Latuda: Indications, Dosage, Precautions, Adverse Effects
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Latuda - Product Information

Manufacture: Sunovion Pharmaceuticals Inc.
Country: Canada
Condition: Bipolar Disorder, Schizophrenia
Class: Atypical antipsychotics
Form: Tablets
Ingredients: lurasidone hydrochloride, carnauba wax, croscarmellose sodium, hypromellose, magnesium stearate, mannitol, Opadry (hypromellose, polyethylene glycol, and titanium dioxide), pregelatinized starch; 80 mg tablet also contains: FDandC Blue No.2 Aluminum Lake and yellow ferric oxide.

Summary product information

Route of
Administration
Dosage Form /
Strength
Nonmedicinal Ingredients

Oral Film-Coated Tablets /
20 mg, 40 mg, 60 mg,
80 mg, and 120 mg
Carnauba wax, croscarmellose sodium,
hypromellose, magnesium stearate, mannitol,
Opadry (hypromellose, polyethylene glycol,
and titanium dioxide), pregelatinized starch;
80 mg tablet also contains: FDandC Blue No.2
Aluminum Lake and yellow ferric oxide.

Indications and clinical use

Adults

Schizophrenia

LATUDA (lurasidone HCl) is indicated for the management of the manifestations of schizophrenia.

The antipsychotic efficacy of LATUDA was established in short-term (6-week) controlled trials [see CLINICAL TRIALS]. The efficacy of LATUDA in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials of patients with manifestations of schizophrenia.

Depressive Episodes Associated with Bipolar I Disorder

LATUDA is indicated as monotherapy or as adjunctive therapy with lithium or valproate for the acute management of depressive episodes associated with bipolar I disorder.

The efficacy of LATUDA for long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled studies. 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.

Geriatrics (>65 years of age):

LATUDA is not indicated in elderly patients with dementia [see WARNINGS AND PRECAUTIONS, Serious Warnings and Precautions Box and Special Populations]. The safety and efficacy of LATUDA in patients 65 years of age or older has not been established.

Pediatrics (<18 years of age):

Safety and efficacy in pediatric patients have not been evaluated and its use is not recommended.

Contraindications

LATUDA (lurasidone HCl) is contraindicated in any patient with a known hypersensitivity to lurasidone HCl or any components in the formulation [for a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING]. Angioedema has been observed with lurasidone [see ADVERSE REACTIONS].

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

Warnings and precautions

Serious Warnings and Precautions

Increased Mortality in Elderly Patients with Dementia.

Elderly patients with dementia treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of thirteen placebo-controlled trials with various atypical antipsychotics (modal duration of 10 weeks) in these patients showed a mean 1.6-fold increase in the death rate in the drug-treated patients. 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 [see WARNINGS AND PRECAUTIONS, Special Populations, Use in Elderly Patients with Dementia].

General

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.

Carcinogenesis and Mutagenesis

For animal data, see TOXICOLOGY.

Cardiovascular

Orthostatic Hypotension and Syncope

LATUDA may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism.

LATUDA should be used with caution in elderly patients and 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.

Assessment of orthostatic hypotension was defined by vital sign changes (≥20 mmHg decrease in systolic blood pressure and ≥10 bpm increase in pulse from sitting to standing or supine to standing positions).

Schizophrenia

The incidence of orthostatic hypotension and syncope reported as adverse events from short- term, placebo-controlled schizophrenia studies was (LATUDA incidence; placebo incidence): orthostatic hypotension (5/1508 or 0.3% LATUDA; 1/708 or 0.1% placebo) and syncope (2/1508 or 0.1% LATUDA; 0/708 or 0% placebo). In short-term clinical trials orthostatic hypotension, as assessed by vital signs and occurring at any post-baseline assessment, occurred with a frequency of 4.2% with LATUDA 40 mg, 3.3% with LATUDA 80 mg, 3.7% with LATUDA 120 mg, and 2.5% with LATUDA 160 mg compared to 1.6% with placebo.

Bipolar Depression
Monotherapy

In the short-term, placebo-controlled monotherapy study, there were no reported adverse events of orthostatic hypotension or syncope. Orthostatic hypotension, as assessed by vital signs and occurring at any post-baseline assessment, occurred with a frequency of 6.8% in the LATUDA 20-60 mg and 4.3% in the LATUDA 80-120 mg flexible-dose groups compared to 1.2% with placebo.

Adjunctive Therapy

In the short-term, flexible-dose, placebo-controlled adjunctive therapy studies, there were no reported adverse events of orthostatic hypotension or syncope. Orthostatic hypotension, as assessed by vital signs and occurring at any post-baseline assessment, occurred with a frequency of 4.5% with LATUDA 20-120 mg compared to 4.9% with placebo.

QT Interval

Thorough QT Study

The effects of LATUDA on the QT/QTc interval were evaluated in a dedicated QT study. The trial involved LATUDA doses of 120 and 600 mg once daily and ziprasidone (80 mg twice daily) as a positive control. The study was conducted in 87 clinically stable patients with schizophrenia. ECG data were collected over an 8 hour time period on the baseline day (Day 0) and on Day 11 of the double-blind treatment period. Statistically significant increases from baseline in the QTcF (N=63) interval were observed from 1 to 8 hour post-dosing with lurasidone 120 mg, lurasidone 600 mg, and ziprasidone 160 mg. The maximum mean increases in QTcF from baseline were 11.6 msec for lurasidone 120 mg (N=22), 9.9 msec for lurasidone 600 mg (N=18), and 21.1 msec for ziprasidone (N=23). There was no apparent dose (exposure)-response relationship in this study. No patients treated with LATUDA experienced QTc increases ≥60 msec from baseline, or a QTc of ≥500 msec.

Phase 2/3 clinical studies

In the short-term, placebo-controlled trials, a single 12-lead ECG was recorded at screening, at baseline in most studies, and at one or more days during the double- blind period, at either pre-dose or at a single post-dosing time point. In the short-term, placebo- controlled trials, no post-baseline QTc prolongations exceeding 500 msec were reported in patients treated with LATUDA or placebo, or any of the active comparators.

The use of LATUDA should be avoided in combination with drugs known to prolong QTc including Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class 3 antiarrhythmics (e.g., amiodarone, sotalol), antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), and antibiotics (e.g., gatifloxacin, moxifloxacin). LATUDA should also be avoided in patients with a history of cardiac arrhythmias and in other circumstances that may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including bradycardia, hypokalemia, or hypomagnesemia; and presence of congenital prolongation of the QT interval.

Venous Thromboembolism

See also WARNINGS AND PRECAUTIONS, Hematologic, Venous Thromboembolism.

Dependence/Tolerance

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 behaviour, 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 behaviour, increases in dose).

Endocrine and Metabolism

Hyperglycemia and Diabetes Mellitus [see ADVERSE REACTIONS]

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. These cases were, for the most part, seen in post-marketing clinical use and epidemiologic studies, and not in clinical trials. Diabetic ketoacidosis (DKA) has occurred in patients treated with antipsychotics with no reported history of hyperglycemia.

In clinical trials, hyperglycemia or exacerbation of pre-existing diabetes has occasionally been reported during treatment with LATUDA.

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, which did not include LATUDA, 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. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.

Patients should have baseline and periodic monitoring of blood glucose and body weight. 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. 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. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control.

