Lurasidone HCL Tablets for Oral Administration

LATUDA is an atypical antipsychotic belonging to the chemical class of benzisothiazol derivatives.

Its chemical name is (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride. Its molecular formula is C28H36N4O2S·HCl and its molecular weight is 529.14.

The chemical structure is:

Lurasidone hydrochloride is a white to off-white powder. It is very slightly soluble in water, practically insoluble or insoluble in 0.1 N HCl, slightly soluble in ethanol, sparingly soluble in methanol, practically insoluble or insoluble in toluene and very slightly soluble in acetone.

LATUDA tablets are intended for oral administration only. Each tablet contains 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® and carnauba wax. Additionally, the 80 mg tablet contains yellow ferric oxide and FD&C Blue No. 2 Aluminum Lake.

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

• Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see BOX WARNING and WARNINGS AND PRECAUTIONS]
• Suicidal Thoughts and Behaviors [see BOX WARNING and WARNINGS AND PRECAUTIONS]
• Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-related Psychosis [see WARNINGS AND PRECAUTIONS]
• Neuroleptic Malignant Syndrome [see WARNINGS AND PRECAUTIONS]
• Tardive Dyskinesia [see WARNINGS AND PRECAUTIONS]
• Metabolic Changes [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]
• Falls [see WARNINGS AND PRECAUTIONS]
• Seizures [see WARNINGS AND PRECAUTIONS]
• Potential for Cognitive and Motor Impairment [see WARNINGS AND PRECAUTIONS]
• Body Temperature Dysregulation [see WARNINGS AND PRECAUTIONS]
• Activation of Mania/Hypomania [see WARNINGS AND PRECAUTIONS]
• Dysphagia [see WARNINGS AND PRECAUTIONS]
• Neurological Adverse Reactions in Patients with Parkinson’s Disease or Dementia with Lewy Bodies [see WARNINGS AND PRECAUTIONS]
.

Clinical Trials Experience

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

Adults

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

Schizophrenia

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

Commonly Observed Adverse Reactions:

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

Adverse Reactions Associated with Discontinuation of Treatment:

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

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

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

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

Dose-Related Adverse Reactions in the Schizophrenia Studies

Akathisia and extrapyramidal symptoms were dose-related. The frequency of akathisia increased with dose up to 120 mg/day (5.6% for LATUDA 20 mg, 10.7% for LATUDA 40 mg, 12.3% for LATUDA 80 mg, and 22.0% for 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. The frequency of extrapyramidal symptoms increased with dose up to 120 mg/day (5.6% for LATUDA 20 mg, 11.5% for LATUDA 40 mg, 11.9% for LATUDA 80 mg, and 22.0% for LATUDA 120 mg).

Bipolar Depression (Monotherapy)

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

Commonly Observed Adverse Reactions:

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

Adverse Reactions Associated with Discontinuation of Treatment:

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

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

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

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

Dose-Related Adverse Reactions in the Monotherapy Study:

In the adult short-term, placebo-controlled study (involving lower and higher LATUDA dose ranges) [see Clinical Studies] the adverse reactions 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%), and extrapyramidal symptoms (4.9%, 9.0%) for LATUDA 20 to 60 mg/day and LATUDA 80 to 120 mg/day, respectively.

Bipolar Depression

The following findings are based on two adult short-term, placebo-controlled premarketing 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 Adverse Reactions:

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

Adverse Reactions Associated with Discontinuation of Treatment:

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

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

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

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

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

Commonly Observed Adverse Reactions:

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

Adverse Reactions Associated with Discontinuation of Treatment:

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

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

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

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

Adults

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

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

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

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

Monotherapy

In the adult short-term, placebo-controlled monotherapy bipolar depression 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 23.

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

Adjunctive Therapy with Lithium or Valproate

In the adult short-term, placebo-controlled adjunctive therapy bipolar depression studies, for LATUDA-treated patients, the incidence of EPS, excluding akathisia and restlessness, was 13.9% versus 8.7% for placebo. 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 24.

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

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

Adults

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

Adolescents

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

onotherapy

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

Adjunctive Therapy with Lithium or Valproate

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

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.

Adults

In the short-term, placebo-controlled schizophrenia clinical studies, 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.

Adolescents

In the short-term, placebo-controlled, adolescent schizophrenia study, dystonia occurred in 1% of LATUDA-treated patients (1% LATUDA 40 mg and 1% LATUDA 80 mg) compared to 0% of patients receiving placebo. No patients discontinued the clinical study due to dystonic events.

