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The Food and Drug Administration said it will require a class of diabetes drugs that includes Avandia and Actos to carry the agency's toughest "black box" warning that the drugs are linked to an increase in heart failure. The makers of the drugs have agreed to add the warnings. Avandia and Actos have long been shown to increase the risk of heart failure, a condition that develops over time and is characterized by the heart's inability to properly pump blood and which is different from a heart attack. The black box warning doesn't address more recent concerns that Avandia could increase the risk of heart attacks, but the FDA is expected to make a decision soon regarding whether or not to include additional warnings concerning heart attacks.
FDA Panel Says Avandia Label Should Include a "Black Box" Warning -
July, 30 2007
An FDA Advisory panel voted 22 to 1 that the widely used diabetes drug Avandia should remain on the market. However, in an earlier 20-3 vote, the panelists said that available data show the drug does increase heart risks. Panelists said the drug's label should include a so-called "black-box" warning, the most severe the FDA can require. Additionally, some suggested the label caution against using the drug together with insulin because doing so may elevate heart risks.
New Study Finds Patients Taking Avandia Face Twice the Risk of Heart Failure - July 27, 2007
A new study finds that patients taking either of the diabetes drugs Avandia or Actos face twice the risk of developing heart failure compared to people not on the popular medications. This means for every 50 patients with type 2 diabetes taking these drugs, one patient will develop heart failure within 26 months, according to the report released Friday and published in the August issue of Diabetes Care.
Study finds little evidence that Avandia improved the quality or length of diabetics' lives - July 18, 2007
German researchers found little evidence that Avandia improved the quality or length of diabetics' lives and concluded it could actually worsen complications of the disease, after studying pooled data from 18 past trials involving 8,000 patients.
Study Shows Increased Risk of Cancer in Woman Taking Avandia and Similar Drugs - June 21, 2007
According to a report, patients with diabetes, especially women, who take thiazolidinediones, which include commonly prescribed drugs such as Avandia and Actos, may have an increased risk of developing cancer. Investigators found that the use of any thiazolidinedione was
associated with a 59-percent increased risk of cancer. The use of
Avandia (rosiglitazone) increased the malignancy risk by 89 percent,
whereas the increased risk associated with Actos (pioglitazone) was not
statistically significant.
The U.S. Food and Drug Administration said it has asked GlaxoSmithKline PLC (GSK) to toughen warnings that its diabetes drug, Avandia, raises the risk of heart failure.
There's already a warning on the drug's label that Avandia raises the risk of heart failure in some patients but the FDA said it is asking for a more prominent "black box" warning.
The FDA's comments were made in the written testimony of FDA Commissioner Andrew von Eschenbach that was prepared for a U.S. House hearing looking at the FDA's role in evaluating safety issues with the drug.
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.
FDA is aware of a potential safety issue related to Avandia (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 Avandia. However, other published and unpublished data from long-term clinical trials of Avandia provide contradictory evidence about the risk of ischemic cardiovascular events in patients taking Avandia. 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 Avandia 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.
This information reflects FDA’s current analysis of available data concerning this drug. Posting this information does not mean that FDA has concluded there is a causal relationship between the drug product and the emerging drug safety issue. Nor does it mean that FDA is advising health care professionals to discontinue prescribing the product. FDA is considering, but has not reached a conclusion about, whether this information warrants any regulatory action. FDA intends to update this sheet when additional information or analyses become available.
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 Avandia, GlaxoSmithKline. The data from these 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 Avandia related to ischemic cardiovascular events is not yet certain.
Recommendations and Considerations
Avandia’s current prescribing information 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: http://www.fda.gov/cder/foi/label/2007/021071s023lbl.pdf. PDF document 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 Avandia 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 Avandia for treatment of type 2 diabetes compared to a variety of alternative therapies. The combined studies included 8,604 patients on Avandia 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 Avandia 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 Avandia-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 Avandia-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 Avandia between 2000 and 2004. The treatment groups were monotherapy with Avandia, 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 Avandia-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 Avandia 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. GSK has shared with FDA an analysis of the data for Avandia alone versus placebo which showed no increased risk of myocardial infarction, stroke or cardiovascular death with Avandia. FDA has not received the DREAM study data so cannot independently evaluate these data at this time. However, GSK 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 Avandia 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 collaborating to evaluate the data from the pooled analysis of 42 randomized clinical trials of Avandia, 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 Avandia 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.
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