2015 WHO Pharmaceuticals

NEWSLETTER No.3

Prepared in collaboration with the WHO Collaborating Centre for International Drug Monitoring, Uppsala Sweden

The WHO Pharmaceuticals Newsletter provides you The aim of the Newsletter is to with the latest information on the safety of medicines disseminate information on the and legal actions taken by regulatory authorities across safety and efficacy of pharmaceutical products, based on the world. It also provides signals based on information communications received from our derived from Individual Case Safety Reports (ICSRs) network of "drug information available in the WHO Global ICSR database, officers" and other sources such as specialized bulletins and journals, VigiBase®. as well as partners in WHO. As the Feature article, we have included a brief report from two recent WHO-led pharmacovigilance training The information is produced in the events. form of résumés in English, full texts of which may be obtained on request from: Safety and Vigilance, EMP-HIS, World Health Organization, 1211 Geneva 27, Switzerland, E-mail address: [email protected]

This Newsletter is also available on our Internet website: http://www.who.int/medicines

Further information on adverse Contents reactions may be obtained from the WHO Collaborating Centre for International Drug Monitoring Box 1051 Regulatory matters 751 40 Uppsala Tel: +46-18-65.60.60 Safety of medicines Fax: +46-18-65.60.80 E-mail: [email protected] Signal Internet: http://www.who-umc.org

Feature

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Table of Contents

Regulatory Matters Agomelatine ...... 5 Amiodarone and hepatitis C treatments containing sofosbuvir ...... 5 Amphetamines and methylphenidate ...... 7 Asunaprevir and daclatasvir hydrochloride ...... 7 Azilsartan ...... 7 BioCSL Fluvax® ...... 8 Cefotaxime sodium ...... 8 Clopidogrel sulphate containing medicines ...... 8 Codeine-containing medicines ...... 8 Cyclophosphamide hydrate ...... 9 Duloxetine hydrochloride ...... 9 Epoetin beta ...... 10 Ferumoxytol ...... 10 Hydroxyzine-containing medicines ...... 11 Methylphenidate ...... 11 Non-steroidal anti-inflammatory drugs and diclofenac ...... 12 Oral ibuprofen ...... 12 Panitumumab ...... 13 Panitumumab and cetuximab ...... 13 Pazopanib hydrochloride ...... 14 Pomalidomide ...... 14 Rebamipide (Ophthalmic solution) ...... 14 Sevoflurane...... 15 Sitagliptin phosphate hydrate ...... 15 Triamcinolone acetonide ...... 15

Safety of medicines Capecitabine and folic acid ...... 17 Ceftolozane and tazobactam ...... 17 Ceftriaxone and calcium containing diluents ...... 17 Clozapine with another antipsychotic drugs ...... 18 Dimethyl fumarate ...... 18 Flurbiprofen-containing topical pain medications ...... 19 Goldenseal (Hydrastis canadensis)...... 19 Guaifenesin ...... 20

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Table of Contents

Hydroxyzine ...... 20 Olanzapine pamoate ...... 21

Signal Prucalopride and Suicidal ideation ...... 22 Vemurafenib and Thrombocytopenia ...... 27

Feature Strengthening pharmacovigilance in countries: a brief report from two WHO events ...... 35

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Regulatory Matters

Agomelatine Reference: pacemaker to regulate their Medicines Safety Update, TGA, heart rhythms. The other Risk of hepatic injury Vol. 6, No. 2, April 2015 patients recovered after (www.tga.gov.au) discontinuing either the Australia. The Therapeutic (See WHO Pharmaceuticals hepatitis C drugs or Goods Administration (TGA) Newsletters No.1, 2015 for risk amiodarone, or both. The has informed health of serious hepatic adverse cause of these events could professionals that the Product reactions with agomelatine in not be determined. The FDA Information (PI) for Ireland, No.6, 2014 for risk of will continue to monitor agomelatine (Valdoxan®) has liver toxicity in Europe and sofosbuvir containing hepatitis been updated to include No.6, 2012 for risk of dose- C drugs for risks of serious further information about the related hepatotoxicity and liver symptomatic bradycardia and risk of hepatic injury. failure in the UK) further investigate the reason why the use of amiodarone Agomelatine is a melatonin with these hepatitis C drugs receptor (MT1 and MT2) agonist led to the heart-related events. and 5-hydroxytryptamine (serotonin) receptor 2C Amiodarone and The FDA recommends heart antagonist. It is indicated for monitoring in an inpatient treatment of major depression hepatitis C hospital setting for the first 48 in adults, including prevention treatments hours. Subsequently, of relapse. monitoring in a doctor’s office containing sofosbuvir or self-monitoring of the heart The updated PI advises caution rate should be done every day should be taken before Serious slowing of the through at least the first 2 initiation of treatment with heart rate with co- weeks of treatment. Patients agomelatine, and there should administration discontinuing amiodarone just be close surveillance of liver prior to starting sofosbuvir function during continuation of Egypt, EU and USA. The containing hepatitis C drugs in treatment. This is important if regulatory authorities have combination with another agomelatine is used in warned of serious symptomatic direct-acting antiviral, should combination with other bradycardia when also undergo similar cardiac medicines associated with risk antiarrhythmic drug monitoring as outlined above. of hepatic injury or where risk amiodarone is used with The FDA is adding information factors for hepatic injury, such hepatitis C treatments about serious slowing of the as overweight/obesity, non- containing sofosbuvir in heart rate, known as alcoholic fatty liver disease, combination with other drugs symptomatic bradycardia, to diabetes and substantial (e.g. ledipasvir, daclatasvir or the labels of sofosbuvir alcohol consumption, are simeprevir). present. containing hepatitis C drugs. Sofosbuvir containing The Egyptian Pharmaceutical In addition, liver function tests medicines (Harvoni® and Vigilance Center (EPVC) has are recommended for all Sovaldi®) are indicated for advised health-care patients before initiation of treatment of chronic hepatitis professionals; treatment and/or after a dose C virus, which can last a  A fixed dose combination increase. Tests should be lifetime and lead to serious with ledipasvir/sofosbuvir repeated at week three, six, liver problems, including should not be co- 12, 24 post initiation of cirrhosis or liver cancer. treatment, after a dose administered with increase and thereafter when The US Food and Drug amiodarone. clinically indicated. Administration (FDA) review of  Sofosbuvir combined with post-market reports of adverse another hepatitis C drug, Treatment should not be events found that patients can such as investigational drug initiated if serum transaminase develop serious and life- daclatasvir or simeprevir, levels are greater than three threatening symptomatic should not be co- times the upper limit of the bradycardia when a sofosbuvir administered with normal range. If pre-treatment containing hepatitis C drug in amiodarone. transaminase levels are combination with another  Patients should be advised greater than the upper limit of direct-acting antiviral is taken to seek medical attention the normal range (but less together with amiodarone. The immediately if they have than three times the upper reports included the death of signs and symptoms of limit), agomelatine should be one patient due to cardiac symptomatic bradycardia used with caution. arrest and three patients including: requiring placement of a

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Regulatory Matters

○ near-fainting or  Encourage patients to read when starting hepatitis C fainting (syncope) the patient information treatment with combination ○ dizziness or light leaflet they receive with of sofosbuvir with headedness their prescription hepatitis ledipasvir, or sofosbuvir ○ malaise C drugs and amiodarone as plus daclatasvir. ○ weakness there may be new  Patients receiving these ○ excessive tiredness information. hepatitis C medicines with ○ shortness of breath amiodarone, with or without Information in EU for health- ○ chest pains other medicines that lower care professionals include: ○ confusion or memory heart rate, should be  Severe bradycardia and problems warned of the symptoms of heart block have been  For patients taking bradycardia and heart block reported in patients taking amiodarone who have no and should be advised to amiodarone and other alternative treatment seek urgent medical advice combination of sofosbuvir options and who will be co- if they experience them. with ledipasvir, or administered either a fixed  The product information for amiodarone and a dose combination with these hepatitis C medicines combination of sofosbuvir ledipasvir/sofosbuvir or will be updated and daclatasvir. Of 8 cases sofosbuvir in combination appropriately. A letter will reviewed up to April 2015, with another direct acting also be sent to health-care one case resulted in fatal antiviral: professionals involved in cardiac arrest and two ○ counsel patients about hepatitis C treatment required pacemaker the risk of serious explaining these risks and intervention. symptomatic the measures to manage  Onset of bradycardia was bradycardia them. within 24 hours of initiating ○ cardiac monitoring in  Because the number of hepatitis C treatment in 6 an in-patient setting patients taking amiodarone cases and within 2 to 12 for the first 48 hours of who have been exposed to days in the other 2 cases. co-administration is combination of sofosbuvir Rechallenge in the context recommended, after with ledipasvir, or of continued amiodarone which outpatient or sofosbuvir plus daclatasvir treatment resulted in self-monitoring of the is unknown, it is not recurrence of symptomatic heart rate would occur possible to estimate the bradycardia in 2 cases. on a daily basis incidence of occurrence of Recurrence was also seen through at least the these events. The on rechallenge with the first 2 weeks of mechanism behind the antivirals 8 days after treatment findings has not been stopping amiodarone, but  Patients who are taking established. not 8 weeks after stopping. either a fixed dose  Amiodarone should only be The regulatory authorities combination with initiated in patients treated recommend that health-care ledipasvir/sofosbuvir or with combination of professionals should not sofosbuvir in combination sofosbuvir with ledipasvir, prescribe sofosbuvir containing with another direct acting or sofosbuvir plus hepatitis C drugs combined antiviral, who need to start daclatasvir, if other with another direct-acting amiodarone therapy due to antiarrhythmics are contra- antiviral drug with amiodarone. no other alternative indicated or not tolerated. However, in cases where treatment options, should  If concomitant use with alternative treatment options undergo similar cardiac amiodarone is unavoidable, are unavailable, patients monitoring as outlined patients should be closely should be closely monitored. above. monitored, particularly As amiodarone persists for a  Due to the long half-life of during the first weeks of long time in the body, amiodarone, patients treatment. Those at high monitoring is also needed if discontinuing amiodarone risk of bradyarrhythmia patients start such hepatitis C just prior to starting a fixed should be monitored in an treatments within a few dose combination with appropriate clinical setting months of stopping ledipasvir/sofosbuvir or for 48 hours after starting amiodarone. sofosbuvir in combination concomitant treatment. with another direct-acting References:  Due to its long half-life, antiviral, should also Newsletter, Egyptian patients who have undergo similar cardiac Pharmaceutical Vigilance discontinued amiodarone monitoring as outlined Center (EPVC), Volume 6, within the past few months above. Issue 5, May 2015 should also be monitored

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Press release, EMA, 24 April and behaviours associated with reactions” subsection of the 2014 (www.ema.europa.eu) amphetamine products and “Adverse reactions” section in methylphenidate has been package insert. Drug Safety Communication, issued. Prescribing information US FDA, 24 March 2015 Erythema multiforme: for all amphetamine products (www.fda.gov) Erythema multiforme may and methylphenidate will be occur. Patients should be updated to include: reports of carefully monitored. If any rare cases of suicidality in abnormalities are observed, patients taking amphetamine administration of this drug products or methylphenidate. Amphetamines and should be discontinued and Although evidence is limited appropriate measures should methylphenidate patients should be monitored be taken. for signs of suicidality. Risk of suicidal thoughts Reference: Risks of suicide related and behaviours Revision of Precautions, thoughts and behaviours MHLW/PMDA, 23 April 2015 Canada. A safety review was associated with the use of (www.pmda.go.jp/english/) initiated to evaluate amphetamine products or information regarding the methylphenidate will be potential risk of suicidal related continued to be monitored and thoughts and behaviours with evaluated. the use of amphetamine Reference: Azilsartan products or methylphenidate. Summary Safety Review, Risk of “hepatic function Amphetamine products Health Canada, 30 March 2015 (amphetamine, (www.hc-sc.gc.ca) disorder” dextroamphetamine and Japan. The MHLW and the lisdexamfetamine) and PMDA have announced the methylphenidate are used for revision of the package insert the treatment of attention- for azilsartan (Azilva®) to deficit hyperactivity disorder Asunaprevir and include risk of hepatic function (ADHD) in adults and children daclatasvir disorder. 6 years of age and older. hydrochloride Azilsartan is indicated for Cases of suicide related events hypertension. have been reported with the Risk of erythema use of amphetamine products multiforme The MHLW/PMDA stated that or methylphenidate cases of hepatic function internationally. ADHD can be Japan. The Ministry of Health disorder have been reported in associated with other mental Labour and Welfare (MHLW) patients treated with azilsartan health conditions that may and the Pharmaceutical and in Japan. increase the risk of suicidal Medical Devices Agency Based on expert advice and related thoughts and (PMDA) have announced the available evidence, the behaviours. Whilst most revision of the package insert MHLW/PMDA have reports originating from for asunaprevir (Sunvepra®) recommended the addition of Canada reported suicidal and daclatasvir hydrochloride the following texts to the thoughts, a small number of (Daklinza®) to include risk of subsection of the “Clinically suicide attempts and suicides erythema multiforme, following significant adverse reactions” were also reported. In general, reports of cases occurring in in the section of “Adverse the review of Canadian cases Japan. reactions” in package insert.” suggests that the use of Asunaprevir and daclatasvir amphetamine products or Hepatic function disorder: hydrochloride are indicated for methylphenidate may Hepatic function disorder treatment of viraemia in contribute to suicidal related associated with elevated AST patients with serogroup 1 thoughts or actions in some (GOT), ALT (GPT), and γ-GTP (genotype I) chronic hepatitis patients with ADHD, either levels may occur. Patients C or compensated cirrhosis alone or in association with should be carefully monitored. type C. other mental conditions. At If any abnormalities are present, there is little Based on expert advice and observed, administration of information in the scientific available evidence, the this drug should be literature to support this MHLW/PMDA have discontinued and appropriate association. recommended the addition of measures should be taken. the following texts to the A communication notifying the Reference: “Clinically significant adverse risk of suicide related thoughts Revision of Precautions, WHO Pharmaceuticals Newsletter No. 3, 2015  7

