Lurasidone Hydrochloride

Lurasidone hydrochloride tablets are indicated for:

• Monotherapy treatment of adult and pediatric patients (10 to 17 years) with major depressive episode associated with bipolar I disorder (bipolar depression)

• Adjunctive treatment with lithium or valproate in adult patients with major depressive episode associated with bipolar I disorder (bipolar depression)

Lurasidone hydrochloride tablets are available in the following shape and color (Table 1) with respective two-sided debossing.

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Increased Mortality in Elderly Patients with Dementia-Related Psychosis
  [see Boxed Warning and Warnings and Precautions (

  5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

  Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6- to 1.7-times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Lurasidone hydrochloride tablets are not approved for the treatment of patients with dementia-related psychosis

  [see Boxed Warning, Warnings and Precautions ].

  )]
• Suicidal Thoughts and Behaviors
  [see Boxed Warning and Warnings and Precautions (

  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 1,000 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 1,000 Patients Treated
  	Increases Compared to Placebo
  <18	14 additional patients
  18 to 24	5 additional patients
  	Decreases Compared to Placebo
  25 to 64	1 fewer patient
  ≥65	6 fewer patients

  It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with MDD that antidepressants delay the recurrence of depression.

  Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing lurasidone hydrochloride tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

  )]
• Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-related Psychosis
  [see Warnings and Precautions (

  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 tablets are not approved for the treatment of patients with dementia-related psychosis

  [see Boxed Warning, Warnings and Precautions ].

  )]
• Neuroleptic Malignant Syndrome
  [see Warnings and Precautions (

  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 tablets and provide intensive symptomatic treatment and monitoring.

  )]
• Tardive Dyskinesia
  [see Warnings and Precautions (

  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 tablets 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 tablets, drug discontinuation should be considered. However, some patients may require treatment with lurasidone hydrochloride tablets despite the presence of the syndrome.

  )]
• Metabolic Changes
  [see Warnings and Precautions (

  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.

  Bipolar Depression

  
  
  

  Adults

  
  
  

  Monotherapy

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

  Table 4: Change in Fasting Glucose in the Adult Monotherapy Bipolar Depression 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 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.

  Table 5: Change in Fasting Glucose in the Adult Adjunctive Therapy Bipolar Depression 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	1.0%	1.3%
  ( 126 mg/dL)	(3/290)	(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 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 bipolar depression, autistic disorder or another 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.

  Bipolar Depression

  Adults

  Monotherapy

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

  Table 7: Change in Fasting Lipids in the Adult Monotherapy Bipolar Depression 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 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 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.

  Table 8: Change in Fasting Lipids in the Adult Adjunctive Therapy Bipolar Depression 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 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 in pediatric patients with bipolar depression, autistic disorder or another 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.

  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.

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

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

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

  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.

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

  	Placebo (n=307)	Lurasidone Hydrochloride 20 to 120 mg/day (n=327)
  All Patients	+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 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% for lurasidone hydrochloride-treated patients and 5.3% for placebo-treated patients.

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

  	Placebo (n=170)	Lurasidone Hydrochloride 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 bipolar depression, autistic disorder or another 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.

  )]
• Hyperprolactinemia
  [see Warnings and Precautions (

  5.7  Hyperprolactinemia

  As with other drugs that antagonize dopamine D₂receptors, 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 ]

  .

  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 ]

  . Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer.

  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.

  Table 16: Median Change in Prolactin (ng/mL) from Baseline in the Adult Monotherapy Bipolar Depression 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% 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 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.

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

  	Placebo	Lurasidone Hydrochloride 20 to 120 mg/day
  All Patients	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% for lurasidone hydrochloride-treated patients and 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).

  )]
• Leukopenia, Neutropenia, and Agranulocytosis
  [see Warnings and Precautions (

  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 tablets 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 <1,000/mm

  ³

  ) should discontinue lurasidone hydrochloride tablets and have their WBC followed until recovery.

  )]
• Orthostatic Hypotension and Syncope
  [see Warnings and Precautions (

  5.9 Orthostatic Hypotension and Syncope

  Lurasidone hydrochloride tablets 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.

  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 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 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 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.

  )]
• Falls
  [see Warnings and Precautions (

  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.

  )]
• Seizures
  [see Warnings and Precautions (

  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.

  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.

  )]
• Potential for Cognitive and Motor Impairment
  [see Warnings and Precautions (

  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 tablets does not affect them adversely.

  In clinical studies with lurasidone hydrochloride, somnolence included: hypersomnia, hypersomnolence, sedation and somnolence.

  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 20 to 60 mg and 80 to 120 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 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 20 to 80 mg/day compared to 5.8% (10/172) of placebo treated patients.

  )]
• Body Temperature Dysregulation
  [see Warnings and Precautions (

  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 tablets 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.

  )]
• Activation of Mania/Hypomania
  [see Warnings and Precautions (

  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 bipolar depression 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.

  )]
• Dysphagia
  [see Warnings and Precautions (

  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 tablets and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

  )]
• Neurological Adverse Reactions in Patients with Parkinson's Disease or Dementia with Lewy Bodies
  [see Warnings and Precautions (

  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.

  )]

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-1-ylmethyl] 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 tablets are intended for oral administration only. Each tablet contains 60 mg of lurasidone hydrochloride.

Inactive ingredients are croscarmellose sodium, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, pregelatinized starch, polyethylene glycol and titanium dioxide.

Lurasidone hydrochloride tablets are available in the following strength and package configuration.

60 mg tablets are white to off white, capsule shaped, film-coated tablets debossed with “353” on one side, “60” on other side and free from physical defects, and are supplied in bottles of 30.

Bottles of 30                    NDC 13668-509-30

Store lurasidone hydrochloride tablets at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature].