2017 WHO Pharmaceuticals

No.5 NEWSLETTER

The WHO Pharmaceuticals Newsletter provides you with the latest information on the safety of medicines

WHO Vision for Medicines Safety and legal actions taken by regulatory authorities around No country left behind: the world. It also provides signals based on information worldwide pharmacovigilance for safer medicines, safer patients derived from the WHO global database of individual case safety reports, VigiBase.

This newsletter includes two brief reports, on the The aim of the Newsletter is to disseminate regulatory Pharmacovigilance Workshop held in Seoul for APEC information on the safety of countries and the workshop on ATC/DDD and drug pharmaceutical products, utilization research held in Rabat. based on communications received from our network of national pharmacovigilance centres and other sources such as specialized bulletins and journals, as well as partners in WHO.

The information is produced in the form of résumés in English, full texts of which may be obtained on request from:

Safety and Vigilance: Medicines, EMP-HIS, World Health Organization, 1211 Geneva 27, Switzerland, Contents E -mail address: [email protected] This Newsletter is also available at: Regulatory matters http://www.who.int/medicines Safety of medicines

Signal

Feature

© World Health Organization 2017

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Table of Contents

Regulatory Matters

Atypical antipsychotics ...... 5 Azithromycin ...... 5 Combined use of or with benzodiazepines or CNS depressants ...... 5 Dabigatran ...... 6 Doxycycline ...... 6 Gadolinium based contrast agents for MRI ...... 6 ampoule ...... 6 Ibrutinib ...... 7 Laninamivir...... 7 Methylprednisolone injections containing lactose ...... 7 Palivizumab ...... 7 Paracetamol (modified- or prolonged-release) ...... 8 Riociguat ...... 8 Selexipag ...... 8 Sodium polystyrene sulfonate ...... 9 based medicines ...... 9 Warfarin ...... 9

Safety of Medicines

Brivudine ...... 10 Corticosteroids ...... 10 Desloratadine...... 10 Direct-acting antivirals (DAAs) ...... 11 Fluindione...... 11 Iron isomaltoside ...... 11 ...... 12 Lithium ...... 12 Obeticholic acid ...... 12 Pembrolizumab ...... 12 Prasugrel ...... 13 Teriflunomide ...... 13

WHO Pharmaceuticals Newsletter No. 5, 2017 • 3 Table of Contents

Signal

Amitriptyline and dry eyes – an ADR overlooked in labelling ...... 14 Insufficiently labelled ADRs: , chest pain and headache while using noscapine ...... 15 Complete loss of libido reported for women on systemic hormonal contraceptive ...... 15

Feature

APEC Harmonization Center (AHC) Pharmacovigilance Workshop, Seoul, 11-12 September 2017 ...... 19 The second workshop to integrate Anatomical Therapeutic Chemical (ATC) and Defined Daily Dose (DDD) in drug utilization research ...... 21

WHO Pharmaceuticals Newsletter No. 5, 2017 • 4 Regulatory Matters

Atypical with the use of atypical (See WHO Pharmaceuticals Newsletter No.5, antipsychotics. In the majority 2016: Risk of acute generalized antipsychotics of these reports, patients exanthematous pustulosis in India) recovered when they stopped Potential risk of sleep the treatment and in some walking and sleep-related cases, the events returned Combined use of eating disorder when patients resumed the treatment. The drug was taken buprenorphine or Canada. Health Canada as recommended and the methadone with recommends that the product events appeared to happen benzodiazepines or safety information for all more often with higher doses. CNS depressants atypical antipsychotics should Overall, the review of these be updated to include risks of case reports suggested a link management sleep walking (SW) and sleep- between the use of atypical can reduce risks of serious related eating disorder (SRED). antipsychotics and SW or SRED. adverse effects Atypical antipsychotics are Reference: USA. The US Food and Drug used to treat mental disorders Summary Safety Review, Administration (FDA) has such as schizophrenia, bipolar Health Canada, 21 September required that drug labels for disorder and depression. 2017 (www.hc-sc.gc.ca) buprenorphine and methadone Health Canada reviewed the potential risk of SW and SRED medicines (medication assisted with the use of atypical treatment, MAT) are updated antipsychotics, following the Azithromycin to include detailed publication of a case report recommendations for which described these events Risk of acute generalized minimizing the use of MAT medicines and benzodiazepines in a patient treated with exanthematous pustulosis ziprasidone. together. Japan. The Ministry of Health, At the time of the review, Medicines containing Labour and Welfare (MHLW) Health Canada had received a buprenorphine or methadone and the Pharmaceuticals and total of 13 unique Canadian as the active ingredient are Medical Devices Agency reports of SW and SRED FDA-approved to treat (PMDA) have announced that suspected to be linked to the addiction and dependency. MAT the package insert for use of atypical antipsychotics. should not be withheld from azithromycin (Zithromax®) has In the review it was suggested patients taking been updated to include the that of these 13 reports, two benzodiazepines or other drugs risk of acute generalized cases of sleep disorder were that depress the central exanthematous pustulosis as a likely to be linked to atypical nervous system (CNS), despite clinically significant adverse antipsychotics use. The the risk of serious adverse reaction. patients recovered when they effects, as harm caused by stopped the treatment. Six Azithromycin is an untreated opioid addiction reports, out of 13, were found antimicrobial used for a usually outweighs risks. to have a possible link. Other number of bacterial infections Careful medication risk factors such as pre- caused by strains of genus management by health-care existing conditions, history of Staphylococcus, Streptococcus, professionals can reduce these sleep disorders or use of other Pneumococcus, Neisseria risks. could have gonorrhoeae, Moraxella contributed to the events; (Branhamella) catarrhalis, The FDA recommended that however, a link could not be Haemophilus influenzae, health-care professionals ruled out. The five remaining Legionella pneumophila, should take several actions and reports could not be assessed Peptostreptococcus, Prevotella, precautions and develop a due to insufficient information. Chlamydia, and Mycoplasma. treatment plan when buprenorphine or methadone is This safety review evaluated One case of acute generalised used in combination with information from 413 exanthematous pustulosis has benzodiazepines or other CNS international reports of SW and been reported in Japan. A depressants. SRED suspected to be causal relationship could not be associated with the use of excluded in this case. In Reference: atypical antipsychotics, but addition, the company core Drug Safety Communication, these reports provided limited datasheet (CCDS) has been US FDA, 6 September 2017 additional information. updated. (www.fda.gov)

In addition, Health Canada Reference: found 23 published case Revision of Precautions, reports of SW and SRED MHLW/PMDA, 8 August 2017 suspected to be associated (www.pmda.go.jp/english/) WHO Pharmaceuticals Newsletter No. 5, 2017 • 5 Regulatory Matters

Dabigatran to this safety issue including (See WHO Pharmaceuticals Newsletters screening of the WHO global No.4, 2017: Restrictions on use in EU, No harmful effects identified with brain Risk of acute hepatic failure, database of Individual Case Safety Reports, VigiBase. In retention in the US and No.5, 2015: Possible hepatic function disorder, risk of brain deposits with repeated use in addition, a literature review and the US) was conducted. Japan. The MHLW and the The SFDA concluded that the PMDA have announced that the available evidence suggests a package insert for dabigatran probable association between Hyoscine (Prazaxa®) has been updated doxycycline and FDE. butylbromide to include the risks of acute ampoule hepatic failure, hepatic function Reference: disorder and jaundice as Based on the communication Caution of use in patients clinically significant adverse from Saudi Food and Drug with pre-existing cardiac Authority, December 2016 reactions. conditions

