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Lurasidone HCl Tablets

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 


WARNING: INCREASED MORTALITY IN ELDERLY PA TIENTS WITH DEMENTIA-RELATED PSYCHOSIS

• Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death [See Warning and Precautions].

• Lurasidone is not approved for use in patients with dementia-related psychosis [See Warning and Precautions ].



1. DESCRIPTION

Lurasidone HCl 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.

Lurasidone tablets are intended for oral administration only. Each tablet contains 20 mg, 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.

2. INDICATIONS AND USAGE

Lurasidone is indicated for the treatment of patients with schizophrenia.

The efficacy of lurasidone in schizophrenia was established in four 6-week controlled studies of adult patients with schizophrenia.

The effectiveness of lurasidone 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 lurasidone for extended periods should periodically re-evalu ate the long-term usefulness of the drug for the individual patient [see Dosage and Administration].

3. DOSAGE AND ADMINISTRATION

3.1. Schizophrenia

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

3.2. Administration Instructions

Lurasidone should be taken with food (at least 350 calories).

3.3. Dose Modifications in Special Populations

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. The dose in these patients should not exceed 80 mg/day [see Use in Specific Populations].

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. The dose in moderate hepatic impairment patients should not exceed 80 mg/day and the dose in severe hepatic impairment patients should not exceed 40 mg/day [see Use in Specific Populations].

3.4 Dose Modifications Due to Drug Interactions

Concomitant Use with Potential CYP3A4 Inhibitors

The dose of lurasidone should not exceed 80 mg/day in combination with a moderate CYP3A4 inhibitor such as diltiazem. Lurasidone should not be used in combination with a strong CYP3A4 inhibitor (e.g., ketoconazole) [see Contraindications; Drug Interactions].

Concomitant Use with Potental CYP3A4 Inducers

Lurasidone should not be used in combination with a strong CYP3A4 inducer (e.g., rifampin) [see Contraindications; Drug Interactions].

4. CONTRAINDICATIONS

Lurasidone is contraindicated in the following:

• Any patient with a known hypersensitivity to lurasidone HCl or any components in the formulation. Angioedema has been observed with lurasidone [see Adverse Reactions].

• Concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole) [see Drug Interactions].

• Concomitant use with strong CYP3A4 inducers (e.g., rifampin) [see Drug Interactions].

5. 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 (5HT2A) receptor antagonism.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category B

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

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

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.

Safe use of lurasidone during pregnancy or lactation has not been established; therefore, use of lurasidone in pregnancy, in nursing mothers, or in women of childbearing potential requires that the benefits of treatment be weighed against the possible risks to mother and child.

Animal Data

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 half of the MRHD based on body surface area.

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 1.5 and 6 times, in rats and rabbits respectively, the maximum recommended human dose (MRHD) of 160 mg/day based on body surface area.

6.2 Nursing Mothers

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

6.3 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

6.4 Geriatric Use

Clinical studies of lurasidone 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. No dose adjustment is necessary in elderly patients.

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

6.5 Other Patient Factors

The effect of intrinsic patient factors on the pharmacokinetics of lurasidone is presented in Figure 1.

Figure 1: Impact of Other Patient Factors on Lurasidone Pharmacokinetics

7. WARNINGS AND PRECAUTIONS

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

7.2. Cerebrovascular Adverse Reactions, 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. Lurasidone is not approved for the treatment of patients with dementia-related psychosis [see also Boxed Warning and Warnings and Precautions].

7.3. 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 lurasidone.

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 dr ugs 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 ph armacological 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.

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

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

7.5. 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 lurasidone was not marketed at the time these studies were performed, it is not known if lurasidone 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 ofhyperglycemia 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 1.

Table 1: Change in Fasting Glucose

In the uncontrolled, longer-term studies (primarily open-label extension studies), lurasidone was associated with a mean change in glucose of +1.6 mg/dL at week 24 (n = 186), +0.3 mg/dL at week 36 (n = 236) and +1.2 mg/dL at week 52 (n = 244).

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 2.

Table 2: Change in Fasting Lipids

In the uncontrolled, longer-term studies (primarily open-label extension studies), lurasidone 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 3. The mean weight gain was 0.75 kg for lurasidone-treated patients compared to 0.26 kg for placebo-treated patients. In study 3 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 lurasidone-treated patients versus 4.0% for placebo-treated patients.

Table 3: Mean Change in Weight (kg) from Baseline

In the uncontrolled, longer-term studies (primarily open-label extension studies), lurasidone 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).

7.6. Hyperprolactinemia

As with other drugs that antagonize dopamine D2 receptors, lurasidone 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 m ay lead to decreased bone density in both female and male patients [see Adverse Reactions].