Hyperprolactinemia

As with other drugs that antagonize dopamine D2 receptors, LATUDA can elevate prolactin levels [see ADVERSE REACTIONS].

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 mineral 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 LATUDA carcinogenicity study conducted in rats and mice [see TOXICOLOGY]. The physiological differences between rats and humans with regard to prolactin make the clinical significance of these findings unclear. To date, neither clinical nor epidemiological studies have shown an association between chronic administration of these drugs and mammary tumorigenesis.

Schizophrenia

In short-term, placebo-controlled trials in patients with schizophrenia, the proportion of patients with prolactin elevations ≥5X ULN was 2.8% for LATUDA-treated patients versus 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥5X ULN was 5.7% for LATUDA-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.

Bipolar Depression
Monotherapy

In the short-term, placebo-controlled monotherapy study, the proportion of patients with prolactin elevations ≥5X ULN was 0.4% for LATUDA-treated patients versus 0.0% for placebo- treated patients. The proportion of female patients with prolactin elevations ≥5X ULN was 0.6% for LATUDA-treated patients versus 0% for placebo-treated female patients. There were no prolactin elevations ≥5X ULN in male patients

Adjunctive Therapy

In the short-term, flexible-dose, placebo-controlled adjunctive therapy studies, there were no patients with prolactin elevations ≥5X ULN.

Weight Gain

Schizophrenia

In pooled short-term (6-week) clinical trials, the mean change in weight was a 0.43 kg increase for LATUDA-treated patients compared to a 0.02 kg decrease for placebo-treated patients. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 4.8% for LATUDA-treated patients versus 3.3% for placebo-treated patients.

Bipolar Depression
Monotherapy

In the short-term, placebo-controlled monotherapy study, the mean weight gain was 0.29 kg for LATUDA-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 LATUDA-treated patients versus 0.7% for placebo-treated patients.

Adjunctive Therapy

In the short-term, flexible-dose, placebo-controlled adjunctive therapy studies, the mean weight gain was 0.11 kg for LATUDA-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 LATUDA-treated patients versus 0.3% for placebo-treated patients.

Gastrointestinal

Antiemetic Effect

Drugs that have dopamine antagonist effects may have an antiemetic effect. Such an effect may mask signs of toxicity due to overdosage of other drugs, or may mask symptoms of disease such as brain tumour or intestinal obstruction.

Genitourinary

Rare cases of priapism have been reported with antipsychotic use, such as LATUDA. This adverse reaction is generally not found to be dose-dependent or correlated with the duration of treatment.

Hematologic

Leukopenia, Neutropenia, and Agranulocytosis

Neutropenia, granulocytopenia, and agranulocytosis have been reported during antipsychotic use. Therefore, it is recommended that patients have their complete blood count (CBC) tested prior to starting LATUDA and then periodically throughout treatment.

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 <1 x 109/L) should discontinue LATUDA and have their WBC followed until recovery.

Venous Thromboembolism

Venous thromboembolism (VTE), including fatal pulmonary embolism, has been reported with antipsychotic drugs, including LATUDA, in case reports and/or observational studies. When prescribing LATUDA all potential risk factors for VTE should be identified and preventative measures undertaken.

Hepatic

See WARNINGS AND PRECAUTIONS, Special Populations, Use in Patients with Hepatic Impairment, DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY.

Neurologic

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 [see ADVERSE REACTIONS].

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.

In arriving at a diagnosis, it is important to identify 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 all antipsychotic drugs, including LATUDA, 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 uncomplicated NMS.

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

Tardive Dyskinesia [see ADVERSE REACTIONS]

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may 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.

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 [see ADVERSE REACTIONS]. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.

Potential for Cognitive and Motor Impairment

LATUDA, like other antipsychotics, has the potential to impair judgement, thinking, or motor skills [see ADVERSE REACTIONS]. Somnolence is a commonly reported adverse event in patients treated with LATUDA.

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.

Schizophrenia

In short-term, placebo-controlled schizophrenia studies, somnolence was reported in 17% of patients treated with LATUDA doses from 20 mg to 160 mg/day.

Bipolar Depression
Monotherapy

In the short-term, placebo-controlled monotherapy study, somnolence was reported by 7.3% (12/164) and 13.8% (23/167) of patients in the LATUDA 20-60 mg and LATUDA 80-120 mg flexible-dose groups, respectively, compared to 6.5% (11/168) of placebo patients.

Adjunctive Therapy

In the short-term, flexible-dose, placebo-controlled adjunctive therapy studies, somnolence was reported by 11.4% (41/360) of patients treated with LATUDA 20-120 mg compared to 5.1% (17/334) of placebo patients.

Psychiatric

Suicide [see ADVERSE REACTIONS]

Suicide/ suicidal thoughts or clinical worsening: Depressive episodes are associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission of depression occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery. In addition to depressive episodes associated with bipolar disorder, depression may be co-morbid with schizophrenia.

Schizophrenia is also associated with an increased risk of suicide-related events, and thus close supervision and appropriate clinical management of high risk patients should accompany drug therapy.

Patients with a history of suicide-related events are also known to be at a greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. 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.

Renal

See WARNINGS AND PRECAUTIONS, Special Populations, Use in Patients with Renal Impairment, DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY.

Special Populations

Pregnant Women

Teratogenic Effects

There are no adequate and well-controlled studies of LATUDA in pregnant woman. Lurasidone was not teratogenic in rats and rabbits [see also TOXICOLOGY, Reproductive and Developmental Toxicity].

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.

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with LATUDA. LATUDA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labour and Delivery

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

Nursing Women

LATUDA was excreted in milk of rats during lactation. It is not known whether LATUDA or its metabolites are excreted in human milk. It is recommended that women receiving LATUDA should not breast-feed.

Pediatrics (<18 years of age)

Safety and efficacy in pediatric patients have not been evaluated and its use is not recommended.

Geriatrics (≥65 years of age)

Clinical studies of LATUDA did not include sufficient numbers of patients aged 65 and older to determine whether or not they respond differently than younger patients. Caution should, thus, be exercised with the use of LATUDA in the elderly patient, recognizing the more frequent hepatic, renal, central nervous system and cardiovascular dysfunctions, and more frequent use of concomitant medications in this population [see also WARNINGS AND PRECAUTIONS,Hepatic, Renal, DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].

Use in Geriatric Patients with Dementia

Overall Mortality: Elderly patients with dementia treated with atypical antipsychotic drugs have an increased mortality compared to placebo in a meta-analysis of 13 controlled trials of various atypical antipsychotic drugs. LATUDA is not indicated in elderly patients with dementia (e.g., dementia-related psychosis) [see Boxed Warning].

Cerebrovascular Adverse Reactions, including Stroke

In placebo-controlled trials with some atypical antipsychotics 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 (e.g., dementia-related psychosis) [see Boxed Warning].

Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including LATUDA. 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.

Use in Patients with Hepatic Impairment

Caution should be exercised when starting LATUDA in patients with hepatic impairment. The recommended starting dose is 20 mg. Patients should be treated with the lowest effective dose that provides optimal clinical response and tolerability, which is expected to be 20-40 mg once daily for most patients with moderate or severe hepatic impairment (Child Pugh Class B and C). The dose should not exceed 40 mg/day in patients with severe hepatic impairment, and 80 mg/day in patients with moderate hepatic impairment [see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY].

