Multaq (Dronedarone)

How does Multaq work?

The exact mechanism of Multaq is not clearly defined. Multaq exhibits antiarrhythmic properties from all four Vaughan-Williams classifications, but the contributions of each activity are unknown. Multaq regulates heart rhythm through a combination of inhibiting sodium channels (Class I), beta-1 receptors (Class II), potassium channels (Class III), and calcium channels (Class IV).

Dosage and How to Use

Multaq is only available in 400 mg tablets.

It is recommended to take Multaq (400 mg) twice daily, one tablet with the morning meal and one tablet with the evening meal.

Treatment with Class I or III antiarrhythmics or medications that are strong CYP3A inhibitors must be stopped before taking Multaq.

Storage

Store at 25°C (77°F); Temperature excursions between 15°C to 30°C (59°F to 86°F) are permitted.

Overdose

If an overdose of Multaq is ingested, seek medical attention immediately. Overdosage treatment should be supportive and focused on relieving the patient’s symptoms. There is no antidote available for Multaq overdosage, and it is not known if Multaq or its metabolites are removed through dialysis.

Side Effects

The most common side effects of Multaq are:

• Diarrhea
• Nausea
• Vomiting
• Abdominal pain
• Indigestion
• Weakness or tiredness
• Skin redness or itching

Rare but serious side effects of Multaq include:

• Slowed heartbeat
• Inflammation, scarring, or thickening of the lungs
  • Contact your doctor immediately if you experience shortness of breath or a dry cough.
• Low potassium or magnesium levels
  • Low potassium or magnesium levels can happen if taking diuretics during treatment with Multaq.
• Changes in kidney function blood tests
• Liver problems, including life-threatening liver failure
  • Contact your doctor immediately if you notice one of the following signs of liver failure:
    • Nausea, vomiting, or loss of appetite
    • Fever or feeling unwell
    • Unusual tiredness
    • Yellowing of the skin or eyes
    • Dark urine
    • Pain in the upper right area of the stomach

This is not a complete list of all possible side effects. Please contact your doctor or pharmacist for more information.

Warnings & Precautions

Boxed Warnings

Cardiovascular Death in NYHA Class IV or Decompensated Heart Failure

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

Cardiovascular Death, Hospitalization for Heart Failure, and Stroke in Patients with Permanent Atrial Fibrillation

• Multaq increases the risk of cardiovascular death, heart failure events, and stroke in patients with permanent atrial fibrillation. Patients taking Multaq need monitoring of cardiac rhythm every three months at a minimum. If indicated, cardiovert the patient to a normal sinus rhythm or discontinue Multaq. Multaq is contraindicated if not in normal sinus rhythm.

Other Warnings & Precautions

New Onset or Worsening Heart Failure

• New onset or worsening heart failure in patients taking Multaq has been reported. Patients should immediately contact their doctor if they develop any of the following signs of heart failure: weight gain, edema, or shortness of breath. If heart failure develops or worsens, Multaq should be discontinued.

Liver injury

• Hepatocellular liver injury, including liver failure requiring transplant, has been reported in patients taking Multaq. Patients should contact their doctor immediately if they experience any of the following signs of liver dysfunction: anorexia, nausea, vomiting, fever, fatigue, pain in the upper right area of the stomach, yellowing of the skin or eyes, itchy skin, or dark urine. If liver injury is suspected, Multaq should be discontinued, and liver function tests should be collected.

Pulmonary toxicity

• Interstitial lung disease, including pneumonitis and pulmonary fibrosis, has been reported in patients taking Multaq. Patients must contact their doctor if they experience shortness of breath or a dry cough. Multaq should be discontinued if pulmonary damage is confirmed.

Hypokalemia and Hypomagnesemia with Potassium-Depleting Diuretics

• Hypokalemia and hypomagnesemia may occur in patients taking diuretics during treatment with Multaq. Potassium and magnesium levels should be monitored in these patients.

QT Interval Prolongation

• Multaq induces a moderate (average of 10 ms) QTc prolongation. If the QTc Bazett interval exceeds 500 ms, Multaq should be discontinued.

Renal impairment and Failure

• Increased serum creatinine, pre-renal azotemia, and acute renal failure have been reported in patients taking Multaq. The effects are often reversible, but renal function should be monitored periodically.

Women of Childbearing Potential

• Women of childbearing potential must use effective contraception while taking Multaq due to the risk of fetal harm.

