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Latuda Drug Description


LATUDA®
(lurasidone HCI) Tablets

WARNING: 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.

Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

LATUDA (lurasidone hcl tablets for oral administration) is not approved for the treatment of patients with dementia-related psychosis, [see WARNINGS AND PRECAUTIONS].

DRUG DESCRIPTION

LATUDA (lurasidone hcl tablets for oral administration) is a psychotropic agent belonging to the chemical class of benzoisothiazol derivatives.

Its chemical name is (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride. Its molecular formula is C28H36N402S•HCI and its molecular weight is 529.14.

The chemical structure is:

 

LATUDA®   (lurasidone HCI) Structural Formula Illustration

Lurasidone hydrochloride is a white to off-white powder. It is very slightly soluble in water, practically insoluble or insoluble in 0.1 N HCI, slightly soluble in ethanol, sparingly soluble in methanol, practically insoluble or insoluble in toluene and very slightly soluble in acetone.

LATUDA (lurasidone hcl tablets for oral administration) tablets are intended for oral administration only. Each tablet contains 40 mg, or 80 mg of lurasidone hydrochloride.

Inactive ingredients are mannitol, pregelatinized starch, croscarmellose sodium, hypromellose, magnesium stearate, Opadry® and camauba wax. Additionally, the 80 mg tablet contains yellow ferric oxide and FD&C Blue No.2 Aluminum Lake.

 

What are the precautions when taking lurasidone hcl tablets for oral administration (Latuda)?

See also Warning section.

Before taking lurasidone, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney problems, liver problems, stroke, breast cancer, diabetes, low blood pressure, seizures, low white blood cell count, dementia (such as Alzheimer's Disease), trouble swallowing.

This drug may make you dizzy or drowsy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Avoid alcoholic...

 

Latuda


Latuda Indications & Dosage


INDICATIONS

LATUDA (lurasidone hcl tablets for oral administration) is indicated for the treatment of patients with schizophrenia.

The efficacy of LATUDA (lurasidone hcl tablets for oral administration) in schizophrenia was established in four 6-week controlled studies of adult patients with schizophrenia [see Clinical Studies].

The effectiveness of LATUDA (lurasidone hcl tablets for oral administration) 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 (lurasidone hcl tablets for oral administration) for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see DOSAGE AND ADMINISTRATION].

DOSAGE AND ADMINISTRATION

Schizophrenia

The recommended starting dose of LATUDA (lurasidone hcl tablets for oral administration) is 40 mg once daily. Initial dose titration is not required. LATUDA (lurasidone hcl tablets for oral administration) has been shown to be effective in a dose range of 40 mg/day to 120 mg/day [see Clinical Studies]. In the 6-week controlled trials, there was no suggestion of added benefit with the 120 mg/day dose, but there was a dose-related increase in certain adverse reactions. Therefore, the maximum recommended dose is 80 mg/day.

Administration Instructions

LATUDA should be taken with food (at least 350 calories) [see CLINICAL PHARMACOLOGY].

Dosage in Special Populations

Dosage adjustments are not recommended on the basis of age, gender, and race [see Use In Specific Populations].

Dose adjustment is recommended in moderate and severe renal impairment patients. The dose in these patients should not exceed 40 mg/day [see Use in Specific Populations].

Dose adjustment is recommended in moderate and severe hepatic impairment patients. The dose in these patients should not exceed 40 mg/day [see Use in Specific Populations].

Dosing recommendation for patients taking LATUDA (lurasidone hcl tablets for oral administration) concomitantly with potential CYP3A4 inhibitors: When coadministration of LATUDA (lurasidone hcl tablets for oral administration) with a moderate CYP3A4 inhibitor such as diltiazem is considered, the dose should not exceed 40 mg/day. LATUDA (lurasidone hcl tablets for oral administration) should not be used in combination with a strong CYP3A4 inhibitor (e.g., ketoconazole) [see CONTRAINDICATIONS; DRUG INTERACTIONS].

Dosing recommendation for patients taking LATUDA (lurasidone hcl tablets for oral administration) concomitantly with potential CYP3A4 inducers: LATUDA (lurasidone hcl tablets for oral administration) should not be used in combination with a strong CYP3A4 inducer (e.g., rifampin) [see CONTRAINDICATIONS; DRUG INTERACTIONS].

HOW SUPPLIED

Dosage Forms and Strengths

LATUDA (lurasidone hcl tablets for oral administration) tablets are available in the following shape and color (Table 1) with respective one-sided debossing: 40 mg (white to off-white, round, "L40"), or 80 mg (pale green, oval, "L80").

Table 1: LATUDA (lurasidone hcl tablets for oral administration) Tablet Presentations

Tablet Strength Tablet Color/Shape Tablet Markings
40 mg white to off-white round "L40"
80 mg pale green oval "L80"

LATUDA (lurasidone hcl tablets for oral administration) tablets are white to off-white, round (40 mg), or pale green, oval (80 mg) and identified with strength specific one-sided debossing , "L40" (40 mg), or "L80" (80 mg). Tablets are supplied in the following strengths and package configurations (Table 11):

Table 11: Package Configuration for LATUDA (lurasidone hcl tablets for oral administration) Tablets

Tablet Strength Package Configuration NDC Code
40 mg Bottles of 30 63402-304-30
Bottles of 90 63402-304-90
Bottles of 500 63402-304-50
Box of 28 4 blister cards, 7 tablets each 63402-304-04 Carton 63402-304-07 Blister
Box of 100 (Hospital Unit Dose) 10 blister cards, 10 tablets each 63402-304-10 Carton 63402-304-01 Blister
80 mg Bottles of 30 63402-308-30
Bottles of 90 63402-308-90
Bottles of 500 63402-308-50
Box of 28 4 blister cards, 7 tablets each 63402-308-04 Carton 63402-308-07 Blister
Box of 100 (Hospital Unit Dose) 10 blister cards, 10 tablets each 63402-308-10 Carton 63402-308-01 Blister

Storage

Store LATUDA (lurasidone hcl tablets for oral administration) tablets at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) [See USP Controlled Room Temperature].

For Customer Service, call 1-888-394-7377.
For Medical Information, call 1-800-739-0565.
To report suspected adverse reactions, call 1-877-737-7226.

