Latuda

6 ADVERSE REACTIONS 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 )] 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 (13-17 years) with schizophrenia: somnolence, nausea, akathisia, EPS (non-akathisia), rhinitis (80 mg 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 Sunovion Pharmaceuticals Inc. at 1-877-737-7226 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 LATUDA consisting of 3799 adult patients exposed to one or more doses of LATUDA for the treatment of schizophrenia, and bipolar depression in placebo-controlled studies. This experience corresponds with a total experience of 1250.9 patient-years. A total of 1106 LATUDA-treated patients had at least 24 weeks and 371 LATUDA-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 LATUDA was administered at daily doses ranging from 20 to 160 mg (n=1508). Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) in patients treated with LATUDA were somnolence, akathisia, extrapyramidal symptoms, and nausea. Adverse Reactions Associated with Discontinuation of Treatment: A total of 9.5% (143/1508) LATUDA-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 LATUDA that were at least 2% and at least twice the placebo rate. Adverse Reactions Occurring at an Incidence of 2% or More in LATUDA-Treated Patients: Adverse reactions associated with the use of LATUDA (incidence of 2% or greater, rounded to the nearest percent and LATUDA 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 LATUDA-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 LATUDA 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 LATUDA (N=1508) (%) 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 LATUDA 20 mg, 10.7% for LATUDA 40 mg, 12.3% for LATUDA 80 mg, and 22.0% for LATUDA 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 LATUDA 20 mg, 11.5% for LATUDA 40 mg, 11.9% for LATUDA 80 mg, and 22.0% for LATUDA 120 mg). Bipolar Depression (Monotherapy) The following findings are based on the adult short-term, placebo-controlled premarketing study for bipolar depression in which LATUDA was administered at daily doses ranging from 20 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 LATUDA were akathisia, extrapyramidal symptoms, somnolence, nausea, vomiting, diarrhea, and anxiety. Adverse Reactions Associated with Discontinuation of Treatment: A total of 6.0% (20/331) LATUDA-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 LATUDA that were at least 2% and at least twice the placebo rate. Adverse Reactions Occurring at an Incidence of 2% or More in LATUDA-Treated Patients: Adverse reactions associated with the use of LATUDA (incidence of 2% or greater, rounded to the nearest percent and LATUDA 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 LATUDA-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) (%) LATUDA 20-60 mg/day (N=164) (%) LATUDA 80-120 mg/day (N=167) (%) All LATUDA(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 LATUDA dose ranges) [ see Clinical Studies ( 14.2 ) ] the adverse reactions that occurred with a greater than 5% incidence in the patients treated with LATUDA 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 LATUDA 20 to 60 mg/day and LATUDA 80 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 LATUDA was administered at daily doses ranging from 20 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 LATUDA were akathisia and somnolence. Adverse Reactions Associated with Discontinuation of Treatment: A total of 5.8% (21/360) LATUDA-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 LATUDA that were at least 2% and at least twice the placebo rate. Adverse Reactions Occurring at an Incidence of 2% or More in LATUDA-Treated Patients: Adverse reactions associated with the use of LATUDA (incidence of 2% or greater, rounded to the nearest percent and LATUDA 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 LATUDA-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) (%) LATUDA 20 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 LATUDA 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 LATUDA were somnolence, nausea, akathisia, extrapyramidal symptoms (non-akathisia, 40 mg only), vomiting, and rhinorrhea/rhinitis (80 mg only). Adverse Reactions Associated with Discontinuation of Treatment: The incidence of discontinuation due to adverse reactions between LATUDA- 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 LATUDA-Treated Patients: Adverse reactions associated with the use of LATUDA (incidence of 2% or greater, rounded to the nearest percent and LATUDA 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 LATUDA-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) LATUDA 40 mg/day (N=110) LATUDA 80 mg/day (N=104) All LATUDA (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 LATUDA 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 LATUDA were nausea, weight increase, and insomnia. Adverse Reactions Associated with Discontinuation of Treatment: The incidence of discontinuation due to adverse reactions between LATUDA- 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 LATUDA-Treated Patients: Adverse reactions associated with the use of LATUDA (incidence of 2% or greater, rounded to the nearest percent and LATUDA 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 LATUDA-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) LATUDA 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 LATUDA-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 LATUDA-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 LATUDA 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 LATUDA-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 LATUDA-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 LATUDA 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 LATUDA-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 LATUDA-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 LATUDA Adverse Event Term Placebo (N=168) (%) 20 to 60 mg/day (N=164) (%) 80 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 LATUDA-treated patients, the incidence of EPS, excluding akathisia and restlessness, was 13.9% and 8.7% for placebo. The incidence of akathisia for LATUDA-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) (%) LATUDA 20 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 LATUDA-treated patients was similar in the LATUDA 20 to 80 mg/day (3.4%) treatment group vs. placebo (3.5%) ; and the incidence of akathisia-related events for LATUDA-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) (%) LATUDA 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 LATUDA-treated patients for the SAS, BAS and AIMS was comparable to placebo-treated patients, with the exception of the Barnes Akathisia Scale global score (LATUDA, 0.1; placebo, 0.0). The percentage of patients who shifted from normal to abnormal was greater in LATUDA-treated patients and placebo for the BAS (LATUDA, 14.4%; placebo, 7.1%), the SAS (LATUDA, 5.0%; placebo, 2.3%) and the AIMS (LATUDA, 7.4%; placebo, 5.8%). Adolescents The mean change from baseline for LATUDA- 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 LATUDA-treated patients and placebo for the BAS (LATUDA, 7.0%; placebo, 1.8%), the SAS (LATUDA, 8.3%; placebo, 2.7%) and the AIMS (LATUDA, 2.8%; placebo, 0.9%). Bipolar Depression Adults Monotherapy The mean change from baseline for LATUDA-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 LATUDA-treated patients and placebo for the BAS (LATUDA, 8.4%; placebo, 5.6%), the SAS (LATUDA, 3.7%; placebo, 1.9%) and the AIMS (LATUDA, 3.4%; placebo, 1.2%). Adjunctive Therapy with Lithium or Valproate The mean change from baseline for LATUDA-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 LATUDA-treated patients and placebo for the BAS (LATUDA, 8.7%; placebo, 2.1%), the SAS (LATUDA, 2.8%; placebo, 2.1%) and the AIMS (LATUDA, 2.8%; placebo, 0.6%). Pediatric Patients (10 to 17 years) The mean change from baseline for LATUDA- 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 LATUDA-treated patients and placebo for the BAS (LATUDA, 4.6%; placebo, 2.4%), the SAS (LATUDA, 0.6%; placebo, 0%) and was the same for the AIMS (LATUDA, 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 LATUDA-treated subjects (0.0% LATUDA 20 mg, 3.5% LATUDA 40 mg, 4.5% LATUDA 80 mg, 6.5% LATUDA 120 mg and 2.5% LATUDA 160 mg) compared to 0.8% of subjects receiving placebo. Seven subjects (0.5%, 7/1508) discontinued clinical trials due to dystonic events – four were receiving LATUDA 80 mg/day and three were receiving LATUDA 120 mg/day. Adolescents In the short-term, placebo-controlled, adolescent schizophrenia study, dystonia occurred in 1% of LATUDA-treated patients (1% LATUDA 40 mg and 1% LATUDA 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 LATUDA-treated subjects (0.0% and 1.8% for LATUDA 20 to 60 mg/day and LATUDA 80 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 LATUDA-treated subjects (20 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 LATUDA-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 LATUDA Following is a list of adverse reactions reported by adult patients treated with LATUDA at multiple doses of ≥ 20 mg once daily within the premarketing database of 2905 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 LATUDA 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 1/1000 patients (infrequent); and those occurring in fewer than 1/1000 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 LATUDA-treated patients compared to +0.02 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 3.0% (43/1453) of LATUDA-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) LATUDA 20 mg/day (N=71) LATUDA 40 mg/day (N=487) LATUDA 80 mg/day (N=538) LATUDA 120 mg/day (N=291) LATUDA 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 LATUDA-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 LATUDA-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 Placebo (N=103) LATUDA 40 mg/day (N=97) LATUDA 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 LATUDA-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 LATUDA-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) LATUDA 20 to 60 mg/day (N=164) LATUDA 80 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 LATUDA-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 LATUDA-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) LATUDA 20 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 LATUDA-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 LATUDA-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) LATUDA 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 LATUDA. 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 HCl or any components in the formulation. Angioedema has been observed with lurasidone [see Adverse Reactions ( 6.1 )] . Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.) [see Drug Interactions ( 7.1 )]. Strong CYP3A4 inducers (e.g., rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine, etc.) [see Drug Interactions ( 7.1 )]. Known hypersensitivity to LATUDA 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 ).

