LAROZA

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

Its chemical name is (3a R,4 S,7 R,7a S )-2-{(1 R,2 R )-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2 H -isoindole-1,3-dione hydrochloride.

Its molecular formula is

C 28 H 36 N 4 O 2 S·HCl and its molecular weight is 529.14.

The chemical structure is

Lurasidone hydrochloride is a white to off-white powder.

It is very slightly soluble in methanol.

Lurasidone hydrochloride tablets are intended for oral administration only.

Each tablet contains 20 mg, 40 mg, 60 mg, 80 mg, or 120 mg of lurasidone hydrochloride.

Inactive ingredients are croscarmellose sodium, hypromellose, magnesium stearate, mannitol, polyethylene glycol, pregelatinized starch (maize), and titanium dioxide. lurasidonehclstructure.

• Treatment of adult and adolescent patients (13 to 17 years) with schizophrenia.

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

• Adjunctive treatment with lithium or valproate in adult patients with major depressive episode associated with bipolar I disorder (bipolar depression) .

• Schizophrenia in adults and adolescents (13 to 17 years).

• Depressive episode associated with Bipolar I Disorder (bipolar depression) in adults and pediatric patients (10 to 17 years) as monotherapy.

• Depressive episode associated with Bipolar I Disorder (bipolar depression) in adults as adjunctive therapy with lithium or valproate.

The mechanism of action of lurasidone in the treatment of schizophrenia and bipolar depression is unclear.

However, its efficacy in schizophrenia and bipolar depression could be mediated through a combination of central dopamine D and serotonin Type 2 (5HT 2A ) receptor antagonism. 12.2 Pharmacodynamics Lurasidone is an antagonist with high affinity binding at the dopamine D 2 receptors (Ki of 1 nM) and the serotonin 5-HT 2A (Ki of 0.5 nM) and 5-HT 7 (Ki of 0.5 nM) receptors.

It also binds with moderate affinity to the human α 2 C 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 α 2A adrenergic receptors (Ki of 41 nM).

Lurasidone exhibits little or no affinity for histamine H and muscarinic M 1 receptors (IC 50 > 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 schizophrenia or schizoaffective disorder, 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 ms and 4.6 ms, for the 120 mg and 600 mg dose groups respectively, observed at to 4 hours after dosing.

In this study, there was no apparent dose (exposure)-response relationship.

In short-term, placebo-controlled studies in schizophrenia and bipolar depression, no post-baseline QT prolongations exceeding 500 msec were reported in patients treated with lurasidone hydrochloride or placebo. 12.3 Pharmacokinetics Adults The activity of lurasidone hydrochloride is primarily due to the parent drug.

The pharmacokinetics of lurasidone hydrochloride tablets are 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.

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

Lurasidone hydrochloride is absorbed and reaches peak serum concentrations in approximately to 3 hours.

It is estimated that to 19% of an administered dose is absorbed.

Following administration of 40 mg of lurasidone hydrochloride tablets, the mean (%CV) apparent volume of distribution was 6173 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 to 1000 calories and was independent of meal fat content.

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

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 [ 14 C]-labeled lurasidone hydrochloride.

Following administration of 40 mg of lurasidone hydrochloride tablets, the mean (%CV) apparent clearance was 3902 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 to 2,400 mg/day or valproate 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.

PK analyses concluded that coadministration of lurasidone has minimal effect on lithium and valproate exposure when it is coadministered with lithium to 2,400 mg/day or valproate to 2,000 mg/day. Figure 1: Impact of Other Drugs on Lurasidone Hydrochloride Pharmacokinetics Figure 2: Impact of Lurasidone Hydrochloride on Other Drugs Studies in Specific Populations The effect of intrinsic patient factors on the pharmacokinetics of lurasidone hydrochloride is presented in Figure 3.

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

Figure 3: Impact of Other Patient Factors on Lurasidone Hydrochloride Pharmacokinetics lurasidonehclfig1 lurasidonehclfig2 lurasidonehclfig3.

• Increased Mortality in Elderly Patients with Dementia-Related Psychosis.

• Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-related Psychosis.

• Adult patients with schizophrenia: somnolence, akathisia, extrapyramidal symptoms, and nausea.

• Adolescent patients (13 to 17 years) with schizophrenia: somnolence, nausea, akathisia, EPS (non-akathisia), rhinitis (80 mg only), and vomiting.

• Adult patients with bipolar depression: akathisia, extrapyramidal symptoms, and somnolence.

