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Lurasidone Hydrochloride Tablets 20 mg,
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NDC: 33342-419-07

Lurasidone Hydrochloride Tablets 20 mg,
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NDC: 33342-419-10

Lurasidone Hydrochloride Tablets 40 mg,
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NDC: 33342-420-07

Lurasidone Hydrochloride Tablets 40 mg,
Pack Count: 90's Container Pack
NDC: 33342-420-10

Lurasidone Hydrochloride Tablets 60 mg,
Pack Count: 30's Container Pack
NDC: 33342-421-07

Lurasidone Hydrochloride Tablets 60 mg,
Pack Count: 90's Container Pack
NDC: 33342-421-10

Lurasidone Hydrochloride Tablets 80 mg,
Pack Count: 30's Container Pack
NDC: 33342-422-07

Lurasidone Hydrochloride Tablets 80 mg,
Pack Count: 90's Container Pack
NDC: 33342-422-10

Lurasidone Hydrochloride Tablets 120 mg,
Pack Count: 30's Container Pack
NDC: 33342-423-07

Lurasidone Hydrochloride Tablets 120 mg,
Pack Count: 90's Container Pack
NDC: 33342-423-10

5 WARNINGS AND PRECAUTIONS

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 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 lurasidone hydrochloride, 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. Lurasidone hydrochloride 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 lurasidone hydrochloride. 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 lurasidone hydrochloride 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, lurasidone hydrochloride 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 lurasidone hydrochloride, drug discontinuation should be considered. However, some patients may require treatment with lurasidone hydrochloride 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. 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.

Table 3: Change in Fasting Glucose in Adult Schizophrenia Studies

Lurasidone Hydrochloride
** Placebo**	20 mg/day	40 mg/day	80 mg/day	120 mg/day	160 mg/day
Mean Change from Baseline (mg/dL)
** n=680**	n=71	n=478	n=508	n=283	n=113
Serum Glucose	-0.0	-0.6	+2.6	-0.4	+2.5	+2.5
Proportion of Patients with Shifts to ≥ 126 mg/dL
Serum Glucose (≥ 126 mg/dL)	8.3% (52/628)	11.7% (7/60)	12.7% (57/449)	6.8% (32/472)	10.0% (26/260)	5.6% (6/108)

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 40 mg/day (n=90), and +1.8 mg/dL for 80 mg/day (n=92).
Other Indication
Adults
Monotherapy
Data from the adult short-term, flexible-dose, placebo-controlled monotherapy Other indication study are presented in Table 4.

Table 4: Change in Fasting Glucose in the Adult Monotherapy Other Indication****Study

Lurasidone Hydrochloride
** Placebo**	20 to 60 mg/day	80 to 120 mg/day
Mean Change from Baseline (mg/dL)
	n=148	n=140	n=143
Serum Glucose	+1.8	-0.8	+1.8
Proportion of Patients with Shifts to ≥ 126 mg/dL
Serum Glucose (≥ 126 mg/dL)	4.3% (6/141)	2.2% (3/138)	6.4% (9/141)

Patients were randomized to flexibly dosed lurasidone hydrochloride 20 to 60 mg/day, lurasidone hydrochloride 80 to 120 mg/day, or placebo

In the uncontrolled, open-label, longer-term other indication 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 other indication studies are presented in Table 5.

Table 5: Change in Fasting Glucose in the Adult Adjunctive Therapy Other Indication Studies

Placebo	Lurasidone Hydrochloride 20 to 120 mg/day
Mean Change from Baseline (mg/dL)
	n=302	n=319
Serum Glucose	-0.9	+1.2
Proportion of Patients with Shifts to ≥ 126 mg/dL
Serum Glucose (≥ 126 mg/dL)	1.0% (3/290)	1.3% (4/316)

Patients were randomized to flexibly dosed Lurasidone hydrochloride 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate.
In the uncontrolled, open-label, longer-term other indication 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 other indication, changes in fasting glucose were similar. In the 6-week, placebo- controlled study of pediatric patients with other indication, 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, other indication, 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.

