LYBALVI olanzapine and samidorphan L-malate 5 mg; 10 mg Tablet, Film Coated, 7-count — NDC 65757-651-40 (Billing 65757-0651-40)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action The mechanism of action of olanzapine is unclear; however, its efficacy in the treatment of schizophrenia or bipolar I disorder could be mediated through a combination of dopamine and serotonin type 2 (5HT 2 ) antagonism. The mechanism of action of samidorphan could be mediated through opioid receptor antagonism.

12.2Pharmacodynamics Olanzapine Olanzapine binds with high affinity to the following receptors: serotonin 5HT 2A/2C , 5HT 6 (K i =4, 11, and 5 nM, respectively), dopamine D 1-4 (K i =11–31 nM), histamine H 1 (K i =7 nM), and adrenergic α 1 receptors (K i =19 nM). Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT 3 (K i =57 nM) and muscarinic M 1-5 (K i =73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds with low affinity to GABA A , BZD, and β-adrenergic receptors (K i >10 μM).

Samidorphan Samidorphan binds to the mu-, kappa-, and delta-opioid receptors (K i =0.052, 0.23, and 2.7 nM, respectively). Samidorphan is an antagonist at the mu-opioid receptors with partial agonist activity at kappa- and delta-opioid receptors. The N-dealkylated major human metabolite binds to the mu-, kappa-, and delta-opioid receptors (K i =0.26, 23, and 56 nM, respectively), and functions as a mu-opioid receptor agonist.

The N-oxide major human metabolite binds to mu-, kappa-, and delta-opioid receptors (K i =8, 110, and 280 nM, respectively) and functions as a mu-opioid receptor antagonist. Cardiac Electrophysiology At doses up to 30 mg/30 mg (1.5 times and 3 times the maximum recommended daily dosage of olanzapine and samidorphan, respectively), LYBALVI does not prolong QTc interval to any clinically relevant extent.

12.3Pharmacokinetics The pharmacokinetics of both olanzapine and samidorphan are linear over the clinical dose range and there is no PK interaction between olanzapine and samidorphan after oral administration of LYBALVI. Steady-state concentrations of olanzapine and samidorphan are reached within 7 days of commencement of once-daily administration of LYBALVI. The primary pharmacological activities of LYBALVI are due to the parent drugs, olanzapine and samidorphan.

Following a single dose administration of LYBALVI (10 mg olanzapine/10 mg samidorphan), the mean AUC 0-inf and C max of olanzapine was 628 ng·h/mL and 16 ng/mL, respectively. The mean AUC 0-inf and C max of olanzapine after 10 mg single dose administration of olanzapine tablet was 610 ng·h/mL and 16 ng/mL, respectively. Pharmacokinetic properties of the components of LYBALVI are provided in Table 6 .

Table 6: Pharmacokinetic Properties of the Components of LYBALVI Parameters Olanzapine Samidorphan Abbreviations: AUC 24h =area under the concentration-time curve over the 24-hour dosing interval; C max =maximum plasma concentration; CYP=cytochrome P450; NA=not applicable; T max =time to C max ; t ½ =terminal elimination half-life; UGT=Uridine 5'-diphospho-glucuronosyltransferase. a Presented as arithmetic mean (standard deviation). b Presented as range of the median across multiple studies. c Geometric mean ratio (90% confidence interval) [high fat meal/fasting].

High fat meal defined as meal containing approximately 900-1000 calories and 50% fat content. No clinically relevant food effect. d Presented as range of the mean across multiple studies. General Steady State Exposure (20 mg olanzapine/10 mg samidorphan) C max (ng/mL) a 64.6 (28.9) 45.1 (11.4) AUC 24h (ng∙hr/mL) a 1086 (556) 364 (112) Time to Reach Steady State 7 days 5 days Accumulation at Steady State 2-fold 1.3-fold Absorption Absolute Oral Bioavailability NA 69% T max (h) b 4.5–7 1–2 Effect of Food C max Ratio c 0.88 (0.82, 0.95) 0.85 (0.76, 0.94) AUC Ratio c 0.93 (0.91, 0.96) 1.03 (1.00, 1.05) Distribution Plasma Protein Binding 93% 23% - 33% Blood-to-Plasma Ratio Not Determined

0.8Elimination t 1/2 (h) d 35–52 7–11 CL/F (L/h) d 15–22 35–45 Metabolism Primary Pathway(s) UGT1A4, CYP1A2 CYP3A4 Minor Pathway(s) CYP2D6 C… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action The mechanism of action of olanzapine is unclear; however, its efficacy in the treatment of schizophrenia or bipolar I disorder could be mediated through a combination of dopamine and serotonin type 2 (5HT 2 ) antagonism. The mechanism of action of samidorphan could be mediated through opioid receptor antagonism.

