WHO Drug Information Vol. 28, No. 2, 2014

Safety and efficacy news

■■Substandard and falsified products the trastuzumab vials had been tampered with. National health and law enforcement Falsified antimalarial medicines authorities are working to identify all in West and Central Africa concerned batches and take appropriate measures to protect the health of EU World Health Organization – WHO citizens. warns about three separate falsified EMA warned that the products with the antimalarial medicines discovered in batch numbers listed in the EMA press Cameroon, Ghana and Liberia. The release must not be used because they medicines concerned are falsely labelled cannot be considered safe or effective. as Rivopharm Laboratories Sulfadoxine/ Health professionals were advised to be Pyrimethamine BP 500mg + 25mg, alert when handling any other batches of Biochemie GmnH Quinine Sulphate 300mg the concerned medicines, and to report B.P. and Weiders Farmasotiske Quinine any suspicion of authenticity immediately Sulphate 300mg USP. They are circulating to the local health authorities. in packs of 1000 tablets with English ►►EMA Press releases, 16 April 2014 and and French labelling containing spelling 17 April 2014. mistakes and bearing a previous WHO Essential Drugs Programme logo, which is no longer in use by WHO. ■■Safety information National regulatory authorities are requested to increase vigilance within the Diacerein-containing formal and informal supply chains for these medicines: restricted use products as described in more detail in the European Union – The Co-ordination WHO Drug Alert. If any other medicines Group for Mutual Recognition and are discovered bearing the discontinued Decentralised Procedures – Human WHO Essential Drugs Programme logo, (CMDh) of the European Medicines Agency steps should be taken to ensure that they (EMA) has endorsed recommendations meet full specifications. to restrict the use of diacerein-containing ►►WHO Drug Alert No. 131, 25 March 2014. medicines in order to manage the risks of severe diarrhoea and effects on the Stolen trastuzumab, liver. Diacerein-containing medicines are currently authorized in the following EU pemetrexed and infliximab in Member States: Austria, Czech Republic, Europe France, Greece, Italy, Portugal, Slovakia European Union – The European and Spain. Medicines Agency (EMA) has informed Diacerein should only be used to treat the public about the theft of trastuzumab, osteoarthritis affecting the hip or knee pemetrexed and infliximab vials in Italy, in patients aged under 65 years who do some of which were later reintroduced not have current or past liver disease. illegally into the supply chain in other Treatment should be initiated by an countries. There is evidence that some of experienced health care professional.

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Treatment should start at half the normal In 2013 the product information was dose for the first 2-4 weeks and should updated to include new contraindications be stopped if diarrhoea or signs of liver for patients with sepsis and patients with problems occur. severe liver disease, as well as changes ►►EMA Press release, 21 March 2014. to the precautions and dosage and administration sections. The safety review has found that the updates are sufficient to Domperidone: adverse effects mitigate the risks. on the heart ►►TGA Safety Advisory, 4 April 2014. European Union – The Pharmacovigilance Risk Assessment Epidural corticosteroid Committee (PRAC) of the European injection: rare but serious Medicines Agency (EMA) has completed neurologic problems its review of domperidone, triggered United States of America – The U.S. by concerns expressed by the Belgian Food and Drug Administration (FDA) is medicines authority about the medicine’s requiring a warning on drug labels that effects on the heart. epidural injection of corticosteroids for may The Committee recommended using result in rare but serious adverse events, domperidone only to manage nausea including loss of vision, stroke, paralysis, and vomiting – not other conditions such and death. as bloating or heartburn – and reducing Injectable corticosteroids include the dose in adults to 10 mg up to three methylprednisolone, hydrocortisone, times daily by mouth or 30 mg twice daily triamcinolone, betamethasone, and as suppositories. Where the medicine is dexamethasone. This safety issue licensed in children weighing less than is unrelated to the contamination of 35 kg it should be given orally at a dose compounded corticosteroid injection of 0.25 mg per kg bodyweight up to three products reported in 2012. times daily. The medicine should not Epidural injection of corticosteroids to normally be used for longer than one week. relieve neck and back pain has been a ►►EMA News, 7 March 2014. widespread practice for many decades; (See also under “Reviews started”) however, the FDA has not approved Hydroxyethyl starch-containing corticosteroids for such use. A panel of experts is working to define the techniques products: increased risk for for such injections which would reduce patients with sepsis preventable harm. The FDA will continue to Australia – The Therapeutic Goods investigate this issue. Administration (TGA) advises the public ►►FDA Safety Announcement, 23 April 2014. that a recent safety review of hydroxylethyl starch-containing products (Voluven® and Volulyte®) has confirmed an increased risk Zolpidem, eszopiclone: of mortality and the need for dialysis when impaired next-day alertness this medicine is used to treat patients with European Union – The European sepsis. Hydroxyethyl starch-containing Medicines Agency (EMA)’s Coordination solutions are administered in clinical Group for Mutual Recognition and situations, including during surgery, to treat Decentralised Procedures – Human and prevent hypovolaemia.

