Drug Interactions between carbamazepine and paliperidone

ADJUST DOSE: Coadministration with dual potent inducers of CYP450 3A4 and P-glycoprotein (P-gp) may decrease the plasma concentrations of paliperidone. In vitro studies suggest that CYP450 2D6 and 3A4 are involved in paliperidone metabolism. However, in vivo data indicate that these isoenzymes play a limited role in the overall elimination of paliperidone and contribute to only a small fraction of total body clearance. Approximately 60% of a paliperidone dose is excreted unchanged in the urine, which may involve active tubular secretion mediated by P-gp efflux transporter. When paliperidone 6 mg (extended-release) once daily was coadministered with the potent CYP450 3A4 and P-gp inducer carbamazepine at a dosage of 200 mg twice daily, mean steady-state paliperidone peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by approximately 37%. The decrease in AUC was largely caused by a 35% increase in renal clearance of paliperidone, which may be attributable to induction of P-gp in renal proximal tubules by carbamazepine. In general, P-gp induction may take 2 to 3 weeks to reach steady state following initiation of an inducer and a similar length of time to wear off following withdrawal of the inducer. Injectable paliperidone has not been studied in combination with carbamazepine or other dual CYP450 3A4/P-gp inducers. In a retrospective study using data from a therapeutic drug monitoring database, the dose-adjusted serum concentrations of paliperidone were reportedly more than 50% lower in three patients who were taking carbamazepine compared to the general study population.

MANAGEMENT: When paliperidone is administered orally, the prescribing information recommends re-evaluating the dosage and increasing if necessary following the addition of a dual potent CYP450 3A4 and P-gp inducer. For patients receiving extended-release injectable formulations of paliperidone, concomitant use of potent inducers should be avoided. If coadministration is required, consideration should be given to use of oral extended-release paliperidone. Changes in efficacy and safety should be carefully monitored with any dosage adjustment. Upon discontinuation of the inducer, paliperidone dosage should be reassessed and readjusted accordingly based on clinical response. The prescribing information for individual paliperidone products should be consulted for specific recommendations regarding concomitant use with potent CYP450 3A4 inducers.