lurasidone hydrochloride

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)] .

Concomitant Use with CYP3A4 Inhibitors

Lurasidone hydrochloride should not be used concomitantly with a strong CYP3A4 inhibitor (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.) [see Contraindications ( 4)] .

If lurasidone hydrochloride is being prescribed and a moderate CYP3A4 inhibitor (e.g. diltiazem, atazanavir, erythromycin, fluconazole, verapamil etc.) is added to the therapy, the lurasidone hydrochloride 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 is 20 mg per day, and the maximum recommended dose of lurasidone hydrochloride is 80 mg per day [see Contraindications ( 4), Drug Interactions ( 7.1)] .

Grapefruit and grapefruit juice should be avoided in patients taking lurasidone hydrochloride, since these may inhibit CYP3A4 and alter lurasidone hydrochloride concentrations [ see Drug Interactions ( 7.1) ].

Concomitant Use with CYP3A4 Inducers

Lurasidone hydrochloride should not be used concomitantly with a strong CYP3A4 inducer (e.g., rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine, etc.) [see Contraindications ( 4); Drug Interactions ( 7.1)] . If lurasidone hydrochloride is used concomitantly with a moderate CYP3A4 inducer, it may be necessary to increase the lurasidone hydrochloride dose after chronic treatment (7 days or more) with the CYP3A4 inducer.

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. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse events in patients treated with the atypical antipsychotics.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Schizophrenia

Adults

Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 3.

In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), lurasidone hydrochloride was associated with a mean change in glucose of +1.8 mg/dL at week 24 (n=355), +0.8 mg/dL at week 36 (n=299) and +2.3 mg/dL at week 52 (n=307).

Adolescents

In studies of adolescents and adults with schizophrenia, changes in fasting glucose were similar. In the short-term, placebo-controlled study of adolescents, fasting serum glucose mean values were -1.3 mg/dL for placebo (n=95), +0.1 mg/dL for 40mg/day (n=90), and +1.8 mg/dL for 80mg/day (n=92).

Bipolar Depression

Adults

Monotherapy

Data from the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study are presented in Table 4.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride as monotherapy in the short-term study and continued in the longer-term study, had a mean change in glucose of +1.2 mg/dL at week 24 (n=129).

Adjunctive Therapy with Lithium or Valproate

Data from the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 5.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in glucose of +1.7 mg/dL at week 24 (n=88).

Pediatric Patients (10 to 17 years)

In studies of pediatric patients 10 to 17 years and adults with bipolar depression, changes in fasting glucose were similar. In the 6-week, placebo-controlled study of pediatric patients with bipolar depression, mean change in fasting glucose was +1.6 mg/dL for lurasidone hydrochloride 20 to 80 mg/day (n=145) and -0.5 mg/dL for placebo (n=145).

Pediatric Patients (6 to 17 years)

In a 104-week, open-label study in pediatric patients with schizophrenia, bipolar depression, or autistic disorder, 7 % of patients with a normal baseline fasting glucose experienced a shift to high at endpoint while taking lurasidone.

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Schizophrenia

Adults

Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 6.

In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), lurasidone hydrochloride was associated with a mean change in total cholesterol and triglycerides of -3.8 (n=356) and -15.1 (n=357) mg/dL at week 24, -3.1 (n=303) and -4.8 (n=303) mg/dL at week 36 and -2.5 (n=307) and -6.9 (n=307) mg/dL at week 52, respectively.

Adolescents

In the adolescent short-term, placebo-controlled study, fasting serum cholesterol mean values were -9.6 mg/dL for placebo (n=95), -4.4 mg/dL for 40mg/day (n=89), and +1.6 mg/dL for 80mg/day (n=92), and fasting serum triglyceride mean values were +0.1 mg/dL for placebo (n=95), -0.6 mg/dL for 40mg/day (n=89), and +8.5 mg/dL for 80mg/day (n=92).

Bipolar Depression

Adults

Monotherapy

Data from the adult short-term, flexible-dosed, placebo-controlled, monotherapy bipolar depression study are presented in Table 7.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride as monotherapy in the short-term and continued in the longer-term study had a mean change in total cholesterol and triglycerides of -0.5 mg/dL (n=130) and -1.0 mg/dL (n=130) at week 24, respectively.