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

2 DOSAGE AND ADMINISTRATION LATUDA should be taken with food (at least 350 calories). Administration with food substantially increases the absorption of LATUDA ( 2.3 , 12.3 ). Indication Starting Dose Recommended Dose Schizophrenia – adults ( 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): LATUDA dose should be reduced to half of the original dose level. Recommended starting dose is 20 mg per day. Maximum recommended dose is 80 mg per day ( 2.6 , 7.1 ). Concomitant Use of a Moderate CYP3A4 Inducer: It may be necessary to increase the dose of LATUDA ( 2.6 , 7.1 ). 2.1 Schizophrenia Adults The recommended starting dose of LATUDA is 40 mg once daily. Initial dose titration is not required. LATUDA has been shown to be effective in a dose range of 40 mg per day to 160 mg per day [see Clinical Studies ( 14.1 )] . The maximum recommended dose is 160 mg per day. Adolescents (13 – 17 years) The recommended starting dose of LATUDA is 40 mg once daily. Initial dose titration is not required. LATUDA has been shown to be effective in a dose range of 40 mg per day to 80 mg per day [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 LATUDA is 20 mg given once daily as monotherapy or as adjunctive therapy with lithium or valproate. Initial dose titration is not required. LATUDA has been shown to be effective in a dose range of 20 mg per day to 120 mg per day as monotherapy or as adjunctive therapy with lithium or valproate [see Clinical Studies ( 14.2 )] . The maximum recommended dose, as monotherapy or as adjunctive therapy with lithium or valproate, is 120 mg per day. In the monotherapy study, the higher dose range (80 mg to 120 mg per day) did not provide additional efficacy, on average, compared to the lower dose range (20 to 60 mg per day) [see Clinical Studies ( 14.2 )] . Pediatric Patients (10 – 17 years) The recommended starting dose of LATUDA is 20 mg given once daily as monotherapy. Initial dose titration is not required. The dose may be increased after one week based on clinical response. LATUDA has been shown to be effective in a dose range of 20 mg per day to 80 mg per day as monotherapy. At the end of the clinical study, most of the patients (67%) received 20 mg or 40 mg once daily [see Clinical Studies ( 14.2 )] . The maximum recommended dose is 80 mg per day. The efficacy of LATUDA in the treatment of mania associated with bipolar disorder has not been established. 2.3 Administration Information LATUDA should be taken with food (at least 350 calories). Administration with food substantially increases the absorption of LATUDA. Administration with food increases the AUC approximately 2-fold and increases the Cmax approximately 3-fold. In the clinical studies, LATUDA was administered with food [see Clinical Pharmacology ( 12.3 )] . The effectiveness of LATUDA for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. Therefore, the physician who elects to use LATUDA for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [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 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 per mg/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 LATUDA should not be used concomitantly with a strong CYP3A4 inhibitor (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.) [see Contraindications ( 4 )] . If LATUDA is being prescribed and a moderate CYP3A4 inhibitor (e.g. diltiazem, atazanavir, erythromycin, fluconazole, verapamil etc.) is added to the therapy, the LATUDA dose should be reduced to half of the original dose level. Similarly, if a moderate CYP3A4 inhibitor is being prescribed and LATUDA is added to the therapy, the recommended starting dose of LATUDA is 20 mg per day, and the maximum recommended dose of LATUDA is 80 mg per day [see Contraindications ( 4 ), Drug Interactions ( 7.1 )] . Grapefruit and grapefruit juice should be avoided in patients taking LATUDA, since these may inhibit CYP3A4 and alter LATUDA concentrations [ see Drug Interactions ( 7.1 ) ]. Concomitant Use with CYP3A4 Inducers LATUDA should not be used concomitantly with a strong CYP3A4 inducer (e.g., rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine, etc.) [see Contraindications ( 4 ); Drug Interactions ( 7.1 )] . If LATUDA is used concomitantly with a moderate CYP3A4 inducer, it may be necessary to increase the LATUDA dose after chronic treatment (7 days or more) with the CYP3A4 inducer.

