MI warning added to rosiglitazone black box.

A warning about the potential increased risk for myocardial infarction associated with rosiglitazone has been added to the existing black box warning for the antidiabetic agent, reflecting the results of the widely publicized meta-analysis of 42 studies that found a signal for such a risk.

The Food and Drug Administration announced the addition of the warning during a November briefing. "We are keeping Avandia on the market because we've concluded that there isn't enough evidence to indicate the risk of cardiac ischemia is higher for Avandia than other type 2 diabetes treatments," Dr. Janet Woodcock, the FDA's chief medical officer and acting director of the agency's Center for Drug Evaluation and Research (CDER), said during the briefing.

The black box for rosiglitazone, marketed as Avandia by GlaxoSmithKline, will now include the following statement: 'A meta-analysis of 42 clinical studies (mean duration 6 months; 14,237 total patients), most of which compared Avandia to placebo, showed Avandia to be associated with an increased risk of myocardial ischemic events such as angina or myocardial infarction. Three other studies (mean duration 41 months; 14,067 patients), comparing Avandia to some other approved oral antidiabetic agents or placebo, have not confirmed or excluded this risk. In their entirety, the available data on the risk of myocardial ischemia are inconclusive."

Dr. Woodcock said that because of these uncertainties, the FDA has requested that GlaxoSmithKline Inc. conduct a randomized, long-term clinical trial to assess the cardiac ischemic risks of rosiglitazone, compared with other oral antidiabetic agents--including the other available thiazolidinedione (TZD), pioglitazone, marketed as Actos by Takeda Pharmaceutical Co. The study is expected to start in November 2008 and last 4-5 years. Interim data will be available before the study is concluded.

"We want to make sure that health care providers and patients are aware that this signal of a risk has been identified," and that they consider this information when making treatment decisions, while waiting for the more definitive study to be completed, Dr. John Jenkins, director of the FDA's Office of New Drugs, said at the briefing. But the agency also wants to make clear that no available data show the other oral antidiabetic drugs, including pioglitazone, reduce cardiovascular risks, he added.

"The overall message ... is we have a signal from the short-term studies included in the meta-analysis, which was largely driven by comparison to placebo," but when compared with other oral antidiabetic agents in the three longer-term studies, the same findings were not observed, he added.

The warning regarding myocardial ischemia will not be added to the pioglitazone label. But the FDA is asking the manufacturer of all approved oral antidiabetic drugs to add a statement to their labels saying that no oral antidiabetic drugs have been shown conclusively to reduce cardiovascular risk. In August, a warning about the risk for heart failure associated with TZDs was added to the black box for rosiglitazone and pioglitazone, emphasizing that the TZDs may "cause or exacerbate congestive heart failure in some patients."

The signal for an increased MI risk associated with rosiglitazone was the topic of a joint meeting of the FDA's Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee in July 2007. At that time, the two panels concluded that data from meta-analyses of the rosiglitazone clinical program showed an increased risk for myocardial ischemia and that information on the potential for an increased risk of MI associated with the drug should be added to the label. But the panels voted 22 to 1 that the drug should remain on the market, pending the availability of more data. The opinions of FDA officials who presented data at the meeting were mixed, with two officials favoring the withdrawal of rosiglitazone from the market.

Dr. Woodcock said that the agency considered a "broad variety of opinions," including the FDA panel recommendations and comments, and also that it was clear during the panel meeting and afterward there were differences in opinion on the appropriate regulatory action. The issue also was referred to a drug safety oversight board, made up of FDA and other federal employees--including several from the National Institutes of Health and the Department of Veterans Affairs--who agreed overall that the drug should remain on the market.

The FDA's decision to keep rosiglitazone on the market and add the information on potential MI risk to the black box warning is "reasonable," said Dr. Barry Goldstein, director of the division of endocrinology, diabetes, and metabolic diseases, Jefferson Medical College, Philadelphia. The wording in the label has received some criticism for being vague, but whether rosiglitazone causes harm is "a completely open question," he said in an interview. He agreed that available data suggest a signal for vascular damage associated with rosiglitazone, but no data provide convincing evidence of this risk.

Although he does think twice about prescribing rosiglitazone, he has patients on the drug, which he said can be useful in getting patients to glycemic goal when combined with other treatments. Because of the side effects with TZDs--such as weight gain, fluid retention, heart failure, and fractures--they have not been widely embraced. But when he does prescribe a TZD, he tends to use the middle dose (4 mg of rosliglita-zone or 30 mg of pioglitazone) to mitigate the side effects of weight gain and fluid retention, and in combination with other treatments, where either "can really help get to glycemic goal," he said. This dosing issue has been lost amid the controversy over rosiglitazone, he emphasized.

Dr. Goldstein said he has conducted clinical trials for various manufacturers of diabetes drugs, including GSK, and has also served as a consultant.

GlaxoSmithKline will prepare a medication guide to explain the risks and benefits of the drug to patients. The revised label also includes a statement that rosiglitazone is not recommended for use in patients who are taking insulin or nitrates, but this is not a contraindication, according to GSK. Rosiglitazone was approved in 1999.

The warnings will also be added to the combination products containing rosiglitazone, Avandaryl (rosiglitazone and glimepiride) and Avandamet (rosiglitazone and metformin).

More information is available at www.fda.gov/cder/drug/infopage/rosiglitazone/default.htm.

BY ELIZABETH MECHCATIE

Senior Writer