What are the side effects of Multaq (dronedarone)?

Multaq (Dronedarone) Side Effects

Multaq causes gastrointestinal side effects in the majority of patients, with diarrhea (9%), nausea (5%), and abdominal pain (4%) being most common, and carries serious risks including potentially fatal hepatotoxicity, increased mortality in heart failure patients, and bradycardia requiring careful monitoring. 1

Common Side Effects (Occurring in >1% of Patients)

Gastrointestinal Effects

• Diarrhea occurs in 9% of patients (compared to 6% with placebo), making it the most frequent adverse effect 1
• Nausea affects 5% of patients, with vomiting in 2% and dyspeptic symptoms in 2% 1
• Abdominal pain develops in 4% of patients taking dronedarone 1
• These gastrointestinal effects are dose-related and represent the most common reason for drug discontinuation (3.2% vs 1.8% placebo) 2, 1

Cardiovascular Effects

• Bradycardia occurs in 3% of patients (vs 1% placebo), requiring monitoring and potential dose adjustment 1
• QT interval prolongation is common, with 28% of patients experiencing QTc prolongation compared to 19% on placebo 1
• Dronedarone induces an average 10 ms QTc prolongation, though much greater effects have been observed 1
• Discontinue dronedarone if QTc Bazett interval reaches ≥500 ms 1

General and Dermatologic Effects

• Asthenic conditions (weakness/fatigue) affect 7% of patients compared to 5% on placebo 1
• Skin reactions including rashes (generalized, macular, maculo-papular, erythematous), pruritus, eczema, and dermatitis occur in 5% of patients 1
• Photosensitivity reactions have been reported at <1% incidence 1

Laboratory Abnormalities

• Early increases in creatinine ≥10% occur in 51% of patients (vs 21% placebo), typically reaching plateau after 7 days 1
• These creatinine elevations result from inhibition of tubular secretion and are generally reversible upon discontinuation 1
• Larger increases in creatinine and blood urea nitrogen have been reported postmarketing, requiring periodic renal function monitoring 1

Serious and Life-Threatening Side Effects

Hepatotoxicity (Black Box Warning)

• Dronedarone can cause severe, potentially fatal hepatic injury including acute liver failure requiring transplantation 1
• Two cases of acute hepatic failure occurred in clinical trials, both requiring transplantation 1
• Obtain hepatic enzymes before treatment and monitor periodically, especially during the first 6 months 1
• Promptly discontinue if hepatic injury is suspected and test AST, ALT, alkaline phosphatase, and bilirubin 1
• Do not restart dronedarone without another explanation for liver injury 1
• Fatal hepatotoxicity has been specifically documented with dronedarone 2

Heart Failure and Mortality Risk (Black Box Warning)

• Dronedarone is contraindicated in patients with NYHA Class IV heart failure or Class II-III with recent decompensation 1
• Dronedarone doubled the risk of death in patients with severe heart failure in the ANDROMEDA trial 1
• Dronedarone doubled mortality in patients with permanent atrial fibrillation in the PALLAS trial 1
• New or worsening heart failure has been reported in postmarketing surveillance 1

Pulmonary Toxicity

• Postmarketing cases of interstitial lung disease, pneumonitis, and pulmonary fibrosis have been reported 1
• Any patient reporting worsening dyspnea or cough should be promptly assessed for pulmonary toxicity 2

Cardiovascular Proarrhythmia

• Dronedarone can cause Torsade de Pointes-type ventricular tachycardia, particularly when combined with other QT-prolonging drugs 1
• Heart block occurs in 1-3% of patients 2
• Amiodarone-induced proarrhythmia occurs at <1% annually, and similar rates are expected with dronedarone 2

Drug Interactions and Contraindications

Absolute Contraindications

• Strong CYP3A4 inhibitors are contraindicated: ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, nefazodone, telithromycin 1
• Dronedarone is contraindicated with dabigatran due to strong effects on plasma levels 2
• QT-prolonging drugs including phenothiazines, tricyclic antidepressants, certain macrolides, and Class I/III antiarrhythmics are contraindicated 1
• Cyclosporine is contraindicated due to drug interaction potential 1

Significant Drug Interactions Requiring Caution

• Digoxin dose must be halved when co-administered with dronedarone, with close monitoring of serum levels 2, 1
• Simvastatin doses >10 mg daily and lovastatin >20 mg daily are not recommended when combined with dronedarone due to increased statin exposure and rhabdomyolysis risk 2
• Dronedarone has moderate interaction potential with edoxaban, requiring caution or dose reduction 2
• Verapamil and diltiazem should be initiated at low doses with ECG monitoring when combined with dronedarone 1

P-glycoprotein and CYP3A4 Effects

• Dronedarone is a moderate CYP3A4 and CYP2D6 inhibitor and P-glycoprotein inhibitor 1
• Avoid grapefruit juice, which increases dronedarone blood levels and side effect risk 1

Special Populations and Monitoring

Women of Childbearing Potential

• Dronedarone is contraindicated in pregnancy due to demonstrated fetal harm in animal studies 1
• Effective contraception is required for premenopausal women taking dronedarone 1
• Dronedarone is contraindicated during breastfeeding 1

Electrolyte Monitoring

• Hypokalemia and hypomagnesemia may occur with concomitant potassium-depleting diuretics 1
• Maintain potassium and magnesium within normal range before and during dronedarone administration 1
• Monitor serum potassium and magnesium levels, particularly with diuretic use 2

Comparative Safety Profile

• Dronedarone has less organ toxicity than amiodarone but is also less effective for rhythm control 3, 4, 5
• Unlike amiodarone, dronedarone lacks iodine and does not cause thyroid toxicity or the full spectrum of amiodarone's organ toxicities 3, 4
• In head-to-head comparison, dronedarone caused more gastrointestinal disorders but fewer thyroid disorders, neurological disorders, and hypersensitivity reactions than amiodarone 6

Clinical Monitoring Algorithm

Before initiating dronedarone:

• Obtain baseline ECG, hepatic enzymes (AST, ALT, alkaline phosphatase, bilirubin), serum creatinine, and electrolytes (potassium, magnesium) 1
• Confirm absence of NYHA Class IV heart failure or recent decompensation 1
• Verify patient is not in permanent atrial fibrillation 1

During treatment:

• Monitor hepatic enzymes periodically, especially during first 6 months 1
• Monitor renal function periodically for creatinine increases beyond expected 0.1 mg/dL elevation 1
• Maintain normal potassium and magnesium levels throughout treatment 1
• Discontinue immediately if QTc ≥500 ms or signs of hepatotoxicity develop 1