No. 3, 2004

EDITORIAL

In addition to the usual updates on recent drug safety and regulatory information for medicines, this issue of the newsletter features an article summarizing the decisions regarding the use of Selective Serotonin Reuptake Inhibitor (SSRI) -antidepressants in children. Most of these products appear to have a negative benefit-risk balance when used in treating major depressive disorder (MDD) in children.

HIV/AIDS was one of the key health issues that figured in the discussions of the recently concluded Fifty-seventh World Health Assembly (WHA) in Geneva. Through Resolution WHA57.14 on HIV/AIDS (http://www.who.int/gb), the WHA requested the Director-General to strengthen the WHO prequalification project managed by the World Health Organization (WHO) for pharmaceutical and diagnostic products to diagnose, treat and manage HIV/AIDS and urged Member States to make best use of WHO's list of prequalified antiretroviral drugs that meet international quality standards (see http://mednet3.who.int/prequal for key facts on the WHO prequalification project).

With the global focus on treating HIV, and consistent with WHO's 3 by 5 initiative to provide treatment to three million HIV patients by the year 2005, it is timely that a training course will be held in September 2004 in South Africa to Contents ‰ encourage the integration of pharmacovigilance for Regulatory matters ‰ antiretrovirals in some sub-Saharan African countries. Details of this course as well as the complete course material will be Safety of medicines ‰ made available on the website of the Department of Essential Feature ‰ Drugs and Medicines Policy (EDM) http://www.who.int/ medicines at a later date, after the course.

TABLE OF CONTENTS

REGULATORY MATTERS

ARIPIPRAZOLE, CLOZAPINE, QUETIAPINE AND OTHER ATYPICAL ANTIPSYCHOTICS -- Label to indicate risk of hyperglycaemia and diabetes... 1 MUROMONAB-CD3 -- Serious adverse reactions in paediatric patients...... 1 NU BAO -- Presence of animal derivatives and human tissue poses health risks...... 1 OTC DRUGS -- New labelling rules to increase safety ...... 2 SHITEK TONGKAT ALI PLUS 400MG -- Presence of tadalafil ...... 2 TOLCAPONE -- Marketing re-authorized, but more stringent monitoring recommended ...... 2 TRAZODONE -- Interactions with CYP3A4 inhibitors/inducers ...... 2

SAFETY OF MEDICINES

CARVEDILOL -- Reports of diarrhoea...... 4 CYCLO-OXYGENASE-2 INHIBITORS -- Reports of visual disturbances ...... 4 FURANOCOUMARINS -- Presence in a herbal preparation...... 4 LEFLUNOMIDE -- Awareness and monitoring can reduce the impact of adverse effects ...... 5 OXANDROLONE -- Warning for interaction with warfarin...... 5 SHUBAO SLIMMING CAPSULES -- Presence of fenfluramine and nitrosofenfluramine...... 5 STATINS -- Important to measure creatine kinase levels ...... 6 TEGASEROD -- Warning about diarrhoea and ischaemic colitis ...... 6 THIOMERSAL IN VACCINES -- Recent evidence supports safety...... 6 ZAFIRLUKAST -- Reports of serious hepatic events ...... 7

