Lumateperone

1 INDICATIONS AND USAGE CAPLYTA is indicated for: Treatment of schizophrenia in adults [see Clinical Studies (14.1) ] . Treatment of depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults, as monotherapy and as adjunctive therapy with lithium or valproate [see Clinical Studies (14.2) ] . Adjunctive therapy with antidepressants for the treatment of major depressive disorder (MDD) in adults [see Clinical Studies ( 14.3 ) ]. CAPLYTA is an atypical antipsychotic indicated for: Treatment of schizophrenia in adults. ( 1 ) Treatment of depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults, as monotherapy and as adjunctive therapy with lithium or valproate. ( 1 ) Adjunctive therapy with antidepressants for the treatment of major depressive disorder (MDD) in adults. ( 1 )

12.1 Mechanism of Action The mechanism of action of lumateperone for the treatment of schizophrenia in adults, for the treatment of depressive episodes associated with bipolar depression (as monotherapy or as adjunctive therapy with lithium or valproate), and as adjunctive therapy with antidepressants for the treatment of MDD is unknown. However, the mechanism of action of lumateperone for these uses could be mediated through a combination of antagonist activity at central serotonin 5-HT 2A receptors, and partial agonist activity at central dopamine D 2 receptors.

2 DOSAGE AND ADMINISTRATION Recommended oral dosage of CAPLYTA is 42 mg once daily with or without food. ( 2.1 ) Moderate hepatic impairment or severe hepatic impairment: Recommended dosage is 21 mg once daily. ( 2.3 , 8.6 ) 2.1 Recommended Dosage The recommended CAPLYTA dosage is 42 mg administered orally once daily with or without food. Dose titration is not needed. 2.2 Dosage Recommendations for Concomitant Use with Moderate or Strong CYP3A4 Inhibitors The recommended CAPLYTA dosage in patients who receive [see Drug Interactions ( 7.1 ) ] : Strong CYP3A4 inhibitors is 10.5 mg once daily. Moderate CYP3A4 inhibitors is 21 mg once daily. 2.3 Dosage Recommendations for Patients with Hepatic Impairment For patients with moderate hepatic impairment (HI) (Child-Pugh class B) or severe HI (Child-Pugh class C), the recommended CAPLYTA dosage is 21 mg once daily [see Use in Specific Populations (8.6) ] . The recommended CAPLYTA dosage in patients with mild HI is the same as those with normal hepatic function.

6 ADVERSE REACTIONS The following adverse reactions are discussed in detail in other sections of the labeling: Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning , Warnings and Precautions (5.1) ] Suicidal Thoughts and Behaviors [see Boxed Warning , Warnings and Precautions (5.2) ] Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-related Psychosis [see Warnings and Precautions (5.3) ] Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.4) ] Tardive Dyskinesia [see Warnings and Precautions (5.5) ] Metabolic Changes [see Warnings and Precautions (5.6) ] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.7) ] Orthostatic Hypotension and Syncope [see Warnings and Precautions (5.8) ] Falls [see Warnings and Precautions (5.9) ] Seizures [see Warnings and Precautions (5.10) ] Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.11) ] Body Temperature Dysregulation [see Warnings and Precautions (5.12) ] Dysphagia [see Warnings and Precautions (5.13) ] Most common adverse reactions in clinical trials (incidence ≥ 5% and greater than twice placebo) were ( 6.1 ): Schizophrenia: somnolence/sedation and dry mouth. Bipolar depression: somnolence/sedation, dizziness, nausea, dry mouth. MDD: dizziness, dry mouth, somnolence/sedation, nausea, fatigue, diarrhea. To report SUSPECTED ADVERSE REACTIONS, contact Intra-Cellular Therapies, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of CAPLYTA has been evaluated in placebo-controlled clinical trials that included 3575 adult patients with schizophrenia, bipolar depression, or major depressive disorder, exposed to one or more CAPLYTA doses. A total of 852 CAPLYTA-treated patients had at least 6 months of treatment and 108 had at least 1 year of treatment with the 42-mg once daily dosage. Adverse Reactions in Patients with Schizophrenia The following adverse reactions are based on the pooled short-term (4- to 6-week), placebo-controlled studies in adult patients with schizophrenia in which CAPLYTA was administered at a dosage of 42 mg once daily (N=406) [see Clinical Studies (14.1) ]. There was no single adverse reaction that led to discontinuation that occurred at a rate of >2% in CAPLYTA-treated patients. The most common adverse reactions (incidence of at least 5% of CAPLYTA-treated patients and greater than twice the rate of placebo-treated patients) were somnolence/sedation and dry mouth. Adverse reactions (incidence of at least 2% in CAPLYTA-treated patients and greater than in placebo-treated patients) are shown in Table 2. Table 2: Adverse Reactions Reported in ≥2% of CAPLYTA-Treated Patients and Greater Incidence Than in Placebo-Treated Patients in 4- to 6-week Schizophrenia Trials CAPLYTA 42 mg (N=406) Placebo (N=412) Somnolence/Sedation 24% 10% Nausea 9% 5% Dry Mouth 6% 2% Dizziness 1 5% 3% Creatine Phosphokinase Increased 4% 1% Fatigue 3% 1% Vomiting 3% 2% Hepatic Transaminases Increased 2 2% 1% Decreased Appetite 2% 1% 1 Dizziness, dizziness postural 2 ALT, AST, “hepatic enzymes” increased, or liver function test abnormal Adverse Reactions in Patients with Bipolar Depression (CAPLYTA Monotherapy) The following adverse reactions are based on the pooled short-term (6-week), placebo-controlled monotherapy bipolar depression studies in adult patients treated with CAPLYTA 42 mg once daily (N=372) [see Clinical Studies (14.2) ] . There was no single adverse reaction leading to discontinuation that occurred at a rate of >2% in CAPLYTA-treated patients. The most common adverse reactions (incidence of at least 5% of CAPLYTA-treated

