Латуда

Латуда is indicated for:

• Treatment of adult and adolescent patients age 13 to 17 years with schizophrenia.
• Monotherapy treatment of adult patients with major depressive episodes associated with bipolar I disorder (bipolar depression).
• Adjunctive treatment with lithium or valproate in adult patients with major depressive episodes associated with bipolar I disorder (bipolar depression).

Schizophrenia

Adults

The recommended starting dose of Латуда is 40 mg once daily. Initial dose titration is not required. Латуда has been shown to be effective in a dose range of 40 mg per day to 160 mg per day. The maximum recommended dose is 160 mg per day.

Adolescents

The recommended starting dose of Латуда is 40 mg once daily. Initial dose titration is not required. Латуда has been shown to be effective in a dose range of 40 mg per day to 80 mg per day. The maximum recommended dose is 80 mg per day.

Depressive Episodes Associated With Bipolar I Disorder

The recommended starting dose of Латуда in adults is 20 mg given once daily as monotherapy or as adjunctive therapy with lithium or valproate. Initial dose titration is not required. Латуда has been shown to be effective in a dose range of 20 mg per day to 120 mg per day as monotherapy or as adjunctive therapy with lithium or valproate. The maximum recommended dose, as monotherapy or as adjunctive therapy with lithium or valproate, is 120 mg per day. In the monotherapy study, the higher dose range (80 mg to 120 mg per day) did not provide additional efficacy, on average, compared to the lower dose range (20 to 60 mg per day).

The efficacy of Латуда in the treatment of mania associated with bipolar disorder has not been established.

Administration Information

Латуда should be taken with food (at least 350 calories). Administration with food substantially increases the absorption of Латуда. Administration with food increases the AUC approximately 2-fold and increases the Cmax approximately 3-fold. In the clinical studies, Латуда was administered with food.

The effectiveness of Латуда 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 Латуда for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Dose Modifications For Renal Impairment

Dose adjustment is recommended in moderate (creatinine clearance: 30 to <50 mL/min) and severe renal impairment (creatinine clearance <30 mL/min) patients. The recommended starting dose is 20 mg per day. The dose in these patients should not exceed 80 mg per day.

Dose Modifications For Hepatic Impairment

Dose adjustment is recommended in moderate (Child-Pugh Score = 7 to 9) and severe hepatic impairment (Child-Pugh Score = 10 to 15) patients. The recommended starting dose is 20 mg per day. The dose in moderate hepatic impairment patients should not exceed 80 mg per day and the dose in severe hepatic impairment patients should not exceed 40 mg/day.

Dose Modifications Due To Drug Interactions Of CYP3A4 Inhibitors And CYP3A4 Inducers

Concomitant Use With CYP3A4 Inhibitors

Латуда should not be used concomitantly with a strong CYP3A4 inhibitor (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.).

If Латуда is being prescribed and a moderate CYP3A4 inhibitor (e.g. diltiazem, atazanavir, erythromycin, fluconazole, verapamil etc.) is added to the therapy, the Латуда dose should be reduced to half of the original dose level. Similarly, if a moderate CYP3A4 inhibitor is being prescribed and Латуда is added to the therapy, the recommended starting dose of Латуда is 20 mg per day, and the maximum recommended dose of Латуда is 80 mg per day.

Grapefruit and grapefruit juice should be avoided in patients taking Латуда, since these may inhibit CYP3A4 and alter Латуда concentrations.

Concomitant Use With CYP3A4 Inducers

Латуда should not be used concomitantly with a strong CYP3A4 inducer (e.g., rifampin, avasimibe, St. John’s wort, phenytoin, carbamazepine, etc.). If Латуда is used concomitantly with a moderate CYP3A4 inducer, it may be necessary to increase the Латуда dose after chronic treatment (7 days or more) with the CYP3A4 inducer.

• Known hypersensitivity to lurasidone HCl or any components in the formulation. Angioedema has been observed with lurasidone.
• Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.).
• Strong CYP3A4 inducers (e.g., rifampin, avasimibe, St. John’s wort, phenytoin, carbamazepine, etc.).

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

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. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Латуда is not approved for the treatment of patients with dementia-related psychosis.

Suicidal Thoughts And Behaviors In Pediatric And Young Adult Patients

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients, and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2.

