Medical symbolDirectory of Drugs: Prescription symbol Avandia - Rosiglitazone maleate



FDA ALERT #1: [8/14/2007]:  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.


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.

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.

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. 

FDA is aware of a potential safety issue related to rosiglitazone maleate. Safety data from a pooled analysis of controlled clinical trials have shown a significant increase in the risk of heart attack and heart-related deaths in patients taking rosiglitazone. However, other published and unpublished data from long-term clinical trials of rosiglitazone provide contradictory evidence about the risk of ischemic cardiovascular events in patients taking rosiglitazone. FDA’s review of all available data is ongoing. FDA has not confirmed the clinical significance of the reported increased risk of ischemic cardiovascular events in the context of other studies. Myocardial ischemic events are currently described in the WARNINGS section of the rosiglitazone label. FDA does not know whether the other approved medication in the same pharmacologic class or other oral drugs for treating type 2 diabetes have less, the same, or greater risks. Switching diabetic patients to other therapies also confers its own risks. For those reasons, FDA is providing this emerging information to prescribers so that they and their patients can make individualized treatment decisions.

FDA has received additional safety information, a pooled analysis of 42 clinical studies for the treatment of type 2 diabetes mellitus, from the manufacturer of rosiglitazone, GlaxoSmithKline. There are three products, all manufactured by GlaxoSmithKline, that contain rosiglitazone: Avandia, Avanadamet (rosiglitazone with metformin), and Avandaryl (rosiglitazone with glimepiride). The data from these 42 studies and the associated analyses are complex and are currently being reviewed by the FDA. In the meantime, FDA is providing information on the initial results of these analyses. The degree of risk of rosiglitazone related to ischemic cardiovascular events is not yet certain.
Recommendations and Considerations

The current prescribing information for rosiglitazone includes data in the WARNINGS section about cardiac adverse events (congestive heart failure and ischemic events).  These warnings can be found in the current prescribing information available at this link:   Healthcare professionals should consider this and other available data when making individual treatment decisions for their patients with type 2 diabetes. 

Background Information and Data

FDA has received data from several different clinical studies of rosiglitazone for treatment of type 2 diabetes.  These studies vary with respect to the study design (e.g., pooled analysis, individual randomized controlled clinical trial, observational epidemiological study), patient populations enrolled, treatment groups, and length of patient follow-up.  The studies analyzed to date have shown different rates of ischemic cardiovascular events.  Based on these data, the risk of ischemic cardiovascular events remains unclear.  Following are summaries of the studies and data.

Clinical Trial Data - Pooled Analysis of 42 Studies

FDA has received the pooled data from 42 separate double-blinded, randomized controlled clinical trials to assess the efficacy of rosiglitazone for treatment of type 2 diabetes compared to a variety of alternative therapies. The combined studies included 8,604 patients on rosiglitazone and 5,633 patients randomized to a variety of alternative therapeutic regimens, including placebo. In general, these studies had differing primary efficacy endpoints; they were not designed to thoroughly investigate cardiovascular safety. Treatment groups varied and included rosiglitazone alone or in combination with insulin, sulfonylureas, and/or metformin. The comparator arms were varied and included placebo alone or as an add-on treatment to other anti-diabetic agents, and other active anti-diabetic treatment regimens. The combined patient population was diverse, including patients with average duration of diabetes ranging from 5 to 13 years as well as patients with significant risk factors for cardiovascular disease (e.g., history of myocardial infarction, bypass surgery, stroke, peripheral vascular disease, and NYHA Class 1 and 2 heart failure). All but four studies were of six months in duration. In this pooled analysis as submitted by GlaxoSmithKline, the overall incidence of myocardial ischemia in rosiglitazone-treated subjects relative to the comparators was 1.99% vs. 1.51% with a hazard ratio of 1.31 (95% CI 1.01-1.70). This risk equates to a more than 30% excess risk of myocardial ischemic events in rosiglitazone-treated patients.

Balanced Cohort Study of Coronary Heart Disease Outcomes in Patients Receiving Anti-diabetic Agents

The Balanced Cohort Study is an observational study of 33,363 patients using a managed care database. Propensity matching was used to match risk factors for cardiovascular disease and other considerations for patients initiating therapy. About 90% of the patients had no history of cardiovascular disease. The composite cardiovascular endpoint was hospitalizations for myocardial infarction and coronary revascularization. Patients included in this study began treatment with rosiglitazone between 2000 and 2004. The treatment groups were monotherapy with rosiglitazone, metformin, or sulfonylurea; oral dual therapy combinations, and insulin combinations. Follow-up was 1.2 years. The incidence of the composite cardiovascular endpoint was 1.75 events per 100 patient-years for the rosiglitazone-containing regimens and 1.76 events per 100 patient-years for other treatments (hazard ratio 0.93; 95% CI 0.80-1.10).