Dabigatran is used to reduce Australia. The Therapeutic the risk of ischemic stroke and Goods Administration (TGA) systemic embolism in patients Gadolinium based has updated product with nonvalvular atrial contrast agents for information for hyoscine fibrillation. MRI butylbromide (Buscopan®) to A total of five cases associated include a caution regarding the with acute hepatic failure, Retention of gadolinium in use of hyoscine ampoules in hepatic function disorder and the brain patients with pre-existing jaundice have been reported in cardiac conditions (for example Japan. Of these, a causal New Zealand. The Medicines cardiac failure, coronary heart relationship could not be and Medical Devices Safety disease). The Australian excluded in one case. Authority (Medsafe) has product information for updated the data sheet for hyoscine butylbromide already Reference: gadolinium based contrast lists tachycardia, decreased Revision of Precautions, agents (GBCAs) with blood pressure and MHLW/PMDA, 12 September information about the retention as potential adverse effects, 2017 (www.pmda.go.jp/english/) of gadolinium in the brain. but the product information Medsafe has stated that has been updated to include a although GBCAs enter the brain, stronger warning in the and so far no harm has been precautions section because Doxycycline identified due to retention, use these adverse events can be should be restricted. more serious in patients with Risk of fixed drug eruptions cardiac conditions. Monitoring GBCAs are used to enhance of these patients is advised and Saudi Arabia. The Saudi Food magnetic resonance (MR) emergency equipment and and Drug Authority (SFDA) has images. personnel trained in its use updated the summary of must be readily available. product characteristics and Medsafe and the Medicines Adverse Reactions Committee patient information leaflet for Hyoscine butylbromide (MARC) recently conducted a doxycycline to include the risk ampoules, administered by safety review of GBCAs. It was of fixed drug eruptions (FDE). intramuscular or slow concluded that the use of intravenous injection, are used Doxycycline is a tetracycline GBCAs should be restricted to to treat , broad-spectrum antibiotic with situations where they are biliary and renal spasms, and bacteriostatic characteristics. It expected to provide additional are used as a diagnostic in is used as treatment or information so that the radiology. prophylaxis against a wide patient’s condition is diagnosed range of susceptible strains of or monitored correctly. There are 28 cases describing gram-negative and gram- tachycardia and/or hypotension Medsafe will continue to positive bacteria and other relating to use of hyoscine monitor the safety of GBCAs, microorganisms. butylbromide in the TGA's provide more information and adverse events database. An The SFDA initiated the take further action if necessary. additional four cases describe investigation based on a signal anaphylactic reactions. There is observed in a published case Reference: insufficient clinical information report examining potential Safety Information, Medsafe, provided to determine whether associations between 21 August 2017 or not these reactions occurred doxycycline and risk of FDE. As (www.medsafe.govt.nz/) in people with pre-existing a result, the SFDA reviewed cardiac conditions. None of the available evidence related

WHO Pharmaceuticals Newsletter No. 5, 2017 • 6 Regulatory Matters these cases reported death, sudden cardiac death in containing lactose will be cardiac arrest or myocardial patients exposed to ibrutinib. revised to include a contra- infarction. The review also identified two indication in patients allergic to spontaneous ADRs of cow's milk proteins. In addition, Reference: ventricular tachyarrhythmia in the vial and packaging of these Medicines Safety Update, TGA, which the role of ibrutinib could medicines will be clearly Vol. 8, No. 4, August- not be excluded. marked with a warning against September 2017 use in patients with cow’s milk (www.tga.gov.au) The review identified eight allergy. cases of hepatitis B (See WHO Pharmaceuticals Newsletter No.2, 2017: Risk of serious adverse effects in reactivation in which the role of Methylprednisolone injections patients with underlying cardiac disease in ibrutinib was considered are used to treat the symptoms the United Kingdom) probable or possible. of severe allergic reactions and other inflammatory conditions. Reference: Drug Safety Update, MHRA, In a review it was found that Ibrutinib Volume 11, issue 1: 1, August methylprednisolone injections 2017 (www.gov.uk/mhra) containing lactose derived from Reports of ventricular cow’s milk may also contain traces of cow’s milk proteins tachyarrhythmia; risk of which can trigger allergic hepatitis B reactivation and Laninamivir reactions. This is of particular opportunistic infections concern in patients already Risk of bronchial spasm, and being treated for an allergic The United Kingdom. The dyspnoea reaction as they are more Medicines and Healthcare prone to developing new Products Regulatory Agency Japan. The MHLW and the allergic reactions. (MHRA) has updated the PMDA have announced that the product information of ibrutinib package insert for laninamivir Considering that (Imbruvica®) to include (Inavir®) has been updated to methylprednisolone is used for ventricular tachyarrhythmia include the risk of bronchial the treatment of severe allergic (common) and hepatitis B virus spasm and dyspnoea as reactions in an emergency reactivation (uncommon) as clinically significant adverse setting where details of the adverse reactions. reactions. patients’ allergies may not Opportunistic infections are always be known, the Co- already listed in the product Laninamivir is indicated for ordination Group for Mutual information of ibrutinib. treatment and prophylaxis of Recognition and Decentralised influenza A and B virus Procedures – Human (CMDh) Ibrutinib is indicated for the infection. confirmed that the most treatment of adult patients effective way of minimising any with: Eight cases associated with risk is to remove cow’s milk • mantle cell lymphoma who bronchial spasm and dyspnoea proteins from the preparation. have received at least one have been reported in Japan. Companies have been asked to prior therapy Of these, a causal relationship provide data allowing the • chronic lymphocytic could not be excluded in three replacement of formulations leukaemia (CLL), including cases. containing lactose from cow’s CLL with deletion 17p Reference: milk; this data should be • Waldenström’s Revision of Precautions, provided by the middle of 2019. macroglobulinaemia MHLW/PMDA, 8 August 2017 Reference: A routine European review (www.pmda.go.jp/english/) News and press releases, EMA, examined the safety profile of 1 August 2017 ibrutinib. Data from (www.ema.europa.eu) randomised controlled trials and the scientific literature Methylprednisolone were assessed. Worldwide injections containing spontaneous suspected lactose adverse drug reaction (ADR) Palivizumab reports were also reviewed. Contraindication to patients allergic to cow's milk Risk of thrombocytopenia In a 2017 study of case reports proteins. of relevant events from post- Japan. The MHLW and the marketing sources and clinical EU. The European Medicines PMDA have announced that the trial data, the authors Agency (EMA) has made an package insert for palivizumab identified 11 cases of announcement that the product (Synagis®) has been updated ventricular information for to include the risk of tachycardia/ventricular methylprednisolone injections thrombocytopenia as a fibrillation and six cases of WHO Pharmaceuticals Newsletter No. 5, 2017 • 7 Regulatory Matters clinically significant adverse immediate-release or modified- may outweigh the benefits in reaction. release products, making it some patients. difficult to decide what type of Palivizumab is indicated for: One case associated with management is needed. The prevention of serious lower adverse reactions has been committee could not identify a respiratory tract diseases reported in patients with way to minimise the risk to caused by respiratory syncytial symptomatic pulmonary patients, or a feasible and virus infection in high-risk hypertension associated with standardised way to adapt the neonates and infants and idiopathic interstitial management of paracetamol children. pneumonias in Japan. overdose across the EU to A total of four cases associated allow for treatment of cases Reference: with thrombocytopenia have that involve modified-release Revision of Precautions, been reported in Japan. Of preparations. It concluded on MHLW/PMDA, 3 August 2017 these, a causal relationship balance that the risk following (www.pmda.go.jp/english/) could not be excluded in one overdose with these medicines (See WHO Pharmaceuticals Newsletters case. outweighs the advantage of No.1, 2017: Contraindicated for use in having a longer-acting Reference: patients with pulmonary hypertension preparation. associated with idiopathic interstitial Revision of Precautions, pneumonia in Malaysia and No. 5, 2016: Reference: MHLW/PMDA, 12 September Contraindicated in patients with pulmonary 2017 (www.pmda.go.jp/english/) News and press releases, EMA, hypertension associated with idiopathic 1 September 2017 interstitial pneumonias in the United (www.ema.europa.eu) Kingdom)

