Lumateperone is an atypical antipsychotic present as lumateperone tosylate salt with the chemical name 4-((6b R ,10a S )-3-methyl-2,3,6b,9,10,10 a -hexahydro-1 H ,7 H -pyrido[3',4':4,5]pyrrolo[1,2,3- de ]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-one 4-methylbenzenesulfonate. Its molecular formula is C 31 H 36 FN 3 O 4 S, and its molecular weight is 565.71 g/mol with the following structure: CAPLYTA (lumateperone) capsules are for oral administration. Each capsule contains: 42 mg of lumateperone (equivalent to 60 mg of lumateperone tosylate), or 21 mg of lumateperone (equivalent to 30 mg of lumateperone tosylate), or 10.5 mg of lumateperone (equivalent to 15 mg of lumateperone tosylate). The capsules include the following inactive ingredients: croscarmellose sodium, gelatin, magnesium stearate, mannitol, and talc. Colorants include FD&C blue #1 and red #3 (42 mg), FDA/E172 black iron oxide, FDA/E172 red iron oxide and FD&C red #3 (10.5 mg), and titanium dioxide (42 mg, 21 mg and 10.5 mg). Chemical Structure

CAPLYTA is indicated for: Treatment of schizophrenia in adults . 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 . Adjunctive therapy with antidepressants for the treatment of major depressive disorder (MDD) in adults . CAPLYTA is an atypical antipsychotic indicated for: Treatment of schizophrenia in adults. 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. Adjunctive therapy with antidepressants for the treatment of major depressive disorder (MDD) in adults.

CAPLYTA capsules are available in three strengths: 42 mg: Blue cap and opaque white body imprinted with “ITI-007 42 mg” 21 mg: Opaque white cap and body imprinted with “ITI-007 21 mg” 10.5 mg: Opaque light pink cap and body imprinted with “ITI-007 10.5 mg” Capsules: 42 mg, 21 mg, 10.5 mg

Recommended oral dosage of CAPLYTA is 42 mg once daily with or without food. Moderate hepatic impairment or severe hepatic impairment: Recommended dosage is 21 mg once daily

Recommended Dosage The recommended CAPLYTA dosage is 42 mg administered orally once daily with or without food. Dose titration is not needed

Dosage Recommendations for Concomitant Use with Moderate or Strong CYP3A4 Inhibitors The recommended CAPLYTA dosage in patients who receive : Strong CYP3A4 inhibitors is 10.5 mg once daily. Moderate CYP3A4 inhibitors is 21 mg once daily

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 . The recommended CAPLYTA dosage in patients with mild HI is the same as those with normal hepatic function.

Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke and transient ischemic attack). Neuroleptic Malignant Syndrome: If NMS is suspected, immediately discontinue CAPLYTA and provide intensive symptomatic treatment and monitoring. Tardive Dyskinesia: If signs and symptoms of TD occur consider discontinuing CAPLYTA treatment. Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain. 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. Orthostatic Hypotension and Syncope: Monitor heart rate and blood pressure in patients who are vulnerable to hypotension. Seizures: Use cautiously in patients with a history of seizures or with other conditions that lower seizure threshold. 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. 5.1 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

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 the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients, especially during the initial few months of anti-depressant drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the health care provider. Consider changing the therapeutic regimen, including possibly discontinuing CAPLYTA, in patients whose depression is persistently worse, or who experience suicidal thoughts or behaviors

Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials, elderly patients with dementia-related psychosis treated with antipsychotics had a higher incidence of stroke and transient ischemic attack, including fatal stroke compared to those treated with placebo. CAPLYTA is not approved for the treatment of patients with dementia-related psychosis

Neuroleptic Malignant Syndrome Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, delirium, and autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue CAPLYTA and provide intensive symptomatic treatment and monitoring

Tardive Dyskinesia Tardive dyskinesia (TD) may develop in patients treated with antipsychotic drugs, including CAPLYTA. TD can develop after a relatively brief treatment period at low dosages and may also occur after discontinuation of treatment. If antipsychotic treatment is discontinued, TD may partially or completely remit. Antipsychotic treatment, however, may suppress or partially suppress the signs and symptoms of TD, and may mask the underlying process. The effect that symptomatic suppression has upon the long-term course of TD is unknown. The TD risk appears to be highest among the elderly, especially elderly women, but it is not possible to predict which patients are likely to develop TD. The TD risk and the likelihood that TD will become irreversible increase with the duration of antipsychotic drug treatment and the cumulative dosage. Periodically reassess the need for continued treatment. If signs and symptoms of TD appear in CAPLYTA-treated patients, consider drug discontinuation. However, some patients may require CAPLYTA treatment despite the presence of TD