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

9.2 Abuse LATUDA 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 LATUDA 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 LATUDA misuse or abuse (e.g., development of tolerance, drug-seeking behavior, increases in dose).

9.1 Controlled Substance LATUDA is not a controlled substance.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance LATUDA is not a controlled substance. 9.2 Abuse LATUDA 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 LATUDA 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 LATUDA 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 LATUDA was identified in one patient who ingested an estimated 560 mg of LATUDA. This patient recovered without sequelae. This patient resumed LATUDA treatment for an additional two months. 10.2 Management of Overdosage No specific antidotes for LATUDA 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 LATUDA. Similarly, the alpha-blocking properties of bretylium might be additive to those of LATUDA, resulting in problematic hypotension. 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 LATUDA-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 LATUDA Table 34: Clinically Important Drug Interactions with LATUDA Strong CYP3A4 Inhibitors Clinical Impact: Concomitant use of LATUDA with strong CYP3A4 inhibitors increased the exposure of lurasidone compared to the use of LATUDA alone [ see Clinical Pharmacology ( 12.3 ) ]. Intervention: LATUDA 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 LATUDA with moderate CYP3A4 inhibitors increased the exposure of lurasidone compared to the use of LATUDA alone [ see Clinical Pharmacology ( 12.3 ) ]. Intervention: LATUDA 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 LATUDA with strong CYP3A4 inducers decreased the exposure of lurasidone compared to the use of LATUDA alone [ see Clinical Pharmacology ( 12.3 ) ]. Intervention: LATUDA 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 LATUDA with moderate CYP3A4 inducers decreased the exposure of lurasidone compared to the use of LATUDA alone [ see Clinical Pharmacology ( 12.3 ) ]. Intervention: LATUDA 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 LATUDA Based on pharmacokinetic studies, no dosage adjustment of LATUDA is required when administered concomitantly with lithium, valproate, or substrates of P-gp or CYP3A4 [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 LATUDA 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 LATUDA 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 LATUDA or placebo. 12.3 Pharmacokinetics Adults The activity of LATUDA is primarily due to the parent drug. The pharmacokinetics of LATUDA is dose-proportional within a total daily dose range of 20 mg to 160 mg. Steady-state concentrations of LATUDA are reached within 7 days of starting LATUDA. Following administration of 40 mg of LATUDA, the mean (%CV) elimination half-life was 18 ( 7 ) hours. Absorption and Distribution: LATUDA is absorbed and reaches peak serum concentrations in approximately 1-3 hours. It is estimated that 9-19% of an administered dose is absorbed. Following administration of 40 mg of LATUDA, the mean (%CV) apparent volume of distribution was 6173 (17.2) L. LATUDA is highly bound (~99%) to serum proteins. In a food effect study, LATUDA 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. LATUDA exposure was not affected as meal size was increased from 350 to 1000 calories and was independent of meal fat content [ see Dosage and Administration ( 2.3 )] . In clinical studies, establishing the safety and efficacy of LATUDA, patients were instructed to take their daily dose with food [see Dosage and Administration ( 2.3 )] . Metabolism and Elimination: LATUDA is metabolized mainly via CYP3A4. The major biotransformation pathways are oxidative N -dealkylation, hydroxylation of norbornane ring, and S -oxidation. LATUDA 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, LATUDA is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP4A11, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 enzymes. Because LATUDA is not a substrate for CYP1A2, smoking is not expected to have an effect on the pharmacokinetics of LATUDA. Transporter proteins: In vitro studies suggest LATUDA is not a substrate of OATP1B1 or OATP1B3, however, is probably a substrate of P-gp and BCRP. In vitro studies indicate that LATUDA is not expected to inhibit transporters OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, MATE2-K and BSEP at clinically relevant concentrations. LATUDA 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 LATUDA. Following administration of 40 mg of LATUDA, the mean (%CV) apparent clearance was 3902 (18.0) mL/min. Drug Interaction Studies Effects of other drugs on the exposure of lurasidone are summarized in Figure 1 . A population PK analyses concluded that coadministration of lithium 300-2400 mg/day or valproate 300-2000 mg/day with lurasidone for up to 6 weeks has minimal effect on lurasidone exposure. And the effects of LATUDA 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 300-2400 mg/day or valproate 300-2000 mg/day. Figure 1: Impact of Other Drugs on LATUDA Pharmacokinetics Figure 2: Impact of LATUDA on Other Drugs Figure 1 Figure 2 Studies in Specific Populations The effect of intrinsic patient factors on the pharmacokinetics of LATUDA is presented in Figure 3 . Pediatric Patients LATUDA 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 LATUDA Pharmacokinetics 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 LATUDA 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 LATUDA 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 LATUDA or placebo.

12.3 Pharmacokinetics Adults The activity of LATUDA is primarily due to the parent drug. The pharmacokinetics of LATUDA is dose-proportional within a total daily dose range of 20 mg to 160 mg. Steady-state concentrations of LATUDA are reached within 7 days of starting LATUDA. Following administration of 40 mg of LATUDA, the mean (%CV) elimination half-life was 18 ( 7 ) hours. Absorption and Distribution: LATUDA is absorbed and reaches peak serum concentrations in approximately 1-3 hours. It is estimated that 9-19% of an administered dose is absorbed. Following administration of 40 mg of LATUDA, the mean (%CV) apparent volume of distribution was 6173 (17.2) L. LATUDA is highly bound (~99%) to serum proteins. In a food effect study, LATUDA 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. LATUDA exposure was not affected as meal size was increased from 350 to 1000 calories and was independent of meal fat content [ see Dosage and Administration ( 2.3 )] . In clinical studies, establishing the safety and efficacy of LATUDA, patients were instructed to take their daily dose with food [see Dosage and Administration ( 2.3 )] . Metabolism and Elimination: LATUDA is metabolized mainly via CYP3A4. The major biotransformation pathways are oxidative N -dealkylation, hydroxylation of norbornane ring, and S -oxidation. LATUDA 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, LATUDA is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP4A11, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 enzymes. Because LATUDA is not a substrate for CYP1A2, smoking is not expected to have an effect on the pharmacokinetics of LATUDA. Transporter proteins: In vitro studies suggest LATUDA is not a substrate of OATP1B1 or OATP1B3, however, is probably a substrate of P-gp and BCRP. In vitro studies indicate that LATUDA is not expected to inhibit transporters OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, MATE2-K and BSEP at clinically relevant concentrations. LATUDA 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 LATUDA. Following administration of 40 mg of LATUDA, the mean (%CV) apparent clearance was 3902 (18.0) mL/min. Drug Interaction Studies Effects of other drugs on the exposure of lurasidone are summarized in Figure 1 . A population PK analyses concluded that coadministration of lithium 300-2400 mg/day or valproate 300-2000 mg/day with lurasidone for up to 6 weeks has minimal effect on lurasidone exposure. And the effects of LATUDA 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 300-2400 mg/day or valproate 300-2000 mg/day. Figure 1: Impact of Other Drugs on LATUDA Pharmacokinetics Figure 2: Impact of LATUDA on Other Drugs Figure 1 Figure 2 Studies in Specific Populations The effect of intrinsic patient factors on the pharmacokinetics of LATUDA is presented in Figure 3 . Pediatric Patients LATUDA 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 LATUDA Pharmacokinetics Figure 3

