REVIEW
Dronedarone: Current Evidence and Future Questions Jeremy A. Schafer, Nicole K. Kjesbo & Patrick P. Gleason Prime Therapeutics LLC, Eagan, MN, USA
Keywords Amiodarone; ATHENA; Atrial fibrillation; Dronedarone. Correspondence Jeremy A Schafer, PharmD, Prime Therapeutics LLC, 1305 Corporate Center Drive, Eagan, MN 55121, USA. Tel.: (612) 777-5097; Fax: (612) 777-5143; E-mail:
[email protected]
doi: 10.1111/j.1755-5922.2009.00112.x
Atrial fibrillation (AF) is the most common sustained arrhythmia, affecting more than 2.2 million Americans. ACC/AHA/ESC guidelines for the management of patients with AF recommend amiodarone for maintaining sinus rhythm. Dronedarone is a derivative of amiodarone indicated for the treatment of AF. To provide an overview of dronedarone with a focus on the phase III trials and discuss unresolved questions of dronedarone. A literature search was conducted via the PubMed database using the keyword “dronedarone.” Search was limited to human trials in english. The FDA website was searched for briefing documents and subcommittee meetings on dronedarone. Clinicaltrials.gov was searched with the keyword dronedarone for upcoming or unpublished clinical trials. Five phase III trials are available for dronedarone: ANDROMEDA, EURIDIS/ADONIS, ATHENA, ERATO, and DIONYSIS. EURIDIS/ADONIS and ATHENA demonstrated a reduction AF recurrence with dronedarone compared to placebo. The ANDROMEDA trial recruited patients with recent hospitalization for heart failure and was terminated due to an excess of deaths in the dronedarone group. The DIONYSIS trial was a comparative effectiveness trial that demonstrated less efficacy for dronedarone but improved tolerability compared to amiodarone. Dronedarone represents an option in the management of AF in select patients. Dronedarone is not appropriate in patients with recently decompensated heart failure or those treated with strong CYP3A4 inhibitors or medications prolonging the QT interval. Dronedarone appears to have improved tolerability at the expense of decreased efficacy when compared to amiodarone. Questions remain on the long-term safety, use in patients with heart failure, retreatment after dronedarone or amiodarone failure, and comparative efficacy with a rate control strategy.
Background Atrial Fibrillation (AF) is a supraventricular tachyarrhythmia characterized by uncoordinated atrial activity with consequent deterioration of atrial mechanical function [1]. AF is the most common sustained arrhythmia, affecting more than 2.2 million Americans [2]. Hospital admissions for AF have increased by 66% over the last 20 years [3]. Reasons for this increase include the aging of the population, a rising prevalence of chronic heart disease, more frequent diagnosis through use of ambulatory monitoring devices, and other factors [1]. The projected number of persons with AF may exceed 12 million by 2050 [4]. AF represents an expensive public health problem. A retrospective analyses of three fed-
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erally funded US databases found the total annual costs for the treatment of AF were estimated at $6.65 billion, including $2.93 billion for hospitalization with principal discharge diagnosis of AF, $1.95 billion for the incremental inpatients cost of AF as a comorbid diagnosis, $1.53 billion for outpatients treatment of AF, and $235 million for prescription drugs [5]. According to the ACC/AHA/ESC guidelines, there are three objectives in the management of patients with AF: rate control, prevention of thromboembolism, and correction of the rhythm disturbance [1]. The initial management decision involves primarily a rate control or rhythm control strategy [1]. AF is considered a chronic disorder and recurrence is likely in the majority of patients. Certain patients may need prophylactic
c 2010 Blackwell Publishing Ltd Cardiovascular Therapeutics 28 (2010) 38–47
Review of Dronedarone
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antiarrhythmic drug therapy to maintain sinus rhythm, suppress symptoms, improve exercise capacity and hemodynamic function, and prevent tachycardia-induced cardiomyopathy due to AF [1]. Amiodarone is the most frequently used drug to maintain normal sinus rhythm (NSR) [6]. ACC/AHA/ESC guidelines for the management of patients with AF recommend amiodarone at the maintenance dose of 200–400 mg/day as an option for maintaining sinus rhythm [1]. In addition, amiodarone can be useful to control the heart rate in patients with AF when other measures are unsuccessful or contraindicated [1]. However, amiodarone is associated with significant adverse effects including decreased blood pressure, pulmonary toxicity, skin discoloration, thyroid toxicity, corneal deposits, optic neuropathy, and sinus bradycardia [7]. R ) is a noniodinated benzofuran Dronedarone (Multaq derivative with an electrophysiological profile resembling that of amiodarone. Dronedarone was developed with the intent of eliminating the noncardiovascular adverse effects of amiodarone [8]. Dronedarone represents a new treatment option for patients with AF. The objective of the review is to provide an overview of dronedarone with a focus on the phase III trials and discuss unresolved questions of this new therapy.