Metabolic Changes Antipsychotic drugs have caused metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma or death, has been reported in patients treated with antipsychotics. There have been reports of hyperglycemia in patients treated with CAPLYTA. Assess fasting plasma glucose before or soon after initiation of CAPLYTA and monitor periodically during long-term treatment. In pooled data from short-term (4- to 6-week), placebo-controlled trials of adult patients with schizophrenia, mean changes from baseline and the proportion of patients with shifts from normal to greater than normal levels of fasting glucose were similar in CAPLYTA-treated and placebo-treated patients. In an uncontrolled open-label trial of CAPLYTA for up to 1 year in adult patients with stable schizophrenia, the percentages of patients with shifts in fasting glucose and insulin values from normal to high were 8% and 12%, respectively. In this trial, 5% of CAPLYTA-treated patients with normal hemoglobin A1c (<6.5%) at baseline developed elevated levels (≥6.5%) post-baseline. In data from short-term (6-week), placebo-controlled monotherapy and adjunctive therapy bipolar depression trials, mean changes from baseline and the proportion of patients with shifts from normal to greater than normal levels of fasting glucose and insulin were similar in CAPLYTA-treated and placebo-treated patients. In pooled data from short-term (6-week), placebo-controlled adjunctive therapy MDD trials, mean changes from baseline and the proportion of patients with shifts from normal to greater than normal levels of fasting glucose were similar in CAPLYTA-treated and placebo-treated patients. Dyslipidemia Antipsychotics have caused adverse alterations in lipids. Before or soon after initiation of antipsychotic medications, obtain a fasting lipid profile at baseline and monitor periodically during treatment. In pooled data from short-term (4- to 6-week), placebo-controlled trials of adult patients with schizophrenia, mean changes from baseline and the proportion of patients with shifts to higher levels of fasting total cholesterol and triglycerides were similar in CAPLYTA-treated and placebo-treated patient. In an uncontrolled open-label trial of CAPLYTA for up to 1 year in patients with stable schizophrenia, the percentages of patients with a shift from normal to high were 8%, 5%, and 4% for total cholesterol, triglycerides, and LDL cholesterol, respectively. In data from short-term (6-week), placebo-controlled monotherapy and adjunctive therapy bipolar depression trials, mean changes from baseline and the proportion of patients with shifts to higher levels of fasting total cholesterol and triglycerides were similar in CAPLYTA-treated and placebo-treated patients. In an uncontrolled open-label trial of CAPLYTA for up to 6 months in patients with bipolar depression, the proportion of patients with a shift from normal to high were 10%, 5%, and 2% for total cholesterol, triglycerides, and LDL cholesterol, respectively. In pooled data from short-term (6-week), placebo-controlled adjunctive therapy MDD trials, mean changes from baseline and the proportion of patients with shifts to higher levels of fasting total cholesterol and triglycerides were similar in CAPLYTA-treated and placebo-treated patients. Weight Gain Weight gain has been observed with use of antipsychotics. Monitor weight at baseline and frequently thereafter. In pooled data from placebo-controlled trials of adult patients with schizophrenia, mean changes from baseline and the proportion of patients with an increase in weight ≥7% from baseline to end of study was similar in CAPLYTA-treated and placebo-treated patients. In an uncontrolled open-label trial of CAPLYTA for up to one year in patients with stable schizophrenia, the mean change in body weight was approximately -2 kg (SD 5.6) at Day 175 and approximately - 3.2 kg (SD 7.4) at Day 350. In data from short-term (6-week), placebo-controlled monotherapy and adjunctive therapy bipolar depression trials, mean changes from baseline and the proportion of patients with an increase in weight ≥7% from baseline to end of study were similar in CAPLYTA-treated and placebo-treated patients. In an uncontrolled open-label trial of CAPLYTA for up to 6 months in patients with bipolar depression, the mean change in body weight was -0.01 kg (SD 3.1) at Day 175. In pooled data from short-term (6-week), placebo-controlled adjunctive therapy MDD trials, mean changes from baseline and the proportion of patients with an increase in weight ≥7% from baseline to end of study were similar in CAPLYTA-treated and placebo-treated patients. In a long-term open-label adjunctive therapy MDD trial of CAPLYTA for up to 6 months, the mean change in body weight was -0.16 kg (SD 3.7) at Week 26