Regulatory Matters

MHLW/PMDA, 23 April 2015 Cefotaxime sodium is an The MHLW/PMDA stated that (www.pmda.go.jp/english/) antibacterial agent used for cases of acute generalised treatment of infections such exanthematous pustulosis

as: sepsis, infective have been reported in patients endocarditis, secondary treated with clopidogrel infections secondary to sulphate in Japan and other BioCSL Fluvax® trauma, thermal burn, surgical countries, and the CCDS has wound, acute bronchitis, been updated. Not for children under pneumonia, and lung abscess. 5 years Based on expert advice and The MHLW/PMDA stated that available evidence, the Australia. The TGA has cases of acute generalised MHLW/PMDA have warned that health exanthematous pustulosis recommended that “acute professionals should be have been reported in patients generalised exanthematous reminded that bioCSL Fluvax® treated with cefotaxime pustulosis” should be added to is registered for use in children sodium in other countries, and the “Clinically significant from the age of 5 years and the company core datasheet adverse reactions” subsection older, and must not be used in (CCDS) has been updated. of the “Adverse reactions” children under 5 years of age section in package insert. due to an increased risk of Based on expert advice and fever and febrile convulsions. available evidence, the Reference: The TGA also advises health MHLW/PMDA have Revision of Precautions, professionals to avoid using recommended that: “acute MHLW/PMDA, 23 April 2015 Fluvax® as a generic term for generalised exanthematous (www.pmda.go.jp/english/) pustulosis” should be added to influenza vaccine to minimise the potential for confusion. the “Clinically significant adverse reactions” subsection The information is reinforced in of the “Adverse reactions” the black box warning in the PI section in package insert. Codeine-containing as follows: medicines WARNING: This season’s Reference: Revision of Precautions, vaccine is indicated for use Not to be used in only in persons aged 5 years MHLW/PMDA, 23 April 2015 (www.pmda.go.jp/english/) children below 12 years and over. It must not be used for cough and cold in children under 5 years. It should only be used in children EU. The EMA announced that aged 5 to under 9 years based the consensus of the on careful consideration of Clopidogrel sulphate Coordination Group for Mutual potential risks and benefits in Recognition and Decentralised the individual. containing medicines Procedures - Human (CMDh) Reference: Risk of acute generalised are introducing new measures Medicines Safety Update, TGA, to minimise the risk of serious exanthematous adverse effects (e.g. breathing Vol. 6, No. 2, April 2015 pustulosis (www.tga.gov.au) problems), with codeine- containing medicines, when Japan. The MHLW and the used for cough and cold in PMDA have announced the children. As a result of these revision of the package insert new measures: for clopidogrel sulphate Cefotaxime sodium  Use of codeine for cough (Plavix®) and clopidogrel and cold is now sulphate/aspirin combination Risk of acute generalised contraindicated in children (Complavin Combination®) to exanthematous below 12 years. include risk of acute pustulosis  Use of codeine for cough generalised exanthematous and cold is not pustulosis. Japan. The MHLW and the recommended in children PMDA have announced the Clopidogrel sulphate containing and adolescents between revision of the package insert medicines are indicated for 12 and 18 years who have for cefotaxime sodium suppression of recurrence after breathing problems. (Claforan® and Cefotax®) to ischaemic cerebrovascular The measures, recommended include risk of acute disorder and inhibition of by the EMA’s generalised exanthematous thrombogenesis/embolization Pharmacovigilance Risk pustulosis. in peripheral arterial disease. Assessment Committee (PRAC) will be directly implemented by

WHO Pharmaceuticals Newsletter No. 3, 2015  8

Regulatory Matters the Member States where the  Codeine is also Rhabdomyolysis characterized medicines are authorised, contraindicated in women by myalgia, feelings of according to an agreed during breastfeeding and weakness, increased creatine timetable. patients known to be kinase (creatine CYP2D6 ultra-rapid phosphokinase), increased Codeine is an opioid medicine metabolisers. blood myoglobin, and that is converted into increased urine myoglobin may morphine in the body. High Reference: occur. Patients should be levels of morphine can lead to Press release, EMA, 24 April carefully monitored. If any serious adverse effects, such 2014 (www.ema.europa.eu) abnormalities are observed, as breathing difficulties. (See WHO Pharmaceuticals administration of this drug Codeine is converted into Newsletters No.5, 2013 for should be discontinued and morphine in children below 12 restrictions on use of codeine appropriate measures should years in a more unpredictable for pain relief in children in be taken. manner, making this Europe and in the UK, No.4, population at special risk of Reference: 2013 for restricted use as such adverse effects. Children Revision of Precautions, analgesic in children and with existing breathing MHLW/PMDA, 24 March 2015 adolescents under 18 in the UK difficulties are more (www.pmda.go.jp/english/) and No.5, 2012 for use in susceptible to respiratory certain children after effects of codeine. Codeine is tonsillectomy and/or widely used for pain relief and adenoidectomy - risk of rare, for the treatment of cough and but life-threatening adverse cold symptoms. In the EU, Duloxetine events or death in the USA) codeine-containing medicines hydrochloride have been approved via national procedures, and are Risk of neuroleptic available either on prescription malignant syndrome or over the counter in the Cyclophosphamide different Member States. Japan. The MHLW and the Codeine is marketed as a hydrate PMDA have announced the single-ingredient medicine or revision of the package insert in combination with other Risk of rhabdomyolysis for duloxetine hydrochloride active substances. (Cymbalta®) to include risk of Japan. The MHLW and the neuroleptic malignant The PRAC also noted that PMDA have announced the syndrome. cough and cold are generally revision of the package insert self-limiting conditions and the for cyclophosphamide hydrate Duloxetine hydrochloride is evidence that codeine is (Endoxan®) to include risk of indicated for effective at treating cough in rhabdomyolysis. depression/depressed state children is limited. and diabetic peripheral Cyclophosphamide hydrate has neuropathic pain. In addition to the new various indications, including measures for children, codeine multiple myeloma, malignant The MHLW/PMDA stated that must also not be used in lymphoma, lung cancer, breast cases of neuroleptic malignant people of any age who are cancer, acute leukaemia, and syndrome have been reported known to convert codeine into bone tumour etc. in patients treated with morphine at a faster rate than duloxetine hydrochloride in The MHLW/PMDA stated that normal (‘ultra-rapid Japan. cases of adverse events metabolisers’) nor in suggestive of rhabdomyolysis breastfeeding mothers, as Based on expert advice and have been reported in patients codeine can harm the baby available evidence, the treated with cyclophosphamide because it passes into breast MHLW/PMDA have hydrate injections in Japan. milk. recommended the addition of the following texts to the Based on expert advice and Information for health-care “Clinically significant adverse available evidence, the professionals: reactions” subsection of the MHLW/PMDA have  Codeine for cough and cold “Adverse reactions” section in recommended the addition of is now contraindicated in package insert. the following to the “Clinically children below 12 years, significant adverse reactions” and not recommended in Neuroleptic malignant subsection of the “Adverse syndrome: children between 12 and reactions” section in package Neuroleptic malignant 18 years with compromised insert. respiratory function. syndrome may occur. If any abnormalities such as fever, Rhabdomyolysis: WHO Pharmaceuticals Newsletter No. 3, 2015  9

Regulatory Matters akinetic mutism, strong muscle preventing anaemia of recommendation against use of rigidity, swallowing difficult, prematurity: ferumoxytol in patients who tachycardia, blood pressure  consider the benefits and have had an allergic reaction fluctuation, diaphoresis, risks, including the possible to any intravenous (IV) iron increased white blood cell risk of retinopathy replacement product. count, increased serum  monitor the infant for At the time of ferumoxytol’s creatine kinase (creatine features of retinopathy approval in 2009, this risk was phosphokinase), etc. are  advise parents or carers described in the Warnings and observed, administration of that their baby’s eyes will Precautions section of the drug this drug should be be carefully monitored for label. Since then, serious discontinued. Then whole-body any ill effects reactions, including deaths, control such as body cooling This recommendation follows have occurred. The FDA is and rehydration should be an European review that continuing to monitor and conducted, and appropriate evaluated current evidence of evaluate the risk of serious measures should be taken. In retinopathy associated with allergic reactions with all IV addition, decreased kidney epoetin beta treatment of iron products. function with myoglobinuria anaemia of prematurity. Two may lead to acute renal failure, Ferumoxytol is in a class of systematic reviews and caution should therefore medicines called IV iron investigating effectiveness also be exercised. replacement products. It is considered adverse effects, used to treat iron-deficiency Reference: including retinopathy of anaemia―a condition in which Revision of Precautions, prematurity. there is a lower than normal MHLW/PMDA, 23 April 2015 Collectively the reviews number of oxygen-carrying red (www.pmda.go.jp/english/) suggest that epoetin beta may blood cells because of too little increase the underlying risk of iron. Ferumoxytol is specifically retinopathy in premature approved for use only in adult infants. patients with iron deficiency anaemia due to chronic kidney Epoetin beta The European review of disease. Increased risk of available data concluded that more data are needed to draw Based on the FDA evaluation, retinopathy in preterm a firm conclusion about the following recommendations infants cannot be erythropoietin and the risk of for health-care professionals excluded retinopathy of prematurity. were made: However, the available data  Only administer IV iron UK. The Medicines and Health- show that an increase in the products to patients who care Products Regulatory underlying risk of retinopathy require IV iron therapy. Agency (MHRA) has warned of in premature infants with early  Do not administer a possible increase in risk of epoetin use cannot be ferumoxytol to patients with retinopathy with epoetin beta excluded. a history of allergic reaction in premature infants, to ferumoxytol or other IV Reference: particularly those with an iron products. Drug Safety Update, MHRA, underlying risk: born before 31  Only administer diluted Volume 8, issue 10: 3, May weeks of gestation, and those ferumoxytol as an IV 2015 (www.gov.uk/mhra) weighing less than 1.25 kg. infusion over a minimum of The summary of product 15 minutes. Ferumoxytol characteristics will be amended should not be given as an to include possible risk of undiluted IV injection. retinopathy. Ferumoxytol  Closely monitor patients for Epoetin beta (NeoRecormon®) signs and symptoms of is indicated for the prevention Risk of fatal allergic serious allergic reactions, of anaemia of prematurity in reactions including monitoring blood infants with a birth weight of pressure and pulse during 0.75 to 1.5 kg and a USA. The FDA has ferumoxytol administration gestational age of less than strengthened an existing and for at least 30 minutes 34 weeks. Epoetin beta is warning of serious, potentially following each infusion. identical to erythropoietin, a fatal allergic reactions with the  Carefully consider the hormone that stimulates the anaemia drug ferumoxytol potential risks and benefits production of red blood cells. (Feraheme®). Prescribing of ferumoxytol instructions were changed to administration in elderly The MHRA has warned that include a Boxed Warning and a patients with multiple or when using epoetin beta for contradiction with a strong serious medical conditions,

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Regulatory Matters

as these patients may rhythms associated with used with caution in experience more severe hydroxyzine and have patients with bradycardia, reactions. concluded that the risk did not or who are taking  Carefully consider the differ between indications and hypokalaemia-inducing potential risks and benefits that such events are most medicines. Care is also of ferumoxytol likely to occur in patients who required when hydroxyzine administration in patients have risk factors. is co-administered with with a history of multiple drugs known to be potent The new measures will be drug allergies. Patients with inhibitors of alcohol directly implemented by the multiple drug allergies may dehydrogenase or Member States where the also be at higher risk. CYP3A4/5. medicines are authorised. In Reference: particular, the product Reference: Drug Safety Communication, information of hydroxyzine- Press release, EMA, 27 March US FDA, 31 March 2015 containing medicines will be 2014 (www.ema.europa.eu) (www.fda.gov) updated with new dosing

recommendations and (See WHO Pharmaceuticals warnings on use in patients Newsletters No.5, 2014 for risk who have risk factors for heart of serious hypersensitivity rhythm disturbances or who Methylphenidate reactions in the UK and No.4, are taking certain medicines. 2014 for hypersensitivity Risk of priapism reaction in Canada) The EMA informed health-care professionals with the Canada. Health Canada

following: announced that the prescribing  The maximum dose in information for all brand name adults should be a total of (Biphentin®, Concerta®, Hydroxyzine- 100 mg daily; in the Ritalin®) and generic containing medicines elderly, if use cannot be methylphenidate products will avoided the maximum daily be updated to include the risk Risks of effects on heart dose should be 50 mg. The of priapism. rhythm maximum daily dose in Methylphenidate products are children up to 40 kg in used for the treatment of EU. The EMA has introduced weight should be ADHD in adults and children 6 new measures to minimise the 2 mg/kg/day; children over years of age and over. risk of effects on heart rhythm 40 kg should be given the with medicines containing the adult dose. Priapism (prolonged and antihistamine hydroxyzine. The  Use of hydroxyzine is painful erection) is a rare but measures include restricting contraindicated in patients serious adverse reaction that use of hydroxyzine in patients with known acquired or requires immediate medical at high risk of problems with congenital QT interval attention to prevent possible heart rhythm and using the prolongation, or with a long-term effects on the penis. medicine at the lowest known risk factor for QT A safety review was initiated effective dose for as short a interval prolongation such following the recommendation time as possible. as cardiovascular disease, by the US FDA stating that all significant electrolyte Hydroxyzine medicines are methylphenidate product labels imbalance (hypokalaemia, available in most EU countries. and patient Medication Guides hypomagnesaemia), family should be updated to include Their approved uses history of sudden cardiac information about the risk of (indications) vary between death, significant priapism. countries and may include bradycardia, or concomitant treatment of anxiety disorders, use of drugs known to Health Canada’s actions were relief of pruritus (itching), prolong the QT interval based on one report of premedication before surgery, and/or induce torsades de priapism associated with the and treatment of sleep pointes. use of methylphenidate disorders. Hydroxyzine has the  Use is not recommended in received at the time of review, potential to block hERG elderly patients, due to together with a small number channels and other types of reduced elimination of of cases of priapism in cardiac channels, resulting in a hydroxyzine in these association with potential risk of QT interval patients and greater methylphenidate products prolongation and cardiac vulnerability to reported internationally and in arrhythmia events. anticholinergic effects and the literature. In nearly half of The EMA PRAC evaluated other adverse reactions. these cases, methylphenidate evidence of abnormal heart The medicine should be WHO Pharmaceuticals Newsletter No. 3, 2015  11