Drug Interactions and Other Interactions

Pharmacodynamic Interactions

• Drugs prolonging the QT interval (leading to Torsades de Pointes)
  • Coadministration with other QT-prolonging drugs (certain phenothiazines, tricyclic antidepressants, macrolide antibiotics, Class I or III antiarrhythmics) is contraindicated due to the risk of Torsades de Pointes.

• Digoxin
  • Patients taking digoxin during treatment with Multaq have shown an increased risk of arrhythmic or sudden cardiac death. Digoxin can exacerbate the bradycardiac effects of Multaq. Multaq also increases the patient’s exposure to digoxin. Consider stopping digoxin, but if continued, reduce the digoxin dose by 50%.

• Calcium channel blockers
  • Calcium channel blockers that slow sinus and AV node conduction may be additive to the effects of Multaq. Start with a low-dose calcium channel blocker and only increase after an ECG showing favorable tolerability.

• Beta-blockers
  • Bradycardia is more common when patients are taking beta-blockers during treatment with Multaq. Start with a low-dose beta-blocker and only increase after an ECG showing favorable tolerability.

Pharmacokinetic Interactions

• Ketoconazole and other strong CYP3A inhibitors
  • Ketoconazole and other strong CYP3A inhibitors such as itraconazole, voriconazole, ritonavir, clarithromycin, and nefazodone are contraindicated because they significantly increase exposure to Multaq.

• Grapefruit juice
  • Patients should avoid grapefruit juice due to increased exposure to Multaq.

• Rifampin and other CYP3A inducers
  • Patients should avoid rifampin and other CYP3A inducers (phenobarbital, carbamazepine, phenytoin, and St. John’s wort) because they significantly reduce exposure to Multaq.

• Calcium channel blockers
  • Verapamil and Diltiazem are moderate inhibitors of CYP3A and increase exposure to Multaq. Start with a low-dose calcium channel blocker and only increase after an ECG showing favorable tolerability.

Effect of Multaq on Other Drugs

• Simvastatin
  • Multaq increases simvastatin exposure. The maximum simvastatin dosage is 10 mg when a patient is on Multaq treatment.
• Other statins
  • There are multiple mechanisms of interaction between statins and Multaq. Please follow statin label recommendations for use with CYP3A and P-gp inhibitors like Multaq.

• Calcium channel blockers
  • Multaq increases exposure to calcium channel blockers. Start with a low-dose calcium channel blocker and only increase after an ECG showing favorable tolerability.

• Sirolimus, tacrolimus, and other CYP3A substrates with a narrow therapeutic window
  • Multaq can increase exposure to sirolimus, tacrolimus, and other CYP3A substrates with a narrow therapeutic window. Monitor plasma concentrations and adjust the dosage if needed.

• Beta-blockers and other CYP2D6 substrates
  • Multaq increases exposure to beta-blockers. Start with a low-dose beta-blocker and only increase after an ECG showing favorable tolerability. Other CYP2D6 substrates may have increased exposure when coadministered with Multaq.

• P-glycoprotein (P-gp) substrates
  • Digoxin
  • Multaq increases digoxin exposure by inhibiting the P-gp transporter. Consider discontinuing digoxin, but if digoxin is continued, decrease the dose by 50%.
  • Dabigatran
    • Multaq increases dabigatran exposure by inhibiting the P-gp transporter. Patients taking dabigatran concomitantly with Multaq should be dosed based on creatine clearance (CrCL): CrCL 30-50 mL/min should receive 75 mg of dabigatran twice daily; CrCL 15-30 mL/min should not use dabigatran.
• Warfarin
  • When warfarin was administered during Multaq treatment, there was slightly increased exposure to S-warfarin. There have been cases of increased INR with or without bleeding.

Contraindications

Multaq is contraindicated in the following scenarios:

• Permanent atrial fibrillation (when normal sinus rhythm cannot be restored)
• Symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV symptoms
• Second or third-degree AV block or sick sinus syndrome (except when used in combination with a functioning pacemaker)
• Heart rate < 50 bpm
• Concomitant use of strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, and ritonavir)
• Liver or lung toxicity experienced with prior use of amiodarone
• QTc Bazett interval of ?500 ms or PR interval >280 ms
• Severe hepatic impairment
• Pregnancy
• Nursing mothers
• Hypersensitivity to dronedarone or any excipient in the formulation