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

Uppsala, Sweden

TheThe aim aim of of the the Newsletter Newsletter is is to to No.No. 1, 3, 2013 2012

disseminatedisseminate information information on on the the

safetysafety and and efficacy efficacy of of

pharmaceuticalpharmaceutical products, products, based on communications received based onfrom communications our network of received "drug from our network of "drug information officers" and other TheThe WHO WHO Pharmaceuticals Pharmaceuticals Newsletter Newsletter provides provides you you wit withh informationsources such officers" as specialized and other sources such as specialized thethe latest latest information information on on the the safety safety of of medicines medicines a andnd bulletins and journals, as well as legallegal actions actions taken taken by by regulatory regulatory authorities authorities acros acrosss the the partnersbulletins in WHO. and journals, The information as well as partners in WHO. The information world.world. It also provides signals from the Uppsala is produced in the form of résumés Monitoring Centre's SIGNAL document inis English,produced full in thetexts form of which of résumés may The feature article in this issue brings you the in English,be obtained full texts on request of which from: may recommendations from the Thirty-fifth Annual Meeting be obtained on request from: of Representatives of National Pharmacovigilance Quality Assurance and Safety: The feature article in this issue gives you… Centres participating in the WHO Programme for Medicines, EMP-HIS, International Drug Monitoring, in Brazil, 11-14 QualityWorld HealthAssurance Organization, and Safety: November 2012. 1211 GenevaMedicines, 27, Switzerland, EMP-HSS, E-mail address: [email protected] World Health Organization, This Newsletter is also available on 1211 Genevaour Internet 27, Switzerland, website:

http://www.who.int/medicineE-mail address: [email protected] Further information on adverse reactions may be obtained from the This Newsletter is also available on WHO Collaborating Centre for Internationalour Drug Internet Monitoring website: http://www.who.int/medicineBox 1051 s 751 40 Uppsala

Tel: +46-18-65.60.60 Further Fax:information +46-18-65.60.80 on adverse reactionsE-mail: may [email protected] obtained from the Internet:WHO http://www.who-umc.org Collaborating Centre for International Drug Monitoring

Box 1051 Contents Contents Regulatory matters Regulatory matters Safety of medicines Safety of medicines Signal Feature Feature

© World Health Organization 2013

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TAB LE OF CONTENTS

Regulatory Matters Botulinum Toxin ...... 4 Dabigatran etexilate mesylate ...... 4 Domperidone ...... 4 Fingolimod ...... 5 Ondansetron ...... 5 Over-the-counter cough and cold medicines for children ...... 6 Sodium oxybate ...... 6 Statins...... 6 Telaprevir ...... 7 Tolvaptan ...... 7 Zolpidem containing products ...... 7

Safety of Medicines Carbamazepine, oxcarbazepine and eslicarbazepine ...... 9 Varenicline ...... 9

Feature Recommendations from the Thirty-fifth Annual Meeting of National Pharmacovigilance Centres ...... 10

