Pharmacology Update
Dronedarone Tablets (Multaq®)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD; Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.
A non-iodinated derivative of amiodarone has been approved by the FDA for the treatment of atrial fibrillation and atrial flutter. Dronedarone is marketed by Sanofi-Aventis as Multaq®.
Dronedarone is indicated to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL) with recent episodes of AF/AFL and associated cardiovascular risk factors. Risks include age 70 years or older, hypertension, diabetes, prior cerebrovascular accident, and left ventricular diameter ≥ 50 mm or ejection fraction < 40%. Dronedarione is indicated for those in sinus rhythm or those who will be converted.1
Dosage
The recommended dose is 400 mg twice daily with morning and evening meals. Food increases the bioavailability of dronedarone. No dosage adjustment is required for patients with renal impairment or moderate hepatic impairment.1 Grapefruit juice should be avoided.
Dronedarone is supplied as 400 mg tablets.
Potential Advantages
Dronedarone reduced cardiovascular hospitalization and AF/AFL recurrence compared to placebo in patients in sinus rhythm with a recent history of AF/AFL.1,2 Dronedarone has a reduced risk of amiodarone-associated thyroid-related and pulmonary toxicity.
Potential Disadvantages
Dronedarone has been reported to increase the risk of mortality and excess hospitalization, compared to placebo, in patients with severe left ventricular systolic dysfunction.1,3 The labeling carries a boxed warning for use in patients with severe heart failure. Most common adverse events (2%-7%) are diarrhea, nausea, abdominal pain, vomiting, asthenia, and bradycardia. Serum creatinine increased (10% or higher) in 51% of patients compared to 21% for placebo. QT-interval prolongation also occurred more frequently (28% vs 19%).1,2 Dronedarone is metabolized by CYP 3A and is a moderate inhibitor of 3A and 2D6.1
Comments
Dronedarone is a benzofuran derivative similar to amiodarone in its electropharmacology. The difference is removal of the iodine moiety and addition of a methane-sulfonyl group that reduces its lipid solubility, shortens its elimination half-life (approximately 24 hours), and reduces tissue accumulation. The effect of the drug on cardiovascular outcomes in high-risk patients with AF/AFL was demonstrated in ATHENA.1,2 Subjects were age 75 years or older, or age 70 or older with at least one risk factor (arterial hypertension, diabetes, previous stroke, transient ischemic attack, or systemic embolism, left atrial diameter ≥ 50 mm, and left ventricular ejection fraction ≤ 40%). These subjects were randomized to dronedarone 400 mg twice daily (n = 2301) or placebo (n = 2327). The primary outcome was time to first hospitalization for cardiovascular reasons or death from any cause. The median follow-up time was 22 months. The primary endpoint occurred in 39.2% of the placebo group compared to 31.6% for the dronedarone group (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.68-0.83; P < 0.001). This was driven primarily by cardiovascular hospitalization (36.8% vs 29.1%). Death from any cause was not statistically different (5.8% vs 5.0%; P = 0.24). Rates of thyroid-related and pulmonary-related adverse events were similar between the two groups. In two identical studies (ADONIS and EURIDIS, n = 1237), dronedarone reduced the risk of first AF/AFL by about 25% and significantly increased the median time to the first AF/AFL in subjects in sinus rhythm with a prior episode of AF or AFL.1,3 In subjects with a previous hospitalization with symptomatic heart failure and severe left ventricular systolic dysfunction (NYHA III or IV, or recent paroxysmal nocturnal dyspnea; ANDROMEDA), dronedarone increased the risk of mortality (8.1% vs 3.8%; HR, 2.13; 95% CI, 1.07-4.25; P = 0.027).1,4 Increased mortality has also been reported with amiodarone in NYHA III patients (HR, 1.44; 95% CI, 1.05-1.97).5 However, amiodarone does not carry the same boxed warning. A comparison between dronedarone and amiodarone is currently in progress (DIONYSUS).
Clinical Implications
Dronedarone is a de-iodinated derivative of amiodarone. It offers advantages but also risks. Its role in therapy remains to be established. The Risk Evaluation and Mitigation Strategy (REMS) developed by Sanofi-Aventis is intended to assist providers in appropriate selection of patients to ensure safe use and inform patients about the risks of dronedarone.
References
1. Multaq Prescribing Information. Bridgewater, NJ: Sanofi-Aventis; July 2009.
2. Hohnloser SH, et al; ATHENA Investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009;360:668-678.
3. Bardy GH, et al; Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225-237.
4. Singh BN, et al; EURIDIS and ADONIS Investigators. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med 2007;357:987-999.
5. Kober L, et al; Dronedarone Study Group. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008;358:2678-2687.
A non-iodinated derivative of amiodarone has been approved by the FDA for the treatment of atrial fibrillation and atrial flutter.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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