LATUDA is an atypical antipsychotic belonging to the chemical class of benzisothiazol derivatives. Its chemical name is (3a R ,4 S ,7 R ,7a S )-2-{(1 R ,2 R )-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2 H -isoindole-1,3-dione hydrochloride. Its molecular formula is C 28 H 36 N 4 O 2 S•HCl and its molecular weight is 529.14. The chemical structure is: Lurasidone hydrochloride is a white to off-white powder. It is very slightly soluble in water, practically insoluble or insoluble in 0.1 N HCl, slightly soluble in ethanol, sparingly soluble in methanol, practically insoluble or insoluble in toluene and very slightly soluble in acetone. LATUDA tablets are intended for oral administration only. Each tablet contains 20 mg, 40 mg, 60 mg, 80 mg, or 120 mg of lurasidone hydrochloride. Inactive ingredients are mannitol, pregelatinized starch, croscarmellose sodium, hypromellose, magnesium stearate, Opadry ® and carnauba wax. Additionally, the 80 mg tablet contains yellow ferric oxide and FD&C Blue No. 2 Aluminum Lake. Chemical Structure

LATUDA is indicated for: Treatment of adult and adolescent patients (13 to 17 years) with schizophrenia . Monotherapy treatment of adult and pediatric patients (10 to 17 years) with major depressive episode associated with bipolar I disorder (bipolar depression) . Adjunctive treatment with lithium or valproate in adult patients with major depressive episode associated with bipolar I disorder (bipolar depression) . LATUDA is an atypical antipsychotic indicated for the treatment of: Schizophrenia in adults and adolescents (13 to 17 years) ( 1 , 14.1 ) Depressive episode associated with Bipolar I Disorder (bipolar depression) in adults and pediatric patients (10 to 17 years) as monotherapy ( 1 , 14.2 ) Depressive episode associated with Bipolar I Disorder (bipolar depression) in adults as adjunctive therapy with lithium or valproate ( 1 , 14.2 )

LATUDA tablets are available in the following shape and color ( Table 1 ) with respective one-sided debossing. Table 1: LATUDA Tablet Presentations Tablet Strength Tablet Color/Shape Tablet Markings 20 mg white to off-white round L20 40 mg white to off-white round L40 60 mg white to off-white oblong L60 80 mg pale green oval L80 120 mg white to off-white oval L120 Tablets: 20 mg, 40 mg, 60 mg, 80 mg and 120 mg

LATUDA should be taken with food (at least 350 calories). Administration with food substantially increases the absorption of LATUDA ( 2.3 , 12.3 ). Indication Starting Dose Recommended Dose Schizophrenia – adults 40 mg per day 40 mg to 160 mg per day Schizophrenia –adolescents (13 to 17 years) 40 mg per day 40 mg to 80 mg per day Bipolar Depression - adults 20 mg per day 20 mg to 120 mg per day Bipolar Depression –pediatric patients (10 to 17 years) 20 mg per day 20 mg to 80 mg per day Moderate and Severe Renal Impairment: Recommended starting dose is 20 mg per day, and the maximum recommended dose is 80 mg per day ( 2.4, 8.6 ). Moderate and Severe Hepatic Impairment: Recommended starting dose is 20 mg per day. The maximum recommended dose is 80 mg per day in moderate hepatic impairment and 40 mg per day in severe hepatic impairment ( 2.5, 8.7 ). Concomitant Use of a Moderate CYP3A4 inhibitor (e.g., diltiazem): LATUDA dose should be reduced to half of the original dose level. Recommended starting dose is 20 mg per day. Maximum recommended dose is 80 mg per day. Concomitant Use of a Moderate CYP3A4 Inducer: It may be necessary to increase the dose of LATUDA

Schizophrenia Adults The recommended starting dose of LATUDA is 40 mg once daily. Initial dose titration is not required. LATUDA has been shown to be effective in a dose range of 40 mg per day to 160 mg per day . The maximum recommended dose is 160 mg per day. Adolescents (13 – 17 years) The recommended starting dose of LATUDA is 40 mg once daily. Initial dose titration is not required. LATUDA has been shown to be effective in a dose range of 40 mg per day to 80 mg per day . The maximum recommended dose is 80 mg per day

Depressive Episodes Associated with Bipolar I Disorder Adults The recommended starting dose of LATUDA is 20 mg given once daily as monotherapy or as adjunctive therapy with lithium or valproate. Initial dose titration is not required. LATUDA has been shown to be effective in a dose range of 20 mg per day to 120 mg per day as monotherapy or as adjunctive therapy with lithium or valproate . The maximum recommended dose, as monotherapy or as adjunctive therapy with lithium or valproate, is 120 mg per day. In the monotherapy study, the higher dose range (80 mg to 120 mg per day) did not provide additional efficacy, on average, compared to the lower dose range (20 to 60 mg per day) . Pediatric Patients (10 – 17 years) The recommended starting dose of LATUDA is 20 mg given once daily as monotherapy. Initial dose titration is not required. The dose may be increased after one week based on clinical response. LATUDA has been shown to be effective in a dose range of 20 mg per day to 80 mg per day as monotherapy. At the end of the clinical study, most of the patients (67%) received 20 mg or 40 mg once daily . The maximum recommended dose is 80 mg per day. The efficacy of LATUDA in the treatment of mania associated with bipolar disorder has not been established

Administration Information LATUDA should be taken with food (at least 350 calories). Administration with food substantially increases the absorption of LATUDA. Administration with food increases the AUC approximately 2-fold and increases the Cmax approximately 3-fold. In the clinical studies, LATUDA was administered with food . The effectiveness of LATUDA for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. Therefore, the physician who elects to use LATUDA for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient

Dose Modifications for Renal Impairment Dose adjustment is recommended in moderate (creatinine clearance: 30 to <50 mL/min) and severe renal impairment (creatinine clearance <30 mL/min) patients. The recommended starting dose is 20 mg per day. The dose in these patients should not exceed 80 mg per day

Dose Modifications for Hepatic Impairment Dose adjustment is recommended in moderate (Child-Pugh Score = 7 to 9) and severe hepatic impairment (Child-Pugh Score = 10 to 15) patients. The recommended starting dose is 20 mg per day. The dose in moderate hepatic impairment patients should not exceed 80 mg per day and the dose in severe hepatic impairment patients should not exceed 40 per mg/day

Dose Modifications Due to Drug Interactions of CYP3A4 Inhibitors and CYP3A4 Inducers Concomitant Use with CYP3A4 Inhibitors LATUDA should not be used concomitantly with a strong CYP3A4 inhibitor (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.) . If LATUDA is being prescribed and a moderate CYP3A4 inhibitor (e.g. diltiazem, atazanavir, erythromycin, fluconazole, verapamil etc.) is added to the therapy, the LATUDA dose should be reduced to half of the original dose level. Similarly, if a moderate CYP3A4 inhibitor is being prescribed and LATUDA is added to the therapy, the recommended starting dose of LATUDA is 20 mg per day, and the maximum recommended dose of LATUDA is 80 mg per day . Grapefruit and grapefruit juice should be avoided in patients taking LATUDA, since these may inhibit CYP3A4 and alter LATUDA concentrations . Concomitant Use with CYP3A4 Inducers LATUDA should not be used concomitantly with a strong CYP3A4 inducer (e.g., rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine, etc.) . If LATUDA is used concomitantly with a moderate CYP3A4 inducer, it may be necessary to increase the LATUDA dose after chronic treatment (7 days or more) with the CYP3A4 inducer.

Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack). Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring. Tardive Dyskinesia: Discontinue if clinically appropriate. Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia and weight gain. Hyperprolactinemia: Prolactin elevations may occur. Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts (CBC) in patients with a pre-existing low white blood cell count (WBC) or a history of leukopenia or neutropenia. Consider discontinuing LATUDA if a clinically significant decline in WBC occurs in the absence of other causative factors. Orthostatic Hypotension and Syncope: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope

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. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 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 rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. LATUDA 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 over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2 . No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about antidepressant drug effect on suicide. Table 2: Risk Differences of the Number of Cases of Suicidal Thoughts or 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 14 additional patients 18-24 5 additional patients Decreases Compared to Placebo 25-64 1 fewer patient ≥65 6 fewer 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 studies in adults with MDD that antidepressants delay the recurrence of depression. Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of 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 healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing LATUDA, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors

Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks), including fatalities, compared to placebo-treated subjects. LATUDA is not approved for the treatment of patients with dementia-related psychosis

Neuroleptic Malignant Syndrome A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including LATUDA. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue LATUDA and provide intensive symptomatic treatment and monitoring

Tardive Dyskinesia Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements that can develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, LATUDA should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic drugs, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on LATUDA, drug discontinuation should be considered. However, some patients may require treatment with LATUDA despite the presence of the syndrome

Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. Schizophrenia Adults Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 3 . Table 3: Change in Fasting Glucose in Adult Schizophrenia Studies LATUDA Placebo 20 mg/day 40 mg/day 80 mg/day 120 mg/day 160 mg/day Mean Change from Baseline (mg/dL) n=680 n=71 n=478 n=508 n=283 n=113 Serum Glucose -0.0 -0.6 +2.6 -0.4 +2.5 +2.5 Proportion of Patients with Shifts to ≥ 126 mg/dL Serum Glucose (≥ 126 mg/dL) 8.3% (52/628) 11.7% (7/60) 12.7% ( 57/449) 6.8% (32/472) 10.0% (26/260) 5.6% (6/108) In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a mean change in glucose of +1.8 mg/dL at week 24 (n=355), +0.8 mg/dL at week 36 (n=299) and +2.3 mg/dL at week 52 (n=307). Adolescents In studies of adolescents and adults with schizophrenia, changes in fasting glucose were similar. In the short-term, placebo-controlled study of adolescents, fasting serum glucose mean values were -1.3 mg/dL for placebo (n=95), +0.1 mg/dL for 40 mg/day (n=90), and +1.8 mg/dL for 80 mg/day (n=92). Bipolar Depression Adults Monotherapy Data from the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study are presented in Table 4 . Table 4: Change in Fasting Glucose in the Adult Monotherapy Bipolar Depression Study LATUDA Placebo 20 to 60 mg/day 80 to 120 mg/day Mean Change from Baseline (mg/dL) Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo n=148 n=140 n=143 Serum Glucose +1.8 -0.8 +1.8 Proportion of Patients with Shifts to ≥ 126 mg/dL Serum Glucose (≥ 126 mg/dL) 4.3% (6/141) 2.2% (3/138) 6.4% (9/141) In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as monotherapy in the short-term study and continued in the longer-term study, had a mean change in glucose of +1.2 mg/dL at week 24 (n=129). Adjunctive Therapy with Lithium or Valproate Data from the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 5 . Table 5: Change in Fasting Glucose in the Adult Adjunctive Therapy Bipolar Depression Studies LATUDA Placebo 20 to 120 mg/day Mean Change from Baseline (mg/dL) Patients were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate. n=302 n=319 Serum Glucose -0.9 +1.2 Proportion of Patients with Shifts to ≥ 126 mg/dL Serum Glucose (≥ 126 mg/dL) 1.0% (3/290) 1.3% (4/316) In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in glucose of +1.7 mg/dL at week 24 (n=88). Pediatric Patients (10 to 17 years) In studies of pediatric patients 10 to 17 years and adults with bipolar depression, changes in fasting glucose were similar. In the 6-week, placebo-controlled study of pediatric patients with bipolar depression, mean change in fasting glucose was +1.6 mg/dL for LATUDA 20 to 80 mg/day (n=145) and -0.5 mg/dL for placebo (n=145). Pediatric Patients (6 to 17 years) In a 104-week, open-label study in pediatric patients with schizophrenia, bipolar depression, or autistic disorder, 7% of patients with a normal baseline fasting glucose experienced a shift to high at endpoint while taking lurasidone. Dyslipidemia Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Schizophrenia Adults Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 6 . Table 6: Change in Fasting Lipids in Adult Schizophrenia Studies LATUDA Placebo 20 mg/day 40 mg/day 80 mg/day 120 mg/day 160 mg/day Mean Change from Baseline (mg/dL) n=660 n=71 n=466 n=499 n=268 n=115 Total Cholesterol -5.8 -12.3 -5.7 -6.2 -3.8 -6.9 Triglycerides -13.4 -29.1 -5.1 -13.0 -3.1 -10.6 Proportion of Patients with Shifts Total Cholesterol (≥ 240 mg/dL) 5.3% (30/571) 13.8% (8/58) 6.2% (25/402) 5.3% (23/434) 3.8% (9/238) 4.0% (4/101) Triglycerides (≥ 200 mg/dL) 10.1% (53/526) 14.3% (7/49) 10.8% (41/379) 6.3% (25/400) 10.5% (22/209) 7.0% (7/100) In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a mean change in total cholesterol and triglycerides of -3.8 (n=356) and -15.1 (n=357) mg/dL at week 24, -3.1 (n=303) and -4.8 (n=303) mg/dL at week 36 and -2.5 (n=307) and -6.9 (n=307) mg/dL at week 52, respectively. Adolescents In the adolescent short-term, placebo-controlled study, fasting serum cholesterol mean values were -9.6 mg/dL for placebo (n=95), -4.4 mg/dL for 40 mg/day (n=89), and +1.6 mg/dL for 80 mg/day (n=92), and fasting serum triglyceride mean values were +0.1 mg/dL for placebo (n=95), -0.6 mg/dL for 40 mg/day (n=89), and +8.5 mg/dL for 80 mg/day (n=92). Bipolar Depression Adults Monotherapy Data from the adult short-term, flexible-dosed, placebo-controlled, monotherapy bipolar depression study are presented in Table 7 . Table 7: Change in Fasting Lipids in the Adult Monotherapy Bipolar Depression Study LATUDA Placebo 20 to 60 mg/day 80 to 120 mg/day Mean Change from Baseline (mg/dL) Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo n=147 n=140 n=144 Total cholesterol -3.2 +1.2 -4.6 Triglycerides +6.0 +5.6 +0.4 Proportion of Patients with Shifts Total cholesterol (≥ 240 mg/dL) 4.2% (5/118) 4.4% (5/113) 4.4% (5/114) Triglycerides (≥ 200 mg/dL) 4.8% (6/126) 10.1% (12/119) 9.8% (12/122) In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as monotherapy in the short-term and continued in the longer-term study had a mean change in total cholesterol and triglycerides of -0.5 mg/dL (n=130) and -1.0 mg/dL (n=130) at week 24, respectively. Adjunctive Therapy with Lithium or Valproate Data from the adult short-term, flexible-dosed, placebo-controlled, adjunctive therapy bipolar depression studies are presented in Table 8 . Table 8: Change in Fasting Lipids in the Adult Adjunctive Therapy Bipolar Depression Studies LATUDA Placebo 20 to 120 mg/day Mean Change from Baseline (mg/dL) Patients were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate. n=303 n=321 Total cholesterol -2.9 -3.1 Triglycerides -4.6 +4.6 Proportion of Patients with Shifts Total cholesterol (≥ 240 mg/dL) 5.7% (15/263) 5.4% (15/276) Triglycerides (≥ 200 mg/dL) 8.6% (21/243) 10.8% (28/260) In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in total cholesterol and triglycerides of -0.9 (n=88) and +5.3 (n=88) mg/dL at week 24, respectively. Pediatric Patients (10 to 17 years) In the 6-week, placebo-controlled bipolar depression study with pediatric patients 10 to 17 years, mean change in fasting cholesterol was -6.3 mg/dL for LATUDA 20 to 80 mg/day (n=144) and -1.4 mg/dL for placebo (n=145), and mean change in fasting triglyceride was -7.6 mg/dL for LATUDA 20 to 80 mg/day (n=144) and +5.9 mg/dL for placebo (n=145). Pediatric Patients (6 to 17 years) In a 104-week, open-label study of pediatric patients with schizophrenia, bipolar depression, or autistic disorder, shifts in baseline fasting cholesterol from normal to high at endpoint were reported in 12% (total cholesterol), 3% (LDL cholesterol), and shifts in baseline from normal to low were reported in 27% (HDL cholesterol) of patients taking lurasidone. Of patients with normal baseline fasting triglycerides, 12% experienced shifts to high. Weight Gain Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Schizophrenia Adults Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 9 . The mean weight gain was +0.43 kg for LATUDA-treated patients compared to -0.02 kg for placebo-treated patients. Change in weight from baseline for olanzapine was +4.15 kg and for quetiapine extended-release was +2.09 kg in Studies 3 and 5 , respectively. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 4.8% for LATUDA-treated patients and 3.3% for placebo-treated patients. Table 9: Mean Change in Weight (kg) from Baseline in Adult Schizophrenia Studies LATUDA Placebo (n=696) 20 mg/day (n=71) 40 mg/day (n=484) 80 mg/day (n=526) 120 mg/day (n=291) 160 mg/day (n=114) All Patients -0.02 -0.15 +0.22 +0.54 +0.68 +0.60 In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a mean change in weight of -0.69 kg at week 24 (n=755), -0.59 kg at week 36 (n=443) and -0.73 kg at week 52 (n=377). Adolescents Data from the short-term, placebo-controlled adolescent schizophrenia study are presented in Table 10 . The mean change in weight gain was +0.5 kg for LATUDA-treated patients compared to +0.2 kg for placebo-treated patients. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 3.3% for LATUDA-treated patients and 4.5% for placebo-treated patients. Table 10: Mean Change in Weight (kg) from Baseline in the Adolescent Schizophrenia Study Placebo (n=111) LATUDA 40 mg/day (n=109) 80 mg/day (n=104) All Patients +0.2 +0.3 +0.7 Bipolar Depression Adults Monotherapy Data from the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study are presented in Table 11 . The mean change in weight gain was +0.29 kg for LATUDA-treated patients compared to -0.04 kg for placebo-treated patients. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 2.4% for LATUDA-treated patients and 0.7% for placebo-treated patients. Table 11: Mean Change in Weight (kg) from Baseline in the Adult Monotherapy Bipolar Depression Study LATUDA Placebo (n=151) 20 to 60 mg/day (n=143) 80 to 120 mg/day (n=147) Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo All Patients -0.04 +0.56 +0.02 In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as monotherapy in the short-term and continued in the longer-term study had a mean change in weight of -0.02 kg at week 24 (n=130). Adjunctive Therapy with Lithium or Valproate Data from the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 12 . The mean change in weight gain was +0.11 kg for LATUDA-treated patients compared to +0.16 kg for placebo-treated patients. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 3.1% for LATUDA-treated patients and 0.3% for placebo-treated patients. Table 12: Mean Change in Weight (kg) from Baseline in the Adult Adjunctive Therapy Bipolar Depression Studies LATUDA Placebo (n=307) 20 to 120 mg/day (n=327) Patients were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate. All Patients +0.16 +0.11 In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with LATUDA, as adjunctive therapy with either lithium or valproate in the short-term and continued in the longer-term study, had a mean change in weight of +1.28 kg at week 24 (n=86). Pediatric Patients (10 to 17 years) Data from the 6-week, placebo-controlled bipolar depression study in patients 10 to 17 years are presented in Table 13 . The mean change in weight gain was +0.7 kg for LATUDA-treated patients compared to +0.5 kg for placebo-treated patients. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 4.0% for LATUDA-treated patients and 5.3% for placebo-treated patients. Table 13: Mean Change in Weight (kg) from Baseline in the Bipolar Depression Study in Pediatric Patients (10 to 17 years) LATUDA Placebo (n=170) 20 to 80 mg/day (n=175) All Patients +0.5 +0.7 Pediatric Patients (6 to 17 years) In a long-term, open-label study that enrolled pediatric patients with schizophrenia, bipolar depression, or autistic disorder from three short-term, placebo-controlled trials, 54% (378/701) received lurasidone for 104 weeks. The mean increase in weight from open-label baseline to Week 104 was 5.85 kg. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for the natural growth of children and adolescents by comparisons to age- and sex-matched population standards. A z-score change <0.5 SD is considered not clinically significant. In this trial, the mean change in z-score from open-label baseline to Week 104 was -0.06 SD for body weight and -0.13 SD for body mass index (BMI), indicating minimal deviation from the normal curve for weight gain

