Lurasidone Hydrochloride

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

2 DOSAGE AND ADMINISTRATION Lurasidone hydrochloride tablets should be taken with food (at least 350 calories). Administration with food substantially increases the absorption of lurasidone hydrochloride tablets (2.3, 12.3). Indication Starting Dose Recommended Dose Schizophrenia – adults (2.1) 40 mg per day 40 mg to 160 mg per day Schizophrenia – adolescents (13 to 17 years) (2.1) 40 mg per day 40 mg to 80 mg per day Bipolar Depression – adults (2.2) 20 mg per day 20 mg to 120 mg per day Bipolar Depression – pediatric patients (10 to 17 years) (2.2) 20 mg per day 20 mg to 80 mg per day Moderate and Severe Renal Impairment: Recommended starting dose is 20 mg per day, and the maximum recommended dose is 80 mg per day (2.4, 8.6). Moderate and Severe Hepatic Impairment: Recommended starting dose is 20 mg per day. The maximum recommended dose is 80 mg per day in moderate hepatic impairment and 40 mg per day in severe hepatic impairment (2.5, 8.7). Concomitant Use of a Moderate CYP3A4 inhibitor (e.g., diltiazem): Lurasidone hydrochloride tablets dose should be reduced to half of the original dose level. Recommended starting dose is 20 mg per day. Maximum recommended dose is 80 mg per day (2.6, 7.1). Concomitant Use of a Moderate CYP3A4 Inducer: It may be necessary to increase the dose of lurasidone hydrochloride tablets (2.6, 7.1). 2.1 Schizophrenia Adults The recommended starting dose of lurasidone hydrochloride tablets is 40 mg once daily. Initial dose titration is not required. Lurasidone hydrochloride tablets have been shown to be effective in a dose range of 40 mg per day to 160 mg per day [see Clinical Studies (14.1)]. The maximum recommended dose is 160 mg per day. Adolescents (13 to 17 years) The recommended starting dose of lurasidone hydrochloride tablets is 40 mg once daily. Initial dose titration is not required. Lurasidone hydrochloride tablets have been shown to be effective in a dose range of 40 mg per day to 80 mg per day [see Clinical Studies (14.1)] . The maximum recommended dose is 80 mg per day. 2.2 Depressive Episodes Associated with Bipolar I Disorder Adults The recommended starting dose of lurasidone hydrochloride tablets is 20 mg given once daily as monotherapy or as adjunctive therapy with lithium or valproate. Initial dose titration is not required. Lurasidone hydrochloride tablets have been shown to be effective in a dose range of 20 mg per day to 120 mg per day as monotherapy or as adjunctive therapy with lithium or valproate [see Clinical Studies (14.2)] . The maximum recommended dose, as monotherapy or as adjunctive therapy with lithium or valproate, is 120 mg per day. In the monotherapy study, the higher dose range (80 mg to 120 mg per day) did not provide additional efficacy, on average, compared to the lower dose range (20 to 60 mg per day) [see Clinical Studies (14.2)] . Pediatric Patients (10 to 17 years) The recommended starting dose of lurasidone hydrochloride tablets is 20 mg given once daily as monotherapy. Initial dose titration is not required. The dose may be increased after one week based on clinical response. Lurasidone hydrochloride tablets have been shown to be effective in a dose range of 20 mg per day to 80 mg per day as monotherapy. At the end of the clinical study, most of the patients (67%) received 20 mg or 40 mg once daily [see Clinical Studies (14.2)] . The maximum recommended dose is 80 mg per day. The efficacy of lurasidone hydrochloride tablets in the treatment of mania associated with bipolar disorder has not been established. 2.3 Administration Information Lurasidone hydrochloride tablets should be taken with food (at least 350 calories). Administration with food substantially increases the absorption of lurasidone hydrochloride tablets. Administration with food increases the AUC approximately 2-fold and increases the C max approximately 3-fold. In the clinical studies, lurasidone hydrochloride tablets were administered with food [see Clinical Pharmacology (12.3)] . The eff…

5 WARNINGS AND PRECAUTIONS Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) (5.3). Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring (5.4). Tardive Dyskinesia: Discontinue if clinically appropriate (5.5). Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia and weight gain (5.6). Hyperprolactinemia: Prolactin elevations may occur (5.7). Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts (CBC) in patients with a preexisting low white blood cell count (WBC) or a history of leukopenia or neutropenia. Consider discontinuing lurasidone hydrochloride tablets if a clinically significant decline in WBC occurs in the absence of other causative factors (5.8). Orthostatic Hypotension and Syncope: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope (5.9). 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6- to 1.7-times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Lurasidone hydrochloride tablets are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.3)] . 5.2 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients, and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2. No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about antidepressant drug effect on suicide. Table 2: Risk Differences of the Number of Cases of Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range D rug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 14 additional patients 18 to 24 5 additional patients Decreases Compared to Placebo 25 to 64 1 fewer patient ≥65 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with MDD that antidepressants delay the recurrence of depression. Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing lurasidone hydro…