Table 6: Change in Fasting Lipids in Adult Schizophrenia Studies

	Lurasidone Hydrochloride
	Placebo	20 mg/day	40 mg/day	80 mg/day	120 mg/day	160 mg/day
Mean Change from Baseline (mg/dL)
	n=660	n=71	n=466	n=499	n=268	n=115
Total Cholesterol	-5.8	-12.3	-5.7	-6.2	-3.8	-6.9
Triglycerides	-13.4	-29.1	-5.1	-13.0	-3.1	-10.6
Proportion of Patients with Shifts
Total Cholesterol (≥ 240 mg/dL)	5.3% (30/571)	13.8% (8/58)	6.2% (25/402)	5.3% (23/434)	3.8% (9/238)	4.0% (4/101)
Triglycerides (≥ 200 mg/dL)	10.1% (53/526)	14.3% (7/49)	10.8% (41/379)	6.3% (25/400)	10.5% (22/209)	7.0% (7/100)

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).

Other Indication
Adults
Monotherapy
Data from the adult short-term, flexible-dosed, placebo-controlled, monotherapy other indication study are presented in Table 7.

Table 7: Change in Fasting Lipids in the Adult Monotherapy Other Indication Study

Placebo	Lurasidone Hydrochloride
20 to 60 mg/day	80 to 120 mg/day
Mean Change from Baseline (mg/dL)
n=147	n=140	n=144
Total cholesterol	-3.2	+1.2	-4.6
Triglycerides	+6.0	+5.6	+0.4
Proportion of Patients with Shifts
Total cholesterol (≥ 240 mg/dL)	4.2% (5/118)	4.4% (5/113)	4.4% (5/114)
Triglycerides (≥ 200 mg/dL)	4.8% (6/126)	10.1% (12/119)	9.8% (12/122)

Patients were randomized to flexibly dosed lurasidone hydrochloride 20 to 60 mg/day, lurasidone hydrochloride 80 to 120 mg/day, or placebo
In the uncontrolled, open-label, longer-term other indication 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 other indication studies are presented in Table 8.

Table 8: Change in Fasting Lipids in the Adult Adjunctive Therapy Other Indication Studies

** Placebo**	Lurasidone Hydrochloride****20 to 120 mg/day
Mean Change from Baseline (mg/dL)
n=303	n=321
Total cholesterol	-2.9	-3.1
Triglycerides	-4.6	+4.6
Proportion of Patients with Shifts
Total cholesterol (≥ 240 mg/dL)	5.7% (15/263)	5.4% (15/276)
Triglycerides (≥ 200 mg/dL)	8.6% (21/243)	10.8% (28/260)

Patients were randomized to flexibly dosed lurasidone hydrochloride 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate.
In the uncontrolled, open-label, longer-term other indication 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 other indication 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, other indication , 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.

Table 9: Mean Change in Weight (kg) from Baseline in Adult Schizophrenia Studies

	Lurasidone Hydrochloride
Placebo (n=696)	20 mg/day (n=71)	40 mg/day (n=484)	80 mg/day (n=526)	120 mg/day (n=291)	160 mg/day (n=114)
All Patients	-0.02	-0.15	+0.22	+0.54	+0.68	+0.60

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.

Table 10: Mean Change in Weight (kg) from Baseline in the Adolescent Schizophrenia Study

	Lurasidone hydrochloride
	Placebo (n=111)	40 mg/day (n=109)	80 mg/day (n=104)
All Patients	+0.2	+0.3	+0.7

Other Indication
Adults
Monotherapy
Data from the adult short-term, flexible-dosed, placebo-controlled monotherapy other indication 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.

Table 11: Mean Change in Weight (kg) from Baseline in the Adult Monotherapy Other Indication Study

		Lurasidone Hydrochloride
	Placebo (n=151)	20 to 60 mg/day (n=143)	80 to 120 mg/day (n=147)
All Patients	-0.04	+0.56	+0.02

Patients were randomized to flexibly dosed lurasidone hydrochloride 20 to 60 mg/day, lurasidone hydrochloride 80 to 120 mg/day, or placebo

In the uncontrolled, open-label, longer-term other indication 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 other indication 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.

Table 12: Mean Change in Weight (kg) from Baseline in the Adult Adjunctive Therapy Other Indication Studies

All Patients	Placebo (n=307)	Lurasidone Hydrochloride 20 to 120 mg/day (n=327)
+0.16	+0.11

Patients were randomized to flexibly dosed lurasidone hydrochloride 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate.

In the uncontrolled, open-label, longer-term other indication 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 other indication 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.

