NEWSLETTER No.4

2015 WHO Pharmaceuticals

NEWSLETTER No.4

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. The Summary of Recommendations from the Twelfth Meeting of the WHO Advisory Committee on Safety of The information is produced in the Medicinal Products (ACSoMP) is included as a feature form of résumés in English, full item together with a small article from the Food and texts of which may be obtained on Drugs Authority in Ghana on patient reporting of request from: adverse reactions. 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 Abiraterone acetate ...... 5 Adefovir pivoxil ...... 5 Anagliptin ...... 5 Asunaprevir and daclatasvir hydrochloride ...... 5 Crizotinib ...... 6 Denosumab ...... 6 Dimethyl fumarate ...... 6 Ethinylestradiol /etonogestrel vaginal ring ...... 7 Ferumoxytol ...... 7 Fusidic acid and HMG-CoA reductase inhibitors ...... 7 Ibuprofen ...... 8 Indapamide ...... 8 Influenza HA vaccine ...... 8 Interferon beta-1a ...... 9 Ivabradine ...... 9 Methotrexate ...... 10 Methylphenidate transdermal system ...... 10 Methylprednisolone (intravenous injection) ...... 10 Non-aspirin Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) ...... 11 Pregabalin ...... 11 Sorafenib ...... 12 Technetium (99mTc) hydroxymethylenediphosphonate injection ...... 12 Tramadol hydrochloride ...... 12 Ustekinumab ...... 13 Ziprasidone ...... 13

Safety of medicines Codeine Cough-and-Cold Medicines in Children ...... 15 Combined hormonal birth control products ...... 15 Denosumab ...... 15 Diazoxide ...... 16 Febuxostat ...... 16

WHO Pharmaceuticals Newsletter No. 4, 2015  3

Table of Contents

Ibuprofen in high dose (≥2400mg/day) ...... 16 Influenza vaccine ...... 17 Latanoprost eye drop ...... 17 Melatonin ...... 18 Sodium glucose co-transporter 2 (SGLT2) inhibitors (canagliflozin, dapagliflozin, empagliflozin) ...... 18 Zoledronic acid infusion ...... 18

Signal Atomoxetine and Dystonia in paediatric patients ...... 20 Vemurafenib and Tumour lysis syndrome ...... 25

Feature Summary of Recommendations from the Twelfth Meeting of the WHO Advisory Committee on Safety of Medicinal Products (ACSoMP) ...... 30 Implementing Patient Reporting of Adverse Reactions in Ghana ...... 32

WHO Pharmaceuticals Newsletter No. 4, 2015  4

Regulatory Matters

Abiraterone acetate chronic liver disease in which abnormality of liver function Risk of fulminant with replication of hepatitis B Intestinal obstruction: hepatitis and hepatic virus is confirmed. Intestinal obstruction may occur. Patients should be failure The MHLW/PMDA stated that carefully monitored. If any cases of fractures have been abnormalities such as severe Japan. The Ministry of Health, reported in patients treated constipation, abdominal Labour and Welfare (MHLW) with adefovir pivoxil in Japan. distension, sustained and the Pharmaceuticals and abdominal pain, or vomiting Medical Devices Agency Based on expert advice and are observed, administration of (PMDA) have announced the available evidence, the revision of the package insert MHLW/PMDA have this drug should be for abiraterone acetate recommended adding risk of discontinued, and appropriate (Zytiga®) to include risk of fracture to the section of measures should be adopted. “Important precautions” and to fulminant hepatitis and hepatic Reference: the subsection of the “Clinically failure. Revision of Precautions, significant adverse reactions” MHLW/PMDA, 7 July 2015 Abiraterone acetate is in the section of “Adverse (www.pmda.go.jp/english/) indicated for castration- reactions” in the package resistant prostate cancer. insert. The MHLW/PMDA stated that Reference: cases of fulminant hepatitis or Revision of Precautions, hepatic failure have been MHLW/PMDA, 7 July 2015 Asunaprevir and reported in patients treated (www.pmda.go.jp/english/) daclatasvir with abiraterone acetate in Japan. hydrochloride Based on expert advice and Risk of hepatic failure available evidence, the Anagliptin MHLW/PMDA have Japan. The MHLW and the recommended the addition of Risk of intestinal PMDA have announced the the description on the risk of obstruction revision of the package inserts fulminant hepatitis and hepatic for asunaprevir (Sunvepra®) failure to the information on Japan. The MHLW and the and daclatasvir hydrochloride hepatic function disorder in the PMDA have announced the (Daklinza®) to include risk of section of “Important revision of the package insert hepatic failure. precaution” and to the for anagliptin (Suiny®) to Asunaprevir and daclatasvir subsection of the “Clinically include risk of intestinal hydrochloride are used for significant adverse reactions” obstruction. improvement of viraemia in in the section of “Adverse patients with serogroup 1 reactions” in the package Anagliptin is indicated for type (genotype I) chronic hepatitis insert. 2 diabetes mellitus. C or compensated cirrhosis Reference: The MHLW/PMDA stated that type C. Revision of Precautions, cases associated with intestinal The MHLW/PMDA stated that MHLW/PMDA, 7 July 2015 obstruction have been reported cases of decreased hepatic (www.pmda.go.jp/english/) in patients treated with anagliptin in Japan. residual function such as decreased albumin level, Based on expert advice and prolonged prothrombin time, available evidence, the ascites, hepatic Adefovir pivoxil MHLW/PMDA have encephalopathy, and those recommended the addition of resulting in hepatic failure Risk of fracture “Patients who have a history of have been reported in patients abdominal surgery or intestinal treated with asunaprevir and Japan. The MHLW and the obstruction” to the section of daclatasvir hydrochloride in PMDA have announced the “Careful administration” in the Japan. revision of the package insert package insert and the for adefovir pivoxil (Hepsera®) addition of the following texts Based on expert advice and to include risk of fracture. to the subsection of the available evidence, the “Clinically significant adverse MHLW/PMDA have Adefovir pivoxil is indicated for reactions” under “Adverse recommended the addition of the inhibition of hepatitis B reactions” in the package an alert on decreased hepatic virus replication in type B insert. residual function to the

WHO Pharmaceuticals Newsletter No. 4, 2015  5

Regulatory Matters subsection relevant to “the administration, should be unhealed lesions from dental assessment of hepatic adopted. or oral surgery. Patient function” in the section of reminder cards about the risk Reference: “Important precautions” and of are being introduced. Revision of Precautions, the addition of hepatic failure MHLW/PMDA, 2 June 2015 Reference: to the subsection of the (www.pmda.go.jp/english/) Drug Safety Update, MHRA, “hepatic function disorder” in Volume 8, issue 12: 1, July the section of “Clinically 2015 (www.gov.uk/mhra) significant adverse reactions section” in the package insert. (See WHO Pharmaceuticals Denosumab Newsletter No.6, 2014 for Risk of Reference: osteonecrosis of the jaw and Revision of Precautions, Further measures to hypocalcaemia in Egypt) MHLW/PMDA, 7 July 2015 (www.pmda.go.jp/english/) minimise risk of osteonecrosis of the jaw

UK. The Medicines and Dimethyl fumarate Healthcare Products Regulatory Crizotinib Agency (MHRA) has reminded Risk of serious allergic health-care professionals to reactions including skin Risk of cardiac failure advise patients to take reactions and precautionary measures to anaphylaxis Japan. The MHLW and the minimise the risk of PMDA have announced the osteonecrosis of the jaw (ONJ) Canada. Canadian prescribing revision of the package insert in patients taking denosumab information for dimethyl for crizotinib (Xalkori®) to and intravenous fumarate has been updated to include risk of cardiac failure. bisphosphonates. inform prescribers and patients Crizotinib is indicated for Denosumab and of hypersensitivity reactions, Anaplastic lymphoma kinase bisphosphonates are used to including angioedema and (ALK)-positive, unresectable, treat osteoporosis, Paget’s anaphylaxis. However, advanced or relapsed non- disease, and as part of some following a safety review, small-cell lung cancer. cancer regimens, particularly Health Canada has concluded that the overall benefits of The MHLW/PMDA stated that for metastatic bone cancer and multiple myeloma. Individual dimethyl fumarate cases of cardiac failure have (Tecfidera®) continue to been reported in patients bisphosphonates and denosumab-containing outweigh the risks if used as treated with crizotinib in recommended. Japan. medicines have different indications (information The Canadian prescribing Based on expert advice and available in the summary of information was also updated available evidence, the product characteristics (SmPC) to mention that the possibility MHLW/PMDA have of the medicine in question). of hypersensitivity or recommended the addition of The advice follows a review anaphylactic reactions should the following texts to the be considered in patients subsection of the “Clinically conducted by MHRA and other EU medicines regulators. experiencing severe flushing significant adverse reactions” reactions (e.g. flushing, hot in the section of “Adverse Patients should be advised to: maintain good oral hygiene, flushes, warmth, redness, reactions” in the package itching, and/or burning insert attend routine dental check- ups and immediately report sensations). These symptoms Cardiac failure: any oral symptoms such as may present similarities with Cardiac failure may occur. dental mobility, pain, or hypersensitivity reactions. Patients should be carefully swelling to a doctor and dentist Dimethyl fumarate is used to monitored. If the fluid before being prescribed oral reduce the number of flare-ups retention (pulmonary oedema, bisphosphonates. Further (relapses) and slow the pleural effusion, pericardial recommendations include: progression of physical effusion, etc.), rapid increased introducing patient reminder disability in multiple sclerosis. weight, cardiac failure cards for denosumab and symptoms (shortness of intravenous bisphosphonates, At the time of this review, breath, dyspnoea, oedema, to inform patients of the risk of Health Canada considered the etc.) are observed, appropriate ONJ and precautions to take evidence provided in both measures such as drug before and during treatment; domestic (nine reports) and suspension, dose reduction, or denosumab 120 mg should be international reports (five discontinuation of contraindicated in patients with reports), including those WHO Pharmaceuticals Newsletter No. 4, 2015  6

Regulatory Matters provided by the product  Presence or history of ATEs used in patients with allergies manufacturer, of or VTEs, such as deep to injectable iron products or hypersensitivity associated venous thrombosis, with multiple drug allergies. with dimethyl fumarate. pulmonary embolism or Another communication for myocardial infarction, or of health-care professionals was Overall, the number of a cerebrovascular accident. issued with advice on how to hypersensitivity reactions  Known predisposition for minimise the risk of serious reported has increased for ATE or VTE. hypersensitivity reactions dimethyl fumarate, with some  Presence or history of during ferumoxytol reports being life-threatening. prodromi of a thrombosis, administration. This increase may be due to a for example transient greater use of dimethyl Ferumoxytol is an injectable ischaemic attack or angina fumarate. iron product used to treat low pectoris. levels of iron in the blood (iron Reference:  History of migraine with deficiency anaemia) in adults Summary Safety Review, focal neurological with chronic kidney disease. Health Canada, 26 June 2015 symptoms. (www.hc-sc.gc.ca)  Diabetes mellitus with This advice follows a safety vascular involvement. review conducted to determine

if current strategies to Presence of severe or multiple minimize the risk were risk factor(s) for ATE or VTE sufficient. Ethinylestradiol may also constitute a contraindication. As of February 28, 2014, there /etonogestrel vaginal were more than 20 Canadian If any of the above conditions reports of serious ring appear for the first time during hypersensitivity reactions, the use of ethinylestradiol/ including 2 deaths, received Thromboembolic risk etonogestrel vaginal ring, it through the Canada Vigilance should be removed Australia. The Therapeutic Program. Over half were immediately. Goods Administration (TGA) reported in a 6 month period. has advised health-care Reference: Many of the international cases professionals that the Product Medicines Safety Update, TGA, of serious or fatal Information for Vol. 6, No. 3, June 2015 hypersensitivity reactions ethinylestradiol/etonogestrel (www.tga.gov.au) vaginal ring (NuvaRing®) has reported with ferumoxytol, (See WHO Pharmaceuticals been updated to provide also documented patients as Newsletters No.6, 2013, No.4, further information about having allergies to other 2013 and No.6, 2004 for related medicines. thromboembolic risks. information) Reference: Ethinylestradiol/etonogestrel vaginal ring is a contraceptive Summary Safety Review, ring for vaginal use, which Health Canada, 3 July 2015 (www.hc-sc.gc.ca) releases ethinylestradiol and Ferumoxytol etonogestrel over a period of (See WHO Pharmaceuticals three weeks. Risk of serious allergic Newsletters No.3, 2015 for Risk of reactions fatal allergic reactions in the US, While ethinylestradiol/ No.5, 2014 for Risk of serious etonogestrel vaginal ring is hypersensitivity reactions in the Canada. Health Canada has delivered vaginally, the active UK and No.4, 2014 for New announced that the Canadian ingredients are the same as restrictions in Canada) prescribing information for combined hormonal oral ferumoxytol (Feraheme®) has contraceptives, and the risks of been updated with advice to arterial and venous avoid giving ferumoxytol in thromboembolism (ATE and patients with a history of drug Fusidic acid and VTE) are similar for all of these allergies, and on how it should products. It is possible that the HMG-CoA reductase be given to reduce the risk of risk of VTE may also increase serious hypersensitivity with the presence of superficial inhibitors reactions. thrombophlebitis and varicose Risk of rhabdomyolysis veins. Health Canada issued both a by drug-drug interaction health-care professional and a Ethinylestradiol/etonogestrel public communication stating vaginal ring should not be used Ireland. The Health Products limitations for ferumoxytol use. in the presence of any of the Regulatory Authority (HPRA) Ferumoxytol should not be following conditions: has stated that cases of WHO Pharmaceuticals Newsletter No. 4, 2015  7

