Latuda

Bushu Pharmaceutical, LTD.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use LATUDA safely and effectively. See full prescribing information for LATUDA.LATUDA (LURASIDONE HCL) tablets for oral administration, Initial U.S. Approval: 2010 BOXED WARNING WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. LATUDA is not approved for the treatment of patients with dementia-related psychosis. (5.1) INDICATIONS AND USAGELATUDA is an atypical antipsychotic agent indicated for the treatment of patients with schizophrenia ( 1 ). Efficacy was established in four 6-week controlled studies of adult patients with schizophrenia ( 14.1 ). DOSAGE AND ADMINISTRATIONThe recommended starting dose of LATUDA is 40 mg once daily. Initial dose titration is not required. The maximum recommended dose is 80 mg once daily. LATUDA should be taken with food ( 2.2 ). DOSAGE FORMS AND STRENGTHSTablets: 40 mg and 80 mg ( 3 ) CONTRAINDICATIONSAny known hypersensitivity to LATUDA or any components in the formulation ( 4 ). Coadministration with a strong CYP3A4 inhibitor (e.g., ketoconazole) and inducer (e.g.,rifampin) ( 4 ). WARNINGS AND PRECAUTIONS Cerebrovascular Adverse Reactions: An increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) has been seen in elderly patients with dementia-related psychoses treated with atypical antipsychotic drugs. ( 5.2 ). Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring ( 5.3 ). Tardive Dyskinesia: Discontinue if clinically appropriate ( 5.4 ). Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain ( 5.5 ). Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes. Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics. Weight Gain: Gain in body weight has been observed, clinical monitoring of weight is recommended. Hyperprolactinemia: Prolactin elevations may occur ( 5.6 ). Leukopenia, Neutropenia, and Agranulocytosis have been reported with antipsychotics. Patients with a pre-existing low white blood cell count (WBC) or a history of leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and LATUDA should be discontinued at the first sign of a decline in WBC in the absence of other causative factors ( 5.7 ). Orthostatic Hypotension and Syncope: Dizziness, tachycardia or bradycardia, and syncope may occur, especially early in treatment. Use with caution in patients with known cardiovascular or cerebrovascular disease, and in antipsychotic-naïve patients ( 5.8 ). Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold ( 5.9 ). Potential for Cognitive and Motor Impairment: Use caution when operating machinery ( 5.10 ). Suicide: The possibility of a suicide attempt is inherent in schizophrenia. Closely supervise high-risk patients ( 5.12 ). See Full Prescribing Information for additional WARNINGS and PRECAUTIONS Side EffectsCommonly observed adverse reactions (incidence ≥5% and at least twice the rate for placebo) included somnolence, akathisia, nausea, parkinsonism and agitation ( 6.2 ). To report SUSPECTED ADVERSE REACTIONS, contact Sunovion Pharmaceuticals Inc. at 877-737-7226 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . DRUG INTERACTIONS LATUDA is not recommended to be used in combination with strong CYP3A4 inhibitors, e.g., ketoconazole. ( 4 and 7.1 ) Dose adjustment is recommended for moderate CYP3A4 inhibitors (e.g. diltiazem) ( 7.1 ) LATUDA is not recommended to be used in combination with strong CYP3A4 inducers, e.g., rifampin. ( 4 and 7.1 ) USE IN SPECIFIC POPULATIONS Geriatric Use: No dose adjustments required. ( 8.5 ) Pregnancy: Use LATUDA during pregnancy only if the potential benefit justifies the potential risk. ( 8.1 ) Nursing Mothers: Breast feeding is not recommended. ( 8.3 ) Pediatric Use: Safety and effectiveness have not been established. ( 8.4 ) Renal Impairment: Dose adjustment is recommended. ( 8.6 ) Hepatic Impairment: Dose adjustment is recommended. ( 8.7 )

