These Highlights Do Not Include All The Information Needed To Use Lurasidone Hydrochloride Tablets Safely And Effectively. See Full Prescribing Information For Lurasidone Hydrochloride Tablets.

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Lurasidone hydrochloride tablets are not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)].

Suicidal Thoughts and Behaviors

Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adults in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors [see Warnings and Precautions (5.2)].

Lurasidone hydrochloride tablets 60 mg

Lurasidone hydrochloride 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 lurasidone hydrochloride tablets did not reveal any tendency for drug-seeking behavior, these observations were not systematic and it is not possible to predict the extent to which a CNS-active drug will be misused, diverted and/or abused once it is marketed. Patients should be evaluated carefully for a history of drug abuse, and such patients should be observed carefully for signs of lurasidone hydrochloride tablets misuse or abuse (e.g., development of tolerance, drug-seeking behavior, increases in dose).

Lurasidone hydrochloride may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

As with other antipsychotic drugs, lurasidone hydrochloride should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold, e.g., Alzheimer’s dementia. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.

Bipolar Depression

Monotherapy

In the adult and pediatric 6-week, flexible-dose, placebo-controlled monotherapy bipolar depression studies, no patients experienced seizures/convulsions.

Adjunctive Therapy with Lithium or Valproate

In the adult short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies, no patient experienced seizures/convulsions.

Risk Summary

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery [see Clinical Considerations]. There are no studies of lurasidone hydrochloride use in pregnant women. The limited available data are not sufficient to inform a drug-associated risk of birth defects or miscarriage. In animal reproduction studies, no teratogenic effects were seen in pregnant rats and rabbits given lurasidone during the period of organogenesis at doses approximately 1.5- and 6-times, the maximum recommended human dose (MRHD) of 160 mg/day, respectively based on mg/m2 body surface area [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately.

Data

Animal Data

Pregnant rats were treated with oral lurasidone at doses of 3, 10, and 25 mg/kg/day during the period of organogenesis.  These doses are 0.2, 0.6, and 1.5 times the MRHD of 160 mg/day based on mg/m^2 body surface area.  No teratogenic or embryo-fetal effects were observed up to 1.5 times the MRHD of 160 mg/day based on mg/m^2.

Pregnant rabbits were treated with oral lurasidone at doses of 2, 10, and 50 mg/kg/day during the period of organogenesis.  These doses are 0.2, 1,2, and 6 times the MRHD of 160 mg/day based on mg/m².  No teratogenic or embryo-fetal effects were observed up to 6 times the MRHD of 160 mg/day based on mg/mg².

Pregnant rats were treated with oral lurasidone at doses of 0.4, 2, and 10 mg/kg/day during the periods of organogenesis and lactation. These doses are 0.02, 0.1 and 0.6 times the MRHD of 160 mg/day based on mg/m². No pre- and postnatal developmental effects were observed up to 0.6 times the MRHD of 160 mg/day, based on mg/m². 

Risk Summary

Lactation studies have not been conducted to assess the presence of lurasidone in human milk, the effects on the breastfed infant, or the effects on milk production.  Lurasidone is present in rat milk.  The development and health benefits of breastfeeding should be considered along with the mother's clinical need for lurasidone hydrochloride and any potential adverse effects on the breastfed infant from lurasidone hydrochloride or from the underlying maternal condition.

Lurasidone hydrochloride 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-1-ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride. Its molecular formula is C₂₈H₃₆N₄O₂S·HCl and its molecular weight is 529.14.

The chemical structure is:

Lurasidone hydrochloride is a white to off-white powder. It is highly soluble in methanol, very slightly soluble in isopropyl alcohol and ethyl acetate, sparingly soluble in dimethylformamide and insoluble in toluene.

Lurasidone hydrochloride tablets are intended for oral administration only. Each tablet contains 60 mg of lurasidone hydrochloride.

Inactive ingredients are croscarmellose sodium, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, pregelatinized starch, polyethylene glycol and titanium dioxide.

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia. Lurasidone hydrochloride tablets and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

Lurasidone Hydrochloride (loo ras' i done hye" droe klor' ide)

Tablets 

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Rx Only

Manufactured by:

Dr. Reddy's Laboratories Limited

Srikakulam-532 409 India.

Manufactured for:

Torrent Pharma Inc.

Basking Ridge, NJ  07920

Revised: 06/2025           

Bipolar Depression

The safety and effectiveness of lurasidone hydrochloride 20 to 80 mg/day for the treatment of bipolar depression in pediatric patients (10 to 17 years) was established in a 6-week, placebo-controlled clinical study in 347 pediatric patients [see Dosage and Administration (2.2), Adverse Reactions (6.1), and Clinical Studies (14.2)].

The safety and effectiveness of lurasidone hydrochloride tablets has not been established in pediatric patients less than 10 years of age with bipolar depression.

Irritability Associated with Autistic Disorder

The effectiveness of lurasidone hydrochloride tablets in pediatric patients for the treatment of irritability associated with autistic disorder has not been established.

Efficacy was not demonstrated in a 6-week study evaluating lurasidone hydrochloride 20 mg/day and 60 mg/day for the treatment of pediatric patients 6 to 17 years of age with irritability associated with autistic disorder diagnosed by Diagnostic and Statistical Manual of Mental Disorders, 4th Ed., Text Revision [DSM-IV-TR] criteria.  The primary objective of the study as measured by improvement from Baseline in the irritability subscale of the Aberrant Behavior Checklist (ABC) at Endpoint (Week 6) was not met.  A total of 149 patients were randomized to lurasidone hydrochloride or placebo. Vomiting occurred at a higher rate than reported in other lurasidone hydrochloride studies (4/49 or 8% for 20 mg, 14/51 or 27% for 60 mg, and 2/49 or 4% for placebo), particularly in children ages 6 to 12 (13 out of 18 patients on lurasidone hydrochloride with vomiting).

In a long-term, open-label study that enrolled pediatric patients (age 6 to 17 years) with bipolar depression, autistic disorder or another disorder from three short-term, placebo-controlled trials, 54% (378/701) received lurasidone for 104 weeks. There was one adverse event in this trial that was considered possibly drug-related and has not been reported in adults receiving lurasidone: a 10 year old male experienced a prolonged, painful erection, consistent with priapism, that led to treatment discontinuation.

In this trial, the mean increase in height from open-label baseline to Week 104 was 4.94 cm. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for the natural growth of children and adolescents by comparisons to age- and sex-matched population standards. A z-score change <0.5 SD is considered not clinically significant. In this trial, the mean change in height z-score from open-label baseline to Week 104 was +0.05 SD, indicating minimal deviation from the normal growth curve.

Juvenile animal studies

Adverse effects were seen on growth, physical and neurobehavioral development at doses as low as 0.2 times the MRHD based on mg/m². Lurasidone was orally administered to rats from postnatal days 21 through 91 (this period corresponds to childhood, adolescence, and young adulthood in humans) at doses of 3, 30, and 150 (males) or 300 (females) mg/kg/day which are 0.2 to 10 times (males) and 20 times (females) the maximum recommended adult human dose (MRHD) of 160 mg/day based on mg/m². The adverse effects included dose-dependent decreases in femoral length, bone mineral content, body and brain weights at 2 times the MRHD in both sexes, and motor hyperactivity at 0.2 and 2 times the MRHD in both sexes based on mg/m². In females, there was a delay in attainment of sexual maturity at 2 times the MRHD, associated with decreased serum estradiol. Mortality occurred in both sexes during early post-weaning period and some of the male weanlings died after only 4 treatments at doses as low as 2 times the MRHD based on mg/m². Histopathological findings included increased colloid in the thyroids and inflammation of the prostate in males at 10 times MRHD based on mg/m² and mammary gland hyperplasia, increased vaginal mucification, and increased ovarian atretic follicles at doses as low as 0.2 times the MRHD based on mg/m². Some of these findings were attributed to transiently elevated serum prolactin which was seen in both sexes at all doses. However, there were no changes at any dose level in reproductive parameters (fertility, conception indices, spermatogenesis, estrous cycle, gestation length, parturition, number of pups born). The no effect dose for neurobehavioral changes in males is 0.2 times the MRHD based on mg/m² and could not be determined in females. The no effect dose for growth and physical development in both sexes is 0.2 times the MRHD based on mg/m².

Clinical studies with lurasidone hydrochloride did not include sufficient numbers of patients aged 65 and older to determine whether or not they respond differently from younger patients.  In elderly patients with psychosis (65 to 85), lurasidone hydrochloride concentrations (20 mg/day) were similar to those in young subjects.  It is unknown whether dose adjustment is necessary on the basis of age alone.

Elderly patients with dementia-related psychosis treated with lurasidone hydrochloride are at an increased risk of death compared to placebo.  Lurasidone hydrochloride tablets are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.1, 5.3)].

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 Boxed Warning and Warnings and Precautions (5.1)]
• Suicidal Thoughts and Behaviors [see Boxed Warning and Warnings and Precautions (5.2)]
• Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-related Psychosis [see Warnings and Precautions (5.3)]
• Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.4)]
• Tardive Dyskinesia [see Warnings and Precautions (5.5)]
• Metabolic Changes [see Warnings and Precautions (5.6)]
• Hyperprolactinemia [see Warnings and Precautions (5.7)]
• Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.8)]
• Orthostatic Hypotension and Syncope [see Warnings and Precautions (5.9)]
• Falls [see Warnings and Precautions (5.10)]
• Seizures [see Warnings and Precautions (5.11)]
• Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.12)]
• Body Temperature Dysregulation [see Warnings and Precautions (5.13)]
• Activation of Mania/Hypomania [see Warnings and Precautions (5.14)]
• Dysphagia [see Warnings and Precautions (5.15)]
• Neurological Adverse Reactions in Patients with Parkinson's Disease or Dementia with Lewy Bodies [see Warnings and Precautions (5.16)]

Reduce the maximum recommended dosage in patients with moderate or severe renal impairment (CLcr<50 mL/minute). Patients with impaired renal function (CLcr<50 mL/minute) had higher exposure to lurasidone than patients with normal renal function [see Clinical Pharmacology (12.3)]. Greater exposure may increase the risk of lurasidone hydrochloride-associated adverse reactions [see Dosage and Administration (2.4)].