Regulatory Matters rhabdomyolysis (including Ibuprofen ibuprofen (2400 mg/day) some with a fatal outcome) are required. suspected to be due to an Small increased interaction between fusidic cardiovascular risk with Reference: acid and a HMG-CoA reductase daily doses at or above Drug Safety Newsletter, HPRA, inhibitor (collectively known as June 2015 “statins”) have been reported 2,400mg to the HPRA and other (See WHO Pharmaceuticals Ireland. The HPRA has European medicines agencies. Newsletter No.3, 2015 for Risk of announced that the product The exact mechanism for this serious heart and stroke adverse information for all systemic interaction is unknown and events at high doses in Canada) ibuprofen containing products therefore may occur with will be updated as soon as some, or all, statins. The possible to reflect small product information for Indapamide increased cardiovascular risk systemic fusidic acid indicates with daily doses at or above that concomitant treatment Risk of Toxic epidermal 2,400mg. with statins is contraindicated, necrolysis (TEN) while the product information Ibuprofen is a non-steroidal Japan. The MHLW and the for the individual statins anti-inflammatory drug PMDA have announced the highlights the need to (NSAID) commonly used for revision of the package insert temporarily discontinue statin the reduction of pain, for indapamide (Natrix® and therapy when treatment with inflammation and fever. fusidic acid is considered Tenaxil®) to include risk of essential. The most recent EU review toxic epidermal necrolysis completed by the (TEN). Statins are a class of Pharmacovigilance Risk Indapamide is indicated for medicines used as an adjunct Assessment Committee (PRAC) Essential hypertension. to diet for the treatment of has confirmed a small increase hypercholesterolaemia, when in the risk of arterial The MHLW/PMDA stated that the response to diet and other thrombotic events (e.g. cases of TEN have been non-pharmacological myocardial infarction or reported in patients treated treatments (e.g. exercise, stroke) in patients taking high with indapamide in Japan. weight reduction) is doses of ibuprofen (at or above inadequate. They are also 2,400mg/day). Based on expert advice and authorised as an adjunct to available evidence, the treatment in the secondary The HPRA has advised health- MHLW/PMDA have prevention of major cardiac care professionals that: recommended the addition of events in patients with  Ibuprofen should be the description on risk of TEN cardiovascular disease. prescribed at the lowest to the subsection of the dose for the shortest “Clinically significant adverse Fusidic acid and its salts duration possible. reactions” in the section of (including sodium fusidate) are  Patients with uncontrolled “Adverse reactions” in package antistaphylococcal agents used hypertension, congestive insert. for the treatment of serious or heart failure (NYHA II-III), deep-seated infections established ischaemic heart Reference: requiring good tissue or bone disease, peripheral arterial Revision of Precautions, penetration, such as disease, and/or MHLW/PMDA, 7 July 2015 osteomyelitis. Systemic cerebrovascular disease (www.pmda.go.jp/english/) formulations of fusidic acid should only be treated with include tablets, suspensions ibuprofen after careful and intravenous infusions. consideration and high Influenza HA vaccine There is no evidence that doses (2400 mg/day) topical formulations (creams should be avoided. Risk of optic neuritis and eye drops) interact with  Careful consideration should Japan. The MHLW and the statins. also be exercised before PMDA have announced the initiating long-term Reference: revision of the package insert treatment of patients with Drug Safety Newsletter, HPRA, for influenza HA vaccine to risk factors for July 2015 include risk of optic neuritis. cardiovascular events (e.g. (See WHO Pharmaceuticals hypertension, Influenza HA vaccine is used in Newsletter No.5, 2012 for Updated hyperlipidaemia, diabetes the prophylaxis of influenza. advice on drug interactions - mellitus, and smoking), The MHLW/PMDA stated that updated contraindications in the particularly if high doses of UK) cases of optic neuritis have

WHO Pharmaceuticals Newsletter No. 4, 2015  8

Regulatory Matters been reported in persons to add the description on the standard chronic heart injected with influenza HA risk of fulminant hepatitis to failure treatment. vaccine in Japan. the subsection in package The contraindications have insert. Based on expert advice and been amended to change available evidence, the Reference: resting heart rate prior to MHLW/PMDA have Revision of Precautions, treatment from '60 bpm' to '70 recommended the addition of MHLW/PMDA, 7 July 2015 bpm', as well as to add the description on the risk of (www.pmda.go.jp/english/) examples of potent optic neuritis to the subsection cytochrome P450 3A4 of the (CYP3A4) inhibitors. A new “Encephalitis/encephalopathy contraindication for and myelitis” in the section of 'combination with verapamil or “Clinically significant adverse Ivabradine diltiazem which are moderate reactions” in the package CYP3A4 inhibitors with heart Risk of cardiovascular insert. rate reducing properties' has events in patients with also been added. Reference: angina Revision of Precautions, The Precautions, Interactions MHLW/PMDA, 7 July 2015 Australia. The TGA has with Other Medicines, Adverse (www.pmda.go.jp/english/) announced that the Product Events and Dosage and Information for ivabradine has Administration sections of the

been updated to reduce the Product Information have also risk of cardiovascular events in been updated to include new patients who take the medicine information to help reduce the Interferon beta-1a for angina. risk of cardiovascular events for patients with angina. Risk of fulminant Ivabradine is a heart rate hepatitis lowering agent, used for These changes follow symptoms of chronic stable preliminary results of a pre- Japan. The MHLW and the angina or treatment of specified subgroup of patients PMDA have announced the symptomatic chronic heart with symptomatic angina in revision of the package insert failure. It works on the cardiac the SIGNIFY phase III study for interferon beta-1a pacemaker current which ('Study assessInG the (Avonex®) to include risk of effects the sinus node and morbidity-mortality beNefits of fulminant hepatitis. regulates heart rate. the If inhibitor ivabradine in patients with coronary artery Interferon beta-1a is used for The approved indications in the disease'). prophylaxis of relapse of Product Information for multiple sclerosis. ivabradine was updated to The SIGNIFY study findings include: indicated that some patients The MHLW/PMDA stated that a  Symptomatic treatment of with angina have a small but case of fulminant hepatitis has chronic stable angina due to statistically significant increase been reported in a patient atherosclerotic coronary in the combined risk of death treated with interferon beta-1a artery disease in patients and non-fatal heart attack with in Japan. with normal sinus rhythm ivabradine compared to Based on expert advice and and heart rate at or above placebo. Analysis of the data available evidence, the 70 beats per minute (bpm), indicates that cardiovascular MHLW/PMDA have who are unable to tolerate adverse events may be recommended the addition of or have a contraindication associated with the patient's the advice for health-care to the use of beta-blockers, heart rate being less than 60 professionals: “Patients should OR in combination with beats per minute. The be instructed to contact a atenolol 50 mg once daily incidence of bradycardia was doctor if they experience the when angina is high for ivabradine compared symptoms of liver disorder” to inadequately controlled. to placebo (17.9% vs 2.1%), the “Important precautions”  Treatment of symptomatic with more than 30% of the section in package insert. chronic heart failure of New patients in the ivabradine York Heart Association group having a resting heart The MHLW/PMDA also Classes II or III and with rate below 50 beats per minute recommended to revise the documented left ventricular on at least one occasion. title of subsection “Serious ejection fraction ≤ 35% in liver disorder” in the section of The TGA is continuing to adult patients in sinus “Clinically significant adverse monitor all adverse events rhythm and with heart rate reactions” to “Hepatitis and reports involving ivabradine. at or above 77 bpm, in hepatic function disorder” and combination with optimal WHO Pharmaceuticals Newsletter No. 4, 2015  9

Regulatory Matters

Reference: that health professionals FAERS cases from April 2006 Medicines Safety Update, TGA, should be provided further to December 2014 and one Vol. 6, No. 3, June 2015 information about this published case that was not (www.tga.gov.au) potential adverse event. recorded in FAERS. The time to onset of leukoderma after (See WHO Pharmaceuticals Reference: starting methylphenidate Newsletters No.1, 2015 for Risk of Medicines Safety Update, TGA, transdermal system ranged cardiovascular events in Europe, Vol. 6, No. 3, June 2015 from 2 months to 4 years. All No.4, 2014 and No.3, 2014 for (www.tga.gov.au) related information) of the patients described a decrease in or loss of skin

colour. In most cases, the loss of skin colour was limited to Methylphenidate the areas around where the Methotrexate patch was rotated. However, a transdermal system small number of patients also Risk of hepatitis B reported skin colour changes reactivation Permanent skin colour on parts of the body where the changes patch was never applied. In all Australia. The TGA has cases, the decreased skin informed health-care USA. The US Food and Drug colour was permanent. professionals of the update of Administration (FDA) has the Product Information for warned that permanent loss of The FDA is recommending that methotrexate to include a skin colour may occur with use health-care professionals precaution regarding of the methylphenidate consider alternative treatments reactivation of hepatitis B transdermal system (Daytrana for patients who experience virus. The TGA also patch®) for Attention Deficit these skin colour changes. recommends that health Hyperactivity Disorder (ADHD). Reference: professionals closely monitor The FDA has added a new Drug Safety Communication, such patients who are already warning to the drug label to US FDA, 24 June 2015 taking methotrexate. describe this skin condition, (www.fda.gov) which is known as chemical Methotrexate is an leukoderma. immunosuppressive agent with the indication for the treatment The methylphenidate of rheumatoid arthritis, severe transdermal system treats psoriasis and certain types of ADHD symptoms in children Methylprednisolone cancers, including breast and adolescents who are (intravenous cancer, gestational overactive, cannot concentrate choriocarcinoma and for very long, or are easily injection) lymphosarcoma. Its principal distracted and impulsive. mechanism of action is the Risk of liver injury competitive inhibition of the Chemical leukoderma is a skin Canada. Health Canada has enzyme folic acid reductase. condition that causes the skin to lose colour due to repeated announced that evidence of an Up until 21 February 2015, the exposure to specific chemical association between TGA has received two reports compounds. The condition is intravenous of possible hepatitis B not physically harmful, but it is methylprednisolone and the reactivation associated with disfiguring. The areas of skin occurrence of liver injury with methotrexate treatment, which colour loss described with the a variable time to onset. The include one published case. methylphenidate transdermal prescribing information for Analysis of these two cases system ranged up to 8 inches Solu-medrol® and Solu- found that they were in diameter. This condition is medrolact-o-vials® have been confounded by other drug not thought to be reversible, updated to reflect the available therapy. However, a causal which may cause emotional evidence regarding the risk of role for methotrexate could not distress. liver injury. Manufacturers of be excluded. generic versions of this drug The FDA reviewed cases of will also be asked to update Considering the seriousness of chemical leukoderma their product information. complications associated with associated with the hepatitis B reactivation and the methylphenidate transdermal Methylprednisolone is a fact that methotrexate is now system reported to the FDA corticosteroid drug typically the most commonly used first- Adverse Event Reporting used for its anti-inflammatory line drug therapy for System (FAERS) database and effects. Administration into a rheumatoid arthritis in described in the medical vein (intravenous) is generally Australia, the TGA concluded literature. FDA identified 51 only used for short periods in WHO Pharmaceuticals Newsletter No. 4, 2015  10