Table 13: Mean Change in Weight (kg) from Baseline in the Other Indication Study in Pediatric Patients (10 to 17 years)

Lurasidone hydrochloride
** Placebo** ** (n=170)**	20 to 80 mg/day (n=175)
All Patients	+0.5	+0.7

Pediatric Patients (6 to 17 years)
In a long-term, open-label study that enrolled pediatric patients with schizophrenia, other indication, 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.

5.7 Hyperprolactinemia

As with other drugs that antagonize dopamine D2 receptors, lurasidone hydrochloride elevates prolactin levels.
Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone density in both female and male patients [see Adverse Reactions (6)].

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in a carcinogenicity study conducted with lurasidone in rats and mice [see Nonclinical Toxicology (13)]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.
Schizophrenia
Adults
In short-term, placebo-controlled schizophrenia studies, the median change from baseline to endpoint in prolactin levels for lurasidone hydrochloride -treated patients was +0.4 ng/mL and was -1.9 ng/mL in the placebo-treated patients. The median change from baseline to endpoint for males was +0.5 ng/mL and for females was -0.2 ng/mL. Median changes for prolactin by dose are shown in Table 14.

Table 14: Median Change in Prolactin (ng/mL) from Baseline in Adult Schizophrenia Studies

		Lurasidone Hydrochloride
All Patients	Placebo -1.9 (n=672)	20 mg/day-1.1 (n=70)	40 mg/da y-1.4 (n=476)	80 mg/day-0.2 (n=495 )	120 mg/day+3.3 (n=284)	160 mg/day+3.3 (n=115)
Females	-5.1 (n=200)	-0.7 (n=19)	-4.0 (n=149)	-0.2 (n=150)	+6.7 (n=70)	+7.1 (n=36)
Males	-1.3 (n=472)	-1.2 (n=51)	-0.7 (n=327)	-0.2 (n=345)	+3.1 (n=214)	+2.4 (n=79)

The proportion of patients with prolactin elevations ≥5× upper limit of normal (ULN) was 2.8% for lurasidone hydrochloride -treated patients and = 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥5x ULN was 5.7% for lurasidone hydrochloride -treated patients and = 2.0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥5x ULN was 1.6% and 0.6% for placebo-treated male patients.

In the uncontrolled longer-term schizophrenia studies (primarily open-label extension studies), lurasidone hydrochloride was associated with a median change in prolactin of -0.9 ng/mL at week 24 (n=357), -5.3ng/mL at week 36 (n=190) and -2.2 ng/mL at week 52 (n=307).

Adolescents
In the short-term, placebo-controlled adolescent schizophrenia study, the median change from baseline to endpoint in prolactin levels for lurasidone hydrochloride -treated patients was +1.1 ng/mL and was +0.1 ng/mL for placebo- treated patients. For lurasidone hydrochloride -treated patients, the median change from baseline to endpoint for males was +1.0ng/mL and for females was +2.6 ng/mL. Median changes for prolactin by dose are shown in Table 15.

Table 15: Median Change in Prolactin (ng/mL) from Baseline in the Adolescent Schizophrenia Study

All Patients	Placebo +0.10 (n=103)	Lurasidone hydrochloride 40 mg/day +0.75 (n=102)	Lurasidone hydrochloride 80 mg/day +1.20 (n=99)
Females	+0.70 (n=39)	+0.60 (n=42)	+4.40 (n=33)
Males	0.00 (n=64)	+0.75 (n=60)	+1.00 (n=66)

The proportion of patients with prolactin elevations ≥5x ULN was 0.5% for lurasidone hydrochloride -treated patients and 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥5x ULN was 1.3% for lurasidone hydrochloride -treated patients and 0% for placebo- treated female patients. The proportion of male patients with prolactin elevations ≥5x ULN was 0% for lurasidone hydrochloride -treated patients and 1.6% for placebo-treated male patients.

Other Indication
Adults
Monotherapy
The median change from baseline to endpoint in prolactin levels, in the adult short-term, flexible-dosed, placebo-controlled monotherapy bother Indication 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 +3.1ng/mL. Median changes for prolactin by dose range are shown in Table 16.