Hyperprolactinemia As with other drugs that antagonize dopamine D 2 receptors, LATUDA elevates prolactin levels. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone density in both female and male patients . Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro , a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in a carcinogenicity study conducted with lurasidone in rats and mice . Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer. Schizophrenia Adults In short-term, placebo-controlled schizophrenia studies, the median change from baseline to endpoint in prolactin levels for LATUDA-treated patients was +0.4 ng/mL and was -1.9 ng/mL in the placebo-treated patients. The median change from baseline to endpoint for males was +0.5 ng/mL and for females was -0.2 ng/mL. Median changes for prolactin by dose are shown in Table 14 . Table 14: Median Change in Prolactin (ng/mL) from Baseline in Adult Schizophrenia Studies LATUDA Placebo 20 mg/day 40 mg/day 80 mg/day 120 mg/day 160 mg/day All Patients -1.9 (n=672) -1.1 (n=70) -1.4 (n=476) -0.2 (n=495) +3.3 (n=284) +3.3 (n=115) Females -5.1 (n=200) -0.7 (n=19) -4.0 (n=149) -0.2 (n=150) +6.7 (n=70) +7.1 (n=36) Males -1.3 (n=472) -1.2 (n=51) -0.7 (n=327) -0.2 (n=345) +3.1 (n=214) +2.4 (n=79) The proportion of patients with prolactin elevations ≥5× upper limit of normal (ULN) was 2.8% for LATUDA-treated patients and = 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥5x ULN was 5.7% for LATUDA-treated patients and = 2.0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥5x ULN was 1.6% and 0.6% for placebo-treated male patients. In the uncontrolled longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a median change in prolactin of -0.9 ng/mL at week 24 (n=357), -5.3 ng/mL at week 36 (n=190) and -2.2 ng/mL at week 52 (n=307). Adolescents In the short-term, placebo-controlled adolescent schizophrenia study, the median change from baseline to endpoint in prolactin levels for LATUDA-treated patients was +1.1 ng/mL and was +0.1 ng/mL for placebo-treated patients. For LATUDA-treated patients, the median change from baseline to endpoint for males was +1.0 ng/mL and for females was +2.6 ng/mL. Median changes for prolactin by dose are shown in Table 15 . Table 15: Median Change in Prolactin (ng/mL) from Baseline in the Adolescent Schizophrenia Study Placebo LATUDA 40 mg/day LATUDA 80 mg/day All Patients +0.10 (n=103) +0.75 (n=102) +1.20 (n=99) Females +0.70 (n=39) +0.60 (n=42) +4.40 (n=33) Males 0.00 (n=64) +0.75 (n=60) +1.00 (n=66) The proportion of patients with prolactin elevations ≥5x ULN was 0.5% for LATUDA-treated patients and 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥5x ULN was 1.3% for LATUDA-treated patients and 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥5x ULN was 0% for LATUDA treated patients and 1.6% for placebo-treated male patients. Bipolar Depression Adults Monotherapy The median change from baseline to endpoint in prolactin levels, in the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study, was +1.7 ng/mL and +3.5 ng/mL with LATUDA 20 to 60 mg/day and 80 to 120 mg/day, respectively compared to +0.3 ng/mL with placebo-treated patients. The median change from baseline to endpoint for males was +1.5 ng/mL and for females was +3.1 ng/mL. Median changes for prolactin by dose range are shown in Table 16 . Table 16: Median Change in Prolactin (ng/mL) from Baseline in the Adult Monotherapy Bipolar Depression Study LATUDA Placebo 20 to 60 mg/day 80 to 120 mg/day Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo All Patients +0.3 (n=147) +1.7 (n=140) +3.5 (n=144) Females 0.0 (n=82) +1.8 (n=78) +5.3 (n=88) Males +0.4 (n=65) +1.2 (n=62) +1.9 (n=56) The proportion of patients with prolactin elevations ≥5x upper limit of normal (ULN) was 0.4% for LATUDA-treated patients and 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥5x ULN was 0.6% for LATUDA-treated patients and 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥5x ULN was 0% and 0% for placebo-treated male patients. In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with LATUDA as monotherapy in the short-term and continued in the longer-term study, had a median change in prolactin of -1.15 ng/mL at week 24 (n=130). Adjunctive Therapy with Lithium or Valproate The median change from baseline to endpoint in prolactin levels, in the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies was +2.8 ng/mL with LATUDA 20 to 120 mg/day compared to 0.0 ng/mL with placebo-treated patients. The median change from baseline to endpoint for males was +2.4 ng/mL and for females was +3.2 ng/mL. Median changes for prolactin across the dose range are shown in Table 17 . Table 17: Median Change in Prolactin (ng/mL) from Baseline in the Adult Adjunctive Therapy Bipolar Depression Studies LATUDA Placebo 20 to 120 mg/day Patients were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate. All Patients 0.0 (n=301) +2.8 (n=321) Females +0.4 (n=156) +3.2 (n=162) Males -0.1 (n=145) +2.4 (n=159) The proportion of patients with prolactin elevations ≥5x upper limit of normal (ULN) was 0.0% for LATUDA-treated patients and 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥5x ULN was 0% for LATUDA-treated patients and 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥5x ULN was 0% and 0% for placebo-treated male patients. In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with LATUDA, as adjunctive therapy with either lithium or valproate, in the short-term and continued in the longer-term study, had a median change in prolactin of -2.9 ng/mL at week 24 (n=88). Pediatric Patients (10 to 17 years) In the 6-week, placebo-controlled bipolar depression study with pediatric patients 10 to 17 years, the median change from baseline to endpoint in prolactin levels for LATUDA-treated patients was +1.10 ng/mL and was +0.50 ng/mL for placebo-treated patients. For LATUDA-treated patients, the median change from baseline to endpoint for males was +0.85 ng/mL and for females was +2.50 ng/mL. Median changes for prolactin are shown in Table 18 . Table 18: Median Change in Prolactin (ng/mL) from Baseline in the Bipolar Depression Study in Pediatric Patients (10 to 17 years) LATUDA Placebo 20 to 80 mg/day All Patients +0.50 (n=157) +1.10 (n=165) Females +0.55 (n=78) +2.50 (n=83) Males +0.50 (n=79) +0.85 (n=82) The proportion of patients with prolactin elevations ≥5x ULN was 0% for LATUDA-treated patients and 0.6% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥5x ULN was 0% for LATUDA-treated patients and 1.3% for placebo-treated female patients. No male patients in the placebo or LATUDA treatment groups had prolactin elevations ≥5x ULN. Pediatric Patients (6 to 17 years) In a 104-week, open-label study of pediatric patients with schizophrenia, bipolar depression, or autistic disorder, the median changes from baseline to endpoint in serum prolactin levels were -0.20 ng/mL (all patients), -0.30 ng/mL (females), and -0.05 ng/mL (males). The proportions of patients with a markedly high prolactin level (≥5 times the upper limit of normal) at any time during open-label treatment were 2% (all patients), 3% (females), and 1% (males). Adverse events among females in this trial that are potentially prolactin-related include galactorrhea (0.6%). Among male patients in this study, decreased libido was reported in one patient (0.2%) and there were no reports of impotence, gynecomastia, or galactorrhea

