Latuda

Warnings and Precautions ( 5.7 ) 1/2025

1 INDICATIONS AND USAGE LATUDA is indicated for: Treatment of adult and adolescent patients (13 to 17 years) with schizophrenia [see Clinical Studies ( 14.1 )] . 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 )] . LATUDA is an atypical antipsychotic indicated for the treatment of: Schizophrenia in adults and adolescents (13 to 17 years) ( 1 , 14.1 ) Depressive episode associated with Bipolar I Disorder (bipolar depression) in adults and pediatric patients (10 to 17 years) as monotherapy ( 1 , 14.2 ) Depressive episode associated with Bipolar I Disorder (bipolar depression) in adults as adjunctive therapy with lithium or valproate ( 1 , 14.2 )

2 DOSAGE AND ADMINISTRATION LATUDA should be taken with food (at least 350 calories). Administration with food substantially increases the absorption of LATUDA ( 2.3 , 12.3 ). Indication Starting Dose Recommended Dose Schizophrenia – adults ( 2.1 ) 40 mg per day 40 mg to 160 mg per day Schizophrenia –adolescents (13 to 17 years) ( 2.1 ) 40 mg per day 40 mg to 80 mg per day Bipolar Depression - adults ( 2.2 ) 20 mg per day 20 mg to 120 mg per day Bipolar Depression –pediatric patients (10 to 17 years) ( 2.2 ) 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 ( 2.4, 8.6 ). 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 ( 2.5, 8.7 ). Concomitant Use of a Moderate CYP3A4 inhibitor (e.g., diltiazem): LATUDA 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 ( 2.6 , 7.1 ). Concomitant Use of a Moderate CYP3A4 Inducer: It may be necessary to increase the dose of LATUDA ( 2.6 , 7.1 ). 2.1 Schizophrenia Adults The recommended starting dose of LATUDA is 40 mg once daily. Initial dose titration is not required. LATUDA has been shown to be effective in a dose range of 40 mg per day to 160 mg per day [see Clinical Studies ( 14.1 )] . The maximum recommended dose is 160 mg per day. Adolescents (13 – 17 years) The recommended starting dose of LATUDA is 40 mg once daily. Initial dose titration is not required. LATUDA has been shown to be effective in a dose range of 40 mg per day to 80 mg per day [see Clinical Studies ( 14.1 )] . The maximum recommended dose is 80 mg per day. 2.2 Depressive Episodes Associated with Bipolar I Disorder Adults The recommended starting dose of LATUDA is 20 mg given once daily as monotherapy or as adjunctive therapy with lithium or valproate. Initial dose titration is not required. LATUDA has 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 – 17 years) The recommended starting dose of LATUDA 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. LATUDA 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 LATUDA in the treatment of mania associated with bipolar disorder has not been established. 2.3 Administration Information LATUDA should be taken with food (at least 350 calories). Administration with food substantially increases the absorption of LATUDA. Administration with food increases the AUC approximately 2-fold and increases the Cmax approximately 3-fold. In the clinical studies, LATUDA was administered with food [see Clinical Pharmacology ( 12.3 )] . The effectiveness of LATUDA 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 LATUDA for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.1and 2.2)] . 2.4 Dose Modifications for Renal Impairment Dose adjustm …

3 DOSAGE FORMS AND STRENGTHS LATUDA tablets are available in the following shape and color ( Table 1 ) with respective one-sided debossing. Table 1: LATUDA Tablet Presentations Tablet Strength Tablet Color/Shape Tablet Markings 20 mg white to off-white round L20 40 mg white to off-white round L40 60 mg white to off-white oblong L60 80 mg pale green oval L80 120 mg white to off-white oval L120 Tablets: 20 mg, 40 mg, 60 mg, 80 mg and 120 mg ( 3 )

4 CONTRAINDICATIONS Known hypersensitivity to lurasidone HCl or any components in the formulation. Angioedema has been observed with lurasidone [see Adverse Reactions ( 6.1 )] . Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.) [see Drug Interactions ( 7.1 )]. Strong CYP3A4 inducers (e.g., rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine, etc.) [see Drug Interactions ( 7.1 )]. Known hypersensitivity to LATUDA or any components in the formulation ( 4 ). Concomitant use with a strong CYP3A4 inhibitor (e.g., ketoconazole) ( 2.6 , 4 , 7.1 ). Concomitant use with a strong CYP3A4 inducer (e.g., rifampin) ( 2.6 , 4 , 7.1 ).

