General Information

Multaq (dronedarone) is a benzofuran derivative with antiarrhythmic properties belonging to all four Vaughan-Williams classes. The exact mechanism of action is unknown.

Multaq is specifically indicated to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors who are in sinus rhythm or who will be cardioverted.

Multaq is supplied as a 400mg tablet designed for oral administration. The recommended initial dose of the drug is 400 mg twice daily, once in the morning with a meal and once in the evening with a meal.

Mechanism of Action

Multaq (dronedarone) is a benzofuran derivative with antiarrhythmic properties belonging to all four Vaughan-Williams classes. The exact mechanism of action is unknown. Dronedarone is a derivative of amiodarone, an effective yet toxic antiarrhythmic drug. Unlike amiodarone, dronedarone does not contain idodine atoms and hence contains the efficacy of amiodarone but without its unique toxicity profile.

Side Effects

Adverse events associated with the use of Multaq may include, but are not limited to, the following:

• Diarrhea
• Asthenic conditions
• Nausea
• Skin infections
• Abdominal pain
• Bradycardia

The Multaq drug label has the following Black Box Warning: Multaq is contraindicated in patients with symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV heart failure. Multaq doubles the risk of death in these patients. Multaq is contraindicated in patients in atrial fibrillation (AF) who will not or cannot be cardioverted into normal sinus rhythm. In patients with permanent AF, Multaq doubles the risk of death, stroke, and hospitalization for heart failure.

Clinical Trial Results

The FDA approval of Multaq was based on the results of three studies:

ATHENA
This multicenter, multinational, double blind, and randomized placebo-controlled study enrolled 4,628 patients with a recent history of AF/AFL who were in sinus rhythm or who were to be converted to sinus rhythm. The subjects were at least 75 years old or at least 70 years old with one risk factor. They were randomized and treated for up to 30 months with either Multaq 400 mg twice daily or placebo, in addition to conventional therapy for cardiovascular diseases. The primary endpoint, time to first hospitalization for cardiovascular reasons or death from any cause, was significantly decreased in the Multaq arm (by 24%) versus placebo (p=0.00000002). Several secondary endpoints were reached as well, including a significant decrease in the risk of cardiovascular death by 30% (p=0.03) with Multaq plus standard therapy. Multaq also significantly decreased the risk of arrhythmic death by 45% (p=0.01) and there were numerically fewer deaths (16%) from any cause in the Multaq group compared to placebo (p=0.17). First cardiovascular hospitalization was reduced by 25% (p=0.000000009).

EURIDIS and ADONIS
These two studies enrolled 1,237 subjects (20 to 88 years) in sinus rhythm with a prior episode of AF or AFL. The subjects were randomized in an outpatient setting and treated with either Multaq 400 mg twice daily or placebo on top of conventional therapies. All subjects had at least one ECG-documented AF/AFL episode during the 3 months prior to study entry but were in sinus rhythm for at least one hour. In the pooled data, as well as in the individual trials, dronedarone delayed the time to first recurrence of AF/AFL (primary endpoint), lowering the risk of first AF/AFL recurrence during the 12-month study period by about 25%, with an absolute difference in recurrence rate of about 11% at 12 months.