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European Medicines Agency, Tim Kelleher

Clinical Articles, Lead Article


The European Medicines Agency (EMA) is reviewing the cardiovascular (CV) risk associated with the anti-arrhythmic drug, dronedarone1 (Multaq®, Sanofi-Aventis), following the company’s recent discontinuation of the phase IIIb PALLAS (Permanent Atrial fibriLLAtion outcome Study using Dronedarone on top of standard therapy) trial after it found increased CV events in those randomised to the drug.

In the PALLAS study Multaq® was being investigated in patients over 65 years of age with permanent atrial fibrillation (AF). The patient population being studied in the PALLAS study is different from the population for which Multaq® is currently approved, which are patients who currently have or have had non-permanent AF. The study was carried out as part of the ongoing development programme for Multaq®. At the time the study was stopped 3,149 patients were enrolled.

First results2 indicated that there was a 2.3 fold increase in the combined endpoint of stroke, systemic arterial embolism, myocardial infarction or cardiovascular death in the dronedarone arm compared to the placebo arm and a 1.5 fold increase in unplanned CV hospitalisation and death in the dronedarone arm as compared to the placebo arm.

The EMA’s Committee for Medicinal Products for Human Use (CHMP) started a review in January 2011 of the overall benefit-risk balance of the drug following reports of severe liver injury.  This review has now been extended to assess new information from the PALLAS study, following a request from the European Commission.1 The decision to terminate the PALLAS was not related to any hepatic adverse event.

The CHMP will continue to assess data from PALLAS in depth, it says, together with other available data on the benefits and risks of Multaq in order to finalise their review in September 2011.3 Further advice will be issued in their final assessment at that time.dr

The U.S. Food and Drug Administration (FDA) is also reviewing data from the PALLAS trial.4 They are evaluating whether and how the preliminary results of the study apply to patients taking Multaq® for paroxysmal or persistent AF or atrial flutter.  At present they consider that the PALLAS study results are preliminary because the data have not undergone quality assurance procedures and have not been completely adjudicated.

They currently advise, however, “do not prescribe Multaq® to patients with permanent atrial fibrillation”.4

Sanofi-Aventis advise that, based on the current data from the PALLAS study, dronedarone’s benefit-risk profile in non permanent AF patients remains unchanged.2 Patients currently taking Multaq® should not stop their therapy and should consult their treating physician should they have any questions, they say.

Requests for further information

If you have any further questions or require additional information, the company advise to please call Medical Information Services at sanofi-aventis, One Onslow Street, Guildford, Surrey, GU1 4YS, UK

Tel: 01483 505515

Fax: 01483 535432



1 European Medicines Agency. European Medicines Agency reviews cardiovascular risk of Multaq [press release]. July 11, 2011.  (Available here:

2 Sanofi Aventis.  Information on the discontinuation of the Multaq Phase IIIb Pallas Trial in permanent AF patient population.  2011 (on file)

3 European Medicines Agency updates on ongoing benefit-risk review of Multaq [press release].  EMA Press Office, July 21 2011. (Available from:

4 FDA Drug Safety Communication: Multaq (dronedarone) and increased risk of death and serious cardiovascular adverse events [press release]. July 21, 2011 (Available from:

Published on: August 2, 2011

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  • ArrhythmiaAlliance
  • Stars
  • Anticoagulation Europe
  • Atrial Fibrillation Association

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