5 WARNINGS AND PRECAUTIONS Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke and transient ischemic attack). ( 5.3 ) Neuroleptic Malignant Syndrome: If NMS is suspected, immediately discontinue CAPLYTA and provide intensive symptomatic treatment and monitoring. ( 5.4 ) Tardive Dyskinesia: If signs and symptoms of TD occur consider discontinuing CAPLYTA treatment. ( 5.5 ) Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain. ( 5.6 ) Leukopenia, Neutropenia, and Agranulocytosis : In patients with pre-existing low white blood cell count (WBC) or history of leukopenia or neutropenia, perform complete blood counts (CBC). Consider discontinuing CAPLYTA if clinically significant decline in WBC occurs in absence of other causative factors. Discontinue CAPLYTA in patients with clinically significant neutropenia or ANC < 1000/mm 3 and monitor closely until the neutropenia resolve. ( 5.7 ) Orthostatic Hypotension and Syncope: Monitor heart rate and blood pressure in patients who are vulnerable to hypotension. ( 5.8 ) Seizures: Use cautiously in patients with a history of seizures or with other conditions that lower seizure threshold. ( 5.10 ) Potential for Cognitive and Motor Impairment: Use caution when operating machinery and driving a motor vehicle until patients are reasonably certain that therapy with CAPLYTA does not affect them adversely. ( 5.11 ) 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. In an analysis of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, the risk of death in antipsychotic drug-treated patients was 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the incidence of death in antipsychotic-treated patients was about 4.5%, compared to an incidence of about 2.6% in placebo-treated patients. Although the causes of death varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia). CAPLYTA is not approved for the treatment of patients with dementia-related psychosis [see Indications and Usage (1) ] . 5.2 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated pediatric and young adult patients was greater than in placebo-treated patients. There were differences in absolute risk of suicidal thoughts and behaviors across the different uses, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 1. Table 1: Risk Differences of the Number of Patients with Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric* and Adult Patients Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 years old 14 additional patients 18-24 years old 5 additional patients Decreases Compared to Placebo 25-64 years old 1 fewer patient > 65 years old 6 fewer patients * CAPLYTA is not approved for use in pediatric patients. It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay th

4 CONTRAINDICATIONS CAPLYTA is contraindicated in patients with history of hypersensitivity reaction to lumateperone or any components of CAPLYTA. Reactions have included pruritus, rash (e.g. allergic dermatitis, papular rash, and generalized rash), and urticaria. CAPLYTA is contraindicated in patients with history of hypersensitivity reaction to lumateperone or any components of CAPLYTA. ( 4 )

10 OVERDOSAGE No specific antidotes for CAPLYTA are known. In managing a CAPLYTA overdose, provide supportive care, including close medical supervision and monitoring and consider the possibility of multiple drug involvement. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.