FEATURE ...... 8

REGULATORY MATTERS

ARIPIPRAZOLE, psychotic agent quetiapine notably cerebral oedema and fumarate (Seroquel), had herniation; nine cases of CLOZAPINE, warned health professionals cerebral oedema have been QUETIAPINE that patients should be reported worldwide since monitored for glucose control 1986, with six deaths due to AND OTHER before starting treatment cerebral herniation. Paediatric ATYPICAL ANTI- with atypical antipsychotics. patients treated with PSYCHOTICS More recently, in April 2004, muromonab-CD3 may also be the company has issued an at increased risk of Label to indicate risk of additional letter that besides lymphoproliferative and hyperglycaemia and pre-treatment monitoring, infectious complications diabetes patients should also be compared to adults. A large monitored periodically for proportion of children may USA. The United States Food worsening of glucose control not have been infected by and Drug Administration throughout treatment. pathogens such as herpes (US FDA) has requested that viruses prior to trans- Bristol-Myers Squibb Com- References: plantation and are therefore pany, the manufacturer of the 1. 'Dear Healthcare Practitioner' letter from Bristol-Myers Squibb more susceptible to atypical antipsychotic drug Company, 25 March 2004. developing primary infections aripiprazole (Abilify) should Available from URL: from the grafted organ update the prescribing www.fda.gov/medwatch following immuno- information for the drug to 2. 'Dear Healthcare Provider' letter suppression with muro- reflect the risk of from Novartis, 01 April 2004. Available from URL: monab-CD3. Janssen-Ortho hyperglycaemia and diabetes http://www.fda.gov/medwatch Inc. is currently working with in patients treated with this 3. 'Dear Healthcare Provider' letter Health Canada to update the drug. More recently, Novartis, from AstraZeneca Canadian Product Monograph under advice from the US Pharmaceuticals LP, 22 April to include the above FDA has also made similar 2004. Available from URL: http://www.fda.gov/medwatch information. changes to the prescribing information for clozapine Reference: (Clozaril) antipsychotic MUROMONAB- Letter to Hospital Chief of Medical Staff, from Janssen-Ortho Inc., 13 tablets. The US FDA has CD3 May 2004. Available from URL: recommended these revisions http://www.hc-sc.gc.ca after reviewing data related Serious adverse reactions in paediatric to the use of atypical NU BAO antipsychotics and hyper- patients Presence of animal glycaemia with its related Canada. Janssen-Ortho Inc., symptoms ( e.g., polydipsia, under advice from Health derivatives and human polyuria, polyphagia and Canada is warning health tissue poses health weakness). The FDA has professionals that muro- risks concluded that all atypical monab-CD3 (ORTHOCLONE antipsychotics should be UK. The patient information OKT*3) is not approved for leaflet for a traditional updated to include infor- paediatric use (age up to 17 mation about the potential for Chinese medicine named Nu years) in Canada. Bao lists human placenta, these adverse events. Muromonab-CD3 is a murine Patients with risk factors for deer antler (Corna cervi monoclonal antibody oantotrichum) and donkey diabetes should undergo indicated for the treatment of baseline screening before skin (Colla cori astini) as the acute renal, cardiac, and ingredients present in the treatment with any atypical hepatic allograft rejection antipsychotic drug and capsules of the product. refractory to conventional Although the information on routine monitoring should anti-rejection therapy or be undertaken throughout the source of these when conventional therapy is ingredients is limited, the therapy to mitigate the risk of contraindicated in adult patients developing serious Medicines and Healthcare patients. Paediatric patients Products Regulatory Agency metabolic complications. In treated with this product may January 2004 AstraZeneca (MHRA) advices that all be at an increased risk of animal and human tissue Pharmaceuticals LP, manu- developing serious neuro- facturer of atypical anti- derivatives carry a potential logical complications, most risk of infectious diseases due