Manufactured for: Sunovion Pharmaceuticals Inc. Marlborough, MA 01752. Sunovion Pharmaceuticals Inc. is a U.S. subsidiary of Dainippon Sumitomo Pharma Co. Ltd. Revised: October 2010

 

 

Latuda


Latuda Side Effects & Drug Interactions


SIDE EFFECTS

Overall Adverse Reaction Profile

The following adverse reactions are discussed in more detail in other sections of the labeling:

  • Use in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and WARNINGS AND PRECAUTIONS]
  • Cerebrovascular Adverse Reactions, Including Stroke [see WARNINGS AND PRECAUTIONS]
  • Neuroleptic Malignant Syndrome [see WARNINGS AND PRECAUTIONS]
  • Tardive Dyskinesia [see WARNINGS AND PRECAUTIONS]
  • Hyperglycemia and Diabetes Mellitus [see WARNINGS AND PRECAUTIONS]
  • Hyperprolactinemia [see WARNINGS AND PRECAUTIONS]
  • Leukopenia, Neutropenia, and Agranulocytosis [see WARNINGS AND PRECAUTIONS]
  • Orthostatic Hypotension and Syncope [see WARNINGS AND PRECAUTIONS]
  • Seizures [see WARNINGS AND PRECAUTIONS]
  • Potential for Cognitive and Motor Impairment [see WARNINGS AND PRECAUTIONS]
  • Body Temperature Regulation [see WARNINGS AND PRECAUTIONS]
  • Suicide [see WARNINGS AND PRECAUTIONS]
  • Dysphagia [see WARNINGS AND PRECAUTIONS]
  • Use in Patients with Concomitant Illness [see WARNINGS AND PRECAUTIONS]

The information below is derived from a clinical study database for LATUDA (lurasidone hcl tablets for oral administration) consisting of over 2096 patients with schizophrenia exposed to one or more doses with a total experience of 624 patient-years. Of these patients, 1004 participated in short-term placebo-controlled schizophrenia studies with doses of 20 mg, 40 mg, 80 mg or 120 mg once daily. A total of 533 LATUDA (lurasidone hcl tablets for oral administration) -treated patients had at least 24 weeks and 238 LATUDA (lurasidone hcl tablets for oral administration) -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 stated frequencies of adverse reactions represent the proportion of individuals who experienced at least once, a treatment-emergent adverse event of the type listed. Treatment-emergent adverse events were defined as adverse experiences, which started or worsened on or after the date of the first dose through seven days after study medication discontinuation. There was no attempt to use investigator causality assessments; i.e., all events meeting the defined criteria, regardless of investigator causality are included. It is important to emphasize that, although the reactions occurred during treatment with LATUDA (lurasidone hcl tablets for oral administration) , they were not necessarily caused by it. The label should be read in its entirety to gain an understanding of the safety profile of LATUDA (lurasidone hcl tablets for oral administration) .

The figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatment, uses and investigators. The cited figures, however, do provide the prescriber with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reaction incidence in the population studied.

Clinical Studies Experience

The following findings are based on the short-term placebo-controlled premarketing studies for schizophrenia in which LATUDA (lurasidone hcl tablets for oral administration) was administered at daily doses ranging from 20 to 120 mg (n = 1004).

Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) in patients treated with LATUDA (lurasidone hcl tablets for oral administration) were somnolence, akathisia, nausea, parkinsonism and agitation.

Adverse Reactions Associated with Discontinuation of Treatment: A total of 9.4% (94/1004) LATUDA (lurasidone hcl tablets for oral administration) -treated patients and 5.9% (27/455) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with LATUDA (lurasidone hcl tablets for oral administration) that were at least 2% and at least twice the placebo rate.

Adverse Reactions Occurring at an Incidence of 2% or More in LATUDA (lurasidone hcl tablets for oral administration) -Treated Patients: Adverse reactions associated with the use of LATUDA (lurasidone hcl tablets for oral administration) (incidence of 2% or greater, rounded to the nearest percent and LATUDA (lurasidone hcl tablets for oral administration) incidence greater than placebo) that occurred during acute therapy (up to 6-weeks in patients with schizophrenia) are shown in Table 6.

Table 6: Adverse Reaction in 2% or More of LATUDA (lurasidone hcl tablets for oral administration) -Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in Short-term Schizophrenia Studies

Percentage of Patients Reporting Reaction
Body System or Organ Class
Dictionary-derived Term
Placebo
(N = 455)
All LATUDA
(N = 1004)
Gastrointestinal Disorders
Nausea 6 12
Vomiting 6 8
Dyspepsia 6 8
Salivary hypersecretion < 1 2
General Disorders and Administration Site Conditions
Fatigue 3 4
Musculoskeletal and Connective Tissue Disorders
Back Pain 3 4
Nervous System Disorders
Somnolence* 10 22
Akathisia 3 15
Parkinsonism** 5 11
Dystonia*** 1 5
Dizziness 3 5
Psychiatric Disorders
Insomnia 7 8
Agitation 3 6
Anxiety 3 6
Restlessness 2 3
Note: Figures rounded to the nearest integer
* Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence
** Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor
*** Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus

Dose-Related Adverse Reactions

Based on the pooled data from the placebo-controlled, short-term, fixed-dose studies, among the adverse reactions that occurred with a greater than 5% incidence in the patients treated with LATUDA (lurasidone hcl tablets for oral administration) , the apparent dose-related adverse reactions were akathisia and somnolence (Table 7).

Table 7: Dose-Related Adverse Events


Extrapyramidal Symptoms

In the short-term, placebo-controlled schizophrenia studies, for LATUDA (lurasidone hcl tablets for oral administration) -treated patients, the incidence of reported EPS-related events, excluding akathisia and restlessness, was 14.7% versus 5.1% for placebo-treated patients; and the incidence of akathisia for LATUDA (lurasidone hcl tablets for oral administration) -treated patients was 15.0% versus 3.3% for placebo-treated patients. Akathisia appeared to be dose-related and the greatest frequency of parkinsonism and dystonia occurred with the highest dose of LATUDA (lurasidone hcl tablets for oral administration) , 120 mg/day (Table 8).

Table 8: Percentage of EPS Compared to Placebo


In the short-term, placebo-controlled schizophrenia studies, data was objectively collected on the Simpson Angus Rating Scale for extrapyramidal symptoms (EPS), the Barnes Akathisia Scale (for akathisia) and the Abnormal Involuntary Movement Scale (for dyskinesias). The mean change from baseline for LATUDA (lurasidone hcl tablets for oral administration) -treated patients was comparable to placebo-treated patients, with the exception of the Barnes Akathisia Scale global score (LATUDA (lurasidone hcl tablets for oral administration) , 0.2; placebo, 0.0). The percentage of patients who shifted from normal to abnormal was greater in LATUDA (lurasidone hcl tablets for oral administration) -treated patients versus placebo for the BAS (LATUDA (lurasidone hcl tablets for oral administration) , 16.0%; placebo, 7.6%) and the SAS (LATUDA (lurasidone hcl tablets for oral administration) , 5.3%; placebo, 2.5%).

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.