• Pediatric patients (10 to 17 years) with bipolar depression: nausea, weight increase, and insomnia.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The information below is derived from an integrated clinical study database for lurasidone hydrochloride consisting of 3799 adult patients exposed to one or more doses of lurasidone hydrochloride for the treatment of schizophrenia, and bipolar depression in placebo-controlled studies.

This experience corresponds with a total experience of 1250.9 patient-years.

A total of 1106 lurasidone hydrochloride -treated patients had at least 24 weeks and 371 lurasidone hydrochloride-treated patients had at least 52 weeks of exposure.

Adverse events during exposure to study treatment were obtained by general inquiry and voluntarily reported adverse experiences, as well as results from physical examinations, vital signs, ECGs, weights and laboratory investigations.

Adverse experiences were recorded by clinical investigators using their own terminology.

In order to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.

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

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

Adverse Reactions Associated with Discontinuation of Treatment: A total of 9.5% (143/1508) lurasidone hydrochloride-treated patients and 9.3% (66/708) of placebo-treated patients discontinued due to adverse reactions.

There were no adverse reactions associated with discontinuation in subjects treated with lurasidone hydrochloride that were at least 2% and at least twice the placebo rate.

Adverse Reactions Occurring at an

Incidence of 2% or More in Lurasidone Hydrochloride-Treated Patients: Adverse reactions associated with the use of lurasidone hydrochloride (incidence of 2% or greater, rounded to the nearest percent and lurasidone hydrochloride incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with schizophrenia) are shown in Table 19.

Table 19: Adverse Reactions in 2% or More of Lurasidone Hydrochloride-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in Adult Short-term Schizophrenia Studies Percentage of Patients Reporting Reaction Lurasidone Hydrochloride Body System or Organ Class Placebo (N=708) (%) 20 mg/day (N=71) (%) 40 mg/day (N=487) (%) 80 mg/day (N=538) (%) 120 mg/day (N=291) (%) 160 mg/day (N=121) (%) All Lurasidone Hydrochloride (N=1508) (%) Gastrointestinal.

Disorders Nausea 5 11 10 9 13 7 10 Vomiting 6 7 6 9 9 7 8 Dyspepsia 5 11 6 5 8 6 6 Salivary Hypersecretion <1 1 1 2 4 2 2 Musculoskeletal and Connective Tissue.

Disorders Back Pain 2 0 4 3 4 0 3 Nervous System.

Disorders Somnolence 7 15 16 15 26 8 17 Akathisia 3 6 11 12 22 7 13 Extrapyramidal Disorder* 6 6 11 12 22 13 14 Dizziness 2 6 4 4 5 6 4 Psychiatric.

Disorders Insomnia 8 8 10 11 9 7 10 Agitation 4 10 7 3 6 5 5 Anxiety 4 3 6 4 7 3 5 Restlessness 1 1 3 1 3 2 2 Note: Figures rounded to the nearest integer Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence * Extrapyramidal symptoms include adverse event terms: bradykinesia, cogwheel rigidity, drooling, dystonia, extrapyramidal disorder, hypokinesia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, tongue spasm, torticollis, tremor, and trismus Dose-Related Adverse Reactions in the Schizophrenia Studies Akathisia and extrapyramidal symptoms were dose-related.

The frequency of akathisia increased with dose up to 120 mg/day (5.6% for lurasidone hydrochloride tablets 20 mg, 10.7% for lurasidone hydrochloride tablets 40 mg, 12.3% for lurasidone hydrochloride tablets 80 mg, and 22.0% for lurasidone hydrochloride tablets 120 mg).

Akathisia was reported by 7.4% (9/121) of patients receiving 160 mg/day. Akathisia occurred in 3.0% of subjects receiving placebo.

The frequency of extrapyramidal symptoms increased with dose up to 120 mg/day (5.6% for lurasidone hydrochloride tablets 20 mg, 11.5% for lurasidone hydrochloride tablets 40 mg, 11.9% for lurasidone hydrochloride tablets 80 mg, and 22.0% for lurasidone hydrochloride tablets 120 mg).

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

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

Adverse Reactions Associated with Discontinuation of Treatment: A total of 6.0% (20/331) lurasidone hydrochloride-treated patients and 5.4% (9/168) of placebo-treated patients discontinued due to adverse reactions.

Incidence of 2% or More in Lurasidone Hydrochloride-Treated Patients: Adverse reactions associated with the use of lurasidone hydrochloride (incidence of 2% or greater, rounded to the nearest percent and lurasidone hydrochloride incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with bipolar depression) are shown in Table 20.