WHO Pharmaceuticals Newsletter No. 1, 2013 • 3

REGULATORY MATTERS

Dabigatran etexilate appropriate anticoagulation Botulinum Toxin treatment. Patients should not mesylate stop taking anticoagulant medications without guidance New labelling Contraindication in from their health-care information for all patients with mechanical professional; stopping products prosthetic heart valves dabigatran etexilate mesylate Canada. Health Canada USA (1). The U.S. Food and or other anticoagulants requested all manufacturers of Drug Administration (FDA) suddenly can increase the risk botulinum toxin products advised health-care of blood clots and stroke. currently available on the professionals and the public Canada (2). Boehringer Canadian market revise their that dabigatran etexilate Ingelheim (Canada) Ltd., in product labels to reflect that mesylate (Pradaxa®) should consultation with Health each product has its own not be used to prevent stroke Canada, has announced that individual potency and as such or blood clots (major dabigatran etexilate is not interchangeable with thromboembolic events) in (Pradaxa™ and Pradax®) other botulinum products.This patients with mechanical heart Product Monograph will be revision is to help prevent valves, also known as revised to include a new medication errors with the use mechanical prosthetic heart contraindication for use in of these products. valves. A clinical trial in Europe patients with prosthetic heart The labelling changes are due (the RE-ALIGN trial) was valves requiring anticoagulant to a risk evaluation of the recently stopped because treatment due to their valvular active ingredients (Clostridium dabigatran users of the drug status. were more likely to experience botulinum toxin type A and (See WHO Pharmaceuticals type B) within these products. strokes, heart attacks, and Newsletters Nos. 1, 3, 4 and 6, Botulinum toxins are produced blood clots forming on the 2012 for previous related by different manufacturing mechanical heart valves than announcements). processes, are obtained by were users of the different techniques and are anticoagulant warfarin. There References: derived from different was also more bleeding after (1) FDA Drug Safety Clostridium strains. As a result valve surgery in the dabigatran Communication, US FDA 19 of these differences, these etexilate mesylate users than December 2012 products cannot be in the warfarin users. (www.fda.gov ). interchanged as these changes Dabigatran etexilate mesylate (2) Advisories, Warnings and can cause unexpected side- is not approved for patients Recalls, Health Canada, 21 effects. with atrial fibrillation caused by December 2012 (www.hc- sc.gc.ca ). Health Canada advised health- heart valve problems by the care professionals that the US FDA. The US FDA is established drug names of the requiring a contraindication of Domperidone botulinum products have not the drug in patients with been changed yet to mechanical heart valves. emphasize the differing dose- Serious ventricular It is recommended that health- arrhythmias and sudden to-potency ratios of these care professionals should cardiac death products. Manufacturers will promptly transition any patient have one year to comply with with a mechanical heart valve Australia. The Therapeutic the labelling change requests. who is taking dabigatran Goods Administration (TGA) Reference: etexilate mesylate to another advised health-care professionals that domperidone Advisories, Warnings and medication. The use of (Motilium®) should be initiated Recalls, Health Canada, dabigatran etexilate mesylate at the lowest possible dose in 21 January 2013 (www.hc- in patients with another type of adults. Recent epidemiological sc.gc.ca ). valve replacement made of natural biological tissue, studies have shown that the known as a bioprosthetic use of domperidone may be valves, has not been evaluated associated with an increased and cannot be recommended. risk of serious ventricular Patients with all types of arrhythmias or sudden cardiac prosthetic heart valve death, particularly in patients replacements taking taking daily doses greater than dabigatran etexilate mesylate 30 mg, and in patients older should talk to their health-care than 60 years of age. professional as soon as possible to determine the most WHO Pharmaceuticals Newsletter No. 1, 2013 • 4

