PERSERIS Risperidone Kit — NDC 12496-0120-1 (Billing 12496-0120-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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 (D 2 ) and serotonin Type 2 (5HT 2 ) 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 D 2 and 5HT 2 may explain some of the other effects of risperidone.

12.2Pharmacodynamics Risperidone is a monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT 2 ), dopamine Type 2 (D 2 ), α 1 and α 2 adrenergic, and H 1 histaminergic receptors. Risperidone showed low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT 1C , 5HT 1D , and 5HT 1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D 1 and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations > 10 -5 M) for cholinergic muscarinic or β 1 and β 2 adrenergic receptors.

12.3Pharmacokinetics The pharmacokinetics of risperidone and total active moiety following subcutaneous injection of PERSERIS was evaluated in patients with clinically stable schizophrenia after single doses (60 mg, 90 mg, and 120 mg) (n = 101) and repeated doses [60 mg, 90 mg, 120 mg, 180 mg (1.5 times the maximum recommended dosage of PERSERIS)] (n = 68) separated by 28 days for up to 4 doses following oral risperidone. Plasma concentrations of risperidone, 9-hydroxyrisperidone and total active moiety approached steady-state levels after the first dose of PERSERIS.

Mean accumulation ratios for risperidone ranged from 1.2 to 1.7 based on mean area under the curve (AUC), and from 0.9 to 1.3 based on overall mean peak plasma concentrations (overall C max ), indicating no to modest accumulation. For 9-hydroxyrisperidone, accumulation ratios ranged from 1.2 to 1.6 (AUC) and 0.99 to 1.3 (overall C max ). For total active moiety, accumulation ratios ranged from 1.2 to 1.6 (AUC tau ) and 0.97 to 1.3 (overall C max ).

Following multiple doses of PERSERIS, plasma exposure (AUC tau and C max ) 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 C max (6.33 to 10.9 ng/mL) and AUC tau (2262 to 3891 ng*hr/mL) for risperidone. For 9-hydroxyrisperidone, a 2-fold increase in dose resulted in a 2.1-fold increase in C max (13.7 to 28.9 ng/mL) and 2-fold increase in AUC tau (5706 to 11658 ng*hr/mL).

For total active moiety, a 2-fold increase in dose resulted in a 2.0-fold increase in C max (19.6 to 38.5 ng/mL) and a 1.9-fold increase in AUC tau (8102 to 15370 ng*hr/mL). Plasma exposures at steady-state were compared between oral risperidone and PERSERIS. The average plasma concentrations (C avg ) of total active moiety were 18.3 ng/mL and 18.1 ng/mL for 3 mg oral risperidone and 90 mg PERSERIS, respectively.

The C avg of total active moiety were 25.2 ng/mL and 22.9 ng/mL for 4 mg oral risperidone and 120 mg PERSERIS, respectively. Absorption PERSERIS contains risperidone in a liquid delivery system. Following subcutaneous injection, it forms a depot that provides sustained plasma levels of risperidone over the monthly dosing interval.

After single subcutaneous injection, PERSERIS shows two absorption peaks for risperidone in plasma. The first peak of risperidone occurs with a T max of 4 to 6 hours and is due to an initial release of the drug during the depot formation process. A second peak of risperidone is observed at 10 to 14 days post-dose and is associated with the slow release of risperidone from the subcutaneous depot.

The first and second peaks of risperidone are of similar magnitude. For both 9-hydroxyrisperidone and total active moiet… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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 (D 2 ) and serotonin Type 2 (5HT 2 ) 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 D 2 and 5HT 2 may explain some of the other effects of risperidone.

12.3Pharmacokinetics The pharmacokinetics of risperidone and total active moiety following subcutaneous injection of PERSERIS was evaluated in patients with clinically stable schizophrenia after single doses (60 mg, 90 mg, and 120 mg) (n = 101) and repeated doses [60 mg, 90 mg, 120 mg, 180 mg (1.5 times the maximum recommended dosage of PERSERIS)] (n = 68) separated by 28 days for up to 4 doses following oral risperidone. Plasma concentrations of risperidone, 9-hydroxyrisperidone and total active moiety approached steady-state levels after the first dose of PERSERIS.