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

Lurasidone is an antagonist with high affinity binding at the dopamine D₂ receptors (Ki of 1 nM) and the serotonin 5-HT_2A (Ki of 0.5 nM) and 5-HT₇ (Ki of 0.5 nM) receptors. It also binds with moderate affinity to the human α_2C adrenergic receptors (Ki of 11 nM), is a partial agonist at serotonin 5-HT_1A (Ki of 6.4 nM) receptors, and is an antagonist at the α2A adrenergic receptors (Ki of 41 nM). Lurasidone exhibits little or no affinity for histamine H1 and muscarinic M1 receptors (IC50 >1,000 nM).

ECG Changes

The effects of lurasidone hydrochloride on the QTc interval were evaluated in a randomized, double-blind, multiple-dose, parallel-dedicated thorough QT study in 43 patients with another indication, who were treated with lurasidone hydrochloride 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 bipolar depression and another indication, no post-baseline QT prolongations exceeding 500 msec were reported in patients treated with lurasidone hydrochloride or placebo.

Adults

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

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

Absorption and Distribution: Lurasidone hydrochloride is absorbed and reaches peak serum concentrations in approximately 1 to 3 hours. It is estimated that 9 to 19% of an administered dose is absorbed. Following administration of 40 mg of lurasidone hydrochloride, the mean (%CV) apparent volume of distribution was 6,173 (17.2) L. Lurasidone hydrochloride is highly bound (~99%) to serum proteins.

In a food effect study, lurasidone hydrochloride mean C_max and AUC were about 3 times and 2 times, respectively, when administered with food compared to the levels observed under fasting conditions. Lurasidone hydrochloride exposure was not affected as meal size was increased from 350 to 1,000 calories and was independent of meal fat content [see Dosage and Administration (2.3)].

In clinical studies, establishing the safety and efficacy of lurasidone hydrochloride, patients were instructed to take their daily dose with food [see Dosage and Administration (2.3)].

Metabolism and Elimination: Lurasidone hydrochloride is metabolized mainly via CYP3A4. The major biotransformation pathways are oxidative N-dealkylation, hydroxylation of norbornane ring, and S-oxidation. Lurasidone hydrochloride 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, lurasidone hydrochloride is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP4A11, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 enzymes. Because lurasidone hydrochloride is not a substrate for CYP1A2, smoking is not expected to have an effect on the pharmacokinetics of lurasidone hydrochloride.

Transporter proteins: In vitro studies suggest lurasidone hydrochloride is not a substrate of OATP1B1 or OATP1B3, however, is probably a substrate of P-gp and BCRP. In vitro studies indicate that lurasidone hydrochloride is not expected to inhibit transporters OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, MATE2-K and BSEP at clinically relevant concentrations. Lurasidone hydrochloride 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 lurasidone hydrochloride.

Following administration of 40 mg of lurasidone hydrochloride, the mean (%CV) apparent clearance was 3,902 (18) 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 to 2,400 mg/day or valproate 300 to 2,000 mg/day with lurasidone for up to 6 weeks has minimal effect on lurasidone exposure.

And the effects of lurasidone hydrochloride 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 to 2,400 mg/day or valproate 300 to 2,000 mg/day.

Figure 1:  Impact of Other Drugs on Lurasidone Hydrochloride Pharmacokinetics

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse events in patients treated with the atypical antipsychotics.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Bipolar Depression

Adults

Monotherapy

Data from the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study are presented in Table 4.

Table 4: Change in Fasting Glucose in the Adult Monotherapy Bipolar Depression Study

Patients were randomized to flexibly dosed lurasidone hydrochloride 20 to 60 mg/day, lurasidone hydrochloride 80 to 120 mg/day, or placebo.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride as monotherapy in the short-term study and continued in the longer term study, had a mean change in glucose of +1.2 mg/dL at week 24 (n=129).

Adjunctive Therapy with Lithium or Valproate

Data from the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 5.

Table 5: Change in Fasting Glucose in the Adult Adjunctive Therapy Bipolar Depression Studies   

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

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in glucose of +1.7 mg/dL at week 24 (n=88).

Pediatric Patients (10 to 17 years)

In studies of pediatric patients 10 to 17 years and adults with bipolar depression, changes in fasting glucose were similar. In the 6-week, placebo-controlled study of pediatric patients with bipolar depression, mean change in fasting glucose was +1.6 mg/dL for lurasidone hydrochloride 20 to 80 mg/day (n=145) and -0.5 mg/dL for placebo (n=145).

Pediatric Patients (6 to 17 years)

In a 104-week, open-label study in pediatric patients with bipolar depression, autistic disorder or another disorder, 7% of patients with a normal baseline fasting glucose experienced a shift to high at endpoint while taking lurasidone.

Dyslipidemia

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

Bipolar Depression

Adults

Monotherapy

Data from the adult short-term, flexible-dosed, placebo-controlled, monotherapy bipolar depression study are presented in Table 7.

Table 7: Change in Fasting Lipids in the Adult Monotherapy Bipolar Depression Study 

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

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride as monotherapy in the short-term and continued in the longer-term study had a mean change in total cholesterol and triglycerides of -0.5 mg/dL (n=130) and -1 mg/dL (n=130) at week 24, respectively.

Adjunctive Therapy with Lithium or Valproate

Data from the adult short-term, flexible-dosed, placebo-controlled, adjunctive therapy bipolar depression studies are presented in Table 8.

Table 8: Change in Fasting Lipids in the Adult Adjunctive Therapy Bipolar Depression Studies

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

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride, as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in total cholesterol and triglycerides of -0.9 (n=88) and +5.3 (n=88) mg/dL at week 24, respectively.

Pediatric Patients (10 to 17 years)

In the 6-week, placebo-controlled bipolar depression study with pediatric patients 10 to 17 years, mean change in fasting cholesterol was -6.3 mg/dL for lurasidone hydrochloride 20 to 80 mg/day (n=144) and -1.4 mg/dL for placebo (n=145), and mean change in fasting triglyceride was 7.6 mg/dL for lurasidone hydrochloride 20 to 80 mg/day (n=144) and +5.9 mg/dL for placebo (n=145).

Pediatric Patients (6 to 17 years)

In a 104-week, open-label study in pediatric patients with bipolar depression, autistic disorder or another disorder, shifts in baseline fasting cholesterol from normal to high at endpoint were reported in 12% (total cholesterol), 3% (LDL cholesterol), and shifts in baseline from normal to low were reported in 27% (HDL cholesterol) of patients taking lurasidone. Of patients with normal baseline fasting triglycerides, 12% experienced shifts to high.

Weight Gain

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

Bipolar Depression

Adults

Monotherapy

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

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

Patients were randomized to flexibly doses lurasidone hydrochloride 20 to 60 mg/day, lurasidone hydrochloride 80 to 120 mg/day, or placebo 

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride as monotherapy in the short-term and continued in the longer-term study had a mean change in weight of -0.02 kg at week 24 (n=130).

Adjunctive Therapy with Lithium or Valproate

Data from the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 12. The mean change in weight gain was +0.11 kg for lurasidone hydrochloride-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 lurasidone hydrochloride-treated patients and 0.3% for placebo-treated patients.

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

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

In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with lurasidone hydrochloride, as adjunctive therapy with either lithium or valproate in the short-term and continued in the longer-term study, had a mean change in weight of +1.28 kg at week 24 (n=86).

Pediatric Patients (10 to 17 years)

Data from the 6-week, placebo-controlled bipolar depression study in patients 10 to 17 years are presented in Table 13. The mean change in weight gain was +0.7 kg for lurasidone hydrochloride-treated patients compared to +0.5 kg for placebo-treated patients. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 4% for lurasidone hydrochloride-treated patients and 5.3% for placebo-treated patients.

Table 13: Mean Change in Weight (kg) from Baseline in the Bipolar Depression Study in Pediatric Patients (10 to 17 years)

Pediatric Patients (6 to 17 years)

In a long-term, open-label study that enrolled pediatric patients with bipolar depression, autistic disorder or another disorder from three short-term, placebo-controlled trials, 54% (378/701) received lurasidone for 104 weeks. The mean increase in weight from open-label baseline to Week 104 was 5.85 kg. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for the natural growth of children and adolescents by comparisons to age- and sex-matched population standards. A z-score change <0.5 SD is considered not clinically significant. In this trial, the mean change in z-score from open-label baseline to Week 104 was -0.06 SD for body weight and -0.13 SD for body mass index (BMI), indicating minimal deviation from the normal curve for weight gain.

Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements that can develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.

The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

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

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

Reduce the maximum recommended dosage in patients with moderate to severe hepatic impairment (Child-Pugh score ≥7). Patients with moderate to severe hepatic impairment (Child-Pugh score ≥7) generally had higher exposure to lurasidone than patients with normal hepatic function [see Clinical Pharmacology (12.3)]. Greater exposure may increase the risk of lurasidone hydrochloride-associated adverse reactions [see Dosage and Administration (2.5)].

