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Two Food and Drug Administration advisory committees recommended this week that the FDA should keep rosiglitazone (Avandia), which is used to treat type 2 diabetes, on the market, despite concerns about the raised risk of heart attack in some patients.
Warnings will be increased, however, about use in subgroups of patients. Whether the warnings will be of the most serious “black box” type is yet to be determined. The FDA usually follows the advice of advisory committees but is not required to. The FDA will consider the committees' discussion and make recommendations for changes to labelling.
The FDA's advisory committees on endocrinological and metabolic drugs and the drug safety and risk management advisory committees met jointly at a crowded public meeting in a hotel near the FDA headquarters, outside Washington, DC, on Monday.
The FDA brought forwards its meeting to consider rosiglitazone's risks in light of a paper by researchers at the Cleveland Clinic that showed a 43% bigger risk of heart attack among patients taking the drug (BMJ 2007;334:1073 doi: 10.1136/bmj.39224.364630.DB and New England Journal of Medicine 2007 May 21 doi: 10.1056/NEJMoa072761).
The committee did not consider the increased risk of congestive heart failure with rosiglitazone and related diabetes drugs, which has been known about for several years. The latest reports of this risk were published a week before the meeting and grabbed media attention in the United Kingdom (Diabetes Care 2007;30:2148-53 doi: 10.2337/dc07-0141).
It has long been known that both rosiglitazone and pioglitazone (Actos) increase the risk of congestive heart failure. In June the FDA placed a black box warning about heart failure on both drugs (BMJ 2007;334:1237 doi: 10.1136/bmj.39244.394456.DB).
The joint committees voted 20 to three that rosiglitazone posed a higher risk of cardiac ischaemic events, but 22 to one that rosiglitazone should stay on the market, albeit with greater warnings.
David Graham, associate director of the FDA's office of surveillance and epidemiology, told the committee that rosiglitazone should be pulled from the market because, he said, it had caused between 40000 and 205000 heart attacks and strokes since 1999.
His superior, Gerald Dal Pan, director of the FDA's office of surveillance and epidemiology, in the Center for Drug Evaluation and Research, said that rosiglitazone's risk-benefit profile was “not favourable.” Robert Meyer, director of the FDA's office of drug evaluation II, said he was undecided about what regulatory action should be taken. He noted disagreements among FDA staff.
GlaxoSmithKline (GSK), the manufacturer of rosiglitazone, strongly defended the drug. It said that meta-analyses to determine the risk of ischaemic cardiac events, such as those by Steven Nissen and Kathy Wolski of the Cleveland Clinic in the New England Journal of Medicine study, studies by the company itself, and studies by the FDA “have significant limitations. GSK believes a full and scientific evaluation of all the data does not confirm the safety questions originally raised.”
GlaxoSmithKline said that several trials showed that rosiglitazone did not increase myocardial ischaemia; that the risk of increased myocardial infarction was small and inconsistent among trials and did not show a difference between rosiglitazone and other antidiabetic agents; that no evidence showed increased cardiovascular deaths with rosiglitazone compared with other antidiabetic agents; and that fewer strokes were seen with rosiglitazone than with other antidiabetic agents.
At a press conference at the conclusion of the meeting, the acting chairman of the committee, Clifford Rosen, said that there were “clear cut reasons” for clinicians not to use rosiglitazone in certain patients with diabetes. The drug should not be used in patients who were prone to congestive heart failure or had previously experienced it; in patients with cardiovascular disease, such as those who had been admitted to hospital for myocardial infarction; in patients who frequently used nitrates; and in patients who were long term users of insulin. “Clinicians have to think twice,” he said, before they prescribe rosiglitazone for such patients, especially patients taking insulin.
Current prescribing information in the United States says that rosiglitazone can be used with caution in patients with New York Heart Association class I or II heart failure. The European Medicines Agency says that the drug should not be prescribed to patients with heart failure.
Committee members said that the data about cardiac ischaemic events in various studies were not always comparable and that the studies had not been designed to look for a risk that had not been anticipated when rosiglitazone was approved. Neither did the committees have a way to compare the risk of rosiglitazone with other diabetes drugs or a way to demand such a comparison, said Dr Meyer.
The FDA's summary is available at www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4308b1-02-fda-backgrounder.pdf. GlaxoSmithKline's summary is available at www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4308b1-01-sponsor-backgrounder.pdf.
See doi: 10.1136/bmj.39294.547326.DB.