ADELPHI, MD. — A Food and Drug Administration panel voted 10-3 that dronedarone, an amiodarone analogue, be approved for treating patients with nonpermanent atrial fibrillation, with recommendations that the label include a boxed warning cautioning against use of the drug in patients with heart failure.
At a meeting of the FDA's Cardiovascular and Renal Drugs Advisory Committee, panelists supporting approval agreed that the claim for dronedarone should be narrower than the primary end point in the ATHENA trial, which was defined as time to first event of cardiovascular hospitalization or death from any cause.
Panelists supporting approval agreed that the indication should make clear that cardiac hospitalizations, but not mortality, were reduced in patients treated with dronedarone in the study.
The multinational ATHENA trial compared 400 mg of dronedarone twice a day to placebo in 4,628 patients (approximately 1,400 in the United States) with at least one episode of atrial fibrillation (AF) or atrial flutter (AFL) and at least one normal ECG during the previous 6 months.
After 2 years, dronedarone was associated with a 24% reduction in the combined risk of cardiovascular hospitalization or all-cause death, a highly statistically significant difference. But most of the benefit was due to the difference in cardiac hospitalizations, and nearly all that effect was due to hospitalizations for AF.
Manufacturer Sanofi Aventis has proposed that dronedarone be approved for treating patients with either a recent history of or current nonpermanent atrial fibrillation or flutter with associated risk factors, and also for the claim that treatment has been shown to decrease the combined risk of cardiovascular hospitalization or death.
Dr. Sanjay Kaul, director of the cardiovascular diseases fellowship training program at Cedars-Sinai Heart Institute in Los Angeles, described his vote as a “cautious yes,” supporting approval for patients at low to intermediate risk who have a history of nonpermanent AF, excluding patients with New York Heart Association (NYHA) class III heart failure, and left ventricular dysfunction (an ejection fraction under 35%). Dr. Kaul said the manufacturer should conduct a long-term study comparing dronedarone to amiodarone, which remains the treatment of choice for patients with structural heart disease.
Dr. Lewis Nelson, director of the medical toxicology fellowship at New York University, voted against approval. He said more information is needed on the drug's effects in patients with renal failure and cardiac failure, drug interactions, and long-term adverse effects.
Sanofi-Adventis has proposed that dronedarone be approved for patients with “a recent history of or current nonpermanent atrial fibrillation or flutter with associated risk factors,” and that it not be used to treat patients with symptoms of heart failure at rest, or with minimal exertion within the immediately preceding month, or patients who have been hospitalized for HF within the immediately preceding month.
The FDA meeting was held almost 4 years after the company first filed for approval of dronedarone in June 2005.
The FDA did not approve dronedarone because it was associated with a greater rate of mortality, hospitalization for heart failure, and hospitalization for cardiovascular causes in the ANDROMEDA (Antiarrhythmic Trial With Dronedarone in Moderate to Severe CHF Evaluating Morbidity Decrease) study, which compared 400 mg of dronedarone twice a day to placebo in patients with NYHA Class class II-IV heart failure, and was stopped early when these associations became evident. The company filed another new drug application in July 2008, which included the previous data and the results of the ATHENA study.
The two populations differed: Those in ANDROMEDA had been recently hospitalized or had had a clinic visit for heart failure, requiring at least intravenous diuretics. In ATHENA, patients with NYHA class IV were excluded, which was the major difference between the two studies.
Gastrointestinal side effects—particularly nausea, vomiting and diarrhea—were the most common side effects associated with dronedarone in ATHENA. In studies, the rate of increases in serum creatinine has been higher among those treated with dronedarone, but this plateaus early and is reversible. Thyroid-related adverse events have been low, and pulmonary-related adverse events, which have been associated with amiodarone, have been uncommon and similar to placebo, according to the company.
If approved, Sanofi-Aventis plans to market dronedarone as Multaq.
The FDA usually follows the recommendations of its advisory panels.