Adjunctive Therapy with Lithium or Valproate

Data from the adult short-term, flexible-dosed, placebo-controlled, adjunctive therapy bipolar depression studies are presented in Table 8.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride, as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in total cholesterol and triglycerides of -0.9 (n=88) and +5.3 (n=88) mg/dL at week 24, respectively.

Pediatric Patients (10 to 17 years)

In the 6-week, placebo-controlled bipolar depression study with pediatric patients 10 to 17 years, mean change in fasting cholesterol was -6.3 mg/dL for lurasidone hydrochloride 20 to 80 mg/day (n=144) and 1.4 mg/dL for placebo (n=145), and mean change in fasting triglyceride was -7.6 mg/dL for lurasidone hydrochloride 20 to 80 mg/day (n=144) and +5.9 mg/dL for placebo (n=145).

Pediatric Patients (6 to 17 years)

In a 104-week, open-label study of pediatric patients with schizophrenia, bipolar depression, or autistic disorder, shifts in baseline fasting cholesterol from normal to high at endpoint were reported in 12% (total cholesterol), 3% (LDL cholesterol), and shifts in baseline from normal to low were reported in 27% (HDL cholesterol) of patients taking lurasidone. Of patients with normal baseline fasting triglycerides, 12% experienced shifts to high.

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Schizophrenia

Adults

Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 9. The mean weight gain was +0.43 kg for lurasidone hydrochloride-treated patients compared to -0.02 kg for placebo-treated patients. Change in weight from baseline for olanzapine was +4.15 kg and for quetiapine extended-release was +2.09 kg in Studies 3 and 5 [see Clinical Studies ( 14.1)] , respectively. The proportion of patients with a ≥ 7% increase in body weight (at Endpoint) was 4.8% for lurasidone hydrochloride-treated patients and 3.3% for placebo-treated patients.

In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), lurasidone hydrochloride was associated with a mean change in weight of -0.69 kg at week 24 (n=755), -0.59 kg at week 36 (n=443) and -0.73 kg at week 52 (n=377).

Adolescents

Data from the short-term, placebo-controlled adolescent schizophrenia study are presented in Table 10. The mean change in weight gain was +0.5 kg for lurasidone hydrochloride-treated patients compared to +0.2 kg for placebo-treated patients. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 3.3% for lurasidone hydrochloride-treated patients and 4.5% for placebo-treated patients.

Bipolar Depression

Adults

Monotherapy

Data from the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study are presented in Table 11. The mean change in weight gain was +0.29 kg for lurasidone hydrochloride-treated patients compared to -0.04 kg for placebo-treated patients. The proportion of patients with a ≥ 7% increase in body weight (at Endpoint) was 2.4% for lurasidone hydrochloride-treated patients and 0.7% for placebo-treated patients.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride as monotherapy in the short-term and continued in the longer-term study had a mean change in weight of -0.02 kg at week 24 (n=130).

Adjunctive Therapy with Lithium or Valproate

Data from the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 12. The mean change in weight gain was +0.11 kg for lurasidone hydrochloride-treated patients compared to +0.16 kg for placebo-treated patients. The proportion of patients with a ≥ 7% increase in body weight (at Endpoint) was 3.1% for lurasidone hydrochloride-treated patients and 0.3% for placebo-treated patients.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with lurasidone hydrochloride, as adjunctive therapy with either lithium or valproate in the short-term and continued in the longer-term study, had a mean change in weight of +1.28 kg at week 24 (n=86).

Pediatric Patients (10 to 17 years)

Data from the 6-week, placebo-controlled bipolar depression study in patients 10 to 17 years are presented in Table 13. The mean change in weight gain was +0.7 kg for lurasidone hydrochloride -treated patients compared to +0.5 kg for placebo-treated patients. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 4.0% for lurasidone hydrochloride -treated patients and 5.3% for placebo-treated patients.

Pediatric Patients (6 to 17 years)

In a long-term, open-label study that enrolled pediatric patients with schizophrenia, bipolar depression, or autistic disorder from three short-term, placebo-controlled trials, 54% (378/701) received lurasidone for 104 weeks. The mean increase in weight from open-label baseline to Week 104 was 5.85 kg. 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 z-score from open-label baseline to Week 104 was -0.06 SD for body weight and -0.13 SD for body mass index (BMI), indicating minimal deviation from the normal curve for weight gain.