20230721

35

3 DOSAGE FORMS AND STRENGTHS LATUDA tablets are available in the following shape and color ( Table 1 ) with respective one-sided debossing. Table 1: LATUDA Tablet Presentations Tablet Strength Tablet Color/Shape Tablet Markings 20 mg white to off-white round L20 40 mg white to off-white round L40 60 mg white to off-white oblong L60 80 mg pale green oval L80 120 mg white to off-white oval L120 Tablets: 20 mg, 40 mg, 60 mg, 80 mg and 120 mg ( 3 )

Latuda lurasidone hydrochloride lurasidone hydrochloride lurasidone mannitol starch, corn croscarmellose sodium hypromellose 2910 (6 MPA.S) magnesium stearate Carnauba Wax white ROUND L;20 Latuda lurasidone hydrochloride lurasidone hydrochloride lurasidone mannitol starch, corn croscarmellose sodium hypromellose 2910 (6 MPA.S) magnesium stearate Carnauba Wax white ROUND L;40 Latuda lurasidone hydrochloride lurasidone hydrochloride lurasidone mannitol starch, corn croscarmellose sodium hypromellose 2910 (6 MPA.S) magnesium stearate Carnauba Wax white OVAL L;60 Latuda lurasidone hydrochloride lurasidone hydrochloride lurasidone mannitol starch, corn croscarmellose sodium hypromellose 2910 (6 MPA.S) magnesium stearate ferric oxide yellow FD&C blue No. 2 Carnauba Wax green OVAL L;80 Latuda lurasidone hydrochloride lurasidone hydrochloride lurasidone mannitol starch, corn croscarmellose sodium hypromellose 2910 (6 MPA.S) magnesium stearate Carnauba Wax white OVAL L;120

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, 100, 300, or 650 mg/kg/day. The lowest dose produced plasma levels (AUC) approximately equal to those in humans receiving the MRHD of 160 mg/day. No increases in tumors were seen in male mice up to the highest dose tested, which produced plasma levels (AUC) 14 times those in humans receiving the MRHD. Lurasidone increased the incidence of mammary gland carcinomas in female rats orally dosed at 12 and 36 mg/kg/day: the lowest dose; 3 mg/kg/day is the no-effect dose which produced plasma levels (AUC) 0.4 times those in humans receiving the MRHD. No increases in tumors were seen in male rats up to the highest dose tested, which produced plasma levels (AUC) 6 times those in humans receiving the MRHD. Proliferative and/or neoplastic changes in the mammary and pituitary glands of rodents have been observed following chronic administration of antipsychotic drugs and are considered to be prolactin-mediated [see Warnings and Precautions ( 5.7 )]. Mutagenesis: Lurasidone did not cause mutation or chromosomal aberration when tested in vitro and in vivo test battery . Lurasidone was negative in the Ames gene mutation test, the Chinese Hamster Lung (CHL) cells, and in the in vivo mouse bone marrow micronucleus test up to 2000 mg/kg which is 61 times the MRHD of 160 mg/day based on mg/m 2 body surface area. Impairment of Fertility: Estrus cycle irregularities were seen in rats orally administered lurasidone at 1.5, 15 and 150 mg/kg/day for 15 consecutive days prior to mating, during the mating period, and through gestation day 7. No effect was seen at the lowest dose of 0.1 mg/kg which is approximately 0.006 times the MRHD of 160 mg/day based on mg/m 2 . Fertility was reduced only at the highest dose, which was reversible after a 14 day drug-free period. The no-effect dose for reduced fertility was approximately equal to the MRHD based on mg/m 2 . Lurasidone had no effect on fertility in male rats treated orally for 64 consecutive days prior to mating and during the mating period at doses up to 9 times the MRHD based on mg/m 2 .

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, 100, 300, or 650 mg/kg/day. The lowest dose produced plasma levels (AUC) approximately equal to those in humans receiving the MRHD of 160 mg/day. No increases in tumors were seen in male mice up to the highest dose tested, which produced plasma levels (AUC) 14 times those in humans receiving the MRHD. Lurasidone increased the incidence of mammary gland carcinomas in female rats orally dosed at 12 and 36 mg/kg/day: the lowest dose; 3 mg/kg/day is the no-effect dose which produced plasma levels (AUC) 0.4 times those in humans receiving the MRHD. No increases in tumors were seen in male rats up to the highest dose tested, which produced plasma levels (AUC) 6 times those in humans receiving the MRHD. Proliferative and/or neoplastic changes in the mammary and pituitary glands of rodents have been observed following chronic administration of antipsychotic drugs and are considered to be prolactin-mediated [see Warnings and Precautions ( 5.7 )]. Mutagenesis: Lurasidone did not cause mutation or chromosomal aberration when tested in vitro and in vivo test battery . Lurasidone was negative in the Ames gene mutation test, the Chinese Hamster Lung (CHL) cells, and in the in vivo mouse bone marrow micronucleus test up to 2000 mg/kg which is 61 times the MRHD of 160 mg/day based on mg/m 2 body surface area. Impairment of Fertility: Estrus cycle irregularities were seen in rats orally administered lurasidone at 1.5, 15 and 150 mg/kg/day for 15 consecutive days prior to mating, during the mating period, and through gestation day 7. No effect was seen at the lowest dose of 0.1 mg/kg which is approximately 0.006 times the MRHD of 160 mg/day based on mg/m 2 . Fertility was reduced only at the highest dose, which was reversible after a 14 day drug-free period. The no-effect dose for reduced fertility was approximately equal to the MRHD based on mg/m 2 . Lurasidone had no effect on fertility in male rats treated orally for 64 consecutive days prior to mating and during the mating period at doses up to 9 times the MRHD based on mg/m 2 .