Paracetamol (modified- or prolonged-release) Riociguat Selexipag

Modified- or prolonged- Increased incidences of Contraindication with release preparations should serious adverse events and potent inhibitors of be suspended from fatal outcomes cytochrome P450 2C8 marketing Spain. The Agencia Española Japan. The MHLW and the de Medicamentos y Productos EU. The EMA has PMDA have announced that the Sanitarios (AEMPS) has recommended that modified- package insert for riociguat informed health-care or prolonged-release (Adempas®) should be professionals that the paracetamol products should updated to include an be suspended from the market. important precaution on the concomitant use of selexipag (Uptravi®) with potent This is in view of the risks to risk of serious adverse events cytochrome P4502C8 (CYP2C8) patients from the complex way and fatal outcomes. these medicines release inhibitors (for example, paracetamol into the body after Riociguat is indicated to treat gemfibrozil) is contraindicated an overdose. inoperable chronic as exposure to the active thromboembolic pulmonary metabolite of selexipag can be Paracetamol is a medicine that hypertension (CTEPH) or increased causing adverse has been widely used for many postoperative persistent or reactions. years to relieve pain and fever recurrent CTEPH, and Selexipag is indicated for the in adults and children. pulmonary arterial long-term treatment of hypertension. The review of modified-release pulmonary arterial paracetamol has been carried A clinical study in patients with hypertension (PAH) in adults out by the EMA’s symptomatic pulmonary (in combination, or, as Pharmacovigilance Risk hypertension associated with monotherapy in certain cases). Assessment Committee (PRAC). idiopathic interstitial In a pharmacokinetic study, The PRAC evaluated published pneumonias (RISE-IIP Study) the number and severity of studies and reports of overdose was terminated early due to adverse reactions reported with these medicines, increased incidences of serious following concomitant consulted experts in the adverse events and fatal administration of selexipag and management of poisoning and outcomes observed in patients assessed how overdose with receiving riociguat compared gemfibrozil (a potent CYP2C98 inhibitor) were higher than paracetamol is managed in the with patients receiving placebo. those reported with selexipag EU and other parts of the world. Similar risks are expected in alone. This is consistent with patients with pulmonary In many cases, it may not be increased levels of the active arterial hypertension known whether an overdose of metabolite. paracetamol involves associated with interstitial pneumopathy and the risks WHO Pharmaceuticals Newsletter No. 5, 2017 • 8 Regulatory Matters

Regarding use in conjunction Reference: Warfarin is used for treatment with CYP2C8 inducers, it was Drug Safety Communication, and prevention of observed that the concomitant US FDA, 6 September 2017 thromboembolism (including use of rifampicin and selexipag (www.fda.gov) venous thrombosis, myocardial does not affect blood levels of infarction, pulmonary embolism, (See WHO Pharmaceuticals Newsletter No6, selexipag but reduces levels of 2015: Potential risk of drug interaction in brain embolism and, slowly the metabolite and it may be US) progressive cerebral necessary to adjust the dose of thrombosis). selexipag if used concomitantly Eleven cases associated with with rifampicin or other calciphylaxis have been inducers of CYP2C8 (e.g. Trimebutine based reported in Japan and there is carbamazepine, phenytoin, medicines an overseas report published in and St. John's wort). Contraindication in children the literature describing The AEMPS has advised health- calciphylaxis with the use of under two years of age care professionals to follow the warfarin. In addition, package recommendations for use France. L’Agence Nationale de inserts in Europe and the established in the technical Sécurité du Médicament et des United States have been data sheet of selexipag and in Produits de Santé (ANSM) has revised. particular, guidance on stated that the use of Reference: interactions with other trimebutine based medicines in Revision of Precautions, medicinal products which may children under two years of age MHLW/PMDA, 8 August 2017 result in a need for dosage is contraindicated. (www.pmda.go.jp/english/) adjustment. Trimebutine is an (See WHO Pharmaceuticals Newsletters Reference: antispasmodic indicated in No.2, 2017: Risk of calciphylaxis in Malaysia Información dirigida a gastroenterology. and No.4, 2016: Reports of calciphylaxis in profesionales sanitarios, AEMPS, the US) 14 June 2017, Spain Cases with neurological (www.aemps.gob.es) (drowsiness and seizures) and cardiac (bradycardia) adverse drug reactions have been reported, particularly in Sodium polystyrene children under the age of two sulfonate years. These were due to overdoses that occurred Potential drug-drug following a medication error. interaction Due to low level of evidence of USA. The US FDA has updated efficacy and the risk of serious the drug labels for sodium adverse drug reactions in polystyrene sulfonate children under the age of two (Kayexalate®) to include years, trimebutine-based information warning patients to medicines are now avoid taking this medicine at contraindicated in this age the same time as other oral group. medicines. Reference: Sodium polystyrene sulfonate Point d’information, ANSM, is used to treat hyperkalaemia, 28 July 2017, France a serious condition in which the (www.ansm.sante.fr) amount of potassium in the blood is too high. A study found that sodium Warfarin polystyrene sulfonate binds to many commonly prescribed Risk of calciphylaxis oral medicines, decreasing the absorption and therefore Japan. The MHLW and the effectiveness of those oral PMDA have announced that the medicines. To reduce this package insert for warfarin has likelihood, the FDA has been updated to include the recommended separating the risk of calciphylaxis as a dosing of sodium polystyrene clinically significant adverse sulfonate from other orally reaction. administered medicines by at least 3 hours.

WHO Pharmaceuticals Newsletter No. 5, 2017 • 9 Safety of Medicines

Brivudine local as well as systemic No.2, 2015, describing cases of administration of abnormal heart rhythm Drug-drug interaction with corticosteroids. suspected to be associated with the use of loratadine and anti-neoplastic Corticosteroids are indicated desloratadine. Desloratadine is chemotherapy agents or for a wide variety of indications used to relieve symptoms of in the treatment or suppression topical 5-fluorouracil seasonal allergy or allergy of inflammatory and allergic preparations caused by pollen or dust (hay disorders, commonly including: fever). Spain. The AEMPS has • asthma and allergic rhinitis reminded health-care • systemic inflammatory At the time of the review, professionals that brivudine disorders, for example, Health Canada had received 10 (Nervinex®) should not be rheumatoid arthritis Canadian reports of abnormal administered to patients • skin conditions, for heart rhythm suspected to be receiving anti-neoplastic example, eczema associated with desloratadine chemotherapy, especially if use. Of these, one case was CSCR is a rare adverse effect they are treated with 5- further assessed. The review of that occurs with all fluorouracil, including topical this case found a possible link formulations and has been preparations. between desloratadine and described after local abnormal heart rhythm. administration of Brivudine is indicated for the However, other factors such as corticosteroids via inhaled and early treatment of acute herpes concomitant medicines may intranasal, epidural, intra- zoster in immunocompromized have played a role. The articular, topical dermal and adults. remaining nine reports were periocular routes. Although excluded from further review blurred vision is a symptom of In June 2012, the AEMPS because the test results to CSCR, it is also an established issued an information note confirm the abnormal heart adverse effect of steroid alerting health-care rhythm were not available. professionals about the treatment. The causes of potentially fatal interaction blurred vision are various and In addition, Health Canada between brivudine and can also include cataract and reviewed 13 international antineoplastic drugs containing glaucoma. reports of abnormal heart 5-fluoropyrimidines: rhythm suspected to be The MHRA has recommended 5-fluorouracil and a associated with the use of that patients are provided with combination of medicinal desloratadine that were guidance to report any vision products containing these provided by the manufacturer. problems or disturbances. If a active ingredients or other Of these, four reports were patient has received treatment 5-fluoropyrimidines. further assessed. A link with local administration of a between these four reports and corticosteroid and presents Despite the information note, abnormal heart rhythm could with visual symptoms, referral the Spanish pharmacovigilance not be established due to other to an ophthalmologist should system continues to receive factors that may have played a be considered. reports of fatal cases due to role such as: concomitant co-administration of brivudine Reference: medicines, underlying heart and 5-fluoropyrimidines Drug Safety Update, MHRA, conditions, and administration containing antineoplastics. Volume 11, issue 1: 2, August of higher than recommended Since the issue of the note in 2017 (www.gov.uk/mhra) doses of desloratadine. 2012, seven new fatal cases have been reported in Spain. A search in the WHO database of Individual Case Safety Reference: Reports, VigiBase identified 35 Notas informativas, AEMPS, Desloratadine cases of abnormal heart 7 September 2017, Spain Potential risk of QT interval rhythm suspected to be (www.aemps.gob.es) associated with desloratadine prolongation: not enough use. A link between the use of evidence desloratadine and the abnormal heart rhythm could Canada. Health Canada has Corticosteroids not be established, as there carried out a safety review to was not enough information in Rare risk of central serous look at the potential risk of QT the reports to draw conclusions. chorioretinopathy interval prolongation with the use of over-the-counter (OTC) Published scientific studies The United Kingdom. The desloratadine-containing have shown that desloratadine MHRA has provided advice to products. This safety review is not associated with abnormal health-care professionals on was triggered by a signal heart rhythm in humans. the risk of central serous publication in the WHO chorioretinopathy (CSCR) with Pharmaceuticals Newsletter WHO Pharmaceuticals Newsletter No. 5, 2017 • 10 Safety of Medicines

Health Canada's review of the Fluindione (Cosmofer®), iron- available information did not isomaltoside (Monoferro®) and establish a link between the Risk of allergic reaction iron-sucrose (Feriv®, use of desloratadine and Venofer®). These products are abnormal heart rhythm. France. The ANSM has used to treat and prevent iron deficiency. Reference: encouraged health-care Summary Safety Review, professionals to be cautious Recently, the Spanish Health Canada, 10 August when initiating therapy with Pharmacovigilance System 2017 (www.hc-sc.gc.ca) fluindione due the risk of (Sistema Español de allergic reactions, particularly Farmacovigilancia; SEFV) has during the first six months of received large number of treatment. reports of suspected serious Direct-acting Fluindione (Préviscan®) is an hypersensitivity reactions antivirals (DAAs) antivitamin K (AVK) class associated with iron- anticoagulant. It is indicated isomaltoside administration. Interaction with warfarin for atrial fibrillation (heart Specifically, as of 5 July 2017, rhythm disorder), venous New Zealand. Medsafe has after a search in the database thrombosis or pulmonary warned that recent evidence of SEFV, Farmacovigilancia embolism. indicates that the use of direct- Española, Datos de Reacciones acting antivirals (DAAs) A survey carried out by the Adversas (FEDRA), a total of together with warfarin may Regional Centre for 108 reported cases of severe result in changes in Pharmacovigilance in Lyon anaphylactic reactions or, of international normalised ratio found that the use of serious clinical situations (INR). In most cases decreases fluindione is more frequently related to anaphylaxis/shock in INR were reported during associated with the occurrence associated with the concomitant treatment. of rare but often severe administration of one of the DRESS-type immuno-allergic intravenous iron preparations DAA regimens are used for the attacks, in particular renal, were identified. treatment of chronic hepatitis C hepatic, haematological or infection. Warfarin Of these 108 severe adverse dermatological disorders. (Coumadin® and Marevan®) is drug reaction reports, 44 were a vitamin K antagonist and is In France, 82% of patients related to the administration of widely used as an treated with AVK received iron-isomaltoside. The rate of anticoagulant. fluindione, 13% of warfarin and reporting on severe 5% of acenocoumarol. These hypersensitivity reactions Medsafe is continuing to data are based on the number (reported cases in relation to monitor reports of adverse of daily defined doses treated patients) is much reactions to DAAs and is consumed in 2016. Warfarin is higher than for other working with companies to the most widely used AVK in intravenous iron preparations. ensure that all DAA data sheets the rest of the world. and consumer medicine All available data are currently information include information Reference: being analyzed in detail, and as on this safety concern. Point d’information, ANSM, a precaution, AEMPS 19 June 2017, France recommends that healthcare Medsafe has recommended (www.ansm.sante.fr) professionals should not start increasing the frequency of INR any new treatment with iron- monitoring during concomitant isomaltoside. treatment and making adjustments when necessary. The AEMPS will report on the Frequent monitoring of INR is Iron isomaltoside final decision to be taken based also required in the post- on the detailed evaluation of all Do not start new treatment treatment follow-up period, available data. particularly if any warfarin dose with iron isomaltoside Reference: adjustment has occurred. Spain. The AEMPS has Notas informativas, AEMPS, Reference: recommended that health-care 19 July 2017, Spain Safety Information, Medsafe, professionals should not start (www.aemps.gob.es) 25 August 2017 any new treatment with iron (www.medsafe.govt.nz/) isomaltoside (Monoferro®) as a precautionary measure. (See WHO Pharmaceuticals Newsletter No.6, 2016: Interaction potential with warfarin In Spain, the following iron and other vitamin K antagonists: changes to preparations for intravenous INR in Ireland) administration are available: iron-carboxymaltose (Ferinject®), iron-dextran

WHO Pharmaceuticals Newsletter No. 5, 2017 • 11 Safety of Medicines

Ketamine information for lithium. A Reference: patient died in 2013 as a result Drug Safety Communication, Risk of severe injury of lithium toxicity and has US FDA, 21 September 2017 prompted this reminder. (www.fda.gov) with repeated and/or prolonged high-dose use As of 17 May 2017, the TGA has received 58 reports in France. The ANSM has which lithium was suspected of Pembrolizumab received reports of serious liver causing toxicity. Two of these injury potentially related to the cases resulted in death. Risk of using repeated and/or prolonged use of high dose ketamine. The Interactions with other pembrolizumab for multiple ASNM has reminded health- medicines were identified as a myeloma in combination care professionals that good contributing factor in 17 cases, with immunomodulatory practice recommendations for and may have played a role in agents use of ketamine should be four other cases. USA. The US FDA has informed implemented. Inappropriate dosing was found the public, health-care to be a contributing cause of It is essential to observe the professionals and oncology toxicity in two cases, and may recommended dosages and clinical investigators about the have contributed to a third monitor the liver function risks associated with the use of case. closely. pembrolizumab (Keytruda®) in Ketamine is indicated as an Reference: combination with anaesthetic agent, alone or in Medicines Safety Update, TGA, dexamethasone and an combination with other Vol. 8, No. 4, August- immunomodulatory agent anaesthetics. September 2017 (lenalidomide or (www.tga.gov.au) pomalidomide) for the Ten cases of serious liver treatment of patients with injuries, including four cases multiple myeloma. leading to , have been reported by health- Pembrolizumab is used for care professionals since 2014. Obeticholic acid certain types of cancers, but is These are cholestatic type not approved for treatment of cholangitis, which may be Risk of serious liver injury multiple myeloma. linked to the repeated and/or USA. The US FDA has warned The FDA statement is based on prolonged administration of that obeticholic acid (Ocaliva®) a review of data from two ketamine. is being incorrectly dosed in clinical trials evaluating the use Reference: some patients with moderate of pembrolizumab combined Point d’information, ANSM, to severe decreases in liver with other treatments in 20 June 2017, France function, resulting in an patients with multiple myeloma. (www.ansm.sante.fr) increased risk of serious liver On 3 July 2017, the FDA injury and death. required that all patients in Obeticholic acid is used to treat these trials should be a rare, chronic liver disease discontinued from further Lithium known as primary biliary investigation with this drug cholangitis (PBC). because, interim results from Risk of toxicity both trials demonstrated an The FDA stated that some increased risk of death for Australia. The TGA has patients are receiving patients receiving reminded health-care excessive doses, at a higher pembrolizumab when it was professionals to remain vigilant than recommended frequency. combined with an for potential signs of lithium Obeticholic acid may also be immunomodulatory agent as toxicity, particularly in patients associated with liver injury in compared to the control group. with risk factors. Early some patients with mild symptoms of lithium toxicity disease who are receiving the The manufacturer was made can occur close to or within the correct dose. The aware of the issue through an serum therapeutic range. recommended dosing and external data monitoring committee recommendation Lithium (Quilonum® and monitoring for patients on and suspended the trials to Lithicarb®), is indicated for the obeticholic acid are described enrolment on 12 June, 2017. treatment of acute mania, in the current drug label. The hypomania and for the FDA is working with the drug Other multiple myeloma clinical prophylaxis of manic- manufacturer, Intercept trials of pembrolizumab and depressive illness. The risk of Pharmaceuticals, to address other combinations are lithium toxicity is adequately these safety concerns. currently undergoing clinical addressed in the product evaluation.

WHO Pharmaceuticals Newsletter No. 5, 2017 • 12 Safety of Medicines

Reference: Reference: injury or nephrolithiasis when Drug Safety Communication, Summary Safety Review, taking teriflunomide. US FDA, 31 August 2017 Health Canada, 28 August Health Canada’s review of the (www.fda.gov) 2017 (www.hc-sc.gc.ca) available information did not

establish a link between the use of teriflunomide and a risk Prasugrel Teriflunomide of sudden onset of renal injury or nephrolithiasis. Potential risk of severe Potential risk of acute renal Reference: cutaneous adverse reactions injury or nephrolithiasis: not Summary Safety Review, (SCAR): not enough enough evidence Health Canada, 4 August 2017 evidence (www.hc-sc.gc.ca) Canada. Health Canada has Canada. Health Canada has reviewed the potential risk of carried out a safety review on sudden onset of acute renal the potential risk of severe injury or nephrolithiasis with cutaneous adverse reactions the use of teriflunomide (SCAR) with the use of (Aubagio®) following safety prasugrel (Effient®) following information received from the cases reported by the manufacturer. manufacturer. Teriflunomide is used to treat Prasugrel is used with low-dose patients with multiple sclerosis acetylsalicylic acid, such as (MS). aspirin, to reduce the risk of At the time of the review, stroke, heart attacks or dying Health Canada received, 55 from a disease related to the reports (all were international) heart or blood vessels. of suspected sudden onset of At the time of the review, injury and 135 reports Health Canada had not (eight of these were Canadian) received any Canadian reports of suspected nephrolithiasis of SCAR linked to the use of with teriflunomide use from the Prasugrel. manufacturer. No additional reports were found in Health The safety review looked at 11 Canada’s Vigilance database. international reports of SCAR in patients treated with prasugrel. Upon review, only two reports In seven of the 11 reports, the of patients with sudden onset link between SCAR and the use of renal injury were considered of prasugrel was considered to to be possibly related to the be possible; however other use of teriflunomide. The factors such as the advanced review of reports of age of the patients and the use nephrolithiasis did not show a of other medications at the link related to the use of same time may have played a teriflunomide. In these reports, role. For the remaining four other factors could have played reports, the condition was a role, such as the MS itself or considered unlikely linked to problems with the bladder. In prasugrel use or there was not addition, information in the enough information to assess reports that described the the link. health of the patient’s kidneys before taking teriflunomide was In the literature, there was no limited. evidence of increased risk of SCAR with the use of prasugrel. In the published scientific literature, there were no Health Canada’s review reports or studies related to concluded that there was not the possible association of enough information available to sudden onset of renal injury or establish a link between the nephrolithiasis with the use of risk of SCAR and the use of teriflunomide. prasugrel. There was limited evidence to suggest that MS patients may be at greater risk of renal

WHO Pharmaceuticals Newsletter No. 5, 2017 • 13 Signal

A signal is defined by WHO as reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Usually more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information. A signal is a hypothesis together with data and arguments and it is important to note that a signal is not only uncertain but also preliminary in nature.