Monotherapy

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

Adjunctive Therapy with Lithium or Valproate

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

Following is a list of adverse reactions reported by adult patients treated with LATUDA at multiple doses of ≥ 20 mg once daily within the premarketing database of 2905 patients with schizophrenia. The reactions listed are those that could be of clinical importance, as well as reactions that are plausibly drug-related on pharmacologic or other grounds. Reactions listed in Table 16 or those that appear elsewhere in the LATUDA label are not included. Although the reactions reported occurred during treatment with LATUDA, they were not necessarily caused by it.

Reactions are further categorized by 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

Cardiac Disorders: Frequent: tachycardia; Infrequent: AV block 1st degree, angina pectoris, bradycardia

Ear and Labyrinth Disorders: Infrequent: vertigo

Eye Disorders: Frequent: blurred vision

Gastrointestinal Disorders: Frequent: abdominal pain, diarrhea; Infrequent: gastritis

General Disorders and Administrative Site Conditions: Rare: sudden death

Investigations: Frequent: CPK increased

Metabolism and Nutritional System Disorders: Frequent: decreased appetite

Musculoskeletal and Connective Tissue Disorders: Rare: rhabdomyolysis

Nervous System Disorders: Infrequent: cerebrovascular accident, dysarthria

Psychiatric Disorders: Infrequent: abnormal dreams, panic attack, sleep disorder

Renal and Urinary Disorders: Infrequent: dysuria; Rare: renal failure

Reproductive System and Breast Disorders: Infrequent: amenorrhea, dysmenorrhea; Rare: breast enlargement, breast pain, galactorrhea, erectile dysfunction

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

Vascular Disorders: Frequent: hypertension

Clinical Laboratory Changes

Adults

Serum Creatinine: In short-term, placebo-controlled trials, the mean change from Baseline in serum creatinine was +0.05 mg/dL for LATUDA-treated patients compared to +0.02 mg/dL 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 threshold for high creatinine value varied from > 0.79 to > 1.3 mg/dL based on the centralized laboratory definition for each study (Table 25).

Table 25: Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in Adult Schizophrenia Studies

Adolescents

Serum Creatinine: In the short-term, placebo-controlled, adolescent schizophrenia study, the mean change from Baseline in serum creatinine was −0.009 mg/dL for LATUDA-treated patients compared to +0.017 mg/dL for placebo-treated patients. A creatinine shift from normal to high (based on the centralized laboratory definition) occurred in 7.2% (14/194) of LATUDA-treated patients and 2.9% (3/103) on placebo (Table 26).

Table 26: Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in the Adolescent Schizophrenia Study

Monotherapy

Serum Creatinine: In the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, the mean change from Baseline in serum creatinine was +0.01 mg/dL for LATUDA-treated patients compared to -0.02 mg/dL 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 27).

Table 27: Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in the Adult Monotherapy Bipolar Depression Study

Adjunctive Therapy with Lithium or Valproate

Serum Creatinine: In adult short-term, placebo-controlled premarketing adjunctive studies for bipolar depression, the mean change from Baseline in serum creatinine was +0.04 mg/dL for LATUDA-treated patients compared to -0.01 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 4.3% (15/360) of LATUDA-treated patients and 1.6% (5/334) on placebo (Table 28).

Table 28: Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in the Adult Adjunctive Therapy Bipolar Depression Studies

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Latuda. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity Reactions: Urticaria, throat swelling, tongue swelling, and dyspnea.

Hyponatremia

Mechanism Of Action

The mechanism of action of lurasidone in the treatment of schizophrenia and bipolar depression is unknown. However, its efficacy in schizophrenia and bipolar depression could be mediated through a combination of central dopamine D2 and serotonin Type 2 (5HT2A) receptor antagonism.

Pharmacodynamics

Lurasidone is an antagonist with high affinity binding at the dopamine D2 receptors (Ki of 1 nM) and the serotonin 5-HT2A (Ki of 0.5 nM) and 5-HT7 (Ki of 0.5 nM) receptors. It also binds with moderate affinity to the human α2C adrenergic receptors (Ki of 11 nM), is a partial agonist at serotonin 5-HT1A (Ki of 6.4 nM) receptors, and is an antagonist at the α2A adrenergic receptors (Ki of 41 nM). Lurasidone exhibits little or no affinity for histamine H1 and muscarinic M1 receptors (IC50 > 1,000 nM).

