Drug Interactions between atazanavir / cobicistat and donepezil

MONITOR: Since acetylcholinesterase inhibitors can cause bradycardia and heart block due to vagotonic effects on the sinoatrial and atrioventricular nodes, additive effects may occur with other agents that also possess bradycardic effects such as beta-blockers, calcium channel blockers, digitalis, some protease inhibitors (atazanavir, lopinavir-ritonavir, saquinavir), amiodarone, dronedarone, moricizine, lacosamide, and mefloquine. A group of French investigators conducted a retrospective analysis of spontaneous reports in the French Pharmacovigilance Database concerning adverse drug reactions (ADRs) associated with use of the acetylcholinesterase inhibitors donepezil, galantamine, and rivastigmine. Two hundred and five cases of potential drug-drug interaction with bradycardic drugs (beta-blockers, calcium channel blockers, amiodarone, digoxin) were identified, 73 of which were associated with serious ADRs including five deaths due to syncope, bradycardia, arrhythmia, or cardiac arrest. However, no details on the individual cases such as patient characteristics or concomitant risk factors were provided, making the contribution of a potential drug interaction difficult to evaluate. The remainder of the cases were of no apparent clinical consequences. In contrast, a phase III trial of donepezil consisting of 1035 patients reported no significant increase in risk ratios for bradycardia during concomitant use of beta-blockers, nondihydropyridine calcium channel blockers, or digoxin.

MANAGEMENT: Caution is advised if acetylcholinesterase inhibitors are used concomitantly with bradycardic drugs. Patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease, or cardiomyopathies may be at increased risk for developing cardiac conduction disturbances and atrioventricular block. Patients should be advised to notify their physician if they experience dizziness, lightheadedness, fainting, or irregular heartbeat.

Coadministration with inhibitors of CYP450 2D6 and/or 3A4 may increase the plasma concentrations of donepezil, which is primarily metabolized by these isoenzymes. In a 7-day crossover study in 18 healthy volunteers, the potent CYP450 3A4 inhibitor ketoconazole (200 mg once daily) increased the mean peak plasma concentration (Cmax) and systemic exposure (AUC) of donepezil (5 mg once daily) by approximately 36% each. The clinical relevance of these increases is unknown. A prolonged duration of monitoring for adverse effects may be required depending on the elimination half-life of the concomitant drug. For example, it should be noted that rolapitant, a moderate CYP450 2D6 inhibitor, can increase plasma concentrations and the risk of adverse effects of donepezil for at least 28 days after administration of rolapitant.