Regulatory Matters products were found to be the obtained from the Advisory Reference: probable cause of priapism. Committee on the Safety of Medicines Safety Update, TGA, Medicines. In addition, a full Vol. 6, No. 2, April 2015 Priapism has been reported safety review of diclofenac was (www.tga.gov.au) during treatment with considered. The reviews found methylphenidate products after (See WHO Pharmaceuticals that OTC NSAIDs were safe if increasing the dose or stopping Newsletters No.2, 2015, No.5, used according to the the product even for a short 2014, No.5, 2013, No.4, 2013 recommended doses for short period of time. and No.6, 2012 for related durations, as instructed on the information) The prescribing information for label. However, inappropriate all brand name and generic use or overuse of these methylphenidate products will medicines could pose a be updated to include the very significant risk of Oral ibuprofen cardiovascular events and, in rare risk of priapism. Health Risk of serious heart and Canada has issued a the case of diclofenac, stroke adverse events at communication to inform hepatotoxicity. health-care professionals and high doses Product labelling for OTC patients about the possibility of diclofenac, naproxen and Canada. Health Canada priapism associated with the ibuprofen did not carry strong announced an update of use of methylphenidate enough warnings regarding prescribing information for products. these risks for all patients, or ibuprofen-containing products, Reference: adequate advice for people to include an increased risk of Summary Safety Review, with cardiovascular disease or serious heart and stroke Health Canada, 21 April 2015 risk factors. adverse events when taken at (www.hc-sc.gc.ca) a daily dose of 2400 mg or TGA has advised health more. (See WHO Pharmaceuticals professionals to: Newsletters No.5, 2014 for risk  avoid using prescription This follows a safety review of of priapism in Australia and NSAIDs in patients who evidence by Health Canada to No.1, 2014 for risk of long- have previously had evaluate the possible link lasting erections in the US) myocardial infarction, between heart and stroke angina, cardiac failure, related adverse events and the

hypovolemia, significant use of ibuprofen especially at peripheral vascular disease high doses compared to other or pre-existing significant NSAIDs, including COX-2 Non-steroidal anti- renal/hepatic dysfunction. selective inhibitors like inflammatory drugs  use these medicines with celecoxib (Celebrex®). caution in patients with and diclofenac identifiable risks factors for Evidence of an association cardiovascular disease, between oral ibuprofen at a Cardiovascular risks undertaking individual daily dose of 2400 mg or more assessment of each patient and an increased risk of heart Australia. The TGA has to ensure the benefits attack and stroke related informed health professionals outweigh the risks. adverse events was found. of changes in PI and labels for  consider advising patients This was not found for OTC use non-steroidal anti- of the increased at the maximum daily doses of inflammatory drugs such as cardiovascular risks of using 1200 mg or less. These diclofenac, naproxen, NSAIDs, including OTC findings were comparable to ibuprofen, celecoxib, products, and educating those associated with COX-2 etoricoxib, indomethacin, them regarding the signs inhibitors. The risk increases meloxicam and piroxicam, to and symptoms of serious when ibuprofen is taken for a include cardiovascular risks. cardiovascular events. long duration and among Diclofenac, naproxen and Instruct them to seek patients having a history of, or ibuprofen are available as OTC medical attention risk factors for heart disease, oral dosage forms (in lower immediately if they stroke, or uncontrolled blood doses). Diclofenac ibuprofen experience any. pressure. and piroxicam are also  be aware that, in rare available as an OTC topical gel. cases, diclofenac has been Ibuprofen is an NSAID used to treat pain, reduce fever, and The changes follow a review of associated with a risk of relieve inflammation. Most approximately 200 hepatotoxicity and should ibuprofen-containing products publications, information from be used at the lowest are sold as OTC preparations companies, reports collected effective dose for only short for use by adults and children. by TGA and expert advice periods of time. WHO Pharmaceuticals Newsletter No. 3, 2015  12

Regulatory Matters

These products contain Japan and in other countries, cancer. Cetuximab is used for 400 mg or less of ibuprofen, and the MHLW/PMDA also the treatment of EGFR- and the maximum stated the CCDS for positive, incurable, recommended daily dose of panitumumab has been revised unresectable, ibuprofen for these products is to include information on advanced/recurrent colorectal 1200 mg. Products containing oculomucocutaneous cancer and head and neck 600 mg of ibuprofen are syndrome. cancer. available by prescription only Based on expert advice and The MHLW/PMDA stated that for use by adults and children available evidence, the the efficacy of treatment in above 12 years to relieve the MHLW/PMDA have patients with or without the symptoms of arthritis recommended the addition of RAS (KRAS and NRAS) gene (osteoarthritis and rheumatoid the following texts to the mutation was retrospectively arthritis). The maximum “Clinically significant adverse analysed in a total of 4 phase recommended daily dose of reactions” subsection of the III studies of panitumumab ibuprofen for these prescription “Adverse reactions” section in and cetuximab involving products is 2400 mg. package insert. patients with colorectal cancer. The overall benefits of The results revealed a trend Oculomucocutaneous ibuprofen continue to outweigh that suggested no add-on syndrome (Stevens–Johnson the risks when used as effect could be expected with syndrome): recommended. Oral ibuprofen coadministration of Oculomucocutaneous may at a daily dose of 2400 mg panitumumab or cetuximab as occur. Patients should be should be avoided in patients, compared with the control carefully monitored. If any with ischemic heart disease, group amongst the patient abnormalities are observed, cerebrovascular disease, population with the RAS gene administration of this drug congestive heart failure or with mutation. should be discontinued and risk factors for cardiovascular appropriate measures should Based on expert advice and disease. be taken. available evidence, the Reference: MHLW/PMDA have Reference: Summary Safety Review, recommended the addition of Revision of Precautions, Health Canada, 23 April 2015 the following information to MHLW/PMDA, 24 March 2015 (www.hc-sc.gc.ca) the Precautions for (www.pmda.go.jp/english/) “Indications” section in

(See WHO Pharmaceuticals package insert: Newsletter No.5, 2012 for risk Prior to initiation of treatment, of necrotising fasciitis in the assess the RAS (KRAS and Panitumumab UK) NRAS) gene mutation status and select the suitable Risk of patients. oculomucocutaneous syndrome (Stevens– Reference: Johnson syndrome) Panitumumab and Revision of Precautions, MHLW/PMDA, 8 April 2015 Japan. The MHLW and the cetuximab (www.pmda.go.jp/english/) PMDA have announced the Necessity of assess the (See WHO Pharmaceuticals revision of the package insert RAS (KRAS and NRAS) Newsletters No.5, 2013 for for panitumumab (Vectibix®) importance of establishing to include information on gene mutation status and select the suitable wildtype RAS (KRAS and NRAS) oculomucocutaneous status before treatment of patients syndrome. metastatic colorectal cancer Panitumumab is indicated for Japan. The MHLW and the with panitumumab in the UK KRAS wild-type, incurable, PMDA have announced the and No.2, 2014 Importance of unresectable, revisions of the package establishing wild type RAS advanced/recurrent colorectal inserts for panitumumab (KRAS and NRAS) status cancer. (Vectibix®) and cetuximab before treatment of metastatic (Erbitux®) to include the need colorectal cancer with The MHLW/PMDA stated that cetuximab in the UK) cases of adverse events to assess RAS gene mutation suggestive of status. oculomucocutaneous syndrome Panitumumab is indicated for (Stevens–Johnson syndrome) KRAS wild-type, incurable, have been reported in patients unresectable, treated with panitumumab in advanced/recurrent colorectal WHO Pharmaceuticals Newsletter No. 3, 2015  13

Regulatory Matters

Pazopanib Pomalidomide ILD occurred approximately 18 months after starting hydrochloride Risks of cardiac failure, pomalidomide. ILD usually interstitial lung disease resolves with steroid treatment Risk of retinal and stopping pomalidomide. detachment and hepatotoxicity The MHRA has advised that UK. The MHRA has informed Japan. The MHLW and the when using pomalidomide: health-care professionals of PMDA have announced the  in patients with cardiac new monitoring instructions to revision of the package insert disease or cardiac risk detect signs/symptoms of for pazopanib hydrochloride factors, use with caution cardiac failure, interstitial lung (Votrient®) to include risk of and if used, monitor for disease (ILD) and retinal detachment. signs or symptoms of hepatotoxicity with use of cardiac failure Pazopanib hydrochloride is pomalidomide.  carefully assess patients indicated for soft tissue with any acute onset or Pomalidomide in combination sarcoma and radically unexplained worsening of with dexamethasone is unresectable or metastatic respiratory symptoms to licensed to treat adults with renal cell carcinoma. relapsed and refractory confirm or exclude ILD; The MHLW/PMDA stated that multiple myeloma who have stop pomalidomide cases of adverse events received at least two treatment during assessment suggestive of retinal treatments, including if ILD is confirmed, treat detachment have been lenalidomide and bortezomib,  appropriately and only reported in patients treated and whose disease has resume pomalidomide with pazopanib hydrochloride worsened since the last in Japan and other countries, treatment. treatment after thoroughly and the MHLW/PMDA also evaluating the benefits and A review by the MHRA and stated that the CCDS for risks other EU medicine regulators pazopanib hydrochloride has  regularly monitor liver concluded that pomalidomide been revised to include function for the first 6 can cause ILD, cardiac failure information on retinal months of pomalidomide and hepatotoxicity. This detachment. treatment and as clinically conclusion was based on data indicated thereafter Based on expert advice and from clinical trials, reports available evidence, the from clinical practice and Reference: MHLW/PMDA have published case reports. Drug Safety Update, MHRA, recommended the addition of Volume 8, issue 10: 2, May The risk of serious hepatic the following texts to the 2015 (www.gov.uk/mhra) events appears to be highest “Clinically significant adverse in the first 6 months of reactions” subsection of the treatment, therefore regular “Adverse reactions” section in liver function monitoring is package insert. recommended during this Rebamipide Retinal detachment: period. (Ophthalmic solution) Retinal detachment may occur. In most cases, cardiovascular Patients should be carefully effects occurred in patients Risk of lacrimal duct monitored. If any with cardiac disease or cardiac obstruction and abnormalities such as muscae risk factors and within 6 dacryocystitis volitantes, photopsia, visual months of starting field defect and reduced visual pomalidomide. The review also Japan. The MHLW and the acuity are observed, concluded that pomalidomide PMDA have announced the ophthalmologic examination can cause atrial fibrillation, revision of the package insert should be performed and which may precipitate cardiac for rebamipide ophthalmic appropriate measures such as failure. solution (Mucosta Ophthalmic discontinuation of Suspension UD®) to include administration should be Pomalidomide can cause ILD risk of lacrimal duct taken. and related events such as obstruction and dacryocystitis. pneumonitis. The review Reference: concluded that this side effect Rebamipide ophthalmic Revision of Precautions, is common. Onset of solution is indicated for dry MHLW/PMDA, 24 March 2015 respiratory symptoms is eyes. (www.pmda.go.jp/english/) usually within 6 months of The MHLW/PMDA stated that starting treatment. However, cases of adverse events there have been cases where suggestive of lacrimal duct WHO Pharmaceuticals Newsletter No. 3, 2015  14

Regulatory Matters obstruction or dacryocystitis Health Canada initiated a Sitagliptin phosphate have been reported in patients safety review to evaluate the treated with rebamipide possible link between a severe hydrate ophthalmic solution in Japan. lowering of the heart rate (a medical condition known as Risk of Based on expert advice and severe bradycardia) and the thrombocytopenia available evidence, the use of the general anaesthetic MHLW/PMDA have sevoflurane in children with Japan. The MHLW and the recommended the addition of Down syndrome. This issue PMDA have announced the the following texts to the was identified by Health revision of the package insert “Clinically significant adverse Canada during routine review for sitagliptin phosphate reactions” subsection of the of safety information provided hydrate (Glactiv® and “Adverse reactions” section in by the manufacturer. Januvia®) to include risk of package insert. thrombocytopenia. At the time of the review, Lacrimal duct obstruction and Health Canada had not Sitagliptin phosphate hydrate dacryocystitis: received any reports of is indicated for type 2 diabetes Lacrimal duct obstruction sevoflurane-associated mellitus. and/or dacryocystitis may bradycardia in children with occur. Patients should be The MHLW/PMDA stated that Down syndrome. International carefully monitored through cases of adverse events of reports of severe bradycardia ophthalmologic examination thrombocytopenia have been in children with Down etc. If any abnormalities are reported in patients treated syndrome suspected to be observed, administration of with sitagliptin phosphate associated with sevoflurane this drug should be hydrate in Japan. use were provided by the discontinued and appropriate company that first marketed Based on expert advice and measures should be taken. sevoflurane. available evidence, the White matters may be MHLW/PMDA have observed in lacrimal passage A review of the scientific and recommended the addition of of patients with lacrimal duct medical literature identified a the following texts to the obstruction and/or number of relevant research “Clinically significant adverse dacryocystitis. articles. Although reports are reactions” subsection of the limted in numbers and quality Reference: “Adverse reactions” section in the literature highlighted the Revision of Precautions, package insert. possibility of sevoflurane- MHLW/PMDA, 24 March 2015 induced bradycardia in children Thrombocytopenia: (www.pmda.go.jp/english/) with Down syndrome. Thrombocytopenia may occur. Patients should be carefully Health Canada advised that monitored. If any the risk of bradycardia abnormalities are observed, (slowing of the heart rate) with Sevoflurane administration of this drug sevoflurane should be should be discontinued and considered for all children. The Severe low heart rate in appropriate measures should existing prescribing be taken. children with Down information for sevoflurane syndrome mentions the risk of Reference: bradycardia in healthy children Revision of Precautions, Canada. Health Canada and in children with MHLW/PMDA, 24 March 2015 announced that the Canadian neuromuscular problems. This (www.pmda.go.jp/english/) prescribing information for will be updated to mention the sevoflurane (Sevorane AF®) occurrence of cases of has been updated to highlight bradycardia in children with the occurrence of cases of Down syndrome. bradycardia in paediatric Triamcinolone patients with Down syndrome. Reference: Manufacturers of generic Summary Safety Review, acetonide Health Canada, 13 May 2015 versions of this drug are in the Risk of tendon rupture process of updating their (www.hc-sc.gc.ca) product information. Japan. The MHLW and the Sevoflurane is used as a PMDA have announced the general anaesthetic during revision of the package insert surgery to make a patient for triamcinolone acetonide unconscious and unable to feel injection (Kenacort-A®) to pain. include risk of tendon rupture.

WHO Pharmaceuticals Newsletter No. 3, 2015  15

Regulatory Matters

Triamcinolone acetonide is used for various treatments including chronic adrenocortical insufficiency, rheumatoid arthritis, lupus erythematosus, nephrosis and nephrotic syndrome, congestive cardiac failure, cirrhosis, encephalomyelitis, malignant lymphoma, acute/chronic otitis media, and allergic rhinitis. The MHLW/PMDA stated that cases of adverse events suggestive of tendon rupture have been reported in patients treated with triamcinolone acetonide in Japan.

Based on expert advice and available evidence, the MHLW/PMDA have recommended the addition of the following to the “Clinically significant adverse reactions” subsection of the “Adverse reactions” section in package insert.