WHO Pharmaceuticals Newsletter No. 3, 2004 • 1 REGULATORY MATTERS to the transmission of SHITEK indicated in the treatment of infective bacteria and viruses. Parkinson's disease. The The MHRA is therefore TONGKAT ALI marketing authorization for advising that consumers PLUS 400MG tolcapone was suspended in should not take this product. Europe in November 1998 Presence of tadalafil Current users should stop following concerns about taking the product and should Malaysia. The Drug Control hepatotoxicity and neurol- consult their doctor if they Authority of Malaysia has eptic malignant syndrome feel unwell. The MHRA has detected the presence of associated with the use of written to suppliers to cease tadalafil in a traditional this drug. However, based on marketing Nu Bao with medicine sold under the its recent safety evaluation, immediate effect. name of Shitek Tongkat Ali the committee has stated Reference: Plus 400mg in Malaysia. The that the drug may be re- Herbal Safety News, May 2004. product had a fraudulent introduced into the European Available from URL: marketing authorization market under stringent http://medicines.mhra.gov.uk number printed on its monitoring for liver function package and was manufac- effects. The committee also OTC DRUGS tured by a contract recommends that the drug should be contraindicated in New labelling rules to manufacturer, Shitek Micro Algae Sdn Bhd. Tadalafil is a patients with certain medical increase safety prescription drug and could histories, including liver USA. New US FDA labelling pose serious health hazards if disease and neuroleptic rules for over-the-counter used without medical malignant syndrome. (OTC) drugs will increase supervision. The Malaysian Reference: safety for patients with Drug Authority has issued a EMEA Press Release, 23 April 2004. certain medical conditions. press release to advise Warning and content labelling people against using the TRAZODONE will be strengthened for oral Shitek Tongkat Ali Plus OTC drugs that contain 400mg capsules. The agency Interactions with calcium, sodium, magnesium has also taken action against CYP3A4 or potassium above specific the contract manufacturer of inhibitors/inducers levels, as they could be the product and the USA. FDA and Bristol Myers harmful to patients with Pharmacy Enforcement Squibb have notified health- special sensitivities. The FDA division has conducted a care professionals of revisions has also proposed an nationwide surveillance to to the Clinical Pharmacology extension to the sodium- seize all batches of the and Precautions sections of labelling rules to include OTC product from the market. the labelling for trazodone rectal drugs containing Reference: (Desyrel) indicating the sodium phosphates, as there Communication from National potential for interactions may be a risk of serious Pharmaceutical Control Bureau, between trazodone and electrolyte imbalances in Ministry of Health, Malaysia, 30 CYP3A4 inhibitors/inducers. patients with certain under- April 2004. Trazodone is indicated for the lying medical conditions. The treatment of depression and new rules came into effect on TOLCAPONE appears to be metabolized by 23 April 2004, with full Marketing re- the CYP450 3A4 (CYP3A4) compliance required by 25 authorized, but more enzyme system (other September 2005. stringent monitoring metabolic pathways may also Reference: recommended be involved). The metabolic FDA News, 25 March 2004. clearance of trazodone could Available from URL: Europe. The scientific be impaired by CYP3A4 http://www.fda.gov committee of the European inhibitors ketoconazole, Medicines Evaluation Agency ritonavir, and indinavir, with (EMEA) has appraised new a resultant increase in plasma data on the safety of trazodone level and a tolcapone (Tasmar) and has potential for adverse drug concluded that the drug can effects. On the other hand, be re-approved for marketing CYP3A4 inducers such as in Europe. Tolcapone is

WHO Pharmaceuticals Newsletter No. 3, 2004 • 2 REGULATORY MATTERS

carbamazepine could enhance the metabolism of trazodone, thus reducing the plasma concentration of the drug, with a potential effect on therapeutic outcome. In one study, the short-term administration of ritonavir (200 mg twice daily, 4 doses) in 10 healthy subjects decreased the plasma clearance of a single dose of trazodone (50 mg) by 52%. Adverse effects including nausea, hypotension and syncope were observed when ritonavir and trazodone were co-administered. The co- administration of carba- mazepine (400mg/day), with trazodone, 100-300 mg daily, reduced plasma concen- trations of trazodone by 76% and 60% respectively. Careful monitoring of patients is thus necessary to see if there is a need for dose adjustment when trazodone is prescribed with any of the above drugs. The product label for trazodone has been appropriately revised to reflect the above information. Reference: 'Dear Healthcare Professional' letter from Bristol-Myers Squibb Company, May 2004. Available from URL: http://www.fda.gov

