(UPDATE 12/19) FDA Drug Safety Communication: Multaq (dronedarone)

Antiarrhythmic drug Multaq increases risk of death and serious cardiovascular adverse events

/ Author:  / Reviewed by: Joseph V. Madia, MD

The U.S. Food and Drug Administration (FDA) is reviewing data from a clinical trial that was evaluating the effects of the antiarrhythmic drug Multaq" data-scaytid="3">Multaq (dronedarone" data-scaytid="5">dronedarone) in patients with permanent atrial fibrillation.

[12-19-2011] The U.S. Food and Drug Administration (FDA) has completed a safety review of the heart drug Multaq (dronedarone). This review showed that Multaq increased the risk of serious cardiovascular events, including death, when used by patients in permanent atrial fibrillation (AF). The review was based on data from two clinical trials, the PALLAS trial (Permanent Atrial FibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy) and the ATHENA trial (which supported Multaq's approval for treatment of non-permanent AF).1,2 FDA is providing new information and recommendations for the use of Multaq to manage the potential serious cardiovascular risks with the drug.

The Multaq drug label has been revised with the following changes and recommendations [see the revised Multaq label for all changes]:

  • Healthcare professionals should not prescribe Multaq to patients with AF who cannot or will not be converted into normal sinus rhythm (permanent AF), because Multaq doubles the rate of cardiovascular death, stroke, and heart failure in such patients.
  • Healthcare professionals should monitor heart (cardiac) rhythm by electrocardiogram (ECG) at least once every 3 months. If the patient is in AF, Multaq should be stopped or, if clinically indicated, the patient should be cardioverted.
  • Multaq is indicated to reduce hospitalization for AF in patients in sinus rhythm with a history of non-permanent AF (known as paroxysmal or persistent AF)
  • Patients prescribed Multaq should receive appropriate antithrombotic therapy.

Patients should contact their healthcare professional if they have any questions or concerns about Multaq. Patients should not stop taking Multaq without talking to their healthcare professional.

FDA is reviewing the risk evaluation and mitigation strategy (REMS) for Multaq to determine the changes necessary to ensure that the benefits of Multaq outweigh the risks of cardiovascular death, stroke, and heart failure. [End Update]

The study was stopped early after the data monitoring committee found a two-fold increase in death, as well as two-fold increases in stroke and hospitalization for heart failure in patients receiving Multaq compared to patients taking a placebo. Currently Multaq is approved for use in a different, but related patient population. The approval of Multaq was based on another trial (ATHENA) in which use of Multaq was associated with a decreased number of deaths compared to placebo.

Facts about Multaq

  • Used 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 [Refer to Multaq label]
  • From approval in July 2009 through June 2011, approximately 1 million Multaq prescriptions were dispensed and approximately 241,000 patients received Multaq prescriptions from U.S. outpatient retail pharmacies.

The Permanent Atrial fibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) study, sponsored by Sanofi Aventis (the maker of Multaq), was being conducted to assess the potential clinical benefit of Multaq in patients over 65 years of age with permanent atrial fibrillation in the reduction of:

  • Major cardiovascular (CV) events (stroke, systemic arterial embolism, myocardial infarction or cardiovascular death), or
  • Unplanned cardiovascular hospitalization or death from any cause

A critical question is whether and how the unfavorable results of the PALLAS study, obtained in patients with permanent atrial fibrillation, apply to patients who use Multaq for the approved indications (non-permanent atrial fibrillation, also known as paroxysmal or persistent atrial fibrillation).

At this time, patients taking Multaq should talk to their healthcare professional about whether they should continue to take Multaq for non-permanent atrial fibrillation. Patients should not stop taking Multaq without talking to a healthcare professional. Healthcare professionals should not prescribe Multaq to patients with permanent atrial fibrillation.

FDA previously issued a Drug Safety Communication (DSC) in January 2011 regarding cases of rare but severe liver injury that have been reported with the use of Multaq.

Today's communication is in keeping with FDA's commitment to inform the public about its ongoing safety review of drugs. FDA will update the public when more information is available.

Additional Information for Patients

  • Talk to your healthcare professional about whether you should continue to take Multaq for paroxysmal or persistent atrial fibrillation. Do not stop taking Multaq without talking to your healthcare professional.
  • Discuss any questions or concerns about Multaq with your healthcare professional.

Data Summary

Sanofi Aventis conducted "A randomized, double blind, placebo controlled, parallel group trial for assessing the clinical benefit of dronedarone 400 mg BID on top of standard therapy in patients with permanent atrial fibrillation and additional risk factors" (PALLAS). This study was a large outcome trial intended to evaluate the effectiveness of dronedarone in patients with permanent atrial fibrillation.

The patients eligible to enroll in PALLAS were 65 years or older, in permanent atrial fibrillation (defined by the presence of atrial fibrillation/atrial flutter for at least 6 months prior to randomization without plans to restore sinus rhythm), and had at least one additional cardiovascular (CV) risk criterion.

In July 2011, the data monitoring committee reviewed the preliminary data and concluded that there was a significant excess of CV events in the Multaq group for both co-primary endpoints (CV death/myocardial infarction/stroke/systemic embolism; death/unplanned CV hospitalization) as well as other CV events. As a result, the PALLAS study was stopped.  

Reviewed by: 
Review Date: 
July 26, 2011