Mean accumulation ratios for risperidone ranged from 1.2 to 1.7 based on mean area under the curve (AUC), and from 0.9 to 1.3 based on overall mean peak plasma concentrations (overall C max ), indicating no to modest accumulation. For 9-hydroxyrisperidone, accumulation ratios ranged from 1.2 to 1.6 (AUC) and 0.99 to 1.3 (overall C max ). For total active moiety, accumulation ratios ranged from 1.2 to 1.6 (AUC tau ) and 0.97 to 1.3 (overall C max ).

Following multiple doses of PERSERIS, plasma exposure (AUC tau and C max ) 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 C max (6.33 to 10.9 ng/mL) and AUC tau (2262 to 3891 ng*hr/mL) for risperidone. For 9-hydroxyrisperidone, a 2-fold increase in dose resulted in a 2.1-fold increase in C max (13.7 to 28.9 ng/mL) and 2-fold increase in AUC tau (5706 to 11658 ng*hr/mL).

For total active moiety, a 2-fold increase in dose resulted in a 2.0-fold increase in C max (19.6 to 38.5 ng/mL) and a 1.9-fold increase in AUC tau (8102 to 15370 ng*hr/mL). Plasma exposures at steady-state were compared between oral risperidone and PERSERIS. The average plasma concentrations (C avg ) of total active moiety were 18.3 ng/mL and 18.1 ng/mL for 3 mg oral risperidone and 90 mg PERSERIS, respectively.

The C avg of total active moiety were 25.2 ng/mL and 22.9 ng/mL for 4 mg oral risperidone and 120 mg PERSERIS, respectively. Absorption PERSERIS contains risperidone in a liquid delivery system. Following subcutaneous injection, it forms a depot that provides sustained plasma levels of risperidone over the monthly dosing interval.

After single subcutaneous injection, PERSERIS shows two absorption peaks for risperidone in plasma. The first peak of risperidone occurs with a T max of 4 to 6 hours and is due to an initial release of the drug during the depot formation process. A second peak of risperidone is observed at 10 to 14 days post-dose and is associated with the slow release of risperidone from the subcutaneous depot.

The first and second peaks of risperidone are of similar magnitude. For both 9-hydroxyrisperidone and total active moiety, the median T max of the first peak ranges from 4 to 48 hours and the second peak ranges from 7 to 11 days. Distribution Following a subcutaneous injection of PERSERIS, the apparent volume of distribution is large.

The extensively large values are because PERSERIS is administered as a depot injection. Risperidone is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is approximately 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%.

Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites. Elimination Metabolism Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme cytochrome CYP2D6 with minor contribution by CYP3A4.

A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone).

CYP2D6, is the enzyme responsible for metabolism… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Risperidone is a monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT 2 ), dopamine Type 2 (D 2 ), α 1 and α 2 adrenergic, and H 1 histaminergic receptors. Risperidone showed low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT 1C , 5HT 1D , and 5HT 1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D 1 and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations > 10 -5 M) for cholinergic muscarinic or β 1 and β 2 adrenergic receptors.

14 CLINICAL STUDIES Efficacy for PERSERIS was demonstrated in an 8-week, randomized, double-blind, placebo-controlled study (Study 1, NCT #02109562). The study evaluated the efficacy, safety and tolerability of PERSERIS (90 and 120 mg subcutaneous every 4-weeks) compared with placebo in adults (age 18- to 55-years, inclusive) experiencing acute exacerbations of schizophrenia. Patients were required to have a Positive and Negative Syndrome Scale (PANSS) total score of 80- to 120-inclusive (moderate to severely ill) at the screening visit, occurring 3- to 8-days before the start of double-blind treatment, without an improvement in the PANSS total score of ≥ 20% between screening and the first dosing day.

At the screening visit, all patients received two doses of 0.25 mg oral risperidone 24-hours apart to establish tolerability. Patients were then placed in an inpatient setting, if not already hospitalized, and tapered off their current oral antipsychotic medication (if they were taking one) over a period of 3- to 8-days. Patients were randomized to receive 2 doses of subcutaneous PERSERIS (90 mg or 120 mg) or placebo 28-days apart (on Day 1 and Day 29).

No supplemental oral risperidone was permitted during the study. The primary endpoint was the change in PANSS total score from baseline to end of study (Day 57). Both PERSERIS 90 and 120 mg doses demonstrated a statistically significant improvement compared with placebo based on the primary endpoint ( Table 8 ).

The results at each scheduled visit are displayed in Figure 14 . Characteristics of the patient population were balanced across the treatment groups. The mean baseline PANSS total score ranged from 94 to 96 across the groups.