WHO Pharmaceuticals Newsletter No. 3, 2004 • 3 SAFETY OF MEDICINES

CARVEDILOL received nine reports of visual FURANO- changes associated with the Reports of diarrhoea use of cyclo-oxygenase-2 COUMARINS New Zealand. The Centre (COX-2) inhibitors, celecoxib Presence in a herbal for Adverse Reactions (six reports) and rofecoxib preparation Monitoring (CARM) has (three reports). The visual UK. The Medicines and received four reports of disturbances included blurred Healthcare products diarrhoea with carvedilol vision, abnormal vision, Regulatory Agency (MHRA) is (Dilatrend), a non- scintillating scotomata, visual alerting herbal interest cardioselective beta-blocker field defect and temporary groups to a report of a severe with alpha-blocking activity, blindness. In all but one adverse skin reaction after a indicated in the management report, the duration to onset patient was prescribed an of essential hypertension, from first taking the COX-2 unlicensed herbal preparation angina pectoris, and as inhibitor was within four containing a mixture of herbal adjunctive therapy in chronic weeks. The eyesight changes ingredients for the treatment heart failure. Patients were were bilateral in eight of the of eczema. The herbal receiving carvedilol in the cases. Blurred vision, preparation was prepared by dose range of 6.25 to 25mg cataract, conjunctivitis, eye the patient as a decoction in daily. In three reports, severe pain and glaucoma are listed boiling water, cooled and diarrhoea developed within a as adverse effects in the then applied to the skin. This week; and in the fourth case, celecoxib (Celebrex) data resulted in severe the diarrhoea was moderate sheet and blurred vision in inflammation and blistering. and began during the first the rofecoxib (Vioxx) The herbal mixture consisted month of carvedilol datasheet. In all of the eight of Cnidium monnieri fruit, treatment. In all cases, reports patients recovered Angelica sinensis root, symptoms improved on quickly on withdrawal of the Atractylodes lancea rhizome, stopping the medicine. COX-2 inhibitor. The visual Coix lacrymajobi seed, Smilax Diarrhoea is a recognised disturbances did not recur glabra tuber, Sophora adverse effect of all beta- during periods of observation flavescens root, Kochia blockers. Prescribers may of up to seven months scoparia fruit, and have to discontinue treatment following withdrawal. Similar Pseudolaricis kaempferi bark. with beta blockers and switch events have also been It is not possible to determine patients to alternative reported with non-specific the herbal ingredient(s) therapy if diarrhoea persists anti-inflammatory agents. responsible for the skin or gets severe. However, the There is evidence that the reaction because of the drug needs to be withdrawn cyclo-oxygenase enzymes complexity of the herbal gradually, over two weeks, COX-1 and COX-2 are mixture. However, since the since abrupt withdrawal can involved in the regulation of adverse reaction was similar precipitate rebound hyper- retinal blood flow. However, to skin reactions with tension, angina or myocardial other mechanisms for the Psoralea fruit, the most likely infarction, especially in observed visual disturbances causative ingredient is individuals with ischaemic with COX-inhibitors remain to thought to be the Cnidium heart disease. be explored. If eyesight changes occur, the anti- monnieri fruit. Cnidium Reference: inflammatory medicine should monnieri fruit is reported to Prescriber Update Review, 8 April contain furanocoumarin 2004. Available from URL: be immediately withdrawn http://www.medsafe.gov.nz and the patient assessed for derivatives, two of which, improvement of visual xanthotoxin and bergapten, CYCLO- symptoms. Future exposure were identified in the herbal to anti-inflammatory agents mixture. However, it is OXYGENASE-2 should be avoided in patients possible that other INHIBITORS with a severe eye disturbance ingredients may also have following first exposure. contributed to the adverse Reports of visual reaction. The MHRA advises disturbances Reference: caution while using any of Prescriber Update Articles, March these herbal ingredients, New Zealand. The 2004. Available from URL: especially Cnidium monnieri, Pharmacovigilance Centre in http://www.medsafe.govt.nz/profs/ PUarticles on the skin. The MHRA is in Dunedin, New Zealand has

