The MFDS has announced that the label for ticagrelor has been revised to include pulmonary haemorrhage as an adverse reaction. Ticagrelor is used as a platelet aggregation inhibitor. Ticagrelor is administered with aspirin and indicated to reduce the rate of cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome. At the time of review, the KIDS had received three domestic and six international reports of pulmonary haemorrhage with ticagrelor through KAERS from 1989 to 2015. Reports for ticagrelor and pulmonary haemorrhage were identified to be statistically significant compared to all the other reports from other drugs. This recommendation announced by MFDS was based on a signal analysis evaluation process in KIDS using adverse events reports.
The MHLW and the PMDA have announced that the package inserts for fluconazole (Diflucan®) and fosfluconazole (Prodif®) have been updated to include the risk of drug-induced hypersensitivity syndrome (DIHS) as a clinically significant adverse reaction. Fluconazole and fosfluconazole (pro-drug of fluconazole) are antifungal medications used for fungal infections with Candida or Cryptococcus. A total of two cases associated with DIHS with fluconazole use have been reported in Japan. Of these, a causal relationship could not be excluded in one of the cases. For fosfluconazole, one case associated with DHIS has been reported. The company core datasheet (CCDS) for fluconazole has also been updated.
The US FDA has warned that obeticholic acid (Ocaliva®) is being incorrectly dosed in some patients with moderate to severe decreases in liver function, resulting in an increased risk of serious liver injury and death. Obeticholic acid is used to treat a rare, chronic liver disease known as primary biliary cholangitis (PBC). The FDA stated that some patients are receiving excessive doses, at a higher than recommended frequency. Obeticholic acid may also be associated with liver injury in some patients with mild disease who are receiving the correct dose. The recommended dosing and monitoring for patients on obeticholic acid are described in the current drug label. The FDA is working with the drug manufacturer, Intercept Pharmaceuticals, to address these safety concerns.
The TGA has reminded health-care professionals to remain vigilant for potential signs of lithium toxicity, particularly in patients with risk factors. Early symptoms of lithium toxicity can occur close to or within the serum therapeutic range. Lithium (Quilonum® and Lithicarb®), is indicated for the treatment of acute mania, hypomania and for the prophylaxis of manic-depressive illness. The risk of lithium toxicity is adequately addressed in the product information for lithium. A patient died in 2013 as a result of lithium toxicity and has prompted this reminder. As of 17 May 2017, the TGA has received 58 reports in which lithium was suspected of causing toxicity. Two of these cases resulted in death. Interactions with other medicines were identified as a contributing factor in 17 cases, and may have played a role in four other cases. Inappropriate dosing was found to be a contributing cause of toxicity in two cases, and may have contributed to a third case.
The ANSM has received reports of serious liver injury potentially related to the repeated and/or prolonged use of high dose ketamine. The ASNM has reminded health-care professionals that good practice recommendations for use of ketamine should be implemented. It is essential to observe the recommended dosages and monitor the liver function closely. Ketamine is indicated as an anaesthetic agent, alone or in combination with other anaesthetics. Ten cases of serious liver injuries, including four cases leading to liver transplantation, have been reported by health-care professionals since 2014. These are cholestatic type cholangitis, which may be linked to the repeated and/or prolonged administration of ketamine.
The ANSM has encouraged health-care professionals to be cautious when initiating therapy with fluindione due to the risk of allergic reactions, particularly during the first six months of treatment. Fluindione (Préviscan®) is an antivitamin K (AVK) class anticoagulant. It is indicated for atrial fibrillation (heart rhythm disorder), venous thrombosis or pulmonary embolism. A survey carried out by the Regional Centre for Pharmacovigilance in Lyon found that the use of fluindione is more frequently associated with the occurrence of rare but often severe DRESS-type immuno-allergic attacks, in particular renal, hepatic, haematological or dermatological disorders. In France, 82% of patients treated with AVK received fluindione, 13% of warfarin and 5% of acenocoumarol. These data are based on the number of daily defined doses consumed in 2016. Warfarin is the most widely used AVK in the rest of the world.
The MHLW and the PMDA have announced that the package insert for laninamivir (Inavir®) has been updated to include the risk of bronchial spasm and dyspnoea as clinically significant adverse reactions. Laninamivir is indicated for treatment and prophylaxis of influenza A and B virus infection. Eight cases associated with bronchial spasm and dyspnoea have been reported in Japan. Of these, a causal relationship could not be excluded in three cases.
