Dronedarone (Monograph)

Brand name: Multaq
Drug class: Class III Antiarrhythmics

Medically reviewed by Drugs.com on Jul 10, 2025. Written by ASHP.

Warning

Contraindicated in patients with NYHA class IV heart failure or symptomatic heart failure with recent decompensation requiring hospitalization.
In the ANDROMEDA study in patients with severe heart failure requiring recent hospitalization or referral to a specialized heart failure clinic for worsening symptoms, dronedarone therapy was associated with a greater than 2-fold increase in mortality rate relative to placebo; do not use dronedarone in such patients.
Contraindicated in patients with permanent atrial fibrillation; doubles the risk of death, stroke, and hospitalization for heart failure in such patients.

Introduction

Predominantly class III antiarrhythmic agent; also appears to exhibit activity in each of the 4 Vaughan-Williams antiarrhythmic classes.

Uses for Dronedarone

Atrial Fibrillation

Used for reduction of hospitalization risk for atrial fibrillation in patients in sinus rhythm who have a history of paroxysmal or persistent atrial fibrillation.

Individualize treatment of atrial fibrillation/flutter based on relative benefits and risks of various therapies (e.g., rhythm versus rate control, nondrug therapies such as ablation and pacemaker implantation), patient age, and patient preference and tolerance of the arrhythmia.

ACC/AHA/ACCP/HRS guideline for diagnosis and management of atrial fibrillation states that antiarrhythmic medications are a reasonable option for long-term maintenance of sinus rhythm in patients who are not candidates for, or decline, catheter ablation or prefer antiarrhythmic therapy.

Per guideline, dronedarone is an option for sinus rhythm maintenance in patients without recent decompensated heart failure or severe left ventricular dysfunction. Patients with permanent atrial fibrillation who have risk factors for cardiovascular events should not receive dronedarone for long-term rate control.

Dronedarone Dosage and Administration

General

Pretreatment Screening

Verify that females of reproductive potential are not pregnant prior to initiating therapy.
Dronedarone should only be initiated in patients in sinus rhythm who are receiving appropriate antithrombotic therapy.
Ensure that potassium levels are within the normal range prior to administration of dronedarone and maintained in the normal range during treatment.

Patient Monitoring

Monitor renal function periodically.
Monitor cardiac rhythm and heart rate by ECG at least every 3 months.
Consider obtaining periodic hepatic serum enzymes, especially during the first 6 months of treatment.

Dispensing and Administration Precautions

The 2023 American Geriatrics Society (AGS) Beers Criteria for Potentially Inappropriate Medication (PIM) Use in Older Adults includes dronedarone on the list of PIMs that are best avoided by older adults in most circumstances or under specific situations, such as certain diseases, conditions, or care settings. The criteria are intended to apply to adults 65 years of age and older in all ambulatory, acute, and institutional settings of care, except hospice and end-of-life care settings. The Beers Criteria Expert Panel recommends to avoid dronedarone in individuals with permanent atrial fibrillation or severe or recently decompensated heart failure, and to use caution in patients with heart failure with reduced ejection fraction (HFrEF) with less severe symptoms (NYHA class I or II).

Administration

Oral Administration

Administer orally twice daily with morning and evening meals (to enhance bioavailability).

Dosage

Available as dronedarone hydrochloride; dosage expressed in terms of dronedarone.

Adults

Atrial Fibrillation

Oral

400 mg twice daily for reduction of risk of hospitalization for atrial fibrillation in patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation.

Must discontinue class I or III antiarrhythmic agents and drugs that are strong CYP3A inhibitors prior to initiating dronedarone.

Special Populations

Hepatic Impairment

No dosage adjustment required in patients with moderate hepatic impairment. Contraindicated in patients with severe hepatic impairment.

Renal Impairment

No dosage adjustment required.

Geriatric Patients

No specific dosage recommendations provided by manufacturer.