Regulatory Matters severe inflammatory the-counter (OTC) non-aspirin US FDA, 9 July 2015 conditions. NSAID Drug Facts labels. (www.fda.gov) A safety review was initiated Prescription NSAID labels will (See WHO Pharmaceuticals following the identification of be revised to reflect the Newsletters No.3, 2015, No.2, 28 published international following information: 2015, No.5, 2014, No.5, 2013, cases of liver injury associated  The risk of heart attack or No.4, 2013 and No.6, 2012 for related information) with intravenous stroke can occur as early as methylprednisolone, four of the first weeks of using an which had a fatal outcome. NSAID. The risk may increase with longer use of Up until December 31, 2013, the NSAID. three Canadian reports were Pregabalin  The risk appears greater at received and only one case of higher doses. Risk of abuse liver injury was possibly  It was previously thought associated with intravenous that all NSAIDs may have a Saudi Arabia. The Saudi Food methylprednisolone. similar risk. Newer and Drug Authority (SFDA) has Among the 28 cases identified information makes it less announced that dispensing of in the literature, the time to clear that the risk for heart pregabalin is now restricted to onset of the liver injury varied attack or stroke is similar hospitals and government from several days to several for all NSAIDs; however, primary care centres only. The months. Of these cases, 27 this newer information is drug should no longer be were considered severe, and not sufficient for us to dispensed in community death was reported in four determine that the risk of pharmacies due to increased cases. Patients’ signs and any particular NSAID is local reports of abuse. symptoms of liver injury definitely higher or lower Pregabalin is a gamma- improved when the treatment than that of any other aminobutyric acid (GABA) was stopped in 22 of these 28 particular NSAID. analogue indicated for the cases. When intravenous  NSAIDs can increase the treatment of peripheral and methylprednisolone was risk of heart attack or central neuropathic pain in restarted, liver injury stroke in patients with or adults, as an adjunctive reappeared in almost half of without heart disease or therapy in adults with partial the cases. risk factors for heart seizures with or without disease. A large number of secondary generalisation, for Reference: studies support this finding, Summary Safety Review, the treatment of Generalised with varying estimates of Anxiety Disorder (GAD) in Health Canada, 18 June 2015 how much the risk is (www.hc-sc.gc.ca) adults and for the increased, depending on the management of fibromyalgia. drugs and the doses studied. In 2013, the SFDA had  In general, patients with received several enquiries Non-aspirin heart disease or risk factors regarding the risk of for it have a greater pregabalin abuse. Although Nonsteroidal Anti- likelihood of heart attack or pregabalin is not recognised as Inflammatory Drugs stroke following NSAID use a drug with high potential than patients without these abuse, literature data showed (NSAIDs) risk factors because they that there is an association have a higher risk at between pregabalin and risk of Increased chance of baseline. abuse and dependence. heart attack or stroke  Patients treated with Moreover, there was a marked NSAIDs following a first increase in the utilization of USA. The US FDA has heart attack were more pregabalin products in Saudi announced the strengthening likely to die in the first year Arabia, which raised some of the existing label warnings after the heart attack concerns. As a result, the of non-aspirin NSAIDs for compared to patients who SFDA requested all marketing increased risk of heart attack were not treated with authorisation holders to update or stroke. Based on the FDAs NSAIDs after their first the SmPC, patient information comprehensive review of new heart attack. leaflet and to distribute direct safety information, the FDA  There is an increased risk of health-care professional has requested updates to the heart failure with NSAID communication (DHPC) to drug labels of all prescription use. advise about the potential risk NSAIDs. The FDA will also of abuse. In addition, the SFDA request updates to the over- Reference: published a safety update on Drug Safety Communication, WHO Pharmaceuticals Newsletter No. 4, 2015  11

Regulatory Matters the website regarding this with the use of sorafenib. treated with these products in issue. Hyperthyroidism is a type of Japan. thyroid gland dysfunction Recently, the SFDA received Based on expert advice and where excessive amounts of 30 new local cases of available evidence, the thyroid hormones are released pregabalin abuse from one of MHLW/PMDA have into the blood that may cause the marketing authorisation recommended the addition of a fast heartbeat, tiredness, holders. In most of these cases, “Contraindications” section and weight loss, nervousness the patients obtained subsequent warning against and/or trembling. pregabalin from community use in “Patients with a history pharmacies without There were many case reports of hypersensitivity to any prescriptions. Several of thyroid gland dysfunction ingredients of this product” to communications have also associated with the use of the new section. The been received from different sorafenib in the scientific MHLW/PMDA have also stakeholders supporting the literature, manufacturer's recommended the addition of increased pregabalin abuse. database and the World Health the following texts in the Organization's database at the section of “Adverse reactions” Based on the available time of this safety review. Up in the package insert. evidence, the SFDA until January 31, 2015, there recommended that dispensing Shock and anaphylaxis: were no Canadian reports of of pregabalin products should Shock and anaphylaxis may thyroid gland dysfunction be restricted to hospitals and occur. Patients should be received through the Canada government primary care carefully monitored. If any Vigilance Program. centres only. In addition, the abnormalities such as SFDA distributed a memo The analysis of the cases dyspnoea, decreased blood regarding this issue to all showed evidence that thyroid pressure, rash, etc. are relevant stakeholders and gland dysfunction may occur observed, appropriate published a new safety with sorafenib use, including, measures should be adopted. communication on its website. very rarely, thyroid storm. Reference: Reference: Reference: Revision of Precautions, Saudi Vigilance, Saudi Food Summary Safety Review, MHLW/PMDA, 2 June 2015 and Drug Authority, Health Canada, 28 May 2015 (www.pmda.go.jp/english/) 29 July 2015 (www.hc-sc.gc.ca)

Tramadol Technetium (99mTc) Sorafenib hydrochloride Risk of thyroid gland hydroxymethylenedip Risk of respiratory dysfunction hosphonate injection depression Canada. Health Canada has Risk of shock and Japan. The MHLW and the updated the Canadian anaphylaxis PMDA have announced the prescribing information for revision of the package insert sorafenib (Nexavar®) to Japan. The MHLW and the for tramadol hydrochloride inform health-care PMDA have announced the (Tramal®) to include risk of professionals, caregivers, and revision of the package insert respiratory depression. patients about the risks of for technetium (99mTc) thyroid dysfunction. Thyroid hydroxymethylenediphosphonate Tramadol is used for relief of function monitoring should be (Clearbone®) to include risk of pain. considered before and during shock and anaphylaxis as a The MHLW/PMDA stated that sorafenib use. contradiction. cases associated with Sorafenib is an anti-cancer Technetium (99mTc) respiratory depression have drug from the multikinase hydroxymethylenediphosphonate been reported in patients inhibitor family of drugs used is used as a diagnostic agent treated with tramadol to treat specific types of liver, for bone diseases with hydrochloride or tramadol kidney, and thyroid cancers in scintigraphic imaging of the hydrochloride/acetaminophen adults. bone. in Japan. A safety review was conducted The MHLW/PMDA stated that Based on expert advice and following a published report of cases of shock and anaphylaxis available evidence, the severe hyperthyroidism, known have been reported in patients MHLW/PMDA have as thyroid storm associated recommended the addition of WHO Pharmaceuticals Newsletter No. 4, 2015  12

Regulatory Matters the following texts in the In other country, cases of Reaction with Eosinophilia and section of “Adverse reactions” exfoliative dermatitis and Systemic Symptoms (DRESS). in the package insert. erythrodermic psoriasis have Ziprasidone is an antipsychotic been reported rarely Respiratory depression: indicated for the treatment of (≥1/10,000 to <1/1,000) in Respiratory depression may schizophrenia, related psoriasis patients receiving occur. Patients should be psychoses, prevention of ustekinumab, some of which carefully monitored. If any relapse and for the occurred days after receiving abnormalities are observed, maintenance of clinical dose. It is acknowledged that administration of this drug improvement during there could be a potential for should be discontinued and continuation therapy. It is also confounding by indication in appropriate measures should indicated for the treatment of these cases. be adopted. manic or mixed episodes The HSA decision follows both associated with bipolar Reference: a PRAC and a Health Canada disorder, with or without Revision of Precautions, review. The PRAC concluded psychotic features. MHLW/PMDA, 7 July 2015 that the package insert for (www.pmda.go.jp/english/) DRESS is a serious adverse ustekinumab should be drug-induced reaction that is updated to include the risk of potentially life-threatening with exfoliative dermatitis and skin a mortality rate of up to 10%. exfoliation. In Canada, a It has a delayed onset, usually communication letter was Ustekinumab appearing two to six weeks issued to inform health-care after initiation of the causative Risk of rare but serious professionals about this safety drug. Manifestations of DRESS concern and changes made to skin reactions may include cutaneous the Canadian prescribing reactions such as rash or Singapore. The Health information. exfoliative dermatitis, fever, Science Authority (HSA) has The HSA has advised health- lymphadenopathy, eosinophilia announced that the package care professionals to take into and other systemic inserts of ustekinumab- consideration the above safety complications such as containing products have been information and signs and hepatitis, nephritis, strengthened to include symptoms of erythrodermic pneumonitis, myocarditis, warnings on severe and life- psoriasis or exfoliative pericarditis and pancreatitis. threatening rare but serious dermatitis, when prescribing skin reactions, which could The HSA has not received any ustekinumab. lead to hospitalisation. adverse drug reaction reports Reference: of DRESS associated with Ustekinumab (Stelara®) is a Product Safety Alerts, HSA, ziprasidone-use in Singapore. fully human IgG1κ monoclonal 29 May 2015 antibody, used for the The US FDA reviewed six (http://www.hsa.gov.sg/) treatment of moderate to worldwide cases of DRESS severe plaque psoriasis in (See WHO Pharmaceuticals associated with the use of adult patients who failed to Newsletters No.2, 2015 for Risk of ziprasidone that were reported respond to, or who have a exfoliative dermatitis in the UK and to the FDA Adverse Event contraindication to, or are No.1, 2015 for Serious skin Reporting System (FAERS). In disorders (Exfoliative dermatitis intolerant to other systemic and erythrodermic psoriasis) in all six cases, the signs and therapies including Canada) symptoms of DRESS appeared cyclosporine, methotrexate, between 11 and 30 days after and psoralen combined with ziprasidone treatment was ultraviolet A (PUVA). It is also initiated. Of these, a used to treat adult patients recurrence of symptoms with active psoriatic arthritis Ziprasidone following the discontinuation when the response to previous and re-initiation of ziprasidone non-biological disease- Risk of Drug Reaction was reported for three cases, modifying anti-rheumatic drug with Eosinophilia and where a faster time to onset of (DMARD) therapy has been Systemic Symptoms the symptoms was observed inadequate. (DRESS) following the re-initiation. Three cases were reported to The HSA has not received any Singapore. The HSA has have concomitant therapy with local reports of exfoliative announced that the package drugs associated with the dermatitis and erythrodermic insert for ziprasidone occurrence of DRESS. While psoriasis associated with the (Zeldox®) has been none of the cases reported uses of ustekinumab. strengthened to include death, serious outcomes warnings on the risk of Drug including hospitalisation had WHO Pharmaceuticals Newsletter No. 4, 2015  13

Regulatory Matters been reported. Based on an assessment of these reports, the FDA concluded that an association between ziprasidone use and the occurrence of DRESS was supported, and issued a drug safety communication in December 2014. The FDA requested the package insert of ziprasidone- containing products to be updated to include warnings on the risk of DRESS in US. Health-care professionals in Singapore have been advised to be vigilant to possible signs and symptoms of DRESS, such as skin rash, fever, lymphadenopathy and eosinophilia, in patients prescribed ziprasidone.

