In an updated safety communication the FDA announced it was adding new warnings to the dronedarone (Multaq, Sanofi) label. Based on results from the PALLAS trial, which was discontinued early due to safety concerns, the drug label will now warn:
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.
In addition, the label will state that people taking dronedarone should have an ECG every 3 months. Dronedarone should be stopped if a patient is found to be in AF or, if clinically indicated, the patient should undergo cardioversion.
The FDA also performed a new analysis of the ATHENA trial, which included only patients with non-permanent AF, and which formed the basis for the drug’s approval and labeling. The analysis reaffirmed the benefits of dronedarone in ATHENA, finding that dronedarone caused a reduction in hospitalizations and was not associated with an increased risk of cardiovascular death, stroke or heart failure.
Here is the FDA updated safety communication:
FDA Drug Safety Communication: Review update of Multaq (dronedarone) and increased risk of death and serious cardiovascular adverse events
This update is in follow-up to the FDA Drug Safety Communication on July 21, 2011 about Multaq (dronedarone) and increased risk of death and serious cardiovascular events
[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.
The PALLAS (Permanent Atrial FibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy) trial was a large outcome trial intended to evaluate the effectiveness of Multaq in patients with permanent AF.1 This clinical trial was terminated early because of a significantly higher number of cardiovascular events in the Multaq-treated group compared to the group of patients given a placebo (i.e., with no active ingredient). FDA issued a Drug Safety Communication (DSC) in July 2011 when the study was terminated.
Table 1. Final results from PALLAS (provided by the manufacturer) showed the following:
|Multaq (dronedarone) N=1619 N||Placebo N=1617 N||Hazard Ratio (95 % Confidence Intervals)|
|Total Deaths||25||13||1.94 (0.99 to 3.79)|
|Death from arrhythmia or Sudden Death||13||4||3.26 (1.06 to 10.0)|
|Stroke||23||10||2.32 (1.11 to 4.88)|
|Hospitalization for Heart Failure||43||24||1.81 (1.10 to 2.99)|
To determine whether the increased risks observed in the PALLAS study population apply to patients for whom the drug is indicated (i.e., patients with non-permanent AF), the FDA reassessed data from theATHENA trial (the clinical trial supporting Multaq’s approval for non-permanent AF), with special attention to arrhythmic death, stroke, and heart failure outcomes .2 The ATHENA trial showed a reduction in the risk of hospitalizations for AF in patients with non-permanent AF who were randomized to receive Multaq. Patients administered Multaq in the ATHENA trial did not have an increased risk of cardiovascular death, stroke or heart failure.
The FDA believes that Multaq provides a benefit for patients with non-permanent AF and recommends that healthcare professionals who prescribe Multaq follow the recommendations in the revised Multaq drug label.
From approval in July 2009 through October 2011, a total of approximately 1.3 million Multaq®prescriptions were dispensed and approximately 278,000 patients received Multaq® prescriptions from U.S. outpatient retail pharmacies. 3
- Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011. DOI: 10.1056/NEJMoa1109867.
- Hohnloser SF, Crijns HJGM, van Eickels M, et al. Effect of Dronedarone on Cardiovascular Events in Atrial Fibrillation. N Engl J Med 2009. DOI: 10.1056/NEJMoa0803778.
- Source: IMS, Vector One®: National (VONA) and Total Patient Tracker (TPT). July 2009 to October 2011. Extracted December 2011.