NDA200603

Latuda

lurasidone hydrochloride

63402-304

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 20 mg, 30 Tablet Label NDC 63402-302-30 30 Tablets Latuda ® (lurasidone HCl) tablets 20 mg ATTENTION DISPENSER: Each time Latuda is dispensed give the patient the accompanying Medication Guide, also provided at www.latuda.com or 1-888-394-7377. Rx Only Sunovion PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 20 mg, 30 Tablet Label

Warnings and Precautions, Metabolic Changes, Hyperprolactinemia ( 5.6 , 5.7 ) 12/2019

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 the 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 [ s ee Warnings and Precautions ( 5.6 )] . Hyperprolactinemia Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of LATUDA. 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 LATUDA [ 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 LATUDA 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 LATUDA 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 LATUDA during pregnancy [see Use in Specific Populations ( 8.1 )] . SUNOVION Manufactured for: Sunovion Pharmaceuticals Inc. Marlborough, MA 01752 USA For Customer Service, call 1-888-394-7377. For Medical Information, call 1-800-739-0565. To report suspected adverse reactions, call 1-877-737-7226. 10092-03 LATUDA is a registered trademark of Sumitomo Pharma Co. Ltd. Sunovion Pharmaceuticals Inc. is a U.S. subsidiary of Sumitomo Pharma Co. Ltd. © 2019 Sunovion Pharmaceuticals Inc.

This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 5/2022 MEDICATION GUIDE LATUDA (luh-TOO-duh) (lurasidone hydrochloride) tablets What is the most important information I should know about LATUDA? LATUDA may cause serious side effects, including: Increased risk of death in elderly people with dementia-related psychosis. Medicines like LATUDA can raise the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). LATUDA is not approved for the treatment of people with dementia-related psychosis. Increased risk of suicidal thoughts or actions in children and young adults. Antidepressant medicines may increase suicidal thoughts or actions in some children and young adults within the first few months of treatment and when the dose is changed. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) depression, bipolar illness (also called manic-depressive illness), or a history of suicidal thoughts or actions. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? Pay close attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. Call a healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. Keep all follow-up visits with the healthcare provider as scheduled. Call a healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying new or worse depression feeling very agitated or restless trouble sleeping (insomnia) acting aggressive, being angry, or violent an extreme increase in activity and talking (mania) attempts to commit suicide new or worse anxiety panic attacks new or worse irritability acting on dangerous impulses other unusual changes in behavior or mood What is LATUDA? LATUDA is a prescription medicine used: To treat people 13 years of age or older with schizophrenia. Alone to treat people 10 years of age and older with depressive episodes that happen with Bipolar I Disorder (bipolar depression). With the medicine lithium or valproate to treat adults with depressive episodes that happen with Bipolar I Disorder (bipolar depression). It is not known if LATUDA is safe and effective in children: less than 13 years of age with schizophrenia. less than 10 years of age with bipolar depression. for the treatment of irritability associated with autistic disorder. Do not take LATUDA if you are: allergic to lurasidone hydrochloride or any of the ingredients in LATUDA. See the end of this Medication Guide for a complete list of ingredients in LATUDA. taking certain other medicines called CYP3A4 inhibitors or inducers including ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, rifampin, avasimibe, St. John's wort, phenytoin, or carbamazepine. Ask your healthcare provider if you are not sure if you are taking any of these medicines. Before taking LATUDA, tell your healthcare provider about all of your medical conditions, including if you: have or have had heart problems or stroke have or have had low or high blood pressure have or have had diabetes or high blood sugar, or have a family history of diabetes or high blood sugar. have or have had high levels of total cholesterol or triglycerides have or have had high prolactin levels have or have had low white blood cell count have or have had seizures have or have had kidney or liver problems are pregnant or plan to become pregnant. It is not known if LATUDA will harm your unborn baby. Talk to your healthcare provider about the risk to your unborn baby if you take LATUDA during pregnancy. Tell your healthcare provider if you become pregnant or think you are pregnant during treatment with LATUDA. If you become pregnant during treatment with LATUDA, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-and-researchprograms/pregnancyregistry/. are breastfeeding or plan to breastfeed. It is not known if LATUDA passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with LATUDA. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. LATUDA and other medicines may affect each other causing possible serious side effects. LATUDA may affect the way other medicines work, and other medicines may affect how LATUDA works. Your healthcare provider can tell you if it is safe to take LATUDA with your other medicines. Do not start or stop any other medicines during treatment with LATUDA without talking to your healthcare provider first. Know the medicines you take. Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine. How should I take LATUDA? Take LATUDA exactly as your healthcare provider tells you to take it. Do not change the dose or stop taking LATUDA without first talking to your healthcare provider. Take LATUDA by mouth, with food (at least 350 calories). If you take too much LATUDA, call your healthcare provider or poison control center or go to the nearest hospital emergency room right away. What should I avoid while taking LATUDA? Do not drive, operate heavy machinery, or do other dangerous activities until you know how LATUDA affects you. LATUDA may make you drowsy. Avoid eating grapefruit or drinking grapefruit juice during treatment with LATUDA. Grapefruit and grapefruit juice may affect the amount of LATUDA in your blood. Do not become too hot or dehydrated during treatment with LATUDA. Do not exercise too much. In hot weather, stay inside in a cool place if possible. Stay out of the sun. Do not wear too much clothing or heavy clothing. Drink plenty of water. What are the possible side effects of LATUDA? LATUDA may cause serious side effects, including: See “ What is the most important information I should know about LATUDA? ” Stroke (cerebrovascular problems) in elderly people with dementia-related psychosis that can lead to death. Neuroleptic malignant syndrome (NMS) a serious condition that can lead to death. Call your healthcare provider or go to the nearest hospital emergency room right away if you have some or all of the following signs and symptoms of NMS: high fever confusion changes in your breathing, heart rate, and blood pressure stiff muscles increased sweating Uncontrolled body movements (tardive dyskinesia). LATUDA may cause movements that you cannot control in your face, tongue, or other body parts. Tardive dyskinesia may not go away, even if you stop taking LATUDA. Tardive dyskinesia may also start after you stop taking LATUDA. Problems with your metabolism such as: high blood sugar (hyperglycemia) and diabetes. Increases in blood sugar can happen in some people who take LATUDA. Extremely high blood sugar can lead to coma or death. If you have diabetes or risk factors for diabetes (such as being overweight or a family history of diabetes), your healthcare provider should check your blood sugar before you start and during treatment with LATUDA. Call your healthcare provider if you have any of these symptoms of high blood sugar during treatment with LATUDA: feel very thirsty feel very hungry feel sick to your stomach need to urinate more than usual feel weak or tired feel confused, or your breath smells fruity increased fat levels (cholesterol and triglycerides) in your blood. weight gain. You and your healthcare provider should check your weight regularly during treatment with LATUDA. Increased prolactin levels in your blood (hyperprolactinemia). Your healthcare provider may do blood tests to check your prolactin levels during treatment with LATUDA. Tell your healthcare provider if you have any of the following signs and symptoms of hyperprolactinemia: Females: absence of your menstrual cycle secretion of breast milk when you are not breastfeeding Males: problems getting or maintaining an erection (erectile dysfunction) enlargement of breasts (gynecomastia) Low white blood cell count. Your healthcare provider may do blood tests during the first few months of treatment with LATUDA. Decreased blood pressure (orthostatic hypotension). You may feel lightheaded or faint when you rise too quickly from a sitting or lying position. Falls. LATUDA may make you sleepy or dizzy, may cause a decrease in your blood pressure when changing position (orthostatic hypotension), and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries. Seizures (convulsions) Problems controlling your body temperature so that you feel too warm. See “ What should I avoid while taking LATUDA? ” Mania or hypomania (manic episodes) in people with a history of bipolar disorder. Symptoms may include: greatly increased energy racing thoughts unusually grand ideas talking more or faster than usual severe problems sleeping reckless behavior excessive happiness or irritability Difficulty swallowing The most common side effects of LATUDA include: Adults with schizophrenia: sleepiness or drowsiness restlessness and feeling like you need to move around (akathisia) difficulty moving, slow movements, muscle stiffness, or tremor nausea Children 13 to 17 years of age with schizophrenia: sleepiness or drowsiness nausea restlessness and feeling like you need to move around (akathisia) difficulty moving, slow movements, muscle stiffness, or tremor runny nose vomiting Adults with bipolar depression: restlessness and feeling like you need to move around (akathisia) difficulty moving, slow movements, muscle stiffness, or tremor sleepiness or drowsiness Children 10 to 17 years of age with bipolar depression: nausea weight gain problems sleeping (insomnia) These are not all of the possible side effects of LATUDA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store LATUDA? Store LATUDA tablets at room temperature between 68°F to 77°F (20°C to 25°C). Keep LATUDA and all medicines out of the reach of children. General information about the safe and effective use of LATUDA. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use LATUDA for a condition for which it was not prescribed. Do not give LATUDA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about LATUDA that is written for health professionals. What are the ingredients in LATUDA? Active ingredient: lurasidone hydrochloride Inactive ingredients: mannitol, pregelatinized starch, croscarmellose sodium, hypromellose, magnesium stearate, Opadry ® and carnauba wax. Additionally, the 80 mg tablet contains yellow ferric oxide and FD&C Blue No. 2 Aluminum Lake Manufactured for: Sunovion Pharmaceuticals Inc. Marlborough, MA 01752 USA LATUDA is a registered trademark of Sumitomo Pharma Co. Ltd.; Sunovion Pharmaceuticals Inc. is a U.S. subsidiary of Sumitomo Pharma Co. Ltd. ©2019 Sunovion Pharmaceuticals Inc. For more information, go to www.LATUDA.com or call 1-888-394-7377.

