ailable as an extended release injectable suspension, for subcutaneous use, in the following strengths of risperidone: 90 mg and 120 mg.
Table 6. PERSERIS Constituted Product Delivered Mass
Component PERSERIS 90 mg PERSERIS 120 mg
Risperidone 90 mg 120 mg
PLGH 228 mg 304 mg
N-methyl-pyrrolidine 282 mg 376 mg
Total mass 600 mg 800 mg
Total volume 0.6 mL 0.8 mL
PLGH poly D,L(lactide co-glycolide); 80:20 molar ratio of lactide to glycolide
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism of action of risperidone, in schizophrenia, is unclear. The drug's therapeutic activity in schizophrenia could be mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor antagonism. The clinical effect from risperidone results from the combined concentrations of risperidone and its major metabolite, 9-hydroxyrisperidone (paliperidone) [see Clinical Pharmacology (12.3)]. Antagonism at receptors other than D2 and 5HT2 may explain some of the other effects of risperidone.
12.2 Pharmacodynamics
Risperidone is a monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), α1 and α2 adrenergic, and H1 histaminergic receptors. Risperidone showed low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D1 and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations > 10-5 M) for cholinergic muscarinic or β1 and β2 adrenergic receptors.
12.3 Pharmacokinetics
The pharmacokinetics of risperidone and total active moiety following subcutaneous injection of PERSERIS was eva luated in subjects with clinically stable schizophrenia after single doses (60 mg, 90 mg, and 120 mg) (n = 101) and repeated doses (60 mg, 90 mg, and 120 mg) (n = 45) separated by 28 days for up to 3 injections following oral risperidone. Risperidone plasma concentrations had a Tmax of 4 to 6 hours and approached steady-state levels after the first subcutaneous injection of PERSERIS. Similar pattern was observed for 9-hydroxyrisperidone and total active moiety. Steady-state plasma concentrations were reached by the end of the second injection for risperidone, 9-hydroxyrisperidone, and total active moiety and were maintained for 4 weeks after the last injection. Mean accumulation ratios for risperidone ranged from 1.2 to 1.7 based on AUC, and from 0.9 to 1.3 based on overall Cmax, indicating no or modest accumulation. For 9-hydroxyrisperidone, accumulation ratios ranged from 1.2 to 1.6 (AUC) and 0.99 to 1.3 (overall Cmax). For total active moiety, accumulation ratios ranged from 1.2 to 1.6 (AUCtau) and 0.97 to 1.3 (overall Cmax).
Total active moiety concentrations reached clinically relevant levels after the first injection without use of a loading dose or any supplemental oral risperidone.
Following multiple doses of PERSERIS, plasma exposure (AUCtau and Cmax) of risperidone, 9-hydroxyrisperidone, and total active moiety increased in an approximately dose proportional manner over the dose range of 60 to 120 mg. At steady-state, a 2-fold increase in dose resulted in a 1.7-fold increase in Cmax (6.33 to 10.9 ng/mL) and AUCtau (2262 to 3891 ng*hr/mL) for risperidone. For 9-hydroxyrisperidone, a 2-fold increase in dose resulted in a 2.1-fold incre |