143 Safety and efficacy news WHO Drug Information Vol. 28, No. 2, 2014

(CMDh) has endorsed new advice to use of the antidepressant mirtazapine minimize the risk of next-morning impaired (Remeron® / Remeron RD®). Most cases driving ability and mental alertness occurred in association with drug overdose associated with the sleeping medication or in patients with preexisting risk factors zolpidem. for QT prolongation. Serious outcomes The product information of zolpidem- including torsades de pointes and death containing medicines will be updated have been reported with mirtazapine to include strengthened warnings and overdose. precautions. The recommended doses Mirtazapine should be used with caution must not be exceeded. Patients should in patients with known cardiovascular take the lowest effective dose of zolpidem disease, a family history of QT prolongation in a single intake, should not take any or concomitant use of QT prolonging alcohol, illicit drugs or medicines affecting medications. Vital signs and cardiac the central nervous system together with rhythm should be monitored in case of a zolpidem, and should not drive or perform mirtazapine overdose. activities that require mental alertness for ►►Health Canada Advisory, 28 March 2014. at least 8 hours after taking zolpidem. ►►EMA Press Release, 25 April 2014. Vemurafenib: liver problems United States of America – The U.S. Canada – Hoffmann-La Roche Limited Food and Drug Administration (FDA) warns (Roche Canada) and Health Canada that eszopiclone – similar in structure to have informed health professionals of zolpidem – is associated with next-day cases of drug-induced liver injury, some of impairment of alertness, often not noticed them severe, reported with vemurafenib by the patient. Eszopiclone-containing (Zelboraf®). Vemurafenib is indicated medicines marketed in the United States for the treatment of certain types of include Lunesta® and generics. unresectable or metastatic melanoma. The recommended starting dose was Health professionals should monitor reduced from 3 mg to 1 mg at bedtime. patients’ liver enzymes and bilirubin before Higher doses can be taken if needed, and during treatment. Liver problems but are more likely to impair next-day should be managed by reducing the alertness. Patients should not drive or dose of vemurafenib, or by interrupting or engage in other activities that require stopping the treatment. mental alertness on the day after taking ►►Health Canada Advisory, 7 April 2014. a 3 mg dose. Product information was updated to include these changes. Filgrastim and pegfilgrastim: ►►FDA Safety announcement, 15 May 2014. capillary leak syndrome Canada – Health Canada in association Mirtazapine: abnormal heart with the manufacturer has warned rhythm about the risk of capillary leak Canada – Merck Canada Inc., in syndrome associated with filgrastim and consultation with Health Canada, has pegfilgrastim, two medicines used to treat informed health professionals of post- neutropenia. Capillary leak syndrome marketing cases of QT prolongation and has been reported in cancer patients torsades de pointes reported with the undergoing chemotherapy who were

144 WHO Drug Information Vol. 28, No. 2, 2014 Safety and efficacy news treated with either of the medicines, and in discontinuation. Liver function should be bone marrow donors undergoing peripheral tested before and during treatment. In case blood progenitor cell mobilization who were of significant abnormalities, the benefits receiving filgrastim. and risks of continuing treatment should be Capillary leak syndrome, the leaking of carefully considered. fluid from the circulatory system into the ►►Health Canada Advisory, 7 May 2014. interstitial space, can cause circulatory shock and may be fatal. In case of suspected symptoms – such as swelling RAS-acting agents: not to be or puffiness, passing water less frequently, used in combination difficulty breathing, and tiredness – European Union – The European treatment must be stopped and the patient Medicines Agency (EMA)’s closely monitored. Pharmacovigilance Risk Assessment ►►Health Canada Advisory, 10 April 2014. Committee (PRAC) has advised against the combined use of two medicines of different classes acting on the renin- Belimumab: opportunistic brain angiotensin (RAS) system. RAS-acting infection agents are used in the treatment of Canada – Health Canada in hypertension and congestive heart association with the manufacturer has failure and include three main classes: warned health professionals about angiotensin-receptor blockers (ARBs or two cases of progressive multifocal “sartans”), angiotensin-converting enzyme leukoencephalopathy (PML), an inhibitors (ACE-inhibitors) and direct renin opportunistic brain infection, reported in inhibitors such as aliskiren. patients receiving belimumab (Benlysta®) In particular, patients with diabetes- for systemic lupus erythematosus. related kidney problems should not be Health professionals should suspect given an ARB with an ACE-inhibitor; where PML in patients with new onset deficits this is absolutely necessary treatment or deterioration in cognition, speech or must be supervised by a specialist with eye functions, seizures and/or motor and close monitoring of kidney function, fluid gait disturbances. A neurologist should be and salt balance and blood pressure. The consulted urgently, and where appropriate combination of aliskiren with an ARB or immunosuppressants including belimumab ACE-inhibitor is strictly contraindicated should be withheld until PML is excluded. in those with kidney impairment or ►►Health Canada Advisory, 22 April 2014. diabetes. This confirms and strengthens the conclusions of a 2012 EMA review of aliskiren. Temozolomide: liver injury ►►EMA News, 11 April 2014. Canada – Health Canada in association with the manufacturer has warned health professionals about cases of liver injury, TNF-alpha inhibitors: including fatal liver failure, reported in reactivation of tuberculosis patients taking temozolomide (Temodal®) United Kingdom – The U.K. Medicines for the treatment of glioblastoma. Liver and Healthcare products Regulatory toxicity may occur several weeks after Agency (MHRA) has warned about initiation of treatment or after temozolomide an increased risk of tuberculosis, or