6 ADVERSE REACTIONS 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 )] Commonly observed adverse reactions (incidence ≥ 5% and at least twice the rate for placebo) were ( 6.1 ): Adult patients with schizophrenia: somnolence, akathisia, extrapyramidal symptoms, and nausea Adolescent patients (13-17 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 (10-17 years) with bipolar depression: nausea, weight increase, and insomnia. To report SUSPECTED ADVERSE REACTIONS, Sumitomo Pharma America, Inc. at 1-877-737-7226 or FDA at 1-800-FDA-1088 or www.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. Adults The information below is derived from an integrated clinical study database for LATUDA consisting of 3799 adult patients exposed to one or more doses of LATUDA for the treatment of schizophrenia, and bipolar depression in placebo-controlled studies. This experience corresponds with a total experience of 1250.9 patient-years. A total of 1106 LATUDA-treated patients had at least 24 weeks and 371 LATUDA-treated patients had at least 52 weeks of exposure. Adverse events during exposure to study treatment were obtained by general inquiry and voluntarily reported adverse experiences, as well as results from physical examinations, vital signs, ECGs, weights and laboratory investigations. Adverse experiences were recorded by clinical investigators using their own terminology. In order to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology. Schizophrenia The following findings are based on the short-term, placebo-controlled premarketing adult studies for schizophrenia in which LATUDA was administered at daily doses ranging from 20 to 160 mg (n=1508). Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) in patients treated with LATUDA were somnolence, akathisia, extrapyramidal symptoms, and nausea. Adverse Reactions Associated with Discontinuation of Treatment: A total of 9.5% (143/1508) LATUDA-treated patients and 9.3% (66/708) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated …

7 DRUG INTERACTIONS 7.1 Drugs Having Clinically Important Interactions with LATUDA Table 34: Clinically Important Drug Interactions with LATUDA Strong CYP3A4 Inhibitors Clinical Impact: Concomitant use of LATUDA with strong CYP3A4 inhibitors increased the exposure of lurasidone compared to the use of LATUDA alone [see Clinical Pharmacology ( 12.3 )] . Intervention: LATUDA should not be used concomitantly with strong CYP3A4 inhibitors [see Contraindications ( 4 )] . Examples: Ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil Moderate CYP3A4 Inhibitors Clinical Impact: Concomitant use of LATUDA with moderate CYP3A4 inhibitors increased the exposure of lurasidone compared to the use of LATUDA alone [see Clinical Pharmacology ( 12.3 )] . Intervention: LATUDA dose should be reduced to half of the original level when used concomitantly with moderate inhibitors of CYP3A4 [see Dosage and Administration ( 2.6 )] . Examples: Diltiazem, atazanavir, erythromycin, fluconazole, verapamil Strong CYP3A4 Inducers Clinical Impact: Concomitant use of LATUDA with strong CYP3A4 inducers decreased the exposure of lurasidone compared to the use of LATUDA alone [see Clinical Pharmacology ( 12.3 )] . Intervention: LATUDA should not be used concomitantly with strong CYP3A4 inducers [see Contraindications ( 4 )] . Examples: Rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine Moderate CYP3A4 Inducers Clinical Impact: Concomitant use of LATUDA with moderate CYP3A4 inducers decreased the exposure of lurasidone compared to the use of LATUDA alone [see Clinical Pharmacology ( 12.3 )] . Intervention: LATUDA dose should be increased when used concomitantly with moderate inducers of CYP3A4 [see Dosage and Administration ( 2.6 )] . Examples: Bosentan, efavirenz, etravirine, modafinil, nafcillin 7.2 Drugs Having No Clinically Important Interactions with LATUDA Based on pharmacokinetic studies, no dosage adjustment of LATUDA is required when administered concomitantly with lithium, valproate, or substrates of P-gp or CYP3A4 [see Clinical Pharmacology ( 12.3 )] .

