lurasidone hydrochloride 20 MG Oral Tablet [Latuda]

INDICATIONS AND USAGE Lurasidone Hydrochloride tablets are indicated for: • Treatment of adult and adolescent patients (13 to 17 years) patients 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 )]. Lurasidone hydrochloride tablets are 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 ).

DOSAGE AND ADMINISTRATION Lurasidone hydrochloride tablets should be taken with food (at least 350 calories). Administration with food substantially increases the absorption of lurasidone hydrochloride tablets ( 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): 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 ( 2.6 , 7.1 ). • Concomitant Use of a Moderate CYP3A4 Inducer: It may be necessary to increase the dose of lurasidone hydrochloride tablets ( 2.6 , 7.1 ). 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 [see Clinical Studies ( 14.1 )] . 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. 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 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 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 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 [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 are 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 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 [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. 2.3 Administration Information Lurasidone hydrochloride tablets should be taken with food (at least 350 calories). Administration with food substantially increases the absorption of lurasidone hydrochloride tablets. 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 [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 ( 2.1 and 2.2 )]. 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 [see Use in Specific Populations ( 8.6 )]. 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 [see Use in Specific Populations ( 8.7 )]. 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.) [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 are 20 mg per day, and the maximum recommended dose of lurasidone hydrochloride tablets are 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 tablets 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.

WARNINGS AND PRECAUTIONS • Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) ( 5.3 ). • Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring ( 5.4 ). • Tardive Dyskinesia: Discontinue if clinically appropriate ( 5.5 ). • Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia and weight gain ( 5.6 ). • Hyperprolactinemia: Prolactin elevations may occur ( 5.7 ). • Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts (CBC) in patients with a pre-existing low white blood cell count (WBC) or a history of leukopenia or neutropenia. Consider discontinuing lurasidone hydrochloride if a clinically significant decline in WBC occurs in the absence of other causative factors ( 5.8 ). • Orthostatic Hypotension and Syncope: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope ( 5.9 ). 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. 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 is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions ( 5.3 )]. 5.2 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients 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 1000 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 Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 14 additional patients 18 to 24 5 additional patients Decreases Compared to Placebo 25 to 64 1 fewer patient ≥65 6 fewer 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, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.3 Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis 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 is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions ( 5.1 )]. 5.4 Neuroleptic Malignant Syndrome A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including 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 and provide intensive symptomatic treatment and monitoring. 5.5 Tardive Dyskinesia 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 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, drug discontinuation should be considered. However, some patients may require treatment with lurasidone hydrochloride despite the presence of the syndrome. 5.6 Metabolic Changes 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

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 lurasidone hydrochloride tablets 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 ).

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 D2 and serotonin Type 2 (5HT2A) receptor antagonism. 12.2 Pharmacodynamics Lurasidone is an antagonist with high affinity binding at the dopamine D2 receptors (Ki of 1 nM) and the serotonin 5-HT2A (Ki of 0.5 nM) and 5-HT7 (Ki of 0.5 nM) receptors. It also binds with moderate affinity to the human α2C adrenergic receptors (Ki of 11 nM), is a partial agonist at serotonin 5-HT1A (Ki of 6.4 nM) receptors, and is an antagonist at the α2A adrenergic receptors (Ki of 41 nM). Lurasidone exhibits little or no affinity for histamine H1 and muscarinic M1 receptors (IC50 > 1,000 nM). 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 (11.7) ms and 4.6 (9.5) ms, for the 120 mg and 600 mg dose groups respectively, observed at 2 to 4 hours after dosing. In this study, there was no apparent dose (exposure)-response relationship. In short-term, placebo-controlled studies in schizophrenia and bipolar depression, no post-baseline QT prolongations exceeding 500 msec were reported in patients treated with 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 (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 tablets, the mean (%CV) apparent volume of distribution was 6173 (17.2) L. Lurasidone hydrochloride is highly bound (~99%) to serum proteins. In a food effect study, lurasidone hydrochloride mean Cmax and AUC were about 3-times and 2-times, respectively, when administered with food compared to the levels observed under fasting conditions. Lurasidone hydrochloride exposure was not affected as meal size was increased from 350 to 1000 calories and was independent of meal fat content [see Dosage and Administration (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 tablets, the mean (%CV) apparent clearance was 3902 (18.0) mL/min. Drug Interaction Studies Effects of other drugs on the exposure of lurasidone are summarized in Figure 1. A population PK analyses concluded that coadministration of lithium 300 to 2400 mg/day or valproate 300 to 2000 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 2400 mg/day or valproate 300 to 2000 mg/day. Figure 1: Impact of Other Drugs on Lurasidone Hydrochloride Pharmacokinetics [Figure 1: Impact of Other Drugs on Lurasidone Hydrochloride Pharmacokinetics] Figure 2: Impact of Lurasidone Hydrochloride on Other Drugs [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. Pediatric Patients Lurasidone hydrochloride exposure (i.e., steady-state Cmax and AUC) in children and adolescent patients (10 to 17 years of age) was generally similar to that in adults across the dose range from 40 to 160 mg, without adjusting for body weight. Figure 3: Impact of Other Patient Factors on Lurasidone Hydrochloride Pharmacokinetics [Figure 3: Impact of Other Patient Factors on Lurasidone Hydrochloride Pharmacokinetics]