REGULATORY MATTERS

Patients should be advised to Domperidone should not be intensify cardiovascular stop taking domperidone and used in children. monitoring after first dose in seek immediate medical EU, No. 2, 2012 in Canada and The Product Information for attention if they experience No.3 2012 for New advice to domperidone has been signs or symptoms of an better manage risk of adverse updated to include the new abnormal heart rate or rhythm effects on the heart in Europe drug dosage and usage while taking domperidone. and the US). recommendations, as well as These include dizziness, information about the risk of Reference: palpitations, syncope or serious ventricular arrhythmias Medicines Safety Update Vol 3, seizures. and sudden cardiac death. No. 6, December 2012 Health-care professionals are (www.tga.gov.au ). (See WHO Pharmaceuticals advised that: Newsletter No.2, 2012 and No. • Domperidone is 2, 2007 for association with Ondansetron contraindicated with serious ventricular arrhythmias ketaconazole, erythromycin and sudden cardiac death in Canada). Product removal due to or other potent CYP3A4 potential for serious inhibitors which prolong Reference: cardiac risks Medicines Safety Update Vol 3, QTc interval such as USA. The US FDA notified fluconazole, voriconazole, No. 6, December 2012 (www.tga.gov.au ). health-care professionals that clarithromycin and the 32 mg, single intravenous amiodarone (IV) dose of ondansetron • Domperidone should be Fingolimod hydrochloride (Zofran®) will used with caution and at no longer be marketed because of the potential for the lowest effective dose in Cardiovascular safety serious cardiac risks. at-risk patients such as risk The 32 mg, single IV dose of those: Australia. The TGA advised ondansetron hydrochloride had o with existing prolongation health-care professionals of been used to prevent of cardiac conduction important cardiovascular chemotherapy-induced nausea safety related changes to the intervals (particularly the and vomiting. A previous Drug fingolimod (Gilenya®) Product QT interval) Safety Communication (DSC), Information. Fingolimod is now o using potent CYP3A4 issued on June 29, 2012, contraindicated in patients with communicated that the 32 mg, inhibitors which may specific cardiac conditions and single IV dose should be increase plasma levels of in patients with concomitant avoided due to the risk of a domperidone such as treatment with Class Ia or specific type of irregular heart Class III anti-arrhythmic drugs itraconazole, amprenavir, rhythm called QT interval during fingolimod initiation. atazanavir, prolongation, which can lead to The Precautions section has fosamprenavir, indinavir, Torsades de Pointes, an been updated to include first- abnormal, potentially fatal nelfinavir, ritonavir, dose monitoring, with heart rhythm. These drugs are saquinavir, diltiazem, emphasis on cardiac sold pre-mixed in solutions of verapamil and aprepitant monitoring, namely pulse, either dextrose or sodium o with significant electrolyte blood pressure and chloride in plastic containers. disturbances (e.g. electrocardiogram. Should a hypokalaemia, patient require The US FDA continues to pharmacological intervention hypomagnesaemia) recommend the intravenous during the first-dose regimen of 0.15 mg/kg o with underlying cardiac observation, overnight administered every 4 hours for diseases such as monitoring in a medical facility three doses to prevent congestive heart failure. should be instituted and the chemotherapy-induced nausea first-dose monitoring strategy and vomiting. Oral dosing of The dose of domperidone may should be repeated after the Ondansetron remains effective be adjusted upward with second dose of fingolimod. for the prevention of caution to achieve the desired chemotherapy-induced nausea (See WHO Pharmaceuticals effect as needed. The expected and vomiting. Newsletter No. 1, 2012 for benefit of an increased dose safety review of a reported should outweigh the potential (See WHO Pharmaceuticals death after the first dose in the risks. The maximum dose of Newsletters No. 5, 2011 for USA and for review of domperidone is 80 mg. risk of abnormal heart rhythms fingolimod and advise to in the USA and Nos. 4 and 6

WHO Pharmaceuticals Newsletter No. 1, 2013 • 5

REGULATORY MATTERS

2012 for dose restriction in Sodium oxybate combinations that raise the intravenous use due to dose- risk of respiratory depression dependent QT interval and death. Patients should not Warning against use prolongation). drink alcohol or take insomnia with alcohol or drugs drugs. Reference: causing respiratory FDA Drug Safety depression Reference: Communication, US FDA FDA Drug Safety 4 December 2012 USA. The US FDA reminded Communication, US FDA (www.fda.gov ). health-care professionals and 17 December 2012 patients that the combined use (www.fda.gov ). of sodium oxybate (Xyrem®) Over-the-counter with alcohol or central nervous system (CNS) depressant Statins cough and cold drugs can markedly impair medicines for consciousness and may lead to Risk of increased blood children severe breathing problems (respiratory depression). The sugar levels and use of alcohol with the drug is diabetes Use in children a new contraindication added Canada. Health Canada Australia. The TGA has to the sodium oxybate label, informed of a labelling update recently completed a review of which already contraindicates for statins regarding the risk of the safety and efficacy of over- its use with insomnia drugs. increased blood sugar levels the-counter cough and cold The use with other CNS and a small increased risk of medicines for use in children. depressant drugs (drugs that diabetes among patients affect the CNS and may lead to The Agency concluded that already at risk for the disease. breathing problems) such as these medicines: Based on the review of all opioid analgesics, available data, Health Canada • should not be given to benzodiazepines, sedating concluded that the risk of children under 6 years of age antidepressants or diabetes appears to be mainly antipsychotics, general • should only be given to in patients with pre-existing anesthetics, and muscle risk factors for diabetes, such children aged 6 to 11 years on relaxants should generally be the advice of a doctor, as high levels of glucose or avoided. The use of sodium triglycerides, obesity or high pharmacist or nurse oxybate along with these blood pressure. Health Canada practitioner products or other CNS continues to believe the overall • should be labelled with depressants increases the risk cardiovascular benefits of warnings and instructions to of breathing problems that statin drugs in reducing blood the above effect may lead to loss of cholesterol outweigh their consciousness, coma, and risks. • should only be available in death. child-resistant packaging. A new warning about the Sodium oxybate is approved to increased blood sugar levels The TGA advised health-care reduce attacks of muscle and the risk of diabetes, professionals that no changes weakness (cataplexy) and including information on how have been made to the treat daytime sleepiness in to identify high-risk patients, scheduling of these medicines patients with narcolepsy by the has been added to the drug and a prescription is not US FDA. Sodium oxybate is labels for the six statins required. A recommendation also known as gamma- currently marketed in Canada: for treatment with these hydroxybutyrate (GHB). GHB is atorvastatin (Lipitor® and medicines for a child less than a known drug of abuse that generics), lovastatin 6 years of age constitutes off- has been associated with (Mevacor® and generics), label use. central nervous system (CNS) rosuvastatin (Crestor® and Existing stock with older adverse events, including generics), simvastatin (Zocor® labelling can still be sold for death. Even at recommended and generics), pravastatin adults and children aged 12 doses, the drug can cause (Pravachol® and generics), years and over (or 6 to 11 confusion, depression, and fluvastatin (Lescol® and years on the advice of a health other neuropsychiatric events. generics). professional) until stocks are The US FDA urged health-care The new labels recommend exhausted. professionals to follow the that health-care professionals Reference: dosing recommendations, carefully monitor the use of Medicines Safety Update Vol 3, contraindications, and boxed statins in patients at a high No. 6, December 2012 warning in the updated drug risk of future diabetes. (www.tga.gov.au ). label and to avoid drug WHO Pharmaceuticals Newsletter No. 1, 2013 • 6

