2019 WHO Pharmaceuticals

No.4 NEWSLETTER

The WHO Pharmaceuticals Newsletter provides you

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

This newsletter also includes update on The aim of the Newsletter is to disseminate regulatory pharmacovigilance strengthening activities in Ethiopia. information on the safety of pharmaceutical products, based on communications received from our network of national pharmacovigilance centres and other sources such as specialized bulletins and journals, as well as partners in WHO.

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

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

Signal

Feature

© World Health Organization 2019

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Printed in Switzerland Table of Contents

Regulatory Matters Alemtuzumab ...... 5 Avelumab ...... 5 Baloxavir marboxil ...... 5 Cedar pollen extract powder, dermatophagoides extract bulk powder .... 5 Codeine, dihydrocodeine, tramadol ...... 6 Epoprostenol ...... 6 Febuxostat, topiroxostat ...... 6 Fenspiride ...... 7 Gentian violet ...... 7 Glucagon-like peptide-1 (GLP-1) receptor agonists ...... 7 Magnesium sulfate ...... 7 Metformin ...... 8 Nivolumab, pembrolizumab ...... 8 Propofol ...... 9 Sodium-glucose co-transporter 2 (SGLT2) inhibitors ...... 9 Tofacitinib ...... 9 Triptans ...... 10

Safety of medicines Cyproterone ...... 11 Ipilimumab, nivolumab ...... 11 Non-steroidal anti-inflammatory drugs (NSAIDs) ...... 11 Proton pump inhibitors (PPIs) ...... 11 Rivaroxaban and other direct-acting oral anticoagulants (DOACs) ...... 12 Tocilizumab ...... 12 Zopiclone ...... 12

Signal Combination products containing guaifenesin, paracetamol, and phenylephrine reported with severe upper abdominal pain ...... 14 and lockjaw...... 18

WHO Pharmaceuticals Newsletter No. 4, 2019  3 Table of Contents

Feature Update on Pharmacovigilance strengthening activities in Ethiopia ...... 27

WHO Pharmaceuticals Newsletter No. 4, 2019  4 Regulatory Matters

Alemtuzumab 17 May 2019 (www.gov.uk/mhra) infections. Baloxavir marboxil inhibits the synthesis of viral (See WHO Pharmaceuticals Newsletter Risk of serious No.3, 2019: Cardiovascular and immune- RNAs. cardiovascular and immune- mediated adverse effects in Europe) A total of 42 cases involving mediated adverse reactions shock or anaphylaxis have been reported in Japan during United Kingdom. The Avelumab the previous three fiscal years. Medicines and Healthcare For 16 cases, a causal Products Regulatory Agency Risk of pancreatitis relationship between the drug (MHRA) has announced that and event could not be the use of alemtuzumab Japan. The Ministry of Health, excluded. Additionally, one of (Lemtrada®) will be restricted Labour and Welfare (MHLW) the cases was fatal. due to the risk of serious and the Pharmaceuticals and cardiovascular and immune- Medical Devices Agency The MHLW and PMDA have mediated adverse drug (PMDA) have announced that concluded that revision of the reactions. Strengthened the package insert for package insert is necessary requirements for monitoring avelumab (Bavencio®) will be based on the results of their investigation of the currently alemtuzumab have been revised to include pancreatitis introduced in addition to an as an adverse drug reaction. available evidence and in urgent safety review conducted consultation with expert by the EU. Avelumab is indicated for advisors. unresectable Merkel cell Alemtuzumab is a monoclonal carcinoma. Reference: antibody indicated for the Revision of Precautions, treatment of adults with Cases of pancreatitis have MHLW/PMDA, 4 June 2019 relapsing-remitting multiple been reported in patients (www.pmda.go.jp/english/) treated with avelumab sclerosis. overseas. Although no Alemtuzumab should only be corresponding cases have been started in new patients with reported in Japan, the MHLW either: highly active relapsing- and the PMDA have concluded Cedar pollen extract remitting multiple sclerosis if that the revision of the all other disease-modifying package insert was necessary powder, therapies are contraindicated; based on their investigation of dermatophagoides or relapsing-remitting multiple the currently available sclerosis that is highly active evidence and because there extract bulk powder despite an adequate course of have been no findings to Risk of anaphylaxis treatment with at least two indicate ethnic differences in other disease-modifying the pharmacokinetics and Japan. The MHLW and the therapies. Patients already on safety profile of the medicine PMDA have announced that the alemtuzumab may continue between Japanese and package inserts for cedar treatment if beneficial and they overseas patients. pollen extract (e.g. Cedartolen have discussed the additional Japanese cedar pollen monitoring requirements with a Reference: sublingual drop®) and health-care professional. Revision of Precautions, MHLW/PMDA, 4 June 2019 dermatophagoides extract bulk New monitoring requirements (www.pmda.go.jp/english/) powder (e.g. Actair house dust and precautions for use mite sublingual tablets®) will include: monitoring vital signs include anaphylaxis as an (e.g. blood pressure) before adverse drug reaction. and periodically during Cedar pollen extract is alemtuzumab infusion, Baloxavir marboxil indicated for cedar pollinosis as monitoring liver function tests desensitization therapy and and immediate evaluation of Risk of shock and dermatophagoides extract bulk patients who develop early anaphylaxis powder is indicated for manifestations of pathologic desensitization therapy against immune activation. Japan. The MHLW and the allergic rhinitis caused by mite PMDA have announced that the Patients should be alerted of package insert for baloxavir antigens. symptoms of: pulmonary marboxil (Xofluza®) will be Patients should be alerted for haemorrhage, myocardial revised to include shock and the onset of anaphylaxis infarction, , hepatic anaphylaxis as adverse drug particularly when engaged in injury and haemophagocytic reactions. intense exercise, alcohol lymphohistiocytosis. consumption or bathing. The Baloxavir marboxil is indicated Reference: for influenza A or B viral reaction can take two or more Drug Safety Update, MHRA, WHO Pharmaceuticals Newsletter No. 4, 2019  5 Regulatory Matters hours to occur following In Japan there are four reports Febuxostat, administration of the extracts. of morphine like toxic symptoms such as respiratory topiroxostat Two cases of anaphylaxis have depression in patients using been reported in Japan during codeine, dihydrocodeine or Potential risk of the previous three fiscal years. tramadol. Mortality has not cardiovascular death The reaction occurred after been reported. exercise or bathing within two Japan. The MHLW and the or more hours after the cedar Reference: PMDA have announced that the pollen extract was taken. Revision of Precautions, package inserts for febuxostat Additionally, two cases of MHLW/PMDA, 9 July 2019 (Feburic®) and topiroxostat anaphylaxis have been (www.pmda.go.jp/english/) (Uriadec®) should be revised reported with the use of (See WHO Pharmaceuticals Newsletter to warn about the potential risk dermatophagoides extract bulk No.1, 2018: Limited use: Only for adults of of cardiovascular death in powder. No patient mortalities 18 years of age and older in USA; No.6, patients with cardiovascular have been reported. 2017: Contraindication in children and ultra- disease. rapid metabolisers in Australia; No.4, 2017: Reference: Cautions against use in children and Febuxostat and topiroxostat Revision of Precautions, teenagers under 18 years of age in Japan) are indicated for gout or MHLW/PMDA, 9 July 2019 hyperuricemia. (www.pmda.go.jp/english/) The PMDA investigated studies conducted overseas. In the US, Epoprostenol the CARES study showed a higher risk of cardiovascular Codeine, Risk of thrombocytopenia death in the study group treated with febuxostat dihydrocodeine, Japan. The MHLW and the compared to the control group tramadol PMDA have announced that the treated with allopurinol. The package insert for epoprostenol FDA restricted the use of Contraindication in children: (Flolan®) should be revised to febuxostat and revised the Risk of serious respiratory include thrombocytopenia as package insert in February depression an adverse drug reaction. 2019 to provide an alert on cardiovascular deaths. Epoprostenol is indicated for Japan. The MHLW and the pulmonary arterial The European Medicines PMDA have announced that the hypertension. Agency (EMA) required the package inserts for products marketing authorization holder containing codeine, A total of 18 cases of of febuxostat to conduct a dihydrocodeine or tramadol thrombocytopenia have been clinical study (FAST study) to should be revised to include reported in Japan during the assess the cardiovascular risks contraindications in children previous three fiscal years. For of febuxostat in patients with under 12 years of age (for all three cases, a causal gout who had a cardiac disease uses), and patients under 18 relationship between the drug The FAST study is ongoing. years of age when used for and event could not be pain relief after tonsillectomy excluded. In Japan, clinical trials do not or adenoidectomy, due to the show evidence of a higher risk of serious respiratory Patients should be monitored incidence of cardiovascular depression. carefully and should have events in the febuxostat study periodic laboratory tests. If any group compared to the control Codeine, dihydrocodeine and abnormalities are observed, groups (placebo group or tramadol are indicated to dose reduction, discontinuation allopurinol group). relieve coughs and pains. or other appropriate measures should be taken. However, considering the Following the announcement of evidence from studies the US Food and Drug Reference: conducted overseas and Administration (FDA) in 2017 Revision of Precautions, available evidence in the of the contraindication of MHLW/PMDA, 9 July 2019 literature, PMDA has concluded products containing codeine, (www.pmda.go.jp/english/) that it is appropriate to add the dihydrocodeine or tramadol in CARES study results children under 12 years, MHLW concerning cardiovascular and PMDA have reviewed death to package insert. available safety information Although no concerns were and concluded that the revision expressed about cardiovascular of package inserts is risks in a similar drug with a necessary. xanthine oxidase inhibitory effect, topiroxostat, it is