12.3Pharmacokinetics The pharmacokinetics of both olanzapine and samidorphan are linear over the clinical dose range and there is no PK interaction between olanzapine and samidorphan after oral administration of LYBALVI. Steady-state concentrations of olanzapine and samidorphan are reached within 7 days of commencement of once-daily administration of LYBALVI. The primary pharmacological activities of LYBALVI are due to the parent drugs, olanzapine and samidorphan.

Following a single dose administration of LYBALVI (10 mg olanzapine/10 mg samidorphan), the mean AUC 0-inf and C max of olanzapine was 628 ng·h/mL and 16 ng/mL, respectively. The mean AUC 0-inf and C max of olanzapine after 10 mg single dose administration of olanzapine tablet was 610 ng·h/mL and 16 ng/mL, respectively. Pharmacokinetic properties of the components of LYBALVI are provided in Table 6 .

Table 6: Pharmacokinetic Properties of the Components of LYBALVI Parameters Olanzapine Samidorphan Abbreviations: AUC 24h =area under the concentration-time curve over the 24-hour dosing interval; C max =maximum plasma concentration; CYP=cytochrome P450; NA=not applicable; T max =time to C max ; t ½ =terminal elimination half-life; UGT=Uridine 5'-diphospho-glucuronosyltransferase. a Presented as arithmetic mean (standard deviation). b Presented as range of the median across multiple studies. c Geometric mean ratio (90% confidence interval) [high fat meal/fasting].

High fat meal defined as meal containing approximately 900-1000 calories and 50% fat content. No clinically relevant food effect. d Presented as range of the mean across multiple studies. General Steady State Exposure (20 mg olanzapine/10 mg samidorphan) C max (ng/mL) a 64.6 (28.9) 45.1 (11.4) AUC 24h (ng∙hr/mL) a 1086 (556) 364 (112) Time to Reach Steady State 7 days 5 days Accumulation at Steady State 2-fold 1.3-fold Absorption Absolute Oral Bioavailability NA 69% T max (h) b 4.5–7 1–2 Effect of Food C max Ratio c 0.88 (0.82, 0.95) 0.85 (0.76, 0.94) AUC Ratio c 0.93 (0.91, 0.96) 1.03 (1.00, 1.05) Distribution Plasma Protein Binding 93% 23% - 33% Blood-to-Plasma Ratio Not Determined

0.8Elimination t 1/2 (h) d 35–52 7–11 CL/F (L/h) d 15–22 35–45 Metabolism Primary Pathway(s) UGT1A4, CYP1A2 CYP3A4 Minor Pathway(s) CYP2D6 CYP3A5, CYP2C19, CYP2C8 Major Circulating Metabolites 10-N-glucuronide and 4′-N-desmethyl-olanzapine. Both metabolites lack pharmacological activity at the therapeutic concentrations N-dealkylated and cis-N-oxide metabolites. Neither metabolite contributes to the pharmacological effects of samidorphan Excretion Primary Route of Elimination Metabolism Metabolism Urine (Unchanged) 7% 18% Urine (Unchanged + metabolites) 57% 67% Feces (Unchanged + metabolites) 30% 16% Specific Populations Geriatric Patients The pharmacokinetics of olanzapine may be altered in geriatric patients [see Dosage and Administration ( 2.5 ), Use in Specific Populations ( 8.5 )] .

In a study involving 24 healthy subjects, the mean elimination half-life of olanzapine was about 1.5 times greater in elderly subjects (≥65 years) than in non-elderly subjects (<65 years). No effect of age on samidorphan pharmacokinetics was found in a study involving 12 elderly [aged 66-80 years old (6 male, 6 female)] and 24 young [aged 18-39 years old (12 male, 12 female)] healthy subjects administered a single oral dose of 10 mg samidorphan. Male and Female Patients Clearance of olanzapine is approximately 30% lower in females than males.