Tendon rupture: Tendon rupture may occur when this drug is injected into the tendon repeatedly. Patients should be carefully monitored. If any abnormalities are observed, appropriate measures such as discontinuation of administration should be taken. Reference: Revision of Precautions, MHLW/PMDA, 24 March 2015 (www.pmda.go.jp/english/)

WHO Pharmaceuticals Newsletter No. 3, 2015  16

Safety of Medicines

Capecitabine and therapy may potentiate the growth of bacteria that can pharmacologic effects of 5- cause illness. folic acid fluorouracil (5-FU). The FDA evaluated seven  A lower dosage of 5-FU or reported cases of medication Risk of enhancement of the pro-drug may be errors that occurred during toxicity of capecitabine required. preparation of the dose in the  Patients should be pharmacy due to confusion Egypt. The EPVC has monitored closely for with the display of the strength publicised a report concerning potential toxicities of 5-FU of individual ingredients on the the risk of enhanced such as neutropenia, product vial labels and carton capecitabine toxicity when thrombocytopenia, labelling. Listing the individual taken with folic acid. stomatitis, gastrointestinal drug strengths led to confusion haemorrhage, severe Capecitabine (Xeloda®) is a because it was different from diarrhoea, vomiting, fluoropyrimidine carbamate labelling for other drugs in the cutaneous reactions, and and a pro-drug of 5’-deoxy-5- beta-lactam/beta-lactamase neuropathy. fluorouridine (5’ DFUR). It is class that express strength as  Patients should be administered orally and is the sum of the two active instructed to avoid taking converted to 5-fluorouracil. It ingredients. In some cases, folic acid supplementation has antineoplastic activity and this led to administration of or multivitamin is used for colon, colorectal 50% more drug than was preparations containing folic and gastric cancer, either as a prescribed. No adverse events acid without first speaking single agent (monotherapy) or were reported among these with their physician. in combination therapy. seven cases.  Caution should be taken Centrum® is a multivitamin when receiving tablets Reference: and mineral supplement. It is containing multivitamins Drug Safety Communication, used to provide extra vitamins with chemotherapy. US FDA, 20 May 2015 and minerals that are not (www.fda.gov) taken in through the diet. Reference: Multivitamins and minerals are Newsletter, Egyptian also used to treat vitamin or Pharmaceutical Vigilance mineral deficiencies caused by Center (EPVC), Volume 6, illness, pregnancy, poor Issue 5, May 2015 Ceftriaxone and nutrition, digestive disorders, calcium containing certain medications, and many other conditions. One of its diluents components is folic acid. Ceftolozane and Drug-drug interaction According to the capecitabine tazobactam Summary of Product Egypt. The EPVC has Dose confusion and Characteristics (SmPC), under reminded health-care section “4.5 Interaction with medication errors professionals of a well-known other medicinal products and interaction that occurs USA. The FDA has issued a other forms of interaction”: between (ceftriaxone sodium) warning to health-care folinic acid has no major effect for injection and calcium- professionals regarding the risk on the pharmacokinetics of containing IV solutions. of dosing errors with the capecitabine and its antibacterial drug Zerbaxa® metabolites. However, folinic Ceftriaxone injection (ceftolozane and tazobactam) acid has an effect on the (cephalosporin antibiotic) is due to confusion about the pharmacodynamics of used to treat certain infections drug strength displayed on the capecitabine. The toxicity of caused by bacteria such as vial and carton labelling. capecitabine may be enhanced gonorrhoea, pelvic inflammatory disease, by folinic acid. This may also The Combination of meningitis and infection of the be relevant with folic acid ceftolozane and tazobactam is lungs, ears, skin, urinary tract, supplementation for folate used to treat complicated bones, blood, joints and deficiency due to the similarity infections in the urinary tract, abdomen. between folinic acid and folic or in combination with the acid. antibacterial drug A small number of cases with metronidazole to treat THE EPVC has recommended fatal outcomes have been complicated infections in the for health-care professionals reported. Cases of crystalline abdomen. Antibacterial drugs that: material observed in the lungs work by killing or stopping the  The co-administration of and kidneys at autopsy have capecitabine with folate been reported in neonates WHO Pharmaceuticals Newsletter No. 3, 2015  17

Safety of Medicines receiving ceftriaxone and studies using adult and  WBC and differential blood calcium-containing fluids. In neonatal plasma from counts must be performed some of these cases, the same umbilical cord blood within 10 days prior to intravenous infusion line was demonstrated that neonates initiating clozapine used for both ceftriaxone and have an increased risk of treatment, weekly after calcium-containing fluids and a precipitation of ceftriaxone- initiation for the first precipitate was observed in the calcium. 18 weeks and then at least intravenous infusion line. at four week intervals Reference: thereafter. Only patients There is a theoretical Newsletter, Egyptian with normal WBC counts possibility for an interaction Pharmaceutical Vigilance and Absolute Neutrophil between ceftriaxone and IV Center (EPVC), Volume 6, Count (ANC) (WBC calcium-containing solutions in Issue 5, May 2015 ≥3500/mm3 and patients other than neonates ANC≥2000mm3) should (i.e. adults), although this has receive the drug. not been reported.  It is mandatory, at any time Prescribing information advises Clozapine with during clozapine treatment that ceftriaxone and IV another to discontinue treatment if calcium-containing solutions WBC<3000 (3x109) and should not be mixed or co- antipsychotic drugs ANC<1500 (1.5x109). If administered to any patient this occurs blood levels Risk of eosinophilia, irrespective of age, even via should be monitored daily different infusion lines at hypo-chromia, until haematological different sites. In addition they leucocytosis and abnormality is resolved, should not be administered erythro-cytosis and patient should be within 48 hours of each other. monitored for infection, Egypt. The EPVC has received without re-exposure. The EPVC recommendations to nine reports of eosinophilia,  In general, clozapine should health-care professionals hypo-chromia, leuco-cytosis not be used in combination include: and erythro-cytosis in patients with other antipsychotics.  Diluents containing calcium, with long term exposure to  Treatment must be such as Ringer’s solution or clozapine in combination with discontinued immediately in Hartmann’s solution should another antipsychotic. The the event of neutropenia or not be used to reconstitute patients varied in age and agranulocytosis. ceftriaxone vials or to gender. Patients also further dilute a presented with chronic Reference: reconstituted vial for IV inflammation and sore throat Newsletter, Egyptian administration because a and recovered after Pharmaceutical Vigilance precipitate can form. administration of an anti– Center (EPVC), Volume 6,  Precipitation of ceftriaxone- inflammatory drug. Issue 5, May 2015 calcium can also occur

when ceftriaxone is mixed Clozapine is an antipsychotic with calcium-containing drug with a broad range of solutions in the same IV antipsychotic activity. administration line. Clozapine has a low affinity for Dimethyl fumarate D2 receptor is not associated Ceftriaxone must not be Fatal PML in an MS administered with extrapyramidal adverse patient with severe, simultaneously with effects. However, due to a risk calcium-containing IV of agranulocytosis, the prolonged lymphopenia solutions, including therapeutic indication is UK. The MHRA has instructed continuous calcium- restricted to schizophrenic that full blood counts should be containing infusions such as patients resistant or intolerant taken prior to prescribing parenteral nutrition via a Y- to other antipsychotics. dimethyl fumarate, and every site. The EPVC has recommended 6 to 12 months after initiation.  However, in patients other that: If progressive multifocal than neonates, ceftriaxone  Clozapine should be limited leukoencephalopathy (PML) is and calcium-containing to schizophrenic patients suspected, treatment should solutions may be who are non-responsive or be stopped immediately. administered sequentially of intolerant to antipsychotic one another if the infusion medication with psychosis Dimethyl fumarate is licensed lines are thoroughly flushed in Parkinson's disease when to treat relapsing remitting between infusions with a other treatment strategies multiple sclerosis in adults. compatible fluid. In vitro have failed. Clinical trials have shown

WHO Pharmaceuticals Newsletter No. 3, 2015  18

Safety of Medicines dimethyl fumarate can cause features to multiple gabapentin, lidocaine, or severe lymphopenia, with a sclerosis because PML prilocaine. decrease of lymphocyte counts is also a demyelinating The FDA recommends that by approximately 30% from disease. people who use topical baseline values. Medicines The licence-holder is working medications containing containing dimethyl fumarate with the European Medicines flurbiprofen should use with and other fumaric acid esters Agency to evaluate the care when applying them in a are not licensed in the UK for evidence for the risk of PML household with pets, as even use in psoriasis. However, the and to consider changes to the very small amounts could be MHRA is aware that these prescribing information. dangerous to these animals. medicines are sometimes Health-care providers who imported as ‘specials’. If Reference: prescribe topical pain considering such use, Drug Safety Update, MHRA, medications containing prescribers should be aware of Volume 8, issue 8: 1, March flurbiprofen, and pharmacists the risks of severe, prolonged 2015 (www.gov.uk/mhra) who fill these prescriptions, lymphopenia and serious should advise patients with opportunistic infections. (See WHO Pharmaceuticals Newsletter No.1, 2015 for Case pets to take care to prevent The MHRA has the following of progressive multifocal exposure of the pet to the advice for health-care leukoencephalopathy with the medication. professionals: use of dimethyl fumarate Reference:  Before prescribing dimethyl reported in the US) Drug Safety Communication, fumarate: US FDA, 17 April 2015 ○ ensure that the full (www.fda.gov) blood count (including lymphocytes) has been checked - note that Flurbiprofen- dimethyl fumarate has containing topical not been studied in Goldenseal patients with pre- pain medications existing lymphopenia (Hydrastis canadensis) or in combination with Illnesses and deaths in Potential herb-drug other pets exposed to immunosuppressive prescription topical pain interaction medicines. medication Canada. Health Canada has ○ explain the risk of initiated a safety review to lymphopenia and USA. The FDA has alerted pet evaluate available information potential risk of PML to owners, veterinarians, health- regarding the potential risk of patients and carers. care providers and pharmacists herb-drug interactions  During dimethyl fumarate that pets are at risk of illness associated with the herbal treatment: and death when exposed to ingredient goldenseal. This ○ monitor patients - topical pain medications review was prompted by an check full blood counts, containing the NSAID article published by the New including lymphocytes, flurbiprofen. Zealand Medicines and Medical every 6 to 12 months The FDA received reports of Devices Safety Authority or more frequently if cats in two households that (MedSafe). This article clinically indicated. became ill or died after their mentioned goldenseal, among ○ monitor patients with owners used topical other herbal ingredients and lymphopenia closely medications containing food products, as having a for features of PML flurbiprofen on themselves to potential risk for interaction (e.g. signs and treat muscle, joint, or other with certain medications symptoms of pain. The pet owners had (through certain cytochrome neurological applied the cream or lotion to P450 enzymes). dysfunction) and other their own neck or feet, and not opportunistic Goldenseal-containing oral directly to the pet. It is not infections. health products are known exactly how the cats ○ stop dimethyl fumarate traditionally used in herbal were exposed to the treatment immediately medicine for aiding or medication. The products and investigate alleviating a variety of contained the NSAID appropriately if you digestive problems such as flurbiprofen and the muscle suspect PML. indigestion or heartburn, relaxer cyclobenzaprine, as ○ consider that PML can infectious and inflammatory well as other varying active present with similar conditions of the digestive ingredients, including baclofen, WHO Pharmaceuticals Newsletter No. 3, 2015  19

Safety of Medicines tract such as inflammation of of related adverse reactions 7 April 2015 the lining of the stomach with goldenseal. (www.medsafe.govt.nz/) (gastritis), or to increase Reference: appetite in Canada. Health Summary Safety Review, Canada has licensed several Health Canada, 30 April 2015 hundred natural health (www.hc-sc.gc.ca) products (NHPs) that have Hydroxyzine goldenseal listed as a Risk of QT interval medicinal ingredient. prolongation and The current available evidence Torsade de Pointes suggests that use of oral Guaifenesin goldenseal may contribute to UK. The MHRA has issued a Reports of tinnitus herb-drug interactions, but the warning not to prescribe data is limited and no domestic NZ. The Medsafe has informed hydroxyzine to people with a or international cases of health-care professionals of prolonged QT interval or risk goldenseal-drug interactions recent reports of tinnitus factors for QT interval are known to Health Canada. associated with the use of prolongation, and has decreased the maximum adult Some published studies have guaifenesin, received at the daily dose of hydroxyzine to shown that goldenseal can Centre of Adverse Reactions 100 mg. slow down the activity of Monitoring (CARM). It was certain enzymes referred to as reported that the patient was Hydroxyzine is an "cytochrome P450 enzymes" taking guaifenesin 600 mg for antihistamine used to treat mainly in the liver. These an upper respiratory tract anxiety in adults, and pruritus enzymes are responsible for infection and experienced in adults and children. processing and eliminating profound tinnitus followed by many substances that are deafness in the right ear with The MHRA has informed orally ingested, including facial and outer ear numbness. health-care professionals, medications (e.g. certain In a second report, a patient when using hydroxyzine: antidepressant drugs). In who was using guaifenesin for  not to prescribe some cases, these enzymes a different indication hydroxyzine to people with convert medications from their experienced hearing loss in the a prolonged QT interval or inactive form to an activate right ear after the guaifenesin who have risk factors for QT form in the body. dose was increased to 600 mg interval prolongation. twice daily. There are no  to avoid use in the elderly - By slowing the activity of these reports of tinnitus, deafness or they are more susceptible enzymes, certain medications numbness with use of than younger patients to could remain in the body for guaifenesin in the literature. the side effects of longer than normal, potentially hydroxyzine. reaching toxic levels. Health Guaifenesin can be an OTC  to consider the risks of QT Canada has identified that expectorant used for the interval prolongation and many other factors can also symptomatic relief of Torsade de Pointes before affect the potential for any productive (chesty) coughs. prescribing to patients herb-drug interaction, Expectorants help to loosen taking medicines that lower including genetics, age and phlegm and thin the mucus in heart rate or potassium health status as well as the the lungs. Guaifenesin is levels. type, dose, timing and available as a single-ingredient  to be aware that the composition of health products product or with other active maximum daily dose is being used together. ingredients for the treatment now: of cough and cold symptoms. ○ 100 mg for adults At this time, Health Canada Tinnitus can be described as ○ 50 mg for the elderly continues to monitor adverse ringing in the ears. Tinnitus is (if use cannot be reaction information for oral not listed as an adverse event avoided) goldenseal-containing health in the guaifenesin (Mucinex®) ○ 2 mg per kg body products, as it does for all data sheet or in the product weight for children up health products, to identify and packaging. to 40 kg in weight assess potential harms. The overall benefit-risk balance  to prescribe the lowest Health Canada published an of guaifenesin remains effective dose for as short a article in the April 2015 issue positive. time as possible. of the Health Product A European review of the InfoWatch to raise awareness Reference: safety and efficacy of and to encourage the reporting Safety Information, Medsafe, hydroxyzine was conducted following concerns of heart WHO Pharmaceuticals Newsletter No. 3, 2015  20

Safety of Medicines rhythm abnormalities reviewed, the FDA is not associated with this medicine. recommending any changes to

The review concluded that the current prescribing or use hydroxyzine is associated with of olanzapine pamoate a small risk of QT interval injection at this time. Patients prolongation and Torsade de should not stop receiving Pointes. Such events are most treatment without first talking likely to occur in patients who to their health-care already have risk factors for professionals. QT prolongation, such as: Olanzapine pamoate may be  concomitant use of used for the treatment of medicines that prolong the schizophrenia symptoms, QT interval which include hearing voices,  cardiovascular disease seeing things that are not  family history of sudden there, and being suspicious or cardiac death withdrawn.  significant electrolyte imbalance (low potassium The FDA informed that Health- or magnesium levels) care professionals should  significant bradycardia. continue to follow the Zyprexa Relprevv® Patient Care Reference: Program Risk Evaluation and Drug Safety Update, MHRA, Mitigation Strategy (REMS) Volume 8, issue 9: 1, April requirements and current label 2015 (www.gov.uk/mhra) recommendations. Notable (See WHO Pharmaceuticals requirements of the REMS Newsletter No.3, 2014 for include: review started on the side  For a patient to receive effects of hydroxyzine- treatment, the prescriber, containing medicines on the health-care facility, patient, heart in Europe) and pharmacy must all be enrolled in the Zyprexa

Relprevv® Patient Care Program.  olanzapine pamoate Olanzapine pamoate injections must be administered at a REMS- Deaths associated with certified health-care facility the injectable with ready access to schizophrenia drug emergency response services. USA. The FDA has announced  Patients must be the outcome of an continuously monitored at investigation into two deaths the REMS-certified health- following injection of long care facility for at least acting olanzapine pamoate 3 hours following an (Zyprexa Relprevv®). intramuscular injection. A study to determine the cause  Patients receiving of elevated levels of the olanzapine pamoate must injectable schizophrenia drug be accompanied to their olanzapine pamoate in two destination from the health- patients who died was care facility. conducted. The study results Reference: were inconclusive. The Drug Safety Communication, possibility that the deaths were US FDA, 23 March 2015 caused by rapid, but delayed, (www.fda.gov) entry of the drug into the bloodstream following (See WHO Pharmaceuticals intramuscular injection could Newsletter No.4, 2013 for not be excluded. However the investigating two deaths drug level increase could have following injection of occurred after death.. On the olanzapine pamoate in the US) basis of all of the information WHO Pharmaceuticals Newsletter No. 3, 2015  21

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 Individual Case Safety Reports (ICSRs) available in the WHO Global ICSR database, VigiBase®. The database contains over 10 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. More information regarding the ICSRs, their limitations and proper use, is provided in the UMC Caveat document available at the end of Signal (page 34). 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. UMC’s vision is to improve worldwide patient safety and welfare by reducing the risk of medicines. 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].

