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brand multaq 400 mg tablet

In stock Manufacturer SANOFI-AVENTIS 00024414260
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Uses

Supraventricular Tachyarrhythmias

Dronedarone hydrochloride is used to reduce the risk of hospitalization for atrial fibrillation in patients in sinus rhythm who have a history of paroxysmal or persistent atrial fibrillation. Current evidence from a comparative trial suggests that dronedarone is less effective than amiodarone in preventing recurrence of atrial fibrillation but has an improved safety profile (based on short-term follow-up) with regard to certain serious adverse effects (e.g., thyroid, neurologic) and potential for drug interactions (e.g., with warfarin). However, long-term data and experience are needed to fully elucidate the relative safety and tolerability of dronedarone versus amiodarone because some adverse effects of amiodarone (e.g., pulmonary toxicity) have been reported to occur up to 2-3 years after initiation of therapy.

Dronedarone should not be used in patients with permanent atrial fibrillation (i.e., patients in whom normal sinus rhythm will not or cannot be restored); results of a clinical trial indicate an increased risk of cardiovascular events and death in such patients.(See Cardiovascular Death and Heart Failure in Patients with Permanent Atrial Fibrillation under Warnings/Precautions: Warnings, in Cautions.)

The efficacy of retreatment with dronedarone in patients who relapse after initial successful treatment or in those who fail therapy with amiodarone remains to be determined. Some clinicians suggest that based on current data, dronedarone should be considered alternative (e.g., second- or third-line) therapy in selected patients in whom control of ventricular rate alone is not feasible or successful and who do not have advanced (i.e., New York Heart Association [NYHA] class IV or recently decompensated class II or III) heart failure and are not receiving drugs that prolong QT interval or strongly inhibit cytochrome P-450 (CYP) isoenzyme 3A4 (CYP3A4).(See Cautions: Contraindications.) Treatment of atrial fibrillation/flutter should be individualized, with consideration given to the relative benefits and risks of various therapies (e.g., rhythm versus rate control, nondrug therapies such as ablation and pacemaker implantation), patient age, as well as patient preference and tolerance of the arrhythmia.

In a multicenter, placebo-controlled, double-blind, parallel-arm trial to assess the efficacy of dronedarone for the prevention of hospitalization for cardiovascular events or death from any cause in patients with atrial fibrillation/flutter (ATHENA study), the incidence of the combined primary outcome (first hospitalization due to cardiovascular events or death from any cause) was reduced with dronedarone compared with placebo. In this study, 4628 patients with a recent history of paroxysmal or persistent atrial fibrillation/flutter were randomized to receive dronedarone (400 mg twice daily) or placebo in addition to conventional therapy for cardiovascular diseases (i.e., β-adrenergic blocking agents, angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, digoxin, calcium-channel blocking agents, HMG-CoA reductase inhibitors, oral anticoagulants, aspirin, other maintenance antiplatelet therapy, and diuretics). Eligible patients included those who were at least 75 years of age or those at least 70 years of age who had one or more risk factors (i.e., hypertension, diabetes, prior cerebrovascular accident, left atrial diameter of 50 mm or greater, left ventricular ejection fraction of 40% or less) and who were in sinus rhythm or were to undergo cardioversion to sinus rhythm. Patients ineligible for participation in the study included, but were not limited to, patients with NYHA class IV heart failure. The median duration of follow-up was 22 months (range: 12-30 months).

In the ATHENA study, the combined primary outcome of first hospitalization due to cardiovascular events or death from any cause occurred in 31.9% of patients who received dronedarone (individual event rates of 29.3 and 2.6% were reported for cardiovascular hospitalization and death from any cause, respectively) compared with 39.4% of patients who received placebo (individual event rates of 36.9 and 2.5% were reported for cardiovascular hospitalizations and death from any cause, respectively). The reduction in the rate of the combined primary outcome with dronedarone was mainly attributable to a reduction in the rate of first hospitalization due to cardiovascular events, principally hospitalization related to atrial fibrillation; the incidence of death from any cause was not substantially reduced. The numbers of first hospitalizations for congestive heart failure (CHF), ventricular arrhythmia, nonfatal cardiac arrest, or syncope were similar for patients who received dronedarone or placebo; however, there were fewer first hospitalizations for acute coronary syndromes in the dronedarone group.

