Brand name: Caplyta
Drug class: Atypical Antipsychotics
- Dopamine Receptor Partial Agonists
ATC class: N05AX15
VA class: CN709
Chemical name: 1-(4-Fluorophenyl)-4-[(10R,15S)-4-methyl-1,4,12-triazatetracyclo[7.6.1.05,16.010,15]hexadeca-5,7,9(16)-trien-12-yl]butan-1-one
Molecular formula: C₂₄H₂₈FN₃O
CAS number: 313368-91-1

Medically reviewed by Drugs.com on Jan 21, 2025. Written by ASHP.

Introduction

Atypical or second-generation antipsychotic agent.

Uses for Lumateperone

Schizophrenia

Treatment of schizophrenia.

American Psychiatric Association (APA) and other experts consider antipsychotic agents first-line drugs for management of schizophrenia. Choice of therapy should be individualized and generally be made in the context of shared decision-making, taking into consideration patient- and drug-related factors (e.g., adverse effect profiles, concurrent medical conditions, drug interactions, pharmacogenomic considerations, patient preferences, prior responses to treatment, available formulations, cost).

Drug therapy should be used as part of a comprehensive, patient-centered treatment plan that includes evidence-based nonpharmacologic and pharmacologic treatments.

Bipolar Disorder

Treatment of depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults, as monotherapy or as adjunctive therapy with lithium or valproate.

Pharmacologic treatments for bipolar depression include mood stabilizers (e.g., lithium, valproate, lamotrigine) and/or antipsychotic agents. Choice of therapy should be individualized, taking into account current and prior drugs used and response, personal preference, safety and tolerability of each agent, and specific clinical features.

Lumateperone may offer an additional treatment option for patients with major depressive episodes associated with bipolar I or bipolar II disorder; however, not known how the drug compares to other second-generation antipsychotics with longer established efficacy.

Lumateperone Dosage and Administration

General

Pretreatment Screening

• Monitor fasting blood glucose concentrations before or soon after initiation of lumateperone therapy.

• Obtain a fasting lipid profile at baseline (prior to or soon after initiation of lumateperone).

• Complete a fall risk assessment when initiating antipsychotic therapy in patients with diseases/conditions or receiving other drugs that could exacerbate the risk of a fall and repeat such testing periodically during long-term therapy.

• Obtain baseline body weight.

Patient Monitoring

• Closely monitor all patients receiving antidepressants for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments. for worsening and emergence of suicidal thoughts and behaviors.

• Assess patients for abnormal involuntary movements at baseline and at each follow-up visit using a structured instrument. APA recommends assessments at least every 6 months in patients at high risk for tardive dyskinesia and at least every 12 months in other patients and whenever new onset or exacerbation of preexisting movements is observed.

• Monitor fasting blood glucose concentrations periodically during long-term therapy.

• Monitor fasting lipid profile periodically during therapy.

• Monitor patient's body weight frequently during therapy.

• Monitor CBC frequently during the first few months of therapy in patients with risk factors for leukopenia and neutropenia.

• Monitor orthostatic vital signs in patients susceptible to hypotension (e.g., geriatric patients, patients with dehydration or hypovolemia, patients receiving concomitant antihypertensive therapy), patients with known cardiovascular disease (e.g., history of MI, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease.

Administration

Oral Administration

Administer orally once daily with or without food.

Dosage

Available as lumateperone tosylate; dosage expressed in terms of lumateperone.

Adults

Schizophrenia

Oral

42 mg once daily. Dosage titration not required.

Concomitant administration with strong CYP3A4 inhibitors: recommended dosage of lumateperone is 10.5 mg once daily.

Concomitant administration with moderate CYP3A4 inhibitors: recommended dosage of lumateperone is 21 mg once daily.

In patients whose symptoms have improved, continued treatment (i.e., maintenance therapy) with an antipsychotic agent is recommended to reduce the risk of relapse. Some experts generally recommend maintenance antipsychotic therapy for at least 1–2 years after the first psychotic episode and for 2–5 years or longer following recurrent episodes. Indefinite maintenance treatment may be necessary; however, periodically assess the benefits and risks of continued antipsychotic therapy in the context of shared decision-making, taking into consideration each patient's risk of relapse, drug-associated adverse effects, course of disease, and specific goals and needs.

Bipolar Disorder

Oral

42 mg once daily as monotherapy or as adjunctive therapy with lithium or valproate. Dosage titration not required.

Concomitant administration with strong CYP3A4 inhibitors: recommended dosage of lumateperone is 10.5 mg once daily.

Concomitant administration with moderate CYP3A4 inhibitors: recommended dosage of lumateperone is 21 mg once daily.