Table 20: Adverse Reactions in 2% or More of Lurasidone Hydrochloride-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the Adult Short-term Monotherapy Bipolar Depression Study Percentage of Patients Reporting Reaction Body System or Organ Class Dictionary-derived Term Placebo (N=168) (%) Lurasidone Hydrochloride to 60 mg/day (N=164) (%) Lurasidone Hydrochloride to 120 mg/day (N=167) (%) All Lurasidone Hydrochloride (N=331) (%) Gastrointestinal.

Disorders Nausea 8 10 17 14 Dry Mouth 4 6 4 5 Vomiting 2 2 6 4 Diarrhea 2 5 3 4.

Infections and Infestations Nasopharyngitis 1 4 4 4 Influenza 1 <1 2 2 Urinary Tract Infection <1 2 1 2 Musculoskeletal and Connective Tissue.

Disorders Back Pain <1 3 <1 2 Nervous System.

Disorders Extrapyramidal Symptoms 2 5 9 7 Akathisia 2 8 11 9 Somnolence* 7 7 14 11 Psychiatric.

Disorders Anxiety 1 4 5 4 Note: Figures rounded to the nearest integer Extrapyramidal symptoms include adverse event terms: bradykinesia, cogwheel rigidity, drooling, dystonia, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, tongue spasm, torticollis, tremor, and trismus * Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence Dose-Related Adverse Reactions in the Monotherapy Study: In the adult short-term, placebo-controlled study (involving lower and higher lurasidone hydrochloride dose ranges) the adverse reactions that occurred with a greater than 5% incidence in the patients treated with lurasidone hydrochloride in any dose group and greater than placebo in both groups were nausea (10.4%, 17.4%), somnolence (7.3%, 13.8%), akathisia (7.9%, 10.8%), and extrapyramidal symptoms (4.9%, 9.0%) for lurasidone hydrochloride tablets to 60 mg/day and lurasidone hydrochloride tablets to 120 mg/day, respectively.

Bipolar Depression Adjunctive Therapy with Lithium or Valproate The following findings are based on two adult short-term, placebo-controlled premarketing studies for bipolar depression in which lurasidone hydrochloride tablets were administered at daily doses ranging from to 120 mg as adjunctive therapy with lithium or valproate (n=360).

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

Adverse Reactions Associated with Discontinuation of Treatment: A total of 5.8% (21/360) lurasidone hydrochloride -treated patients and 4.8% (16/334) of placebo-treated patients discontinued due to adverse reactions.

Incidence of 2% or More in Lurasidone Hydrochloride-Treated Patients: Adverse reactions associated with the use of lurasidone hydrochloride (incidence of 2% or greater, rounded to the nearest percent and lurasidone hydrochloride incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with bipolar depression) are shown in Table 21.

Table 21: Adverse Reactions in 2% or More of Lurasidone Hydrochloride-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the Adult Short-term Adjunctive Therapy Bipolar Depression Studies Percentage of Patients Reporting Reaction Body System or Organ Class Dictionary-derived Term Placebo (N=334) (%) Lurasidone Hydrochloride to 120 mg/day (N=360) (%) Gastrointestin.

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. 10.2 Management of Overdosage No specific antidotes for lurasidone hydrochloride 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 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.

• Known hypersensitivity to lurasidone HCl or any components in the formulation.

Angioedema has been observed with lurasidone.

• Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc). .

• Strong CYP3A4 inducers (e.g., rifampin, avasimibe, St. John’s wort, phenytoin, carbamazepine, etc). .

• Known hypersensitivity to lurasidone hydrochloride tablets or any components in the formulation.

• Concomitant use with a strong CYP3A4 inhibitor (e.g., ketoconazole).

• Concomitant use with a strong CYP3A4 inducer (e.g., rifampin).

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

Administration with food substantially increases the absorption of lurasidone hydrochloride tablets.

Schizophrenia – adults 40 mg per day 40 mg to 160 mg per day Schizophrenia – adolescents (13 to 17 years) 40 mg per day 40 mg to 80 mg per day Bipolar Depression.

• adults 20 mg per day 20 mg to 120 mg per day Bipolar Depression – pediatric patients (10 to 17 years) 20 mg per day 20 mg to 80 mg per day.

• Moderate and Severe Renal Impairment: Recommended starting dose is 20 mg per day, and the maximum recommended dose is 80 mg per day.

• Moderate and Severe Hepatic Impairment: Recommended starting dose is 20 mg per day. The maximum recommended dose is 80 mg per day in moderate hepatic impairment and 40 mg per day in severe hepatic impairment.

