2018 WHO Pharmaceuticals

No. 2 NEWSLETTER

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

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

This newsletter includes a feature article titled PV The aim of the Newsletter is to disseminate regulatory strengthening in Armenia and Kyrgyzstan using smart information on the safety of safety surveillance approach; identifying gaps. pharmaceutical products, based on communications received from our network of national pharmacovigilance centres and other sources such as specialized bulletins and journals, as well as partners in WHO.

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

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

Signal

Feature

© World Health Organization 2018

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Table of Contents

Regulatory Matters Antihistamines (first generation, oral sedating) ...... 5 Clarithromycin ...... 5 Clopidogrel and selexipag interaction ...... 5 Daclizumab beta ...... 5 Dipeptidylpeptidase-4 inhibitors ...... 6 Efavirenz...... 6 Flupirtine ...... 6 Gadolinium-containing contrast agents ...... 7 Hydroxyethyl-starch solution ...... 7 Iohexol, Iomeprol ...... 7 Kampo medicines containing Gardenia fruit ...... 8 Miconazole and warfarin interaction ...... 8 Mycophenolate mofetil, mycophenolic acid ...... 8 Radium-223 dichloride ...... 8 Retinoids ...... 9 Sterile talc ...... 9 Tolvaptan ...... 9

Safety of medicines Artemisia annua extract in grape seed oil ...... 10 Aspirin in chloroform ...... 10 Clozapine ...... 10 Dabigatran ...... 10 Direct-acting antivirals (DAAs) ...... 11 Eribulin ...... 11 Idarucizumab ...... 11 Ruxolitinib ...... 11 Sodium-glucose Cotransporter-2 (SGLT2) inhibitors ...... 12 Suvorexant ...... 12 Ulipristal acetate ...... 12

WHO Pharmaceuticals Newsletter No. 2, 2018 • 3 Table of Contents

Signal Artemether/Lumefantrine and Stevens-Johnson syndrome: a recommendation for continued vigilance in malaria-endemic areas ...... 14 Quetiapine and valproic acid interactions: signal strengthening ...... 19

Feature Enhancing Pharmacovigilance in Low and Middle Income Countries using Smart Safety Surveillance ...... 26

WHO Pharmaceuticals Newsletter No. 2, 2018 • 4 Regulatory Matters

Antihistamines (first Clarithromycin Selexipag is indicated for pulmonary arterial generation, oral Potential risk of heart hypertension. Clopidogrel is sedating) problems or death in indicated for suppression of recurrent ischemic patients with heart disease Potential for fatal cerebrovascular disorder. respiratory depression in USA . The US Food and Drug Clopidogrel is a potent CYP2C8 children under two years of Administration (FDA) has inhibitor and there is a age added a new warning about an possibility of an onset of increased risk of death in adverse drug reactions and/or Australia . The Therapeutic patients with heart disease to symptom exacerbation arising Goods Administration (TGA) the drug labels for from an increase in blood will work with manufacturers to clarithromycin (Baxin®). In concentrations of selexipag and strengthen warnings in the addition, the FDA has added its active metabolite. MHLW product information (PI) and the results of a clinical trial that and PMDA have conducted an consumer medicine information indicate this increased risk to investigation and have (CMI) for first generation oral clarithromycin drug labels. concluded that the revision of antihistamines, to emphasize Clarithromycin is used to treat the package inserts of both that they should not be used in a variety of infections and is products should include children under two years of age not approved to treat heart language regarding the risks due to the potential risk disease. associated with co- respiratory depression. In administration of clopidogrel. addition, TGA will be seeking to The FDA’s recommendation is Reference: include a mandatory warning based on a review of the Revision of Precautions, statement on labels of over- results of a 10-year follow-up MHLW/PMDA, 20 March 2018 the-counter (OTC) liquid oral study of patients with coronary (www.pmda.go.jp/english/) formulations of first-generation heart disease form a large oral sedating antihistamines clinical trial that first observed (See WHO Pharmaceuticals Newsletters about the contra-indication of this safety issue. Results from No.5, 2017: Contraindication with potent use in children under two years. the trial provide evidence of inhibitors of cytochrome P450 2C8 in Spain) the increased risk compared to The TGA recently reviewed a placebo. Other observational fatal case of respiratory studies showed mixed findings. Daclizumab beta depression in a 74-day old The FDA is unable to determine infant who was treated with why the risk of death is greater Immediate suspension: risk OTC promethazine oral liquid. for patients with heart disease. Although the infant's death was of serious inflammatory not attributed to use of Reference: brain disorders promethazine, the case raised Safety Alerts for Human a safety concern. Medical Products, US FDA, Europe. The European 2 February 2018 (www.fda.gov) Medicines Agency (EMA) has Up until 15 November 2017, recommended the immediate the TGA database of adverse suspension and recall of event notifications contained daclizumab beta (Zinbryta®) 45 reports of adverse events in Clopidogrel and following 12 reports of serious children aged under two years selexipag interaction inflammatory brain disorders in which a first-generation oral worldwide, including sedating anti-histamine is Co-administration is encephalitis and listed as the sole-suspected contraindicated due to meningoencephalitis in patients medicine. These reports increased blood with multiple sclerosis. Three of document a range of adverse the cases were fatal. events including concentrations of selexipag hypersensitivity reactions, Daclizumab beta is indicated Japan . The Ministry of Health, agitation, abnormal for treating relapsing forms of Labour and Welfare (MHLW) movements, vomiting and multiple sclerosis. Following a and the Pharmaceuticals and diarrhoea. 2017 review of the medicine’s Medical Devices Agency effects on the liver, the use of Reference: (PMDA) have announced that the medicine was restricted to Medicines Safety Update, TGA, the package inserts for patients who have tried at least Vol. 9, No. 1, February-March clopidogrel containing products two other disease-modifying 2018 (www.tga.gov.au ) (Plavix®, ComPlavin®) and treatments and cannot be selexipag (Uptravi®)) should treated with other multiple be revised to include that co- sclerosis treatments. administration of selexipag and clopidogrel is contraindicated. Also, the available evidence indicate that immune reactions WHO Pharmaceuticals Newsletter No. 2, 2018 • 5 Regulatory Matters observed in the reported cases potential bullous pemphigoid patients treated with anagliptin. may be linked to the use of with the use of alogliptin (16) MHLW and PMDA have daclizumab beta. and saxagliptin (8) were concluded that revision of the identified by manufacturers package insert was necessary To protect patients’ health, and from a search in the following the investigation of EMA is recommending the Canada vigilance database. All available evidence and immediate suspension of the 24 reports were considered to consultations with expert medicine’s marketing show a possible link between advisors. authorisation in the EU and a the skin reaction and the drug. recall of batches from Reference: Of the 24 reports, three deaths pharmacies and hospitals. Revision of Precautions, were reported, one of which MHLW/PMDA, 20 March 2018 was considered to be possibly EMA advises that no new (www.pmda.go.jp/english/) patient should start treatment linked to bullous pemphigoid with daclizumab beta. Health- from using the DPP-4 inhibitor. care professionals should Health Canada’s review immediately contact patients Efavirenz concluded that there may be a currently being treated with link between any of the DPP-4 daclizumab beta, stop Risk of prolonged QT inhibitors and the risk of treatment, and consider bullous pemphigoid. Health alternatives. Patients stopping Japan . MHLW and PMDA have Canada will publish a notice in treatment must be followed up concluded that revision of the the Health Product InfoWatch for at least six months. package insert for efavirenz to inform Canadians and (Stocrin Tablets®) should be EMA’s recommendation to health-care professionals of revised to include the risk of suspend daclizumab beta and this new safety information. prolonged QT as a precaution. recall the product is being sent Health Canada will continue to to the European Commission Efavirenz is indicated for HIV-1 monitor safety information for a legally binding decision. infection. Prolonged QT interval involving DPP-4 inhibitors to was observed in conjunction The company that markets identify and assess potential with increased blood daclizumab beta has already harms. concentrations of efavirenz in voluntarily requested a Reference: an overseas clinical study withdrawal of the medicine’s Summary Safety Review, investigating the effect of this marketing authorisation and Health Canada, 25 January drug on the QT interval. informed EMA of its intention to 2018 (www.hc-sc.gc.ca ) Several cases of prolonged QT stop clinical studies. have also been reported in patients treated with efavirenz Reference: overseas. No cases involving EMA, 2 and 7 March 2018 2. Risk of acute pancreatitis prolonged QT have been (www.ema.europa.eu) (anagliptin, linagliptin, reported in the last three fiscal teneligliptin) years in Japan. Japan . MHLW and PMDA have Reference: Dipeptidylpeptidase-4 announced that the package Revision of Precautions, inhibitors inserts for anagliptin (Suiny®), MHLW/PMDA, 13 February linagliptin (Trazenta®), and 2018 (www.pmda.go.jp/english/) 1. Potential risk of a skin teneligliptin containing reaction (bullous products (Tenelia®, Canalia pemphigoid) Combination®) should include acute pancreatitis and Flupirtine Canada . Health Canada has pemphigoid (anagliptin) as Withdrawal due to serious clinically significant adverse requested that the product liver problems information for reactions. dipeptidylpeptidase-4 (DPP-4) Dipeptidyl peptidase-4 (DPP-4) Europe. The EMA has inhibitors (alogliptin, inhibitors and are indicated to recommended that the market saxagliptin, sitagliptin, and treat hyperglycemia in adults authorization for flupirtine linagliptin) is updated to with two diabetes mellitus. should be withdrawn due to the include the risk of bullous risk of serious liver injury. The pemphigoid. Cases of acute pancreatitis Co-ordination Group for Mutual have been reported in patients DPP-4 inhibitors, known as Recognition and Decentralised treated with anagliptin (four Procedures – Human (CMDh) gliptins are prescription cases), linagliptin (19 cases), medicines indicated for type-2 has endorsed the EMA’s and teneligliptin hydrobromide decision. diabetes in adults. hydrate (9 cases) in Japan. In A total of 24 serious addition, seven cases of Flupirtine is used to treat acute international reports of pemphigoid were reported in pain (up to 2 weeks) in WHO Pharmaceuticals Newsletter No. 2, 2018 • 6 Regulatory Matters patients who cannot use other for use and a product recall of HES solutions for infusion are painkillers such as opioids or any existing unexpired stock is used for the management of nonsteroidal anti-inflammatory underway, due to risk of hypovolaemia caused by acute medicines (NSAIDs). gadolinium deposition in the blood loss, where treatment brain with use of linear with alternative infusion The EMA’s recommendation gadolinium-containing contrast solutions known as crystalloids was an outcome following a agents. In addition, the linear alone is not considered to be review of flupirtine carried out agents gadobenic acid and sufficient. by EMA’s Pharmacovigilance gadoxetic acid (Primovist®) Risk Assessment Committee A review of the safety of HES will be limited for use in liver (PRAC), who looked at the solutions for infusion has been imaging and when imaging in available data including studies carried out by EMA’s PRAC. the delayed phase liver is evaluating whether risk HES solutions have continued required. minimization measures set in to be used in critically ill 2013 were followed in clinical Gadolinium-containing contrast patients and patients with practice. agents (GdCAs) are indicated sepsis despite the introduction for the enhancement of of restrictions on use in these Since 2013, there were reports magnetic resonance imaging patients in 2013. The final of serious liver injury with (MRI). GdCAs can be divided decision to withdraw the flupirtine use. These included into two groups: linear and market authorization license, 23 cases of acute liver failure, macrocyclic. The use of linear however, will be taken by the some of which were fatal or led GdCAs has decreased markedly European Commission. to transplantation. in the UK, following advice Reference: PRAC concluded that the published in 2006 which aimed EMA, 26 January 2018 to reduce risk of nephrogenic restrictions introduced in 2013 (www.ema.europa.eu) have not been sufficiently systemic fibrosis (NSF). followed, and cases of serious In view of evidence of retention (See WHO Pharmaceuticals Newsletters liver injury, including liver No.6, 2017: New review of benefit-risk of gadolinium in brain and failure, still occurred. balance in Europe; No.4, 2017: Acute kidney other tissues, the risks of injury in non-critically ill patients: not The CMDh therefore agreed gadodiamide and intravenous enough evidence in Canada; No.1, 2015: that patients taking flupirtine- gadopentetic acid are Contraindications and warnings in the containing medicines continue considered to outweigh their United Kingdom and Canada) to be exposed to serious risks benefits. which outweigh the benefits of these medicines. Alternative There are other GdCAs that will Iohexol, Iomeprol treatment options to flupirtine remain on the market, but are available. should only be used when Risk of acute generalized diagnostic information is exanthematous pustulosis Reference: EMA, 23 March essential and not available with 2018 (www.ema.europa.eu) unenhanced MRI. (See WHO Pharmaceuticals Newsletters Japan . MHLW and PMDA have No.3, 2013: Review started due to concerns Reference: requested the revision of the over liver problems in Europe) Drug Safety Update, MHRA, package inserts for iohexol 6 February 2018 (Omnipaque®) and iomeprol (www.gov.uk/mhra) (Iomeron®) to include the risk (See WHO Pharmaceuticals Newsletters of acute generalized Gadolinium- No.1, 2018; No.4 and 5, 2017; No.5, 2015; exanthematous pustulosis as a No.6, 2013: for related information) clinically significant adverse containing contrast reaction. agents Hydroxyethyl-starch Iohexol and imeprol are Omniscan® and intravenous indicated for various solution angiography and x-ray iv Magnevist® no longer procedures. authorised; and restrictions Risk of kidney injury and of use for other linear death in certain patient Two cases of acute generalized exanthematous pustulosis were agents populations reported in patients who used United Kingdom. The Europe. The EMA has iomeprol and iohexol in the last Medicines and Healthcare recommended the withdrawal three fiscal years in Japan. A Products Regulatory Agency of the market authorization causal relationship with the (MHRA) has announced that license for hydroxyethyl-starch products could not be excluded two gadolinium-containing (HES) solutions for infusion due for those patients. No fatal contrast agents (Omniscan® to risk of kidney injury. This cases have been reported. and intravenous Magnevist®) has been endorsed by CMDh. Reference: are now no longer authorized Revision of Precautions,

