WHO PHARMACEUTICALS NEWSLETTER
prepared in collaboration with the WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden
The aim of this Newsletter is to No. 4, 2005 disseminate information on the safety and efficacy of pharmaceutical products, based on information received from our network of “drug
information officers” and other sources such as specialized bulletins News & Issues and journals, as well as partners in WHO. The information is produced This issue comes to you close on the heels of the recently in the form of résumés in English, concluded Annual meeting of national pharmacovigilance full texts of which may be obtained centres here in Geneva. Over forty countries were on request from: represented, with the WHO venue providing the perfect opportunity to promote pharmacovigilance within several Quality Assurance and Safety: Medicines, PSM–HTP public health programmes: of interest were the interactions World Health Organization, with HIV /AIDS, malaria, helminths and the tuberculosis 1211 Geneva 27, Switzerland programmes. Working group exercises on these topics and E-mail address: [email protected] the sessions on vaccines, patient safety, and classification systems highlighted the future trends and issues in This newsletter is also available on our Internet website: pharmacovigilance. The guest lecture 'Patient safety: a http://www.who.int/medicines global challenge' by Sir Liam Donaldson, Chief Medical Officer, United Kingdom and Chair of the World Alliance for Further information on adverse Patient Safety, was significant in highlighting the common reactions may be obtained from the concerns across professions in promoting patient care. It is WHO Collaborating Centre for International Drug Monitoring, clear that future efforts will have to build on collaborations, Stora Torget 3, given the widening scope and expanding role of 753 20 Uppsala, Sweden pharmacovigilance. We take the opportunity to thank all the Tel: 46-18-65.60.60 participants for their enthusiasm and active participation Fax: 46-18-65.60.80 while summarizing the recommendations from three of the E-mail: [email protected] working group exercises. Internet:http://www.who-umc.org ______Contents Regulatory matters Safety of medicines Feature
© World Health Organization 2005
All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel: +41 22 791 2476; fax: +41 22 791 4857; email: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; email: [email protected]).
The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.
The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either express or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use.
This publication contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the World Health Organization.
TABLE OF CONTENTS
Regulatory Matters
Amfetamine -- Reintroduced with revised prescribing and patient information ...... 1 Atomoxetine -- Risk of suicidal thoughts...... 1 Bacitracin, Fusafungine, Gramicidin, Tyrothricin -- Locally administered products withdrawn ...... 2 Cetuximab -- Recommendations for electrolyte monitoring...... 2 Duloxetine -- Reports of adverse hepatic effects ...... 2 Fentanyl transdermal system -- Labels updated for safe and appropriate use...... 2 Hexavac -- Suspended due to concerns about long-term effects against hepatitis B...... 3 Medroxyprogesterone -- Loss of bone marrow density ...... 3 Meloxicam -- Juvenile rheumatoid arthritis indication: label updated ...... 3 Nabumetone -- Stronger labelling for renal effects...... 4 Non-selective NSAIDs -- No changes to current prescribing practice...... 4 Paroxetine -- Potential risk in pregnancy ...... 4 Thioridazine -- Sale discontinued in Canada ...... 5
Safety of Medicines
Anti-TNF alpha products -- New measures to prevent activation of latent tuberculosis ...... 6 Beta-2 agonists -- Increased risks of asthma-related deaths...... 6 Cabergoline -- Use linked to gambling...... 6 Codeine & hydrocodeine -- Akathisia with long-term use ...... 6 Ezetimibe -- Reports of muscle pain...... 7 Hydromorphone -- Co-ingestion with alcohol harmful...... 7 Ibuprofen -- Reports of Stevens-Johnson syndrome...... 7 Isotretinoin -- Strengthened risk management programme ...... 8 Trastuzumab -- Addition to chemotherapy increases toxicity ...... 8 Vinca alkaloids -- Intrathecal administration reported...... 8
Feature
Twenty-eighth Annual Meeting of Representatives of the National Centres participating in the WHO Programme for International Drug Monitoring: Observations from Working Group Exercises...... 10
REGULATORY MATTERS
recommended doses of the advise patients of the risks agent. See WHO associated with atomoxetine Amfetamine Pharmaceuticals Newsletter (Strattera) and precautions that Reintroduced with No. 2, 2005). can be taken, should be revised prescribing and distributed to patients when patient information Reference: atomoxetine (Strattera) is Dear Health-care Professional' dispensed. The increased risk of Canada. Health Canada is letter from Shire Biochem Inc., suicidal thinking in children was allowing Shire BioChem Inc.'s 31 August 2005 identified in a combined mixed-salts amfetamine (http://www.hc-sc.gc.ca). analysis of 12 short-term (6-18 preparation containing neutral weeks) placebo-controlled trials sulfate salts of dextro- (11 in ADHD and 1 in enuresis). amfetamine and amfetamine Atomoxetine The analysis showed a greater (Adderall XR) back on the Risk of suicidal risk of suicidal thinking during Canadian market following a thoughts the first few months of recommendation from the treatment in those receiving independent New Drug UK, USA. Atomoxetine atomoxetine (Strattera) Committee, who reviewed the (Strattera), is a drug approved compared to placebo-treated suspension of the sale of the for the treatment of Attention patients. The FDA has drug. Health Canada says that, Deficit Hyperactivity (ADHD) in recommended the following for in accordance with the paediatric and adult patients. inclusion in the boxed warning: Committee's recommendations, The UK Medicines and it will allow the product Healthcare products Regulatory • Atomoxetine (Strattera) (Adderall XR) to be Agency (MHRA) has issued a increases the risk of suicidal reintroduced after steps have Press Release with updated thinking in children and been taken, including the warnings on the risk of suicidal adolescents with ADHD. revision of the product's thoughts with atomoxetine prescribing and patient (Strattera). According to the • Anyone considering the use information to reinforce the Press Release Lilly, the of atomoxetine (Strattera) in safe use of the drug and to manufacturer of atomoxetine a child or adolescent for highlight the safety concerns (Strattera) in the UK, has ADHD must balance the associated with its use submitted data that do identify increased risk of suicidal (including the risk of sudden an increased risk of suicidal thinking with the clinical cardiac death in paediatrics). thoughts in children receiving need for the drug. Shire BioChem Inc. has been the drug. The MHRA is planning recommended to issue a `Dear to look into the health risks and • Patients who are started on Health Professional' letter that benefits of atomoxetine therapy should be observed advises of the drug's associated (Strattera). In the mean time, closely for clinical worsening, risks, and to support the Agency is advising health- suicidal thinking or independent continuing medical care professionals that patients behaviours, or unusual education for Canadian should be carefully monitored changes in behaviour. physicians to strengthen their for signs of depression, suicidal understanding of issues thoughts or suicidal behaviour • Families and caregivers regarding sudden/cardiac death and referred for alternative should be advised to closely in paediatrics. Health Canada treatment if necessary. Updated observe the patient and to also states that the agency is warning will be put on the communicate changes or committed to enhancing post- patient information leaflet (PIL) concerning behaviours with marketing surveillance of all for atomoxetine (Strattera) the prescriber. stimulants used for attention about the risk of suicidal deficit hyperactivity disorder thoughts and behaviour. A similar analysis in adult management, and that Shire patients treated with the drug BioChem Inc. will be requested The United States Food and for either ADHD or major to provide the agency with Drug Administration (US FDA) depressive disorder (MDD) regular safety information. has directed Eli Lilly, the found no increased risk of (Readers may recall that in manufacturer of atomoxetine suicidal ideation or behaviour in February 2005, Health Canada (Strattera), to include a boxed this age-group. instructed Shire BioChem Inc. warning and additional warning to withdraw their amphetamine statements that alert health- Reference: preparation (Adderall) due to care providers to an increased 1. Press Release. The Medicines safety information concerning risk of suicidal thinking in and Healthcare products sudden deaths, heart-related children and adolescents being Regulatory Agency (MHRA), deaths and strokes in children treated with the drug. The FDA 29 September 2005 and adults receiving has also decided that a Patient (http://www.mhra.gov.uk). Medication Guide, which will
WHO Pharmaceuticals Newsletter No. 4, 2005 • 1
REGULATORY MATTERS
2. Public Health Advisory. been revised with who take duloxetine (Cymbalta) United States Food and Drug recommendations for may be at increased risk for Administration, electrolyte monitoring and further liver damage. In view of 29 September 2005 longer observation periods these reports, the product label (http://www.fda.gov). following cetuximab infusion, which cautioned against using following an increased incidence duloxetine (Cymbalta) in of hypomagnesaemia in clinical patients with substantial alcohol Bacitracin, trials. The Warnings section has use, has now been revised to Fusafungine, been updated to recommend a extend the caution to include 1-hour observation period also those patients with chronic Gramicidin, following cetuximab infusion, liver disease. Tyrothricin and longer observation periods Locally administered in patients who have infusion Reference: reactions. The Dosage and 'Dear Health-care Professional' products withdrawn Administration section has also letter from Eli Lilly and France. Effective been updated to advise that Company, 5 October 2005 30 September 2005, the French patients who have infusion (http://www.fda.gov). medicines regulatory agency, reactions may require longer Agence française de securité observation periods. The Fentanyl sanitaire des produits de Santé Precautions and Adverse (AFSSAPS), has ordered that Reactions sections have been transdermal preparations of the antibiotics updated with recommendations system bacitracin, fusafungine, for electrolyte monitoring gramicidin or tyrothricin, which during and after cetuximab Labels updated for safe are locally administered therapy. These and appropriate use (nasally or by oropharynx recommendations follow the route) should be withdrawn observation in clinical trials of Canada. The Canadian from the market due to a lack an increased incidence of labelling for fentanyl of therapeutic efficacy. The hypomagnesaemia associated transdermal system (Duragesic) agency is of the opinion that with cetuximab, alone or in has been updated to highlight such a move would also prevent combination with important Health Canada- the emergence of strains of chemotherapy, compared with endorsed safety information antibiotic-resistant bacteria. best supportive care or regarding safe and appropriate Two years ago, the agency had chemotherapy alone; about half use of the drug, according to a ordered the withdrawal of three of the cetuximab recipients `Dear Health-care Professional' other antibiotics, framycetin, experienced hypomagnesaemia letter and a Public Advisory neomycin and and 10−15% experienced issued by Janssen-Ortho (1, 2). sulfasuccinamide, for similar severe hypomagnesaemia.The reasons. These measures are companies advise that the time The revised labelling highlights consistent with AFSSAPS' to onset of electrolyte that: abnormalities has ranged from recently completed review of • fentanyl transdermal system days to months after cetuximab locally administered antibiotics (Duragesic) contains a high initiation, and that the time to as part of a national and concentration of fentanyl resolution is not well known. European action programme to that has been associated promote the proper use of with fatal overdose; Reference: antibiotics. consumers should be aware 'Dear Health-care Provider' of fentanyl overdose letter from Bristol Myers Squibb Reference: symptoms, and should seek Company, 13 September 2005 Letter to prescribers. immediate medical attention (http://www.fda.gov). AFSSAPS, 19 July 2005 if such symptoms are noted (http://recherche.sante.gouv.fr). (2); Duloxetine • there have been Canadian Cetuximab Reports of adverse reports of serious and life- Recommendations for hepatic effects threatening hypoventilation associated with fentanyl electrolyte monitoring USA. Eli Lilly and Company has transdermal system received post-marketing reports USA. ImClone Systems (Duragesic), and prescribers of hepatic injury (including Incorporated and Bristol-Myers should be aware of, and hepatitis and jaundice) Squibb have issued a 'Dear monitor patients for, factors associated with duloxetine Health-care Provider' letter to that may increase this risk (Cymbalta) use. Some of these announce that the US labelling including drug interactions, reports indicate that patients for cetuximab (Erbitux) has alcohol and other CNS with pre-existing liver disease
WHO Pharmaceuticals Newsletter No. 4 2005 • 2 REGULATORY MATTERS
depressant use, fever, Hexavac The revised boxed warning exposure to external heat section states that: sources, use in elderly or Suspended due to debilitated patients, and concerns about long- • medroxyprogesterone fentanyl transdermal system term effects against (Depo-Provera) has been (Duragesic) use that is not hepatitis B associated with BMD loss in accordance with that may not be completely prescribing information (1); Europe. The European reversible, and BMD loss is Medicines Agency has greater with increasing • fentanyl transdermal system recommended the suspension duration of use; (Duragesic) is indicated for of the marketing authorization the management of for Hexavac. This is a • it is unknown if adolescent persistent, moderate-to- precautionary measure taken or early-adulthood use of severe, chronic pain that amidst concerns about the medroxyprogesterone cannot be treated by other vaccine's long-term protection (Depo-Provera) reduces means in patients already against hepatitis B following the peak bone mass and receiving opioids, and should identification of a decreased increases osteoporotic not be used in opioid-naïve immunogenicity of the fracture risk in later life; patients (1), or be used for hepatitis B component in the intermittent, short-term or vaccine. Hexavac is a vaccine • medroxyprogesterone post-operative pain (2); for infants and children against (Depo-Provera) should be diphtheria, tetanus, whooping • fentanyl transdermal system used for endometriosis cough (pertussis), hepatitis B (Duragesic) is not therapy or birth control only virus, polio virus and recommended for patients if other treatments are Hemophilus influenzae type b. aged < 18 years; there have unacceptable or unsuitable, The current concern does not been Canadian reports of and for the shortest affect the protection against death in children using the duration possible; the diphtheria, tetanus, whooping benefits and risks of product (2); cough, polio and Hemophilus medroxyprogesterone • there is a potential for the influenzae type b. Sanofi therapy should be regularly misuse, diversion and abuse Pasteur MSD, the marketing re-evaluated in all users. of fentanyl transdermal authorization holder, has been system (Duragesic) patches; directed to design a specific Other sections of the there have been reports of surveillance programme to medroxyprogesterone labelling death involving misuse and determine whether infant and have also been revised to abuse in Canada (1); children, already vaccinated include relevant information consumers should be with Hexavac, would need to be and warnings regarding the risk advised to protect fentanyl revaccinated at a later stage, to of BMD. transdermal system ensure long-term protection (Duragesic) from misuse or against hepatitis B. Reference: theft, and be made aware of Public Advisory. Health Canada, the importance of proper Reference: 30 June 2005 disposal and safe storage of Press release. European (http://www.hc-sc.gc.ca). the product. Medicines Agency, 15 September 2005 (See WHO Pharmaceuticals (http://www.emea.eu.int). Meloxicam Newsletter No. 3, 2005 for a Juvenile rheumatoid related Public Health Advisory Medroxy- arthritis indication: from the US FDA). label updated References: progesterone USA. The US meloxicam 1. 'Dear Health-care Loss of bone mineral (Mobic) label has been updated Professional' letter from density to include warnings about non- Janssen-Ortho Inc., steroidal anti-inflammatory 13 September 2005 Canada. Health Canada has drug (NSAID)-related (http://www.hc-sc.gc.ca). issued a Public Advisory about recent findings that showed cardiovascular (CV) and 2. Public Advisory. Health medroxyprogesterone (Depo- gastrointestinal (GI) risks Canada, 16 September 2005 Provera) may cause significant following the addition of a (http://www.hc-sc.gc.ca). bone mineral density (BMD) juvenile rheumatoid arthritis loss in women. Black-box indication. The revised warnings with these findings meloxicam (Mobic) labelling have been added to the includes a black box warning Canadian product label. that states that NSAIDs may
WHO Pharmaceuticals Newsletter No. 4, 2005 • 3
REGULATORY MATTERS