REGULATORY MATTERS

Health Canada recommended occur, all three components of and potentially fatal liver patients who are on statins Incivek combination treatment, injury. and experience symptoms including peginterferon alfa The US FDA recommended associated with increased and ribavirin, must be that health-care providers blood sugar, such as severe immediately discontinued, and should perform liver tests frequent urination, thirst or the patient should receive promptly in patients who hunger, to contact their urgent medical care. report symptoms that may health-care professional. Consideration should also be indicate liver injury, including given to stopping any other Reference: fatigue, anorexia, right upper medications that may be Advisories, Warnings and abdominal discomfort, dark associated with serious skin Recalls, Health Canada, 24 urine or jaundice. If hepatic reactions. January 2013 (www.hc- injury is suspected, tolvaptan sc.gc.ca ). Reference: should be promptly FDA Drug Safety discontinued, appropriate Communication, US FDA 19 treatment should be instituted, Telaprevir December 2012 and investigations should be (www.fda.gov ). performed to determine New boxed warning - probable cause. tolvaptan serious skin reactions should not be re-initiated in Tolvaptan patients unless the cause for USA. The US FDA announced the observed liver injury is that it received reports of definitively established to be serious skin reactions, some Potential risk of liver unrelated to treatment with fatal, in patients taking the injury tolvaptan. hepatitis C drug telaprevir USA. The US FDA and Otsuka, (Incivek®) in combination with the manufacturer of tolvaptan Reference: peginterferon alfa and ribavirin (Samsca®), notified health- FDA Drug Safety (Incivek combination care professionals of significant Communication, US FDA 25 treatment). Some patients liver injury associated with the January 2012 (www.fda.gov ). died when they continued to drug. In a double-blind, 3- receive Incivek combination year, placebo-controlled trial in treatment after developing a about 1400 patients with Zolpidem containing worsening, or progressive rash Autosomal Dominant Polycystic products and systemic symptoms Kidney Disease (ADPKD) and (symptoms affecting the entire its open-label extension trial, 3 Lower recommended body). The US FDA added a patients treated with the drug boxed warning to telaprevir developed significant increases doses required drug label stating that Incivek in serum alanine USA. The US FDA combination treatment must aminotransferase (ALT) with recommended that the be immediately stopped in concomitant, clinically bedtime dose of zolpidem be patients experiencing the significant increases in serum lowered because new data above. total bilirubin. In the trials the show that blood levels in some maximum daily dose of patients may be high enough Telaprevir is a hepatic C virus tolvaptan administered (90 mg the morning after use to impair NS3/4A protease inhibitor in the morning and 30 mg in activities that require indicated in combination with the afternoon) was higher than alertness, including driving. peginterferon alfa and ribavirin the maximum 60 mg daily This announcement focuses on for the treatment of genotype dose approved for the zolpidem products approved 1 chronic hepatitis C in adult treatment of hyponatremia. for bedtime use, which are patients with compensated marketed as generics and liver disease, including patients Most of the liver enzyme under the brand names who have cirrhosis, are abnormalities were observed Ambien®, Ambien CR®, treatment-naïve, or who have during the first 18 months of Edluar®, and Zolpimist™. been previously received therapy. Following interferon-based treatment. discontinuation of treatment, Data showed that the risk for all 3 patients improved. These next-morning impairment is Health-care professionals are data are not adequate to highest for patients taking the recommended to make sure exclude the possibility that extended-release forms of patients know that rash may patients receiving tolvaptan for these drugs (Ambien CR® and occur with Incivek combination its indicated use of clinically generics). Women appear to treatment, and explain the significant hypervolemic and be more susceptible to this risk signs and symptoms of severe euvolemic hyponatremia are at because they eliminate skin reaction and when to seek increased risk for irreversible zolpidem from their bodies care. If serious skin reactions WHO Pharmaceuticals Newsletter No. 1, 2013 • 7