14 CLINICAL STUDIES 14.1 Schizophrenia Adults The efficacy of LATUDA 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 18-72) 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 LATUDA (40 or 120 mg/day), both doses of LATUDA 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 LATUDA (80 mg/day), LATUDA 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 LATUDA (40 or 120 mg/day) and an active control (olanzapine), both LATUDA 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 LATUDA (40, 80 or 120 mg/day), only the 80 mg/day dose of LATUDA 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 LATUDA (80 or 160 mg/day) and an active control (quetiapine extended-release), both LATUDA doses and the active control at Endpoint were superior to placebo on the PANSS total score, and the CGI-S. Thus, the efficacy of LATUDA at doses of 40, 80, 120 and 160 mg/day has been established ( Table 35 ). Table 35: Primary Efficacy Results for Studies in Adult Patients with Schizophrenia (BPRSd or PANSS Scores) 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. Study Treatment Group Primary Efficacy Measure: BPRSd Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference a (95% CI) 1 LATUDA (40 mg/day)* 54.2 (8.8) -9.4 (1.6) -5.6 (-9.8, -1.4) LATUDA (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 LATUDA (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 LATUDA (40 mg/day)* 96.6 (10.7) -25.7 (2.0) -9.7 (-15.3, -4.1) LATUDA (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 LATUDA (40 mg/day) 96.5 (11.5) -19.2 (1.7) -2.1 (-7.0, 2.8) LATUDA (80 mg/day)* 96.0 (10.8) -23.4 (1.8) -6.4 (-11.3, -1.5) LATUDA (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 LATUDA (80 mg/day)* 97.7 (9.7) -22.2 (1.8) -11.9 (-16.9, -6.9) LATUDA (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 LATUDA 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 LATUDA (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, LATUDA 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) LATUDA (40 mg/day)* 94.5 (10.97) -18.6 (1.59) -8.0 (-12.4, -3.7) LATUDA (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 LATUDA, 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 LATUDA (20 to 60 mg/day, or 80 to 120 mg/day) or placebo. The primary rating instrument used to assess depressive symptoms in this study was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale with total scores ranging from 0 (no depressive features) to 60 (maximum score). The primary endpoint was the change from baseline in MADRS score at Week 6. The key secondary instrument was the Clinical Global Impression-Bipolar-Severity of Illness scale (CGI-BP-S), a clinician-rated scale that measures the subject's current illness state on a 7-point scale, where a higher score is associated with greater illness severity. For both dose groups, LATUDA was superior to placebo in reduction of MADRS and CGI-BP-S scores at Week 6. The primary efficacy results are provided in Table 37 . The high dose range (80 to 120 mg per day) did not provide additional efficacy on average, compared to the low dose range (20 to 60 mg per day). Adjunctive Therapy with Lithium or Valproate The efficacy of LATUDA, 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 LATUDA 20 to 120 mg/day or placebo. The primary rating instrument used to assess depressive symptoms in this study was the MADRS. The primary endpoint was the change from baseline in MADRS score at Week 6. The key secondary instrument was the CGI-BP-S scale. LATUDA 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. Study Treatment Group Primary Efficacy Measure: MADRS Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference a (95% CI) Monotherapy study LATUDA (20-60 mg/day)* 30.3 (5.0) -15.4 (0.8) -4.6 (-6.9, -2.3) LATUDA (80-120 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 LATUDA (20-120 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 LATUDA 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 LATUDA 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 CGI-BP-S depression score. LATUDA 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) LATUDA (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 LATUDA 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), LATUDA 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 LATUDA are at an increased risk of death compared to placebo. LATUDA is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning , Warnings and Precautions ( 5.1 , 5.3 )] .