Lurasidone hydrochloride tablets are indicated for:

• Monotherapy treatment of adult and pediatric patients (10 to 17 years) with major depressive episode associated with bipolar I disorder (bipolar depression) [see Clinical Studies (14.2)].

• Adjunctive treatment with lithium or valproate in adult patients with major depressive episode associated with bipolar I disorder (bipolar depression) [see Clinical Studies (14.2)].

The mechanism of action of lurasidone in the treatment of bipolar depression is unclear. However, its efficacy in bipolar depression could be mediated through a combination of central dopamine D₂ and serotonin Type 2 (5HT_2A) receptor antagonism.

As with other drugs that antagonize dopamine D₂ receptors, lurasidone hydrochloride elevates prolactin levels.

Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone density in both female and male patients [see Adverse Reactions (6)].

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in a carcinogenicity study conducted with lurasidone in rats and mice [see Nonclinical Toxicology (13)] . Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer.

Bipolar Depression

Adults

Monotherapy

The median change from baseline to endpoint in prolactin levels, in the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study, was +1.7 ng/mL and +3.5 ng/mL with lurasidone hydrochloride 20 to 60 mg/day and 80 to 120 mg/day, respectively compared to +0.3 ng/mL with placebo-treated patients. The median change from baseline to endpoint for males was +1.5 ng/mL and for females was +3.1 ng/mL. Median changes for prolactin by dose range are shown in Table 16.

Table 16: Median Change in Prolactin (ng/mL) from Baseline in the Adult Monotherapy Bipolar Depression Study 

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

The proportion of patients with prolactin elevations ≥5x upper limit of normal (ULN) was 0.4% for lurasidone hydrochloride-treated patients and 0% for placebo-treated patients.  The proportion of female patients with prolactin elevations ≥5x ULN was 0.6% for lurasidone hydrochloride-treated patients and 0% for placebo-treated female patients.  The proportion of male patients with prolactin elevations ≥5x ULN was 0% and 0% for placebo-treated male patients.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with lurasidone hydrochloride as monotherapy in the short-term and continued in the longer term study, had a median change in prolactin of -1.15 ng/mL at week 24 (n=130).

Adjunctive Therapy with Lithium or Valproate

The median change from baseline to endpoint in prolactin levels, in the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies was +2.8 ng/mL with lurasidone hydrochloride 20 to 120 mg/day compared to 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.  Median changes for prolactin across the dose range are shown in Table 17.

Table 17: Median Change in Prolactin (ng/mL) from Baseline in the Adult Adjunctive Therapy Bipolar Depression Studies 

Patients were randomized to flexibly dosed lurasidone hydrochloride 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate

The proportion of patients with prolactin elevations ≥5x upper limit of normal (ULN) was 0% for lurasidone hydrochloride-treated patients and 0% for placebo-treated patients.  The proportion of female patients with prolactin elevations ≥5x ULN was 0% for lurasidone hydrochloride-treated patients and 0% for placebo-treated female patients.  The proportion of male patients with prolactin elevations ≥5x ULN was 0% and 0% for placebo-treated male patients.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with lurasidone hydrochloride, as adjunctive therapy with either lithium or valproate, in the short-term and continued in the longer-term study, had a median change in prolactin of -2.9 ng/mL at week 24 (n=88).

Lurasidone hydrochloride is not a controlled substance.

Lurasidone hydrochloride tablets are available in the following shape and color (Table 1) with respective two-sided debossing.

Table 1: Lurasidone Hydrochloride Tablet Presentations

The following adverse reactions have been identified during postapproval use of lurasidone hydrochloride. 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, dyspnea, and rash.

Metabolism and Nutrition Disorders: Hyponatremia

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

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

Hypotension and circulatory collapse should be treated with appropriate measures. Epinephrine and dopamine should not be used, or other sympathomimetics with beta-agonist activity, since beta stimulation may worsen hypotension in the setting of lurasidone hydrochloride-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.

• Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure (8.1).

Lurasidone hydrochloride tablets should be taken with food (at least 350 calories). Administration with food substantially increases the absorption of lurasidone hydrochloride. Administration with food increases the AUC approximately 2-fold and increases the C_max approximately 3-fold. In the clinical studies, lurasidone hydrochloride was administered with food [see Clinical Pharmacology (12.3)].

The effectiveness of lurasidone hydrochloride tablets for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. Therefore, the physician who elects to use lurasidone hydrochloride tablets for extended periods should periodically re-evaluate the long term usefulness of the drug for the individual patient [see Dosage and Administration (2.2)].

No dosage adjustment for lurasidone hydrochloride is required on the basis of a patient’s sex, race, or smoking status [see Clinical Pharmacology (12.3)].

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Suicidal Thoughts and Behavior

Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down and instruct them to report such symptoms to the healthcare provider [see Boxed Warning, Warnings and Precautions (5.2)].

Neuroleptic Malignant Syndrome

Counsel patients about a potentially fatal adverse reaction referred to as Neuroleptic Malignant Syndrome (NMS). Advise patients, family members, or caregivers to contact the healthcare provider or to report to the emergency room if they experience signs and symptoms of NMS [see Warnings and Precautions (5.4)].

Tardive Dyskinesia

Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [see Warnings and Precautions (5.5)].

Metabolic Changes

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.6)].

Hyperprolactinemia

Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of lurasidone hydrochloride tablets. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction or gynecomastia in males [see Warnings and Precautions (5.7)].

Leukopenia/Neutropenia

Advise  patients  with  a  pre-existing  low  WBC  or  a  history  of  drug-induced leukopenia/neutropenia that they should have their CBC monitored while taking lurasidone hydrochloride tablets [see Warnings and Precautions (5.8)].

Orthostatic Hypotension

Educate patients about the risk of orthostatic hypotension, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions (5.9)].

Interference with Cognitive and Motor Performance

Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that lurasidone hydrochloride therapy does not affect them adversely [see Warnings and Precautions (5.12)].

Heat Exposure and Dehydration

Educate patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.13)].

Activation of Mania or Hypomania

Advise patients and their caregivers to observe for signs of activation of mania/hypomania [see Warnings and Precautions (5.14)].

Concomitant Medication

Advise patients to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, because there is a potential for drug interactions [see Drug Interactions (7)].

Pregnancy

Advise patients that lurasidone hydrochloride tablets may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients to notify their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations (8.1)]. 

Rx only

Manufactured by:

Dr. Reddy’s Laboratories Limited

Srikakulam-532 409, India

Manufactured for:

Torrent Pharma, Inc

Basking Ridge, NJ 07920

Revised: 06/2025   

Antidepressant treatment can increase the risk of developing a manic or hypomanic episode, particularly in patients with bipolar disorder. Monitor patients for the emergence of such episodes.  

In the adult bipolar depression monotherapy and adjunctive therapy (with lithium or valproate) studies, less than 1% of subjects in the lurasidone hydrochloride and placebo groups developed manic or hypomanic episodes.

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including lurasidone hydrochloride. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

If NMS is suspected, immediately discontinue lurasidone hydrochloride tablets and provide intensive symptomatic treatment and monitoring.

Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing lurasidone hydrochloride tablets 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.

Lurasidone hydrochloride tablets are available in the following strength and package configuration.

60 mg tablets are white to off white, capsule shaped, film-coated tablets debossed with “353” on one side, “60” on other side and free from physical defects, and are supplied in bottles of 30.

Bottles of 30                    NDC 13668-509-30

Storage

Store lurasidone hydrochloride tablets at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature].

Lurasidone hydrochloride tablets may cause orthostatic hypotension and syncope, perhaps due to its α1-adrenergic receptor antagonism. Associated adverse reactions can include dizziness, lightheadedness, tachycardia, and bradycardia. Generally, these risks are greatest at the beginning of treatment and during dose escalation. Patients at increased risk of these adverse reactions or at increased risk of developing complications from hypotension include those with dehydration, hypovolemia, treatment with antihypertensive medication, history of cardiovascular disease (e.g., heart failure, myocardial infarction, ischemia, or conduction abnormalities), history of cerebrovascular disease, as well as patients who are antipsychotic-naïve. In such patients, consider using a lower starting dose and slower titration, and monitor orthostatic vital signs.

Orthostatic hypotension, as assessed by vital sign measurement, was defined by the following vital sign changes: ≥20 mm Hg decrease in systolic blood pressure and ≥10 bpm increase in pulse from sitting to standing or supine to standing position.

Bipolar Depression

Adults

Monotherapy

In the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, there were no reported adverse events of orthostatic hypotension and syncope.

Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0.6% with lurasidone hydrochloride 20 to 60 mg and 0.6% with lurasidone hydrochloride 80 to 120 mg compared to 0% with placebo.

Adjunctive Therapy with Lithium or Valproate

In the adult short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression therapy studies, there were no reported adverse events of orthostatic hypotension and syncope. Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 1.1% with lurasidone hydrochloride 20 to 120 mg compared to 0.9% with placebo.

Pediatric Patients (10 to 17 years)

In the 6-week, placebo-controlled bipolar depression study in pediatric patients 10 to 17 years, there were no reported adverse events of orthostatic hypotension or syncope.

Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 1.1% with lurasidone hydrochloride 20 to 80 mg/day, compared to 0.6% with placebo.

Dose adjustment is recommended in moderate (creatinine clearance: 30 to <50 mL/min) and severe renal impairment (creatinine clearance <30 mL/min) patients. The recommended starting dose is 20 mg per day. The dose in these patients should not exceed 80 mg per day [see Use in Specific Populations (8.6)].

