DailyMed Label: Lurasidone Hydrochloride

DailyMed Label: Lurasidone Hydrochloride

2024

DailyMed Prescription

Lurasidone Hydrochloride

Lurasidone Hydrochloride

REMEDYREPACK INC.

NDC: 70518-3961

NDC: 70518-3961

Lurasidone hydrochloride 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-1­ylmethyl] 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. Lurasidone hydrochloride 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, alginic acid, pregelatinized corn starch, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol and carnauba wax. The 80 mg tablets also contain yellow iron oxide, FD&C Blue#1 aluminum lake and black iron oxide. spl-lurasidone-chemical-structure

Lurasidone hydrochloride tablet is indicated for: Treatment of adult and adolescent patients (13 to 17 years) with schizophrenia [see Clinical Studies (14.1)]. Monotherapy treatment of adult and pediatric patients (10 to 17 years) with major depressive episode associated with bipolar I disorder (bipolar depression) [see Clinical Studies (14.2)]. Adjunctive treatment with lithium or valproate in adult patients with major depressive episode associated with bipolar I disorder (bipolar depression) [see Clinical Studies (14.2)]. Lurasidone hydrochloride 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)

Lurasidone hydrochloride tablets should be taken with food (at least 350 calories). Administration with food substantially increases the absorption of lurasidone hydrochloride tablets (2.3, 12.3). Indication Starting Dose Recommended Dose Schizophrenia – adults (2.1) 40 mg per day 40 mg to 160 mg per day Schizophrenia – adolescents (13 to 17 years) (2.1) 40 mg per day 40 mg to 80 mg per day Bipolar Depression – adults (2.2) 20 mg per day 20 mg to 120 mg per day Bipolar Depression – pediatric patients (10 to 17 years) (2.2) 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): Lurasidone hydrochloride tablets 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 (2.6, 7.1). Concomitant Use of a Moderate CYP3A4 Inducer: It may be necessary to increase the dose of lurasidone hydrochloride tablets (2.6, 7.1). Adults The recommended starting dose of lurasidone hydrochloride tablets is 40 mg once daily. Initial dose titration is not required. Lurasidone hydrochloride tablets have been shown to be effective in a dose range of 40 mg per day to 160 mg per day [see Clinical Studies (14.1)]. The maximum recommended dose is 160 mg per day. Adolescents (13 to 17 years) The recommended starting dose of lurasidone hydrochloride tablets is 40 mg once daily. Initial dose titration is not required. Lurasidone hydrochloride tablets have been shown to be effective in a dose range of 40 mg per day to 80 mg per day [see Clinical Studies (14.1)] . The maximum recommended dose is 80 mg per day. Adults The recommended starting dose of lurasidone hydrochloride tablets is 20 mg given once daily as monotherapy or as adjunctive therapy with lithium or valproate. Initial dose titration is not required. Lurasidone hydrochloride tablets have 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 [see Clinical Studies (14.2)] . 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) [see Clinical Studies (14.2)] . Pediatric Patients (10  to 17 years) The recommended starting dose of lurasidone hydrochloride tablets 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. Lurasidone hydrochloride tablets have 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 [see Clinical Studies (14.2)] . The maximum recommended dose is 80 mg per day. The efficacy of lurasidone hydrochloride tablets in the treatment of mania associated with bipolar disorder has not been established. Lurasidone hydrochloride tablets should be taken with food (at least 350 calories). Administration with food substantially increases the absorption of lurasidone hydrochloride tablets. Administration with food increases the AUC approximately 2-fold and increases the C max approximately 3-fold. In the clinical studies, lurasidone hydrochloride tablets were administered with food [see Clinical Pharmacology (12.3)] . The effectiveness of lurasidone hydrochloride tablets 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 lurasidone hydrochloride tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.1 and 2.2)] . 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 [see Use in Specific Populations (8.6)]. 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 [see Use in Specific Populations (8.7)]. Concomitant Use with CYP3A4 Inhibitors Lurasidone hydrochloride tablets should not be used concomitantly with a strong CYP3A4 inhibitor (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.) [see Contraindications (4)] . If lurasidone hydrochloride tablets are being prescribed and a moderate CYP3A4 inhibitor (e.g. diltiazem, atazanavir, erythromycin, fluconazole, verapamil etc.) is added to the therapy, the lurasidone hydrochloride tablets dose should be reduced to half of the original dose level. Similarly, if a moderate CYP3A4 inhibitor is being prescribed and lurasidone hydrochloride tablet is added to the therapy, the recommended starting dose of lurasidone hydrochloride tablets is 20 mg per day, and the maximum recommended dose of lurasidone hydrochloride tablets is 80 mg per day [see Contraindi cations (4 ), Drug Intera ctions (7.1 ) ]. Grapefruit and grapefruit juice should be avoided in patients taking lurasidone hydrochloride tablets, since these may inhibit CYP3A4 and alter lurasidone hydrochloride concentrations [ s ee Drug I ntera c ti ons (7.1 ) ]. Concomitant Use with CYP3A4 Inducers Lurasidone hydrochloride tablets should not be used concomitantly with a strong CYP3A4 inducer (e.g., rifampin, avasimibe, St. John’s wort, phenytoin, carbamazepine, etc.) [ s ee Co nt rai n dic at io ns (4 ); Drug Int era ct io ns (7. 1 ) ] . If lurasidone hydrochloride tablets are used concomitantly with a moderate CYP3A4 inducer, it may be necessary to increase the lurasidone hydrochloride tablets dose after chronic treatment (7 days or more) with the CYP3A4 inducer.

Lurasidone hydrochloride tablets are available in the following shape and color (Table 1) with respective one-sided debossing. Table 1: Lurasidone Hydrochloride Tablet Presentations T ablet Strength Tablet Color/Shape Tablet Markings 20 mg white to off-white round 578 40 mg white to off-white round 684 60 mg white to off white modified capsule 639 80 mg pale green oval 685 120 mg white to off-white oval 579 Tablets: 20 mg (3)

Known  hypersensitivity  to  lurasidone  hydrochloride or  any  components  in  the  formulation. Angioedema has been observed with lurasidone [see Adverse Reactions (6.1)] . Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.) [see Drug Interactions (7.1)]. Strong CYP3A4  inducers  (e.g.,  rifampin,  avasimibe,  St.  John’s wort, phenytoin, carbamazepine, etc.) [see Drug Interactions (7.1)]. Known hypersensitivity to lurasidone hydrochloride tablets or any components in the formulation (4). Concomitant use with a strong CYP3A4 inhibitor (e.g., ketoconazole) (2.6, 4, 7.1). Concomitant use with a strong CYP3A4 inducer (e.g., rifampin) (2.6, 4, 7.1).

Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) (5.3). Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring (5.4). Tardive Dyskinesia: Discontinue if clinically appropriate (5.5). Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia and weight gain (5.6). Hyperprolactinemia: Prolactin elevations may occur (5.7). Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts (CBC) in patients with a preexisting low white blood cell count (WBC) or a history of leukopenia or neutropenia. Consider discontinuing lurasidone hydrochloride tablets if a clinically significant decline in WBC occurs in the absence of other causative factors (5.8). 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 (5.9). 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. Lurasidone hydrochloride tablets are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.3)] . 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 to 24 5 additional patients Decreases Compared to Placebo 25 to 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 lurasidone hydrochloride tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 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. Lurasidone hydrochloride tablets are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.1)]. A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including lurasidone hydrochloride tablets. 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 lurasidone hydrochloride tablets and provide intensive symptomatic treatment and monitoring. 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, lurasidone hydrochloride tablets 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 (1) is known to respond to antipsychotic drugs, and (2) 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 lurasidone hydrochloride tablets, drug discontinuation should be considered. However, some patients may require treatment with lurasidone hydrochloride tablets despite the presence of the syndrome. 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 A dults  Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 3. Table 3: Change in Fasting Glucose in Adult Schizophrenia Studies Lurasidone Hydrochloride Tablets 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), lurasidone hydrochloride tablets were 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 Lurasidone Hydrochloride Tablets Placebo 20 to 60 mg/day 80 to 120 mg/day Mean Change from Baseline (mg/dL) 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)  Patients were randomized to flexibly dosed lurasidone hydrochloride tablets 20 to 60 mg/day, lurasidone hydrochloride tablets 80 to 120 mg/day, or placebo In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride tablets 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 Placebo Lurasidone Hydrochloride Tablets 20 to 120 mg/day Mean Change from Baseline (mg/dL) 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) Patients were randomized to flexibly dosed lurasidone hydrochloride tablets 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate. In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride tablets 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 lurasidone hydrochloride tablets 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 Lurasidone Hydrochloride Tablets 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), lurasidone hydrochloride tablets were 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 Placebo Lurasidone Hydrochloride Tablets 20 to 60 mg/day 80 to 120 mg/day Mean Change from Baseline (mg/dL) 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) Patients were randomized to flexibly dosed lurasidone hydrochloride tablets 20 to 60 mg/day, lurasidone hydrochloride tablets 80 to 120 mg/day, or placebo In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride tablets 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 Placebo Mean Change from Baseline (mg/dL) Lurasidone Hydrochloride Tablets 20 to 120 mg/day 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) Patients were randomized to flexibly dosed lurasidone hydrochloride tablets 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate. In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride tablets, 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 lurasidone hydrochloride tablets 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 lurasidone hydrochloride tablets 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 lurasidone hydrochloride tablets-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 [see Clinical Studies (14.1)], respectively. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 4.8% for lurasidone hydrochloride tablets-treated patients and 3.3% for placebo-treated patients. Table 9: Mean Change in Weight (kg) from Baseline in Adult Schizophrenia Studies Lurasidone Hydrochloride Tablets 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), lurasidone hydrochloride tablets were 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 lurasidone hydrochloride tablets-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 lurasidone hydrochloride tablets-treated patients and 4.5% for placebo-treated patients. Table 10: Mean Change in Weight (kg) from Baseline in the Adolescent Schizophrenia Study Lurasidone Hydrochloride Tablets Placebo (n=111) 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 lurasidone hydrochloride tablets-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 lurasidone hydrochloride tablets-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 Lurasidone Hydrochloride Tablets Placebo (n=151) 20 to 60 mg/day (n=143) 80 to 120 mg/day (n=147) All Patients -0.04 +0.56 +0.02 Patients were randomized to flexibly dosed lurasidone hydrochloride tablets 20 to 60 mg/day, lurasidone hydrochloride tablets 80 to 120 mg/day, or placebo In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride tablets 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 lurasidone hydrochloride tablets-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 lurasidone hydrochloride tablets-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 Placebo (n=307) Lurasidone Hydrochloride Tablets 20 to 120 mg/day (n=327) All Patients +0.16 +0.11 Patients were randomized to flexibly dosed lurasidone hydrochloride tablets 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate. In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with lurasidone hydrochloride tablets, 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 lurasidone hydrochloride tablets-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 lurasidone hydrochloride tablets-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) Placebo (n=170) Lurasidone Hydrochloride Tablets 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. As with other drugs that antagonize dopamine D2 receptors, lurasidone hydrochloride tablets 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 [see Adverse Reactions (6)] . 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 [see Nonclinical Toxicology (13)]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive. Schizophrenia Adults In short-term, placebo-controlled schizophrenia studies, the median change from baseline to endpoint in prolactin levels for lurasidone hydrochloride tablets-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 Lurasidone Hydrochloride Tablets 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 lurasidone hydrochloride tablets-treated patients and = 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 5.7% for lurasidone hydrochloride tablets-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), lurasidone hydrochloride tablets were 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 lurasidone hydrochloride tablets-treated patients was +1.1 ng/mL and was +0.1 ng/mL for placebo-treated patients. For lurasidone hydrochloride tablets-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  Lurasidone Hydrochloride Tablets 40 mg/day Lurasidone Hydrochloride Tablets 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 lurasidone hydrochloride tablets-treated patients and 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 1.3% for lurasidone hydrochloride tablets-treated patients and 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations 5x ULN was 0% for lurasidone hydrochloride tablets 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 lurasidone hydrochloride tablets 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 Lurasidone Hydrochloride Tablets Placebo 20 to 60 mg/day 80 to 120 mg/day 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) Patients were randomized to flexibly dosed lurasidone hydrochloride tablets 20 to 60 mg/day, lurasidone hydrochloride tablets 80 to 120 mg/day, or placebo The proportion of patients with prolactin elevations 5x upper limit of normal (ULN) was 0.4% for lurasidone hydrochloride tablets-treated patients and 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 0.6% for lurasidone hydrochloride tablets-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 lurasidone hydrochloride tablets 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 lurasidone hydrochloride tablets 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 Placebo Lurasidone Hydrochloride Tablets 20 to 120 mg/day 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) Patients were randomized to flexibly dosed lurasidone hydrochloride tablets 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate. The proportion of patients with prolactin elevations 5x upper limit of normal (ULN) was 0.0% for lurasidone hydrochloride tablets-treated patients and 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 0% for lurasidone hydrochloride tablets-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 lurasidone hydrochloride tablets, 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 lurasidone hydrochloride tablets-treated patients was +1.10 ng/mL and was +0.50 ng/mL for placebo-treated patients. For lurasidone hydrochloride tablets -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) Placebo Lurasidone Hydrochloride Tablets 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 lurasidone hydrochloride tablets-treated patients and 0.6% for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 0% for lurasidone hydrochloride tablets-treated patients and 1.3% for placebo-treated female patients. No male patients in the placebo or lurasidone hydrochloride tablets 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 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 preexisting low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a preexisting 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 lurasidone hydrochloride tablets 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/mm3) should discontinue lurasidone hydrochloride tablets and have their WBC followed until recovery. Lurasidone hydrochloride tablets 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 (lurasidone hydrochloride tablets 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 lurasidone hydrochloride tablets 40 mg, 2.1% with lurasidone hydrochloride tablets 80 mg, 1.7% with lurasidone hydrochloride tablets 120 mg and 0.8% with lurasidone hydrochloride tablets 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 lurasidone hydrochloride tablets-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 lurasidone hydrochloride tablets 40 mg and 2.9% with lurasidone hydrochloride tablets 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 lurasidone hydrochloride tablets 20 to 60 mg and 0.6% with lurasidone hydrochloride tablets 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 lurasidone hydrochloride tablets 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 lurasidone hydrochloride tablets 20 to 80 mg/day, compared to 0.6% with placebo. Lurasidone hydrochloride tablets 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. As with other antipsychotic drugs, lurasidone hydrochloride tablets 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 lurasidone hydrochloride tablets 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. Lurasidone hydrochloride tablets, 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 lurasidone hydrochloride tablets does not affect them adversely. In clinical studies with lurasidone hydrochloride tablets, 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 lurasidone hydrochloride tablets (15.5% lurasidone hydrochloride tablets 20 mg, 15.6% lurasidone hydrochloride tablets 40 mg, 15.2% lurasidone hydrochloride tablets 80 mg, 26.5% lurasidone hydrochloride tablets 120 mg and 8.3% lurasidone hydrochloride tablets 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 lurasidone hydrochloride tablets (15.5% lurasidone hydrochloride tablets 40 mg and 13.5% lurasidone hydrochloride tablets 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 lurasidone hydrochloride tablets 20 to 60 mg and 80 to120 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 lurasidone hydrochloride tablets 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 lurasidone hydrochloride tablets 20 to 80 mg/day compared to 5.8% (10/172) of placebo treated patients. Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing lurasidone hydrochloride tablets 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 . 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 lurasidone hydrochloride tablets and placebo groups developed manic or hypomanic episodes. 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. Lurasidone hydrochloride tablets and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. 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.