WHO Pharmaceuticals Newsletter No. 3, 2004 • 4 SAFETY OF MEDICINES

the process of gathering more resolution of some of the Time (PT). When oxandrolone information on the extent of reactions but regular is prescribed to patients actual usage, nature of usage monitoring and patient being treated with warfarin, etc. before deciding on education of early warning doses of warfarin may need further advice and action, if signs (e.g. easy bruising, to be decreased significantly any. tiredness, pallor, skin lesions, to maintain a desirable INR Reference: shortness of breath etc.) can level and diminish the risk of Communication to Herbal Interest reduce morbidity. To potentially serious bleeding. Groups from MHRA, 19 April 2004. minimize the risk of serious Patients should be carefully Available from URL: blood and liver adverse monitored for INR or PT http://www.mhra.gov.uk reactions, all patients taking values and for signs and leflunomide should have their symptoms of occult bleeding. LEFLUNOMIDE haematological and liver Reference: Awareness and function monitored. Pre- 'Dear Healthcare Professional' letter monitoring can reduce treatment baseline values from Savient Pharmaceuticals Inc., should be established for 20 April 2004. Available from URL: the impact of adverse these functions first before http://www.fda.gov effects starting therapy, every New Zealand. According to a month after initiating therapy SHUBAO recent Prescriber Update for the first six months and, SLIMMING article available from every six to eight weeks Medsafe, New Zealand, thereafter. Ongoing monthly CAPSULES serious multi-system adverse monitoring is recommended if Presence of effects are possible with methotrexate is used fenfluramine and leflunomide, an effective concurrently. nitrosofenfluramine disease modifying agent for Reference: rheumatoid arthritis. The Prescriber Update Articles, April UK. The Medicines and adverse reactions associated 2004. Available from URL: Healthcare products with the use of this drug http://www.medsafe.govt.nz/Profs/ Regulatory Agency (MHRA) is PUarticles/Arava.htm involve haematological, alerting herbal interest hepatic, immune, dermatol- groups and consumers about ogical and respiratory OXANDROLONE the presence of fenfluramine systems. International Warning for interaction and nitrosofenfluramine in an unlicensed traditional Chinese reports include liver failure with warfarin (15 cases, nine with fatal medicine preparation, Shubao outcome), neutropenia, USA. Savient Pharma- Slimming Capsules, supplied thrombocytopenia, thrombo- ceuticals Inc., in consultation illegally as a slimming agent cytosis, severe pancytopenia, with US FDA has issued a in the UK. Fenfluramine is an Stevens Johnson syndrome, letter to health professionals appetite suppressant and was bullous eruptions and skin regarding the potential for banned globally in 1997 due necrosis, interstitial pneumo- interaction when to concerns about the drug's nitis and pulmonary oxandrolone, an anabolic effect on the heart while infiltration and infections due androgenic steroid and nitrosofenfluramine is known to immune response warfarin, an anticoagulant, to be toxic to the liver. impairments including sepsis. are prescribed together. Globally the illegal Post-marketing experience Oxandrolone is used as adulteration of slimming with leflunomide estimates adjunctive therapy to products with nitroso- the frequency of severe promote weight gain in fenfluramine and fenflur- hepatic, dermatological, patients following extensive amine has been associated respiratory, haematological surgery, chronic infections, with a large number of and infection reactions as etc. According to a recent reports of liver toxicity. There being very rare (less than 1 clinical study, concurrent was one report of liver failure in 10 000) and for blood dosing of oxandrolone and in a patient receiving Shubao dyscrasias as being rare warfarin might prolong the Slimming Capsules in the UK; (between 1 in 1000 and 1 in half-life of warfarin with a the patient required a liver 10 000). According to the resultant increase in the transplant. The MHRA has article, the long half-life of International Normalized directed that the supply and leflunomide may delay Ratio (INR) or Prothrombin sale of Shubao capsules

WHO Pharmaceuticals Newsletter No. 3, 2004 • 5 SAFETY OF MEDICINES should be stopped weekly and specialist advice • serious consequences of immediately and has sought if there is a moderate diarrhoea, including hypo- requested cooperation from increase in CK levels (3-10 x volemia, hypotension, and the herbal sector in upper limit of normal). Health syncope have been minimizing the risks to professionals are also reported in clinical studies consumers posed by the reminded that other and during marketed use illegal inclusion of concomitant medicines may of tegaserod (Zelnorm); fenfluramine and nitroso- increase risk of myopathy, • rare cases of ischaemic fenfluramine in these particularly if they can cause colitis and other forms of capsules. myopathy on their own (e.g. intestinal ischaemia have Reference: fibrates). Such a potentiation been reported in patients Communication to Herbal Interest of risk could also occur when receiving tegaserod Groups from MHRA, 28 April 2004. the concomitant drugs are during marketed use of Available from URL: potent inhibitors of the CYP the drug; http://medicines.mhra.gov.uk 3A4 enzyme system (e.g. • tegaserod should be erythromycin, itraconazole, discontinued immediately STATINS amiodarone, verapamil) in patients who develop Important to measure because several statins such hypotension or syncope, creatine kinase levels as simvastatin and and in patients who atorvastatin are CYP 3A4 develop symptoms of New Zealand. A Prescriber substrates. To minimize the ischaemic colitis such as Update article from Medsafe, risk of interaction, lower rectal bleeding, bloody New Zealand, while referring starting doses of simvastatin diarrhoea or new or to the risk of myopathy and and atorvastatin should be worsening abdominal rhabdomyolysis associated used in patients already being pain; with the use of statins, treated with fibrates, • patients should be reminds prescribers to cyclosporine, amiodarone, advised to stop taking measure creatine kinase (CK) verapamil and other potent tegaserod in case of levels in patients presenting CYP 3A4 inhibitors; if a above symptoms and with muscle pain or patient is already on statins, should seek medical weakness. Muscle pain or the dose of statins should be advice if they experience weakness accompanied by a reduced before starting new or worsening CK level more than 10 times concomitant therapy with abdominal pain, with or the upper limit of normal other interacting drugs. without rectal bleeding would suggest clinical Reference: and/or blood in the stool. myopathy. Rhabdomyolysis, a Prescriber Update Articles, May References: severe form of myopathy with 2004. Available from URL: 1. 'Dear Healthcare Professional' muscle breakdown leading to http://www.medsafe.govt.nz/profs/ letter from Novartis myoglobinuria, may result in PUarticles/Statinmyop.htm Pharmaceuticals Corporation, 26 renal failure and death. April 2004. Available from URL: http://www.fda.gov/medwatch Monitoring helps improve TEGASEROD 2. 'Dear Healthcare Professional' outcome. CK measurements Warning about letter from Novartis must be performed when diarrhoea and Pharmaceuticals Canada Inc., symptoms occur. Patients 28 April 2004. Available from ischaemic colitis with additional risk factors URL: http://www.hc-sc.gc.ca (diabetes, older age, USA, Canada. Novartis hypothyroidism, liver or renal Pharmaceuticals has issued a THIOMERSAL IN disease) may be more at risk letter to health professionals VACCINES of rhabdomyolysis and should regarding serious conse- be observed closely for signs quences of diarrhoea with Recent evidence and symptoms of myopathy. new information about rare supports safety Statin treatment should be reports of ischaemic colitis Europe. The EMEA has discontinued immediately if with tegaserod, a drug issued a public statement an elevated CK level is found indicated in the symptomatic that recent evidence supports (CK>10 x upper limit of treatment of irritable bowel safety of thiomersal- normal) or where mypopathy syndrome with constipation containing vaccines for is suspected or diagnosed. CK (IBS-C) in female patients. human use. Thiomersal is an levels should be monitored According to Novartis