In clinical trials, however, there were no apparent differences between males and females in efficacy or adverse reactions. In clinical studies and population pharmacokinetic analysis, LYBALVI pharmacokinetics were consistent with that of olanzapine (as monotherapy) with no apparent effect of sex on samidorphan pharmacokinetics. Racial or Ethnic Groups In vivo studies of olanzapine as monotherapy have shown that olanzapine exposures are similar among Japanese, Chinese, and Caucasians, especially after normal… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Olanzapine Olanzapine binds with high affinity to the following receptors: serotonin 5HT 2A/2C , 5HT 6 (K i =4, 11, and 5 nM, respectively), dopamine D 1-4 (K i =11–31 nM), histamine H 1 (K i =7 nM), and adrenergic α 1 receptors (K i =19 nM). Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT 3 (K i =57 nM) and muscarinic M 1-5 (K i =73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds with low affinity to GABA A , BZD, and β-adrenergic receptors (K i >10 μM).

Samidorphan Samidorphan binds to the mu-, kappa-, and delta-opioid receptors (K i =0.052, 0.23, and 2.7 nM, respectively). Samidorphan is an antagonist at the mu-opioid receptors with partial agonist activity at kappa- and delta-opioid receptors. The N-dealkylated major human metabolite binds to the mu-, kappa-, and delta-opioid receptors (K i =0.26, 23, and 56 nM, respectively), and functions as a mu-opioid receptor agonist.

The N-oxide major human metabolite binds to mu-, kappa-, and delta-opioid receptors (K i =8, 110, and 280 nM, respectively) and functions as a mu-opioid receptor antagonist. Cardiac Electrophysiology At doses up to 30 mg/30 mg (1.5 times and 3 times the maximum recommended daily dosage of olanzapine and samidorphan, respectively), LYBALVI does not prolong QTc interval to any clinically relevant extent.

14 CLINICAL STUDIES

14.1Schizophrenia The efficacy of LYBALVI in the treatment of schizophrenia in adults is based, in part, upon adequate and well-controlled studies of orally administered olanzapine. Efficacy of LYBALVI was also evaluated in a 4-week, randomized, double-blind, placebo- and active-controlled study (Study 1). In Study 1 (NCT02634346), adult patients who met DSM-5 criteria for schizophrenia were randomized in a 1:1:1 ratio to LYBALVI, olanzapine, or placebo for 4 weeks of daily dosing.

Dosing was flexible based on clinical response and tolerability for the first 2 weeks of the study; doses thereafter were fixed. Patients assigned to LYBALVI could receive either 10 mg/10 mg or 20 mg/10 mg, and patients assigned to olanzapine could receive either 10 mg or 20 mg. The study was designed to compare LYBALVI with placebo, not with olanzapine.

Eligible patients were 18 to 70 years of age, with a body mass index (BMI) of 18.0–40.0 kg/m 2 , Positive and Negative Syndrome Scale (PANSS) total score of ≥80, and a score of ≥4 on at least 3 of the selected Positive Scale items. Patients were also required to have a Clinical Global Impression-Severity (CGI-S) score ≥4. The primary efficacy endpoint was change from baseline in PANSS total score at Week 4.

The PANSS is a 30-item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme). Total PANSS scores range from 30 to 210, with a higher score reflecting greater symptom severity. The secondary efficacy endpoint was defined as the change from baseline in CGI-S score at Week 4.

The CGI-S is a validated scale that requires clinicians to rate a patient's current illness severity and overall clinical state based on experience with the illness population. Scores range from 1 (normal, not at all ill) to 7 (extremely ill). Compared with patients on placebo, a statistically significant improvement in the change from baseline in PANSS total score at Week 4 was observed in patients treated with LYBALVI ( Table 7 ).

The inclusion of samidorphan in LYBALVI did not appear to negatively impact the antipsychotic efficacy of olanzapine. Table 7: Primary Efficacy Results for Change from Baseline in PANSS Total Score at Week 4 in Patients with Schizophrenia (Study 1) Treatment Group Total PANSS Score Baseline Mean Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference a (95% CI) Abbreviations: CI: confidence interval; LS: least squares; SD: standard deviation; SE: standard error. a Difference (drug minus placebo) in least squares mean change from baseline.

A negative value for the placebo subtracted difference represents improvement. LYBALVI (10 mg/10 mg, 20 mg/10 mg) (N=132) 101.8 (11.6) -23.9 (1.3) -6.4 (-10.0, -2.8) Placebo (N=133) 102.7 (11.9) -17.5 (1.3) -- Olanzapine (10 mg, 20 mg) (N=132) 100.6 (12.1) -22.8 (1.3) -5.3 (-8.9, -1.7) The change from baseline in PANSS total score in Study 1 is displayed in Figure 4 . Figure 4: Change from Baseline in PANSS Total Score by Time (Week) in Patients with Schizophrenia (Study 1) Error bars represent standard error.