In 2 other multicenter, double-blind, placebo-controlled trials in outpatients with atrial fibrillation/flutter receiving dronedarone for the maintenance of sinus rhythm (the EURIDIS study in 12 European countries and the ADONIS study in the US, Canada, Australia, South Africa, and Argentina), patients who received dronedarone had a longer median time to first recurrence of atrial fibrillation/flutter (116 versus 53 days) and a lower rate of recurrence at 12 months (64.1 versus 75.2%) than those who received placebo. In these studies, a total of 1237 patients 21 years of age or older who had at least one episode of atrial fibrillation/flutter (as documented by electrocardiogram [ECG]) during the previous 3 months and were in sinus rhythm for at least 1 hour were randomized to receive dronedarone (400 mg twice daily) or placebo, in addition to conventional therapy, for 12 months. Patients ineligible for participation in the studies included, but were not limited to, patients with NYHA class III or IV congestive heart failure. The primary outcome was time from randomization to first documented recurrence of atrial fibrillation/flutter, which was defined as an episode lasting for at least 10 minutes and confirmed by 2 consecutive ECG or transtelephonic recordings taken 10 minutes apart.

In another double-blind, placebo-controlled trial of dronedarone therapy in patients with moderate to severe CHF (ANDROMEDA study), the study was terminated prematurely (after enrollment of 627 of 1000 planned patients and a median follow-up of 63 days) because of excess mortality, mainly as a result of worsening heart failure, in the dronedarone group (8.1%) compared with the placebo group (3.8%). However, at study termination, the combined primary end point of death from any cause or hospitalization for worsening heart failure was not significantly different between patients who received dronedarone or placebo (crude estimate: 17.1 versus 12.6%). After an additional 6 months of follow-up without study treatment, the rate of mortality and the percentage of patients who had reached the combined primary end point were not significantly different between the 2 groups.

In the ANDROMEDA study, patients 18 years of age or older who were hospitalized with new or worsening heart failure and who had at least one episode of shortness of breath on minimal exertion or at rest (NYHA class III or IV heart failure) or paroxysmal nocturnal dyspnea within the previous month and a wall-motion index of 1.2 or less (ejection fraction of about 35% or less) were randomized to receive dronedarone (400 mg twice daily) or placebo. Outcomes were assessed up to the day active treatment was discontinued, 1 month after the date of cessation of the active-treatment phase, and at the end of a 6-month follow-up phase following completion of the study. The study was originally scheduled to last for 2 years and each patient was to be treated for a minimum of 12 months; however, 7 months after the first patient was assigned to a study group, enrollment and treatment were discontinued for safety reasons on the recommendation of the data and safety monitoring board. Dronedarone is contraindicated in patients with NYHA class IV heart failure or heart failure with recent decompensation requiring hospitalization.(See Cautions: Contraindications and also see Cardiovascular Death in Decompensated Heart Failure under Warnings/Precautions: Warnings, in Cautions.)

Dronedarone appears to be less effective than amiodarone in preventing recurrence of atrial fibrillation but may be less likely to cause serious adverse effects, at least in the short term. In a randomized, double-blind study (DIONYSOS) in 504 amiodarone-naive patients (mean age: 64 years) with persistent atrial fibrillation, the primary composite (efficacy/safety) end point (time to first ECG-documented recurrence of atrial fibrillation or premature discontinuance of the study drug due to lack of efficacy or intolerance) was reached in 75.1% of patients receiving dronedarone (400 mg twice daily) compared with 58.8% of those receiving amiodarone (600 mg daily for 28 days, then 200 mg daily) at 12 months; the median duration of treatment was 7 months (maximum treatment duration of 13.8 months in both groups).