WHO Pharmaceuticals Newsletter No. 4, 2019  6 Regulatory Matters considered appropriate to add Gentian violet (exenatide, liraglutide and the same precautions to the dulaglutide) are updated to package insert of topiroxostat. Risk of cancer include advice on reducing insulin dosage using a stepwise Reference: approach and monitoring of Revision of Precautions, Canada. Health Canada has blood glucose to minimize the MHLW/PMDA, 9 July 2019 announced that there is risk of diabetic ketoacidosis. (www.pmda.go.jp/english/) potential evidence of a link between the use of gentian GLP-1 is indicated to treat (See WHO Pharmaceuticals Newsletter violet and cancer. No.9, 2019: Increased risk of death in USA; adults with type-2 diabetes and No.6, 2017: Potential risk of heart-related Gentian violet is a non- are not substitutes for insulin. death in USA; No.3, 2016: Risk of heart prescription medicine used to There have been reports of failure in Canada) treat cutaneous and diabetic ketoacidosis in mucocutaneous infections. patients with type-2 diabetes Following a review of the on a combination of a GLP-1 scientific literature and risk receptor agonist and insulin Fenspiride assessment on violet when the concomitant insulin is containing human therapeutic rapidly reduced. Withdrawal due to the risk products, Health Canada An EU review concluded that of heart rhythm problems concluded that the evidence the reported cases of diabetic from animal studies in the ketoacidosis could be attributed Europe. The EMA’s scientific literature suggests a to abrupt discontinuation or Pharmacovigilance Risk potential link between gentian dose reduction of insulin while Assessment Committee (PRAC) violet and cancer. initiating GLP-1 receptor has recommended that the The assessments were agonist therapy, resulting in marketing authorizations for triggered by a recommendation poor glycaemic control. cough medicines containing from the WHO’s Codex fenspiride (Elofen®, Epistat®, Health-care professionals are Alimentarius Commission which Eurefin®) should be revoked, advised that if the insulin dose advised regulatory authorities due to the risk of heart rhythm is to be reduced, a stepwise to prevent exposure to gentian problems. approach is recommended. violet in food due to a potential Also, they should monitor for Fenspiride is used to relieve cause of cancer. of diabetic cough resulting from lung Health Canada notified the ketoacidosis and risk factors diseases in adults and children manufacturer of gentian violet with patients. of two years and older. of the assessment results. The Reference: The PRAC considered all manufacturer agreed to Drug Safety Update, MHRA, available evidence from cases voluntarily discontinue 19 June 2019 (www.gov.uk/mhra) of QT prolongation and marketing of their product in torsades de pointes in patients Canada and the health product using fenspiride. Heart rhythm drug licence for gentian violet problems can be serious, occur has been cancelled. suddenly, and it is not always Reference: Magnesium sulfate possible to identify patients at Summary Safety Review, risk in advance. The use of Health Canada, 12 and 27 June Risk of skeletal adverse fenspiride for treatment of 2019 (www.hc-sc.gc.ca) effects in neonates cough is considered to be non- serious, and therefore the United Kingdom. The MHRA PRAC recommends that has announced that the fenspiride should no longer be product information for marketed. Glucagon-like products containing Reference: magnesium sulfate will be peptide-1 (GLP-1) updated to warn of skeletal EMA, 17 May 2019 (www.ema.europa.eu) receptor agonists adverse effects observed with administration for more than (See WHO Pharmaceuticals Newsletter Risk of diabetic ketoacidosis five to seven days during No.3, 2019: Potential risk of problems with pregnancy. heart rhythm in Europe) United Kingdom. The Magnesium sulfate is indicated MHRA has requested that the for the prevention of further

Summaries of Product associated with Characteristics and Patient eclampsia in pregnancy and for Information Leaflets for the treatment of magnesium Glucagon-like peptide-1 deficiency in hypomagnesemia. (GLP-1) receptor agonists

WHO Pharmaceuticals Newsletter No. 4, 2019  7 Regulatory Matters

In 2013, the US FDA issued a Metformin is indicated to treat treatment including malignant safety recommendation against type-2 diabetes. melanoma, unresectable, the use of magnesium sulfate advanced or recurrent non- There was a concern that for more than five to seven small cell lung cancer and patients with renal impairment days when used as a tocolytic relapsed or refractory classical would be at a higher risk of (an indication not authorized in Hodgkin . They are lactic acidosis because the the UK). Such prolonged classified as anti-programmed blood concentration of exposure may result in cell death protein-1 (PD-1) metformin increases due to a significantly higher cumulative antibody medicines. delay in its excretion. doses than those encountered Therefore, it was Cases of tuberculosis have with use in the UK for contraindicated in patients with been reported in patients eclampsia or foetal renal impairment including mild treated with anti-PD-1 antibody neuroprotection. impairment. medicines in Japan and The MHRA is not aware of any overseas. In recent years, the FDA and reports in the UK of skeletal the EMA have reviewed A total of 14 cases involving adverse effects or relevant published papers and both tuberculosis have been biochemical effects in the organizations have concluded reported in Japan during the neonate following use of that metformin may be used in previous three fiscal years. For magnesium sulfate but, patients with mild to moderate 10 cases, a causal relationship considering that there is an renal impairment. between the drug and the increase in the usage in the event could not be excluded. UK, the decision to update The PMDA considered the product labels was made, available information on The MHLW and PMDA have based on the recommendations pharmacokinetics, overseas concluded that revision of the from the Paediatric Medicines published literature and package insert is necessary Expert Advisory Group. The guidelines, and concluded that based on the results of their MHRA advises health-care metformin may be safely used investigation of the currently professionals to consider in patients with moderate renal available evidence and in monitoring neonates for impairment if risks are consultation with expert abnormal calcium and minimized. Also, the package advisors. magnesium levels and skeletal insert should include advise on Reference: adverse effects if maternal low dose initiation of Revision of Precautions, treatment with magnesium treatment, dose adjustments MHLW/PMDA, 4 June 2019 sulfate is prolonged. depending on the patient’s (www.pmda.go.jp/english/) condition, careful follow-up, Reference: and other required precautions Drug Safety Update, MHRA, in patients with renal 17 May 2019 (www.gov.uk/mhra) impairment. 2. Risk of enteritis (See WHO Pharmaceuticals Newsletter No.6, 2015: Risk of hypermagnesaemia in Reference: Japan. The MHLW and the Japan) Revision of Precautions, PMDA have announced that the MHLW/PMDA, 18 June 2019 package inserts for nivolumab (www.pmda.go.jp/english/) and pembrolizumab should be revised to include enteritis as (See WHO Pharmaceuticals Newsletter an adverse drug reaction. No.3, 2016: Warnings for certain patients Metformin with reduced kidney function in USA) A total of 10 cases of enteritis, 35 cases of intestinal Contraindication removed perforation and 35 cases of

Japan. The MHLW and the ileus have been reported in patients treated with PMDA have announced that the Nivolumab, package inserts for products nivolumab or pembrolizumab in containing metformin (e.g. pembrolizumab Japan during the previous metformin, Glycoran®; three fiscal years. For seven vildagliptin/metformin, 1. Risk of tuberculosis cases of enteritis, eight cases EquMet®; of intestinal perforation and pioglitazone/metformin, Japan. The MHLW and the two cases of ileus, a causal PMDA have announced that the METACT®) should be revised relationship could not be package inserts for nivolumab to remove a previous excluded. (Opdivo®) and pembrolizumab contraindication in patients (Keytruda®) should be revised Before the revision, colitis and with mild renal impairment. severe diarrhoea were written to include tuberculosis as an Treatment in patients with as adverse drug reactions; but adverse drug reaction. severe renal impairment is still MHLW and PMDA concluded a contraindication. Nivolumab and pembrolizumab that revision of the package are indicated for cancer insert is necessary based on WHO Pharmaceuticals Newsletter No. 4, 2019  8 Regulatory Matters the results of the investigation that the product information Tofacitinib is an oral, of the currently available for sodium-glucose co- immunomodulatory disease- evidence. transporter 2 (SGLT2) modifying anti-rheumatic inhibitors will be revised to medicine, indicated for the Reference: include a warning of the risk of treatment of rheumatoid Revision of Precautions, Fournier’s gangrene. arthritis, psoriatic arthritis and MHLW/PMDA, 9 July 2019 severe ulcerative colitis. (www.pmda.go.jp/english/) Cases of Fournier’s gangrene (necrotising fasciitis of the The PRAC’s recommendation

