Drug Interaction Report

MONITOR: Coadministration with dronedarone may increase the plasma concentrations of some beta-blockers. The mechanism is dronedarone inhibition of CYP450 2D6, the isoenzyme responsible for the metabolic clearance of beta-blockers like metoprolol and propranolol. According to the product labeling, dronedarone increased metoprolol systemic exposure (AUC) by 1.6-fold and propranolol AUC by 1.3-fold. Pharmacodynamically, beta-blockers can potentiate the depressant effects of dronedarone on the sinus and AV nodes. In clinical trials, bradycardia was more frequently observed when dronedarone was given in combination with beta-blockers.

MANAGEMENT: Caution is advised if dronedarone is coadministered with a beta-blocker, including ophthalmic formulations. The dosage of the beta-blocker should start low and increased only after ECG verification of good tolerability. Patients should be advised to promptly report potential symptoms of toxicity such as excessive fatigue, fainting, difficulty breathing, chest pain or tightness, bradycardia, or arrhythmia.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of dronedarone. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. According to the product labeling, administration with grapefruit juice resulted in a 2.5-fold increase in dronedarone peak plasma concentration and a 3-fold increase in systemic exposure. Because dronedarone is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of dronedarone. The mechanism of interaction is unknown. According to the product labeling, the absolute bioavailability of dronedarone increases from about 4% when administered in the fasted state to approximately 15% when administered with a high-fat meal.

MANAGEMENT: Patients treated with dronedarone should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Dronedarone should be taken twice daily with the morning and evening meals.

MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. Patients should also avoid driving or operating hazardous machinery until they know how the medications affect them.