Patients enrolled in the DIONYSOS study had documented atrial fibrillation of more than 72 hours' duration, and almost all (95.6%) were receiving concomitant oral anticoagulant therapy. Recurrence of atrial fibrillation (including documented atrial fibrillation after successful conversion, unsuccessful electrical cardioversion, and no spontaneous conversion and no electrical cardioversion on days 10-28) accounted for the largest component of the composite primary end point (63.5 or 42% for dronedarone or amiodarone, respectively) compared with the premature drug discontinuance component (10.4 or 13.3% for dronedarone or amiodarone, respectively). Recurrence of atrial fibrillation after successful conversion was more frequent with dronedarone than with amiodarone (36.5 versus 24.3%, respectively). The incidence of the predefined main safety end point, which included thyroid, hepatic, pulmonary, neurologic, skin, ocular, and GI adverse effects as well as premature drug discontinuance, was similar for dronedarone and amiodarone at 12 months. Bradycardia and QTc (QT interval corrected for rate, Bazett's formula) prolongation, thyroid and neurologic events, and premature drug discontinuance due to adverse effects were less frequent with dronedarone; however, GI events, none of which were serious (mainly diarrhea), occurred at a higher incidence in the dronedarone group. However, when GI events were excluded, the relative risk of the main safety end point was reduced by 39% with dronedarone. In addition, the proportion of patients with supratherapeutic INR levels (exceeding 4.5) was smaller and the incidence of hemorrhagic events was reduced with dronedarone compared with amiodarone therapy.

In the PALLAS study, patients with permanent atrial fibrillation (defined as the presence of atrial fibrillation or atrial flutter for at least 6 months prior to randomization and patient and clinician decision not to make further efforts to restore sinus rhythm) and additional cardiovascular risk factors who received dronedarone had a higher incidence of heart failure, stroke, and cardiovascular death than those receiving placebo, and the study was terminated early for safety reasons. In this study, patients received dronedarone (400 mg twice daily) or placebo in addition to standard therapy (e.g., drugs to control heart rate, digoxin, anticoagulation with a vitamin K antagonist [e.g., warfarin]). Patients were at least 65 years of age and considered at high risk for vascular events because of the presence of at least one of the following risk factors: coronary artery disease, previous stroke or transient ischemic attack (TIA); symptomatic heart failure, left ventricular ejection fraction of 40% or less; peripheral arterial disease; or the combination of age exceeding 75 years, hypertension, and diabetes. Dronedarone therapy was associated with a more-than-twofold increase in the rate of the first coprimary outcome (stroke, myocardial infarction, systemic embolism, or cardiovascular death) and a near-doubling of the second coprimary outcome (unplanned hospitalization for cardiovascular causes or death). Dronedarone is contraindicated in patients with permanent atrial fibrillation. (See Cautions: Contraindications and see Cardiovascular Death and Heart Failure in Patients with Permanent Atrial Fibrillation under Warnings/Precautions: Warnings, in Cautions.)

Dosage and Administration

Administration

Dronedarone hydrochloride is administered orally twice daily with the morning and evening meals (to enhance bioavailability).(See Description.)

Dosage

Dosage of dronedarone hydrochloride is expressed in terms of dronedarone.

Supraventricular Tachyarrhythmias

The recommended dosage of dronedarone to reduce the risk of hospitalization for atrial fibrillation in selected patients in sinus rhythm who have a history of paroxysmal or persistent atrial fibrillation (See Uses: Supraventricular Tachyarrhythmias) is 400 mg twice daily with the morning and evening meals.

In a small dose-response study, patients with recurrent atrial fibrillation received dronedarone dosages of 400, 600, or 800 mg twice a day; dosages above 400 mg twice daily were not more effective and were less well tolerated.

Treatment with class I or III antiarrhythmic agents or drugs that are potent inhibitors of the cytochrome P-450 (CYP) 3A isoenzyme must be discontinued prior to initiating dronedarone therapy.(See Cautions: Contraindications and also see Drug Interactions.)

Special Populations

No dosage adjustment is required in patients with moderate hepatic impairment. However, dronedarone is contraindicated in patients with severe hepatic impairment.(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

No dosage adjustment is required in patients with renal impairment.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

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

Cautions

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 (less than 50 beats/minute).