Dose adjustment is recommended in moderate (Child-Pugh Score = 7 to 9) and severe hepatic impairment (Child-Pugh Score = 10 to 15) patients. The recommended starting dose is 20 mg per day. The dose in moderate hepatic impairment patients should not exceed 80 mg per day and the dose in severe hepatic impairment patients should not exceed 40 per mg/day [see Use in Specific Populations (8.7)].

Lurasidone hydrochloride, like other antipsychotics, has the potential to impair judgment, thinking or motor skills. Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with lurasidone hydrochloride tablets does not affect them adversely.

In clinical studies with lurasidone hydrochloride, somnolence included: hypersomnia, hypersomnolence, sedation and somnolence.

Bipolar Depression

Adults

Monotherapy

In the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study, somnolence was reported by 7.3% (12/164) and 13.8% (23/167) with lurasidone hydrochloride 20 to 60 mg and 80 to 120 mg, respectively compared to 6.5% (11/168) of placebo patients.

Adjunctive Therapy with Lithium or Valproate

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

Pediatric Patients (10 to 17 years)

In the 6-week, placebo-controlled bipolar depression study in pediatric patients 10 to 17 years, somnolence was reported by 11.4% (20/175) of patients treated with lurasidone hydrochloride 20 to 80 mg/day compared to 5.8% (10/172) of placebo treated patients.

Leukopenia/neutropenia   has   been   reported   during   treatment   with   antipsychotic   agents. Agranulocytosis (including fatal cases) has been reported with other agents in the class.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and lurasidone hydrochloride tablets 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 <1,000/mm ³ ) should discontinue lurasidone hydrochloride tablets and have their WBC followed until recovery.

Carcinogenesis: Lurasidone increased incidences of malignant mammary gland tumors and pituitary gland adenomas in female mice orally dosed with 30, 100, 300, or 650 mg/kg/day. The lowest dose produced plasma levels (AUC) approximately equal to those in humans receiving the MRHD of 160 mg/day. No increases in tumors were seen in male mice up to the highest dose tested, which produced plasma levels (AUC) 14 times those in humans receiving the MRHD.

Lurasidone increased the incidence of mammary gland carcinomas in female rats orally dosed at 12 and 36 mg/kg/day: the lowest dose; 3 mg/kg/day is the no-effect dose which produced plasma levels (AUC) 0.4 times those in humans receiving the MRHD. No increases in tumors were seen in male rats up to the highest dose tested, which produced plasma levels (AUC) 6 times those in humans receiving the MRHD.

Proliferative and/or neoplastic changes in the mammary and pituitary glands of rodents have been observed following chronic administration of antipsychotic drugs and are considered to be prolactin-mediated [see Warnings and Precautions (5.7)].

Mutagenesis: Lurasidone did not cause mutation or chromosomal aberration when tested in vitro and in vivo test battery. Lurasidone was negative in the Ames gene mutation test, the Chinese Hamster Lung (CHL) cells, and in the in vivo mouse bone marrow micronucleus test up to 2,000 mg/kg which is 61 times the MRHD of 160 mg/day based on mg/m2 body surface area.

Impairment of Fertility: Estrus cycle irregularities were seen in rats orally administered lurasidone at 1.5, 15 and 150 mg/kg/day for 15 consecutive days prior to mating, during the mating period, and through gestation day 7. No effect was seen at the lowest dose of 0.1 mg/kg which is approximately 0.006 times the MRHD of 160 mg/day based on mg/m2. Fertility was reduced only at the highest dose, which was reversible after a 14 day drug-free period. The no-effect dose for reduced fertility was approximately equal to the MRHD based on mg/m².

Lurasidone had no effect on fertility in male rats treated orally for 64 consecutive days prior to mating and during the mating period at doses up to 9 times the MRHD based on mg/m².

Adults

The recommended starting dose of lurasidone hydrochloride tablets is 20 mg given once daily as monotherapy or as adjunctive therapy with lithium or valproate. Initial dose titration is not required. Lurasidone hydrochloride have been shown to be effective in a dose range of 20 mg per day to 120 mg per day as monotherapy or as adjunctive therapy with lithium or valproate [see Clinical Studies (14.2)]. The maximum recommended dose, as monotherapy or as adjunctive therapy with lithium or valproate, is 120 mg per day. In the monotherapy study, the higher dose range (80 mg to 120 mg per day) did not provide additional efficacy, on average, compared to the lower dose range (20 to 60 mg per day) [see Clinical Studies (14.2)].

Pediatric Patients (10 to 17 years)

The recommended starting dose of lurasidone hydrochloride tablets is 20 mg given once daily as monotherapy. Initial dose titration is not required. The dose may be increased after one week based on clinical response. Lurasidone hydrochloride has been shown to be effective in a dose range of 20 mg per day to 80 mg per day as monotherapy. At the end of the clinical study, most of the patients (67%) received 20 mg or 40 mg once daily [see Clinical Studies (14.2)]. The maximum recommended dose is 80 mg per day.

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

Adults

Monotherapy

The efficacy of lurasidone hydrochloride, 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 lurasidone hydrochloride (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 subjects current illness state on a 7-point scale, where a higher score is associated with greater illness severity.

For both dose groups, lurasidone hydrochloride was superior to placebo in reduction of MADRS and CGI-BP-S scores at Week 6. The primary efficacy results are provided in Table 37. The high dose range (80 to 120 mg per day) did not provide additional efficacy on average, compared to the low dose range (20 to 60 mg per day).

Adjunctive Therapy with Lithium or Valproate

The efficacy of lurasidone hydrochloride, 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 lurasidone hydrochloride 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.

Lurasidone hydrochloride 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 37).

Table 37:  Primary Efficacy Results for Adult Studies in Depressive Episodes Associated with Bipolar I Disorder (MADRS Scores) 

SD: standard deviation; SE: standard error; LS Mean: least squares mean; CI: confidence interval, unadjusted for multiple comparisons.

^aDifference (drug minus placebo) in least-squares mean change from baseline.

^*Treatment group statistically significantly superior to placebo.

Pediatric Patients (10 to 17 years)

The efficacy of lurasidone hydrochloride was established in a 6-week, multicenter, randomized, double-blind, placebo-controlled study of pediatric patients (10 to 17 years) who met DSM-5 criteria for a major depressive episode associated with bipolar I disorder, with or without rapid cycling, and without psychotic features (N=343). Patients were randomized to flexibly dosed lurasidone hydrochloride 20 to 80 mg/day or placebo. At the end of the clinical study, most patients (67%) received 20 mg/day or 40 mg/day.

The primary rating scale used to assess depressive symptoms in this study was the Childrens Depression Rating Scale, Revised (CDRS-R) total score. The CDRS‑R is a 17-item clinician-rated scale with total scores ranging from 17 to 113. The primary endpoint was the change from baseline in CDRS-R score at Week 6. The key secondary endpoint was the change from baseline in CGI-BP-S depression score.

Lurasidone hydrochloride was superior to placebo in reduction of CDRS-R total score and CGI‑BP-S depression score at Week 6. The primary efficacy results are provided in Table 38.

Table 38: Primary Efficacy Results for the Study in Depressive Episodes Associated with Bipolar I Disorder (CDRS-R Total Score) in Pediatric Patients (10 to 17 years)

SD: standard deviation; SE: standard error; LS Mean; least-squares mean; CI: confidence interval, unadjusted for multiple comparisons.

^a Difference (drug minus placebo) in least-squares mean change from baseline.

^* Treatment group significantly superior to placebo.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6- to 1.7-times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Lurasidone hydrochloride tablets are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.3)].

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients, and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 2.

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

Table 2: Risk Differences of the Number of Cases of Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients

It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with MDD that antidepressants delay the recurrence of depression.

Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing lurasidone hydrochloride tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

Based on pharmacokinetic studies, no dosage adjustment of lurasidone hydrochloride is required when administered concomitantly with lithium, valproate, or substrates of P-gp or CYP3A4 [see Clinical Pharmacology (12.3)].

Concomitant Use with CYP3A4 Inhibitors

Lurasidone hydrochloride tablets should not be used concomitantly with a strong CYP3A4 inhibitor (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.) [see Contraindications (4)].

If lurasidone hydrochloride tablets are being prescribed and a moderate CYP3A4 inhibitor (e.g. diltiazem, atazanavir, erythromycin, fluconazole, verapamil etc.) is added to the therapy, the lurasidone hydrochloride tablets dose should be reduced to half of the original dose level. Similarly, if a moderate CYP3A4 inhibitor is being prescribed and lurasidone hydrochloride tablets are added to the therapy, the recommended starting dose of lurasidone hydrochloride tablets is 20 mg per day, and the maximum recommended dose of lurasidone hydrochloride tablets is 80 mg per day [see Contraindications (4), Drug Interactions (7.1)].

Grapefruit and grapefruit juice should be avoided in patients taking lurasidone hydrochloride tablets, since these may inhibit CYP3A4 and alter lurasidone hydrochloride concentrations [see Drug Interactions (7.1)].

Concomitant Use with CYP3A4 Inducers

Lurasidone hydrochloride tablets should not be used concomitantly with a strong CYP3A4 inducer (e.g., rifampin, avasimibe, St. John’s wort, phenytoin, carbamazepine, etc.) [see Contraindications (4); Drug Interactions (7.1)]. If lurasidone hydrochloride tablets are used concomitantly with a moderate CYP3A4 inducer, it may be necessary to increase the lurasidone hydrochloride tablets dose after chronic treatment (7 days or more) with the CYP3A4 inducer.

Patients with Parkinson’s Disease or Dementia with Lewy Bodies are reported to have an increased sensitivity to antipsychotic medication. Manifestations of this increased sensitivity include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome.

