Lurasidone hydrochloride

6 ADVERSE REACTIONS Commonly observed adverse reactions (incidence ≥ 5% and at least twice the rate for placebo) were ( 6.1 ): Adult patients with schizophrenia: somnolence, akathisia, extrapyramidal symptoms, and nausea Adolescent patients (13 to 17 years) with schizophrenia: somnolence, nausea, akathisia, EPS (non-akathisia), rhinitis (80mg only), and vomiting Adult patients with bipolar depression: akathisia, extrapyramidal symptoms, and somnolence Pediatric patients (10-17 years) with bipolar depression: nausea, weight increase, and insomnia. To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following adverse reactions are discussed in more detail in other sections of the labeling: Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions ( 5.1 )] Suicidal Thoughts and Behaviors [see Boxed Warning and Warnings and Precautions ( 5.2 )] Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-related Psychosis [see Warnings and Precautions ( 5.3 )] Neuroleptic Malignant Syndrome [see Warnings and Precautions ( 5.4 )] Tardive Dyskinesia [see Warnings and Precautions ( 5.5 )] Metabolic Changes [see Warnings and Precautions ( 5.6 )] Hyperprolactinemia [see Warnings and Precautions ( 5.7 )] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions ( 5.8 )] Orthostatic Hypotension and Syncope [see Warnings and Precautions ( 5.9 )] Falls [see Warnings and Precautions ( 5.10 )] Seizures [see Warnings and Precautions ( 5.11 )] Potential for Cognitive and Motor Impairment [see Warnings and Precautions ( 5.12 )] Body Temperature Dysregulation [see Warnings and Precautions ( 5.13 )] Activation of Mania/Hypomania [see Warnings and Precautions ( 5.14 )] Dysphagia [see Warnings and Precautions ( 5.15 )] Neurological Adverse Reactions in Patients with Parkinson's Disease or Dementia with Lewy Bodies [see Warnings and Precautions ( 5.16 )] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adults The information below is derived from an integrated clinical study database for lurasidone hydrochloride consisting of 3,799 adult patients exposed to one or more doses of lurasidone hydrochloride for the treatment of schizophrenia and bipolar depression in placebo-controlled studies. This experience corresponds with a total experience of 1,250.9 patient-years. A total of 1,106 lurasidone hydrochloride-treated patients had at least 24 weeks and 371 lurasidone hydrochloride-treated patients had at least 52 weeks of exposure. Adverse events during exposure to study treatment were obtained by general inquiry and voluntarily reported adverse experiences, as well as results from physical examinations, vital signs, ECGs, weights and laboratory investigations. Adverse experiences were recorded by clinical investigators using their own terminology. In order to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology. Schizophrenia The following findings are based on the short-term, placebo-controlled premarketing adult studies for schizophrenia in which lurasidone hydrochloride tablets was administered at daily doses ranging from 20 mg to 160 mg (n=1,508). Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) in patients treated with lurasidone hydrochloride were somnolence, akathisia, extrapyramidal symptoms, and nausea. Adverse Reactions Associated with Discontinuation of Treatment: A total of 9.5% (143/1,508) lurasidone hydrochloride-treated patients and 9.3% (66/708) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with lurasidone hydrochloride that were at least 2% and at least twice the placebo rate. Adverse Reactions Occurring at an Incidence of 2% or More in lurasidone hydrochloride-treated Patients: Adverse reactions associated with the use of lurasidone hydrochloride (incidence of 2% or greater, rounded to the nearest percent and lurasidone hydrochloride incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with schizophrenia) are shown in Table 19. Table 19 Adverse Reactions in 2% or More of Lurasidone Hydrochloride-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in Adult Short-term Schizophrenia Studies Note: Figures rounded to the nearest integer * Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence ** Extrapyramidal symptoms include adverse event terms: bradykinesia, cogwheel rigidity, drooling, dystonia, extrapyramidal disorder, hypokinesia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, tongue spasm, torticollis, tremor, and trismus Percentage of Patients Reporting Reaction Lurasidone Hydrochloride Tablets Body System or Organ Class Placebo (N=708) (%) 20 mg/day (N=71) (%) 40 mg/day (N=487) (%) 80 mg/day (N=538) (%) 120 mg/day (N=291) (%) 160 mg/day (N=121) (%) All Lurasidone hydrochloride Tablets (N=1,508) (%) Gastrointestinal Disorders Nausea 5 11 10 9 13 7 10 Vomiting 6 7 6 9 9 7 8 Dyspepsia 5 11 6 5 8 6 6 Salivary Hypersecretion < 1 1 1 2 4 2 2 Musculoskeletal and Connective Tissue Disorders Back Pain 2 0 4 3 4 0 3 Nervous System Disorders Somnolence* 7 15 16 15 26 8 17 Akathisia 3 6 11 12 22 7 13 Extrapyramidal Disorder** 6 6 11 12 22 13 14 Dizziness 2 6 4 4 5 6 4 Psychiatric Disorders Insomnia 8 8 10 11 9 7 10 Agitation 4 10 7 3 6 5 5 Anxiety 4 3 6 4 7 3 5 Restlessness 1 1 3 1 3 2 2 Dose-Related Adverse Reactions in the Schizophrenia Studies Akathisia and extrapyramidal symptoms were dose-related. The frequency of akathisia increased with dose up to 120 mg/day (5.6% for lurasidone hydrochloride tablets 20 mg, 10.7% for lurasidone hydrochloride tablets 40 mg, 12.3% for lurasidone hydrochloride tablets 80 mg, and 22.0% for lurasidone hydrochloride tablets 120 mg). Akathisia was reported by 7.4% (9/121) of patients receiving 160 mg/day. Akathisia occurred in 3.0% of subjects receiving placebo. The frequency of extrapyramidal symptoms increased with dose up to 120 mg/day (5.6% for lurasidone hydrochloride tablets 20 mg, 11.5% for lurasidone hydrochloride tablets 40 mg, 11.9% for lurasidone hydrochloride tablets 80 mg, and 22.0% for lurasidone hydrochloride tablets 120 mg). Bipolar Depression (Monotherapy) The following findings are based on the adult short-term, placebo-controlled premarketing study for bipolar depression in which lurasidone hydrochloride tablets were administered at daily doses ranging from 20 mg to 120 mg (n=331). Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥ 5%, in either dose group, and at least twice the rate of placebo) in patients treated with lurasidone hydrochloride were akathisia, extrapyramidal symptoms, somnolence, nausea, vomiting, diarrhea, and anxiety. Adverse Reactions Associated with Discontinuation of Treatment: A total of 6.0% (20/331) lurasidone hydrochloride-treated patients and 5.4% (9/168) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with lurasidone hydrochloride that were at least 2% and at least twice the placebo rate. Adverse Reactions Occurring at an Incidence of 2% or More in lurasidone hydrochloride-treated Patients: Adverse reactions associated with the use of lurasidone hydrochloride (incidence of 2% or greater, rounded to the nearest percent and lurasidone hydrochloride incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with bipolar depression) are shown in Table 20. Table 20 Adverse Reactions in 2% or More of Lurasidone Hydrochloride-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the Adult Short-term Monotherapy Bipolar Depression Study Note: Figures rounded to the nearest integer *Extrapyramidal symptoms include adverse event terms: bradykinesia, cogwheel rigidity, drooling, dystonia, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, tongue spasm, torticollis, tremor, and trismus ** Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence Percentage of Patients Reporting Reaction Body System or Organ Class Dictionary-derived Term Placebo (N=168) (%) Lurasidone Hydrochloride Tablets 20 mg/day to 60 mg/day (N=164) (%) Lurasidone Hydrochloride Tablets 80 mg/day to 120 mg/day (N=167) (%) All Lurasidone Hydrochloride Tablets (N=331) (%) Gastrointestinal Disorders Nausea 8 10 17 14 Dry Mouth 4 6 4 5 Vomiting 2 2 6 4 Diarrhea 2 5 3 4 Infections and Infestations Nasopharyngitis 1 4 4 4 Influenza 1 < 1 2 2 Urinary Tract Infection < 1 2 1 2 Musculoskeletal and Connective Tissue Disorders Back Pain < 1 3 < 1 2 Nervous System Disorders Extrapyramidal Symptoms* 2 5 9 7 Akathisia 2 8 11 9 Somnolence** 7 7 14 11 Psychiatric Disorders Anxiety 1 4 5 4 Dose-Related Adverse Reactions in the Monotherapy Study: In the adult short-term, placebo-controlled study (involving lower and higher lurasidone hydrochloride tablets dose ranges) [see Clinical Studies (14.2)] the adverse reactions that occurred with a greater than 5% incidence in the patients treated with lurasidone hydrochloride tablets in any dose group and greater than placebo in both groups were nausea (10.4%, 17.4%), somnolence (7.3%, 13.8%), akathisia (7.9%, 10.8%), and extrapyramidal symptoms (4.9%, 9.0%) for lurasidone hydrochloride tablets 20 mg/day to 60 mg/day and lurasidone hydrochloride tablets 80 mg/day to 120 mg/day, respectively. Bipolar Depression Adjunctive Therapy with Lithium or Valproate The following findings are based on two adult short-term, placebo-controlled premarketing studies for bipolar depression in which lurasidone hydrochloride tablets were administered at daily doses ranging from 20 mg to 120 mg as adjunctive therapy with lithium or valproate (n=360). Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) in subjects treated with lurasidone hydrochloride were akathisia and somnolence. Adverse Reactions Associated with Discontinuation of Treatment: A total of 5.8% (21/360) lurasidone hydrochloride-treated patients and 4.8% (16/334) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with lurasidone hydrochloride that were at least 2% and at least twice the placebo rate. Adverse Reactions Occurring at an Incidence of 2% or More in lurasidone hydrochloride-treated Patients: Adverse reactions associated with the use of lurasidone hydrochloride (incidence of 2% or greater, rounded to the nearest percent and lurasidone hydrochloride incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with bipolar depression) are shown in Table 21. Table 21 Adverse Reactions in 2% or More of Lurasidone Hydrochloride-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the Adult Short-term Adjunctive Therapy Bipolar Depression Studies Note: Figures rounded to the nearest integer * Extrapyramidal symptoms include adverse event terms: bradykinesia, cogwheel rigidity, drooling, dystonia, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, tongue spasm, torticollis, tremor, and trismus ** Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence Percentage of Patients Reporting Reaction Body System or Organ Class Dictionary-derived Term Placebo (N=334) (%) Lurasidone Hydrochloride Tablets 20 mg/day to 120 mg/day (N=360) (%) Gastrointestinal Disorders Nausea 10 14 Vomiting 1 4 General Disorders Fatigue 1 3 Infections and Infestations Nasopharyngitis 2 4 Investigations Weight Increased < 1 3 Metabolism and Nutrition Disorders Increased Appetite 1 3 Nervous System Disorders Extrapyramidal Symptoms * 9 14 Somnolence ** 5 11 Akathisia 5 11 Psychiatric Disorders Restlessness < 1 4 Adolescents Schizophrenia The following findings are based on the short-term, placebo-controlled adolescent study for schizophrenia in which lurasidone hydrochloride was administered at daily doses ranging from 40 (N=110) to 80 mg (N=104). Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) in adolescent patients (13 to 17 years) treated with lurasidone hydrochloride were somnolence, nausea, akathisia, extrapyramidal symptoms (non-akathisia, 40mg only), vomiting, and rhinorrhea/rhinitis (80 mg only). Adverse Reactions Associated with Discontinuation of Treatment The incidence of discontinuation due to adverse reactions between lurasidone hydrochloride- and placebo-treated adolescent patients (13 to 17 years) was 4% and 8%, respectively. Adverse Reactions Occurring at an Incidence of 2% or More in Lurasidone Hydrochloride-Treated Patients Adverse reactions associated with the use of lurasidone hydrochloride (incidence of 2% or greater, rounded to the nearest percent and lurasidone hydrochloride incidence greater than placebo) that occurred during acute therapy (up to 6-weeks in adolescent patients with schizophrenia) are shown in Table 22. Table 22 Adverse Reactions in 2% or More of Lurasidone Hydrochloride-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the Adolescent Short-term Schizophrenia Study Note: Figures rounded to the nearest integer * Somnolence includes adverse event terms: hypersomnia, sedation, and somnolence ** Viral Infection includes adverse event terms: nasopharyngitis, influenza, viral infection, upper respiratory tract infection *** Rhinitis incudes adverse event terms: rhinitis, allergic rhinitis, rhinorrhea, and nasal congestion Percentage of Patients Reporting Reaction Body System or Organ Class Dictionary-derived Term Placebo (N=112) Lurasidone Hydrochloride Tablets 40 mg/day (N=110) Lurasidone Hydrochloride Tablets 80 mg/day (N=104) All Lurasidone Hydrochloride Tablets (N=214) Gastrointestinal Disorders Nausea 3 13 14 14 Vomiting 2 8 6 8 Diarrhea 1 3 5 4 Dry Mouth 0 2 3 2 Infections and Infestations Viral Infection** 6 11 10 10 Rhinitis*** 2 <1 8 4 Oropharyngeal pain 0 <1 3 2 Tachycardia 0 0 3 1 Nervous System Disorders Somnolence* 7 15 13 15 Akathisia 2 9 9 9 Dizziness 1 5 5 5 Pediatric Patients (10 to 17 years) Bipolar Depression The following findings are based on the 6-week, placebo-controlled study for bipolar depression in pediatric patients 10 to 17 years in which lurasidone hydrochloride was administered at daily doses ranging from 20 to 80 mg (N=175). Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥5%, and at least twice the rate of placebo) in pediatric patients (10 to 17 years) treated with lurasidone hydrochloride were nausea, weight increase, and insomnia. Adverse Reactions Associated with Discontinuation of Treatment: The incidence of discontinuation due to adverse reactions between lurasidone hydrochloride - and placebo-treated pediatric patients 10 to 17 years was 2% and 2%, respectively. Adverse Reactions Occurring at an Incidence of 2% or More in lurasidone hydrochloride -Treated Patients: Adverse reactions associated with the use of lurasidone hydrochloride (incidence of 2% or greater, rounded to the nearest percent and lurasidone hydrochloride incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in pediatric patients with bipolar depression) are shown in Table 23. Table 23 Adverse Reactions in 2% or More of Lurasidone Hydrochloride -Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the 6 Week Bipolar Depression Study in Pediatric Patients (10 to 17 years) Note: Figures rounded to the nearest integer *Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence **EPS includes adverse event terms: akathisia, cogwheel rigidity, dyskinesia, dystonia, hyperkinesia, joint stiffness, muscle rigidity, muscle spasms, musculoskeletal stiffness, oculogyric crisis, parkinsonism, tardive dyskinesia, and tremor Percentage of Patients Reporting Reaction Body System or Organ Class Dictionary-derived Term Placebo (N=172) Lurasidone Hydrochloride Tablets 20 to 80 mg/day (N=175) Gastrointestinal Disorders Nausea 6 16 Vomiting 4 6 Abdominal Pain Upper 2 3 Diarrhea 2 3 Abdominal Pain 1 3 General Disorders And Administration Site Conditions Fatigue 2 3 Investigations Weight Increased 2 7 Metabolism and Nutrition Disorders Decreased Appetite 2 4 Nervous System Disorders Somnolence* 6 11 Extrapyramidal symptoms** 5 6 Dizziness 5 6 Psychiatric Disorders Insomnia 2 5 Abnormal Dreams 2 2 Respiratory, Thoracic and Mediastinal Disorders Oropharyngeal Pain 2 2 Extrapyramidal Symptoms Schizophrenia Adults In the short-term, placebo-controlled schizophrenia studies, for lurasidone hydrochloride-treated patients, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness, was 13.5% and 5.8% for placebo-treated patients. The incidence of akathisia for lurasidone hydrochloride-treated patients was 12.9% and 3.0% for placebo-treated patients. Incidence of EPS by dose is provided in Table 24. Table 24 Incidence of EPS Compared to Placebo in Adult Schizophrenia Studies Note: Figures rounded to the nearest integer * Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus ** Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor Lurasidone Hydrochloride Tablets Adverse Event Term Placebo (N=708) (%) 20 mg/day (N=71) (%) 40 mg/day (N=487) (%) 80 mg/day (N=538) (%) 120 mg/day (N=291) (%) 160 mg/day (N=121) (%) All EPS events 9 10 21 23 39 20 All EPS events, excluding Akathisia/Restlessness 6 6 11 12 22 13 Akathisia 3 6 11 12 22 7 Dystonia* < 1 0 4 5 7 2 Parkinsonism** 5 6 9 8 17 11 Restlessness 1 1 3 1 3 2 Adolescents In the short-term, placebo-controlled, study of schizophrenia in adolescents, the incidence of EPS, excluding events related to akathisia, for lurasidone hydrochloride-treated patients was higher in the 40 mg (10%) and the 80 mg (7.7%) treatment groups vs. placebo (3.6%); and the incidence of akathisia-related events for lurasidone hydrochloride-treated patients was 8.9% vs. 1.8% for placebo-treated patients. Incidence of EPS by dose is provided in Table 25. Table 25 Incidence of EPS Compared to Placebo in the Adolescent Schizophrenia Study Note: Figures rounded to the nearest integer * Dystonia includes adverse event terms: dystonia, trismus, oculogyric crisis, oromandibular dystonia, tongue spasm, and torticollis ** Parkinsonism includes adverse event terms: bradykinesia, drooling, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, parkinsonism, and psychomotor retardation Lurasidone Hydrochloride Tablets Adverse Event Term Placebo (N=112) (%) 40 mg/day (N=110) (%) 80 mg/day (N=104) (%) All EPS events 5 14 14 All EPS events, excluding Akathisia/Restlessness 4 7 7 Akathisia 2 9 9 Parkinsonism** <1 4 0 Dyskinesia <1 <1 1 Dystonia* 0 <1 1 Bipolar Depression Adults Monotherapy In the adult short-term, placebo-controlled monotherapy bipolar depression study, for lurasidone hydrochloride-treated patients, the incidence of reported events related to EPS, excluding akathisia and restlessness was 6.9% and 2.4% for placebo-treated patients. The incidence of akathisia for lurasidone hydrochloride-treated patients was 9.4% and 2.4% for placebo-treated patients. Incidence of EPS by dose groups is provided in Table 26. Table 26 Incidence of EPS Compared to Placebo in the Adult Monotherapy Bipolar Depression Study Note: Figures rounded to the nearest integer * Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus ** Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor Lurasidone Hydrochloride Tablets Adverse Event Term Placebo (N=168) (%) 20 mg/day to 60 mg/day (N=164) (%) 80 mg/day to 120 mg/day (N=167) (%) All EPS events 5 12 20 All EPS events, excluding Akathisia/Restlessness 2 5 9 Akathisia 2 8 11 Dystonia* 0 0 2 Parkinsonism** 2 5 8 Restlessness < 1 0 3 Adjunctive Therapy with Lithium or Valproate In the adult short-term, placebo-controlled adjunctive therapy bipolar depression studies, for lurasidone hydrochloride-treated patients, the incidence of EPS, excluding akathisia and restlessness, was 13.9% and 8.7% for placebo. The incidence of akathisia for lurasidone hydrochloride-treated patients was 10.8% and 4.8% for placebo-treated patients. Incidence of EPS is provided in Table 27. Table 27 Incidence of EPS Compared to Placebo in the Adult Adjunctive Therapy Bipolar Depression Studies Note: Figures rounded to the nearest integer * Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus ** Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor Adverse Event Term Placebo (N=334) (%) Lurasidone Hydrochloride Tablets 20 mg/day to 120 mg/day (N=360) (%) All EPS events 13 24 All EPS events, excluding Akathisia/Restlessness 9 14 Akathisia 5 11 Dystonia * < 1 1 Parkinsonism ** 8 13 Restlessness < 1 4 In the short-term, placebo-controlled schizophrenia and bipolar depression studies, data was objectively collected on the Simpson Angus Rating Scale (SAS) for extrapyramidal symptoms (EPS), the Barnes Akathisia Scale (BAS) for akathisia and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesias. Pediatric Patients (10 to 17 years) In the 6-week, placebo-controlled study of bipolar depression in pediatric patients 10 to 17 years, the incidence of EPS, excluding events related to akathisia, for lurasidone hydrochloride-treated patients was similar in the lurasidone hydrochloride 20 to 80 mg/day (3.4%) treatment group vs. placebo (3.5%); and the incidence of akathisia-related events for lurasidone hydrochloride-treated patients was 2.9% vs. 3.5% for placebo-treated patients. Incidence of EPS by dose is provided in Table 28. Table 28 Incidence of EPS Compared to Placebo in the Bipolar Depression Study in Pediatric Patients (10 to 17 years) Note: Figures rounded to the nearest integer * EPS include adverse event terms: akathisia, cogwheel rigidity, dyskinesia, dystonia, hyperkinesia, joint stiffness, muscle rigidity, muscle spasms, musculoskeletal stiffness, oculogyric crisis, parkinsonism, tardive dyskinesia, and tremor ** Parkinsonism includes adverse event terms: bradykinesia, drooling, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, parkinsonism, and psychomotor retardation ***Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus Adverse Event Term Placebo (N=172) (%) Lurasidone Hydrochloride Tablets 20 to 80 mg/day (N=175) (%) All EPS events * 5 6 All EPS events, excluding Akathisia/Restlessness 4 3 Akathisia 4 3 Parkinsonism** <1 <1 Dystonia*** 1 <1 Salivary hypersecretion <1 <1 Psychomotor hyperactivity 0 <1 Tardive Dyskinesia <1 0 Schizophrenia Adults The mean change from baseline for lurasidone hydrochloride-treated patients for the SAS, BAS and AIMS was comparable to placebo-treated patients, with the exception of the Barnes Akathisia Scale global score (lurasidone hydrochloride, 0.1; placebo, 0.0). The percentage of patients who shifted from normal to abnormal was greater in lurasidone hydrochloride-treated patients and placebo for the BAS (lurasidone hydrochloride, 14.4%; placebo, 7.1%), the SAS (lurasidone hydrochloride, 5.0%; placebo, 2.3%) and the AIMS (lurasidone hydrochloride, 7.4%; placebo, 5.8%). Adolescents The mean change from baseline for lurasidone hydrochloride - treated patients with adolescent schizophrenia for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in lurasidone hydrochloride -treated patients and placebo for the BAS (Lurasidone hydrochloride, 7.0%; placebo, 1.8%), the SAS (Lurasidone hydrochloride, 8.3%; placebo, 2.7%) and the AIMS (Lurasidone hydrochloride, 2.8%; placebo, 0.9%). Bipolar Depression Adults Monotherapy The mean change from baseline for lurasidone hydrochloride-treated adult patients for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in lurasidone hydrochloride-treated patients and placebo for the BAS (lurasidone hydrochloride, 8.4%; placebo, 5.6%), the SAS (lurasidone hydrochloride, 3.7%; placebo, 1.9%) and the AIMS (lurasidone hydrochloride, 3.4%; placebo, 1.2%). Adjunctive Therapy with Lithium or Valproate The mean change from baseline for lurasidone hydrochloride-treated adult patients for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in lurasidone hydrochloride-treated patients and placebo for the BAS (lurasidone hydrochloride, 8.7%; placebo, 2.1%), the SAS (lurasidone hydrochloride, 2.8%; placebo, 2.1%) and the AIMS (lurasidone hydrochloride, 2.8%; placebo, 0.6%). Pediatric Patients (10 to 17 years) The mean change from baseline for lurasidone hydrochloride - treated pediatric patients 10 to 17 years with bipolar depression for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in Lurasidone hydrochloride -treated patients and placebo for the BAS (Lurasidone hydrochloride, 4.6%; placebo, 2.4%), the SAS (Lurasidone hydrochloride, 0.6%; placebo, 0%) and was the same for the AIMS (Lurasidone hydrochloride, 0%; placebo, 0%). Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Schizophrenia Adults In the short-term, placebo-controlled schizophrenia clinical studies, dystonia occurred in 4.2% of lurasidone hydrochloride-treated subjects (0.0% lurasidone hydrochloride tablets 20 mg, 3.5% lurasidone hydrochloride tablets 40 mg, 4.5% lurasidone hydrochloride tablets 80 mg, 6.5% lurasidone hydrochloride tablets 120 mg and 2.5% lurasidone hydrochloride tablets 160 mg) compared to 0.8% of subjects receiving placebo. Seven subjects (0.5%, 7/1,508) discontinued clinical trials due to dystonic events – four were receiving lurasidone hydrochloride tablets 80 mg/day and three were receiving lurasidone hydrochloride tablets 120 mg/day. Adolescents In the short-term, placebo-controlled, adolescent schizophrenia study, dystonia occurred in 1% of lurasidone hydrochloride -treated patients (1% lurasidone hydrochloride 40 mg and 1% lurasidone hydrochloride 80 mg) compared to 0% of patients receiving placebo. No patients discontinued the clinical study due to dystonic events. Bipolar Depression Adults Monotherapy In the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, dystonia occurred in 0.9% of lurasidone hydrochloride-treated subjects (0.0% and 1.8% for lurasidone hydrochloride tablets 20 mg/day to 60 mg/day and lurasidone hydrochloride tablets 80 mg/day to 120 mg/day, respectively) compared to 0.0% of subjects receiving placebo. No subject discontinued the clinical study due to dystonic events. Adjunctive Therapy with Lithium or Valproate In the adult short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies, dystonia occurred in 1.1% of lurasidone hydrochloride tablets-treated subjects (20 mg to 120 mg) compared to 0.6% of subjects receiving placebo. No subject discontinued the clinical study due to dystonic events. Pediatric Patients (10 to 17 years) In the 6-week, placebo-controlled bipolar depression study in pediatric patients 10 to 17 years, dystonia occurred in 0.6% of lurasidone hydrochloride -treated patients compared to 1.2% of patients receiving placebo. No patients discontinued the clinical study due to dystonic events. Other Adverse Reactions Observed During the Premarketing Evaluation of lurasidone hydrochloride Following is a list of adverse reactions reported by adult patients treated with lurasidone hydrochloride tablets at multiple doses of ≥ 20 mg once daily within the premarketing database of 2,905 patients with schizophrenia. The reactions listed are those that could be of clinical importance, as well as reactions that are plausibly drug-related on pharmacologic or other grounds. Reactions listed in Table 19 or those that appear elsewhere in the lurasidone hydrochloride label are not included. Reactions are further categorized by organ class and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (frequent) (only those not already listed in the tabulated results from placebo-controlled studies appear in this listing); those occurring in 1/100 to 1/1,000 patients (infrequent); and those occurring in fewer than 1/1,000 patients (rare). Blood and Lymphatic System Disorders: Infrequent: anemia Cardiac Disorders: Frequent: tachycardia; Infrequent: AV block 1st degree, angina pectoris, bradycardia Ear and Labyrinth Disorders: Infrequent: vertigo Eye Disorders: Frequent: blurred vision Gastrointestinal Disorders: Frequent: abdominal pain, diarrhea; Infrequent: gastritis General Disorders and Administrative Site Conditions: Rare: sudden death Investigations: Frequent: CPK increased Metabolism and Nutritional System Disorders: Frequent: decreased appetite Musculoskeletal and Connective Tissue Disorders: Rare: rhabdomyolysis Nervous System Disorders: Infrequent: cerebrovascular accident, dysarthria Psychiatric Disorders: Infrequent: abnormal dreams, panic attack, sleep disorder Renal and Urinary Disorders: Infrequent: dysuria; Rare: renal failure Reproductive System and Breast Disorders: Infrequent: amenorrhea, dysmenorrhea; Rare: breast enlargement, breast pain, galactorrhea, erectile dysfunction, priapism Skin and Subcutaneous Tissue Disorders: Frequent: rash, pruritus; Rare: angioedema Vascular Disorders: Frequent: hypertension Clinical Laboratory Changes Schizophrenia Adults Serum Creatinine : In short-term, placebo-controlled trials, the mean change from Baseline in serum creatinine was +0.05 mg/dL for lurasidone hydrochloride-treated patients compared to +0.02 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 3.0% (43/1,453) of lurasidone hydrochloride-treated patients and 1.6% (11/681) on placebo. The threshold for high creatinine value varied from > 0.79 to > 1.3 mg/dL based on the centralized laboratory definition for each study (Table 29). Table 29 Serum Creatinine Shifts from Normal at Baseline to High at Study End- Point in Adult Schizophrenia Studies Laboratory Parameter Placebo (N=708) Lurasidone Hydrochloride Tablets 20 mg/day (N=71) Lurasidone hydrochloride Tablets 40 mg/day (N=487) Lurasidone hydrochloride Tablets 80 mg/day (N=538) Lurasidone hydrochloride Tablets 120 mg/day (N=291) Lurasidone hydrochloride Tablets 160 mg/day (N=121) Serum Creatinine Elevated 2% 1% 2% 2% 5% 7% Adolescents Serum Creatinine : In the short-term, placebo-controlled, adolescent schizophrenia study, the mean change from Baseline in serum creatinine was -0.009 mg/dL for lurasidone hydrochloride-treated patients compared to +0.017 mg/dL for placebo-treated patients. A creatinine shift from normal to high (based on the centralized laboratory definition) occurred in 7.2% (14/194) of lurasidone hydrochloride-treated patients and 2.9% (3/103) on placebo (Table 30). Table 30 Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in the Adolescent Schizophrenia Study Laboratory Parameter Lurasidone Hydrochloride Tablets Placebo (N=103) Lurasidone Hydrochloride Tablets 40 mg/day (N=97) Lurasidone Hydrochloride Tablets 80 mg/day (N=97) Serum Creatinine Elevated 2.9% 7.2% 7.2% Bipolar Depression Adults Monotherapy Serum Creatinine : In the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, the mean change from Baseline in serum creatinine was +0.01 mg/dL for lurasidone hydrochloride-treated patients compared to -0.02 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 2.8% (9/322) of lurasidone hydrochloride-treated patients and 0.6% (1/162) on placebo (Table 31). Table 31 Serum Creatinine Shifts from Normal at Baseline to High at Study End- Point in the Adult Monotherapy Bipolar Depression Study Laboratory Parameter Placebo (N=168) Lurasidone Hydrochloride Tablets 20 mg/day to 60 mg/day (N=164) Lurasidone Hydrochloride Tablets 80 mg/day to 120 mg/day (N=167) Serum Creatinine Elevated <1% 2% 4% Adjunctive Therapy with Lithium or Valproate Serum Creatinine : In adult short-term, placebo-controlled premarketing adjunctive studies for bipolar depression, the mean change from Baseline in serum creatinine was +0.04 mg/dL for lurasidone hydrochloride-treated patients compared to -0.01 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 4.3% (15/360) of lurasidone hydrochloride-treated patients and 1.6% (5/334) on placebo (Table 32). Table 32 Serum Creatinine Shifts from Normal at Baseline to High at Study End- Point in the Adult Adjunctive Therapy Bipolar Depression Studies Laboratory Parameter Placebo (N=334) Lurasidone Hydrochloride Tablets 20 mg/day to 120 mg/day (N=360) Serum Creatinine Elevated 2% 4% Pediatric Patients (10 to 17 years) Serum Creatinine : In the 6-week, placebo-controlled bipolar depression study in pediatric patients 10 to 17 years, the mean change from Baseline in serum creatinine was +0.021 mg/dL for lurasidone hydrochloride-treated patients compared to +0.009 mg/dL for placebo-treated patients. A creatinine shift from normal to high (based on the centralized laboratory definition) occurred in 6.7% (11/163) of lurasidone hydrochloride-treated patients and 4.5% (7/155) on placebo (Table 33). Table 33 Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in the Bipolar Depression Study in Pediatric Patients (10 to 17 years) Laboratory Parameter Placebo (N=155) Lurasidone Hydrochloride Tablets 20 to 80 mg/day (N=163) Serum Creatinine Elevated 4.5% 6.7% Pediatric Patients (6 to 17 years) In a 104-week, open-label study in pediatric patients with schizophrenia, bipolar depression, or autistic disorder, the mean change from baseline to Week 104 in serum creatinine was +0.07 mg/dL. In patients with a normal serum creatinine at baseline, 6% experienced a shift to high at endpoint 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of lurasidone hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity Reactions: Urticaria, throat swelling, tongue swelling, dyspnea, and rash. Metabolism and Nutrition Disorders: Hyponatremia

