Dronedarone

DRONEDARONE

Dronedarone is a structural analog of amiodarone in which the iodine atoms have been removed from the phenyl ring and a meth-anesulfonyl group added to the benzofuran ring. The design was intended to eliminate action of the parent drug on thyroxine metabolism and to modify the half-life of the drug. No thyroid dysfunction or pulmonary toxicity has been reported in short-term studies. However, liver toxicity, including two severe cases requiring liver transplantation, has been reported. Like amiodarone, drone-darone has multichannel actions, including blocking I_Kr, I_Ks, I_Ca, and I_Na. It also has β-adrenergic–blocking action. The drug has a half-life of 24 hours and can be administered twice daily at a fixed dose of 400 mg. Dronedarone absorption increases twofold to threefold when taken with food, and this information should be communicated to patients as a part of the dosing instructions. Dronedarone elimination is primarily non-renal. However, it inhib-its tubular secretion of creatinine, resulting in a 10–20% increase in serum creatinine. However, because glomerular filtration rate is unchanged, no adjustments are required. Dronedarone is both a sub-strate and an inhibitor of CY3A4 and should not be co-administered with potent inhibitors of this enzyme, such as the azole and similar antifungal agents, and protease inhibitors.

Dronedarone restores sinus rhythm in a small percentage of patients (< 15%) with atrial fibrillation. It produces a 10- to 15-bpm reduction of the ventricular rate compared to placebo. Dronedarone doubled the interval between episodes of atrial fibrillation recurrence in patients with paroxysmal atrial fibrillation. Initial studies suggested a reduction in mortality or hospitalization in patients with atrial fibrillation. However, a study of dronedarone’s effects in permanent atrial fibrillation was terminated in 2011 because of increased risk of death, stroke, and heart failure. Similarly, a trial of dronedarone in advanced heart failure was terminated prematurely because of an increase in mortality. The drug carries a “black box” warning against its use in acute decompensated or advanced (class IV) heart failure.