Bipolar Depression

Adults

Monotherapy

The median change from baseline to endpoint in prolactin levels, in the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study, was +1.7 ng/mL and +3.5 ng/mL with lurasidone hydrochloride 20 to 60 mg/day and 80 to 120 mg/day, respectively compared to +0.3 ng/mL with placebo-treated patients. The median change from baseline to endpoint for males was +1.5 ng/mL and for females was +3.1 ng/mL. Median changes for prolactin by dose range are shown in Table 16.

The proportion of patients with prolactin elevations ≥ 5x upper limit of normal (ULN) was 0.4% for lurasidone hydrochloride-treated patients and 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥ 5x ULN was 0.6% for lurasidone hydrochloride-treated patients and 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥ 5x ULN was 0% and 0% for placebo-treated male patients.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with lurasidone hydrochloride as monotherapy in the short-term and continued in the longer-term study, had a median change in prolactin of -1.15 ng/mL at week 24 (n=130).

Adjunctive Therapy with Lithium or Valproate

The median change from baseline to endpoint in prolactin levels, in the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies was +2.8 ng/mL with lurasidone hydrochloride 20 to 120 mg/day compared to 0.0 ng/mL with placebo-treated patients. The median change from baseline to endpoint for males was +2.4 ng/mL and for females was +3.2 ng/mL. Median changes for prolactin across the dose range are shown in Table 17.

The proportion of patients with prolactin elevations ≥ 5x upper limit of normal (ULN) was 0.0% for lurasidone hydrochloride-treated patients and 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥ 5x ULN was 0% for lurasidone hydrochloride-treated patients and 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥ 5x ULN was 0% and 0% for placebo-treated male patients.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with lurasidone hydrochloride, as adjunctive therapy with either lithium or valproate, in the short-term and continued in the longer-term study, had a median change in prolactin of -2.9 ng/mL at week 24 (n=88).

Pediatric Patients (10 to 17 years)

In the 6-week, placebo-controlled bipolar depression study with pediatric patients 10 to 17 years, the median change from baseline to endpoint in prolactin levels for lurasidone hydrochloride-treated patients was +1.10 ng/mL and was +0.50 ng/mL for placebo-treated patients. For lurasidone hydrochloride -treated patients, the median change from baseline to endpoint for males was +0.85 ng/mL and for females was +2.50 ng/mL. Median changes for prolactin are shown in Table 18.

The proportion of patients with prolactin elevations ≥5x ULN was 0% for lurasidone hydrochloride-treated patients and 0.6% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥5x ULN was 0% for lurasidone hydrochloride-treated patients and 1.3% for placebo-treated female patients. No male patients in the placebo or lurasidone hydrochloride treatment groups had prolactin elevations ≥5x ULN.

Pediatric Patients (6 to 17 years)

In a 104-week, open-label study of pediatric patients with schizophrenia, bipolar depression, or autistic disorder, the median changes from baseline to endpoint in serum prolactin levels were -0.20 ng/mL (all patients), -0.30 ng/mL (females), and -0.05 ng/mL (males). The proportions of patients with a markedly high prolactin level (≥5 times the upper limit of normal) at any time during open-label treatment were 2% (all patients), 3% (females), and 1% (males).

Adverse events among females in this trial that are potentially prolactin-related include galactorrhea (0.6%). Among male patients in this study, decreased libido was reported in one patient (0.2%) and there were no reports of impotence, gynecomastia, or galactorrhea.

Schizophrenia

Adults

The incidence of orthostatic hypotension and syncope reported as adverse events from short-term, placebo-controlled schizophrenia studies was (lurasidone hydrochloride incidence, placebo incidence): orthostatic hypotension [0.3% (5/1508), 0.1% (1/708)] and syncope [0.1% (2/1508), 0% (0/708)].

In short-term schizophrenia clinical studies, orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0.8% with lurasidone hydrochloride 40 mg, 2.1% with lurasidone hydrochloride 80 mg, 1.7% with lurasidone hydrochloride 120 mg and 0.8% with lurasidone hydrochloride 160 mg compared to 0.7% with placebo.

Adolescents

The incidence of orthostatic hypotension reported as adverse events from the short-term, placebo-controlled adolescent schizophrenia study was 0.5% (1/214) in lurasidone hydrochloride-treated patients and 0% (0/112) in placebo-treated patients. No syncope event was reported. Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0% with lurasidone hydrochloride 40 mg and 2.9% with lurasidone hydrochloride 80 mg, compared to 1.8% with placebo.

