Pharmnewsletter6 11.Pdf

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

The aim of the Newsletter is to No. 6, 2011 disseminate information on the safety and efficacy of pharmaceutical products, based on communications received The WHO Pharmaceuticals Newsletter provides you with from our network of "drug the latest information on the safety of medicines and information officers" and other legal actions taken by regulatory authorities across the sources such as specialized world. Recent events and topics of concern are bulletins and journals, as well as addressed in the Feature section. This issue includes a partners in WHO. The information brief summary of a training course on the active is produced in the form of résumés monitoring of the safety of antiretroviral medicines. in English, full texts of which may be obtained on request from:

Quality Assurance and Safety: Medicines, EMP-HSS,

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/medicine s

Further information on adverse reactions may be obtained from the WHO Collaborating 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 Feature

© World Health Organization 2011

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TABLE OF CONTENTS

Regulatory Matters

Atomoxetine...... 4 Buflomedil-containing medicines ...... 4 Dasatinib ...... 5 Drotrecogin alfa (activated)...... 5 Drospirenone-containing combined oral contraceptives ...... 5 Fenofibric acid ...... 6 Fluoroquinolone ...... 6 Lenalidomide ...... 7 Modafinil ...... 7 Pioglitazone...... 8 Rosiglitazone ...... 8

Safety of medicines

Angiotensin II receptor antagonists ...... 9 Buccal midazolam ...... 9 Citalopram ...... 9 Linezolid ...... 10 Methylene Blue ...... 10 Pholcodine...... 11 Tumor Necrosis Factor (TNF) blockers, Azathioprine and/or Mercaptopurine...... 11

Feature

A training course on Cohort Event Monitoring of medicines used in HIV treatment programmes ...... 12

WHO Pharmaceuticals Newsletter No. 6, 2011 • 3

REGULATORY MATTERS

atomoxetine is started, after EMA advised patients using Atomoxetine the dose is increased, and buflomedil-containing periodically during treatment medicines to make an to detect possible clinically appointment with their doctor Association with important increases, at a convenient time to discuss increased blood pressure particularly during the first few their ongoing treatment. and heart rate months of therapy. The CHMP considered all Canada. Eli Lilly Canada Inc. (See WHO Pharmaceuticals available data on the benefits in collaboration with Health Newsletter No. 2, 2006 for new and risks of buflomedil, Canada informed of important recommended warnings in UK). including the benefit-risk information from clinical assessment carried out by Reference: studies regarding the risk of France, data from clinical increased blood pressure and Advisories, Warnings and studies, post-marketing heart rate with the use of Recalls, Health Canada, surveillance and published atomoxetine (Strattera®). The 21 October 2011 literature, as well as from monograph has recently been (www.hc-sc.gc.ca ). poison control centres in the revised to include these new EU. safety findings. Atomoxetine is a selective norepinephrine Following review of these data reuptake inhibitor indicated for Buflomedil- the Committee concluded that: • there was a risk of serious treatment of Attention- containing Deficit/Hyperactivity Disorder neurological and cardiac side (ADHD) in children and adults. medicines effects in patients taking buflomedil under normal conditions of use and that risk Recommendations are: Suspension of all • Atomoxetine is minimization measures such as buflomedil-containing contraindicated in patients with changes to the packaging of symptomatic cardiovascular medicines recommended the medicine, diseases, moderate to severe recommendations on adjusting hypertension or severe Europe. The European the dose for patients with cardiovascular disorders whose Medicines Agency (EMA)’s kidney problems and condition would be expected to Committee for Medicinal restrictions on the medicines’ deteriorate if they experienced Products for Human Use use in certain patients had not increases in blood pressure or (CHMP) concluded a review of been able to reduce these risks in heart rate that could be the safety and efficacy of to an acceptable level; clinically important; buflomedil, stating that the • due to the narrow • Atomoxetine should be risks of these medicines, therapeutic index (i.e. the used with caution in patients particularly the risks of severe small difference between whose underlying medical cardiological and neurological buflomedil’s therapeutic dose conditions could be worsened adverse reactions, are greater and its toxic dose) there was a by increases in blood pressure than their limited benefits in significant risk of adverse or heart rate, such as patients the treatment of patients with events, particularly in elderly with hypertension, tachycardia, chronic peripheral arterial patients and in patients with or cardiovascular or occlusive disease (PAOD). The certain conditions such as cerebrovascular disease; Committee therefore kidney problems, which are • Atomoxetine should be recommended that the common in PAOD; used with caution in patients marketing authorisations of all • data in support of the with congenital or acquired buflomedil-containing benefit of the medicine for long QT syndrome or a family medicines be suspended in all patients were limited and of history of QT prolongation; European Union (EU) Member poor quality. • patients should be States where they are screened for pre-existing or currently authorized. The Committee was therefore underlying cardiovascular or of the opinion that the benefits cerebrovascular conditions The EMA advised that doctors of buflomedil-containing before initiation of treatment should stop using buflomedil medicines do no longer with atomoxetine and and consider alternative outweigh their risks, and monitored during the course of treatment options, including recommended that marketing treatment; managing underlying health of these medicines should be • it is recommended that problems which can increase suspended throughout the EU. heart rate and blood pressure the risk of PAOD, such as be measured in all patients diabetes, high blood pressure (See WHO Pharmaceuticals before treatment with as well as smoking. And the Newsletter No. 2, 2011 for the

WHO Pharmaceuticals Newsletter No. 6, 2011 • 4

REGULATORY MATTERS decision by Afssaps to suspend (See WHO Pharmaceuticals in hospital intensive care units marketing authorizations, Newsletter No. 5, 2011 for to treat patients at a high risk No. 3, 2011 for Safety information regarding of death due to serious recommendation for pulmonary arterial complications of a blood suspension of oral buflomedil- hypertension in Canada). infection (called sepsis or containing medicines in Europe septic shock). and reports in WHO global Reference: ICSR database). FDA Drug Safety The withdrawal is in light of a Communication, US FDA, large international clinical trial, Reference: 11 October 2011 known as the PROWESS- Press release, EMA, (www.fda.gov ). SHOCK study that showed no 17 November 2011 benefit for patients receiving (www.ema.europa.eu ). drotrecogin alfa compared to patients who did not receive it. Drotrecogin alfa (See WHO Pharmaceuticals (activated) Dasatinib Newsletter No. 2, 2009 for increased risk of serious Market Withdrawal - bleeding events and death in the US). Risk of pulmonary Failure to Show Survival arterial hypertension Benefit Reference:

USA. The U.S. Food and Drug (1) FDA Drug Safety USA (1). The U.S. Food and Administration (US FDA) Communication, US FDA, Drug Administration (US FDA) notified healthcare 25 October 2011 notified healthcare professionals that dasatinib (www.fda.gov ). professionals and the public (Sprycel®) may increase the (2) Advisories, Warnings and that on 25 October 2011, Eli risk of a rare but serious Recalls, Health Canada, Lilly and Company announced condition in which there is an 25 October 2011 a worldwide voluntary market abnormally high blood (www.hc-sc.gc.ca ). withdrawal of drotrecogin alfa pressure in the arteries of the (activated) (Xigris®). In a lungs (pulmonary arterial recently completed clinical trial hypertension [PAH]). (PROWESS-SHOCK trial), Drospirenone- Symptoms of PAH may include drotrecogin alfa (activated) containing combined shortness of breath, fatigue failed to show a survival and swelling of the body (such oral contraceptives benefit for patients with severe as the ankles and legs). In sepsis and septic shock. reported cases, patients Possible increased risk developed PAH after starting Drotrecogin alfa (activated) is dasatinib, including after more of blood clots indicated for the reduction of than one year of treatment. mortality in adult patients with Information about this risk has Australia (1). The severe sepsis who have a high been added to the Warnings Therapeutic Goods risk of death. and Precautions section of the Administration (TGA)