perineum) have been reported follows results from an ongoing with the use of SGLT2 study, which showed an inhibitors. increased risk of blood clots in Propofol the lungs and death with 19 SGLT2 inhibitors are indicated cases of pulmonary embolism for the treatment of type-2 Potential risk of priapism when the 10 mg twice daily diabetes. Medicines registered dose was used. This is double in Egypt include dapagliflozin, Canada. Health Canada has the recommended dose for canagliflozin and empagliflozin. requested that the rheumatoid arthritis. Once the manufacturers of propofol Fournier’s gangrene is a rare review is concluded, updated containing products update the but serious and potentially life- guidance will be provided to Canadian product safety threatening infection that patients and health-care information to include occurs mostly in men. Patients professionals. information on the potential should be advised to seek link between propofol Patients are advised not to stop urgent medical attention if they containing products and the or change their dose of experience severe pain, risk of priapism. tofacitinib without talking to tenderness, erythema or their doctor. Patients receiving swelling in genital or perineal Propofol containing products tofacitinib, irrespective of the area accompanied by or are used to make a patient indication, should be monitored malaise. If Fournier’s gangrene relax, calm, sleepy (sedation) for the signs and symptoms of is suspected, the SGLT2 or unconscious (anesthesia) pulmonary embolism. during surgery or medical inhibitor should be stopped and procedures in children and treatment started promptly. Reference: adults. EMA, 17 May 2019 Reference: (www.ema.europa.eu) Priapism is a prolonged, and Newsletter, EPVC, May 2019 usually painful, erection of the (www.epvc.gov.eg) penis not caused by sexual (See WHO Pharmaceuticals Newsletter 2. United Kingdom. The stimulation. It is a rare, but No.3, 2019: Risk of necrotising fasciitis of MHRA has announced that a potentially serious medical the perineum (Fournier’s gangrene) in new contraindication for use of condition. Singapore and in Japan; No.2, 2019: Risk of tofacitinib has been introduced. Fournier’s gangrene in UK; No.5, 2018: Risk The 10 mg twice-daily dose or Health Canada had received of serious infection of the genital area in one Canadian report of USA) tofacitinib must not be used in priapism related to the use of patients at high risk of propofol-containing products. A pulmonary embolism. review of this report found a Patients already being treated possible link between the drug Tofacitinib with the 10 mg twice-daily and priapism. dose of tofacitinib who are at Reference: Risk of pulmonary embolism high risk of pulmonary Summary Safety Review, embolism should be switched Health Canada, 12 July 2019 1. Europe. The EMA’s PRAC to alternative treatments. (www.hc-sc.gc.ca) has recommended, as a temporary measure, that Reference: doctors must not prescribe the Drug Safety Update, MHRA, 17 May 2019 (www.gov.uk/mhra) 10 mg twice-daily dose of tofacitinib (Xeljanz®) in (See WHO Pharmaceuticals Newsletter Sodium-glucose co- patients who are at high risk of No.3, 2019: Increased risk of blood clots in blood clots in the lungs (e.g. lungs and death in Europe; No.2, 2019: transporter 2 (SGLT2) patients who have heart Increased risk of blood clots in the lungs and death in USA) inhibitors failure, cancer, inherited blood clotting disorders or a history Risk of Fournier’s gangrene of blood clots) due to the risk of pulmonary embolism and Egypt. The Egyptian overall mortality. Pharmaceutical Vigilance Center (EPVC) has announced WHO Pharmaceuticals Newsletter No. 4, 2019  9 Regulatory Matters

Triptans Risk of headaches due to medication overuse

Japan. The MHLW and the PMDA have announced that the package inserts for triptans such as sumatriptan (Imigran®), naratriptan (Amerge®), eletriptan (Relpax®), zolmitriptan (Zomig®) and rizatriptan (Maxalt®) should be revised to include headache caused by medication overuse as an adverse drug reaction. Triptans are indicated for treatment of migraine. Six cases of headaches due to medication overuse have been reported in Japan during the previous three fiscal years. For all of the six cases, a causal relationship between the drug and event could not be excluded. Although only a small number of cases of headaches due to medication overuse have been reported in patients treated with triptans in Japan, the MHLW and PMDA have concluded that revision of the package insert is necessary based on the results of the investigation of the currently available evidence and in consultation with expert advisors. Reference: Revision of Precautions, MHLW/PMDA, 4 June 2019 (www.pmda.go.jp/english/)

WHO Pharmaceuticals Newsletter No. 4, 2019  10 Safety of Medicines

Cyproterone Health Canada has received The MARC reviewed the one Canadian report of a cardiovascular safety of Risk of meningioma cancer patient who developed NSAIDs including two clinical HLH after treatment with trials and two meta-analyses. Europe. The EMA’s PRAC has nivolumab in combination with MARC concluded that it is started a review of cyproterone ipilimumab. The report was currently not possible to (e.g. Androcur®) which will considered serious and resulted differentiate or rank NSAIDs by investigate the risk of in death. Additionally, Health their individual cardiovascular meningioma, a rare, usually Canada reviewed 21 risk profiles. international reports of HLH non-malignant tumour of the NSAIDs should be avoided in following treatment with membranes covering the brain patients with established nivolumab and ipilimumab, and spinal cord. cardiovascular disease, and either used alone or in patients should be informed of Cyproterone is a steroidal combination. All reports were the risk of NSAIDs. If required, antiandrogen, indicated for the considered serious, and six of NSAIDs should be used at the treatment of a range of 21 cases were fatal. However, lowest effective dose for the conditions, including excessive Health Canada could not shortest duration possible. hair growth, prostate cancer, confirm a causal relationship acne, and in hormone between the medicines and Reference: replacement therapy. death in these cases. The Prescriber Update, Vol. 40, A recent study in France medical literature suggests a No.2, Medsafe, June 2019 suggested a risk of potential link between the use (www.medsafe.govt.nz/) of the medicines and the meningioma with cyproterone (See WHO Pharmaceuticals Newsletter development of HLH. use. The PRAC will examine No.4, 2015: Small increased cardiovascular available evidence and make Reference: risk with daily doses at or above 2,400mg in recommendations. Summary Safety Review, Ireland) Reference: Health Canada, 24 June 2019 EMA, 11 July 2019 (www.hc-sc.gc.ca) (www.ema.europa.eu) (See WHO Pharmaceuticals Newsletter Proton pump No.2, 2019: Risk of serious blood disorder in

Japan) inhibitors (PPIs) Ipilimumab, Risk of rebound acid nivolumab hypersecretion (RAHS) New Zealand. Medsafe has Potential risk of Non-steroidal anti- announced that rebound acid hemophagocytic inflammatory drugs hypersecretion (RAHS) has lymphohistiocytosis (HLH) been reported in patients after (NSAIDs) stopping prolonged treatment Canada. Health Canada will with proton pump inhibitors work with the manufacturers of Risk of cardiovascular (PPIs). ipilimumab and nivolumab to adverse events determine appropriate label PPIs (omeprazole, lansoprazole changes to the product safety New Zealand. Medsafe has and pantoprazole) inhibit information to include the announced that all non- gastric acid secretion and have potential risk of steroidal anti-inflammatory several indications such as the hemophagocytic drugs (NSAIDs) increase the short-term treatment of benign lymphohistiocytosis (HLH). risk of a cardiovascular adverse duodenal and gastric ulcers event. and the eradication of HLH is a condition where large Helicobacter pylori in numbers of immune cells NSAIDs reduce inflammation combination with destroy other blood cells. by inhibiting the production of antibacterials. cyclo-oxygenase (COX)-1 and Ipilimumab and nivolumab are 2, and are generally indicated RAHS is the recurrence of indicated to treat different to reduce pain, decrease fever symptoms due to an increase types of cancers, including and decrease inflammation. in gastric acid secretion above cancers of the skin, kidney, pretreatment levels after lung and liver. Since the Medicines Adverse stopping PPI therapy. Reactions Committee (MARC) Symptoms of RAHS may Health Canada conducted a previously discussed the include heartburn, safety review of the risk of HLH cardiovascular safety of regurgitation or dyspepsia. associated with the use of diclofenac and ibuprofen, ipilimumab or nivolumab several new studies on the For many people, short-term following reports of HLH cardiovascular safety of PPI use (4-8 weeks) is published in medical literature. NSAIDs have been published. appropriate. A step-down WHO Pharmaceuticals Newsletter No. 4, 2019  11 Safety of Medicines approach should be considered DOACs such as apixaban, aminotransferase (ALT) or when stopping PPI therapy. edoxaban and dabigatran in aspartate aminotransferase Stepping down involves patients with antiphospholipid (AST). The TGA is reviewing gradually reducing the dose syndrome, therefore available the data on hepatotoxicity with over time before stopping the data for these medicines are tocilizumab and may medicine completely. limited. However, available recommend changes to the Alternative treatments such as data suggest that other DOACs Product Information. histamine H2-receptor may also be associated with a Reference: antagonists or antacids may be similarly increased risk of Medicines Safety Update, TGA, useful to manage rebound recurrent thrombotic events as 11 July 2019 (www.tga.gov.au) symptoms. with use of rivaroxaban.

Reference: Health-care professionals are 2. United Kingdom. The Prescriber Update, Vo. 40, advised to review whether MHRA has announced that No.2, Medsafe, June 2019 continued treatment with a serious liver injury has been (www.medsafe.govt.nz/) DOAC is appropriate for reported in patients treated patients diagnosed with with tocilizumab antiphospholipid syndrome and (RoActemra®), with an onset consider switching to a vitamin ranging from two weeks to K antagonist such as warfarin. Rivaroxaban and more than five years after other direct-acting Reference: initiation. Liver injury includes Drug Safety Update, MHRA, acute liver failure and hepatitis, oral anticoagulants 19 June 2019 (www.gov.uk/mhra) and some cases required liver (DOACs) transplantation. A recent EU cumulative review Increased risk of recurrent Tocilizumab found that treatment was thrombotic events associated with severe liver Risk of hepatotoxicity injury. The review of data from United Kingdom. The clinical trials, non- MHRA has announced that a 1. Australia. The Therapeutic interventional studies, clinical trial has shown that Goods Administration (TGA) spontaneous reports, and the there is an increased risk of has announced that serious published literature identified recurrent thrombotic events drug-induced liver injuries, eight cases of tocilizumab- associated with rivaroxaban including acute liver failure, related drug-induced liver (Xarelto®) use compared to hepatitis and jaundice, have injury worldwide. warfarin, in patients with been observed with the antiphospholipid syndrome and administration of tocilizumab ALT and AST levels should be a history of thrombosis. (Actemra®). measured before starting treatment with tocilizumab and Direct-acting oral Indications of tocilizumab monitored every four to eight anticoagulants (DOACs) are include treatment of weeks for the first six months indicated for the treatment and rheumatoid arthritis, giant cell of treatment followed by every prevention of venous arteritis in adults, and 12 weeks thereafter. thromboembolism, and polyarticular juvenile idiopathic prevention of stroke and arthritis in patients of two Reference: systemic embolism in patients years of age and older. Drug Safety Update, MHRA, with non-valvular atrial Tocilizumab is known to cause 17 July 2019 (www.gov.uk/mhra) with one or more transient or intermittent mild risk factors. DOACs available to moderate elevation of are rivaroxaban, apixaban hepatic transaminases. (Eliquis®), edoxaban (Lixiana®) and dabigatran The TGA advises patients Zopiclone (Pradaxa®). treated with tocilizumab to be closely monitored for liver Risk of central nervous A clinical trial compared adverse events and advised to system adverse events rivaroxaban to warfarin in 120 seek immediate medical advice patients and showed that use if they have signs or symptoms New Zealand. Medsafe has of rivaroxaban in patients with of hepatotoxicity such as announced that the higher antiphospholipid syndrome jaundice, dark urine, itch, loss dose (7.5 mg) of zopiclone could be associated with of appetite, nausea or (Imovane®) is likely to cause increased rates of recurrent vomiting. central nervous system thrombotic events compared to adverse events in the elderly. therapy with warfarin. The current Product Information does not Zopiclone is indicated for short- There have been no completed recommend treatment in term treatment of insomnia. clinical trials for use of other patients with elevated alanine The approved adult dose is 7.5 mg, WHO Pharmaceuticals Newsletter No. 4, 2019  12 Safety of Medicines up to a maximum of four weeks. The recommended dose for elderly patients is 3.75 mg. In elderly, the elimination half- life of zopiclone is prolonged to approximately seven hours, compared with five hours in younger adults. The risk of next-day hangover effects such as drowsiness, cognitive impairment and dizziness is, therefore higher in the elderly. Also, psychiatric adverse events, including depression, suicidality, psychosis and schizophrenia have been associated with the use of zopiclone, and are more likely to occur in the elderly. Reference: Prescriber Update, Vo. 40, No.2, Medsafe, June 2019 (www.medsafe.govt.nz/) (See WHO Pharmaceuticals Newsletter No.6, 2014: Risk of next-day impairment in Canada)