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

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

Pharmacokinetics

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

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

Absorption and Distribution

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

In a food effect study, LATUDA mean Cmax and AUC were about 3-times and 2-times, respectively, when administered with food compared to the levels observed under fasting conditions. LATUDA 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 LATUDA, patients were instructed to take their daily dose with food [see DOSAGE AND ADMINISTRATION].

Metabolism and Elimination

LATUDA is metabolized mainly via CYP3A4. The major biotransformation pathways are oxidative N-dealkylation, hydroxylation of norbornane ring, and S-oxidation. LATUDA is metabolized into two active metabolites (ID-14283 and ID-14326) and two major non-active metabolites (ID-20219 and ID-20220). Based on in vitro studies, LATUDA is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP4A11, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 enzymes. Because LATUDA is not a substrate for CYP1A2, smoking is not expected to have an effect on the pharmacokinetics of LATUDA.

Transporter Proteins

In vitro studies suggest LATUDA is not a substrate of OATP1B1 or OATP1B3, however, is probably a substrate of P-gp and BCRP. In vitro studies indicate that LATUDA is not expected to inhibit transporters OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, MATE2-K and BSEP at clinically relevant concentrations. LATUDA is not a clinically significant inhibitor of P-gp. However, it may inhibit BCRP.

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 LATUDA.

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

Drug Interaction Studies

Effects of other drugs on the exposure of lurasidone are summarized in Figure 1. A population PK analyses concluded that coadministration of lithium 300-2400 mg/day or valproate 300-2000 mg/day with lurasidone for up to 6 weeks has minimal effect on lurasidone exposure.

And the effects of LATUDA on the exposures of other drugs are summarized in Figure 2. A population PK analyses concluded that coadministration of lurasidone has minimal effect on lithium and valproate exposure when it is coadministered with lithium 300-2400 mg/day or valproate 300-2000 mg/day.

Figure 1: Impact of Other Drugs on LATUDA Pharmacokinetics

Figure 2:Impact of LATUDA on Other Drugs

Studies In Specific Populations

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

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

Figure 3: Impact of Other Patient Factors on LATUDA Pharmacokinetics

Clinical Studies

Schizophrenia

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

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

1. Positive and Negative Syndrome Scale (PANSS), is a multi-item inventory of general psychopathology used to evaluate the effects of drug treatment in schizophrenia. PANSS total scores may range from 30 to 210.
2. Brief Psychiatric Rating Scale derived (BPRSd), derived from the PANSS, is a multi-item inventory primarily focusing on positive symptoms of schizophrenia, whereas the PANSS includes a wider range of positive, negative and other symptoms of schizophrenia. The BPRSd consists of 18 items rated on a scale of 1 (not present) to 7 (severe). BPRSd scores may range from 18 to 126.
3. The Clinical Global Impression severity scale (CGI-S) is a clinician-rated scale that measures the subject’s current illness state on a 1-to 7-point scale.

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

The results of the studies follow:

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

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

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

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

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

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

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

The primary efficacy results are provided in Table 31.

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

Depressive Episodes Associated With Bipolar I Disorder

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

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

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

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

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

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

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

Lurasidone is not for use in psychotic conditions related to dementia. Lurasidone may cause heart failure, sudden death, or pneumonia in older adults with dementia-related conditions.

You should not use this medication if you are allergic to lurasidone, or if you are also using ketoconazole (Extina, Ketozole, Nizoral, Xolegal) or rifampin (Rifater, Rifadin, Rifamate).

Before you take lurasidone, tell your doctor if you have liver disease, kidney disease, heart disease, high blood pressure, heart rhythm problems, a history of heart attack or stroke, high cholesterol or triglycerides, low white blood cell (WBC) counts, seizures, diabetes, Parkinson's disease, trouble swallowing, or a history of breast cancer or suicidal thoughts.

While you are taking lurasidone, you may be more sensitive to temperature extremes such as very hot or cold conditions. Avoid getting too cold, or becoming overheated or dehydrated. Drink plenty of fluids, especially in hot weather and during exercise. It is easier to become dangerously overheated and dehydrated while you are taking lurasidone.

Lurasidone may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert. Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Drinking alcohol can increase certain side effects of lurasidone.

Stop using lurasidone and call your doctor at once if you have very stiff (rigid) muscles, high fever, sweating, confusion, fast or pounding heartbeats, feeling like you might pass out, tremors, or twitching or uncontrollable movements of your eyes, lips, tongue, face, arms, or legs.

There are many other drugs that can interact with lurasidone. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

Your pharmacist can provide more information about lurasidone.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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