QT interval corrected for rate (Bazett's formula, QTc) of 500 milliseconds or greater or PR interval exceeding 280 milliseconds.(See Other Warnings and Precautions: Prolongation of QT Interval, under Cautions: Warnings/Precautions.)

Concomitant use of potent inhibitors of the cytochrome P-450 (CYP) 3A isoenzyme (e.g., clarithromycin, cyclosporine, itraconazole, ketoconazole, nefazodone, ritonavir, telithromycin, voriconazole).(See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes and also see Drug Interactions: Drugs Metabolized by Hepatic Microsomal Enzymes.)

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, phenothiazine antipsychotics, tricyclic antidepressants, certain oral macrolides [e.g., erythromycin]).(See Drug Interactions: Drugs that Prolong the QT Interval.)

Liver toxicity related to previous use of amiodarone.(See Other Warnings and Precautions: Severe Hepatic Injury, under Warnings/Precautions, in Cautions.)

Severe hepatic impairment.(See Hepatic Impairment under Warnings/Precautions: Specific Populations.)

Women who are or may become pregnant.(See Other Warnings and Precautions: Fetal/Neonatal Morbidity and Mortality under Cautions: Warnings/Precautions.)

Nursing women.

Warnings/Precautions

Warnings

Cardiovascular Death in Decompensated Heart Failure

Dronedarone should not be used in patients with NYHA Class IV heart failure or symptomatic heart failure and recent decompensation requiring hospitalization because of a twofold increase in cardiovascular death in such patients receiving the drug.(See Cautions: Contraindications.)

Cardiovascular Death and Heart Failure in Patients with Permanent Atrial Fibrillation

Dronedarone doubles the risk of cardiovascular death (principally due to arrhythmia) and heart failure in patients with permanent atrial fibrillation (i.e., those who cannot or will not be converted to normal sinus rhythm); the drug offers no benefit and is contraindicated in such patients.

Patients receiving dronedarone should have heart rate monitored by electrocardiogram (ECG) at least every 3 months. Patients who have atrial fibrillation should have dronedarone therapy discontinued or, if clinically indicated, should undergo cardioversion.

Increased Risk of Stroke in Patients with Permanent Atrial Fibrillation

Dronedarone should only be initiated in patients in sinus rhythm who are receiving appropriate antithrombotic therapy. In a placebo-controlled study in patients with permanent atrial fibrillation, dronedarone therapy was associated with an increased risk of stroke, particularly during the first 2 weeks of therapy.

Other Warnings and Precautions

New-Onset or Worsening Heart Failure

New-onset or worsening heart failure has been reported in patients receiving dronedarone during postmarketing experience. In a placebo-controlled study in patients with permanent atrial fibrillation, increased rates of heart failure were observed in patients with normal left ventricular function and no history of symptomatic heart failure, and also in those with a history of heart failure or left ventricular dysfunction. If heart failure develops or worsens, dronedarone therapy should be discontinued. In addition, the manufacturer states that dronedarone is contraindicated in patients with NYHA class IV heart failure or heart failure with recent decompensation requiring hospitalization.(See Cautions: Contraindications.)

Severe Hepatic Injury

Severe hepatocellular injury, including acute hepatic failure requiring liver transplantation, has been reported during postmarketing experience in patients receiving dronedarone. Hepatic failure requiring transplantation was reported in 2 women 4.5 and 6 months, respectively, after initiation of dronedarone therapy. No alternative etiologies for hepatic failure were identified in either case; in both cases, the explanted liver showed evidence of extensive hepatocellular necrosis. A causal relationship between dronedarone exposure and hepatic failure has not been established because these events were reported voluntarily from a population of unknown size.

Patients should be advised to contact a clinician immediately if they experience manifestations of hepatic injury (e.g., anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine, itching) while taking dronedarone. Clinicians should consider periodic monitoring of serum hepatic enzymes in patients receiving dronedarone, especially during the first 6 months of therapy; it is not known whether routine periodic monitoring of hepatic enzymes will prevent development of severe hepatic injury. If hepatic injury is suspected, dronedarone therapy should be discontinued promptly and serum hepatic enzymes (AST, ALT, and alkaline phosphatase) and bilirubin assessed. Appropriate therapy should be initiated if hepatic injury is found, and the probable cause of such injury should be investigated. Dronedarone should not be reinitiated in patients who experience hepatic injury without another explanation for such injury.