Sprycel drug label. Dasatinib is announced that new The FDA recommended that used to treat certain adult information about the risk of drotrecogin alfa (activated) patients with Philadelphia venous thromboembolism treatment should not be chromosome-positive chronic (VTE) is being included in the started in new patients and myeloid leukemia (CML) or Product Information should be stopped in patients acute lymphoblastic leukemia documents for drospirenone- currently being treated. All (ALL). containing combined oral remaining products should be contraceptives (Yaz®, returned to the supplier from FDA recommended that Yasmin®) as a result of a whom they were purchased. healthcare professionals should recent safety review by the evaluate patients for signs and TGA. Canada (2). Health Canada symptoms of underlying informed Candians of the cardiopulmonary disease prior TGA reminded health withdrawal of drotrecogin alfa to starting dasatinib and also professionals that oral (Xigris®) from the Canadian during treatment. If PAH is contraceptives are market, in light of the confirmed, dasatinib should be contraindicated in women with company's decision to permanently discontinued. severe or multiple risk withdraw the products from factor(s) for venous or arterial the market worldwide. Drotrecogin alfa is used solely

WHO Pharmaceuticals Newsletter No. 6, 2011 • 5

REGULATORY MATTERS thrombosis. Risk factors Fluoroquinolone include, for example, USA. The US FDA notified ages > 35 years, smoking and healthcare professionals that prolonged immobilisation. The the cholesterol-lowering Patients with clinical needs of patients medicine fenofibric acid myasthenia gravis may should be weighed against the (Trilipix®) may not lower a risk increased muscle possible slight increase in the patient's risk of having a heart weakness risk of VTE, and patients attack or stroke. The FDA should be educated to reviewed the data from the Canada. Health Canada recognize the signs and Action to Control informed that patients with a symptoms of VTE. Cardiovascular Risk in Diabetes rare condition known as (ACCORD) Lipid trial. The myasthenia gravis who take a USA (2). The US FDA notified ACCORD Lipid trial found no fluoroquinolone antibiotic may healthcare professionals of the significant difference in the risk risk a worsening of their release of the final report of of experiencing a major symptoms, including muscle the FDA-funded study that adverse cardiac event between weakness or breathing evaluated the risk of blood the group treated with problems and recommended clots in users of several fenofibrate plus simvastatin that use of fluoroquinolone different hormonal compared with simvastatin antibiotics should be avoided in contraceptives. The FDA’s alone. Information from the patients with a known history review of the results of this trial has been added to the of myasthenia gravis. study, specifically those results Important Limitations of Use According to Health Canada, related to drospirenone- and Warnings and Precautions the risk is considered rare, but containing birth control pills, sections of the fenofibric acid serious. The risk to myasthenia will be presented and physician label and to the gravis patients appears to discussed at the joint meeting patient Medication Guide. apply to formulations taken by of the Reproductive Health mouth (liquids and Drugs Advisory Committee and Fenofibric acid was approved tablets/extended release the Drug Safety and Risk by the FDA in 2008 to treat tablets) or that are injected Management Advisory cholesterol in the blood by intravenously (into a vein). Committee on lowering the total amount of Based on available data, the 8 December 2011. triglycerides and low-density risk does not appear to apply lipoprotein (LDL) cholesterol, to ear or eye drops. (See WHO Pharmaceuticals and increasing the high- Newsletter No. 3, 2010 and density lipoprotein (HDL) Fluoroquinolone drugs No. 4, 2011 for update on the cholesterol. currently marketed in Canada risk of venous are moxifloxacin, ciprofloxacin, thromboembolism in the UK According to the FDA, levofloxacin, norfloxacin and and No. 4 and No. 5, 2011 in fenofibrate at a dose ofloxacin. the USA). equivalent to 135 mg of Trilipix® was not shown to Myasthenia gravis is a rare, Reference: reduce coronary heart disease chronic (long-lasting and (1) Medicines Safety Update morbidity and mortality in recurring) disease that causes Vol. 2, No. 5, October 2011 patients in two large progressive muscle weakness. (www.tga.gov.au ). randomized controlled trials of Muscles affected by this (2) FDA Drug Safety patients with type 2 diabetes condition include eye and face Communication, US FDA mellitus. The FDA muscles, neck and throat 27 October 2011 recommended that healthcare muscles, and limb muscles. (www.fda.gov ). professionals should consider Activity makes the muscle the benefits and risks of weakness worse, and fenofibric acid when deciding symptoms generally improve to prescribe the drug to with rest. Fenofibric acid patients, and counsel patients about those benefits and risks. Health Canada has notified the Canadian manufacturers of Reference: Label Change: found no fluoroquinolone antibiotics to significant difference in FDA Drug Safety update the labelling to include the risk of a major Communication, US FDA, a warning on this risk. adverse cardiac event 9 November 2011 (www.fda.gov ). between the group Reference: Advisories, Warnings and treated with or without fenofibrate Recalls, Health Canada, 7 November 2011

WHO Pharmaceuticals Newsletter No. 6, 2011 • 6

REGULATORY MATTERS

( www.hc-sc.gc.ca ). The MHRA concluded that the • following additional safety possibility of second information should be included malignancy should be in the Product Information: considered in all patients multi-organ hypersensitivity Lenalidomide treated with lenalidomide reactions; psychiatric disorders because the available data do including exacerbation of pre- not allow identification of existing psychiatric disorders Risk of second primary potential risk factors for the and psychiatric symptoms malignancy—update development of second occurring de novo; primary malignancy. cardiovascular disease; UK. The Medicines and dependence potential; use in Healthcare products (See WHO Pharmaceuticals children and adolescents; and Regulatory Agency (MHRA) Newsletter No. 3, 2011 for dose-related adverse advised that healthcare investigation of risk of second reactions; professionals should consider primary malignancies in • the benefits of modafinil the possibility of second myeloma in the UK and No. 5, continued to outweigh the risks primary malignancy in patients 2011 for the risk of new for the indications to improve treated with lenalidomide. The cancers but benefit-risk wakefulness in patients with MHRA also advised that use of balance remains positive in EU excessive daytime sleepiness lenalidomide in unlicensed and reports in WHO global associated with narcolepsy and indications is not ICSR database). in patients with obstructive recommended unless it takes sleep apnoea/hypopnoea place as part of a clinical trial syndrome as an adjunct to Reference: and that patients should be continuous positive airway carefully evaluated before and Drug Safety Update, November pressure (CPAP); during treatment with 2011, Vo.5, issue 4, A1, MHRA, • the indication to treat lenalidomide using routine (www.mhra.gov.uk ). excessive sleepiness cancer screening for associated with moderate-to- occurrence of second primary severe chronic shift work sleep malignancy; treatment should disorder should be revised to be instituted as indicated. Modafinil include only patients where non-pharmacological The available evidence interventions (e.g. planned suggests that there may be a Product information napping) are unsuccessful or small increased risk of updated inappropriate. development of second primary malignancy. Overall in Australia. The Therapeutic The TGA recommended that the trials this was Goods Administration (TGA) modafinil should only be used compensated by greater announced that several safety- as an adjunct to CPAP when overall survival and related changes and used to improve wakefulness progression-free survival in recommendations have been in patients with obstructive patients treated with included in the recently sleep apnoea/hypopnoea lenalidomide for relapsed or updated Product Information syndrome, because modafinil refractory myeloma. The for modafinil (Modavigil®) as a can improve the symptom of balance of benefits and risks result of a recent benefit-risk excessive sleepiness but does for lenalidomide remains review by the TGA. not treat the underlying cause. favourable in its licensed Treatment with modafinil indication. The TGA has reviewed the should be initiated and available clinical trial data, supervised by physicians with In clinical trials of newly national and international post- appropriate experience in the diagnosed multiple myeloma marketing spontaneous treatment of sleep disorders (unauthorised indication), a adverse event data and who have access to sleep four-fold increased incidence of published literature relating to laboratory diagnostic facilities. second primary malignancy modafinil adverse drug Modafinil is contraindicated in has been observed in patients reactions from 1 October 2010. pregnancy. receiving lenalidomide (7%) This review was initiated compared with controls (1.8%). because of post-market The TGA also recommended The median follow-up for reports of serious skin, that the effectiveness of oral participants with newly psychiatric, nervous system contraceptives may be diagnosed myeloma in clinical and cardiovascular adverse impaired due to the induction trials ranges from 27.2 months events. of the metabolising enzyme to 36.5 months. cytochrome P450 3A4. The TGA concluded that: Evaluate cardiovascular,

WHO Pharmaceuticals Newsletter No. 6, 2011 • 7

REGULATORY MATTERS psychiatric and substance possible signs or symptoms of abuse status before starting bladder cancer such as blood Reference: modafinil and monitor patients in the urine, urinary urgency, FDA Drug Safety regularly for skin reactions, pain on urination, or back or Communication, US FDA, cardiovascular disease, abdominal pain. 4 November 2011 psychiatric illness and signs of (www.fda.gov ). modafinil abuse. Start with the (See WHO Pharmaceuticals lowest recommended dose and Newsletter No. 5, 2010 for monitor the patient at every ongoing safety review on dose adjustment. potential increased risk of bladder cancer in the USA and (See WHO Pharmaceuticals No. 4, 2011 for the suspension Newsletter No. 5, 2010 for a in France and risk- review of the benefits and risks characterization study in EU of modafinil in Europe and and reports in WHO global No. 1, 2011 for restriction of ICSR database) the use to narcolepsy in the UK). Reference: Medicines Safety Update Reference: Vol. 2, No. 5, October 2011 Medicines Safety Update (www.tga.gov.au ). Vol. 2, No. 5, October 2011 (www.tga.gov.au ).

Rosiglitazone

Pioglitazone Risk Evaluation and Mitigation Strategy An increased risk of (REMS) - Risk of bladder cancer cardiovascular events

includes Avandia, Australia. The Therapeutic Avandamet and Goods Administration (TGA) Avandaryl advised health professionals to consider the risk of bladder USA. The US FDA announced cancer when prescribing that healthcare providers must pioglitazone and to avoid enrol in the Avandia- pioglitazone in patients with Rosiglitazone Medicines Access bladder cancer or a history of Program if they wish to bladder cancer. prescribe rosiglitazone

medicines to outpatients or According to the TGA, this patients in long-term care advice is based on the facilities after assumption that pioglitazone 18 November 2011. or a metabolite may affect bladder cancer initiation, (See WHO Pharmaceuticals promotion or progression, Newsletter No. 2, 2011 for rather than on clinical evidence suspension of marketing of deterioration in patients authorizations in New Zealand, with bladder cancer or No. 6, 2010 for new recurrence in patients with a restrictions due to the risk of history of bladder cancer. cardiovascular events in

Canada, No. 5, 2010 for The TGA also advised to suspension of marketing consider the risk of bladder authorizations in Europe, new cancer in the care of all restrictions in the USA and patients treated with reports in WHO global ICSR pioglitazone and to advise database and No. 3, 2011 in patients of a small absolute the USA). increased risk of bladder cancer with use of pioglitazone, and ask them to report any