Cautions for Dronedarone

Contraindications

Permanent atrial fibrillation (patients in whom normal sinus rhythm will not or cannot be restored).
Symptomatic heart failure with NYHA class IV symptoms or recent decompensation requiring hospitalization.
Second- or third-degree atrioventricular (AV) block or sick sinus syndrome (except in patients with a functioning pacemaker).
Bradycardia (<50 beats/minute).
QT interval corrected for rate (QT_c) of >500 msec or PR interval >280 msec.
Concomitant use of strong inhibitors of CYP3A (e.g., clarithromycin, cyclosporine, itraconazole, ketoconazole, nefazodone, ritonavir, voriconazole).
Concomitant use of erythromycin.
Concomitant use with drugs or herbal supplements that prolong the QT interval and may increase the risk of torsades de pointes (e.g., class I and III antiarrhythmic agents, phenothiazine antipsychotics, tricyclic antidepressants, certain oral macrolides).
Liver or lung toxicity related to previous use of amiodarone.
Severe hepatic impairment.
Hypersensitivity to dronedarone or any excipients in the formulation.

Warnings/Precautions

Warnings

Cardiovascular Death in Patients with Decompensated Heart Failure

Contraindicated in patients with NYHA class IV heart failure or symptomatic heart failure and recent decompensation requiring hospitalization; 2-fold increase in cardiovascular death in such patients (see Boxed Warning).

Cardiovascular Death and Heart Failure in Patients with Permanent Atrial Fibrillation

Offers no benefit and is contraindicated in patients with permanent atrial fibrillation (i.e., those who cannot or will not be converted to normal sinus rhythm) due to doubling of risk of cardiovascular death (principally due to arrhythmia) and heart failure (see Boxed Warning).

Monitor heart rate via ECG at least every 3 months. Discontinue therapy in patients who have atrial fibrillation, or perform cardioversion if clinically indicated.

Increased Risk of Stroke in Patients with Permanent Atrial Fibrillation

Associated with increased risk of stroke in patients with permanent atrial fibrillation, particularly in first 2 weeks of therapy. Initiate only in patients in sinus rhythm who are receiving appropriate antithrombotic therapy (see Boxed Warning).

Other Warnings and Precautions

New-Onset or Worsening Heart Failure

New-onset or worsening heart failure reported. If heart failure develops or worsens, discontinue dronedarone therapy.

Contraindicated in patients with NYHA class IV heart failure or heart failure with recent decompensation requiring hospitalization.

Hepatic Injury

Severe hepatic injury reported. Acute liver failure requiring transplantation reported in at least 2 patients; in both cases, explanted liver showed evidence of extensive hepatocellular necrosis.

Consider periodic monitoring of serum hepatic enzymes, especially during first 6 months of therapy.

If hepatic injury suspected (e.g., anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine, itching), discontinue dronedarone therapy promptly and assess AST, ALT, alkaline phosphatase, and bilirubin values; initiate appropriate therapy if hepatic injury found.

Do not reinitiate dronedarone therapy in patients who experience hepatic injury without another explanation for such injury.

Pulmonary Toxicity

Interstitial lung disease, including pneumonitis and pulmonary fibrosis, reported in postmarketing setting.

Patients who develop dyspnea or non-productive cough may have pulmonary toxicity and should be carefully evaluated. If pulmonary toxicity is confirmed, dronedarone should be discontinued.

Hypokalemia and Hypomagnesemia with Potassium-Depleting Diuretics

Possible hypokalemia or hypomagnesemia with concomitant use of potassium-depleting diuretics. Ascertain that serum potassium concentrations are within normal range prior to initiation of dronedarone; maintain within normal range during therapy.

Prolongation of QT Interval

Dronedarone is associated with concentration-dependent QT_cF interval prolongation (estimated QT_cF increase of 15 ms with a dosage of 400 mg twice daily with food)_c .

Discontinue dronedarone if QT_c interval >500 ms.

Renal Impairment

Small increases in S_cr (about 0.1 mg/dL) reported following dronedarone treatment initiation; result of inhibition of creatinine tubular secretion. Creatinine elevation has rapid onset and reaches plateau after 7 days.

Larger increases in S_cr, pre-renal azotemia, and acute renal failure after dronedarone initiation also reported, often in the heart failure setting.

Effects generally reversible upon drug discontinuance.

Monitor renal function periodically.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity demonstrated in animals at dosages equivalent to those used in humans.

Avoid pregnancy during therapy. Advise females of reproductive potential to use effective contraception during therapy and for 5 days after the last dose. If dronedarone used during pregnancy or if patient becomes pregnant while receiving the drug, apprise of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm if administered during pregnancy. No available data in pregnant women; however, in animal reproduction studies, visceral and skeletal fetal malformations observed.

