GlaxoSmithKline has announced that it is implementing changes to the US product label for Avandia (rosiglitazone maleate), based on an extensive and thorough review by the FDA of myocardial ischemia data on Avandia, the most widely studied oral anti-diabetic medicine available.
The existing boxed warning has been revised to add the FDA's conclusion that, while an FDA meta-analysis of short-term studies -- mostly against placebo -- showed an association between Avandia and an increase in myocardial ischemic events, that risk was not confirmed or excluded in three long-term clinical trials comparing Avandia against both placebo and other oral anti- diabetes medicines. The box will state that the available data on the risk of myocardial ischemia are inconclusive.
The FDA has also concluded there is insufficient information available to determine whether any oral anti-diabetic medicine reduces cardiovascular risk. The FDA has directed that the sentence -- "There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Avandia or any other oral antidiabetic drugs" -- will be added as a warning on the labels of all oral anti-diabetic medicines.
The Avandia label also has been updated to add that Avandia is not recommended -- though not contraindicated -- for use with patients who are taking insulin or nitrates. The label summarizes the data on myocardial ischemia to help doctors continue to evaluate which patients could benefit from taking Avandia, and those for whom alternative treatment should be considered.
The changes are now included in labeling for Avandia, and will be incorporated into future revised labeling for all approved rosiglitazone-containing products, including Avandamet (rosiglitazone maleate and metformin hydrochloride), and Avandaryl (rosiglitazone maleate and glimepiride). GSK is also preparing a Medication Guide to help educate patients about potential benefits and risks and to provide other information on Avandia.
"Avandia remains a safe and effective medicine for most patients with type 2 diabetes when used appropriately," said Dr. Ronald Krall, GSK Chief Medical Officer. "Given the severity of this disease and the importance of Avandia in helping patients manage their diabetes, we will continue to work with the FDA to conduct more studies about the safety and benefits of our medicine."
As previously stated by GSK, two long-term trials in diabetic patients comparing Avandia to other oral anti-diabetic medicines show no increased risk for cardiovascular events compared to other commonly used medications, other than the well-known risk of congestive heart failure with TZDs. One trial -- ADOPT -- shows no increased myocardial ischemic risk compared to metformin or sulfonylurea. The interim results of a second long-term trial -- RECORD -- also show no increased risk of major cardiovascular events (death, heart attack and stroke) between Avandia and other medications; however, firm conclusions cannot be drawn because the trial has not yet been completed. The updated label includes data from ADOPT and RECORD plus a third long-term trial in pre-diabetic patients (DREAM) which show there was no increased risk of
Avandia over comparators with regard to myocardial infarction, mortality, or other non-heart failure cardiovascular events.
GSK believes data from ongoing and future clinical trials will provide additional scientific support for both the benefit and safety of Avandia. GSK has agreed to work with the FDA to plan and carry out a clinical trial to further investigate the cardiovascular effects of Avandia.