Lurasidone

492.67604

492.68

1308068-626-2

22IC88528T

N05AE05|N - Nervous system

85

4.89 (est)

1.273

623.4±55.0 °C at 760 mmHg

9.7 deg C (49.5 deg F) - closed cup

1.637

In water, 5.32X10-2 mg/L at 25 deg C (est)

Conditions for safe storage, including any incompatibilities: Keep container tightly closed in a dry and well-ventilated place. Containers which are opened must be carefully resealed and kept upright to prevent leakage. Recommended storage temperature -20 deg C

1.33X10-16 mm Hg at 25 deg C (est)

Henry's Law constant = 3.74 atm-cu m/mol at 25 °C (est)

pKa1 = 1.96 (imine); pKa2 = 8.50 (amine) (est)

White to off-white powder; MP 215-217 °C; sparingly soluble in methanol; slightly soluble in ethanol; very slightly soluble in acetone, water; practically insoluble in 0.1 N HCl, toluene /Lurasidone hydrochloride/|Hydroxyl radical reaction rate constant = 3.69X10-10 cu cm/molec-sec at 25 °C (est)

Stable under recommended storage conditions.

P201, P202, P261, P264, P270, P271, P272, P280, P281, P301+P312, P302+P352, P304+P312, P304+P340, P308+P313, P312, P321, P330, P333+P313, P363, P405, P501

H302+H332

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.|SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Incompatible materials: Acids, Oxidizing agents, Alkali metals, Strong oxidizing agents, Strong acids, Acid chlorides, Acid anhydrides, Reducing agents, Strong reducing agents, Phosphorus halides

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including lurasidone hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Lurasidone hydrochloride/

|Warning|H302+H332 (50%): Harmful if swallowed or if inhaled [Warning Acute toxicity, oral; acute toxicity, inhalation]|P201, P202, P261, P264, P270, P271, P272, P280, P281, P301+P312, P302+P352, P304+P312, P304+P340, P308+P313, P312, P321, P330, P333+P313, P363, P403+P233, P405, and P501|Aggregated GHS information provided by 2 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|Danger|H225: Highly Flammable liquid and vapor [Danger Flammable liquids]|P210, P233, P240, P241, P242, P243, P260, P261, P264, P270, P271, P280, P301+P310, P302+P352, P303+P361+P353, P304+P340, P307+P311, P311, P312, P321, P322, P330, P361, P363, P370+P378, P403+P233, P403+P235, P405, and P501

Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face respirator with multipurpose combination (US) or type ABEK (EN 14387) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).|Body Protection: Complete suit protecting against chemicals, Flame retardant antistatic protective clothing., The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.|Skin protection: Handle with gloves.|Eye/face protection: Face shield and safety glasses Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary. Use water spray to cool unopened containers.|Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

ACCIDENTAL RELEASE MEASURES. Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid breathing vapours, mist or gas. Ensure adequate ventilation. Remove all sources of ignition. Evacuate personnel to safe areas. Beware of vapours accumulating to form explosive concentrations. Vapours can accumulate in low areas.; Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains.; Methods and materials for containment and cleaning up: Contain spillage, and then collect with an electrically protected vacuum cleaner or by wet-brushing and place in container for disposal according to local regulations.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.|Appropriate engineering controls: Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product.|Precautions for safe handling: Avoid contact with skin and eyes. Avoid inhalation of vapour or mist. Use explosion-proof equipment.Keep away from sources of ignition - No smoking.Take measures to prevent the build up of electrostatic charge.

