LURASIDONE HYDROCHLORIDE- lurasidone hydrochloride_tablet

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 2A Lurasidone is an antagonist with high affinity binding at the dopamine D 2 2A 7 2C 2A 1 5 0 ECG Changes The effects of lurasidone hydrochloride on the QTc interval were evaluated in a randomized, double-blind, multiple-dose, parallel-dedicated thorough QT study in 43 patients with schizophrenia or schizoaffective disorder, who were treated with lurasidone hydrochloride 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. 7) ms and 4. 5) ms, for the 120 mg and 600 mg dose groups respectively, observed at 2 to 4 hours after dosing. In this study, there was no apparent dose (exposure)-response relationship. In short-term, placebo-controlled studies in schizophrenia and bipolar depression, no post- baseline QT prolongations exceeding 500 msec were reported in patients treated with lurasidone hydrochloride or placebo. Adults The activity of lurasidone hydrochloride is primarily due to the parent drug. The pharmacokinetics of lurasidone hydrochloride is dose-proportional within a total daily dose range of 20 mg to 160 mg. Steady-state concentrations of lurasidone hydrochloride are reached within 7 days of starting lurasidone hydrochloride. Following administration of 40 mg of lurasidone hydrochloride, the mean (%CV) elimination half-life was 18 (7) hours. Absorption and Distribution: Lurasidone hydrochloride is absorbed and reaches peak serum concentrations in approximately 1to 3 hours. It is estimated that 9 to 19% of an administered dose is absorbed. Following administration of 40 mg of lurasidone hydrochloride, the mean (%CV) apparent volume of distribution was 6173 (17. Lurasidone hydrochloride is highly bound (~99%) to serum proteins. In a food effect study, lurasidone hydrochloride mean C max [ Dosage and Administration ( 2. 3 In clinical studies, establishing the safety and efficacy of lurasidone hydrochloride, patients were instructed to take their daily dose with food [see Dosage and Administration ( 2. 3 Metabolism and Elimination: Lurasidone hydrochloride is metabolized mainly via CYP3A4. The major biotransformation pathways are oxidative N S in vitro Transporter proteins: In vitro In vitro 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 Following administration of 40 mg of lurasidone hydrochloride, the mean (%CV) apparent clearance was 3902 (18. Drug Interaction Studies Effects of other drugs on the exposure of lurasidone are summarized in Figure 5. A population PK analyses concluded that coadministration of lithium 300 to 2400 mg/day or valproate 300 to 2000 mg/day with lurasidone for up to 6 weeks has minimal effect on lurasidone exposure. And the effects of lurasidone hydrochloride on the exposures of other drugs are summarized in Figure 2. A population PK analyses concluded that coadministration of lurasidone has minimal effect on lithium and valproate exposure when it is coadministered with lithium 300 to 2400 mg/day or valproate 300 to 2000 mg/day. Fi gure 1: Impact of Other Drugs on Lurasidone Hydrochloride Pharmacokinetics Figure 2: Impact of Lurasidone Hydrochloride on Other Drugs Studies in Specific Populations The effect of intrinsic patient factors on the pharmacokinetics of lurasidone hydrochloride is presented in Figure 3. Pediatric Patients: Lurasidone hydrochloride exposure (i. , steady-state Cmax and AUC) in children and adolescent patients (10 to 17 years of age) was generally similar to that in adults across the dose range from 40 to 160 mg, without adjusting for body weight. Figure 3: Impact of Other Patient Factors on Lurasidone Hydrochloride Pharmacokinetics image-02 image-03 image-04.

Lurasidone hydrochloride tablets are indicated for: Treatment of adult and adolescent patients (13 to 17 years) with schizophrenia [see Clinical Studies ( 14. 1 Monotherapy treatment of adult and pediatric patients (10 to 17 years) with major depressive episode associated with bipolar I disorder (bipolar depression) [see Clinical Studies ( 14. 2 Adjunctive treatment with lithium or valproate in adult patients with major depressive episode associated with bipolar I disorder (bipolar depression) [see Clinical Studies ( 14. 2 Lurasidone hydrochloride is an atypical antipsychotic indicated for the treatment of: Schizophrenia in adults and adolescents (13 to 17 years) ( 1 14. 1 Depressive episode associated with Bipolar I Disorder (bipolar depression) in adults and pediatric patients (10 to 17 years) as monotherapy ( 1 14. 2 Depressive episode associated with Bipolar I Disorder (bipolar depression) in adults as adjunctive therapy with lithium or valproate ( 1 14.