The following adverse reactions are discussed in more detail in other sections of the labeling:

Table 34: Clinically Important Drug Interactions with Lurasidone Hydrochloride Strong CYP3A4 Inhibitors Clinical Impact: Concomitant use of lurasidone hydrochloride tablets with strong CYP3A4 inhibitors increased the exposure of lurasidone compared to the use of lurasidone hydrochloride tablets alone [see Clinical Pharmacology (12.3)] . Intervention: Lurasidone hydrochloride tablets should not be used concomitantly with strong CYP3A4 inhibitors [see Contraindications (4)] . Examples: Ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil Moderate CYP3A4 Inhibitors Clinical Impact: Concomitant use of lurasidone hydrochloride tablets with moderate CYP3A4 inhibitors increased the exposure of lurasidone compared to the use of lurasidone hydrochloride tablets alone [see Clinical Pharmacology (12.3)] . Intervention: Lurasidone hydrochloride tablets dose should be reduced to half of the original level when used concomitantly with moderate inhibitors of CYP3A4 [see Dosage and Administration (2.6)] . Examples: Diltiazem, atazanavir, erythromycin, fluconazole, verapamil Strong CYP3A4 Inducers Clinical Impact: Concomitant use of lurasidone hydrochloride tablets with strong CYP3A4 inducers decreased the exposure of lurasidone compared to the use of lurasidone hydrochloride tablets alone [see Clinical Pharmacology (12.3)] . Intervention: Lurasidone hydrochloride tablets should not be used concomitantly with strong CYP3A4 inducers [see Contraindications (4)] . Examples: Rifampin, avasimibe, St. John’s wort, phenytoin, carbamazepine Moderate CYP3A4 Inducers Clinical Impact: Concomitant use of lurasidone hydrochloride tablets with moderate CYP3A4 inducers decreased the exposure of lurasidone compared to the use of lurasidone hydrochloride tablets alone [see Clinical Pharmacology (12.3)] . Intervention: Lurasidone hydrochloride tablets dose should be increased when used concomitantly with moderate inducers of CYP3A4 [see Dosage and Administration (2.6)] . Examples: Bosentan, efavirenz, etravirine, modafinil, nafcillin Based on pharmacokinetic studies, no dosage adjustment of lurasidone hydrochloride tablets is required when administered concomitantly with lithium, valproate, or substrates of P-gp or CYP3A4 [see Clinical Pharmacology (12.3)] .

