Multaq

Generic Name: Dronedarone Hydrochloride
Class: Class III Antiarrhythmics
VA Class: CV300
Chemical Name: N-[2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-5-benzofuranyl]-methanesulfonamide monohydrochloride
Molecular Formula: C₃₁H₄₄N₂O₅S•HCl
CAS Number: 141625-93-6

Special Alerts:

[Posted 07/21/2011] ISSUE: FDA notified healthcare professionals that it is reviewing data from a clinical trial that evaluated the effects of the antiarrhythmic drug dronedarone (Multaq) in patients with permanent atrial fibrillation. The study was stopped early after the data monitoring committee found a two-fold increase in death, as well as two-fold increases in stroke and hospitalization for heart failure in patients receiving dronedarone compared to patients taking a placebo. FDA is evaluating whether and how the preliminary results of the PALLAS study apply to patients taking dronedarone for paroxysmal or persistent atrial fibrillation or atrial flutter. The PALLAS study results are considered preliminary at this time because the data have not undergone quality assurance procedures and have not been completely adjudicated. FDA will update the public when more information is available.

BACKGROUND: Dronedarone is approved for use to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors, who are in sinus rhythm or who will be cardioverted.

RECOMMENDATION: At this time, patients taking dronedarone should talk to their healthcare professional about whether they should continue to take dronedarone for non-permanent atrial fibrillation. Patients should not stop taking dronedarone without talking to a healthcare professional. Healthcare professionals should not prescribe dronedarone to patients with permanent atrial fibrillation. See the Data Summary in the Drug Safety Communication for additional details at: . For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for dronedarone hydrochloride to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of dronedarone hydrochloride and consists of the following: medication guide and communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

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  Contraindicated in patients with NYHA class IV heart failure or NYHA class II or III heart failure with recent decompensation requiring hospitalization or referral to a specialized heart failure clinic.¹ (See Heart Failure under Cautions.)

  
  


• 
  

  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 twofold increase in mortality rate relative to placebo;^{1 4} do not use dronedarone in such patients.¹

  
  

Introduction

Class III antiarrhythmic agent;^{5 6 7} also appears to exhibit activity in each of the 4 Vaughan-Williams antiarrhythmic classes.^{1 5 6 8}

Uses for Multaq

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Supraventricular Tachyarrhythmias

Reduction of risk of hospitalization for cardiovascular events in patients with paroxysmal or persistent atrial fibrillation or atrial flutter who have had a recent episode of atrial fibrillation/flutter and who have associated cardiovascular risk factors (i.e., >70 years of age, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≥50 mm, or left ventricular ejection fraction <40%); used in such patients who are in sinus rhythm or who will undergo cardioversion.^{1 9} (See Boxed Warningand also see Contraindications and see Heart Failure under Cautions.)

Less effective than amiodarone in preventing recurrence of atrial fibrillation but appears to have an improved safety profile (based on short-term data).^{4 5 8 9 14 16 19 24} Long-term data and experience needed to elucidate relative safety and tolerability of dronedarone versus amiodarone because of some late-onset adverse effects of amiodarone (e.g., pulmonary toxicity).^{6 8 14 16 18 19}

Efficacy of retreatment with dronedarone in patients who relapse after initial successful treatment or in those who fail therapy with amiodarone not established.^{17 21}

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.^{15 17 18 20 21 22 23 24 26}

Multaq Dosage and Administration

General

Risk Evaluation and Mitigation Strategy

• 
  

  FDA-required Risk Evaluation and Mitigation Strategy (REMS) implemented to assist healthcare professionals with identification of appropriate patients to receive dronedarone and ensure safe use while minimizing risk.^{10 11 12}

  
  


• 
  

  Goals of program (mPACT: MULTAQ Partnership for Appropriate Care and Treatment) are to educate prescribers about the increased risk of mortality associated with use of dronedarone in patients with NYHA class IV heart failure and in those who have NYHA class II or III heart failure with recent decompensation requiring hospitalization or referral to a specialized heart failure clinic, and to prevent use of the drug in such patients.¹² Also designed to inform patients about serious risks associated with dronedarone, including an increased rate of mortality in patients with severe, unstable heart failure.¹² (See Contraindicationsand also see Heart Failure under Cautions.) REMS program consists of educational materials for healthcare professionals and patients, including a medication guide to be dispensed with every dronedarone prescription.^{1 10 11 12}

  
  


• 
  

  For additional information, consult the Multaq website at .¹⁰

  
  

Administration

Oral Administration

Administer orally twice daily with morning and evening meals (to enhance bioavailability).¹ (See Food under Pharmacokinetics.)