WHO Pharmaceuticals Newsletter No. 2, 2018 • 7 Regulatory Matters

MHLW/PMDA, 13 February and yeast infections of the skin Women of child bearing 2018 (www.pmda.go.jp/english/) or vagina. potential should use at least one form of reliable Miconazole inhibits one of the contraception before starting main cytochrome P450 treatment, during treatment Kampo medicines isoenzymes involved in and for six weeks after warfarin metabolism (CYP2C9), containing Gardenia stopping treatment. Two forms which can result in reduced of contraception are preferred. fruit warfarin clearance and an enhanced anticoagulant effect. Reference: Risk of mesenteric Drug Safety Newsletter, HPRA, This can lead to supra- phlebosclerosis 16 March 2018 (www.hpra.ie) therapeutic international

Japan . MHLW and PMDA have normalised ratio (INR) values recommended that the package and subsequent bleeding United Kingdom. MHRA has insert for Japanese traditional complications. Bleeding events updated contraception advice medicines containing Gardenia can have fatal outcomes. for male patients on mycophenolate mofetil. fruit should be revised to The TGA has reminded health include the risk of mesenteric professionals that, while the The available clinical evidence phlebosclerosis as a number of Australian reports of does not indicate an increased precaution. warfarin and miconazole risk of malformations or interactions are low, the miscarriage in pregnancies Gardenia fruit preparations have various indications, for potential of an interaction can where the father was taking example coughing, be life-threatening. mycophenolate medicines, but there is insufficient evidence to constipation, obesity and Reference: exclude any risk. others. Medicines Safety Update, TGA, A total of 86 cases of Vol. 9, No. 1, February-March As a precautionary measure for mesenteric phlebosclerosis 2018 (www.tga.gov.au ) male patients, it is now were reported in the last three (See WHO Pharmaceuticals Newsletters recommended that either the fiscal years in Japan. A causal No.6, 2016: Risk of bleeding due to drug- patient or their female partner relationship was evaluated in drug interaction in Japan; No.4, 2016: use reliable contraception the 20 cases out of 86 cases. A Potential for serious drug-drug interactions during treatment with causal relationship could not be with warfarin in the United Kingdom) mycophenolate medicines and excluded in 14 cases. No fatal for at least 90 days after cases were reported. stopping. Female patients of Mycophenolate childbearing potential receiving Reference: mofetil, mycophenolate should always Revision of Precautions, use contraception. MHLW/PMDA, 13 February mycophenolic acid 2018 (www.pmda.go.jp/english/) Reference: Contraception is Drug Safety Update, MHRA, 6 February 2018 (www.gov.uk/mhra) recommended Miconazole and (See WHO Pharmaceuticals Newsletters Ireland. Mycophenolate No.2, 2016: Contraindications relating to warfarin interaction (mycophenolate mofetil and pregnancy and breastfeeding in Australia; mycophenolic acid) is No.1, 2016: New pregnancy-prevention Reminder of reduced authorized to prevent advice for women and men in the United warfarin clearance transplant rejection, and is a kingdom) major human teratogen known Australia . TGA has requested to cause miscarriages and that a warning statement about congenital malformation in Radium-223 the potential interaction with pregnant women. Also, dichloride warfarin is added to product mycophenolate medicines are labels for miconazole genotoxic. Not to be used together containing products. In with abiraterone and addition, TGA will also work The Health Products Regulatory with manufacturers to Authority (HPRA) has updated prednisone/prednisolone strengthen warnings in the contraceptive advice for male Europe. EMA recommends that patient information (PI) and patients. Male patients taking radium-223 dichloride consumer medicines mycophenolate-containing (Xofigo®) should not be used information (CMI) documents. medicines or their partners should use reliable in combination with abiraterone Miconazole is an antifungal contraception during treatment acetate (Zytiga®) and medication used to treat and for 90 days after finishing prednisone/prednisolone, due ringworm, pityriasis versicolor, treatment.

WHO Pharmaceuticals Newsletter No. 2, 2018 • 8 Regulatory Matters to an increased risk of death skin are used to treat various Tolvaptan and fractures. skin conditions including mild to moderate acne. Radium-223 is used to treat Risk of acute hepatic failure prostate cancer in adult men. The review confirmed that oral It is authorised for use when retinoids can harm the unborn Japan . MHLW and PMDA have medical or surgical castration child and must not be used announced that the package does not work, and when the during pregnancy. insert for tolvaptan (Samsca®) cancer has spread to the bones should be revised to include Data on neuropsychiatric and is causing symptoms such risk of hepatic failure. adverse events was not as pain but is not known to sufficient to assess the risk Tolvaptan is indicated for have spread to other internal with retinoid use. However, treatment of fluid retention in organs. considering that patients with heart failure and hepatic EMA’s PRAC has reviewed severe skin conditions may be cirrhosis when treatment with preliminary data from an more vulnerable to other diuretics is not ongoing clinical study in neuropsychiatric disorders due sufficiently effective; and to metastatic prostate cancer to the nature of the disease, slow the progression of patients. In this study 34.7% the prescribing information for autosomal dominant polycystic of patients treated with oral retinoids will be updated to kidney disease. radium-223, abiraterone and include a warning about this Cases of acute hepatic failure prednisone/prednisolone have possible risk. have been reported in patients died, compared with 28.2% of Reference: EMA, 23 March treated with tolvaptan in Japan. patients given placebo, 2018 (www.ema.europa.eu) A total of 11 cases associated abiraterone and (See WHO Pharmaceuticals Newsletters with acute hepatic failure have prednisone/prednisolone. No.1, 2015: Possible risk of psychiatric been reported to date The restriction in use is a disorders in the United Kingdom) (including four cases for which temporary measure until the a causal relationship with the ongoing in-depth review of the product could not be ruled out). Seven of these 11 cases were benefits and risks of radium- Sterile talc 223 is complete. The EMA will fatal (including three cases for which a causal relationship with communicate further once the Risk of shock and review has been concluded. the product could not be ruled anaphylaxis out). Reference: EMA, 9 March 2018 (www.ema.europa.eu) Japan . MHLW and PMDA have Reference: announced that the package Revision of Precautions, insert for sterile talc (Unitalc MHLW/PMDA, 20 March 2018

Retinoids Intrapleural Suspensions®) (www.pmda.go.jp/english/) should be revised to include (See WHO Pharmaceuticals Newsletters Updated measures for shock and anaphylaxis as No.3, 2013: Limits duration and usage due pregnancy prevention and clinically significant adverse to possible liver injury leading to organ transplant or death in the United States; potential risk of reactions. Sterile talc is indicated for No.2, 2013: New warning regarding a neuropsychiatric disorders potential risk of liver damage in Canada; prevention of recurrent No1, 2013: Potential risk of liver injury in the malignant pleural effusion. United States) Europe. EMA’s PRAC has A total of three cases completed a review of retinoid associated with shock and/or medicines and has anaphylaxis were reported in recommended that pregnancy patients treated with sterile prevention measures need to talc in Japan. Based on the be updated. In addition, results of an investigation of prescribing information for oral available evidence and in retinoids should be updated to consultation with expert include a warning on the advisors, MHLW and PMDA possibility of neuropsychiatric have concluded that revision of disorders. the package insert was Oral retinoids are used to treat necessary. various forms of severe acne, Reference: severe hand eczema that does Revision of Precautions, not respond to treatment with MHLW/PMDA, 20 March 2018 corticosteroids, severe forms of (www.pmda.go.jp/english/) psoriasis and other skin conditions, and certain types of cancer. Retinoids applied to the