Bipolar Depression

Adults

Monotherapy

In the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, there were no reported adverse events of orthostatic hypotension and syncope.

Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0.6% with lurasidone hydrochloride tablets 20 to 60 mg and 0.6% with lurasidone hydrochloride tablets 80 to 120 mg compared to 0% with placebo.

Adjunctive Therapy with Lithium or Valproate

In the adult short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression therapy studies, there were no reported adverse events of orthostatic hypotension and syncope. Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 1.1% with lurasidone hydrochloride tablets 20 to 120 mg compared to 0.9% with placebo.

Pediatric Patients (10 to 17 years)

In the 6-week, placebo-controlled bipolar depression study in pediatric patients 10 to 17 years, there were no reported adverse events of orthostatic hypotension or syncope.

Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 1.1% with lurasidone hydrochloride 20 to 80 mg/day, compared to 0.6% with placebo.

Bipolar Depression

Monotherapy

In the adult and pediatric 6-week, flexible-dose, placebo-controlled monotherapy bipolar depression studies, no patients experienced seizures/convulsions.

Adjunctive Therapy with Lithium or Valproate

In the adult short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies, no patient experienced seizures/convulsions.

Schizophrenia

Adults

In short-term, placebo-controlled schizophrenia studies, somnolence was reported by 17.0% (256/1508) of patients treated with lurasidone hydrochloride (15.5% lurasidone hydrochloride 20 mg, 15.6% lurasidone hydrochloride 40 mg, 15.2% lurasidone hydrochloride 80 mg, 26.5% lurasidone hydrochloride 120 mg and 8.3% lurasidone hydrochloride 160 mg/day) compared to 7.1% (50/708) of placebo patients.

Adolescents

In the short-term, placebo-controlled adolescent schizophrenia study, somnolence was reported by 14.5% (31/214) of patients treated with lurasidone hydrochloride (15.5% lurasidone hydrochloride 40 mg and 13.5% lurasidone hydrochloride 80 mg,/day) compared to 7.1% (8/112) of placebo patients.

Bipolar Depression

Adults

Monotherapy

In the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study, somnolence was reported by 7.3% (12/164) and 13.8% (23/167) with lurasidone hydrochloride tablets 20 to 60 mg and 80 to120 mg, respectively compared to 6.5% (11/168) of placebo patients.

Adjunctive Therapy with Lithium or Valproate

In the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies, somnolence was reported by 11.4% (41/360) of patients treated with lurasidone hydrochloride tablets 20 to 120 mg compared to 5.1% (17/334) of placebo patients.

Pediatric Patients (10 to 17 years)

In the 6-week, placebo-controlled bipolar depression study in pediatric patients 10 to 17 years, somnolence was reported by 11.4% (20/175) of patients treated with lurasidone hydrochloride tablets 20 to 80 mg/day compared to 5.8% (10/172) of placebo treated patients.

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: The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) in patients treated with lurasidone hydrochloride were somnolence, akathisia, extrapyramidal symptoms, and nausea.

Adverse Reactions Associated with Discontinuation of Treatment: A total of 9.5% (143/1508) lurasidone hydrochloride-treated patients and 9.3% (66/708) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with lurasidone hydrochloride that were at least 2% and at least twice the placebo rate.

Adverse Reactions Occurring at an Incidence of 2% or More in lurasidone hydrochloride -Treated Patients: Adverse reactions associated with the use of lurasidone hydrochloride (incidence of 2% or greater, rounded to the nearest percent and lurasidone hydrochloride incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with schizophrenia) are shown in Table 19.

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 22.0% for lurasidone hydrochloride 120 mg).

Bipolar Depression (Monotherapy)

The following findings are based on the adult short-term, placebo-controlled premarketing study for bipolar depression in which lurasidone hydrochloride tablets were administered at daily doses ranging from 20 to 120 mg (n=331).

Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥ 5%, in either dose group, and at least twice the rate of placebo) in patients treated with lurasidone hydrochloride were akathisia, extrapyramidal symptoms, somnolence, nausea, vomiting, diarrhea, and anxiety.