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
• 1. LATUDA INDICATIONS AND USAGE
• 2. LATUDA DOSAGE AND ADMINISTRATION
  • 2.1. Schizophrenia
  • 2.2. Administration Instructions
  • 2.3. Dosage in Special Populations
• 3. DOSAGE FORMS AND STRENGTHS
• 4. LATUDA CONTRAINDICATIONS
• 5. WARNINGS AND PRECAUTIONS
  • 5.1. Increased Mortality in Elderly Patients with Dementia-Related Psychosis
  • 5.2. Cerebrovascular Adverse Reactions, Including Stroke
  • 5.3. Neuroleptic Malignant Syndrome
  • 5.4. Tardive Dyskinesia
  • 5.5. Metabolic Changes
  • 5.6. Hyperprolactinemia
  • 5.7. Leukopenia, Neutropenia and Agranulocytosis
  • 5.8. Orthostatic Hypotension and Syncope
  • 5.9. Seizures
  • 5.10. Potential for Cognitive and Motor Impairment
  • 5.11. Body Temperature Regulation
  • 5.12. Suicide
  • 5.13. Dysphagia
  • 5.14. Use in Patients with Concomitant Illness
• 6. LATUDA ADVERSE REACTIONS
  • 6.1. Overall Adverse Reaction Profile
  • 6.2. Clinical Studies Experience
  • 6.3. Dose-Related Adverse Reactions
  • 6.4. Extrapyramidal Symptoms
  • 6.5. Laboratory Test Abnormalities and ECG Changes in Clinical Studies
  • 6.6. Other Adverse Reactions Observed During the Premarketing Evaluation of LATUDA
• 7. DRUG INTERACTIONS
  • 7.1. Potential for Other Drugs to Affect LATUDA
  • 7.2. Potential for LATUDA to Affect Other Drugs
• 8. USE IN SPECIFIC POPULATIONS
  • 8.1. Pregnancy
  • 8.2. Labor and Delivery
  • 8.3. Nursing Mothers
  • 8.4. Pediatric Use
  • 8.5. Geriatric Use
  • 8.6. Renal Impairment
  • 8.7. Hepatic Impairment
  • 8.8. Gender
  • 8.9. Race
  • 8.10. Smoking Status
• 9. DRUG ABUSE AND DEPENDENCE
  • 9.1. Controlled substance
  • 9.2. Abuse
• 10. OVERDOSAGE
  • 10.1. Human Experience
  • 10.2. Management of Overdosage
• 11. LATUDA DESCRIPTION
• 12. CLINICAL PHARMACOLOGY
  • 12.1. Mechanism of Action
  • 12.2. Pharmacodynamics
  • 12.3. Pharmacokinetics
• 13. NONCLINICAL TOXICOLOGY
• 14. CLINICAL STUDIES
  • 14.1. Schizophrenia
• 16. HOW SUPPLIED/STORAGE AND HANDLING
• 17. PATIENT COUNSELING INFORMATION
  • 17.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis
  • 17.2 Neuroleptic Malignant Syndrome
  • 17.3 Hyperglycemia and Diabetes Mellitus
  • 17.4 Orthostatic Hypotension
  • 17.5 Leukopenia/Neutropenia
  • 17.6 Interference with Cognitive and Motor Performance
  • 17.7 Pregnancy and Nursing
  • 17.8 Concomitant Medication and Alcohol
  • 17.9 Heat Exposure and Dehydration

FULL PRESCRIBING INFORMATION

1. INDICATIONS AND USAGE

LATUDA is indicated for the treatment of patients with schizophrenia.

The efficacy of LATUDA in schizophrenia was established in four 6-week controlled studies of adult patients with schizophrenia [see Clinical Studies ( 14.1 )].

The effectiveness of LATUDA for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. Therefore, the physician who elects to use LATUDA for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration ( 2 )].

2. DOSAGE AND ADMINISTRATION

2.1. Schizophrenia

The recommended starting dose of LATUDA is 40 mg once daily. Initial dose titration is not required. LATUDA has been shown to be effective in a dose range of 40 mg/day to 120 mg/day [see Clinical Studies ( 14.1 )]. In the 6-week controlled trials, there was no suggestion of added benefit with the 120 mg/day dose, but there was a dose-related increase in certain adverse reactions. Therefore, the maximum recommended dose is 80 mg/day.

2.2. Administration Instructions

LATUDA should be taken with food (at least 350 calories) [see Clinical Pharmacology ( 12 )].

2.3. Dosage in Special Populations

Dosage adjustments are not recommended on the basis of age, gender, and race [see Use in Specific Populations ( 8 )].

Dose adjustment is recommended in moderate and severe renal impairment patients. The dose in these patients should not exceed 40 mg/day [see Use in Specific Populations ( 8 )].

Dose adjustment is recommended in moderate and severe hepatic impairment patients. The dose in these patients should not exceed 40 mg/day [see Use in Specific Populations ( 8 )].

Dosing recommendation for patients taking LATUDA concomitantly with potential CYP3A4 inhibitors: When coadministration of LATUDA with a moderate CYP3A4 inhibitor such as diltiazem is considered, the dose should not exceed 40 mg/day. LATUDA should not be used in combination with a strong CYP3A4 inhibitor (e.g., ketoconazole) [see Contraindications ( 4 ); Drug Interactions ( 7.1 )].

Dosing recommendation for patients taking LATUDA concomitantly with potential CYP3A4 inducers: LATUDA should not be used in combination with a strong CYP3A4 inducer (e.g., rifampin) [see Contraindications ( 4 ); Drug Interactions ( 7.1 )].

3. DOSAGE FORMS AND STRENGTHS

LATUDA tablets are available in the following shape and color (Table 1) with respective one-sided debossing: 40 mg (white to off-white, round, “L40”), or 80 mg (pale green, oval, “L80”).

4. CONTRAINDICATIONS

LATUDA is contraindicated in any patient with a known hypersensitivity to lurasidone HCl or any components in the formulation. Angioedema has been observed with lurasidone [see Adverse Reactions ( 6.6 )].

LATUDA is contraindicated with strong CYP3A4 inhibitors (e.g., ketoconazole) and strong CYP3A4 inducers (e.g., rifampin) [see Drug Interactions (7.1)].

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. LATUDA is not approved for the treatment of dementia-related psychosis [see Boxed Warning ].

5.2. Cerebrovascular Side Effects, Including Stroke

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

5.3. Neuroleptic Malignant Syndrome

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including LATUDA.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. It is important to exclude cases where the clinical presentation includes both serious medical illness (e.g. pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. If reintroduced, the patient should be carefully monitored, since recurrences of NMS have been reported.

5.4. 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.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, LATUDA should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on LATUDA, drug discontinuation should be considered. However, some patients may require treatment with LATUDA despite the presence of the syndrome.

5.5. 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 treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Because LATUDA was not marketed at the time these studies were performed, it is not known if LATUDA is associated with this increased risk.

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.

Pooled data from short-term, placebo-controlled studies are presented in Table 2.

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Pooled data from short-term, placebo-controlled studies are presented in Table 3.

In the uncontrolled, longer-term studies (primarily open-label extension studies), LATUDA was associated with a mean change in total cholesterol and triglycerides of -4.2 (n=186) and -13.6 (n=187) mg/dL at week 24, -1.9 (n = 238) and -3.5 (n = 238) mg/dL at week 36 and -3.6 (n=243) and -6.5 (n=243) mg/dL at week 52, respectively.

Weight Gain

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

Pooled data from short-term, placebo-controlled studies are presented in Table 4. The mean weight gain was 0.75 kg for LATUDA-treated patients compared to 0.26 kg for placebo-treated patients. In study 3 [see Clinical Studies (14.1)] change in weight from baseline for olanzapine was 4.15 kg. The proportion of patients with a ≥ 7% increase in body weight (at Endpoint) was 5.6% for LATUDA-treated patients versus 4.0% for placebo-treated patients.

In the uncontrolled, longer-term studies (primarily open-label extension studies), LATUDA was associated with a mean change in weight of -0.38 kg at week 24 (n = 531), -0.47 kg at week 36 (n = 303) and -0.71 kg at week 52 (n = 244).

5.6. Hyperprolactinemia

As with other drugs that antagonize dopamine D₂ receptors, LATUDA 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 )].

In short-term placebo-controlled studies, the median change from baseline to endpoint in prolactin levels for LATUDA-treated patients was 1.1 ng/mL and was - 0.6 ng/mL in the placebo-treated patients. The increase in prolactin was greater in female patients; the median change from baseline to endpoint for females was 1.5 ng/mL and was 1.1 ng/mL in males. The increase in prolactin concentrations was dose-dependent (Table 5).

The proportion of patients with prolactin elevations ≥ 5× ULN was 3.6% for LATUDA-treated patients versus 0.7% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥ 5x ULN was 8.3% for LATUDA-treated patients versus 1% for placebo-treated female patients. The proportion of male patients with prolactin elevations > 5x ULN was 1.9% versus 0.6% for placebo-treated male patients.

In the uncontrolled longer-term studies (primarily open-label extension studies), LATUDA was associated with a median change in prolactin of -1.9 ng/mL at week 24 (n = 188), -5.4 ng/mL at week 36 (n=189) and -3.3 ng/mL at week 52 (n = 243).

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 LATUDA carcinogenicity study conducted 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.

5.7. 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 LATUDA 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 LATUDA and have their WBC followed until recovery.

5.8. Orthostatic Hypotension and Syncope

LATUDA may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism. The incidence of orthostatic hypotension and syncope events from short-term, placebo-controlled studies was (LATUDA incidence, placebo incidence): orthostatic hypotension [0.4% (4/1004), 0.2 % (1/455)] and syncope [< 0.1% (1/1004), 0%]. Assessment of orthostatic hypotension defined by 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 positions). In short-term clinical trials orthostatic hypotension occurred with a frequency of 0.8% with LATUDA 40 mg, 1.4% with LATUDA 80 mg and 1.7% with LATUDA 120 mg compared to 0.9% with placebo.

LATUDA should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction, ischemia, or conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.

5.9. Seizures

As with other antipsychotic drugs, LATUDA 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.

In short-term placebo-controlled trials, seizures/convulsions occurred in < 0.1% (1/1004) of patients treated with LATUDA compared to 0.2% (1/455) placebo-treated patients.

5.10. Potential for Cognitive and Motor Impairment

LATUDA, like other antipsychotics, has the potential to impair judgment, thinking or motor skills.

In short-term, placebo-controlled trials, somnolence was reported in 22.3% (224/1004) of patients treated with LATUDA compared to 9.9% (45/455) of placebo patients, respectively. The frequency of somnolence increases with dose; somnolence was reported in 26.5% (77/291) of patients receiving LATUDA 120 mg/day. In these short-term trials, somnolence included: hypersomnia, hypersomnolence, sedation and somnolence.

Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with LATUDA does not affect them adversely.

5.11. Body Temperature Regulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing LATUDA 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 [see Patient Counseling Information ( 17.9 )].

5.12. Suicide

The possibility of a suicide attempt is inherent in psychotic illness and close supervision of high-risk patients should accompany drug therapy. Prescriptions for LATUDA should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.

In short-term, placebo-controlled studies in patients with schizophrenia, the incidence of treatment-emergent suicidal ideation was 0.6% (6/1004) for LATUDA treated patients compared to 0.4% (2/455) on placebo. No suicide attempts or completed suicides were reported in these studies.

5.13. 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. LATUDA is not indicated for the treatment of dementia-related psychosis, and should not be used in patients at risk for aspiration pneumonia.

5.14. Use in Patients with Concomitant Illness

Clinical experience with LATUDA in patients with certain concomitant systemic illnesses is limited [see Use in Specific Populations ( 8.6 , 8.7 )]. LATUDA has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical studies [see Warnings and Precautions ( 5.1 , 5.8)].