The signals in this Newsletter are based on information derived from reports of suspected adverse drug reactions available in the WHO global database of individual case safety reports (ICSRs), VigiBase. The database contains over 16 million reports of suspected adverse drug reactions, submitted by National Pharmacovigilance Centres participating in the WHO Programme for International Drug Monitoring. VigiBase is, on behalf of the WHO, maintained by the Uppsala Monitoring Centre (UMC) and periodic analysis of VigiBase data is performed in accordance with UMC’s current routine signal detection process. Signals are first communicated to National Pharmacovigilance Centres through SIGNAL (a restricted document from UMC), before being published in this Newsletter. Signal texts from UMC might be edited to some extent by WHO and may differ from the original version. More information regarding the ICSRs, their limitations and proper use, is provided in the UMC Caveat document available at the end of Signal (page 18). For information on the UMC Measures of Disproportionate Reporting please refer to WHO Pharmaceuticals Newsletter Issue No. 1, 2012.

UMC, a WHO Collaborating Centre, is an independent foundation and a centre for international service and scientific research within the field of pharmacovigilance. For more information, visit www.who-umc.org. To leave a comment regarding the signals in this Newsletter, please contact: the Uppsala Monitoring Centre, Box 1051, SE-751 40 Uppsala, Sweden. E-mail: [email protected].

Amitriptyline and dry eyes – an ADR overlooked in labelling Dr Henric Taavola, Uppsala Monitoring Centre

During the joint UMC/Lareb signal detection sprint direct mention of dry eyes or reduced tear flow focusing on patient reports, the adverse reaction in the section for adverse reactions.4,5 ‘dry eyes’ was highlighted for the drug amitriptyline Of the 40 reports of dry eyes in relation to in the WHO global database of individual case amitriptyline in VigiBase, 37 concern female safety reports, VigiBase. As of January 2017, there patients, two male patients, while one lacks were 40 reports on this drug and adverse drug information on patient sex. Half of the reports reaction (ADR) combination in VigiBase, and if the come from the United States, one from New search is extended to all similar drugs with the Zealand and the remainder from various same ATC code (N06AA non-selective monoamine European countries. Among the 40 reports for reuptake inhibitors) the number increases to 60. the combination, 14 have amitriptyline as the Amitriptyline belongs to the class of tricyclic only suspected drug, nine reports have a antidepressants and is used for the treatment of positive dechallenge and one report has a depression, anxiety and chronic pain. It has positive rechallenge. One report told the story effects, inhibiting the of a patient sustaining a corneal ulceration due present in the to eye dryness, a marked reduction in visual central and peripheral nervous systems. This acuity and longstanding eye-problems. Another inhibition has effects on several autonomous patient described the eye dryness as painful. functions such as decreased saliva production, There was also a case where a pre-existing decreased mucus production in the nose and throat, problem with dry eyes was aggravated by the decreased sweating, increased body temperature, use of amitriptyline. dilation of the pupils and reduced bowel movements. One reason, why this adverse reaction may As well as these effects, there is also the reduced have been overlooked in the labelling, could be production of tears, causing the eyes to feel dry.1 that it is well known to many health-care The official labelling in the United States and the professionals as being a consequence of the United Kingdom both mention the anticholinergic anticholinergic effect of amitriptyline, effects of amitriptyline in general along with some especially since ‘anticholinergic effect’ itself is examples, but neither of them mention dry eyes or labelled. However, as it would be far from reduced tear production.2,3 obvious to patients, it would be useful to For the similar drugs and , update the patient information leaflet and the Swedish labels, under the section “Warnings summary of product characteristics of and precautions”, state that contact lens wearers amitriptyline to explicitly list eye dryness as an can sustain injuries to the cornea due to the adverse effect. reduced production of tears. However, there is no

WHO Pharmaceuticals Newsletter No. 5, 2017 • 14 Signal

References 4. FASS. Summary of Product Characteristics 1. Rang HP, Dale MM. Rang and Dale’s for klomipramin (synonym for clomipramine, Pharmacology. 6th ed. Edinburgh: Churchill Anafranil®). Available from: http://www. Livingstone; 2007. fass.se/LIF/product?userType=0&nplId= 2. US DailyMed: Product label for amitriptyline. 19741004000068. Accessed: 24 January Available from: https://dailymed.nlm.nih.gov/ 2017. dailymed/drugInfo.cfm?setid=61d2da8d-b435- 5. FASS. Summary of Product Characteristics 4ada-a013-401786f7cace. Accessed: 24 January for maprotilin (synonym for maprotiline, 2017. Ludiomil®). Available from: http://www. 3. Electronic Medicines Compendium: Summary of fass.se/LIF/product?userType=0&nplId= pro- duct characteristics for amitriptyline. 19790406000046. Accessed: 24 January Available from: https://www. 2017. medicines.org.uk/emc/medicine/25741. Accessed: 24 January 2017.

Insufficiently labelled ADRs: abdominal pain, chest pain and headache while using noscapine Ms Ellen Ederveen, the Netherlands Pharmacovigilance Centre Lareb

During the joint UMC/Lareb signal detection sprint “very painful, feels like your belly/stomach is in October 2016, focusing on patient reports, wrung out”. noscapine, a drug indicated for cough, and various The reported ADRs are not listed in every adverse drug reactions (ADRs) were highlighted in summary of product characteristics (SmPC) or VigiBase, the WHO global database of individual patient information leaflet (PIL). Also, the case safety reports. The most notable ADRs that severity of some of these ADRs is not were reported were abdominal pain, headache, sufficiently described in the label information chest pain and chest discomfort, with a total of 130 for all products. Therefore, it is advisable to individual case safety reports as of 1 November, mention these adverse reactions and to 2016. Of the reports, 99.2% originated from five highlight the possible severity in all SmPCs and countries: Sweden, Norway, Germany, Denmark PILs. and the Netherlands, although noscapine is marketed in several countries worldwide. In the The countries with insufficient labelling have latter two countries, these ADRs are not sufficiently been sent a full assessment. Should it be of labelled. Several patients highlighted the severity of interest, the full assessment is available upon the symptoms. For instance, “terrible pain, I was request. quite sure I had a heart attack or an aneurysm”, “feels like I can hardly breathe”, “terrible abdominal Please email [email protected]. pain, I cried out because of the intense pain”, and

Complete loss of libido reported for women on systemic hormonal contraceptive Ms Sarah Watson, Uppsala Monitoring Centre

The MedDRA preferred term 'loss of libido' was libido' are covered in most summary of product initialy highlighted for two systemic hormonal characteristics and patient information leaflets contraceptives (desogestrel and ethinylestradiol/ for systemic hormonal contraceptives, a levonorgestrel) in the joint UMC/Lareb signal complete loss of libido as reported and detection sprint focusing on patient reports that described by these patients is rarely took place in October 2016. Although the terms mentioned.1,2 'decreased libido', 'increased libido' or 'changes in WHO Pharmaceuticals Newsletter No. 5, 2017 • 15 Signal