No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about antidepressant drug effect on suicide.

Table 2: Risk Differences of the Number of Cases of Suicidal Thoughts or Behaviors in the

Латуда is not approved for use in pediatric patients with depression.

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 Латуда, 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

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. Латуда is not approved for the treatment of patients with dementia-related psychosis.

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 Латуда.

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 creatine 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.

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

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 Латуда was not marketed at the time these studies were performed, it is not known if Латуда 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.

Schizophrenia

Adults

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

Table 3: Change in Fasting Glucose in Adult Schizophrenia Studies

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

Adolescents

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

Bipolar Depression

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

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received Латуда 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

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received Латуда 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).

Dyslipidemia

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

Schizophrenia

Adults

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

Table 6: Change in Fasting Lipids in Adult Schizophrenia Studies

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

Adolescents

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

Bipolar Depression

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

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received Латуда 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 (n=130) and -1.0 (n=130) mg/dL 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

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received Латуда, 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.

Weight Gain

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

Schizophrenia

Adults

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

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

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

Adolescents

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

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

Bipolar Depression

Monotherapy

Data from the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study are presented in Table 11. The mean weight gain was +0.29 kg for Латуда-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 Латуда-treated patients versus 0.7% for placebo-treated patients.

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

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received Латуда 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 weight gain was +0.11 kg for Латуда-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 Латуда-treated patients versus 0.3% for placebo-treated patients.

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

Patients were randomized to flexibly dosed Латуда 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 Латуда, 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).

Hyperprolactinemia

As with other drugs that antagonize dopamine D₂ receptors, Латуда 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.

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. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.

Schizophrenia

Adults

In short-term, placebo-controlled schizophrenia studies, the median change from baseline to endpoint in prolactin levels for Латуда-treated patients was +0.4 ng/mL and was -1.9 ng/mL in the placebo-treated patients. The median change from baseline to endpoint for males was +0.5 ng/mL and for females was -0.2 ng/mL. Median changes for prolactin by dose are shown in Table 13.

Table 13: Median Change in Prolactin (ng/mL) from Baseline in Adult Schizophrenia Studies

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

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

Adolescents

In the short-term, placebo-controlled adolescent schizophrenia study, the median change from baseline to endpoint in prolactin levels for Латуда-treated patients was +1.1 ng/mL and was +0.1 ng/mL for placebo-treated patients. For Латуда-treated patients, the median change from baseline to endpoint for males was +1.0 ng/mL and for females was +2.6 ng/mL. Median changes for prolactin by dose are shown in Table 14.

Table 14: Median Change in Prolactin (ng/mL) from Baseline in the Adolescent Schizophrenia Study

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

Bipolar Depression

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 Латуда 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 f

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

• Increased Mortality in Elderly Patients with Dementia-Related Psychosis
• Suicidal Thoughts and Behaviors
• Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-related Psychosis
• Neuroleptic Malignant Syndrome
• Tardive Dyskinesia
• Metabolic Changes
• Hyperprolactinemia
• Leukopenia, Neutropenia, and Agranulocytosis
• Orthostatic Hypotension and Syncope
• Falls
• Seizures
• Potential for Cognitive and Motor Impairment
• Body Temperature Dysregulation
• Activation of Mania/Hypomania
• Dysphagia
• Neurological Adverse Reactions in Patients with Parkinson’s Disease or Dementia with Lewy Bodies
.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adults

The information below is derived from an integrated clinical study database for Латуда consisting of 3799 adult patients exposed to one or more doses of Латуда for the treatment of schizophrenia, and bipolar depression in placebo-controlled studies. This experience corresponds with a total experience of 1250.9 patient-years. A total of 1106 Латуда-treated patients had at least 24 weeks and 371 Латуда-treated patients had at least 52 weeks of exposure.

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

Schizophrenia

The following findings are based on the short-term, placebo-controlled premarketing adult studies for schizophrenia in which Латуда was administered at daily doses ranging from 20 to 160 mg (n=1508).

Commonly Observed Adverse Reactions:

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

Adverse Reactions Associated with Discontinuation of Treatment:

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

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

Adverse reactions associated with the use of Латуда (incidence of 2% or greater, rounded to the nearest percent and Латуда incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with schizophrenia) are shown in Table 17.

