Multaq

— THERAPEUTIC CATEGORIES —
  • CHF and arrhythmias
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Multaq Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Dronedarone 400mg; tabs.

    Pharmacological Class

    Antiarrhythmic.

    How Supplied

    Tabs—60, 100, 500

    How Supplied

    400mg white film-coated tablets for oral administration, oblong-shaped, engraved with a double wave marking on one side and “4142” code on the other side.

    Storage

    Store at 25°C (77°F): excursions permitted to 15°C-30°C (59°F-86°F).

    Manufacturer

    Sanofi U.S.

    Generic Availability

    NO

    Mechanism of Action

    Dronedarone has antiarrhythmic properties belonging to all four Vaughan-Williams classes, but the contribution of each of these activities to the clinical effect is unknown.

    Multaq Indications

    Indications

    To reduce the risk of hospitalization for atrial fibrillation (AF) in patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation.

    Multaq Dosage and Administration

    Prior to Treatment Evaluations

    Treatment with Class I or III antiarrhythmics s (eg, amiodarone, flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol) or drugs that are strong inhibitors of CYP3A (eg, ketoconazole) must be stopped before starting Multaq.

     

    Adult

    ≥18yrs: 400mg twice daily (AM & PM) with meals.

    Children

    <18yrs: not established.

    Administration

    Should be taken as 1 tablet with the morning meal and 1 tablet with the evening meal. Do not take with grapefruit juice. Missed dose: Take next dose at regularly scheduled time; do not double the dose.

    Multaq Contraindications

    Contraindications

    Permanent AF (normal sinus rhythm will not or cannot be restored). Symptomatic heart failure (HF) with recent decompensation requiring hospitalization or NYHA Class IV HF. 2nd- or 3rd-degree AV block or sick sinus syndrome, unless paced. Bradycardia (<50bpm). Concomitant strong CYP3A inhibitors (eg, ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, ritonavir). Concomitant erythromycin. Concomitant agents that can cause QTc prolongation (eg, phenothiazines, tricyclics, certain oral macrolide antibiotics, Class I and III antiarrhythmics). Liver or lung toxicity related to previous amiodarone use. QTc interval ≥500ms (discontinue if occurs). PR interval >280ms. Severe hepatic impairment.

    Multaq Boxed Warnings

    Boxed Warning

    Increased risk of death, stroke, and heart failure in patients with decompensated heart failure or premanent atrial fibrillation.

    Multaq Warnings/Precautions

    Warnings/Precautions

    Increased risk of death, stroke, or HF in decompensated HF or permanent AF. Monitor cardiac rhythm every 3 months during therapy; discontinue or cardiovert if AF is detected. Ensure appropriate antithrombotic therapy before starting. Discontinue if worsening HF develops and requires hospitalization or if pulmonary toxicity is confirmed. Monitor hepatic enzymes during 1st 6 months of therapy. Discontinue if hepatic injury is suspected; if confirmed, evaluate and initiate treatment; do not restart Multaq without another explanation. Maintain normal serum K+ and Mg2+ levels. Monitor renal function periodically. Embryo-fetal toxicity. Advise females of reproductive potential to use effective contraception during and for 5 days after the last dose. Pregnancy: exclude status prior to initiation. Nursing mothers: not recommended (during and for 5 days after the last dose).

    Warnings/Precautions

    Cardiovascular (CV) Death in NYHA Class IV or Decompensated Heart Failure 

    • Multaq is contraindicated in patients with NYHA Class IV heart failure or symptomatic heart failure with recent decompensation requiring hospitalization.
    • May double the risk of death.

    CV Death and Heart Failure in Permanent Atrial Fibrillation

    • In patients with permanent atrial fibrillation, Multaq doubles the risk of CV death (largely arrhythmic) and heart failure events.
    • Patients on dronedarone: monitor cardiac rhythm no less than every 3 months.
    • Cardiovert patients who are in atrial fibrillation (if clinically indicated) or discontinue dronedarone.
    • Multaq offers no benefit in patients in permanent atrial fibrillation.