WHO Pharmaceuticals Newsletter No. 4, 2019  13 Signal

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

The signals in this Newsletter are based on information derived from reports of suspected adverse drug reactions available in the WHO global database of individual case safety reports (ICSRs), VigiBase. The database contains over 20 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. International pharmaceutical companies, when identified as uniquely responsible for the drug concerned, are invited to comment on the signal text. Signals are thereafter communicated to National Pharmacovigilance Centres, before being published in this Newsletter. Signal texts from UMC might be edited to some extent by WHO and may differ from the original version. More information regarding the ICSRs, their limitations and proper use, is provided in the UMC Caveat document available at the end of Signal (page 26). For information on the UMC Measures of Disproportionate reporting please refer to WHO Pharmaceuticals Newsletter Issue No. 1, 2012.

UMC, a WHO Collaborating Centre, is an independent foundation and a centre for international service and scientific research within the field of pharmacovigilance. For more information, on the UMC Measures of Disproportionate Reporting etc., 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].

Combination products containing guaifenesin, paracetamol, and phenylephrine reported with severe upper abdominal pain Dr. Kristina Star, Uppsala Monitoring Centre and Annet van Erp-van Boekel, the Netherlands Pharmacovigilance centre Lareb

Summary symptoms associated with colds, flu, headaches, blocked nose, sore throat, chills, fever, and chesty In April 2018, a signal detection screening in coughs.1 These products are marketed worldwide VigiBase, the WHO global database of individual and are mostly sold over-the-counter.2 case safety reports, was designed to detect safety concerns reported by patients. A case series with There are several brands on the market with upper abdominal pain following intake of various dosage strengths and formulations, e.g., combination products containing guaifenesin, liquid, tablet, capsule and powder for oral solutions. paracetamol, and phenylephrine was highlighted as In the United Kingdom (UK), the strengths are meriting further assessment. The in-depth review of either 100 or 200 mg for guaifenesin; 250, 500, the 29 cases in VigiBase, encompassing all reports 1000 mg for paracetamol; and 5, 6.1, 10, 12.2 mg with gastrointestinal (GI) related pain, revealed a for phenylephrine hydrochloride.1 In the United pattern where patients described severe upper States (US), there is a range of products with other abdominal pain following the intake of these formulations and strengths.3 Products are approved products, frequently with a sudden onset and from the age of 12, or of 16 in the UK1, and from recovery after stopping the drug. The patient six years of age in the US.3 information leaflets (PIL) for these combination The MedDRA (Medical Dictionary for Regulatory products describe abdominal/stomach discomfort or Activities) preferred terms (PT) ‘abdominal pain’ stomach aches/upsets. However, in some of the and ‘abdominal pain upper’ include long lists of PILs, the only GI-related adverse reactions listed lowest level terms, such as stomach ache, stomach are nausea and vomiting. Patients might not or stomach pain but these terms in recognise the descriptions in the PIL as a reflection themselves do not cover the severity of the adverse of their experiences of severe abdominal pain (one reaction. patient almost called the ambulance), so consideration should be made to better describe abdominal pain in the information to patients. Reports in VigiBase

In April 2018, a signal detection screening in Introduction VigiBase, the WHO global database of individual case safety reports, was designed to detect safety Combination products containing guaifenesin, concerns reported by patients. A case series with paracetamol, and phenylephrine are approved for WHO Pharmaceuticals Newsletter No. 4, 2019  14 Signal upper abdominal pain following the intake of from the patients: combination products with guaifenesin,  ”Sharp/cramping pains in stomach. Right in paracetamol, and phenylephrine was highlighted as between the ribs. Centre of stomach …. Nearly meriting in-depth assessment as the patient phoned ambulance. Pain was unbearable at one descriptions of the event differed from that in the point.” product information.  “Sudden severe stomach cramps, dizziness, In October 2018, VigiBase contained 197 reports raised temperature and sudden severe with combination products containing guaifenesin, vomiting” paracetamol, and phenylephrine, of which  “…experienced severe stomach pain with 10 gastrointestinal (GI) disorders were the most minutes [sic] of taking the tablets I then felt frequently reported MedDRA system organ class, sick and vomited twice. I then felt ok apart from with ‘abdominal pain upper’ (22 reports), vomiting my cold symptoms.” (16) and nausea (15) listed as the most frequently  “…experienced extreme stomach pain and reported PTs. When searching the MedDRA high vomiting just minutes after the medicine was level term ‘gastrointestinal and abdominal pains taken, lasted about 30 minutes before returning (excl. oral and throat)’ with the combination to normal.” product, 29 unique reports were retrieved after  “Within seconds of taking experienced severe exclusion of one duplicate report. Summary pain in the stomach causing collapse and characteristics are given in Table 1. projectile vomiting. …the pain was so extreme ... collapse to the floor in pain.” The patients in this case series described  “Severe abdominal pain, abdominal cramps and experiences of severe and often sudden abdominal diarrhoea.” pain in temporal association of starting combination products with guaifenesin, paracetamol, and phenylephrine. In all but one report, the Disproportionality analysis for the combination product was recorded as the single combination product and single substances suspect drug. Patients described their upper abdominal pain with or without nausea, vomiting, Based on the overall reporting of the MedDRA PT diarrhea, malaise and dizziness. Additional co- ‘abdominal pain upper’ for combination products reported symptoms were general discomfort, other containing guaifenesin, paracetamol, and pains or GI symptoms. Co-reported events phenylephrine, IC analysis found the association to concerned mere symptoms, except for one case, be disproportionally reported.4,5 Table 2 displays the co-reported with the diagnosis legionella statistics for PTs ‘abdominal pain upper’ with the pneumonia, which referred to a published literature combination product and the single substances. case. One 71-year-old male patient reported gastrointestinal polyp haemorrhage together with ‘Abdominal pain upper’ for the combination product upper abdominal pain. Concomitant drugs for this and the single substances was, except for patient were tamsulosin, atenolol, and gabapentin. phenylephrine, disproportionally reported in Further details for this case were not registered in VigiBase. VigiBase. Chronic concomitant use of medicines was recorded Literature and Labelling with the combination product for nine patients, such as levothyroxine, citalopram, fluticasone and the The Summary of Product Characteristics (SmPC) for combination product estradiol and norethisterone. combination products with guaifenesin, Eight patients were recorded with paracetamol paracetamol, and phenylephrine in the UK list concomitantly. One young adult was co-reported abdominal discomfort, nausea and vomiting in with two paracetamol products but information on relation to guaifenesin; nausea, vomiting and timing and dosages for paracetamol were missing diarrhoea in relation to phenylephrine; and pallor, from these reports. nausea, vomiting, anorexia and abdominal pain in the overdose section for paracetamol.1 The dosage forms of the suspected combination products for the VigiBase reports were, where it In some of the Patient Information Leaflets (PILs), could be determined, liquids (12), tablets (1), the only gastrointestinal related adverse reactions capsules (7), and powder for oral solution (1). listed are nausea and vomiting, and where Dosage strengths recorded in these reports were abdominal discomfort is mentioned, it is expressed within normal ranges for adults. as abdominal/stomach discomfort or stomach aches/upsets.1

Combination products with these substances in the Patients’ descriptions of abdominal pains US list upset stomach or stomach pain as signs of 6 The following are some of the free text descriptions liver problems.

WHO Pharmaceuticals Newsletter No. 4, 2019  15 Signal

Table 1. Summary characteristics of 29 VigiBase reports with combination products containing guaifenesin, paracetamol, and phenylephrine and the MedDRA high level term ‘gastrointestinal and abdominal pains (excl. oral and throat)’, October 2018. Characteristic Case series under assessment Age (median / range) 41 years / 18-71 years Patient sex distribution 23 females / 6 males Geographical spread Czech Republic, Hungary, Italy, Latvia, Portugal and Romania (n=1 each), United Kingdom (n=21), United States of America (n=2) Reporter types 26 consumers; 2 other health professionals; 1 pharmacist Single suspect drug 28 reports* Single reported drug 11 reports Time-to-onset 17 reports same day, 6 reports after 1 day, 1 report after 2 days Withdrawal/Recovered 18 reports with drug withdrawn and reaction abated 4 reports with drug withdrawn but no effect observed *The 29th report listed ‘Covonia dry and tickly cough’ containing glycerol as a co-suspected drug.