Table 17: Adverse Reactions in 2% or More of Латуда-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in Adult Short-term Schizophrenia Studies

Dose-Related Adverse Reactions in the Schizophrenia Studies

Akathisia and extrapyramidal symptoms were dose-related. The frequency of akathisia increased with dose up to 120 mg/day (5.6% for Латуда 20 mg, 10.7% for Латуда 40 mg, 12.3% for Латуда 80 mg, and 22.0% for Латуда 120 mg). Akathisia was reported by 7.4% (9/121) of patients receiving 160 mg/day. Akathisia occurred in 3.0% of subjects receiving placebo. The frequency of extrapyramidal symptoms increased with dose up to 120 mg/day (5.6% for Латуда 20 mg, 11.5% for Латуда 40 mg, 11.9% for Латуда 80 mg, and 22.0% for Латуда 120 mg).

Bipolar Depression (Monotherapy)

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

Commonly Observed Adverse Reactions:

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

Adverse Reactions Associated with Discontinuation of Treatment:

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

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

Adverse reactions associated with the use of Латуда (incidence of 2% or greater, rounded to the nearest percent and Латуда incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with bipolar depression) are shown in Table 18.

Table 18: Adverse Reactions in 2% or More of Латуда-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the Adult Short-term Monotherapy Bipolar Depression Study

Dose-Related Adverse Reactions in the Monotherapy Study:

In the adult short-term, placebo-controlled study (involving lower and higher Латуда dose ranges) the adverse reactions that occurred with a greater than 5% incidence in the patients treated with Латуда in any dose group and greater than placebo in both groups were nausea (10.4%, 17.4%), somnolence (7.3%, 13.8%), akathisia (7.9%, 10.8%), and extrapyramidal symptoms (4.9%, 9.0%) for Латуда 20 to 60 mg/day and Латуда 80 to 120 mg/day, respectively.

Bipolar Depression

Adjunctive Therapy With Lithium Or Valproate

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

Commonly Observed Adverse Reactions:

The most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) in subjects treated with Латуда were akathisia and somnolence.

Adverse Reactions Associated with Discontinuation of Treatment:

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

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

Adverse reactions associated with the use of Латуда (incidence of 2% or greater, rounded to the nearest percent and Латуда incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with bipolar depression) are shown in Table 19.

Table 19: Adverse Reactions in 2% or More of Латуда-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the Adult Short-term Adjunctive Therapy Bipolar Depression Studies

Adolescents

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

Commonly Observed Adverse Reactions:

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

Adverse Reactions Associated with Discontinuation of Treatment:

The incidence of discontinuation due to adverse reactions between Латуда-and placebo-treated adolescent patients (13 to 17 years) was 4% and 8%, respectively.

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

Adverse reactions associated with the use of Латуда (incidence of 2% or greater, rounded to the nearest percent and Латуда incidence greater than placebo) that occurred during acute therapy (up to 6-weeks in adolescent patients with schizophrenia) are shown in Table 20.

Table 20: Adverse Reactions in 2% or More of Латуда-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the Adolescent Short-term Schizophrenia Study

Extrapyramidal Symptoms

Schizophrenia

Adults

In the short-term, placebo-controlled schizophrenia studies, for Латуда-treated patients, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness, was 13.5% versus 5.8% for placebo-treated patients. The incidence of akathisia for Латуда-treated patients was 12.9% versus 3.0% for placebo-treated patients. Incidence of EPS by dose is provided in Table 21.

Table 21: Incidence of EPS Compared to Placebo in Adult Schizophrenia Studies

Adolescents

In the short-term, placebo-controlled, study of schizophrenia in adolescents, the incidence of EPS, excluding events related to akathisia, for Латуда-treated patients was higher in the 40 mg (10%) and the 80 mg (7.7%) treatment groups vs. placebo (3.6%); and the incidence of akathisia-related events for Латуда-treated patients was 8.9% vs. 1.8% for placebo-treated patients. Incidence of EPS by dose is provided in Table 22.