Reference: Product Safety Alerts, HSA, 29 May 2015 (http://www.hsa.gov.sg/) (See WHO Pharmaceuticals Newsletter No.1, 2015 for Rare but potentially fatal skin reactions in the US)

WHO Pharmaceuticals Newsletter No. 4, 2015  14

Safety of Medicines

Codeine Cough-and- be used in children below 12 years obese women compared to non for cough and cold in Europe and obese women when using Cold Medicines in No.5, 2013, No.4, 2013 and No.5, combined hormonal birth 2012 for related information) Children control products. Health Canada will continue to Potential risk of serious monitor this issue. side effects Reference: Combined hormonal Summary Safety Review, USA. The US FDA has birth control Health Canada, 23 July 2015 announced the investigation of (www.hc-sc.gc.ca) the safety of codeine- products containing medicines used to treat coughs and colds in Evaluating effectiveness children under 18 years in women who are obese because of the potential for Denosumab serious side effects, including Canada. Health Canada has slowed or difficult breathing. requested that labels for newly No evidence of increased FDA has recommended that marketed combined hormonal risk of cardiovascular parents and caregivers should birth control products in events stop giving their child codeine Canada should contain and seek medical attention information regarding the Canada. After conducting a immediately if they notice any weight and Body Mass Index safety review, Health Canada signs of slow or shallow (BMI) of the people studied in announced that the available breathing, difficult or noisy clinical trials. This information evidence does not support an breathing, confusion, or is not required for older association between unusual sleepiness in their combined hormonal birth denosumab (Prolia®) and the child. control products as it may not risk of cardiovascular adverse be available (for example, BMI events at this time. The risk of Codeine is a specific type of may not have been collected low blood calcium and its narcotic medicine called an during the clinical trials). This effects on heart rhythm (e.g. opioid that is used to treat mild information is being added for QT interval prolongation) is to moderate pain and also to specificity to provide further already described in the reduce coughing. It is usually context on the parameters of prescribing information for combined with other the studies even though, at denosumab. medications in prescription and this time, the current safety Denosumab is a unique OTC cough-and-cold review did not find a higher immune system protein medicines. risk of pregnancy in obese (monoclonal antibody), which women. In April 2015, the European works by binding to, and Medicines Agency (EMA) Combined hormonal birth inhibiting, specific cells that announced that codeine must control products containing remove bone mass, to slow not be used to treat cough and forms of estrogen and bone loss and increase bone cold in children under 12 progestin are used to prevent strength. It is used to treat years, and that codeine is not pregnancy. These products are weak and brittle bones recommended in children and available as pills, skin patches (osteoporosis) and to increase adolescents between 12 and and vaginal rings. The pill is bone mass. 18 years who have breathing the most common form. problems, including those with As of June 30, 2014, Health asthma and other chronic A safety review evaluated Canada identified three cases breathing problems. FDA will information about the risk of of heart rhythm problems (QT continue to evaluate this safety decreased effectiveness of interval prolongation) as issue and will consider the EMA combined hormonal birth possibly related to low blood recommendations. Final control products when used by calcium (hypocalcaemia) due conclusions and women who are obese. Obesity to use of denosumab. Cases of recommendations will be was calculated using a BMI, a cardiovascular events in those communicated when the FDA measure of fat based on a taking denosumab reported review is complete. person's height and weight. internationally, occurred in Women in the safety review patients who had other pre- Reference: were considered obese if they existing risk factors or Drug Safety Communication, had a BMI of 30 kg/m2 or information about the patients US FDA, 1 July 2015 greater. were incomplete. It was (www.fda.gov) therefore difficult to determine The safety review did not find whether the cardiovascular (See WHO Pharmaceuticals a higher risk of pregnancy in Newsletters No.3, 2015 for not to adverse events were caused by WHO Pharmaceuticals Newsletter No. 4, 2015  15

Safety of Medicines the use of denosumab or were congenital heart disease. agranulocytosis. In both cases, due to other reasons. In Diazoxide treatment should be while the patients may have addition, four research articles stopped if pulmonary been exposed to other were identified in the hypertension is identified. medications that could have literature. The frequency of contributed to this reaction, Reference: cardiovascular adverse events the use of febuxostat was Drug Safety Communication, associated with the use of considered the probable cause US FDA, 16 July 2015 denosumab was comparable to of the neutropenia. (www.fda.gov) placebo (sugar pill). Overall, Reference: the link between the use of Summary Safety Review, denosumab and cardiovascular Health Canada, 28 May 2015 adverse events could not be (www.hc-sc.gc.ca) concluded. Febuxostat

Reference: Risk of agranulocytosis Summary Safety Review, Health Canada, 29 May 2015 (severe reduction in the (www.hc-sc.gc.ca) number of white blood Ibuprofen in high cells) dose (≥2400mg/day) Canada. Health Canada has Small increase in requested the manufacturer of cardiovascular risk Diazoxide febuxostat (Uloric®) to submit information updates on the UK. The MHRA and other EU Reports of pulmonary safety of febuxostat. Health medicines regulators have hypertension in infants Canada will monitor and assess reviewed the safety of high- and newborns this information. dose ibuprofen, following the publication of a meta-analysis USA. The US FDA has issued a Febuxostat is an oral of clinical trial data and have warning of potential pulmonary medication used to lower uric concluded that there is an hypertension, (high pressure in acid levels in patients with increase in risk of the blood vessels leading to gout (a painful form of cardiovascular events in people the lungs), in infants and arthritis). taking high dose ibuprofen newborns treated with A safety review was initiated (≥2400 mg). Meta-analysis diazoxide (Proglycem®) for following the identification of data showed that people low blood sugar. international cases of taking ≥2400 mg of ibuprofen The FDA identified 11 cases of febuxostat-associated per day are at a higher risk of pulmonary hypertension in agranulocytosis. arterial thrombotic events infants and newborns treated Agranulocytosis is a condition (heart attack, stroke) than with diazoxide, since the drug involving a severe reduction in people taking placebo. The was approved in 1973. In all the number of white blood review confirmed that this cases, the pulmonary cells, increasing the risk of higher risk is similar to that hypertension resolved or infections. seen with COX-2 inhibitors and improved after diazoxide was At the time of this review, diclofenac. stopped. The FDA is continuing there were no reported cases The European review also to investigate this safety issue of agranulocytosis suspected of considered the latest data on and will determine whether being associated with the use the possible interaction changes are needed in of febuxostat in Canada, between ibuprofen and low- diazoxide prescribing however, the World Health dose aspirin. The latest information. Organization (WHO) Global experimental data confirm Diazoxide is usually given in Individual Case Safety Reports previous findings that the hospital, and health-care database (VigiBase®) ibuprofen competitively inhibits professionals should closely contained 13 international the effect of low-dose aspirin monitor babies receiving it, cases of agranulocytosis on platelet aggregation in vivo, especially those with risk suspected of being associated ex vivo and in vitro. It is factors for pulmonary with the use of febuxostat. uncertain if these data can be hypertension such as Two cases of febuxostat extrapolated to the clinical meconium aspiration associated neutropenia were situation, and clinical data do syndrome, respiratory distress published in the scientific not support a clinically syndrome, transient tachypnea literature. Although meaningful interaction. of the newborn, pneumonia, neutropenia can occur without However, the possibility that sepsis, congenital agranulocytosis, it is an long-term, daily use of diaphragmatic hernia, and important component of ibuprofen might reduce the WHO Pharmaceuticals Newsletter No. 4, 2015  16

Safety of Medicines cardioprotective effects of low-  To consider that these balance of the influenza dose aspirin cannot be recommendations also vaccination remains positive. excluded. apply to dexibuprofen (a Medsafe is continuing to high dose of dexibuprofen is Occasional ibuprofen use is monitor reports of adverse 1200 mg or more per day, unlikely to have a clinically events to the seasonal which is equivalent to 2400 meaningful effect on the influenza vaccination. mg of ibuprofen). benefits of low-dose aspirin.  To consider that no increase Table: Percentage of reports No increased risk of arterial in cardiovascular risk is with hypersensitivity events thrombotic events is seen with seen with ibuprofen at associated with seasonal ibuprofen at doses up to 1200 doses up to 1200 mg per trivalent influenza vaccines mg per day (the highest OTC day (the highest dose since 2011 dose available) compared with available over the counter) Hyper- Hyper- % of Hyper- not taking ibuprofen. There are compared with not taking Year sensitivity sensitivity sensitivity limited data on the risk with ibuprofen. Reactions Reports /Total Reports ibuprofen at doses between Reference: 2011 79 53 23.4 1200 mg and 2400 mg per Drug Safety Update, MHRA, 2012 79 58 29.4 day. It is uncertain whether Volume 8, issue 11: 2, June 2013 146 101 34.6 such doses are associated with 2015 (www.gov.uk/mhra) an increased cardiovascular 2014 110 75 29.4 risk compared with not taking (See page 8 for the action taken 2015* 76 53 36.8 ibuprofen. by Ireland on the same risk) * to 20th May The MHRA has warned health- care professionals when Products Affected: prescribing or dispensing Influenza vaccine The influenza vaccination is ibuprofen: used for prophylaxis against  To avoid use of high-dose Mild hypersensitivity specific strains of the influenza ibuprofen (≥2400 mg per virus in adults and children reactions day) in patients with older than six months of age established: New Zealand. The Medsafe (with the exception of ○ ischaemic heart Fluvax®, which should not be disease. announced that the Centre for Adverse Reactions Monitoring used in children under five ○ peripheral arterial years of age). disease. (CARM) has received an ○ cerebrovascular increased proportion of reports Product name Sponsor of hypersensitivity and local disease. Fluarix® GlaxoSmithKline (NZ) ○ congestive heart failure reactions with the seasonal Fluvax® bioCSL (NZ) (New York Heart influenza vaccination as Association [NYHA] compared with previous years Influvac® BPG Products classification II-III). (see Table). A similar situation Vaxigrip® Sanofi-Aventis ○ uncontrolled has also been reported in hypertension. Australia. Reference:  To review the treatment of Hypersensitivity and local Safety Information, Medsafe, patients with the above reactions reported to the CARM 22 June 2015 conditions who are taking include dyspnoea (shortness of (www.medsafe.govt.nz/) high-dose ibuprofen at their breath), pruritus (itching), next routine appointment. paraesthesias (tingling or  To carefully consider the burning of the skin) and benefits and risks before injection site inflammation, starting long-term redness and pain. In the Latanoprost eye drop ibuprofen treatment for majority of reports the events patients with significant risk were considered to be mild. Increased reporting of factors for cardiovascular None of the cases reported eye irritation since events (e.g. hypertension, have required hospitalisation reformulation hyperlipidaemia, diabetes or been life threatening. mellitus, smoking), UK. The MHRA has particularly if high doses The Medsafe has reminded recommended that health-care are required. health-care professionals and professionals advise patients to  To remind that ibuprofen is consumers that immunization inform a health professional if contraindicated in patients remains the best defence they experience severe eye with severe heart failure. against the influenza virus and irritation with the use of the overall benefit harm latanoprost eye drops.