Table 2. Combination and single substances with guaifenesin, paracetamol, and phenylephrine reported with MedDRA preferred term abdominal pain upper in VigiBase*

Suspected Number of reports Number of reports with Calculated expected IC IC025 Number of substance for substance abdominal pain upper number of reports countries*** Guaifenesin; 197 22 1.5 3.51 2.84 6 Paracetamol; Phenylephrine Guaifenesin 5 218 97** 39 1.30 1.00 2 Paracetamol 119 001 1 208** 892 0.44 0.35 41 Phenylephrine 1 914 7** 14 -0.99 -2.25 3 *VigiBase data up to 28 October 2018. **Individual case assessment was not done for single substances, so alternative explanations for the abdominal pain in these reports could exist. ***Number of countries from which reports were sent

Discussion abdominal pain have been received in VigiBase for phenylephrine as a single substance. One case in It is uncertain which of the substances in the the literature describes a 70-year-old woman with combination product most likely caused the sudden phenylephrine-associated ischaemic colitis abdominal pain. Guaifenesin has been described as presenting with nausea, vomiting, abdominal pain, inducing gastrointestinal discomfort, nausea and diarrhoea, and acute onset of haematochezia vomiting,2 and these reactions are listed in following ‘a lot’ of aspirin and phenylephrine use for connection to guaifenesin in the SmPCs for these sinusitis and nasal congestion.9 This case is combination products.1 It is unclear why guaifenesin interesting in the light of the 71-year-old male in would induce sudden gastric pain in some the VigiBase case series, who experienced individuals, but it does not seem unreasonable gastrointestinal polyp haemorrhage together with because of its stimulation of mucosa receptors in upper abdominal pain following use of the the gastrointestinal tract.7 Paracetamol overdose combination product. Further investigation of more can cause abdominal pain as a first sign of liver serious consequences of phenylephrine use may be damage, but in none of the 29 VigiBase cases was warranted. an over dosage suggested, however, eight patients used paracetamol concomitantly with the In a study investigating the bioavailability of a new combination product. None of these cases included oral syrup product containing guaifenesin, information on dosages for these co-reported paracetamol, and phenylephrine, 45 patients were products, so a possibility of overdose cannot be enrolled. Two patients reported GI adverse events excluded. Phenylephrine hydrochloride acts with (nothing more was specified) following the use of alpha-1 receptor stimulation, resulting in the test product consisting of the new oral syrup, vasoconstriction in vessels of the skin, abdominal and four patients reported GI adverse events viscera and kidney, and theoretically abdominal following the use of the reference product consisting pain could result from a decreased blood flow to the of an established oral liquid containing the same gastrointestinal tract.8 Only a few reports of combination of substances. The authors considered

WHO Pharmaceuticals Newsletter No. 4, 2019  16 Signal the reported GI adverse events in this study as guaifenesin;paracetamol;phenylephrine related to the liquid formulation, without any products. Available from: further discussion.10 In the VigiBase case series, the https://www.medicines.org.uk/emc/search?q= drug formulations used by the patients were liquid, guaifenesin%2C+paracetamol%2C+phenyleph tablet, capsule, and powder for oral solution, but rine+hydrochloride. Accessed: 29 October patients in this case series still experienced sudden, 2018. severe abdominal pain in temporal association with 2. Martindale: The complete drug reference. these products. Lemsip Max All in One Cold & Flu. 2018. There is a possibility that some of the excipients in Available from: the products used by the patients in the VigiBase https://www.medicinescomplete.com/#/conten case series would cause abdominal pain. Sorbitol t/martindale/999938-n3701- has been reported to be associated with abdominal f?hspl=guaifenesin,&hspl=paracetamol,&hspl= pain, bloating and diarrhoea11, and was listed as the phenylephrine%20 hydrochloride. Accessed: cause for abdominal pain in the label for one of the 29 October 2018. Swedish guaifenesin products.12 However, the 3. Drugs.com. Dosages for products used by the patients in the VigiBase series Acetaminophen/guaifenesin/phenylephrine. did not always include sorbitol, so this excipient Available from: would not be the contender in many of the cases https://www.drugs.com/dosage/acetaminophe included in this signal. n-guaifenesin-phenylephrine.html. Accessed: An obvious confounding factor is the underlying 29 October 2018. disease in these cases, where abdominal pain, 4. Bate A, Lindquist M, Edwards IR, Olsson S, nausea and vomiting could occur. However, for Orre R, Lansner A, et al. A Bayesian neural many cases, the upper abdominal pain had a network method for adverse drug reaction sudden onset after drug intake, and there was signal generation. Eur J Clin Pharmacol. recovery reported after stopping the drug, 1998;54(4):315-321. suggesting a causal relationship to the combination product. 5. Norén GN, Hopstadius J, Bate A. Shrinkage observed-to-expected ratios for robust and

transparent large-scale pattern discovery. Stat Conclusion Methods Med Res. 2013;22(1):57-69. The VigiBase reports revealed a pattern where 6. Drugs.com. Side effects for Acetaminophen/ patients described severe upper abdominal pain guaifenesin/phenylephrine. Available from: following the intake of combination products https:// www.drugs.com/sfx/acetaminophen- containing guaifenesin, paracetamol, and guaifenesin- phenylephrine-side-effects.html. phenylephrine, many times with a sudden onset Accessed: 29 October 2018. and recovery after stopping the drug. The PILs for 7. Albrecht HH, Dicpinigaitis PV, Guenin EP. Role these products describe abdominal/stomach of guaifenesin in the management of chronic discomfort or stomach aches/upsets, however in bronchitis and upper respiratory tract some PILs, the only GI-related adverse reactions infections. Multidiscip Respir Med. 2017;12:31. listed are nausea and vomiting. Patients might not recognise the descriptions in the PILs as a reflection 8. Martindale: The complete drug reference. of their severe experiences of abdominal pain, so Phenylephrine. 2018. Available from: https:// consideration should be made to better describe www.medicinescomplete.com/#/content/ abdominal pains in the information to patients. martindale/9512-a?hspl=Phenylephrine#2094- g. Accessed: 29 October 2018.

9. Ward PW, Shaneyfelt TM, Roan RM. Acute References ischaemic colitis associated with oral 1. Electronic Medicines Compendium. Summary phenylephrine decongestant use. BMJ Case of product characteristics for Rep. 2014;2014.

WHO Pharmaceuticals Newsletter No. 4, 2019  17 Signal

Methylphenidate and lockjaw Marian Attalla and Magnus Ekelo, Uppsala Monitoring Centre

Summary Trismus, or lockjaw, is the inability to open the mouth, usually because of muscle . Causes Methylphenidate and trismus (lockjaw) was include physical trauma, oral/dental surgery, identified as a potential signal in a screening of infections, and disease VigiBase, the WHO global database of individual (e.g. rheumatoid arthritis). Trismus can also be part case safety reports, focusing on patient reports. The of a drug-induced dystonic reaction. association is disproportionately over-reported (e.g. risperidone, aripiprazole) and antiemetics (e.g. compared to the overall rate in VigiBase with 27 metoclopramide) are known to cause dystonia, and observed cases, compared to the expected 8.3 it seems to be caused by an abnormal dopaminergic (review of VigiBase on 2 May 2018). All cases which activity involving the basal ganglia.4 reported any of the terms “trismus”, “ stiffness”, “jaw joint rigid state of”, “tightness in jaw” or Dystonia is characterized by “muscular contractions “tightness of jaw muscles”, were included in this or spasms that result in abnormal fixed postures or assessment. In total, 38 reports were analysed. positions of the jaw, neck, shoulders, trunk, and Overall, the cases support an association between extremities”.5 It can also result in twisting and methylphenidate and trismus, with the majority repetitive movements. The symptoms are reporting methylphenidate as the only suspect drug associated with pain and distress, and can cause and with eight cases reporting a positive difficulty with walking, speech, head turning, and dechallenge, of which one also reported a positive swallowing. , on the other hand is rechallenge. In addition, the dopamine-altering characterized by abnormal, involuntary, repetitive effect of methylphenidate provides a plausible and persistent movements affecting the mouth and mechanism behind trismus, which in these cases face, extremities and the trunk.6 Tardive dyskinesia was thought to be a dystonic reaction. Trismus or can develop after treatment with dopamine lockjaw is not labelled for methylphenidate in either receptor-blocking agents, usually one month after the Summary of Product Characteristics or the starting treatment.5 Symptoms are not painful but Patient Information Leaflet. However, the similar can still be debilitating. terms muscle tightness, muscle spasms, muscle Trismus, or any other jaw-related event, is not twitching and muscle cramps are described. labelled for methylphenidate, but muscle tightness, Nonetheless, for patients, it might not be obvious muscle spasms, muscle twitching and muscle enough from these terms that jaw-related reactions cramps are described.1,7 The labelled events are might occur, and therefore they could benefit from general and may not be specific enough for the more clarity as that might assist them in deciding to patient to be able to connect them to trismus. start or continue their treatment. Hence, the possible association of methylphenidate and trismus was investigated further. Introduction In April 2018, during a screening of VigiBase, the Reports in VigiBase WHO global database of individual case safety The association of methylphenidate and trismus is reports, focusing on patient reports, the disproportionately over-reported compared to the combination of methylphenidate and muscle overall reporting rate in VigiBase (IC025: 1.04). A tightness was identified as needing further in-depth total of 27 cases was observed, compared to the assessment. Several cases described jaw tightness, expected 8.3 (2 May 2018). and further exploration of VigiBase revealed many cases of trismus (lockjaw). Cases which reported the MedDRA preferred term (PT) “trismus” or any of the lowest level terms Methylphenidate is a centrally acting (LLTs) “jaw joint rigid state of”, “jaw stiffness”, sympathomimetic indicated for the treatment of “tightness in jaw” or “tightness of jaw muscles”, Attention-Deficit/Hyperactivity Disorder (ADHD).1 were included in the assessment (see table 2 for The US Food and Drug Administration (FDA) first which search terms were applied, displayed in the approved methylphenidate back in 1955, for various context of the MedDRA hierarchy). psychological disorders, and in the 1970s it was introduced to treat ADHD.2 Even though the drug The 44 cases retrieved from VigiBase had been has been on the market for a long time, the entered between 1 November 2000 and 2 May mechanism by which it exerts its therapeutic effect 2018. Six suspected duplicate reports were is still not clearly established. It is thought to excluded leaving 38 cases for analysis, of which 29 facilitate the action of dopamine and norepinephrine had been coded with trismus. The characteristics of through three mechanisms: 1) inhibition of the case series are summarized in Table 1. For reuptake, 2) facilitation of release into the synaptic more details on the individual cases, please refer to cleft, and, 3) inhibition of the catabolic activity of Table 3. Cases which reported oromandibular monoamine oxidase.3 dystonia (PT) were reviewed, but since they WHO Pharmaceuticals Newsletter No. 4, 2019  18 Signal concerned events quite different from trismus such increased in one, the dose was not changed in five, as lingual dystonia (affecting the tongue), they and the action taken with the drug was unknown in were not included in our analysis. 13 cases. For the four remaining cases, trismus occurred upon withdrawal or dose reduction of Methylphenidate was the only suspected drug in 27 methylphenidate (the cases are described further cases (of which three cases reported other down). concomitant drugs). The drug was withdrawn in 14 cases, the dose was reduced in one, the dose was

