CHF and arrhythmias:

Indications for: MULTAQ

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

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).

Adult Dosage:

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

Children Dosage:

<18yrs: not established.

MULTAQ 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 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 Bazett interval ≥500ms. PR interval >280ms. Severe hepatic impairment. Pregnancy (Cat.X) (use effective contraception). Nursing mothers.

Boxed Warning:

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

MULTAQ 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 develops. Maintain normal serum K+ and Mg2+ levels. Monitor renal function periodically.

MULTAQ Classification:

Antiarrhythmic.

MULTAQ 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.

Adverse Reactions:

Diarrhea, nausea, abdominal pain, vomiting, asthenia; increased serum creatinine, liver injury, QT prolongation, interstitial lung disease, heart failure, hypokalemia, hypomagnesemia.

Metabolism:

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

Drug Elimination:

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

 

Generic Drug Availability:

NO

How Supplied:

Tabs—60, 180, 500