In the short-term, placebo-controlled clinical trials, dystonia occurred in 4.7% of LATUDA (lurasidone hcl tablets for oral administration) -treated subjects (0.0% LATUDA (lurasidone hcl tablets for oral administration) 20 mg, 4.2% LATUDA (lurasidone hcl tablets for oral administration) 40 mg, 4.6% LATUDA (lurasidone hcl tablets for oral administration) 80 mg and 6.5% LATUDA (lurasidone hcl tablets for oral administration) 120 mg) compared to 0.7% of subjects receiving placebo. Seven subjects (0.7%, 7/1004) discontinued clinical trials due to dystonic events - 4 were receiving LATUDA (lurasidone hcl tablets for oral administration) 80 mg/day and 3 were receiving LATUDA (lurasidone hcl tablets for oral administration) 120 mg/day.

Laboratory Test Abnormalities and ECG Changes in Clinical Studies

Laboratory Test Abnormalities

In a between-group comparison of the pooled data from short-term, placebo-controlled studies, there were no clinically important changes in total cholesterol measurements; triglycerides or glucose from Baseline to Endpoint [see WARNINGS AND PRECAUTIONS]. There were also no clinically important differences between LATUDA (lurasidone hcl tablets for oral administration) and placebo in mean change from baseline to endpoint in routine hematology, urinalysis, or serum chemistry. LATUDA (lurasidone hcl tablets for oral administration) was associated with a dose-related increase in prolactin concentration [see WARNINGS AND PRECAUTIONS]

Creatinine: In short-term, placebo-controlled trials, the mean change from Baseline in creatinine was 0.06 mg/dL for LATUDA (lurasidone hcl tablets for oral administration) -treated patients compared to 0.03 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 3.1% (30/977) of LATUDA (lurasidone hcl tablets for oral administration) -treated patients and 1.4% (6/439) on placebo. The threshold for high creatinine value varied from ≥ 1.1 to ≥ 1.3 mg/dL based on the centralized laboratory definition for each study [see Dosage in Special Population; Use in Specific Populations]

Transaminases: The mean changes in AST and ALT for LATUDA (lurasidone hcl tablets for oral administration) - and placebo-treated patients were similar. The proportion of patients with transaminases (AST and ALT) elevations ≥ 3 times ULN was similar for all LATUDA (lurasidone hcl tablets for oral administration) -treated patients (0.8% and 0.8%, respectively) to placebo-treated patients (0.9% and 1.1%, respectively).

ECG Changes

Electrocardiogram (ECG) measurements were taken at various time points during the LATUDA (lurasidone hcl tablets for oral administration) clinical trial program. No post-baseline QT prolongations exceeding 500 msec were reported in patients treated with LATUDA (lurasidone hcl tablets for oral administration) . Within a subset of patients defined as having an increased cardiac risk, no potentially important changes in ECG parameters were observed. No cases of torsade de pointes or other severe cardiac arrhythmias were observed in the pre-marketing clinical program.

The effects of LATUDA (lurasidone hcl tablets for oral administration) on the QT/QTc interval were evaluated in a dedicated QT study involving 87 clinically stable patients with schizophrenia or schizoaffective disorder, who were treated with LATUDA (lurasidone hcl tablets for oral administration) doses of 120 mg daily, 600 mg daily, or ziprasidone 160 mg daily. Holter monitor-derived electrocardiographic assessments were obtained over an eight hour period at baseline and steady state. No patients treated with LATUDA (lurasidone hcl tablets for oral administration) experienced QTc increases > 60 msec from baseline, nor did any patient experience a QTc of > 500 msec.

Other Adverse Reactions Observed During the Premarketing Evaluation of LATUDA (lurasidone hcl tablets for oral administration)

Following is a list of MedDRA terms that reflect adverse reactions reported by patients treated with LATUDA (lurasidone hcl tablets for oral administration) at multiple doses of ≥ 20 mg once daily during any phase of a study within the database of 2096 patients. 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 6 are not included. Although the reactions reported occurred during treatment with LATUDA (lurasidone hcl tablets for oral administration) , they were not necessarily caused by it.

Reactions are further categorized by MedDRA system 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; Rare: leukopenia, neutropenia

Cardiac Disorders: Frequent: tachycardia; Infrequent: AVblock 1st degree, angina pectoris, bradycardia

Ear and Labyrinth Disorders: Infrequent: vertigo

Eve disorders: Frequent: blurred vision

Gastrointestinal Disorders: Frequent: abdominal pain, diarrhea; Infrequent: gastritis, dysphagia

General Disorders and Administrative Site Conditions: Rare: Sudden death

Investigations: Frequent: CPK increased

Metabolic and Nutritional System Disorders: Frequent: decreased appetite

Musculoskeletal and Connective Tissue Disorders: Rare: rhabdomyolysis

Nervous System Disorders: Infrequent: tardive dyskinesia, cerebrovascular accident, dysarthria, syncope; Rare: neuroleptic malignant syndrome, seizure

Psychiatric Disorders: Infrequent: abnormal dreams, panic attack, sleep disorder, Rare: suicidal behavior

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

Skin and Subcutaneous Tissue Disorders: Frequent: rash, pruritus; Rare: angioedema

Vascular Disorders: Infrequent: hypertension, orthostatic hypotension

DRUG INTERACTIONS

Given the primary CMS effects of LATUDA (lurasidone hcl tablets for oral administration) , caution should be used when it is taken in combination with other centrally acting drugs and alcohol.

Potential for Other Drugs to Affect LATUDA (lurasidone hcl tablets for oral administration)

LATUDA (lurasidone hcl tablets for oral administration) is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP4A11, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 enzymes. This suggests that an interaction of LATUDA (lurasidone hcl tablets for oral administration) with drugs that are inhibitors or inducers of these enzymes is unlikely.

LATUDA (lurasidone hcl tablets for oral administration) is predominantly metabolized by CYP3A4; interaction of LATUDA (lurasidone hcl tablets for oral administration) with strong and moderate inhibitors or inducers of this enzyme has been observed (Table 9). LATUDA (lurasidone hcl tablets for oral administration) should not be used in combination with strong inhibitors or inducers of this enzyme [see CONTRAINDICATIONS].

Table 9: Summary of Effect of Coadministered Drugs on Exposure to LATUDA (lurasidone hcl tablets for oral administration) in Healthy Subjects or Patients with Schizophrenia


Potential for LATUDA (lurasidone hcl tablets for oral administration) to Affect Other Drugs

Digoxin (P-gp substrate): Coadministration of LATUDA (lurasidone hcl tablets for oral administration) (120 mg/day) at steady state with a single dose of digoxin (0.25 mg) increased Cmax and AUC(0-24) for digoxin by approximately 9% and 13%, respectively relative to digoxin alone. Digoxin dose adjustment is not required when Coadministered with LATUDA (lurasidone hcl tablets for oral administration) .

Midazolam (CYP3A4 substrate): Coadministration of LATUDA (lurasidone hcl tablets for oral administration) (120 mg/day) at steady state with a single dose of 5 mg midazolam increased midazolam Cmax and AUC(0-24) by approximately 21% and 44%, respectively relative to midazolam alone. Midazolam dose adjustment is not required when Coadministered with LATUDA (lurasidone hcl tablets for oral administration) .

