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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Last Update: January 5, 2018.



Dronedarone is an antiarrhythmic and a synthetic derivative of amiodarone that is used for maintaining sinus rhythm for patients with atrial fibrillation or flutter. Dronedarone is associated with a variable rate of serum enzyme elevations during therapy and to rare instances of clinically apparent liver injury, which can be severe and have resulted in deaths and need for liver transplantation.


Dronedarone (droe ne’ da rone) is a synthetic derivative of amiodarone, a benzofuran derivative that is a structural analogue of thyroid hormone. However, unlike amiodarone and thyroxine, dronedarone is not iodinated and was specifically designed to avoid some of the end-organ adverse effects associated with amiodarone use. Dronedarone, like amiodarone, has a multitude of electrophysiologic properties, including inhibition of several potassium currents as well as sodium and slow L-type calcium channels. In clinical trials, dronedarone improved maintenance of sinus rhythm in patients with atrial fibrillation or flutter. Dronedarone was approved for use in the United States in 2009 and its current indications are for oral treatment of paroxysmal or persistent atrial fibrillation or flutter. Dronedarone is available in tablets of 400 mg under the brand name Multaq and the recommended maintenance dose in adults in 400 mg twice daily (an initial loading dose of twice that amount if usually recommended). Side effects of dronedarone include gastrointestinal upset, nausea, diarrhea, headache and mild elevations in serum creatinine. Recent large, long term trials of dronedarone have suggested that its use is associated with an increased risk in cardiovascular events, heart failure, stokes and deaths in certain populations.


Chronic therapy with dronedarone has been associated with mild serum enzyme elevations in up to 12% of patients, but similar rates were found in comparator arms and even in placebo recipients. The serum aminotransferase elevations that occur during chronic dronedarone therapy are generally mild-to-moderate in severity and asymptomatic, rarely requiring discontinuation or dose modification. In preapproval clinical trials, clinically apparent liver injury was not described. Since its approval and more wide scale use, however, dronedarone has been linked to several cases of clinically apparent liver injury with jaundice, some of which have been severe. The onset of injury ranged from 2 to 11 months and the clinical presentation was similar to acute viral hepatitis, with symptoms of fatigue and abdominal discomfort followed by jaundice and a hepatocellular pattern of serum enzyme elevations. Several instances have resulted in acute liver failure requiring emergency liver transplantation. However, specific clinical features of cases of clinically apparent liver injury from dronedarone have not been well defined and the relationship of dronedarone to the described liver injury has not always been well documented.

Likelihood score: C (probable cause of clinically apparent liver injury).

Mechanism of Injury

The cause of dronedarone hepatotoxicity is not clear. The clinical presentation of injury is somewhat different than that described commonly associated with amiodarone which shares clinical features with alcoholic liver injury marked by insidious onset, minimal serum enzyme elevations, and liver histology showing steatosis and ballooning degeneration with fibrosis and Mallory bodies. Dronedarone is extensively metabolized by the cytochrome P450 system (predominantly CYP 3A) and the liver injury may be due to a toxic metabolite.

Outcome and Management

The liver injury attributed to dronedarone can be severe and lead to liver failure and death. There are no known specific therapies for reversing dronedarone effects. There is also no information about cross sensitivity with hepatic injury from amiodarone, but other approaches to atrial arrhythmia control are probably advisable.

Drug Class: Antiarrhythmic Agents



Dronedarone – Multaq®


Antiarrhythmic Agents


Product labeling at DailyMed, National Library of Medicine, NIH


Dronedarone 141626-36-0 C31-H44-N2-O5-S
Dronedarone Chemical Structure


References updated: 05 January 2018

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    (Expert review of hepatotoxicity published in 1999; patterns of liver injury associated with amiodarone include frequent minor serum enzyme elevations [14-83%] and, less commonly, chronic liver disease resembling alcoholic hepatitis and cirrhosis, acute hepatitis with jaundice, phospholipidosis, Reye syndrome and cholestasis; dronedarone is not discussed).
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    (Review of hepatotoxicity of cardiovascular drugs mentions that two cases of acute liver failure attributed to dronedarone that were reported after its approval in 2009, which led to an FDA warning and recommendation for routine periodic monitoring of liver tests, the effectiveness of which has not been shown).
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  • Davy JM, Herold M, Hoglund C, Timmermans A, Alings A, Radzik D, Van Kempen L; ERATO Study Investigators. Dronedarone for the control of ventricular rate in permanent atrial fibrillation: the Efficacy and safety of dronedarone for the control of ventricular rate during atrial fibrillation (ERATO) study. Am Heart J 2008; 156: 527. [PubMed: 18760136]
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    (Controlled trial of dronedarone vs placebo in 627 patients with symptomatic heart failure was terminated early because of excess mortality in dronedarone [8.1%] compared to placebo treated subjects [3.8%], largely due to worsening of heart failure; no mention of hepatotoxicity).
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    (Controlled trial of dronedarone vs amiodarone in 504 patients with persistent atrial fibrillation found higher rate of recurrence with dronedarone, whereas thyroid, neurologic, skin and ocular adverse events were less; ALT or AST elevations [2 times ULN] occurred at similar rates [12% vs 10.6%]).
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  • Connolly SJ, Camm AJ, Halperin JL, Joyner C, Alings M, Amerena J, Atar D, et al; PALLAS Investigators. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011; 365: 2268-76. [PubMed: 22082198]
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  • In brief: FDA warning on dronedarone (Multaq). Med Lett Drugs Ther 2011; 53 (1359): 17. [PubMed: 21383666]
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    (75 year old man developed abdominal pain, nausea and liver test abnormalities a week after starting dronedarone [bilirubin 1.9 mg/dL, ALT 478 U/L, Alk P normal], symptoms resolving rapidly and all values falling into the normal range within 3 weeks of stopping).
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  • Arif SA, Drury R, Ader P. Impact of Food and Drug Administration hepatotoxicity warning on prescribing and monitoring of dronedarone in a tertiary teaching hospital. Int J Pharm Pract 2015; 23: 456-60. [PubMed: 26382915]
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    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 5 cases were attributed to amiodarone and 2 to dronedarone).


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