Many health-care professionals may know that most experience this adverse drug reaction: “Why systemic hormonal contraceptives are known to be use birth control pills if you never want to have able to affect the libido and in some cases cause a sex?”. The risk of non-compliance in cases like complete loss of libido. The full extent of this effect this is quite evident if the primary reason for does not, however, always seem to be known the patient to take the contraceptive is to among the women using these products. A decrease prevent a . in libido, as listed in many of the patient Another female described how her libido information leaflets, may be acceptable to some gradually disappeared over two years while patients, but a loss of libido as an adverse effect of taking her hormonal contraceptive. When she contraceptive use would be less so. started to have unexpected bleedings, she As of 6 October 2016, there were 694 reports of stopped taking the contraceptive and her libido loss of libido for hormonal contraceptives for returned completely after about one week. systemic use (ATC code G03A) in VigiBase, the A third woman explained that her libido did WHO global database of individual case safety return after discontinuation of the hormonal reports (ICSRs). The top 10 reported drugs within contraceptive, but that she was still struggling this category are shown in Table 1. All have a in her sex life because the reaction to the positive IC value, which means that the adverse 025 effects of the contraceptive had become reaction is reported more often for that drug than associated with so many negative emotions. what would be expected compared to the background of the database, with a statistical Different needs among women and couples significance.3 The reports originate from all influence their decision on which contraceptive continents. Most of the reports concern women in method to use. The potential risk of hormonal the 18 to 44 age group (65%, with an even contraceptives influencing their libido needs to distribution within the age group), which is be communicated to women when prescribing, consistent with the age group most commonly using to enable women who experience this problem hormonal contraceptives. The five most commonly to reconsider their choice of contraceptive co-reported terms are depression, headache, mood method. In a response to one of the patient swings, weight increased and anxiety. Depression is reports the manufacturer made the following a confounder for loss of libido and was co-reported statement: “Since ‘libido decreased’ is listed, on 245 of the reports. The term “libido decreased” therefore loss of libido is considered listed”. has 1743 reports for hormonal contraceptives for However, this does not seem to be sufficiently systemic use in VigiBase, and “libido increased” has informative to patients. 55 reports. Whether or not decrease and loss of libido are more common as adverse drug reactions Although depression could be a confounder for than an increase in libido, or that they are a more loss of libido, there is a sufficient number of serious problem which makes patients more prone reports in VigiBase without this confounder to report, is not possible to say from this data. present. There are also several with depression co-reported that have recorded positive The majority of the 694 reports in VigiBase lack dechallenges. information about any actions taken with the hormonal contraceptives. There are, however, 114 These reports highlight the importance of reports where the causal relationship between the helping consumers make well-informed drug and the adverse drug reaction is strengthened decisions about their treatments and being by positive de- or rechallenges of loss of libido. For aware of potential adverse reactions. Users 112 of the reports, there is a recorded positive who lose their libido while on these dechallenge and two of them documents a positive contraceptives might need to change their rechallenge. Reports with depression co-reported method of birth control in order to sustain their are included in these figures and concern 44 of life quality and reduce the risk of non- these reports. Seventy-seven of the 112 reports compliance. A clearer message in the patient were submitted by consumers/non health information leaflet about the potential loss of professionals. The women describe in their own libido is recommended. words how the complete loss of libido affected their lives and that they were not aware of a possible correlation to their contraceptive. References One user switched from an oral contraceptive with 1. Electronic Medicines Compendium: which she had experienced a decrease in libido to Summary of Product Characteristics for another oral contraceptive and as a result suffered systemic hormonal contraceptives. Available a complete loss of libido during a period of one year. from: www.medicnies.org.uk/ emc/. Once she had stopped the second contraceptive Accessed: 1 November 2016. regime for a month, her libido returned and she 2. US DailyMed: Product label for systemic realised that the loss of libido probably was related to her contraceptive drug. She questioned the hormonal contraceptives. Available from: information about this potential side effect and https://dailymed.nlm.nih. gov/dailymed/. commented that the pills are of no use when you Accessed: 1 November 2016.

WHO Pharmaceuticals Newsletter No. 5, 2017 • 16 Signal

3. Norén GN, Hopstadius J, Bate A. Shrinkage observed-to-expected ratios for robust and transparent large-scale pattern discovery. Stat Methods Med Res. Feb 2013;22(1):57-69.

Table 1. Top 10 reported systemic hormonal contraceptives (ATC G03A) for the MedDRA preferred term loss of libido in VigiBase

Drug No of reports IC025 No of reporting countries

Levonorgestrel 406 3.37 17

Medoxprogesterone 87 2.80 4

Drospirenone/Ethinylestradiol 52 1.68 9

Etonorgestrel 43 2.04 7

Ethinylestradiol/Etonorgestrel 31 2.22 8

Ethinylestradiol/Levonorgestrel 29 1.90 10

Desogestrel 23 3.84 3

Ethinylestradiol/Noregelgestromin 16 0.47 3

Ethinylestradiol/Norgestimate 9 1.11 2

Desogestrel/Ethinylestradiol 7 0.20 4

WHO Pharmaceuticals Newsletter No. 5, 2017 • 17 Signal

CAVEAT DOCUMENT

Accompanying statement to data released from VigiBase, the WHO international database of suspected adverse drug reactions

Uppsala Monitoring Centre (UMC) in its role as the World Confidential data Health Organization (WHO) Collaborating Centre for According to WHO policy and UMC Guidelines, ADR International Drug Monitoring receives reports of reports sent from the WHO PIDM member countries suspected adverse reactions to medicinal products from to VigiBase are anonymized, but they are still to be National Centres in countries participating in the WHO considered sensitive due to the nature of the data. pharmacovigilance network, the WHO Programme for When receiving and using adverse reaction data International Drug Monitoring (PIDM). The information is (“Data”), the user agrees and acknowledges that it stored in VigiBase, the WHO international database of will be the controller of any such Data. Accordingly, suspected adverse drug reactions (ADRs). It is important the user shall adhere to all applicable legislation such to understand the limitations and qualifications that apply as, but not limited to, EU and national legislation to this information and its use. regarding protection of personal data (e.g. the Data The reports submitted to UMC generally describe no more Protection Directive 95/46/EC and Regulation (EC) than suspicions which have arisen from observation of an No 45/2001, as applicable). Transfer of sensitive unexpected or unwanted event. In most instances it data to a third party is generally prohibited subject cannot be proven that a specific medicinal product (rather to limited exceptions explicitly stated in applicable than, for example, underlying illness or other concomitant legislation. medication) is the cause of an event. As the controller of the Data, the user shall be liable Reports submitted to National Centres come from both for any and all processing of the Data and shall regulated and voluntary sources. Some National Centres indemnify and hold the UMC harmless against any accept reports only from medical practitioners; other claim from a data subject or any other person or National Centres accept reports from a broader range of entity due to a breach of any legislation or other reporters, including patients. Some National Centres regulation regarding the processing of the Data. include reports from pharmaceutical companies in the Non-permitted use of VigiBase Data includes, but is information submitted to UMC; other National Centres do not limited to: not. • patient identification or patient targeting The volume of reports for a particular medicinal product • identification, profiling or targeting of general may be influenced by the extent of use of the product, practitioners or practice publicity, the nature of the reactions and other factors. No Any publication, in whole or in part, of information information is provided on the number of patients exposed obtained from UMC must include a statement: to the product. (i) regarding the source of the information Some National Centres that contribute information to (ii) that the information comes from a variety of VigiBase make an assessment of the likelihood that a sources, and the likelihood that the suspected medicinal product caused the suspected reaction, while adverse reaction is drug-related is not the same others do not. Time from receipt of a report by a National in all cases, Centre until submission to UMC varies from country to (iii) that the information does not represent the country. Information obtained from UMC may therefore opinion of the World Health Organization. differ from those obtained directly from National Centres. Omission of this statement may exclude the If in doubt or in need of help for interpretation of country responsible person or organization from specific data, UMC recommends to contact the concerned receiving further information from VigiBase. NC before using the data. UMC may, in its sole discretion, provide further For the above reasons interpretations of adverse instructions to the user, responsible person and/or reaction data, and particularly those based on organization in addition to those specified in this comparisons between medicinal products, may be statement and the user, responsible person and/or misleading. The supplied data come from a variety organization undertakes to comply with all such of sources. The likelihood of a causal relationship is instructions. not the same in all reports. Any use of this Uppsala Monitoring Centre (UMC) Box 1051, SE-751 40 Uppsala, Sweden information must take these factors into account. Tel: +46-18-65 60 60, E-mail: [email protected] www.who-umc.org