IDENTIFICATION AND USE: Lurasidone is indicated for the treatment of patients with schizophrenia, as monotherapy for the treatment of patients with major depressive episodes associated with bipolar I disorder (bipolar depression), and as adjunctive therapy with either lithium or valproate for the treatment of patients with major depressive episodes associated with bipolar I disorder (bipolar depression). HUMAN EXPOSURE AND TOXICITY: An increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies. The manufacturer states that lurasidone is not approved for the treatment of patients with dementia-related psychosis. Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported in patients receiving antipsychotic agents, including lurasidone. Rash and pruritus have been reported frequently and angioedema has been reported rarely in patients receiving lurasidone. Adverse effects occurring in 5% or more of patients receiving lurasidone for schizophrenia and at a frequency at least twice that reported with placebo include somnolence (including hypersomnia, hypersomnolence, and sedation), akathisia, nausea, parkinsonism, and agitation. Akathisia and somnolence appear to be dose-related adverse effects.The effect of lurasidone on labor and delivery is unknown. It is not known whether lurasidone and/or its metabolites are distributed into milk in humans. In geriatric patients (65-85 years of age) with psychosis, serum lurasidone concentrations were similar to those observed in younger adults. Geriatric patients with dementia-related psychosis treated with lurasidone are at an increased risk of death compared with those treated with placebo. Safety and effectiveness of lurasidone in pediatric and adolescent patients have not been established. ANIMAL STUDIES: Lurasidone increased the incidence of mammary gland carcinomas in females rats orally dosed at 12 and 36 mg/kg/day: the lowest dose; 3 mg/kg/day is the no-effect dose which produced plasma levels (AUC) 0.4-times those in humans receiving the MRHD. No increases in tumors were seen in male rats up to the highest dose tested, which produced plasma levels (AUC) 6-times those in humans receiving the MRHD. Lurasidone is distributed into milk in rats. Estrus cycle irregularities were seen in rats orally administered lurasidone at 1.5, 15 and 150 mg/kg/day for 15 consecutive days prior to mating, during the mating period, and through day 7 of gestation. The no-effect dose is 0.1 mg/kg which is approximately 0.006-times the MRHD of 160 mg/day based on body surface area. Fertility was reduced only at the highest dose, which was reversible after a 14-day drug-free period. The no-effect dose for reduced fertility was 15 mg/kg, which is approximately equal to the MRHD based on body surface area. Lurasidone had no effect on fertility 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 (9-times the MRHD based on mg/m sq body surface area). The drug did not cause mutation or chromosomal aberration when tested in vitro and in vivo. It was negative in the Ames gene mutation test, the Chinese Hamster Lung (CHL) cells, and in the in vivo mouse bone marrow micronucleus test up to 2000 mg/kg (61 times the MRHD of 160 mg/day based on mg/ sq m body surface area).

Liver test abnormalities occur in 1% to 3% of patients on long term therapy with lurasidone, but similar rates have been reported with placebo therapy and with comparator agents. The ALT elevations are usually mild, transient and often resolve even without dose modification or drug discontinuation. There have been no published reports of clinically apparent liver injury with symptoms or jaundice attributed to lurasidone therapy.

Lurasidone is not a substrate for CYP1A2 in vitro; therefore, smoking should not alter the pharmacokinetics of the drug.|Concomitant administration of rifampin (600 mg daily for 8 days), a strong CYP3A4 inducer, and lurasidone (single 40-mg dose) decreased peak serum lurasidone concentrations and AUCs by approximately 86 and 80%, respectively. Rifampin should not be concurrently administered with lurasidone.|Concomitant administration of lurasidone (40 mg daily at steady state) with an oral contraceptive containing ethinyl estradiol and norgestimate resulted in equivalent peak plasma concentrations and AUCs of ethinyl estradiol and norgestimate relative to oral contraceptive administration alone. Sex hormone binding globulin concentrations also were not substantially affected by concurrent administration of the drugs. Oral contraceptive dosage adjustment is not required in patients receiving lurasidone concurrently.|Concomitant administration of lurasidone (120 mg daily at steady state) with a single 5-mg dose of midazolam, a CYP3A4 substrate, increased peak plasma concentrations and AUCs of midazolam by approximately 21 and 44%, respectively. Midazolam dosage adjustment is not required in patients receiving lurasidone concurrently.|For more Interactions (Complete) data for Lurasidone (11 total), please visit the HSDB record page.

Esophageal dysmotility and aspiration have been associated with the use of antipsychotic agents. Aspiration pneumonia is a common cause of morbidity and mortality in geriatric patients, particularly in those with advanced Alzheimer's dementia. Lurasidone is not approved for the treatment of patients with dementia-related psychosis and should not be used in patients at risk for aspiration pneumonia.|Neonates exposed to antipsychotic agents during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Symptoms reported to date have included agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder. Neonates exhibiting such symptoms should be monitored. The complications have varied in severity; some neonates recovered within hours to days without specific treatment while others have required intensive care unit support and prolonged hospitalization. The effect of lurasidone on labor and delivery is unknown.|Similar to other antipsychotic agents and drugs with dopamine D2 antagonistic activity, lurasidone can elevate serum prolactin concentrations. In short-term clinical trials, the median change from baseline to end point in prolactin concentrations for lurasidone-treated patients was an increase of 1.1 mg/mL compared with a decrease of 0.6 mg/mL in the placebo group. The increase in prolactin was greater in female patients. The proportion of patients with prolactin elevations 5 or more times the upper limit of normal was 3.6% for lurasidone-treated patients compared with 0.7% for placebo recipients. Clinical disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been associated with prolactin-elevating drugs. In addition, chronic hyperprolactinemia associated with hypogonadism may lead to decreased bone density in both female and male patients. If lurasidone therapy is considered in a patient with previously detected breast cancer, clinicians should consider that approximately one-third of human breast cancers are prolactin-dependent in vitro.|In short-term clinical trials, seizures occurred in less than 0.1% of patients receiving lurasidone compared with 0.2% of patients receiving placebo. As with other antipsychotic agents, lurasidone should be used with caution in patients with a history of seizures or with conditions that may lower the seizure threshold (e.g., dementia of the Alzheimer's type); conditions that lower the seizure threshold may be more prevalent in patients 65 years of age or older.|For more Populations at Special Risk (Complete) data for Lurasidone (7 total), please visit the HSDB record page.