4 CONTRAINDICATIONS Known hypersensitivity to lurasidone hydrochloride 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 ). 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 )].

11 DESCRIPTION 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-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 solid. It is slightly soluble in methanol. 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 citric acid monohydrate, croscarmellose sodium, hypromellose, iron oxide yellow (only for 20 mg and 80 mg), lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, polyethylene glycol, pregelatinised starch, poloxamer, titanium dioxide and talc. Lurasidone hydrochloride tablets

2 DOSAGE AND ADMINISTRATION Lurasidone hydrochloride tablets should be taken with food (at least 350 calories). Administration with food substantially increases the absorption of lurasidone hydrochloride ( 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 ) 2.1 Schizophrenia 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. 2.2 Depressive Episodes Associated with Bipolar I Disorder 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 mg to 60 mg per day) [see Clinical Studies ( 14.2 )] . Pediatric Patients (10 – 17 years) The recommended starting dose of lurasidone hydrochloride 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 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 [see Clinical Studies ( 14.2 )] . The maximum recommended dose is 80 mg per day. The efficacy of lurasidone hydrochloride in the treatment of mania associated with bipolar disorder has not been established. 2.3 Administration Information Lurasidone hydrochloride tablets should be taken with food (at least 350 calories). Administration with food substantially increases the absorption of lurasidone hydrochloride. 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 )] . 2.4 Dose Modifications for Renal Impairment Dose adjustment is recommended in moderate (creatinine clearance: 30 mL/min 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 )]. 2.5 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 mg per day [see Use in Specific Populations ( 8.7 )]. 2.6 Dose Modifications Due to Drug Interactions of CYP3A4 Inhibitors and CYP3A4 Inducers Concomitant Use with CYP3A4 Inhibitors Lurasidone hydrochloride should not be used concomitantly with a strong CYP3A4 inhibitor (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.) [see Contraindications ( 4 )] . If lurasidone hydrochloride is 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 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 Contraindications ( 4 ), Drug Interactions ( 7.1 )] . Grapefruit and grapefruit juice should be avoided in patients taking lurasidone hydrochloride, since these may inhibit CYP3A4 and alter lurasidone hydrochloride concentrations [ see Drug Interactions ( 7.1 ) ]. Concomitant Use with CYP3A4 Inducers Lurasidone hydrochloride should not be used concomitantly with a strong CYP3A4 inducer (e.g., rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine, etc.) [see Contraindications ( 4 ); Drug Interactions ( 7.1 )] . If lurasidone hydrochloride is 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.

1 INDICATIONS AND USAGE Lurasidone hydrochloride is indicated for: Treatment of adult patients 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 tablets are 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 )

9.2 Abuse Lurasidone hydrochloride has not been systematically studied in humans for its potential for abuse or physical dependence or its ability to induce tolerance. While clinical studies with lurasidone hydrochloride did not reveal any tendency for drug-seeking behavior, these observations were not systematic and it is not possible to predict the extent to which a CNS-active drug will be misused, diverted and/or abused once it is marketed. Patients should be evaluated carefully for a history of drug abuse, and such patients should be observed carefully for signs of lurasidone hydrochloride misuse or abuse (e.g., development of tolerance, drug-seeking behavior, increases in dose).

9.1 Controlled Substance Lurasidone hydrochloride is not a controlled substance.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Lurasidone hydrochloride is not a controlled substance. 9.2 Abuse Lurasidone hydrochloride has not been systematically studied in humans for its potential for abuse or physical dependence or its ability to induce tolerance. While clinical studies with lurasidone hydrochloride did not reveal any tendency for drug-seeking behavior, these observations were not systematic and it is not possible to predict the extent to which a CNS-active drug will be misused, diverted and/or abused once it is marketed. Patients should be evaluated carefully for a history of drug abuse, and such patients should be observed carefully for signs of lurasidone hydrochloride misuse or abuse (e.g., development of tolerance, drug-seeking behavior, increases in dose).

10 OVERDOSAGE 10.1 Human Experience In premarketing clinical studies, accidental or intentional overdosage of lurasidone hydrochloride tablets was identified in one patient who ingested an estimated 560 mg of lurasidone hydrochloride. This patient recovered without sequelae. This patient resumed lurasidone hydrochloride treatment for an additional two months. 10.2 Management of Overdosage No specific antidotes for lurasidone hydrochloride are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. If an overdose occurs, consult a Certified Poison Control Center (1-800-222-1222 or www.poison.org). Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with an acute overdose of lurasidone hydrochloride. Similarly, the alpha-blocking properties of bretylium might be additive to those of lurasidone hydrochloride, resulting in problematic hypote nsion. Hypotension and circulatory collapse should be treated with appropriate measures. Epinephrine and dopamine should not be used, or other sympathomimetics with beta-agonist activity, since beta stimulation may worsen hypotension in the setting of lurasidone hydrochloride-induced alpha blockade. In case of severe extrapyramidal symptoms, anticholinergic medication should be administered. Gastric lavage (after intubation if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.

7 DRUG INTERACTIONS 7.1 Drugs Having Clinically Important Interactions with Lurasidone Hydrochloride Table 34 Clinically Important Drug Interactions with Lurasidone Hydrochloride Strong CYP3A4 Inhibitors Clinical Impact: Concomitant use of lurasidone hydrochloride with strong CYP3A4 inhibitors increased the exposure of lurasidone compared to the use of lurasidone hydrochloride alone [ see Clinical Pharmacology ( 12.3 ) ]. Intervention: Lurasidone hydrochloride 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 with moderate CYP3A4 inhibitors increased the exposure of lurasidone compared to the use of lurasidone hydrochloride alone [ see Clinical Pharmacology ( 12.3 ) ]. Intervention: Lurasidone hydrochloride 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 with strong CYP3A4 inducers decreased the exposure of lurasidone compared to the use of lurasidone hydrochloride alone [ see Clinical Pharmacology ( 12.3 ) ]. Intervention: Lurasidone hydrochloride 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 with moderate CYP3A4 inducers decreased the exposure of lurasidone compared to the use of lurasidone hydrochloride alone [ see Clinical Pharmacology ( 12.3 ) ]. Intervention: Lurasidone hydrochloride dose should be increased when used concomitantly with moderate inducers of CYP3A4 [ see Dosage and Administration ( 2.6 ) ]. Examples: Bosentan, efavirenz, etravirine, modafinil, nafcillin 7.2 Drugs Having No Clinically Important Interactions with Lurasidone Hydrochloride Based on pharmacokinetic studies, no dosage adjustment of Lurasidone hydrochloride is required when administered concomitantly with lithium, valproate, or substrates of P-gp or CYP3A4 [see Clinical Pharmacology ( 12.3 )] .