WHO Pharmaceuticals Newsletter No. 2, 2018 • 9 Safety of Medicines

Artemisia annua and pharmacy technicians and During routine safety review is used in the treatment of post activities, concerns were raised extract in grape seed herpetic neuralgia. A study about whether or not processes oil conducted in 1993 found that to monitor agranulocytosis chloroform did not improve the were effective. Health Canada Potential risk of harm to the efficacy of the topical aspirin reviewed all of the available preparation, but improved its evidence related to the liver solubility. There is no effectiveness of the white blood New Zealand. The Medicines convincing evidence in the cell monitoring measures and Medical Devices Safety scientific literature to indicate currently in place for clozapine. that aspirin dissolved in Authority (Medsafe) has From 1991 to the time of the chloroform is effective for post- advised health-care review, Health Canada has herpetic neuralgia. professionals to consider liver received 92 Canadian reports toxicity as a possible adverse Chloroform is classified by the of low numbers of white blood effect of Artemisia annua International Agency for cells in patients using clozapine. (Arthrem®). Research on Cancer (IARC) as A review of these reports found Artemisia annua is a natural a group 2B carcinogen, being that 11 of them were possibly dietary supplement used for possibly carcinogenic to linked to clozapine use. humans. Significant exposure maintaining and supporting The review concluded that to chloroform has been joint health and mobility. monitoring measures that are associated with hepatotoxicity in place to detect low numbers The Centre for Adverse in humans. This is a potential of white blood cells are Reactions Monitoring (CARM) risk for patients who are acceptable, however this risk received 14 reports of liver applying aspirin in chloroform should still be monitored. toxicity associated with the use multiple times per day for Therefore, Health Canada has of artemisia annua. Many of extended periods of time. the reports included jaundice asked that the manufacturers as a reaction. All of the Given the lack of evidence for of clozapine submit a report, in patients stopped taking efficacy and significant risk of two years, of all the data artemisia annua, and at the harm, the benefit-risk balance related to the risk of time of reporting most had for topical aspirin in chloroform agranulocytosis with clozapine already recovered or were is unfavourable and prescribers use. should use alternative improving. Reference: medicines for their patients. Summary Safety Review, Medsafe advises health-care professionals to advise Reference: Health Canada, 9 March 2018 (www.hc-sc.gc.ca ) patients/consumers Safety Information, Medsafe, 1 (See WHO Pharmaceuticals Newsletters experiencing liver problems March 2018 (www.medsafe.govt.nz/) No.5, 2015: Modifications for monitoring and taking artemisia annua or neutropenia in the United) other natural health products, to stop taking the product and contact their general Clozapine practitioners. Dabigatran Risk of agranulocytosis Reference: Possible risk of gout or Safety Information, Medsafe, Canada. Health Canada has gout-like symptoms 15 February 2018 requested that manufacturers (www.medsafe.govt.nz/) of clozapine (Clozaril®) submit New Zealand. Medsafe

a report, in two years, of all highlighted a possible risk of data collected in relation to gout or gout-like symptoms Aspirin in chloroform agranulocytosis with use of with the use of dabigatran clozapine. (Pradaxa®). Potential risk of harm to the Clozapine is indicated to treat liver Dabigatran is used in symptoms of schizophrenia in conditions such as: prevention adults when other drugs have New Zealand. Medsafe has of stroke and systemic announced that CARM received not helped. Agranulocytosis is embolism; prevention of a report of a death of a female, a known adverse drug reaction venous thromboembolism; who developed hepatotoxicity that can occur in association treatment and prevention of with clozapine use. For this suspected by the treating deep vein thrombosis and/or physicians to be linked to reason, white blood cell levels pulmonary embolism. are monitored periodically in topical application of aspirin in chloroform. patients treated with clozapine In September 2017 a report of to make sure that they do not aggravation of gout after Aspirin in chloroform is become too low. compounded by pharmacists starting treatment with WHO Pharmaceuticals Newsletter No. 2, 2018 • 10 Safety of Medicines dabigatran was received by the Medsafe will re-investigate this Health Canada, 12 March 2018 CARM. The patient experienced concern should more (www.hc-sc.gc.ca ) a marked increase in episodes information become available. (See WHO Pharmaceuticals Newsletters of gout after starting No.2, 2016Risks of oculomucocutaneous Reference: syndrome (Stevens-Johnson Syndrome) and dabigatran and improved after Safety Information, Medsafe, erythema multiforme in Japan) treatment with dabigatran was 31 January 2018 stopped, without other (www.medsafe.govt.nz/) interventions. Idarucizumab Gout is not a known adverse No.2, 2017: Possible effects on blood effect of dabigatran and is not glucose control when used in patients with included in the data sheet. A type 2 diabetes: added to the medicine A second dose may be search of the WHO global monitoring scheme in New Zealand) needed database for Individual Case New Zealand. Prescribers are Safety Reports, VigiBase to date, revealed 71 reports Eribulin alerted to the possibility that worldwide of gout or gout-like some patients may need a symptoms, suspected to be Potential risk of severe skin second dose of idarucizumab associated with dabigatran use. adverse effects (Praxbind®) to reverse the effects of dabigatran Medsafe is placing this safety Canada. Health Canada (Pradaxa®) for patients concern on the medicines reviewed the risk of rare, requiring emergency monitoring scheme to obtain severe skin adverse effects procedures with a risk of further information on these (Severe Cutaneous Adverse uncontrolled bleeding. possible adverse reactions. Reactions, SCAR) with the use Idarucizumab is used for rapid Also, Medsafe calls for reports of eribulin (Halaven®), reversal of dabigatran’s following a Canadian report of of cases of gout or gout-like anticoagulant effect for symptoms in patients taking erythema multiforme which emergency surgery/urgent dabigatran. was a potential case of SCAR. procedures, or in life- threatening or uncontrolled Reference: Eribline is a prescription drug bleeding. Safety Information, Medsafe, that is indicated to treat 31 January 2018 various types of breast and soft The recommended dose of (www.medsafe.govt.nz/) tissue cancers (liposarcomas). idarucizumab is 5 g

There is no Canadian report of administered intravenously. SCAR. This safety review Post-marketing experience with dabigatran has shown that a Direct-acting looked at 22 international cases of SCAR with the use of second dose of idarucizumab is antivirals (DAAs) eribline from the sometimes required. manufacturer’s global safety Administration of a second 5 g Possible effects on blood database. Of these 22 cases, dose of idarucizumab may be glucose control when used five cases were found to be considered in patients with in patients with type 2 possibly linked to the use of prolonged clotting times who diabetes Eribline. develop a recurrence of Both Stevens-Johnson bleeding or who require a New Zealand. Medsafe Syndrome (SJS) and Toxic second emergency investigated the association of Epidermal Necrolysis (TEN) surgery/urgent procedure. direct-acting antivirals (DAAs) have already been included in Medsafe advices referring to and effects on blood glucose the product safety information the data sheet for further control when used in patients by Health Canada, the information. with type 2 diabetes. During European Medicines Agency Reference: the medicines monitoring (EMA), and US FDA. period (13 March 2017 to 31 Safety Information, Medsafe, 1 March 2018 December 2017), no cases of Health Canada’s review abnormal glucose levels were concluded that there was not (www.medsafe.govt.nz/) reported to the CARM. enough evidence to establish a direct link between the use of Effects of the use of DAAs on eribline and the potential risk blood glucose control, when of SCAR. The current product Ruxolitinib used in patients with type 2 safety information covers the Potential risk of liver injury diabetes, could not be potential risk of SCAR and not confirmed. additional warnings are Canada. Health Canada The balance of benefits and required. reviewed safety information on risks of harm for DAAs remains Reference: the risk of liver injury with positive and no further action is Summary Safety Review, ruxolitinib (Jakavi®) use. required at this time. WHO Pharmaceuticals Newsletter No. 2, 2018 • 11 Safety of Medicines

Ruxolitinib is used to treat encephalopathy syndrome paralysis, gait disturbance, certain types of blood cancers. (PRES) in patients were treated hallucination, headache and with sodium-glucose co- paraesthesia. The review was carried out transporter 2 (SGLT2) following an international Reference: inhibitors and developed report of a suspected serious Medicines Safety Update, TGA, diabetic ketoacidosis. liver injury from an ongoing Vol. 9, No. 1, February-March study that used ruxolitinib to SGLT2 inhibitors lower blood 2018 (www.tga.gov.au ) treat patients. sugar in adults with type 2

diabetes. Although the risk of liver injury is not mentioned in the safety At the time of the review, Ulipristal acetate information for ruxolitinib, it is Health Canada had received recommended that health-care two unique Canadian reports of Potential risk of liver injury professionals test the patient’s PRES in patients treated with blood before and during SGLT2 inhibitors who had Europe. EMA’s PRAC is treatment for signs of liver developed DKA. Both reports currently reviewing the benefits problems. involved canagliflozin and and risks with ulipristal acetate suggested that PRES could (Esmya®), following reports of Health Canada reviewed one possibly be associated with the serious liver injury, including Canadian report of liver injury medicine. However, other risk liver failure leading to and 25 international patient factors such as DKA and severe transplantation. reports of liver injury or liver infection could have played a failure with the use of Ulipristal was authorized in the role in the events. ruxolitinib. A possible link EU in 2012 for the treatment of between liver problems and the Health Canada’s review of the moderate to severe symptoms use of ruxolitinib was found in available information did not of uterine fibroids. 11 reports, but it was not find a link between the use of As a temporary measure while possible to determine whether SGLT2 inhibitors and the risk of the review is ongoing, the ruxolitinib itself caused the PRES in patients who have PRAC has recommended liver problems as patients developed DKA. regular liver monitoring for either took other medicines or Health Canada encourages women taking ulipristal for had co-existing diseases that consumers and healthcare uterine fibroids. could cause liver injury. professionals to report any All women taking ulipristal Health Canada’s review adverse effects related to the should have a liver function concluded that the evidence use of these health products. test at least once a month does not show a link between Health Canada will continue to during treatment. If the test is ruxolitinib and the risk of liver monitor the safety of SGLT2 abnormal (liver enzyme levels injury. The safety information inhibitors. more than two times the upper for the drug is appropriate at Reference: limit of normal), the health- this time. Health Canada will Summary Safety Review, care professional should stop continue to monitor the safety Health Canada, 8 February treatment and closely monitor of ruxolitinib. 2018 (www.hc-sc.gc.ca ) the patient. Liver tests should Reference: be repeated two to four weeks Summary Safety Review, after stopping treatment. Health Canada, 26 February Suvorexant The PRAC is also 2018 (www.hc-sc.gc.ca ) recommending that no new Next day residual effects patients should be started on ulipristal and no patients who Australia . TGA has advised have completed a course of Sodium-glucose health professionals to discuss treatment should start another Cotransporter-2 potential adverse events, one for the time being. A link especially next day residual between ulipristal and cases of (SGLT2) inhibitors effects (drowsiness), with serious liver injury is under patients before prescribing Potential risk of a rare brain suvorexant (Belsomra®). review. condition (posterior An EU-wide review of ulipristal Suvorexant is indicated for the reversible encephalopathy started in December 2017 treatment of insomnia, syndrome) in patients who following reports of serious developed diabetic characterised by difficulties with sleep onset and/or sleep liver injury in women using the medicine. The review is ketoacidosis maintenance. ongoing; however, temporary Canada. Health Canada has Since registration, the TGA has safety measures were reviewed the potential risk of received a number of reports of considered necessary following posterior reversible adverse events, including sleep receipt of the fifth case of