WHO Pharmaceuticals Newsletter No. 3, 2004 • 6 SAFETY OF MEDICINES

antimicrobial organic mercury ment of vaccines without and/or pale stools) or compound used either in the thiomersal or with the development of abnormal early stages of manufac- lowest possible levels of transaminase and/or bilirubin turing, or as a preservative in thiomersal and other levels. Serum testing should some vaccines. The mercury containing be done at baseline and antimicrobial action of preservatives should periodically during zafirlukast thiomersal relates to continue to be promoted. treatment. Physicians should ethylmercury, which is Reference: be aware of, and educate released after breakdown of EMEA Statement, patients on the symptoms of thiomersal into ethylmercury EMEA/CPMP/VEG/1194/04/Adopted, liver injury. Zafirlukast is not and thiosalicylate. Previously, 24 March 2004. Available from URL: recommended for patients the Committee for Proprietary http://www.emea.eu.int with hepatic impairment Medicinal Products (CPMP), including hepatic cirrhosis. while stating that thiomersal ZAFIRLUKAST Reference: vaccines posed no health risk, Reports of serious 'Dear Healthcare Professional' letter had advised the general use hepatic events from AstraZeneca Canada Inc., 14 of vaccines without thiomer- April 2004. Available from URL: sal and other mercury Canada. AstraZeneca http://www.hc-sc.gc.ca containing preservatives as a Canada Inc., in consultation global measure for reducing with Health Canada is environmental exposure to warning health professionals mercury. In March 2004, the about post-marketing reports CPMP reviewed the latest of serious hepatic effects evidence relating to the associated with the use of safety of thiomersal- zafirlukast (Accolate). From containing vaccines including 1997 to 31 December 2003 several well-designed one case of hepatitis, four epidemiological studies. cases of hepatobiliary Based on this review, the disorders or possible CPMP has concluded that hepatitis, one case of • there is no association hydrocholecystitis and four between vaccination with cases of elevated liver thiomersal-containing enzymes have been reported vaccines and specific in Canadian patients receiving neurodevelopmental zafirlukast (Accolate). World- disorders; wide a total of 46 reports of • the immunisation with hepatitis, 14 reports of liver vaccines containing failure, and 59 reports of thiomersal continues to other significant liver dys- offer outstanding benefits function have been noted; a to the general population, fatal outcome was seen in including infants; seven cases. The exposure to • the presence of zafirlukast is estimated to be thiomersal and other more than 1.9 million patient preservatives should be years worldwide. Health stated on the label of the professionals are being vaccine and a warning informed that elevations in regarding the risk of serum transaminases could sensitization in relation to represent early evidence of thiomersal and other hepatotoxicity. Immediate preservatives should be termination of zafirlukast included in the Summary treatment is advised following of Product Characteristics the appearance of signs and and package leaflets of symptoms of hepatotoxicity such preparations; (malaise, lack of energy, loss • in line with the global goal of appetite, pain on right side of reducing exposure to of stomach just below ribs, mercury, the develop- dark urine and discoloured

