Drug Interaction Report

MONITOR CLOSELY: Coadministration with cobicistat may significantly increase the plasma concentrations of certain antiarrhythmic agents such as amiodarone, bepridil, disopyramide, flecainide, propafenone, and quinidine. The mechanism involves inhibition of CYP450 2D6 (flecainide, propafenone) and/or 3A4 (amiodarone, bepridil, disopyramide, quinidine) metabolism, as cobicistat is a potent inhibitor of both isoenzymes. The interaction has not been specifically studied, but could conceivably lead to serious and/or life-threatening reactions including cardiac arrhythmias and other toxicities if levels are significantly increased. The use of these antiarrhythmic agents has been associated with dose-related prolongation of the QT interval, thus elevated plasma levels may potentiate the risk of ventricular arrhythmias such as ventricular tachycardia and torsade de pointes as well as cardiac arrest and sudden death.

MANAGEMENT: Caution is advised if cobicistat must be used concomitantly with antiarrhythmic agents that are primarily metabolized by CYP450 2D6 and/or 3A4. Pharmacologic response and plasma antiarrhythmic drug levels should be monitored more closely whenever cobicistat is added to or withdrawn from therapy, and the antiarrhythmic dosage adjusted as necessary.

MONITOR: Smoking cessation may lead to elevated plasma concentrations and enhanced pharmacologic effects of drugs that are substrates of CYP450 1A2 (and possibly CYP450 1A1) and/or certain drugs with a narrow therapeutic index (e.g., flecainide, pentazocine). One proposed mechanism is related to the loss of CYP450 1A2 and 1A1 induction by polycyclic aromatic hydrocarbons in tobacco smoke; when smoking cessation agents are initiated and smoking stops, the metabolism of certain drugs may decrease leading to increased plasma concentrations. The mechanism by which smoking cessation affects narrow therapeutic index drugs that are not known substrates of CYP450 1A2 or 1A1 is unknown. The clinical significance of this interaction is unknown as clinical data are lacking.

MANAGEMENT: Until more information is available, caution is advisable if smoking cessation agents are used concomitantly with drugs that are substrates of CYP450 1A2 or 1A1 and/or those with a narrow therapeutic range. Patients receiving smoking cessation agents may require periodic dose adjustments and closer clinical and laboratory monitoring of medications that are substrates of CYP450 1A2 or 1A1.