Drug Interaction Report

MONITOR: Coadministration with obeticholic acid may increase the plasma concentrations of drugs that are substrates of the CYP450 1A2 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 1A2 activity by obeticholic acid and its glycine and taurine conjugates. When a single 200 mg dose of caffeine (a probe CYP450 1A2 substrate) was administered with obeticholic acid 10 mg once daily, caffeine peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 6% and 42%, respectively.

MANAGEMENT: Caution is advised when obeticholic acid is prescribed with drugs that undergo metabolism by CYP450 1A2, particularly those with a narrow therapeutic range such as theophylline or tizanidine. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever obeticholic acid is added to or withdrawn from therapy.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.