WHO Pharmaceuticals Newsletter No. 3, 2004 • 7 FEAT URE

SELECTIVE profession. Several recent fluvoxamine in paediatric recommendations have been MDD, and therefore this SEROTONIN issued by the government product should not be REUPTAKE and industry cautioning used in this age group. against the use of SSRIs in 4. Fluoxetine has been INHIBITORS children below 18 years of demonstrated to have (SSRIs): age following reports of positive benefit-risk bal- increased suicidal ideations in ance in the treatment of Use in children with children being treated with MDD in children under 18. Major Depressive some of these drugs. Below is However, fluoxetine does Disorder a summary of recent opinions not have a marketing Depressive disorder is the and directives on the use of authorization for MDD in fourth most important cause SSRIs: this age group; any of disability worldwide1. decision to prescribe Several adverse drug Though less recognized and fluoxetine for paediatric reactions advisory com- lesser studied, the disorder MDD in a patient under 18 mittees worldwide (Australia, affects a sizeable percentage should be made with Ireland, Netherlands, UK, of children and adolescent specialist advice. USA) have acknowledged the population. For example, the 5. Young people with international concern about a lifetime prevalence of major depressive illness currently possibility of increased depressive disorder in taking any SSRI other suicidal ideation and self- adolescence has been than fluoxetine should not harm behaviour in children estimated to range from 15- stop taking their medicine and adolescents treated with 20 percent2. but should consult their SSRIs for major depressive doctor for advice on Complexities of diagnosis disorder (MDD). The US FDA treatment. coupled with the ethics of and the UK Committee on conducting clinical trial Safety of Medicines have both In view of the UK position research in children have independently evaluated on the use of SSRIs in limited our understanding of clinical data from trials in children, the Irish Medicines childhood depression and the MDD in children and Board (IMB)4 has reminded development of anti- adolescents for the SSRIs and health professionals and the depressant drugs for specific a related drug venlafaxine. It public that SSRIs have never use in this sub-population of may be noted that none of been licensed for the depressives. However, it is these drugs is approved for treatment of MDD in children known that physicians, for the treatment of MDD in under the age of 18 in want of treatment alterna- children although off-label Ireland. The IMB will continue tives in children, often resort use of these drugs for this to monitor the quality, safety to off-label prescribing of purpose is known. and efficacy of SSRIs and many antidepressants that initiate any further regulatory In December 2003 the UK are licensed only for adult- 3 action, as appropriate. CSM stated that: use. 5 Health Canada has 1. The risks of treating Of all the available advised that patients under depressive illness in antidepressants the SSRIs or 18 years of age, who are children under 18 years of Selective Serotonin Reuptake currently being treated with age with certain SSRIs Inhibitors have received an SSRI or an SNRI outweigh the benefits of much recognition as being a (Serotonin Noradrenaline treatment. safer and more acceptable Reuptake Inhibitors) should 2. Based on available data, treatment of depression in consult their physician to the SSRIs paroxetine, adults. However, the safety of determine if the benefits of sertraline, citalopram, prescribing SSRIs to children these drugs still outweigh escitalopram and the and adolescents, particularly their risks in light of recent related drug venlafaxine in the absence of adequate safety concerns. Health are now contraindicated in safety and efficacy studies Canada also notes that none paediatric MDD in the with SSRIs in this population, of the drugs bupropion, under 18s. has been the subject of citalopram, fluvoxamine, 3. There are no data on the increasing concern in the mirtazapine, paroxetine, safety and efficacy of community and the medical sertraline and venlafaxine are