In short-term placebo-controlled studies, the median change from baseline to endpoint in prolactin levels for lurasidone-treated patients was an increase of -1.1 ng/mL compared to a decrease of 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 compared to an increase of 1.1 ng/ml in males. The increase in prolactin concentrations was dose-dependent (Table 4).

Table 4: Median Change in Prolactin (ng/mL) from Baseline

The proportion of patients with prolactin elevations ≥ 5x ULN was 3.6% for lurasidone-treated patients versus 0.7% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥ 5x ULN was 8.3% for lurasidone-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), lurasidone 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 lurasidone carcinogenicity study conducted 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.

7.7. Leukopenia, Neutropenia and Agranulocytosis

Leukopenia/neutropenia has been reported during treatment with antip sychotic 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 LAT UDA should be discontinued at the first sign of decline in WBC, in the absence of other causative factors.

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

7.8. Orthostatic Hypotension and Syncope

Lurasidone 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 (lurasidone 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 lurasidone 40 mg, 1.4% with lurasidone 80 mg and 1.7% with lurasidone 120 mg compared to 0.9% with placebo.

Lurasidone 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.

7.9. Seizures

As with other antipsychotic drugs, lurasidone 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 lurasidone compared to 0.2% (1/455) placebo-treated patients.

7.10. Potential for Cognitive and Motor Impairment

Lurasidone, 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 lurasidone 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 lurasidone 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 lurasidone does not affect them adversely.

7.11. 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 lurasidone 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.

7.12. 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 lurasidone should be written for the sm allest 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 lurasidone treated patients compar ed to 0.4% (2/455) on placebo. No suicide attempts or completed suicides were reported in these studies.

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

7.14. Use in Patients with Concomitant Illness

Clinical experience with lurasidone in patients with certain concomitant systemic illnesses is limited [see Use in Specific Populations]. Lurasidone 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].

8. ADVERSE REACTIONS

8.1. 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]

• Cerebrovascular Adverse Reactions, Including Stroke [see Warnings an d Precautions]

• Neuroleptic Malignant Syndrome [see Warnings and Precautions]

• Tardive Dyskinesia [see Warnings and Precautions]

• Hyperglycemia and Diabetes Mellitus [see Warnings and Precautions]

• Hyperprolactinemia [see Warnings and Precautions]

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

• Orthostatic Hypotension and Syncope [see Warnings and Precautions]

• Seizures [see Warnings and Precautions]

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

• Body Temperature Regulation [see Warnings and Precautions]

• Suicide [see Warnings and Precautions]

• Dysphagia [see Warnings and Precautions]

• Use in Patients with Concomitant Illness [see Warnings and Precautions]

The information below is derived from a clinical study database for lurasidone 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 sch izophrenia studies with doses of 20 mg, 40 mg, 80 mg or 120 mg once daily. A total of 533 lurasidone-treated patients had at least 24 weeks and 238 lurasidone-treated patients had at least 52 weeks of exposure.

8.2. Clinical Studies Experience

The following findings are based on the short-term placebo-controlled premarketing studies for schizophrenia in which lurasidone 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 lurasidone were somnolence, akathisia, nausea, parkinsonism and agitation.

Adverse Reactions Associated with Discontinuation of Treatment: A total of 9.4% (94/1004) lurasidone-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 lurasidone that were at least 2% and at least twice the placebo rate.

Adverse Reactions Occurring at an Incidence of 2% or More in Lurasidone-Treated Patients: Adverse reactions associated with the use of lurasidone (incidence of 2% or greater, rounded to the nearest percent and lurasidone incidence greater than placebo) that occurred during acute therapy (up to 6-weeks in patients with schizophrenia) are shown in Table 5.

Table 5: Adverse Reaction in 2% or More of Lurasidone-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in Short-term Schizophrenia Studies

Note: Figures rounded to the nearest integer

* Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence

** Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor

*** Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus

8.3. Dose-Related Adverse Reactions

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 lurasidone, the apparent dose-related adverse reactions were akathisia and somnolence (Table 6).

Table 6: Dose-Related Adverse Events

Note: Figures rounded to the nearest integer

* Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence

8.4. Extrapyramidal Symptoms

In the short-term, placebo-controlled schizophrenia studies, for lurasidone-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 lurasidone-treated patients was 15.0% versus 3.3% for placebo-treated patients. Akathisia appeared to be dose-related and the greatest f requency of parkinsonism and dystonia occurred with the highest dose of L ATUDA, 120 mg/day (Table 7).

