Bysanti Milsaperidone 1 mg Tablet, 60-count — NDC 43068-701-02 (Billing 43068-0701-02)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action The mechanism of action of milsaperidone in the treatment of schizophrenia in adults and the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults is unknown. However, the efficacy of milsaperidone in these conditions could be mediated through a combination of dopamine type 2 (D 2 ) and serotonin type 2 (5-HT 2 ) antagonism. Milsaperidone and iloperidone rapidly interconvert in vivo.

Milsaperidone has an in vitro receptor binding profile similar to iloperidone.

12.2Pharmacodynamics Milsaperidone acts as an antagonist with moderate to strong affinity at the norepinephrine NE α1 , NEα 2B , NE α2C receptors (Ki values of 8.3, 60, and 16 nM, respectively), the dopamine D 1 ,D 2 , D 3 , D 4 (Ki values of 96, 16, 68, and 35 nM, respectively), the histamine H 1 (Ki value of 26 nM), and the serotonin 5-HT 1B , 5-HT 2A , and 5-HT 2C sites (Ki values of 51, 0.28, and 66 nM, respectively). Milsaperidone has relatively weak affinity at the norepinephrine NE α2A , serotonin 5-HT 1A , and 5-HT 6 sites (Ki values of 363, 427, and 776 nM, respectively).

Iloperidone acts as an antagonist with high (nM) affinity binding to serotonin 5-HT 2A , dopamine D 2 and D 3 receptors, and norepinephrine NEα1 receptors (K i values of 5.6, 6.3, 7.1, and 0.36 nM, respectively). Iloperidone has moderate affinity for dopamine D 4 , and serotonin 5-HT 6 and 5-HT 7 receptors (K i values of 25, 43, and 22 nM respectively), and low affinity for the serotonin 5-HT 1A , dopamine D 1 , and histamine H 1 receptors (K i values of 168, 216, and 437 nM, respectively). Iloperidone has no appreciable affinity (K i >1000 nM) for cholinergic muscarinic receptors.

The metabolite P95 only shows affinity for 5-HT 2A (K i value of 3.91) and the NE α1A , NE α1B , NE α1D , and NE α2C receptors (K i values of 4.7, 2.7, 8.8, and 4.7 nM, respectively). Cardiac Electrophysiology In an open-label QTc study in patients with schizophrenia or another psychiatric disorder (n=160), administration of iloperidone (12 mg twice daily) was associated with QTc prolongation of 9 msec. The effect of iloperidone on the QT interval was augmented by the presence of CYP2D6 inhibition (paroxetine 20 mg once daily) or CYP2D6 and CYP3A4 inhibition (paroxetine 20 mg once daily + ketoconazole 200 mg twice daily).

Under conditions of metabolic inhibition for both CYP2D6 and CYP3A4, iloperidone 12 mg twice daily was associated with a mean QTcF increase from baseline of about 19 msec [see Warnings and Precautions (5.3) ] .

12.3Pharmacokinetics Following oral administration of iloperidone (iloperidone and milsaperidone rapidly interconvert in vivo), the plasma exposure of milsaperidone increased approximately proportionally over the therapeutic dosage range and plasma exposure of iloperidone increased slightly more than dose proportional. Steady-state concentrations of milsaperidone are attained within 3 to 4 days of dosing. Accumulation of iloperidone is at least 2-fold with twice daily dosing regimen after administration of oral iloperidone tablets.

After administration of oral iloperidone tablets (iloperidone and milsaperidone rapidly interconvert in vivo) in CYP2D6 normal metabolizers, the major metabolite P95, milsaperidone, and iloperidone accounted for approximately 48%, 20% and 9% of the total plasma exposure, respectively. After administration of oral iloperidone tablets in CYP2D6 poor metabolizers, the major metabolite P95, milsaperidone, and iloperidone accounted for 23%, 34%, and 16% of the total exposure, respectively. Absorption Following oral administration of BYSANTI or oral iloperidone tablets, no clinically significant differences in the pharmacokinetics of milsaperidone and its metabolites, iloperidone and P95 were observed with the two treatments.Following oral administration of BYSANTI, the time to peak plasma concentrations (T max ) occurred within 4 hours for milsaperidone, 2 hours for iloperidone, and 6… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action The mechanism of action of milsaperidone in the treatment of schizophrenia in adults and the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults is unknown. However, the efficacy of milsaperidone in these conditions could be mediated through a combination of dopamine type 2 (D 2 ) and serotonin type 2 (5-HT 2 ) antagonism. Milsaperidone and iloperidone rapidly interconvert in vivo.