Most patients were male (74 to 83% per group), and the mean ages were 40 to 43 in each group. Most patients in this study were black or African American (71 to 75% per group). Of the 354 patients randomized to treatment, 337 were included in the intent-to-treat (ITT) population, and 259 (73%) completed the study.

Subgroup analyses by gender, age, and race did not suggest any clear evidence of differential responsiveness to PERSERIS. Table 8 Primary Efficacy Analysis Results for Study 1 ITT: intent-to-treat; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval ªDifference (drug minus placebo) in least-squares mean change from baseline *Doses that are statistically significantly superior to placebo Primary Efficacy Measure: PANSS Treatment Group N (# ITT patients) Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference a (95% CI) PERSERIS 90 mg* 111 95.5 (9.23) -19.86 (1.56) -6.50 (-10.87, -2.13)* PERSERIS 120 mg* 114 94.9 (8.09) -23.61 (1.58) -10.24 (-14.64, -5.85)* Placebo 112 94.1 (8.89) -13.37 (1.58) -- Figure 14.

Least Square Mean Change from Baseline (+/- Standard Error) in PANSS Total Scores by Days The secondary efficacy endpoint was defined as the CGI-S score at Day 57. Both PERSERIS treatment groups demonstrated statistically significantly better CGI-S scores versus placebo. Figure

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenicity studies were conducted with subcutaneous risperidone suspension. Carcinogenicity studies were conducted with oral risperidone in mice and rats. Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats.

These doses are equivalent to approximately 0.2, 0.75, and 3 times (mice) and 0.4, 1.5, and 6 times (rats) the oral MHRD of 16 mg/day, based on a mg/m 2 body surface area. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas.

The table below summarizes the multiples of the human oral dose on a mg/m 2 (mg/kg) basis at which these tumors occurred. Table 7 Summary of Tumor Occurrence at the Multiples of the Human Dose on a mg/m 2 (mg/kg) Basis with Oral Risperidone Dosing Multiples of Maximum Human Oral Dose in mg/m 2 (mg/kg) Tumor Type Species Sex Lowest Effect Level Highest No-Effect Level Pituitary adenomas mouse Female 0.75 (9.4) 0.2 (2.4) Endocrine pancreas adenomas rat Male 1.5 (9.4) 0.4 (2.4) Mammary gland adenocarcinomas mouse Female 0.2 (2.4) None rat Female 0.4 (2.4) None rat Male 6 (37.5) 1.5 (9.4) Mammary gland neoplasm, Total rat Male 1.5 (9.4) 0.4 (2.4) Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents.

Serum prolactin levels were not measured during the risperidone carcinogenicity studies; however, measurements during subchronic toxicity studies showed that risperidone elevated serum prolactin levels 5- to 6-fold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear [see Warnings and Precautions ( 5.6 )] .

Mutagenesis No evidence of mutagenic or clastogenic potential for risperidone was found in the in vitro tests of Ames gene mutation, the mouse lymphoma assay, rat hepatocyte DNA-repair assay, the chromosomal aberration test in human lymphocytes, Chinese hamster ovary cells, or in the in vivo oral micronucleus test in mice and the sex-linked recessive lethal test in Drosophila. No evidence of mutagenic potential was observed with risperidone subcutaneous injectable suspension or its delivery system alone at doses of 150 mg/kg risperidone or 943 mg/kg delivery system in an in vivo micronucleus test in rats.

The safety margins of risperidone were 12 to 19 times the maximum monthly plasma risperidone concentration observed for humans at the monthly MRHD of 120 mg risperidone based on plasma exposure, and 13 times the delivery system amount present in monthly 120 mg risperidone. Impairment of Fertility No mating and fertility studies were conducted with subcutaneous risperidone suspension. Oral risperidone (0.16 to 5 mg/kg) impaired mating, but not fertility, in rat reproductive studies at doses 0.1 to 3 times the oral maximum recommended human dose (MRHD), of 16 mg/day based on mg/m 2 body surface area.

The effect appeared to be in females, since impaired mating behavior was not noted in the male fertility study. In a subchronic study in Beagle dogs in which risperidone was administered orally at doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to 10 times the oral MRHD based on mg/m 2 body surface area. Dose-related decreases were also noted in serum testosterone at the same doses.

Serum testosterone and sperm parameters partially recovered, but remained decreased after treatment was discontinued. A no-effect dose could not be determined in either rat or dog. Subcutaneous administration of the delivery system… [Excerpted — this section continues on DailyMed.]