~99% bound to serum proteins.

Treatment of schizophrenia.|FDA Label|Treatment of schizophrenia in adults aged 18 years and over.

Lurasidone is a second generation (atypical) antipsychotic agent that is used in the treatment of schizophrenia and bipolar depression. Lurasidone is associated with a low rate of serum aminotransferase elevations during therapy, but has not been linked to instances of clinically apparent acute liver injury.

Antipsychotic Agents

Latuda is indicated for the treatment of patients with schizophrenia. /Included in US product label/|Latuda is indicated as monotherapy for the treatment of patients with major depressive episodes associated with bipolar I disorder (bipolar depression). /Included in US product label/|Latuda is indicated as adjunctive therapy with either lithium or valproate for the treatment of patients with major depressive episodes associated with bipolar I disorder (bipolar depression). /Included in US product label/|The efficacy of Latuda in the treatment of mania associated with bipolar disorder has not been established.|The effectiveness of Latuda for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. Therefore, the physician who elects to use Latuda for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient

/BOXED WARNING/ WARNINGS: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; AND SUICIDAL THOUGHTS AND BEHAVIORS. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Latuda is not approved for use in patients with dementia-related psychosis. Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber.|Contraindications: Known hypersensitivity to lurasidone hydrochloride or any components in the formulation. Angioedema has been reported. Concurrent administration of strong cytochrome P-450 (CYP) isoenzyme 3A4 (CYP3A4) inhibitors (e.g., ketoconazole) or strong CYP3A4 inducers (e.g., rifampin).|Geriatric patients with dementia-related psychosis treated with antipsychotic drugs appear to be at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks) revealed an approximate 1.6- to 1.7-fold increase in mortality among geriatric patients receiving atypical antipsychotic drugs (i.e., aripiprazole, olanzapine, quetiapine, risperidone) compared with that observed in patients receiving placebo. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with 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 antipsychotics, treatment with conventional (first-generation) antipsychotics 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 remains unclear. The manufacturer states that lurasidone is not approved for the treatment of patients with dementia-related psychosis.|An increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies. The manufacturer states that lurasidone is not approved for the treatment of patients with dementia-related psychosis.|For more Drug Warnings (Complete) data for Lurasidone (27 total), please visit the HSDB record page.

Lurasidone is a benzothiazol derivative that is an antagonist and binds with high affinity to Dopamine-2 (D2) (Ki = 0.994 nM), 5-HT2A (Ki = 0.47 nM) receptors, and 5-HT7 receptors (Ki = 0.495 nM). It also binds with moderate affinity to alpha-2C adrenergic receptors (Ki = 10.8 nM) and is a partial agonist at 5-HT1A receptors (Ki = 6.38 nM). Its actions on histaminergic and muscarinic receptors are negligible.

Drugs that bind to and block the activation of ADRENERGIC ALPHA-2 RECEPTORS. (See all compounds classified as Adrenergic alpha-2 Receptor Antagonists.)|Agents that control agitated psychotic behavior, alleviate acute psychotic states, reduce psychotic symptoms, and exert a quieting effect. They are used in SCHIZOPHRENIA; senile dementia; transient psychosis following surgery; or MYOCARDIAL INFARCTION; etc. These drugs are often referred to as neuroleptics alluding to the tendency to produce neurological side effects, but not all antipsychotics are likely to produce such effects. Many of these drugs may also be effective against nausea, emesis, and pruritus. (See all compounds classified as Antipsychotic Agents.)|Compounds and drugs that bind to and inhibit or block the activation of DOPAMINE D2 RECEPTORS. (See all compounds classified as Dopamine D2 Receptor Antagonists.)|Drugs that bind to but do not activate SEROTONIN 5-HT2 RECEPTORS, thereby blocking the actions of SEROTONIN or SEROTONIN 5-HT2 RECEPTOR AGONISTS. Included under this heading are antagonists for one or more specific 5-HT2 receptor subtypes. (See all compounds classified as Serotonin 5-HT2 Receptor Antagonists.)

