ADELPHI, Md. – A Food and Drug Administration advisory panel split on whether to recommend that sibutramine be withdrawn from the market because of concerns over its cardiovascular safety.
Sibutramine is a norepinephrine reuptake inhibitor approved as a weight-loss agent in 1997.
At a Sept. 15 meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, held to discuss the results of a large cardiovascular outcomes study of the drug, 8 of the 16 panelists recommended that sibutramine be withdrawn from the U.S. market because of concerns over cardiovascular safety, its modest weight loss effect, and lack of evidence of health benefits associated with treatment. Another two panelists recommended that it remain on the market, with the addition of a boxed warning to the label warning that treatment is associated with an increased risk for cardiac events and that blood pressure and pulse need to be closely monitored in patients during treatment.
The remaining six panelists recommended that it be allowed to remain on the market with this boxed warning – as well as limiting the drug’s use by restricting its distribution.
Sibutramineis marketed as Meridia by Abbott Laboratories as a weight-loss agent in obese or overweight people.
The modest increases in heart rate and blood pressure associated with sibutramine treatment have been a concern since it was approved, and, in 2002, contraindications were added to the label for the following populations: patients with a history of cardiovascular disease, heart failure, tachycardia, peripheral artery disease, arrhythmias, and cerebrovascular disease; patients with inadequately controlled hypertension; and patients older than 65 years. These additions were made because of concerns over data indicating that the risk of MIs and strokes was increased in patients with cardiovascular disease treated with sibutramine.
These concerns prompted the Sibutramine Cardiovascular Outcomes trial (SCOUT), a randomized, double-blind trial that compared placebo to sibutramine in almost 10,000 obese men and women, aged 51-88 years, with pre-existing cardiovascular disease, type 2 diabetes, or both. The study was conducted at the request of European health authorities and was the focus of the Sept. 15 meeting.
Over a mean 3.4 years, the risk of nonfatal MI, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death (the primary end point) was increased by 16% among those treated with sibutramine over those on placebo. The increased risk was driven by the greater rate of nonfatal MIs (4.1%) and nonfatal strokes (2.6%) among those on sibutramine, compared to those on placebo (3.2% and 1.9%, respectively); the risk of cardiovascular mortality was not increased. The risk of the nonfatal events was increased among sibutramine users with pre-existing cardiovascular disease and with cardiovascular disease and type 2 diabetes, but not among those with type 2 diabetes alone.
Abbott proposed a risk management plan to address the risks, which would include a single pharmacy and a boxed warning to reinforce the contraindications in people with a CVD history and dispensing of the drug from a single pharmacy, to ensure treatment is started only in appropriate patients.
The FDA usually follows the recommendations of its advisory panels. Members of advisory panels have been cleared of having conflicts related to the topic of meetings. Occasionally, the agency grants a waiver to a panelist who has conflicts, but not at this meeting.