REGULATORY MATTERS more slowly than men. Because use of lower doses of zolpidem will result in lower blood levels in the morning, the US FDA required the manufacturers of these drugs to lower the recommended dose. The recommended doses of Intermezzo®, a lower dose zolpidem product approved for middle-of-the-night awakenings, are not changing. At the time of Intermezzo’s approval in November 2011, the label already recommended a lower dosage for women than for men.

The US FDA reminded the public that all drugs taken for insomnia can impair driving and activities that require alertness the morning after use.

The US FDA recommended that; • The dose of zolpidem for women should be lowered from 10 mg to 5 mg for

immediate-release products (Ambien®, Edluar®, and Zolpimist™) and from 12.5 mg to 6.25

mg for extended-release products (Ambien CR®). • For zolpidem and other insomnia drugs, the

lowest dose that treats the patient’s symptoms should be prescribed. • Patients should be

informed that impairment from sleep drugs can be present despite feeling fully awake.

The US FDA is continuing to evaluate the risk of impaired mental alertness with other insomnia drugs, including over-the-counter (OTC) drugs available without a prescription. Reference:

FDA Drug Safety Communication, US FDA 10 January 2013

(www.fda.gov ).

WHO Pharmaceuticals Newsletter No. 1, 2013 • 8

SAFETY OF MEDICINES

consideration of the benefits or sudden onset of weakness, Carbamazepine, and risks. numbness, or difficulty Reference: speaking. Patients should also oxcarbazepine and contact their health-care Drug Safety Update, December eslicarbazepine professional if they have any 2012, Volume 6, issue 5, A1 questions or concerns about MHRA, (www.mhra.gov.uk ). Potential risk of serious varenicline. skin reactions associated (See WHO Pharmaceuticals with the HLA-A* 3101 Varenicline Newsletters No. 4, 2011 for allele. risk of certain cardiovascular UK. The Medicines and Updated safety review adverse events with Healthcare products on the risk of varenicline in the USA). Regulatory Agency (MHRA) cardiovascular adverse Reference: reported that the risk of events FDA Drug Safety serious skin-related adverse USA. The US FDA informed the Communication, US FDA 12 drug reactions, including public about the results of a December 2012 Stevens-Johnson syndrome, large, combined analysis (www.fda.gov ). occurring with carbamazepine (called a meta-analysis) of (Tegretol®) may be increased clinical trials that compared in the presence of the HLA- patients who received the A*3101 allele in patients of smoking cessation drug European descent or Japanese varenicline (Chantix®) to origin. patients who received a placebo. A higher occurrence Human leukocyte antigens (HLA) are involved in some of major adverse drug-specific abnormal cardiovascular events (a immune responses including combined outcome of

