s.
Following a single subcutaneous injection of PERSERIS, the apparent terminal half-life of risperidone ranges between 9 and 11 days on average. This half-life is related to the slow release of risperidone from the subcutaneous depot and subsequent absorption of risperidone into the systemic circulation. The mean apparent terminal half-life ranges between 8 to 9 days for both 9-hydroxyrisperidone and total active moiety, on average.
Drug Interaction Studies
No specific drug interaction studies have been performed with PERSERIS. The drug interaction data provided in this section is based on studies with oral risperidone. Effects of other drugs on the exposures of risperidone, 9-hydroxyrisperidone and total active moiety as well as the effects of risperidone on the exposures of other drugs is summarized below.
Effects of Other Drugs on Risperidone, 9-hydroxyrisperidone and Total Active Moiety Pharmacokinetics
Strong CYP2D6 Inhibitors (Fluoxetine and Paroxetine)
Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily), potent CYP2D6 inhibitors, have been shown to increase the plasma concentration of risperidone by 2.5- to 2.8-fold and 3- to 9-fold, respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied.
Moderate CYP3A4 Inhibitor (Erythromycin)
There were no significant interactions between oral risperidone and erythromycin, a moderate CYP3A4 inhibitor.
Strong CYP3A4 Inducer (Carbamazepine)
Carbamazepine co-administration with oral risperidone decreased the steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine did not appear to be affected. Co-administration of other known CYP3A4 enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may cause similar decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of PERSERIS.
Amitriptyline, Cimetidine, Ranitidine, Clozapine, Topiramate
Clinically meaningful pharmacokinetic interaction between PERSERIS and other drugs, such as amitriptyline, cimetidine, ranitidine and clozapine, is not expected.
Amitriptyline did not affect the pharmacokinetics of risperidone or of risperidone and 9-hydroxyrisperidone combined following concomitant administration with oral risperidone.
Cimetidine and ranitidine increased the bioavailability of oral risperidone by 64% and 26%, respectively. However, cimetidine did not affect the AUC of risperidone and 9-hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and 9-hydroxyrisperidone combined by 20%.
Chronic administration of clozapine with oral risperidone have shown to affect the clearance of risperidone, however, clinical relevance is unknown.
There was no clinically relevant effect of oral risperidone (1 to 6 mg/day) on the pharmacokinetics of topiramate 400 mg/day.
Effects of Oral Risperidone on Pharmacokinetics of Other Drugs
Lithium
Repeated doses of oral risperidone (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (Cmax) of lithium (n = 13).
Valproate
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