WHO Pharmaceuticals Newsletter No. 6, 2011 • 8

SAFETY OF MEDICINES

not show an increased risk of salt may be better absorbed in Angiotensin II cancer with ARBs. the buccal cavity, there are adequate studies with receptor antagonists (See WHO Pharmaceuticals midazolam hydrochloride that Newsletter No. 4, 2010 for support the dosing schedule Review of evidence does ongoing safety review for authorized for Buccolam. A cancer risk in the USA.) hospital paediatric unit has not suggest any link with recently published its cancer Reference: experience of transferring Press release, EMA, patients to licensed Buccolam Europe. The European 20 October 2011 Medicines Agency (EMA)’s (www.ema.europa.eu ). The MHRA also notified the Committee for Medicinal following safety information: Products for Human Use • hypersensitivity to the (CHMP) has reviewed the midazolam, benzodiazepines, possible link between the use Buccal midazolam or to any of the excipients may of angiotensin II receptor occur; antagonists (blockers) (ARBs) • Midazolam should be used and the occurrence of new Care needed when with caution in patients with cancers, and concluded that transferring from chronic respiratory the evidence does not support unlicensed formulations insufficiency because it may any increased risk of cancer in further depress respiration; patients using these medicines. UK. The Medicines and • Midazolam may accumulate in patients with chronic renal The review was formally Healthcare products Regulatory Agency (MHRA) failure, or impaired hepatic or requested by the Italian cardiac function and should Medicines Agency following the announced that several factors should be considered when therefore be used with caution publication of a meta-analysis in these individuals; which showed a small transferring patients to the authorized buccal midazolam • the most common adverse increased risk of new cancers reactions in clinical trials of (particularly lung cancer) with (Buccolam®) product when an unlicensed medicine other than buccal midazolam were ARBs compared with placebo sedation, somnolence, and other heart medicines Buccolam has been used previously. depressed levels of (7.2% versus 6%). consciousness, respiratory

Buccolam is a new authorized depression, and nausea and The CHMP reviewed all vomiting. available data on the risk of treatment for prolonged acute convulsive seizures and should cancer in patients taking ARBs, Reference: only be used by parents or including the meta-analysis. It Drug Safety Update, October found that the evidence from carers where the patient has been diagnosed with epilepsy. 2011, Vol. 5, issue 3, A2, the meta-analysis was weak, MHRA, (www.mhra.gov.uk ). noting several problems with For infants aged three to six months, treatment should only the quality of the data, specifically that patients in the be in hospital, where trials were not followed up for monitoring is possible and long enough to clearly resuscitation equipment is Citalopram establish a link between ARBs available. Buccal midazolam may be considered as an and cancer, information on the Review and assess the risk of cancer before start of alternative to rectal diazepam need for revised dosing treatment was lacking, and for the treatment of prolonged there was a possibility of seizures. Various buccal recommendations publication bias, whereby midazolam preparations have studies that showed a link with been used in children as Canada. Health Canada cancer were more likely to unlicensed medicines, including announced that it is reviewing have been included in the Buccolam prior to authorization. the heart-related safety of analysis. citalopram in light of new Buccolam is half the strength study data suggesting that The CHMP also reviewed data of some other unlicensed high doses (60 mg/day) can from large population-based preparations. It contains affect the electrical activity of studies and more complete hydrochloride salt, whereas the heart. The changes in meta-analyses that did not some other preparations electrical activity could have the same methodological contain the maleate salt of potentially lead to serious, problems as the original meta- midazolam. Although it is possibly fatal abnormal heart analysis, and the results did suggested that the maleate rhythms.