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as dronedarone hydrochloride; dosage expressed in terms of dronedarone.¹

Adults

Supraventricular Tachyarrhythmias

Oral

Reduction of risk of hospitalization due to cardiovascular events in selected patients with paroxysmal or persistent atrial fibrillation/flutter: 400 mg twice daily with morning and evening meals.¹

Must discontinue class I or III antiarrhythmic agents and drugs that are potent inhibitors of cytochrome P450 (CYP) isoenzyme 3A prior to initiating dronedarone.^{1 9} (See Contraindications under Cautions and also see Interactions.)

Special Populations

The manufacturer states that no dosage other than 400 mg twice daily of dronedarone is recommended for any population at this time.⁹

Hepatic Impairment

No dosage adjustment required in patients with moderate hepatic impairment.¹ Contraindicated in patients with severe hepatic impairment.¹ (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment required.¹ (See Renal Impairment under Cautions.)

Cautions for Multaq

Contraindications

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  NYHA Class IV heart failure or NYHA Class II or III heart failure with recent decompensation requiring hospitalization or referral to a specialized heart failure clinic.¹ (See Boxed Warning and also see Heart Failure under Cautions.)

  
  


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  Second- or third-degree AV block or sick sinus syndrome (except in patients with a functioning pacemaker).¹

  
  


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  Bradycardia (<50 beats/minute).¹

  
  


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  QT interval corrected for rate, Bazett’s formula (QT_c) of ≥500 msec or PR interval >280 msec.^{1 9} (See Prolongation of QT Interval under Cautions.)

  
  


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  Concomitant use of potent inhibitors of CYP3A (e.g., clarithromycin, cyclosporine, itraconazole, ketoconazole, nefazodone, ritonavir, telithromycin, voriconazole).¹ (See Drugs Affecting Hepatic Microsomal Enzymes and also see Drugs Metabolized by Hepatic Microsomal Enzymes under Interactions.)

  
  


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  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 or III antiarrhythmic agents, phenothiazines, tricyclic antidepressants, certain oral macrolides).^{1 9} (See Drugs that Prolong the QT Interval under Interactions.)

  
  


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  Severe hepatic impairment.¹ (See Hepatic Impairment and also see Severe Hepatic Injury under Cautions.)

  
  


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  Women who are or may become pregnant.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  
  


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  Nursing women.¹

  
  

Warnings/Precautions

Heart Failure

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

In ANDROMEDA study, greater than twofold increase relative to placebo in rate of mortality in dronedarone-treated patients with severe heart failure requiring recent hospitalization or referral to a specialized heart failure clinic for worsening symptoms; do not use dronedarone in such patients.^{1 4}

Limited clinical experience available in patients with atrial fibrillation/flutter who develop worsening heart failure during therapy with dronedarone.¹ Worsening heart failure complicated by multiorgan dysfunction (e.g., acute renal and hepatic failure) in the setting of dronedarone initiation reported during postmarketing surveillance in at least one patient with atrial fibrillation and history of NYHA class III-IV heart failure and multiple recent hospitalizations for heart failure.²⁶

If heart failure develops or worsens, consider interrupting or discontinuing therapy.¹

Contraindicated in patients with NYHA class IV heart failure or NYHA class II or III heart failure with recent decompensation requiring hospitalization or referral to a specialized heart failure clinic.¹ (See Boxed Warningand also see Contraindications under Cautions.)