A Diabetes Outcomes Progression Trial (ADOPT)

ADOPT is a randomized, double-blind study of 4,351 patients that compared rosiglitazone, metformin, or glyburide monotherapy on the improvement of and maintenance of glycemic control in patients newly diagnosed with type 2 diabetes.  Patients with underlying cardiovascular disease were excluded.  Median follow-up was 4 years.  The myocardial ischemic event hazard ratios for rosiglitazone vs. metformin; rosiglitazone vs. glyburide; and metformin vs. glyburide were 0.96 (95% CI 0.66, 1.38), 1.16 (95% CI 0.78, 1.73) and 1.22 (95% CI 0.082, 1.80), respectively.  The results of the ADOPT trial have been published, see the New England Journal of Medicine 355;23 pg 2427-2443 December 7, 2006.  These data do not support an ischemic risk of rosiglitazone relative to metformin (the first line therapy for type 2 diabetes and a drug that has been shown to lower long term cardiovascular risk).

The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) Study

The DREAM study is a placebo-controlled, randomized, double-blind clinical trial in pre-diabetic patients designed to determine if the use of early treatment with medication could forestall the development of overt type 2 diabetes. The study was conducted in nearly 5,300 patients who were randomized to either rosiglitazone or placebo and were followed-up for a mean duration of 3 years. The study also was intended to examine whether rosiglitazone and/or ramipril delayed onset of overt type 2 diabetes. Therefore the trial used a factorial design, with patients randomized to any of four treatment arms: placebo with placebo; rosiglitazone with placebo; placebo with ramipril; and rosiglitazone with ramipril. This study, as reported in the Lancet, showed an effect of rosiglitazone in delaying the development of type 2 diabetes (not found with ramipril) in these prediabetic patients. GlaxoSmithKline has shared with FDA an analysis of the data for rosiglitazone alone versus placebo which showed no increased risk of myocardial infarction, stroke or cardiovascular death with rosiglitazone. FDA has not received the DREAM study data so cannot independently evaluate these data at this time. However, GlaxoSmithKline recently received the data from McMaster University and will be submitting it soon to FDA for review.

The Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) Study

The RECORD study is a large, ongoing, randomized, open-label trial evaluating cardiovascular outcomes in patients treated with rosiglitazone as add-on therapy to either metformin or sulfonylurea in comparison to metformin and a sulfonylurea. It is a post-marketing, non-inferiority safety study of rosiglitazone vs. combined controls with a primary endpoint of cardiovascular death and hospitalization (including congestive heart failure). Cardiac events are being adjudicated in a blinded fashion to treatment assignment by a Cardiovascular Endpoints Committee.

Over 300 study centers in 25 countries in Europe are involved in the conduct of this study with each center attempting to enroll 10 to 20 patients.  This non-IND study (done outside the United States and without input to the protocol or study design by the FDA) started in 2001 and completed enrollment in 2003, with over 4400 patients enrolled and proposed to be followed for 5 years.  This study is still ongoing with the last patient reaching the duration of follow-up targeted in late 2008.   This study has regularly been monitored by a data monitoring committee aware of the apparent elevation in cardiovascular ischemic risk from the pooled analysis.  The Committee has not called for study cessation.  Further, FDA has been allowed to see the results of a recent interim safety analysis and these interim data will be taken into account in FDA’s considerations and actions.  However, to preserve the study integrity, FDA is not explicitly commenting on these analyses. 

Next Steps for FDA

FDA’s Office of New Drugs, Office of Surveillance and Epidemiology, and Office of Biostatistics are ollaborating to evaluate the data from the pooled analysis of 42 randomized clinical trials of rosiglitazone, in the context of all other available data. As information becomes available from the continued analysis of the 42 clinical studies and from other ongoing clinical studies, FDA will communicate this information to ensure that healthcare professionals and patients have the information necessary to make appropriate therapeutic decisions. FDA will take the issue of cardiovascular risk associated with rosiglitazone and other drugs in this pharmaceutical class to a public Advisory Committee meeting as soon as one can be convened. In the interim, healthcare professionals should factor this new information into their individual treatment decisions for their patients.

Date created: August 29, 2007


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