Dronedarone

Dronedarone

File:Dronedarone-2d-skeletal.png
Systematic (IUPAC) name
N-(2-Butyl-3-(p-(3-(dibutylamino)propoxy)benzoyl)- 5-benzofuranyl)methanesulfonamide
Clinical data
[[Regulation of therapeutic goods |Template:Engvar data]]	US FDA: Dronedarone
Routes of administration	Oral
Legal status
Legal status	Prescription
Pharmacokinetic data
Metabolism	hepatic
Biological half-life	24 hours
Excretion	feces
Identifiers
CAS Number	141626-36-0
ATC code	none
PubChem	CID 208898
Chemical data
Formula	C31H44N2O5S
Molar mass	556.758[[]]

Dronedarone (also known as SR33589 and marketed as Multaq) is a drug by Sanofi-Aventis, mainly for the indication of cardiac arrhythmias (irregular heartbeat). It was approved by the FDA on July 2, 2009. It is now available as 400 mg tablets in 60 count bottles. It is used for the treatment of atrial fibrillation and atrial flutter in patients whose hearts have either returned to normal rhythm or who undergo drug therapy or electric shock treatment to maintain normal rhythm. However, the FDA did not approve dronedarone for reducing deaths. A trial of the drug in heart failure was stopped as an interim analysis showed a possible increase in heart failure deaths.

In order for dronedarone to be FDA approved the manufacturer had to add a Black box warning to the package insert. The Black box warning is as follows, " WARNING: HEART FAILURE: MULTAQ is contraindicated in patients with NYHA Class IV heart failure, or NYHA Class II–III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic. In a placebo-controlled study in patients with severe heart failure requiring recent hospitalization or referral to a specialized heart failure clinic for worsening symptoms (the ANDROMEDA Study), patients given dronedarone had a greater than two-fold increase in mortality. Such patients should not be given dronedarone. "

Chemistry

Chemically, dronedarone is a benzofuran derivative related to amiodarone, a popular antiarrhythmic the use of which is limited by toxicity due its high iodine content (pulmonary fibrosis, thyroid disease) as well as by liver disease.

In dronedarone, the iodine moieties were removed, to reduce toxic effects on the thyroid and other organs; and a methylsulfonamide group was added, to reduce solubility in fats (lipophilicity) and thus reduce neurotoxic effects. Yet it displays amiodarone-like class III antiarrhythmic activity in vitro and in clinical trials.

Pharmacokinetics

Dronedarone is less lipophilic than amiodarone, has a much smaller volume of distribution, and has an elimination half-life of 24 hours—this stands in contrast to amiodarone's half-life of several weeks. As a result of these pharmacokinetic characteristics, dronedarone dosing may be less complicated than amiodarone.

Clinical trials

Clinical trials have compared dronedarone to placebo and to amiodarone, for its ability to reduce atrial fibrillation, to reduce mortality overall and from cardiac causes, and for its adverse effects, including excess mortality.

In the EURIDIS and ADONIS trials in atrial fibrillation (2007), dronedarone was significantly more effective than placebo in maintaining sinus rhythm, with no difference in lung and thyroid function in the short term.

However, in the ANDROMEDA study (2007), dronedarone doubled the death rate compared to placebo, and the trial was halted early. ANDROMEDA enrolled patients with moderate to severe congestive heart failure, a relatively sicker patient population.

In a more recent atrial fibrillation trial, ATHENA, with 4628 subjects, dronedarone was significantly more effective than placebo in reducing the composite endpoint of first hospitalization due to cardiovascular events or death. There was a significant reduction in the rate of cardiovascular death, but not in the rate of death from any cause.. Later post-hoc analysis of the ATHENA-results showed a significant reduction in the rate of stroke.

Patients randomized to dronedarone were more likely to develop bradycardia and QT-interval prolongation (but only 1 case of Torsades). Nausea, diarrhea, rash, and creatinine elevation also were more common in the dronedarone arm.

Electro-Cardio Conversion results

Recently, Multaq has been used by the Veteran's Administration to prepare patients for electro-conversion to Sinus rythmn. A patient who had failed conversion 5 times with electro-shock alone, returned to Sinus mode after more than 6 years of continuous A-fibrillation. Doctors prepared for conversion with a ten month loading course of Multaq.

Regulatory review

Originally submitted as a New Drug Application in 2005, dronedarone was reviewed and approved on March 18, 2009 by an Advisory Committee of the United States Food and Drug Administration (FDA). The FDA is not bound by the Committee's recommendation, but it takes its advice into consideration when reviewing new drug applications. The FDA approved dronedarone on July 2, 2009.

Health Canada was the second major regulatory body to approve the drug, giving its approval on August 12, 2009. The approval is for "treatment of patients with a history of, or current atrial fibrillation to reduce their risk of cardiovascular hospitalization due to this condition."

The European Medicines Agency issued a Summary of Positive Opinion regarding dronedarone on 24 September 2009 recommending to the European Commission to grant a marketing authorization within the European Union.

Synthesis

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Mellin, C.; 1998, U.S. Patent 5,854,282.

References

de:Dronedaron