Milsaperidone has an in vitro receptor binding profile similar to iloperidone.

12.3Pharmacokinetics Following oral administration of iloperidone (iloperidone and milsaperidone rapidly interconvert in vivo), the plasma exposure of milsaperidone increased approximately proportionally over the therapeutic dosage range and plasma exposure of iloperidone increased slightly more than dose proportional. Steady-state concentrations of milsaperidone are attained within 3 to 4 days of dosing. Accumulation of iloperidone is at least 2-fold with twice daily dosing regimen after administration of oral iloperidone tablets.

After administration of oral iloperidone tablets (iloperidone and milsaperidone rapidly interconvert in vivo) in CYP2D6 normal metabolizers, the major metabolite P95, milsaperidone, and iloperidone accounted for approximately 48%, 20% and 9% of the total plasma exposure, respectively. After administration of oral iloperidone tablets in CYP2D6 poor metabolizers, the major metabolite P95, milsaperidone, and iloperidone accounted for 23%, 34%, and 16% of the total exposure, respectively. Absorption Following oral administration of BYSANTI or oral iloperidone tablets, no clinically significant differences in the pharmacokinetics of milsaperidone and its metabolites, iloperidone and P95 were observed with the two treatments.Following oral administration of BYSANTI, the time to peak plasma concentrations (T max ) occurred within 4 hours for milsaperidone, 2 hours for iloperidone, and 6 hours for P95.

Effect of Food: Following administration of BYSANTI with high-fat meal (approximately 1000 calories, 50% fat), no clinically significant differences in the pharmacokinetics of milsaperidone and its metabolites were observed compared to the fasted state. Distribution Milsaperidone and iloperidone have an apparent volume of distribution of 1715-2343 L and 1340-2800 L, respectively. At therapeutic concentrations, the unbound fraction in plasma is approximately 8% for milsaperidone, 3% for iloperidone and 8% for P95.

Elimination In CYP2D6 normal metabolizers, the observed mean elimination half-lives were 26 hours for milsaperidone, 18 hours for iloperidone, and 23 hours for P95. In CYP2D6 poor metabolizers, the mean elimination half-lives were 37 hours for milsaperidone, 33 hours for iloperidone, and 31 hours for P95. Milsaperidone and iloperidone have an apparent clearance (clearance/bioavailability) of 32 to 69 L/h and 47 to 102 L/h, respectively.

Metabolism: Milsaperidone undergoes oxidation to form iloperidone and iloperidone undergoes a stereospecific carbonyl reduction to form milsaperidone. Elimination of milsaperidone and iloperidone is mainly through hepatic metabolism. Iloperidone is metabolized primarily by 3 biotransformation pathways: carbonyl reduction, hydroxylation (mediated by CYP2D6) and O-demethylation (mediated by CYP3A4).

Excretion: Studies of iloperidone showed the majority of the radioactive materials were recovered in the urine. The mean recovery was 58% in CYP2D6 normal metabolizers and 45% in CYP2D6 poor metabolizers, with feces accounting for 20% in CYP2D6 normal metabolizers and 22% in CYP2D6 poor metabolizers of the administered radioactivity. Specific Populations No pharmacokinetics (PK) studies with BYSANTI have been performed in specific populations.

The PK of milsaperidone is based on PK studies of iloperidone. Patients with Renal Impairment: Studies of iloperidone show patients with severe renal impairment (creatinine clearance <30 mL/minute) had minimal effect on C max of iloperidone, milsaperidone and P95 compared to those with normal kidney function; AUC inf was increased by 24% for iloperidone, decreased by 6% for milsaperidone and increased by 52% for P95. Patients with Hepatic Impairment: In patients with moderate hepatic impairment (HI), a 2-fold higher free plasma exposure for milsaperidone was observed and these exposures were variable (these changes are clinically significant), whereas there was a 19% increase in iloperidone exposure and a 5% decrease in P95 exposure.… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Milsaperidone acts as an antagonist with moderate to strong affinity at the norepinephrine NE α1 , NEα 2B , NE α2C receptors (Ki values of 8.3, 60, and 16 nM, respectively), the dopamine D 1 ,D 2 , D 3 , D 4 (Ki values of 96, 16, 68, and 35 nM, respectively), the histamine H 1 (Ki value of 26 nM), and the serotonin 5-HT 1B , 5-HT 2A , and 5-HT 2C sites (Ki values of 51, 0.28, and 66 nM, respectively). Milsaperidone has relatively weak affinity at the norepinephrine NE α2A , serotonin 5-HT 1A , and 5-HT 6 sites (Ki values of 363, 427, and 776 nM, respectively).