WHO Pharmaceuticals Newsletter No. 6, 2011 • 9

SAFETY OF MEDICINES

Linezolid methylene blue and Health Canada is currently serotonergic psychiatric reviewing the available data medications. Most cases from and assessing the need for Serious CNS reactions the FDA's Adverse Event revised dosing possible in patients Reporting System (AERS) of recommendations and will take taking certain serotonin syndrome in patients appropriate action based on psychiatric medications given serotonergic psychiatric the outcome of the review, medications and methylene including working with the USA. The US FDA updated blue occurred in the context of companies to update the information on the potential parathyroid surgery, which prescribing information. New drug interaction between involved the intravenous safety information will be linezolid (Zyvox®) and administration of methylene communicated to healthcare serotonergic psychiatric blue as a visualizing agent. professionals and the public as medications. Not all Methylene blue doses ranged soon as possible, once the serotonergic psychiatric drugs from 1 mg/kg to 8 mg/kg. review is complete. have an equal capacity to cause serotonin syndrome with According to the FDA, it is not Health Canada recommended linezolid. Most cases from the known whether there is a risk that patients with questions or FDA's Adverse Event Reporting of serotonin syndrome in concerns about citalopram System (AERS) of serotonin patients taking serotonergic should talk to their healthcare syndrome with linezolid psychiatric medications who professional first. Patients occurred in patients taking are given methylene blue by should not stop taking specific serotonergic other routes (e.g. orally or by citalopram or change dose psychiatric drugs, namely a local tissue injection) or at without first talking to selective serotonin reuptake intravenous doses lower than healthcare professional, as this inhibitor (SSRI) or a serotonin 1 mg/kg, because methylene can cause side effects such as norepinephrine reuptake blue is not an FDA-approved dizziness, feelings of agitation inhibitor (SNRI). It is unclear drug at this time, and limited or anxiety, difficulty at this time whether linezolid data exist regarding its use in concentrating, abnormal administration in patients various settings. dreams, nausea or vomiting. receiving other psychiatric drugs with lesser degrees of In addition, not all serotonergic Health Canada also serotonergic activity poses a psychiatric drugs have an recommended to seek comparable risk. equal capacity to cause immediate care if patients serotonin syndrome with experience an abnormal (See WHO Pharmaceuticals methylene blue. The cases of heartbeat, shortness of breath, Newsletter No. 4, 2011 for serotonin syndrome with dizziness, or fainting while Serious CNS reactions possible methylene blue occurred in taking citalopram and advised in patients taking certain patients taking specific that if patients have an psychiatric medications in the serotonergic psychiatric drugs, underlying heart condition US). namely a selective serotonin and/or have a history of low reuptake inhibitor (SSRI), a levels of potassium or Reference: serotonin norepinephrine magnesium in the blood, the FDA Drug Safety reuptake inhibitor (SNRI), or patients may be at a higher Communication, US FDA, clomipramine. It is unclear at risk of developing an abnormal 21 October 2011 this time whether intravenous heart rhythm. (www.fda.gov ). methylene blue administration in patients receiving other (See WHO Pharmaceuticals psychiatric drugs with lesser Newsletter No. 5, 2011 for degrees of serotonergic activity abnormal heart rhythms poses a comparable risk. associated with high dose in Methylene Blue the USA). (See WHO Pharmaceuticals Newsletter No. 4, 2011 for Serious CNS reactions Reference: stronger warnings on risk of Advisories, Warnings and possible when given to abnormal muscle movements Recalls, Health Canada, patients taking certain in the US). 13 October 2011 psychiatric medications (www.hc-sc.gc.ca ). Reference: USA. The US FDA updated FDA Drug Safety healthcare professionals and Communication, US FDA, the public on the potential 21 October 2011 drug interaction between (www.fda.gov ).

WHO Pharmaceuticals Newsletter No. 6, 2011 • 10

SAFETY OF MEDICINES

anaphylactic reactions during • outcomes of malignancy surgery. The Committee also (treatments, event outcome). Pholcodine noted that pholcodine- containing medicines have (See WHO Pharmaceuticals been available for the Newsletter No. 3, 2011 for No firm evidence of treatment of non-productive update on reports of cross-sensitization cough in the EU for decades hepatosplenic T-cell lymphoma between pholcodine and and existing data confirm a in adolescents and young neuromuscular blocking positive benefit-risk balance of adults in the US). these medicines. The agents used during Committee was therefore of Reference: surgery the opinion that the marketing FDA Drug Safety authorisations of pholcodine Communication, US FDA, Europe. The EMA’s CHMP should be maintained in all EU 4 November 2011 confirmed that the benefits of Member States where it is www.fda.gov pholcodine-containing cough ( ). currently authorized and that medicines outweigh their risks no further regulatory action is and that these medicines necessary. should remain available for the treatment of non-productive Reference: (dry) cough in children and Press release, EMA, adults. Patients taking 18 November 2011 pholcodine-containing (www.ema.europa.eu ). medicines can continue to do so, and should contact their doctor or pharmacist if they have any questions. Tumor Necrosis The review of pholcodine- Factor (TNF) containing medicines was blockers, initiated because of concerns that there could be cross- Azathioprine and/or sensitization between Mercaptopurine pholcodine and neuromuscular blocking agents (NMBAs). It was suspected that this in turn Update on reports of could lead to anaphylactic hepatosplenic T-cell reactions in some patients lymphoma in adolescents receiving NMBAs during and young adults emergency surgery who had previously taken pholcodine- USA. The US FDA announced containing cough medicines. that healthcare professionals These concerns were raised by should remain vigilant for a study that indicated that the cases of malignancy in patients reduction of pholcodine treated with TNF blockers, and consumption following its report such cases to MedWatch. withdrawal from the market in The reports should include: Sweden and Norway was • patient characteristics associated with a decrease of (age, gender, no patient reports of anaphylactic identifiers); reactions to NMBAs in these • risk factors for two countries. malignancy; • exposure to other immune Following a thorough review of suppressing products or all available data on the safety products with risk of and efficacy of pholcodine- malignancy; containing cough medicines, • indication for TNF blocker the Committee found no firm treatment; evidence to substantiate the • TNF blocker exposure hypothesis of cross- (duration, dose); sensitization between • cancer diagnosis (date of pholcodine and NMBAs and a diagnosis, stage); subsequent increased risk of • biopsy results;