Table 7: Percentage of EPS Compared to Placebo

Note: Figures rounded to the nearest integer

* Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus

** Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, droo ling, extrapyramidal disorder, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor

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 lurasidone-treated subjects (0.0% lurasidone 20 mg, 4.2% lurasidone 40 mg, 4.6% lurasidone 80 mg and 6.5% lurasidone 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 lurasidone 80 mg/day and 3 were receiving lurasidone 120 mg/day.

8.5. 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]. There were also no clinically important differences between lurasidone and placebo in mean change from baseline to endpoint in routine hematology, urinalysis, or serum chemistry. Lurasidone was associated with a dose-related increase in prolactin concentration [see Warnings and Precautions].

Creatinine: In short-term, placebo-controlled trials, the mean change from Baseline in creatinine was 0.06 mg/dL for lurasidone-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 lurasidone-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; Use in Specific Populations].

Transaminases: The mean changes in AST and ALT for lurasidone- and placebo-treated patients were similar. The proportion of patients with transaminases (AST and ALT) elevations ≥ 3 times ULN was similar for all lurasidone-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 lurasidone clinical trial program. No post-baseline QT prolongations exceeding 500 msec were reported in patients treated with lurasidone. 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 lurasidone 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 lurasidone 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 lurasidone experienced QTc increases > 60 msec from baseline, nor did any patient experience a QTc of > 500 msec.

9. OVERDOSAGE

9.1. Human Experience

In premarketing clinical studies involving more than 2095 patients and/or healthy subjects, accidental or intentional overdosage of lurasidone was identified in one patient who ingested an estimated 560 mg of lurasidone. This patient recovered without sequelae. This patient resumed lurasidone treatment for an additional two months.

9.2. Management of Overdosage

Consult a Certified Poison Control Center for up-to-date guidance and advice. There is no specific antidote to lurasidone, 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 lurasidone. Similarly the alpha-blocking properties of bretylium might be additive to those of lurasidone, resulting in problematic hypotension.

Hypotension and circulatory collapse should be treated with appropriate measures. Epinephrine and dopamine should not be used, or other sympathomimetics with beta-agonist activity, since beta stimulation may worsen hypotension in the setting of lurasidone-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 dyston ic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.

10. DRUG INTERACTIONS

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

10.1. Potential for Other Drugs to Affect Lurasidone

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

Lurasidone is predominantly metabolized by CYP3A4; interaction of lurasidone with strong and moderate inhibitors or inducers of this enzyme has been observed (Table 8). Lurasidone should not be used in combination with strong inhibitors or inducers of this enzyme [see Contraindications].

Table 8: Summary of Effect of Coadministered Drugs on Exposure to Lurasidone in Healthy Subjects or Patients with Schizophrenia

10.2. Potential for Lurasidone to Affect Other Drugs

Digoxin (P-gp substrate): Coadministration of lurasidone (120 mg/day) at steady state with a single dose of digoxin (0.25 mg) increased Cmax and AUC0-24 for digoxin by approximately 9% and 13%, respectively relative to digoxin alone. Digoxin dose adjustment is not required when coadministered with lurasidone.

Midazolam (CYP3A4 substrate): Coadministration of lurasidone (120 mg/day) at steady state with a single dose of 5 mg midazolam increased midazolam Cmax and AUC0-24 by approximately 21% and 44%, respectively relative to midazolam alone. Midazolam dose adjustment is not required when coadministered with lurasidone.

Oral Contraceptive (estrogen/progesterone): Coadministration of lurasidone (40 mg/day) at steady state with an oral contraceptive (OC) containing ethinyl estradiol and norelgestimate resulted in equivalent AUC0-24 and Cmax of ethinyl estradiol and norelgestromin relative to OC administration alone. Also, sex hormone binding globulin levels were not meaningfully affected by coadministration of lurasidone and OC. Dose adjustment of OC dose is not required when coadministered with lurasidone.

11. 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 lurasidone.

Following administration of 40 mg of lurasidone, 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 lurasidone, 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 Cmax 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].

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

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 lurasidone, the mean (%CV) apparent clearance was 3902 (18.0) mL/min.

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: LATUDA, by SUNOVION PHARMA, INC.

b) Generic drugs: None.

2) How Supplied:

LATUDA tablets are white to off-white, round (20 mg or 40 mg), pale green, oval (80 mg) or white to off-white, oval (120 mg) and identified with strength-specific one-sided debossing, “L20” (20 mg), “L40” (40 mg), “L80” (80 mg) or “L120” (120 mg). Tablets are supplied in the following strengths and package configurations (Table 9):

Table 9: Package Configuration for LATUDA Tablets

3) Storage:

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

Rx only

Rev 12/12