Leukopenia, Neutropenia and Agranulocytosis Leukopenia/neutropenia has been reported during treatment with antipsychotic agents. Agranulocytosis (including fatal cases) has been reported with other agents in the class. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and LATUDA should be discontinued at the first sign of decline in WBC, in the absence of other causative factors. Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1000/mm 3 ) should discontinue LATUDA and have their WBC followed until recovery

Orthostatic Hypotension and Syncope LATUDA may cause orthostatic hypotension and syncope, perhaps due to its α1-adrenergic receptor antagonism. Associated adverse reactions can include dizziness, lightheadedness, tachycardia, and bradycardia. Generally, these risks are greatest at the beginning of treatment and during dose escalation. Patients at increased risk of these adverse reactions or at increased risk of developing complications from hypotension include those with dehydration, hypovolemia, treatment with antihypertensive medication, history of cardiovascular disease (e.g., heart failure, myocardial infarction, ischemia, or conduction abnormalities), history of cerebrovascular disease, as well as patients who are antipsychotic-naïve. In such patients, consider using a lower starting dose and slower titration, and monitor orthostatic vital signs. Orthostatic hypotension, as assessed by vital sign measurement, was defined by the following vital sign changes: ≥ 20 mm Hg decrease in systolic blood pressure and ≥10 bpm increase in pulse from sitting to standing or supine to standing position. Schizophrenia Adults The incidence of orthostatic hypotension and syncope reported as adverse events from short-term, placebo-controlled schizophrenia studies was (LATUDA incidence, placebo incidence): orthostatic hypotension [0.3% (5/1508), 0.1% (1/708)] and syncope [0.1% (2/1508), 0% (0/708)]. In short-term schizophrenia clinical studies, orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0.8% with LATUDA 40 mg, 2.1% with LATUDA 80 mg, 1.7% with LATUDA 120 mg and 0.8% with LATUDA 160 mg compared to 0.7% with placebo. Adolescents The incidence of orthostatic hypotension reported as adverse events from the short-term, placebo-controlled adolescent schizophrenia study was 0.5% (1/214) in LATUDA-treated patients and 0% (0/112) in placebo-treated patients. No syncope event was reported. Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0% with LATUDA 40 mg and 2.9% with LATUDA 80 mg, compared to 1.8% with placebo. Bipolar Depression Adults Monotherapy In the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, there were no reported adverse events of orthostatic hypotension and syncope. Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0.6% with LATUDA 20 to 60 mg and 0.6% with LATUDA 80 to 120 mg compared to 0% with placebo. Adjunctive Therapy with Lithium or Valproate In the adult short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression therapy studies, there were no reported adverse events of orthostatic hypotension and syncope. Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 1.1% with LATUDA 20 to 120 mg compared to 0.9% with placebo. Pediatric Patients (10 to 17 years) In the 6-week, placebo-controlled bipolar depression study in pediatric patients 10 to 17 years, there were no reported adverse events of orthostatic hypotension or syncope. Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 1.1% with LATUDA 20 to 80 mg/day, compared to 0.6% with placebo

