Multaq (dronedarone)

Multaq is a prescription medicine used to lower the chance that you will need to go into the hospital for atrial fibrillation. It is meant for people who have had certain types of atrial fibrillation (paroxysmal or persistent AF) in the past, but are now in normal rhythm.

It is not known if Multaq is safe and effective in children younger than age 18 years old.

INCREASED RISK OF DEATH, STROKE AND HEART FAILURE IN PATIENTS WITH DECOMPENSATED HEART FAILURE OR PERMANENT ATRIAL FIBRILLATION

In patients with symptomatic heart failure and recent decompensation requiring hospitalization or NYHA Class IV heart failure; Multaq doubles the risk of death. Multaq is contraindicated in patients with symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV heart failure.

In patients with permanent atrial fibrillation, Multaq doubles the risk of death, stroke and hospitalization for heart failure. Multaq is contraindicated in patients in atrial fibrillation (AF) who will not or cannot be cardioverted into normal sinus rhythm.

Multaq may cause serious side effects, including:

• Slowed heartbeat (bradycardia)
• Inflammation of the lungs, including scarring and thickening. Call your doctor if you develop shortness of breath or a dry cough during treatment with Multaq.
• Low potassium and magnesium levels in your blood. This can happen if you take certain water pills (diuretics) during treatment with Multaq. Your doctor may check you for this problem before and during treatment.
• Changes in kidney function blood tests after starting Multaq. Your doctor may check you for this during treatment.

The most common side effects of Multaq include:

• diarrhea
• nausea
• vomiting
• stomach area (abdominal) pain
• indigestion
• feeling tired and weak
• skin problems such as redness, rash, and itching

Tell your doctor about any side effect that bothers you or that does not go away. These are not all the possible side effects of Multaq. For more information ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

The recommended dosage of Multaq is 400 mg twice daily in adults. Multaq should be taken as one tablet with the morning meal and one tablet with the evening meal.

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

Pharmacodynamic Interactions

Drugs Prolonging The QT Interval (Inducing Torsade de Pointes)

• Coadministration of drugs prolonging the QT interval (such as certain phenothiazines, tricyclic antidepressants, certain macrolide antibiotics, and Class I and III antiarrhythmics) is contraindicated because of the potential risk of torsade de pointes-type ventricular tachycardia.

Digoxin

• In the ANDROMEDA (patients with recently decompensated heart failure) and PALLAS (patients with permanent AF) trials baseline use of digoxin was associated with an increased risk of arrhythmic or sudden death in dronedarone-treated patients compared to placebo.
• In patients not taking digoxin, no difference in risk of sudden death was observed in the dronedarone versus placebo groups.
• Digoxin can potentiate the electrophysiologic effects of dronedarone (such as decreased AV-node conduction). Dronedarone increases exposure to digoxin.
• Consider discontinuing digoxin. If digoxin treatment is continued, halve the dose of digoxin, monitor serum levels closely, and observe for toxicity.

Calcium Channel Blockers

• Calcium channel blockers with depressant effects on the sinus and AV nodes could potentiate dronedarone's effects on conduction.
• Give a low dose of calcium channel blockers initially and increase only after ECG verification of good tolerability.

Beta-Blockers

• In clinical trials, bradycardia was more frequently observed when dronedarone was given in combination with beta-blockers.
• Give a low dose of beta-blockers initially, and increase only after ECG verification of good tolerability.

Effects Of Other Drugs On Dronedarone

Ketoconazole And Other Potent CYP 3A Inhibitors

• Concomitant use of ketoconazole as well as other potent CYP 3A inhibitors such as itraconazole, voriconazole, ritonavir, clarithromycin, and nefazodone is contraindicated because exposure to dronedarone is significantly increased.

Grapefruit Juice

• Patients should avoid grapefruit juice beverages while taking Multaq because exposure to dronedarone is significantly increased.

Rifampin And Other CYP 3A Inducers

• Avoid rifampin or other CYP 3A inducers such as phenobarbital, carbamazepine, phenytoin, and St. John's wort because they decrease exposure to dronedarone significantly.

Calcium Channel Blockers

• Verapamil and diltiazem are moderate CYP 3A inhibitors and increase dronedarone exposure.
• Give a low dose of calcium channel blockers initially and increase only after ECG verification of good tolerability.

Effects Of Dronedarone On Other Drugs

Simvastatin

• Dronedarone increased simvastatin/simvastatin acid exposure. Avoid doses greater than 10 mg once daily of simvastatin.

Other Statins

• Because of multiple mechanisms of interaction with statins (CYPs and transporters), follow statin label recommendations for use with CYP 3A and P-gp inhibitors such as dronedarone.

Calcium Channel Blockers

• Dronedarone increased the exposure of calcium channel blockers (verapamil, diltiazem or nifedipine).
• Give a low dose of calcium channel blockers initially and increase only after ECG verification of good tolerability.

Sirolimus, Tacrolimus, And Other CYP3A Substrates With Narrow Therapeutic Range

• Dronedarone can increase plasma concentrations of tacrolimus, sirolimus, and other CYP 3A substrates with a narrow therapeutic range when given orally. Monitor plasma concentrations and adjust dosage appropriately.

Beta-Blockers And Other CYP2D6 Substrates

• Dronedarone increased the exposure of propranolol and metoprolol.
• Give low doses of beta-blockers initially, and increase only after ECG verification of good tolerability.
• Other CYP2D6 substrates, including other beta-blockers, tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs) may have increased exposure upon coadministration with dronedarone.

P-glycoprotein Substrates

Digoxin

• Dronedarone increased digoxin exposure by inhibiting the P-gp transporter. Consider discontinuing digoxin. If digoxin treatment is continued, halve the dose of digoxin, monitor serum levels closely, and observe for toxicity.

Dabigatran

• Exposure to dabigatran is higher when it is administered with dronedarone than when it is administered alone.
• Other P-gp substrates are expected to have increased exposure when coadministered with dronedarone.

Warfarin

• When coadministered with dronedarone exposure to S-warfarin was slightly higher than when warfarin was administered alone. There were no clinically significant increases in INR.
• More patients experienced clinically significant INR elevations (≥ 5) usually within 1 week after starting dronedarone versus placebo in patients taking oral anticoagulants in ATHENA. However, no excess risk of bleeding was observed in the dronedarone group.
• Postmarketing cases of increased INR with or without bleeding events have been reported in warfarin-treated patients initiated on dronedarone. Monitor INR after initiating dronedarone in patients taking warfarin.

• Multaq may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
• It is not known whether Multaq is excreted in human milk. Dronedarone and its metabolites are excreted in rat milk.
• During a prenatal and postnatal study in rats, maternal dronedarone administration was associated with minor reduced body-weight gain in the offspring.
• Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Multaq, discontinue nursing or discontinue the drug.