WHO Pharmaceuticals Newsletter No. 3, 2004 • 8 FEATURE

approved for use in patients etine, sertraline, paroxetine, children or adolescents. The under 18 years of age in fluvoxamine, citalopram, MARC is awaiting further data Canada. The prescribing of escitalopram, bupropion, on the use of these drugs in these drugs in this population venlafaxine, nefazodone and children. In the meantime, is therefore a physician's mirtazapine to include the health professionals are responsibility. following in their product advised that pharmacological labelling: treatment is only the second- The Australian Adverse 1. Health-care providers line therapy in the treatment Drug Reactions Advisory should carefully monitor of MDD in children; children Committee (ADRAC)6 reminds patients receiving anti- and adolescents who are that none of the SSRIs are depressants for possible responding well to SSRI approved for the treatment of worsening of depression or therapy should complete the MDD in children or in suicidality, especially at the usual course of treatment and adolescents in Australia. The beginning of therapy or when if response is inadequate, ADRAC considers that the the dose is either increased specialist advice should be current data are not or decreased. sought. conclusive regarding the 2. Anxiety, agitation, panic efficacy and safety of SSRIs The Medicines Evaluation attacks, insomnia, irritability, in MDD in children and Board (MEB) in the hostility, impulsivity, adolescents and therefore Netherlands has called for akathisia, hypomania and recommends that any SSRI caution in the use of SSRIs in mania have been reported in use in children should be children with depressive adult and paediatric patients undertaken only within the disorders9. It has drawn being treated with anti- context of comprehensive attention to the existing depressants for MDD as well management of the patient statement in the Product as for other indications. There according to clinical practice Information on SSRIs in the is concern that patients who guidelines for depression in Netherlands: that the safety experience one or more of young people, with careful and efficacy of short-term use these symptoms may be at monitoring for the emergence of these drugs have not yet increased risk for worsening of suicidal ideation and been investigated adequately depressions or suicidality and behaviour. The choice of the in children with depressive therapy may need to be SSRI for children with MDD disorders. No product is discontinued when symptoms should be made only after currently indicated for the are severe, abrupt in onset or taking into account recent treatment of depression in are not part of the patients evaluation of clinical trial data children and adolescents in presenting symptoms. and the Product Information. the Netherlands. 3. Patients, their families and ADRAC draws attention to the caregivers should be The current scenario with fact that the current instructed to recognize and the SSRIs emphasizes, yet Australian product infor- report the emergence of the again, how important it is to mation for paroxetine and above symptoms as well as continuously evaluate the venlafaxine recommends symptoms of agitation and benefit-risk profile of all against their use in children irritability. medicines. and adolescents. 4. If a decision is made to 7 References: The US FDA's assessment discontinue treatment, the 1. Murray CJ, Lopez AD. Regional of the SSRIs is in broad medication should be tapered patterns of disability-free life agreement with the UK CSM and not withdrawn abruptly. expectancy and disability- conclusions. In March 2004 adjusted life expectancy: global The Medicines Adverse burden of disease study. Lancet the US FDA issued a Public Reactions Committee (MARC) 1997; 349:1347-52. Health Advisory about a in New Zealand has reviewed 2. Birmaher, B. et al. Childhood possible increased risk of and adolescent depression: a the efficacy and safety of suicidality with these review of the past 10 years. Part SSRIs when used to treat medications. The FDA warns I. J Am Acad Child Adolesc MDD in children under 18 Psychiatry 1996; 35(11): 1427- that only fluoxetine is years of age and considers 39. approved for the treatment of the data to be inconclusive8. paediatric major depressive In New Zealand none of the disorder. The FDA has SSRIs have been approved directed manufacturers of for use in treating MDD in antidepressant drugs fluox-

WHO Pharmaceuticals Newsletter No. 3, 2004 • 9 FEAT URE

3. 'Dear Colleague' letter from Chairman, CSM, 10 December 2003. Available from http://medicines.mhra.gov.uk 4. Statement on Behalf of the Irish Medicines Board, 10 December 2003. Available from URL: http://www.imb.ie 5. Warnings and Advisories from Health Canada, 2 February 2004. Available from URL: http://www.hc-sc.gc.ca 6. Statement from the Chair, Adverse Drug Reactions Advisory Committee, Australian Drug Evaluation Committee, 11 March 2004. Available from URL: http://www.health.gov.au 7. FDA Public Health Advisory, 22 March 2004. Available from URL: http://www.fda.gov 8. 'Dear Health Professional' letter from MEDSAFE, New Zealand Medicines and Medical Devices Safety Authority, 22 March 2004. Available from URL: http://www.medsafe.govt.nz 9. News and Publications from the Netherlands Medicines Evaluation Board, 23 April 2004. Available from URL: http://www.cbg-meb.nl

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