Oral Contraceptive (estrogen/progesterone): Coadministration of LATUDA (lurasidone hcl tablets for oral administration) (40 mg/day) at steady state with an oral contraceptive (OC) containing ethinyl estradiol and norelgestimate resulted in equivalent AUC(0-24) and Cmax of ethinyl estradiol and norelgestromin relative to OC administration alone. Also, sex hormone binding globulin levels were not meaningfully affected by Coadministration of LATUDA (lurasidone hcl tablets for oral administration) and OC. Dose adjustment of OC dose is not required when Coadministered with LATUDA (lurasidone hcl tablets for oral administration) .

Drug Abuse And Dependence

Controlled substance

LATUDA (lurasidone hcl tablets for oral administration) is not a controlled substance.

Abuse

LATUDA (lurasidone hcl tablets for oral administration) has not been systematically studied in humans for its potential for abuse or physical dependence or its ability to induce tolerance. While clinical studies with LATUDA (lurasidone hcl tablets for oral administration) did not reveal any tendency for drug-seeking behavior, these observations were not systematic and it is not possible to predict the extent to which a CNS-active drug will be misused, diverted and/or abused once it is marketed. Patients should be evaluated carefully for a history of drug abuse, and such patients should be observed carefully for signs of LATUDA (lurasidone hcl tablets for oral administration) misuse or abuse (e.g., development of tolerance, drug-seeking behavior, increases in dose).

 

Latuda


Latuda Warnings & Precautions


WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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. LATUDA (lurasidone hcl tablets for oral administration) is not approved for the treatment of dementia-related psychosis [see Boxed Warning].

Cerebrovascular Adverse Reactions, Including Stroke

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. LATUDA (lurasidone hcl tablets for oral administration) is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning].

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 LATUDA (lurasidone hcl tablets for oral administration) .

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. It is important to exclude cases where the clinical presentation includes both serious medical illness (e.g. pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. If reintroduced, the patient should be carefully monitored, since recurrences of NMS have been reported.

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.

There is no known treatment for established cases of tardive dyskinesia, although 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, LATUDA (lurasidone hcl tablets for oral administration) 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 LATUDA (lurasidone hcl tablets for oral administration) , drug discontinuation should be considered. However, some patients may require treatment with LATUDA (lurasidone hcl tablets for oral administration) despite the presence of the syndrome.

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 cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Because LATUDA (lurasidone hcl tablets for oral administration) was not marketed at the time these studies were performed, it is not known if LATUDA (lurasidone hcl tablets for oral administration) is associated with this increased risk.

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

Pooled data from short-term, placebo-controlled studies are presented in Table 2.

Table 2: Change in Fasting Glucose

Placebo LATUDA
20 mg/day
LATUDA
40 mg/day
LATUDA
80 mg/day
LATUDA
120 mg/day
Mean Change from Baseline (mg/dL)
n=438 n=71 n=352 n=270 n=283
Serum Glucose -0.7 -0.6 2.5 -0.9 2.5
Proportion of Patients with Shifts to ≥ 126 mg/dL
Serum Glucose ( ≥ 126 mg/dL) 8.6% (34/397) 11.7% (7/60) 14.3% (47/328) 10.0% (24/241) 10.0% (26/260)

In the uncontrolled, longer-term studies (primarily open-label extension studies), LATUDA (lurasidone hcl tablets for oral administration) was associated with a mean change in glucose of +1.6 mg/dL at week 24 (n = 186), +0.3 mg/dL at week 36 (n = 236) and +1.2 mg/dL at week 52 (n = 244).

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Pooled data from short-term, placebo-controlled studies are presented in Table 3.

Table 3: Change in Fasting Lipids

Placebo LATUDA
20 mg/day
LATUDA
40 mg/day
LATUDA
80 mg/day
LATUDA
120 mg/day
Mean Change from Baseline (mg/dL)
n=418 n=71 n=341 n=263 n=268
Total cholesterol -8.5 -12.3 -9.4 -9.8 -3.8
Triglycerides -15.7 -29.1 -6.2 -14.2 -3.1
Proportion of Patients with Shifts
Total Cholesterol ( ≥ 240 mg/dL) 6.6% (23/350) 13.8% (8/58) 7.3% (21/287) 6.9% (15/216) 3.8% (9/238)
Triglycerides ( ≥ 200 mg/dL) 12.5% (39/312) 14.3% (7/49) 14.0% (37/264) 8.7% (17/196) 10.5% (22/209)

In the uncontrolled, longer-term studies (primarily open-label extension studies), LATUDA (lurasidone hcl tablets for oral administration) was associated with a mean change in total cholesterol and triglycerides of-4.2 (n=186) and -13.6 (n=187) mg/dL at week 24, -1.9 (n = 238) and -3.5 (n = 238) mg/dL at week 36 and -3.6 (n=243) and -6.5 (n=243) mg/dL at week 52, respectively.

Weight Gain

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

Pooled data from short-term, placebo-controlled studies are presented in Table 4. The mean weight gain was 0.75 kg for LATUDA (lurasidone hcl tablets for oral administration) -treated patients compared to 0.26 kg for placebo-treated patients. In study 3 [see Clinical Studies] change in weight from baseline for olanzapine was 4.15 kg. The proportion of patients with a ≥ 7% increase in body weight (at Endpoint) was 5.6% for LATUDA (lurasidone hcl tablets for oral administration) -treated patients versus 4.0% for placebo-treated patients.

Table 4: Mean Change in Weight (kg) from Baseline

Placebo
(n=450)
LATUDA (lurasidone hcl tablets for oral administration)
20 mg/day
(n=71)
LATUDA (lurasidone hcl tablets for oral administration)
40 mg/day
(n=358)
LATUDA (lurasidone hcl tablets for oral administration)
80 mg/day
(n=279)
LATUDA (lurasidone hcl tablets for oral administration)
120 mg/day
(n=291)
All Patients 0.26 -0.15 0.67 1.14 0.68

In the uncontrolled, longer-term studies (primarily open-label extension studies), LATUDA (lurasidone hcl tablets for oral administration) was associated with a mean change in weight of -0.38 kg at week 24 (n = 531), -0.47 kg at week 36 (n = 303) and -0.71 kg at week 52 (n = 244).

Hyperprolactinemia

As with other drugs that antagonize dopamine D2 receptors, LATUDA (lurasidone hcl tablets for oral administration) elevates prolactin levels.

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

In short-term placebo-controlled studies, the median change from baseline to endpoint in prolactin levels for LATUDA (lurasidone hcl tablets for oral administration) -treated patients was 1.1 ng/mL and was - 0.6 ng/mL in the placebo-treated patients. The increase in prolactin was greater in female patients; the median change from baseline to endpoint for females was 1.5 ng/mL and was 1.1 ng/mL in males. The increase in prolactin concentrations was dose-dependent (Table 5).

