Lumateperone

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.

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 )

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 1-888-611-4824 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 patients and greater than twice the rate in placebo-treated patients) were somnolence/sedation, dizziness, nausea, and dry mouth. Adverse reactions associated with CAPLYTA (incidence of at least 2% in CAPLYTA-treated patients and greater than placebo-treated patients) are shown in Table 3. Table 3: Adverse Reactions Reported in ≥2% of CAPLYTA-Treated Patients and Greater Incidence than in Placebo-Treated Patients in Pooled 6-week Monotherapy Bipolar Depression Trials CAPLYTA 42 mg (N=372) Placebo (N=374) Headache 14% 8% Somnolence/Sedation 13% 3% Dizziness 1 8% 4% Nausea 8% 3% Dry mouth 5% 1% Diarrhea 4% 2% Vomiting 4% 0% Abdominal pain 2 2% 1% Upper respiratory tract infection 2% 1% 1 Dizziness, dizziness postural 2 Abdominal discomfort, abdominal pain, abdominal pain upper and lower Adverse Reactions in Patients with Bipolar Depression (Concomitant Treatment with CAPLYTA and Lithium or Valproate) The adverse reactions below are based on a 6-week, placebo-controlled adjunctive therapy

7 DRUG INTERACTIONS CYP3A4 inducers: Avoid concomitant use with CAPLYTA. ( 7.1 ) Strong CYP3A4 inhibitors: Recommended dosage is 10.5 mg once daily. ( 2.2 , 7.1 ) Moderate CYP3A4 inhibitors: Recommended dosage is 21 mg once daily. ( 2.2 , 7.1 ) 7.1 Drugs Having Clinically Important Interactions with CAPLYTA Clinically important drug interactions with CAPLYTA are presented in Table 6. Table 6: Clinically Important Drug Interactions with CAPLYTA CYP3A4 Inducers* Prevention or Management Avoid concomitant use of CAPLYTA with CYP3A4 inducers . Clinical Impact Concomitant use of CAPLYTA with CYP3A4 inducers decreases the exposure of lumateperone [see Clinical Pharmacology ( 12.3 ) ]. Moderate or Strong CYP3A4 Inhibitors* Prevention or Management Reduce the CAPLYTA dosage when used concomitantly with moderate or strong CYP3A4 inhibitors [see Dosage and Administration ( 2.2 ) ]. Clinical Impact Concomitant use of CAPLYTA with moderate or strong CYP3A4 inhibitors increases lumateperone exposure [see Clinical Pharmacology ( 12.3 ) ] , which may increase the risk of adverse reactions. S erotonin Reuptake Inhibitors Prevention or Management Increased monitoring for SRI- associated adverse reactions is recommended. Clinical Impact Although no clinically significant drug interactions with adjunctive SSRI/SNRIs in MDD were observed in CAPLYTA clinical trials, CAPLYTA’s moderate serotonin transporter (SERT) activity may increase the risk of SRI-associated adverse reactions (e.g., serotonin syndrome, hyponatremia). * See www.fda.gov/CYPandTransporterInteractingDrugs for examples of CYP3A4 Inducers and Moderate or Strong CYP3A4 Inhibitors