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

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Lurasidone hydrochloride tablets are not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)].

Suicidal Thoughts and Behaviors

Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adults in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors [see Warnings and Precautions (5.2)].

Lurasidone hydrochloride tablets 60 mg

Lurasidone hydrochloride 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 lurasidone hydrochloride tablets did not reveal any tendency for drug-seeking behavior, these observations were not systematic and it is not possible to predict the extent to which a CNS-active drug will be misused, diverted and/or abused once it is marketed. Patients should be evaluated carefully for a history of drug abuse, and such patients should be observed carefully for signs of lurasidone hydrochloride tablets misuse or abuse (e.g., development of tolerance, drug-seeking behavior, increases in dose).

Lurasidone hydrochloride may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

As with other antipsychotic drugs, lurasidone hydrochloride should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold, e.g., Alzheimer’s dementia. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.

Bipolar Depression

Monotherapy

In the adult and pediatric 6-week, flexible-dose, placebo-controlled monotherapy bipolar depression studies, no patients experienced seizures/convulsions.

Adjunctive Therapy with Lithium or Valproate

In the adult short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies, no patient experienced seizures/convulsions.

Risk Summary

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery [see Clinical Considerations]. There are no studies of lurasidone hydrochloride use in pregnant women. The limited available data are not sufficient to inform a drug-associated risk of birth defects or miscarriage. In animal reproduction studies, no teratogenic effects were seen in pregnant rats and rabbits given lurasidone during the period of organogenesis at doses approximately 1.5- and 6-times, the maximum recommended human dose (MRHD) of 160 mg/day, respectively based on mg/m2 body surface area [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately.

Data

Animal Data

Pregnant rats were treated with oral lurasidone at doses of 3, 10, and 25 mg/kg/day during the period of organogenesis.  These doses are 0.2, 0.6, and 1.5 times the MRHD of 160 mg/day based on mg/m^2 body surface area.  No teratogenic or embryo-fetal effects were observed up to 1.5 times the MRHD of 160 mg/day based on mg/m^2.

Pregnant rabbits were treated with oral lurasidone at doses of 2, 10, and 50 mg/kg/day during the period of organogenesis.  These doses are 0.2, 1,2, and 6 times the MRHD of 160 mg/day based on mg/m².  No teratogenic or embryo-fetal effects were observed up to 6 times the MRHD of 160 mg/day based on mg/mg².

Pregnant rats were treated with oral lurasidone at doses of 0.4, 2, and 10 mg/kg/day during the periods of organogenesis and lactation. These doses are 0.02, 0.1 and 0.6 times the MRHD of 160 mg/day based on mg/m². No pre- and postnatal developmental effects were observed up to 0.6 times the MRHD of 160 mg/day, based on mg/m². 

Risk Summary

Lactation studies have not been conducted to assess the presence of lurasidone in human milk, the effects on the breastfed infant, or the effects on milk production.  Lurasidone is present in rat milk.  The development and health benefits of breastfeeding should be considered along with the mother's clinical need for lurasidone hydrochloride and any potential adverse effects on the breastfed infant from lurasidone hydrochloride or from the underlying maternal condition.

Lurasidone hydrochloride 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-1-ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride. Its molecular formula is C₂₈H₃₆N₄O₂S·HCl and its molecular weight is 529.14.

The chemical structure is:

Lurasidone hydrochloride is a white to off-white powder. It is highly soluble in methanol, very slightly soluble in isopropyl alcohol and ethyl acetate, sparingly soluble in dimethylformamide and insoluble in toluene.

Lurasidone hydrochloride tablets are intended for oral administration only. Each tablet contains 60 mg of lurasidone hydrochloride.

Inactive ingredients are croscarmellose sodium, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, pregelatinized starch, polyethylene glycol and titanium dioxide.

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia. Lurasidone hydrochloride tablets and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

Lurasidone Hydrochloride (loo ras' i done hye" droe klor' ide)

Tablets 

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Rx Only

Manufactured by:

Dr. Reddy's Laboratories Limited

Srikakulam-532 409 India.

Manufactured for:

Torrent Pharma Inc.

Basking Ridge, NJ  07920

Revised: 06/2025           

Bipolar Depression

The safety and effectiveness of lurasidone hydrochloride 20 to 80 mg/day for the treatment of bipolar depression in pediatric patients (10 to 17 years) was established in a 6-week, placebo-controlled clinical study in 347 pediatric patients [see Dosage and Administration (2.2), Adverse Reactions (6.1), and Clinical Studies (14.2)].

The safety and effectiveness of lurasidone hydrochloride tablets has not been established in pediatric patients less than 10 years of age with bipolar depression.

Irritability Associated with Autistic Disorder

The effectiveness of lurasidone hydrochloride tablets in pediatric patients for the treatment of irritability associated with autistic disorder has not been established.

Efficacy was not demonstrated in a 6-week study evaluating lurasidone hydrochloride 20 mg/day and 60 mg/day for the treatment of pediatric patients 6 to 17 years of age with irritability associated with autistic disorder diagnosed by Diagnostic and Statistical Manual of Mental Disorders, 4th Ed., Text Revision [DSM-IV-TR] criteria.  The primary objective of the study as measured by improvement from Baseline in the irritability subscale of the Aberrant Behavior Checklist (ABC) at Endpoint (Week 6) was not met.  A total of 149 patients were randomized to lurasidone hydrochloride or placebo. Vomiting occurred at a higher rate than reported in other lurasidone hydrochloride studies (4/49 or 8% for 20 mg, 14/51 or 27% for 60 mg, and 2/49 or 4% for placebo), particularly in children ages 6 to 12 (13 out of 18 patients on lurasidone hydrochloride with vomiting).

In a long-term, open-label study that enrolled pediatric patients (age 6 to 17 years) with bipolar depression, autistic disorder or another disorder from three short-term, placebo-controlled trials, 54% (378/701) received lurasidone for 104 weeks. There was one adverse event in this trial that was considered possibly drug-related and has not been reported in adults receiving lurasidone: a 10 year old male experienced a prolonged, painful erection, consistent with priapism, that led to treatment discontinuation.

In this trial, the mean increase in height from open-label baseline to Week 104 was 4.94 cm. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for the natural growth of children and adolescents by comparisons to age- and sex-matched population standards. A z-score change <0.5 SD is considered not clinically significant. In this trial, the mean change in height z-score from open-label baseline to Week 104 was +0.05 SD, indicating minimal deviation from the normal growth curve.

Juvenile animal studies

Adverse effects were seen on growth, physical and neurobehavioral development at doses as low as 0.2 times the MRHD based on mg/m². Lurasidone was orally administered to rats from postnatal days 21 through 91 (this period corresponds to childhood, adolescence, and young adulthood in humans) at doses of 3, 30, and 150 (males) or 300 (females) mg/kg/day which are 0.2 to 10 times (males) and 20 times (females) the maximum recommended adult human dose (MRHD) of 160 mg/day based on mg/m². The adverse effects included dose-dependent decreases in femoral length, bone mineral content, body and brain weights at 2 times the MRHD in both sexes, and motor hyperactivity at 0.2 and 2 times the MRHD in both sexes based on mg/m². In females, there was a delay in attainment of sexual maturity at 2 times the MRHD, associated with decreased serum estradiol. Mortality occurred in both sexes during early post-weaning period and some of the male weanlings died after only 4 treatments at doses as low as 2 times the MRHD based on mg/m². Histopathological findings included increased colloid in the thyroids and inflammation of the prostate in males at 10 times MRHD based on mg/m² and mammary gland hyperplasia, increased vaginal mucification, and increased ovarian atretic follicles at doses as low as 0.2 times the MRHD based on mg/m². Some of these findings were attributed to transiently elevated serum prolactin which was seen in both sexes at all doses. However, there were no changes at any dose level in reproductive parameters (fertility, conception indices, spermatogenesis, estrous cycle, gestation length, parturition, number of pups born). The no effect dose for neurobehavioral changes in males is 0.2 times the MRHD based on mg/m² and could not be determined in females. The no effect dose for growth and physical development in both sexes is 0.2 times the MRHD based on mg/m².

Clinical studies with lurasidone hydrochloride did not include sufficient numbers of patients aged 65 and older to determine whether or not they respond differently from younger patients.  In elderly patients with psychosis (65 to 85), lurasidone hydrochloride concentrations (20 mg/day) were similar to those in young subjects.  It is unknown whether dose adjustment is necessary on the basis of age alone.

Elderly patients with dementia-related psychosis treated with lurasidone hydrochloride are at an increased risk of death compared to placebo.  Lurasidone hydrochloride tablets are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.1, 5.3)].

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 Boxed Warning and Warnings and Precautions (5.1)]
• Suicidal Thoughts and Behaviors [see Boxed Warning and Warnings and Precautions (5.2)]
• Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-related Psychosis [see Warnings and Precautions (5.3)]
• Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.4)]
• Tardive Dyskinesia [see Warnings and Precautions (5.5)]
• Metabolic Changes [see Warnings and Precautions (5.6)]
• Hyperprolactinemia [see Warnings and Precautions (5.7)]
• Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.8)]
• Orthostatic Hypotension and Syncope [see Warnings and Precautions (5.9)]
• Falls [see Warnings and Precautions (5.10)]
• Seizures [see Warnings and Precautions (5.11)]
• Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.12)]
• Body Temperature Dysregulation [see Warnings and Precautions (5.13)]
• Activation of Mania/Hypomania [see Warnings and Precautions (5.14)]
• Dysphagia [see Warnings and Precautions (5.15)]
• Neurological Adverse Reactions in Patients with Parkinson's Disease or Dementia with Lewy Bodies [see Warnings and Precautions (5.16)]

Reduce the maximum recommended dosage in patients with moderate or severe renal impairment (CLcr<50 mL/minute). Patients with impaired renal function (CLcr<50 mL/minute) had higher exposure to lurasidone than patients with normal renal function [see Clinical Pharmacology (12.3)]. Greater exposure may increase the risk of lurasidone hydrochloride-associated adverse reactions [see Dosage and Administration (2.4)].

