Posted: 04-05-10 Categories:
Avandia FDA Alerts

Avandia FDA Warning – Heart Attack Risk added to Avandia Black Box Warning

FDA Safety Alert on Avandia Issued May 21, 2007

The U.S. Food and Drug Administration (FDA) is aware of a potential safety issue related to Avandia (rosiglitazone), a drug approved to treat type 2 diabetes. Safety data from controlled clinical trials have shown that there is a potentially significant increase in the risk of heart attack and heart-related deaths in patients taking Avandia. However, other published and unpublished data from long-term clinical trials of Avandia, including an interim analysis of data from the RECORD trial (a large, ongoing, randomized open label trial) and unpublished reanalyses of data from DREAM (a previously conducted placebo-controlled, randomized trial) provide contradictory evidence about the risks in patients treated with Avandia.

Patients who are taking Avandia, especially those who are known to have underlying heart disease or who are at high risk of heart attack should talk to their doctor about this new information as they evaluate the available treatment options for their type 2 diabetes.

FDA’s analyses of all available data are ongoing. FDA has not confirmed the clinical significance of the reported increased risk in the context of other studies. Pending questions include whether the other approved treatment from the same class of drugs, pioglitazone, has less, the same or greater risks. Furthermore, there is inherent risk associated with switching patients with diabetes from one treatment to another even in the absence of specific risks associated with particular treatments. For these reasons, FDA is not asking GlaxoSmithKline, the drug’s sponsor, to take any specific action at this time. FDA is providing this emerging information to prescribers so that they, and their patients, can make individualized treatment decisions.

“FDA remains committed to assuring that doctors and patients have the latest information available to make treatment and medication use decisions. In this case, FDA is carefully weighing several complex sources of data, some of which show conflicting results, related to the risk of heart attack and heart-related deaths in patients treated with Avandia,” said Steven Galson, M.D., M.P.H., director of FDA’s Center for Drug Evaluation and Research. “We will complete our analyses and make the results available as soon as possible. FDA will take the issue of cardiovascular risk associated with Avandia and other drugs in this class to an Advisory Committee as soon as one can be convened.”

Avandia was approved in 1999 for treatment of type 2 diabetes, a serious and life threatening disease that affects about 18 to 20 million Americans. Diabetes is a leading cause of coronary heart disease, blindness, kidney failure and limb amputation. Since the drug was approved, FDA has been monitoring several heart-related adverse events (e.g., fluid retention, edema and congestive heart failure) based on signals seen in previous controlled clinical trials of Avandia alone and in combination with other drugs, and from postmarketing reports. FDA has updated the product’s labeling on several occasions to reflect these new data, most recently in 2006. The most recent labeling change for Avandia also included a new warning about a potential increase in heart attacks and heart-related chest pain in some individuals using Avandia. This new warning was based on the result of a controlled clinical trial in patients with existing congestive heart failure.

Recently, the manufacturer of Avandia provided FDA with a pooled analysis (meta analysis) of 42 randomized, controlled clinical trials in which Avandia was compared to either placebo or other anti-diabetic therapies in patients with type 2 diabetes. The pooled analysis suggested that patients receiving short-term (most studies were 6-months duration) treatment with Avandia may have a 30-40 percent greater risk of heart attack and other heart-related adverse events than patients treated with placebo or other anti-diabetic therapy. These data, if confirmed, would be of significant concern since patients with diabetes are already at an increased risk of heart disease.

Avandia is manufactured by GlaxoSmithKline, which is based in Research Triangle Park, N.C.

Avandia FDA Alert: 5/21/2007, updated 11/19/2007

This update highlights changes to the prescribing information for rosiglitizone including a new BOXED WARNING and changes to the WARNINGS, PRECAUTIONS, and INDICATIONS sections of the label2 [PDF] about the potential increased risk of myocardial ischemia. FDA also has requested that the manufacturer, GlaxoSmithKline, develop a Medication Guide for patients that provides information about the safe use of rosiglitazone. Healthcare professionals should factor this new information into their individual treatment decisions for their patients.

This information reflects FDA’s current analysis of data available to FDA concerning this drug. FDA intends to update this sheet when additional information or analyses become available.

To report any unexpected adverse or serious events associated with the use of this drug, please contact the FDA MedWatch program either online, by regular mail or by fax, using the contact information at the bottom of this page.

The rosiglitazone full prescribing information [PDF] includes new information in the BOXED WARNING, WARNINGS and PRECAUTIONS, and INDICATION sections about the risk of myocardial ischemia.

Recommendations and Considerations for Healthcare Professionals

  • Rosiglitazone may cause myocardial ischemia in some patients.
  • Co-administration of rosiglitazone and insulin is not recommended. A higher risk of myocardial ischemia was observed in controlled, double-blind clinical trials where rosiglitazone was added on to established insulin therapy.
  • Rosiglitazone is not recommended for patients with heart disease who are taking nitrates. A subgroup analysis of 42 clinical studies identified that patients with heart disease who are taking nitrates are at an increased risk of myocardial ischemia.

Information for Patients

  • Patients should be informed about the possible increased risk of myocardial ischemia.
  • Patients should be asked if they are taking insulin or nitrates and informed that taking rosiglitazone and insulin or rosiglitazone with nitrates may increase the risk of myocardial ischemia.
  • Patients should be asked to watch for and report immediately to a healthcare professional any signs and symptoms of myocardial ischemia, including chest pain or pressure, or pain that radiates to the jaw or down the arm, and shortness of breath. Such symptoms may require urgent medical treatment.

Background Information and Data

On May 21, 2007, FDA issued Information for Healthcare Professionals that described the potential risk of ischemic cardiovascular events in patients taking rosiglitazone based on safety data from controlled clinical trials. However, other data were inconclusive about these risks. For this reason, FDA convened a joint meeting of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) and the Drug Safety and Risk Management Advisory Committee (DSaRM) on July 30, 2007 for further evaluation and discussion of the available safety data.

The Committee members were asked to consider the evidence for increased cardiac ischemic risk for rosiglitazone and to advise CDER on whether the drug product should remain on the market. The Committee recommended that rosiglitazone remain on the market and that information about ischemic cardiovascular risks be added to the label.

At the request of FDA, the manufacturer of rosiglitazone, GlaxoSmithKline, has updated the prescribing information for rosiglitazone to include information about the risk of myocardial ischemic events in a boxed warning. In addition, FDA has requested that the manufacturer develop a Medication Guide for patients that describes the risk of myocardial ischemia and provides additional information about the recommended use of rosiglitazone.

FDA will continue to evaluate the benefits and risk of rosiglitazone and has requested that the manufacturer of rosiglitazone, GlaxoSmithKline, conduct further studies to examine cardiovascular risks. FDA will communicate additional information as it becomes available.

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