WHO Pharmaceuticals Newsletter No. 4, 2015  17

Safety of Medicines

Treatment should be reviewed occurred the same night It is recommended that if patients mention severe eye melatonin was taken. In two of patients are informed of the irritation. the three reports, no other signs and symptoms of DKA medicines were reported and (e.g. nausea, vomiting, Latanoprost (Xalatan®) is an in all three reports, symptoms anorexia, abdominal pain, eye-drop licensed for the improved once the medicine excessive thirst, difficulty reduction of intraocular was stopped. Hallucinations breathing, confusion, unusual pressure in adults and children are not currently listed in the fatigue or sleepiness) and are with ocular hypertension and New Zealand data sheet for tested for raised ketones if open angle glaucoma. melatonin. presented with these signs and In 2013, the pH of latanoprost symptoms. Reference: eye drop was reduced from 6.7 Safety Information, Medsafe, The underlying mechanism for to 6.0 to allow for long-term 20 July 2015 SGLT2 inhibitor-associated storage at room temperature. (www.medsafe.govt.nz/) DKA has not been established. Following this reformulation The MHRA will communicate there has been an increase in further advice as appropriate the number of reports of eye once the investigation is irritation from across the EU. complete. The MHRA received no Yellow Sodium glucose co- Card reports of eye irritation in Reference: people using latanoprost eye transporter 2 (SGLT2) Drug Safety Update, MHRA, drop in the year before the inhibitors Volume 8, issue 11: 1, June reformulation, compared with 2015 (www.gov.uk/mhra) 22 reports in the year after (canagliflozin, reformulation. dapagliflozin, Reference: empagliflozin) Drug Safety Update, MHRA, Zoledronic acid Volume 8, issue 12: 2, July Risk of diabetic infusion 2015 (www.gov.uk/mhra) ketoacidosis Risk of acute phase UK. The MHRA has announced response and renal investigations into the risk of diabetic ketoacidosis (DKA) effects Melatonin associated with sodium glucose New Zealand. The Medsafe co-transporter 2 (SGLT2) Possible risk of has reminded health-care inhibitors. hallucinations professionals that patients may SGLT2 inhibitors are licensed experience an acute phase New Zealand. Medsafe has for use in adults with type 2 response or adverse effects on issued an early warning diabetes to improve glycaemic renal function following communicating the potential control. administration of zoledronic risk of hallucinations acid infusion. associated with melatonin Serious and life-threatening (Circadin®). cases of DKA have been Zoledronic acid (Aclasta® and reported in patients taking Zometa®) is a bisphosphonate This reaction has not been SGLT2 inhibitors (canagliflozin, administered to patients by reviewed in detail, however, dapagliflozin or empagliflozin). intravenous infusion. the overall benefit-risk balance of melatonin remains positive. In several cases, blood glucose The CARM has received 153 levels were only moderately reports of musculoskeletal Melatonin prolonged-release elevated (e.g. <14 mmol/L or adverse reactions starting tablets are indicated for the 250 mg/dL), which is atypical within one month after a short term treatment of for DKA. This atypical zoledronic acid infusion. The primary insomnia characterised presentation could delay CARM also received 26 reports by poor quality of sleep in diagnosis and treatment. Half of ocular adverse reactions and patients who are aged 55 or of the cases occurred during 33 reports of urinary adverse over. The recommended dose the first 2 months of reactions within one month is 2 mg once daily and may be treatment. Some cases following an infusion. continued for up to 13 weeks. occurred shortly after stopping Acute phase reactions may the SGLT2 inhibitor. One third The CARM has received three present with the following of the cases involved off-label reports of hallucinations symptoms: chills, fever, use in patients with type 1 associated with melatonin use. influenza-like symptoms, night diabetes. Hallucinations generally sweats, rigors and shivering,

WHO Pharmaceuticals Newsletter No. 4, 2015  18

Safety of Medicines diffuse musculoskeletal pain, gastrointestinal effects, and eye inflammation. Acute phase responses can occur at any time up to approximately two weeks following an infusion. The majority of patients will experience symptoms within the first three days after an infusion. These reactions are usually self-limiting and resolve completely within 24 to 48 hours. However, in some patients symptoms may persist for longer periods. Renal reactions can also occur shortly after infusion.

Adequate hydration can help to reduce the risk of renal deterioration after a zoledronic acid infusion. Renal deterioration, progression to renal failure and dialysis has been reported in patients following the initial dose of zoledronic acid.

If patients show signs of renal function decline after infusion, the benefits and risks of harm of continued treatment should be evaluated. Reference: Prescriber update, Medsafe,

Vol. 36 No.2, June 2015

WHO Pharmaceuticals Newsletter No. 4, 2015  19

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 29). 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].

Atomoxetine and Dystonia in paediatric patients Dr Ian Boyd, Australia

Summary the adolescent and paediatric population. A possible mechanism may be based on inhibition of Atomoxetine is a relatively potent inhibitor of the dopamine uptake. presynaptic noradrenaline transporter, a moderate inhibitor of 5HT uptake, and a weak inhibitor of dopamine uptake with minimal affinity for the Introduction other noradrenergic receptors. It is indicated for the treatment of attention deficit hyperactivity Atomoxetine is a relatively potent inhibitor of the disorder (ADHD) as defined by DSM-IV criteria in presynaptic noradrenaline transporter, a moderate children 6 years of age and older, adolescents and inhibitor of 5HT uptake, and a weak inhibitor of adults. After the elimination of suspected dopamine uptake with minimal affinity for the duplicates there are currently (1 September 2014) other noradrenergic receptors. Atomoxetine has 31 individual case safety reports (ICSRs) in the moderate affinity for 5HT2 and GABAA receptors WHO Global ICSR database, VigiBase® of dystonia but poor affinity for most other receptors. It is in association with atomoxetine for children and indicated for the treatment of attention deficit adolescents up to 17 years of age. The reports are hyperactivity disorder (ADHD) as defined by DSM- from Australia, Canada, Germany, Italy, Japan, IV criteria in children 6 years of age and older, New Zealand, South Africa, Spain, Switzerland and adolescents and adults. The most frequent adverse the United States. Atomoxetine was the only drug reactions reported during clinical trials of suspected in 21 of the 31 cases. The outcome of atomoxetine in children and adolescents include the dystonia was indicated in 17 reports. The gastrointestinal reactions, increased blood patients were reported as recovered or recovering pressure and heart rate, decreased appetite, in 16 cases and not recovered in the remaining decreased weight and skin reactions. Common case. In the cases where recovery was reported, neuropsychiatric reactions reported included the drug was withdrawn in 13 cases, continued in dizziness, mood swings, somnolence, insomnia, one case and the fate of the drug was unknown in irritability and depression.1 the remaining two cases. Dystonia denotes abnormal movements that are Case reports in VigiBase® suggest that there is a slow or so sustained that they may appear as possible signal for the association of atomoxetine abnormal postures. These abnormal movements of and dystonia. The fact there was a positive groups of muscles or body segments include dechallenge in 13 of the 16 reports where grimacing, torticollis, blepharospasm and limb recovery was documented is suggestive of a drug- torsions. Generally, they are absent during sleep induced effect. However, the possible association and exacerbated by emotional stress or voluntary of atomoxetine with dystonia appears restricted to activity. Dystonia occurs as an occasional

WHO Pharmaceuticals Newsletter No. 4, 2015  20

Signal complication of treatment with neuroleptic and In seven of these 10 cases, at least one of these dopaminergic drugs and many others. Drug- drugs (olanzapine, ziprasidone, risperidone, induced dystonia may be early (onset within one chlorpromazine) is a likely cause. Antipsychotic week of commencement of treatment) or late drugs are a well-known cause of dystonia and the (onset after several weeks, months or years of four drugs listed above all refer to dystonia as a treatment). Late persistent dystonia is usually possible adverse effect in their product termed tardive dyskinesia.2 information.3 Concomitant drugs were reported in 20 of the 31 cases and showed a similar trend to Dystonia is a preferred term in WHO-ART with a that observed with the co-suspected drugs with number of included terms including trismus and considerable use of antipsychotic, anticonvulsant, various spasms (facial, infantile, cervical, and antidepressant drugs along with the use of oropharyngeal, tongue). other treatments for ADHD.

Time to onset was reported in only two of the Reports in VigiBase® reports and ranged from the same day the drug was administered to 24 days. The outcome of the As of 1 September 2014, after the elimination of dystonia was indicated in 17 reports. The patients suspected duplicates, there are a total of 40 were reported as recovered or recovering in 16 individual case safety reports (ICSRs) of dystonia cases and not recovered in the remaining case. In in association with atomoxetine in the WHO Global the cases where recovery was reported, the drug ICSR database, VigiBase®. Out of these reports was withdrawn in 13 cases, continued in one case there are 31cases of dystonia in children and and the fate of the drug was unknown in the adolescents up to 17 years of age (Table 1). Of remaining two cases. In the case where the the remaining reports one is a 51 year old and one patient had not recovered, the drug was a 24 year old and the rest are have reported age continued. unknown. The reports from children and adolescents were submitted from the United The indication for use was stated in 23 reports and States (20 reports), Australia (2), South Africa (2), indicated ADHD or a related disease in all 23 Canada, Germany, Italy, Japan, New Zealand, cases. Dosage ranged from 10 mg to 160 mg Spain and Switzerland (1 each). The patients (median: 25 mg) in the 16 cases which reported ranged in age from 5 to 17 years with a median of this information. 9 years. There were 23 males and 8 females. Other reactions were reported in 26 of the 31 Atomoxetine was the only drug suspected in 21 of reports. Other neuropsychiatric reactions were the 31 cases. There were other drugs also reported in 23 of those reports and six reports suspected in the remaining 10 cases and they described gastrointestinal reactions. Changes in included drugs for treatment of psychotic disorders drug levels, changes in therapeutic response or in seven cases, drugs for treatment of depression medicine ineffective were reported in eight cases. (3 cases), epilepsy (3 cases) and ADHD (3 cases).

Table 1. Case overview of reports from children and adolescents in VigiBase® of dystonia in association with atomoxetine

Case Age/Sex Other suspected (S) or concomitant Reactions (WHO-ART preferred terms) Outcome

1 10/M Buspirone, citalopram, diphenhydramine, Dystonia, drug interaction, drug level decreased, EEG Unknown methylphenidate, risperidone, valproic abnormal, muscle contractions involuntary, saliva increased,

acid (all C) somnolence, mental status changes*

2 16/F Olanzapine (S) Dystonia, coma, tongue disorder Unknown

Valproic acid (C)

3 10/M Fluvoxamine, quetiapine (both C) Dystonia, agitation, anxiety, asthenia, nausea, paraesthesia, Recovered SGOT increased, somnolence, drug level changed*, pain in

extremity*

4 7/M None Dystonia, abdominal pain, azotaemia, dyskinesia, eye Unknown abnormality, fever, hypercalcaemia, leukocytosis, opisthotonos,

pharyngitis, phosphatase alkaline increased, therapeutic

response decreased, varicella, vomiting, eye injury*, eye

penetration*, treatment noncompliance*

5 9/F Olanzapine (S) Dystonia, therapeutic response increased Recovered

Dexamfetamine sulfate/amfetamine sulfate/dexamfetamine saccharate/

amfetamine aspartate (C)

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6 16/F Dexamfetamine sulfate/amfetamine Dystonia, hallucination, medication error, muscle contractions Recovered sulfate/dexamfetamine saccharate/ involuntary

amfetamine aspartate (C)

7 15/F Dexamfetamine sulfate/amfetamine Dystonia, diplopia, hallucination, medication error, muscle Recovered sulfate/dexamfetamine saccharate/ contractions involuntary, mydriasis, self-medication*

amfetamine aspartate (C)

8 16/F Levosalbutamol (C) Dystonia, blepharospasm, dizziness, drug interaction, Unknown

hypokinesia, speech disorder, tremor

9 8/F Risperidone (C) Dystonia Recovered

10 12/F None Dystonia, blepharospasm, dyskinesia, pruritus, therapeutic Recovered

response decreased

11 9/M Bupropion, oxcarbazepine, quetiapine, Dystonia Unknown

risperidone, valproic acid (all S)

12 9/M Methylphenidate, ziprasidone (both S) Dystonia, anorexia, choreoathetosis, convulsions grand mal, Recovered

saliva increased, jaw disorder*

Valproic acid (C)

13 10/M Oxybutynin (S) Dystonia, drug interaction, dyspnoea, extrapyramidal Recovered disorder, face oedema, mental deficiency, muscle contractions

involuntary, musculoskeletal disorder, neuralgia, pain, skeletal

pain, speech disorder, tachycardia, tenderness NOS, tetany

14 17/M Guaifenesin/dextromethorphan Dystonia, tachycardia, therapeutic response increased, Unknown

hydrobromide (C) amphetamines positive*

15 13/M None Dystonia, condition aggravated, muscle contractions Recovered

involuntary

16 8/M None Dystonia, medicine ineffective, muscle contractions involuntary Recovering