Table 16: Median Change in Prolactin (ng/mL) from Baseline in the Adult Monotherapy Other Indication Study

Placebo	Lurasidone hydrochloride
20 to 60 mg/day	80 to 120 mg/day
All Patients	+0.3 (n=147)	+1.7 (n=140)	+3.5 (n=144)
Females	0.0 (n=82)	+1.8 (n=78)	+5.3 (n=88)
Males	+0.4 (n=65)	+1.2 (n=62)	+1.9 (n=56)

Patients were randomized to flexibly dosed lurasidone hydrochloride 20 to 60 mg/day, lurasidone hydrochloride 80 to 120 mg/day, or placebo

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 other Indication 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 other Indication studies was +2.8 ng/mL with lurasidone hydrochloride 20 to 120 mg/day compared to 0.0ng/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.

Table 17: Median Change in Prolactin (ng/mL) from Baseline in the Adult Adjunctive Therapy Other Indication Studies

All Patients	Placebo	Lurasidone Hydrochloride 20 to 120 mg/day
0.0 (n=301)	+2.8 (n=321)
Females	+0.4 (n=156)	+3.2 (n=162)
Males	-0.1 (n=145)	+2.4 (n=159)

Patients were randomized to flexibly dosed lurasidone hydrochloride 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate.

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 other Indication 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 other Indication 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.

Table 18: Median Change in Prolactin (ng/mL) from Baseline in the Other Indication Study in Pediatric Patients (10 to 17 years)

All Patients	Placebo 0.50 (n=157)	Lurasidone Hydrochloride 20 to 80 mg/day +1.10 (n=165)
Females	+0.55 (n=78)	+2.50 (n=83)
Males	+0.50 (n=79)	+0.85 (n=82)

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, other Indication , 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.

5.8 Leukopenia, Neutropenia and Agranulocytosis

Leukopenia/neutropenia has been reported during treatment with antipsychotic agents. Agranulocytosis (including fatal cases) has been reported with other agents in the class.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and lurasidone hydrochloride should be discontinued at the first sign of decline in WBC, in the absence of other causative factors.

Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1000/mm3) should discontinue lurasidone hydrochloride and have their WBC followed until recovery.

5.9 Orthostatic Hypotension and Syncope

Lurasidone hydrochloride may cause orthostatic hypotension and syncope, perhaps due to its α1-adrenergic receptor antagonism. Associated adverse reactions can include dizziness, lightheadedness, tachycardia, and bradycardia. Generally, these risks are greatest at the beginning of treatment and during dose escalation. Patients at increased risk of these adverse reactions or at increased risk of developing complications from hypotension include those with dehydration, hypovolemia, treatment with antihypertensive medication, history of cardiovascular disease (e.g., heart failure, myocardial infarction, ischemia, or conduction abnormalities), history of cerebrovascular disease, as well as patients who are antipsychotic-naïve. In such patients, consider using a lower starting dose and slower titration, and monitor orthostatic vital signs.
Orthostatic hypotension, as assessed by vital sign measurement, was defined by the following vital sign changes: ≥ 20 mm Hg decrease in systolic blood pressure and ≥10 bpm increase in pulse from sitting to standing or supine to standing position.

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.

Other Indication
Adults
Monotherapy
In the adult short-term, flexible-dose, placebo-controlled monotherapy other indication 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 20 to 60 mg and 0.6% with lurasidone hydrochloride 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 other indication 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 20 to 120 mg compared to 0.9% with placebo.

Pediatric Patients (10 to 17 years)
In the 6-week, placebo-controlled other indication 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.

5.10 Falls

Lurasidone hydrochloride may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.11 Seizures

As with other antipsychotic drugs, lurasidone hydrochloride should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold, e.g., Alzheimer’s dementia. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.

Schizophrenia
In adult short-term, placebo-controlled schizophrenia studies, seizures/convulsions occurred in 0.1% (2/1508) of patients treated with lurasidone hydrochloride compared to 0.1% (1/708) placebo-treated patients.

Other Indication
Monotherapy
In the adult and pediatric 6-week, flexible-dose, placebo-controlled monotherapy other indication studies, no patients experienced seizures/convulsions.
Adjunctive Therapy with Lithium or Valproate
In the adult short-term, flexible-dose, placebo-controlled adjunctive therapy other indication studies, no patient experienced seizures/convulsions.

5.12 Potential for Cognitive and Motor Impairment

Lurasidone hydrochloride, like other antipsychotics, has the potential to impair judgment, thinking or motor skills. Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with lurasidone hydrochloride does not affect them adversely.
In clinical studies with lurasidone hydrochloride, somnolence included: hypersomnia, hypersomnolence, sedation and somnolence.
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.