Falls LATUDA may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy

Seizures As with other antipsychotic drugs, LATUDA should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold, e.g., Alzheimer's dementia. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older. Schizophrenia In adult short-term, placebo-controlled schizophrenia studies, seizures/convulsions occurred in 0.1% (2/1508) of patients treated with LATUDA compared to 0.1% (1/708) placebo-treated patients. Bipolar Depression Monotherapy In the adult and pediatric 6-week, flexible-dose, placebo-controlled monotherapy bipolar depression studies, no patients experienced seizures/convulsions. Adjunctive Therapy with Lithium or Valproate In the adult short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies, no patient experienced seizures/convulsions

Potential for Cognitive and Motor Impairment LATUDA, like other antipsychotics, has the potential to impair judgment, thinking or motor skills. Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with LATUDA does not affect them adversely. In clinical studies with LATUDA, somnolence included: hypersomnia, hypersomnolence, sedation and somnolence. Schizophrenia Adults In short-term, placebo-controlled schizophrenia studies, somnolence was reported by 17.0% (256/1508) of patients treated with LATUDA (15.5% LATUDA 20 mg, 15.6% LATUDA 40 mg, 15.2% LATUDA 80 mg, 26.5% LATUDA 120 mg and 8.3% LATUDA 160 mg/day) compared to 7.1% (50/708) of placebo patients. Adolescents In the short-term, placebo-controlled adolescent schizophrenia study, somnolence was reported by 14.5% (31/214) of patients treated with LATUDA (15.5% LATUDA 40 mg and 13.5% LATUDA 80 mg,/day) compared to 7.1% (8/112) of placebo patients. Bipolar Depression Adults Monotherapy In the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study, somnolence was reported by 7.3% (12/164) and 13.8% (23/167) with LATUDA 20 to 60 mg and 80 to 120 mg, respectively compared to 6.5% (11/168) of placebo patients. Adjunctive Therapy with Lithium or Valproate In the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies, somnolence was reported by 11.4% (41/360) of patients treated with LATUDA 20-120 mg compared to 5.1% (17/334) of placebo patients. Pediatric Patients (10 to 17 years) In the 6-week, placebo-controlled bipolar depression study in pediatric patients 10 to 17 years, somnolence was reported by 11.4% (20/175) of patients treated with LATUDA 20 to 80 mg/day compared to 5.8% (10/172) of placebo treated patients

Body Temperature Dysregulation Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing LATUDA for patients who will be experiencing conditions that may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration

Activation of Mania/Hypomania Antidepressant treatment can increase the risk of developing a manic or hypomanic episode, particularly in patients with bipolar disorder. Monitor patients for the emergence of such episodes. In the adult bipolar depression monotherapy and adjunctive therapy (with lithium or valproate) studies, less than 1% of subjects in the LATUDA and placebo groups developed manic or hypomanic episodes

Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. LATUDA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia

Neurological Adverse Reactions in Patients with Parkinson's Disease or Dementia with Lewy Bodies Patients with Parkinson's Disease or Dementia with Lewy Bodies are reported to have an increased sensitivity to antipsychotic medication. Manifestations of this increased sensitivity include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome.

7.1 Drugs Having Clinically Important Interactions with LATUDA Table 34: Clinically Important Drug Interactions with LATUDA Strong CYP3A4 Inhibitors Clinical Impact: Concomitant use of LATUDA with strong CYP3A4 inhibitors increased the exposure of lurasidone compared to the use of LATUDA alone . Intervention: LATUDA should not be used concomitantly with strong CYP3A4 inhibitors . Examples: Ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil Moderate CYP3A4 Inhibitors Clinical Impact: Concomitant use of LATUDA with moderate CYP3A4 inhibitors increased the exposure of lurasidone compared to the use of LATUDA alone . Intervention: LATUDA dose should be reduced to half of the original level when used concomitantly with moderate inhibitors of CYP3A4 . Examples: Diltiazem, atazanavir, erythromycin, fluconazole, verapamil Strong CYP3A4 Inducers Clinical Impact: Concomitant use of LATUDA with strong CYP3A4 inducers decreased the exposure of lurasidone compared to the use of LATUDA alone . Intervention: LATUDA should not be used concomitantly with strong CYP3A4 inducers . Examples: Rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine Moderate CYP3A4 Inducers Clinical Impact: Concomitant use of LATUDA with moderate CYP3A4 inducers decreased the exposure of lurasidone compared to the use of LATUDA alone . Intervention: LATUDA dose should be increased when used concomitantly with moderate inducers of CYP3A4 . Examples: Bosentan, efavirenz, etravirine, modafinil, nafcillin 7.2 Drugs Having No Clinically Important Interactions with LATUDA Based on pharmacokinetic studies, no dosage adjustment of LATUDA is required when administered concomitantly with lithium, valproate, or substrates of P-gp or CYP3A4 .