This Alert highlights important revisions to the full prescribing information for rosiglitazone maleate (marketed as Avandia, Avandamet, and Avandaryl). The updated information includes a new BOXED WARNING, and additional updated WARNINGS, PRECAUTIONS and CONTRAINDICATIONS to emphasize that rosiglitazone may cause or exacerbate heart failure, particularly in certain patient populations. The implications of this new labeling for healthcare professionals who prescribe Avandia, Avandamet, and Avandaryl are summarized below.
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.
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
Information for the Patient
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.
In three 26-week trials in patients with type 2 diabetes, 216 received 4 mg of Avandia plus insulin, 322 received 8 mg of Avandia plus insulin, and 338 received insulin alone. These trials included patients with long-standing diabetes and a high prevalence of pre-existing medical conditions, including peripheral neuropathy, retinopathy, ischemic heart disease, vascular disease, and congestive heart failure. In these clinical studies an increased incidence of edema,cardiac failure, and other cardiovascular adverse events was seen in patients on Avandia andinsulin combination therapy compared to insulin and placebo. Patients who experienced cardiovascular events were on average older and had a longer duration of diabetes. These cardiovascular events were noted at both the 4 mg and 8 mg daily doses of Avandia. In this population, however, it was not possible to determine specific risk factors that could be used to identify all patients at risk of heart failure and other cardiovascular events on combination therapy. Three of 10 patients who developed cardiac failure on combination therapy during the double-blind part of the fixed-dose studies had no known prior evidence of congestive heart failure, or pre-existing cardiac condition.
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.