration of neuraminidase inhibitor medicines and SJS or TEN is indicated for treatment of suspected, the medicine should be uncomplicated illness due to discontinued and the patient influenza A and B in patients should be promptly referred to a seven years of age or older who dermatologist. have been symptomatic for no more than two days. Zanamivir Reference: (Relenza) is also indicated for Pharmaceuticals and Medical prophylaxis of influenza in Devices Safety Information patients seven years of age or No.261, MHLW, September 2009 older. (www.pmda.go.jp/english/)

WHO Pharmaceuticals Newsletter No. 6, 2009 & No. 1, 2010 • 21

FEATURE

Prequalification of Quality Control Laboratories Prequalification of Medicines Programme, WHO

Background

In order to achieve the Millennium Development Goals it is necessary to increase the availability and supply of good quality Essential Medicines in countries that need these medicines. However, several international funders and suppliers of these medicines have faced difficulties in monitoring the quality of these medicines because quality control laboratories are either not available or the quality of their work cannot be assured in those very countries where the medicines are to be used. Thus, international donors and suppliers have often had these medicines analysed in quality control laboratories situated in other countries, in Europe or Northern America. This is not consistent with WHO’s programmes for sustainable development because it does not build capacity on the ground. The World Health Organization (WHO) in collaboration with UNAIDS, UNICEF, UNFPA, the Global Fund, UNITAID and with the support of the World Bank started the prequalification of quality control laboratories in 2004. The objective was to help build quality control laboratories that meet recommended international norms and standards for the analysis of products prequalified or being considered for prequalification by the WHO Medicines Prequalification (WHO PQ) Programme. In the first phase WHO invited Expressions of Interest from Quality Control Laboratories in Africa committed to providing a service of testing of pharmaceutical products, including but not limited to HIV/AIDS, Tuberculosis and Malaria products at affordable prices, to UN agencies. In September 2007 the scope of the procedure was extended and currently the invitations are not limited to quality control laboratories from Africa or any other specific region. WHO, however, reserves the right to prioritize the assessment of national quality control laboratories or those laboratories which provide testing services to the government in the respective country, and quality control laboratories in areas where UN agencies and their partners (such as UNITAID) identify the need for quality testing. The invitation for Expression of Interest to participate in the prequalification procedure is published at WHO web site (1).The invitation is published in accordance with the Procedure for assessing the acceptability, in principle, of quality control laboratories for use by United Nations agencies, adopted by the WHO Expert Committee on Specifications for Pharmaceutical Preparations in 2003 and subsequently amended in 2007 (2). Participation in the prequalification procedure is voluntary and any laboratory (governmental or private) can participate. Currently, the participation is free of charge, but the procedure enables WHO to charge for the quality assessment procedure on a cost-recovery basis.

General information

The procedure established by WHO for assessment of quality control laboratories includes the evaluation of the information submitted by a laboratory (Laboratory Information file, LIF) and an on- site inspection of the laboratory to assess the compliance with the guidelines on Good Practices for National Pharmaceutical Control Laboratories (3) and Good Manufacturing Practices (4) as recommended by WHO for such laboratories. All the related guidelines are published at the WHO web site (5). Certification such as ISO (in terms of ISO/IEC 17025) is encouraged and is considered in the prequalification procedure. If assessment demonstrates that a laboratory meets WHO recommended standards, it is included in the WHO List of Prequalified Quality Control Laboratories that are considered to be acceptable for use by United Nations agencies as well as other interested parties (6).

WHO Pharmaceuticals Newsletter No. 6, 2009 & No. 1, 2010 • 22

FEATURE

Once a laboratory is included in the WHO List of Prequalified Quality Control Laboratories, ongoing monitoring of its activities is performed including re-inspections at regular intervals, evaluation of results from participation in an appropriate proficiency testing scheme, and monitoring and investigation of complaints concerning the results of analysis or service provided by the listed laboratories. To facilitate the monitoring each prequalified laboratory is requested to submit a brief annual report on its activities related to quality control of medicines , which should be submitted by the end of March of the following year. An outline of the content of an annual report is published on the WHO web site (7).

A laboratory will be removed from the list if, as a result of re-inspection, it is found that it no longer complies with the specified standards.

Outcomes of the prequalification procedure

As at the end of February 2010, twelve laboratories have been prequalified by the WHO. Five prequalified laboratories are located in the WHO Africa Region, three in Western Pacific Region and one in each of the three regions: Americas, Eastern Mediterranean, Europe and South-East Asia.