17 10/M Risperidone, sertraline (both C) Dystonia, dysphagia, accident NOS Unknown

18 8/M Loratadine (C) Dystonia, abdominal pain, dizziness, insomnia, muscle Recovered

contractions involuntary, nausea, somnolence

19 5/M Risperidone (C) Dystonia, muscle contractions involuntary Unknown

20 11/M Lamotrigine (C) Dystonia Not recovered

21 6/M None Dystonia, extrapyramidal disorder, muscle contractions Unknown

involuntary, jaw disorder*

22 15/M None Dystonia, paraesthesia Recovered

23 15/F Fluoxetine (S) Dystonia, agitation, amnesia, anxiety, coma, convulsions grand Unknown mal, headache, hypertension, oculogyric crisis, tachycardia,

Bupropion, fluoxetine (both C) urinary incontinence, tongue biting*

24 9/M Methylphenidate (S) Dystonia, extrapyramidal disorder Unknown

25 5/M Risperidone (S) Dystonia Recovered Valproic acid (C)

26 9/M Acetylsalicylic acid, risperidone, valproic Dystonia, dyskinesia Unknown acid (S)

27 8/M Periciazine (C) Dystonia Recovered

28 9/M Fluticasone, paracetamol, salbutamol, Dystonia, anxiety Recovered salmeterol (C)

29 13/M Risperidone (C) Dystonia, diarrhoea bloody, extrapyramidal disorder, fatigue, Unknown gastritis, hepatic enzymes increased, oedema generalised, urine abnormal, vomiting, weight decrease

30 5/M Amfetamine, aripiprazole, carbamazepine, Dystonia, aggressive reaction, anxiety, choreoathetosis, crying Unknown chlorpromazine, clonidine, dexamfetamine, abnormal, coordination abnormal, depression, dyskinesia, iloperidone, lisdexamfetamine, lithium, emotional lability, fatigue, hyperkinesia, infection bacterial, methylphenidate, quetiapine, valproic acid, insomnia, medicine ineffective, nervousness, sleep disorder, ziprasidone (S) speech disorder, suicide ideation, teeth-grinding, decreased eye contact*, homicidal ideation*, oppositional defiant disorder*

31 5/M Risperidone (S) Dystonia, convulsions Recovered

NOS = Not otherwise specified *MedDRA terms

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Literature and Labelling a possible mechanism. It is also possible that children and adolescents may be at greater risk as The product literature does not refer to dystonia it is known that younger age is a risk factor for the although it does mention that very common, development of dystonia in patients receiving common or uncommonly reported neurological antipsychotic treatment.3 reactions included headache, dizziness, somnolence including sedation, insomnia, syncope and tremor. Post-marketing adverse neurological Conclusion events reported very rarely include seizures, paraesthesia in children and adolescents, In summary, there are 31 reports associating hypoaesthesia and tics.1 No reports of dystonia in dystonia with the use of atomoxetine from children association atomoxetine could be found in the and adolescents. Atomoxetine was the only drug literature. suspected in 21 of the 31 cases. The fact there was a positive dechallenge in 13 of the 16 reports

where recovery was documented is suggestive of a Discussion drug-induced effect. However, the possible association of atomoxetine with dystonia appears Case reports in VigiBase® suggest that there is a restricted to the adolescent and paediatric possible signal for the association of atomoxetine population. A possible mechanism may be based and dystonia in children and adolescents. on inhibition of dopamine uptake. Atomoxetine was the only drug suspected in 21 of the 31 cases. In the remaining 10 cases, other suspected drugs would appear to be a more likely References cause in seven reports but atomoxetine would appear an equally likely cause in the other three 1. Therapeutic Goods Administration. Product cases. Information for Strattera. URL: Time to onset was reported in only two of the https://www.ebs.tga.gov.au/ebs/ reports and ranged from the same day the drug picmi/picmirepository.nsf/pdf?OpenAgent&id= was administered to 24 days. The outcome of the CP2010-PI-04269-3. Accessed: 30 January dystonia was indicated in 17 reports. The patients 2015. were reported as recovered or recovering in 16 2. The Council for International Organizations of cases and not recovered in the remaining case. In the cases where recovery was reported, the drug Medical Sciences (CIOMS). Reporting Adverse was withdrawn in 13 cases, continued in one case Drug Reactions: Definitions of Terms and and the fate of the drug was unknown in the Criteria for their Use. CIOMS, Geneva, 1999. remaining two cases. In the case where the URL: http://www.cioms.ch/publications/ patient had not recovered, the drug was reporting_adverse_drug.pdf. Accessed: continued. The fact there was a positive 30 January 2015. dechallenge in 13 of the 16 reports where 3. Jimenez-Jimenez FJ, Garcia-Ruiz PJ, Molena recovery was documented is suggestive of a drug- induced effect. JA. Drug-induced movement disorders. Drug Saf. 1997;16:180-204. The possible association of atomoxetine with 4. Casey DE. Neuroleptic drug-induced dystonia appears restricted to the adolescent and extrapyramidal symptoms and tardive paediatric population. There is a total of 33 reports of dystonia in association with atomoxetine in the dyskinesia. Schizo Res 1991;4:109-20. total population where the age is known. Thirty- one of these reports were reported in the adolescent and paediatric age groups which represents 93.9% of all the reports. While it may be considered that atomoxetine is used preferentially in the younger age groups, overall reporting in VigiBase® indicates that of the 16,592 reports submitted, the age group from 2 to 17 years represents 72.3% of the total reports in which the age is known.

The pathophysiological mechanisms underlying acute extrapyramidal symptoms such as dystonia are usually attributed to the effects of dopamine receptor blockade in the basal ganglia.4 As atomoxetine is a weak inhibitor of dopamine uptake, it is possible that this may be the basis of

WHO Pharmaceuticals Newsletter No. 4, 2015  23

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Response from Eli Lilly & associated with dystonic or other similar movement effects and hence, may also possibly be Company confounded. Based on in vivo preclinical data, atomoxetine Thank you for the opportunity to provide our enhances dopamine release in the prefrontal comments on the thorough assessment conducted cortex, but not in the basal ganglia (i.e. striatum; by Dr Boyd. Eli Lilly & Company (Lilly) routinely Bymaster et al. 2002). Therefore, the mechanism queries reported adverse events in databases by which atomoxetine could stimulate an induced (Lilly’s internal safety database and FDA Adverse dystonia via the dopaminergic pathway is unclear. Event Reporting System) for early signs of In the current report, no rechallenge information potential adverse drug reactions in patients was included, so Lilly presumes that none of the treated with Lilly drugs. Lilly recognizes the case reports involved a rechallenge situation. importance of early signal detection and also Positive dechallenge was, however, described in acknowledges that database queries are only one 13 of the 16 reports where recovery was method that can be employed. Additionally, Lilly’s documented. The significance of this information is reviews of the spontaneously reported adverse not entirely clear as it was not mentioned if events involve medical assessment of the atomoxetine alone was stopped or if any narratives where information provided and not concomitant medications (neuroleptics, captured in the standard fields often helps to antidepressants, stimulants, or other drugs) were refine the assessment. stopped at the same time as atomoxetine or if the Consistent with the Uppsala Monitoring Centre, dystonia events may have been treated with Lilly recognizes that signals are uncertain and pharmacological intervention. All of these factors preliminary in nature (Uppsala Monitoring Centre, would confound the assessment. Signals selected by UMC and the clinical review Although Lilly regularly conducts ongoing panel: How the process works). This is because, surveillance, including automated signal detection for any given adverse event report considered in for all its medications, Lilly has not previously generating a signal, there is no certainty that the identified a signal for dystonia with atomoxetine adverse event was caused by the suspected drug. from any of our available data sources, including Rather, the adverse event could have resulted clinical trials. As noted in Dr Boyd’s evaluation, no from the underlying condition being treated, a reports of dystonia in association with atomoxetine comorbid condition, a concomitant medication, or could be found in the literature. Nevertheless, Lilly may simply be the result of chance. takes the information provided by the Uppsala Treatment-emergent dystonias have been Monitoring Centre seriously, and therefore, based associated with reduced dopamine on the possible signal reported by Dr Boyd, plans neurotransmission in the basal ganglia, as typically to conduct a comprehensive review of dystonia described with antipsychotic medications such as events in atomoxetine-treated patients. risperidone or quetiapine (Tarsy and Simon, 2006). In this respect, it is pertinent that References atomoxetine and other attention deficit hyperactivity disorder (ADHD) medications are not 1. Bymaster FP, Katner JS, Nelson DL, Hemrick- infrequently given in conjunction with concomitant Luecke SK, Threlkeld PG, Heiligenstein JH, medications including antipsychotic medications to Morin SM, Gehlert DR, Perry KW. Atomoxetine treat the commonly occurring comorbid conditions increases extracellular levels of associated with ADHD. Furthermore, as Dr Boyd norepinephrine and dopamine in prefrontal mentioned in his assessment, younger individuals may be at greater risk of developing dystonia cortex of rat: a potential mechanism for when they receive antipsychotic treatment. Lilly efficacy in attention deficit/hyperactivity agrees with Dr Boyd’s observation that in seven of disorder. Neuropsychopharmacology. the 31 cases co-suspect antipsychotic medications 2002;27(5):699-711. were a likely cause. Lilly also agrees with 2. Tarsy D, Simon DK. Dystonia. N Engl J Med. Dr Boyd’s comment that, upon review of the data 2006;355:818-829. in Table 1, concomitant drugs were reported in 20 of the 31 cases and that these showed a similar trend to that observed with the co-suspected drugs with considerable use of antipsychotic, anticonvulsant, and antidepressant drugs. This observation seems to indicate that, although not considered suspect per se, many cases involved concomitant medications that have been

WHO Pharmaceuticals Newsletter No. 4, 2015  24

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Vemurafenib and Tumour lysis syndrome Dr Birgitta Grundmark, Sweden and Uppsala Monitoring Centre

Summary While the VigiBase® cases herein are few and contain a relative scarcity of data and TLS is Tumour Lysis Syndrome (TLS) in relation to considered by some merely as a consequence or a treatment of malignant melanoma with sign of effective treatment regardless of type, the vemurafenib has been identified and filtered as a TLS finding is discussed here as a signal of a new potential signal from the WHO Global Individual adverse drug reaction for vemurafenib. Case Safety Report (ICSR) database, VigiBase®. TLS is a rare, potentially fatal syndrome caused by a sudden massive lysis of tumour tissue with Reports in VigiBase® severe electrolyte disturbances and threat of kidney failure as a result. TLS has classically been A search in VigiBase® in August 2014 retrieved observed in association with chemotherapeutic four reports on TLS associated with vemurafenib agents in the treatment of hematologic and treatment. The cases originated from Germany lymphatic malignancies. With the arrival of new and the US, and presented with varying degree of targeted drugs in oncology and their growing and information. important role, during the last decades TLS has increasingly begun to be reported in association Case 1: A 24-year-old male study patient was with the treatment of solid tumours, including treated for malignant melanoma with vemurafenib malignant melanoma. In this setting the possibility at a dose of 960 mg twice daily. Dates of of TLS could initially be overlooked with the risk of treatment and onset of symptoms, medical history detrimental effects for the patient. Analysis of or concurrent illness, and concomitant or past current available information suggests that medication were not recorded. The patient was vemurafenib may cause TLS and that informing admitted to hospital with severe worsening of oncologists about this rare event would be of value general condition, abdominal complaints, flank to increase patient safety. pain, nausea, vomiting and proteinuria and was diagnosed with TLS. The therapy, outcome and any causality assessment by the reporter was not provided. The marketing authorisation holder Introduction (MAH) assessed the TLS as related to Four cases of Tumour Lysis Syndrome (TLS) in vemurafenib. association with vemurafenib treatment have been Case 2: A 58-year-old female patient was treated identified and filtered as a potential signal from for malignant melanoma with vemurafenib in a the WHO Global Individual Case Safety Report dose of 960 mg twice daily. Concomitant (ICSR) database, VigiBase®. medications were enoxaparin, metoclopramide, Vemurafenib is a B-Raf enzyme inhibitor indicated betamethasone, orlistat, levothyroxine, for the treatment of malignant melanoma.1 It was omeprazole, and paracetamol. The diagnosis of first approved in 2011 in the US, and has since TLS was reported after five days of vemurafenib been approved in other countries including treatment. The patient recovered within three Canada, and in the EU. Vemurafenib causes weeks. No further relevant information was programmed cell death and works in about 60% of provided but the narrative mentions a previous melanoma patients whose cancer has either a TLS report on a 40-year-old female for which the V600E BRAF mutation or the more rare BRAF investigator assessed vemurafenib to be related to V600K mutation. Melanoma cells without these the event. Among the concomitant medications mutations are not inhibited by vemurafenib; noted in this case was the corticosteroid instead the drug paradoxically stimulates normal betamethasone. Corticosteroids are among the BRAF and may promote tumour growth in such agents classically associated with TLS. Treatment cases. time and time to onset was not reported in relation to the concomitant drug betamethasone, TLS is a rare and potentially fatal syndrome where and it was not clear whether the drug was a sudden, rapid and massive lysis of tumour tissue administered before or as treatment after the occurs, resulting in severe disturbances in event. electrolytes and renal failure.2 TLS has predominantly been observed in association with Case 3: A patient of unknown gender and age was various treatments for hematologic malignancies treated for malignant melanoma with vemurafenib but has also been described with the treatment of with an unknown dose. The patient’s medical solid tumours; e.g. a handful of cases having been history, concomitant medication, concurrent reported in scientific literature in patients under conditions and past drugs were not reported. After treatment for malignant melanoma.3,4,5,6,7,8 an unspecified amount of time the patient died due to TLS; in the opinion of the reporter this was WHO Pharmaceuticals Newsletter No. 4, 2015  25