8.4 Pediatric Use Schizophrenia The safety and effectiveness of LATUDA 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 LATUDA has not been established in pediatric patients less than 13 years of age with schizophrenia. Bipolar Depression The safety and effectiveness of LATUDA 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 LATUDA has not been established in pediatric patients less than 10 years of age with bipolar depression. Irritability Associated with Autistic Disorder The effectiveness of LATUDA 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 LATUDA 20 mg/day and 60 mg/day for the treatment of pediatric patients 6 to 17 years of age with irritability associated with autistic disorder diagnosed by Diagnostic and Statistical Manual of Mental Disorders, 4th Ed., Text Revision [DSM-IV-TR] criteria. The primary objective of the study as measured by improvement from Baseline in the irritability subscale of the Aberrant Behavior Checklist (ABC) at Endpoint (Week 6) was not met. A total of 149 patients were randomized to LATUDA or placebo. Vomiting occurred at a higher rate than reported in other LATUDA 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 LATUDA with vomiting). In a long-term, open-label study that enrolled pediatric patients (age 6 to 17 years) with schizophrenia, bipolar depression, or autistic disorder from three short-term, placebo-controlled trials, 54% (378/701) received lurasidone for 104 weeks. There was one adverse event in this trial that was considered possibly drug-related and has not been reported in adults receiving lurasidone: a 10 year old male experienced a prolonged, painful erection, consistent with priapism, that led to treatment discontinuation. In this trial, the mean increase in height from open-label baseline to Week 104 was 4.94 cm. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for the natural growth of children and adolescents by comparisons to age- and sex-matched population standards. A z-score change <0.5 SD is considered not clinically significant. In this trial, the mean change in height z-score from open-label baseline to Week 104 was +0.05 SD, indicating minimal deviation from the normal growth curve. Juvenile animal studies Adverse effects were seen on growth, physical and neurobehavioral development at doses as low as 0.2 times the MRHD based on mg/m 2 . Lurasidone was orally administered to rats from postnatal days 21 through 91 (this period corresponds to childhood, adolescence, and young adulthood in humans) at doses of 3, 30, and 150 (males) or 300 (females) mg/kg/day which are 0.2 to 10 times (males) and 20 times (females) the maximum recommended adult human dose (MRHD) of 160 mg/day based on mg/m 2 . The adverse effects included dose-dependent decreases in femoral length, bone mineral content, body and brain weights at 2 times the MRHD in both sexes, and motor hyperactivity at 0.2 and 2 times the MRHD in both sexes based on mg/m 2 . In females, there was a delay in attainment of sexual maturity at 2 times the MRHD, associated with decreased serum estradiol. Mortality occurred in both sexes during early post-weaning period and some of the male weanlings died after only 4 treatments at doses as low as 2 times the MRHD based on mg/m 2 . Histopathological findings included increased colloid in the thyroids and inflammation of the prostate in males at 10 times MRHD based on mg/m 2 and mammary gland hyperplasia, increased vaginal mucification, and increased ovarian atretic follicles at doses as low as 0.2 times the MRHD based on mg/m 2 . Some of these findings were attributed to transiently elevated serum prolactin which was seen in both sexes at all doses. However, there were no changes at any dose level in reproductive parameters (fertility, conception indices, spermatogenesis, estrous cycle, gestation length, parturition, number of pups born). The no effect dose for neurobehavioral changes in males is 0.2 times the MRHD based on mg/m 2 and could not be determined in females. The no effect dose for growth and physical development in both sexes is 0.2 times the MRHD based on mg/m 2 .

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LATUDA during pregnancy. For more information, contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ . Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery [see Clinical Considerations ] . There are no studies of LATUDA use in pregnant women. The limited available data are not sufficient to inform a drug-associated risk of birth defects or miscarriage. In animal reproduction studies, no teratogenic effects were seen in pregnant rats and rabbits given lurasidone during the period of organogenesis at doses approximately 1.5- and 6-times, the maximum recommended human dose (MRHD) of 160 mg/day, respectively based on mg/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 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Data Animal Data Pregnant rats were treated with oral lurasidone at doses of 3, 10, and 25 mg/kg/day during the period of organogenesis. These doses are 0.2, 0.6, and 1.5 times the MRHD of 160 mg/day based on mg/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, 10, and 50 mg/kg/day during the period of organogenesis. These doses are 0.2, 1.2 and 6 times the MRHD of 160 mg/day based on mg/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, 2, and 10 mg/kg/day during the periods of organogenesis and lactation. These doses are 0.02, 0.1 and 0.6 times the MRHD of 160 mg/day based on mg/m 2 . No pre- and postnatal developmental effects were observed up to 0.6 times the MRHD of 160 mg/day, based on mg/m 2 .

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 LATUDA during pregnancy. For more information, contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ . Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery [see Clinical Considerations ] . There are no studies of LATUDA use in pregnant women. The limited available data are not sufficient to inform a drug-associated risk of birth defects or miscarriage. In animal reproduction studies, no teratogenic effects were seen in pregnant rats and rabbits given lurasidone during the period of organogenesis at doses approximately 1.5- and 6-times, the maximum recommended human dose (MRHD) of 160 mg/day, respectively based on mg/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 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Data Animal Data Pregnant rats were treated with oral lurasidone at doses of 3, 10, and 25 mg/kg/day during the period of organogenesis. These doses are 0.2, 0.6, and 1.5 times the MRHD of 160 mg/day based on mg/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, 10, and 50 mg/kg/day during the period of organogenesis. These doses are 0.2, 1.2 and 6 times the MRHD of 160 mg/day based on mg/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, 2, and 10 mg/kg/day during the periods of organogenesis and lactation. These doses are 0.02, 0.1 and 0.6 times the MRHD of 160 mg/day based on mg/m 2 . No pre- and postnatal developmental effects were observed up to 0.6 times the MRHD of 160 mg/day, based on mg/m 2 . 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 LATUDA and any potential adverse effects on the breastfed infant from LATUDA or from the underlying maternal condition. 8.4 Pediatric Use Schizophrenia The safety and effectiveness of LATUDA 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 LATUDA has not been established in pediatric patients less than 13 years of age with schizophrenia. Bipolar Depression The safety and effectiveness of LATUDA 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 LATUDA has not been established in pediatric patients less than 10 years of age with bipolar depression. Irritability Associated with Autistic Disorder The effectiveness of LATUDA 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 LATUDA 20 mg/day and 60 mg/day for the treatment of pediatric patients 6 to 17 years of age with irritability associated with autistic disorder diagnosed by Diagnostic and Statistical Manual of Mental Disorders, 4th Ed., Text Revision [DSM-IV-TR] criteria. The primary objective of the study as measured by improvement from Baseline in the irritability subscale of the Aberrant Behavior Checklist (ABC) at Endpoint (Week 6) was not met. A total of 149 patients were randomized to LATUDA or placebo. Vomiting occurred at a higher rate than reported in other LATUDA 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 LATUDA with vomiting). In a long-term, open-label study that enrolled pediatric patients (age 6 to 17 years) with schizophrenia, bipolar depression, or autistic disorder from three short-term, placebo-controlled trials, 54% (378/701) received lurasidone for 104 weeks. There was one adverse event in this trial that was considered possibly drug-related and has not been reported in adults receiving lurasidone: a 10 year old male experienced a prolonged, painful erection, consistent with priapism, that led to treatment discontinuation. In this trial, the mean increase in height from open-label baseline to Week 104 was 4.94 cm. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for the natural growth of children and adolescents by comparisons to age- and sex-matched population standards. A z-score change <0.5 SD is considered not clinically significant. In this trial, the mean change in height z-score from open-label baseline to Week 104 was +0.05 SD, indicating minimal deviation from the normal growth curve. Juvenile animal studies Adverse effects were seen on growth, physical and neurobehavioral development at doses as low as 0.2 times the MRHD based on mg/m 2 . Lurasidone was orally administered to rats from postnatal days 21 through 91 (this period corresponds to childhood, adolescence, and young adulthood in humans) at doses of 3, 30, and 150 (males) or 300 (females) mg/kg/day which are 0.2 to 10 times (males) and 20 times (females) the maximum recommended adult human dose (MRHD) of 160 mg/day based on mg/m 2 . The adverse effects included dose-dependent decreases in femoral length, bone mineral content, body and brain weights at 2 times the MRHD in both sexes, and motor hyperactivity at 0.2 and 2 times the MRHD in both sexes based on mg/m 2 . In females, there was a delay in attainment of sexual maturity at 2 times the MRHD, associated with decreased serum estradiol. Mortality occurred in both sexes during early post-weaning period and some of the male weanlings died after only 4 treatments at doses as low as 2 times the MRHD based on mg/m 2 . Histopathological findings included increased colloid in the thyroids and inflammation of the prostate in males at 10 times MRHD based on mg/m 2 and mammary gland hyperplasia, increased vaginal mucification, and increased ovarian atretic follicles at doses as low as 0.2 times the MRHD based on mg/m 2 . Some of these findings were attributed to transiently elevated serum prolactin which was seen in both sexes at all doses. However, there were no changes at any dose level in reproductive parameters (fertility, conception indices, spermatogenesis, estrous cycle, gestation length, parturition, number of pups born). The no effect dose for neurobehavioral changes in males is 0.2 times the MRHD based on mg/m 2 and could not be determined in females. The no effect dose for growth and physical development in both sexes is 0.2 times the MRHD based on mg/m 2 . 8.5 Geriatric Use Clinical studies with LATUDA 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), LATUDA 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 LATUDA are at an increased risk of death compared to placebo. LATUDA 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 LATUDA-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 LATUDA-associated adverse reactions [ see Dosage and Administration ( 2.5 )]. 8.8 Other Specific Populations No dosage adjustment for LATUDA 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 LATUDA tablets are white to off-white, round (20 mg or 40 mg), white to off-white, oblong (60 mg), pale green, oval (80 mg) or white to off-white, oval (120 mg) and identified with strength-specific one-sided debossing, “L20” (20 mg), “L40” (40 mg), “L80” (80 mg) or “L120” (120 mg). Tablets are supplied in the following strengths and package configurations ( Table 39 ). Table 39: Package Configuration for LATUDA Tablets Tablet Strength Package Configuration NDC Code 20 mg Bottles of 30 63402-302-30 Bottles of 90 63402-302-90 Bottles of 500 63402-302-50 Box of 100 (Hospital Unit Dose) 10 blister cards, 10 tablets each 63402-302-10 Carton 63402-302-01 Blister 40 mg Bottles of 30 63402-304-30 Bottles of 90 63402-304-90 Bottles of 500 63402-304-50 Box of 100 (Hospital Unit Dose) 10 blister cards, 10 tablets each 63402-304-10 Carton 63402-304-01 Blister 60 mg Bottles of 30 63402-306-30 Bottles of 90 63402-306-90 Bottles of 500 63402-306-50 Box of 100 (Hospital Unit Dose) 10 blister cards, 10 tablets each 63402-306-10 Carton 63402-306-01 Blister 80 mg Bottles of 30 63402-308-30 Bottles of 90 63402-308-90 Bottles of 500 63402-308-50 Box of 100 (Hospital Unit Dose) 10 blister cards, 10 tablets each 63402-308-10 Carton 63402-308-01 Blister 120 mg Bottles of 30 63402-312-30 Bottles of 90 63402-312-90 Bottles of 500 63402-312-50 Box of 100 (Hospital Unit Dose) 10 blister cards, 10 tablets each 63402-312-10 Carton 63402-312-01 Blister Storage Store LATUDA tablets at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [See USP Controlled Room Temperature] .

Storage Store LATUDA tablets at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [See USP Controlled Room Temperature] .

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS 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. LATUDA 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 )]. 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. LATUDA 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 ).