Lurasidone Hcl Drug Information

Lurasidone hydrochloride tablets are indicated for: 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).

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.

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

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

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 Cmax approximately 3-fold.

In the clinical studies, lurasidone hydrochloride tablets were 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.

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 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.

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. 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.

The following adverse reactions are discussed in more detail in other sections of the labeling: Increased Mortality in Elderly Patients with Dementia-Related Psychosis Suicidal Thoughts and Behaviors Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-related Psychosis Neuroleptic Malignant Syndrome Tardive Dyskinesia Metabolic Changes Hyperprolactinemia Leukopenia, Neutropenia, and Agranulocytosis Orthostatic Hypotension and Syncope Falls Seizures Potential for Cognitive and Motor Impairment Body Temperature Dysregulation Activation of Mania/Hypomania Dysphagia Neurological Adverse Reactions in Patients with Parkinson’s Disease or Dementia with Lewy Bodies 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 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.

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 lurasidone hydrochloride tablets were 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 lurasidone hydrochloride were somnolence, akathisia, extrapyramidal symptoms, and nausea. 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 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 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 Vomiting Dyspepsia Salivary Hypersecretion Musculoskeletal and Connective Tissue Disorders Back Pain Nervous System Disorders Somnolence* Akathisia Extrapyramidal Disorder* Dizziness Psychiatric Disorders Insomnia Agitation Anxiety Restlessness Dose-Related Adverse Reactions in the Schizophrenia Studies Akathisia and extrapyramidal symptoms were dose-related. Akathisia was reported by 7.4% (9/121) of patients receiving 160 mg/day.

Akathisia occurred in 3.0% of subjects receiving placebo. Bipolar 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 20 to 120 mg (n=331). 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 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 Percentage of Patients Reporting Reaction Body System or Organ Class Dictionary-derived Term Placebo (N=168) (%) Lurasidone Hydrochloride 20 to 60 mg/day (N=164) (%) Lurasidone Hydrochloride 80 to 120 mg/day (N=167) (%) All Lurasidone Hydrochloride (N=331) (%) Gastrointestinal Disorders Nausea Dry Mouth Vomiting Diarrhea Infections and Infestations Nasopharyngitis Influenza Urinary Tract Infection Musculoskeletal and Connective Tissue Disorders Back Pain Nervous System Disorders Extrapyramidal Symptoms* Akathisia Somnolence* Psychiatric Disorders Anxiety 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 20 to 60 mg/day and lurasidone hydrochloride tablets 80 to 120 mg/day, respectively.

Table 22: 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 Adolescent Short-term Schizophrenia Study Note: Figures rounded to the nearest integer Somnolence includes adverse event terms: hypersomnia, sedation, and somnolence Viral Infection includes adverse event terms: nasopharyngitis, influenza, viral infection, upper respiratory tract infection Rhinitis incudes adverse event terms: rhinitis, allergic rhinitis, rhinorrhea, and nasal congestion Percentage of Patients Reporting Reaction Body System or Organ Class Dictionary-derived Term Placebo (N=112) Lurasidone Hydrochloride 40 mg/day Lurasidone Hydrochloride 80 mg/day All Lurasidone Hydrochloride (N=110) (N=104) (N=214) Gastrointestinal Disorders Nausea Vomiting Diarrhea Dry Mouth Infections and Infestations Viral Infection* Rhinitis* Oropharyngeal pain Tachycardia Nervous System Disorders Somnolence* Akathisia Dizziness Pediatric Patients (10 to 17 years) Bipolar Depression The following findings are based on the 6-week, placebo-controlled study for bipolar depression in pediatric patients 10 to 17 years in which lurasidone hydrochloride was administered at daily doses ranging from 20 to 80 mg (N=175). Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥5%, and at least twice the rate of placebo) in pediatric patients (10 to 17 years) treated with lurasidone hydrochloride were nausea, weight increase, and insomnia. The incidence of akathisia for lurasidone hydrochloride-treated patients was 12.9% and 3.0% for placebo-treated patients.

Incidence of EPS by dose is provided in Table 24. Table 24: Incidence of EPS Compared to Placebo in Adult Schizophrenia Studies Note: Figures rounded to the nearest integer Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor Lurasidone Hydrochloride Adverse Event Term 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 EPS events All EPS events, excluding Akathisia/Restlessness Akathisia Dystonia* Parkinsonism* Restlessness Adolescents In the short-term, placebo-controlled, study of schizophrenia in adolescents, the incidence of EPS, excluding events related to akathisia, for lurasidone hydrochloride-treated patients was higher in the 40 mg (10%) and the 80 mg (7.7%) treatment groups vs. placebo (3.6%); and the incidence of akathisia-related events for lurasidone hydrochloride-treated patients was 8.9% vs. 1.8% for placebo-treated patients. Incidence of EPS is provided in Table 27.

Table 27: Incidence of EPS Compared to Placebo in the Adult Adjunctive Therapy Bipolar Depression Studies Note: Figures rounded to the nearest integer Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor Adverse Event Term Placebo (N=334) (%) Lurasidone Hydrochloride 20 to 120 mg/day (N=360) (%) All EPS events 13 24 All EPS events, excluding Akathisia/Restlessness 9 14 Akathisia 5 11 Dystonia* <1 1 Parkinsonism* 8 13 Restlessness <1 4 In the short-term, placebo-controlled schizophrenia and bipolar depression studies, data was objectively collected on the Simpson Angus Rating Scale (SAS) for extrapyramidal symptoms (EPS), the Barnes Akathisia Scale (BAS) for akathisia and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesias. Adolescents The mean change from baseline for lurasidone hydrochloride-treated patients with adolescent schizophrenia for the SAS, BAS and AIMS was comparable to placebo-treated patients. Bipolar Depression Adults Monotherapy The mean change from baseline for lurasidone hydrochloride-treated adult patients for the SAS, BAS and AIMS was comparable to placebo-treated patients.

