Drug Interactions between Phenytoin Sodium, Extended Release and risperidone

ADJUST DOSE: Coadministration with potent inducers of CYP450 3A4 and/or P-glycoprotein (P-gp) may decrease the plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone. Both risperidone and 9-hydroxyrisperidone are substrates of the CYP450 3A4 isoenzyme and P-gp efflux transporter. Since 9-hydroxyrisperidone has similar pharmacological activity as the parent drug, the clinical effect of risperidone results from the combined plasma concentrations of both entities. When oral risperidone 3 mg twice daily was coadministered with the potent CYP450 3A4 and P-gp inducer carbamazepine at an average dosage of 573 mg/day (+/-168 mg/day) in study patients, steady-state peak plasma concentration (Cmax) and systemic exposure (AUC) values for the total active moiety (risperidone plus 9-hydroxyrisperidone) decreased by 45% and 49%, respectively. Plasma concentrations of carbamazepine did not appear to be affected. Rifampin, another potent 3A4 and P-gp inducer, decreased the Cmax and AUC of the total active moiety by 41% and 45%, respectively, following a single 1 mg oral dose of risperidone. The interaction was suspected in a case report of two patients treated with risperidone who developed parkinsonian symptoms several weeks following the discontinuation of carbamazepine. The symptoms resolved completely in both cases within a week after risperidone dosage was reduced. In addition, when two or more medications with similar adverse effect profiles are given concurrently, the likelihood of experiencing these adverse reactions may be increased. For example, coadministration with other agents that can prolong the QT interval (e.g., apalutamide, encorafenib, enzalutamide) may result in additive effects and an increased risk of ventricular arrhythmias like torsade de pointes.

MANAGEMENT: When risperidone is administered orally, some authorities recommend increasing (up to double) the usual dosage gradually (e.g., over 1 to 2 weeks) following the addition of a potent CYP450 3A4/P-gp inducer. For extended-release injectable formulations of risperidone, patients should be closely monitored for the first 4 to 8 weeks after starting treatment with a potent CYP450 3A4/P-gp inducer. A dosage increase or supplemental oral risperidone therapy may be required in some cases. Changes in efficacy and safety should be carefully monitored with any dosage adjustment. If the CYP450 3A4 inducer also carries a risk of prolonging the QT interval, then obtaining more frequent electrocardiograms (ECGs) to monitor the QT interval may be advisable. Patients should be counseled to seek immediate medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, syncope, palpitations, irregular heartbeat, and/or shortness of breath. Upon discontinuation of the inducer, risperidone dosage should be reassessed and readjusted accordingly for the anticipated increase in plasma concentrations of risperidone and 9-hydroxyrisperidone. The prescribing information for individual risperidone products should be consulted for specific recommendations regarding concomitant use with potent CYP450 3A4 inducers.