Pregnancy: May cause extrapyramidal and or/withdrawal symptoms in neonates with third trimester exposure (8.1). Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lurasidone hydrochloride tablets during pregnancy. For more information, contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery [see Clinical Considerations]. There are no studies of lurasidone hydrochloride tablets use in pregnant women. The limited available data are not sufficient to inform a drug-associated risk of birth defects or miscarriage. In animal reproduction studies, no teratogenic effects were seen in pregnant rats and rabbits given lurasidone during the period of organogenesis at doses approximately 1.5- and 6-times, the maximum recommended human dose (MRHD) of 160 mg/day, respectively based on mg/m2 body surface area [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Data Animal Data Pregnant rats were treated with oral lurasidone at doses of 3, 10, and 25 mg/kg/day during the period of organogenesis. These doses are 0.2, 0.6, and 1.5 times the MRHD of 160 mg/day based on mg/m2 body surface area. No teratogenic or embryo-fetal effects were observed up to 1.5 times the MRHD of 160 mg/day, based on mg/m 2 . Pregnant rabbits were treated with oral lurasidone at doses of 2, 10, and 50 mg/kg/day during the period of organogenesis. These doses are 0.2, 1.2 and 6 times the MRHD of 160 mg/day based on mg/m2. No teratogenic or embryo-fetal effects were observed up to 6 times the MRHD of 160 mg/day based on mg/m 2 . Pregnant rats were treated with oral lurasidone at doses of 0.4, 2, and 10 mg/kg/day during the periods of organogenesis and lactation. These doses are 0.02, 0.1 and 0.6 times the MRHD of 160 mg/day based on mg/m 2 . No pre- and postnatal developmental effects were observed up to 0.6 times the MRHD of 160 mg/day, based on mg/m 2 . Risk Summary Lactation studies have not been conducted to assess the presence of lurasidone in human milk, the effects on the breastfed infant, or the effects on milk production. Lurasidone is present in rat milk. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for lurasidone hydrochloride tablets and any potential adverse effects on the breastfed infant from lurasidone hydrochloride tablets or from the underlying maternal condition. Schizophrenia The safety and effectiveness of lurasidone hydrochloride tablets 40-mg/day and 80-mg/day for the treatment of schizophrenia in adolescents (13 to 17 years) was established in a 6-week, placebo-controlled clinical study in 326 adolescent patients [see Dosage and Administration (2.1), Adverse Reactions (6.1), and Clinical Studies (14.1)] . The safety and effectiveness of lurasidone hydrochloride tablets have not been established in pediatric patients less than 13 years of age with schizophrenia. Bipolar Depression The safety and effectiveness of lurasidone hydrochloride tablets 20 to 80 mg/day for the treatment of bipolar depression in pediatric patients (10 to 17 years) was established in a 6-week, placebo-controlled clinical study in 347 pediatric patients [see Dosage and Administration (2.2), Adverse Reactions (6.1), and Clinical Studies (14.2)]. The safety and effectiveness of lurasidone hydrochloride tablets have not been established in pediatric patients less than 10 years of age with bipolar depression. Irritability Associated with Autistic Disorder The effectiveness of lurasidone hydrochloride tablets in pediatric patients for the treatment of irritability associated with autistic disorder has not been established. Efficacy was not demonstrated in a 6-week study evaluating lurasidonehydrochloride tablets 20 mg/day and 60 mg/day for the treatment of pediatric patients 6 to 17 years of age with irritability associated with autistic disorder diagnosed by Diagnostic and Statistical Manual of Mental Disorders, 4th Ed., Text Revision [DSM-IV-TR] criteria. The primary objective of the study as measured by improvement from Baseline in the irritability subscale of the Aberrant Behavior Checklist (ABC) at Endpoint (Week 6) was not met. A total of 149 patients were randomized to lurasidonehydrochloride tablets or placebo. Vomiting occurred at a higher rate than reported in other lurasidonehydrochloride tablets studies (4/49 or 8% for 20mg, 14/51 or 27% for 60mg, and 2/49 or 4% for placebo), particularly in children ages 6 to 12 (13 out of 18 patients on lurasidonehydrochloride tablets with vomiting). In a long-term, open-label study that enrolled pediatric patients (age 6 to 17 years) with schizophrenia, bipolar depression, or autistic disorder from three short-term, placebo-controlled trials, 54% (378/701) received lurasidone for 104 weeks. There was one adverse event in this trial that was considered possibly drug-related and has not been reported in adults receiving lurasidone: a 10 year old male experienced a prolonged, painful erection, consistent with priapism, that led to treatment discontinuation. In this trial, the mean increase in height from open-label baseline to Week 104 was 4.94 cm. 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 height z-score from open-label baseline to Week 104 was +0.05 SD, indicating minimal deviation from the normal growth curve. Juvenile animal studies Adverse effects were seen on growth, physical and neurobehavioral development at doses as low as 0.2 times the MRHD based on mg/m 2 . Lurasidone was orally administered to rats from postnatal days 21 through 91 (this period corresponds to childhood, adolescence, and young adulthood in humans) at doses of 3, 30, and 150 (males) or 300 (females) mg/kg/day which are 0.2 to 10 times (males) and 20 times (females) the maximum recommended adult human dose (MRHD) of 160 mg/day based on mg/m 2 . The adverse effects included dose-dependent decreases in femoral length, bone mineral content, body and brain weights at 2 times the MRHD in both sexes, and motor hyperactivity at 0.2 and 2 times the MRHD in both sexes based on mg/m 2 . In females, there was a delay in attainment of sexual maturity at 2 times the MRHD, associated with decreased serum estradiol. Mortality occurred in both sexes during early post-weaning period and some of the male weanlings died after only 4 treatments at doses as low as 2 times the MRHD based on mg/m 2 . Histopathological findings included increased colloid in the thyroids and inflammation of the prostate in males at 10 times MRHD based on mg/m 2 and mammary gland hyperplasia, increased vaginal mucification, and increased ovarian atretic follicles at doses as low as 0.2 times the MRHD based on mg/m 2 . Some of these findings were attributed to transiently elevated serum prolactin which was seen in both sexes at all doses. However, there were no changes at any dose level in reproductive parameters (fertility, conception indices, spermatogenesis, estrous cycle, gestation length, parturition, number of pups born). The no effect dose for neurobehavioral changes in males is 0.2 times the MRHD based on mg/m 2 and could not be determined in females. The no effect dose for growth and physical development in both sexes is 0.2 times the MRHD based on mg/m 2 . Clinical studies with lurasidone hydrochloride tablets did not include sufficient numbers of patients aged 65 and older to determine whether or not they respond differently from younger patients. In elderly patients with psychosis (65 to 85), lurasidone hydrochloride tablets concentrations (20 mg/day) were similar to those in young subjects. It is unknown whether dose adjustment is necessary on the basis of age alone. Elderly patients with dementia-related psychosis treated with lurasidone hydrochloride tablets are at an increased risk of death compared to placebo. Lurasidone hydrochloride tablet is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.1, 5.3)] . Reduce the maximum recommended dosage in patients with moderate or severe renal impairment (CLcr<50 mL/minute). Patients with impaired renal function (CLcr<50 mL/minute) had higher exposure to lurasidone than patients with normal renal function [see Clinical Pharmacology (12.3)] . Greater exposure may increase the risk of lurasidone hydrochloride tablets-associated adverse reactions [see Dosage and Administration (2.4)]. Reduce the maximum recommended dosage in patients with moderate to severe hepatic impairment (Child-Pugh score ≥7). Patients with moderate to severe hepatic impairment (Child-Pugh score ≥7) generally had higher exposure to lurasidone than patients with normal hepatic function [see Clinical Pharmacology (12.3)] . Greater exposure may increase the risk of lurasidonehydrochloride tablets-associated adverse reactions [see Dosage and Administration (2.5)] . No dosage adjustment for lurasidone hydrochloride tablets is required on the basis of a patient’s sex, race, or smoking status [see Clinical Pharmacology (12.3)].