Table 1. Characteristics of the case series for trismus (PT), jaw joint rigid state of, jaw stiffness, tightness in jaw and tightness of jaw muscles (all LLTs) in association with methylphenidate. Number of reports 38 Reporting countries USA (14), Netherlands (14), Canada (3), Denmark (1), France (2), Iceland (1), New Zealand (1), Norway (1), South Africa (1) Sex 17 females, 20 males, 1 unknown Age Range: 5 – 60 years Median: 21 years Mean: 25 years Age was unknown in one case Time-to-onset (TTO) Range: 30 minutes – 1 year TTO reported in 22 cases. TTO was within one day in ten of these cases. In four cases trismus occurred after abrupt withdrawal (3) or dose reduction (1) of methylphenidate

Upon dechallenge or dose reduction, the reaction which she recovered from without changing the abated in eight cases, no effect was observed in administration of methylphenidate. four cases and in three cases the outcome was unknown. In seven of the eight cases of positive dechallenge, methylphenidate was the only suspect Table 2. MedDRA terms in bold were used for drug, with no other concomitants reported. In one retrieval of cases with jaw-related events case (20), a positive rechallenge was reported. The case describes a 40-year-old female who MedDRA preferred term MedDRA lowest level term experienced extrapyramidal symptoms consisting of Trismus Jaw involuntary movement of the tongue and trismus 30 Jaw movements disturbance minutes after methylphenidate administration. The Jaw drug was withdrawn, and the patient recovered. Locked jaw The patient was then treated with methylphenidate Rigidity masticatory slow-release and the symptoms were reported to be Spasm temporomandibular less severe. The case was first described in a signal Trismus published by the Netherlands Pharmacovigilance Centre Lareb.8 Joint stiffness Ankle stiffness Arthrosclerosis In three cases, trismus resolved spontaneously Early morning joint stiffness without changing the methylphenidate treatment. Jaw joint rigid state of One case (3) concerned a 29-year-old female who Jaw stiffness experienced one episode of trismus after increasing Joint stiffness the methylphenidate dose from 30 to 40 mg. The adverse event resolved spontaneously, and the Joint tightness patient did not experience similar events later. No Stiff joint other concomitant drugs were reported. In another Stiff knees case (22), a 21-year-old female experienced Stiffness hip trismus two days after administration of Stiffness joints methylphenidate. The patient was reported to be Muscle tightness Muscle tension recovering without changing the drug treatment. Muscle tightness She also used oestrogen with levonorgestrel Neck tightness (treatment with propranolol was also reported Periorial tension which started after trismus occurred). The third case (38) describes a 35-year-old female Tightness in jaw experiencing tightness of jaw muscles within a Tightness of back muscles month after starting methylphenidate treatment Tightness of jaw muscles

WHO Pharmaceuticals Newsletter No. 4, 2019  19 Signal

Concomitant treatment with antipsychotics series only five cases have concomitant (aripiprazole, risperidone and/or ziprasidone) was medications, of which two are reported in five cases and were reported as literature reports.12,13 suspected in four of the cases. Antipsychotics are However, there are few literature cases of dystonia known to cause dystonia, although trismus is not associated with methylphenidate-only treatment. specifically labelled as an adverse reaction except Tekin et al describe a 15-year-old female who for ziprasidone.9 In three of these cases (2, 12, 23), experienced involuntary extensor muscular onset of trismus followed abrupt discontinuation of contraction of her right hand and wrist together methylphenidate whilst on concomitant treatment with tension and severe pain, nine days after taking with antipsychotic drugs. In case 12, 27 mg of modified-release methylphenidate.16 She diphenhydramine was also withdrawn. was diagnosed with acute focal dystonic reaction In another case (24) the patient was not treated which subsided after diazepam administration. A with antipsychotics but still experienced trismus few years prior, the patient had experienced after a rapid decrease in the methylphenidate dose. muscular contraction in her foot when she took The patient had used methylphenidate for one year immediate-release methylphenidate, which and was normally treated with 80-120 mg/day. On disappeared when the drug was stopped. In another the same day as she took only 20 mg, she case, a 7-year-old female diagnosed with ADHD was developed trismus and jaw pain. The patient was prescribed 5 mg of immediate-release also taking metoprolol and sumatriptan for methylphenidate twice daily.17 After her third dose, migraine, both reported as suspected. she developed dystonic movements characterized by turning the neck sideways and twisted facial

muscles. Literature and Labelling

Trismus (or any other jaw-related adverse reaction) Discussion is not described in the UK Summary of Product Characteristics (SmPC) or in the US FDA label for The mechanism behind trismus reported in the methylphenidate.1,7 However, muscle tightness, cases was thought to be a dystonic reaction induced muscle spasms, muscle twitching and muscle by the dopamine-altering mechanism of cramps are all described although they don’t refer methylphenidate. A VigiBase search on 13 August specifically to the jaw or mouth. 2018 revealed that there were 213 reports of methylphenidate and dystonias (MedDRA High Level In the UK Patient Information Leaflet (PIL), the Term, HLT). Among these, only 74 cases reported following adverse reactions are described: “muscle concomitant treatment with antipsychotics spasms which you cannot control affecting your (aripiprazole, olanzapine, quetiapine, risperidone eyes, head, neck, body and nervous system”, and/or ziprasidone) which are known to cause “muscle tightness, muscle cramps”, “muscle pain, dystonia. We restricted the in-depth assessment to muscle twitching”.10 cases with reports of jaw-related events because we Jaw-specific reactions are not covered in the leaflet, thought patients would benefit from knowing about although “uncontrolled speech and body these specific reactions as these can be distressing movements” and “clenching or grinding your teeth” and painful. The product information does not are. describe dystonia as an adverse reaction, but it could be argued its symptoms are covered by the In 2012, the Netherlands Pharmacovigilance Centre mention of muscle tightness, spasms, and cramps, Lareb published a signal describing the association while lacking a description of specific body parts between trismus and the use of methylphenidate affected. and dexamphetamine.8 At the time of the assessment, their database contained seven cases The mechanism behind dystonia is unclear but it of jaw cramp/trismus associated with seems to be caused by an abnormal dopaminergic methylphenidate use (all of which are included in activity involving the basal ganglia. Two contrasting this assessment) and two cases of trismus hypotheses have been proposed: 1) dopaminergic associated with dexamphetamine use. Trismus and hypofunction within basal ganglia leading to methylphenidate was disproportionately reported in overactivity of the cholinergic system, and 2) the Lareb database, in the WHO global database hyperactivity of dopaminergic pathways.5 Therefore, and in the Eudravigilance database. In 2013, any drug that alters dopamine signalling, whether Prescrire wrote about methylphenidate and trismus, by inhibiting it (such as for antipsychotics), or by referring to Lareb’s signal, and argued that trismus increasing it, could in theory cause dystonic should be recognised as an adverse reaction in reactions. So, it could be hypothesized that patients exposed to methylphenidate.11 methylphenidate can cause dystonic reactions such as trismus, through its stimulatory effect on There are several published case reports of dopamine signalling (inhibits reuptake and methylphenidate-associated dystonic reactions in facilitates release of monoamines into synaptic connection to concomitant use of antipsychotic cleft). drugs, including cases of dystonia occurring after abrupt methylphenidate withdrawal.12-15 In our case For six cases there was some doubt about whether the patients experienced the reported trismus or if WHO Pharmaceuticals Newsletter No. 4, 2019  20 Signal they experienced dyskinetic reactions. Dyskinesia is patient has all the necessary information which labelled for methylphenidate. The narrative in these might affect their decision to start or continue a cases described reactions such as “jaw moving back specific treatment. Since trismus is likely to be a and forth”, “constantly drops jaw and mouth”, “jaw dystonic reaction and dystonia is not specifically twitching”, “jaw movements” and “motorial included in the label for methylphenidate, dystonia, agitation” reflecting a possible coding issue. as a possible adverse reaction to methylphenidate, should undergo in-depth case-assessment. Three patients in this assessment recovered from trismus without changing the methylphenidate treatment. These observations might somewhat References weaken the hypothesis that methylphenidate may induce trismus. 1. electronic Medicines Compendium: Summary of Product Characteristics for methylphenidate However, the literature reports of dystonia (Concerta®). Available from: associated with methylphenidate withdrawal12-15 https://www.medicines.org.uk/emc/product/68 suggest that methylphenidate could cause 72/smpc. Accessed: 10 July 2018. dystonic reactions by disrupting the dopamine balance. In these cases, the patients were treated 2. Gilman V. Ritalin. Chem Eng News. with both methylphenidate which stimulates 2005;83(25). dopamine action, and with antipsychotics which block dopamine action and seemed to have 3. Solanto, MV. Neuropsychopharmacological reached a balance in dopamine levels. They only mechanisms of drug action in experienced dystonic reactions when attention-deficit hyperactivity disorder: a review methylphenidate was withdrawn, that is when the and integration. Behav Brain Res. dopamine balance was disrupted. 1998;94(1):127-152. Having trismus can be painful and distressing for 4. Scully C. Oral and maxillofacial medicine: the the patient. For example, in one case the patient basis of diagnosis and treatment. 3rd ed. New could not sleep because of it. In another case, the York;Edinburgh: Churchill Livingstone/Elsevier; patient was unable to move his jaw or close his 2013. mouth. He was taken to the emergency room and 5. Tisdale JE, Miller DA. Drug-induced diseases: prescribed diphenhydramine to treat it, but his jaw prevention, detection, and management. 2nd would still lock up. Therefore, being able to ed. Bethesda: American Society of Health- connect that trismus could be an adverse effect of System Pharmacists; 2010. methylphenidate could play a role in deciding whether to start or continue with the treatment, 6. Merrill RM, Lyon JL, Matiaco PM. Tardive and especially if it is a recurring problem. spontaneous dyskinesia incidence in the general population. BMC Psychiatry. 2013;13:152.