The numbers under the figure indicate the number of patients at each timepoint. Compared with patients on placebo, a statistically significant improvement in CGI-S score at Week 4 was observed in patients treated with LYBALVI. Figure 4 Evaluation of Weight Changes in Patients with Schizophrenia In Study 2 (NCT02694328), adult patients who met DSM-5 criteria for schizophrenia were randomized in a 1:1 ratio to LYBALVI or olanzapine for 24 weeks of daily dosing.

Dosing was flexible for the first 4 weeks of the study, and doses were fixed thereafter. Patients were treated with doses of LYBALVI of 10 mg/10 mg or 20 mg/10 mg, or with doses of olanzapine of 10 mg or 20 mg. Eligible patients were 18 to 55 years of age with a body mass index (BMI) of 18 to 30 kg/m 2 , PANSS total sc… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Olanzapine Oral carcinogenicity studies were conducted in mice and rats. Olanzapine was administered to mice in two 78-week studies at doses of 3, 10, 30/20 mg/kg/day (equivalent to 0.8 to 5 times the MRHD of 20 mg/day based on mg/m 2 body surface area) and 0.25, 2, 8 mg/kg/day (equivalent to 0.06 to 2 times the MRHD based on mg/m 2 body surface area). Rats were dosed for 2 years at doses of 0.25, 1, 2.5, 4 mg/kg/day (males) and 0.25, 1, 4, 8 mg/kg/day (females) (equivalent to 0.13 to 2 and 0.13 to 4 times the MRHD based on mg/m 2 body surface area, respectively).

The incidence of liver hemangiomas and hemangiosarcomas was significantly increased in 1 mouse study in female mice dosed at 8 mg/kg/day (2 times the MRHD based on mg/m 2 body surface area). These tumors were not increased in another mouse study in females dosed at 10 or 30/20 mg/kg/day (2 to 5 times the MRHD based on mg/m 2 body surface area); in this study, there was a high incidence of early mortalities in males of the 30/20 mg/kg/day group. The incidence of mammary gland adenomas and adenocarcinomas was significantly increased in female mice dosed at ≥2 mg/kg/day and in female rats dosed at ≥4 mg/kg/day (0.5 and 2 times the MRHD based on mg/m 2 body surface area, respectively).

Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the olanzapine carcinogenicity studies; however, measurements during subchronic toxicity studies showed that olanzapine elevated serum prolactin levels up to 4-fold in rats at the same doses used in the carcinogenicity study. An increase in mammary gland 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 finding of prolactin mediated endocrine tumors in rodents is unknown [see Warnings and Precautions ( 5.17 )] . Samidorphan Samidorphan did not increase the incidence of tumors in rats administered oral doses of 20, 35, or 75 mg/kg/day (males) and 15, 30, or 60 mg/kg/day (females) for 96 (males) and 95 (females) weeks, which are up to 32 and 237 times the MRHD of 10 mg/day in males and females, respectively based on AUC. Samidorphan did not increase the incidence of tumors in transgenic rasH2 mice administered oral doses of 125, 250, or 500 mg/kg/day for 26 weeks.

Mutagenesis Olanzapine No evidence of genotoxic potential for olanzapine was found in the Ames reverse mutation test, in vivo micronucleus test in mice, the chromosome aberration test in Chinese hamster ovary cells, unscheduled DNA synthesis test in rat hepatocytes, induction of forward mutation test in mouse lymphoma cells, or in vivo sister chromatid exchange test in bone marrow of Chinese hamsters. Samidorphan No evidence of genotoxicity of samidorphan was found in the in vitro Ames bacterial reverse mutation test, the in vitro chromosome aberration assay in human peripheral blood lymphocytes or in the in vivo mouse bone marrow micronucleus assay.

Impairment of Fertility Olanzapine In an oral fertility and reproductive performance study in rats, male mating performance, but not fertility, was impaired at a dose of 22.4 mg/kg/day and female fertility was decreased at a dose of 3 mg/kg/day (11 and 1.5 times the MRHD of 20 mg/day based on mg/m 2 body surface area, respectively). Discontinuance of olanzapine treatment reversed the effects on male mating performance. In female rats, the precoital period was increased and the mating index reduced at 5 mg/kg/day (2.5 times the MRHD based on mg/m 2 body surface area).

Diestrus was prolonged and estrus delayed at 1.1 mg/kg/day (0.6 times the daily oral MRHD based on mg/m 2 body surface area); therefore, olanzapine may produce a delay in ovulation. Samidorphan Samidorphan did not impair fertility when administered orally to female rats… [Excerpted — this section continues on DailyMed.]