6. ADVERSE REACTIONS

6.1. Overall Adverse Reaction Profile

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

• Use in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions ( 5.1 )]
• Cerebrovascular Adverse Reactions, Including Stroke [see Warnings and Precautions (5.2)]
• Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.3)]
• Tardive Dyskinesia [see Warnings and Precautions (5.4)]
• Hyperglycemia and Diabetes Mellitus [see Warnings and Precautions (5.5)]
• Hyperprolactinemia [see Warnings and Precautions (5.6)]
• Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.7 )]
• Orthostatic Hypotension and Syncope [see Warnings and Precautions (5.8)]
• Seizures [see Warnings and Precautions (5.9)]
• Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.10)]
• Body Temperature Regulation [see Warnings and Precautions (5.11)]
• Suicide [see Warnings and Precautions (5.12)]
• Dysphagia [see Warnings and Precautions (5.13)]
• Use in Patients with Concomitant Illness [see Warnings and Precautions (5.14)]

The information below is derived from a clinical study database for LATUDA consisting of over 2096 patients with schizophrenia exposed to one or more doses with a total experience of 624 patient-years. Of these patients, 1004 participated in short-term placebo-controlled schizophrenia studies with doses of 20 mg, 40 mg, 80 mg or 120 mg once daily. A total of 533 LATUDA-treated patients had at least 24 weeks and 238 LATUDA-treated patients had at least 52 weeks of exposure.

Adverse events during exposure to study treatment were obtained by general inquiry and voluntarily reported adverse experiences, as well as results from physical examinations, vital signs, ECGs, weights and laboratory investigations. Adverse experiences were recorded by clinical investigators using their own terminology. In order to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced at least once, a treatment-emergent adverse event of the type listed. Treatment-emergent adverse events were defined as adverse experiences, which started or worsened on or after the date of the first dose through seven days after study medication discontinuation. There was no attempt to use investigator causality assessments; i.e., all events meeting the defined criteria, regardless of investigator causality are included. It is important to emphasize that, although the reactions occurred during treatment with LATUDA, they were not necessarily caused by it. The label should be read in its entirety to gain an understanding of the safety profile of LATUDA.

The figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatment, uses and investigators. The cited figures, however, do provide the prescriber with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reaction incidence in the population studied.

6.2. Clinical Studies Experience

The following findings are based on the short-term placebo-controlled premarketing studies for schizophrenia in which LATUDA was administered at daily doses ranging from 20 to 120 mg (n = 1004).

Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) in patients treated with LATUDA were somnolence, akathisia, nausea, parkinsonism and agitation.

Adverse Reactions Associated with Discontinuation of Treatment: A total of 9.4% (94/1004) LATUDA-treated patients and 5.9% (27/455) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with LATUDA that were at least 2% and at least twice the placebo rate.

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

6.3. Dose-Related Side Effects

Based on the pooled data from the placebo-controlled, short-term, fixed-dose studies, among the adverse reactions that occurred with a greater than 5% incidence in the patients treated with LATUDA, the apparent dose-related adverse reactions were akathisia and somnolence (Table 7).

6.4. Extrapyramidal Symptoms

In the short-term, placebo-controlled schizophrenia studies, for LATUDA-treated patients, the incidence of reported EPS-related events, excluding akathisia and restlessness, was 14.7% versus 5.1% for placebo-treated patients; and the incidence of akathisia for LATUDA-treated patients was 15.0% versus 3.3% for placebo-treated patients. Akathisia appeared to be dose-related and the greatest frequency of parkinsonism and dystonia occurred with the highest dose of LATUDA, 120 mg/day (Table 8).

In the short-term, placebo-controlled schizophrenia studies, data was objectively collected on the Simpson Angus Rating Scale for extrapyramidal symptoms (EPS), the Barnes Akathisia Scale (for akathisia) and the Abnormal Involuntary Movement Scale (for dyskinesias). The mean change from baseline for LATUDA-treated patients was comparable to placebo-treated patients, with the exception of the Barnes Akathisia Scale global score (LATUDA, 0.2; placebo, 0.0). The percentage of patients who shifted from normal to abnormal was greater in LATUDA-treated patients versus placebo for the BAS (LATUDA, 16.0%; placebo, 7.6%) and the SAS (LATUDA, 5.3%; placebo, 2.5%).

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.

In the short-term, placebo-controlled clinical trials, dystonia occurred in 4.7% of LATUDA-treated subjects (0.0% LATUDA 20 mg, 4.2% LATUDA 40 mg, 4.6% LATUDA 80 mg and 6.5% LATUDA 120 mg) compared to 0.7% of subjects receiving placebo. Seven subjects (0.7%, 7/1004) discontinued clinical trials due to dystonic events – 4 were receiving LATUDA 80 mg/day and 3 were receiving LATUDA 120 mg/day.