7. US Food and Drug Administration: Product label Conclusion for methylphenidate (Concerta®). Available In conclusion, there is a signal for methylphenidate from: and trismus. Overall, the VigiBase cases presented https://dailymed.nlm.nih.gov/dailymed/drugInf here support this hypothesis, since: o.cfm?setid=1a88218c-5b18-4220-8f56- 526de1a276c-d&audience=consumer. • the majority of cases (70%) report Accessed: 10 July 2018. methylphenidate as the only suspect drug. 8. Netherlands Pharmacovigilance Centre Lareb. • eight cases report a positive dechallenge, of Methylphenidate, dexamphetamine and trismus. which one reported a positive rechallenge. 2012. Available from: https://databankws.lareb.nl/Downloads/KWB_2 there was a plausible dopamine-altering • 012_4_methyl1.pdf. Accessed: 3 July 2018. pharmacological mechanism. 9. US Food and Drug Administration: Product label • trismus is plausible when considering other, for ziprasidone. Available from: more general, labelled events for https://dailymed.nlm.nih.gov/dailymed/drugInf methylphenidate such as muscle tightness, o.cfm?setid=315e24 c2-2f8c-47d9-b1b1- muscle spasms, and muscle cramps. ce006646098a&audience=consumer. Accessed: • over-reporting of the association compared with 13 August 2018. the overall reporting in VigiBase. 10. Electronic Medicines Compendium: Patient Trismus or lockjaw is not labelled for Information Leaflet for methylphenidate methylphenidate in either the SmPC or the PIL. (Concerta®). Available from: Similar reactions are described in the label, but they https://www.medicines.org.uk/emc/files/pil.687 do not specifically refer to the jaw. Patients may not 2.pdf. Accessed: 10 July 2018. therefore recognize trismus or other jaw-related 11. Prescrire. Methylphenidate: trismus. Prescrire reactions as an adverse drug reaction and could Int. 2013 Jul;22(140):185. benefit from clearer labels. It is important that the

WHO Pharmaceuticals Newsletter No. 4, 2019  21 Signal

12. LeRiger M, Williams J, Duncan-Wiebe G, Shukry 15. Párraga HC, Sherman BC. Acute Dystonia After M. Acute masseter dystonia in a pediatric Stimulant Discontinuation in 2 ADHD Children patient receiving aripiprazole and Receiving Aripiprazole. J Clin Psychopharmacol. methylphenidate following induction of general 2015 Aug 1;35(4):480-1. anesthesia. Paediatr Anaesth. 2017 16. Tekin U, Soyata AZ, Oflaz S. Acute focal Aug;27(8):863-864. dystonic reaction after acute methylphenidate 13. McLaren JL, Cauble S, Barnett RJ. Aripiprazole treatment in an adolescent patient. J Clin induced acute dystonia after discontinuation of Psychopharmacol. 2015 Apr;35(2):209-11. a stimulant medication. J Clin Psychopharmacol. 17. Uzun ME, Korkmaz MF, Ekici A, Kaymaz N. 2010 Feb;30(1):77-8. Methylphenidate induce acute dystonic reaction. 14. Grau-López L, Daigre C, Mercado N, Casas M, Indian J Pediatr. 2018 Jul;85(7):577. Roncero C. Dystonia in Methylphenidate Withdrawal: A Case Report. J Addict Med. 2017 Mar/Apr;11(2):154-156.

Table 3. Characteristics of case reports in VigiBase of trismus in association with methylphenidate Case Age/ Suspected (S), Reactions (MedDRA Time-to-onset Action taken with drug Outcome number Sex interacting (I) or preferred terms) (dechallenge/rechallenge) concomitant (C) drugs 1 5/M Methylphenidate (S) Eye disorder, Trismus, Vision Within 1 month after Dose increased/No effect Not blurred starting treatment but observed recovered within 1 day after It is unclear if the dose dose increase (from increase refers to the 18 to 27 mg) increase from 18 to 27 mg which occurred before reaction onset. 2 11/M Aripiprazole, Jaw disorder, Oromandibular - - Recovered Methylphenidate, dystonia, Trismus Propofol (all S) Comment: reaction occurred upon abrupt Clonidine, Fentanyl, withdrawal of Rocuronium, Sevoflurane methylphenidate while still (all C) on concomitant treatment with antipsychotics The authors of this literature report suspect chronic aripiprazole and methylphenidate usage combined with propofol administration in he short- term absence of methylphenidate made this patient susceptible to dystonic reactions. 3 29/F Methylphenidate (S) Decreased appetite, Dry mouth, - Dose not changed/Reaction Recovered Trismus abated

Comment: trismus occurred after methylphenidate dose was increased from 30 to 40 mg. The event then resolved spontaneously without changing the dose. 4 -/F Methylphenidate (S) Depression, Drug effect - - Unknown incomplete, Irritability, Joint stiffness (LLT: Jaw stiffness), Musculoskeletal stiffness,

WHO Pharmaceuticals Newsletter No. 4, 2019  22 Signal

Case Age/ Suspected (S), Reactions (MedDRA Time-to-onset Action taken with drug Outcome number Sex interacting (I) or preferred terms) (dechallenge/rechallenge) concomitant (C) drugs 5 48/F Methylphenidate (S) Joint stiffness (LLT: Jaw 11.7 months Drug withdrawn/Reaction Recovered stiffness), Mood altered abated 6 42/F Methylphenidate (S) Alopecia, Hypoaesthesia, 2-3 days Drug withdrawn/No effect Not Hypoaesthesia oral, Muscle observed recovered spasms, Trismus 7 14/M Methylphenidate (S) Chest discomfort, - - - Hypoaesthesia, Muscle tightness (LLT: Tightness in jaw), Tachycardia 8 40/F Methylphenidate (S) Finger deformity, Muscle - Drug withdrawn/- Unknown tightness (LLT: Tightness of jaw muscles) 9 6/M Methylphenidate (S) , Eating disorder, 0 days Dose reduced/- Unknown Tongue biting, Trismus Dose given in the morning before patient went to school and developed adverse reaction in the afternoon 10 60/M Methylphenidate (S) Feeling jittery, Mouth swelling, 30 minutes Drug withdrawn/Reaction Recovered Muscle tightness (LLT: abated Tightness in jaw), Palpitations, Swollen tongue, Trismus 11 8/F Diphenhydramine, Dyspnoea, Insomnia, Trismus 4 hours -/No effect observed Not Methylphenidate (both S) recovered 12 15/M Diphenhydramine, Pain, Swollen tongue, Tongue - - Recovered Methylphenidate (both S) spasm, Trismus Comment: patient Bupropion, Ziprasidone experienced the adverse (both C) reactions after withdrawal of both methylphenidate and diphenhydramine. Patient was treated with methylphenidate for 1.5 years before the withdrawal. 13 5/M Methylphenidate (S) Dyskinesia, Eye disorder, Gait Within 1 day Drug withdrawn/Reaction Recovered disturbance, Muscle twitching, abated Tongue disorder, Trismus 14 16/M Methylphenidate, Decreased appetite, Dizziness, - - - Oxybate sodium (both S) Dystonia, Trismus, Weight decreased All other therapeutic products* (C) 15 42/M Methylphenidate (S) Anxiety, Cluster headache, Within 1 day Dose not changed/Reaction Recovered Dizziness, Hyperhidrosis, abated Hypertension, Palpitations, Therapeutic response Comment: the report unexpected, , Trismus narrative states that the methylphenidate dose was reduced from 108 to 90 mg after one year of treatment and withdrawn completely after four years. reports.