Lurasidone is readily absorbed and quickly reaches maximal concentrations (Cmax) within 1-4 hours. When taken with food, there is a two-fold increase in exposure and time to maximal concentration is increased by 0.5-1.5 hours. This occurs regardless of fat or caloric content. Bioavailability = 9-19%.|Urine (~9%) and feces (~80%)|6173 L|3902 mL/min|Following administration of a single radiolabeled dose of lurasidone, approximately 80 and 9% of the dose is excreted in feces and urine, respectively.|Lurasidone is rapidly absorbed following oral administration and reaches peak serum concentrations within about 1-3 hours. Approximately 9-19% of an administered dose is absorbed orally. Steady-state concentrations of the drug are achieved within 7 days.

Lurasidone is metabolized by CYP3A4 in which its major active metabolite is referred to as ID-14283 (25% of parent exposure). Its two minor metabolites are referred to as ID14326 and ID11614 which make up 3% and 1% of parent exposure respectively. Its two non-active metabolites are referred to as ID-20219 and ID-20220.|Lurasidone is highly bound (99.8%) to serum proteins, including albumin and alpha1-acid glycoprotein. The drug is metabolized mainly via CYP3A4. The major biotransformation pathways are oxidative N-dealkylation, hydroxylation of the norbornane ring, and S-oxidation. Lurasidone is metabolized into 2 active metabolites (ID-14283 and ID-14326) and 2 major inactive metabolites (ID-20219 and ID-20220).

40 mg dose= 18 hours 120 mg - 160 mg dose = 29-37 hours

Lurasidone is an atypical antipsychotic that is a D2 and 5-HT2A (mixed serotonin and dopamine activity) to improve cognition. It is thought that antagonism of serotonin receptors can improve negative symptoms of psychoses and reduce the extrapyramidal side effects that are often associated with typical antipsychotics.|Lurasidone is a benzisothiazol-derivative antipsychotic agent and has been referred to as an atypical or second-generation antipsychotic agent. Lurasidone has also been described as an azapirone-derivative. Although the exact mechanism of action of lurasidone and other antipsychotic agents in schizophrenia is unknown, it has been suggested that the efficacy of lurasidone is mediated through a combination of antagonist activity at central dopamine type 2 (D2) and serotonin type 2 (5-hydroxytryptamine [5-HT2A]) receptors. Lurasidone is an antagonist that exhibits high affinity for D2, 5-HT2A, and 5-HT7 receptors and moderate affinity for a2C-adrenergic receptors in vitro. The drug acts as a partial agonist at 5-HT1A receptors and is an antagonist at alpha2A-adrenergic receptors in vitro. Lurasidone exhibits weak affinity for alpha1-adrenergic receptors and little or no affinity for histamine (H1) receptors and muscarinic (M1) receptors.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ The effects of LATUDA on the QTc interval were evaluated in a randomized, double-blind, multiple-dose, parallel-dedicated thorough QT study in 43 patients with schizophrenia or schizoaffective disorder, who were treated with LATUDA doses of 120 mg daily, 600 mg daily and completed the study. The maximum mean (upper 1-sided, 95% CI) increase in baseline-adjusted QTc intervals based on individual correction method (QTcI) was 7.5 (11.7) ms and 4.6 (9.5) ms, for the 120 mg and 600 mg dose groups respectively, observed at 2 to 4 hours after dosing. In this study, there was no apparent dose (exposure)-response relationship. In short-term, placebo-controlled studies in schizophrenia and bipolar depression, no post-baseline QT prolongations exceeding 500 msec were reported in patients treated with LATUDA or placebo.|/SIGNS AND SYMPTOMS/ Known hypersensitivity to lurasidone hydrochloride or any components in the formulation. Angioedema has been reported. Concurrent administration of strong cytochrome P-450 (CYP) isoenzyme 3A4 (CYP3A4) inhibitors (e.g., ketoconazole) or strong CYP3A4 inducers (e.g., rifampin).|/SIGNS AND SYMPTOMS/ An increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies. The manufacturer states that lurasidone is not approved for the treatment of patients with dementia-related psychosis.|/SIGNS AND SYMPTOMS/ Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported in patients receiving antipsychotic agents, including lurasidone.|For more Human Toxicity Excerpts (Complete) data for Lurasidone (16 total), please visit the HSDB record page.

13496, SM

Table: Lurasidone Hydrochloride Preparations [Table#8221]

Human drugs -> Latuda -> EMA Drug Category|Psycholeptics -> Human pharmacotherapeutic group