Prucalopride and Suicidal ideation Mr Alessio Gasparotto and Dr Rebecca E Chandler, Uppsala Monitoring Centre

Summary symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate Suicidal ideation has been identified in association relief.1,2 with the gastrointestinal prokinetic agent, prucalopride, as a potential signal from the WHO Serotonin or 5-hydroxytryptamine (5-HT) acts as a Global Individual Case Safety Report database, neurotransmitter and paracrine agent that VigiBase®. Prucalopride is the third 5-HT4 receptor mediates a wide variety of functions, including agonist licensed as a prokinetic agent but its cognitive and emotional processes, regulation of highly selective nature represents an advantage sleep and food intake, as well as cardiovascular over the previously licensed products cisapride and and gastrointestinal mechanisms. To date 14 tegaserod which have both been withdrawn due to different 5-HT receptors, classified into seven adverse cardiac effects. While the total number of subclasses, have been identified.3 case reports for suicidal ideation and prucalopride Prucalopride is a dihydro-benzofurancarboxamide is small, there is evidence of psychiatric events, derivative which is highly selective and has high specifically anxiety, confusional state, and affinity for serotoninergic 5-HT receptors. 5-HT depression, from clinical trial data as well as a 4 4 receptors are located both in the central nervous notable number of reports of suicidal ideation for system (CNS) and in the peripheral tissues, tegaserod. Of potential concern is the specifically the gastrointestinal tract. Activation of inconsistency in the labelling for CNS events 5-HT in the gastrointestinal tract promotes between the EU and Canada, the two regions in 4 gastrointestinal motility and mucosal secretion. which prucalopride has been approved. The Experimental models both in vitro and in vivo have potential for psychiatric adverse events should be demonstrated that prucalopride facilitates acknowledged in the EU as has been done in gastrointestinal motility by promoting longitudinal Canada. Furthermore, with the identification of smooth muscle contractility while suppressing the these case reports of suicidal ideation, a possible resistance to propulsion due to circular smooth recommendation would be for increased muscle contraction.4 surveillance for such events related to suicide. Additionally, the potential for a relationship The highly selective nature of prucalopride for the between adverse events with prucalopride and 5-HT4 receptor represents an advantage over certain 5-HT4 polymorphisms should be explored. previous prokinetic non-selective 5-HT4 agonists, such as cisapride and tegaserod. Both of these Introduction agents have appreciable affinity for other Prucalopride was licensed for use by the European receptors, channels or transporters [e.g. cisapride: Medicines Agency in July 2009 and in Canada in human ether-a-go-go-related gene (hERG)/K+ December 2011 with an indication for use in the channel and tegaserod: 5-HT1D and 5-HT2B WHO Pharmaceuticals Newsletter No. 3, 2015  22

Signal receptors] which resulted in adverse event profiles database, VigiBase® as of December 2014 which (QT prolongation and cardiovascular ischemic reported suicidal ideation in association with events, respectively) which limited their clinical prucalopride. success.5-7 The four case reports were submitted from three The European Summary of Product Characteristics countries: Germany, the United Kingdom, and (SmPC) for prucalopride notes the most commonly Italy. All case reports were received from health- occurring events to be headache, nausea, care professionals. One of the reports was diarrhoea, abdominal pain. Other commonly determined to be a duplicate. Two of the reports occurring events were dizziness, fatigue, described events occurring in females, ages 44 pollakiuria, vomiting, dyspepsia, rectal and 61; one report described events occurring in a haemorrhage, flatulence, and abnormal bowel male whose age was not reported. Time to onset sounds. Uncommon events included palpitations, was reported in all cases and ranged from “hours anorexia, and tremors.8 The labelling for Health after the first dose” to 16 days after initiation of Canada in contrast notes the following events from prucalopride. Prucalopride was withdrawn and the the Psychiatric disorders SOC: anxiety, confusional outcome was reported as recovered in all of the state, and depression.9 cases. Suicidal ideation is defined as thoughts about self- One of the reported cases was the subject of a harm, with deliberate consideration or planning of published case report.14 It describes a 61 year old possible techniques of causing one’s own death.10 female who was in reportedly good health and not Suicidal ideation is more common than suicide taking any other medications. She was initiated on attempts or completed suicide.11 A 1995 study prucalopride 2 mg per day for the treatment of found that 3.3 percent of patients in an urban chronic constipation. Within a few hours after oral primary care outpatient clinic reported suicidal administration, she experienced suicidal ideation, ideation.12 Risk factors for suicidal behaviours visual hallucinations, disorientation, and a loss of include female gender, younger age, fewer years balance and memory. The drug was withdrawn of education, unmarried status and the presence and symptoms resolved within 24 hours. She had of a mental disorder, with psychiatric comorbidity never previously experienced similar symptoms. significantly increasing risk.13 In addition, some There were an additional 27 case reports of suicide prescription drugs, such as selective serotonin re- ideation with another 5-HT agonist, tegaserod. uptake inhibitors, can have suicidal ideation as a 4 There were a total of 24 cases from the USA, two side effect. from Canada, and one from Mexico. Several of the 27 cases report depression and are complicated by the use of multiple concomitant medications. Reports in VigiBase® However, five of these reports document a positive There were a total of four case reports in the WHO dechallenge. Global Individual Case Safety Report (ICSR)

Table 1. Characteristics of reports for prucalopride and suicidal ideation in VigiBase®

Case Age/ Medical Suspected (S) or Time to Indication Dechallenge/ ADR terms (WHO- Outcome Sex history concomitant drugs (C) onset Rechallenge ART)

1 -/M Not provided Prucalopride (S) 3-4 days Chronic Withdrawn Suicidal ideation, Recovered Beta blocking agents (C) constipation off-label use

2 44/F Not provided Prucalopride (S) 16 days Constipation Positive Suicidal ideation, Recovered Paracetamol, mebeverine, dechallenge thoughts of self harm, tramadol, fluocinonide, depression levothyroxine, omeprazole, propantheline, pregabalin, morphine, hyoscine (all C)

3 61/F None Prucalopride (S) Hours after Chronic Positive Suicidal ideation, Recovered Brotizolam (C) first dose constipation dechallenge balance difficulty, with sequelae prostration, hallucination visual, amnesia, disorientation

WHO Pharmaceuticals Newsletter No. 3, 2015  23

Signal

Literature and Labelling these studies, depression was elicited at a higher incidence than anxiety (3.5% versus 1.9%) with Three 5-HT receptor agonists have been variously 4 the 2 mg dose.”2 approved for use as prokinetic agents. The first approved agent was cisapride which has The 5-HT4 receptor (5-HT4-R) is located both in subsequently been removed from both the US and the CNS and in the peripheral tissues. In the EU markets secondary to cardiovascular events, human brain, 5-HT4-Rs have been localized in the specifically QT-prolongation. basal ganglia, the hippocampal formation and the cortical mantle.3 It could be hypothesized that A second agent, tegaserod, was initially licensed in prucalopride, acting upon the 5-HT receptors in the US for the treatment of irritable bowel 4 the basal ganglia could lead to a syndrome of syndrome, but an observed increased risk in dysphoria and suicidal ideation, as substantia myocardial infarctions and strokes led to its nigra hyperactivity has been implicated in withdrawal five years after approval. Tegaserod schizophrenia.11 Also, available evidence for was never approved for use in the EU. In the another serotonin receptor agonist, refusal assessment report from the EMA’s metoclopromide, suggest that different Committee for Human Medicinal Products (CHMP), polymorphisms in 5-HT receptor HTR4 genes are it is noted that findings in mice safety 4 associated with adverse events and clinical pharmacology studies suggest certain CNS related effectiveness. There is the potential that only effects, such as increased activity, abnormal gait, patients with certain genetic variations in the 5- and hypothermia at doses 10 to 100-fold higher HT receptor are susceptible to neuropsychiatric than therapeutically relevant. Furthermore, it is 4 side effects.16 reported that 2.1% of all tegaserod subjects reported adverse events in the Psychiatric disorders SOC (compared to 1.6% in placebo Discussion and Conclusion subjects). There were a total of six deaths in subjects taking tegaserod during clinical The signal for a possible association between development, two of which were reported as prucalopride and suicidal ideation is based upon suicide (12,032 total subjects in the safety only three cases. It is notable that in none of the database received tegaserod); no deaths were felt cases are there any past histories of depression or by the investigator to be related to study drug. concomitant medication use implying a history of CNS/psychiatric events were considered to be an psychiatric disorders. Furthermore, the time to outstanding safety issue.15 onset is relatively short for two of the cases, within hours to days. All cases had documentation Prucalopride is the third 5-HT receptor agonist. It 4 of resolution of symptoms after drug withdrawal. has not been approved for licensure in the US; however, it was approved for use in chronic The highly selective nature of prucalopride has constipation in the EU in 2009 and in Canada in been the focal point of the development of this 2011. In the Committee for Medicinal Products for agent given the limitations of its predecessors. To Human Use approval assessment report, it is this end, multiple preclinical investigations into the noted that in single dose toxicity studies cardiac effects have been completed and showed a performed on mice that there were CNS effects lack of interaction with the hERG potassium seen “at very high doses” However, there was no channel and 5-HT1D and 5-HT2B receptors. Both discussion in the report regarding events from the approval reports from the EU and Canada Psychiatric disorders SOC. There were two deaths thoroughly described this data. However, there is in the double-blind placebo controlled trials and an inconsistency in the presentation of data four deaths in open-label studies. The report notes regarding potential psychiatric effects between the only that none of the deaths were considered EU and the Canadian reports. As a result, there is related to treatment by the investigator. Neither no labelling for such events in the EU SmPC (or suicidal ideation nor other CNS events are included inclusion of these events into the Risk in the risk management plan for prucalopride.1 In Management Plan) but the inclusion of the events contrast, the Summary Basis of Decision for Health of anxiety, confusional state, and depression in the Canada notes that prucalopride: “…may act on Canadian label. receptors in the brain having the following 5- It is clear that prucalopride represents therapeutic hydroxytryptamine (5-HT) receptors: 5-HT1; 5- alternative with an improved safety profile and HT2; and 5-HT3; that could be involved in anxiety that the signal for an association with suicidal and depression. It is unclear whether 5-HT4 may be related to depression and anxiety. However, ideation is weak at the current time. However, the anxiety has been reported in many clinical studies potential for psychiatric adverse events should be and some cases were reported as serious events. acknowledged in the EU as has been done in The open-label studies recorded anxiety in 1.9% Canada. Furthermore, with the identification of of the patients treated with the 2 mg dose, and these case reports of suicidal ideation, a possible similar results were found with 4 mg dose. In recommendation would be for increased

WHO Pharmaceuticals Newsletter No. 3, 2015  24

Signal surveillance for such events related to suicide. 10. American Psychiatric Association. (2013). Additionally, the potential for a relationship Diagnostic and statistical manual of mental between adverse events with prucalopride and disorders (5th ed.). Washington, DC. ISBN certain 5-HT4 polymorphisms should be explored. 978-0-89042-555-8. 11. Marzuk PM. Suicidal behavior and HIV illnesses. Int Rev Psychiatry. 1991;3:365-71. References 12. Zimmerman M, Lish JD, Lush DT, Faber NJ, 1. Approval assessment report for Resolor Plescia G, Kuzma MA. Suicidal ideation among (prucalopride). URL: http://www.ema.europa. urban medical outpatients. J Gen Intern Med. eu/docs/en_GB/docu-ment_library/EPAR_- 1995;10:573-6. _Public_assessment_report/ human/001012/WC500053997.pdf. Accessed: 13. Nock MK, Borges G, Bromet EJ, Alonso J, 4 February 2015. Angermeyer M, BeautraisA et al. Cross- national prevalence and risk factors for 2. Summary Basis of Decision for Resotran suicidal ideation, plans and attempts. Brit J (prucalopride). URL: http://www.hc-sc.gc.ca/ Psychiatr. Feb 2008;192(2):98-105. dhp-mps/prodpharma/sbd-smd/drug- med/sbd_smd_2012_resotran_141157- 14. Carovale C, Pellegrino P, Perrone V, eng.php#a334. Accessed: 10 February 2015. Antoniazzi S, Pozzi M, Nisic A et al. Neurological and psychiatric adverse events 3. Hoyer D, Clarke DE, Fozard JR, Hartig PR, with prucalopride: case report and possible Martin GR, Mylecharane EJ et al. International mechanisms. J Clin Pharm Ther. Union of Pharmacology classification of 2013;83:524-5. receptors for 5-hydroxy-tryptamine (serotonin). Pharmacol Rev. 1994;46:157- 15. Refusal assessment report for Zelnorm 203. (tegaserod). URL: http://www.ema.europa. eu/docs/en_GB/docu-ment_library/EPAR_- 4. Wong BS, Manabe N, Camilleri C. Role of _Public_assessment_report/ prucalopride, a serotonin (5-HT4) receptor human/000621/WC500058849.pdf. Accessed: agonist, for the treatment of chronic 04 February 2015. constipation. Clin Exp Gastroentrol. 2019;3:49-56. 16. Parkman HP, Mishra A, Jacobs M et al. Clinical response and side effects of 5. Mohammad S, Zhou Z, Gong Q, January CT. methoclopromide: associations with clinical, Blockage of the HERG human cardiac K+ demographic, and pharmacogenetic channel by the gastrointestinal prokinetic parameters. J Clin Gastroenterol. agent cisapride. Am J Physiol Hear Circ 2012;46:494-503. Physiol. 1997;273(5):H2534-8.

6. Wysowski DK, Corken A, Gallo-Torres H, Talarico L, Rodriguez EM. Postmarketing reports of QT prolongation and ventricular

arrhythmia in association with cisapride and FDA regulatory actions. Am J Gastroentrol. 2001;96(6):1698-703.

7. De Maeyer JH, Lefebvre RA, Schuurkes JA. 5- HT4 receptor agonists: similar but not the same. Neurogastroenterol Motil. 2008;20(2):99-112.

8. Electronic Medicines Compendium UK. Resolor (prucalopride). URL: http://www.ema.europa. eu/docs/en_GB/document_library/EPAR_- _Product_Information/ human/001012/WC500053998.pdf. Accessed: 4 February 2015. 9. Product Information for Resotran (prucalopride). URL: http://webprod5.hc- sc.gc.ca/dpd-bdpp/info. do?code=86259&lang =eng. Accessed: 4 February 2015.