SJS and TEN, and the HLA cardiovascular-related death, allele HLA-B*1502 is known to nonfatal heart attack, and be highly associated with nonfatal stroke) was observed carbamazepine-induced SJS in patients using the drug and TEN in certain Asian compared to placebo. These populations. More recently, a events were uncommon in new genetic marker, HLA- both varenicline and placebo A*3101 , has been identified in groups, and the increased risk Japanese individuals and was not statistically significant, individuals of European which means it is uncertain whether the excess risk for the descent for serious carbamazepine-induced varenicline group was due to cutaneous adverse drug the drug or due to chance. reactions such as SJS, TEN, Health-care professionals are and drug rash with eosinophilia advised to weigh the risks of (DRESS), and less severe varenicline against the benefits reactions such as acute of its use. It is important to generalised exanthematous note that smoking is a major pustulosis (AGEP) and risk factor for cardiovascular maculopapular rash. disease, and the drug is However, there are currently effective in helping patients to insufficient data supporting a quit smoking and abstain from recommendation for HLA- it for as long as one year. The A*3101 screening before health benefits of quitting starting carbamazepine or smoking are immediate and chemically-related medicines. substantial. Patients of European descent Patients are advised to contact or Japanese origin who are their health-care professional if known to be positive for this they experience new or allele should only receive worsening symptoms of carbamazepine, oxcarbazepine cardiovascular disease, such as (Trileptal®) or eslicarbazepine chest pain, shortness of (Zebinix®) after careful breath, calf pain when walking,

WHO Pharmaceuticals Newsletter No. 1, 2013 • 9

FEATURE

Recommendations from the Thirty-fifth Annual Meeting of National Pharmacovigilance Centres

The Annual Meeting of Representatives of National Pharmacovigilance Centres participating in the WHO Programme for International Drug Monitoring was held in Brazil, 11-14 Nov 2012. At the meeting eight working groups discussed various pertinent issues in pharmacovigilance (PV). A summary of these discussions is provided.

1. Good Management Practices for national PV centres

Pharmacovigilance is a science that needs good management practices to ensure that the aims and objectives of a country’s National PV system are met in the light of limited resources. The group discussed the principles of good management practices and how and why they should be applied to pharmacovigilance. The following recommendations were made. National PV centres to: 1. Harmonize activities on a global level (coordinated by WHO/UMC) 2. Collaborate with other national centres at the regional level 3. Support each other and share experiences.

WHO and its Collaborating Centres to: 1. Provide guidance on grant applications 2. Provide a list of all available PV resources, with web links , updates and processes to access these resources

2. Wider access to data in WHO database: optimizing data utilization via VigiLyze

The objective was to discuss the optimal use of information and data extracted from the WHO Individual Case Safety Reports (ICSR) database. Four different user ‘personas’ were identified with distinct needs and use of the database information: the user group that needs easy-to-use interface with instant information on specific medicines issues; senior management who need evidence to provide / request funding and collaborations; the intermediate group that needs the information for decision making; and the general user group with a broad interest in the information. The group concluded that the first version of VigiLyze, the new search and statistics tool being developed by the Uppsala Monitoring Centre (UMC), needs to first address the requirement of the most immediate user from within these personas. The following recommendations were made. 1. UMC to focus on the needs of the front- line user in the first phase of VigiLyze development 2. Needs of other users should be considered in future releases 3. A user/ working group should be set up to establish user groups, confirm needs and further refine VigiLyze.

3. Building capacity for safety monitoring of new vaccines

Although, hundreds of millions of doses of vaccines are used every year in developing countries, assessments by WHO demonstrate that some countries still do not have the ability to monitor and ensure the safe use of vaccines. This working group discussed capacity building for monitoring adverse events following immunization (AEFI). The group agreed that effectiveness and safety of vaccines might vary across countries. The following recommendations were made.