Other Indication
Adults
Monotherapy
In the adult short-term, flexible-dosed, placebo-controlled monotherapy other Indication study, somnolence was reported by 7.3% (12/164) and 13.8% (23/167) with lurasidone hydrochloride 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 other Indication studies, somnolence was reported by 11.4% (41/360) of patients treated with lurasidone hydrochloride 20-120 mg compared to 5.1% (17/334) of placebo patients.

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

5.13 Body Temperature Dysregulation

Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing lurasidone hydrochloride for patients who will be experiencing conditions that may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

5.14 Activation of Mania/Hypomania

Antidepressant treatment can increase the risk of developing a manic or hypomanic episode, particularly in patients with bipolar disorder. Monitor patients for the emergence of such episodes.

In the adult other Indication monotherapy and adjunctive therapy (with lithium or valproate) studies, less than 1% of subjects in the lurasidone hydrochloride and placebo groups developed manic or hypomanic episodes.

5.15 Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia. Lurasidone hydrochloride and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

5.16 Neurological Adverse Reactions in Patients with Parkinson's Disease or

Dementia with Lewy Bodies

Patients with Parkinson’s Disease or Dementia with Lewy Bodies are reported to have an increased sensitivity to antipsychotic medication. Manifestations of this increased sensitivity include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome.

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 with strong CYP3A4 inhibitors increased the exposure of lurasidone compared to the use of lurasidone hydrochloride alone [see Clinical Pharmacology (12.3)].
Intervention:	Lurasidone hydrochloride should not be used concomitantly with strong CYP3A4 inhibitors [see Contraindications (4)].
Examples:	Ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil
Moderate CYP3A4 Inhibitors
Clinical Impact:	Concomitant use of lurasidone hydrochloride with moderate CYP3A4 inhibitors increased the exposure of lurasidone compared to the use of lurasidone hydrochloride alone [see Clinical Pharmacology (12.3)].
Intervention:	Lurasidone hydrochloride dose should be reduced to half of the original level when used concomitantly with moderate inhibitors of CYP3A4 [see Dosage and Administration (2.6)].
Examples:	Diltiazem, atazanavir, erythromycin, fluconazole, verapamil
Strong CYP3A4 Inducers
Clinical Impact:	Concomitant use of lurasidone hydrochloride with strong CYP3A4 inducers decreased the exposure of lurasidone compared to the use of lurasidone hydrochloride alone [see Clinical Pharmacology (12.3)].
Intervention:	Lurasidone hydrochloride should not be used concomitantly with strong CYP3A4 inducers [see Contraindications (4)].
Examples:	Rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine
Moderate CYP3A4 Inducers
Clinical Impact:	Concomitant use of lurasidone hydrochloride with moderate CYP3A4 inducers decreased the exposure of lurasidone compared to the use of lurasidone hydrochloride alone [see Clinical Pharmacology (12.3)].
Intervention:	Lurasidone hydrochloride dose should be increased when used concomitantly with moderate inducers of CYP3A4 [see Dosage and Administration (2.6)].
Examples:	Bosentan, efavirenz, etravirine, modafinil, nafcillin

7.2 Drugs Having No Clinically Important Interactions with Lurasidone

Hydrochloride

Based on pharmacokinetic studies, no dosage adjustment of lurasidone hydrochloride is required when administered concomitantly with lithium, valproate, or substrates of P-gp or CYP3A4 [see Clinical Pharmacology (12.3)].

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Lurasidone hydrochloride is not a controlled substance.

9.2 Abuse

Lurasidone hydrochloride has not been systematically studied in humans for its potential for abuse or physical dependence or its ability to induce tolerance. While clinical studies with lurasidone hydrochloride did not reveal any tendency for drug-seeking behavior, these observations were not systematic and it is not possible to predict the extent to which a CNS-active drug will be misused, diverted and/or abused once it is marketed. Patients should be evaluated carefully for a history of drug abuse, and such patients should be observed carefully for signs of lurasidone hydrochloride misuse or abuse (e.g., development of tolerance, drug-seeking behavior, increases in dose).

10 OVERDOSAGE

10.1 Human Experience

In premarketing clinical studies, accidental or intentional overdosage of lurasidone hydrochloride was identified in one patient who ingested an estimated 560 mg of lurasidone hydrochloride. This patient recovered without sequelae. This patient resumed lurasidone hydrochloride treatment for an additional two months.