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Dosage adjustment not necessary.

Moderate or severe hepatic impairment (Child-Pugh class B or C): Recommended dosage is 21 mg once daily.

Renal Impairment

Dosage adjustment not necessary.

Geriatric Patients

No specific dosage recommendations.

Cautions for Lumateperone

Contraindications

• Known hypersensitivity to lumateperone or any components in the formulation. Hypersensitivity reactions, including pruritus, rash (e.g. allergic dermatitis, papular rash, generalized rash), and urticaria, reported.

Warnings/Precautions

Warnings

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Increased risk of death with antipsychotic agents in geriatric patients with dementia-related psychosis. (See Boxed Warning.)

Analyses of 17 placebo-controlled trials in geriatric patients mainly receiving atypical antipsychotic agents revealed an approximate 1.6- to 1.7-fold increase in mortality compared with that in patients receiving placebo.

Most fatalities appeared to result from cardiovascular-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).

Lumateperone is not approved for the treatment of dementia-related psychosis.

Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults

Antidepressants increase risk of suicidal thoughts and behaviors compared with placebo in children, adolescents, and young adults (<24 years of age) receiving antidepressants for major depressive disorder and other indications. (See Boxed Warning.)

Closely monitor all patients receiving antidepressants for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.

Consider changing or discontinuing therapy in patients whose depression is persistently worse or in those with emerging suicidal thoughts or behaviors.

Other Warnings and Precautions

Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis

Increased incidence of adverse cerebrovascular events (cerebrovascular accidents and TIAs), including fatalities, observed in geriatric patients with dementia treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies.

Lumateperone is not approved for the treatment of patients with dementia-related psychosis.

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome characterized by hyperpyrexia, muscle rigidity, delirium, and autonomic instability, reported with antipsychotic agents.

If NMS is suspected, immediately discontinue therapy and provide intensive symptomatic treatment and monitoring.

Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary dyskinetic movements, reported with use of antipsychotic agents.

Reserve long-term antipsychotic treatment for patients with chronic illness known to respond to antipsychotic agents, and for whom alternative, effective, but potentially less harmful treatments are not available or appropriate. In patients requiring chronic treatment, use lowest dosage and shortest duration of treatment needed to achieve a satisfactory clinical response; periodically reassess need for continued therapy.

APA recommends clinically assessing patients receiving atypical antipsychotic agents for abnormal involuntary movements at baseline and at each follow-up visit using a structured instrument. Assessments are recommended at least every 6 months in patients at high risk for tardive dyskinesia and at least every 12 months in other patients as well as if new onset or exacerbation of preexisting movements is observed at any visit.

Consider discontinuance of lumateperone if signs and symptoms of tardive dyskinesia appear. However, some patients may require treatment with lumateperone despite presence of the syndrome.

APA recommends that patients who have moderate to severe or disabling tardive dyskinesia associated with antipsychotic therapy be treated with a vesicular monoamine transporter 2 (VMAT2) inhibitor (e.g., deutetrabenazine, valbenazine, tetrabenazine); may also consider VMAT2 inhibitor therapy in patients with mild tardive dyskinesia based on factors such as patient preference, associated impairment, and effect on psychosocial functioning.

Metabolic Changes

Atypical antipsychotic agents have been associated with metabolic changes, including hyperglycemia and diabetes mellitus, dyslipidemia, and weight gain. While all atypical antipsychotics produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, reported in patients receiving atypical antipsychotic agents. Hyperglycemia has been reported in patients treated with lumateperone.

Monitor fasting blood glucose concentrations before or soon after initiation of lumateperone and monitor periodically during long-term therapy.

Dyslipidemia

Antipsychotic agents have been associated with undesirable changes in lipid parameters.

Obtain a fasting lipid profile at baseline (prior to or soon after initiation of lumateperone) and monitor periodically during therapy with the drug.

Weight Gain

Antipsychotic agents have been associated with weight gain.

Manufacturer recommends baseline and frequent monitoring of body weight during therapy.

Leukopenia, Neutropenia, and Agranulocytosis

Leukopenia and neutropenia reported with antipsychotic agents, including lumateperone. Agranulocytosis (including fatal cases) reported with other antipsychotic agents.

Possible risk factors for leukopenia and neutropenia include preexisting low WBC count or ANC and a history of drug-induced leukopenia or neutropenia. Monitor CBC frequently during the first few months of therapy in patients with such risk factors. Consider discontinuance of lumateperone at the first sign of a clinically important decline in WBC count in the absence of other causative factors.