Iloperidone acts as an antagonist with high (nM) affinity binding to serotonin 5-HT 2A , dopamine D 2 and D 3 receptors, and norepinephrine NEα1 receptors (K i values of 5.6, 6.3, 7.1, and 0.36 nM, respectively). Iloperidone has moderate affinity for dopamine D 4 , and serotonin 5-HT 6 and 5-HT 7 receptors (K i values of 25, 43, and 22 nM respectively), and low affinity for the serotonin 5-HT 1A , dopamine D 1 , and histamine H 1 receptors (K i values of 168, 216, and 437 nM, respectively). Iloperidone has no appreciable affinity (K i >1000 nM) for cholinergic muscarinic receptors.

The metabolite P95 only shows affinity for 5-HT 2A (K i value of 3.91) and the NE α1A , NE α1B , NE α1D , and NE α2C receptors (K i values of 4.7, 2.7, 8.8, and 4.7 nM, respectively). Cardiac Electrophysiology In an open-label QTc study in patients with schizophrenia or another psychiatric disorder (n=160), administration of iloperidone (12 mg twice daily) was associated with QTc prolongation of 9 msec. The effect of iloperidone on the QT interval was augmented by the presence of CYP2D6 inhibition (paroxetine 20 mg once daily) or CYP2D6 and CYP3A4 inhibition (paroxetine 20 mg once daily + ketoconazole 200 mg twice daily).

Under conditions of metabolic inhibition for both CYP2D6 and CYP3A4, iloperidone 12 mg twice daily was associated with a mean QTcF increase from baseline of about 19 msec [see Warnings and Precautions (5.3) ] .

14 CLINICAL STUDIES

14.1Schizophrenia The effectiveness of BYSANTI in the treatment of schizophrenia in adults has been established from adequate and well-controlled studies of iloperidone tablets (referred to as “iloperidone” (iloperidone and milsaperidone rapidly interconvert in vivo)) in adults with schizophrenia. Below is a display of the efficacy results of iloperidone in these adequate and well-controlled studies. Iloperidone was studied in two placebo- and active-controlled short-term trials (a 6-week trial (Study 1) and a 4-week trial (Study 2)) and one long-term placebo-controlled randomized withdrawal trial (Study 3) in adult patients who met the DSM-III/IV criteria for schizophrenia.

In Studies 1, 2, and 3, three instruments were used to assess psychiatric signs and symptoms: the Positive and Negative Syndrome Scale (PANSS), the Brief Psychiatric Rating Scale (BPRS) (both multi-item inventories of general psychopathology), and the Clinical Global Impression (CGI) assessment which reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. Study 1 Study 1 (n=706) included two flexible dosage ranges of iloperidone (12 mg to 16 mg/day or 20 mg to 24 mg/day) compared to placebo and an active control (risperidone).

For the 12 mg to 16 mg/day group, the iloperidone titration schedule was 1 mg twice daily on Days 1 and 2, 2 mg twice daily on Days 3 and 4, 4 mg twice daily on Days 5 and 6, and 6 mg twice daily on Day 7. For the 20 mg to 24 mg/day group, the iloperidone titration schedule was 1 mg twice daily on Day 1, 2 mg twice daily on Day 2, 4 mg twice daily on Day 3, 6 mg twice daily on Days 4 and 5, 8 mg twice daily on Day 6, and 10 mg twice daily on Day 7. In Study 1, the primary endpoint was change from baseline on the BPRS total score at the end of treatment (Day 42).

Both the 12 mg to 16 mg/day and the 20 mg to 24 mg/day iloperidone treatment groups were superior to the placebo group on the BPRS total score. The active control antipsychotic drug (risperidone) appeared to be superior to iloperidone in this trial within the first 2 weeks, a finding that may in part be explained by the more rapid titration that was possible for risperidone. For patients in Study 1 who remained on treatment for at least 2 weeks, iloperidone appeared to have had comparable efficacy to risperidone.