Table 5: Median Change in Prolactin (ng/mL) from Baseline

Placebo LATUDA
20 mg/day
LATUDA
40 mg/day
LATUDA
80 mg/day
LATUDA
120 mg/day
All Patients -0.6 (n=430) -1.1 (n=70) 0.3 (n=351) 1.1 (n=259) 3.3 (n=284)
Females -1.5 (n=102) -0.7 (n=19) -0.9 (n=99) 2.0 (n=78) 6.7 (n=70)
Males -0.5 (n=328) -1.2 (n=51) 0.5 (n=252) 0.9 (n=181) 3.1 (n=214)

The proportion of patients with prolactin elevations ≥ 5 x ULN was 3.6% for LATUDA (lurasidone hcl tablets for oral administration) -treated patients versus 0.7% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥ 5 x ULN was 8.3% for LATUDA (lurasidone hcl tablets for oral administration) -treated patients versus 1% for placebo-treated female patients. The proportion of male patients with prolactin elevations > 5x ULN was 1.9% versus 0.6% for placebo-treated male patients.

In the uncontrolled longer-term studies (primarily open-label extension studies), LATUDA (lurasidone hcl tablets for oral administration) was associated with a median change in prolactin of -1.9 ng/mL at week 24 (n = 188), -5.4 ng/mL at week 36 (n=189) and -3.3 ng/mL at week 52 (n = 243).

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in a LATUDA (lurasidone hcl tablets for oral administration) carcinogenicity study conducted in rats and mice [see Nonclinical Toxicology]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.

Leukopenia, Neutropenia and Agranulocytosis

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

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and LATUDA (lurasidone hcl tablets for oral administration) should be discontinued at the first sign of decline in WBC, in the absence of other causative factors.

Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1000/mm3) should discontinue LATUDA (lurasidone hcl tablets for oral administration) and have their WBC followed until recovery.

Orthostatic Hypotension and Syncope

LATUDA (lurasidone hcl tablets for oral administration) may cause Orthostatic hypotension, perhaps due to its a1-adrenergic receptor antagonism. The incidence of Orthostatic hypotension and syncope events from short-term, placebo-controlled studies was (LATUDA (lurasidone hcl tablets for oral administration) incidence, placebo incidence): Orthostatic hypotension [0.4% (4/1004), 0.2 % (1/455)] and syncope [ < 0.1% (1/1004), 0%]. Assessment of Orthostatic hypotension defined by vital sign changes ( ≥ 20 mm Hg decrease in systolic blood pressure and ≥ 10 bpm increase in pulse from sitting to standing or supine to standing positions). In short-term clinical trials Orthostatic hypotension occurred with a frequency of 0.8% with LATUDA (lurasidone hcl tablets for oral administration) 40 mg, 1.4% with LATUDA (lurasidone hcl tablets for oral administration) 80 mg and 1.7% with LATUDA (lurasidone hcl tablets for oral administration) 120 mg compared to 0.9% with placebo.

LATUDA (lurasidone hcl tablets for oral administration) should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction, ischemia, or conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of Orthostatic vital signs should be considered in patients who are vulnerable to hypotension.

Seizures

As with other antipsychotic drugs, LATUDA (lurasidone hcl tablets for oral administration) should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold, e.g., Alzheimer's dementia. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.

In short-term placebo-controlled trials, seizures/convulsions occurred in < 0.1% (1/1004) of patients treated with LATUDA (lurasidone hcl tablets for oral administration) compared to 0.2% (1/455) placebo-treated patients.

Potential for Cognitive and Motor Impairment

LATUDA (lurasidone hcl tablets for oral administration) , like other antipsychotics, has the potential to impair judgment, thinking or motor skills.

In short-term, placebo-controlled trials, somnolence was reported in 22.3% (224/1004) of patients treated with LATUDA (lurasidone hcl tablets for oral administration) compared to 9.9% (45/455) of placebo patients, respectively. The frequency of somnolence increases with dose; somnolence was reported in 26.5% (77/291) of patients receiving LATUDA (lurasidone hcl tablets for oral administration) 120 mg/day. In these short-term trials, somnolence included: hypersomnia, hypersomnolence, sedation and somnolence.

Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with LATUDA (lurasidone hcl tablets for oral administration) does not affect them adversely.

Body Temperature Regulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing LATUDA (lurasidone hcl tablets for oral administration) for patients who will be experiencing conditions that may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration [see PATIENT INFORMATION].

Suicide

The possibility of a suicide attempt is inherent in psychotic illness and close supervision of high-risk patients should accompany drug therapy. Prescriptions for LATUDA (lurasidone hcl tablets for oral administration) should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.

In short-term, placebo-controlled studies in patients with schizophrenia, the incidence of treatment-emergent suicidal ideation was 0.6% (6/1004) for LATUDA (lurasidone hcl tablets for oral administration) treated patients compared to 0.4% (2/455) on placebo. No suicide attempts or completed suicides were reported in these studies.

Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. LATUDA (lurasidone hcl tablets for oral administration) is not indicated for the treatment of dementia-related psychosis, and should not be used in patients at risk for aspiration pneumonia.

Use in Patients with Concomitant Illness

Clinical experience with LATUDA (lurasidone hcl tablets for oral administration) in patients with certain concomitant systemic illnesses is limited [see Use In Specific Populations]. LATUDA (lurasidone hcl tablets for oral administration) has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical studies.

Nonclinical Toxicology

Carcinogenesis: Lifetime carcinogenicity studies were conducted in ICR mice and Sprague-Dawley rats. Lurasidone was administered orally at doses of 30,100,300, or 650 (the high dose was reduced from 1200 in males) mg/kg/day to ICR mice and 3, 12, or 36 (high dose reduced from 50) mg/kg/day to Sprague-Dawley rats.

In the mouse study, there were increased incidences of malignant mammary gland tumors and pituitary gland adenomas in females at all doses; the lowest dose tested produced plasma levels (AUC) 2 times those in humans receiving the maximum recommended human dose (MRHD) of 80 mg/day. No increases in tumors were seen in male mice up to the highest dose tested, which produced plasma levels (AUC) 15-25 times those in humans receiving the MRHD.

In rats, an increased incidence of mammary gland carcinomas was seen in females at the two higher doses; the no-effect dose of 3 mg/kg produced plasma levels (AUC) 0.7 times those in humans receiving the MRHD. No increases in tumors were seen in male rats up to highest dose tested, which produced plasma levels (AUC) 10 times those in humans receiving the MRHD.

Proliferative and/or neoplastic changes in the mammary and pituitary glands of rodents have been observed following chronic administration of antipsychotic drugs and are considered to be prolactin mediated. The relevance of this increased incidence of prolactin-mediated pituitary or mammary gland tumors in rodents in terms of human risk is unknown [see WARNINGS AND PRECAUTIONS].