Lurasidone hydrochloride tablets are available as follows: 20 mg: White to off-white, round, film-coated tablet, debossed with '578' on one side and plain on other side. NDC: 70518-3961-00 PACKAGING: 30 in 1 BLISTER PACK Storage Store lurasidone hydrochloride tablets at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

The mechanism of action of lurasidone in the treatment of schizophrenia and bipolar depression is unclear. However, its efficacy in schizophrenia and bipolar depression could be mediated through a combination of central dopamine D2 and serotonin Type 2 (5HT2A) receptor antagonism. Lurasidone is an antagonist with high affinity binding at the dopamine D2 receptors (Ki of 1 nM) and the serotonin 5-HT2A (Ki of 0.5 nM) and 5-HT7 (Ki of 0.5 nM) receptors. It also binds with moderate affinity to the human α2C adrenergic receptors (Ki of 11 nM), is a partial agonist at serotonin 5-HT1A (Ki of 6.4 nM) receptors, and is an antagonist at the α2A adrenergic receptors (Ki of 41 nM). Lurasidone exhibits little or no affinity for histamine H1 and muscarinic M1 receptors (IC50 > 1,000 nM). ECG Changes The effects of lurasidonehydrochloride tablets on the QTc interval were evaluated in a randomized, double-blind, multiple-dose, parallel-dedicated thorough QT study in 43 patients with schizophrenia or schizoaffective disorder, who were treated with lurasidonehydrochloride tablets doses of 120 mg daily, 600 mg daily and completed the study. The maximum mean (upper 1-sided, 95% CI) increase in baseline-adjusted QTc intervals based on individual correction method (QTcI) was 7.5 (11.7) ms and 4.6 (9.5) ms, for the 120 mg and 600 mg dose groups respectively, observed at 2 to 4 hours after dosing. In this study, there was no apparent dose (exposure)-response relationship. In short-term, placebo-controlled studies in schizophrenia and bipolar depression, no post-baseline QT prolongations exceeding 500 msec were reported in patients treated with lurasidonehydrochloride tablets or placebo. Adults The activity of lurasidone hydrochloride tablets is primarily due to the parent drug. The pharmacokinetics of lurasidone hydrochloride tablets is dose-proportional within a total daily dose range of 20 mg to 160 mg. Steady-state concentrations of lurasidone hydrochloride tablets are reached within 7 days of starting lurasidone hydrochloride tablets. Following administration of 40 mg of lurasidone hydrochloride tablets, the mean (%CV) elimination half-life was 18 (7) hours. Absorption and Distribution: Lurasidone hydrochloride tablets are absorbed and reaches peak serum concentrations in approximately 1 to 3 hours. It is estimated that 9 to 19% of an administered dose is absorbed. Following administration of 40 mg of lurasidone hydrochloride tablets, the mean (%CV) apparent volume of distribution was 6173 (17.2) L. Lurasidone hydrochloride tablets are highly bound (~99%) to serum proteins. In a food effect study, lurasidone hydrochloride tablets mean Cmax and AUC were about 3-times and 2-times, respectively, when administered with food compared to the levels observed under fasting conditions. Lurasidone hydrochloride tablets exposure was not affected as meal size was increased from 350 to 1000 calories and was independent of meal fat content [ see Dosage and Administration (2.3)] . In clinical studies, establishing the safety and efficacy of lurasidone hydrochloride tablets, patients were instructed to take their daily dose with food [see Dosage and Administration (2.3)] . Metabolism and Elimination: Lurasidone hydrochloride tablets are metabolized mainly via CYP3A4. The major biotransformation pathways are oxidative N -dealkylation, hydroxylation of norbornane ring, and S -oxidation. Lurasidone hydrochloride tablets are metabolized into two active metabolites (ID-14283 and ID-14326) and two major non-active metabolites (ID-20219 and ID-20220). Based on in vitro studies, lurasidone hydrochloride tablet is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP4A11, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 enzymes. Because lurasidone hydrochloride is not a substrate for CYP1A2, smoking is not expected to have an effect on the pharmacokinetics of lurasidone hydrochloride tablets. Transporter proteins: In vitro studies suggest lurasidone hydrochloride is not a substrate of OATP1B1 or OATP1B3, however, is probably a substrate of P-gp and BCRP. In vitro studies indicate that lurasidone hydrochloride is not expected to inhibit transporters OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, MATE2-K and BSEP at clinically relevant concentrations. Lurasidone hydrochloride tablets are not a clinically significant inhibitor of P-gp. However, it may inhibit BCRP. Total excretion of radioactivity in urine and feces combined was approximately 89%, with about 80% recovered in feces and 9% recovered in urine, after a single dose of [ 14 C]-labeled lurasidone hydrochloride tablets. Following administration of 40 mg of lurasidone hydrochloride tablets, the mean (%CV) apparent clearance was 3902 (18.0) mL/min. Drug Interaction Studies Effects of other drugs on the exposure of lurasidone are summarized in Figure 1. A population PK analyses concluded that coadministration of lithium 300 to 2,400 mg/day or valproate 300 to 2,000 mg/day with lurasidone for up to 6 weeks has minimal effect on lurasidone exposure. And the effects of lurasidone hydrochloride tablets on the exposures of other drugs are summarized in Figure 2. A population PK analyses concluded that coadministration of lurasidone has minimal effect on lithium and valproate exposure when it is coadministered with lithium 300 to 2,400 mg/day or valproate 300 to 2,000 mg/day. Figure 1: Impact of Other Drugs on Lurasidone Hydrochloride Tablets Pharmacokinetics Figure 2: Impact of Lurasidone Hydrochloride Tablets on Other Drugs Studies in Specific Populations The effect of intrinsic patient factors on the pharmacokinetics of lurasidone hydrochloride tablets are presented in Figure 3. Pediatric Patients Lurasidone hydrochloride tablets exposure (i.e., steady-state C max and AUC) in children and adolescent patients (10 to 17 years of age) was generally similar to that in adults across the dose range from 40 to 160 mg, without adjusting for body weight. Figure 3: Impact of Other Patient Factors on Lurasidone Hydrochloride Tablets Pharmacokinetics spl-lurasidone-figure1 spl-lurasidone-figure2 spl-lurasidone-figure3