Lurasidone hydrochloride should be taken with food (at least 350 calories). Administration with food substantially increases the absorption of lurasidone hydrochloride ( 2. 3 Indication Starting Dose Recommended Dose Schizophrenia - adults ( 2. 1 40 mg per day 40 mg to 160 mg per day Schizophrenia en dash 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 en dash pediatric patients (10 to 17 years) ( 2. 2 20 mg per day 20 mg to 80 mg per day Moderate and Severe Renal Impairment 2. 6 Moderate and Severe Hepatic Impairment: 2. 7 Concomitant Use of a Moderate CYP3A4 inhibitor (e. , diltiazem): Lurasidone hydrochloride tablets dose should be reduced to half of the original dose level. 1 Concomitant Use of a Moderate CYP3A4 Inducer: 2. 1 Adults The recommended starting dose of Lurasidone hydrochloride tablets is 40 mg once daily. Initial dose titration is not required. Lurasidone hydrochloride tablets have been shown to be effective in a dose range of 40 mg per day to 160 mg per day [see Clinical Studies ( 14. 1 Adolescents (13 to 17 years) The recommended starting dose of Lurasidone hydrochloride tablets is 40 mg once daily. Lurasidone hydrochloride tablets 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 Adults The recommended starting dose of Lurasidone hydrochloride tablets are 20 mg given once daily as monotherapy or as adjunctive therapy with lithium or valproate. Lurasidone hydrochloride tablets have been shown to be effective in a dose range of 20 mg per day to 120 mg per day as monotherapy or as adjunctive therapy with lithium or valproate [see Clinical Studies ( 14. 2 [see Clinical Studies ( 14. 2 Pediatric Patients (10 to 17 years) The recommended starting dose of Lurasidone hydrochloride tablets is 20 mg given once daily as monotherapy. The dose may be increased after one week based on clinical response. Lurasidone hydrochloride tablets 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 efficacy of lurasidone hydrochloride tablets in the treatment of mania associated with bipolar disorder has not been established. Lurasidone hydrochloride tablets should be taken with food (at least 350 calories). Administration with food substantially increases the absorption of lurasidone hydrochloride. Administration with food increases the AUC approximately 2-fold and increases the Cmax approximately 3-fold. In the clinical studies, lurasidone hydrochloride tablets were administered with food [see Clinical Pharmacology ( 12. 3 The effectiveness of lurasidone hydrochloride tablets for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. Therefore, the physician who elects to use lurasidone hydrochloride tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration ( 2. 2 Dose adjustment is recommended in moderate (creatinine clearance: 30 to <50 mL/min) and severe renal impairment (creatinine clearance <30 mL/min) patients. The recommended starting dose is 20 mg per day. The dose in these patients should not exceed 80 mg per day [see Use in Specific Populations ( 8. 6 Dose adjustment is recommended in moderate (Child-Pugh Score = 7 to 9) and severe hepatic impairment (Child-Pugh Score = 10 to 15) patients. The dose in moderate hepatic impairment patients should not exceed 80 mg per day and the dose in severe hepatic impairment patients should not exceed 40 per mg/day [see Use in Specific Populations ( 8. 7 Concomitant Use with CYP3A4 Inhibitors Lurasidone hydrochloride tablets should not be used concomitantly with a strong CYP3A4 inhibitor (e. , ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc. ) [see Contraindications ( 4 If lurasidone hydrochloride tablets are being prescribed and a moderate CYP3A4 inhibitor (e. diltiazem, atazanavir, erythromycin, fluconazole, verapamil etc. ) is added to the therapy, the lurasidone hydrochloride tablets dose should be reduced to half of the original dose level. Similarly, if a moderate CYP3A4 inhibitor is being prescribed and lurasidone hydrochloride is added to the therapy, the recommended starting dose of lurasidone hydrochloride tablets is 20 mg per day, and the maximum recommended dose of lurasidone hydrochloride tablets is 80 mg per day [see Contraindications ( 4 7. 1 Grapefruit and grapefruit juice should be avoided in patients taking lurasidone hydrochloride tablets, since these may inhibit CYP3A4 and alter lurasidone hydrochloride tablets concentrations [ see Drug Interactions ( 7. 1 Concomitant Use with CYP3A4 Inducers Lurasidone hydrochloride tablets should not be used concomitantly with a strong CYP3A4 inducer (e. , rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine, etc. ) [see Contraindications ( 4 7.

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 5. 1 Suicidal Thoughts and Behaviors [see Boxed Warning arnings 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 Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www. gov/medwatch. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adults The information below is derived from an integrated clinical study database for lurasidone hydrochloride consisting of 3799 adult patients exposed to one or more doses of lurasidone hydrochloride for the treatment of schizophrenia, and bipolar depression in placebo-controlled studies. This experience corresponds with a total experience of 1250. 9 patient-years. A total of 1106 lurasidone hydrochloride-treated patients had at least 24 weeks and 371 lurasidone hydrochloride -treated patients had at least 52 weeks of exposure. Adverse events during exposure to study treatment were obtained by general inquiry and voluntarily reported adverse experiences, as well as results from physical examinations, vital signs, ECGs, weights and laboratory investigations. Adverse experiences were recorded by clinical investigators using their own terminology. In order to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology. Schizophrenia The following findings are based on the short-term, placebo-controlled premarketing adult studies for schizophrenia in which lurasidone hydrochloride was administered at daily doses ranging from 20 to 160 mg (n=1508). Commonly Observed Adverse Reactions : Adverse Reactions Associated with Discontinuation of Treatment: Adverse Reactions Occurring at an Incidence of 2% or More in Lurasidone Hydrochloride-Treated Patients: Table 19: Adverse Reactions in 2% or More of Lurasidone Hydrochloride-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in Adult Short-term Schizophrenia Studies Note: Figures rounded to the nearest integer Percentage of Patients Reporting Reaction Lurasidone Hydrochloride Body System or Organ Class Placebo (N=708) (%) 20 mg/day (N=71) (%) 40 mg/day (N=487) (%) 80 mg/day (N=538) (%) 120 mg/day (N=291) (%) 160 mg/day (N=121) (%) All Lurasidone Hydrochloride (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 <1 1 1 2 4 2 2 Hypersecretion Musculoskeletal and Connective Tissue Disorders Back Pain 2 0 4 3 4 0 3 Nervous System Disorders Somnolence Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence 7 15 16 15 26 8 17 Akathisia 3 6 11 12 22 7 13 Extrapyramidal 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 6 6 11 12 22 13 14 Dizziness 2 6 4 4 5 6 4 Psychiatric Disorders Insomnia 8 8 10 11 9 7 10 Agitation 4 10 7 3 6 5 5 Anxiety 4 3 6 4 7 3 5 Restlessness 1 1 3 1 3 2 2 Dose-Related Adverse Reactions in the Schizophrenia Studies Akathisia and extrapyramidal symptoms were dose-related. The frequency of akathisia increased with dose up to 120 mg/day (5. 