Drug Interaction Report

MONITOR: Coadministration with cenobamate may decrease the plasma concentrations and pharmacologic effects of CYP450 3A4 substrates. The proposed mechanism is cenobamate-mediated induction of the CYP450 3A4 isoenzyme. According to the manufacturer, multiple doses of cenobamate (200 mg once daily) reduced the mean Cmax and AUC of midazolam, a CYP450 3A4 substrate, by 61% and 72%, respectively.

MANAGEMENT: Caution is advised if cenobamate is used concomitantly with drugs that are substrates of CYP450 3A4, particularly those with a narrow therapeutic index. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever cenobamate is added to or withdrawn from therapy.

GENERALLY AVOID: Some beverages such as tonic water contain varying amounts of quinine. Coadministration of a single 430 mg dose of quinine has been shown to increase plasma concentrations of astemizole and its metabolite, desmethylastemizole. Elevated levels of these agents may cause a prolongation of the electrocardiographic QT interval and potentially fatal ventricular arrhythmias. Although pharmacokinetic data have indicated that the amounts of quinine in beverages (up to 80 mg quinine in 32 oz of tonic water) are not sufficient to produce a significant effect, the potential for an interaction exists if large amounts of tonic water are ingested. Also, grapefruit juice has been shown to inhibit CYP450 enzymes, which may lead to increased serum astemizole concentrations. The risk of life-threatening ventricular arrhythmias may be increased.

MANAGEMENT: Patients should be counseled to limit consumption of quinine-containing beverages and avoid grapefruit juice while they are taking astemizole.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.