Drug Interaction Report

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 Lacosamide dose adjustments may be necessary whenever a strong CYP450 3A4 and/or 2C9 inhibitor is added to or withdrawn from therapy in patients with renal and/or hepatic impairment.

Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.