WHO Pharmaceuticals Newsletter No. 2, 2018 • 12 Safety of Medicines hepatic failure (the fourth that required liver transplantation). Reference: EMA, 9 February 2018 (www.ema.europa.eu)

WHO Pharmaceuticals Newsletter No. 2, 2018 • 13 Signal

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

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

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

Artemether/Lumefantrine and Stevens-Johnson syndrome: a recommendation for continued vigilance in malaria-endemic areas

Dr. Birgitta Grundmark, Uppsala Monitoring Centre and Pramod Kumar Adusumilli, the National Coordination Centre for Pharmacovigilance Programme of India

Summary Stevens-Johnson syndrome (SJS) is a severe mucocutaneous immune reaction, A signal was detected on the serious cutaneous characterized by necrosis and detachment of adverse drug reaction (ADR) Stevens-Johnson the epidermis of the skin through apoptosis syndrome (SJS) in relation to the anti-malarial 3 fixed drug combination Artemether/Lumefantrine of keratinocytes. Common prodromal (ALU) during a signal detection screening focused symptoms of SJS are flu-like symptoms such on reporting patterns in Africa, Asia and Latin as fever, sore throat, headache and fatigue, America. In the WHO global database of individual which may initially be misdiagnosed as an case safety reports, VigiBase, as of March 2017 infection and treated as such. Typically, a there were 19 reports on this drug-ADR maculopapular blistering skin rash abruptly combination. Most reported cases contain relatively arises on the face, torso and may spread to little information, the time to onset is somewhat arms, legs and soles. Oral, ocular or genital atypical and alternative explanations may have mucous membranes are affected in a contributed. As other cutaneous reaction terms majority of patients. describing conditions with a clinical closeness to The most common cause of SJS is drugs, SJS are included in labelling for ALU in parts of the including anti-malarials. The condition may world, this, along with the seriousness of the also be triggered by malignant disease and reaction, is the reason to signal the combination to infections, and regarding the latter, protozoal raise awareness of this issue. infections such as malaria and trichomoniasis 4 have been described as causal factors. In a significant proportion of the cases no clear Introduction causal factor can be identified. Genetic Fixed-dose combinations of factors such as being a slow acetylator may Artemether/Lumefantrine (ALU) are available predispose to SJS. Stevens-Johnson globally and recommended as one of the first line syndrome and the closely related syndrome treatments of uncomplicated malaria (Pl. of toxic epidermal necrolysis (TEN) are 1 Falciparum) in infants, children and adults. The variants of a disease continuum where in SJS skin detachment is <10% of the body surface combination is neither indicated for severe malaria nor for prevention of malaria. A typical treatment area; in SJS/TEN overlap the area is 10-30% and in TEN involves detachment of >30% of course would be six doses consisting of 1-4 tablets 5,6 2 the body surface. Onset is described as 1- per dose over three days. 30 days after start of instigating factor. WHO Pharmaceuticals Newsletter No. 2, 2018 • 14 Signal

eye or genital ulcerations. A few cases note a general spreading of the syndrome giving a Literature and Labelling suspicion they would fulfil the clinical definition United Kingdom, Australian and Swiss labels of SJS/TEN or TEN. In many reports the full (Riamet ®) are very similar and include as course of ALU appears to have been given acknowledged adverse reactions of the drug although onset of symptoms occurred very combination: rash, urticaria and hypersensitivity, rapidly after treatment initiation. One report 2 explicitly mentions a positive malaria test the latter without any further specification. whereas most cases state that the patient was Angioedema and face edema are mentioned as treated for malaria or just states ‘fever’ as the reported from post marketing experience. An treatment indication without providing further ® example of an Indian package insert (Lumerax ) information. None of the reports contain any includes rash, pruritus, urticaria, and relevant history of previous use of, or 7 angioedema. The United States Food and Drug reactions to, this or other drugs. ® Administration (US FDA) label (Coartem ) mentions the following regarding the post marketing experience: “ hypersensitivity reactions: ALU monotherapy cases like […] serious skin reactions (bullous eruption) In seven cases where ALU was the only have been reported” . This could evidently reported drug, the time to onset (TTO) was encompass SJS while SJS is not included per se in 8 reported as the same day in two cases, 1 day the labelling. in two cases, 3 and 5 days in two other cases In an article describing an ADR reporting survey and in one case with a fatal outcome where performed in Uganda one case is described as the TTO was unknown, the patient died 10 reported from a doctor where a “52 year old days after onset. female on Coartem oral route developed sores on the whole body”. No further information is available on the case which can be suspected of Non-Monotherapy cases 9 describing SJS or TEN. In all the 12 cases which mention more than one drug as co-suspect or concomitant, at

least one of the co-reported drugs is known to Reports in VigiBase have the ability to cause SJS, e.g. phenytoin, valproic acid, carbamazepine, ceftriaxone, In VigiBase, the WHO global database of individual benzthiazine/triamterene, albendazole, non- case safety reports, as of March 2017 there were steroidal anti-inflammatory drugs (NSAIDs), 19 cases of the combination ALU and SJS among acetylsalicylic acid (ASA), carbamazepine and 832 reports in total for ALU. The reports originate paracetamol. The median TTO of SJS from from Tanzania (7), Ghana (5), India (3), Kenya (2), start of ALU in these cases was 1.5 days Democratic Republic of Congo (1) and Zambia (1), (unknown in two cases). and were entered into the database from 2008 onwards. In the eight cases with co-reported paracetamol the starting date and hence the In the 19 cases the median age of patients was 29 TTO (when noted) was the same as for ALU years, ranging from 2 to 64 years. Eleven of the whereas in three cases reporting other co- cases concern males, five females, two reports reported/suspect drugs TTO for these were contain ambiguous gender information and in one 3-27 days and one noted as “long term use”. report the gender information is missing. Reporters In most paracetamol cases, there was no end were one patient and 18 health care professionals date noted, hence it is unknown whether this (HCPs), e.g. physicians, pharmacists and other drug was continued or not. HCPs.

All cases were reported as fulfilling serious criteria, with five explicitly stating the condition to be life- Discussion threatening and with one having a fatal outcome. At At the time of data retrieval there were 19 the time of reporting and apart from the patient reports of SJS in relation to ALU treatment in who died, 13 of the patients had recovered or were VigiBase. The US labelling mentions serious recovering, two had not yet recovered and for three skin reactions (bullous eruption) in the post the outcome was unknown or not reported. 8 marketing experience.

As prodromal symptoms of SJS are fever, Clinical case histories headache, sore throat and fatigue, there are In most reports the case descriptions are very brief alternative explanations to the association with only limited clinical data. Some merely state between ALU and SJS. An early stage SJS the diagnosis SJS while others describe in more caused by another factor could be mistaken detail skin blistering with desquamation and mouth, for malaria and treated as such or the malarial disease could be causing the SJS. The short WHO Pharmaceuticals Newsletter No. 2, 2018 • 15 Signal

TTO of 0-2 days in most of the reported cases is syndrome/home/ovc-20317097. Accessed: somewhat atypical and does weaken the suspicion September 2017. of a causal association between the drug and the 4. Foster CS, Ba-Abbad R, Letko E, Parrillo SJ. reaction while not excluding it. The insidious start Stevens-Johnson Syndrome. Dec 15, 2016. of SJS further makes an exact onset of the Available from: condition difficult to establish. There is limited http://emedicine.medscape.com/article/11 information in the described cases on their 97450-overview. Accessed: September respective diagnostic certainty of malaria. 2017. The presence of paracetamol, NSAIDs or ASA as 5. Bastuji-Garin S, Rzany B, Stern RS, Shear concomitant treatment in malaria or SJS would be NH, Naldi L, Roujeau JC. Clinical expected but obviously also obscures any causality classification of cases of toxic epidermal assessment. Since case descriptions and necrolysis, Stevens-Johnson syndrome, and information are sparse, other potential but erythema multiforme. Arch Dermatol. unaccounted-for causes of the SJS appearing 1993;129:92-6. within a reasonable timeframe are not possible to rule out, e.g. other infections and other drugs or 6. Roujeau JC. Stevens-Johnson syndrome traditional remedies used. and toxic epidermal necrolysis are severity variants of the same disease which differs

from erythema multiforme. J Dermatol. Conclusion 1997;24:726-9. The US labelling mentions serious bullous skin 7. Indian Label: Lumerax Package insert, Ipca reactions which could potentially include cases of Laboratories, 2017. SJS. The VigiBase case series gives some suspicion 8. US Food and Drug Administration: Product of a causal association between ALU and SJS albeit label for artemether/lumefantrine some arguments against such an association are (Coartem®) Available from: also present within it. While a firm conclusion on https://www.accessdata.fda.gov/drugsatfd causality cannot be drawn at this point, national a_docs/ label/2015/022268s012lbl.pdf. centres in malaria endemic areas should be aware Accessed: September 2017. of this potential issue, monitor and be prepared to take precautionary steps nationally if considered 9. Kiguba R, Karamagi C, Waako P, Ndagije necessary. HB, Bird SM. Rare, serious, and comprehensively described suspected

adverse drug reactions reported by Acknowledgement: Professor Ambrose Isah, surveyed healthcare professionals in Nigeria and Daniele Sartori, Uppsala Monitoring Uganda. PLoS One. 2015 Apr Centre for valuable input. 23;10(4):e0123974.

References Addendum regarding similar anti-malaria drugs: In VigiBase there is one report on the 1. Guidelines for the treatment of malaria, second combination Artemether-SJS from Kenya, one edition. Authors: WHO. Number of pages: 194. report on ALU-TEN from India and one report Publication date: 2010. Languages: English. on Artemether-TEN from France. Regarding ISBN 978-92-4-154792-5 other artemisinin class drugs or combinations, 2. Electronic Medicines Compendium: Summary of VigiBase contained 10 reports of SJS and 4 of Product Characteristics for Riamet®. Available TEN. The observed number did not exceed the from: statistically expected for any of the http://www.medicines.org.uk/emc/medicine/91 combinations. 10 of the 14 reports were 96. Accessed: September 2017. related to the use of artesunate and present a picture similar to the described for ALU, i.e. 3. Mayo Clinic. Stevens-Johnson syndrome. sparse information, predominately short times Available from: to onset and several co-suspect concomitant http://www.mayoclinic.org/diseases- drugs. Neither rash nor more severe conditions/stevens-johnson- (systemic) skin reactions appear to be labelled for artesunate.