Mutagenesis: Lurasidone was not genotoxic in the Ames test, the in vitro chromosomal aberration test in Chinese Hamster Lung (CHL) cells, or the in vivo mouse bone marrow micronucleus test.

Impairment of Fertility: Lurasidone was administered orally to female rats at doses of 0.1,1.5,15, or 150 mg/kg/day for 15 consecutive days prior to mating, during the mating period, and through day 7 of gestation. Estrus cycle irregularities were seen at 1.5 mg/kg and above; the no-effect dose of 0.1 mg/kg is approximately 0.01 times the maximum recommended human dose (MRHD) of 80 mg/day based on body surface area. Fertility was reduced only at the highest dose and this was shown to be reversible after a 14 day drug-free period. The no-effect dose for reduced fertility was 15 mg/kg, which is 1.8 times the MRHD based on body surface area.

Fertility was not affected in male rats treated orally with lurasidone for 64 consecutive days prior to mating and during the mating period at doses up to 150 mg/kg/day (12 times the MRHD based on body surface area).

Use In Specific Populations

Pregnancy

Teratogenic Effects - Pregnancy Category B

Lurasidone was not teratogenic in rats and rabbits. There are no adequate and well-controlled studies of LATUDA (lurasidone hcl tablets for oral administration) in pregnant women.

No teratogenic effects were seen in studies in which pregnant rats and rabbits were given lurasidone during the period of organogenesis at doses up to 25 and 50 mg/kg/day, respectively. These doses are 3 and 12 times, in rats and rabbits respectively, the maximum recommended human dose (MRHD) of 80 mg/day based on body surface area.

No adverse developmental effects were seen in a study in which pregnant rats were given lurasidone during the period of organogenesis and continuing through weaning at doses up to 10 mg/kg/day; this dose is approximately equal to the MRHD based on body surface area.

Non-teratogenic Effects

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

LATUDA (lurasidone hcl tablets for oral administration) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

The effect of LATUDA (lurasidone hcl tablets for oral administration) on labor and delivery in humans is unknown.

Nursing Mothers

LATUDA (lurasidone hcl tablets for oral administration) was excreted in milk of rats during lactation. It is not known whether LATUDA (lurasidone hcl tablets for oral administration) or its metabolites are excreted in human milk. Breast feeding in women receiving LATUDA (lurasidone hcl tablets for oral administration) should be considered only if the potential benefit justifies the potential risk to the child.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of LATUDA (lurasidone hcl tablets for oral administration) in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 and older to determine whether or not they respond differently from younger patients. In elderly patients with psychosis (65 to 85), lurasidone concentrations (20 mg/day) were similar to those in young subjects [see CLINICAL PHARMACOLOGY]. No dose adjustment is necessary in elderly patients.

Elderly patients with dementia-related psychosis treated with LATUDA (lurasidone hcl tablets for oral administration) are at an increased risk of death compared to placebo. LATUDA (lurasidone hcl tablets for oral administration) is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning].

Renal Impairment

It is recommended that LATUDA (lurasidone hcl tablets for oral administration) dose should not exceed 40 mg/day in patients with moderate and severe renal impairment (Clcr ≥ 10 mL/min to < 50 mL/min).

After administration of a single dose of 40 mg LATUDA (lurasidone hcl tablets for oral administration) to patients with mild, moderate and severe renal impairment, mean Cmax increased by 40%, 92% and 54%, respectively and mean AUC(o-∞) increased by 53%, 91% and 2- times, respectively compared to healthy matched subjects.

Hepatic Impairment

It is recommended that LATUDA (lurasidone hcl tablets for oral administration) dose should not exceed 40 mg/day in patients with moderate and severe hepatic impairment (Child-Pugh Class B and C). In a single-dose study of LATUDA (lurasidone hcl tablets for oral administration) 20 mg, lurasidone mean AUC(0-last) was 1.5-times higher in subjects with mild hepatic impairment (Child-Pugh Class A), 1.7-times higher in subjects with moderate hepatic impairment (Child-Pugh Class B) and 3-times higher in subjects with severe hepatic impairment (Child-Pugh Class C) compared to the values for healthy matched subjects. Mean Cmax was 1.3,1.2 and 1.3-times higher for mild, moderate and severe hepatically impaired patients respectively, compared to the values for healthy matched subjects.

Gender

Population pharmacokinetic evaluation indicated that the mean AUC of LATUDA (lurasidone hcl tablets for oral administration) was 18% higher in women than in men, and correspondingly, the apparent oral clearance of LATUDA (lurasidone hcl tablets for oral administration) was lower in women. Mean Cmax of LATUDA (lurasidone hcl tablets for oral administration) was similar between women and men. No dosage adjustment of LATUDA (lurasidone hcl tablets for oral administration) is recommended based on gender.

Race

Although no specific pharmacokinetic study was conducted to investigate the effects of race on the disposition of LATUDA (lurasidone hcl tablets for oral administration) , population pharmacokinetic evaluation revealed no evidence of clinically significant race-related differences in the pharmacokinetics of LATUDA (lurasidone hcl tablets for oral administration) . No dosage adjustment of LATUDA (lurasidone hcl tablets for oral administration) is recommended based on race.

Smoking Status

Based on in vitro studies utilizing human liver enzymes, LATUDA (lurasidone hcl tablets for oral administration) is not a substrate for CYP1A2; smoking is therefore not expected to have an effect on the pharmacokinetics of LATUDA (lurasidone hcl tablets for oral administration) .

Latuda


Latuda Overdosage & Contraindications


OVERDOSE

Human Experience

In premarketing clinical studies involving more than 2096 patients and/or healthy subjects, accidental or intentional overdosage of LATUDA (lurasidone hcl tablets for oral administration) was identified in one patient who ingested an estimated 560 mg of LATUDA (lurasidone hcl tablets for oral administration) . This patient recovered without sequelae. This patient resumed LATUDA (lurasidone hcl tablets for oral administration) treatment for an additional two months.

Management of Overdosage

Consult a Certified Poison Control Center for up-to-date guidance and advice. There is no specific antidote to LATUDA (lurasidone hcl tablets for oral administration) , therefore, appropriate supportive measures should be instituted and close medical supervision and monitoring should continue until the patient recovers.

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 (lurasidone hcl tablets for oral administration) . Similarly the alpha-blocking properties of bretylium might be additive to those of LATUDA (lurasidone hcl tablets for oral administration) , 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 (lurasidone hcl tablets for oral administration) -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.

CONTRAINDICATIONS

LATUDA (lurasidone hcl tablets for oral administration) is contraindicated in any patient with a known hypersensitivity to lurasidone HCI or any components in the formulation. Angioedema has been observed with lurasidone [see ADVERSE REACTIONS].

LATUDA (lurasidone hcl tablets for oral administration) is contraindicated with strong CYP3A4 inhibitors (e.g., ketoconazole) and strong CYP3A4 inducers (e.g., rifampin) [see DRUG INTERACTIONS].