Severe Hepatic Injury

Severe hepatic injury reported rarely with dronedarone therapy.²⁸ Acute hepatic failure requiring liver transplantation reported in at least 2 patients; in both cases, explanted liver showed evidence of extensive hepatocellular necrosis.²⁸

Consider periodic monitoring of serum hepatic enzymes, especially during first 6 months of therapy.²⁸ 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 serum hepatic enzymes and bilirubin; initiate appropriate therapy if hepatic injury found.²⁸ Do not reinitiate dronedarone therapy in patients who experience hepatic injury without another explanation for such injury.²⁸

Hypokalemia and Hypomagnesemia

Possible hypokalemia and hypomagnesemia with concomitant use of potassium-depleting diuretics.¹ Ascertain that serum potassium and magnesium concentrations are within normal range prior to initiation of dronedarone; maintain within normal range during therapy.^{1 9 24}

Prolongation of QT Interval

Moderate prolongation of QT_c interval reported; QT_c interval increased by an average of about 10 msec, however, greater prolongation reported.¹ Discontinue dronedarone if QT_c interval is ≥500 msec.¹ (See Contraindications under Cautions.)

Increased Serum Creatinine Concentrations

Increase in S_cr of about 0.1 mg/dL reported following initiation of drug; however, may not necessarily indicate decline in renal function.^{1 2 4 5 13 16} Increase in S_cr and decrease in Cl_cr by about 10–15 or 18%, respectively, observed in clinical studies in healthy individuals and patients receiving the drug; however, no clinically important change in glomerular filtration rate, renal plasma flow or electrolyte exchanges, or any structural renal damage reported.^{1 2 3 4 13} Change in S_cr may result from a specific partial inhibition of tubular organic cation transporters and inhibition of tubular secretion of creatinine by dronedarone.^{1 5 13 16}

Increases in S_cr appear to have a rapid onset, reach a plateau after 7 days, and are reversible following discontinuance of the drug.^{1 13} If an increase in the S_cr occurs and plateaus, use this increased value as the patient’s new baseline S_cr.¹

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity demonstrated in animals.¹

Avoid pregnancy during therapy; women of childbearing potential (i.e., premenopausal women who have not undergone hysterectomy or oophorectomy) must use effective contraception.¹ If used during pregnancy or if patient becomes pregnant, apprise patient of potential fetal hazard.¹ (See Advice to Patients.)

Contraindicated in women who are or may become pregnant.¹

Specific Populations

Pregnancy

Category X.¹ (See Fetal/Neonatal Morbidity and Mortality and also see Contraindications under Cautions.)

Lactation

Dronedarone and its metabolites distributed into milk in rats; not known whether distributed into milk in humans.¹ Discontinue nursing or the drug.¹ Contraindicated in nursing women.¹

Pediatric Use

Safety and efficacy not established in children or adolescents <18 years of age.¹

Geriatric Use

No substantial differences in safety and efficacy relative to those in younger adults.¹ (See Special Populations under Pharmacokinetics.)

Hepatic Impairment

Not studied in patients with severe hepatic impairment; limited clinical experience available in patients with moderate hepatic impairment.¹ Severe liver injury reported rarely with dronedarone therapy.²⁸ (See Severe Hepatic Injury under Cautions.) Contraindicated in patients with severe hepatic impairment.¹ (See Special Populations under Pharmacokinetics.)

Renal Impairment

No dosage adjustment required because dronedarone undergoes minimal renal excretion.¹ (See Special Populations and also see Elimination Route under Pharmacokinetics.)

Common Adverse Effects

Increased S_cr (increase of ≥10% five days after initiation of drug),¹ prolonged QT_c interval (>450 msec [males] or >470 msec [females]),¹ diarrhea,^{1 2 14} asthenia,¹ nausea,^{1 2} skin reactions (e.g., rash [generalized, macular, maculo-papular, erythematous], pruritus, eczema, dermatitis, allergic dermatitis),^{1 2} abdominal pain,¹ bradycardia,^{1 2} vomiting,¹ dyspepsia.¹ (See Contraindications and see Prolongation of QT Interval and also see Increased Serum Creatinine Concentrations under Cautions.)

Interactions for Multaq

Metabolized mainly by CYP isoenzyme 3A.¹

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

Drugs Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP3A: Pharmacokinetic interaction (increased exposure to and peak plasma concentrations of dronedarone).¹ Concomitant use contraindicated.¹

Inhibitors of CYP3A: Potential pharmacokinetic interaction (altered concentrations of dronedarone).¹

Inducers of CYP3A: Potential pharmacokinetic interaction (substantially decreased exposure to dronedarone).¹ Avoid concomitant use.¹

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Potential pharmacokinetic interaction (possible increased plasma concentrations of the CYP3A substrate).^{1 9 25} Monitor plasma concentrations and appropriately adjust dosage of CYP3A substrates with a narrow therapeutic index when administered orally.^{1 9} Some clinicians state that dronedarone should be used with caution in patients receiving drugs with a narrow therapeutic index that are metabolized by CYP3A4.²⁵

Substrates of CYP2D6: Potential pharmacokinetic interaction (possible increased exposure to the CYP2D6 substrate).¹

Drugs that Prolong the QT Interval

Pharmacologic interaction (potential risk of torsades de pointes-type ventricular tachycardia) with drugs or herbal supplements that prolong the QT interval; concomitant use contraindicated.^{1 9} (See Contraindications under Cautions.)