Hypokalemia and Hypomagnesemia

Hypokalemia or hypomagnesemia may occur in patients receiving dronedarone concomitantly with potassium-depleting diuretics. Serum potassium and magnesium concentrations should be within the normal range prior to initiation of dronedarone therapy and maintained within the normal range during dronedarone therapy.

Prolongation of QT Interval

Dronedarone prolongs the QTc interval by an average of about 10 milliseconds; however, much greater prolongation of the QTc interval has been observed. If the QTc interval is 500 milliseconds or greater, dronedarone should be discontinued.(See Cautions: Contraindications.)

Increased Serum Creatinine Concentrations

Small increases in serum creatinine concentrations (about 0.1 mg/dL) following initiation of dronedarone therapy have been reported to result from inhibition of the tubular secretion of creatinine by dronedarone.

Larger increases in serum creatinine after dronedarone initiation have been reported during postmarketing experience. In clinical studies, a 10-15% increase in serum creatinine concentration has been observed in healthy individuals and patients receiving dronedarone without any clinical or laboratory evidence of structural renal damage. The increase in serum creatinine concentration associated with dronedarone has a rapid onset, reaches a plateau after 7 days, and is reversible following discontinuance of the drug. In some cases, increases in BUN were also reported. These effects generally appear to be reversible upon drug discontinuance. Renal function should be monitored periodically in patients receiving dronedarone.

Fetal/Neonatal Morbidity and Mortality

Dronedarone may cause fetal harm; teratogenicity has been demonstrated in animals at dosages equivalent to human dosages. Pregnancy should be avoided during therapy. Women of childbearing potential (i.e., premenopausal women who have not undergone hysterectomy or oophorectomy) should be counseled regarding appropriate contraceptive choices and must use effective contraception while receiving dronedarone. If dronedarone is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.(See Advice to Patients.) Dronedarone is contraindicated in women who are or may become pregnant.

Specific Populations

Pregnancy

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

Lactation

Dronedarone and its metabolites are distributed into milk in rats. It is not known whether dronedarone is distributed into human milk. Because of the potential for serious adverse reactions to dronedarone in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman. Dronedarone is contraindicated in nursing women.

Pediatric Use

Safety and efficacy have not been established in children or adolescents younger than 18 years of age.

Geriatric Use

No substantial differences in safety and efficacy have been observed in geriatric patients compared with younger adults. In clinical studies, exposure to dronedarone was increased by 23% in patients 65 years of age or older compared with younger adults.

Hepatic Impairment

Dronedarone has not been studied in patients with severe hepatic impairment and limited clinical experience is available in patients with moderate hepatic impairment. Dronedarone is contraindicated in patients with severe hepatic impairment.

Severe liver injury has been reported rarely with dronedarone therapy.(See Severe Hepatic Injury under Warnings/Precautions, in Cautions.)

In patients with moderate hepatic impairment, the mean exposure to dronedarone increased by 1.3-fold compared with that in individuals with normal hepatic function, and the mean exposure to the N-debutyl metabolite decreased by about 50%. The pharmacokinetics of dronedarone have not been studied in patients with severe hepatic impairment.

Renal Impairment

Because dronedarone undergoes minimal renal excretion, the manufacturer states that dosage adjustment in patients with renal impairment is not necessary.

No apparent differences in the pharmacokinetics of dronedarone have been observed in individuals with mild or moderate renal impairment versus those with normal renal function or in patients with atrial fibrillation with mild to severe renal impairment versus those with normal renal function.(See Dosage and Administration: Special Populations.)

Common Adverse Effects

Adverse effects reported in at least 1% of patients receiving dronedarone and more frequently than with placebo include early increases in serum creatinine (at least 10% increase), prolonged QT interval corrected for rate (QTc, Bazett's formula), diarrhea, asthenic conditions, nausea, skin reactions (e.g., rash [generalized, macular, maculopapular, erythematous], pruritus, eczema, dermatitis, allergic dermatitis), abdominal pain, bradycardia, vomiting, and dyspeptic manifestations.(See Cautions: Contraindications and also see Other Warnings and Precautions: Prolongation of QT Interval and Other Warnings and Precautions: Increased Serum Creatinine Concentrations under Cautions: Warnings/Precautions.)