Use in Patients with Renal Impairment

Caution should be exercised when starting LATUDA in patients with renal impairment. The recommended starting dose is 20 mg. Patients should be treated with the lowest effective dose that provides optimal clinical response and tolerability, which is expected to be 20-40 mg once daily for most patients with moderate and severe renal impairment (Clcr ≥10 mL/min to <50 mL/min). The dose should not exceed 80 mg/day in patients with moderate and severe renal impairment [see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY].

Use in Patients with Concomitant Illness

Clinical experience with LATUDA in patients with certain concomitant systemic illnesses is limited. 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.

Adverse reactions

Adverse Drug Reaction Overview

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

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Short-Term, Placebo-Controlled Trials of Patients with Schizophrenia

The following findings are based on the 7 short-term, placebo-controlled premarketing studies for schizophrenia in which LATUDA was administered at daily doses ranging from 20 to 160 mg (n=1508) for up to 6 weeks [see also CLINICAL TRIALS].

Commonly Observed Treatment-emergent Adverse Events

The most common adverse events (incidence ≥5% in all pooled lurasidone patients in the short-term trials and at least twice the rate of placebo) in patients treated with LATUDA were: nausea, somnolence, akathisia, and parkinsonism (see Table 1).

Treatment-emergent Adverse Events Associated with Discontinuation of Treatment

A total of 9.5% (143/1508) of LATUDA-treated patients and 9.3% (66/708) of placebo-treated patients discontinued due to adverse events. There were no adverse events associated with discontinuation in subjects treated with LATUDA that were at least 2% and at least twice the placebo rate. The most frequent adverse events leading to discontinuation in LATUDA-treated patients were psychiatric events related to worsening of schizophrenia (3.4%) and EPS events (1.9%). Of the EPS events, akathisia was 1.4%.

Treatment-emergent Adverse Events Occurring at an Incidence of 2% or More in LATUDA- treated Patients

Adverse events associated with the use of LATUDA by dose group (pooled from different studies for the 40 mg, 80 mg, and 120 mg doses) and all doses pooled (incidence of 2% or greater, rounded to the nearest percent, and LATUDA incidence greater than placebo in all doses pooled) that occurred during acute therapy (up to 6-weeks in patients with schizophrenia) are shown in Table 1.

Table 1: Treatment-emergent Adverse Events in 2% or More of LATUDA-treated
Patients and that Occurred at Greater Incidence than in the Placebo-treated
Patients in Short-term Schizophrenia Studies
Percentage of Patients Reporting Event
Body System or
Organ Class
Placebo
(N=708)
LATUDA
20 mg/d
(N=71)
LATUDA
40 mg/d
(N=487)
LATUDA
80 mg/d
(N=538)
LATUDA
120 mg/d
(N=291)
LATUDA
160 mg/d
(N=121)
ALL
LATUDA
(N=1508)
Gastrointestinal Disorders
Nausea 5% 11% 10% 9% 13% 7% 10%
Vomiting 6% 7% 6% 9% 9% 7% 8%
Dyspepsia 5% 11% 6% 5% 8% 6% 6%
Salivary
Hypersecretion
<1% 1% 1% 2% 4% 2% 2%
Musculoskeletal and Connective Tissue Disorders
Back Pain 2% 0% 4% 3% 4% 0% 3%
Nervous System Disorders
Somnolence* 7% 15% 16% 15% 26% 8% 17%
Akathisia 3% 6% 11% 12% 22% 7% 13%
Parkinsonism** 5% 6% 9% 8% 17% 11% 10%
Dizziness 2% 6% 4% 4% 5% 6% 4%
Dystonia*** <1% 0% 3% 4% 7% 2% 4%
Psychiatric Disorders
Insomnia 8% 8% 10% 11% 9% 7% 10%
Agitation 4% 10% 7% 3% 6% 5% 5%
Anxiety 4% 3% 6% 4% 7% 3% 5%
Restlessness 1% 1% 3% 1% 3% 2% 2%

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

Short-Term, Placebo-Controlled Trials of Patients with Bipolar Depression

Monotherapy

The following findings are based on the short-term, placebo-controlled, monotherapy study for bipolar depression (involving lower and higher dose ranges) in which LATUDA was administered at daily doses ranging from 20 to 120 mg (n=331).

Commonly Observed Treatment-emergent Adverse Events:The most common adverse events (incidence ≥ 5% and at least twice the rate of placebo) in patients treated with LATUDA were akathisia and parkinsonism.

Treatment-emergent Adverse Events Associated with Discontinuation of Treatment:A total of 6.0% (20/331) of LATUDA-treated patients and 5.4% (9/168) of placebo-treated patients discontinued due to adverse events. There were no adverse events associated with discontinuation in subjects treated with LATUDA that were at least 2% and at least twice the placebo rate.

Treatment-emergent Adverse Events Occurring at an Incidence of 2% or More in LATUDA- treated Patients:Adverse events 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 bipolar depression) are shown in Table 2.

Table 2: Treatment-emergent Adverse Events in 2% or More of LATUDA-treated Patients (Monotherapy) and that Occurred at Greater Incidence than in the Placebo-treated Patients in a Short-term Bipolar Depression Study
Percentage of Patients Reporting Reaction
Body System or Organ Class
Dictionary-derived Term
Placebo
(N=168)
(%)
LATUDA
20-60
mg/day
(N=164)
(%)
LATUDA
80-120
mg/day
(N=167)
(%)
All
LATUDA(
N=331)
(%)
Gastrointestinal Disorders
Nausea 8 10 17 14
Dry Mouth 4 6 4 5
Vomiting 2 2 6 4
Diarrhea 2 5 3 4
Infections and infestations
Nasopharyngitis 1 4 4 4
Influenza 1 <1 2 2
Urinary Tract Infection <1 2 1 2
Musculoskeletal and Connective Tissue
Disorders
Back Pain <1 3 <1 2
Nervous System Disorders
Extrapyramidal Symptoms* 2 5 9 7
Somnolence** 7 7 14 11
Akathisia 2 8 11 9
Psychiatric Disorders
Anxiety 1 4 5 4

Note: Figures rounded to the nearest integer

*Extrapyramidal symptoms includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, dystonia, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, tongue spasm, torticollis, tremor, and trismus

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

Adjunctive Therapy

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

Commonly Observed Treatment-emergent Adverse Events:The most common adverse events (incidence >5% and at least twice the rate of placebo) in subjects treated with Latuda were akathisia and somnolence.

Treatment-emergent Adverse Events Associated with Discontinuation of Treatment:A total of 5.8% (21/360) of LATUDA-treated patients and 4.8% (16/334) of placebo-treated patients discontinued due to adverse events. There were no adverse events associated with discontinuation in subjects treated with LATUDA that were at least 2% and at least twice the placebo rate.

Treatment-emergent Adverse Events Occurring at an Incidence of 2% or More in LATUDA- treated Patients:Adverse events 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 bipolar depression) are shown in Table 3.