Adverse Reactions Associated with Discontinuation of Treatment: A total of 6.0% (20/331) lurasidone hydrochloride-treated patients and 5.4% (9/168) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with lurasidone hydrochloride that were at least 2% and at least twice the placebo rate.

Adverse Reactions Occurring at an Incidence of 2% or More in lurasidone hydrochloride-Treated Patients: Adverse reactions associated with the use of lurasidone hydrochloride (incidence of 2% or greater, rounded to the nearest percent and lurasidone hydrochloride incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with bipolar depression) are shown in Table 20.

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)] the adverse reactions that occurred with a greater than 5% incidence in the patients treated with lurasidone hydrochloride in any dose group and greater than placebo in both groups were nausea (10.4%, 17.4%), somnolence (7.3%, 13.8%), akathisia (7.9%, 10.8%), and extrapyramidal symptoms (4.9%, 9.0%) for lurasidone hydrochloride 20 to 60 mg/day and lurasidone hydrochloride 80 to 120 mg/day, respectively.

Bipolar Depression

Adjunctive Therapy with Lithium or Valproate

The following findings are based on two adult short-term, placebo-controlled premarketing studies for bipolar depression in which lurasidone hydrochloride tablets were administered at daily doses ranging from 20 to 120 mg as adjunctive therapy with lithium or valproate (n=360).

Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) in subjects treated with lurasidone hydrochloride were akathisia and somnolence.

Adverse Reactions Associated with Discontinuation of Treatment: A total of 5.8% (21/360) lurasidone hydrochloride-treated patients and 4.8% (16/334) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with lurasidone hydrochloride that were at least 2% and at least twice the placebo rate.

Adverse Reactions Occurring at an Incidence of 2% or More in Lurasidone Hydrochloride -Treated Patients: Adverse reactions associated with the use of lurasidone hydrochloride (incidence of 2% or greater, rounded to the nearest percent and lurasidone hydrochloride incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with bipolar depression) are shown in Table 21.

Adolescents

Schizophrenia

The following findings are based on the short-term, placebo-controlled adolescent study for schizophrenia in which lurasidone hydrochloride was administered at daily doses ranging from 40 (N=110) to 80 mg (N=104).

Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) in adolescent patients (13 to 17 years) treated with lurasidone hydrochloride were somnolence, nausea, akathisia, extrapyramidal symptoms (non-akathisia, 40mg only), vomiting, and rhinorrhea/rhinitis (80mg only).

Adverse Reactions Associated with Discontinuation of Treatment: The incidence of discontinuation due to adverse reactions between lurasidone hydrochloride-and placebo-treated adolescent patients (13 to 17 years) was 4% and 8%, respectively.

Adverse Reactions Occurring at an Incidence of 2% or More in Lurasidone Hydrochloride -Treated Patients:

Adverse reactions associated with the use of lurasidone hydrochloride (incidence of 2% or greater, rounded to the nearest percent and lurasidone hydrochloride incidence greater than placebo) that occurred during acute therapy (up to 6-weeks in adolescent patients with schizophrenia) are shown in Table 22.

Note: Figures rounded to the nearest integer
* Somnolence includes adverse event terms: hypersomnia, sedation, and somnolence
** Viral Infection includes adverse event terms: nasopharyngitis, influenza, viral infection, upper respiratory tract infection
*** Rhinitis incudes adverse event terms: rhinitis, allergic rhinitis, rhinorrhea, and nasal congestion

Pediatric Patients (10 to 17 years)

Bipolar Depression

The following findings are based on the 6-week , placebo-controlled study for bipolar depression in pediatric patients 10 to 17 years in which lurasidone hydrochloride was administered at daily doses ranging from 20 to 80 mg (N=175).

Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥5%, and at least twice the rate of placebo) in pediatric patients (10 to 17 years) treated with lurasidone hydrochloride were nausea, weight increase, and insomnia.

Adverse Reactions Associated with Discontinuation of Treatment: The incidence of discontinuation due to adverse reactions between lurasidone hydrochloride and placebo-treated pediatric patients 10 to 17 years was 2% and 2%, respectively.

Adverse Reactions Occurring at an Incidence of 2% or More in Lurasidone Hydrochloride -Treated Patients:

Adverse reactions associated with the use of lurasidone hydrochloride (incidence of 2% or greater, rounded to the nearest percent and lurasidone hydrochloride incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in pediatric patients with bipolar depression) are shown in Table 23.