The MHLW and the PMDA Japan have announced that the package insert for moxifloxacin (Avelox®) has been updated to include the risk of rhabdomyolysis as a clinically significant adverse reaction. Moxifloxacin is an antibiotic used for the treatment of a number of bacterial infections. Two cases associated with rhabdomyolysis have been reported in Japan, of which causal relationship could not be excluded.
Health Canada has recommended that the product safety information for all non-prescription fluconazole products should be updated to include the potential risk of pregnancy loss and birth defects and state that these products are not recommended for use by women who are trying to become pregnant. Non-prescription (oral, 150 mg) fluconazole products are authorized to treat vaginal yeast infections. Health Canada reviewed the potential risk of unwanted effects in pregnancy, including pregnancy loss (i.e., miscarriage or stillbirth) or birth defects (i.e., major congenital malformations) with non-prescription fluconazole use, in part because a recently published study suggested that such a risk may exist.
The Therapeutic Goods Administration (TGA) Australia has updated the product information documents for all prescription codeine preparations to include the restriction of use in children and ultra-rapid metabolisers. More specifically, codeine products should no longer be used in children under 12 years of age, or in children aged 12-18 years who have recently undergone surgery to remove their tonsils or adenoids. Codeine should also not be used by breastfeeding mothers or in patients known to be ultra-rapid metabolisers. Most product information for over-the-counter codeine preparations now have warnings not to use them in children aged under12 years.
The Ministry of Health, Labour and Welfare (MHLW) and the Pharmaceuticals and Medical Devices Agency (PMDA) Japan have announced that the package inserts for amoxicillin preparations have been updated to include the risk of thrombocytopenia as a clinically significant adverse reaction. Amoxicillin is an antibiotic used for the treatment of a number of bacterial infections.
Azithromycin
The Ministry of Health, Labour and Welfare (MHLW) and the Pharmaceuticals and Medical Devices Agency (PMDA) have announced that the package insert for azithromycin (Zithromax®) has been updated to include the risk of acute generalized exanthematous pustulosis as a clinically significant adverse reaction. Azithromycin is an antimicrobial used for a number of bacterial infections caused by strains of genus Staphylococcus, Streptococcus, Pneumococcus, Neisseria gonorrhoeae, Moraxella (Branhamella) catarrhalis, Haemophilus influenzae, Legionella pneumophila, Peptostreptococcus, Prevotella, Chlamydia, and Mycoplasma. One case of acute generalised exanthematous pustulosis has been reported in Japan. A causal relationship could not be excluded in this case. In addition, the company core datasheet (CCDS) has been updated.
Doxycycline
The Saudi Food and Drug Authority (SFDA) has updated the summary of product characteristics and patient information leaflet for doxycycline to include the risk of fixed drug eruptions (FDE). Doxycycline is a tetracycline broad-spectrum antibiotic with bacteriostatic characteristics. It is used as treatment or prophylaxis against a wide range of susceptible strains of gram-negative and gram-positive bacteria and other microorganisms. The SFDA initiated the investigation based on a signal observed in a published case report examining potential associations between doxycycline and risk of FDE. As a result, the SFDA reviewed the available evidence related to this safety issue including screening of the WHO global database of Individual Case Safety Reports, VigiBase. In addition, a literature review was conducted. The SFDA concluded that the available evidence suggests a probable association between doxycycline and FDE.
Paracetamol (modified- or prolonged-release)
The EMA has recommended that modified- or prolonged-release paracetamol products should be suspended from the market. This is in view of the risks to patients from the complex way these medicines release paracetamol into the body after an overdose. Paracetamol is a medicine that has been widely used for many years to relieve pain and fever in adults and children. The review of modified-release paracetamol has been carried out by the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC). The PRAC evaluated published studies and reports of overdose with these medicines, consulted experts in the management of poisoning and assessed how overdose with paracetamol is managed in the EU and other parts of the world. In many cases, it may not be known whether an overdose of paracetamol involves immediate-release or modified-release products, making it difficult to decide what type of management is needed. The committee could not identify a way to minimise the risk to patients, or a feasible and standardised way to adapt the management of paracetamol overdose across the EU to allow for treatment of cases that involve modified-release preparations. It concluded that the risk following overdose with these medicines outweighs the advantage of having a longer-acting preparation.