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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 D 2 and serotonin Type 2 (5HT 2A ) receptor antagonism. 12.2 Pharmacodynamics Lurasidone is an antagonist with high affinity binding at the dopamine D 2 receptors (Ki of 1 nM) and the serotonin 5-HT 2A (Ki of 0.5 nM) and 5-HT 7 (Ki of 0.5 nM) receptors. It also binds with moderate affinity to the human α 2C adrenergic receptors (Ki of 11 nM), is a partial agonist at serotonin 5-HT 1A (Ki of 6.4 nM) receptors, and is an antagonist at the α 2A adrenergic receptors (Ki of 41 nM). Lurasidone exhibits little or no affinity for histamine H 1 and muscarinic M 1 receptors (IC 50 > 1,000 nM). ECG Changes The effects of lurasidone hydrochloride 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 lurasidone hydrochloride 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 lurasidone hydrochloride or placebo. 12.3 Pharmacokinetics Adults The activity of lurasidone hydrochloride 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 are reached within 7 days of starting lurasidone hydrochloride . Following administration of 40 mg of lurasidone hydrochloride tablets, the mean (%CV) elimination half-life was 18 (7) hours. Absorption and Distribution: Lurasidone hydrochloride is 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 6,173 (17.2) L. Lurasidone hydrochloride is highly bound (~99%) to serum proteins. In a food effect study, lurasidone hydrochloride mean C max and AUC were about 3-times and 2-times, respectively, when administered with food compared to the levels observed under fasting conditions. Lurasidone hydrochloride exposure was not affected as meal size was increased from 350 calories to 1,000 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, patients were instructed to take their daily dose with food [see Dosage and Administration ( 2.3 )] . Metabolism and Elimination: Lurasidone hydrochloride is metabolized mainly via CYP3A4. The major biotransformation pathways are oxidative N -dealkylation, hydroxylation of norbornane ring, and S -oxidation. Lurasidone hydrochloride is 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 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. 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 is 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 3,902 (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 mg/day to 2,400 mg/day or valproate 300 mg/day to 2,000 mg/day with lurasidone for up to 6 weeks has minimal effect on lurasidone exposure. And the effects of lurasidone hydrochloride 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 mg/day to 2,400 mg/day or valproate 300 mg/day to 2,000 mg/day. Figure 1 Impact of Other Drugs on Lurasidone Hydrochloride Pharmacokinetics Figure 2 Impact of Lurasidone Hydrochloride on Other Drugs Studies in Specific Populations The effect of intrinsic patient factors on the pharmacokinetics of lurasidone hydrochloride is presented in Figure 3. Pediatric Patients Lurasidone hydrochloride exposure (i.e., steady-state Cmax 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 Pharmacokinetics Figure 1 Figure 2 Figure 3

12.1 Mechanism of Action 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 D 2 and serotonin Type 2 (5HT 2A ) receptor antagonism.

12.2 Pharmacodynamics Lurasidone is an antagonist with high affinity binding at the dopamine D 2 receptors (Ki of 1 nM) and the serotonin 5-HT 2A (Ki of 0.5 nM) and 5-HT 7 (Ki of 0.5 nM) receptors. It also binds with moderate affinity to the human α 2C adrenergic receptors (Ki of 11 nM), is a partial agonist at serotonin 5-HT 1A (Ki of 6.4 nM) receptors, and is an antagonist at the α 2A adrenergic receptors (Ki of 41 nM). Lurasidone exhibits little or no affinity for histamine H 1 and muscarinic M 1 receptors (IC 50 > 1,000 nM). ECG Changes The effects of lurasidone hydrochloride 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 lurasidone hydrochloride 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 lurasidone hydrochloride or placebo.

12.3 Pharmacokinetics Adults The activity of lurasidone hydrochloride 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 are reached within 7 days of starting lurasidone hydrochloride . Following administration of 40 mg of lurasidone hydrochloride tablets, the mean (%CV) elimination half-life was 18 (7) hours. Absorption and Distribution: Lurasidone hydrochloride is 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 6,173 (17.2) L. Lurasidone hydrochloride is highly bound (~99%) to serum proteins. In a food effect study, lurasidone hydrochloride mean C max and AUC were about 3-times and 2-times, respectively, when administered with food compared to the levels observed under fasting conditions. Lurasidone hydrochloride exposure was not affected as meal size was increased from 350 calories to 1,000 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, patients were instructed to take their daily dose with food [see Dosage and Administration ( 2.3 )] . Metabolism and Elimination: Lurasidone hydrochloride is metabolized mainly via CYP3A4. The major biotransformation pathways are oxidative N -dealkylation, hydroxylation of norbornane ring, and S -oxidation. Lurasidone hydrochloride is 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 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. 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 is 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 3,902 (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 mg/day to 2,400 mg/day or valproate 300 mg/day to 2,000 mg/day with lurasidone for up to 6 weeks has minimal effect on lurasidone exposure. And the effects of lurasidone hydrochloride 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 mg/day to 2,400 mg/day or valproate 300 mg/day to 2,000 mg/day. Figure 1 Impact of Other Drugs on Lurasidone Hydrochloride Pharmacokinetics Figure 2 Impact of Lurasidone Hydrochloride on Other Drugs Studies in Specific Populations The effect of intrinsic patient factors on the pharmacokinetics of lurasidone hydrochloride is presented in Figure 3. Pediatric Patients Lurasidone hydrochloride exposure (i.e., steady-state Cmax 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 Pharmacokinetics

20230621

6

3 DOSAGE FORMS AND STRENGTHS Tablets: 20 mg, 40 mg, 60 mg, 80 mg and 120 mg ( 3 ) Lurasidone hydrochloride tablets are available in the following shape and color with respective one-sided debossing: 20 mg lurasidone hydrochloride tablets are yellow to light yellow, round shaped, coated tablets, debossed with "C31" on one side and plain on the other side. 40 mg lurasidone hydrochloride tablets are white to off white, round shaped, coated tablets, debossed with "C32" on one side and plain on the other side. 60 mg lurasidone hydrochloride tablets are white to off white, modified capsule shaped, coated tablets, debossed with "C33" on one side and plain on the other side. 80 mg lurasidone hydrochloride tablets are yellow to light yellow, oval shaped, coated tablets, debossed with "C34" on one side and plain on the other side. 120 mg lurasidone hydrochloride tablets are white to off white, oval shaped, coated tablets, debossed with "C35" on one side and plain on the other side.