Signal related to the treatment with vemurafenib. The hypocalcaemia, hyperphosphataemia, patient was enrolled in a healthcare providers’ hyperkalaemia with subsequent risk of acute programme for malignant melanoma. The kidney failure, cardiac arrhythmia and seizures1 narrative indicated that this case actually with a case classification definition suggested by described two different patients experiencing the Cairo and Bishop in 2004.9 The incidence of TLS in event as described above. different diagnoses is not known in any detail due to the variability of patients in cohorts investigated Case 4: A male patient was reported to have and a lack of standard diagnostic criteria used in experienced TLS while receiving treatment with studies. The vast majority of data on TLS vemurafenib. No further relevant information was incidence refer to hematologic malignancies with provided. an incidence range between 0 and 23% and a As is noted from the case descriptions above, the fatality rate ranging between 0 and 2.5%.1 The four cases of TLS reported in relation to treatment high end incidence in some publications may with vemurafenib do not themselves contain appear to include cases of TLS diagnosed based on enough background information to allow for a high laboratory data without significant clinical quality causality assessment. manifestation. In solid tumours data is scarce with an incidence of TLS of 0.02% reported for In VigiBase® a total of 1,157 reports of TLS for all colorectal cancer.1 drugs in the database were present as of 12 August, 2014. The cases were predominately TLS has been described in association with from the US, a majority of them concerned men, different treatment modalities including middle-aged and older, and almost all of them had chemotherapy, radiation and steroids and when been reported after 1 January, 2001. none of these modalities is present even as occurring spontaneously.2 Among solid tumours Between 1 January and 12 August, 2014, One TLS has been seen - as expected - in both highly hundred ten TLS cases were reported to chemosensitive tumours (e.g. small cell VigiBase®. Half (55) of these cases concerned carcinomas and germ cell tumours) and also in treatments for hematologic malignancies, 30 tumours less sensitive to treatment such as patients were treated for solid malignancies and malignant melanoma.2,4,5,6,7,8 25 were treated for an unknown indication. Most commonly reported solid malignancy treatment In TLS case histories reported in literature, in indications were breast cancer (n=5) and association with malignant melanoma, the TLS has colorectal cancer (n=6). Among TLS cases in solid occurred spontaneously or within hours to days of malignancies and cases of unknown indication two treatment described as corticosteroids, classic thirds were treated with modern biologic/targeted chemotherapy, monoclonal antibodies, interleukin, therapy while one third were reportedly treated interferon and combinations of these. with classic chemotherapy agents or steroids only. The detailed mechanism by which TLS is induced The signal for vemurafenib may be seen as a part in malignant melanoma and other malignancies is of a larger pattern increasing reporting of TLS in largely unknown although any drug causing death cancer treatments in general, in line with of cancer cells by any mechanism may lead to TLS increased effectiveness of modern targeted anti- in certain circumstances. In lymphatic tumours, cancer drugs. corticosteroids may induce the production of endonucleases in the malignant cells of melanoma, which leads to DNA fragmentation and eventually 2 Literature and Labelling cell lysis. According to the approved EU SPC the most Treatment of TLS includes supportive care common side effects of vemurafenib treatment are including preservation of renal function, prevention arthralgia, fatigue, skin reactions, light sensitivity of cardiac arrhythmias and seizures. Preventive reactions, nausea, alopecia and pruritus.3 TLS, or measures for high risk patients with lymphomas signs and symptoms associated with TLS such as and leukaemias include prophylactic allopurinol or 10 acute renal failure, other renal side effects, rasburicase. hyperuricaemia, hypocalcaemia, hyperphosphataemia, and hyperkalaemia are not labelled side effects of vemurafenib according to Discussion and Conclusion the EU SPC. The four VigiBase® cases of TLS reported in TLS is a feared acute and potentially fatal side relation to treatment with the new biologic drug effect of treatment of primarily hematologic or vemurafenib do not contain sufficient background lymphatic malignancies caused by abrupt, massive information to allow for a high quality causality tumour cell death. It is a complication of the assessment. In the literature a handful of cases of treatment of bulky, highly proliferative, TLS in relation to malignant melanoma have ever chemoresponsive disease. Signs and symptoms been published, none of which concern treatment associated with TLS are hyperuricaemia,

WHO Pharmaceuticals Newsletter No. 4, 2015  26

Signal with vemurafenib but rather with other drugs or Nephrol Dial Transplant. 2001 Jan;16(1):188- drug combinations. 9. The reporting pattern in VigiBase® of TLS as an 8. Castro MP, VanAuken J, Spencer-Cisek P, adverse drug reaction for any drug during recent Legha S, Sponzo RW. Acute tumor lysis years would suggest an overall increase in the syndrome associated with concurrent incidence of TLS in association to targeted cancer biochemotherapy of metastatic melanoma: a therapy and in solid tumour indications. In line case report and review of the literature. with this some authors have noted that TLS would Cancer. 1999 Mar 1;85(5):1055-9. be expected to increase also in non-hematologic malignancies with more effective treatment, i.e. 9. Cairo MS, Bishop M. Tumour lysis syndrome: targeted therapy, including vemurafenib. A causal new therapeutic strategies and classification. relationship between vemurafenib and TLS is in Br. J Haematol. 2004 Oct;127(1):3-11. light of this and with the reported cases not 10. Bose P, Qubaiah O. A review of tumour lysis unlikely, as any effective cancer therapy can lead syndrome with targeted therapies and the to TLS. As mentioned previously, while being a role of rasburicase. J Clin Pharm Ther. 2011 signal of a serious side effect, the association Jun;36(3):299-326. could equally be seen as a sign of an effective treatment. Physicians treating solid tumours should be made aware of the apparent increased risk of TLS with vemurafenib or other targeted therapies to be able to determine on a case-by- case basis the need for immediate treatment Response from Roche should TLS appear and also for appropriate prophylaxis. In November 2014 the WHO collaborating centre for international drug monitoring in Uppsala References invited Roche to comment on a potential signal of TLS in melanoma patients treated with 1. EU-SPC for vemurafenib. URL: vemurafenib. They cited 4 cases of TLS associated http://www.ema. with vemurafenib treatment in their global ICSR europa.eu/docs/en_GB/document_library/EPA database, VigiBase®. The report concluded that R_-_ Product_Information/human/002409/ the information was insufficient for causality WC500124317. pdf. Accessed: August 2012. analysis, but raised concerns over the lack of 2. Howard SC, Jones DP, Pui CH. The tumor lysis clinician awareness of TLS and potential causality syndrome. N Engl J Med 2011; 364:1844-54. with vemurafenib. 3. Mouallem M, Zemer-Wassercug N, Kugler E, TLS is an uncommon but potentially fatal Sahar N, Shapira-Frommer R, Schiby G. syndrome caused by massive tumour cell lysis. Tumor lysis syndrome and malignant This leads to severe electrolyte abnormalities and is often accompanied by acute renal failure. TLS melanoma. Med Oncol. 2013;30(3):364. most often occurs after cytotoxic therapy for 4. Borne E, Serafi R, Piette F, Mortier L. Tumour certain types of lymphoma and leukaemia. TLS lysis syndrome induced by corticosteroid in also occurs in other tumour types that possess metastatic melanoma presenting with initial high proliferative rate, large tumour burden, or hyperkalemia. J Eur Acad Dermatol Venereol. high sensitivity to cytotoxic therapy. In addition, 2009 Jul;23(7):855-6. TLS has been described to occur spontaneously 5. Nakamura Y, Nakamura Y, Hori E, Furuta J, and with other treatment modalities such as radiation and corticosteroids1. TLS in solid tumours Ishii Y, Takahashi T, et al. Tumor lysis is felt to be a rare phenomenon, and in 2010 an syndrome after transcatheter arterial infusion expert panel2 did not recommend routine TLS of cisplatin and embolization therapy for liver prophylaxis for solid tumours as the estimated risk metastases of melanoma. Int J Dermatol. was below 1 percent. 2009 Jul;48(7):763-7. Vemurafenib inhibits mutant BRAFV600 and is 6. Habib GS, Saliba WR. Tumor lysis syndrome approved for the treatment of metastatic after hydrocortisone treatment in metastatic melanoma (mM) harbouring this mutation. To melanoma: a case report and review of the date, there has been no described mechanistic literature. Am J Med Sci. 2002 association between the RAF/MEK/ERK pathway Mar;323(3):155-7. Review. and TLS. TLS has also not been described with dabrafenib, another BRAF inhibitor. Currently the 7. Stoves J, Richardson D, Patel H. Tumour lysis vemurafenib reference safety information does not syndrome in a patient with metastatic include TLS as an adverse drug reaction. melanoma treated with biochemotherapy.