Drugs Affected by the P-glycoprotein Transport System

Potential pharmacokinetic interaction (increased exposure to substrates of P-glycoprotein transport system [e.g., digoxin] expected) when used concomitantly with dronedarone.¹ Some clinicians state that dronedarone should be used with caution in patients receiving drugs with a narrow therapeutic index that are metabolized by the P-glycoprotein transport system.²⁵

Specific Drugs and Food

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 tachycardia1	Concomitant use contraindicated1
Anticoagulants, oral (e.g., warfarin)	Increased exposure to S-warfarin in healthy individuals; no change in exposure to R-warfarin or clinically important increases in the INR1 No excess risk of bleeding observed with concomitant use of dronedarone and oral anticoagulants in patients with atrial fibrillation/flutter1	Monitor INR according to manufacturers’ labeling for warfarin1
Antidepressants, SSRI	Possible increased exposure to SSRI1
Antidepressants, tricyclic	Potential risk of torsades de pointes-type ventricular tachycardia1 Possible increased exposure to tricyclic antidepressants1	Concomitant use contraindicated1
β-Adrenergic blocking agents (e.g., metoprolol, propranolol)	Increased incidence of bradycardia observed1 Increased exposure to metoprolol and propranolol; possible increased exposure to other β-adrenergic blocking agents that are CYP2D6 substrates1	If used with β-adrenergic blocking agents, use lower initial dosage of the β-adrenergic blocking agent and increase dosage of β-adrenergic blocker only if well tolerated as documented by ECG1 9
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 dronedarone1 Dronedarone increases exposure to calcium-channel blocking agents (verapamil, diltiazem, nifedipine); verapamil and diltiazem increase exposure to dronedarone1	If used with calcium-channel blocking agents, use lower initial dosage of the calcium-channel blocking agent and increase dosage of calcium-channel blocker only if well tolerated as documented by ECG1 9
Carbamazepine	Substantially decreased exposure to dronedarone due to CYP3A induction1	Avoid concomitant use1
Cyclosporine	Increased peak plasma concentrations of, and exposure to, dronedarone1	Concomitant use contraindicated1
Digoxin	Possible potentiation of electrophysiologic effects of dronedarone (e.g., decreased AV node conduction)1 Increased exposure to digoxin and increased digoxin concentrations1 Increased incidence of GI disorders observed1	When initiating dronedarone therapy, reassess need for continued digoxin therapy; discontinue digoxin or reduce digoxin dosage by 50%1 Monitor serum digoxin concentrations; close observation for signs of digoxin toxicity recommended1
Grapefruit juice	Increased peak plasma concentrations of, and exposure to, dronedarone1	Avoid grapefruit juice during dronedarone therapy1 9
HMG-CoA reductase inhibitors (statins)	Increased exposure to simvastatin and simvastatin acid1	Consult manufacturer’s labeling for the respective statin for specific recommendations regarding concomitant use with CYP3A or P-glycoprotein transport system inhibitors such as dronedarone1
Itraconazole	Increased peak plasma concentrations of, and exposure to, dronedarone1	Concomitant use contraindicated1
Ketoconazole	Increased peak plasma concentrations of, and exposure to, dronedarone1	Concomitant use contraindicated1
Losartan	No drug interaction observed1
Macrolides	Clarithromycin, telithromycin: Increase exposure to and peak plasma concentrations of dronedarone1 Certain oral macrolides: Potential risk of torsades de pointes-type ventricular tachycardia1	Clarithromycin, telithromycin, and certain oral macrolides: Concomitant use with dronedarone contraindicated1
Nefazodone	Increased peak plasma concentrations of, and exposure to, dronedarone1	Concomitant use contraindicated1
Oral contraceptives	No decreases in ethinyl estradiol or levonorgestrel concentrations observed in healthy individuals1
Pantoprazole	No clinically important effect on the pharmacokinetics of dronedarone1
Phenobarbital	Substantially decreased exposure to dronedarone due to CYP3A induction1	Avoid concomitant use1
Phenothiazines	Potential risk of torsades de pointes-type ventricular tachycardia1	Concomitant use contraindicated1
Phenytoin	Substantially decreased exposure to dronedarone due to CYP3A induction1	Avoid concomitant use1
Potassium-depleting diuretics	Possible hypokalemia or hypomagnesemia1	Ascertain that serum potassium and magnesium concentrations are within normal range prior to initiation of dronedarone; maintain within normal range during therapy1
Rifampin	Decreased exposure to dronedarone due to CYP3A induction1	Avoid concomitant use1
Ritonavir	Increased peak plasma concentrations of, and exposure to, dronedarone1	Concomitant use contraindicated1
St. John’s wort	Substantially decreased exposure to dronedarone due to CYP3A induction1	Avoid concomitant use1
Sirolimus	Possible increased plasma concentrations of sirolimus;1 initiation of dronedarone therapy in one patient receiving sirolimus post-kidney transplantation resulted in a threefold increase in trough sirolimus concentrations from baseline25	Monitor plasma concentrations of sirolimus and adjust dosage appropriately when used concomitantly with dronedarone1 Some clinicians recommend avoidance of concurrent use of sirolimus and dronedarone when possible. If concurrent administration cannot be avoided, a 50–75% reduction in sirolimus dosage prior to dronedarone initiation has been suggested; monitor trough sirolimus concentrations regularly (possibly even daily) during titration phase25
Tacrolimus	Possible increased plasma concentrations of tacrolimus1	Monitor plasma concentrations of tacrolimus and adjust dosage appropriately during concomitant use1
Theophylline	No apparent increase in steady-state exposure to theophylline1
Voriconazole	Increased peak plasma concentrations of, and exposure to, dronedarone1	Concomitant use contraindicated1