increase the risk of fatal (Relafen's) Clinical that the revised prescribing myocardial infarction, CV Pharmacology and Dosage & advice adopted in June 2005 for thrombotic events and stroke, Administration sections have selective COX-2 inhibitors (eg and that the drug is been updated to reflect the celecoxib, etoricoxib, contraindicated for the renal impairment lumiracoxib and parecoxib) treatment of perioperative pain recommendations; updates to remains unchanged. (The June in the coronary bypass setting; the Warnings heading includes 2005 advice was based on a a strengthened warning has the addition of oral review that had identified an also been added regarding GI corticosteroids as a risk factor increase in the risk of adverse events. The Indications for GI bleeding if combined with thrombotic adverse section has been updated to NSAIDs. GlaxoSmithKline states cardiovascular reactions such advise consumers to consider that a separate labelling as heart attack or stroke with meloxicam's benefits and risks revision proposal that reflects selective COX-2 inhibitors). and other treatment options the US FDA's NSAID labelling before using meloxicam, and to recommendations for References: use the lowest effective dose cardiovascular and GI risk has Press Release. European for the shortest duration. been submitted to the agency. Medicines Agency, 29 July 2005 Similar language highlighting (http://www.emea.eu.int). the CV risk has been added Reference: under the Warnings heading, Relafen labelling revision and language concerning the includes stronger renal effects Paroxetine risk of GI ulceration, perforation precaution. FDA Reports - Pink Potential risk in and bleeding has been updated. Sheet - Prescription pregnancy Warnings of stroke, Pharmaceuticals and USA. GlaxoSmithKline (GSK) hypertension and congestive Biotechnology, 22 August 2005, and the US FDA have notified heart failure, and warnings that 67: 16, No. 34. health-care professionals of NSAIDs can cause skin changes to the reactions have also been added Pregnancy/PRECAUTIONS to the label. Information Non-selective section of the Prescribing concerning toxicity and renal NSAIDs Information for paroxetine injury has moved to the No changes to current (Paxil and Paxil CR Controlled- Warnings section from the prescribing practice Release Tablets) to describe the Precautions section. results of a GSK retrospective
Europe. Based on the epidemiologic study of major Reference: assessment of available congenital malformations in Mobic adds juvenile rheumatoid evidence on thrombotic risk infants born to women taking arthritis indication, associated with non-selective antidepressants during the first cardiovascular black box non-steroidal anti-inflammatory trimester of pregnancy. This warnings. FDA Reports - Pink drugs (NSAIDs), and pending study suggested an increase in Sheet - Prescription the ongoing review of other the risk of overall major Pharmaceuticals and safety issues, the European congenital malformations for Biotechnology, 22 August 2005, Medicines Agency's Committee paroxetine as compared to 67: 15, No. 34. on Medicinal Products for other antidepressants. Health- Human Use (CHMP) does not care professionals are advised Nabumetone currently recommend any to carefully weigh the potential changes to the advice to risks and benefits of using Stronger labelling for prescribers and patients. The renal effects paroxetine therapy in women CHMP highlights that the overall during pregnancy and to safety profiles of non-selective USA. The US labelling for discuss these findings as well as NSAIDs and the risk factors for nabumetone (Relafen) has been treatment alternatives with each patient should be the revised to include a stronger their patients. Paroxetine is basis for prescribing decisions, precaution on the renal effects indicated for the treatment of and that non-selective NSAIDs of the drug. Nabumetone's major depressive disorder, should be used at the lowest (Relafen's) revised labelling obsessive-compulsive disorder, effective dose for the shortest include dosing panic disorder, social anxiety period necessary for symptom recommendations (including disorder, generalized anxiety control. Non-selective NSAIDs maximum starting and daily disorder and premenstrual reviewed by the CHMP include doses, and dosing adjustments) dysphoric disorder. diclofenac, etodolac, ibuprofen, for patients with moderate or indomethacin, ketoprofen, severe renal impairment, and Reference: meloxicam, nabumetone, states that caution is required 'Dear Health-care Professional' naproxen and nimesulide. In its when the drug is prescribed to letter from GlaxoSmithKline, press release, the Agency notes these patients. Nabumetone's
WHO Pharmaceuticals Newsletter No. 4 2005 • 4 REGULATORY MATTERS
27 September 2005 pharmacokinetic (http://www.fda.gov). interactions, rebound symptoms, extrapyramidal features (in particular Thioridazine involuntary movement Sale discontinued in disorders) and cardiac Canada arrhythmia associated with QT prolongation, when Canada. According to Health switching to an alternate Canda, thioridazine sales have anti-psychotic medications. been discontinued in Canada by Health Canada states that 30 September 2005 due to the pharmacies will be permitted to lack of convincing safety continue dispensing remaining information that supports the thioridazine supplies after continued safe use of the drug 30 September 2005 to allow as an antipsychotic. The Agency patients time to switch to says that thioridazine is another antipsychotic associated with QT prolongation medication. Thioridazine will that predisposes to potentially also be available through the fatal cardiac arrhythmia Special Access Programme for including sudden death and patients who can not be torsade de pointes. The Agency adequately managed on states that it has received three alternative therapies, says the reports of death, between 2000 agency. and 2005, that were possibly related to thioridazine. The References: innovator preparation of 1. Advisories/Warnings. Health thioridazine (Novartis' Mellaril) Canada, 8 September 2005 was voluntarily withdrawn from (http://www.hc-sc.gc.ca). the Canadian market in July 2001 due to safety concerns, 2. 'Dear Health-care but several other generic Professional' letter from Health thioridazine products continued Canada, 31 August 2005 to be marketed in Canada, says (http://www.hc-sc.gc.ca). the agency(1).