6% for lurasidone hydrochloride 20 mg, 10. 7% for lurasidone hydrochloride 40 mg, 12. 3% for lurasidone hydrochloride 80 mg, and 22. 0% for lurasidone hydrochloride 120 mg). Akathisia was reported by 7. 4% (9/121) of patients receiving 160 mg/day. Akathisia occurred in 3. 0% of subjects receiving placebo. The frequency of extrapyramidal symptoms increased with dose up to 120 mg/day (5. 6% for lurasidone hydrochloride 20 mg, 11. 5% for lurasidone hydrochloride 40 mg, 11. 9% for lurasidone hydrochloride 80 mg, and 22. Bipolar Depression (Monotherapy) The following findings are based on the adult short-term, placebo-controlled premarketing study for bipolar depression in which lurasidone hydrochloride was administered at daily doses ranging from 20 to 120 mg (n=331). Commonly Observed Adverse Reactions: Adverse Reactions Associated with Discontinuation of Treatment: Adverse Reactions Occurring at an Incidence of 2% or More in Lurasidone Hydrochloride-Treated Patients: Table 20: Adverse Reactions in 2% or More of Lurasidone Hydrochloride-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the Adult Short-term Monotherapy Bipolar Depression Study Note: Figures rounded to the nearest integer Percentage of Patients Reporting Reaction Body System or Organ Class Placebo (N=168) (%) Lurasidone Hydrochloride 20 to 60 mg/day (N=164) (%) Lurasidone Hydrochloride 80 to 120 mg/day (N=167) (%) All Lurasidone Hydrochloride (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 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 2 5 9 7 Akathisia 2 8 11 9 Somnolence Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence 7 7 14 11 Psychiatric Disorders Anxiety 1 4 5 4 Dose-Related Adverse Reactions in the Monotherapy Study: In the adult short-term, placebo-controlled study (involving lower and higher lurasidone hydrochloride dose ranges) [see Clinical Studies (14. 2)] Bipolar Depression Adjunctive Therapy with Lithium or Valproate The following findings are based on two adult short-term, placebo-controlled premarketing studies for bipolar depression in which lurasidone hydrochloride was administered at daily doses ranging from 20 to 120 mg as adjunctive therapy with lithium or valproate (n=360). Commonly Observed Adverse Reactions: Adverse Reactions Associated with Discontinuation of Treatment: Adverse Reactions Occurring at an Incidence of 2% or More in Lurasidone Hydrochloride-Treated Patients: Table 21: Adverse Reactions in 2% or More of Lurasidone Hydrochloride-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the Adult Short-term Adjunctive Therapy Bipolar Depression Studies Note: Figures rounded to the nearest integer Percentage of Patients Reporting Reaction Body System or Organ Class Dictionary-derived Term Placebo (N=334) (%) Lurasidone Hydrochloride 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 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 9 14 Somnolence Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence 5 11 Akathisia 5 11 Psychiatric Disorders Restlessness <1 4 Adolescents Schizophrenia: The following findings are based on the short-term, placebo-controlled adolescent study for schizophrenia in which lurasidone hydrochloride was administered at daily doses ranging from 40 (N=110) to 80 mg (N=104). Commonly Observed Adverse Reactions : Adverse Reactions Associated with Discontinuation of Treatment: Adverse Reactions Occurring at an Incidence of 2% or More in lurasidone hydrochloride en dashTreated Patients: Adverse reactions associated with the use of lurasidone hydrochloride (incidence of 2% or greater, rounded to the nearest percent and lurasidone hydrochloride incidence greater than placebo) that occurred during acute therapy (up to 6-weeks in adolescent patients with schizophrenia) are shown in Table 22. Table 22 Adverse Reactions in 2% or More of Lurasidone Hydrochloride-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the Adolescent Short-term Schizophrenia Study Note: Figures rounded to the nearest integer Percentage of Patients Reporting Reaction Body System or Organ Class Dictionary-derived Term Placebo (N=112) Lurasidone hydrochloride 40 mg/Day (N=110) Lurasidone hydrochloride 80 mg/Day (N=104) All Lurasidone hydrochloride (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 Viral Infection includes adverse event terms: nasopharyngitis, influenza, viral infection, upper respiratory tract infection 6 11 10 10 Rhinitis Rhinitis incudes adverse event terms: rhinitis, allergic rhinitis, rhinorrhea, and nasal congestion. 2 <1 8 4 Oropharyngeal pain 0 <1 3 2 Tachycardia 0 0 3 1 Nervous System Disorders Somnolence Somnolence includes adverse event terms: hypersomnia, sedation, and somnolence 7 15 13 15 Akathisia 2 9 9 9 Dizziness 1 5 5 5 Pediatric Patients (10 to 17 years) Bipolar Depression: The following findings are based on the 6-week , placebo-controlled study for bipolar depression in pediatric patients 10 to 17 years in which lurasidone hydrochloride was administered at daily doses ranging from 20 to 80 mg (N=175). Commonly Observed Adverse Reactions: Adverse Reactions Associated with Discontinuation of Treatment: Adverse Reactions Occurring at an Incidence of 2% or More in lurasidone hydrochloride -Treated Patients: Table 23: Adverse Reactions in 2% or More of Lurasidone Hydrochloride-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the 6-Week Bipolar Depression Study in Pediatric Patients (10 to 17 years) Note: Figures rounded to the nearest integer Percentage of Patients Reporting Reaction Body System or Organ Class Dictionary-derived Term Placebo (N=172) Lurasidone hydrochloride 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 Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence 6 11 Extrapyramidal symptoms 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 5 6 Dizziness 5 6 Psychiatric Disorders Insomnia 2 5 Abnormal Dreams 2 2 Respiratory, Thoracic and Mediastinal Disorders Oropharyngeal Pain 2 2 Extrapyramidal Symptoms Schizophrenia: Adults In the short-term, placebo-controlled schizophrenia studies, for lurasidone hydrochloride-treated patients, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness, was 13. 