Note: Figures rounded to the nearest integer
*Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence
**EPS includes adverse event terms: akathisia, cogwheel rigidity, dyskinesia, dystonia, hyperkinesia, joint stiffness, muscle rigidity, muscle spasms, musculoskeletal stiffness, oculogyric crisis, parkinsonism, tardive dyskinesia, and tremor

Extrapyramidal Symptoms

Schizophrenia

Adults

In the short-term, placebo-controlled schizophrenia studies, for lurasidone hydrochloride-treated patients, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness, was 13.5% and 5.8% for placebo-treated patients. The incidence of akathisia for lurasidone hydrochloride-treated patients was 12.9% and 3.0% for placebo-treated patients. Incidence of EPS by dose is provided in Table 24.

Adolescents

In the short-term, placebo-controlled, study of schizophrenia in adolescents, the incidence of EPS, excluding events related to akathisia, for lurasidone hydrochloride-treated patients was higher in the 40 mg (10%) and the 80 mg (7.7%) treatment groups vs. placebo (3.6%); and the incidence of akathisia-related events for lurasidone hydrochloride-treated patients was 8.9% vs. 1.8% for placebo-treated patients. Incidence of EPS by dose is provided in Table 25.

Note: Figures rounded to the nearest integer
* Dystonia includes adverse event terms: dystonia, trismus, oculogyric crisis, oromandibular dystonia, tongue spasm, and torticollis
** Parkinsonism includes adverse event terms: bradykinesia, drooling, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, parkinsonism, and psychomotor retardation

Bipolar Depression

Adults

Monotherapy

In the adult short-term, placebo-controlled monotherapy bipolar depression study, for lurasidone hydrochloride-treated patients, the incidence of reported events related to EPS, excluding akathisia and restlessness was 6.9% and 2.4% for placebo-treated patients. The incidence of akathisia for lurasidone hydrochloride-treated patients was 9.4% and 2.4% for placebo-treated patients. Incidence of EPS by dose groups is provided in Table 26.

Adjunctive Therapy with Lithium or Valproate

In the adult short-term, placebo-controlled adjunctive therapy bipolar depression studies, for lurasidone hydrochloride-treated patients, the incidence of EPS, excluding akathisia and restlessness, was 13.9% and 8.7% for placebo. The incidence of akathisia for lurasidone hydrochloride-treated patients was 10.8% and 4.8% for placebo-treated patients. Incidence of EPS is provided in Table 27.

In the short-term, placebo-controlled schizophrenia and bipolar depression studies, data was objectively collected on the Simpson Angus Rating Scale (SAS) for extrapyramidal symptoms (EPS), the Barnes Akathisia Scale (BAS) for akathisia and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesias.

Pediatric Patients (10 to 17 years)

In the 6-week, placebo-controlled study of bipolar depression in pediatric patients 10 to 17 years, the incidence of EPS, excluding events related to akathisia, for lurasidone hydrochloride treated patients was similar in the lurasidone hydrochloride 20 to 80 mg/day (3.4%) treatment group vs. placebo (3.5%); and the incidence of akathisia-related events for lurasidone hydrochloride treated patients was 2.9% vs. 3.5% for placebo-treated patients. Incidence of EPS by dose is provided in Table 28.

Note: Figures rounded to the nearest integer
* EPS include adverse event terms: akathisia, cogwheel rigidity, dyskinesia, dystonia, hyperkinesia, joint stiffness, muscle rigidity, muscle spasms, musculoskeletal stiffness, oculogyric crisis, parkinsonism, tardive dyskinesia, and tremor
** Parkinsonism includes adverse event terms: bradykinesia, drooling, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, parkinsonism, and psychomotor retardation
***Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus

Schizophrenia

Adults

The mean change from baseline for lurasidone hydrochloride-treated patients for the SAS, BAS and AIMS was comparable to placebo-treated patients, with the exception of the Barnes Akathisia Scale global score (lurasidone hydrochloride, 0.1; placebo, 0.0). The percentage of patients who shifted from normal to abnormal was greater in lurasidone hydrochloride-treated patients and placebo for the BAS (lurasidone hydrochloride, 14.4%; placebo, 7.1%), the SAS (lurasidone hydrochloride, 5.0%; placebo, 2.3%) and the AIMS (lurasidone hydrochloride, 7.4%; placebo, 5.8%).