Table 22: Incidence of EPS Compared to Placebo in the Adolescent Schizophrenia Study

Bipolar Depression

Monotherapy

In the adult short-term, placebo-controlled monotherapy bipolar depression study, for Латуда-treated patients, the incidence of reported events related to EPS, excluding akathisia and restlessness was 6.9% versus 2.4% for placebo-treated patients. The incidence of akathisia for Латуда-treated patients was 9.4% versus 2.4% for placebo-treated patients. Incidence of EPS by dose groups is provided in Table 23.

Table 23: Incidence of EPS Compared to Placebo in the Adult Monotherapy Bipolar Depression Study

Adjunctive Therapy with Lithium or Valproate

In the adult short-term, placebo-controlled adjunctive therapy bipolar depression studies, for Латуда-treated patients, the incidence of EPS, excluding akathisia and restlessness, was 13.9% versus 8.7% for placebo. The incidence of akathisia for Латуда-treated patients was 10.8% versus 4.8% for placebo-treated patients. Incidence of EPS is provided in Table 24.

Table 24: Incidence of EPS Compared to Placebo in the Adult Adjunctive Therapy Bipolar Depression Studies

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

Schizophrenia

Adults

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

Adolescents

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

Bipolar Depression

onotherapy

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

Adjunctive Therapy with Lithium or Valproate

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

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

Human Experience

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

Management Of Overdosage

No specific antidotes for Латуда are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. If an overdose occurs, consult a Certified Poison Control Center (1-800-222-1222 or www.poison.org).

Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with an acute overdose of Латуда. Similarly, the alpha-blocking properties of bretylium might be additive to those of Латуда, 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 Латуда-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.

Lurasidone is an antagonist with high affinity binding at the dopamine D₂ receptors (Ki of 1 nM) and the serotonin 5-HT_2A (Ki of 0.5 nM) and 5-HT₇ (Ki of 0.5 nM) receptors. It also binds with moderate affinity to the human α₂C adrenergic receptors (Ki of 11 nM), is a partial agonist at serotonin 5-HT_1A (Ki of 6.4 nM) receptors, and is an antagonist at the α₂A adrenergic receptors (Ki of 41 nM). Lurasidone exhibits little or no affinity for histamine H₁ and muscarinic M₁ receptors (IC₅₀ > 1,000 nM).

ECG Changes

The effects of Латуда on the QTc interval were evaluated in a randomized, double-blind, multiple-dose, parallel-dedicated thorough QT study in 43 patients with schizophrenia or schizoaffective disorder, who were treated with Латуда doses of 120 mg daily, 600 mg daily and completed the study. The maximum mean (upper 1-sided, 95% CI) increase in baseline-adjusted QTc intervals based on individual correction method (QTcI) was 7.5 (11.7) ms and 4.6 (9.5) ms, for the 120 mg and 600 mg dose groups respectively, observed at 2 to 4 hours after dosing. In this study, there was no apparent dose (exposure)-response relationship.

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

Figure 2:Impact of Латуда on Other Drugs

Studies In Specific Populations

The effect of intrinsic patient factors on the pharmacokinetics of Латуда is presented in Figure 3.

Pediatric Patients

Латуда exposure (i.e., steady-state Cmax and AUC) in children and adolescent patients (10 to 17 years of age) was generally similar to that in adults across the dose range from 40 to 160 mg, without adjusting for body weight.

Figure 3: Impact of Other Patient Factors on Латуда Pharmacokinetics

Clinical Studies

Schizophrenia

Adults

The efficacy of Латуда for the treatment of schizophrenia was established in five short-term (6-week), placebo-controlled studies in adult patients (mean age of 38.4 years, range 18-72) who met DSM-IV criteria for schizophrenia. An active-control arm (olanzapine or quetiapine extended-release) was included in two studies to assess assay sensitivity.