Health Canada advises (2):
• patients using thioridazine to not stop taking the drug, and to see their health care provider as soon as possible to be switched to an alternative treatment;
• health professionals to
switch patients from
thioridazine to an
alternative therapy at the
earliest medically feasible
point, individualize the
switching strategy for each
patient, and gradually
reduce the thioridazine
dosage over several weeks
to prevent cholinergic
rebound and the
recurrence of symptoms of
the underlying condition;
• prescribers to monitor for any potentially occurring phenomena of major relevance, including
WHO Pharmaceuticals Newsletter No. 4, 2005 • 5
SAFETY OF MEDICINES
information on the asthma • medical attention should be medications formoterol sought if a patient's asthma Anti-TNF alpha (Novartis' Foradil; medication becomes less products AstraZeneca's Oxeze), effective or if patient needs New measures to salmeterol and the combination more inhalations than usual; products of an inhaled prevent activation of • asthma therapy should not corticosteroid with salmeterol be stopped or reduced latent tuberculosis (Advair) or formoterol without first consulting the (Symbicort). The advisory is France. Agence française de prescribing physician. based on a Health Canada securité sanitaire des produits analysis of findings from the de Santé (AFSSAPS), the Reference: Salmeterol Multi-center Asthma French Medicines Agency, has Advisories/Warnings. Health Research Trial (the SMART recommended new measures to Canada, 4 October 2005 study) in the US which showed prevent and treat any activation (http://www.hc-sc.gc.ca). of latent tuberculosis that might that salmeterol appeared to develop during a course of increase the risks of asthma- treatment with anti-tumour related death and other serious Cabergoline necrosis factor (anti-TNF) alpha respiratory-related events; data Use linked to gambling products. The updated advice from a SMART post-hoc analysis includes etanercept (Wyeth's suggested that these risks may Australia. Four reports of Enbrel) and adalimumab be greater in African-American gambling associated with (Abbott's Humira), both of patients and in patients not cabergoline (Cabaser) have which are marketed in France. using inhaled corticosteroids at been reported to the Australian According to the advice, study entry. The increased risk Adverse Drug Reactions patients should undergo a skin- with salmeterol may also apply Advisory Committee (ADRAC), reaction test for tuberculosis to other long-acting beta-2 all of which were received in (TB) before a course of anti- agonists such as formoterol the past two years, according to TNF alpha products and during although there is no current the Australian Adverse Drug treatment as well, should they data to confirm this. Reactions Bulletin. The affected present with symptoms of TB; patients were receiving long- Health Canada recommends term levodopa, and started patients should be treated for that: TB if the tuberculin skin-test their excessive gambling a reaction is larger than 5 mm • salmeterol and formoterol number of months after (as opposed to the previous can only be used with an cabergoline initiation. In three advice of 10 mm). The agency appropriate dose of inhaled of these cases, the patients also advises that a larger dose of corticosteroid as determined developed obsessive, abnormal isoniazid (5 mg/kg/day as by a physician; or inappropriate behaviour. In opposed to the previously all four cases, the gambling and • long-acting β2-agonists are recommended dose of other behavioural disorders not a substitute for inhaled resolved on cabergoline 4 mg/kg/day) should be used to or oral corticosteroids; treat these cases of TB. discontinuation. ADRAC advises However, 4mg/kg/day is still • salmeterol (Serevent), prescribers to be alert to the the recommended dose if formoterol (Foradil), or the development of gambling in isoniazid is used along with combination of an inhaled patients receiving concomitant rifampicin. corticosteroid with levodopa and dopamine salmeterol (Advair) should receptor agonists. Reference: never be used to treat acute AFSSAPS, 26 July 2005 or sudden onset of asthma Reference: (http://recherche.sante.gouv.fr). symptoms and attacks; Adverse Drug Reactions Advisory Committee. • the combination product of Pathological gambling with Beta-2 agonists an inhaled corticosteroid cabergoline. Australian Adverse Increased risks of with formoterol (Symbicort) Drug Reactions Bulletin, asthma-related deaths is not indicated for the August 2005, 24(4):15. treatment of sudden asthma symptoms and attacks; Canada. Health Canada is Codeine & warning Canadians of the • AstraZeneca's formoterol possible increased risks of (Oxeze Turbuhaler) may be hydrocodeine asthma-related deaths used on demand to treat Akathisia with long- associated with the use of a acute symptoms in patients term use class of asthma drugs known as aged ≥ 12 years; UK. The manufacturers of over- long-acting β2-agonists. The advisory includes safety the-counter (OTC) analgesics
WHO Pharmaceuticals Newsletter No. 4, 2005 • 6 SAFETY OF MEDICINES
that contain codeine and therapy concomitantly; in these release formulation to contact dihydrocodeine have been cases, the patients had typically their doctor with regards to asked to voluntarily update received long-term statin obtaining an alternative drug. their labelling and Patient therapy, then developed muscle To investigate if the same effect Information Leaflets by the UK pain or increased serum occurs with other slow-release Medicines and Healthcare creatine levels within drugs, Health Canada requests Regulatory Agency (MHRA). The three months of ezetimibe that all manufacturers of these MHRA says that the updated initiation. Four patients products provide information on labelling and Patient recovered following the interaction between their Information Leaflets will discontinuation of ezetimibe, drug and alcohol; if this is not highlight that regular, long- and one patient tolerated the possible, studies investigating term codeine use may lead to withdrawal of ezetimibe and product interactions with dependence that might cause reintroduction of atorvastatin alcohol are to be conducted and akathisia and irritability when 80 mg/day. completed within six months. the drug is discontinued. The Health Canada states that the agency states that the updated Reference: data will be assessed within a information will advise patients Adverse Drug Reactions three-month period and that to contact their pharmacist or Advisory Committee. Ezetimibe further action will be taken if doctor if their OTC treatment is and muscle disorder. required, but, until then, the required for a period of more Australian Adverse Drug issue of possible `dose than three days at a time, and Reactions Bulletin, dumping' associated with warns that taking an analgesic August 2005, 24(4):15. alcohol will be temporarily to alleviate a headache may included in the prescribing worsen the symptom if the drug information for all slow-release is taken too frequently or for Hydromorphone opioids. too long. Co-ingestion with
alcohol harmful Reference: Reference: Advisory. Health Canada, Media Release. Medicines and Canada. Health Canada has 3 August 2005 Healthcare Products Regulatory issued an Advisory to warn of (http://www.hc-sc.gc.ca). Agency, 15 August 2005 serious health risks associated (http://www.mhra.gov.uk). with the consumption of alcohol while taking any slow-release Ibuprofen Ezetimibe opioid analgesics, following Reports of Stevens- data from Purdue Pharma that Johnson syndrome Reports of muscle pain indicated that the co-ingestion of its hydromorphone slow- Australia. Of the 144 adverse Canada. Health Canada has release formulation (Palladone reaction reports associated with received four reports of XL) with any quantity of alcohol ezetimibe (Ezetrol) received by suspected ibuprofen-associated may cause serious and ADRAC since registration of the Stevens-Johnson syndrome potentially fatal complications. drug in June 2003, 44 were of between 1 January 1973 and 21 The Agency states that when muscular disorders, including February 2005, according to the these capsules are taken with pain, cramp and weakness. Canadian Adverse Reaction alcohol, potentially dangerous Three of these reports Newsletter. All four reports levels of hydromorphone are described symptoms that were received after April 2001 released into the blood quickly possibly indicated an allergic and involved patients aged (dose-dumping) instead of over reaction, and five involved 13−34 years who had received 24 hours. Health Canada states increased serum creatine kinase ibuprofen 200−1200 mg/day. that there are no supplies of levels. According to ADRAC, a The time to reaction onset hydromorphone slow-release history of muscular disorders or ranged from the day of formulation (Palladone XL) on increased creatine kinase levels administration to about 15 days the Canadian market. The in association with statin after ibuprofen initiation, and Agency advises patients therapy was reported in carbamazepine was also receiving other slow-release 21 patients. In almost half of identified as a suspect drug in opioids to be aware that these the 44 cases, the time to onset one report. At the time of the products may react in a similar of muscular disorders was reports, the outcome was way to hydromorphone slow- ≤ 2 weeks after ezetimibe unknown for one patient and release formulation when co- initiation, but the time to onset three of the patients had not ingested with alcohol and to ranged from hours to recovered. consult their pharmacists if they approximately four months. In have any questions. Health five of the 44 cases, along with Reference: Canada advises patients two published cases, patients Canadian Adverse Reaction receiving hydromorphone slow- received ezetimibe and statin Newsletter July 2005, No. 3.
WHO Pharmaceuticals Newsletter No. 4, 2005 • 7
SAFETY OF MEDICINES
Isotretinoin current isotretinoin warnings, 4.3%. The 3-year cumulative patient information and incidence of New York Heart Strengthened risk informed consent document, to Association Class III and IV management help prescribers and patients congestive heart failure and programme identify and manage the risks cardiac death was significantly of depression and psychiatric increased in the trastuzumab USA. The US FDA has approved disorders before and after (Herceptin) group compared a strengthened isotretinoin isotretinoin prescription. with the chemotherapy alone (Accutane and generics) risk group (4.1% vs 0.8%). One management programme References: cardiac death was reported in (iPLEDGE) in an effort to 1. Public Health Advisory. the control group, but none prevent use of the drug during United States Food and Drug were reported in the pregnancy; the agency warns Administration, trastuzumab (Herceptin) group. that exposure to isotretinoin 12 August 2005 The company also reports that during pregnancy may (http://www.fda.gov). a final analysis of the cardiac significantly increase the risk of 2. Press Release. United States safety data is ongoing. congenital disorders. Food and Drug According to the FDA, Administration, (*National Surgical Adjuvant isotretinoin sponsors will be 12 August 2005 Breast and Bowel Project study implementing a programme in (http://www.fda.gov). B-31. Treatment consisted of which prescribers, pharmacies, doxorubicin and cyclo- wholesalers and patients, who phosphamide (4 cycles) agree to accept specific Trastuzumab followed by paclitaxel every responsibilities, will be required Addition to three weeks (4 cycles). Patients to register in iPLEDGE before chemotherapy in the trastuzumab (Herceptin) receiving authorization to increases toxicity group received the drug at the prescribe, dispense, distribute approved dose and schedule for or obtain isotretinoin; the USA. Genentech Inc. has one year, during and following responsibilities are designed to issued a `Dear Health-care paclitaxel). reduce the risk of exposure to Provider' letter to advise that isotretinoin during pregnancy. the addition of trastuzumab Reference: From 1 November 2005, only (Herceptin) to chemotherapy 'Dear Health-care Provider' iPLEDGE-registered wholesalers has been associated with letter from Genentech Inc., will be able to obtain increased cardiotoxicity August 2005 isotretinoin from the compared with chemotherapy (http://www.fda.gov). manufacturers and only alone in a recent study. In the iPLEDGE-registered pharmacies letter, Genentech presents will be able to receive results from a preliminary Vinca alkaloids isotretinoin from registered analysis of safety data from a Intrathecal wholesalers. From Phase III trial, in which 2043 administration 31 December 2005, pharmacies women with operable, human reported will be required to receive epidermal growth factor iPLEDGE authorization before receptor 2 (HER2)-over- France. Another case of dispensing an isotretinoin expressing breast cancer were inadvertent intrathecal prescription, and only randomized to receive vindesine (Eldisine) prescriptions from registered trastuzumab (Herceptin) in administration, involving a prescribers for registered addition to chemotherapy patient who was supposed to patients will be accepted. Prior (n = 1019) or chemotherapy have received IV vindesine and to isotretinoin prescription, alone (*). Among the evaluable intrathecal methotrexate, has iPLEDGE prescribers will be patients with adequate heart been received, according to responsible for pregnancy function who were able to Dr Françoise Goebel from the counselling of women of child- receive trastuzumab Pharmacovigilance Unit of bearing potential, and for (Herceptin), 30.5% had ≥ 1 AFSSAPS. Dr Goebel says that obtaining a negative pregnancy dose delay because of it is difficult to assess the test that will be entered into asymptomatic Left Ventricular number of such incidents in the iPLEDGE system. Using Ejection Fraction (LVEF) France, because they are likely iPLEDGE, isotretinoin sponsors decrease or heart disorders, to be under-reported. The will implement a system for and trastuzumab (Herceptin) national drug surveillance reporting and collecting was discontinued before system has received four information on isotretinoin- completion of therapy because similar cases in the last related serious adverse events, of an asymptomatic LVEF three years, involving and monitor compliance and decrease in 14.3%, or because vincristine (n = 3) and pregnancy rates. The FDA has of other heart disorders in vindesine (1). Three of the also approved changes to the
WHO Pharmaceuticals Newsletter No. 4, 2005 • 8 SAFETY OF MEDICINES
incidents occurred in adults and one in a child; despite rapid and appropriate medical care, all four patients died. According to Dr Goebel, in the 20 years to 2002, Lilly Research Laboratories had documented 66 such cases worldwide associated with vindesine, vinblastine or vincristine. Dr Goebel warns that the scheduling of intrathecal and IV chemotherapy at the same time can cause confusion and may result in medication errors. He advises that it has been recommended that drugs given intravenously and intrathecally should no longer be administered on the same day in children with acute lymphoblastic leukaemia, and says that some adult oncology services administer IV injections in the morning and intrathecal injections in the afternoon. Dr Goebel comments that the intrathecal vinca alkaloid-associated risk of death is known, and is mentioned in the product information for vindesine (Eldisine), vinblastine (Velbé) and vincristine (Oncovin).
Reference: Goebel F. Accidental intrathecal administration of vinca- alkaloids: risk of death. Vigilances, August 2005, 28:3.
WHO Pharmaceuticals Newsletter No. 4, 2005 • 9 FEATURE
Twenty-eighth Annual Meeting of Representatives of the National Centres participating in the WHO Programme for International Drug Monitoring
Observations from Working Group Exercises
The Twenty-eighth Annual Meeting of Representatives of the National Centres participating in the WHO Programme for International Drug Monitoring was held from 26 to 29 September 2005, in Geneva, Switzerland. In this meeting, working group exercises focused on several key issues in pharmacovigilance including:
• how pharmacovigilance centres react to high profile (drug) withdrawals • pharmacovigilance in public health programmes • reporting adverse events following immunization (AEFI) • developing an international taxonomy for patient safety events • reporting and learning from patient safety events • the relevance of the International Classification of Diseases (ICD) in pharmacovigilance.
Below is a summary of key concepts and conclusions from three of the exercises:
1. Improving the effectiveness of pharmacovigilance centres' responses to high profile withdrawals
Regulatory authorities have the responsibility for undertaking several procedures prior to withdrawing a medicine from the market. They must collate and review available data and conduct a risk/benefit assessment. They must also communicate the risk that they identify to prescribers in an adequate manner and identify alternative product options. However, depending on the capacity of the agency, there is much divergence among regulatory agencies in carrying out one or more of these procedures. Well-resourced, and well-established regulatory bodies have access to and capacity to analyse company trial data, local adverse drug reactions (ADR) data, data from the global ADR database and medical literature. Countries with less-developed regulatory systems are restricted by resource and /or capacity constraints. They may be limited to reviewing local data, and although trials may be ongoing in their country they may not have access to the company trial data. They may therefore have to rely on communications from regulatory authorities in developed countries on regulatory actions taken.