WHO Pharmaceuticals Newsletter No. 3, 2015  25

Signal

Response from Shire For Shire, Anders Lindholm MD, PhD Therapeutic Area Head, Pharmacovigilance & Risk Management, Shire Suicide-related events include passive and active References thinking, planning, and finally taking action to commit suicide. Passive death thoughts are common in the general population. In a cross- 1. Nock MK; Borges, G; Bromet EJ, et al. Cross- national (17 countries) sample, Nock et al National Prevalence and Risk Factors for estimated the lifetime prevalence of suicidal Suicidal Ideation, Plans, and Attempts. Br J ideation at 9.2% (1). Psychiatry 2008;192:98-105. For prucalopride there was no signal for suicide- 2. “FDA Warns of Suicide Risk for Tramadol.” related events in the developmental clinical trials http://www.medscape.com/viewarticle/ of this product for chronic constipation. 722488 (accessed 23-Mar-15) The Shire global safety database contains the 3. “Ultram (tramadol hydrochloride), Ultracet same postmarketing reports tabulated by the (tramadol hydrochloride/acetaminophen): authors and, except for one duplicate, no other Label Change.” http:// www.fda.gov/Safety/ report of suicide-related events. MedWatch/SafetyInformation/ SafetyAlertsforHumanMedicalProducts/ucm21 In review of the three postmarketing cases in the 3264.htm (accessed 23-Mar-15) database, the first case involved a male of unknown age and was derived from sparse 4. Young Hee Shin, Myung Hee Kim, Jung Jin documentation which included no information on Lee, Soo Joo Choi, Mi Sook Gwak, Ae Ryoung medical history or concurrent disorders. The Lee, et al. The effect of midazolam dose and second case involved a 44-year old female who age on the paradoxical midazolam reaction in was concomitantly treated with tramadol, a Korean pediatric patients. Korean J medication with a known association with suicidal Anesthesiol 2013 July 65(1): 9-13 events and depression (2,3). 5. Voaklander DC, Rowe BH, Dryden DM, Pahal The third and most recent case was presented as a J, Saar P, Kelly KD. Medical illness, published case report where suicidal thoughts medication use and suicide in seniors: a were reported amongst a plethora of other events population-based case-control study. J including balance difficulty, prostration, visual Epidemiol Community Health. 2008 hallucinations, amnesia and disorientation. Feb;62(2):138-46. Interestingly, the publication failed to mention this patient’s concomitant treatment with brotizolam, a benzodiazepine. The constellation of events described is considered to be clinically compatible with a paradoxical benzodiazepine reaction given that such reactions may typically include hallucinations, inconsolable crying, agitation, restlessness, disorientation, aggressive behaviour and/other psychological phenomena (4). Additionally, benzodiazepine use has been identified in at least one published study as among a number of variables associated with suicide in older adults (5).

In summary, suicide-related events did not constitute a signal during clinical development of prucalopride. In the postmarketing review, 2 of the 3 case reports of suicidal ideation were confounded by potentially relevant concomitant medication exposures, and the third case report was poorly documented. Based on the information available at this time, Shire does not believe there is sufficient evidence to support a causal association of suicidal ideation with the use of prucalopride.

WHO Pharmaceuticals Newsletter No. 3, 2015  26

Signal

Vemurafenib and Thrombocytopenia Dr Geraldine Hill, New Zealand

Summary types of malignancy carrying the BRAF V600E mutation. Vemurafenib is a protein kinase inhibitor with activity against mutated B-RAF protein; it is used Thrombocytopenia is defined as a platelet count of in the treatment of metastatic or unresectable less than 150 x 109/L (150 000 per μL). A grading malignant melanoma that carries the BRAF V600E system for thrombocytopenia has been developed mutation. B-RAF protein acts in the RAS-RAF-MEK- by the United States National Cancer Institute in ERK intracellular signalling pathway that leads to which platelet counts between 75 x 109/L and 150 cell growth and proliferation: by targeting mutated x 109/L are classified as Grade 1, while platelet B-RAF, vemurafenib inhibits the growth of counts below 25 x 109/L are classified as Grade 4.4 melanoma cells containing the mutated B-RAF Patients with platelet counts above 20 x 109/L are gene. At the time of assessment (March 2015), usually asymptomatic, but the risk of spontaneous The WHO Global Individual Case Safety Report mucocutaneous bleeding (gingival bleed, epistaxis, (ICSR) database, VigiBase® contains 28 ICSRs in menorrhagia, petechiae and ecchymoses) and life- which vemurafenib is associated with threatening, spontaneous intracranial hemorrhage thrombocytopenia (after exclusion of two or gastrointestinal bleeding increases rapidly with duplicates). One case provides information that platelet counts below 10 x 109/L. suggests a ‘certain’ causal relationship between Thrombocytopenia in the context of metastatic vemurafenib and thrombocytopenia, four cases malignancy may result from a number of causes suggest a ‘probable’ causal relationship and a including metastatic infiltration of the bone further 14 cases can be assessed to have a marrow, sepsis, disseminated intravascular ‘possible’ causal relationship to vemurafenib. Six coagulation (DIC), radiation and drugs. Drug- cases include co-reported ADR terms that indicate induced thrombocytopenia (DIT) is associated with a more widespread myelosuppression, rather than many drugs and results from either decreased an isolated thrombocytopenia. The RAS-RAF-MEK- platelet production or increased platelet ERK intracellular signalling pathway is involved in consumption. Decreased platelet production as a the production and differentiation of consequence of generalized myelosuppression is a haematopoietic progenitor cells. It is possible that relatively common adverse effect of many thrombocytopenia associated with vemurafenib chemotherapeutic drugs, while selective may be part of a spectrum of drug induced suppression of megakaryocyte production leading myelosuppression, possibly brought about through to isolated thrombocytopenia has been associated an effect on the RAS-RAF-MEK-ERK intracellular with thiazide diuretics, alcohol and tolbutamide. signalling pathway in haematopoietic progenitor Increased platelet destruction is further cells. categorized as either immune or non-immune: drug-induced immunologic thrombocytopenia (DITP) is associated with a large number of drugs Introduction (most notably heparin) and several immunologic Vemurafenib is a serine-threonine protein kinase mechanisms have been identified. Non-immune inhibitor that inhibits the kinase activity of platelet destruction such as TTP-HUS (thrombotic mutated B-RAF protein. The RAS-RAF-MEK-ERK thrombocytopenic purpura – haemolytic uraemic mitogen activated protein kinase (MAPK) cascade syndrome) occurs less commonly, in association is an important cytoplasmic signalling pathway with a small number of anti-neoplastic agents.5 involved in the regulation of normal somatic cell proliferation. Mutations in the genes encoding components of this pathway have been associated Reports in VigiBase® with a number of human cancers.1 An activating At the time of assessment (March 2015), there mutation in the BRAF gene, which encodes the were 30 individual case safety reports (ICSRs) of serine-threonine protein kinase B-RAF, has been thrombocytopenia in association with vemurafenib found to be present in 40-60 percent of in the WHO Global ICSR database, VigiBase®. Two melanomas, most commonly the BRAF V600E duplicates were identified bringing the number of mutation.2 Vemurafenib is indicated for the assessed case reports to 28. The reports came treatment of metastatic or unresectable from melanomas that carry the BRAF V600E mutation. The recommended dose is 960 mg twice daily and 10 countries: United States (9), France (8), it is currently available in 240 mg tablets.3 Germany (4) and Austria, Colombia, Italy, Vemurafenib has also been used off-label for other Netherlands, Norway, Turkey and United Kingdom

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(1 each). Twenty-three of the ICSRs were serious Literature and Labelling and three reports were fatal. Thrombocytopenia is not listed as a possible ADR The cases concerned 9 males and 19 females. Age for vemurafenib in any of the sources that were was reported for 24 cases and ranged from 37 to checked, including the EMA6, UK Summary of 70 years (median age 56.5 years). Product Characteristics7 and the US FDA Product Label.3 Neutropenia is the only haematological The indication for treatment was reported as ADR listed in the product information. malignant melanoma in 21 cases, colorectal cancer in one case and hairy cell leukaemia in one case; in the remaining five cases, the indication for Discussion treatment was reported either as unknown (three cases) or was not stated (two cases). Vemurafenib In this series of 28 ICSRs in which vemurafenib is was the only suspected drug in 21 of the 28 cases: associated with thrombocytopenia, one case met in 14 of these cases, vemurafenib was the only the criteria for a ‘certain’ causal relationship reported drug while the other seven cases between the suspected drug and the reported ADR reported concomitant medicines. In the remaining according to the WHO-UMC System for Case seven cases, other medicines for which Causality Assessment.8 Four cases had sufficient thrombocytopenia is a known potential adverse evidence to suggest a ‘probable’ association and a effect were also suspected, including oxaliplatin, further 14 cases could be considered ‘possible’. fluorouracil, cladribine, fotemustine, rituximab, These 19 cases are summarised in Table 1. Bony aflibercept, levetiracetam, valproic acid, carvedilol, infiltration associated with metastatic malignant spironolactone, piperacillin/tazobactam and a melanoma (the indication for 21 of the 23 cases in combination medicine containing which this information was provided) should be chlorpheniramine. Two of these ICSRs also considered a risk factor for thrombocytopenia in reported co-suspected medicines that are not each of these cases. known to be associated with thrombocytopenia, including clobazam, folinic acid and Case 22 provides the strongest evidence in this caffeine/paracetemol/papaver somniferum latex. series for a causal relationship between The total daily dose of vemurafenib was reported vemurafenib and thrombocytopenia in that it has a in half of the cases and ranged from 240 mg to plausible time relationship to drug exposure, no 1920 mg (median dose 1920 mg). alternative explanation for the ADR, a positive dechallenge and a positive rechallenge. The case The time-to-onset was reported for 12 cases and concerns a 65 year old female with a history of ranged from 3 to 225 days, with a median time- end-stage renal disease, arterial hypertension and to-onset of 20 days. Vemurafenib was withdrawn a previous DVT. Thrombocytopenia and anaemia following the onset of thrombocytopenia in 12 developed 19 days after initiation of treatment cases: dechallenge was positive in eight of these with vemurafenib for melanoma, and pancytopenia cases, negative in one case and the outcome of with febrile neutropenia developed on day 22 of dechallenge was not stated in the remaining three therapy. Platelets were transfused. Vemurafenib cases. In one case the dechallenge action was was stopped for six days, during which time the reported as dose reduced but the dechallenge platelet count improved; vemurafenib was then outcome was not reported. In six cases the reintroduced at half the original dose but three dechallenge action was reported as ‘dose not days later the platelet count had again dropped, changed’: thrombocytopenia resolved in two of consistent with a positive rechallenge. these cases, no effect was observed in two cases Vemurafenib was stopped definitively and the and the effect was unknown in two cases. The platelet count returned to normal. Clinical dechallenge action was reported as unknown in investigations ruled out alternative explanations four cases, was not reported in three cases and for the thrombocytopenia. was not applicable in two cases (due to the death of the patient). In three of the cases with a Cases 2, 3, 5 and 13 could be considered to have positive dechallenge, vemurafenib was a ‘probable’ causal relationship. The time-to-onset subsequently reintroduced at a lower dose: one (TTO) for three of these cases ranged from 15-29 case reported recurrence of thrombocytopenia days; TTO was not stated for the fourth case but (positive rechallenge) while the remaining two other information provided in the report indicates cases reported no recurrence. The outcome for that the reaction occurred between 6 and 10 thrombocytopenia was reported in 19 of the cases weeks after starting vemurafenib. In each of these as follows: recovered (7), recovering (4), not four cases vemurafenib was withdrawn and the recovered (6) and died (2). For the remaining nine thrombocytopenia resolved; in Case 2, the drug cases, the outcome was reported as unknown. was subsequently restarted at a lower dose with no recurrence of the ADR. No other drugs were suspected in any of the four cases (in three cases vemurafenib was the only reported drug).

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The remaining 14 cases shown in Table 1 could be signalling pathway in melanoma cells to prevent considered to have a ‘possible’ causal relationship cell growth and proliferation. This same pathway is to vemurafenib. The time-to-onset for these 14 also present in haematopoietic progenitor cells and cases, where reported, ranged from 3 to 169 days. plays a role in haematopoietic cell Two of the cases reported co-suspected medicines differentiation,9,10 suggesting a possible known to be associated with thrombocytopenia: mechanism by which vemurafenib might cause piperacillin/ tazobactam (Case 17) and carvedilol, thrombocytopenia. Platelets (thrombocytes) are spironolactone (Case 20). The latter case also formed from megakaryocytes, which derive from reported the combination analgesic the multipotential hematopoietic stem cell (HSC). caffeine/paracetemol/papaver somniferum latex as The HSC gives rise to progressively committed suspected, but it is not known to be associated progenitor cells, including the common myeloid with thrombocytopenia. Levetiracteam, which is progenitor (CMP) and the megakaryocyte- known to be associated with thrombocytopenia, erythroid progenitor (MEP). MEPs in turn give rise was listed as a concomitant medicine in Case 11. to both megakaryocytic and erythroid cell Among these 14 cases, three cases reported lineages. Multiple transcription factors are involved evidence of a positive dechallenge (Cases 7, 12 in the differentiation of these MEPs to and 23), one of which subsequently restarted megakaryocytes, the most important of which is vemurafenib with no recurrence of thrombopoietin (TPO). Binding of TPO to the TPO thrombocytopenia (Case 23). Concurrent receptor on the MEP cell surface membrane infections including pneumonia and urinary sepsis activates the intracellular signaling protein Jak2, may have accounted for the thrombocytopenia in which in turn activates several intracellular each of these cases, and Case 23 was also signaling cascades, including the RAS-RAF-MEK- confounded by other medicines. ERK cascade.11 The remaining six cases (not shown in Table 1) Six of the cases shown in Table 1 include co- lacked sufficient evidence to suggest a causal reported ADR terms that indicate a more relationship between vemurafenib and widespread myelosuppression, rather than an thrombocytopenia. In Case 8, the patient received isolated thrombocytopenia (Cases, 5, 11, 13, 18, radiation therapy to the lumbar vertebrae one day 22 and 26). These co-reported terms are prior to starting treatment with vemurafenib and highlighted in bold in Table 1. Granulocytopenia the thrombocytopenia improved while treatment has previously been signalled for vemurafenib with vemurafenib continued; in Cases 9 and 16, (SIGNAL, issue 3, 2013) and neutropenia has the thrombocytopenia appears to have preceded since been added to the US, UK and EMA product treatment with vemurafenib, and in Cases 25, 29 information sheets, adding support to the notion and 30, the temporal relationship to other that vemurafenib may affect the RAS-RAF-MEK- medicines provides a more plausible alternative ERK cascade in haematopoietic cells. It is possible explanation for the thrombocytopenia. Causality that all of these cases in which vemurafenib is could not be assessed for the remaining three associated with depression of various blood cell cases (Cases1, 4 and 10) due to a lack of lineages may represent a spectrum of drug information in the reports. induced myelosuppression, possibly brought about through an effect on the RAS-RAF-MEK-ERK Vemurafenib acts on mutated B-RAF protein to intracellular signalling pathway in haematopoietic inhibit the RAS-RAF-MEK-ERK intracellular progenitor cells.

