• FDA ALERT #1: 5/21/2007, updated 11/19/2007: FDA adds a new warning about the risk of myocardial ischemia to the boxed warning for Avandia, for treatment of Type 2 Diabetes.
  
  
• FDA ALERT #2: 8/14/2007: Important revisions to the full prescribing information (labeling) highlighting increased risks of congestive heart failure associated with rosiglitazone.

FDA ALERT #1: 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 label 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 and complete a form on line at http://www.fda.gov/medwatch/report/hcp.htm or report by fax to 1-800-FDA-0178, by mail using the postage-paid address form provided on line, or by telephone to 1-800-FDA-1088.

The rosiglitazone full prescribing information 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.

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.

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 and complete a form on line at http://www.fda.gov/medwatch/report/hcp.htm or report by fax to 1-800-FDA-0178, by mail using the postage-paid address form provided on line, or by telephone to 1-800-FDA-1088.

Rosiglitazone maleate is a thiazolidinedione (TZD) approved as an oral antidiabetic agent.  TZDs are selective ligands of the nuclear transcription factor peroxisome-proliferator-activator-receptor- γ (PPAR-γ) which improve glycemic control by increasing insulin sensitivity.  Three products, all manufactured by GlaxoSmithKline, contain rosiglitazone maleate: Avandia (rosiglitazone), Avandamet (rosiglitazone with metformin), and Avandaryl (rosiglitazone with glimepiride).  Fluid retention, weight gain, edema, and heart failure are known side-effects of TZDs.  Continued post-marketing reports of heart failure have prompted the FDA to increase the prominence of this safety concern in the labels for these drugs.  This cardiovascular concern is separate from a recent concern of increased myocardial ischemia risk.

Recommendations and Considerations

• Thiazolidinediones, including Avandia, Avandamet, and Avandaryl, may cause or exacerbate congestive heart failure in some patients.
• Initiation of these drugs in patients with established NYHA Class III or IV heart failure is contraindicated.
• After initiation of Avandia, Avandamet, or Avandaryl, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). 
• If these signs and symptoms develop and heart failure is confirmed, appropriate management of heart failure should be initiated.  Discontinuation or dose reduction of Avandia, Avandamet, and Avandaryl should be considered.

 Information for the Patient

• Patients should be informed that Avandia, Avandamet, and Avandaryl, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. 
• Patients should be asked to watch for and report to their healthcare professional any signs and symptoms of heart failure, including edema from fluid retention, shortness of breath or trouble breathing, unusually fast increase in weight, and unusual tiredness.

Background Information and Data

FDA has received data from clinical studies of rosiglitazone for treatment of type 2 diabetes.  The studies analyzed to date have shown different rates of congestive heart failure. Based on these data, the risk of CHF has been highlighted in a new BOXED WARNING. Following are summaries of the studies and data.

Clinical Trial Data

A 52-week, double-blind, placebo-controlled echocardiographic study was conducted in 224 patients with type 2 diabetes mellitus (T2DM) and NYHA Class 1 or 2 CHF (ejection fraction ≤ 45%) on background antidiabetic and CHF therapy. Patients with NYHA Class 3 and 4 cardiac status were not studied during the clinical trials.  Although no treatment difference in change from baseline of ejection fractions was observed, the risk of worsening heart failure was higher in the Avandia-treated group compared to placebo.  Heart failure exacerbation occurred in 6% of the Avandia group versus 4% in the placebo group.  Worsening edema, worsening dyspnea, and increases in heart failure medications were observed in 25%, 26%, and 33% of the Avandia-treated patients compared to 9%, 17%, and 18% of the placebo group.

Next Steps

Healthcare professionals should factor this new labeling information into their individual treatment decisions for their patients.  FDA will continue to monitor post-marketing reports of heart failure and will analyze any additional studies for this, as well as other important adverse effects.  The agency will consider further regulatory action and communication as additional information becomes available.