Country Region Number of PQ laboratories Algeria Africa 1 Canada Americas 1 France Europe 1 India South-East Asia 1 Kenya Africa 2 Morocco Eastern Mediterranean 1 Singapore Western Pacific 2 South Africa Africa 2 Vietnam Western Pacific 1

Apart from these twelve prequalified laboratories, there are thirty one quality control laboratories participating in the procedure by the end of February 2010. The majority of participating laboratories (32 of 43) are national quality control laboratories.

As part of the capacity building component of the WHO PQ Programme national quality control laboratories participating in the prequalification procedure are, if needed, provided with technical assistance in the form of a pre-audit or 1-3 weeks stay of an expert in the laboratory. WHO PQ also organizes trainings for national quality control laboratories and for laboratories providing testing services to the government in the respective country.

Inspections

An inspection team consists of a WHO PQ inspector based in Geneva and a co-inspector appointed by WHO from a Pharmaceutical Inspection Cooperation Scheme (PIC/S) member inspectorate. An inspector (or inspectors) from the National Drug Regulatory Authority of the country, in which the laboratory is located, is invited to participate as an observer. Pre-qualified laboratories are re-inspected on regular basis, usually every 3 years.

WHO Pharmaceuticals Newsletter No. 6, 2009 & No. 1, 2010 • 23

FEATURE

Quality control laboratory inspections were started in March 2004 and up to September 2009, 14 inspections had been performed by WHO.

Non-compliances observed during inspections over the years included the following observations:

• The system of reference substances was insufficient in that: o Authorized written standardized operation procedures for handling of reference substances were not available, e.g.: ƒ packing of working reference substances ƒ labelling of working reference substances ƒ acceptance criteria for working substances o Inappropriate labelling of working standards o Use of reference substances was not documented • Stocks of reagents and retention samples were not maintained under the appropriate storage conditions • The training system was insufficient in that: o Authorized written standardized operation procedure for training was not available o Training was not appropriately documented and assessed • Authorized written standardized operation procedure for internal audits was not available • Reagents were not managed properly in that: o The labels of some reagents did not specify shelf-life, o Certificates of analysis were not available for all reagents o Reagents were not properly labelled • Responsibilities, competencies and functions were not clearly defined in current job descriptions • The computer software developed by the users were not appropriately validated or verified. Procedures were not established and implemented for protecting the integrity of data • Authorized written standardized operation procedure for the calibration of critical equipment was not available, for example HPLC, GC, dissolution and disintegration instruments. Equipment calibration and maintenance schedule were not available. Equipment were not regularly qualified, IQ, OQ and PQ protocols/reports were not available • Validation of microbiological laboratory autoclave was not done in accordance to current guidelines • Pharmacopoeia test methods were not verified • Failures to meet specifications (‘out of specifications’) were not recorded and handled properly

References: 1. http://www.who.int/prequal/info_applicants/eoi/EOI-QCLabsV3.pdf 2. Prequalification of quality control laboratories. Procedure for assessing the acceptability, in principle, of quality control laboratories for use by United Nations agencies. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-first report. Geneva, World Health Organization, 2007, Annex 5 (WHO Technical Report Series, No. 943) . http://www.who.int/prequal/info_general/documents/TRS943/TRS943.pdf#page=111 3. Good Practices for National Pharmaceutical Control Laboratories. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty -sixth report. Geneva, World Health Organization, 2002, Annex 3 (WHO Technical Report Series, No. 902). http://www.who.int/prequal/info_general/documents/TRS902/WHO_TRS_902.pdf#page=37 4. Quality Assurance of pharmaceuticals. A compendium of guidelines and related materials. Volume 2, Second updated edition. Good manufacturing practices and inspection. Geneva, World Health Organization, Geneva, 2007. http://www.who.int/medicines/areas/quality_safety/quality_assurance/production/en/index.html 5. http://www.who.int/prequal/info_applicants/qclabs/prequal_quality_control_labs.htm

6. http://www.who.int/prequal/lists/PQ_QCLabsList.pdf http://www.who.int/prequal/info_applicants/qclabs/Annual-Report_Labs.pdf

WHO Pharmaceuticals Newsletter No. 6, 2009 & No. 1, 2010 • 24

FEATURE

Thirty-second annual meeting of representatives of national centres participating in the WHO Programme for International Drug Monitoring

2-5 November 2009

There were eight breakout sessions at the annual meeting of pharmacovigilance centres in Rabat, Morocco. Below is a summary of recommendations from these sessions.

Patient safety, including medication errors This working group looked specifically at improving the yellow card form to facilitate detection of medication errors. The group took the definition of a medication error as “any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is under the control of the health care professional, patient, or consumer”.