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

Lurasidone is an antagonist with high affinity binding at the dopamine D₂ receptors (Ki of 1 nM) and the serotonin 5-HT_2A (Ki of 0.5 nM) and 5-HT₇ (Ki of 0.5 nM) receptors. It also binds with moderate affinity to the human α_2C adrenergic receptors (Ki of 11 nM), is a partial agonist at serotonin 5-HT_1A (Ki of 6.4 nM) receptors, and is an antagonist at the α2A adrenergic receptors (Ki of 41 nM). Lurasidone exhibits little or no affinity for histamine H1 and muscarinic M1 receptors (IC50 >1,000 nM).

ECG Changes

The effects of lurasidone hydrochloride on the QTc interval were evaluated in a randomized, double-blind, multiple-dose, parallel-dedicated thorough QT study in 43 patients with another indication, who were treated with lurasidone hydrochloride 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 bipolar depression and another indication, no post-baseline QT prolongations exceeding 500 msec were reported in patients treated with lurasidone hydrochloride or placebo.

Adults

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

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

Absorption and Distribution: Lurasidone hydrochloride is absorbed and reaches peak serum concentrations in approximately 1 to 3 hours. It is estimated that 9 to 19% of an administered dose is absorbed. Following administration of 40 mg of lurasidone hydrochloride, the mean (%CV) apparent volume of distribution was 6,173 (17.2) L. Lurasidone hydrochloride is highly bound (~99%) to serum proteins.

In a food effect study, lurasidone hydrochloride mean C_max and AUC were about 3 times and 2 times, respectively, when administered with food compared to the levels observed under fasting conditions. Lurasidone hydrochloride exposure was not affected as meal size was increased from 350 to 1,000 calories and was independent of meal fat content [see Dosage and Administration (2.3)].

In clinical studies, establishing the safety and efficacy of lurasidone hydrochloride, patients were instructed to take their daily dose with food [see Dosage and Administration (2.3)].

Metabolism and Elimination: Lurasidone hydrochloride is metabolized mainly via CYP3A4. The major biotransformation pathways are oxidative N-dealkylation, hydroxylation of norbornane ring, and S-oxidation. Lurasidone hydrochloride 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, lurasidone hydrochloride is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP4A11, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 enzymes. Because lurasidone hydrochloride is not a substrate for CYP1A2, smoking is not expected to have an effect on the pharmacokinetics of lurasidone hydrochloride.

Transporter proteins: In vitro studies suggest lurasidone hydrochloride is not a substrate of OATP1B1 or OATP1B3, however, is probably a substrate of P-gp and BCRP. In vitro studies indicate that lurasidone hydrochloride is not expected to inhibit transporters OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, MATE2-K and BSEP at clinically relevant concentrations. Lurasidone hydrochloride 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 lurasidone hydrochloride.

Following administration of 40 mg of lurasidone hydrochloride, the mean (%CV) apparent clearance was 3,902 (18) 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 to 2,400 mg/day or valproate 300 to 2,000 mg/day with lurasidone for up to 6 weeks has minimal effect on lurasidone exposure.

And the effects of lurasidone hydrochloride 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 to 2,400 mg/day or valproate 300 to 2,000 mg/day.

Figure 1:  Impact of Other Drugs on Lurasidone Hydrochloride Pharmacokinetics

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse events in patients treated with the atypical antipsychotics.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Bipolar Depression

Adults

Monotherapy

Data from the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study are presented in Table 4.

Table 4: Change in Fasting Glucose in the Adult Monotherapy Bipolar Depression Study

Patients were randomized to flexibly dosed lurasidone hydrochloride 20 to 60 mg/day, lurasidone hydrochloride 80 to 120 mg/day, or placebo.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride as monotherapy in the short-term study and continued in the longer term study, had a mean change in glucose of +1.2 mg/dL at week 24 (n=129).

Adjunctive Therapy with Lithium or Valproate

Data from the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 5.

Table 5: Change in Fasting Glucose in the Adult Adjunctive Therapy Bipolar Depression Studies   

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

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in glucose of +1.7 mg/dL at week 24 (n=88).

Pediatric Patients (10 to 17 years)

In studies of pediatric patients 10 to 17 years and adults with bipolar depression, changes in fasting glucose were similar. In the 6-week, placebo-controlled study of pediatric patients with bipolar depression, mean change in fasting glucose was +1.6 mg/dL for lurasidone hydrochloride 20 to 80 mg/day (n=145) and -0.5 mg/dL for placebo (n=145).

Pediatric Patients (6 to 17 years)

In a 104-week, open-label study in pediatric patients with bipolar depression, autistic disorder or another disorder, 7% of patients with a normal baseline fasting glucose experienced a shift to high at endpoint while taking lurasidone.

Dyslipidemia

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

Bipolar Depression

Adults

Monotherapy

Data from the adult short-term, flexible-dosed, placebo-controlled, monotherapy bipolar depression study are presented in Table 7.

Table 7: Change in Fasting Lipids in the Adult Monotherapy Bipolar Depression Study 

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

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride as monotherapy in the short-term and continued in the longer-term study had a mean change in total cholesterol and triglycerides of -0.5 mg/dL (n=130) and -1 mg/dL (n=130) at week 24, respectively.

Adjunctive Therapy with Lithium or Valproate

Data from the adult short-term, flexible-dosed, placebo-controlled, adjunctive therapy bipolar depression studies are presented in Table 8.

Table 8: Change in Fasting Lipids in the Adult Adjunctive Therapy Bipolar Depression Studies

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

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride, as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in total cholesterol and triglycerides of -0.9 (n=88) and +5.3 (n=88) mg/dL at week 24, respectively.

Pediatric Patients (10 to 17 years)

In the 6-week, placebo-controlled bipolar depression study with pediatric patients 10 to 17 years, mean change in fasting cholesterol was -6.3 mg/dL for lurasidone hydrochloride 20 to 80 mg/day (n=144) and -1.4 mg/dL for placebo (n=145), and mean change in fasting triglyceride was 7.6 mg/dL for lurasidone hydrochloride 20 to 80 mg/day (n=144) and +5.9 mg/dL for placebo (n=145).

Pediatric Patients (6 to 17 years)

In a 104-week, open-label study in pediatric patients with bipolar depression, autistic disorder or another disorder, shifts in baseline fasting cholesterol from normal to high at endpoint were reported in 12% (total cholesterol), 3% (LDL cholesterol), and shifts in baseline from normal to low were reported in 27% (HDL cholesterol) of patients taking lurasidone. Of patients with normal baseline fasting triglycerides, 12% experienced shifts to high.

Weight Gain

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

Bipolar Depression

Adults

Monotherapy

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

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

Patients were randomized to flexibly doses lurasidone hydrochloride 20 to 60 mg/day, lurasidone hydrochloride 80 to 120 mg/day, or placebo 

In the uncontrolled, open-label, longer-term bipolar depression study, patients who received lurasidone hydrochloride as monotherapy in the short-term and continued in the longer-term study had a mean change in weight of -0.02 kg at week 24 (n=130).

Adjunctive Therapy with Lithium or Valproate

Data from the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 12. The mean change in weight gain was +0.11 kg for lurasidone hydrochloride-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 lurasidone hydrochloride-treated patients and 0.3% for placebo-treated patients.

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

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

In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with lurasidone hydrochloride, as adjunctive therapy with either lithium or valproate in the short-term and continued in the longer-term study, had a mean change in weight of +1.28 kg at week 24 (n=86).

Pediatric Patients (10 to 17 years)

Data from the 6-week, placebo-controlled bipolar depression study in patients 10 to 17 years are presented in Table 13. The mean change in weight gain was +0.7 kg for lurasidone hydrochloride-treated patients compared to +0.5 kg for placebo-treated patients. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 4% for lurasidone hydrochloride-treated patients and 5.3% for placebo-treated patients.

Table 13: Mean Change in Weight (kg) from Baseline in the Bipolar Depression Study in Pediatric Patients (10 to 17 years)

Pediatric Patients (6 to 17 years)

In a long-term, open-label study that enrolled pediatric patients with bipolar depression, autistic disorder or another disorder from three short-term, placebo-controlled trials, 54% (378/701) received lurasidone for 104 weeks. The mean increase in weight from open-label baseline to Week 104 was 5.85 kg. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for the natural growth of children and adolescents by comparisons to age- and sex-matched population standards. A z-score change <0.5 SD is considered not clinically significant. In this trial, the mean change in z-score from open-label baseline to Week 104 was -0.06 SD for body weight and -0.13 SD for body mass index (BMI), indicating minimal deviation from the normal curve for weight gain.

Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements that can develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.

The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

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

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

Reduce the maximum recommended dosage in patients with moderate to severe hepatic impairment (Child-Pugh score ≥7). Patients with moderate to severe hepatic impairment (Child-Pugh score ≥7) generally had higher exposure to lurasidone than patients with normal hepatic function [see Clinical Pharmacology (12.3)]. Greater exposure may increase the risk of lurasidone hydrochloride-associated adverse reactions [see Dosage and Administration (2.5)].

