Drug Interaction Report

MONITOR: Coadministration with glycerol phenylbutyrate may decrease the systemic exposure to and therapeutic efficacy of drugs that are substrates of CYP450 3A4. Glycerol phenylbutyrate, its active moiety phenylbutyrate, and active metabolite phenylacetic acid are considered weak CYP450 3A4 inducers in vivo. In healthy subjects, coadministration of glycerol phenylbutyrate (4.4 g orally three times daily for 3 days) with oral midazolam, a sensitive CYP450 3A4 substrate, decreased the peak plasma concentration (Cmax) and systemic exposure (AUC) of midazolam of approximately 25% and 32%, respectively, and increased the mean Cmax and AUC of its metabolite 1-hydroxy midazolam, by 28% and 58%, respectively, compared to administration of midazolam alone. The clinical significance has not been established.

MANAGEMENT: Concomitant use of glycerol phenylbutyrate with sensitive CYP450 3A4 substrates (e.g., oral midazolam) or CYP450 3A4 substrates with a narrow therapeutic index (e.g., alfentanil, oral contraceptives, quinidine, and cyclosporine) should be done with caution and monitoring for reduced efficacy. Dosage adjustment as well as clinical and laboratory monitoring may be appropriate whenever glycerol phenylbutyrate is added to or withdrawn from therapy.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.