After reviewing the advantages and limitations of current means of detecting medication errors, the group looked at the yellow card itself. The working group proposed adding the following: frequency of administration, batch number, expiry date, and source. (It was noted that the batch number is not always easy to find; hence the need to include the source of the medicine.). The members also proposed adding: frequency of administration, units (e.g. mg, mcg), and either dose administered or dosage form, comorbidity (other diseases, e.g. renal failure), risk factors (e.g. alcohol, smoking), allergy, and diluent and possible interactions.

Reporting and database needs and practicalities This working group had looked at the problem of an apparent fall in reporting to UMC from European Union (EU) countries. Eleven European countries submitted no cases to UMC between October 2008 and October 2009. UMC had sent out a questionnaire to 28 European countries to try to establish the reasons for this and to find a solution. The 25 countries that responded had used a variety of ways of submitting data to UMC. Under EU requirements, countries had to submit data on adverse reactions to medicines to the European Medicines Agency (EMEA) via the EudraVigilance network. Some found it extra work to submit data to UMC as well.

The working group recommended that WHO-UMC should be a recipient of data submitted via the EudraVigilance gateway (as requested by 10 EU countries in their responses to the UMC survey since this would require them to submit the data only once). The group said that the EMEA and WHO should collaborate to facilitate this communication technically, bearing in mind national data protection laws. While there was concern that EudraVigilance requires submission of only serious individual case safety reports, as opposed to UMC’s VigiBase which requests all reports, the group was informed that this situation would be harmonized through a European Commission legislative proposal (whereby all reports will be required by EudraVigilance as from 2011−2012).

The current UMC requirement of reporting every 90 days was seen to have disadvantages in terms of the high workload every quarter and the delay in signal detection. The working group recommended a reporting interval of 30 days to UMC (though for EU reports, UMC would accept the same timeline as the EMEA). The group also suggested that UMC should send more frequent feedback to national centres to encourage regular reporting (and improved quality of reporting).

In terms of UMC’s VigiFlow reporting system, the working group recommended there should be discussion between the EMEA and UMC regarding how to support current and future EU members who are VigiFlow users. In addition, the VigiFlow interface should be translated into more languages, and it was agreed that case narratives may be entered in local languages.

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Interaction with academia/regulation In daily practice many national centres already have drug advisory committees and play a role in education and training. Many contacts – both formal and informal – already take place between pharmacovigilance centres and academia.

Expressing a clear need for pharmacovigilance to be a part of the curriculum of health care professionals, the members of the working group acknowledged that the most practical way of achieving this was to start with a series of lectures and move on to having a fixed module in masters programmes. Examples were given of a pharmacovigilance module in medical school in Senegal and a place in pharmacology training in Ethiopia. There was also felt to be a need to introduce pharmacovigilance at preclinical level.

The working group stated that health professionals need to have a basic knowledge of pharmacovigilance, but that this scientific discipline needs to be made more interesting for them. The working group felt that a strong statement by WHO concerning the need for education would be helpful, and that academia and regulators should cooperate and support each other.

Use of pregnancy and other registers in pharmacovigilance This working group looked at registers in pharmacovigilance and, where they exist, asked whether they are useful. The group agreed that registers should collect data on the disease, the conditions and specific products, and that they should include information for all patients within a defined area (with a denominator and information on deviations in the group, e.g. a register on congenital malformation). However, before setting up a register it would be necessary to know what data should be collected so that the information available can be used for making useful decisions, especially in the area of medicine surveillance.

Members of the working group felt that registers would be useful for new products about which there is little information. In such cases there could be follow-up with special groups of patients (e.g. the elderly, children, pregnant women) to monitor for long-term side-effects. Pregnancy registers were judged to be useful because few, if any, trials are conducted in pregnant women, and a register is the only way to find out information about the effects of a medicine on pregnant women and the extent of complications.

The working group recommended that guidelines should be provided for the minimum information to be collected in each register so that information can be shared at both national and global levels.

The role of generic manufacturers in pharmacovigilance: old and new issues There is consensus that generic medicines should be of proven pharmaceutical quality and should have proven equivalence (or bioequivalence) to the originator product. Regulations vary between countries on, for instance, the number of generic suppliers permitted or the inspection of manufacturers or importers before the market launch. A number of concerns were noted, such as the lack of resources for GMP inspections, unclear supply chains that are difficult to control, stability problems in different climates, and the lack of harmonized pharmacopoeia requirements.

Specific pharmacovigilance concerns about generics include pressure to grant a licence because of urgent needs so there is little time to carry out an in-depth assessment of the dossier or evidence, and the fact that generics may contain old substances that have not been reviewed so it is unclear if they are as safe as they should be by current standards. In addition, governments and insurance companies may require the prescription (and use) of generic medicines for cost reasons, yet there remains the question of how and by whom to monitor safety (the manufacterer, a national agency, or within a public health programme).