Leukopenia, Neutropenia, and Agranulocytosis Leukopenia and neutropenia have been reported during treatment with antipsychotic drugs, including CAPLYTA. Agranulocytosis (including fatal cases) has been reported with other antipsychotic drugs. Possible risk factors for antipsychotic drug-leukopenia and neutropenia include pre-existing low white blood cell count (WBC) or absolute neutrophil count (ANC) and history of drug-induced leukopenia or neutropenia. In patients with a pre-existing low WBC or ANC or a history of drug-induced leukopenia or neutropenia, perform complete blood count (CBC) monitoring during the first few months of CAPLYTA therapy. Consider discontinuing CAPLYTA in patients who have a clinically significant decline in WBC in the absence of other causative factors. Discontinue CAPLYTA in patients with clinically significant neutropenia or ANC < 1000/mm 3 and monitor closely until the neutropenia resolves

Orthostatic Hypotension and Syncope Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose administration. Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension (e.g., elderly patients, patients with dehydration, hypovolemia, and concomitant treatment with antihypertensive drugs), patients with known cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. CAPLYTA has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease. Such patients were excluded from pre-marketing clinical trials. In pooled data from short-term (4- to 6-week), placebo-controlled schizophrenia trials, the frequencies of orthostatic hypotension in CAPLYTA-treated and placebo-treated patients were 0.7% and 0%, respectively. The incidence of syncope for CAPLYTA-treated and placebo-treated patients were 0.2% and 0.2%. In data from short-term (6-week), placebo-controlled monotherapy and adjunctive therapy bipolar depression trials, the frequencies of orthostatic hypotension for CAPLYTA-treated and placebo-treated patients were both 0%. The incidence of syncope for CAPLYTA and placebo were 0.3% and 0.5%, respectively in the monotherapy trials, and there were no reports of syncope in the adjunctive therapy trial. In pooled data from short-term (6-week), placebo-controlled adjunctive therapy MDD trials, the frequencies of orthostatic hypotension for CAPLYTA-treated and placebo-treated patients were 6.6% and 6.2%, respectively. The incidence of syncope for CAPLYTA-treated and placebo-treated patients were 0.2% and 0%, respectively

Falls Antipsychotics, including CAPLYTA, may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls and, consequently, fractures and other injuries. If patients have a condition (or take concomitant drugs) that could exacerbate these effects, complete fall risk assessments when initiating CAPLYTA treatment and periodically during long-term treatment

Seizures Like other antipsychotic drugs, CAPLYTA may cause seizures. The risk of antipsychotic drug-associated seizures is greatest in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in older patients. Use CAPLYTA cautiously in patients with a history of seizures or with other conditions that lower seizure threshold

Potential for Cognitive and Motor Impairment CAPLYTA, like other antipsychotics, may cause somnolence and has the potential to impair judgment, thinking, and motor skills. Patients should be cautioned about operating hazardous machinery and motor vehicles until they are reasonably certain that therapy with CAPLYTA does not affect them adversely. In short-term (i.e., 4- to 6-week), placebo-controlled clinical trials of patients with schizophrenia, somnolence and sedation were reported in 24% of CAPLYTA-treated patients, compared to 10% of placebo-treated patients. In short term (6-week), placebo-controlled monotherapy and adjunctive therapy bipolar depression clinical trials, somnolence and sedation were reported in 13% of CAPLYTA-treated patients, compared to 3% of placebo-treated patients. In short term (6-week), placebo-controlled adjunctive therapy MDD trials, somnolence and sedation were reported in 12% of CAPLYTA-treated patients, compared to 2% of placebo-treated patients

Body Temperature Dysregulation Atypical antipsychotics may disrupt the body’s ability to reduce core body temperature. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic drugs may contribute to an elevation in core body temperature. Use CAPLYTA with caution in patients who may experience these conditions

Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Antipsychotic drugs, including CAPLYTA, should be used cautiously in patients at risk for aspiration.

CYP3A4 inducers: Avoid concomitant use with CAPLYTA. Strong CYP3A4 inhibitors: Recommended dosage is 10.5 mg once daily. Moderate CYP3A4 inhibitors: Recommended dosage is 21 mg once daily

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 . Moderate or Strong CYP3A4 Inhibitors* Prevention or Management Reduce the CAPLYTA dosage when used concomitantly with moderate or strong CYP3A4 inhibitors . Clinical Impact Concomitant use of CAPLYTA with moderate or strong CYP3A4 inhibitors increases lumateperone exposure , 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