Drug Interactions between atazanavir / cobicistat and lacosamide

MONITOR CLOSELY: Atazanavir has been shown to prolong the PR interval of the electrocardiogram in some patients. Theoretically, coadministration with other agents that prolong the PR interval (e.g., beta blockers, digoxin, lacosamide, mefloquine, verapamil) may result in elevated risk of conduction disturbances and atrioventricular block. In a pharmacokinetic study, no substantial additive effect on the PR interval was observed during coadministration of atazanavir (400 mg once a day) and atenolol (50 mg once a day). However, an additive effect cannot be excluded because data are limited and atazanavir has not been studied in combination with other agents that prolong the PR interval.

MANAGEMENT: Caution is advised if atazanavir is used concomitantly with other agents that prolong the PR interval, particularly those that are metabolized by CYP450 3A4 (e.g., verapamil), since atazanavir is an inhibitor of that isoenzyme.

MONITOR: Coadministration of strong inhibitors of CYP450 3A4 and/or CYP450 2C9 in patients with renal or hepatic impairment may significantly increase lacosamide plasma concentrations and increase the risk of lacosamide toxicity. The presumed mechanism is additive reduction in lacosamide clearance. Pharmacokinetic studies have shown lacosamide systemic exposure (AUC) may increase by 25% to 60% in patients with renal and/or hepatic impairment. Additional increases in lacosamide plasma concentrations are possible due to inhibition of the CYP450 3A4 and 2C9-mediated formation of O-desmethyl metabolite (inactive). Approximately 30% of a lacosamide dose is excreted as O-desmethyl metabolite in the urine. This interaction has not been established in vivo but is possible based on in vitro data.

MANAGEMENT: For patients with renal and/or hepatic impairment concomitantly receiving a strong CYP450 3A4 and/or CYP450 2C9 inhibitor, lacosamide dose reductions in addition to those recommended for renal and/or hepatic impairment may be necessary. Manufacturer labeling should be consulted for dose recommendations in renal and/or hepatic impairment. Patients should be advised to notify their physician if they experience dizziness, lightheadedness, fainting, or irregular heartbeat. Lacosamide dose adjustments may be necessary whenever a strong CYP450 3A4 and/or 2C9 inhibitor is added to or withdrawn from therapy in patients with renal and/or hepatic impairment.