Warfarin
The MHLW and the PMDA have announced that the package insert for warfarin has been updated to include the risk of calciphylaxis as a clinically significant adverse reaction. Warfarin is used for treatment and prevention of thromboembolism (including venous thrombosis, myocardial infarction, pulmonary embolism, brain embolism and, slowly progressive cerebral thrombosis). Eleven cases associated with calciphylaxis have been reported in Japan and there is an overseas report published in the literature describing calciphylaxis with the use of warfarin. In addition, package inserts in Europe and the United States have been revised.
Desloratadine
Health Canada has carried out a safety review to look at the potential risk of QT interval prolongation with the use of over-the-counter (OTC) desloratadine-containing products. This safety review was triggered by a signal publication in the WHO Pharmaceuticals Newsletter No.2, 2015, describing cases of abnormal heart rhythm suspected to be associated with the use of loratadine and desloratadine. Desloratadine is used to relieve symptoms of seasonal allergy or allergy caused by pollen or dust (hay fever). At the time of the review, Health Canada had received 10 Canadian reports of abnormal heart rhythm suspected to be associated with desloratadine use. In addition, Health Canada reviewed 13 international reports of abnormal heart rhythm suspected to be associated with the use of desloratadine that were provided by the manufacturer. A search in the WHO database of Individual Case Safety Reports, VigiBase identified 35 cases of abnormal heart rhythm suspected to be associated with desloratadine use. A link between the use of desloratadine and the abnormal heart rhythm could not be established, as there was not enough information in the reports to draw conclusions. Published scientific studies have shown that desloratadine is not associated with abnormal heart rhythm in humans.
The MHLW and the PMDA have announced that the package inserts for diclofenac preparations (Voltaren® and Rectos®) have been updated to include the risk of gastrointestinal stenosis and obstruction as clinically significant adverse reactions. A total of five cases of gastrointestinal stenosis or obstruction associated with the use of diclofenac have been reported in Japan. In addition, the company core datasheet (CCDS) has been updated.
Health Canada is working with the Drug Safety and Effectiveness Network to further investigate the extent of ondansetron (Zofran®) use during pregnancy and the risk to the foetus. Health Canada has requested that manufacturers submit information they may have regarding birth defects and use of ondansetron during pregnancy. At the time of the review, Health Canada had received 14 reports of birth defects in the newborn babies of mothers treated with ondansetron. Findings from published scientific studies were inconsistent and inconclusive. There were concerns with study design, and the majority had a number of limitations such as use of concomitant medications. Available information were not sufficient to establish a link between the use of ondansetron during pregnancy and the risk of birth defects. Health Canada will continue to monitor safety information involving the use.
Health Canada has concluded in a review that there is not enough evidence to confirm a link between incretin-based therapies and pancreatic cancer. During the last few years, a small number of studies have found a possible link between the use of incretin-based therapies and an increased risk of pancreatic cancer. This led Health Canada to conduct a review. At the time of the review, 15 cases of pancreatic cancer that may have been linked to the use of incretin-based therapies had been reported to Health Canada. Although some non-clinical studies using animal or human models have suggested that the use of incretin-based therapies may be linked to an increased risk of pancreatic cancer, results from clinical trials and many studies looking at the patterns, causes, and effects of health and disease conditions in people, do not support this link.
The HPRA has issued advice to health-care professionals on monitoring the international normalised ratio (INR) more closely in patients concurrently treated with vitamin K antagonists. A signal of a potential drug interaction leading to a reduced INR has recently been identified with co-administration of direct-acting antivirals and vitamin K antagonists. The case reports on which the signal was based were reviewed by the EMA’s PRAC. The PRAC has recommended that the product information of direct-acting antivirals should be updated to include a recommendation for close monitoring of INR in patients treated with vitamin K antagonists, as liver function may change during treatment with direct-acting antivirals. While no change in the pharmacokinetics of warfarin is expected, close monitoring of INR is recommended with all vitamin K antagonists.
The MHLW and the PMDA have announced that the package inserts for warfarin and miconazole (Florid®) have been updated to include a contraindication of administering warfarin and miconazole concomitantly due to increased risk of bleeding. The package inserts for other antifungal drugs (voriconazole, itraconazole, fluconazole and fosfluconazole) have also been updated to include precautions about concomitant administration with warfarin. A total of 41 cases associated with serious bleeding during concomitant administration or, after discontinuation of concomitant administration of miconazole and warfarin have been reported in Japan. Due to the contraindication of concomitant administration of miconazole and warfarin, the use of other azole drugs, including those recommended as first-line treatments is expected. Thus, MHLW/PMDA considered that caution is also required for concomitant administration of warfarin and other azole antifungal drugs.
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