FDA approves dronedarone for patients with atrial fibrillation or atrial flutter

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Sanofi-aventis announced on 2 July 2009 that the FDA has approved Multaq (dronedarone) 400mg tablets. Patients with atrial fibrillation (AF) or atrial flutter (AFL) soon will have a new treatment option to help improve current management of their disease. Multaq is the first drug approved in the United States that has shown a clinical benefit to reduce cardiovascular hospitalisation in patients with AF/AFL.

Multaq is an anti-arrhythmic indicated to reduce the risk of cardiovascular hospitalisation in patients with paroxysmal or persistent atrial fibrillation or atrial flutter, with a recent episode of AF/AFL and associated cardiovascular risk factors, who are in sinus rhythm or who will be cardioverted. Associated cardiovascular risk factors include age over 70 years, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter greater than or equal to 50mm or left ventricular ejection fraction <40%. The FDA approval is based on five international, multicentre, randomised clinical trials involving nearly 6,300 patients.


The landmark ATHENA trial evaluated the efficacy and safety of Multaq in patients with AF/AFL or a recent history of these conditions (71% of these patients had no heart failure, 29% were in NYHA class I-III with stable heart failure). This trial showed that dronedarone 400 mg BID, in addition to standard therapy, reduced the combined endpoint of cardiovascular hospitalisation or death from any cause by 24% (p<0.001) when compared to placebo, meeting the study’s primary endpoint.


This reduction was generally consistent across study subgroups based on baseline characteristics or medications. Patients taking Multaq had higher rates of diarrhea, nausea, bradycardia, QT-interval prolongation and cutaneous rash than patients taking placebo.


Initiation of Multaq treatment is contraindicated in patients with severe heart failure (NYHA class IV) or NYHA Class II-III heart failure with a recent decompensation requiring hospitalisation or referral to a specialised heart failure clinic. This unstable population corresponds to the population of the ANDROMEDA trial in which patients receiving dronedarone had a greater than 2-fold increase in mortality compared to placebo.


The ATHENA and ANDROMEDA trials provided two sets of data supporting the assessment of the product’s benefit risk ratio in two significantly different patient populations.


To ensure the use of Multaq in the appropriate patient population, sanofi-aventis US LLC also announced the launch of mPACT-Multaq Partnership for Appropriate Care and Treatment – the Risk Evaluation and Mitigation Strategy (REMS) developed by sanofi-aventis US LLC. The mPACT Partnership was developed to assist healthcare professionals (HCPs) with the identification of appropriate patients and to ensure the safe use of Multaq while minimising risk. The risk mitigation program consists of a Communication Plan for HCPs, a medication guide for patients and post-marketing surveillance.


“It is exciting that Multaq will now be available as a treatment option for patients with paroxysmal or persistent atrial fibrillation or atrial flutter,” said Stuart Connolly, Professor of Medicine & Director, Division of Cardiology, McMaster University, Hamilton, Canada, and co-principal investigator in the ATHENA study. “Based on clinical studies, Multaq reduces the risk of cardiovascular hospitalisations in patients with atrial fibrillation/atrial flutter, this outcome could change the way we approach the management of the disease.”


Multaq is to be given twice daily as a 400mg tablet and should be taken as one tablet with the morning and evening meals. Treatment with Multaq can be initiated in an outpatient setting. Most common adverse reactions are diarrhea, nausea, vomiting, abdominal pain, asthenia and cutaneous rash.


A registration dossier of Multaq is also under regulatory review by the European Medicines Agency.

More about dronedarone
The efficacy and safety of Multaq(R) 400 mg twice daily was evaluated in five controlled studies, ATHENA, ANDROMEDA, EURIDIS, ADONIS, and DAFNE, involving nearly 6,300 patients including more than 3200 patients who received Multaq(R).


The ATHENA trial, which involved 4,628 patients with AF or AFL and more than 2,300 patients receiving Multaq on top of standard therapy, demonstrated a 24% reduction in time to first cardiovascular hospitalisation or all-cause mortality (p<0.001) compared with placebo meeting the primary endpoint.


The ANDROMEDA study, was terminated prematurely after enrolment of 627 of 1,000 planned patients with congestive heart failure, in relation to excess mortality due to worsening heart failure in the dronedarone group [n=25 vs. 12 (placebo), p=0.027].


The patient population enrolled in the ANDROMEDA and ATHENA studies was significantly different. The patients enrolled in ANDROMEDA had relatively severe heart failure and had been hospitalised, or referred to a specialty heart failure clinic for worsening symptoms. Patients were predominantly NYHA II and III and only 25% had a history of AF/AFL at randomisation. In contrast, in ATHENA, all patients had a history of AF/AFL, and 71% of patients had no heart failure, 25% were NYHA class I or II, and only 4% were class III.


The ANDROMEDA and ATHENA trials were published in the New England Journal of Medicine respectively in 2008 and 2009.


Multaq should not be co-administered with strong CYP 3A inhibitors or medicinal products that prolong the QT interval.


In patients with new or worsening heart failure, the suspension or discontinuation of Multaq should be considered.


Serum creatinine levels increase by about 0.1mg/dL following Multaq treatment initiation. The elevation has a rapid onset, reaches a plateau after seven days and is reversible after discontinuation.


Hypokalemia and hypomagnesemia may occur with concomitant administration of potassium-depleting diuretics. Potassium levels should be maintained in the normal range pre and during administration.