Carcinogenesis: Lurasidone increased incidences of malignant mammary gland tumors and pituitary gland adenomas in female mice orally dosed with 30, 100, 300, or 650 mg/kg/day. The lowest dose produced plasma levels (AUC) approximately equal to those in humans receiving the MRHD of 160 mg/day. No increases in tumors were seen in male mice up to the highest dose tested, which produced plasma levels (AUC) 14 times those in humans receiving the MRHD. Lurasidone increased the incidence of mammary gland carcinomas in female rats orally dosed at 12 and 36 mg/kg/day: the lowest dose; 3 mg/kg/day is the no-effect dose which produced plasma levels (AUC) 0.4 times those in humans receiving the MRHD. No increases in tumors were seen in male rats up to the highest dose tested, which produced plasma levels (AUC) 6 times those in humans receiving the MRHD. Proliferative and/or neoplastic changes in the mammary and pituitary glands of rodents have been observed following chronic administration of antipsychotic drugs and are considered to be prolactin-mediated [see Warnings and Precautions (5.7)]. Mutagenesis: Lurasidone did not cause mutation or chromosomal aberration when tested in vitro and in vivo test battery . Lurasidone was negative in the Ames gene mutation test, the Chinese Hamster Lung (CHL) cells, and in the in vivo mouse bone marrow micronucleus test up to 2,000 mg/kg which is 61 times the MRHD of 160 mg/day based on mg/m 2 body surface area. Impairment of Fertility: Estrus cycle irregularities were seen in rats orally administered lurasidone at 1.5, 15 and 150 mg/kg/day for 15 consecutive days prior to mating, during the mating period, and through gestation day 7. No effect was seen at the lowest dose of 0.1 mg/kg which is approximately 0.006 times the MRHD of 160 mg/day based on mg/m 2 . Fertility was reduced only at the highest dose, which was reversible after a 14 day drug-free period. The no-effect dose for reduced fertility was approximately equal to the MRHD based on mg/m 2 . Lurasidone had no effect on fertility in male rats treated orally for 64 consecutive days prior to mating and during the mating period at doses up to 9 times the MRHD based on mg/m 2 .