Response from Novartis

Property of Novartis May not be used, divulged, published or otherwise Confidential disclosed without the consent of Novartis

WHO Pharmaceuticals Newsletter No. 2, 2018 • 16 Signal

Introduction atovaquone and proguanil HCl [Malarone, SmPC] and mefloquine HCl [Lariam, SmPC]. SJS and TEN This document provides Novartis’ comment on the are also reported to occur at a higher incidence in draft of “Artemether/Lumefantrine and Stevens- HIV-infected persons [Knight et al, 2014]. Johnson syndrome: continued prospective pharmacovigilance suggested” which will be Reported incidence rates of SJS/TEN range from published in Signal from UMC – WHO Collaborating 1.4 to 12.7 cases per million person-years Centre for International Drug Monitoring. [Diphoorn et al., 2016; Rzany et al., 1996]. In a 1:4 matched case-control analysis Frey et al [Frey

et al, 2017] found, that black and Asian patients The draft report concludes: “The US labelling were at a 2-fold risk of SJS/TEN when compared mentions serious bullous skin reactions which with white patients. This finding is particularly could potentially include cases of SJS. The relevant because of the malaria endemic regions. VigiBase case series gives suspicion of a causal Difficulties in obtaining definitive diagnoses of SJS association between ALU and SJS although some and TEN are also a hurdle in estimating an arguments against such an association are also accurate incidence [Yang et al 2016]. present within it. While a firm conclusion on causality cannot be drawn at this point, national centres should be aware of this potential issue, Methodology monitor and be prepared to take precautionary steps nationally if considered necessary.” Novartis global safety database was searched cumulatively through 30th Sep 2017 with SMQ

narrow scope “Severe cutaneous adverse Background reactions” with Coartem/Riamet. Coartem/Riamet (artemether/lumefantrine) was A literature review was also conducted based on first registered in 1998 and Novartis Pharma is searches in Medline, Embase and Biosis databases. currently the MAH in over 67 countries. The combined cumulative exposure for all formulations of Coartem/Riamet is estimated to be over 970 Results million patients (8 million PTY). Novartis safety database search Serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis A total of eight cases were retrieved from the (TEN) are being closely monitored in the Novartis global safety database [Angola (3), Coartem/Riamet PSURs as potential risk. In the Cameroon (1), France (1), Kenya (2) and Malawi last PSUR (01 Nov 2013 – 01 Oct 2016) (1)]. All cases were reported by health care assessment Report, the Pharmacovigilance Risk professionals. Assessment Committee (PRAC) agreed with the Of these 8 cases, one was a clinical trial case company’s assessment that no label change is concerning a female child of unknown age. The warranted and monitoring of the topic should event “bullous rash on the face and anterior trunk continue. associated with fever and septicemia” with a fatal The Coartem USPI mentions under Postmarketing outcome was assessed as not suspected to be Experience serious skin reactions (bullous related to the study medication by the eruption), also stating that due to the voluntary investigator. reporting it is not always possible to establish a Among the remaining seven spontaneous reports, causal relationship to drug exposure. the relevant events reported were Stevens- It should be noted that, there are several generic Johnson syndrome (n=5), Toxic epidermal formulations of artemether (synthetic and necrolysis (n=1) and Toxic skin eruption (n=1); in natural)-lumefantrine combinations on the market, three cases the events were reported with a fatal including substandard or counterfeit medications. outcome. The age group distribution of these seven cases was as follows: two infants (19 months and 2 Epidemiology years), one child (7 years) and four adults (27, 36, 45 and 54 years). Three reports concerned SJS and TEN are rare but life-threatening females and four males. The time to onset mucocutaneous diseases [Harr T et al., 2010]. calculated from the start of the Coartem/Riamet Several drugs are associated with an increased therapy was provided only in four cases and risk of SJS/TEN including antiepileptics, ranged from 2-7 days. antipsychotics, antimicrobials, antivirals, [Hirapara et al, 2017], allopurinol, analgesics like In all of the cases medications which are strongly paracetamol [Khawaja et al 2012, Biswal et al, associated with risk of SJS/TEN were given 2014], NSAIDs, COX-2 inhibitors, sertraline, concomitantly, like: phenobarbital, amoxicillin, [Roujeau et al., 1995; Mockenhaupt et al., 2008] paracetamol, sulfamethoxazole-trimethoprim, and non-ACT antimalarials like lopinavir, tenofovir and ritonavir (as part of HIV sulfadoxine/pyrimethamine [Fansidar, PIL], treatment), allopurinol, methyldopa, WHO Pharmaceuticals Newsletter No. 2, 2018 • 17 Signal chloramphenicol, ibuprofen and captopril. In one Stevens-Johnson syndrome (SJS) and toxic of these cases, the concomitant medication epidermal necrolysis (TEN) in northern Italy: (amoxicillin and paracetamol) was started on the data from the REACT registry same day as Coartem. In all of the remaining Pharmacoepidemiol Drug Saf, 25 (2016), pp. cases, the exact start and end dates for the co- 196-203. medications were not provided. In two cases with 3. Frey N, Jossi J, Bodmer M, Bircher A, Jick SS, multiple co-medications, SJS was reported in the Meier CR, Spoendlin J. The Epidemiology of medical history with the possibility that the Stevens - Johnson syndrome and Toxic reported event occurred in the context of drug re- Epidermal Necrolysis in the UK. J Invest challenge. Some of the cases were also poorly Dermatol. 2017 Jun; 137(6):1240-1247. documented with not much information provided for a proper assessment. 4. Fansidar tablets (500 mg sulfadoxine and 25 mg pyrimethamine) Australian label

Roche Products Pty Limited, 2008. Literature 5. Harr T, French LE. Toxic epidermal Cumulative review identified the below relevant necrolysis and Stevens-Johnson publication: syndrome. Orphanet J Rare Dis. 2010;5:39. [Matthew O et al 2013], compared the treatment outcome among patients treated with 6. Hirapara H N, Patel T K, Barvaliya M J, artesunate/amodiaquine to those treated with Tripathi C. Drug-induced Stevens–Johnson artemether-lumefantrine for acute uncomplicated syndrome in Indian population: A malaria. One case of Steven Johnson-like reaction multicentric retrospective analysis. Niger J was observed with artemether-lumefantrine in the Clin Pract [serial online] 2017 [cited 2017 study starting on the third day, after completion of Nov 3];20:978-83. therapy. This was adequately treated at the centre 7. Khawaja A, Shahab A, Hussain SA. and no other complaint was received from the Acetaminophen induced Steven Johnson patient. syndrome-toxic epidermal necrolysis Comment: No further details were provided about overlap.J Pak Med Assoc. 2012 concomitant drugs and the authors have reported May;62(5):524-7. only SJS-like reaction. 8. Knight L, Muloiwa R, Dlamini S, Lehloenya RJ. Factors Associated with Increased Mortality in a Predominantly HIV-Infected Discussion and Conclusion Population with Stevens Johnson Syndrome The review revealed that in all cases, there were and Toxic Epidermal Necrolysis. Hoshino Y, alternative explanations in the form of additional ed. PLoS ONE. 2014;9(4):e93543. suspect or concomitant medications which are 9. Lariam 250 mg Tablets - Summary strongly associated with the risk of severe skin of Product Characteristics. 2017. reactions. Some cases contained limited information, which precluded adequate 10. Malarone 250 mg/100 mg film- assessment. coated tablets-Summary of Product Characteristics. 2016. The reporting frequency with Coartem/Riamet is 0.01 case per million PTY that is far below the 11. Matthew O, Sunday JN, Emmanuel reported incidences in the general population (1.4 OI, E, et al. Comparative to 12.7 cases per million PTY) even when assessment of two artemisinin considering underreporting or ethnic differences. based combination therapies in the treatment of uncomplicated malaria In conclusion, in line with the PRAC conclusions, among University students in Novartis believes that the current data does not Nigeria. International Journal of warrant for a change of the relevant product Drug Development and Research. information and will continue close monitoring the 2013;5(2):211-221. safety topic in the frame of the PSURs. 12. Mockenhaupt M, Viboud C, Dunant

A, Naldi L, Halevy S, Bouwes References Bavinck JN, et al. Stevens-Johnson syndrome and toxic epidermal 1. Biswal S, Sahoo SS. Paracetamol induced necrolysis: assessment of Stevens-Johnson syndrome--toxic medication risks with emphasis on epidermal necrolysis overlap syndrome. recently marketed drugs. The Int J Dermatol. 2014 Aug; 53(8):1042-4. EuroSCAR-study. J Invest Dermatol. 2. Diphoorn J, Cazzaniga S, Gamba C, Schröder 2008 Jan; 128(1):35-44. J, Citterio A, Rivolta AL, et al. Incidence, 13. Roujeau, JC. et al. Medication use causative factors and mortality rates of and the risk of Stevens-Johnson WHO Pharmaceuticals Newsletter No. 2, 2018 • 18 Signal

syndrome or toxic epidermal registry. J Clin Epidemiol. 1996; 49, necrolysis. N. Engl. J. Med.1995; pp. 769-773. 333, 1600-1607. 15. Yang M, Lee J, Kim J, Kim G, Kim B, 14. Rzany, M. Mockenhaupt, S. Baur, W. Kim J, et al. Incidence of Stevens- Schröder, U. Stocker, J. Mueller, et Johnson syndrome and toxic al. Epidemiology of erythema epidermal necrolysis: a nationwide exsudativum multiforme majus, population-based study using Stevens-Johnson syndrome, and national health insurance Database toxic epidermal necrolysis in in Korea. PLoS One, 11 (11) (2016), Germany (1990-1992): structure p. e0165933. and results of a population-based