Lactation

Dronedarone and its metabolites distributed into milk in rats; not known whether distributed into milk in humans. When a drug is present in animal milk, it is likely to be present in human milk. Effects of dronedarone on the breastfed infant or on milk production not known.

Advise patients not to breastfeed during treatment with dronedarone and for 5 days after last dose.

Females and Males of Reproductive Potential

Dronedarone may cause fetal harm; verify that females of reproductive potential are not pregnant prior to initiating therapy. Advise female patients of reproductive potential to use effective contraception during treatment and for 5 days after final dose.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No substantial differences in safety and efficacy in geriatric patients relative to those in younger adults.

Hepatic Impairment

Not studied in patients with severe hepatic impairment; limited clinical experience available in patients with moderate hepatic impairment. Severe liver injury reported rarely with dronedarone therapy. Contraindicated in patients with severe hepatic impairment.

Renal Impairment

No dosage adjustment required because dronedarone undergoes minimal renal excretion.

Common Adverse Effects

Most common adverse reactions (≥2%) include diarrhea, nausea, abdominal pain, vomiting, dyspepsia, bradycardia, skin issues, asthenia.

Drug Interactions

Metabolized mainly by CYP isoenzyme 3A.

Moderate inhibitor of CYP isoenzymes 3A and 2D6; does not appear to substantially inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2C8, or 2B6.

May inhibit P-glycoprotein transport system.

Dronedarone or metabolites are weak inhibitors of organic cation transporter (OCT1), organic anion transporting polypeptide (OATP1B1, OATP1B3), and organic anion transporter (OAT3) in vitro.

Drugs Affecting Hepatic Microsomal Enzymes

Strong inhibitors of CYP3A: Pharmacokinetic interaction (increased peak plasma concentrations of and exposure to dronedarone). Concomitant use contraindicated.

Inducers of CYP3A: Potential pharmacokinetic interaction (substantially decreased exposure to dronedarone). Avoid concomitant use.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Potential pharmacokinetic interaction (possible increased plasma concentrations of the CYP3A substrate). Monitor plasma concentrations and appropriately adjust dosage of CYP3A substrates with a narrow therapeutic index when administered orally. Some clinicians state that dronedarone should be used with caution in patients receiving drugs with a narrow therapeutic index that are metabolized by CYP3A4.

Substrates of CYP2D6: Potential pharmacokinetic interaction (possible increased exposure to the CYP2D6 substrate).

Drugs that Prolong the QT Interval

Pharmacologic interaction (potential risk of torsades de pointes-type ventricular tachycardia) with drugs that prolong the QT interval; concomitant use contraindicated.

Drugs Affected by the P-glycoprotein Transport System

Potential pharmacokinetic interaction (increased exposure to substrates of P-glycoprotein transport system). Some clinicians state that dronedarone should be used with caution in patients receiving drugs with a narrow therapeutic index that are affected by the P-glycoprotein transport system.