6.5. Laboratory Test Abnormalities and ECG Changes in Clinical Studies

Laboratory Test Abnormalities

In a between-group comparison of the pooled data from short-term, placebo-controlled studies, there were no clinically important changes in total cholesterol measurements; triglycerides or glucose from Baseline to Endpoint [see Warnings and Precautions ( 5.5 )]. There were also no clinically important differences between LATUDA and placebo in mean change from baseline to endpoint in routine hematology, urinalysis, or serum chemistry. LATUDA was associated with a dose-related increase in prolactin concentration [see Warnings and Precautions ( 5.6 )]

Creatinine: In short-term, placebo-controlled trials, the mean change from Baseline in creatinine was 0.06 mg/dL for LATUDA-treated patients compared to 0.03 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 3.1% (30/977) of LATUDA-treated patients and 1.4% (6/439) on placebo. The threshold for high creatinine value varied from ≥ 1.1 to ≥ 1.3 mg/dL based on the centralized laboratory definition for each study [see Dosage in Special Population ( 2.3 ); Use in Specific Populations ( 8 )].

Transaminases: The mean changes in AST and ALT for LATUDA- and placebo-treated patients were similar. The proportion of patients with transaminases (AST and ALT) elevations ≥ 3 times ULN was similar for all LATUDA-treated patients (0.8% and 0.8%, respectively) to placebo-treated patients (0.9% and 1.1%, respectively).

ECG Changes

Electrocardiogram (ECG) measurements were taken at various time points during the LATUDA clinical trial program. No post-baseline QT prolongations exceeding 500 msec were reported in patients treated with LATUDA. Within a subset of patients defined as having an increased cardiac risk, no potentially important changes in ECG parameters were observed. No cases of torsade de pointes or other severe cardiac arrhythmias were observed in the pre-marketing clinical program.

The effects of LATUDA on the QT/QTc interval were evaluated in a dedicated QT study involving 87 clinically stable patients with schizophrenia or schizoaffective disorder, who were treated with LATUDA doses of 120 mg daily, 600 mg daily, or ziprasidone 160 mg daily. Holter monitor-derived electrocardiographic assessments were obtained over an eight hour period at baseline and steady state. No patients treated with LATUDA experienced QTc increases > 60 msec from baseline, nor did any patient experience a QTc of > 500 msec.

6.6. Other Side Effects Observed During the Premarketing Evaluation of LATUDA

Following is a list of MedDRA terms that reflect adverse reactions reported by patients treated with LATUDA at multiple doses of ≥ 20 mg once daily during any phase of a study within the database of 2096 patients. 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 6 are not included. Although the reactions reported occurred during treatment with LATUDA, they were not necessarily caused by it.

Reactions are further categorized by MedDRA system 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; Rare: leukopenia, neutropenia

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, dysphagia

General Disorders and Administrative Site Conditions : Rare : Sudden death

Investigations: Frequent: CPK increased

Metabolic and Nutritional System Disorders: Frequent: decreased appetite

Musculoskeletal and Connective Tissue Disorders: Rare: rhabdomyolysis

Nervous System Disorders: Infrequent : tardive dyskinesia, cerebrovascular accident, dysarthria, syncope; Rare: neuroleptic malignant syndrome, seizure

Psychiatric Disorders: Infrequent: abnormal dreams, panic attack, sleep disorder; Rare: suicidal behavior

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

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

Vascular Disorders: Infrequent: hypertension, orthostatic hypotension

7. DRUG INTERACTIONS

Given the primary CNS effects of LATUDA, caution should be used when it is taken in combination with other centrally acting drugs and alcohol.

7.1. Potential for Other Drugs to Affect LATUDA

LATUDA is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP4A11, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 enzymes. This suggests that an interaction of LATUDA with drugs that are inhibitors or inducers of these enzymes is unlikely.

LATUDA is predominantly metabolized by CYP3A4; interaction of LATUDA with strong and moderate inhibitors or inducers of this enzyme has been observed (Table 9). LATUDA should not be used in combination with strong inhibitors or inducers of this enzyme [see Contraindications ( 4 )].

7.2. Potential for LATUDA to Affect Other Drugs

Digoxin (P-gp substrate): Coadministration of LATUDA (120 mg/day) at steady state with a single dose of digoxin (0.25 mg) increased C_max and AUC_(0-24) for digoxin by approximately 9% and 13%, respectively relative to digoxin alone. Digoxin dose adjustment is not required when coadministered with LATUDA.

Midazolam (CYP3A4 substrate): Coadministration of LATUDA (120 mg/day) at steady state with a single dose of 5 mg midazolam increased midazolam Cmax and AUC_(0-24) by approximately 21% and 44%, respectively relative to midazolam alone. Midazolam dose adjustment is not required when coadministered with LATUDA.

Oral Contraceptive (estrogen/progesterone): Coadministration of LATUDA (40 mg/day) at steady state with an oral contraceptive (OC) containing ethinyl estradiol and norelgestimate resulted in equivalent AUC_(0-24) and C_max of ethinyl estradiol and norelgestromin relative to OC administration alone. Also, sex hormone binding globulin levels were not meaningfully affected by coadministration of LATUDA and OC. Dose adjustment of OC dose is not required when coadministered with LATUDA.

8. USE IN SPECIFIC POPULATIONS

8.1. Pregnancy

Teratogenic Effects

Pregnancy Category B

Lurasidone was not teratogenic in rats and rabbits. There are no adequate and well-controlled studies of LATUDA in pregnant women.

No teratogenic effects were seen in studies in which pregnant rats and rabbits were given lurasidone during the period of organogenesis at doses up to 25 and 50 mg/kg/day, respectively. These doses are 3 and 12 times, in rats and rabbits respectively, the maximum recommended human dose (MRHD) of 80 mg/day based on body surface area.