Study 2 Study 2 (NCT00254202) (n=604) compared one fixed-dose of iloperidone (24 mg/day) to placebo and an active control (ziprasidone). The titration schedule for Study 2 was similar to the titration schedule for Study 1. In Study 2, the titration of iloperidone started at 1 mg twice daily on Day 1 and increased to 2, 4, 6, 8, 10, and 12 mg twice daily on Days 2, 3, 4, 5, 6, and 7, respectively.

In Study 2, the primary endpoint was change from baseline on the PANSS total score at the end of treatment (Day 28). The 24 mg/day iloperidone treatment group was superior to the placebo treatment group in the PANSS total score. In Study 2, iloperidone appeared to have similar efficacy as ziprasidone which also needed a slow titration to the target dosage.

Study 3 Study 3 (NCT01291511) included clinically stable adult outpatients (n=303) who met DSM-IV criteria for schizophrenia. After a one-week iloperidone titration, patients who remained clinically stable received 12 weeks of open-label treatment with a flexible iloperidone dosage (4 mg to 12 mg administered twice daily (8 mg to 24 mg per day, respectively). Stabilization during the open-label phase was defined as being on an established iloperidone dosage that was unchanged due to efficacy in the 4 weeks prior to randomization, having CGI-Severity score of ≤4 and PANSS total score ≤70, a score of ≤4 on each of the following individual PANSS items (P1-delusions, P2-conceptual disorganization, P3-hallucinatory behavior, P6-suspiciousness/persecution, P7-hostility, or G8-uncooperativeness), and no hospitaliz… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Lifetime carcinogenicity studies were conducted with iloperidone (iloperidone and milsaperidone rapidly interconvert in vivo) in CD-1 mice and Sprague Dawley rats. Iloperidone was administered orally at doses of 2.5, 5, and 10 mg/kg/day to CD-1 mice and 4, 8, and 16 mg/kg/day to Sprague Dawley rats (0.5, 1, and 2 times and 1.6, 3.2, and 6.5 times, respectively, the MRHD of 24 mg/day on a mg/m 2 basis). The safety margins for milsaperidone are expected to be the same as those seen with iloperidone because exposure to iloperidone, milsaperidone, and their major metabolites are similar when either iloperidone tablets or BYSANTI (milsaperidone) tablets are administered in humans.

There was an increased incidence of malignant mammary gland tumors in female mice treated with the lowest dose (2.5 mg/kg/day) only. There were no treatment-related increases in neoplasia in rats. The carcinogenic potential of the milsaperidone metabolite P95, which is a major circulating metabolite of milsaperidone in humans but is not present at significant amounts in mice or rats, was assessed in a lifetime carcinogenicity study in Wistar rats at oral doses of 25, 75, and 200 mg/kg/day in males and 50, 150, and 250 (reduced from 400) mg/kg/day in females.

Drug-related neoplastic changes occurred in males, in the pituitary gland (pars distalis adenoma) at all doses and in the pancreas (islet cell adenoma) at the high dose. Plasma levels of P95 (AUC) in males at the tested doses (25, 75, and 200 mg/kg/day) were approximately 0.4, 3, and 23 times, respectively, the human exposure to P95 at the MRHD of milsaperidone. Mutagenesis Milsaperidone was not mutagenic in the Bacterial Reverse Mutation (Ames) Test conducted in multiple bacterial strains with and without metabolic activation.

Milsaperidone did not induce structural chromosomal damage in an in vitro cytogenetic assay using Chinese Hamster Ovary (CHO) cells with and without metabolic activation. Iloperidone was negative in the Ames test and in the in vivo mouse bone marrow and rat liver micronucleus tests. Iloperidone induced chromosomal aberrations in Chinese Hamster Ovary (CHO) cells in vitro at concentrations which also caused some cytotoxicity.

The iloperidone metabolite P95 was negative in the Ames test, the V79 chromosome aberration test, and an in vivo mouse bone marrow micronucleus test. Impairment of Fertility Iloperidone decreased fertility at 12 and 36 mg/kg in a study in which both male and female rats were treated. The no-effect dose was 4 mg/kg, which is 1.6 times the MRHD of 24 mg/day on a mg/m 2 basis.