Drug Interaction Report

MONITOR: Coadministration with oxcarbazepine may decrease the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is accelerated clearance due to induction of CYP450 3A4 activity by oxcarbazepine. In one study, administration of a single 600 mg dose of oxcarbazepine to eight healthy male volunteers had no effect on the pharmacokinetics of the CYP450 3A4 substrate felodipine (10 mg once daily), while repeated doses (450 mg twice a day) reduced the felodipine peak plasma concentration (Cmax) and systemic exposure (AUC) by 34% and 28%, respectively. Likewise, in a case study of a kidney transplant patient receiving cyclosporine 270 mg/day, investigators reported that cyclosporine trough concentrations declined to subtherapeutic levels approximately two weeks after the addition of oxcarbazepine. Trough concentrations returned to therapeutic range following an increase of the cyclosporine dosage to 290 mg/day and a reduction of the oxcarbazepine dosage from 750 mg/day to 600 mg/day. These results indicate that enzymatic induction occurs after multiple doses of oxcarbazepine.

MANAGEMENT: Caution is advised if oxcarbazepine must be used concurrently with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever oxcarbazepine is added to or withdrawn from therapy. When initiating treatment or changing the dosage, it may take 2 to 3 weeks to reach the corresponding level of induction. Similarly, the induction is expected to gradually decrease over 2 to 3 weeks following discontinuation of oxcarbazepine.

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.