Lurasidone hydrochloride Lurasidone hydrochloride LURASIDONE HYDROCHLORIDE LURASIDONE CELLULOSE, MICROCRYSTALLINE CITRIC ACID MONOHYDRATE CROSCARMELLOSE SODIUM FERRIC OXIDE YELLOW HYPROMELLOSES LACTOSE MONOHYDRATE MAGNESIUM STEARATE POLOXAMER 407 POLYETHYLENE GLYCOL, UNSPECIFIED POLYVINYL ALCOHOL, UNSPECIFIED STARCH, CORN TALC TITANIUM DIOXIDE YELLOW TO LIGHT YELLOW ROUND C31 Lurasidone hydrochloride Lurasidone hydrochloride LURASIDONE HYDROCHLORIDE LURASIDONE CELLULOSE, MICROCRYSTALLINE CITRIC ACID MONOHYDRATE CROSCARMELLOSE SODIUM HYPROMELLOSES LACTOSE MONOHYDRATE MAGNESIUM STEARATE POLOXAMER 407 POLYETHYLENE GLYCOL, UNSPECIFIED POLYVINYL ALCOHOL, UNSPECIFIED STARCH, CORN TALC TITANIUM DIOXIDE WHITE TO OFF WHITE ROUND C32 Lurasidone hydrochloride Lurasidone hydrochloride LURASIDONE HYDROCHLORIDE LURASIDONE CELLULOSE, MICROCRYSTALLINE CITRIC ACID MONOHYDRATE CROSCARMELLOSE SODIUM HYPROMELLOSES LACTOSE MONOHYDRATE MAGNESIUM STEARATE POLOXAMER 407 POLYETHYLENE GLYCOL, UNSPECIFIED POLYVINYL ALCOHOL, UNSPECIFIED STARCH, CORN TALC TITANIUM DIOXIDE WHITE TO OFF WHITE MODIFIED CAPSULE C33 Lurasidone hydrochloride Lurasidone hydrochloride LURASIDONE HYDROCHLORIDE LURASIDONE CELLULOSE, MICROCRYSTALLINE CITRIC ACID MONOHYDRATE CROSCARMELLOSE SODIUM FERRIC OXIDE YELLOW HYPROMELLOSES LACTOSE MONOHYDRATE MAGNESIUM STEARATE POLOXAMER 407 POLYETHYLENE GLYCOL, UNSPECIFIED POLYVINYL ALCOHOL, UNSPECIFIED STARCH, CORN TALC TITANIUM DIOXIDE YELLOW TO LIGHT YELLOW OVAL C34 Lurasidone hydrochloride Lurasidone hydrochloride LURASIDONE HYDROCHLORIDE LURASIDONE CITRIC ACID MONOHYDRATE CROSCARMELLOSE SODIUM HYPROMELLOSES LACTOSE MONOHYDRATE MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE POLYETHYLENE GLYCOL, UNSPECIFIED STARCH, CORN POLOXAMER 407 TITANIUM DIOXIDE TALC POLYVINYL ALCOHOL, UNSPECIFIED WHITE TO OFF WHITE OVAL C35

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Lurasidone increased incidences of malignant mammary gland tumors and pituitary gland adenomas in female mice orally dosed with 30 mg/kg/day, 100 mg/kg/day, 300 mg/kg/day, 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 mg/kg/day 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 mg/kg/day, 15 mg/kg/day 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 .

ANDA208052

Lurasidone hydrochloride

Lurasidone hydrochloride

68382-968

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL NDC 68382-965-06 Lurasidone hydrochloride tablets, 20 mg 30 tablets Rx only Zydus SL-20mg-30c NDC 68382-966-06 Lurasidone hydrochloride tablets, 40 mg 30 tablets Rx only Zydus NDC 68382-859-06 Lurasidone hydrochloride tablets, 60 mg 30 tablets Rx only Zydus SL-60mg-30c NDC 68382-967-06 Lurasidone hydrochloride tablets, 80 mg 30 tablets Rx only Zydus SL-80mg-30c NDC 68382-968-06 Lurasidone hydrochloride tablets, 120 mg 30 tablets Rx only Zydus SL-120mg-30c Lurasidone hydrochloride tablets 40 mg Lurasidone hydrochloride tablets Lurasidone hydrochloride tablets Lurasidone hydrochloride tablets

Manufactured by: Zydus Lifesciences Ltd. Ahmedabad, India. Distributed by: Zydus Pharmaceuticals (USA) Inc. Pennington, NJ 08534 Rev.: 06/23

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) Suicidal Thoughts and Behavior Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down and instruct them to report such symptoms to the healthcare provider [ see Boxed Warning , Warnings and Precautions ( 5.2 ) ]. Neuroleptic Malignant Syndrome Counsel patients about a potentially fatal adverse reaction referred to as Neuroleptic Malignant Syndrome (NMS). Advise patients, family members, or caregivers to contact healthcare provider or to report to the emergency room if they experience signs and symptoms of NMS [ see Warnings and Precautions ( 5.4 ) ]. Tardive Dyskinesia Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [ see Warnings and Precautions ( 5.5 ) ]. Metabolic Changes Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [ see Warnings and Precautions ( 5.6 ) ]. Hyperprolactinemia Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of lurasidone hydrochloride. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction or gynecomastia in males [ see Warnings and Precautions ( 5.7 ) ]. Leukopenia/Neutropenia Advise patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia that they should have their CBC monitored while taking lurasidone hydrochloride [ s ee Warnings and Precautions ( 5.8 )] . Orthostatic Hypotension Educate patients about the risk of orthostatic hypotension, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [ see Warnings and Precautions ( 5.9 ) ]. Interference with Cognitive and Motor Performance Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that lurasidone hydrochloride therapy does not affect them adversely [ see Warnings and Precautions ( 5.12 ) ]. Heat Exposure and Dehydration Educate patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions ( 5.13 )] . Activation of Mania or Hypomania Advise patients and their caregivers to observe for signs of activation of mania/hypomania [ see Warnings and Precautions ( 5.14 ) ]. Concomitant Medication Advise patients to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, because there is a potential for drug interactions [see Drug Interactions ( 7 )] . Pregnancy Advise patients that lurasidone hydrochloride may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients to notify their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations ( 8.1 )] . Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lurasidone hydrochloride during pregnancy [see Use in Specific Populations ( 8.1 )] . Medication Guide available at www.zydususa.com/medguides or call 1-877-993-8779.

14 CLINICAL STUDIES 14.1 Schizophrenia Adults The efficacy of lurasidone hydrochloride 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: 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. 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. 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: Study 1: In a 6-week, placebo-controlled trial (N=145) involving two fixed doses of lurasidone hydrochloride tablets (40 mg/day 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. 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. Study 3: In a 6-week, placebo- and active-controlled trial (N=473) involving two fixed doses of lurasidone hydrochloride tablets (40 mg/day 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. Study 4: In a 6-week, placebo-controlled trial (N=489) involving three fixed doses of lurasidone hydrochloride tablets (40 mg/day, 80 mg/day 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. Study 5: In a 6-week, placebo- and active-controlled trial (N=482) involving two fixed doses of lurasidone hydrochloride tablets (80 mg/day 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 mg/day, 80 mg/day, 120 mg/day 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) 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. Primary Efficacy Measure: BPRSd Study Treatment Group Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference a (95% CI) 1 Lurasidone hydrochloride (40 mg/day) * 54.2 (8.8) -9.4 (1.6) -5.6 (-9.8, -1.4) Lurasidone hydrochloride (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 (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 (40 mg/day) * 96.6 (10.7) -25.7 (2.0) -9.7 (-15.3, -4.1) Lurasidone hydrochloride (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 (40 mg/day) 96.5 (11.5) -19.2 (1.7) -2.1 (-7.0, 2.8) Lurasidone hydrochloride (80 mg/day) * 96.0 (10.8) -23.4 (1.8) -6.4 (-11.3, -1.5) Lurasidone hydrochloride (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 (80 mg/day) * 97.7 (9.7) -22.2 (1.8) -11.9 (-16.9, -6.9) Lurasidone hydrochloride (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) -- 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 (13-17 years) The efficacy of lurasidone hydrochloride, 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 was 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 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. 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) -- 14.2 Depressive Episodes Associated with Bipolar I Disorder Adults Monotherapy The efficacy of lurasidone hydrochloride, 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 mg/day to 60 mg/day, or 80 mg/day 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 mg per day to 120 mg per day) did not provide additional efficacy on average, compared to the low dose range (20 mg per day to 60 mg per day). Adjunctive Therapy with Lithium or Valproate The efficacy of lurasidone hydrochloride, 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 mg/day 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 was 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) 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. Primary Efficacy Measure: MADRS Study Treatment Group Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference a (95% CI) Monotherapy study Lurasidone hydrochloride (20 mg/day to 60 mg/day)* 30.3 (5.0) -15.4 (0.8) -4.6 (-6.9, -2.3) Lurasidone hydrochloride (80 mg/day 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 (20 mg/day 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) -- Pediatric Patients (10 to 17 years) The efficacy of lurasidone hydrochloride was 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 was 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) 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. Treatment Group Primary Efficacy Measure: CDRS-R Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo- subtracted Difference a (95% CI) 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) --

8.5 Geriatric Use Clinical studies with lurasidone hydrochloride 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 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 are at an increased risk of death compared to placebo. Lurasidone hydrochloride is not approved for the treatment of patients with dementia-related psychosis [ see Boxed Warning , Warnings and Precautions ( 5.1 , 5.3 )] .