8% for placebo-treated patients. The incidence of akathisia for lurasidone hydrochloride-treated patients was 12. 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 Lurasidone Hydrochloride 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 Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus <1 0 4 5 7 2 Parkinsonism Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor 5 6 9 8 17 11 Restlessness 1 1 3 1 3 2 Adolescents In the short-term, placebo-controlled, study of schizophrenia in adolescents, the incidence of EPS, excluding events related to akathisia, for Lurasidone Hydrochloride -treated patients was higher in the 40 mg (10%) and the 80 mg (7. 7%) treatment groups vs. 6%); and the incidence of akathisia-related events for Lurasidone Hydrochloride-treated patients was 8. 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 Lurasidone Hydrochloride 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, 4 7 7 Akathisia 2 9 9 Parkinsonism Parkinsonism includes adverse event terms: bradykinesia, drooling, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, parkinsonism, and psychomotor retardation <1 4 0 Dyskinesia <1 <1 1 Dystonia Dystonia includes adverse event terms: dystonia, trismus, oculogyric crisis, oromandibular dystonia, tongue spasm, and torticollis 0 <1 1 Bipolar Depression: Adults Monotherapy: In the adult short-term, placebo-controlled monotherapy bipolar depression study, for lurasidone hydrochloride-treated patients, the incidence of reported events related to EPS, excluding akathisia and restlessness was 6. 4% for placebo-treated patients. The incidence of akathisia for lurasidone hydrochloride-treated patients was 9. 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 Lurasidone Hydrochloride 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 Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus 0 0 2 Parkinsonism Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor 2 5 8 Restlessness <1 0 3 Adjunctive Therapy with Lithium or Valproate In the adult short-term, placebo-controlled adjunctive therapy bipolar depression studies, for lurasidone hydrochloride-treated patients, the incidence of EPS, excluding akathisia and restlessness, was 13. 7% for placebo. The incidence of akathisia for lurasidone hydrochloride-treated patients was 10. 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 Adverse Event Term Placebo (N=334) (%) Lurasidone Hydrochloride 20 to 120 mg/day (N=360) (%) All EPS events 13 24 All EPS events, excluding Akathisia/Restlessness 9 14 Akathisia 5 11 Dystonia Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus <1 1 Parkinsonism Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor 8 13 Restlessness <1 4 In the short-term, placebo-controlled schizophrenia and bipolar depression studies, data was objectively collected on the Simpson Angus Rating Scale (SAS) for extrapyramidal symptoms (EPS), the Barnes Akathisia Scale (BAS) for akathisia and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesias. Pediatric Patients (10 to 17 years) In the 6-week, placebo-controlled study of bipolar depression in pediatric patients 10 to 17 years, the incidence of EPS, excluding events related to akathisia, for lurasidone hydrochloride-treated patients was similar in the lurasidone hydrochloride 20 to 80 mg/day (3. 4%) treatment group vs. 5%); and the incidence of akathisia-related events for lurasidone hydrochloride-treated patients was 2. 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 Adverse Event Term Placebo (N=172) (%) Lurasidone Hydrochloride 20 to 120 mg/day (N=175) (%) All EPS events * 5 6 All EPS events, excluding Akathisia/Restlessness 4 3 Akathisia 4 3 4 3 Parkinsonism Parkinsonism includes adverse event terms: bradykinesia, drooling, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, parkinsonism, and psychomotor retardation <1 <1 Dystonia Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus 1 <1 Salivary hypersecretion <1 <1 <1 <1 Psychomotor hyperactivity 0 <1 0 <1 Tardive Dyskinesia <1 0 <1 0 All EPS events 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 5 6 All EPS events, excluding Akathisia/Restlessness 4 3 Schizophrenia: Adults The mean change from baseline for lurasidone hydrochloride-treated patients for the SAS, BAS and AIMS was comparable to placebo-treated patients, with the exception of the Barnes Akathisia Scale global score (lurasidone hydrochloride, 0. 1; placebo, 0. The percentage of patients who shifted from normal to abnormal was greater in lurasidone hydrochloride-treated patients and placebo for the BAS (lurasidone hydrochloride, 14. 4%; placebo, 7. 1%), the SAS (lurasidone hydrochloride, 5. 0%; placebo, 2. 3%) and the AIMS (lurasidone hydrochloride, 7. 4%; placebo, 5. Adolescents The mean change from baseline for lurasidone hydrochloride- treated patients with adolescent schizophrenia for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in Lurasidone hydrochloride -treated patients and placebo for the BAS (lurasidone hydrochloride, 7. 0%; placebo, 1. 8%), the SAS (lurasidone hydrochloride, 8. 3%; placebo, 2. 7%) and the AIMS (lurasidone hydrochloride, 2. 8%; placebo, 0. Bipolar Depression: Adults Monotherapy: The mean change from baseline for lurasidone hydrochloride-treated adult patients for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in lurasidone hydrochloride-treated patients and placebo for the BAS (lurasidone hydrochloride, 8. 6%), the SAS (lurasidone hydrochloride, 3. 7%; placebo, 1. 9%) and the AIMS (lurasidone hydrochloride, 3. 4%; placebo, 1. Adjunctive Therapy with Lithium or Valproate: The mean change from baseline for lurasidone hydrochloride-treated adult patients for the SAS, BAS and AIMS was comparable to placebo-treated patients. 7%; placebo, 2. 1%), the SAS (lurasidone hydrochloride, 2. 8%; placebo, 2. 1%) and the AIMS (lurasidone hydrochloride, 2. Pediatric Patients (10 to 17 years) The mean change from baseline for lurasidone hydrochloride - treated pediatric patients 10 to 17 years with bipolar depression for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater lurasidone hydrochloride-treated patients and placebo for the BAS (lurasidone hydrochloride, 4. 