    Increased Risk of Stroke in Permanent Atrial Fibrillation

    • Dronedarone was associated with an increased risk of stroke, particularly in the first 2 weeks, in a placebo-controlled study in patients with permanent atrial fibrillation.
    • Only initiate Multaq in patients in sinus rhythm who are receiving appropriate antithrombotic therapy.

    New Onset or Worsening Heart Failure

    • New onset or worsening failure has been reported with Multaq.
    • Placebo-controlled trial in patients with permanent atrial fibrillation: Increased rates of heart failure in patients with normal ventricular function and no history of symptomatic heart failure, as well as in those with a history of heart failure or left ventricular dysfunction.
    • Discontinue Multaq if heart failure develops or worsens and requires hospitalization.

    Liver Injury

    • Liver injury, including acute liver failure requiring transplantation, have been reported with Multaq.
    • Consider period liver enzyme monitoring, especially during the first 6 months of treatment.
    • Discontinue Multaq if hepatic injury is suspected; test AST, ALT, alkaline phosphatase, serum bilirubin to establish whether there is liver injury.
    • Do not restart Multaq without another explanation for the liver injury.

    Pulmonary Toxicity

    • Interstitial lung disease including pneumonitis and pulmonary fibrosis have been reported with Multaq.
    • Evaluate new onset of dyspnea or nonproductive cough.
    • If pulmonary toxicity is confirmed, discontinue Multaq.

    Hypokalemia and Hypomagnesemia With Potassium-Depleting Diuretics

    • Hypokalemia or hypomagnesemia may occur with concomitant potassium-depleting diuretics.
    • Prior to administering Multaq, ensure potassium levels are in normal range.
    • Potassium levels should be maintained in normal range while on Multaq. 

    QT Interval Prolongation

    • Multaq is associated with concentration-dependent QTcF interval prolongation (estimated QTcF increase for 400mg BID with food is 15ms).
    • Discontinue Multaq if QTc interval ≥500 ms.

    Renal Impairment and Failure

    • Increases in serum creatinine, pre-renal azotemia and acute renal failure have been reported with Multaq, often in the setting of heart failure or hypovolemia.
    • May be reversible upon drug discontinuation.
    • Monitor renal function periodically.
    • Small increases in creatinine levels (about 0.1mg/dL) following treatment initiation may be a result of inhibition of tubular secretion; this elevation has a rapid onset, reaches plateau after 7 days, and is reversible after discontinuation.

    Embryo-Fetal Toxicity

    • Multaq may cause fetal harm.
    • Verify that females of reproductive potential are not pregnant prior to initiation.
    • Advise females of reproductive potential to use effective contraception during and for 5 days (about 6 half-lives) after the last dose.

    Pregnancy Considerations

    Dronedarone can cause harm when administered to a pregnant woman. 

    Nursing Mother Considerations

    Advise patients not to breastfeed during and for 5 days (about 6 half-lives) after the last dose.

    Pediatric Considerations

    Safety and efficacy in children <18 years of age have not been established. 

    Geriatric Considerations

    Over 4500 patients aged 65 years and older were included in clinical trials (>2000 were 75 years or older). Efficacy and safety were similar in elderly and younger patients.

    Renal Impairment Considerations

    No dosing alteration is needed as renal excretion of dronedarone is minimal.

    Hepatic Impairment Considerations

    Dronedarone is contraindicated in patients with severe hepatic impairment as the drug is extensively metabolized by the liver. No dosage adjustment is recommended for moderate hepatic impairment.

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential

    • Verify pregnancy status in females of reproductive potential prior to initiation.
    • Contraception: Advise females of reproductive potential to use effective contraception during and for 5 days after the last dose.

    Multaq Pharmacokinetics

    Absorption

    Peak plasma concentrations of dronedarone and the main circulating active metabolite (N-debutyl metabolite) are reached within 3–6 hours after oral administration in fed conditions.

    Steady state is reached within 4–8 days of treatment (repeated administration of 400mg twice daily).

    Distribution

    Plasma protein binding of dronedarone and its N-debutyl metabolite is >98%; both bind mainly to albumin.

    Metabolism

    Extensively metabolized mainly by CYP3A. Monoamine oxidases contribute partially to the metabolism of the active metabolite of dronedarone.

