Dronedarone makes FDA watch list five straight times

July 19, 2011

Silver Spring, MD - The US FDA has published its latest quarterly list of drugs to monitor after having identified potential signs of serious risks or new safety information, and dronedarone (Multaq, Sanofi-Aventis) appears on it for the fifth straight time.

The new watch list covers the first three months of 2011. During this time, the FDA detected potential signs of renal impairment and failure with dronedarone, approved in July 2009 to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL). The four watch lists covering 2010 reported different potential signals of risk, three of which preceded related label changes for the drug this year.

The FDA compiles these quarterly lists based on data collected through its adverse event reporting system (AERS). The FDA cautions that a drug's appearance on the list does not mean that the agency has determined that the drug actually poses the health risk reported through AERS. However, the agency will study these drugs to determine whether there is a causal link. If a link is established, the agency would then consider regulatory action, such as revising the drug's label, requiring a risk evaluation and mitigation strategy (REMS) or gathering more data to better characterize the risk.

In the meantime, physicians should not stop prescribing these drugs nor should patients stop taking them, according to the FDA.

Past potential signals include CHF, warfarin interaction, liver failure

In the case of dronedarone, reports of several potential signals of risk reported for 2010 were followed by regulatory action:

  • The AERS watch list for the first quarter of 2010 cited potential signals of congestive heart failure (CHF) with the drug. On February 22, 2011, the FDA revised the warnings and precautions section of dronedarone's label regarding patients with new or worsening heart failure during treatment to state that postmarketing cases of such problems have been reported. The label had originally stated that there were limited data for patients with AF/AFL who develop worsening heart failure during dronedarone therapy but nevertheless advised clinicians to consider suspending or discontinuing the drug if heart failure commences or worsens.

  • In the second quarter, AERS identified potential signals of torsade de pointes.

  • The list for the third quarter of 2010 listed a potential signal for an interaction with warfarin that increases its anticoagulant effect. On March 21, 2011, the drug interactions section of dronedarone's label was changed to mention postmarketing cases of higher INR clotting times with or without bleeding events in patients taking warfarin. Physicians were advised to monitor INR in such individuals. The label had originally stated that in clinical trials, "there was no observed excess risk of bleeding compared with placebo" when dronedarone was coadministered with oral anticoagulants to patients with AF/AFL and that INR should be monitored according to the warfarin label.

  • Potential signals of liver failure for dronedarone appeared in the watch list for the last three months of 2010. On February 11, 2011, the FDA changed the warnings and precautions section of the label to mention postmarketing cases of hepatocellular liver injury and acute liver failure and the need to promptly discontinue dronedarone if such an injury is suspected. Other parts of the label were revised accordingly.

There were two other label changes for dronedarone in 2011 that do not appear to be directly related to potential risk signals detected in 2010. On January 31, 2011, the FDA revised the drug interaction section to state that exposure to dabigatran is higher when it is administered with dronedarone as opposed to alone. And on June 21, 2011, the FDA revised the adverse-reaction section to state that postmarketing cases of interstitial lung disease including pneumonitis and pulmonary fibrosis have surfaced.

The release of the latest AERS watch list comes at a time when dronedarone is undergoing regulatory scrutiny in Europe. As reported last week by heartwire , the European Medicines Agency (EMA) will review the cardiovascular risks of dronedarone after the recent decision by Sanofi-Aventis to suspend the phase 3 PALLAS trial—designed to test the drug in patients with permanent AF—because of an increase in cardiovascular events in those randomized to receive dronedarone.

Asked by heart wire whether five repeat appearances on the AERS watch list is out of the ordinary, an FDA spokesperson responded saying, "The FDA acknowledges that the appearance of Multaq on five consecutive 921 reports may appear to be uncommon. . . . These FDA activities are examples of our continuous safety monitoring for marketed products and should not be used as a surrogate marker for a product's overall safety profile. The FDA closely looks at new safety signals and conducts further evaluations when new signals arise."

Data still support "favorable benefit/risk profile," says company

During phase 3 testing and early postapproval, dronedarone had been viewed by many as potentially less effective but safer than amiodarone for treating AF. Asked about dronedarone's safety profile in light of its regular appearances on the AERS watch list and the label changes since its approval, Sanofi-Aventis responded saying, "Approximately 400 000 patients have been treated with dronedarone worldwide, and postmarketing surveillance continues to support the favorable benefit/risk profile of Multaq in its approved indication in nonpermanent atrial fibrillation."


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