Quetiapine and valproic acid interactions: signal strengthening

Daniele Sartori, Uppsala Monitoring Centre and Prof. Alfonso Carvajal, Spain

Summary treatment of acute moderate to severe manic episodes in bipolar disorder and as The co-administration of quetiapine and valproic maintenance treatment of bipolar disorder acid is a relatively unexplored option for the acute (prevention of a manic, mixed or depressive and maintenance treatment of bipolar disorder. 1,2 According to the European Union Summary of episode) in adults. Limited evidence shows Product Characteristics, the two drugs are known to that co-administration of quetiapine and interact but the co-treatment is “well tolerated”. valproic acid in bipolar disorder is more effective than use on their own, both for acute Despite the limited clinical significance of the 3-6 interaction, some have advised therapeutic drug symptoms and maintenance. Relatively high monitoring. In December 2016, VigiBase, the WHO co-prescription as opposed to monotherapy global database of individual case safety reports, emphasizes the need for better understanding held over 1500 reports of quetiapine and valproic of the efficacy of antipsychotics, including acid as co-suspect or interacting. Five MedDRA quetiapine, in conjunction with lithium, 7 preferred terms: blood creatine phosphokinase lamotrigine or valproic acid, contrasting. increased, coma, depressed level of consciousness, disorientation and rhabdomyolysis were selected Recommended doses of quetiapine in adjunct through shrinkage odds ratios. The resulting series to valproic acid, for both acute and of 20 cases was assessed: at least six cases had maintenance bipolar disorder treatment, are been reported in the literature, there were more 400-800 mg per day. Immediate release male than female rhabdomyolysis patients (4:1), quetiapine is initiated at 100 mg per day in and quetiapine raised plasma concentrations hinted manic episodes and may be increased up to at a valproic acid-mediated pharmacokinetic 800 mg/day over six days, with increments interaction. Most cases (15/20) were reported as no higher than 200 mg/day. For extended serious, and therefore, despite confounding by release: 300 mg/day for the first two days, neuroleptic malignant syndrome and the potential with 400-800 mg/day by day three. Valproic for genetic polymorphisms, the evidence presented acid doses in mania are mostly documented may justify an update to the current safety as monotherapy at 600-750 mg/day. The understanding of the two medicines. dose should be increased by 200 mg/day every three days, up to a total of 2500 8,9 mg/day in uncontrolled mania. Introduction The polymorphic nature of psychotic disorders Quetiapine is an atypical antipsychotic, with poses a challenge to standard posology recommendations or specific combination antagonistic activity for serotonin 5-HT 1A /5-HT 2, treatments. Off-label use is common in dopamine D /D , histamine H and noradrenaline α 1 2 1 1 psychiatry, to explore treatments to which and α receptors. It is indicated for schizophrenia, 2 each patient responds most favourably. bipolar disorder I, and as add-on treatment for major depressive disorder. Valproic acid is an antiepileptic, thought to increase gamma 1,2 Literature and Labelling aminobutyric acid concentrations in the brain. The European Union Summary of Product In the United States (US) and Europe, quetiapine Characteristics (EU SmPC) for quetiapine and valproic acid together are licensed for the mentions an increased risk of antipsychotic- WHO Pharmaceuticals Newsletter No. 2, 2018 • 19 Signal induced side effects when valproic acid is co- recently been increased to the maximum daily administered, but adds that the combination of dose of 800 mg, but quetiapine plasma levels 16 quetiapine and valproic acid was well tolerated. were not measured. A 19-year-old patient The US Food and Drug Administration label cites affected by Batten disease (neuronal ceroid an Astra Zeneca sponsored study from 2007, lipofuscinosis – a rare genetic disorder), fell which found that adding 1000 mg/day of into a hyperammonemic coma three weeks divalproex, a valproic acid formulation, to 300 mg/ after valproic acid treatment was added to day of quetiapine produced a 17% mean increase quetiapine 200 mg/day. The patient recovered in maximum plasma quetiapine concentration at after valproic acid discontinuation, but the steady state. At the same daily doses, valproic 17 authors did not suspect an interaction. In acid maximum plasma concentration at steady another case quetiapine was suspected of 10 state was found to be reduced by 10-12%. having promoted a hyperosmolar- Conversely, a smaller study showed an increase in hyperglycaemic coma in the presence of up to 77% of plasma quetiapine concentrations, 18 valproic acid. An increased exposure to 11 when given together with valproic acid. quetiapine due to valproic acid may have Rhabdomyolysis, creatine phosphokinase (CPK) occurred, but both drugs have the potential to increase and coma (including hyperglycaemic trigger this condition. coma) are on the EU SmPC for quetiapine, while the valproic acid EU SmPC includes hyperammonemic coma and consciousness Reports in VigiBase clouding. As of December 2016 there were 1522 ICSRs Stockley’s Drug Interactions describe the evidence of quetiapine and valproic acid, co-reported as on a pharmacokinetic interaction between suspected or interacting, in VigiBase. During a quetiapine and valproic acid as “limited”, adding signal detection screening focusing on drug- that the two do not appear to alter each other’s drug-interactions, 50 quetiapine-valproic acid- exposure. Based on the evidence considered, dose interaction combinations were highlighted. adjustments are not deemed necessary in 12 concurrent use. To limit the cases to a number manageable for manual assessment, we performed an The literature reveals several serious cases on automatic case series features comparison 19 concurrent quetiapine and valproic acid use, using shrinkage odds ratios (see vigiPoint ). describing musculoskeletal and neuropsychiatric Five MedDRA preferred terms (PTs) were suspected adverse reactions attributed to one of the identified as relevant and selected: blood drugs or to interaction between the two. Six cases creatine phosphokinase increased, coma, presented here were published and reported to depressed level of consciousness, VigiBase, the WHO global database of individual disorientation and rhabdomyolysis. Suicide case safety reports (ICSRs). attempts were excluded, along with cases A 26-year-old male, with a history of CPK increases which contained over three co-suspects, to under quetiapine, was reported to have CPK-raised minimize polypharmacy confounding. Twenty blood levels under quetiapine/valproic acid. After cases remained; the full results of the analysis the valproic treatment was stopped due to a are available upon request. suspicion of hepatic toxicity and the quetiapine The 20 reports originated from the United dose was doubled, the patient complained of States (5 cases), Germany (4), Switzerland myalgia accompanied by increased CPK. From this, (3), Canada (2), Australia, Denmark, Italy, quetiapine was thought to have caused the 13 Turkey, South Korea and Spain (1 case each). reaction. An 85-year-old female treated for four Patient sex was mostly male (13 vs 7), with days with quetiapine and valproic acid was found to an average age of 49 years. The indication have CPK increase. The authors did not exclude the given was: bipolar disorder in seven cases, possibility of an interaction with pipamperone, nor schizoaffective disorder in two, paranoid a pharmacodynamic one with subtherapeutic schizophrenia in one, psychotic 14 quetiapine. Rhabdomyolysis and increased CPK disorder/psychosis in two, depression in two, were also described in a 37-year-old male who and patient restraint, Batten disease and complained of neck muscles stiffness and malaise. posttraumatic stress disorder in one case The authors postulated a pharmacokinetic each. Five cases reported “Blood creatine interaction between valproic acid and quetiapine phosphokinase increased”, five “Coma”, eight had resulted in the inhibition of CYP3A4, one of “Depressed level of consciousness”, four 15 quetiapine’s main metabolic pathways. “Disorientation” and four “Rhabdomyolysis”, all at PT level. Most cases (15/20) were A 66-year-old patient experienced depressed level reported as serious. of consciousness and reversible parkinsonism due to a suspected pharmacokinetic interaction Two groups of reported events can be between quetiapine and valproic acid. The identified: musculoskeletal and psychiatric. symptoms appeared after the quetiapine dose had For these two groups, time to onset, de- and re-challenges, and outcomes were WHO Pharmaceuticals Newsletter No. 2, 2018 • 20 Signal determined for a given reported MedDRA PT. When by concomitant diseases, co-reported terms or two events of the same group were in the same co-administered medicines. report, the more severe of them was selected. The musculoskeletal subgroup contributes with 4 males and 1 female to the uneven sex ratio in the case series (13 males and 7 females). Musculoskeletal reported adverse events Fat-to-muscle ratio differences between sexes PTs: Rhabdomyolysis/blood creatinine can account for rhabdomyolysis. Other phosphokinase increased alternative explanations include: potentially undiagnosed glycolysis, glycogenolysis, and Six cases (1 to 6 in the table), in two of which pentose phosphate pathways enzymatic quetiapine and valproic acid were reported as polymorphism, mitochondrial toxicity and interacting, and one case which included the term 21 calcium homeostasis dysregulation. “Drug interaction”. The highest dose of Quetiapine per patient ranged from 50-500 mg/day, while the Additionally, rhabdomyolysis is part of the highest for valproic acid was 250-1500 mg/day. neuroleptic malignant syndrome (NMS) clinical Time to onset ranged from 4 days after valproic presentation, which is known to be more 22 acid introduction to 75 days (median 11 days). frequent in men. In case 4, a quetiapine- The outcome was recovery in all six patients. valproate pharmacokinetic interaction was Case 6 features also disorientation, a suspected to have induced rhabdomyolysis as neuropsychiatric event (see below), but CPK part of an abortive NMS form. The patient’s measurements allowed for rhabdomyolysis to be symptoms began with neck stiffness, which selected as the main term. resembles a cervical dystonia literature case, suspected to have been a pharmacokinetic interaction between quetiapine and valproic 23 Neuropsychiatric reported adverse events acid. Cases 5 and 6 are confounded by respiratory infection and NMS respectively. In PTs: Depressed level of consciousness/Coma case 1, the reporter concluded that the patient Twelve cases in total (7 to 18 in the table). In four, was predisposed to valproic acid quetiapine and valproic acid were reported as hepatotoxicity on the basis of repeated interacting. The highest dose of quetiapine per positive rechallenges, and that quetiapine was patient ranged from 200-950 mg/day, while the responsible for the CPK increase. After highest for valproic acid was 300-2500 mg/day. withdrawal of valproate, the patient recovered Time to onset ranged from 1 day after valproic acid from hepatic complications, after quetiapine introduction to 16 months (median 17 days). The dechallenge his CPK went back to normal. outcome was recovery in seven patients and Reiche et al. (case 2) suggest a blood CPK unknown with reaction abated in two. increase caused by valproic acid resulting from prolonged clearance due to interaction with In the narrative of case 7 there is a mention of CPK concomitant pipamperone. They do not, increase, but the information is incomplete. however, exclude the possibility of a Therefore, coma was chosen as main term. pharmacodynamic interaction between valproic PT: Disorientation acid and quetiapine, adding that quetiapine was below therapeutic levels at admission to Two cases (19 and 20 in the table). Neither hospital. reported the two drugs as interacting. The highest dose of Quetiapine per patient ranged from 400- Accounting for potential confounders in the 600 mg/day, while the highest for valproic acid was neuropsychiatric group, consciousness 1.5-500 mg/ day (one of which is possibly 1.5 fluctuations and coma are also symptoms of grams due to entry mistake). Time to onset was 17 NMS. In case 7, marked increases of days and 3 years. The outcome was recovery in antipsychotic plasma levels due to both cases. pharmacokinetic interaction could have induced NMS. Alternatively, valproic acid encephalopathy can also reasonably explain Discussion decreased consciousness and coma. Valproic acid metabolites can inhibit the urea cycle and 17 Quetiapine and valproic acid are known to interact cause hyperammonemia, as in case 17. Wu as two central nervous system (CNS) depressant et al. (case 18) suggest that the patient’s agents. The interaction is not thought to be hyperglycaemic coma was promoted by high clinically significant and is regarded as “well dose quetiapine and possibly complicated by tolerated”, however, therapeutic drug monitoring 20 valproic acid co-administration, but worsened has been recommended. By contrast, most of the by high sugar consumption. Cases which did assessed cases (15/20) were reported as serious. not co-report any of the above discussed For rhabdomyolysis and increases in blood CPK, the conditions are 9 and 10, both describing a time to onset is consistent with a drug induced decrease in consciousness. Both could be effect, yet the reactions per se could be explained quetiapine dose-related: the first reports a