 

Latuda


Latuda Clinical Pharmacology


CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of action of lurasidone, as with other drugs having efficacy in schizophrenia, is unknown. It has been suggested that the efficacy of lurasidone in schizophrenia is mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism.

Pharmacodynamics

In vitro receptor binding studies revealed that lurasidone is an antagonist with high affinity at dopamine D2 receptors (Ki = 0.994 nM) and the 5-hydroxytryptamine (5-HT, serotonin) receptors 5-HT2A (Ki = 0.47 nM) and 5-HT7 (Ki = 0.495 nM), is an antagonist with moderate affinity at human α2C adrenergic receptors (Ki = 10.8 nM), is a partial agonist at serotonin 5-HT1A (Ki = 6.38 nM) receptors, and is an antagonist at α2A adrenergic receptors (Ki = 40.7 nM). Lurasidone exhibits little or no affinity for histamine H1 and muscarinic Mi receptors (IC50 ≥ 1,000 nM and > 1,000 nM, respectively).

Pharmacokinetics

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

Following administration of 40 mg of LATUDA (lurasidone hcl tablets for oral administration) , the mean (%CV) elimination half-life was 18 (7) hours.

Absorption and Distribution: Lurasidone is absorbed and reaches peak serum concentrations in approximately 1-3 hours. It is estimated that 9-19% of an administered dose is absorbed. Following administration of 40 mg of LATUDA (lurasidone hcl tablets for oral administration) , the mean (%CV) apparent volume of distribution was 6173 (17.2) L. Lurasidone is highly bound (~99%) to serum proteins.

In a food effect study, lurasidone mean Cmaxand AUC were about 3-times and 2-times, respectively, when administered with food compared to the levels observed under fasting conditions. Lurasidone 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].

In clinical studies, establishing the safety and efficacy of LATUDA, patients were instructed to take their daily dose with food [see DOSAGE AND ADMINISTRATION].

Metabolism and Elimination: Lurasidone is metabolized mainly via CYP3A4. The major biotransformation pathways are oxidative N-dealkylation, hydroxylation of norbornane ring, and S-oxidation. Lurasidone is metabolized into two active metabolites (ID-14283 and ID-14326) and two major non-active metabolites (ID-20219 and ID-20220).

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.

Following administration of 40 mg of LATUDA (lurasidone hcl tablets for oral administration) , the mean (%CV) apparent clearance was 3902 (18.0) mL/min.

Clinical Studies

Schizophrenia

The efficacy of LATUDA (lurasidone hcl tablets for oral administration) for the treatment of schizophrenia was established in four short-term (6-week), placebo-controlled studies in adult patients (mean age of 38.8 years, range 18-72) who met DSM-IV criteria for schizophrenia. One study included an active-control arm (olanzapine) to assess assay sensitivity.

Several instruments were used for assessing psychiatric signs and symptoms in these studies:

  1. Positive and Negative Syndrome Scale (PANSS), is a multi-item inventory of general psychopathology used to evaluate the effects of drug treatment in schizophrenia. PANSS total scores may range from 30 to 210.
  2. Brief Psychiatric Rating Scale derived (BPRSd), derived from the PANSS, is a multi-item inventory primarily focusing on positive symptoms of schizophrenia, whereas the PANSS includes a wider range of positive, negative and other symptoms of schizophrenia. BPRSd scores may range from 18 to 126.
  3. The Clinical Global Impression severity scale (CGI-S) is a validated clinician-rated scale that measures the subject's current illness state on a 1 to 7-point scale.

The endpoint associated with each instrument is change from baseline in the total score to the end of week 6. These changes are then compared to placebo changes for the drug and control groups.

The results of the studies follow:

  1. In a 6-week, placebo-controlled trial (N=145) involving two fixed doses of LATUDA (lurasidone hcl tablets for oral administration) (40 or 120 mg/day), both doses of LATUDA (lurasidone hcl tablets for oral administration) at Endpoint were superior to placebo on the BPRSd total score, and the CGI-S.
  2. In a 6-week, placebo-controlled trial (N=180) involving a fixed dose of LATUDA (lurasidone hcl tablets for oral administration) (80 mg/day), LATUDA (lurasidone hcl tablets for oral administration) at Endpoint was superior to placebo on the BPRSd total score, and the CGI-S.
  3. In a 6-week, placebo and active-controlled trial (N=473) involving two fixed doses of LATUDA (lurasidone hcl tablets for oral administration) (40 or 120 mg/day) and an active control (olanzapine), both LATUDA (lurasidone hcl tablets for oral administration) doses and the active control at Endpoint were superior to placebo on the PANSS total score, and the CGI-S.
  4. In a 6-week, placebo-controlled trial (N=489) involving three fixed doses of LATUDA (lurasidone hcl tablets for oral administration) (40, 80 or 120 mg/day), only the 80 mg/day dose of LATUDA (lurasidone hcl tablets for oral administration) at Endpoint was superior to placebo on the PANSS total score, and the CGI-S.

Thus, the efficacy of LATUDA (lurasidone hcl tablets for oral administration) at doses of 40, 80 and 120 mg/day was established in two studies for each dose. However, the 120 mg dose did not appear to add additional benefit over the 40 mg dose (Table 10).

Table 10: Summary of Results for Primary Efficacy Endpoints

Study Number Primary Endpoint LS Mean (SE)a Difference from Placebo in Change from Baseline
LATUDA
40 mg/day
LATUDA
80 mg/day
LATUDA
120 mg/day
Olanzapine
15 mg/day
1 BPRSd -5.6* (2.1) - -6.7* (2.2) -
2 BPRSd - -4.7* (1.8) - -
3 PANSS -g.r(2.9) - -7.5* (3.0) -12.6* (2.8)
4 PANSS -2.1 (2.5) -6.4* (2.5) -3.5 (2.5) -
* adjusted p-value < 0.05 (except for olanzapine)
a Least Squares Mean (Standard Error)

Examination of population subgroups based on age (there were few patients over 65), gender and race did not reveal any clear evidence of differential responsiveness.

 

Latuda


Latuda Medication Guide


PATIENT INFORMATION

Physicians are advised to discuss with patients for whom they prescribe LATUDA (lurasidone hcl tablets for oral administration) all relevant safety information including, but not limited to, the following:

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Patients and caregivers should be advised that elderly patients with dementia-related psychoses treated with atypical antipsychotic drugs are at increased risk of death compared with placebo. LATUDA (lurasidone hcl tablets for oral administration) is not approved for elderly patients with dementia-related psychosis [see Boxed Warning; WARNINGS AND PRECAUTIONS].

Neuroleptic Malignant Syndrome

Patients and caregivers should be counseled that a potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see WARNINGS AND PRECAUTIONS)].

