Dronedarone increases the risk of death and serious cardiovascular events in people with permanent atrial fibrillation, and its use should be limited to the approved indication: the treatment of nonpermanent AF, the Food and Drug Administration has concluded.

In a statement issued Dec. 19, the FDA announced that its safety review of dronedarone (Multaq), an antiarrhythmic drug approved in July 2009, has been completed. "The FDA believes that Multaq provides a benefit for patients with nonpermanent AF and recommends that healthcare professionals who prescribe Multaq follow the recommendations in the revised Multaq drug label," the FDA statement said.

Dronedarone, marketed as Multaq by Sanofi-Aventis, is indicated to "reduce hospitalizations for AF in patients in sinus rhythm with a history of nonpermanent AF."

The FDA’s conclusions are based on a review of a large outcomes study that was meant to evaluate the effectiveness of dronedarone in more than 3,000 patients with permanent AF, but was terminated early when it became clear that cardiovascular events were higher among those treated with the drug than in those on placebo. In that study, PALLAS (Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy), the risk of total deaths was increased twofold among those treated with dronedarone, compared with those on placebo. Also increased were the risks of death from arrhythmia or sudden death (hazard ratio, 3.26), stroke (HR, 2.32), and hospitalization for heart failure (HR, 1.81) over placebo.

The FDA’s reanalysis of the data from ATHENA, the clinical trial that supported the approval of dronedarone in patients with nonpermanent AF, found no increased risk of cardiovascular death, stroke, or heart failure among those on dronedarone, compared with those on placebo, and treatment was associated with a reduced the risk of hospitalizations.

The prescribing information for dronedarone has been revised to reflect the results of the safety review, and now advises against prescribing dronedarone to patients with AF "who will not or cannot be converted into normal sinus rhythm," because "it doubles the rate of cardiovascular death, stroke, and heart failure in such patients." The label also recommends an electrocardiogram to monitor heart rhythm in patients on the drug "at least once every three months," and if a patient is in AF, treatment should be stopped or, "if clinically indicated," the patient should be cardioverted. Patients on dronedarone should also be on "appropriate antithrombotic therapy," the label now states.

The FDA announced in July that the safety review was underway, when the termination of the PALLAS study was announced.

From July 2009 through October 2011, about 1.3 million dronedarone prescriptions were dispensed, and about 278,000 patients received prescriptions for the drug from U.S. outpatient retail pharmacies, according to the FDA.

The FDA notice is available at www.fda.gov/Drugs/DrugSafety/ucm283933.htm. Serious adverse events associated with dronedarone should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/medwatch/.

12/19/11  

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FROM THE FOOD AND DRUG ADMINISTRATION

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