WHO Pharmaceuticals Newsletter No. 4, 2019  23 Signal

Case Age/ Suspected (S), Reactions (MedDRA Time-to-onset Action taken with drug Outcome number Sex interacting (I) or preferred terms) (dechallenge/rechallenge) concomitant (C) drugs However, it is unclear whether the patient recovered from jaw cramps before or after the dose reduction/withdrawal. 16 30/F Methylphenidate, Drug interaction, Hypertonia, 1 hour Drug withdrawn/Reaction Recovered Omeprazole, Paroxetine Trismus abated (all I) Ethinylestradiol;

Levonorgestrel (C) 17 14/M Methylphenidate (S) Joint stiffness (LLT: Jaw “days” Drug withdrawn/Reaction Recovered stiffness), Peripheral coldness abated 18 5/M Amfetamine, Aggression, Anxiety, Bruxism, - - - Aripiprazole, Coordination abnormal, Crying, Atomoxetine, Decreased eye contact, Carbamazepine, Depressed mood, Drug Chlorpromazine, ineffective, Dyskinesia, Clonidine, Fatigue, Homicidal ideation, Dexamfetamine, Insomnia, Irritability, Mood Iloperidone, altered, Oppositional defiant Lisdexamfetamine, disorder, Poor quality sleep, Lithium, Psychomotor hyperactivity, Methylphenidate, Sleep disorder, Speech disorder, Quetiapine, Valproic acid, Streptococcal infection, Ziprasidone (all S) Suicidal ideation, Sydenham's chorea, Trismus 19 24/M Methylphenidate (S) Dyskinesia, Trismus 4 months Drug withdrawn/No effect Not observed recovered 20 40/F Methylphenidate (S) Extrapyramidal disorder, 30 minutes Drug withdrawn/Reaction Recovered Trismus abated Rechallenge positive 21 59/M Methylphenidate (S) Bruxism, Trismus - - Unknown 22 21/F Methylphenidate (S) Trismus 2 days Dose not changed/Reaction Recovering Ethinylestradiol; abated Levonorgestrel, Propranolol (both C) 23 11/- Aripiprazole, Affect lability, Aggression, - - Recovered Methylphenidate (both S) Dystonia, Intentional self- injury, Joint stiffness (LLT: Comment: reaction Clonidine, Lithium (both Joint stiffness), Muscle occurred upon abrupt C) contracture, Trismus withdrawal of methylphenidate while still on concomitant treatment with antipsychotics. Patient had used the drug for four years but the reaction occurred 33 hours after the last dose. 24 37/F Methylphenidate, Pain in jaw, Trismus 1 year since starting - Recovered Metoprolol, Sumatriptan treatment with (S) methylphenidate but Comment: reaction on same day as dose occurred upon abrupt was reduced reduction of methylphenidate dose (from 80-120 mg to 20 mg). Patient had used the drug

WHO Pharmaceuticals Newsletter No. 4, 2019  24 Signal

Case Age/ Suspected (S), Reactions (MedDRA Time-to-onset Action taken with drug Outcome number Sex interacting (I) or preferred terms) (dechallenge/rechallenge) concomitant (C) drugs for one year and the reaction occurred on the same day as dose was reduced. 25 41/F Methylphenidate (S) Trismus 10 months -/Reaction abated Recovering

Simvastatin (C) 26 11/M Cetirizine, Clonidine, Hypersensitivity, Trismus - - Not Methylphenidate, recovered Montelukast, Salbutamol (all S) 27 55/F Methylphenidate (S) Joint stiffness (LLT: Jaw - - Not stiffness), Sleep disorder, recovered Duloxetine, Metformin Tourette's disorder (both C) 28 8/F Methylphenidate (S) , Logorrhoea, 8 h Drug withdrawn/Reaction Recovered Restlessness, Trismus abated 29 38/M Methylphenidate (S) Trismus 35 days Dose not changed/No effect Not observed recovered 30 8/M Methylphenidate, Facial spasm, Pain in jaw, - Drug withdrawn/No effect - Risperidone (both S) Somnolence, Tic, Trismus observed 31 41/F Methylphenidate (S) Disturbance in attention, Joint - - Unknown stiffness (LLT: Jaw stiffness), Sleep disorder 32 7/M Methylphenidate (S) Trismus - Drug witdrawn/No effect Not observed recovered 33 18/M Methylphenidate (S) Blood pressure increased, 7 days Drug withdrawn/- Unknown Dizziness, Trismus 34 30/F Amfetamine;Dexamfetam Ear pain, Facial pain, Gingival - - - ine, Methylphenidate disorder, Hyperacusis, (both S) Hypoaesthesia, Mastication disorder, Mobility decreased, Muscle spasms, Myalgia, Pain in jaw, Paraesthesia, Trismus 35 15/M Methylphenidate (S) Trismus “years” - Unknown 36 8/M Methylphenidate (S) Crying, Neurological symptom, 1 day Drug withdrawn/Reaction - Torticollis, Trismus, Vision abated blurred 37 22/F Methylphenidate (S) Joint stiffness (LLT: Jaw 31 minutes - Not stiffness), Hyperhidrosis, recovered Tongue disorder 38 35/F Methylphenidate (S) Decreased appetite, Dry mouth, Same month as Dose not changed/Reaction Recovered Headache, Muscle tightness starting treatment abated (LLT: Tightness of jaw (exact unknown) muscles), Sedation, Vertigo *As reported, exact unknown

WHO Pharmaceuticals Newsletter No. 4, 2019  25 Signal

CAVEAT DOCUMENT

Statement of reservations, limitations and conditions relating to data released from VigiBase, the WHO global database of individual case safety reports (ICSRs). Understanding and accepting the content of this document are formal conditions for the use of VigiBase data.

Uppsala Monitoring Centre (UMC) in its role as the World For these reasons, interpretations of adverse effect Health Organization (WHO) Collaborating Centre for data, and particularly those based on comparisons International Drug Monitoring receives reports of between medicinal products, may be misleading. suspected adverse reactions to medicinal products from The data comes from a variety of sources and the National Centres in countries participating in the WHO likelihood of a causal relationship varies across Programme for International Drug Monitoring. The reports. Any use of VigiBase data must take these information is stored in VigiBase, the WHO global significant variables into account. database of individual case safety reports (ICSRs). It is Prohibited use of VigiBase Data includes, but is not important to understand the limitations and qualifications limited to: that apply to this information and its use.  patient identification or patient targeting Tentative and variable nature of the data  identification, profiling or targeting of general Uncertainty: The reports submitted to UMC generally practitioners or practice describe no more than suspicions which have arisen from observation of an unexpected or unwanted event. In most Any publication, in whole or in part, of information instances it cannot be proven that a specific medicinal obtained from VigiBase must include a statement: product is the cause of an event, rather than, for example, (i) recording ‘VigiBase, the WHO global database of underlying illness or other concomitant medication. individual case safety reports (ICSRs)’ as the source Variability of source: Reports submitted to national of the information centres come from both regulated and voluntary sources. (ii) explaining that the information comes from a variety Practice varies: some national centres accept reports only of sources, and the probability that the suspected from medical practitioners; others from a broader range of adverse effect is drug-related is not the same in all reporters, including patients, some include reports from cases pharmaceutical companies. (iii) affirming that the information does not represent the Contingent influences: The volume of reports for a opinion of the UMC or the World Health Organization. particular medicinal product may be influenced by the extent of use of the product, publicity, the nature of the Omission of this statement may exclude the adverse effects and other factors. responsible person or organization from receiving further information from VigiBase. No prevalence data: No information is provided on the UMC may, in its sole discretion, provide further number of patients exposed to the product, and only a instructions to the user, responsible person and/or small part of the reactions occurring are reported. organization in addition to those specified in this Time to VigiBase: Some national centres make an statement and the user, responsible person and/or assessment of the likelihood that a medicinal product organization undertakes to comply with all such caused the suspected reaction, while others do not. Time instructions. from receipt of an ICSR by a national centre until submission to UMC varies from country to country. Uppsala Monitoring Centre (UMC) Information obtained from UMC may therefore differ from Box 1051, SE-751 40 Uppsala, Sweden that obtained directly from national centres. Tel: +46-18-65 60 60, E-mail: [email protected] www.who-umc.org

WHO Pharmaceuticals Newsletter No. 4, 2019  26 Feature

Update on Pharmacovigilance strengthening activities in Ethiopia

WHO has been working closely with the Ethiopian Food and Drug Administration (EFDA) to strengthen their pharmacovigilance system as part of the Smart Safety Surveillance project plan (see feature article in WHO Pharmaceuticals Newsletter, 2019, No2). Recent activities included: on-site discussions on improving reporting of adverse events (AEs) with health-care professionals at two health facilities in Addis Ababa; introduction of reporting tools; and organizing two pharmacovigilance strengthening workshops in Adama, Ethiopia. On 3 July 2019 WHO delegates visited the Black Lion hospital, and St Petros Hospital, to gain an understanding of the current AE reporting situation, build awareness and introduce potential technological solutions to ease future reporting, manage data collection and prevent duplication of work. Tools such as the Med Safety app1, and data management tool, Vigiflow were discussed. The test version of the med safety app is now available, and the launch campaign is planned for September 2019. Additionally, online reporting will be available towards the end of August 2019, and VigiFlow is now available at the seven regional pharmacovigilance sites. Health-care professionals at the two hospital sites expressed excitement over the new technological solutions and pharmacovigilance activities. In August 2019, WHO organized two workshops: a basic pharmacovigilance training aimed for health-care professionals to build awareness in pharmacovigilance and promote AE reporting; and an advanced pharmacovigilance workshop on data management and analysis for pharmacovigilance regional centres and disease programmes in Ethiopia. The Medicines and Healthcare Products Regulatory Agency (MHRA) and the WHO Collaborating Centre for International Drug Monitoring, (Uppsala Monitoring Centre) collaborated with WHO in these workshops.

1 The Med Safety app has previously been introduced in Burkina Faso, Zambia (see feature article in WHO Pharmaceuticals Newsletter, 2019 No3) and more recently in Ghana. WHO Pharmaceuticals Newsletter No. 4, 2019  27