Multaq Pharmacokinetics

Absorption and Distribution

Bioavailability

Low systemic bioavailability; undergoes first-pass metabolism.¹ Absolute bioavailability about 4% when administered without food.¹

Steady-state concentrations achieved within 4–8 days following repeated oral administration of dronedarone 400 mg twice daily.¹

Food

Food increases bioavailability; bioavailability approximately 15% when administered with a high-fat meal.¹

Peak plasma concentrations of dronedarone and N-debutyl metabolite reached within 3–6 hours following oral administration with food.¹

Special Populations

Exposure to dronedarone increased by 23% in patients ≥65 years of age compared with that in younger adults.¹ (See Geriatric Use under Cautions.)

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%.¹ (See Hepatic Impairment under Cautions.)

Pharmacokinetics not studied in patients with severe hepatic impairment; contraindicated in such patients.¹

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.^{1 9} (See Renal Impairment under Cautions.)

Exposure to dronedarone averages 30% higher in women than in men.¹

Pharmacokinetic differences related to race not formally studied.¹ However, based on a cross-study comparison, exposure to dronedarone twofold higher in Asian men (of Japanese ancestry) than in Caucasian men following single-dose administration of dronedarone 400 mg.¹

Distribution

Extent

Dronedarone and its metabolites distributed into milk in rats; not known whether distributed into human milk.¹

Plasma Protein Binding

Dronedarone and N-debutyl metabolite are >98% bound to plasma proteins (mainly albumin); binding not saturable.¹

Elimination

Metabolism

Extensively metabolized, mainly by CYP3A.¹

Initial metabolic pathway includes N-debutylation to form active N-debutyl metabolite, oxidative deamination to form inactive propanoic acid metabolite, and direct oxidation.¹ Metabolites further metabolized to >30 uncharacterized metabolites.¹ N-debutyl metabolite exhibits pharmacodynamic activity; only up to one-third as potent as dronedarone.¹

Elimination Route

Excreted in urine (6%) and in feces (84%) mainly as metabolites; no unchanged drug excreted in urine.¹

Half-life

13–19 hours following IV administration.¹

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹

Actions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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  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.^{1 5}

  
  