Adolescents

The mean change from baseline for lurasidone hydrochloride-treated patients with adolescent schizophrenia for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in lurasidone hydrochloride -treated patients and placebo for the BAS (lurasidone hydrochloride, 7.0%; placebo, 1.8%), the SAS (lurasidone hydrochloride, 8.3%; placebo, 2.7%) and the AIMS (lurasidone hydrochloride, 2.8%; placebo, 0.9%).

Bipolar Depression

Adults

Monotherapy

The mean change from baseline for lurasidone hydrochloride-treated adult patients for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in lurasidone hydrochloride-treated patients and placebo for the BAS (lurasidone hydrochloride, 8.4%; placebo, 5.6%), the SAS (lurasidone hydrochloride, 3.7%; placebo, 1.9%) and the AIMS (lurasidone hydrochloride, 3.4%; placebo, 1.2%).

Adjunctive Therapy with Lithium or Valproate

The mean change from baseline for lurasidone hydrochloride-treated adult patients for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in lurasidone hydrochloride-treated patients and placebo for the BAS (lurasidone hydrochloride, 8.7%; placebo, 2.1%), the SAS (lurasidone hydrochloride, 2.8%; placebo, 2.1%) and the AIMS (lurasidone hydrochloride, 2.8%; placebo, 0.6%).

Pediatric Patients (10 to 17 years)

In the 6-week, placebo-controlled bipolar depression study in pediatric patients 10 to 17 years, dystonia occurred in 0.6% of lurasidone hydrochloride-treated patients compared to 1.2% of patients receiving placebo. No patients discontinued the clinical study due to dystonic events.

Dystonia

Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Schizophrenia

Adults

In the short-term, placebo-controlled schizophrenia clinical studies, dystonia occurred in 4.2% of lurasidone hydrochloride -treated subjects (0.0% lurasidone hydrochloride 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 – 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 (0.0% and 1.8% for lurasidone hydrochloride 20 to 60 mg/day and lurasidone hydrochloride 80 to 120 mg/day, respectively) compared to 0.0% of subjects receiving placebo. No subject discontinued the clinical study due to dystonic events.

Adjunctive Therapy with Lithium or Valproate

In the adult short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies, dystonia occurred in 1.1% of lurasidone hydrochloride-treated subjects (20 to 120 mg) compared to 0.6% of subjects receiving placebo. No subject discontinued the clinical study due to dystonic events.

Pediatric Patients (10 to 17 years)

In the 6-week, placebo-controlled bipolar depression study in pediatric patients 10 to 17 years, dystonia occurred in 0.6% of lurasidone hydrochloride-treated patients compared to 1.2% of patients receiving placebo. No patients discontinued the clinical study due to dystonic events.

Other Adverse Reactions Observed During the Premarketing Evaluation of lurasidone hydrochloride

Following is a list of adverse reactions reported by adult patients treated with lurasidone hydrochloride 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: anemia

Cardiac Disorders: Frequent: tachycardia; Infrequent: AV block 1st degree, angina pectoris, bradycardia

Ear and Labyrinth Disorders: Infrequent: vertigo

Eye Disorders: Frequent: blurred vision

Gastrointestinal Disorders: Frequent: abdominal pain, diarrhea; Infrequent: gastritis

General Disorders and Administrative Site Conditions: Rare: sudden death

Investigations: Frequent: CPK increased

Metabolism and Nutritional System Disorders: Frequent: decreased appetite

Musculoskeletal and Connective Tissue Disorders: Rare: rhabdomyolysis

Nervous System Disorders: Infrequent: cerebrovascular accident, dysarthria

Psychiatric Disorders: Infrequent: abnormal dreams, panic attack, sleep disorder

Renal and Urinary Disorders: Infrequent: dysuria; Rare: renal failure

Reproductive System and Breast Disorders: Infrequent: amenorrhea, dysmenorrhea; Rare: breast enlargement, breast pain, galactorrhea, erectile dysfunction, priapism

Skin and Subcutaneous Tissue Disorders: Frequent: rash, pruritus; Rare: angioedema

Vascular Disorders: Frequent: hypertension

Clinical Laboratory Changes

Schizophrenia

Adults

Serum Creatinine: In short-term, placebo-controlled trials, the mean change from Baseline in serum creatinine was +0.05 mg/dL for lurasidone hydrochloride-treated patients compared to +0.02 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 3.0% (43/1453) of lurasidone hydrochloride-treated patients and 1.6% (11/681) on placebo. The threshold for high creatinine value varied from > 0.79 to > 1.3 mg/dL based on the centralized laboratory definition for each study ( Table 29).