145 Safety and efficacy news WHO Drug Information Vol. 28, No. 2, 2014 reactivation of latent tuberculosis, during Serotonin-blocking medicines: treatment with tumour necrosis factor alpha serotonin syndrome (TNF-alpha) inhibitors. Canada – Health Canada has completed Tuberculosis in patients receiving TNF- a safety review of the serotonin-blocking alpha inhibitors can be life-threatening, and drugs dolasetron (Anzemet®), granisetron deaths from tuberculosis have occurred (Kytril® and generics), ondansetron in these patients. TNF-alpha inhibitors (Zofran® and generics) and palonosetron are therefore contraindicated in patients (Aloxi®), which are used for treating with active tuberculosis or other severe nausea and vomiting. This review identified infections. a potential risk of serotonin syndrome, Patients should be screened for active caused by serotonin accumulation in the and latent tuberculosis before starting body. treatment with a TNF-alpha inhibitor, Early diagnosis is vital as serotonin and should be monitored closely for syndrome can be fatal if not treated. tuberculosis and other infectious diseases Symptoms may include agitation, before, during, and after treatment. confusion, fast heartbeat, muscle twitching ►►MHRA Drug Safety Update 7(9); April 2014. or stiffness, fever, loss of consciousness or coma. Arsenic-containing dental The product monographs for the pastes: genotoxicity affected serotonin-blocking products on the Canadian market are being updated to European Union – The European include this new safety information. Medicines Agency (EMA)’s Committee ►►Health Canada Advisory, 14 May 2014. for Medicinal Products for Human Use (CHMP) has recommended that the marketing authorizations for the dental Panitumumab: rare but severe pastes containing arsenic trioxide skin reactions (Caustinerf arsenical®, Yranicid arsenical® Canada – Health Canada and the and associated names) be revoked in the manufacturer has informed health EU due to concerns over genotoxic effects professionals of rare cases of Stevens- that could increase the risk of cancer, and Johnson syndrome and toxic epidermal the risk of cell death if the product leaks necrolysis reported in patients treated with into tissues around the teeth. panitumumab (Vectibix®), approved for The dental pastes have been used to the treatment of certain types of metastatic remove damaged nerves in the dental pulp. colorectal cancer. The product monograph The CHMP considered that restrictions and is being updated accordingly. additional guidance to dentists would not reduce the risks to an acceptable level. ►►Health Canada Advisory, 27 May 2014. ►►EMA Press release, 25 April 2014.

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■■Reviews started

Overview of safety reviews started Medicine Uses Concerns Reviewing authority reference Natalizumab Treatment of Melanoma ►►TGA Monitoring relapsing-remitting communication, multiple sclerosis 18 March 2014 Domperidone Relief of symptoms of Adverse effects on the ►►TGA Monitoring nausea and vomiting, heart communication, and delayed stomach 2 April 2014 emptying ►►Medsafe Monitoring communication, 31 March 2014 Oral methadone Relief of withdrawal Kidney failure possibly ►►EMA Press release, medicines symptoms in patients linked to misuse 11 April 2014 containing dependent on opioids povidone Codeine- Cough and cold in Morphine toxicity ►►EMA Press release, containing children 11 April 2014 medicines Testosterone- Treatment of Heart problems ►►EMA Press release, containing hypogonadism 11 April 2014 medicines (See also FDA Safety announcement, 31 January 2014) Ambroxol and Expectorants; Allergic reactions and ►►EMA Press release, bromhexine treatment of breathing severe skin reactions 11 April 2014 disorders in newborns Ivabradine Treatment of Increased combined ►►EMA Press release, symptoms in adults risk of cardiovascular 8 May 2014 with long-term stable death or non-fatal heart angina or long-term attack in patients with heart failure symptomatic angina Hydroxyzine- Various, including Adverse effects on the ►►EMA Press release, containing treatment of heart 8 May 2014 medicines anxiety disorders, sleep disorders premedication before surgery, relief of itching

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