Adults The efficacy of lurasidone hydrochloride tablets for the treatment of schizophrenia was established in five short-term (6-week), placebo-controlled studies in adult patients (mean age of 38.4 years, range 18 to 72) who met DSM-IV criteria for schizophrenia. An active-control arm (olanzapine or quetiapine extended-release) was included in two studies to assess assay sensitivity. Several instruments were used for assessing psychiatric signs and symptoms in these studies: 1.  Positive and Negative Syndrome Scale (PANSS), is a multi-item inventory of general psychopathology used to evaluate the effects of drug treatment in schizophrenia. PANSS total scores may range from 30 to 210. 2.  Brief Psychiatric Rating Scale derived (BPRSd), derived from the PANSS, is a multi-item inventory primarily focusing on positive symptoms of schizophrenia, whereas the PANSS includes a wider range of positive, negative and other symptoms of schizophrenia. The BPRSd consists of 18 items rated on a scale of 1 (not present) to 7 (severe). BPRSd scores may range from 18 to 126. 3.  The Clinical Global Impression severity scale (CGI-S) is a clinician-rated scale that measures the subject’s current illness state on a 1- to 7-point scale. The endpoint associated with each instrument is change from baseline in the total score to the end of week 6. These changes are then compared to placebo changes for the drug and control groups. The results of the studies follow: 1.  Study 1:  In a 6-week, placebo-controlled trial (N=145) involving two fixed doses of lurasidone hydrochloride tablets (40 or 120 mg/day), both doses of lurasidone hydrochloride tablets at Endpoint were superior to placebo on the BPRSd total score, and the CGI-S. 2.  Study 2: In a 6-week, placebo-controlled trial (N=180) involving a fixed dose of lurasidone hydrochloride tablets (80 mg/day), lurasidone hydrochloride tablets at Endpoint was superior to placebo on the BPRSd total score, and the CGI-S. 3.  Study 3: In a 6-week, placebo- and active-controlled trial (N=473) involving two fixed doses of lurasidone hydrochloride tablets (40 or 120 mg/day) and an active control (olanzapine), both lurasidone hydrochloride tablets doses and the active control at Endpoint were superior to placebo on the PANSS total score, and the CGI-S. 4.  Study 4: In a 6-week, placebo-controlled trial (N=489) involving three fixed doses of lurasidone hydrochloride tablets (40, 80 or 120 mg/day), only the 80 mg/day dose of lurasidone hydrochloride tablets at Endpoint was superior to placebo on the PANSS total score, and the CGI-S. 5.  Study 5: In a 6-week, placebo- and active-controlled trial (N=482) involving two fixed doses of lurasidone hydrochloride tablets (80 or 160 mg/day) and an active control (quetiapine extended-release), both lurasidone hydrochloride tablets doses and the active control at Endpoint were superior to placebo on the PANSS total score, and the CGI-S.  Thus, the efficacy of lurasidone hydrochloride tablets at doses of 40, 80, 120 and 160 mg/day has been established (Table 35). Table 35: Primary Efficacy Results for Studies in Adult Patients with Schizophrenia (BPRSd or PANSS Scores) Study Treatment Group Primary Efficacy Measure: BPRSd Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo ‐ subtracted Difference a (95% CI) 1 Lurasidone hydrochloride tablets (40 mg/day)* 54.2 (8.8) ‐9.4 (1.6) ‐5.6 (‐9.8, ‐1.4) Lurasidone hydrochloride tablets (120 mg/day)* 52.7 (7.6) ‐11.0 (1.6) ‐6.7 (‐11.0, ‐2.5) Placebo 54.7 (8.1) ‐3.8 (1.6) ‐‐ 2 Lurasidone hydrochloride tablets (80 mg/day) * 55.1 (6.0) ‐8.9 (1.3) ‐4.7 (‐8.3, ‐1.1) Placebo 56.1 (6.8) ‐4.2 (1.4) ‐‐ Primary Efficacy Measure: PANSS 3 Lurasidone hydrochloride tablets (40 mg/day) * 96.6 (10.7) ‐25.7 (2.0) ‐9.7 (‐15.3, ‐4.1) Lurasidone hydrochloride tablets (120 mg/day) * 97.9 (11.3) ‐23.6 (2.1) 7.5 (‐13.4, ‐1.7) Olanzapine (15 mg/day) *b 96.3 (12.2) ‐28.7 (1.9) ‐12.6 (‐18.2, ‐7.9) Placebo 95.8 (10.8) ‐16.0 (2.1) ‐‐ 4 Lurasidone hydrochloride tablets (40 mg/day) 96.5 (11.5) ‐19.2 (1.7) ‐2.1 (‐7.0, 2.8) Lurasidone hydrochloride tablets (80 mg/day) * 96.0 (10.8) ‐23.4 (1.8) ‐6.4 (‐11.3, ‐1.5) Lurasidone hydrochloride tablets (120 mg/day) 96.0 (9.7) ‐20.5 (1.8) ‐3.5 (‐8.4, 1.4) Placebo 96.8 (11.1) ‐17.0 (1.8) ‐‐ 5 Lurasidone hydrochloride tablets (80 mg/day) * 97.7 (9.7) ‐22.2 (1.8) ‐11.9 (‐16.9, ‐6.9) Lurasidone hydrochloride tablets (160 mg/day) * 97.5 (11.8) ‐26.5 (1.8) ‐16.2 (‐21.2, ‐11.2) Quetiapine Extended‐ release (600 mg/day) *b 97.7 (10.2) ‐27.8 (1.8) ‐17.5 (‐22.5, ‐12.4) Placebo 96.6 (10.2) ‐10.3 (1.8) ‐‐ SD: standard deviation; SE: standard error; LS Mean: least‐squares mean; CI: confidence interval, unadjusted for multiple comparisons. a Difference (drug minus placebo) in least‐squares mean change from baseline. b Included for assay sensitivity. * Doses statistically significantly superior to placebo. Examination of population subgroups based on age (there were few patients over 65), gender and race did not reveal any clear evidence of differential responsiveness. Adolescents (13 to 17 years) The efficacy of lurasidone hydrochloride tablets, was established in a 6-week, multicenter, randomized, double-blind, placebo-controlled study of adolescents (13 to 17 years) who met DSM-IV-TR criteria for schizophrenia (N=326). Patients were randomized to one of two fixed-doses of lurasidone hydrochloride tablets (40 or 80 mg/day) or placebo. The primary rating instrument used to assess psychiatric signs and symptoms was the PANSS. The key secondary instrument was the CGI-S. For both dose groups, lurasidone hydrochloride tablets were superior to placebo in reduction of PANSS and CGI-S scores at Week 6. On average, the 80 mg/day dose did not provide additional benefit compared to the 40 mg/day dose. The primary efficacy results are provided in Table 36. Table 36: Primary Efficacy Results (PANSS Total Score) for the Adolescent Schizophrenia Study Treatment Group Primary Efficacy Measure: PANSS Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo‐subtracted Difference a (95% CI) Lurasidone hydrochloride tablets (40 mg/day) * 94.5 (10.97) -18.6 (1.59) -8.0 (-12.4, -3.7) Lurasidone hydrochloride tablets (80 mg/day) * 94.0 (11.12) -18.3 (1.60) -7.7 (-12.1, -3.4) Placebo 92.8 (11.08) -10.5 (1.59) ‐‐ SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, unadjusted for multiple comparisons. a Difference (drug minus placebo) in least-squares mean change from baseline. * Doses statistically significantly superior to placebo. Adults Monotherapy The efficacy of lurasidone hydrochloride tablets, as monotherapy, was established in a 6-week, multicenter, randomized, double-blind, placebo-controlled study of adult patients (mean age of 41.5 years, range 18 to 74) who met DSM-IV-TR criteria for major depressive episodes associated with bipolar I disorder, with or without rapid cycling, and without psychotic features (N=485). Patients were randomized to one of two flexible-dose ranges of lurasidone hydrochloride tablets (20 to 60 mg/day, or 80 to 120 mg/day) or placebo. The primary rating instrument used to assess depressive symptoms in this study was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale with total scores ranging from 0 (no depressive features) to 60 (maximum score). The primary endpoint was the change from baseline in MADRS score at Week 6. The key secondary instrument was the Clinical Global Impression-Bipolar-Severity of Illness scale (CGI-BP-S), a clinician-rated scale that measures the subject’s current illness state on a 7-point scale, where a higher score is associated with greater illness severity. For both dose groups, lurasidone hydrochloride tablets were superior to placebo in reduction of MADRS and CGI-BP-S scores at Week 6. The primary efficacy results are provided in Table 37. The high dose range (80 to 120 mg per day) did not provide additional efficacy on average, compared to the low dose range (20 to 60 mg per day). Adjunctive Therapy with Lithium or Valproate The efficacy of lurasidone hydrochloride tablets, as an adjunctive therapy with lithium or valproate, was established in a 6-week, multicenter, randomized, double-blind, placebo-controlled study of adult patients (mean age of 41.7 years, range 18 to 72) who met DSM-IV-TR criteria for major depressive episodes associated with bipolar I disorder, with or without rapid cycling, and without psychotic features (N=340). Patients who remained symptomatic after treatment with lithium or valproate were randomized to flexibly dosed lurasidone hydrochloride tablets 20 to 120 mg/day or placebo. The primary rating instrument used to assess depressive symptoms in this study was the MADRS. The primary endpoint was the change from baseline in MADRS score at Week 6. The key secondary instrument was the CGI-BP-S scale. Lurasidone hydrochloride tablets were superior to placebo in reduction of MADRS and CGI-BP-S scores at Week 6, as an adjunctive therapy with lithium or valproate (Table 37). Table 37: Primary Efficacy Results for Adult Studies in Depressive Episodes Associated with Bipolar I Disorder (MADRS Scores) Study Treatment Group Primary Efficacy Measure: MADRS Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo ‐subtracted Difference a (95% CI) Monotherapy study Lurasidone hydrochloride tablets (20 to 60 mg/day) * 30.3 (5.0) ‐15.4 (0.8) ‐4.6 (‐6.9, ‐2.3) Lurasidone hydrochloride tablets (80 to 120 mg/day) * 30.6 (4.9) ‐15.4 (0.8) ‐4.6 (‐6.9, ‐2.3) Placebo 30.5 (5.0) ‐10.7 (0.8) ‐‐ Adjunctive Therapy study Lurasidone hydrochloride tablets (20 to 120 mg/day) * + lithium or valproate 30.6 (5.3) ‐17.1 (0.9) ‐3.6 (‐6.0, ‐1.1) Placebo + lithium or valproate 30.8 (4.8) ‐13.5 (0.9) ‐‐ SD: standard deviation; SE: standard error; LS Mean: least‐squares mean; CI: confidence interval, unadjusted for multiple comparisons. a Difference (drug minus placebo) in least‐squares mean change from baseline. * Treatment group statistically significantly superior to placebo. Pediatric Patients (10 to 17 years) The efficacy of lurasidone hydrochloride tablets were established in a 6-week, multicenter, randomized, double-blind, placebo-controlled study of pediatric patients (10 to 17 years) who met DSM-5 criteria for a major depressive episode associated with bipolar I disorder, with or without rapid cycling, and without psychotic features (N=343). Patients were randomized to flexibly dosed lurasidone hydrochloride tablets 20 to 80 mg/day or placebo. At the end of the clinical study, most patients (67%) received 20 mg/day or 40 mg/day. The primary rating scale used to assess depressive symptoms in this study was the Children’s Depression Rating Scale, Revised (CDRS-R) total score. The CDRS-R is a 17-item clinician-rated scale with total scores ranging from 17 to 113. The primary endpoint was the change from baseline in CDRS-R score at Week 6. The key secondary endpoint was the change from baseline in CGI­BP-S depression score. Lurasidone hydrochloride tablets were superior to placebo in reduction of CDRS-R total score and CGI-BP-S depression score at Week 6. The primary efficacy results are provided in Table 38. Table 38: Primary Efficacy Results for the Study in Depressive Episodes Associated with Bipolar I Disorder (CDRS-R Total Score) in Pediatric Patients (10 to 17 years) Treatment Group Primary Efficacy Measure: CDRS-R Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo ‐subtracted Difference a (95% CI) Lurasidone hydrochloride tablets (20 to 80 mg/day) * 59.2 (8.24) -21.0 (1.06) -5.7 (-8.4,-3.0) Placebo 58.6 (8.26) -15.3 (1.08) ‐‐ SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, unadjusted for multiple comparisons. a Difference (drug minus placebo) in least-squares mean change from baseline. * Treatment group statistically significantly superior to placebo.

DRUG: Lurasidone Hydrochloride GENERIC: Lurasidone Hydrochloride DOSAGE: TABLET ADMINSTRATION: ORAL NDC: 70518-3961-0 COLOR: white SHAPE: ROUND SCORE: No score SIZE: 6 mm IMPRINT: 578 PACKAGING: 30 in 1 BLISTER PACK ACTIVE INGREDIENT(S): LURASIDONE HYDROCHLORIDE 20mg in 1 INACTIVE INGREDIENT(S): MANNITOL ALGINIC ACID STARCH, CORN CROSCARMELLOSE SODIUM SILICON DIOXIDE MAGNESIUM STEARATE HYPROMELLOSES TITANIUM DIOXIDE POLYETHYLENE GLYCOL, UNSPECIFIED CARNAUBA WAX Remedy_Label