6%; placebo, 2. 4%), the SAS (lurasidone hydrochloride, 0. 6%; placebo, 0%) and was the same for the AIMS (lurasidone hydrochloride, 0%; placebo, 0%). Dystonia: Class Effect: Schizophrenia: Adults In the short-term, placebo-controlled schizophrenia clinical studies, dystonia occurred in 4. 2% of lurasidone hydrochloride-treated subjects (0. 0% lurasidone hydrochloride 20 mg, 3. 5% lurasidone hydrochloride 40 mg, 4. 5% lurasidone hydrochloride 80 mg, 6. 5% lurasidone hydrochloride 120 mg and 2. 5% lurasidone hydrochloride 160 mg) compared to 0. 8% of subjects receiving placebo. Seven subjects (0. 5%, 7/1508) discontinued clinical trials due to dystonic events en dash four were receiving lurasidone hydrochloride 80 mg/day and three were receiving lurasidone hydrochloride 120 mg/day. Adolescents In the short-term, placebo-controlled, adolescent schizophrenia study, dystonia occurred in 1% of lurasidone hydrochloride-treated patients (1% lurasidone hydrochloride 40 mg and 1% Lurasidone hydrochloride 80 mg) compared to 0% of patients receiving placebo. No patients discontinued the clinical study due to dystonic events. Bipolar Depression: Adults Monotherapy: In the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, dystonia occurred in 0. 9% of lurasidone hydrochloride-treated subjects (0. 8% for lurasidone hydrochloride 20 to 60 mg/day and lurasidone hydrochloride 80 to 120 mg/day, respectively) compared to 0. No subject discontinued the clinical study due to dystonic events. Adjunctive Therapy with Lithium or Valproate: In the adult short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies, dystonia occurred in 1. 1% of lurasidone hydrochloride-treated subjects (20 to 120 mg) compared to 0. 6% of subjects receiving placebo. Pediatric Patients (10 to 17 years) In the 6-week, placebo-controlled bipolar depression study in pediatric patients 10 to 17 years, dystonia occurred in 0. 6% of lurasidone hydrochloride-treated patients compared to 1. 2% of patients receiving placebo. Other Adverse Reactions Observed During the Premarketing Evaluation of Lurasidone Hydrochloride: Following is a list of adverse reactions reported by adult patients treated with lurasidone hydrochloride 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 lurasidone hydrochloride label are not included. Reactions are further categorized by organ class and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (frequent) (only those not already listed in the tabulated results from placebo-controlled studies appear in this listing); those occurring in 1/100 to 1/1000 patients (infrequent); and those occurring in fewer than 1/1000 patients (rare). Blood and Lymphatic System Disorders: Infrequent: Cardiac Disorders: Frequent: Infrequent: Ear and Labyrinth Disorders: Infrequent: Eye Disorders: Frequent: Gastrointestinal Disorders: Frequent: Infrequent: General Disorders and Administrative Site Conditions: Rare: Investigations: Frequent: Metabolism and Nutritional System Disorders: Frequent: Musculoskeletal and Connective Tissue Disorders: Rare: Nervous System Disorders: Infrequent: Psychiatric Disorders: Infrequent: Renal and Urinary Disorders: Infrequent: Rare: Reproductive System and Breast Disorders: Infrequent: Rare: Skin and Subcutaneous Tissue Disorders: Frequent: Rare: Vascular Disorders: Frequent: Clinical Laboratory Changes Schizophrenia: Adults Serum Creatinine : Table 29: Serum Creatinine Shifts from Normal at Baseline to High at Study End- Point in Adult Schizophrenia Studies Laboratory Parameter Placebo (N=708) Lurasidone Hydrochloride 20 mg/day (N=71) Lurasidone Hydrochloride 40 mg/day (N=487) Lurasidone Hydrochloride 80 mg/day (N=538) Lurasidone Hydrochloride 120 mg/day (N=291) Lurasidone Hydrochloride 160 mg/day (N=121) Serum Creatinine Elevated 2% 1% 2% 2% 5% 7% Adolescents Serum Creatinine: In the short-term, placebo-controlled, adolescent schizophrenia study, the mean change from Baseline in serum creatinine was -0. 009 mg/dL for Lurasidone Hydrochloride -treated patients compared to +0. 017 mg/dL for placebo-treated patients. A creatinine shift from normal to high (based on the centralized laboratory definition) occurred in 7. 2% (14/194) of Lurasidone Hydrochloride -treated patients and 2. 9% (3/103) on placebo (Table 30). Table 30: Serum Creatinine Shifts from Normal at Baseline to High at Study End- Point in Adult Schizophrenia Studies Laboratory Parameter Placebo (N=103) Lurasidone Hydrochloride 40 mg/day (N=97) Lurasidone Hydrochloride 80 mg/day (N=97) Serum Creatinine Elevated 2. 2% Bipolar Depression: Adults Monotherapy: Serum Creatinine: In the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, the mean change from Baseline in serum creatinine was +0. 01 mg/dL for lurasidone hydrochloride-treated patients compared to -0. 02 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 2. 8% (9/322) of lurasidone hydrochloride-treated patients and 0. 6% (1/162) on placebo (Table 31). Table 31: Serum Creatinine Shifts from Normal at Baseline to High at Study End- Point in the Adult Monotherapy Bipolar Depression Study Laboratory Parameter Placebo (N=168) Lurasidone Hydrochloride 20 to 60 mg/day (N=164) Lurasidone Hydrochloride 80 to 120 mg/day (N=167) Serum Creatinine Elevated <1% 2% 4% Adjunctive Therapy with Lithium or Valproate: Serum Creatinine : Table 32: Serum Creatinine Shifts from Normal at Baseline to High at Study End- Point in the Adult Adjunctive Therapy Bipolar Depression Studies Laboratory Parameter Placebo (N=334) Lurasidone Hydrochloride 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 Lurasidone Hydrochloride-treated patients compared to +0. 009 mg/dL for placebo-treated patients. A creatinine shift from normal to high (based on the centralized laboratory definition) occurred in 6. 7% (11/163) of Lurasidone Hydrochloride-treated patients and 4. 5% (7/155) on placebo (Table 33). Table 33: Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in the Bipolar Depression Study in Pediatric Patients (10 to 17 years) Laboratory Parameter Placebo (N=155) Lurasidone Hydrochloride 20 to 80 mg/day (N=163) Serum Creatinine Elevated 4. 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. In patients with a normal serum creatinine at baseline, 6% experienced a shift to high at endpoint. The following adverse reactions have been identified during postapproval use of lurasidone hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity Reactions Urticaria, throat swelling, tongue swelling, dyspnea, and rash Metabolism and Nutrition Disorders Hyponatremia.