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On the reporting of adverse reactions to medicines of generics, working group members felt that the CIOMS form was widely accepted and there was no need for an additional form, but that guidance was required on the need to report serious adverse reactions, clusters of reactions, and medication errors that result in injury. There should be rules, the working group said, that make responsibilities very clear (for the manufacturer, pharmacist, physician, nurse etc). Companies should have a pharmacovigilance system in place, they should notify changes of suppliers or vendors, and in case of safety concerns regulators should have the right to request post-authorization safety studies (PASS).

The working group said there should be guidance on risk management plans and their implementation. It would be important to have prequalification lists of manufacturers, vendors and suppliers, lists of risk management plans, and medicine master files. From the EU, periodic safety update reports (PSURs) could be useful (available at http://www.emea.europa.eu/).

Mobilizing resources for pharmacovigilance A recent survey of pharmacovigilance activities in 55 low-income and middle-income countries identified lack of resources as one of the major challenges facing pharmacovigilance centres in these countries. The working group suggested that, when a country is admitted to the WHO Programme for International Drug Monitoring, it should be informed not only of the need to have a certain number of reports but also the need to advocate for budgetary allocations.

Sustainability of pharmacovigilance requires a structured training programme which will necessitate introducing a pharmacovigilance curriculum into the training programmes of health care professionals and setting up a career progression scheme for pharmacovigilance practitioners, the working group said. The members further stressed the need for both social marketing and high-level advocacy, and emphasized that each national centre should draw up a clearly articulated plan with evaluation indicators. They proposed integrating pharmacovigilance into regional and subregional networks and setting up a web site to share ideas for (and experiences of) success.

Funds that could be tapped include those allocated for pharmacovigilance in public health programmes (which are often underutilized). Pharmacovigilance centres could set aside a certain amount of funds from the registration of medicines for monitoring of such medicines, or charging a retainer fee for re- registration (though this was not successful in Europe), or by generating resources through pharmacovigilance services.

The working group proposed a list of “actionable points” for resource mobilization, such as presenting pharmacovigilance as a public health emergency, showing that monitoring safety is cost-effective, and incorporating pharmacovigilance into all public health programmes. It was proposed that WHO and UMC should lead global collaboration in resource mobilization and that the meeting of national centres should set up an informal committee to develop advocacy and promotional materials for the social marketing of pharmacovigilance.

Pharmacovigilance for medicines in neglected diseases The working group decided that any discussion of this topic must start with the assumption that neglected diseases are a global problem and should be tackled accordingly. The group focused specifically on large-scale infectious diseases which seem to be spreading and affecting more people. The reasons for this include the decreased efficacy of existing therapies (resistance), low compliance with medicines for chronic diseases, and the decreased efficacy of insecticides used to control vectors. For the pharmaceutical industry, it is necessary to have a market that will be profitable and for investments in intellectual property to be secure.

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Some of the major neglected diseases are in countries with limited pharmacovigilance capacity and limited resources. Therefore much depends on the approach of the government. Some may control the manufacture, treatment and supply of medicines for large-scale infectious diseases and implement specialized pharmacovigilance tools (as in the case of Brazil with HIV medicines, benznidazole and thalidomide), while others may rely on the market to supply the medicines people need. In many cases there are difficulties in treating neglected diseases due to lack of available treatments, absence of real- time evaluation and pharmacovigilance measures, and the problem of counterfeit products. If there is a developed system of pharmacovigilance, then risk minimization measures are normally effective, but in other countries specific disease programmes (e.g. HIV in Brazil, malaria in Ghana) may include the pharmacovigilance functions. Some countries collaborate with NGOs to try to implement safety monitoring measures.

Vaccines In discussing vaccines and pharmacovigilance, this working group recommended that staff of national pharmacovigilance centres should be trained to identify adverse events following immunization (AEFIs). The working group also suggested that guidelines should be developed to assist national centre staff in reporting of AEFIs. Identifying a need for early education on vaccine safety, the group proposed that member countries should introduce vaccine surveillance activities into their medical school curricula.

Because of the lack of resources to monitor AEFIs, national centres were encouraged to collaborate with existing programmes (e.g. WHO-EPI, UNICEF programmes). National centres were also asked to provide feedback on any issues (positive or negative) that may result from the collaboration. The working group proposed that the AEFI case definitions from the Brighton Collaboration should be translated into other languages and that a short list of new AEFI terms should be added to the existing WHOART list.

The working group stressed the need for a vaccine dictionary that would include vaccine excipients and dosage contents and recommended that this should be a topic for discussion at the 33rd annual meeting of national centres in 2010.

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