Table 3: Treatment-emergent Adverse Events in 2% or More of LATUDA-treated Patients (Adjunctive Therapy) and that Occurred at Greater Incidence than in the Placebo-treated Patients in a Short-term Bipolar Depression Study
Percentage of Patients Reporting Reaction
Body System or Organ Class
Dictionary-derived Term
Placebo
(N=334)
LATUDA
(N=360)
Gastrointestinal Disorders
Nausea 10 14
Vomiting 1 4
General Disorders
Fatigue 1 3
Infections and Infestations
Nasopharyngitis 2 4
Investigations
Weight increased 1 3
Metabolism and Nutrition Disorders
Increased Appetite13
Nervous System Disorders
Extrapyramidal disorder** 9 14
Somnolence* 5 11
Akathisia 5 11
Psychiatric Disorders
Restlessness 1 4

Note: Figures rounded to the nearest integer

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

**Extrapyramidal symptoms includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, dystonia, extrapyramidal disorder, hypokinesia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, tongue spasm, torticollis, tremor, and trismus

Treatment-emergent Adverse Events by Concomitant Use of Lithium or Valproate:A higher incidence of treatment-emergent adverse-events was reported for LATUDA administered with lithium compared with LATUDA administered with valproate. Treatment-emergent adverse events associated with use of LATUDA and lithium-treated subjects with an incidence ≥ 5% and at least twice the rate of LATUDA and valproate-treated subjects were parkinsonism (19% versus 8%).

Dose-Related Adverse Events:

Schizophrenia

In pooled data from the short-term, placebo-controlled, fixed-dose studies, there were no dose- related adverse events (greater than 5% incidence) in patients treated with LATUDA across the 20 mg/day to 160 mg/day dose range. However, the frequency of akathisia increased with dose up to 120 mg/day (5.6% LATUDA 20 mg, 10.7% LATUDA 40 mg, 12.3% LATUDA 80 mg, and 22.0% LATUDA 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.

Bipolar Depression
Monotherapy

In the short-term, placebo-controlled monotherapy study (involving lower and higher LATUDA dose ranges), the adverse events that occurred with a greater than 5% incidence in the patients treated with LATUDA 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%), parkinsonism (4.9%, 7.8%), and insomnia (4.9%, 6.6%) for LATUDA 20-60 mg/day and LATUDA 80-120 mg/day flexible-dose groups, respectively.

Extrapyramidal Symptoms:

Schizophrenia

In the short-term, placebo-controlled schizophrenia studies, for LATUDA-treated patients, the incidence of reported EPS-related events, excluding akathisia and restlessness, was 13.5% versus 5.8% for placebo-treated patients. The incidence of akathisia for LATUDA-treated patients was 12.9% versus 3.0% for placebo-treated patients. The frequency of EPS events in general increased with dose up to 120 mg/day. Incidence of EPS by dose is provided in Table 4.

Percentage of EPS Compared to Placebo in Short-term Schizophrenia
Studies
Adverse Event Term Placebo
(N=708)

(%)
LATUDA
20 mg/day
(N=71)

(%)
LATUDA
40 mg/day
(N=487)

(%)
LATUDA
80 mg/day
(N=538)

(%)
LATUDA
120
mg/day

(N=291)

(%)
LATUDA
160
mg/day

(N=121)

(%)
All EPS events 9 10 21 23 39 20
All EPS events,excluding Akathisia/Restlessness 6 6 11 12 22 13
Akathisia 3 6 11 12 22 7
Dystonia* <1 0 4 5 7 2
Parkinsonism** 5 6 9 8 17 11
Restlessness 1 1 3 1 3 2

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, drooling, extrapyramidal disorder, hypokinesia, muscle rigidity, ph5arkinsonism, psychomotor retardation, and tremor

Bipolar Depression
Monotherapy

In the short-term, placebo-controlled monotherapy study, for LATUDA-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 LATUDA-treated patients was 9.4% versus 2.4% for placebo-treated patients. Incidence of EPS by dose groups is provided in Table 5.

Table 5: Percentage of EPS Compared to Placebo in the Monotherapy Bipolar Depression Study
LATUDA
Adverse Event Term Placebo
(N=168)
(%)
20 to 60 mg/day
(N=164)
(%)

80 to 120 mg/day
(N=167)
(%)
All EPS events 5 12 20
All EPS events,
excluding
Akathisia/Restlessness
2 5 9
Akathisia 2 8 11
Dystonia* 0 0 2
Parkinsonism** 2 5 8
Restlessness <1 0 3

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, drooling, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor

Adjunctive Therapy

In the short-term, flexible-dose, placebo-controlled adjunctive therapy studies, for LATUDA- treated patients, the incidence of reported events related to EPS, excluding akathisia and restlessness, was 13.9% versus 8.7% for placebo-treated patients. The incidence of akathisia for LATUDA-treated patients was 10.8 % versus 4.8% for placebo-treated patients. Incidence of EPS is provided in Table 6.

Table 6: Percentage of EPS Compared to Placebo in the Adjunctive Therapy Bipolar Depression Studies
Adverse Event Term Placebo
(N=334)
(%)
All LATUDA
(N=360)
(%)
All EPS events 13 24
All EPS events,excludingAkathisia/Restlessness 9 14
Akathisia 5 11
Dystonia* 1 1
Parkinsonism** 8 13
Restlessness 1 4

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, drooling, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor

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

The mean change from baseline to last assessment for LATUDA-treated patients was comparable to placebo-treated patients, with the exception of the BAS total score (LATUDA, 0.2; placebo, 0.0) and global clinical assessment score (LATUDA, 0.1; placebo, 0.0). The percentage of patients who shifted from normal/questionable at baseline to abnormal at any post- baseline assessment was greater in LATUDA-treated patients versus placebo for the BAS global clinical assessment (LATUDA, 18.0%; placebo, 7.8%) and the SAS score (LATUDA, 14.9%; placebo, 6.2%).

Bipolar Depression
Monotherapy

The mean change from baseline for LATUDA-treated patients for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal/questionable at baseline to abnormal at any post-baseline assessment was greater in LATUDA-treated patients versus placebo for the BAS global clinical assessment (LATUDA, 12.1%; placebo, 3.7%) and the SAS score (LATUDA, 8.4%; placebo, 4.3%).

Adjunctive Therapy

The mean change from baseline for LATUDA-treated patients for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal/questionable at baseline to abnormal at any post-baseline assessment was greater in LATUDA-treated patients versus placebo for the BAS global clinical assessment (LATUDA, 12.2%; placebo, 3.2%) and the SAS score (LATUDA, 8.2%; placebo, 6.1%) and the AIMS (LATUDA 1.7%, placebo 0.6%).

Dystonia

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.

Schizophrenia

In the short-term, placebo-controlled clinical trials, dystonia occurred in 4.2% of LATUDA- treated subjects (0.0% LATUDA 20 mg, 3.5% LATUDA 40 mg, 4.5% LATUDA 80 mg, 6.5% LATUDA 120 mg, and 2.5% LATUDA 160 mg) compared to 0.8% of subjects receiving placebo. Seven subjects (0.5%, 7/1508) discontinued clinical trials due to dystonic events – four were receiving LATUDA 80 mg/day and three were receiving LATUDA 120 mg/day.

Bipolar Depression
Monotherapy

In the short-term, placebo-controlled monotherapy study, dystonia occurred in 0.9% of LATUDA-treated subjects (0.0% and 1.8% for LATUDA 20-60 mg/day and LATUDA 80-120 mg/day flexible-dose groups, respectively) compared to 0.0% of subjects receiving placebo. No subject discontinued the clinical study due to dystonic events.