Specific Drugs and Foods

Drug	Interaction	Comments
Antiarrhythmic agents, class I or III (e.g., amiodarone, disopyramide, dofetilide, flecainide, propafenone, quinidine, sotalol)	Potential risk of torsades de pointes-type ventricular tachycardia due to QT-interval prolongation	Concomitant use contraindicated
Anticoagulants, oral (e.g., warfarin)	Slightly increased exposure to S-warfarin in healthy individuals; no change in exposure to R-warfarin or clinically important increases in INR No excess risk of bleeding observed with concomitant use of dronedarone and oral anticoagulants in patients with atrial fibrillation/flutter; cases of increased INR with/without bleeding reported during postmarketing experience	Monitor INR after initiating dronedarone in patients taking warfarin
Antidepressants, SSRI	Possible increased exposure to SSRI
Antidepressants, tricyclic	Potential risk of torsades de pointes-type ventricular tachycardia due to QT-interval prolongation Possible increased exposure to tricyclic antidepressants	Concomitant use contraindicated
β-Adrenergic blocking agents (e.g., metoprolol, propranolol)	Increased incidence of bradycardia Increased exposure to propranolol and metoprolol	Use lower initial dosage of the β-adrenergic blocking agent and increase dosage of β-adrenergic blocker only if well tolerated as documented by ECG
Calcium-channel blocking agents (e.g., diltiazem, nifedipine, verapamil)	Calcium-channel blocking agents with depressant effects on the sinus and AV nodes may potentiate the conduction effects of dronedarone Dronedarone increases exposure to verapamil, diltiazem, and nifedipine; verapamil and diltiazem increase exposure to dronedarone	Use lower initial dosage of the calcium-channel blocking agent and increase dosage of calcium-channel blocker only if well tolerated as documented by ECG
Carbamazepine	Substantially decreased exposure to dronedarone due to CYP3A induction	Avoid concomitant use
Cyclosporine	Increased peak plasma concentrations of and exposure to dronedarone	Concomitant use contraindicated
Dabigatran	Increased exposure to dabigatran	In patients with moderate renal impairment (Cl_cr 30–50 mL/minute), reduce dosage of dabigatran to 75 mg twice daily when used concomitantly with dronedarone; in patients with severe renal impairment (Cl_cr 30–50 mL/minute), avoid concomitant use
Digoxin	Possible potentiation of electrophysiologic effects of dronedarone (e.g., decreased AV node conduction) Increased digoxin concentrations and exposure Increased incidence of GI disorders	When initiating dronedarone therapy, reassess need for continued digoxin therapy; discontinue digoxin or reduce digoxin dosage by 50% Monitor serum digoxin concentrations; close observation for signs of digoxin toxicity recommended
Grapefruit juice	Increased peak plasma concentrations of and exposure to dronedarone	Avoid concomitant use
HMG-CoA reductase inhibitors	Increased exposure to simvastatin and simvastatin acid	Avoid simvastatin dosages >10 mg daily Consult respective statin manufacturer’s labeling for specific recommendations regarding concomitant use
Itraconazole	Increased peak plasma concentrations of and exposure to dronedarone	Concomitant use contraindicated
Ketoconazole	Increased peak plasma concentrations of and exposure to dronedarone	Concomitant use contraindicated
Macrolides (e.g., clarithromycin, erythromycin)	Clarithromycin: Increase exposure to and peak plasma concentrations of dronedarone Certain oral macrolides (e.g., erythromycin): Potential risk of torsades de pointes-type ventricular tachycardia due to QT-interval prolongation	Clarithromycin, and certain oral macrolides (e.g., erythromycin): Concomitant use contraindicated
Nefazodone	Increased peak plasma concentrations of and exposure to dronedarone	Concomitant use contraindicated
Phenobarbital	Substantially decreased exposure to dronedarone due to CYP3A induction	Avoid concomitant use
Phenothiazines	Potential risk of torsades de pointes-type ventricular tachycardia due to QT-interval prolongation	Concomitant use contraindicated
Phenytoin	Substantially decreased exposure to dronedarone due to CYP3A induction	Avoid concomitant use
Potassium-depleting diuretics	Possible hypokalemia or hypomagnesemia	Ascertain that serum potassium concentrations are within normal range prior to initiation of dronedarone; maintain within normal range during therapy
Rifampin	Substantially decreased exposure to dronedarone due to CYP3A induction	Avoid concomitant use
Ritonavir	Increased peak plasma concentrations of and exposure to dronedarone	Concomitant use contraindicated
St. John’s wort	Substantially decreased exposure to dronedarone due to CYP3A induction	Avoid concomitant use
Sirolimus	Possible substantial increase in plasma concentrations of sirolimus	Monitor sirolimus concentrations and adjust dosage as needed If concurrent administration cannot be avoided, consider reducing sirolimus dosage by 50–75% prior to dronedarone initiation; monitor trough sirolimus concentrations regularly (possibly even daily) during titration phase
Tacrolimus	Possible substantial increase in plasma concentrations of tacrolimus	Monitor tacrolimus concentrations and adjust dosage as needed
Voriconazole	Increased peak plasma concentrations of and exposure to dronedarone	Concomitant use contraindicated

Dronedarone Pharmacokinetics

Absorption and Distribution

Bioavailability

Undergoes first-pass metabolism. Absolute bioavailability low (about 4%) when administered without food.