WHO Pharmaceuticals Newsletter No. 2, 2018 • 21 Signal prescribed overdose, and the second an 2. US Food and Drug Administration. unintentional four-fold overdose due to lack of Product label for quetiapine patient adherence. Some cases list extrapyramidal (Seroquel ®). Available from: symptoms, a known side effect of antipsychotics. http://www.accessdata.fda.gov/dr Case 12 reports pseudoparkinsonism induced by ugsatfda_docs/ increased plasma levels of quetiapine. Similarly, label/2016/020639s064lbl.pdf. case 13 lists parkinsonism and depressed Accessed: 11 January 2017. consciousness, attributed to a pharmacokinetic interaction leading to increased quetiapine plasma 3. Sachs G, Chengappa KN, Suppes T, levels and a recovery after dose reduction. In Mullen JA, Brecher M, Devine NA, et al. another patient (case 11), depressed consciousness Quetiapine with lithium or divalproex for co-occurred with gait disturbances and around the the treatment of bipolar mania: a same time of a quetiapine dose increase. The randomized, double-blind, placebo- reported off-label indication was depression, and controlled study. Bipolar Disord. the incremental dosing occurred according to the 2004;6(3):213-23. label. In case 8, extrapyramidal symptoms and 4. Sokolski KN, Denson TF. Adjunctive depressed level of consciousness are co-reported quetiapine in bipolar patients partially after quetiapine dose increase. Quetiapine overdose responsive to lithium or valproate. Prog leads to CNS depression and increased plasma Neuropsychopharmacol Biol Psychiatry. levels due to pharmacokinetic interactions can have 2003;27(5):863-6. the same effect. 5. Suppes T, Vieta E, Gustafsson U, Ekholm In addition to polytherapy-induced interactions, B. Maintenance treatment with quetiapine smoking, alcohol, and drug abuse are prevalent in 24 when combined with either lithium or patients affected by psychotic disorders. divalproex in bipolar I disorder: analysis of Quetiapine pharmacokinetics do not seem to be two large randomized, placebo-controlled altered by smoking. Nicotine however, is trials. Depress Anxiety. metabolized by CYP2A6, the same cytochrome 2013;30(11):1089-98. 25,26 which hydroxylates valproic acid. These 6. Yatham LN, Paulsson B, Mullen J, Vågerö considerations are applicable to case 7, a smoker. AM. Quetiapine versus placebo in Smoker status, alcohol or substance abuse could combination with lithium or divalproex for have been unreported in the rest of the case series. the treatment of bipolar mania. J Clin Psychopharmacol. 2004;24(6):599-606. Conclusion 7. Haeberle A, Greil W, Russmann S, Grohmann R. Mono- and combination drug therapies in The potential for quetiapine-valproic acid hospitalized patients with bipolar interactions has been extensively described in the depression. Data from the European literature, with at least six case reports published in journals. The assessed case series features drug surveillance program AMSP. BMC musculoskeletal and psychiatric events that Psychiatry. 2012;12(1):153. occurred after dose increases of quetiapine, or 8. Sanofi. Product Information for valproic acid where the reporter suspected a pharmacokinetic ® interaction. Bearing reported confounders in mind, (Epilim ). Available from: such as NMS, or individual predisposing factors, http://www.sanofi.com.au/products/ current information could still be considered for aus_pi_epilim.pdf. Accessed: 11 January updating. In particularly, the co-administration of 2017. quetiapine and valproic acid is regarded as well 9. Electronic Medicines Compendium. tolerated, yet 15 out of 20 cases were serious. Summary of Product Characteristics for While psychiatrists and clinical pharmacologists valproic acid (Depakote ®). Available from: might be aware of the events described here, https://www.medicines.org.uk/emc/ general practitioners might not be, stressing the medicine/25929. Accessed: 11 January relevance of strengthening the safety 2017. understanding and available documentation on the two medicines. 10. Winter HR, DeVane CL, Figueroa C, Ennis DJ, Hamer-Maansson JE, Davis

PC, et al. Open-label steady-state References pharmacokinetic drug interaction study on co-administered quetiapine fumarate and 1. Electronic Medicines Compendium. Summary divalproex sodium in patients with of Product Characteristics for quetiapine schizophrenia, schizoaffective disorder, or (Seroquel 25 mg, 100 mg, 200 mg, 300 mg bipolar disorder. Hum Psychopharmacol. film-coated tablets). Available from: 2007;22(7):469-76. https://www.medicines.org.uk/emc/ medicine/2295. Accessed: 11 January 2017. 11. Aichhorn W, Marksteiner J, Walch T, Zernig G, Saria A, Kemmler G. Influence WHO Pharmaceuticals Newsletter No. 2, 2018 • 22 Signal

of age, gender, body weight and valproate 2017;26(10):1256-65. comedication on quetiapine plasma 20. Vella T, Mifsud J. Interactions between concentrations. Int Clin Psychopharmacol. valproic acid and quetiapine/olanzapine 2006;21(2):81-5. in the treatment of bipolar disorder and 12. Stockley’s, Drug, Interactions. Quetiapine + the role of therapeutic drug monitoring. Valproate [Online]. London: Pharmaceutical Press; J Pharm Pharmacol. 2014;66(6):747- 2016 [Available from: 59. http://www.medicinescomplete.com/. Accessed: 21. Hohenegger M. Drug induced 11 January 2017. rhabdomyolysis. Curr Opin Pharmacol. 13. Erdoğan S, Çelikel FÇ. Massive creatine 2012;12(3):335-9. kinase and hepatic enzyme elevation due to 22. Pelonero AL, Levenson JL, Pandurangi quetiapine and valproic acid treatment: a AK. Neuroleptic malignant syndrome: a case report. Archives of Neuropsychiatry review. Psychiatr serv. 2011;53(4):238-40. 1998;49(9):1163-72. 14. Reiche I, Tröger U, Postel SC, Wolf R, Bode- 23. Habermeyer B, Rabovsky K, Jentzsch C, Böger SM. Valproic acid-induced myopathy in a Pinhard K, Müller-Spahn F. Cervical patient with schizoaffective disorder. J Clin dystonia due to interaction of valproic Psychopharmacol. 2009;29(4):402-3. acid and quetiapine. J Clin 15. Jahn H, Kiefer F, Arlt J. Rhabdomyolysis Psychopharmacol. 2007;27(4):396-7. with quetiapine. German Journal of 24. Hartz SM, Pato CN, Medeiros H, Psychiatry 2008;11(2):79-80. Cavazos-Rehg P, Sobell JL, Knowles JA, 16. De Dios C, Fudio S, Lorenzo A. Reversible et al. Comorbidity of severe psychotic parkinsonism and cognitive decline due to a disorders with measures of substance possible interaction of valproic acid and use. JAMA psychiatry. 2014;71(3):248- quetiapine. J Clin Pharm Ther. 54. 2011;36(3):430-2. 25. Messina ES, Tyndale RF, Sellers EM. A 17. Larsen EP, Ostergaard JR. Valproate-induced Major Role for CYP2A6 in Nicotine C- hyperammonemia in juvenile ceroid oxidation by human liver microsomes. J lipofuscinosis (Batten disease). Seizure. Pharmacol Exp Ther. 2014;23(6):429-34. 1997;282(3):1608-14. 18. Wu CY, Mitchell SR, Seyfried LS. Quetiapine- 26. Kiang TK, Ho PC, Anari MR, Tong V, induced hyperglycemic crisis and severe Abbott FS, Chang TK. Contribution of hyperlipidemia: a case report and review of CYP2C9, CYP2A6, and CYP2B6 to the literature. Psychosomatics.55(6):686-91. valproic acid metabolism in hepatic microsomes from individuals with the 19. Juhlin K, Star K, Norén GN. A method for CYP2C9*1/*1 genotype. Toxicol Sci. data-driven exploration to pinpoint key 2006;94(2):261-71. features in medical data and facilitate expert review. Pharmacoepidemiol Drug Saf.

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Table 1. Overview of selected case reports of blood creatine phosphokinase increased, coma, depressed level of consciousness, disorientation and rhabdomyolysis in association with quetiapine (Q) and valproic acid (VA) in VigiBase