Hyperglycemia and Diabetes Mellitus

Patients should be aware of the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus. Patients who are diagnosed with diabetes, those with risk factors for diabetes, or those that develop these symptoms during treatment should have their blood glucose monitored at the beginning of and periodically during treatment [see WARNINGS AND PRECAUTIONS].

Orthostatic Hypotension

Patients should be advised of the risk of orthostatic hypotension, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see WARNINGS AND PRECAUTIONS].

Leukopenia/Neutropenia

Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should be advised that they should have their CBC monitored while taking LATUDA [see WARNINGS AND PRECAUTIONS].

Interference with Cognitive and Motor Performance

Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that LATUDA therapy does not affect them adversely [see WARNINGS AND PRECAUTIONS].

Pregnancy and Nursing

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with LATUDA [see Use in Specific Populations].

Concomitant Medication and Alcohol

Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions. Patients should be advised to avoid alcohol while taking LATUDA [see DRUG INTERACTIONS].

Heat Exposure and Dehydration

Patients should be advised regarding appropriate care in avoiding overheating and dehydration [see WARNINGS AND PRECAUTIONS].

 

Latuda


Latuda Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

 

LURASIDONE - ORAL

 

(loo-RAS-i-done)

 

COMMON BRAND NAME(S): Latuda

 

WARNING: There may be a slightly increased risk of serious, possibly fatal side effects (such as heart failure, pneumonia, stroke) when this medication is used in older adults with dementia. This medication is not approved for the treatment of dementia-related behavior problems. Discuss the risks and benefits of this medication, as well as other effective and possibly safer treatments for dementia-related behavior problems, with the doctor.

 

USES: This medication is used to treat a certain mental/mood disorder (schizophrenia). Lurasidone helps you to think more clearly, feel less nervous, and take part in everyday life. It may also help to decrease hallucinations (hearing/seeing things that are not there). Lurasidone is a psychiatric medication that belongs to the class of drugs called atypical antipsychotics. It works by helping to restore the balance of certain natural substances in the brain.

 

HOW TO USE: Take this medication by mouth with food as directed by your doctor, usually once daily. Dosage is based on your medical condition, other drugs you are taking, and your response to treatment.

Take this medication regularly to get the most benefit from it. To help you remember, take it at the same time each day.

Continue taking this medication exactly as prescribed, even if you are feeling better and thinking more clearly. Do not increase your dose or take this drug more often than prescribed. Your symptoms will not improve any faster, and your risk of side effects will increase. Do not stop taking this medication without consulting your doctor.

Tell your doctor if your condition does not improve or if it worsens. It may take several weeks before you feel the full benefit of this medication.

 

Latuda


Latuda Consumer (continued)

SIDE EFFECTS: Drowsiness, dizziness, nausea, shaking, muscle stiffness, mask-like facial expression, inability to keep still, and agitation may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly. Your doctor may order another medication to lessen these effects.

This medication may cause a serious drop in blood pressure, especially when starting this medication. To reduce your risk of side effects from low blood pressure (such as dizziness), get up slowly when rising from a sitting or lying position.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor right away if any of these serious side effects occur: drooling/trouble swallowing, fainting, fast/irregular heartbeat, signs of infection (such as persistent cough, fever).

Infrequently, this medication may cause face/muscle twitching and uncontrollable movements (tardive dyskinesia). In some cases, this condition may be permanent. Tell your doctor immediately if you develop any uncontrollable movements such as lip smacking, mouth puckering, tongue thrusting, chewing, or unusual arm/leg movements.

This drug may rarely make your blood sugar level rise, which can cause or worsen diabetes. Weight gain from this drug may increase the risk of this side effect. Tell your doctor immediately if you develop symptoms of high blood sugar such as increased thirst and urination. If you already have diabetes, be sure to check your blood sugar level regularly.

In rare cases, lurasidone may increase your level of a certain substance made by the body (prolactin). For females, this increase in prolactin may result in unwanted breast milk, missed/stopped periods, or difficulty becoming pregnant. For males, it may result in decreased sexual ability, inability to produce sperm, or enlarged breasts. If you develop any of these symptoms, tell your doctor immediately.

Rarely, males may have a painful or prolonged erection lasting 4 or more hours. If this occurs, stop using this drug and get medical help right away, or permanent problems could occur.

This drug may rarely cause a serious (sometimes fatal) nervous system problem (neuroleptic malignant syndrome-NMS). Get medical help right away if you notice any of the following side effects: unexplained fever, stiff muscles, increased sweating, fast/irregular heartbeat, sudden mental/mood changes (such as confusion, loss of consciousness).

Get medical help right away if any of these serious side effects occur: seizure, signs of stroke (such as weakness on one side of the body, slurred speech, sudden vision changes, confusion).

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

 

PRECAUTIONS: See also Warning section.

Before taking lurasidone, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney problems, liver problems, stroke, breast cancer, diabetes, low blood pressure, seizures, low white blood cell count, dementia (such as Alzheimer's Disease), trouble swallowing.

This drug may make you dizzy or drowsy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Avoid alcoholic beverages.

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

This medication may decrease your ability to sweat, making you more likely to get heat stroke. Avoid activities that may cause you to overheat (such as doing strenuous work/exercise in hot weather, using hot tubs). When the weather is hot, drink plenty of fluids and dress lightly. If you become overheated, promptly seek cooler shelter and stop exercising. Get medical help right away if you develop a fever, mental/mood changes, headache, or dizziness.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor. Do not stop taking this medication unless directed by your doctor. Babies born to mothers who have used this drug during the last 3 months of pregnancy may infrequently develop symptoms including muscle stiffness or shakiness, drowsiness, feeding/breathing difficulties, or constant crying. If you notice any of these symptoms in your newborn anytime during their first month, tell the doctor right away.

It is unknown if this medication passes into breast milk. Consult your doctor before breast-feeding.

 

Latuda


Latuda Consumer (continued)

DRUG INTERACTIONS: Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Other medications can affect the removal of lurasidone from your body, which may affect how lurasidone works. Examples include diltiazem, azole antifungals (such as ketoconazole, itraconazole), HIV drugs (such as ritonavir), macrolide antibiotics (such as clarithromycin), rifamycins (such as rifampin, rifabutin), antidepressants (such as fluoxetine, paroxetine, nefazodone), among others.

Tell your doctor or pharmacist if you are taking other products that cause dizziness or drowsiness, including alcohol, antihistamines (such as cetirizine, diphenhydramine), drugs for sleep or anxiety (such as alprazolam, diazepam, zolpidem), muscle relaxants, and narcotic pain relievers (such as codeine).

Check the labels on all your medicines (such as allergy or cough-and-cold products) because they may contain ingredients that cause dizziness or drowsiness. Ask your pharmacist about using those products safely.

 

OVERDOSE: If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

 

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (such as blood sugar level, complete blood count, blood pressure) may be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

 

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

 

STORAGE: Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

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