Drug Interaction Report

MONITOR: Coadministration with clobazam may increase the plasma concentrations of drugs that are primarily metabolized by CYP450 2D6. The mechanism is decreased clearance due to inhibition of CYP450 2D6 activity by clobazam. In an in vivo phenotypic cocktail drug-drug interaction study consisting of 18 subjects, dextromethorphan peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 59% and 90%, respectively, when a single dose of the CYP probe substrate cocktail containing dextromethorphan (CYP450 2D6 substrate), midazolam (CYP450 3A4 substrate), caffeine (CYP450 1A2 substrate), and tolbutamide (CYP450 2C9 substrate) was administered with repeated once-daily doses of clobazam 40 mg.

MANAGEMENT: Caution is advised if clobazam must be used concomitantly with medications that undergo metabolism by CYP450 2D6, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever clobazam is added to or withdrawn from therapy.

GENERALLY AVOID: Theoretically, the coadministration with grapefruit juice may increase the plasma concentrations of pimozide. The mechanism is decreased clearance of pimozide due to inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. The use of pimozide alone has been associated with dose-dependent prolongation of the QT interval. Although clinical data are lacking, this interaction may result in potentiation of the proarrhythmic effect of pimozide and consequently an increased risk of ventricular arrhythmias such as ventricular tachycardia and torsade de pointes. In addition, alcohol may potentiate some of the pharmacologic effects of pimozide. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: The manufacturer recommends avoiding grapefruit juice (and probably grapefruits) during therapy with pimozide. Patients should also be advised to avoid or limit consumption of alcohol.

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.