Drug Interactions

Dronedarone is metabolized mainly by the cytochrome P-450 (CYP) 3A isoenzyme.

Dronedarone is a moderate inhibitor of CYP 3A and 2D6; however, the drug does not appear to substantially inhibit CYP 1A2, 2C9, 2C19, 2C8, or 2B6. Dronedarone may potentially inhibit the P-glycoprotein transport system. Dronedarone or its 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

Potent inhibitors of CYP3A (e.g., clarithromycin, cyclosporine, itraconazole, ketoconazole, nefazodone, ritonavir, telithromycin, voriconazole): Pharmacokinetic interaction (increased peak plasma concentrations of and exposure to dronedarone). Concomitant use is contraindicated.

Moderate inhibitors of CYP3A (e.g., diltiazem, verapamil): Potential pharmacokinetic interaction (increased exposure to dronedarone). Initiate calcium-channel blocking agents at a low dosage and increase dosage only after ECG verification of good tolerability.

Inducers of CYP3A (e.g., carbamazepine, phenobarbital, phenytoin, rifampin, St. John's wort [Hypericum perforatum]): Potential pharmacokinetic interaction (substantially decreased exposure to dronedarone). Concomitant use should be avoided.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Potential pharmacokinetic interaction (possible increased plasma concentrations of the CYP3A substrate). Initiation of dronedarone therapy in one patient receiving sirolimus following kidney transplantation resulted in a threefold increase in trough sirolimus concentrations compared with the patient's baseline trough concentration. The manufacturer states that plasma concentrations of sirolimus, tacrolimus, and other CYP3A substrates with a narrow therapeutic index when administered orally should be monitored and dosage of these drugs should be adjusted appropriately when used concomitantly with dronedarone. Some clinicians state that dronedarone should be used with caution in patients receiving drugs with a narrow therapeutic index that are metabolized by CYP3A4. Due to the potential for sirolimus toxicity and excessive immunosuppression, some clinicians recommend that concurrent use of sirolimus and dronedarone be avoided when possible. However, if concurrent administration cannot be avoided, these clinicians suggest a 50-75% reduction in sirolimus dosage prior to dronedarone initiation and regular monitoring (possibly even daily) of trough sirolimus concentrations during the titration phase.

Substrates of CYP2D6 (e.g., β-adrenergic blocking agents, selective serotonin-reuptake inhibitors [SSRIs], tricyclic antidepressants): 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). Concomitant use of dronedarone with drugs that prolong the QT interval (e.g., class I or III antiarrhythmic agents such as amiodarone, disopyramide, dofetilide, flecainide, propafenone, quinidine, sotalol; tricyclic antidepressants; certain phenothiazines; certain oral macrolides) is contraindicated.

Drugs Affected by the P-glycoprotein Transport System

Potential pharmacokinetic interaction; increased exposure to substrates of the P-glycoprotein transport system (e.g., dabigatran, digoxin) is expected when such drugs are used concomitantly with dronedarone. 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.

β-Adrenergic Blocking Agents

Potential pharmacologic and pharmacokinetic interactions. In clinical studies, bradycardia was observed more frequently when dronedarone was given concomitantly with β-adrenergic blocking agents. Dronedarone increases exposure to propranolol and metoprolol.

If dronedarone is used concomitantly with a β-adrenergic blocking agent, a lower initial dosage of the β-adrenergic blocking agent is recommended and the dosage should be increased only if well tolerated as documented by electrocardiogram (ECG).(Also see Drug Interactions: Drugs Metabolized by Hepatic Microsomal Enzymes.)