In general, from a regulator's perspective, access to drug safety information is often compromised by artificial or inappropriate timelines for reporting, confidentiality requirements, media and government pressure and gaps in human resources and skills.
Inadequate information hampers appropriate and timely regulatory measures, which in turn often erode professional and public confidence in the regulator in particular, and in pharmacovigilance, in general.
Recommendations for improving global-regulatory efficiency should focus around:
• improving information-sharing and multilateral collaborations; • strengthening regulatory capacity by releasing, in a timely fashion, ADR reports, their evaluation, and all risk-communication material even while still in development; • promoting electronic exchange and discussion on safety issues of global concerns (eg through Vigimed, E-Drug) and • undertaking literature review of high risk products and creating a data bank for such literature.
2. Pharmacovigilance in public health programmes
The group identified that there are compelling reasons for including pharmacovigilance into public health programmes including those designed to treat HIV/AIDS, malaria, TB and helminth infections: Many new drugs are used to treat HIV/AIDS, malaria, TB and helminth infections on the basis of efficacy-focused clinical trials of limited duration with little knowledge of their long-term adverse effects. Available data on drug toxicity are mainly from industrialized countries (e.g. in HIV/AIDS treatments), which have a different clinical and operational context in developing countries. Drugs are used in combinations not assessed in developed countries. Life threatening side effects, co-morbidities and co-treatments impact on selection of preferential and alternative drugs
At present few if any public health programmes include a pharmacovigilance component in their design. In several countries that run public health programmes, there are no pharmacovigilance centres and hence, there are no
WHO Pharmaceuticals Newsletter No. 4, 2005 • 10 FEATURE
systematic methods for collecting ADR reports in these countries. In those countries where both systems exist, they often function in parallel, with little communication between the national pharmacovigilance centres and the public health programmes.
United Republic of Tanzania, a case example: The Tanzanian drug monitoring programme was created as a result of the malaria treatment programme in the country. It started as a process of active collection of ADR reports in the malaria treatment programme, the country now has a fully-fledged pharmacovigilance system and was recognized as a full member of the WHO programme for International Drug Monitoring in 1993.
Recommendations:
• All public health programmes should be required to build pharmacovigilance into their agenda. • As a first step, the concepts in the ICH E2E guideline on Pharmacovigilance Planning should be used to develop a system for meeting the needs of specific infectious diseases and drug treatment related safety concerns in public health programmes. This guideline describes a method for summarizing the important identified risks of a drug, important potential risks, and important missing information, including the potentially at-risk populations and situations where the product is likely to be used that have not been studied. It proposes a structure for a Pharmacovigilance Plan and sets out principles of good practice for the design and conduct of observational studies. • The spontaneous reporting system could be used for flagging-off initial concerns which could be further verified using targeted active-surveillance programmes for specific ADR issues. These may be further reinforced with randomized clinical trials, if warranted. • Where pharmacovigilance centres exist, it is incumbent upon the staff of these centres to establish communications with the relevant staff in the public health programmes, to visit and instruct public health workers in the importance, benefits and methods of reporting an ADR.
3. Vaccines: How to improve AEFI reporting to the WHO global ADR database
There are many barriers to reporting adverse events following immunization programmes. These include: a split between ADR and AEFI pharmacovigilance groups, with the two systems developing as parallel fiefdoms; issues of data ownership; lack of communication between immunization programmes and pharmacovigilance centres; differing objectives (e.g. vaccines programmes may focus more on procurement and storage issues than on pharmacovigilance); lack of education on the importance and benefits of AEFI reporting; insufficient AEFI-oriented elements in current pharmacovigilance training programmes; current taxonomy and definitions of adverse events / reactions being drug (ADR) based; and insufficient vaccine-centres' participation in WHO annual meeting of pharmacovigilance centres.
If this situation is to change there must be an improvement in the following areas:
1. Political will and commitment. Officials at higher levels of authority must be involved to introduce AEFI- reporting into national health agendas and there must be active participation of regulators, with appropriate legislation to empower AEFI reporting. 2. Communication, media and visibility: There must be improved communication between all partners, across and within systems, nationally and internationally, linking vaccines programmes with pharmacovigilance centres. Vaccine-related topics should be included in popular and reader-friendly journals such as Viewpoint, for increasing awareness about AEFI-issues. Vaccines should be a topic in all WHO annual meetings of national pharmacovigilance centres. 3. Education and training: Elements of vaccine-safety and AEFI reporting should be included in the curriculum of undergraduate training of all health professionals. Additional vaccine-safety courses in French, English and in vernacular languages should be organized. 4. Terminology: A focus should be on specific AEFI needs and terms. The WHO Collaborating Centre for International Drug Monitoring should analyse the most frequent text terms focusing only on vaccines. The ATC classification system for vaccines should be improved. 5. Harmonization: A common reporting system should be developed while retaining a focus on country specific issues. AEFI terms relevant to patient safety should be harmonized. Lot numbers of biological products should be collected in the AEFI reports, as well as details such as private versus publicly provided vaccines for facilitating 'track and search' functions. Common elements and synergies between AEFI and ADR reporting systems should be explored and developed such that both systems benefit mutually.
WHO Pharmaceuticals Newsletter No. 4, 2005 • 11