Rosiglitazone to Stay on US Market With New Warnings About MI

November 14, 2007

November 14, 2007 (Rockville MD) -- The US FDA has decided to allow the diabetes drug rosiglitazone (Avandia, GlaxoSmithKline [GSK]) to stay on the market with increased warnings about the risk of cardiovascular events, while further studies are conducted to investigate the issue.

The Canadian authorities have taken similar action, albeit with a more strongly worded warning.

An FDA press release, issued today, states: "At this time, FDA has concluded that there isn't enough evidence to indicate that the risks of heart attacks or death are different between Avandia and some other oral type 2 diabetes treatments. Therefore, FDA has requested that GSK conduct a new long-term study to evaluate the potential cardiovascular risk of Avandia, compared with an active control agent. GSK has agreed to conduct the study, and FDA will ensure it is initiated promptly."

More black-box warnings

The existing boxed warning on the product's labeling will have the following statement added: "A meta-analysis of 42 clinical studies (mean duration six months; 14 237 total patients), most of which compared Avandia with 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 with 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." The boxed warning already cautions that rosiglitazone may worsen heart failure, a warning that is also on the labeling for pioglitazone (Actos, Takeda Pharmaceuticals).

The Avandia label also has been updated to add that the drug is not recommended--although not contraindicated--for use with patients who are taking insulin or nitrates.

Lack of CV risk reduction to be highlighted for all diabetes drugs

The FDA notes that, to date, no oral antidiabetes drug has been conclusively shown to reduce cardiovascular risk, and it will therefore also be requesting that labeling of all approved oral antidiabetes drugs contain language describing the lack of such data.

The agency says that people with type 2 diabetes who have underlying heart disease or who are at high risk of heart attack should talk with their healthcare provider about the revised warning for rosiglitazone as they evaluate treatment options. It also advises healthcare providers to closely monitor rosiglitazone patients for cardiovascular risks.

Canadian warning stronger

The Canadian regulatory authorities have also updated the labeling for rosiglitazone but have used stronger language, stating that "rosiglitazone is no longer approved for use alone or in combination with a sulfonylurea drug to treat type 2 diabetes, except when metformin use is contraindicated or not tolerated."

The updated warnings for rosiglitazone follow recommendations made at a US FDA advisory committee meeting in July that the drug should stay on the market with extra warnings, pending a review of additional data. The advisory meeting was called to discuss a meta-analysis by Nissen and Wolski published in the New England Journal of Medicine in May that suggested an increase in cardiovascular events with rosiglitazone and several other subsequent analyses of cardiovascular risk with the drug.

Nissen wanted stronger US warning

Commenting on the FDA's actions, Dr Steven Nissen (Cleveland Clinic, OH) said that while he welcomed the addition of the black-box warning on ischemic heart disease in the US labeling for rosiglitazone, he would have preferred stronger language to have been used. "I would have preferred a warning with greater clarity. I strongly preferred the language chosenby the Canadian authorities. But having said that, a black box is the strongest warning the FDA can make, short of drug withdrawal, and I think the message is unmistakable. By putting a black-box warning on a drug you are telling people to be extremely careful, and I think that message will be heard," he told heart wire .

Nissen added that while the proposed study to investigate cardiovascular risk with rosiglitazone was desirable, the results would not be available until 2014. "This is too long to wait. Patients need our advice now," he said.

Kaul happy

Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA), who coauthored a paper criticizing Nissen's meta-analysis, said he was happy with the FDA's warning. "The FDA's decision accurately reflects the uncertainty surrounding the cardiovascular risk associated with rosiglitazone. Clearly, more data are needed to adjudicate this uncertainty. Only prospective clinical trials designed for the specific purpose of establishing the cardiovascular benefit or risk of rosiglitazone will resolve the controversy about its safety. I am pleased to learn that the FDA has requested that GSK conduct a new long-term study to evaluate the potential cardiovascular risk of rosiglitazone and that GSK has agreed to conduct the study. Reason and logic seem to have prevailed over publicity blitz and fear-mongering," he commented to heart wire . "In the face of uncertainty, the best advice for the clinician is a 'don't stop, don't start' strategy. No need to stop rosiglitazone in patients who have tolerated it long term without any adverse events and whose blood sugars are under good control. No need to start patients on rosiglitazone before exhausting safer treatment options," he added.

GSK statement

GSK says the latest changes are now included in the labeling for Avandia and will be incorporated into future revised labeling for all approved rosiglitazone-containing products. It is also preparing a medication guide to help educate patients about potential benefits and risks and to provide other information on the drug. GSK chief medical officer Dr Ronald Krall commented: "Avandia remains a safe and effective medicine for most patients with type 2 diabetes when used appropriately. Given the severity of this disease and the importance of Avandia in helping patients manage their diabetes, we will continue to work with the FDA to conduct more studies about the safety and benefits of our medicine."

The complete contents of Heart wire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

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