Dronedarone

Dronedarone (development codename SR33589 and marketed as Multaq) is a drug by Sanofi-Aventis, mainly for the indication of cardiac arrhythmias. It was approved by the FDA on July 2, 2009. It was recommended as an alternative to amiodarone for the treatment of atrial fibrillation and atrial flutter in people 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 patients with moderate to severe CHF.

In order for dronedarone to be FDA approved the manufacturer had to add a Black box warning, stating that 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."  The FDA alerted healthcare professionals to rare cases of severe liver damage associated with the use of dronedarone.

Chemistry
Chemically, dronedarone is a benzofuran derivative related to amiodarone, a popular antiarrhythmic. The use of amiodarone is limited by toxicity due its high iodine content (pulmonary fibrosis, thyroid disease) as well as by liver disease. In dronedarone, the iodine moieties are not present, reducing toxic effects on the thyroid and other organs. A methylsulfonamide group is added to reduce solubility in fats (lipophilicity) and thus reduce neurotoxic effects.

Dronedarone displays amiodarone-like class III antiarrhythmic activity in vitro and in clinical trials. The drug also appears to exhibit activity in each of the 4 Vaughan-Williams antiarrhythmic classes.

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.

Mechanism of action
Dronedarone has been termed a “multichannel blocker” however it is unclear which channel(s) play a pivotal role in its success. Thus dronedarones actions at the cellular level are controversial with most studies suggesting an inhibition in multiple inward potassium currents including rapid delayed rectifier, slow delayed rectifier and Ach-activated inward rectifier. It is also believed to reduce inward rapid Na current and L-type Ca channels. The reduction in K current in some studies was shown to be due to the inhibition of K-Ach channel or associated GTP-binding proteins. Reduction of K+ current by 69% lead to increased AP duration and increased effective refractory periods, thus shown to suppress pacemaker potential of the SA node and return patients to a normal heart rhythm. In a European trial, the average time to recurrence of an arrhythmia was 41 days in the placebo group vs. 96 days in the dronedarone group (similar results obtained in the non-European trial, 59 and 158 days respectively).

Cautions

 * NYHA (New York Heart Association) Class IV heart failure or NYHA Class II or III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic.
 * Second or third degree atrioventricular (AV) block or sick sinus syndrome (exception in patients with a functional pacemaker)
 * Bradycardia less than 50 beats per minute
 * QT interval corrected for rate of 500 msec or greater
 * PR interval exceeding 280 msec
 * Use of cytochrome P-450 (CYP) 3a isoenzyme inhibitors (includes: clarithromycin, cyclosporine, itraconazole, ketoconazole, nefazodone, ritonavir, telithromycin, voriconazole)
 * Use with drugs or herbal supplements that prolong QT interval or increase risk of torsades de points (Class I or III antiarrhythmic agents, phenothiazines, tricyclic antidepressants, certain oral macrolides, ephedra)
 * Hepatic impairment. In Jan 2011 the FDA advised about cases of rare, but severe, liver injury, including two cases of acute liver failure leading to liver transplant in patients treated with dronedarone (Multaq). It is not known whether routine periodic monitoring of serum liver enzymes (ALT, AST, and alkaline phosphatase) and bilirubin in patients taking dronedarone will prevent the development of severe liver injury.
 * Women who are or may become pregnant
 * Nursing women

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. Dronedarone is a non-iodinated class III anti-arrhythmic drug which helps patients return to normal sinus rhythm. This treatment for AF is also known to reduce associated mortality and hospitalizations compared to other similar antiarrhythmic agents.

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.

The PALLAS trial (2011) was stopped for safety concerns due to the finding that "dronedarone increased rates of heart failure, stroke, and death from cardiovascular causes in patients with permanent atrial fibrillation who were at risk for major vascular events". A Black Box warning was subsequently added by the FDA stating that the risk of death, stroke, and hospitalization for congestive heart failure doubled in patients with permanent atrial fibrillation.

Electro-Cardio conversion results
Multaq has been used by the Veteran's Administration to prepare patients for electro-conversion to sinus rhythm. A patient who had failed conversion 5 times with electro-shock alone, returned to sinus mode after more than 6 years of continuous afibrillation. 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 recommended for approval 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.