Steady-state concentrations achieved within 4–8 days following repeated oral administration of dronedarone 400 mg twice daily.

Food

Food increases bioavailability; bioavailability approximately 15% when administered with a high-fat meal.

Peak plasma concentrations of dronedarone and N-debutyl metabolite reached within 3–6 hours following oral administration with food.

Special Populations

Exposure to dronedarone increased by 23% in patients ≥65 years of age compared with that in younger adults.

Mean exposure to dronedarone increased by 1.3-fold in patients with moderate hepatic impairment compared with individuals with normal hepatic function; mean exposure to N-debutyl metabolite decreased by about 50%.

Pharmacokinetics not studied in patients with severe hepatic impairment.

No apparent differences in pharmacokinetics observed in healthy individuals with mild or moderate renal impairment versus those with normal renal function, or in patients with atrial fibrillation and mild to severe renal impairment versus those with normal renal function.

Distribution

Extent

Dronedarone and its metabolites distributed into milk in rats; not known whether distributed into human milk.

Plasma Protein Binding

Dronedarone and N-debutyl metabolite are >98% bound to plasma proteins (mainly albumin); binding not saturable.

Elimination

Metabolism

Extensively metabolized, mainly by CYP3A.

Initial metabolic pathway includes N-debutylation to form active N-debutyl metabolite, oxidative deamination to form inactive propanoic acid metabolite, and direct oxidation. Monoamine oxidase contributes to metabolism of active metabolite. Metabolites further metabolized to >30 uncharacterized metabolites. N-debutyl metabolite exhibits pharmacodynamic activity; only up to one-third as potent as dronedarone.

Elimination Route

Excreted in urine (6%) and in feces (84%) mainly as metabolites; no unchanged drug excreted in urine.

Half-life

13–19 hours following IV administration.

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).

Actions

Mechanism of antiarrhythmic action not fully elucidated; exact contribution of activities in each of the 4 Vaughan-Williams antiarrhythmic classes to the clinical effect of the drug unknown.
Benzofuran derivative structurally related to amiodarone, but with structural modifications that include removal of the iodine group and addition of a methane-sulfonyl group.
Removal of the iodine group intended to reduce risk of nontarget organ (e.g., thyroid, pulmonary) adverse effects associated with amiodarone therapy; addition of the methane-sulfonyl group aimed at reducing lipophilicity, decreasing risk of neurotoxic adverse effects, and shortening half-life of dronedarone.
Electrophysiologic profile similar to amiodarone, but with different relative effects on individual ion channels.
Prolongs action potential duration (APD) mainly by inhibition of potassium channels, including transmembrane delayed rectifier, ultrarapid delayed rectifier, inward rectifier, and transient outward potassium currents.
Inhibits sodium currents (at rapid pacing rates), calcium channels and slow L-type calcium currents, and demonstrates noncompetitive, antiadrenergic (α- and β-blocking) activity.
Prolongs PR interval and slows sinus rate by prolonging atrial and ventricular refractory periods.
Prolongs RR and QT intervals.
Produces a dose-dependent increase in PR interval and a moderate prolongation of the QT_c interval similar to amiodarone.

Advice to Patients

Advise patients to read the FDA-approved patient labeling (Medication Guide).
Advise patients to contact their clinician if they develop signs or symptoms of heart failure (e.g., weight gain, dependent edema, increasing shortness of breath) during dronedarone treatment.
Risk of hepatic injury, including life-threatening hepatic failure. Advise patients to immediately report symptoms suggesting hepatic injury (e.g., anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain or discomfort, jaundice, dark urine, itching).
Advise patients to inform their clinicians immediately if they are or plan to become pregnant or plan to breast-feed. Advise female patients of reproductive potential to use effective contraception during treatment and for 5 days after the final dose. If pregnancy occurs, advise patients of risk to the fetus. Advise patients not to breastfeed during treatment with dronedarone and for 5 days after the final dose.
Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses (e.g., heart failure, rhythm disturbance other than atrial fibrillation/flutter, uncorrected hypokalemia).
Advise patients to take dronedarone exactly as prescribed (e.g., with meals). If a dose of dronedarone is missed, advise patients to take the next dose at the regularly scheduled time and to not double the dose. Advise patients to consult with a physician prior to stopping treatment.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.