Calcium-channel Blocking Agents

Potential pharmacologic and pharmacokinetic interactions. Calcium-channel blocking agents associated with depressant effects on the sinus and AV nodes may potentiate the myocardial conduction effects of dronedarone. In addition, dronedarone may increase exposure to calcium-channel blocking agents (diltiazem, nifedipine, verapamil). Initiate calcium-channel blocking agents at a low dosage and increase dosage only after ECG verification of good tolerability.

In addition, verapamil and diltiazem (moderate CYP3A inhibitors) may increase exposure to dronedarone.(See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Clopidogrel

Concomitant administration of dronedarone does not require dosage adjustment of clopidogrel.

Dabigatran

Potential pharmacokinetic interaction. Concomitant administration of dronedarone may increase systemic exposure to dabigatran.(See Drug Interactions: Drugs Affected by the P-glycoprotein Transport System.)

Digoxin

Potential pharmacologic and pharmacokinetic interactions. Digoxin may potentiate the electrophysiologic effects of dronedarone (e.g., decreased AV node conduction). In clinical studies, increased serum digoxin concentrations and an increased incidence of GI disorders were reported with concomitant use of dronedarone and digoxin. When dronedarone therapy is initiated in patients receiving digoxin, the need for continued digoxin therapy should be reassessed and digoxin discontinued if appropriate; if digoxin therapy is continued, a 50% reduction in digoxin dosage is recommended when dronedarone therapy is initiated. In addition, serum digoxin concentrations should be monitored carefully and patients should be observed closely for signs of digoxin toxicity if dronedarone and digoxin are used concomitantly.(See Drug Interactions: Drugs Affected by the P-glycoprotein Transport System.)

Grapefruit Juice

Potential pharmacokinetic interaction (grapefruit juice increases exposure to dronedarone by threefold); use of grapefruit juice during dronedarone therapy should be avoided.

HMG-CoA Reductase Inhibitors (Statins)

Simvastatin: Potential pharmacokinetic interaction; dronedarone increases exposure to simvastatin and simvastatin acid by fourfold and twofold, respectively. Simvastatin dosages exceeding 10 mg once daily should be avoided.

Other statins (e.g., atorvastatin, rosuvastatin): The manufacturer's labeling for the respective statin should be consulted for specific recommendations regarding concomitant use with CYP3A or P-glycoprotein transport system inhibitors, such as dronedarone. Concomitant administration of dronedarone does not require adjustment of atorvastatin or rosuvastatin dosage.

Ketoconazole

Pharmacokinetic interaction; concomitant administration of ketoconazole, a potent CYP3A inhibitor, results in substantially increased exposure to dronedarone. Concomitant use of ketoconazole and dronedarone is contraindicated.

Losartan

No losartan dosage adjustment required with concomitant administration of dronedarone and losartan.

Metformin

No dosage adjustment to metformin hydrochloride required with concomitant dronedarone.

Oral Contraceptives

No dosage adjustments to ethinyl estradiol or levonorgestrel required with concomitant dronedarone.

Omeprazole

No dosage adjustment to omeprazole required with concomitant dronedarone.

Pantoprazole

Pantoprazole does not necessitate dosage adjustment of concomitant dronedarone.

Potassium-depleting Diuretics

Potential pharmacologic interaction (possible risk of hypokalemia or hypomagnesemia) with concomitant use of dronedarone and potassium-depleting diuretics.(See Other Warnings and Precautions: Hypokalemia and Hypomagnesemia under Cautions: Warnings/Precautions.)

Rifampin

Potential pharmacokinetic interaction (rifampin substantially decreases exposure to dronedarone); concomitant use of dronedarone and rifampin should be avoided.

Theophylline

No adjustment of theophylline dosage is required with concomitant dronedarone.

Warfarin

Concomitant administration of dronedarone and warfarin resulted in slightly increased exposure to S-warfarin; however, there was no clinically important increase in the international normalized ratio (INR). In the ATHENA study, more patients experienced clinically important increases in INR (INR >=5) usually within 1 week after adding dronedarone to warfarin therapy compared with placebo, but an excess risk of bleeding was not observed in such patients. However, cases of increased INR with or without bleeding events have been reported during postmarketing experience in warfarin-treated patients who received dronedarone. The INR should be monitored after initiation of dronedarone therapy in patients taking warfarin.

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