    Elimination

    Elimination half-life of dronedarone ranges from 13–19 hours. Mainly fecal excretion (84%).

     

    Multaq Interactions

    Interactions

    See Contraindications. Avoid concomitant antiarrhythmics, rifampin, other CYP3A inducers (eg, phenobarbital, carbamazepine, phenytoin, St. John's wort), grapefruit juice. Consider discontinuing digoxin; if continued, reduce digoxin dose by ½, and monitor. Avoid doses >10mg once daily of simvastatin. Reduce dose and monitor Ca+ channel blockers, β-blockers (bradycardia), other CYP2D6 substrates. Verapamil, diltiazem increase dronedarone levels. Dronedarone increases verapamil, diltiazem, nifedipine levels. May potentiate dabigatran and other P-gP substrates, some statins, sirolimus, tacrolimus, other narrow-therapeutic range CYP3A substrates: adjust dose and monitor. Monitor other CYP3A or CYP2D6 substrates (eg, SSRIs, tricyclics). Monitor INR with warfarin.

    Interactions

    Drugs Prolonging QT Interval

    • Coadministration with certain phenothiazines, tricyclic antidepressants, certain macrolides, and Class I and III antiarrhythmics is contraindicated.
    • Potential for torsades de pointes-type ventricular tachycardia.

    Digoxin

    • In clinical trials, baseline use of digoxin was associated with an increased risk of arrhythmic or sudden death in patients treated with dronedarone; no difference in risk of sudden death was seen in patients not taking digoxin.
    • Digoxin can potentiate the electrophysologic effects of dronedarone (such as decreased AV-node conduction).
    • Dronedarone increases exposure to digoxin.
    • Consider discontinuing digoxin; if needed, halve the dose of digoxin, monitor and observe for toxicity.

    Calcium Channel Blockers (CCB)

    • Dronedarone increases the exposure of CCBs (eg, verapamil, diltiazem, nifedipine).
    • Initial dose of CCB should be low; increase only after ECG verification of good tolerability.

    Sirolimus, Tacrolimus, Other CYP3A Substrates With Narrow Therapeutic Range

    • Dronedarone can increase plasma concentrations of tacrolimus, sirolimus, and other CYP3A substrates with a narrow therapeutic range.
    • Monitor, adjust dose as needed.

    Beta-Blockers and Other CYP2D6 Substrates

    • Propranolol, metoprolol exposure increased by dronedarone.
    • Initial dose of  beta-blocker should be low; increase only after ECG verification of good tolerability.
    • Other CYP2D6 substrates (eg, beta blockers, tricyclic antidepressants, SSRIs) may have increased exposure upon coadministration.

    Dabigatran

    • Dronedarone increases dabigatran plasma exposure by inhibiting the P-gp transporter.
    • Moderate renal impairment (CrCl 30-50mL/min): Reduce dose of dabigatran to 75mg twice daily when given with dronedarone.
    • Severe renal impairment (CrCl 15-30mL/min): Avoid concomitant use.

    Warfarin

    • Exposure to S-warfarin slightly higher with concomitant dronedarone.
    • No clinically significant increases in INR.
    • ATHENA study: Clinically significant INR elevations observed usually within 1 week after starting dronedarone vs placebo in patients taking oral anticoagulants; no excess risk of bleeding was observed in the dronedarone group.
    • Monitor INR after initiating dronedarone in patients taking warfarin; increased INR with and without bleeding events has been reported postmarket.

    Multaq Adverse Reactions

    Adverse Reactions

    Diarrhea, nausea, abdominal pain, vomiting, dyspepsia, bradycardia, rash, pruritus, eczema, dermatitis, dermatitis allergic, asthenia; increased serum creatinine, liver injury, QT prolongation, interstitial lung disease, heart failure, hypokalemia, hypomagnesemia.