8.2 Lactation 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 and any potential adverse effects on the breastfed infant from lurasidone hydrochloride or from the underlying maternal condition.

8.4 Pediatric Use 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 has 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 has 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 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 lurasidone hydrochloride 20 mg/day and 60 mg/day for the treatment of pediatric patients 6 years 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 lurasidone hydrochloride or placebo. Vomiting occurred at a higher rate than reported in other lurasidone hydrochloride studies (4/49 or 8% for 20 mg, 14/51 or 27% for 60 mg, and 2/49 or 4% for placebo), particularly in children ages 6 to 12 (13 out of 18 patients on lurasidone hydrochloride 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 mg/kg/day, 30 mg/kg/day, and 150 (males) mg/kg/day or 300 (females) mg/kg/day which are 0.2 times 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 times 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 .

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lurasidone hydrochloride during pregnancy. For more information, contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-andresearchprograms/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 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-times and 6-times, the maximum recommended human dose (MRHD) of 160 mg/day, respectively based on mg/m 2 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 mg/kg/day, 10 mg/kg/day, and 25 mg/kg/day during the period of organogenesis. These doses are 0.2 times, 0.6 times, and 1.5 times the MRHD of 160 mg/day based on mg/m 2 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 mg/kg/day, 10 mg/kg/day, and 50 mg/kg/day during the period of organogenesis. These doses are 0.2 times, 1.2 times and 6 times the MRHD of 160 mg/day based on mg/m 2 . 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 mg/kg/day, 2 mg/kg/day, and 10 mg/kg/day during the periods of organogenesis and lactation. These doses are 0.02 times, 0.1 times 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 .

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause extrapyramidal and or/withdrawal symptoms in neonates with third trimester exposure ( 8.1 ). 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lurasidone hydrochloride during pregnancy. For more information, contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-andresearchprograms/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 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-times and 6-times, the maximum recommended human dose (MRHD) of 160 mg/day, respectively based on mg/m 2 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 mg/kg/day, 10 mg/kg/day, and 25 mg/kg/day during the period of organogenesis. These doses are 0.2 times, 0.6 times, and 1.5 times the MRHD of 160 mg/day based on mg/m 2 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 mg/kg/day, 10 mg/kg/day, and 50 mg/kg/day during the period of organogenesis. These doses are 0.2 times, 1.2 times and 6 times the MRHD of 160 mg/day based on mg/m 2 . 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 mg/kg/day, 2 mg/kg/day, and 10 mg/kg/day during the periods of organogenesis and lactation. These doses are 0.02 times, 0.1 times 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 . 8.2 Lactation 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 and any potential adverse effects on the breastfed infant from lurasidone hydrochloride or from the underlying maternal condition. 8.4 Pediatric Use 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 has 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 has 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 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 lurasidone hydrochloride 20 mg/day and 60 mg/day for the treatment of pediatric patients 6 years 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 lurasidone hydrochloride or placebo. Vomiting occurred at a higher rate than reported in other lurasidone hydrochloride studies (4/49 or 8% for 20 mg, 14/51 or 27% for 60 mg, and 2/49 or 4% for placebo), particularly in children ages 6 to 12 (13 out of 18 patients on lurasidone hydrochloride 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 mg/kg/day, 30 mg/kg/day, and 150 (males) mg/kg/day or 300 (females) mg/kg/day which are 0.2 times 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 times 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 . 8.5 Geriatric Use Clinical studies with lurasidone hydrochloride 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 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 are at an increased risk of death compared to placebo. Lurasidone hydrochloride is not approved for the treatment of patients with dementia-related psychosis [ see Boxed Warning , Warnings and Precautions ( 5.1 , 5.3 )] . 8.6 Renal Impairment 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-associated adverse reactions [ see Dosage and Administration ( 2.4 ) ]. 8.7 Hepatic Impairment 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 lurasidone hydrochloride-associated adverse reactions [ see Dosage and Administration ( 2.5 ) ]. 8.8 Other Specific Populations No dosage adjustment for lurasidone hydrochloride is required on the basis of a patient's sex, race, or smoking status [see Clinical Pharmacology ( 12.3 ) ].

16 HOW SUPPLIED/STORAGE AND HANDLING 20 mg lurasidone hydrochloride tablets are yellow to light yellow, round shaped, coated tablets, debossed with "C31" on one side and plain on the other side and are supplied as: NDC 68382-965-06 in bottle of 30 tablets with child-resistant closure NDC 68382-965-16 in bottle of 90 tablets with child-resistant closure NDC 68382-965-01 in bottle of 100 tablets NDC 68382-965-05 in bottle of 500 tablets NDC 68382-965-77 in cartons of 100 tablets (10 x 10 unit-dose) 40 mg lurasidone hydrochloride tablets are white to off white, round shaped, coated tablets, debossed with "C32" on one side and plain on the other side and are supplied as: NDC 68382-966-06 in bottle of 30 tablets with child-resistant closure NDC 68382-966-16 in bottle of 90 tablets with child-resistant closure NDC 68382-966-01 in bottle of 100 tablets NDC 68382-966-05 in bottle of 500 tablets NDC 68382-966-77 in cartons of 100 tablets (10 x 10 unit-dose) 60 mg lurasidone hydrochloride tablets are white to off white, modified capsule shaped, coated tablets, debossed with "C33" on one side and plain on the other side and are supplied as: NDC 68382-859-06 in bottle of 30 tablets with child-resistant closure NDC 68382-859-16 in bottle of 90 tablets with child-resistant closure NDC 68382-859-01 in bottle of 100 tablets NDC 68382-859-05 in bottle of 500 tablets NDC 68382-859-77 in cartons of 100 tablets (10 x 10 unit-dose) 80 mg lurasidone hydrochloride tablets are yellow to light yellow, oval shaped, coated tablets, debossed with "C34" on one side and plain on the other side and are supplied as: NDC 68382-967-06 in bottle of 30 tablets with child-resistant closure NDC 68382-967-16 in bottle of 90 tablets with child-resistant closure NDC 68382-967-01 in bottle of 100 tablets NDC 68382-967-05 in bottle of 500 tablets NDC 68382-967-77 in cartons of 100 tablets (10 x 10 unit-dose) 120 mg lurasidone hydrochloride tablets are white to off white, oval shaped, coated tablets, debossed with "C35" on one side and plain on the other side and are supplied as: NDC 68382-968-06 in bottle of 30 tablets with child-resistant closure NDC 68382-968-16 in bottle of 90 tablets with child-resistant closure NDC 68382-968-01 in bottle of 100 tablets NDC 68382-968-05 in bottle of 500 tablets NDC 68382-968-77 in cartons of 100 tablets (10 x 10 unit-dose) Storage Store lurasidone hydrochloride tablets at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature].

WARNING:INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Lurasidone hydrochloride is not approved for the treatment of patients with dementia-related psychosis ( 5.1 ). Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adult patients. Closely monitor for clinical worsening and emergence of suicidal thoughts and behaviors. ( 5.2 ). 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. Lurasidone hydrochloride is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions ( 5.1 )] . Suicidal Thoughts and Behaviors Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adults in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. [ see Warnings and Precautions ( 5.2 ) ].