Case Serious Age/Sex Suspected (S), Q|VA dose Reactions (MedDRA Time to Dechallenge/Rechalle Outcome Comments interacting (I) or terms, main event in onset nge concomitant (C) bold) drugs 1 Y 26/M Q, VA (both S) 200 mg/day Blood creatine 11 days Q: Dechallenge Recovered Literature reference: Erdogan et al . Lithium (C) 400 mg/day after phosphokinase positive VA levels: 50 mg/l, thyroid function normal. valproate stopped increased , creatine AST, ALT, LDH elevation linked to VA, |1500 mg/day kinase MB increased, VA: Dechallenge while CPK and CPK-MB increase to Q. hepatic enzymes positive History of hepatic enzyme increases while increased on VA and CPK increase on Q. VA withdrawn first, with lowering of hepatic enzymes. Followed by increase in CPK after Q dose was raised to 400 mg/day. Q then discontinued and CPK values back to normal. 2 Y 85/F Q, VA, 200 mg/day|600 Drug clearance 4 days Q: Dechallenge Recovered Literature reference: Reiche et al . pipamperone (all mg/day decreased, drug after VA positive/ Rechallenge Suspected interaction between VA and S) Acetylsalicylic interaction, myopathy, introducti negative pipamperone as well as between VA and acid, blood creatine on Q. Q levels below therapeutic: 25 ng/ml levothyroxine, phosphokinase VA: Dechallenge (reference 70-170 ng/ml), VA levels within nifedipine, torasemide, increased, muscle pain, positive therapeutic range: 46 mcg/ml (reference 30- furosemide (all C) muscle weakness, 100 mcg/ml). myoglobin blood increased 3 - 27/M Q, VA, venlafaxine (all 200 mg/day|250 Rhabdomyolysis , - -/- Recovered - S) mg/day muscle pain, creatine kinase increased 4 Y 37/M Q (I), VA (S) 500 mg/day Rhabdomyolysis , 2.5 months Q: Dechallenge Recovered Literature reference: Jahn et al . |1000 mg/day muscle pain, positive VA: Dose Suspect of abortive neuroleptic malignant musculoskeletal not changed syndrome with fever (37.9 C), tremor in stiffness, muscle rigidity, extremities. VA 82.4 mg/l. muscle weakness, malaise, creatine kinase increased, body temperature increased, drug interaction 5 Y 54/M Q, VA, paliperidone (all 50 mg/day Bronchopneumonia, 2 months Q: Dechallenge Recovered - S) |1000 mg/day rhabdomyolysis , renal positive Paroxetine, failure acute flurazepam, VA: Dechallenge delorazepam (all positive C) 6 Y 64/M Q, VA (both I) 50 mg/day Neuroleptic malignant 4 days Q: -/- Recovered - Indapamide, titrated to 100 syndrome, hydrochlorothiazide/li mg/day over 1 rhabdomyolysis , renal VA: Dechallenge sinopril, amlodipine day failure acute, acidosis positive (all C) |300 mg/day metabolic, hypotension, extrapyramidal disorder, fever, disorientation 7 Y 65/M Q, VA, pipamperone Titrated from Neuroleptic malignant 1 month Q: Dechallenge Recovered Q above studied doses. Mental disorders (all S) 100 mg to 950 syndrome, tremor, positive VA: Dose due to brain damage. Chronic obstructive mg/day in 17 rigors, muscle spasticity, not changed pulmonary disease, smoker, fever 38.1 C. Q days depressed level of plasma concentration: 3498 nmol/l |150 mg titrated consciousness , fever, (reference 183-442 nmol/l) 1 day after to 300 mg in 1 confusion, dysarthria withdrawal. C-reactive protein: 83 mg/l. day Pipamperone was taken for 9 days, in overlap with Q/VA. 8 Y 66/M Q, VA (both I), lithium 200 mg/day Depressed level of 3 days after Q: Dechallenge Recovered Acute cholecystitis. Developed reactions after (S) |1500 mg/day consciousness , surgery positive/ Reintroduced surgery, lithium- induced diabetes insipidus Ceftriaxone, Quetiapine up extrapyramidal disorder, at lower dose without pre-existing, hypernatraemia due to metronidazole, heparin to 500 mg/day diabetes insipidus, Several reaction decreased consciousness and subsequent (all C) after surgery hypernatraemia years of reduced liquids intake. Recent increase of Q. treatment VA: Dechallenge with both positive/ Rechallenge medicines negative 9 Y 56/M Q, VA, perazine 100 mg/day titrated Depressed level of 1 day after Q: Dose Recovered Q above studied doses. Q at 191 ng/ml (all S) to 900 mg/day consciousness , valproate reduced VA: (reference 70-170 ng/ ml). VA at 11.2 Acetylsalicylic over 1 month consciousness introduction Dose mcg/ml (reference 50-100 mcg/ml). acid, clopidogrel, |300 mg/day decreased, drug reduced Reactions occurred at the day of peak Q hydrochlorothiazide/val interaction, restlessness, concentration. VA was introduced the same sartan, ramipril, prescribed overdose day. Perazine cannot be excluded, but was pantoprazole (all C) introduced five days before valproate.

WHO Pharmaceuticals Newsletter No. 2, 2018 • 24 Signal

Case Serio Age/Sex Suspected (S), Q|VA dose Reactions (MedDRA Time to Dechallenge/Rechalle Outcome Comments us interacting (I) or terms, main event in onset nge concomitant (C) bold) drugs 10 Y 39/F Q, VA (both S) 200 mg/day Affect lability, depressed 5 days Q: Dechallenge - Hospitalized due to fever and suspected |1000 mg/day level of consciousness , (after positive pneumonia, treated with levofloxacin. inappropriate schedule of hospitalizati VA: Dechallenge Antipsychotic regimen had not been taken by drug administration, on and positive patient and was started during hospital stay. pneumonia, pyrexia, treatment somnolence, treatment re-start) noncompliance 11 Y 54/F Q, VA (both S) 50 mg/day titrated Depressed level of 12 days Q: -/Rechallenge - The overdose was not intentional but reported to 400 mg/day consciousness , gait positive by the patient as she considered her physician over 12 days disturbance, overdose, to be overdosing her. |700 mg/day pain, physical assault, VA: Dechallenge speech disorder positive 12 Y 66/F Q, VA (both I) 300 mg/day Hemiparesis, depressed 17 days Q: Dechallenge Recovered Literature reference: De Dios et al . titrated to level of consciousness , positive Cortical-subcortical atrophy. VA: 78 mg/l after 800 mg/day parkinsonism, temporal VA: Dechallenge events. over follow- disorientation, memory unknown ups deficit, cognitive |1000 mg/day deterioration titrated up to 1500 mg/day over follow-ups 13 Y 74/M Q, VA, 50 mg/day Drug interaction, 19 days Q: Dose Recovered History: benign prostatic hyperplasi a, lacunar aripiprazole (all I) titrated to 500 depressed level of after Q reduced infarction, nervous system disorder NOS, mg/day in 19 consciousness, introducti VA: Dose cerebral degeneration, emergency care, Finasteride, days parkinsonism, coma , on reduced hospitalization, chronic kidney disease. alfuzosin, lithium |1600 mg/day blood thyroid stimulating Q was added on VA and lithium. (all C) brought to hormone decreased, 2400 mg/day altered state of VA dose brought up from 900 mg per day to after 9 days consciousness 1600 mg per day on the day Q was started. Q: 283 mcg/l (reference: 70-170 mcg/l); VA within therapeutic levels; aripiprazole below therapeutic levels. 14 Y -/M Q, VA, lorazepam (all “high doses” of Dehydration, depressed - -/- - - S) both drugs level of consciousness, coma 15 - -/F Q, VA, sertraline (all S) - Convulsions, coma - -/- - - 16 - 57/F Q, VA, nifedipine (all S) - Hypotension, coma - -/- - - 17 Y 19/M Q, VA, oxcarbazepine 200 mg/day Anticonvulsant drug level 3 weeks Q: -/- Recovered Literature reference: Erling et al . (all S) |1000 mg/day above therapeutic, after VA Hyperammonemic coma due to VA. VA: coma , hyperammonemic introductio VA: Dechallenge 756 mcmol/l (no reference provided but encephalopathy, n above therapeutic). hyperammonemia, positive drowsiness 18 Y 39/M Q, VA (both I), 700 -800 mg/day Hyperosmolar state, 16 months Q: Dechallenge Recovered Literature reference: Wu et al . lorazepam (S) |2500 mg/day hypercapnia, lipids positive Coma/depressed consciousness due to increased, hypoxia, VA: Dose not hyperglycaemia (high- sugar dieting habits). diabetes mellitus, coma , changed Patient without history of diabetes. blood cholesterol increased, drug interaction, hypertriglyceridemia, hyperglycaemia, diabetic ketoacidosis, weight increased 19 N 38/F Q, VA, lithium (all S) 600 mg/day Disorientation 17 days Q: Dose reduced Recovered VA introduced after 11 days of Q use. Q can |500 mg/day increase plasma concentration of lithium. VA: Dechallenge positive 20 - 21/M Q, VA, fluvoxamine (all 400 mg/day Thinking abnormal, 3 years -/- Recovered Possible error in reporting VA dose (mg instead S) |1.5 mg/day concentration impaired, of grams). disorientation , dizziness, nausea

WHO Pharmaceuticals Newsletter No. 2, 2018 • 25 Feature

Enhancing Pharmacovigilance in Low and Middle Income Countries using Smart Safety Surveillance

Access to priority medicines and vaccines in low and middle-income countries (LMICs) has improved significantly in the last few years. With the urgent need for novel treatments for diseases such as tuberculosis, malaria and HIV, more and more medicinal products are expected to be released on an accelerated, fast-track basis. However, there has not been a proportionate improvement in pharmacovigilance (PV). This is of great concern, as effective safety monitoring systems are essential to learn about the safety of novel treatments, manage adverse effects and minimize risks. In addition, a lack of functional PV system is a barrier to access as many new products require safety monitoring as a condition to authorization of a license for use. In 2016, the World Health Organization, (WHO) in collaboration with the Bill and Melinda Gates Foundation (BMGF) launched the Smart Safety Surveillance or Project 3S to help LMICs identify, assess and adequately manage the risks associated with new medicines and vaccines. The 3S approach proposes strengthening of PV systems and practices in LMICs, to support the introduction of new health products through identification, assessment, and management of any risks associated with them. Although the 3S approach was borne out of a WHO-BMGF grant agreement, the Bedaquiline stock in a hospital in approach is equally valid for strengthening PV systems in countries Kyrgyzstan supported by other donors such as UNITAID.

One of the products that will be used as a pathfinder to test the concept of the 3S approach is bedaquiline. Bedaquiline (BDQ), is a new class of medicines against M. Tuberculosis indicated for the use of multi-drug resistant tuberculosis (MDR-TB). The emergence of drug-resistant tuberculosis (TB) is a major threat to global TB care and control, and even more so when there is resistance to multiple drugs. Bedaquiline was approved for use in the treatment of MDR-TB under the United States Food and Drug Administration (U.S FDA) accelerated-approval regulations and conditional under the European Medicines Agency (EMA). Subsequently, the World Health Organization (WHO) issued conditional recommendations for its use through an interim policy guidance published in 2013. One of the conditional requirements is pharmacovigilance and proper management of adverse drug reactions and prevention of drug–drug interactions. So far, WHO estimates that bedaquiline has been introduced and used in over 46 countries worldwide, under various mechanisms of compassionate use, expanded access programmes, donation programmes, import waiver and registered market access. Armenia and Kyrgyzstan are among 27 countries in the world with a high burden of multidrug-resistant tuberculosis (MDR-TB) and among the 18 high-priority countries for TB in the WHO European Region. In March 2018, representatives from WHO Safety and Vigilance team at Headquarters in Geneva, WHO regional office in Europe, and WHO country offices in Armenia and Kyrgyzstan visited TB clinics and national PV centres in Armenia and Kyrgyzstan to gain insight on existing PV systems and explore how the 3S Hospital Staff in a TB hospital in principles can be applied to strengthen existing Kyrgyzstan systems.

All partners around the table Through various meetings and discussions, WHO has gained an understanding of to discuss PV needs in structural components such as legislations, existence of guidelines and standard Armenia operating procedures, human resources and access to information, in both countries. The team also gained a good understanding of the reporting process, analysis and level of decision making was also acquired. WHO representatives also met with a few non-governmental agencies such a Médecins for sans Frontièrs (MSF) and KNCV to clarify roles, activities and future plans under the scope of PV. The team gathered information on areas of PV that require support, so that countries are prepared for the safety monitoring of new medicinal products. WHO, together with the countries, and other partners such as the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK is designing a work plan to address identified gaps and needs, with the aim of strengthening the PV systems in countries.

WHO Pharmaceuticals Newsletter No. 2, 2018 • 26