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. , ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc. ) [see Drug Interactions ( 7. 1 Strong CYP3A4 inducers (e. , rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine, etc. 1 Known hypersensitivity to lurasidone hydrochloride or any components in the formulation ( 4 Concomitant use with a strong CYP3A4 inhibitor (e. , ketoconazole) ( 2. 1 Concomitant use with a strong CYP3A4 inducer (e. , rifampin) ( 2.

Pregnancy: May cause extrapyramidal and or/withdrawal symptoms in neonates with third trimester exposure ( 8. 1 Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lurasidone hydrochloride 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] 2 [ s e e 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. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to20%, 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. 5 times the MRHD of 160 mg/day based on mg/m 2 2 Pregnant rabbits were treated with oral lurasidone at doses of 2, 10, and 50 mg/kg/day during the period of organogenesis. 2 and 6 times the MRHD of 160 mg/day based on mg/m 2 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. 6 times the MRHD of 160 mg/day based on mg/m 2 2 Risk Summary Lactation studies have not been conducted to assess the presence of lurasidone in human milk, the effects on the breastfed infant, or the effects on milk production. Lurasidone is present in rat milk. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for lurasidone hydrochloride and any potential adverse effects on the breastfed infant from lurasidone hydrochloride or from the underlying maternal condition. Schizophrenia The safety and effectiveness of lurasidone hydrochloride 40-mg/day and 80-mg/day for the treatment of schizophrenia in adolescents (13 to 17 years) was established in a 6-week, placebocontrolled clinical study in 326 adolescent patients [see Dosage and Administration ( 2. 1 ), Adverse Reactions ( 6. 1 ), and Clinical Studies ( 14. The safety and effectiveness of lurasidone hydrochloride has not been established in pediatric patients less than 13 years of age with schizophrenia. Bipolar Depression The safety and effectiveness of lurasidone hydrochloride 20 to 80 mg/day for the treatment of bipolar depression in pediatric patients (10 to 17 years) was established in a 6-week, placebocontrolled clinical study in 347 pediatric patients [see Dosage and Administration ( 2. 2 ), Adverse Reactions ( 6. 2 The safety and effectiveness of lurasidone hydrochloride has not been established in pediatric patients less than 10 years of age with bipolar depression. Irritability Associated with Autistic Disorder The effectiveness of lurasidone hydrochloride in pediatric patients for the treatment of irritability associated with autistic disorder has not been established. Efficacy was not demonstrated in a 6-week study evaluating lurasidone hydrochloride 20 mg/day and 60 mg/day for the treatment of pediatric patients 6 to 17 years of age with irritability associated with autistic disorder diagnosed by Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. , Text Revision [DSM-IV-TR] criteria. The primary objective of the study as measured by improvement from Baseline in the irritability subscale of the Aberrant Behavior Checklist (ABC) at Endpoint (Week 6) was not met. A total of 149 patients were randomized to lurasidone hydrochloride or placebo. Vomiting occurred at a higher rate than reported in other lurasidone hydrochloride studies (4/49 or 8% for 20mg, 14/51 or 27% for 60mg, and 2/49 or 4% for placebo), particularly in children ages 6 to 12 (13 out of 18 patients on lurasidone hydrochloride with vomiting). In a long-term, open-label study that enrolled pediatric patients (age 6 to 17 years) with schizophrenia, bipolar depression, or autistic disorder from three short-term, placebo-controlled trials, 54% (378/701) received lurasidone for 104 weeks. There was one adverse event in this trial that was considered possibly drug-related and has not been reported in adults receiving lurasidone: a 10 year old male experienced a prolonged, painful erection, consistent with priapism, that led to treatment discontinuation. In this trial, the mean increase in height from open-label baseline to Week 104 was 4. 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 2 2 2 2 2 2 2 Clinical studies with lurasidone hydrochloride did not include sufficient numbers of patients aged 65 and older to determine whether or not they respond differently from younger patients. In elderly patients with psychosis (65 to 85), lurasidone hydrochloride concentrations (20 mg/day) were similar to those in young subjects. It is unknown whether dose adjustment is necessary on the basis of age alone. Elderly patients with dementia-related psychosis treated with lurasidone hydrochloride are at an increased risk of death compared to placebo. Lurasidone hydrochloride is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions ( 5. 3 Reduce the maximum recommended dosage in patients with moderate or severe renal impairment (CLcr <50 mL/minute). Patients with impaired renal function (CLcr <50 mL/minute) had higher exposure to lurasidone than patients with normal renal function [see Clinical Pharmacology ( 12. 3 [see Dosage and Administration ( 2. 4 Reduce the maximum recommended dosage in patients with moderate to severe hepatic impairment (Child-Pugh score >=7). Patients with moderate to severe hepatic impairment (Child- Pugh score >=7) generally had higher exposure to lurasidone than patients with normal hepatic function [see Clinical Pharmacology ( 12. 5 No dosage adjustment for lurasidone hydrochloride is required on the basis of a patient's sex, race, or smoking status [see Clinical Pharmacology ( 12.