Adjunctive Therapy with Lithium or Valproate The mean change from baseline for lurasidone hydrochloride-treated adult patients for the SAS, BAS and AIMS was comparable to placebo-treated patients. Pediatric Patients (10 to 17 years) The mean change from baseline for lurasidone hydrochloride- treated pediatric patients 10 to 17 years with bipolar depression for the SAS, BAS and AIMS was comparable to placebo-treated patients. Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment.

Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

No patients discontinued the clinical study due to dystonic events. Adjunctive Therapy with Lithium or Valproate In the adult short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies, dystonia occurred in 1.1% of lurasidone hydrochloride tablets-treated subjects (20 to 120 mg) compared to 0.6% of subjects receiving placebo. Other Adverse Reactions Observed During the Premarketing Evaluation of Lurasidone Hydrochloride Following is a list of adverse reactions reported by adult patients treated with lurasidone hydrochloride tablets at multiple doses of ≥ 20 mg once daily within the premarketing database of 2905 patients with schizophrenia.

The reactions listed are those that could be of clinical importance, as well as reactions that are plausibly drug-related on pharmacologic or other grounds. Reactions listed in Table 19 or those that appear elsewhere in the lurasidone hydrochloride label are not included. Reactions are further categorized by organ class and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (frequent) (only those not already listed in the tabulated results from placebo-controlled studies appear in this listing); those occurring in 1/100 to 1/1000 patients (infrequent); and those occurring in fewer than 1/1000 patients (rare).

Blood and Lymphatic System Disorders: Infrequent: anemia Cardiac Disorders: Frequent: tachycardia; Infrequent: AV block 1st degree, angina pectoris, bradycardia Ear and Labyrinth Disorders: Infrequent: vertigo Eye Disorders: Frequent: blurred vision Gastrointestinal Disorders: Frequent: abdominal pain, diarrhea; Infrequent: gastritis General Disorders and Administrative Site Conditions: Rare: sudden death Investigations: Frequent: CPK increased Metabolism and Nutritional System Disorders: Frequent: decreased appetite Musculoskeletal and Connective Tissue Disorders: Rare: rhabdomyolysis Nervous System Disorders: Infrequent: cerebrovascular accident, dysarthria Psychiatric Disorders: Infrequent: abnormal dreams, panic attack, sleep disorder Renal and Urinary Disorders: Infrequent: dysuria; Rare: renal failure Reproductive System and Breast Disorders: Infrequent: amenorrhea, dysmenorrhea; Rare: breast enlargement, breast pain, galactorrhea, erectile dysfunction, priapism Skin and Subcutaneous Tissue Disorders: Frequent: rash, pruritus; Rare: angioedema Vascular Disorders: Frequent: hypertension Clinical Laboratory Changes Schizophrenia Adults Serum Creatinine: In short-term, placebo-controlled trials, the mean change from Baseline in serum creatinine was +0.05 mg/dL for lurasidone hydrochloride-treated patients compared to +0.02 mg/dL for placebo-treated patients. The threshold for high creatinine value varied from > 0.79 to > 1.3 mg/dL based on the centralized laboratory definition for each study (Table 29). Table 29: Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in Adult Schizophrenia Studies Laboratory Parameter Placebo (N=708) Lurasidone Hydrochloride 20 mg/day (N=71) Lurasidone Hydrochloride 40 mg/day (N=487) Lurasidone Hydrochloride 80 mg/day (N=538) Lurasidone Hydrochloride 120 mg/day (N=291) Lurasidone Hydrochloride 160 mg/day (N=121) Serum Creatinine Elevated Adolescents Serum Creatinine: In the short-term, placebo-controlled, adolescent schizophrenia study, the mean change from Baseline in serum creatinine was -0.009 mg/dL for lurasidone hydrochloride-treated patients compared to +0.017 mg/dL for placebo-treated patients.

Table 30: Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in the Adolescent Schizophrenia Study Laboratory Parameter Placebo (N=103) Lurasidone Hydrochloride 40 mg/day (N=97) Lurasidone Hydrochloride 80 mg/day (N=97) Serum Creatinine Elevated 2.9% 7.2% 7.2% Bipolar Depression Adults Monotherapy Serum Creatinine: In the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, the mean change from Baseline in serum creatinine was +0.01 mg/dL for lurasidone hydrochloride-treated patients compared to -0.02 mg/dL for placebo-treated patients. Table 31: Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in the Adult Monotherapy Bipolar Depression Study Laboratory Parameter Placebo (N=168) Lurasidone Hydrochloride 20 to 60 mg/day (N=164) Lurasidone Hydrochloride 80 to 120 mg/day (N=167) Serum Creatinine Elevated <1% 2% 4% Adjunctive Therapy with Lithium or Valproate Serum Creatinine: In adult short-term, placebo-controlled premarketing adjunctive studies for bipolar depression, the mean change from Baseline in serum creatinine was +0.04 mg/dL for lurasidone hydrochloride-treated patients compared to -0.01 mg/dL for placebo-treated patients. In patients with a normal serum creatinine at baseline, 6% experienced a shift to high at endpoint 6.2 Postmarketing Experience 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

Drugs Having No Clinically Important Interactions with Lurasidone Hydrochloride 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.

Known hypersensitivity to lurasidone hydrochloride 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.).

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 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.