Adjunctive Therapy

In the short-term, flexible-dose, placebo-controlled adjunctive therapy studies, dystonia occurred in 1.1% of LATUDA-treated subjects (20-120 mg) compared to 0.6% of subjects receiving placebo. No subject discontinued the clinical study due to dystonic events.

Weight Gain:

Schizophrenia

Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 7. The mean weight change was a 0.43 kg increase for LATUDA-treated patients compared to a 0.02 kg decrease for placebo-treated patients. In two 6-week studies that included active comparators, the mean weight gain at the last assessment in the study was 0.98 kg for LATUDA 40 mg, 1.05 kg for LATUDA 120 mg, and 4.15 kg for olanzapine 15 mg in one study, and 0.62 kg for LATUDA 80 mg, 0.60 kg for LATUDA 160 mg, and 2.09 kg for quetiapine XR 600 mg in another study. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 4.8% for LATUDA-treated patients versus 3.3% for placebo-treated patients.

Table 7:Mean Change in Weight (kg) from Baseline to Last Assessment in Short-term Studies in Schizophrenia Studies
Placebo
(n=696)
LATUDA
20 mg/day
(n=71)
LATUDA
40 mg/day
(n=484)
LATUDA
80 mg/day
(n=526)
LATUDA
120 mg/day
(n=291)
LATUDA
160 mg/day
(n=114)
All Patients -0.02 -0.15 0.22 0.54 0.68 0.60
Bipolar Depression
Monotherapy

Data from the short-term, placebo-controlled monotherapy study are presented in Table 8. The mean weight gain was 0.29 kg for LATUDA-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 LATUDA-treated patients versus 0.7% for placebo-treated patients.

Table 8: Mean Change in Weight (kg) from Baseline in the Monotherapy Bipolar Depression Study
LATUDA
Placebo
(n=151)
20 to 60 mg/day
(n=143)
80 to 120 mg/day
(n=147)
All Patients -0.04 0.56 0.02

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

Adjunctive Therapy

Data from the short-term, flexible-dose, placebo-controlled adjunctive therapy studies are presented in Table 9. The mean weight gain was 0.11 kg for LATUDA-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 LATUDA-treated patients versus 0.3% for placebo-treated patients.

Table 9: Mean Change in Weight (kg) from Baseline in the Adjunctive Therapy Bipolar Depression Studies
LATUDA
Placebo
(n=334)
20 to 120 mg/day
(n=360)
All Patients 0.16 0.11

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

Constipation

Patients should be advised of the risk of severe constipation during LATUDA treatment, and they should tell their doctor if constipation occurs or worsens, since they may need laxatives.

Less Common Clinical Trial Adverse Drug Reactions (<2%)

Following is a list of MedDRA terms that reflect adverse events reported by patients treated with LATUDA at multiple doses of ≥20 mg once daily during any phase of a study within the database of 2905 patients. The events listed are those that could be of clinical importance, as well as events that are plausibly drug-related on pharmacologic or other grounds. Events listed in Table 1 are not included. Although the events reported occurred during treatment with LATUDA, they were not necessarily caused by it.

Events 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, ventricular extrasystoles, arrhythmia

Ear and Labyrinth Disorders:

Infrequent: tinnitus, vertigo

Eye Disorders:

Frequent: blurred vision;

Infrequent: visual impairment

Gastrointestinal Disorders:

Frequent: abdominal pain, constipation, diarrhea, dry mouth;

Infrequent: gastritis, gastroesophageal reflux disease, dysphagia, tongue disorder;

Rare: swollen tongue

General Disorders and Administrative Site Conditions:

Frequent: fatigue, pyrexia;

Infrequent: asthenia, gait disturbance, irritability, peripheral edema, sudden death

Hepatobiliary Disorders:

Infrequent: hepatic function abnormal, hepatic steatosis, jaundice

Immune System Disorders:

Rare: drug hypersensitivity

Investigations:

Frequent: blood prolactin increased, blood triglycerides increased, CPK increased, weight increased, weight decreased;

Infrequent: blood pressure decreased, blood uric acid increased, body temperature increased, white blood cell count increased;

Rare: electrocardiogram T wave inversion

Metabolism and Nutritional System Disorders:

Frequent: decreased appetite;

Infrequent: anorexia, dehydration, diabetes mellitus, increased appetite

Musculoskeletal and Connective Tissue Disorders:

Frequent: musculoskeletal stiffness, myalgia;

Rare: rhabdomyolysis

Nervous System Disorders:

Frequent: dyskinesia;

Infrequent: tardive dyskinesia, cerebrovascular accident, convulsion, dysarthria, dysgeusia, hypoaesthesia, paresthesia, syncope;

Rare: neuroleptic malignant syndrome, seizure

Psychiatric Disorders:

Frequent: depression;

Infrequent: abnormal dreams, apathy, confusional state, hostility, panic attack, sleep disorder, suicidal ideation, completed suicide, suicide attempt;

Rare: somnambulism, suicidal behavior

Renal and Urinary Disorders:

Infrequent: dysuria, urinary incontinence;

Rare: renal failure

Reproductive System and Breast Disorders:

Infrequent: amenorrhea, dysmenorrhea, menstruation irregular, erectile dysfunction;

Rare: breast enlargement, breast pain, galactorrhea

Respiratory disorders:

Infrequent: dyspnea;

Rare: pneumonia aspiration

Skin and Subcutaneous Tissue Disorders:

Frequent: rash (including erythematous, exfoliative, generalized, maculopapular, papular rash, pruritic; atopic, allergic, contact, seborrheic dermatitis, neurodermatitis), pruritus; Infrequent: hyperhidrosis, urticaria;

Rare: angioedema

Vascular Disorders:

Frequent: hypertension;

Infrequent: hot flush, hypotension, orthostatic hypotension;

Rare: thrombophlebitis superficial

Abnormal Hematologic and Clinical Chemistry Findings

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 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].

Glucose:

Schizophrenia

Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 10.

Table 10: Change in Fasting Glucose in Schizophrenia Studies from Baseline to Last Study Assessment in Pooled Short-term Studies
Placebo LATUDA
20 mg/day
LATUDA
40 mg/day
LATUDA
80 mg/day
LATUDA
120 mg/day
LATUDA
160 mg/day
Mean Change from Baseline (mmol/L)
n=601 n=70 n=417 n=481 n=220 N=97
Serum Glucose 0.03 -0.11 0.13 -0.01 0.12 0.21
Proportion of Patients with Shifts ≥7 mmol/L
Serum Glucose
( ≥7 mmol/L)
5.8%
(33/565)
8.2%
(5/61)
9.6%
(38/395)
5.3%
(24/452)
4.8%
(10/209)
5.3%
(5/95)
Bipolar Depression
Monotherapy

Data from the short-term, placebo-controlled monotherapy study are presented in Table 11.

Table 11: Change in Fasting Glucose in the Monotherapy Bipolar Depression Study
LATUDA
Placebo 20 to 60 mg/day 80 to 120 mg/day
Mean Change from Baseline (mmol/L)
n=148 n=140 n=143
Serum Glucose 0.10 -0.04 0.10
Proportion of Patients with Shifts to ≥7 mmol/L
Serum Glucose
(≥7 mmol/L)
4.3%
(6/141)
2.2%
(3/138)
6.4%
(9/141)

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

Adjunctive Therapy

Data from the short-term, flexible-dose, placebo-controlled adjunctive therapy studies are presented in Table 12.