    Multaq Clinical Trials

    Clinical Trials

    ATHENA

    • Double-blind, randomized, placebo-controlled study in 4628 patients with a recent history of AF/AFL who were in sinus rhythm or who were to be converted to sinus rhythm.
    • Age range: 23 to 97 years; 42% were 75 years or older.
    • Median ejection fraction was 60%; 29% had heart failure; 86% had hypertension; 60% had structural heart disease.
    • Patients were randomly assigned to receive Multaq 400mg twice daily (n=2301) or placebo (n=2327), in addition to conventional therapy for cardiovascular diseases; median follow-up: 22 months.
    • Primary endpoint: Time to first hospitalization for cardiovascular reasons or death from any cause.
    • Multaq reduced the combined endpoint of cardiovascular hospitalization or death from any cause by 24.2% vs placebo; difference was attributed entirely to its effect on cardiovascular hospitalization, mainly hospitalization related to AF.
    • Results were consistent in all subgroups based on baseline characteristics or medications (eg, ACE inhibitors or ARBS, beta blockers, digoxin, statins, calcium channel blockers, diuretics).

    EURIDIS and ADONIS

    • 1237 patients in sinus rhythm with a prior episode of AF or AFL were randomly assigned in an outpatient setting to receive either Multaq 400mg twice daily (n=828) or placebo (n=409) in addition to conventional therapies.
    • Age range: 20 to 88 years; 70% male; 97% Caucasian.
    • Most common comorbidities: Hypertension (56.8%), structural heart disease (41.5%).
    • Patients were followed for 12 months.
    • Pooled analysis: Dronedarone delayed the time to first recurrence of AF/AFL (primary endpoint), lowering the risk of first AF/AFL recurrence during the 12-month period by about 25%, with absolute difference in recurrence rate of about 11% at 12 months.

    ANDROMEDA

    • Patients recently hospitalized with symptomatic heart failure and severe left ventricular systolic dysfunction (wall motion index ≤1.2) were randomly assigned to receive either Multaq 400mg twice daily or placebo.
    • Patients were predominantly NYHA Class II (40%) and III (57%); only 25% had AF at randomization.
    • Primary endpoint: Composite of all-cause mortality or hospitalization for heart failure.
    • 627 patients had a median follow-up of 63 days; the trial was terminated due to excess mortality in the dronedarone group.
    • 25 patients in the dronedarone group died vs 12 patients in the placebo group (hazard ratio, 2.13; 95% CI, 1.07-4.25).
    • Worsening heart failure was the main reason for death.
    • Baseline digoxin therapy was reported in 6/16 dronedarone patients vs 1/16 placebo patients who died of arrhythmia.
    • No excess risk of arrhythmic death was observed in patients without baseline use of digoxin in the dronedarone vs placebo groups.
    • Excess hospitalizations for cardiovascular reasons were also observed in the dronedarone group (71 vs 51 for placebo).

    PALLAS

    • Patients with permanent AF and additional risk factors for thromboembolism were randomly assigned to dronedarone 400mg twice daily (n=1619) or placebo (n=1617).
    • Median follow-up: 3.7 months for placebo and 3.9 months for dronedarone.
    • Study was terminated early because of a significant increase in mortality, stroke, and hospitalizations for heart failure in the dronedarone group vs placebo.
    • Mortality: 25 vs 13 (hazard ratio [HR], 1.94; 95% CI, 0.99-3.79); majority of deaths in dronedarone group were classified as arrhythmic/sudden deaths (HR, 3.26; 95% CI, 1.06-10.0). In patients without baseline use of digoxin, no excess risk of arrhythmic death was observed in the dronedarone vs placebo groups.
    • Stroke: 23 vs 10 (HR, 2.32; 95% CI, 1.11-4.88); increased risk with dronedarone first observed in the first 2 weeks of treatment (10 dronedarone vs 1 placebo). Most of the dronedarone-treated patients did not have an INR of 2.0-3.0.
    • Hospitalizations for heart failure: 43 vs 24 (HR, 1.81; 95% CI, 1.10-2.99).

    Multaq Note

    Not Applicable

    Multaq Patient Counseling

    Patient Counseling

    Multaq should be taken with a meal. Do not take with grapefruit juice.

    Report signs/symptoms of heart failure (eg, weight gain, dependent edema, shortness of breath).

    Report symptoms suggesting hepatic injury (eg, anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine, itching).

    Report new medications as Multaq may interact with these drugs.

    Cost Savings Program

    Multaq Savings Card Program

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