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Preclinical studies do not support an association cases of TLS in mM induced by corticosteroid with TLS. therapy alone4. The literature describes TLS as rare in mM3, and The second case involved an adult female patient there is no epidemiological assessment of the true treated with vemurafenib for mM. TLS was incidence of TLS in mM. Our literature search via diagnosed 31 days after vemurafenib initiation PubMed current as of 3 December 2014 revealed a when the patient developed fevers and chills. The total of 11 case reports of TLS in mM patients only laboratory results available were white blood since 1994. All 11 cases described patients with cell counts, neutrophil counts, and LDH, which bulky or widely metastatic disease with liver were all normal. Vemurafenib was stopped on the involvement. TLS was attributed to chemotherapy same day but was resumed on an unspecified date in 5 cases, biological therapy in 1 case, and TLS was reported as resolved on day 36. This corticosteroids alone in 2 cases, radiation alone in case failed to meet case definition for TLS and was 1 case, and occurred spontaneously in 1 case. notable for the unusually long latency between Acute renal failure occurred in 10 patients. therapy initiation and TLS onset. As of August 2014, the estimated number of We identified 6 cases of TLS in our safety patients exposed to vemurafenib was 28,809 and database, but 4 cases lacked sufficient information calculated patient-years of 17,729. The Roche for further analysis. Of the remaining 2 cases, 1 Global Safety Database (RGSD) contained 6 cases case failed to meet case definition for TLS of TLS, and included all 4 cases described in the primarily due to long latency. In the lone case that WHO report. We further analysed these 6 cases by did meet the case definition for TLS, it was applying the case definition of TLS established by confounded by concomitant corticosteroids. Our Cairo and Bishop2. The Cairo and Bishop overall assessment showed temporal association classification of laboratory TLS stipulates that 2 or and a plausible mechanism of action. This signal, more of the following lab changes occur within 3 however, lacked statistical correlation, was not days before and 7 days after starting therapy. specific, and was not supported by experimental These lab changes are: hyperuricaemia, evidence or an analogous drug reaction. We found hyperkalaemia, hyperphosphatemia, and no convincing evidence in our analysis to support a hypocalcaemia. Clinical TLS occurs when these lab causal relationship between vemurafenib and TLS changes are accompanied by increased creatinine at this time. Roche recognizes this signal involving level, seizures, cardiac dysrhythmia, or death. TLS and vemurafenib in mM and will continue to monitor the events of TLS through routine All 6 cases of TLS in the RGSD were medically pharmacovigilance activities. confirmed; 5 patients were treated with vemurafenib for mM and 1 patient for hairy cell leukaemia. These 6 cases reflect a crude reporting References rate of 3.4 per 10,000 patient-years. Excluding the hairy cell leukaemia case the 5 cases involving mM 1. McBride A, Westervelt P. Recognizing and reflect a crude reporting rate of 2.8 per 10,000 managing the expanded risk of tumor lysis patient-years. Of the 6 cases, 1 case had acute syndrome in hematologic and solid renal failure and 1 case had a fatal outcome, both malignancies. Journal of Hematology & involving mM patients. It was unclear if the fatal outcome was associated with TLS. A quality Oncology 2012; 5:75. assessment was not possible for 4 cases that 2. Cairo M. S., Coiffier B., Reiter A., Younes A. failed to contain sufficient information to apply the and on behalf of the TLS Expert Panel. TLS case definition. These 4 cases also failed to Recommendations for the evaluation of risk provide the timing of vemurafenib initiation and prophylaxis of tumour lysis syndrome relative to the onset of TLS and did not provide (TLS) in adults and children with malignant sufficient clinical information to support the diseases: an expert TLS panel consensus. diagnosis of TLS. Therefore the case definition was applied to the remaining 2 cases. British Journal of Haematology 2010; 149: 578–586. The first case involved an adult female patient who 3. Mouallem M, Zemer-Wassercug N, Kugler E, was treated with vemurafenib for mM. TLS was diagnosed 5 days after vemurafenib initiation but Sahar N, Shapira-Frommer R, Schiby G. the patient eventually recovered from the event. Tumor lysis syndrome and malignant This case met the case definition of TLS based on melanoma. Medical Oncology 2013; 30:364. laboratory abnormalities and acute renal failure. 4. Habib GS, Saliba WR. Tumor lysis syndrome Vemurafenib was stopped on day 6 but resumed after hydrocortisone treatment in metastatic on day 22, while TLS was reported as resolved on melanoma: A case report and review of the day 58. This patient had risk factors for TLS literature. The American Journal of the including bulky tumour and concomitant glucocorticoid therapy. The literature contains Medical Sciences 2002; 323(3):155-7.

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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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Summary of Recommendations from the Twelfth Meeting of the WHO Advisory Committee on Safety of Medicinal Products (ACSoMP) 15-16 April 2015, Geneva

The WHO Advisory Committee on Safety of Medicinal Products (ACSoMP) has been constituted to provide advice on Pharmacovigilance (PV) policy and issues related to the safety and effectiveness of medicinal products. A summary of recommendations from the 12th meeting of ACSoMP is included below.

Specific recommendations:

 WHO should establish a strategic sub-group of the Committee to help align the ACSoMP Terms of Reference with the requirements of the reorganised Safety & Vigilance (SAV) Team in WHO and to guide the work of all five WHO Collaborating Centres1 that support the work of WHO Safety & Vigilance Team.  WHO/SAV should work with its Collaborating Centres to develop a pharmacovigilance (PV) strategy with a road map and an annual work plan for the programme; and manage and sustain resources for the activities.  WHO and its Collaborating Centres should work with countries to strengthen PV systems, and to decrease the lag times between the general occurrence of a medicine-related adverse event and recording the event in VigiBase (the WHO global database of Individual Case Safety Reports (ICSRs).  The WHO/SAV and its Collaborating Centres should meet regularly, and co-ordinate and plan training programmes collectively to ensure they complement each other.  The algorithm developed by the Uppsala Monitoring Centre (UMC) to detect substandard/spurious/falsely- labelled/falsified/counterfeit (SSFFC) medical products in large ICSR databases should be tested in regions such as the East African Community (EAC). A sub-committee should be established to work with WHO/SAV team and the EAC to take this forward and link with ongoing counter-SSFFC initiatives.  WHO/SAV should develop a follow-on document to the WHO handbooks on Cohort Event Monitoring (CEM), to define and describe the criteria and various scenarios in which CEM could be used, together with examples of research questions in public health programmes that may be addressed by CEM. A working group from ACSoMP should review the value added with CEM, analyse the cost-benefit of CEM, and options for managing and analysing data from CEM.  UMC should develop guidelines for national pharmacovigilance centres on how best to manage their PV data. Clear guidance should also be provided on the roles and responsibilities of various stakeholders involved in different aspects of data management.  SAV to establish a sub-committee within ACSoMP to work with WHO/SAV and Neglected Tropical Disease (NTD) teams for integrating PV within neglected tropical disease prevention and treatment programmes.  In 2012, WHO made a recommendation for the implementation of seasonal malaria chemoprevention (SMC) in areas of Sahel sub-regions where highly seasonal malaria transmission occurs. This consists of a combination of amodiaquine and sulfadoxinepyrimethamine (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. ACSoMP recommends that all adverse events (both serious and non-serious events) should be collected in countries where SMC will be launched; WHO (SAV and TDR, the special programme for Research and Training in Tropical Diseases) should work with partners to ensure this. ACSoMP also recommends that an independent regional committee should be established by WHO TDR and its consortium of partners engaged in the SMC initiative, to review the safety

1 WHO Collaborating centres: WHO Collaborating Centre for International Drug Monitoring, The Uppsala Monitoring Centre, Uppsala, Sweden; WHO Collaborating Centre for Drug Statistics and Methodology, Oslo, Norway; WHO Collaborating Centre for Advocacy & Training in Pharmacovigilance, Accra, Ghana; WHO Collaborating Centre for Pharmacovigilance, Rabat, Morocco; Pharmacovigilance in Education and Patient Reporting, ’s-Hertogenbosch, the Netherlands.

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data from the SMC initiative and to report to ACSoMP at its next meeting in 2016, or through other ad hoc meetings if needed. PV support for SMC should build on existing systems; in the absence of a PV system in a country, SMC should be leveraged to introduce PV within the country.  The ACSoMP will remain prepared to advise, if needed, on the deployment of therapeutics, vaccines and health system strengthening initiatives in relation to the WHO response to Ebola Virus Disease (EVD). WHO/SAV should keep the Committee informed on current developments and WHO initiatives related to EVD-response.  The African Medicines Regulatory Harmonization (AMRH) Initiative was established in 2009 following the efforts of WHO, the New Partnership for Africa’s Development (NEPAD), World Bank and others. AMRH aims to improve the access to safe and effective medicines in Africa through regulatory harmonization in the continent. Pharmacovigilance has been included as a component within the AMRH initiative. WHO has reviewed and discussed the PV proposal with ACSoMP. ACSoMP will guide WHO/SAV in drafting a document to highlight the importance of including pharmacovigilance in the AMRH initiative, clarifying the vision and priorities for PV within the initiative, incorporating lessons learnt from other harmonization models, and building on good science, existing systems and networks.  WHO/SAV routinely receives requests from WHO Member States from individuals working in pharmacovigilance in low- and middle- income countries for learning opportunities in PV through exchange visits with well-resourced regulatory agencies such as the US FDA, MHRA, EMA etc. SAV will follow up with a strategy to manage such requests and facilitate learning opportunities through various mechanisms including bilateral cooperative agreements with selected regulatory agencies.

General Recommendations

 Early involvement of WHO/SAV in WHO public health programmes is recommended, commencing already at the planning stage of the programme, together with relevant resources for SAV, to better plan and support PV requirements and applications within these programmes.  Risk management plans should be an inherent part of all public health programmes.  Public health programmes can learn from each other, hence it is recommended that public health programmes share what they are doing in PV, for example, through a conference day on PV, facilitated by the SAV team, to discuss common PV needs and shared solutions.

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Implementing Patient Reporting of Adverse Reactions in Ghana Mrs Delese Mimi Darko and Mr George Sabblah (Food and Drugs Authority, Ghana)

Background

The contribution of patients towards ensuring the safety of marketed drugs and vaccines cannot be underestimated. First of all patients can communicate their own adverse experiences with medicines better than health-care professionals. And secondly, patients are more motivated and better placed to observe the signs and symptoms of their adverse events more comprehensively than health-care professionals. Patients will therefore record with precision, any adverse experiences with their medicines and other health products.

Patients’ Contribution to Spontaneous Reporting

Since Ghana joined the WHO Programme for International Drug Monitoring in November 2001, adverse drug reaction reports from patients have been received mainly through their health-care professionals. Direct reporting by patients has been discussed in the past, but has not been fully implemented; the National Pharmacovigilance Centre (NPvC) has received only two reports directly from patients since 2005. The NPvC at the Food and Drugs Authority (FDA) in Ghana has made good progress with its plans to introduce patient reporting. It is expected that the FDA will fully launch patient reporting by the fourth quarter of 2015. It is hoped that implementing this programme will improve the adverse reaction reporting rate and contribute to the generation of signals and early detection of safety problems with drugs, vaccines and other health products being marketed in Ghana. The NPvC receives on an average 12 adverse drug reaction reports per 1,000,000 inhabitants per year for a population of approximately 27,000,000. This figure is less than the Uppsala Monitoring Centre (UMC) experience, that a fully functional pharmacovigilance system receives 200-250 reports per million inhabitants per year. Due to a high level of underreporting it is possible that safety problems with medicines used in Ghana will go undetected. In view of this the NPvC is being supported by the United Kingdom’s Department for International Development (DFID), to introduce patient/consumer reporting in an attempt to boost adverse reaction reporting, and also increase the chances of early detection of safety problems.

Benefits of Patient Reporting

There are also several other benefits of patient reporting: 1) Patient reports are direct, detailed and unambiguous because these reports describe exactly how the patient feels. 2) Reports from patients will usually provide information on concomitant medicines, including herbal medicines and over-the-counter medicines. This is an important aspect given the high level of self- medication in the country. 3) Spontaneous reporting by patients has important benefits beyond pharmacovigilance because the patient plays an active role in his or her treatment regimen instead of being a largely passive recipient of treatment. 4) In the process of actively reporting any adverse reactions to their medicines, the patient learns how to manage his/her medicines and to communicate more effectively with, and better provide critical information to their health professionals.

The Strategy in Ghana

The NPvC is working with the Pharmaceutical Society of Ghana through the Community Pharmacy Practice Association (CPPA) to promote Patient Reporting by designating participating Community Pharmacies as “Patient Safety Centres”. Community Pharmacies have been chosen to introduce this concept because of easy accessibility to patients within the community and also on account of the services they offer, which are quicker and meet the primary

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Feature health-care needs of the population. Since most patients visit Community Pharmacies as compared to hospitals and clinics, it is expected that greater number of safety issues with health products will be reported to these pharmacies. Community Pharmacies that apply to participate will then be responsible for teaching patients how to complete the BlueForm® (the Patient Reporting Form), making the forms available to patients who visit their facilities and collating the forms for onward submission to the NPvC. The patient reporting concept will also be promoted through the print and electronic media using posters, billboards, advertisement in newspapers, television and radio, text messaging, social media and other internet platforms.

Motivation for Professionals and Benefits for Health-care

In addition to the overall goal of promoting patient safety, the NPvC believes these activities will also motivate pharmacies to participate in the programme. Pharmacies that perform exceptionally well will be awarded with varying levels of certificates (Bronze, Silver and Gold) and ultimately, a plaque. It will also improve confidence of patients in services provided by pharmacies, contribute to rational use of drugs and improve pharmaceutical care provided by community pharmacies in Ghana.

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