10.2 Management of Overdosage

No specific antidotes for lurasidone hydrochloride are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. If an overdose occurs, consult a Certified Poison Control Center (1-800-222-1222 or www.poison.org).
Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with an acute overdose of lurasidone hydrochloride. Similarly, the alpha-blocking properties of bretylium might be additive to those of lurasidone hydrochloride, resulting in problematic hypotension.
Hypotension and circulatory collapse should be treated with appropriate measures. Epinephrine and dopamine should not be used, or other sympathomimetics with beta-agonist activity, since beta stimulation may worsen hypotension in the setting of lurasidone hydrochloride-induced alpha blockade. In case of severe extrapyramidal symptoms, anticholinergic medication should be administered.
Gastric lavage (after intubation if patient is unconscious) and administration of activated charcoal together with a laxative should be considered.
The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.

11 DESCRIPTION

Lurasidone hydrochloride is an atypical antipsychotic belonging to the chemical class of benzisothiazol derivatives.
Its chemical name is (3aR, 4S, 7R, 7aS)-2-{(1R, 2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1yl-methyl] cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride. Its molecular formula is C28H36N4O2S•HCl and its molecular weight is 529.14.

The chemical structure is:

Lurasidone hydrochloride is a white to off-white powder. It is very slightly soluble in water, practically insoluble or insoluble in 0.1 N HCl, slightly soluble in ethanol, sparingly soluble in methanol, practically insoluble or insoluble in toluene and very slightly soluble in acetone.
Lurasidone hydrochloride tablets are intended for oral administration only. Each tablet contains 20 mg, 40 mg, 60 mg, 80 mg, or 120 mg of lurasidone hydrochloride.
Inactive ingredients are mannitol, pregelatinized starch, croscarmellose sodium, hypromellose, magnesium stearate. The film-coating consists of polyethylene glycol, titanium dioxide and yellow iron oxide (80 mg only).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

Carcinogenesis: Lurasidone increased incidences of malignant mammary gland tumors and pituitary gland adenomas in female mice orally dosed with 30, 100, 300, or 650 mg/kg/day. The lowest dose produced plasma levels (AUC) approximately equal to those in humans receiving the MRHD of 160 mg/day. No increases in tumors were seen in male mice up to the highest dose tested, which produced plasma levels (AUC) 14 times those in humans receiving the MRHD.
Lurasidone increased the incidence of mammary gland carcinomas in female rats orally dosed at 12 and 36 mg/kg/day: the lowest dose; 3 mg/kg/day is the no- effect dose which produced plasma levels (AUC) 0.4 times those in humans receiving the MRHD. No increases in tumors were seen in male rats up to the highest dose tested, which produced plasma levels (AUC) 6 times those in humans receiving the MRHD.
Proliferative and/or neoplastic changes in the mammary and pituitary glands of rodents have been observed following chronic administration of antipsychotic drugs and are considered to be prolactin-mediated [see Warnings and Precautions (5.7)].
Mutagenesis: Lurasidone did not cause mutation or chromosomal aberration when tested in vitro and in vivotest 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/m2 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/m2. 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/m2 .
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/m2.

16 HOW SUPPLIED/STORAGE AND HANDLING

Lurasidone hydrochloride tablets are white to off-white, round (20 mg or 40 mg), white to off-white, capsule (60 mg), light yellow, oval (80 mg) or white to off-white, oval (120 mg) and identified with strength-specific one-sided debossing, “F3” (20 mg), “F4” (40 mg), “F5” (60 mg), “F6” (80 mg) or “F7” (120 mg). Tablets are supplied in the following strengths and package configurations (Table 39).

Table 39: Package Configuration for Lurasidone Hydrochloride Tablets

Tablet Strength	Package Configuration	NDC Code
20 mg	Bottle of 30	33342-419-07
Bottle of 90	33342-419-10
40 mg	Bottles of 30	33342-420-07
Bottles of 90	33342-420-10
60 mg	Bottles of 30	33342-421-07
Bottles of 90	33342-421-10
80 mg	Bottles of 30	33342-422-07
Bottles of 90	33342-422-10
120 mg	Bottles of 30	33342-423-07
Bottles of 90	33342-423-10

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].