Table 1: Cases of interest in VigiBase® of Vemurafenib and thrombocytopenia

Case Age/ Other suspected (S) or Other reported ADRs (WHO-ART Preferred Term)* Time to onset Dechallenge/ Outcome at Sex concominant (C) drugs (Reported terms in italic- included where more informative) (days) Rechallenge time of reporting

2 58/F Zolendronic acid (C) Bilirubinaemia, rash 20 Withdrawn, Recovered reaction abated Subsequently reintroduced at a lower dose with no recurrence

3 66/M - Oedema, generalised oedema, neoplasm, musculoskeletal - Withdrawn, Recovered pain, pulmonary oedema, duodenal ulcer, GI haemorrhage reaction abated

5 51/M - Leukopenia, pancytopenia, paralysis facial 29 Withdrawn, Recovered reaction abated

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6 53/F - - < 7 Withdrawn Unknown

7 58/M - - (Pneumonia)** 46 Withdrawn, Recovering reaction abated

11 53/M Levetiracetam, Anaemia, leukopenia 43 - Died omeprazole (both C)

12 -/F - Bronchitis, black eye 4 Withdrawn, Recovering reaction abated

13 68/F - Haemorrhage, leukopenia 15 Withdrawn, Recovering reaction abated

14 68/F - - 7 Unknown Not recovered

15 61/M Gabapentin (C) Disseminated intravascular coagulation, haematoma, 3 Withdrawn Not venipuncture site haemorrhage, urinary tract infection, soft recovered tissue haemorrhage, haematuria, fibrinolysis increased, C- reactive protein increased, leukocytosis, skin haemorrhage, haematoma, anaemia, metabolic disorder

17 70/F Piperacillin/tazobactam (S) Palmar-plantar erythrodysaesthesia, bronchitis, infection - Not applicable Unknown Allopurinol, amlodipine, bacterial, AST increased, acidosis, pulmonary congestion, clonidine, colchicine, hyperglycaemia, pancreatitis, pleural effusion, gastric daptomycin, darbepoetin dilatation, infection staphylococcal, fibrillation atrial, alfa, diphenhydramine, cerebral disorder, renal failure chronic, hyperuricaemia, enoxaparin, famotidine, bilirubinaemia, tachycardia ventricular, ECG abnormal insulin glargine, specific, candidiasis, alkaline phosphatase increased, ipratropium, lisinopril, medical device complication, respiratory insufficiency, megestrol, urinary tract infection, failure to thrive, atelectasis, methylprednisolone, bilirubinaemia, cardiac arrest, neuropathy peripheral, ALT omeprazole, prednisolone, increased, dermatitis exfoliative salbutamol, simvastatin, sodium bicarbonate, sulfamethoxazole/trimetho prim, tigecycline, timolol, tobramycin (all C)

18 52/F - Dehydration, disease progression, white blood count - Not applicable Died decreased, infection

20 44/M Carvedilol, spironolactone - 163 Dose not Not , changed, no recovered saffeine/paracetemol/papa effect ver somniferum latex (all S)

22 65/F Atenolol, sodium Anaemia, pancytopenia, febrile neutropenia 19 Withdrawn, Recovered polystyrene sulfonate, reaction abated furosemide, losartan, Restarted 6 sevelamer, calcifediol, days later with prasozin, paracetamol, recurrence of esloratadine (all C) thrombocytope nia

23 56/F Folic acid, cyanocobalamin Fever, urinary tract infection, arthropathy, arthrosis, rash, - Drug Unknown (both C) mass, rash erythematous, hypokalaemia, haemorrhage withdrawn, nos, alopecia, pruritis, hepatic enzymes increased, reaction abated arthralgia, arthritis, joint swelling Drug restarted with no recurrence of thrombocytope nia

24 64/F - - 169 - Not recovered

26 38/F Fotemustine, polyvalent Neutropenia 79 Dose not Not immunoglobulins (both C) changed, no recovered effect

27 37/F - - 55 Dose not Unknown changed, outcome unknown

28 38/F - Purpura, bruising of leg > 122 Dose not Unknown changed, outcome unknown *Co-reported ADR terms highlighted in bold suggest a more widespread myelosuppression rather than isolated thrombocytopenia **Case 7: Narrative states that patient was hospitalised for pneumonia when thrombocytopenia was diagnosed WHO Pharmaceuticals Newsletter No. 3, 2015  30

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Conclusion The data provided in the case series strongly Response from Roche supports a signal for the association between vemurafenib and thrombocytopenia. The suggestion of a possible mechanism, although In March 2015 the WHO Monitoring centre in speculative, adds further support for the signal. Uppsala invited Roche to comment on a signal of thrombocytopenia in patients treated with vemurafenib. WHO cited 28 cases of References thrombocytopenia associated with vemurafenib 1. Davies H, , Bignell GR, Cox C, Stephens P, treatment in the VigiBase®. The report concluded Edkins S, Clegg S et al. Mutations of the BRAF that the data provided in their case series strongly gene in human cancer. Nature supports a signal for the association between 2002;417(6892):949-54. vemurafenib and thrombocytopenia. 2. Roberts PJ, Der CJ. Targeting the Raf-MEK- Drug induced thrombocytopenia has a reported ERK mitogen-activated protein kinase cascade frequency of approximately 19% to 25% in acutely for the treatment of cancer. Oncogene ill patients. Clinical manifestation usually consists 2007;26(22):3291-310. of moderate to severe thrombocytopenia (platelet count of less than 50 × 109/L) and spontaneous 3. US Food and Drug Administration. Zelboraf bleeding which could be potentially life Label (Nov 2014) http://www.accessdata.fda. threatening. (Visentin & Liu, 2007) Typically, the gov/drugsatfda_ docs/label/2014/ thrombocytopenia occurs 1 to 2 weeks after the 202429s006lbl.pdf. Accessed: 3 March 2015. introduction of a new drug or 2-3 days after a 4. National Cancer Institute, Common single dose when a drug has previously been taken Terminology Criteria for Adverse Events intermittently. Demonstration of drug-dependent (CTCAE) Version 4.03. 2010, U.S. Department anti-platelet antibodies is important to confirm the of Health and Human Services etiology of drug-induced thrombocytopenia. Recovery from drug-induced thrombocytopenia 5. Visentin GP, Liu CY. Drug Induced usually begins within 1 to 2 days of stopping the Thrombocytopenia. Hematology/oncology drug and is typically completed within a week. clinics of North America 2007;21(4):685-96. Drug-dependent antibodies can persist for many 6. European Medicines Agency, Zelboraf : EPAR - years. Product Information http://www.ema.europa. Several mechanisms have been described in the eu/docs/en_GB/ document_library/EPAR_- pathogenesis of drug-induced thrombocytopenia, _Product_Information/ with accelerated platelet destruction in the human/002409/WC500124317.pdf. Accessed: presence of the offending drug as the most 3 March 2015. common immune mechanism. Non immune 7. Electronic Medicines Compendium UK. platelet destruction associated with a small Zelboraf 240 mg film-coated tablets number of antineoplastic agents, such as http://www.medicines.org.uk/emc/medicine bleomycin, can occur in thrombotic microangiopathy and its variant form, hemolytic /26056. Accessed 3 Mar 2015. uremic syndrome. (Goerge & Aster, 2009) 8. Uppsala Monitoring Centre. The use of the WHO-UMC system for standardised case The literature describes case reports of causality assessment. [pdf] 2012 [cited 2015 thrombocytopenia in metastatic melanoma 3 March] http://www.who-umc.org/Graphics/ patients as part of massive bone marrow 26649.pdf. infiltration (Deepali, Daga, & et Al, 2007), secondary to chemotherapy or immunotherapy 9. Chung E, Kondo M. Role of Ras/Raf/MEK/ERK (e.g., ipilimumab, high dose IL2), and secondary signaling in physiological hematopoiesis and to platelet consumption in disseminated leukemia development. Immunol Res. intravascular coagulation (Lepelley-Dupont, 2011;49(1-3):248-68. Chevrant-Breton J, & et Al, 2009). We performed an analysis on the background incidence rate of 10. Hsu CL, Kikuchi K and Kondo M. Activation of secondary thrombocytopenia and all mitogen-activated protein kinase kinase thrombocytopenia in patients with metastatic (MEK)/ extracellular signal–regulated kinase melanoma using the Truven Healthcare (ERK) signaling pathway is involved in MarketScan® Commercial Claims and Encounters myeloid lineage commitment. Blood (Commercial) database. The incidence of 2007;110(5):1420-8. thrombocytopenia following a diagnosis of 11. Geddis AE, Megakaryopoiesis. Seminars in metastatic melanoma was estimated as 5.93 hematology 2010;47(3):212-9.

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(secondary thrombocytopenia) and 42.2 (all Median latency was 24 days with a range of 3-225 thrombocytopenia) per 1,000 patient years. days. Vemurafenib inhibits mutant BRAFV600 and is Thirteen of these 20 cases had a latency of ≤ 30 approved for the treatment of adult patients with days. metastatic melanoma harboring this mutation. Based on medical review, 6 out of the 45 cases Currently the vemurafenib label does not include were assessed to have a likely causal association thrombocytopenia as an adverse drug reaction. to vemurafenib. The remaining cases were: Preclinical studies do not support a direct a. lacking vital information that makes meaningful association with thrombocytopenia, however one assessment difficult (n=20), case of bone marrow necrosis was noted in one of b. have an unlikely causal association based on two moribund sacrificed dogs in the prematurely strong alternative etiology for the event of terminated 39-week dog study (Roche, 2015). In thrombocytopenia such as concomitant use of the Phase III trial, <1 % of 337 patients dosed fotemustine, bone marrow infiltration by with vemurafenib reported thrombocytopenia. melanoma cells, or secondary to As of March 24, 2015, there are 45 cases of microangiopathy or DIC (n=13); and thrombocytopenia related adverse events (AEs) c. assessed to have possible causal association reported with vemurafenib use in the Roche safety based on the latency that was longer than database, thirty-two of which were assessed as expected for drug-induced thrombocytopenia or serious. Median age was 59.5 years (31-80). a negative dechallenge/ rechallenge (n=6). Gender was provided for 43 cases of which 22 Table 1 below provides the case details on the 6 were males and 21 were females. Indication was cases that are assessed to have a likely causal provided for 33 cases of which 32 were malignant association based on case presentation, temporal melanoma cases and one case was hairy cell association, and dechallenge information. Of the 6 leukemia. Latency was provided for 20 of the 45 cases, two cases had associated depression of cases. other blood cell lineage.

Table 1: Cases of interest in Roche Vemurafenib Safety Database

Case Age Concom Indication Initial Adverse Other Highest AE Latency Event Reporter Vem Dechall Rechall Gender Medication total Event Term Reported CTCAE Duration (days) outcome Causality outcome daily Adverse Severity (days) dose Events Grade 1 Unk Unknown 1920mg Platelet count Lower 3 Not 4 Resolving Related D/C Positive N/A Female indication decreased respiratory tract reported infection Periorbital contusion 2 66 Malignant 1920mg Thrombocyto Gastrointestinal 2 7 15 Resolved Related D/C Positive N/A Male melanoma penia haemorrhage Duodenal ulcer Pulmonary oedema Musculoskeleta l pain Neoplasm Generalised oedema

3 Unk Saquinavir Malignant 1920mg Platelet count Rash 4 N/A 11 Resolving Related D/C Positive N/A Male Bisoprolol melanoma abnormal Pruritus Aspirin Simvastatin Allopurinol Prednisolon e 4 51 Malignant 480mg Thrombocyto Leukopenia 3 7 29 Resolved Related D/C Positive N/A Male melanoma penia Facial paresis

5* 65 Furosemide Malignant Not Thrombocyto Anemia 4 8; 22; Resolving Related Interrupte Positive* Positive Female Losartan Melanoma reported penia Pancytopenia 17 (2nd 3 (2nd to grade d and *; ; Sevelamer Febrile episode) episode) 1; dose Positive N/A Atenolol neutropenia Resolved reduced; Prozosine (2nd D/C (2nd episode) episode) 6 58 Zoledronic Unknown 1920mg Thrombocyto Rash 2 NR 20 Resolved Not Interrupte Positive Negativ Female Acid indication penia Blood bilirubin reported d and e increased dose reduced Legend: *Case number 22 in the WHO report; vem = vemurafenib; D/C = discontinued; N/A = not applicable; dechalle=dechallenge; rechalle=rechallenge; ** confounded by platelet treatment

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AER number 1351266 was identified in the WHO Report as case 22 and where causal relationship between vemurafenib and thrombocytopenia was described as “certain” in that report. Similarly, Roche assessed this case to be likely associated with vemurafenib treatment. The 6 cases of thrombocytopenia yield a crude reporting rate of 0.67 cases per 1000 patient years based on an estimated cumulative patient exposure to vemurafenib of 17,729 patient years. Using a conservative approach, the crude reporting rate of 45 cases is 2.54 per 1,000 patient years. These rates are significantly lower than expected for the metastatic melanoma population based on the Marketscan analysis.

Roche acknowledges the signal for thrombocytopenia raised by the WHO. This event including other cell lines and pancytopenia are closely monitored. Bone marrow toxicity remains a potential risk for vemurafenib and is included in the Risk Management Plan (RMP) for the drug. The assessment of this event, as part of bicytopenia or pancytopenia in the context of bone marrow suppression is currently being investigated by Roche.

References 1. Bluteau, D., Raslova, H., & et Al. (2014). Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation. The Journal of Clinical Investigations, 124(2), 580-91. 2. Clerico, M., et Al, & Turrisi G. (2006). Persistent thrombocytopenia during melanoma treatment with fotemustine. Melanoma Research, 16(6), 543-4.

3. Deepali, J., Daga, M., & et Al. (2007).

Metastatic Malignant Mellanoma in Bone Marrow with Occult Primary Site - a Case Report with Review of Literature. Diagnostic

Pathology, 2(38).

4. Goerge, J., & Aster, R. (2009). Drug-induced thrombocytopenia: pathogenesis, evaluation, and management. ASH education book, 1, 153-8. 5. Lepelley-Dupont, C., Chevrant-Breton J, & et Al. (2009). Melanoma-associated disseminated intravascular coagulation. Journal of the European Academoy of Dermatology and Venerology, 23(6), 720-1. 6. Roche, F. H.-L. (2015). Investigator’s Brochure for vemurafenib.

7. Visentin, G., & Liu, C. (2007). Drug induced thrombocytopenia. Hematology Oncology clinics of Norht America, 21(4), 685-96.