No adverse developmental effects were seen in a study in which pregnant rats were given lurasidone during the period of organogenesis and continuing through weaning at doses up to 10 mg/kg/day; this dose is approximately equal to the MRHD based on body surface area.

Non-teratogenic Effects

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

LATUDA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.2. Labor and Delivery

The effect of LATUDA on labor and delivery in humans is unknown.

8.3. Nursing Mothers

LATUDA was excreted in milk of rats during lactation. It is not known whether LATUDA or its metabolites are excreted in human milk. Breast feeding in women receiving LATUDA should be considered only if the potential benefit justifies the potential risk to the child.

8.4. Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5. Geriatric Use

Clinical studies of LATUDA in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 and older to determine whether or not they respond differently from younger patients. In elderly patients with psychosis (65 to 85), lurasidone concentrations (20 mg/day) were similar to those in young subjects [see Clinical Pharmacology ( 12.3 )]. No dose adjustment is necessary in elderly patients.

Elderly patients with dementia-related psychosis treated with LATUDA are at an increased risk of death compared to placebo. LATUDA is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning].

8.6. Renal Impairment

It is recommended that LATUDA dose should not exceed 40 mg/day in patients with moderate and severe renal impairment (Cl_cr ≥ 10 mL/min to < 50 mL/min).

After administration of a single dose of 40 mg LATUDA to patients with mild, moderate and severe renal impairment, mean C_max increased by 40%, 92% and 54%, respectively and mean AUC_(0-∞) increased by 53%, 91% and 2- times, respectively compared to healthy matched subjects.

8.7. Hepatic Impairment

It is recommended that LATUDA dose should not exceed 40 mg/day in patients with moderate and severe hepatic impairment (Child-Pugh Class B and C). In a single-dose study of LATUDA 20 mg, lurasidone mean AUC_(0-last) was 1.5-times higher in subjects with mild hepatic impairment (Child-Pugh Class A), 1.7-times higher in subjects with moderate hepatic impairment (Child-Pugh Class B) and 3-times higher in subjects with severe hepatic impairment (Child-Pugh Class C) compared to the values for healthy matched subjects. Mean C_max was 1.3, 1.2 and 1.3-times higher for mild, moderate and severe hepatically impaired patients respectively, compared to the values for healthy matched subjects.

8.8. Gender

Population pharmacokinetic evaluation indicated that the mean AUC of LATUDA was 18% higher in women than in men, and correspondingly, the apparent oral clearance of LATUDA was lower in women. Mean C_max of LATUDA was similar between women and men. No dosage adjustment of LATUDA is recommended based on gender.

8.9. Race

Although no specific pharmacokinetic study was conducted to investigate the effects of race on the disposition of LATUDA, population pharmacokinetic evaluation revealed no evidence of clinically significant race-related differences in the pharmacokinetics of LATUDA. No dosage adjustment of LATUDA is recommended based on race.

8.10. Smoking Status

Based on in vitro studies utilizing human liver enzymes, LATUDA is not a substrate for CYP1A2; smoking is therefore not expected to have an effect on the pharmacokinetics of LATUDA.

9. DRUG ABUSE AND DEPENDENCE

9.1. Controlled substance

LATUDA is not a controlled substance.

9.2. Abuse

LATUDA 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 LATUDA 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 LATUDA misuse or abuse (e.g., development of tolerance, drug-seeking behavior, increases in dose).

10. OVERDOSAGE

10.1. Human Experience

In premarketing clinical studies involving more than 2096 patients and/or healthy subjects, accidental or intentional overdosage of LATUDA was identified in one patient who ingested an estimated 560 mg of LATUDA. This patient recovered without sequelae. This patient resumed LATUDA treatment for an additional two months.

10.2. Management of Overdosage

Consult a Certified Poison Control Center for up-to-date guidance and advice. There is no specific antidote to LATUDA, therefore, appropriate supportive measures should be instituted and close medical supervision and monitoring should continue until the patient recovers.

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 LATUDA. Similarly the alpha-blocking properties of bretylium might be additive to those of LATUDA, 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 LATUDA-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

LATUDA is a psychotropic agent belonging to the chemical class of benzoisothiazol 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 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.

LATUDA tablets are intended for oral administration only. Each tablet contains 40 mg, or 80 mg of lurasidone hydrochloride.

Inactive ingredients are mannitol, pregelatinized starch, croscarmellose sodium, hypromellose, magnesium stearate, Opadry® and carnauba wax. Additionally, the 80 mg tablet contains yellow ferric oxide and FD&C Blue No.2 Aluminum Lake.

12. CLINICAL PHARMACOLOGY

12.1. Mechanism of Action

The mechanism of action of lurasidone, as with other drugs having efficacy in schizophrenia, is unknown. It has been suggested that the efficacy of lurasidone in schizophrenia is mediated through a combination of central dopamine Type 2 (D₂) and serotonin Type 2 (5HT_2A) receptor antagonism.

12.2. Pharmacodynamics

In vitro receptor binding studies revealed that lurasidone is an antagonist with high affinity at dopamine D₂ receptors (Ki = 0.994 nM) and the 5-hydroxytryptamine (5-HT, serotonin) receptors 5-HT_2A (Ki = 0.47 nM) and 5-HT₇ (Ki = 0.495 nM), is an antagonist with moderate affinity at human α_2C adrenergic receptors (Ki = 10.8 nM), is a partial agonist at serotonin 5-HT_1A (Ki = 6.38 nM) receptors, and is an antagonist at α_2A adrenergic receptors (Ki = 40.7 nM). Lurasidone exhibits little or no affinity for histamine H₁ and muscarinic M₁ receptors (IC₅₀ ≥ 1,000 nM and > 1,000 nM, respectively).

12.3. Pharmacokinetics

The activity of lurasidone is primarily due to the parent drug. The pharmacokinetics of lurasidone is dose-proportional within a total daily dose range of 20 mg to 160 mg. Steady-state concentrations of lurasidone are reached within 7 days of starting LATUDA.

Following administration of 40 mg of LATUDA, the mean (%CV) elimination half-life was 18 (7) hours.

Absorption and Distribution: Lurasidone is absorbed and reaches peak serum concentrations in approximately 1-3 hours. It is estimated that 9-19% of an administered dose is absorbed. Following administration of 40 mg of LATUDA, the mean (%CV) apparent volume of distribution was 6173 (17.2) L. Lurasidone is highly bound (~99%) to serum proteins.

In a food effect study, lurasidone mean C_max and AUC were about 3-times and 2-times, respectively, when administered with food compared to the levels observed under fasting conditions. Lurasidone exposure was not affected as meal size was increased from 350 to 1000 calories and was independent of meal fat content [see Dosage and Administration ( 2.2 )].

In clinical studies, establishing the safety and efficacy of LATUDA, patients were instructed to take their daily dose with food [see Dosage and Administration ( 2.2 )].

Metabolism and Elimination: Lurasidone is metabolized mainly via CYP3A4. The major biotransformation pathways are oxidative N-dealkylation, hydroxylation of norbornane ring, and S-oxidation. Lurasidone is metabolized into two active metabolites (ID-14283 and ID-14326) and two major non-active metabolites (ID-20219 and ID-20220).

Total excretion of radioactivity in urine and feces combined was approximately 89%, with about 80% recovered in feces and 9% recovered in urine, after a single dose of [¹⁴C]-labeled lurasidone.

Following administration of 40 mg of LATUDA, the mean (%CV) apparent clearance was 3902 (18.0) mL/min.

13. NONCLINICAL TOXICOLOGY

Carcinogenesis: Lifetime carcinogenicity studies were conducted in ICR mice and Sprague-Dawley rats. Lurasidone was administered orally at doses of 30, 100, 300, or 650 (the high dose was reduced from 1200 in males) mg/kg/day to ICR mice and 3, 12, or 36 (high dose reduced from 50) mg/kg/day to Sprague-Dawley rats.

In the mouse study, there were increased incidences of malignant mammary gland tumors and pituitary gland adenomas in females at all doses; the lowest dose tested produced plasma levels (AUC) 2 times those in humans receiving the maximum recommended human dose (MRHD) of 80 mg/day. No increases in tumors were seen in male mice up to the highest dose tested, which produced plasma levels (AUC) 15-25 times those in humans receiving the MRHD.

In rats, an increased incidence of mammary gland carcinomas was seen in females at the two higher doses; the no-effect dose of 3 mg/kg produced plasma levels (AUC) 0.7 times those in humans receiving the MRHD. No increases in tumors were seen in male rats up to highest dose tested, which produced plasma levels (AUC) 10 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. The relevance of this increased incidence of prolactin-mediated pituitary or mammary gland tumors in rodents in terms of human risk is unknown [see Warnings and Precautions (5.6)].

Mutagenesis: Lurasidone was not genotoxic in the Ames test, the in vitro chromosomal aberration test in Chinese Hamster Lung (CHL) cells, or the in vivo mouse bone marrow micronucleus test.

Impairment of Fertility: Lurasidone was administered orally to female rats at doses of 0.1, 1.5, 15, or 150 mg/kg/day for 15 consecutive days prior to mating, during the mating period, and through day 7 of gestation. Estrus cycle irregularities were seen at 1.5 mg/kg and above; the no-effect dose of 0.1 mg/kg is approximately 0.01 times the maximum recommended human dose (MRHD) of 80 mg/day based on body surface area. Fertility was reduced only at the highest dose and this was shown to be reversible after a 14 day drug-free period. The no-effect dose for reduced fertility was 15 mg/kg, which is 1.8 times the MRHD based on body surface area.

Fertility was not affected in male rats treated orally with lurasidone for 64 consecutive days prior to mating and during the mating period at doses up to 150 mg/kg/day (12 times the MRHD based on body surface area).

14. CLINICAL STUDIES

14.1. Schizophrenia

The efficacy of LATUDA for the treatment of schizophrenia was established in four short-term (6-week), placebo-controlled studies in adult patients (mean age of 38.8 years, range 18-72) who met DSM-IV criteria for schizophrenia. One study included an active-control arm (olanzapine) to assess assay sensitivity.

Several instruments were used for assessing psychiatric signs and symptoms in these studies:

• Positive and Negative Syndrome Scale (PANSS), is a multi-item inventory of general psychopathology used to evaluate the effects of drug treatment in schizophrenia. PANSS total scores may range from 30 to 210.
• Brief Psychiatric Rating Scale derived (BPRSd), derived from the PANSS, is a multi-item inventory primarily focusing on positive symptoms of schizophrenia, whereas the PANSS includes a wider range of positive, negative and other symptoms of schizophrenia. BPRSd scores may range from 18 to 126.
• The Clinical Global Impression severity scale (CGI-S) is a validated clinician-rated scale that measures the subject's current illness state on a 1 to 7-point scale.

The endpoint associated with each instrument is change from baseline in the total score to the end of
week 6. These changes are then compared to placebo changes for the drug and control groups.

The results of the studies follow:

• In a 6-week, placebo-controlled trial (N=145) involving two fixed doses of LATUDA (40 or 120 mg/day), both doses of LATUDA at Endpoint were superior to placebo on the BPRSd total score, and the CGI-S.
• In a 6-week, placebo-controlled trial (N=180) involving a fixed dose of LATUDA (80 mg/day), LATUDA at Endpoint was superior to placebo on the BPRSd total score, and the CGI-S.
• In a 6-week, placebo and active-controlled trial (N=473) involving two fixed doses of LATUDA (40 or 120 mg/day) and an active control (olanzapine), both LATUDA doses and the active control at Endpoint were superior to placebo on the PANSS total score, and the CGI-S.
• In a 6-week, placebo-controlled trial (N=489) involving three fixed doses of LATUDA (40, 80 or 120 mg/day), only the 80 mg/day dose of LATUDA at Endpoint was superior to placebo on the PANSS total score, and the CGI-S.

Thus, the efficacy of LATUDA at doses of 40, 80 and 120 mg/day was established in two studies for each dose. However, the 120 mg dose did not appear to add additional benefit over the 40 mg dose (Table 10).

Examination of population subgroups based on age (there were few patients over 65), gender and race did not reveal any clear evidence of differential responsiveness.

16. HOW SUPPLIED/STORAGE AND HANDLING

LATUDA tablets are white to off-white, round (40 mg), or pale green, oval (80 mg) and identified with strength specific one-sided debossing , “L40” (40 mg), or “L80” (80 mg). Tablets are supplied in the following strengths and package configurations (Table 11):

Storage

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

17. PATIENT COUNSELING INFORMATION

Physicians are advised to discuss with patients for whom they prescribe LATUDA all relevant safety information including, but not limited to, the following:

17.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Patients and caregivers should be advised that elderly patients with dementia-related psychoses treated with atypical antipsychotic drugs are at increased risk of death compared with placebo. LATUDA is not approved for elderly patients with dementia-related psychosis [see Boxed Warning; Warnings and Precautions ( 5.1)].

17.2 Neuroleptic Malignant Syndrome

Patients and caregivers should be counseled that a potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions ( 5.3 )].

17.3 Hyperglycemia and Diabetes Mellitus

Patients should be aware of the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus. Patients who are diagnosed with diabetes, those with risk factors for diabetes, or those that develop these symptoms during treatment should have their blood glucose monitored at the beginning of and periodically during treatment [see Warnings and Precautions ( 5.5 )].

17.4 Orthostatic Hypotension

Patients should be advised of the risk of orthostatic hypotension, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions ( 5.8 )].

17.5 Leukopenia/Neutropenia

Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should be advised that they should have their CBC monitored while taking LATUDA [see Warnings and Precautions ( 5.7 )].

17.6 Interference with Cognitive and Motor Performance

Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that LATUDA therapy does not affect them adversely [see Warnings and Precautions ( 5.10 )].

17.7 Pregnancy and Nursing

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with LATUDA [see Use in Specific Populations (8.1)].

17.8 Concomitant Medication and Alcohol

Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions. Patients should be advised to avoid alcohol while taking LATUDA [see Drug Interactions (7)].

17.9 Heat Exposure and Dehydration

Patients should be advised regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.11)].

SUNOVION

Manufactured for:
Sunovion Pharmaceuticals Inc.
Marlborough, MA 01752,

For Customer Service, call 1-888-394-7377.
For Medical Information, call 1-800-739-0565.
To report suspected adverse reactions, call 1-877-737-7226.

Revised: October 2010
901456R01

LATUDA is a registered trademark of Dainippon Sumitomo Pharma Co. Ltd.
Sunovion Pharmaceuticals Inc. is a U.S. subsidiary of Dainippon Sumitomo Pharma Co. Ltd.

© 2010 Sunovion Pharmaceuticals Inc.

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 40 mg

LURASIDONE Hydrochloride tablets 40 mg 
NDC 51148-001-01

Caution
For Manufacture, Processing or Repacking. Rx Only
Store at 25ºC(77ºF). Excursions Permitted to 15-30ºC (59-86ºF)

Bushu Pharmaceuticals Ltd.
Takeno, Kawagoe, Saitama, 350-0801, Japan

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 80 mg

LURASIDONE Hydrochloride tablets 80 mg 
NDC 51148-002-01

Caution
For Manufacture, Processing or Repacking. Rx Only
Store at 25ºC(77ºF). Excursions Permitted to 15-30ºC (59-86ºF)

Bushu Pharmaceuticals Ltd.
Takeno, Kawagoe, Saitama, 350-0801, Japan