Table 34: Clinically Important Drug Interactions with Lurasidone Hydrochloride Strong CYP3A4 Inhibitors Clinical Impact: Concomitant use of lurasidone hydrochloride with strong CYP3A4 inhibitors increased the exposure of lurasidone compared to the use of lurasidone hydrochloride alone [see Clinical Pharmacology ( 12. 3 Intervention: Lurasidone hydrochloride should not be used concomitantly with strong CYP3A4 inhibitors [see Contraindications ( 4 Examples: Ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil Moderate CYP3A4 Inhibitors Clinical Impact: Concomitant use of lurasidone hydrochloride with moderate CYP3A4 inhibitors increased the exposure of lurasidone compared to the use of lurasidone hydrochloride alone [see Clinical Pharmacology ( 12. 3 Intervention: Lurasidone hydrochloride dose should be reduced to half of the original level when used concomitantly with moderate inhibitors of CYP3A4 [see Dosage and Administration ( 2. 6 Examples: Diltiazem, atazanavir, erythromycin, fluconazole, verapamil Strong CYP3A4 Inducers Clinical Impact: Concomitant use of lurasidone hydrochloride with strong CYP3A4 inducers decreased the exposure of lurasidone compared to the use of lurasidone hydrochloride alone [see Clinical Pharmacology ( 12. 3 Intervention: Lurasidone hydrochloride should not be used concomitantly with strong CYP3A4 inducers [see Contraindications ( 4 Examples: Rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine Moderate CYP3A4 Inducers Clinical Impact: Concomitant use of lurasidone hydrochloride with moderate CYP3A4 inducers decreased the exposure of lurasidone compared to the use of lurasidone hydrochloride alone [see Clinical Pharmacology ( 12. 3 Intervention: Lurasidone hydrochloride dose should be increased when used concomitantly with moderate inducers of CYP3A4 [see Dosage and Administration ( 2. 6 Examples: Bosentan, efavirenz, etravirine, modafinil, nafcillin Based on pharmacokinetic studies, no dosage adjustment of lurasidone hydrochloride is required when administered concomitantly with lithium, valproate, or substrates of P-gp or CYP3A4 [see Clinical Pharmacology ( 12.

OVERDOSAGE
In premarketing clinical studies, accidental or intentional overdosage of lurasidone hydrochloride was identified in one patient who ingested an estimated 560 mg of lurasidone hydrochloride. This patient recovered without sequelae. This patient resumed lurasidone hydrochloride treatment for an additional two months. No specific antidotes for lurasidone hydrochloride are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. If an overdose occurs, consult a Certified Poison Control Center (1-800-222-1222 or www. Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with an acute overdose of lurasidone hydrochloride. Similarly, the alpha-blocking properties of bretylium might be additive to those of lurasidone hydrochloride, resulting in problematic 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 lurasidone hydrochloride-induced alpha blockade. In case of severe extrapyramidal symptoms, anticholinergic medication should be administered. Gastric lavage (after intubation if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.
NONCLINICAL TOXICOLOGY
Carcinogenesis: 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: in vitro in vivo test battery in vivo 2 Impairment of Fertility: 2 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 m g/m 2
CLINICAL STUDIES
Adults The efficacy of lurasidone hydrochloride for the treatment of schizophrenia was established in five short-term (6-week), placebo-controlled studies in adult patients (mean age of 38. 4 years, range 18 to 72) who met DSM-IV criteria for schizophrenia. An active-control arm (olanzapine or quetiapine extended-release) was included in two studies to assess assay sensitivity. Several instruments were used for assessing psychiatric signs and symptoms in these studies: Positive and Negative Syndrome Scale (PANSS), is a multi-item inventory of general psychopathology used to evaluate the effects of drug treatment in schizophrenia. PANSS total scores may range from 30 to 210. Brief Psychiatric Rating Scale derived (BPRSd), derived from the PANSS, is a multi-item inventory primarily focusing on positive symptoms of schizophrenia, whereas the PANSS includes a wider range of positive, negative and other symptoms of schizophrenia. The BPRSd consists of 18 items rated on a scale of 1 (not present) to 7 (severe). BPRSd scores may range from 18 to 126. The Clinical Global Impression severity scale (CGI-S) is a clinician-rated scale that measures the subject''s current illness state on a 1- to 7-point scale. The endpoint associated with each instrument is change from baseline in the total score to the end of week 6. These changes are then compared to placebo changes for the drug and control groups. The results of the studies follow: Study 1: In a 6-week, placebo-controlled trial (N=145) involving two fixed doses of lurasidone hydrochloride (40 or 120 mg/day), both doses of lurasidone hydrochloride at Endpoint were superior to placebo on the BPRSd total score, and the CGI-S. Study 2: In a 6-week, placebo-controlled trial (N=180) involving a fixed dose of lurasidone hydrochloride (80 mg/day), lurasidone hydrochloride at Endpoint was superior to placebo on the BPRSd total score, and the CGI-S. Study 3: In a 6-week, placebo- and active-controlled trial (N=473) involving two fixed doses of lurasidone hydrochloride (40 or 120 mg/day) and an active control (olanzapine), both lurasidone hydrochloride doses and the active control at Endpoint were superior to placebo on the PANSS total score, and the CGI-S. Study 4: In a 6-week, placebo-controlled trial (N=489) involving three fixed doses of lurasidone hydrochloride (40, 80 or 120 mg/day), only the 80 mg/day dose of lurasidone hydrochloride at Endpoint was superior to placebo on the PANSS total score, and the CGI-S. Study 5: In a 6-week, placebo- and active-controlled trial (N=482) involving two fixed doses of lurasidone hydrochloride (80 or 160 mg/day) and an active control (quetiapine extended-release), both lurasidone hydrochloride doses and the active control at Endpoint were superior to placebo on the PANSS total score, and the CGI-S. Thus, the efficacy of lurasidone hydrochloride 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. Primary Efficacy Measure: BPRSd Study Treatment Group Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline. 1 Lurasidone Hydrochloride Doses statistically significantly superior to placebo. 