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WHO Collaborating Centre Tel: +46-18-65 60 60 for International Drug Monitoring Fax: +46-18-65 60 88 Box 1051, SE-751 40 Uppsala, Sweden E-mail: [email protected]

CAVEAT DOCUMENT

Accompanying statement to data released from the Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring

Uppsala Monitoring Centre (UMC) in its role as the WHO Some National Centres that contribute information to Collaborating Centre for International Drug Monitoring VigiBase® make an assessment of the likelihood that a receives reports of suspected adverse reactions to medicinal product caused the suspected reaction, while medicinal products from National Centres in countries others do not. participating in the WHO pharmacovigilance network, Time from receipt of a report by a National Centre until the WHO Programme for International Drug Monitoring. submission to UMC varies from country to country. Limited details about each suspected adverse reaction Information obtained from UMC may therefore differ are received by the UMC. The information is stored in from those obtained directly from National Centres. the WHO Global Individual Case Safety Report

database, VigiBase®. It is important to understand the For the above reasons interpretations of adverse limitations and qualifications that apply to this reaction data, and particularly those based on information and its use. comparisons between medicinal products, may be misleading. The supplied data come from a The reports submitted to UMC generally describe no variety of sources. The likelihood of a causal more than suspicions which have arisen from relationship is not the same in all reports. Any observation of an unexpected or unwanted event. In use of this information must take these factors most instances it cannot be proven that a specific into account. medicinal product (rather than, for example, underlying illness or other concomitant medication) is the cause of Some National Centres strongly recommend that anyone who intends to use their information should an event. contact them for interpretation. Reports submitted to National Centres come from both Any publication, in whole or in part, of information regulated and voluntary sources. Some National obtained from UMC must include a statement: Centres accept reports only from medical practitioners; other National Centres accept reports from a broader (i) regarding the source of the information, range of reporters, including patients. Some National (ii) that the information comes from a variety of Centres include reports from pharmaceutical companies sources, and the likelihood that the suspected in the information submitted to UMC; other National adverse reaction is drug-related is not the same Centres do not. in all cases, (iii) that the information does not represent the The volume of reports for a particular medicinal product opinion of the World Health Organization. may be influenced by the extent of use of the product, publicity, the nature of the reactions and other factors. Omission of this statement may exclude the responsible person or organization from receiving No information is provided on the number of patients further information from VigiBase®. exposed to the product.

2011

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Feature

Strengthening pharmacovigilance in countries: a brief report from two WHO events

Pharmacovigilance workshop, Indonesia, April 2015

Access to new drugs and vaccines in low and middle income countries has been made easier through various Public Health initiatives. Many of these treatments have the potential to save and improve the quality of many lives, however many counties in which these products are deployed do not have the capacity to effectively monitor their post market safety. This is of particular concern with medications that are being introduced through an accelerated approval process, well before all phases of clinical trials can be completed. Pharmacovigilance (PV) and the management of adverse drug reactions are essential when introducing such fast-tracked, novel medications. The focus on PV presents an opportunity to strengthen and build PV systems in countries where such medications will be introduced but where there is little or no capacity for pharmacovigilance. The national TB programme in Indonesia plans to introduce bedaquiline (BDQ) in August 2015. BDQ is a new medication for the treatment of MDR TB and has received accelerated marketing approval in some countries (1, 2). The Badan POM (BPOM), the National Agency of Drug and Food Control (NADFC) in Indonesia, have recognized the need to improve PV capacity in the country, for the effective monitoring of safety of drugs such as BDQ and other medicines used in its Public Health Programmes. A collaboration between BPOM, WHO country office in Indonesia and WHO/EMPa led to the planning of a successful PV workshop in Bogor, Indonesia. The workshop was supported through a grant from the Access and Delivery Partnership project that is funded by the Government of Japan, coordinated and led by United Nations Development Programme, with WHO/TDRb as one of the project partners involved in strengthening capacity for safety monitoring with technical support from WHO/EMP. The workshop aimed to strengthen PV and networking between PV staff and public health programs, build PV capacity and introduce the principles of cohort event monitoring, an active pharmacovigilance method developed by the WHO Department of Essential Medicines and Health products (EMP) (3-6). The workshop was also an opportunity to review basic PV concepts and principles, with a view to strengthening key technical areas in PV in Indonesia.

There were approximately 40 participants and the workshop consisted of: academics (from the main universities in Indonesia), BPOM staff, health-care professionals from hospitals (clinicians and pharmacists), staff from provincial health offices (Jakarta, East and West Java), staff from the KNCV TB foundation, members of WHO Indonesia country office, and staff working under the ministry of health, dedicated to Public Health Disease Programmes such as national TB, HIV and Malaria Programmes, and the Directorate of Pharmaceutical Services. Representatives from the WHO collaborating centre for Advocacy and Training in Pharmacovigilance in Accra, Ghana, staff from WHO HQ (Geneva) and a PV specialist from the National Agency for Food and Drug Administration and Control (NAFDAC) in Nigeria presented and facilitated the workshop activities.

The three-day workshop was officially opened by Director of Distribution Control of Therapeutic products from the Ministry of Health, Dr Arustiyono. Dr Salma Burton from the WHO country office in Indonesia also spoke at the opening session, linking PV to access, priority medicines, and universal health coverage. On Day 1, a presentation from BPOM described the national PV centre in the country, its organization, roles and responsibilities. Fundamental principles of PV were presented, and the importance of integrating PV in public health programmes was introduced. Presentations on VigiFlow and VigiLyze highlighted different levels of baseline knowledge of PV and experience amongst participants. PV is a centralized function in Indonesia and BPOM faces many challenges in implementation and resources, given the size and spread of the country

a Essential Medicines and Health Products, Medicines Safety Unit. b The Special Programme for Research and Training in Tropical Diseases at the World Health Organization.

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Feature over several provinces and island states. BPOM is discussing the concept of centres of excellence in some of the teaching hospitals, to increase its outreach, competence and capacity to provide training in key aspects within PV. Day 2 consisted of interactive sessions on CEM, and causality assessments. Participants were trained through working groups on assessments, and mock-up exercises of CEM methodology and its implementation. A more intensive training on causality assessments was requested as one of the future activities. Presentations on communication, crises management, and benefit harm analysis were well received on Day 3. Participants shared examples of escalated miscommunications that have occurred in public health programmes, emphasizing the importance of good communication and training. Examples of cases where the regulators had faced difficult decisions about registering or continuing a product were shared. From the participants’ feedback it would appear that the workshop achieved its objectives, of improving basic knowledge and capacity for PV in the country. It also provided an opportunity to strengthen collaborations between the public health programmes and the national PV Centre in Indonesia.

As a follow up, BPOM will establish a PV and risk assessment / safety advisory committee in the country, with the relevant expertise and experience in benefit risk assessment and patient safety management.

References: 1. FDA News Release. In FDA U.S. Food and Drug Administration , Protecting and Promoting Your Health:[http://ww.fda.gov]. USA: U.S. Department of Health and Human Services; 2012 (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm333695.htm, accessed 19 June 2015) 2. European Medicines Agency recommends approval of a new medicine for multidrug-resistant tuberculosis. In: European Medicines Agency, Science Medicines Health [http://www.ema.europa.eu/ema/]. London: European Medicines Agency; 2013 (http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/12/news_ detail_001999.jsp&mid=WC0b01ac058004d5c1, accessed 19 June 2015) 3. Pal SN, Duncombe C, Falzon D, Olsson S. WHO strategy for collecting safety data in public health programmes: complementing spontaneous reporting systems. Drug Saf, 2013, 36(2):75-81.doi: 10.1007/s40264-012-0014-6. 4. A practical handbook on the pharmacovigilance of antimalarial medicines. Geneva: World Health Organization.; 2008 (http://www.who.int/malaria/publications/atoz/malaria-pharmavigil.pdf, accessed 22 June 2015). 5. A practical handbook on the pharmacovigilance of antiretroviral medicines. Geneva: World Health Organization.; 2009 (http://apps.who.int/medicinedocs/documents/s16882e/s16882e.pdf, accessed 22 June 2015) 6. A practical handbook on the pharmacovigilance of medicines used in the treatment of tuberculosis. Geneva: World Health Organization; 2012 (http://www.who.int/medicines/publications/pharmacovigilance_tb/en/, accessed 22 June 2015)

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Seasonal Malaria Chemoprevention and Pharmacovigilance, Morocco, May 2015

Severe malaria is a life-threatening disease that occurs mostly among children living in Africa, where it is estimated that a child dies every minute from malaria (1). Natural immunity to malaria is usually acquired in children living in malaria endemic areas by the age of seven-ten (2, 3). However younger children living in these areas have inadequate immunity and are at greater risk of developing severe malaria. There are several approaches to malaria control such as vector control through the use of insecticide treated mosquito nets and indoor residual spraying with insecticides. Another measure is the use of medications as a preventive measure. This can be through daily or weekly doses of a medication, or alternatively, the medication can be given as a preventive treatment at regular intervals during transmission season. The latter is known as seasonal malaria chemoprevention SMC, (previously known as intermittent treatment), defined as the intermittent administration of full treatment courses of an antimalarial medicine during the malaria season to prevent malaria illness with the objective of maintaining therapeutic antimalarial drug concentrations in the blood throughout the period of greatest malarial risk (4). In 2012, WHO made a recommendation for the implementation of SMC in areas of highly seasonal malaria transmission across the Sahel sub-regions (4). This consists of a combination of amodiaquine and sulfadoxine-pyrimethamine (AQ + SP) which will be administered to children aged between 3 and 59 months at monthly intervals, beginning at the start of the transmission season, to a maximum of four doses during the malaria transmission season, provided both drugs retain sufficient antimalarial activity. The policy also recommends that PV should be strengthened where it exists, and where there is no PV, it should be instituted. ACCESS-SMC is a UNITAID-funded project, led by the malaria Consortium in partnership with Catholic Relief Services, which is scaling up access to SMC across the malaria endemic sub-Saharan countries (5). The project will last three years in collaboration or with technical support from the London School of Hygiene and Tropical Medicine, Centre de Support de Santé International, Management Sciences for Health, Medicines for Malaria Venture, and Speak Up Africa. It will provide 30 million SMC treatments annually to 7.5 million children less than five years of age in Burkina Faso, Chad, the Gambia, Guinea, Mali, Niger and Nigeria (6). PV in SMC will involve the participation of staff from the National PV Centre and the health facility and health- care workers/volunteers. Health-care workers/volunteers will be trained on various aspects of basic skills, such as how to administer medication, what advice to provide to parents, and to refer adverse events to health-care facilities. They will be responsible for providing the medications to the parents of the children. Health-care staff working in local health facilities will be trained on reporting adverse events (as one aspect of overall training). National PV centres will be responsible for analysing data on potential drug-related adverse events, and for signal detection. The countries providing SMC vary in their PV capacity. Some have an established PV system, and others have no formal national centres for PV and are not part of the WHO Programme for International Drug Monitoring (PIDM). And then there are those with a rudimentary PV system that is not fully functional. In order to build and / or strengthen PV systems in SMC countries, the WHO Collaborating Centre for PV in Rabat, Morocco hosted a workshop in May 2015. The workshop was conducted in collaboration with the London School of Hygiene and Tropical medicine WHO/EMP, WHO/TDR, the, University of Cheikh Anta Diop and Access-SMC. The aim of the workshop was to help Sub-Saharan African countries develop an appropriate PV plan in preparation for the implementation of SMC scheduled to commence between July and August 2015. Participants included representatives of national PV centres and those responsible for PV in National Malaria Control Programmes in the following countries: Burkina Faso, Chad, the Gambia, Guinea, Mali, Niger and Nigeria. Countries presented their national PV systems and identified focal PV persons (if present). Countries that are not members of the WHO PIDM were given guidance on steps needed to join the WHO PIDM. The programme for the workshop consisted of presentations on the SMC programme, previous experience of SMC in Senegal, the WHO Programme for International Drug Monitoring, use of VigiFlow as a data management system, causality assessment, signal detections and risk minimizations plans. The majority of countries have had experience using VigiFlow as a data management system. Concerns over the time taken for reports to reach VigiBasec were expressed. Working groups discussed PV training needs for community health workers, health facilities and national PV centres. c VigiBase® is the name of the WHO Global ICSR database; it consists of reports of adverse reactions received from member countries since 1968. VigiBase® is updated with incoming ICSRs on a continuous basis. National centres are recommended to send reports at least quarterly; most national centres adhere to these guidelines, and several report more frequently.

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The workshop discussed the adverse events to report, when to refer patients to health facilities; and which adverse events would require SMC to be discontinued, resources required to manage serious adverse reactions such as anaphylaxis.. It was recommended that all adverse events should be reported initially in order to build the safety profile of medications used in the younger age groups. Community workers should refer patients with adverse events to healthcare facilities. More information on the safety profile of the medications will help the proposed regional committee for safety monitoring to develop a risk management plan and a decision tree on how to manage adverse events and when to continue or stop SMC. . Next steps, for WHO and Access-SMC partners will be: supporting non WHO PIDM members to join the programme; developing training material for actors involved in SMC deployment; and supporting countries to develop a PV plan which will strengthen systems for the sustainable monitoring of adverse events.

References: 1. Malaria. In: WHO/Mediacentre [http://www.who.int]. Geneva: World Health Organization, 2015 (http://www.who.int/mediacentre/factsheets/fs094/en/, accessed 19 June 2015) 2. Branch OH, Udhayakumar V, Hightower AW, Oloo AJ, Hawley WA, Nahlen BL, et al. A longitudinal investigation of IgG and IgM antibody responses to the merozoite surface protein-1 19-kiloDalton domain of Plasmodium falciparum in pregnant women and infants: associations with febrile illness, parasitemia, and anemia. Am J Trop Med Hyg. 1998; 58(2):211-9. 3. Warrell DA. "To search and Studdy out the secrett of Tropical Diseases by way of Experiment". Lancet. 2001; 358(9297):1983-8. 4. WHO Global Malaria Programme: WHO policy recommendation: Seasonal malaria chemoprevention (SMC) for Plasmodium falciparum malaria control in highly seasonal transmission areas of the Sahel sub- region in Africa. Geneva: World Health Organization; 2012 (http://www.who.int/malaria/publications/atoz/smc_policy_recommendation_en_032012.pdf, accessed 22 June 2015). 5. Tine RC, Ndour CT, Faye B, Cairns M, Sylla K, Ndiaye M, et al. Feasibility, safety and effectiveness of combining home based malaria management and seasonal malaria chemoprevention in children less than 10 years in Senegal: a cluster-randomised trial. Trans R Soc Trop Med Hyg. 2014; 108(1):13-21. 6. Access-SMC. In Malaria consortium, disease control, better health [http://www.malariaconsortium.org/]. United Kingdom: Malaria Consortium Headquarters; Malaria Consortium. (http://www.malariaconsortium.org/pages/access-smc.htm, accessed 19 June 2015)

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2nd Conference of the African Society of Pharmacovigilance (ASoP) 2015 Call for Abstracts

La Palm Royal Beach Hotel in Accra, Ghana 25th to 27th November, 2015

Pharmacovigilance in Africa: New Methods, New Opportunities, New Challenges

Abstract Submission and Registration is Now Open!

www.asop2015.com Deadline: September 15, 2015

Registration is required for all attendees.

All interested in Pharmacovigilance in Africa are strongly encouraged to attend.

WHO Pharmaceuticals Newsletter No. 3, 2015  39