A) US FDA advisory committee meeting²

Pooled data from 42 clinical trials

The US Food and Drug Administration (FDA) convened a public Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee meeting on 30 July 2007 to review the cardiovascular profile of rosiglitazone. The FDA conducted their own analysis on the 42 double-blind, randomized, controlled clinical trials which were used in Nissen and Wolski's paper. In their analysis, an increased risk of myocardial ischaemia with rosiglitazone versus pooled comparators was observed (odds ratio 1.4, 95% CI 1.1, 1.8). An increased risk of myocardial ischaemic* events with rosiglitazone was observed in the placebo-controlled studies, but not in the active-controlled studies. (* angina pectoris, angina pectoris aggravated, unstable angina, cardiac arrest, chest pain, coronary artery occlusion, dyspnoea, myocardial infarction, coronary thrombosis, myocardial ischaemia, coronary artery disease / disorder.)

The UK Medicines and Healthcare Products Regulatory Agency (MHRA), European Medicines Agency (EMEA), Health Canada and the US FDA have all taken the similar stance that there were insufficient evidence to indicate that the risks of myocardial infarction or death are different between rosiglitazone and some other oral type 2 diabetes mellitus treatments, and the benefits of rosiglitazone in the treatment of type 2 diabetes continue to outweigh their risks. However, in all the various jurisdictions, the product information of rosiglitazone-containing products will be updated to include warning that in patients with ischaemic heart disease, rosiglitazone should only be used after careful evaluation of each patient's individual risk.

In Canada, it has been announced that rosiglitazone is no longer approved as monotherapy for type 2 diabetes, nor for use in combination with sulfonylurea, except when metformin use is contraindicated or not tolerated. Treatment with all rosiglitazone products is now contraindicated in patients with any stage of heart failure (i.e. NYHA Class I, II, III or IV). The product information for Avandia® is currently under review by Health Canada.

Based on the available data to-date, there is insufficient evidence at this point to conclude that the risks of myocardial infarction and cardiovascular death is higher for rosiglitazone compared to other type 2 diabetes treatments. However, to enhance safer use of this drug, HSA is working with the company to strengthen the prescribing information in the local package inserts of Avandia® and Avandamet®. Information on cardiac ischaemia will be included in the adverse reactions and clinical studies sections of the package insert, and the initiation of rosiglitazone will be contraindicated in patients with NYHA Class III and IV heart failure.

Healthcare professionals are encouraged to report all serious adverse effects suspected to be associated with the thiazolidinediones class of medicines, namely, rosiglitazone and pioglitazone, to the Pharmacovigilance Unit.