WHO Pharmaceuticals Newsletter No. 1, 2013 • 10

FEATURE

1. WHO to improve the availability of background data in low and middle income countries (LMIC) by pooling placebo data from clinical trials 2. National centres and countries to improve collaborations between medicines and vaccines PV systems; and share experiences on the introduction of new vaccines in their settings 3. Both national centres and WHO to: 1. Offer more training and build capacity in vaccine PV, especially in LMIC 2. Translate the ‘online’ WHO vaccine PV course into more languages 3. Develop and implement new methodologies in AEFI data collection, causality assessment and signal detection

4. The ATC/DDD system: a tool linking drug consumption and adverse drug reaction data

The Anatomical, Therapeutic and Chemical (ATC) classification system and the Defined Daily Dose (DDD) are recommended by WHO for measuring drug utilization in countries. The WHO Collaborating Centre for Drug Statistics Methodology in Oslo, Norway (WHO CC, Oslo), develops and maintains the ATC/DDD system. The objective of this working group was to ascertain ways of raising awareness and promoting the use of the ATC/DDD system in PV. The following recommendations were made: WHO and national centres to : 1. Organize capacity building and training activities for implementing ATC/DDD 2. Build links between medicine consumption and adverse drug reaction databases 3. Promote use of ATC/DDD in studying and sharing data on consumption and trends in use of specific drugs such as sibutramine; monitor the use of medicines in children in chronic diseases.

5. The PV Toolkit and its further development

The PV Toolkit is a collection of resources and information needed for the practice of PV. The main aim is to ensure that PV practitioners get access to information on the processes and activities involved in PV from a reliable source. The group discussed the further development of the Toolkit. The following recommendations were made. WHO/WHO Collaborating Centre for Training and Advocacy in Pharmacovigilance, Accra, Ghana should 1. Facilitate the translation of the Toolkit into various WHO official languages 2. Include a URL link to all National PV centres in the Toolkit 3. Make the Toolkit more interactive and user friendly 4. Use the Toolkit as a platform for sharing experiences amongst national centres 5. Promote the Toolkit to all national centres through advocacy 6. Include Information on pharmacovigilance for special groups such as children and the elderly 7. Include standard PV training modules in the Toolkit for national centres

6. Centralized or decentralized PV system –Pros and Cons This working group discussed the pros and cons of both centralized and decentralized PV systems, examples of such models in countries and challenges faced in implementing and maintaining such systems. A centralized model provides a single point of entry for information, with less financial needs; however there is decreased patient accessibility and less effective communication to health professionals. A decentralized system on the other hand is more accessible to patients and improves communication. However, decentralizing requires coordination, more funding and resources for capacity building. It was concluded that the choice of having a centralized or decentralized system will depend on the size of the country, complexity of the national health system and support from government authorities and other key stakeholders. The

WHO Pharmaceuticals Newsletter No. 1, 2013 • 11

FEATURE group recommended that WHO should develop guidelines on setting up centralized and decentralized PV systems, highlighting the pros and cons of each system.

7. The role of industry in national PV programmes

The objectives of PV within the industry are essentially the same as those of regulatory agencies; that is, to protect patients from unnecessary harm by identifying previously unrecognised drug hazards, elucidating pre- disposing factors, and quantifying risk in relation to benefit. Although the perspectives of companies and the regulatory agencies may be different, they now work more and more closely together and share information. The objective of the working group was to discuss the challenges and value for national pharmacovigilance programmes in collaborating with industry. The group recommended that national centres should :

1. Provide guidance to Industry on obligations, procedures and protocols 2. Perform independent research in certain cases 3. Have the ability to monitor Marketing Authorization Holders (MAHs) risk minimization activities and obligate the MAH to carry out post-marketing studies. 4. Engage in open communication with industry

8. Harmonizing PV with health economics for outcome measurements – setting the research agenda

PV is a form of intervention in the healthcare system with economic benefits, to the system, to individuals and to society. Health economics analysis (HEA) can demonstrate the cost-effectiveness of PV but only few studies have been done in this regard. The working group discussed savings to health expenditure through PV and how the cost-benefit of PV could be measured. The following recommendations were made. WHO to: 1. Develop guidelines or protocols and standardized methods for studying the cost benefit of PV 2. Promote the concept of cost-benefit of PV and its measurement in PV training programmes

National Centres to: 1. Carry out studies to establish the cost-benefit of PV activities

WHO Pharmaceuticals Newsletter No. 1, 2013 • 12