4) Lurasidone Hydrochloride 52. 5) Placebo 54. 6) -- 2 Lurasidone Hydrochloride 55. 1) Placebo 56. 4) -- Primary Efficacy Measure: PANSS 3 Lurasidone Hydrochloride 96. 1) Lurasidone Hydrochloride 97. 7) Olanzapine (15 mg/day) * Included for assay sensitivity. 9) Placebo 95. 1) -- 4 Lurasidone Hydrochloride 96. 8) Lurasidone Hydrochloride 96. 5) Lurasidone Hydrochloride 96. 4) Placebo 96. 8) -- 5 Lurasidone Hydrochloride 97. 9) Lurasidone Hydrochloride 97. 2) Quetiapine Extended-release * 97. 8) -- Examination of population subgroups based on age (there were few patients over 65), gender and race did not reveal any clear evidence of differential responsiveness. Adolescents (13-17 years) The efficacy of lurasidone hydrochloride, was established in a 6-week, multicenter, randomized, double-blind, placebo-controlled study of adolescents (13 to 17 years) who met DSM-IV-TR criteria for schizophrenia (N=326). Patients were randomized to one of two fixed-doses of Lurasidone hydrochloride (40 or 80 mg/day) or placebo. The primary rating instrument used to assess psychiatric signs and symptoms was the PANSS. The key secondary instrument was the CGI-S. For both dose groups, lurasidone hydrochloride was superior to placebo in reduction of PANSS and CGI-S scores at Week 6. On average, the 80 mg/day dose did not provide additional benefit compared to the 40 mg/day dose. The primary efficacy results are provided in Table 36. Table 36: Primary Efficacy Results (PANSS Total Score) for the Adolescent Schizophrenia Study SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, unadjusted for multiple comparisons. a Primary Efficacy Measure: PANSS Treatment Group Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference a (95% CI) Lurasidone Hydrochloride Doses statistically significantly superior to placebo. 7) Lurasidone Hydrochloride 94. 4) Placebo 92. 59) -- Adults Monotherapy: The efficacy of lurasidone hydrochloride, as monotherapy, was established in a 6-week, multicenter, randomized, double-blind, placebo-controlled study of adult patients (mean age of 41. 5 years, range 18 to 74) who met DSM-IV-TR criteria for major depressive episodes associated with bipolar I disorder, with or without rapid cycling, and without psychotic features (N=485). Patients were randomized to one of two flexible-dose ranges of lurasidone hydrochloride (20 to 60 mg/day, or 80 to 120 mg/day) or placebo. The primary rating instrument used to assess depressive symptoms in this study was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale with total scores ranging from 0 (no depressive features) to 60 (maximum score). The primary endpoint was the change from baseline in MADRS score at Week 6. The key secondary instrument was the Clinical Global Impression-Bipolar-Severity of Illness scale (CGI-BP-S), a clinician-rated scale that measures the subject''s current illness state on a 7-point scale, where a higher score is associated with greater illness severity. For both dose groups, lurasidone hydrochloride 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 lurasidone hydrochloride, as an adjunctive therapy with lithium or valproate, was established in a 6-week, multicenter, randomized, double-blind, placebo-controlled study of adult patients (mean age of 41. 7 years, range 18 to 72) who met DSM-IV-TR criteria for major depressive episodes associated with bipolar I disorder, with or without rapid cycling, and without psychotic features (N=340). Patients who remained symptomatic after treatment with lithium or valproate were randomized to flexibly dosed lurasidone hydrochloride 20 to 120 mg/day or placebo. The primary rating instrument used to assess depressive symptoms in this study was the MADRS. The key secondary instrument was the CGI-BP-S scale. Lurasidone hydrochloride was superior to placebo in reduction of MADRS and CGI-BP-S scores at Week 6, as an adjunctive therapy with lithium or valproate (Table 37). Table 37: Primary Efficacy Results for Adult Studies in Depressive Episodes Associated with Bipolar I Disorder (MADRS Scores) SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, unadjusted for multiple comparisons. Study Treatment Group Primary Efficacy Measure: MADRS Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline. Monotherapy study Lurasidone hydrochloride 30. 3) Lurasidone hydrochloride 30. 3) Placebo 30. 8) -- Adjunctive Therapy study Lurasidone hydrochloride 30. 1) Placebo + lithium or valproate 30. 9) -- Pediatric Patients (10 to 17 years) The efficacy of lurasidone hydrochloride was established in a 6-week, multicenter, randomized, double-blind, placebo-controlled study of pediatric patients (10 to 17 years) who met DSM-5 criteria for a major depressive episode associated with bipolar I disorder, with or without rapid cycling, and without psychotic features (N=343). Patients were randomized to flexibly dosed Lurasidone hydrochloride 20 to 80 mg/day or placebo. At the end of the clinical study, most patients (67%) received 20 mg/day or 40 mg/day. The primary rating scale used to assess depressive symptoms in this study was the Children''s Depression Rating Scale, Revised (CDRS-R) total score. The CDRS-R is a 17-item clinician-rated scale with total scores ranging from 17 to 113. The primary endpoint was the change from baseline in CDRS-R score at Week 6. The key secondary endpoint was the change from baseline in CGIBP-S depression score. Lurasidone hydrochloride was superior to placebo in reduction of CDRS-R total score and CGI-BP-S depression score at Week 6. The primary efficacy results are provided in Table 38. Table 38: Primary Efficacy Results for the Study in Depressive Episodes Associated with Bipolar I Disorder (CDRS-R Total Score) in Pediatric Patients (10 to 17 years) SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, unadjusted for multiple comparisons. a Primary Efficacy Measure: CDRS-R Treatment Group Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference a Lurasidone hydrochloride Treatment group statistically significantly superior to placebo. 0) Placebo 58.

Lupin Pharmaceuticals, Inc.

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