• Concomitant Use of a Moderate CYP3A4 inhibitor (e.g., diltiazem): Lurasidone hydrochloride tablets dose should be reduced to half of the original dose level.

Recommended starting dose is 20 mg per day. Maximum recommended dose is 80 mg per day.

• Concomitant Use of a Moderate CYP3A4 Inducer: It may be necessary to increase the dose of lurasidone hydrochloride tablets. 2.1 Schizophrenia Adults The recommended starting dose of lurasidone hydrochloride tablets is 40 mg once daily.

Initial dose titration is not required.

Lurasidone hydrochloride tablets have been shown to be effective in a dose range of 40 mg per day to 160 mg per day.

The maximum recommended dose is 160 mg per day. Adolescents (13 to 17 years) The recommended starting dose of lurasidone hydrochloride tablets is 40 mg once daily.

Lurasidone hydrochloride tablets have been shown to be effective in a dose range of 40 mg per day to 80 mg per day.

The maximum recommended dose is 80 mg per day. 2.2 Depressive Episodes Associated with Bipolar I Disorder 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.

Lurasidone hydrochloride tablets 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.

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) .

Patients (10 to 17 years) The recommended starting dose of lurasidone hydrochloride tablets are 20 mg given once daily as monotherapy.

The dose may be increased after one week based on clinical response.

Lurasidone hydrochloride tablets have 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.

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. 2.3 Administration Information Lurasidone hydrochloride tablets should be taken with food (at least 350 calories).

Administration with food increases the

AUC approximately 2-fold and increases the C max approximately 3-fold.

In the clinical studies, lurasidone hydrochloride tablets was administered with food.

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. 2.4 Dose Modifications for Renal Impairment Dose adjustment is recommended in moderate (creatinine clearance: 30 to <50 mL/min) and severe renal impairment (creatinine clearance <30 mL/min) patients.

The recommended starting dose is 20 mg per day. The dose in these patients should not exceed 80 mg per day. 2.5 Dose Modifications for Hepatic Impairment Dose adjustment is recommended in moderate (Child-Pugh Score = 7 to 9) and severe hepatic impairment (Child-Pugh Score = 10 to 15) patients.

The recommended starting dose is 20 mg per day. The dose in moderate hepatic impairment patients should not exceed 80 mg per day and the dose in severe hepatic impairment patients should not exceed 40 per mg/day. 2.6 Dose Modifications Due to Drug Interactions of CYP3A4 Inhibitors and CYP3A4 Inducers 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). .

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 are 20 mg per day, and the maximum recommended dose of lurasidone hydrochloride tablets are 80 mg per day.

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

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). .

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.

Tablets 20 mg: White to off white, round, biconvex tablets, debossed with "L" on one side and "1" on the other side.

NDC: 70518-4563-00 PACKAGING: 30 in 1 BLISTER PACK Storage Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15° to 30°C (59° to 86°F) .

Suite #4 Indiana, PA 1-724-465-8762.

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.

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/m 2 body surface area.

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 to 4% and to 20%, respectively.

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.

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/m 2.

No teratogenic or embryo-fetal effects were observed up to 6 times the MRHD of 160 mg/day based on mg/m 2.

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/m 2.

No pre.

• and postnatal developmental effects were observed up to 0.6 times the MRHD of 160 mg/day, based on mg/m 2.

The safety and effectiveness of lurasidone hydrochloride 40-mg/day and 80-mg/day for the treatment of schizophrenia in adolescents (13 to 17 years) was established in a 6-week, placebo-controlled clinical study in 326 adolescent patients.

The safety and effectiveness of lurasidone hydrochloride has not been established in pediatric patients less than 13 years of age with schizophrenia.

The safety and effectiveness of lurasidone hydrochloride 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.

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

The effectiveness of lurasidone hydrochloride 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 tablets 20 mg/day and 60 mg/day for the treatment of pediatric patients 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 to 12 (13 out of 18 patients on lurasidone hydrochloride with vomiting).

In a long-term, open-label study that enrolled pediatric patients (age to 17 years) with schizophrenia, bipolar depression, or autistic 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 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 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/m 2.

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/m 2.

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/m 2.

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/m 2.

Histopathological findings included increased colloid in the thyroids and inflammation of the prostate in males at 10 times MRHD based on mg/m 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/m 2.

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/m 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/m 2.

Clinical studies with lurasidone hydrochloride did not include sufficient numbers of patients aged and older to determine whether or not they respond differently from younger patients.

In elderly patients with psychosis (65 to 85), lurasidone hydrochloride tablets 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 is not approved for the treatment of patients with dementia-related psychosis.