Table 12: Change in Fasting Glucose in the Adjunctive Therapy Bipolar Depression Studies
LATUDA
Placebo 20 to 120 mg/day
Mean Change from Baseline (mmol/L)
n=302 n=319
Serum Glucose 0.05 0.07
Proportion of Patients with Shifts to ≥ 7 mmol/L
Serum Glucose
(≥ 7 mmol/L)
1.0%
(3/290)
1.3%
(4/316)

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

Cholesterol and Triglycerides:

Schizophrenia

Pooled data from short-term, placebo-controlled schizophrenia studies with lurasidone are presented in Table 13.

Table 13: Change in Fasting Lipids in Schizophrenia Studies from Baseline to Last Study Assessment in Pooled Short-term Studies
Placebo LATUDA
20 mg/day
LATUDA
40 mg/day
LATUDA
80 mg/day
LATUDA
120 mg/day
LATUDA
160 mg/day
Mean Change from Baseline (mmol/L)
n=567 n=70 n=387 n=465 n=182 n=100
Total cholesterol -0.15 -0.29 -0.12 -0.15 -0.13 -0.19
Triglycerides -0.17 -0.36 -0.11 -0.18 -0.06 -0.17
Proportion of Patients with Shifts
Total cholesterol
( ≥6.2 mmol/L)
5.2%
(26/497)
12.1%
(7/58)
5.6%
(19/339)
5.2%
(21/405)
2.5%
(4/161)
4.5%
(4/88)
Triglycerides
( ≥2.3 mmol/L)
7.7%
(36/467)
10.0%
(5/50)
7.4%
(24/323)
5.9%
(22/371)
6.5%
(10/154)
4.7%
(4/85)
Bipolar Depression
Monotherapy

Data from the short-term, placebo-controlled, monotherapy study are presented in Table 14.

Table 14: Change in Fasting Lipids in the Monotherapy Bipolar Depression Study
LATUDA
Placebo 20 to 60 mg/day 80 to 120 mg/day
Mean Change from Baseline (mmol/L)
n=133 n=125 n=134
Total cholesterol -0.09 0.04 -0.13
Triglycerides 0.02 0.08 0.02
Proportion of Patients with Shifts
Total cholesterol
(≥ 6.2 mmol/L)
3.8%
(4/104)
3.9%
(4/102)
4.7%
(5/107)
Triglycerides
(≥ 2.3 mmol/L)
3.5%
(4/114)
11.1%
(12/108)
10.4%
(12/115)

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

Adjunctive Therapy

Data from the short-term, flexible-dose, placebo-controlled, adjunctive therapy studies are presented in Table 15.

Table 15: Change in Fasting Lipids in the Adjunctive Therapy Bipolar Depression Studies
LATUDA
Placebo 20 to 120 mg/day
Mean Change from Baseline (mmol/L)
n=273 n=290
Total cholesterol -0.08 -0.10
Triglycerides -0.11 0.11
Proportion of Patients with Shifts
Total cholesterol
(≥ 6.2 mmol/L)
6.0%
(14/235)
5.6%
(14/251)
Triglycerides
(≥ 2.3 mmol/L)
8.6%
(19/220)
10.8%
(26/240)

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

Hyperprolactinemia:

Schizophrenia

In short-term, placebo-controlled schizophrenia studies, the median change from baseline to endpoint in prolactin levels for LATUDA-treated patients was 0.4 ng/mL and -1.9 ng/mL in 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. The mean change from baseline to endpoint in prolactin levels in LATUDA-treated patients with normal prolactin levels at baseline (n=1039) was 8.6 ng/mL compared to 0.4 ng/mL in placebo-treated patients (n=460), and was higher in female patients (18.4 ng/mL) compared to male patients (4.8 ng/mL).

The proportion of patients with prolactin elevations ≥5X ULN was 2.8% for LATUDA-treated patients versus 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥5X ULN was 5.7% for LATUDA-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. The proportion of patients with elevations (≥5X ULN) in prolactin at any post-baseline assessment in the pooled short-term studies is shown in Table 16.

Table 16: Proportion of Patients with Elevations (≥5X ULN) in Prolactin (ng/mL) at any Post-baseline Assessment in Pooled Short-term Schizophrenia Studies
Placebo LATUDA
20 mg/day
LATUDA
40 mg/day
LATUDA
80 mg/day
LATUDA
120 mg/day
LATUDA
160 mg/day
All Patients 1.0%
(n=673)
2.9%
(n=70)
2.9%
(n=476)
2.2%
(n=495)
4.2%
(n=284)
0.9%
(n=115)
Females 2.0%
(n=200)
10.5%
(n=19)
6.0%
(n=149)
3.3%
(n=150)
10.0%
(n=70)
2.8%
(n=36)
Males 0.6%
(n=473)
0%
(n=51)
1.5%
(n=327)
1.7%
(n=345)
2.3%
(n=214)
0%
(n=79)
Bipolar Depression
Monotherapy

The median change from baseline to endpoint in prolactin levels, in the short-term, placebo- controlled monotherapy study, was 1.7 ng/mL and 3.5 ng/mL with LATUDA 20-60 mg/day and LATUDA 80-120 mg/day flexible-dose groups, respectively, compared to 0.3 ng/mL with placebo-treated patients. The median change from baseline to endpoint for males was 1.5 ng/mL and for females was 3.1 ng/mL, the mean change from baseline to endpoint in prolactin levels in LATUDA-treated patients with normal prolactin levels at baseline (n=260) was 6.5 ng/mL compared to 1.4 ng/mL in placebo-treated patients (n=130), and was higher in female patients (7.7 ng/mL) compared to male patients (4.9 ng/mL).

The proportion of patients with prolactin elevations ≥5X upper limit of normal (ULN) was 0.4% for LATUDA-treated patients versus 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥5x ULN was 0.6% for LATUDA-treated patients versus 0% for placebo-treated female patients. There were no prolactin elevations ≥5x ULN in male patients. The proportion of patients with elevations (≥5X ULN) in prolactin at any post- baseline assessment is shown in Table 17.

Table 17: Proportion of Patients with Elevations (≥5X ULN) in Prolactin (ng/mL) at any Post-baseline Assessment in the Monotherapy Bipolar Depression Study
Placebo LATUDA
20 to 60 mg/day
LATUDA
80 to 120 mg/day
All Patients 0%
(n=147)
0.7%
(n=140)
0%
(n=144)
Females 0%
(n=82)
1.3%
(n=78)
0%
(n=88)
Adjunctive Therapy

The median change from baseline to endpoint in prolactin levels, in the short-term, flexible-dose, placebo-controlled adjunctive therapy studies, was 2.8 ng/mL with LATUDA 20-120 mg/day compared to 0.0 ng/mL with placebo-treated patients. The median change from baseline to endpoint for males was 2.4 ng/mL and for females was 3.2 ng/mL. The mean change from baseline to endpoint in prolactin levels in LATUDA-treated patients with normal prolactin levels at baseline (n=291) was 6.2 ng/mL compared to 0.9 ng/mL in placebo-treated patients (n=274), and was higher in female patients (8.4 ng/mL) compared to male patients (3.9 ng/mL). There were no patients with prolactin elevations ≥5X ULN.

Creatinine:

Schizophrenia

In short-term, placebo-controlled trials, the mean change from baseline in creatinine was 5.3 μ mol/L for LATUDA-treated patients compared to 1.7 μmol/L for placebo-treated patients. A creatinine shift from normal to high occurred in 3.0% (43/1453) of LATUDA-treated patients and 1.6% (11/681) on placebo. The mean changes from baseline and the proportion of shifts to high generally increased with increased lurasidone doses (Table 18). The threshold for high creatinine values varied from >70 to >115 μmol/L based on the centralized laboratory definition for each study [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS, Special Populations].

Table 18:Change in Creatinine from Baseline to Last Study Assessment in Pooled
Placebo LATUDA
20 mg/day
LATUDA
40 mg/day
LATUDA
80 mg/day
LATUDA
120 mg/day
LATUDA
160 mg/day
Mean Change from Baseline (μmol/L)
n=681 n=71 n=478 n=506 n=283 n=115
Creatinine 1.8 2.7 3.5 4.4 6.2 8.8
Proportion of Patients with Shifts from Normal to Abnormal
Creatinine 1.6%
(11/681)
1.4%
(1/71)
1.9%
(9/478)
2.2%
(11/506)
4.9%
(14/283)
7.0%
(8/115)
Bipolar Depression
Monotherapy

In the short-term, placebo-controlled monotherapy study, the mean change from Baseline in creatinine was 0.9 μmol/L for LATUDA-treated patients compared to -1.8 μmol/L for placebo- treated patients. A creatinine shift from normal to high occurred in 2.8% (9/322) of LATUDA- treated patients and 0.6% (1/162) on placebo (Table 19).

Table 19:Change in Creatinine from Baseline to Last Study Assessment in the
Placebo LATUDA
20 to 60 mg/day
LATUDA
80 to 120 mg/day
Mean Change from Baseline (μmol/L)
n=162 n=161 n=161
Creatinine -1.8 0.9 1.8
Proportion of Patients with Shifts from Normal to Abnormal
Creatinine 0.6%
(1/162)
1.9%
(3/161)
3.7%
(6/161)
Adjunctive Therapy

In the short-term, flexible-dose, placebo-controlled adjunctive therapy studies, the mean change from Baseline in creatinine was 3.5 μ mol/L for LATUDA-treated patients compared to -0.9 μ mol/L for placebo-treated patients. A creatinine shift from normal to high occurred in 4.3% (15/348) of LATUDA-treated patients and 1.6% (5/316) on placebo (Table 20).

Table 20:Change in Creatinine from Baseline to Last Study Assessment in the
Placebo LATUDA
20 to 120 mg/day
Mean Change from Baseline (μmol/L)
n=316 n=348
Creatinine -0.9 3.5
Proportion of Patients with Shifts from Normal to Abnormal
Creatinine 1.6%
(5/316)
4.3%
(15/348)

Drug interactions

Overview

LATUDA is contraindicated with strong CYP3A4 inhibitors (e.g., ketoconazole) and strong CYP3A4 inducers (e.g., rifampin) [see CONTRAINDICATIONS]. LATUDA should be started at a dose of 20 mg/day, and the dose should not exceed 40 mg/day if coadministered with moderate CYP3A4 inhibitors.

The use of LATUDA should be avoided in combination with drugs known to prolong QTc interval or cause electrolyte disturbances [see WARNINGS AND PRECAUTIONS,Cardiovascular, QT Interval].

Drug-Drug Interactions

Potential for Other Drugs to Affect LATUDA

LATUDA is predominantly metabolized by CYP3A4; interaction of LATUDA with strong and moderate inhibitors or inducers of this enzyme has been observed (Table 21). LATUDA is contraindicated in combination with strong inhibitors or inducers of this enzyme [see CONTRAINDICATIONS].

Table 21:Summary of Effect of Coadministered Drugs on Exposure to LATUDA in
Coadministered
Drug
Ref Dose Schedule Effect on LATUDA
Pharmacokinetics
Recommendation
Coadministered
Drug
LATUDA Cmax AUC
Ketoconazole


(strong CYP3A4

inhibitor)
CT 400 mg/day
for 5 days
10 mg
single dose
6.9-times

LATUDA

alone
9.0-times
LATUDA
alone
Contraindicated in

combination with

LATUDA
Diltiazem


(moderate CYP3A4

inhibitor)
CT 240 mg/day
for 5 days
20 mg
single dose
2.1-times

LATUDA

alone
2.2-times

LATUDA

alone
LATUDA dose

should not exceed

40 mg/day if

coadministered
Rifampin


(strong CYP3A4

inducer)
CT 600 mg/day
for 8 days
40 mg
single dose
1/7th
of
LATUDA
alone
1/5th
of
LATUDA
alone
Contraindicated in

combination with

LATUDA
Lithium CT 600 mg BID
for 8 days
120 mg/day
for 8 days
0.9-times

LATUDA

alone
1.1-times

LATUDA

alone
No LATUDA dose

adjustment required.

Legend: CT = Clinical Trial

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 mean Cmax and AUC(0-24) for digoxin by approximately 9% and 13%, respectively, relative to digoxin alone. Digoxin dose adjustment is not generally 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 norelgestromin 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 LATUDA and OC. Dose adjustment of OC dose is not required when coadministered with LATUDA.

Drug-Food Interactions

LATUDA should be taken with food (at least 350 calories independent of fat content) [see ACTION AND CLINICAL PHARMACOLOGY].

Grapefruit, grapefruit juice, and products containing grapefruit extract should be avoided during treatment with LATUDA because of the potential to inhibit CYP3A4.

Drug-Herb Interactions

Interactions with herbal products have not been studied.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been identified.

Drug-Lifestyle Interactions

Alcohol/CNS Drugs

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

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.

Dosage and administration

Dosing Considerations

  • LATUDA should be administered with food (at least 350 calories independent of fat content). The Cmax of lurasidone is increased approximately 3-fold and the AUC is increased approximately 2-fold in the presence of food.

Recommended Dose and Dosage Adjustment

Schizophrenia

The recommended starting dose of LATUDA is 40 mg once daily. In placebo-controlled clinical trials, once daily doses of 40, 80, 120, and 160 mg were shown to be effective. Patients should be treated with the lowest effective dose that provides optimal clinical response and tolerability, which is expected to be 40 mg or 80 mg once daily for most patients. Doses above 80 mg may be considered for certain patients based on individual clinical judgement.

Doses below 40 mg have not been shown to be effective in patients with schizophrenia.

Bipolar Depression

The recommended starting dose of LATUDA is 20 mg given once daily as monotherapy or as adjunctive therapy with lithium or valproate. In placebo-controlled trials, once daily doses in the range of 20 mg/day to 120 mg/day as monotherapy or as adjunctive therapy with lithium or valproate were studied. In the only study that compared different LATUDA dosage strengths, efficacy of LATUDA was demonstrated in both 20 mg-60mg/day and 80-120 mg/day dosage arms. No additional benefit however, was seen in the higher dose arm (See Part II: CLINICALTRIALS). Thus, a usual treatment dose range of 20 mg-60 mg/day as monotherapy or adjunctive therapy with lithium or valproate is recommended. As the incidence of certain adverse events increase with dose (see ADVERSE REACTIONS) patients should be treated with the lowest effective dose of LATUDA.