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

7 DRUG INTERACTIONS 7.1 Drugs Having Clinically Important Interactions with Lurasidone Hydrochloride Table 34: Clinically Important Drug Interactions with Lurasidone Hydrochloride Strong CYP3A4 Inhibitors Clinical Impact: Concomitant use of lurasidone hydrochloride tablets with strong CYP3A4 inhibitors increased the exposure of lurasidone compared to the use of lurasidone hydrochloride tablets alone [see Clinical Pharmacology (12.3)] . Intervention: Lurasidone hydrochloride tablets should not be used concomitantly with strong CYP3A4 inhibitors [see Contraindications (4)] . Examples: Ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil Moderate CYP3A4 Inhibitors Clinical Impact: Concomitant use of lurasidone hydrochloride tablets with moderate CYP3A4 inhibitors increased the exposure of lurasidone compared to the use of lurasidone hydrochloride tablets alone [see Clinical Pharmacology (12.3)] . Intervention: Lurasidone hydrochloride tablets dose should be reduced to half of the original level when used concomitantly with moderate inhibitors of CYP3A4 [see Dosage and Administration (2.6)] . Examples: Diltiazem, atazanavir, erythromycin, fluconazole, verapamil Strong CYP3A4 Inducers Clinical Impact: Concomitant use of lurasidone hydrochloride tablets with strong CYP3A4 inducers decreased the exposure of lurasidone compared to the use of lurasidone hydrochloride tablets alone [see Clinical Pharmacology (12.3)] . Intervention: Lurasidone hydrochloride tablets should not be used concomitantly with strong CYP3A4 inducers [see Contraindications (4)] . Examples: Rifampin, avasimibe, St. John’s wort, phenytoin, carbamazepine Moderate CYP3A4 Inducers Clinical Impact: Concomitant use of lurasidone hydrochloride tablets with moderate CYP3A4 inducers decreased the exposure of lurasidone compared to the use of lurasidone hydrochloride tablets alone [see Clinical Pharmacology (12.3)] . Intervention: Lurasidone hydrochloride tablets dose should be increased when used concomitantly with moderate inducers of CYP3A4 [see Dosage and Administration (2.6)] . Examples: Bosentan, efavirenz, etravirine, modafinil, nafcillin 7.2 Drugs Having No Clinically Important Interactions with Lurasidone Hydrochloride Based on pharmacokinetic studies, no dosage adjustment of lurasidone hydrochloride tablets is required when administered concomitantly with lithium, valproate, or substrates of P-gp or CYP3A4 [see Clinical Pharmacology (12.3)] .

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lurasidone hydrochloride tablets during pregnancy. For more information, contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery [see Clinical Considerations]. There are no studies of lurasidone hydrochloride tablets use in pregnant women. The limited available data are not sufficient to inform a drug-associated risk of birth defects or miscarriage. In animal reproduction studies, no teratogenic effects were seen in pregnant rats and rabbits given lurasidone during the period of organogenesis at doses approximately 1.5- and 6-times, the maximum recommended human dose (MRHD) of 160 mg/day, respectively based on mg/m2 body surface area [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Data Animal Data Pregnant rats were treated with oral lurasidone at doses of 3, 10, and 25 mg/kg/day during the period of organogenesis. These doses are 0.2, 0.6, and 1.5 times the MRHD of 160 mg/day based on mg/m2 body surface area. No teratogenic or embryo-fetal effects were observed up to 1.5 times the MRHD of 160 mg/day, based on mg/m 2 . Pregnant rabbits were treated with oral lurasidone at doses of 2, 10, and 50 mg/kg/day during the period of organogenesis. These doses are 0.2, 1.2 and 6 times the MRHD of 160 mg/day based on mg/m2. No teratogenic or embryo-fetal effects were observed up to 6 times the MRHD of 160 mg/day based on mg/m 2 . Pregnant rats were treated with oral lurasidone at doses of 0.4, 2, and 10 mg/kg/day during the periods of organogenesis and lactation. These doses are 0.02, 0.1 and 0.6 times the MRHD of 160 mg/day based on mg/m 2 . No pre- and postnatal developmental effects were observed up to 0.6 times the MRHD of 160 mg/day, based on mg/m 2 .

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 to 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 to 17 years) with bipolar depression: nausea, weight increase, and insomnia. To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 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 lurasidone hydrochloride tablets consisting of 3799 adult patients exposed to one or more doses of lurasidone hydrochloride tablets 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 tablets-treated patients had at least 24 weeks and 371 lurasidone hydrochloride tablets-treated patients had at least 52 weeks of exposure. Adverse events during exposure to study treatment were obtained by general inquiry and voluntarily reported adverse experiences, as well as results from physical examinations, vital signs, ECGs, weights and laboratory investigations. Adverse experiences were recorded by clinical investigators using their own terminology. In order to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology. Schizophrenia The following findings are based on the short-term, placebo-controlled premarketing adult studies for schizophrenia in which lurasidone hydrochloride tablets were 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 lurasidone hydrochloride tablets were somnolence, akathisia, extrapyramidal symptoms, and nausea. Adverse Reactions Associated with Discontinuation of Treatment: A total of 9.5% (143/1508) lurasid…