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.

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).

Adjunctive Therapy with Lithium or Valproate

Serum Creatinine: In adult short-term, placebo-controlled premarketing adjunctive studies for bipolar depression, the mean change from Baseline in serum creatinine was +0.04 mg/dL for lurasidone hydrochloride-treated patients compared to -0.01 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 4.3% (15/360) of lurasidone hydrochloride-treated patients and 1.6% (5/334) on placebo ( Table 32).

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)

Pediatric Patients (6 to 17 years)

In a 104-week, open-label study in pediatric patients with schizophrenia, bipolar depression, or autistic disorder, the mean change from baseline to Week 104 in serum creatinine was +0.07 mg/dL. In patients with a normal serum creatinine at baseline, 6% experienced a shift to high at endpoint.

Risk Summary

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery [see Clinical Considerations] . There are no studies of lurasidone hydrochloride use in pregnant women. The limited available data are not sufficient to inform a drug-associated risk of birth defects or miscarriage. In animal reproduction studies, no teratogenic effects were seen in pregnant rats and rabbits given lurasidone during the period of organogenesis at doses approximately 1.5- 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/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.

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 7.5 (11.7) ms and 4.6 (9.5) ms, for the 120 mg and 600 mg dose groups respectively, observed at 2 to 4 hours after dosing. In this study, there was no apparent dose (exposure)-response relationship.

In short-term, placebo-controlled studies in schizophrenia and bipolar depression, no post-baseline QT prolongations exceeding 500 msec were reported in patients treated with lurasidone hydrochloride or placebo.

Carcinogenesis: Lurasidone increased incidences of malignant mammary gland tumors and pituitary gland adenomas in female mice orally dosed with 30, 100, 300, or 650 mg/kg/day. The lowest dose produced plasma levels (AUC) approximately equal to those in humans receiving the MRHD of 160 mg/day. No increases in tumors were seen in male mice up to the highest dose tested, which produced plasma levels (AUC) 14 times those in humans receiving the MRHD.

Lurasidone increased the incidence of mammary gland carcinomas in female rats orally dosed at 12 and 36 mg/kg/day: the lowest dose; 3 mg/kg/day is the no-effect dose which produced plasma levels (AUC) 0.4 times those in humans receiving the MRHD. No increases in tumors were seen in male rats up to the highest dose tested, which produced plasma levels (AUC) 6 times those in humans receiving the MRHD.

Proliferative and/or neoplastic changes in the mammary and pituitary glands of rodents have been observed following chronic administration of antipsychotic drugs and are considered to be prolactin-mediated. [see Warnings and Precautions ( 5.7)] .

Mutagenesis: Lurasidone did not cause mutation or chromosomal aberration when tested in vitro and in vivo test battery. Lurasidone was negative in the Ames gene mutation test, the Chinese Hamster Lung (CHL) cells, and in the in vivo mouse bone marrow micronucleus test up to 2000 mg/kg which is 61 times the MRHD of 160 mg/day based on mg/m ² body surface area.

Impairment of Fertility: Estrus cycle irregularities were seen in rats orally administered lurasidone at 1.5, 15 and 150 mg/kg/day for 15 consecutive days prior to mating, during the mating period, and through gestation day 7. No effect was seen at the lowest dose of 0.1 mg/kg which is approximately 0.006 times the MRHD of 160 mg/day based on mg/m ². Fertility was reduced only at the highest dose, which was reversible after a 14 day drug-free period. The no-effect dose for reduced fertility was approximately equal to the MRHD based on mg/m ².

Lurasidone had no effect on fertility in male rats treated orally for 64 consecutive days prior to mating and during the mating period at doses up to 9 times the MRHD based on mg/m ².

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 primary endpoint was the change from baseline in MADRS score at Week 6. The key secondary instrument was the CGI-BP-S scale.

Lurasidone hydrochloride was superior to placebo in reduction of MADRS and CGI-BP-S scores at Week 6, as an adjunctive therapy with lithium or valproate ( Table 37).

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 CGI-BP-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.