Lurasidone hydrochloride tablets are indicated for:

• Monotherapy treatment of adult and pediatric patients (10 to 17 years) with major depressive episode associated with bipolar I disorder (bipolar depression) [see Clinical Studies (14.2)].

• Adjunctive treatment with lithium or valproate in adult patients with major depressive episode associated with bipolar I disorder (bipolar depression) [see Clinical Studies (14.2)].

The mechanism of action of lurasidone in the treatment of bipolar depression is unclear. However, its efficacy in bipolar depression could be mediated through a combination of central dopamine D₂ and serotonin Type 2 (5HT_2A) receptor antagonism.

As with other drugs that antagonize dopamine D₂ receptors, lurasidone hydrochloride elevates prolactin levels.

Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone density in both female and male patients [see Adverse Reactions (6)].

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in a carcinogenicity study conducted with lurasidone in rats and mice [see Nonclinical Toxicology (13)] . Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer.

Bipolar Depression

Adults

Monotherapy

The median change from baseline to endpoint in prolactin levels, in the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study, was +1.7 ng/mL and +3.5 ng/mL with lurasidone hydrochloride 20 to 60 mg/day and 80 to 120 mg/day, respectively compared to +0.3 ng/mL with placebo-treated patients. The median change from baseline to endpoint for males was +1.5 ng/mL and for females was +3.1 ng/mL. Median changes for prolactin by dose range are shown in Table 16.

Table 16: Median Change in Prolactin (ng/mL) from Baseline in the Adult Monotherapy Bipolar Depression Study 

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

The proportion of patients with prolactin elevations ≥5x upper limit of normal (ULN) was 0.4% for lurasidone hydrochloride-treated patients and 0% for placebo-treated patients.  The proportion of female patients with prolactin elevations ≥5x ULN was 0.6% for lurasidone hydrochloride-treated patients and 0% for placebo-treated female patients.  The proportion of male patients with prolactin elevations ≥5x ULN was 0% and 0% for placebo-treated male patients.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with lurasidone hydrochloride as monotherapy in the short-term and continued in the longer term study, had a median change in prolactin of -1.15 ng/mL at week 24 (n=130).

Adjunctive Therapy with Lithium or Valproate

The median change from baseline to endpoint in prolactin levels, in the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies was +2.8 ng/mL with lurasidone hydrochloride 20 to 120 mg/day compared to 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.  Median changes for prolactin across the dose range are shown in Table 17.

Table 17: Median Change in Prolactin (ng/mL) from Baseline in the Adult Adjunctive Therapy Bipolar Depression Studies 

Patients were randomized to flexibly dosed lurasidone hydrochloride 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate

The proportion of patients with prolactin elevations ≥5x upper limit of normal (ULN) was 0% for lurasidone hydrochloride-treated patients and 0% for placebo-treated patients.  The proportion of female patients with prolactin elevations ≥5x ULN was 0% for lurasidone hydrochloride-treated patients and 0% for placebo-treated female patients.  The proportion of male patients with prolactin elevations ≥5x ULN was 0% and 0% for placebo-treated male patients.

In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with lurasidone hydrochloride, as adjunctive therapy with either lithium or valproate, in the short-term and continued in the longer-term study, had a median change in prolactin of -2.9 ng/mL at week 24 (n=88).

Lurasidone hydrochloride is not a controlled substance.

Lurasidone hydrochloride tablets are available in the following shape and color (Table 1) with respective two-sided debossing.

Table 1: Lurasidone Hydrochloride Tablet Presentations

The following adverse reactions have been identified during postapproval use of lurasidone hydrochloride. 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, dyspnea, and rash.

Metabolism and Nutrition Disorders: Hyponatremia

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

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

Hypotension and circulatory collapse should be treated with appropriate measures. Epinephrine and dopamine should not be used, or other sympathomimetics with beta-agonist activity, since beta stimulation may worsen hypotension in the setting of lurasidone hydrochloride-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.

• Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure (8.1).

Lurasidone hydrochloride tablets should be taken with food (at least 350 calories). Administration with food substantially increases the absorption of lurasidone hydrochloride. Administration with food increases the AUC approximately 2-fold and increases the C_max approximately 3-fold. In the clinical studies, lurasidone hydrochloride was administered with food [see Clinical Pharmacology (12.3)].

The effectiveness of lurasidone hydrochloride tablets for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. Therefore, the physician who elects to use lurasidone hydrochloride tablets for extended periods should periodically re-evaluate the long term usefulness of the drug for the individual patient [see Dosage and Administration (2.2)].

No dosage adjustment for lurasidone hydrochloride is required on the basis of a patient’s sex, race, or smoking status [see Clinical Pharmacology (12.3)].

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Suicidal Thoughts and Behavior

Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down and instruct them to report such symptoms to the healthcare provider [see Boxed Warning, Warnings and Precautions (5.2)].

Neuroleptic Malignant Syndrome

Counsel patients about a potentially fatal adverse reaction referred to as Neuroleptic Malignant Syndrome (NMS). Advise patients, family members, or caregivers to contact the healthcare provider or to report to the emergency room if they experience signs and symptoms of NMS [see Warnings and Precautions (5.4)].

Tardive Dyskinesia

Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [see Warnings and Precautions (5.5)].

Metabolic Changes

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.6)].

Hyperprolactinemia

Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of lurasidone hydrochloride tablets. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction or gynecomastia in males [see Warnings and Precautions (5.7)].

Leukopenia/Neutropenia

Advise  patients  with  a  pre-existing  low  WBC  or  a  history  of  drug-induced leukopenia/neutropenia that they should have their CBC monitored while taking lurasidone hydrochloride tablets [see Warnings and Precautions (5.8)].

Orthostatic Hypotension

Educate patients about the risk of orthostatic hypotension, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions (5.9)].

Interference with Cognitive and Motor Performance

Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that lurasidone hydrochloride therapy does not affect them adversely [see Warnings and Precautions (5.12)].

Heat Exposure and Dehydration

Educate patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.13)].

Activation of Mania or Hypomania

Advise patients and their caregivers to observe for signs of activation of mania/hypomania [see Warnings and Precautions (5.14)].

Concomitant Medication

Advise patients to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, because there is a potential for drug interactions [see Drug Interactions (7)].

Pregnancy

Advise patients that lurasidone hydrochloride tablets may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients to notify their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations (8.1)]. 

Rx only

Manufactured by:

Dr. Reddy’s Laboratories Limited

Srikakulam-532 409, India

Manufactured for:

Torrent Pharma, Inc

Basking Ridge, NJ 07920

Revised: 06/2025   

Antidepressant treatment can increase the risk of developing a manic or hypomanic episode, particularly in patients with bipolar disorder. Monitor patients for the emergence of such episodes.  

In the adult bipolar depression monotherapy and adjunctive therapy (with lithium or valproate) studies, less than 1% of subjects in the lurasidone hydrochloride and placebo groups developed manic or hypomanic episodes.

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including lurasidone hydrochloride. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

If NMS is suspected, immediately discontinue lurasidone hydrochloride tablets and provide intensive symptomatic treatment and monitoring.

Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing lurasidone hydrochloride tablets 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.

Lurasidone hydrochloride tablets are available in the following strength and package configuration.

60 mg tablets are white to off white, capsule shaped, film-coated tablets debossed with “353” on one side, “60” on other side and free from physical defects, and are supplied in bottles of 30.

Bottles of 30                    NDC 13668-509-30

Storage

Store lurasidone hydrochloride tablets at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature].

Lurasidone hydrochloride tablets may cause orthostatic hypotension and syncope, perhaps due to its α1-adrenergic receptor antagonism. Associated adverse reactions can include dizziness, lightheadedness, tachycardia, and bradycardia. Generally, these risks are greatest at the beginning of treatment and during dose escalation. Patients at increased risk of these adverse reactions or at increased risk of developing complications from hypotension include those with dehydration, hypovolemia, treatment with antihypertensive medication, history of cardiovascular disease (e.g., heart failure, myocardial infarction, ischemia, or conduction abnormalities), history of cerebrovascular disease, as well as patients who are antipsychotic-naïve. In such patients, consider using a lower starting dose and slower titration, and monitor orthostatic vital signs.

Orthostatic hypotension, as assessed by vital sign measurement, was defined by the following vital sign changes: ≥20 mm Hg decrease in systolic blood pressure and ≥10 bpm increase in pulse from sitting to standing or supine to standing position.

Bipolar Depression

Adults

Monotherapy

In the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, there were no reported adverse events of orthostatic hypotension and syncope.

Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0.6% with lurasidone hydrochloride 20 to 60 mg and 0.6% with lurasidone hydrochloride 80 to 120 mg compared to 0% with placebo.

Adjunctive Therapy with Lithium or Valproate

In the adult short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression therapy studies, there were no reported adverse events of orthostatic hypotension and syncope. Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 1.1% with lurasidone hydrochloride 20 to 120 mg compared to 0.9% with placebo.

Pediatric Patients (10 to 17 years)

In the 6-week, placebo-controlled bipolar depression study in pediatric patients 10 to 17 years, there were no reported adverse events of orthostatic hypotension or syncope.

Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 1.1% with lurasidone hydrochloride 20 to 80 mg/day, compared to 0.6% with placebo.

Dose adjustment is recommended in moderate (creatinine clearance: 30 to <50 mL/min) and severe renal impairment (creatinine clearance <30 mL/min) patients. The recommended starting dose is 20 mg per day. The dose in these patients should not exceed 80 mg per day [see Use in Specific Populations (8.6)].