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

1. 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.
2. 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. The BPRSd consists of 18 items rated on a scale of 1 (not present) to 7 (severe). BPRSd scores may range from 18 to 126.
3. The Clinical Global Impression severity scale (CGI-S) is a 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:

1. Study 1: In a 6-week, placebo-controlled trial (N=145) involving two fixed doses of Латуда (40 or 120 mg/day), both doses of Латуда at Endpoint were superior to placebo on the BPRSd total score, and the CGI-S.
2. Study 2: In a 6-week, placebo-controlled trial (N=180) involving a fixed dose of Латуда (80 mg/day), Латуда at Endpoint was superior to placebo on the BPRSd total score, and the CGI-S.
3. Study 3: In a 6-week, placebo-and active-controlled trial (N=473) involving two fixed doses of Латуда (40 or 120 mg/day) and an active control (olanzapine), both Латуда doses and the active control at Endpoint were superior to placebo on the PANSS total score, and the CGI-S.
4. Study 4: In a 6-week, placebo-controlled trial (N=489) involving three fixed doses of Латуда (40, 80 or 120 mg/day), only the 80 mg/day dose of Латуда at Endpoint was superior to placebo on the PANSS total score, and the CGI-S.
5. Study 5: In a 6-week, placebo-and active-controlled trial (N=482) involving two fixed doses of Латуда (80 or 160 mg/day) and an active control (quetiapine extended-release), both Латуда doses and the active control at Endpoint were superior to placebo on the PANSS total score, and the CGI-S.

Thus, the efficacy of Латуда at doses of 40, 80, 120 and 160 mg/day has been established (Table 30).

Table 30: Primary Efficacy Results for Studies in Adult Patients with Schizophrenia (BPRSd or PANSS Scores)

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.

Adolescents

The efficacy of Латуда, was established in a 6-week, multicenter, randomized, double-blind, placebo-controlled study of adolescents (13 to 17 years) who met DSM-IV-TR criteria for schizophrenia (N=326). Patients were randomized to one of two fixed-doses of Латуда (40 or 80 mg/day) or placebo.

The primary rating instrument used to assess psychiatric signs and symptoms was the PANSS. The key secondary instrument was the CGI-S.

For both dose groups, Латуда was superior to placebo in reduction of PANSS and CGI-S scores at Week 6. On average, the 80 mg/day dose did not provide additional benefit compared to the 40 mg/day dose.

The primary efficacy results are provided in Table 31.

Table 31: Primary Efficacy Results (PANSS Total Score) for the Adolescent Schizophrenia Study

Depressive Episodes Associated With Bipolar I Disorder

Monotherapy

The efficacy of Латуда, as monotherapy, was established in a 6-week, multicenter, randomized, double-blind, placebo-controlled study of adult patients (mean age of 41.5 years, range 18 to 74) who met DSM-IV-TR criteria for major depressive episodes associated with bipolar I disorder, with or without rapid cycling, and without psychotic features (N=485). Patients were randomized to one of two flexible-dose ranges of Латуда (20 to 60 mg/day, or 80 to 120 mg/day) or placebo.

The primary rating instrument used to assess depressive symptoms in this study was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale with total scores ranging from 0 (no depressive features) to 60 (maximum score). The primary endpoint was the change from baseline in MADRS score at Week 6. The key secondary instrument was the Clinical Global Impression-Bipolar-Severity of Illness scale (CGI-BP-S), a clinician-rated scale that measures the subject’s current illness state on a 7-point scale, where a higher score is associated with greater illness severity.

For both dose groups, Латуда was superior to placebo in reduction of MADRS and CGI-BP-S scores at Week 6. The primary efficacy results are provided in Table 32. The high dose range (80 to 120 mg per day) did not provide additional efficacy on average, compared to the low dose range (20 to 60 mg per day).

Adjunctive Therapy With Lithium Or Valproate

The efficacy of Латуда, as an adjunctive therapy with lithium or valproate, was established in a 6-week, multicenter, randomized, double-blind, placebo-controlled study of adult patients (mean age of 41.7 years, range 18 to 72) who met DSM-IV-TR criteria for major depressive episodes associated with bipolar I disorder, with or without rapid cycling, and without psychotic features (N=340). Patients who remained symptomatic after treatment with lithium or valproate were randomized to flexibly dosed Латуда 20 to 120 mg/day or placebo.

The primary rating instrument used to assess depressive symptoms in this study was the MADRS. The primary endpoint was the change from baseline in MADRS score at Week 6. The key secondary instrument was the CGI-BP-S scale.

Латуда was superior to placebo in reduction of MADRS and CGI-BP-S scores at Week 6, as an adjunctive therapy with lithium or valproate (Table 32).

Table 32: Primary Efficacy Results for Adult Studies in Depressive Episodes Associated with Bipolar I Disorder (MADRS Scores)