Pharmacokinetics/Pharmacology The structure of dronedarone is similar to amiodarone; however, there are two differences: (1) dronedarone
does not have iodine groups and (2) dronedarone has a methylsulfonamide group on the benzofuran ring. These two structural changes lead to decreased inorganic iodine exposure and reduced tissue penetration, respectively (Table 1) [7,9]. Compared with amiodarone, dronedarone has a shorter half-life and a smaller volume of distribution [1,7] (Table 1). Steady-state concentrations are achieved in 4–8 days [10]. Similar to amiodarone, dronedarone exhibits pharmacologic effects from all four Vaughan Williams classifications [8,11]. The antiarrhythmic effects occur by blocking of potassium, calcium, and sodium channels [8]. In animals, dronedarone has shown potent coronary vasodilation and α and β-blocking properties [8]. The pharmacologic action results in decreased heart rate and blood pressure and lengthening of PR and QTc intervals [12]. Severe renal impairment does not significantly influence the pharmacokinetics of dronedarone or amiodarone. Serum creatinine levels increase by ∼0.1 mg/dL following initiation of treatment with dronedarone [13]. The elevation has a rapid onset and reaches a plateau after 7 days [13]. Creatinine level increases have been shown to be the result of an inhibition of creatinines’s tubular secretion, with no effect on the glomerular filtration rate [13]. The effect on serum creatinine is reversible upon discontinuation. Dronedarone and amiodarone are extensively metabolized by the liver. Moderate hepatic impairment increases steady-state dronedarone exposure by 1.3-fold and active metabolite exposure decreased by 1.6- to 1.9-fold [8]. No dosage adjustment is recommended for moderate hepatic
Table 1 Pharmacokinetics of dronedarone and amiodarone [7,10,14] Dronedarone Absolute bioavailability
Without food: 4% With food: 15% due to significant first pass metabolism(2–3 fold higher with food) Peak plasma concentrations 3–6 h under fed conditions Vd ∼12 L/kg∗
Protein binding Metabolism Elimination half-life Excretion
Renal impairment Hepatic impairment
>98% in human plasma Primarily CYP3A4 13–19 h Feces: 84%
Amiodarone 20–86%, but averages 50%19
3–7 h after a single dose ∼60 L/kg because of extensive accumulation in various sites, especially adipose tissue and highly perfused organs, such as the liver, lung, and spleen approximately 96% CYP3A4 and CYP2C8 58 days Eliminated hepatically; although biliary excretion may play a small role
Renal: 6% No dosage adjustment recommended No dosage adjustment recommended No dosage adjustment recommended for moderate hepatic Limited data. Monitoring recommended. impairment Contraindicated in patients with severe hepatic impairment.
c 2010 Blackwell Publishing Ltd Cardiovascular Therapeutics 28 (2010) 38–47
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Review of Dronedarone
impairment [10]. Dronedarone is contraindicated in patients with severe hepatic impairment [10].
J.A. Schafer et al.
farin with amiodarone increases the prothrombin time by 100% after 3–4 days, the dose of anticoagulant should be reduced by one-third to one-half, and prothrombin times should be monitored closely [7].
Drug Interactions Dronedarone is primarily metabolized by CYP3A4 and is an inhibitor of the CYP3A enzyme group [10]. Amiodarone shares similar drug interactions to dronedarone including grapefruit juice, statins, calcium channel blockers, beta-blockers, digoxin, and medications that prolong the QT interval. Concomitant use of strong CYP3A inhibitors (ketoconazole, clarithromycin, etc.) with dronedarone is contraindicated [10]. Patients should avoid grapefruit juice due to an increase in dronedarone exposure [10]. Dronedarone may increase drug concentrations of medications frequently used in AF and HF including statins and calcium channel blockers. The coadministration of dronedarone and simvastatin increased simvastatin levels by 4-fold [8]. Dronedarone may also increase exposure of lovastatin and atorvastatin [8]. Dronedarone can increase the exposure of calcium channel blockers (verapamil or diltiazem) by 1.4- to 1.7-fold [8]. Calcium-channel blockers with depressant effects on the sinus and AV nodes can potentiate dronedarone’s effects on conduction. Dronedarone is an inhibitor of CYP2D6 and pglycoprotein. Concomitant dronedarone increases propranolol exposure by ∼1.3-fold and metoprolol exposure by 1.6-fold [8]. Inhibition of P-glycoprotein transporter with dronedarone can increase digoxin exposure by 2.5-fold and may potentiate the electrophysiologic effects [10]. Gastrointestinal disorders may be increased with co-administration of dronedarone and digoxin [10]. If digoxin must be continued, the dose of digoxin should be reduced by half and serum levels should be monitored [10]. Dronedarone may induce QTc prolongation. Concomitant use of medications (tricyclic antidepressants, Class I or III antiarrhythmics, etc.) or herbal products that prolong the QT interval is contraindicated and may increase the risk of Torsades de Pointes [10]. One case of Torsades de Pointes occurred in a patient treated with dronedarone in the ATHENA trial [15]. No cases of Torsades occurred in the ANDROMEDA, ERATO, or EURIDIS/ADONIS trials [16,17,18]. There was no observed excess risk of bleeding compared to placebo in patients taking both warfarin and dronedarone. No dosage adjustments are recommended but INR should be monitored [10]. In contrast, concomitant amiodarone and oral anticoagulation potentiates the anticoagulant response and can result in serious or fatal bleeding. Since the concomitant administration of war-
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Phase III Clinical Trials ANDROMEDA The Antiarrhythmic Trial with Dronedarone in Moderate to Severe CHF Evaluating Morbidity Decrease (ANDROMEDA) was a double blind, placebo controlled, randomized trial comparing dronedarone and placebo in patients with AF and heart failure [19]. Patients hospitalized with new or worsening heart failure and at least one episode of shortness of breath on minimal or no exertion (New York Functional Class [NYHA] III or IV) or paroxysmal nocturnal dyspnea within a month before admission were enrolled [19]. Individuals with an ejection fraction ≤35% (wall motion index ≤1.2) were eligible for enrollment [19]. Exclusion criteria, in part, included myocardial infarction within seven days of screening, heart rate