Dose adjustment is recommended in moderate (Child-Pugh Score = 7 to 9) and severe hepatic impairment (Child-Pugh Score = 10 to 15) patients. The recommended starting dose is 20 mg per day. The dose in moderate hepatic impairment patients should not exceed 80 mg per day and the dose in severe hepatic impairment patients should not exceed 40 per mg/day [see Use in Specific Populations (8.7)].

Lurasidone hydrochloride, like other antipsychotics, has the potential to impair judgment, thinking or motor skills. Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with lurasidone hydrochloride tablets does not affect them adversely.

In clinical studies with lurasidone hydrochloride, somnolence included: hypersomnia, hypersomnolence, sedation and somnolence.

Bipolar Depression

Adults

Monotherapy

In the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study, somnolence was reported by 7.3% (12/164) and 13.8% (23/167) with lurasidone hydrochloride 20 to 60 mg and 80 to 120 mg, respectively compared to 6.5% (11/168) of placebo patients.

Adjunctive Therapy with Lithium or Valproate

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

Pediatric Patients (10 to 17 years)

In the 6-week, placebo-controlled bipolar depression study in pediatric patients 10 to 17 years, somnolence was reported by 11.4% (20/175) of patients treated with lurasidone hydrochloride 20 to 80 mg/day compared to 5.8% (10/172) of placebo treated patients.

Leukopenia/neutropenia   has   been   reported   during   treatment   with   antipsychotic   agents. Agranulocytosis (including fatal cases) has been reported with other agents in the class.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and lurasidone hydrochloride tablets 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 <1,000/mm ³ ) should discontinue lurasidone hydrochloride tablets and have their WBC followed until recovery.

Carcinogenesis: Lurasidone increased incidences of malignant mammary gland tumors and pituitary gland adenomas in female mice orally dosed with 30, 100, 300, or 650 mg/kg/day. The lowest dose produced plasma levels (AUC) approximately equal to those in humans receiving the MRHD of 160 mg/day. No increases in tumors were seen in male mice up to the highest dose tested, which produced plasma levels (AUC) 14 times those in humans receiving the MRHD.

Lurasidone increased the incidence of mammary gland carcinomas in female rats orally dosed at 12 and 36 mg/kg/day: the lowest dose; 3 mg/kg/day is the no-effect dose which produced plasma levels (AUC) 0.4 times those in humans receiving the MRHD. No increases in tumors were seen in male rats up to the highest dose tested, which produced plasma levels (AUC) 6 times those in humans receiving the MRHD.

Proliferative and/or neoplastic changes in the mammary and pituitary glands of rodents have been observed following chronic administration of antipsychotic drugs and are considered to be prolactin-mediated [see Warnings and Precautions (5.7)].

Mutagenesis: Lurasidone did not cause mutation or chromosomal aberration when tested in vitro and in vivo test battery. Lurasidone was negative in the Ames gene mutation test, the Chinese Hamster Lung (CHL) cells, and in the in vivo mouse bone marrow micronucleus test up to 2,000 mg/kg which is 61 times the MRHD of 160 mg/day based on mg/m2 body surface area.

Impairment of Fertility: Estrus cycle irregularities were seen in rats orally administered lurasidone at 1.5, 15 and 150 mg/kg/day for 15 consecutive days prior to mating, during the mating period, and through gestation day 7. No effect was seen at the lowest dose of 0.1 mg/kg which is approximately 0.006 times the MRHD of 160 mg/day based on mg/m2. Fertility was reduced only at the highest dose, which was reversible after a 14 day drug-free period. The no-effect dose for reduced fertility was approximately equal to the MRHD based on mg/m².

Lurasidone had no effect on fertility in male rats treated orally for 64 consecutive days prior to mating and during the mating period at doses up to 9 times the MRHD based on mg/m².

Adults

The recommended starting dose of lurasidone hydrochloride tablets is 20 mg given once daily as monotherapy or as adjunctive therapy with lithium or valproate. Initial dose titration is not required. Lurasidone hydrochloride have been shown to be effective in a dose range of 20 mg per day to 120 mg per day as monotherapy or as adjunctive therapy with lithium or valproate [see Clinical Studies (14.2)]. The maximum recommended dose, as monotherapy or as adjunctive therapy with lithium or valproate, is 120 mg per day. In the monotherapy study, the higher dose range (80 mg to 120 mg per day) did not provide additional efficacy, on average, compared to the lower dose range (20 to 60 mg per day) [see Clinical Studies (14.2)].

Pediatric Patients (10 to 17 years)

The recommended starting dose of lurasidone hydrochloride tablets is 20 mg given once daily as monotherapy. Initial dose titration is not required. The dose may be increased after one week based on clinical response. Lurasidone hydrochloride has been shown to be effective in a dose range of 20 mg per day to 80 mg per day as monotherapy. At the end of the clinical study, most of the patients (67%) received 20 mg or 40 mg once daily [see Clinical Studies (14.2)]. The maximum recommended dose is 80 mg per day.

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

Adults

Monotherapy

The efficacy of lurasidone hydrochloride, 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 lurasidone hydrochloride (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 subjects current illness state on a 7-point scale, where a higher score is associated with greater illness severity.

For both dose groups, lurasidone hydrochloride was superior to placebo in reduction of MADRS and CGI-BP-S scores at Week 6. The primary efficacy results are provided in Table 37. The high dose range (80 to 120 mg per day) did not provide additional efficacy on average, compared to the low dose range (20 to 60 mg per day).

Adjunctive Therapy with Lithium or Valproate

The efficacy of lurasidone hydrochloride, 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 lurasidone hydrochloride 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.

Lurasidone hydrochloride 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 37).

Table 37:  Primary Efficacy Results for Adult Studies in Depressive Episodes Associated with Bipolar I Disorder (MADRS Scores) 

SD: standard deviation; SE: standard error; LS Mean: least squares mean; CI: confidence interval, unadjusted for multiple comparisons.

^aDifference (drug minus placebo) in least-squares mean change from baseline.

^*Treatment group statistically significantly superior to placebo.

Pediatric Patients (10 to 17 years)

The efficacy of lurasidone hydrochloride was established in a 6-week, multicenter, randomized, double-blind, placebo-controlled study of pediatric patients (10 to 17 years) who met DSM-5 criteria for a major depressive episode associated with bipolar I disorder, with or without rapid cycling, and without psychotic features (N=343). Patients were randomized to flexibly dosed lurasidone hydrochloride 20 to 80 mg/day or placebo. At the end of the clinical study, most patients (67%) received 20 mg/day or 40 mg/day.

The primary rating scale used to assess depressive symptoms in this study was the Childrens Depression Rating Scale, Revised (CDRS-R) total score. The CDRS‑R is a 17-item clinician-rated scale with total scores ranging from 17 to 113. The primary endpoint was the change from baseline in CDRS-R score at Week 6. The key secondary endpoint was the change from baseline in CGI-BP-S depression score.

Lurasidone hydrochloride was superior to placebo in reduction of CDRS-R total score and CGI‑BP-S depression score at Week 6. The primary efficacy results are provided in Table 38.

Table 38: Primary Efficacy Results for the Study in Depressive Episodes Associated with Bipolar I Disorder (CDRS-R Total Score) in Pediatric Patients (10 to 17 years)

SD: standard deviation; SE: standard error; LS Mean; least-squares mean; CI: confidence interval, unadjusted for multiple comparisons.

^a Difference (drug minus placebo) in least-squares mean change from baseline.

^* Treatment group significantly superior to placebo.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6- to 1.7-times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Lurasidone hydrochloride tablets are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.3)].

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients, and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 2.

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

Table 2: Risk Differences of the Number of Cases of Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients

It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with MDD that antidepressants delay the recurrence of depression.

Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing lurasidone hydrochloride tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

Based on pharmacokinetic studies, no dosage adjustment of lurasidone hydrochloride is required when administered concomitantly with lithium, valproate, or substrates of P-gp or CYP3A4 [see Clinical Pharmacology (12.3)].

Concomitant Use with CYP3A4 Inhibitors

Lurasidone hydrochloride tablets should not be used concomitantly with a strong CYP3A4 inhibitor (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.) [see Contraindications (4)].

If lurasidone hydrochloride tablets are being prescribed and a moderate CYP3A4 inhibitor (e.g. diltiazem, atazanavir, erythromycin, fluconazole, verapamil etc.) is added to the therapy, the lurasidone hydrochloride tablets dose should be reduced to half of the original dose level. Similarly, if a moderate CYP3A4 inhibitor is being prescribed and lurasidone hydrochloride tablets are added to the therapy, the recommended starting dose of lurasidone hydrochloride tablets is 20 mg per day, and the maximum recommended dose of lurasidone hydrochloride tablets is 80 mg per day [see Contraindications (4), Drug Interactions (7.1)].

Grapefruit and grapefruit juice should be avoided in patients taking lurasidone hydrochloride tablets, since these may inhibit CYP3A4 and alter lurasidone hydrochloride concentrations [see Drug Interactions (7.1)].

Concomitant Use with CYP3A4 Inducers

Lurasidone hydrochloride tablets should not be used concomitantly with a strong CYP3A4 inducer (e.g., rifampin, avasimibe, St. John’s wort, phenytoin, carbamazepine, etc.) [see Contraindications (4); Drug Interactions (7.1)]. If lurasidone hydrochloride tablets are used concomitantly with a moderate CYP3A4 inducer, it may be necessary to increase the lurasidone hydrochloride tablets dose after chronic treatment (7 days or more) with the CYP3A4 inducer.

Patients with Parkinson’s Disease or Dementia with Lewy Bodies are reported to have an increased sensitivity to antipsychotic medication. Manifestations of this increased sensitivity include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome.

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