WHO Pharmaceuticals Newsletter No. 6, 2011 • 11

FEATURE

A training course on Cohort Event Monitoring of medicines used in HIV treatment programmes

Sten Olsson, Uppsala Monitoring Centre (UMC), Sweden

A one-week training course on Cohort Event Monitoring (CEM) of anti-retroviral (ARV) treatment was organized in Kiev, Ukraine, 21 – 25 November, 2011, initiated through the Monitoring Medicines project. Monitoring Medicines was developed by WHO and is coordinated by the Uppsala Monitoring Centre (UMC) with funding from the Seventh Framework (FP-7) Programme of the European Commission. The course was opened by Kees de Joncheere, WHO Representative to Ukraine, and Vasyl’ Blikhar, Head, State Expert Centre, Ministry of Health, Ukraine. One of the main objectives of the training was to bring together key representatives of the HIV/AIDS and pharmacovigilance programmes in Belarus, Moldova and Ukraine and to stimulate a discussion on how to better study medication related problems and how to improve the safety of patients treated with ARVs in these countries. The course was attended by 25 HIV and pharmacovigilance specialists from the three countries.

The training started with an overview of commonly used methodological approaches in pharmacovigilance. Trainers included Pia Caduff-Janossa, Swissmedic, Switzerland, Shanthi Pal, WHO, Alex Dodoo, UMC-Africa and Sten Olsson UMC. An overview of treatment options in HIV/AIDS and common and important patient risk scenarios were provided by Justina Kowalska from the HIV-Programme of Copenhagen University, a Monitoring Medicines partner. Training on the specifics of the CEM methodology and the CemFlow record management system was provided by Geraldine Hill, University of Dunedin, New Zealand, Henry Irunde, TFDA, Tanzania, Comfort Suku, NAFDAC, Nigeria and Magnus Wallberg, UMC. Steve Corquaye, an HIV patient counsellor from Accra, Ghana, shared his knowledge of patient perceptions of medication related risks and how to manage them. Lectures were carried out using simultaneous translation between English and Russian.

At the end of the training the country representatives were requested to start working on a draft proposal for a pilot Cohort Event Monitoring programme of ARVs to be carried out in their respective countries. Once the proposals are completed and submitted to WHO in early 2012, one will be selected for a limited implementation grant from the Monitoring Medicines project. Course participants and trainers highly appreciated the unique opportunity to discuss methods and approaches to improve the safety situation of patients on ARVs in the three countries: Belarus, Moldova and Ukraine. The local host, Ihor Perehinets of the WHO office in Ukraine, was given much praise for his efficient arrangements and the hospitability organized for the participants.

Announcement:

The Asia Pacific Conference on National Medicines Policies (APCNMP) will take place in Sydney, Australia from 26 to 29 May 2012. This conference is being held in collaboration with National Prescribing Service (NPS): Better Choices, Better Health (Australia's independent quality use of medicines implementation body), the Australian Government Department of Health and Ageing, the University of Newcastle and the World Health Organization.

Further details are available at: http://www.apcnmp2012.com.au/

WHO Pharmaceuticals Newsletter No. 6, 2011 • 12