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  Benzofuran derivative structurally related to amiodarone, but with structural modifications that include removal of the iodine group and addition of a methane-sulfonyl group.^{1 2 3 5 6 7 8 16}

  
  


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  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.^{2 3 5 6 8 16}

  
  


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  Electrophysiologic profile similar to amiodarone, but with different relative effects on individual ion channels.^{2 3 4 5 6}

  
  


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  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.^{5 6}

  
  


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  Inhibits sodium currents (at rapid pacing rates), calcium channels and slow L-type calcium currents, and demonstrates noncompetitive, antiadrenergic (α- and β-blocking) activity.^{5 6 8 16}

  
  


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  Prolongs PR interval and slows sinus rate by prolonging atrial and ventricular refractory periods.^{1 8}

  
  


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  Prolongs RR and QT intervals.^{5 6}

  
  


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  Produces a dose-dependent increase in PR interval and a moderate prolongation of the QT_c interval similar to amiodarone.^{1 5 8}

  
  

Advice to Patients

• 
  

  Importance of instructing patients to carefully read the manufacturer’s patient information (medication guide) before initiating therapy and each time the prescription is refilled.¹

  
  


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  Importance of informing clinician if signs or symptoms of heart failure (e.g., weight gain, dependent edema, increasing shortness of breath) occur.¹

  
  


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  Importance of advising patients receiving dronedarone to immediately report symptoms suggesting hepatic injury (e.g., anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine, itching).²⁸

  
  


• 
  

  Importance of taking dronedarone with a meal.¹

  
  


• 
  

  Importance of advising patients to avoid grapefruit juice while taking dronedarone.¹ (See Specific Drugs and Food under Interactions.)

  
  


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  Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed; necessity of advising women to avoid pregnancy and breast-feeding during dronedarone therapy.^{1 9} Necessity of advising women of childbearing potential to use an effective method of contraception while receiving therapy and importance of advising these patients regarding appropriate contraceptive choices (taking into consideration their underlying medical conditions and lifestyle preferences).¹ If pregnancy occurs, advise patient of risk to the fetus.¹

  
  


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  Importance of informing 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).¹

  
  


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  Importance of advising patients that if a dose of dronedarone is missed, the next dose should be taken at the regularly scheduled time; the dose should not be doubled.¹

  
  


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  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

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

Dronedarone Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	400 mg (of dronedarone)	Multaq	Sanofi-Aventis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Multaq 400MG Tablets (SANOFI-AVENTIS U.S.): 60/$276.00 or 180/$766.01

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Sanofi-Aventis. Multaq (dronedarone hydrochloride) tablets prescribing information. Bridgewater, NJ; 2009 Jul.

2. Hohnloser SH, Crijns HJ, van Eickels M et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009; 360:668-78. [PubMed 19213680]

3. Singh BN, Connolly SJ, Crijns HJ et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007; 357:987-99. [PubMed 17804843]

4. Køber L, Torp-Pedersen C, McMurray JJ et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med. 2008; 358:2678-87. [PubMed 18565860]

5. Hoy SM, Keam SJ. Dronedarone. Drugs. 2009; 69:1647-63. [PubMed 19678715]

6. Riera AR, Uchida AH, Ferreira C et al. Relationship among amiodarone, new class III antiarrhythmics, miscellaneous agents and acquired long QT syndrome. Cardiol J. 2008; 15:209-19. [PubMed 18651412]

7. Coletta AP, Cleland JG, Cullington D et al. Clinical trials update from Heart Rhythm 2008 and Heart Failure 2008: ATHENA, URGENT, INH study, HEART and CK-1827452. Eur J Heart Fail. 2008; 10:917-20. [PubMed 18678526]

8. Garcia D, Cheng-Lai A. Dronedarone: a new antiarrhythmic agent for the treatment of atrial fibrillation. Cardiol Rev. 2009 Sep-Oct; 17:230-4.

9. Sanofi-Aventis, Bridgewater, NJ: Personal communication.

10. Sanofi-Aventis. Healthcare professional information sheet for Multaq (dronedarone). 2009 Jul. Available from website. Accessed 2010 Mar 11.

11. Sanofi-Aventis. Prescribing Multaq: Information for health care professionals. 2009 Dec. Available from website. Accessed 2010 Mar 18.

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