Dronedarone ( Multaq ) is indicated for rhythm and rate control in patients with atrial fibrillation ( AF ) / atrial flutter ( AFL ), to maintain sinus rhythm or to decrease ventricular rate. Dronedarone demonstrates electrophysiological characteristics belonging to all 4 Vaughan-Williams classes of antiarrhythmic compounds. These characteristics are in line with Amiodarone ( Cordarone ), another anti-arrhythmic agent, which has been shown to be one of the most effective agents for this indication, but also one of the most toxic.

Dronaderone an even more complex interaction potential than Amiodarone, being both a substrate and an inhibitor of CYP P450 enzymes, including CYP3A4, that can lead to major problems in daily practice.

The clinical trials submitted did show that Dronedarone in a dose of 400 mg BID can significantly prolong median time to AF recurrence by approximately 50 days and reduce incidence of atrial fibrillation after 12 months by approximately 10%.
In patients with AF ventricular rate decreased by 10-12 bpm at rest up to 31 bpm at maximal exercise.
Whether these findings can be considered as surrogate for clinical benefit remains to be established.

Dronaderone’s altered pharmacokinetics compared to Amiodarone can certainly affect not only safety, but also efficacy.

Patients with atrial flutter were not included in the studies.

Safety data indicate that tolerability was acceptable, although gastrointestinal symptoms did occur dose-dependently.
Amiodarone-like extracardiac toxicity, in particular at the thyroid or pulmonary level did not occur, which could potentially be an advantage.
Both an increase in serum creatinine and/or differences in long term outcome, however, could negate this advantage.
Although increase in serum creatinine might in part be related to inhibition of tubular secretion of creatinine, this may affect the management of the patients negatively, as creatine levels cannot be used as a marker for renal function.
Similar to Amiodarone, ECG effects can occur, including prolongation of the PR-interval and QTc, which may also affect outcome.

One survival study was carried out in patients with a recent hospitalization for a severe symptomatic episode of CHF ( NYHA class III or IV ) and with LVEF less than or equal to 35% with a negative effect on mortality. Although differences in management, in particular regarding co-medication of ACE-inhibitors and AII receptor blockers ( sartans ) could be one explanation, it cannot be ruled out that other causes may have also contributed.

Finally, the absence of dosing alternatives to the investigated 400 mg BID reduces the clinical potential of Dronedarone. Higher exposure may lead to reduction of efficacy while safety risks increase.
In the DAFNE study no significant effect was observed in the 600 mg BID group, which remains unexplained. This can occur in special patient groups, like elderly females, and during concomitant medication and may negatively influence the benefit/risk profile.

Source: EMEA, 2006

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