In bipolar depression, the safety of doses above 120 mg/day has not been evaluated. In addition, the efficacy of doses below 20mg/day has not been studied.

Switching from Other Antipsychotics

There are no systematically collected data to specifically address switching patients from other antipsychotics to LATUDA or concerning concomitant administration with other antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized.

Dosing Considerations for Special Populations

Geriatrics (>65 years of age):

LATUDA is not indicated in elderly patients with dementia [see WARNINGS AND PRECAUTIONS, Serious Warnings and Precautions Box and Special Populations].

The safety and efficacy of LATUDA in patients 65 years of age or older has not been established. Caution should, thus, be exercised with the use of LATUDA in the elderly patient, recognizing the more frequent hepatic, renal, central nervous system and cardiovascular dysfunctions, and more frequent use of concomitant medications in this population.

Age, Gender, and Race

Dosage adjustments are not recommended on the basis of age, gender, and race [see ACTION AND CLINICAL PHARMACOLOGY].

Renal Impairment

Dose adjustment is recommended in moderate and severe renal impairment patients. Caution should be exercised when starting LATUDA in patients with renal impairment. The recommended starting dose is 20 mg. Patients should be treated with the lowest effective dose that provides optimal clinical response and tolerability, which is expected to be 20-40 mg once daily for most patients with moderate or severe renal function impairment. The dose should not exceed 80 mg/day in patients with moderate and severe renal impairment [see ACTION AND CLINICAL PHARMACOLOGY].

Hepatic Impairment

Dose adjustment is recommended in moderate and severe hepatic impairment patients. Caution should be exercised when starting LATUDA in patients with hepatic impairment. The recommended starting dose is 20 mg. Patients should be treated with the lowest effective dose that provides optimal clinical response and tolerability, which is expected to be 20-40 mg once daily for most patients with moderate or severe hepatic impairment (Child Pugh Class B and C). The dose in these patients should not exceed 40 mg/day in patients with severe hepatic impairment, and 80 mg/day in patients with moderate hepatic impairment [see ACTION AND CLINICAL PHARMACOLOGY].

Patients taking LATUDA Concomitantly with Potential CYP3A4 Inhibitors

When coadministration of LATUDA with a moderate CYP3A4 inhibitor, such as diltiazem, is considered, LATUDA should be started at a dose of 20 mg/day, and the dose should not exceed 40 mg/day. LATUDA is contraindicated in combination with a strong CYP3A4 inhibitor (e.g., ketoconazole) [see CONTRAINDICATIONS and DRUG INTERACTIONS].

Patients taking LATUDA Concomitantly with Potential CYP3A4 Inducers

LATUDA is contraindicated in combination with a strong CYP3A4 inducer (e.g., rifampin) [see CONTRAINDICATIONS and DRUG INTERACTIONS].

Administration

LATUDA should be administered with food (at least 350 calories independent of fat content). The Cmax of lurasidone is increased approximately 3-fold and the AUC is increased approximately 2-fold in the presence of food.

Overdosage

Human Experience

In pre-marketing clinical studies, accidental or intentional overdosage of LATUDA (lurasidone HCl) 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.

Management of Overdosage

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.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action and clinical pharmacology

Mechanism of Action

The mechanism of action of lurasidone, as with other drugs having efficacy in schizophrenia and bipolar depression, is unknown. It has been suggested that the efficacy of lurasidone in schizophrenia and bipolar depression could be mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism.

Pharmacodynamics

in vitro receptor binding studies revealed that lurasidone is an antagonist with high affinity at dopamine D2 receptors (Ki = 0.994 nM), the 5-hydroxytryptamine (5-HT, serotonin) receptors 5- HT2A (Ki = 0.47 nM), and 5-HT7 (Ki = 0.495 nM); is an antagonist with moderate affinity at α2C adrenergic receptors (Ki = 10.8) and α2A adrenergic receptors (Ki = 40.7 nM), α1 adrenergic receptors (Ki = 47.9 nM) and is a partial agonist with moderate affinity at serotonin 5-HT1A(Ki = 6.38 nM) receptors.. Lurasidone exhibits little or no affinity for histamine H1 and muscarinic M1 receptors (IC50 >1,000 nM).

Pharmacokinetics

The activity of lurasidone is primarily due to the parent drug. The pharmacokinetics of lurasidone are 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 (lurasidone HCl). Following administration of 40 mg of LATUDA, the mean (%CV) elimination half-life was 18 (7) hours.

Absorption

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.

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.

In clinical studies, establishing the safety and efficacy of LATUDA, patients were instructed to take their daily dose with food.

Distribution

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.

Metabolism

Lurasidone is metabolized mainly via CYP3A4 enzyme. 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).

Excretion

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.

Special Populations and Conditions

Geriatrics

In elderly patients with psychosis (65 to 85), lurasidone concentrations (20 mg/day) were, on average, similar to those in young subjects [see also WARNINGS AND PRECAUTIONS,Special Populations, Geriatrics].

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 Cmax of LATUDA was similar between women and men. No dosage adjustment is recommended based on gender.

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 is recommended based on race.

Hepatic Insufficiency

Dose adjustment is recommended in patients with moderate or severe hepatic impairment. The recommended starting dose is 20 mg. Patients should be treated with the lowest effective dose that provides optimal clinical response and tolerability, which is expected to be 20-40 mg once daily for most patients with moderate or severe hepatic impairment (Child Pugh Class B and C). The dose should not exceed 40 mg/day in patients with severe hepatic impairment (Child-Pugh Class C), and 80 mg/day in patients with moderate hepatic impairment (Child-Pugh Class B). In a single-dose study of LATUDA 20 mg, lurasidone AUC0-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 Cmax 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.

Renal Insufficiency

Dose adjustment is recommended in patients with moderate or severe renal function impairment. The recommended starting dose is 20 mg. Patients should be treated with the lowest effective dose that provides optimal clinical response and tolerability, which is expected to be 20-40 mg once daily for most patients with moderate and severe renal impairment (Clcr ≥10 mL/min to <50 mL/min). The dose should not exceed 80 mg/day in patients with moderate and severe renal impairment. After administration of a single dose of 40 mg LATUDA to patients with mild, moderate, and severe renal impairment, mean Cmax increased by 40%, 92%, and 54%, respectively, and mean AUC(0-∞) increased by 53%, 91%, and 2- times, respectively, compared to healthy matched subjects.

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.

Storage and stability

Store LATUDA tablets at 15o - 30oC.

Special handling instructions

None.

Dosage forms, composition and packaging

LATUDA (lurasidone HCl) tablets are white to off-white, round (20 mg and 40 mg), white to off-white, capsule shaped (60 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), “L60” (60mg), “L80” (80 mg), or “L120” (120 mg).

Each tablet contains 20 mg, 40 mg, 60 mg, 80 mg, or 120 mg of lurasidone hydrochloride. Inactive ingredients are mannitol, pregelatinized starch, croscarmellose sodium, hypromellose, magnesium stearate, Opadry (hypromellose, titanium dioxide, and polyethylene glycol), and carnauba wax. Additionally, the 80 mg tablet contains yellow ferric oxide and FDandC Blue No.2 Aluminum Lake.

Tablets are supplied in bottles of 30 tablets and boxes of 28 (Physician Samples - 4 blister cards, 7 tablets each).