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause extrapyramidal and or/withdrawal symptoms in neonates with third trimester exposure ( 8.1 ). 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LATUDA during pregnancy. For more information, contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. 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 LATUDA 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 [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 2-4% and 15-20%, 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/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 . 8.2 Lactation 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 LATUDA and any potential adverse effects on the breastfed infant from LATUDA or from the underlying maternal condition. 8.4 Pediatric Use Schizophrenia The safety and effectiveness of LATUDA 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 [see Dosage and Administration ( 2.1 ), Adverse Reactions ( 6.1 ), and Clinical Studies ( 14.1 )] . The safety and effectiveness of LATUDA has not been established in pediatric …

12.1 Mechanism of Action 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 2 and serotonin Type 2 (5HT 2A ) receptor antagonism.

11 DESCRIPTION LATUDA 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 water, practically insoluble or insoluble in 0.1 N HCl, slightly soluble in ethanol, sparingly soluble in methanol, practically insoluble or insoluble in toluene and very slightly soluble in acetone. LATUDA tablets are intended for oral administration only. Each tablet contains 20 mg, 40 mg, 60 mg, 80 mg, or 120 mg of lurasidone hydrochloride. Inactive ingredients are mannitol, pregelatinized starch, croscarmellose sodium, hypromellose, magnesium stearate, Opadry ® and carnauba wax. Additionally, the 80 mg tablet contains yellow ferric oxide and FD&C Blue No. 2 Aluminum Lake. Chemical Structure

10 OVERDOSAGE 10.1 Human Experience In premarketing clinical studies, accidental or intentional overdosage of LATUDA was identified in one patient who ingested an estimated 560 mg of LATUDA. This patient recovered without sequelae. This patient resumed LATUDA treatment for an additional two months. 10.2 Management of Overdosage No specific antidotes for LATUDA 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 LATUDA. Similarly, the alpha-blocking properties of bretylium might be additive to those of LATUDA, resulting in problematic hypotension. Hypotension and circulatory collapse should be treated with appropriate measures. Epinephrine and dopamine should not be used, or other sympathomimetics with beta-agonist activity, since beta stimulation may worsen hypotension in the setting of LATUDA-induced alpha blockade. In case of severe extrapyramidal symptoms, anticholinergic medication should be administered. Gastric lavage (after intubation if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.

16 HOW SUPPLIED/STORAGE AND HANDLING LATUDA tablets are white to off-white, round (20 mg or 40 mg), white to off-white, oblong (60 mg), pale green, oval (80 mg) or white to off-white, oval (120 mg) and identified with strength-specific one-sided debossing, “L20” (20 mg), “L40” (40 mg), “L80” (80 mg) or “L120” (120 mg). Tablets are supplied in the following strengths and package configurations ( Table 39 ). Table 39: Package Configuration for LATUDA Tablets Tablet Strength Package Configuration NDC Code 20 mg Bottles of 30 63402-302-30 Bottles of 90 63402-302-90 Bottles of 500 63402-302-50 Box of 100 (Hospital Unit Dose) 10 blister cards, 10 tablets each 63402-302-10 Carton 63402-302-01 Blister 40 mg Bottles of 30 63402-304-30 Bottles of 90 63402-304-90 Bottles of 500 63402-304-50 Box of 100 (Hospital Unit Dose) 10 blister cards, 10 tablets each 63402-304-10 Carton 63402-304-01 Blister 60 mg Bottles of 30 63402-306-30 Bottles of 90 63402-306-90 Bottles of 500 63402-306-50 Box of 100 (Hospital Unit Dose) 10 blister cards, 10 tablets each 63402-306-10 Carton 63402-306-01 Blister 80 mg Bottles of 30 63402-308-30 Bottles of 90 63402-308-90 Bottles of 500 63402-308-50 Box of 100 (Hospital Unit Dose) 10 blister cards, 10 tablets each 63402-308-10 Carton 63402-308-01 Blister 120 mg Bottles of 30 63402-312-30 Bottles of 90 63402-312-90 Bottles of 500 63402-312-50 Box of 100 (Hospital Unit Dose) 10 blister cards, 10 tablets each 63402-312-10 Carton 63402-312-01 Blister Storage Store LATUDA tablets at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [See USP Controlled Room Temperature] .