Lurasidone Hydrochloride

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 )

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 )

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 ).

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 pre-existing low white blood cell count (WBC) or a history of leukopenia or neutropenia. Consider discontinuing LATUDA 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. LATUDA is 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 Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 14 additional patients 18-24 5 additional patients Decreases Compared to Placebo 25-64 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 LATUDA, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.3 Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks), including fatalities, compared to placebo-treated subjects. LATUDA is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning , Warnings and Precautions ( 5.1 )].

5.4 Neuroleptic Malignant Syndrome A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including LATUDA. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue LATUDA and provide intensive symptomatic treatment and monitoring.

5.5 Tardive Dyskinesia Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements that can develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, LATUDA should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on LATUDA, drug discontinuation should be considered. However, some patients may require treatment with LATUDA despite the presence of the syndrome.

5.6 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. […]

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, Sumitomo Pharma America, 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 . […]

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 )] .

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 . […]

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.