WHO Pharmaceuticals Newsletter No. 5, 2017 • 18 Feature

APEC Harmonization Center (AHC) Pharmacovigilance Workshop, Seoul, 11-12 September 2017

The 2017 Asia-Pacific Economic Cooperation (APEC) Harmonization Center (AHC) Pharmacovigilance workshop was held 11-12 September, 2017 in Seoul, Republic of Korea. This workshop was organized by AHC as part of the APEC Regulatory Harmonization Steering Committee (RHSC) under the Roadmap to promote regulatory convergence on Pharmacovigilance (PV) framework. The AHC, in partnership with APEC RHSC, has been providing similar workshops for building PV capacity and serving as an educational platform for regulatory priorities among APEC member economies since 2012. The aim of this two day workshop was to impart knowledge and understanding of the best practices in PV, including the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) ‘E2 series’ guidelines, as well as the ongoing efforts for strengthening collaboration among stakeholders. There were approximately 260 participants from regulatory authorities, academia, industry and national PV centres, representing 20 economies. Experts from the Ministry of Food and Drug Safety (MFDS) in Korea, US Food and Drug Administration (US FDA), WHO, The WHO Collaborating Centre for International Drug Monitoring, Uppsala Monitoring Centre, the International Society of Pharmacovigilance (ISoP), among others, presented and facilitated the programme. The topics covered during the two-day workshop included: • Understanding ICH Guideline • Risk management in pharmacovigilance • Pharmacovigilance in biotherapeutics • Assessing the impact of pharmacovigilance • Promoting international partnership in pharmacovigilance • Collaborative efforts among regulatory authorities, patients, industry and academia The workshop was officially opened by Dr Sun Hee Lee, Director of the AHC, followed by remarks from Dr Hee- Mok Won, Chairman of the Korea Pharmaceutical and Bio-Pharma Manufacturers Association, and keynote speech from Mr Sang-Hyun Kim, Deputy Director of the Pharmaceutical Safety Division, MFDS.

WHO Pharmaceuticals Newsletter No. 5, 2017 • 19 Feature

On Day 1, PV specialists, speakers from the European Medicines Agency (EMA) and the US FDA and others introduced concept of ICH E2-series guidelines, its application and challenges in practice. Key principles and history of revisions were presented in detail, and considerations for local requirements were shared. A session on risk management provided an overview of current practices from regulatory and industry perspectives. Challenges in global and local environments were shared and the HSA highlighted the importance of timely and accurate communication. Lastly, PV in biotherapeutics covered unique characteristics and considerations for biotherapeutic products. Varying approaches and measures among regulatory authorities were presented, and the importance of PV at the levels of products and batches was emphasized. Day 2 of the program consisted of topics on measuring the impact of PV and efforts for international collaboration. In the morning, key findings and challenges from assessment of PV activities were introduced, and the Pharmaceuticals and Medical Devices Agency (PMDA) shared Japan’s experiences in utilizing electronic medical records. In subsequent sessions, updates on international activities and collaborative efforts were provided. Building a trusted and constructive relationship with stakeholders was highlighted as a key feature to such partnerships, and WEB-RADR was introduced as a new platform for mobile phone-based reporting ADR. Furthermore, existing gaps in national PV systems and WHO’s PV activities beyond APEC region were presented to raise awareness on the continuous need for harmonization. The participants expressed that the workshop provided valuable opportunity to broaden their knowledge and understanding on ICH guidelines and current international activities. In particular, participants found the session on risk management in PV practical and relevant to their daily work. Feedback and comments from the participants and speakers will be analyzed and used to modify the program so that it addresses the needs of APEC economies. The AHC expressed its commitment to continue to provide training programs for regulatory convergence to support this important dialogue. WHO will continue to support PV activities in the APEC region as well as other PV activities with regional cooperation.

WHO Pharmaceuticals Newsletter No. 5, 2017 • 20 Feature

The second workshop to integrate Anatomical Therapeutic Chemical (ATC) and Defined Daily Dose (DDD) in drug utilization research

The second workshop to integrate the ATC/DDD system, pharmacovigilance and drug utilization research for promoting the quality use of medicine was held on 20-21 September 2017 in Rabat, Morocco.

The two-day workshop on the ATC/DDD methodology to integrate its use in pharmacovigilance and drug utilization research consisted of lectures, discussions and interactive hands-on exercises. Experts from the WHO Collaborating Centre for Drug Statistics Methodology (WHOCC in Oslo; Norwegian Institute of Public Health), WHO Collaborating Centre for Strengthening Pharmacovigilance Practices (WHOCC in Rabat; Centre Anti Poison et de Pharmacovigilance du Maroc) and WHO facilitated this workshop. The aims of the workshop were; • to introduce the principles of ATC classification and DDD; and their use in drug utilization monitoring and research, including pharmacovigilance • to introduce the principles of drug utilization research, data sources and methods for collecting data on drug use • to introduce the principles of investigating quality use of medicines, and to share country experiences on medicines use surveillance for selected products (e.g. anti-influenza products).

This workshop targeted pharmacovigilance and health-care professionals in low and middle income countries participating in the WHO Programme for International Drug Monitoring. In order to allow for good interactive learning, a small number of participants (around 20 in total) were invited to the workshop. The participants were from; Burkina Faso, Ethiopia, Ghana, Kenya, Mali, Morocco, Senegal, Sudan, and Uganda.

Overall, there was positive feedback from participants. Given the need to promote and support the use of this tool, WHO will continue to organise workshops on ATC/DDD system in collaboration with WHOCC in Oslo, WHOCC in Rabat and other experts. This will be in addition to the annual course in Oslo (https://www.whocc.no/courses/). Please visit the following websites to learn about the ATC/DDD system and methodology: • http://www.who.int/medicines/regulation/medicines-safety/utilization/en/ • http://www.who.int/medicines/regulation/medicines-safety/toolkit/en/ • https://www.whocc.no/

WHO Pharmaceuticals Newsletter No. 5, 2017 • 21