Carefully monitor patients with neutropenia for fever and other signs and symptoms of infection and treat promptly if they occur. Discontinue lumateperone if severe neutropenia (ANC <1000/mm³) occurs; monitor WBC count until recovery occurs.

Orthostatic Hypotension and Syncope

Risk of orthostatic hypotension and syncope with atypical antipsychotics, particularly during initiation of therapy.

Monitor orthostatic vital signs in patients susceptible to hypotension (e.g., geriatric patients, patients with dehydration or hypovolemia, patients receiving concomitant antihypertensive therapy), patients with known cardiovascular disease (e.g., history of MI, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease.

Lumateperone has not been evaluated in patients with a recent history of MI or unstable cardiovascular disease.

Falls

May cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries.

In patients with diseases or conditions or receiving other drugs that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic therapy and repeat such testing periodically during long-term therapy.

Seizures

Lumateperone may cause seizures. Higher risk in patients with a history of seizures or with conditions that lower the seizure threshold; conditions that lower seizure threshold may be more prevalent in older patients.

Cognitive and Motor Impairment

Somnolence and impairment of judgment, thinking, or motor skills may occur.

Body Temperature Dysregulation

Atypical antipsychotic agents may disrupt body's ability to reduce core body temperature. Use with caution in patients who may experience conditions that contribute to an elevation in core body temperature (e.g., strenuous exercise, extreme heat, dehydration, concomitant use of agents with anticholinergic activity).

Dysphagia

Esophageal dysmotility and aspiration associated with the use of antipsychotic agents. Use with caution in patients at risk for aspiration.

Specific Populations

Pregnancy

Insufficient data to date in pregnant women. In animals, teratogenicity not observed but increased perinatal death in pups occurred at dosages higher than the maximum recommended human dosage.

Risk for extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, feeding disorder) in neonates exposed to antipsychotic agents during the third trimester; monitor neonates for such symptoms and manage as appropriate. Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive support and prolonged hospitalization.

National Pregnancy Registry for Atypical Antipsychotics: 866-961-2388 and [Web].

Lactation

Not known whether lumateperone and its metabolites are distributed into human or animal milk; also not known if the drug has any effects on milk production or the nursing infant.

In animals, formation of aniline metabolites of lumateperone has been associated with toxicity. Although aniline metabolites not present in adult humans in quantifiable concentrations, not known if infants exposed to lumateperone through breast milk will exhibit comparable metabolic and elimination pathways as adults. In addition, sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) reported in infants exposed to antipsychotic agents through breast milk.

Based on toxicity findings in animal studies and the potential for serious adverse reactions to lumateperone in nursing infants, breast-feeding is not recommended during lumateperone therapy.

Females and Males of Reproductive Potential

Based on findings from animal studies, may impair male and female fertility.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

Clinical efficacy trials of lumateperone did not include any patients ≥65 years of age to determine whether they respond differently than younger adults.

Geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death; increased incidence of cerebrovascular events also observed with certain atypical antipsychotic agents. Lumateperone is not approved for the treatment of patients with dementia-related psychosis.

Hepatic Impairment

Dosage adjustment not necessary in patients with mild hepatic impairment (Child-Pugh class A).

In patients with moderate or severe hepatic impairment (Child-Pugh class B or C), dosage reduction is recommended.

Renal Impairment

Dosage adjustment not necessary in patients with renal impairment.

Common Adverse Effects

Patients with schizophrenia: Adverse effects (≥5%) include somnolence/sedation and dry mouth.

Patients with bipolar depression: Adverse effects (≥5%) include somnolence/sedation, dizziness, nausea, dry mouth.

Drug Interactions

Extensively metabolized via multiple pathways, including CYP isoenzymes 3A4, 2C8, and 1A2; uridine 5'-diphospho-glucuronosyltransferase (UGT) isoenzymes 1A1, 1A4, and 2B15; and aldo-keto reductase isoenzymes 1C1, 1B10, and 1C4.

Drugs Affecting Hepatic Microsomal Enzymes

Moderate or strong CYP3A4 inhibitors: Potential increased systemic exposure to lumateperone and increased risk of adverse effects. Reduce dosage of lumateperone.

Weak CYP3A inhibitors: Effects on lumateperone exposure not expected to be clinically important.

CYP3A4 inducers: Potential decreased systemic exposure to lumateperone. Avoid concomitant use.

Specific Drugs and Foods

Lumateperone Pharmacokinetics

Absorption

Bioavailability

High interpatient variability in pharmacokinetics observed. Exhibits dose-proportional pharmacokinetics.

Peak plasma concentrations occur approximately 1–2 hours following oral administration. Steady-state concentrations achieved in about 5 days.

Absolute oral bioavailability of capsules is approximately 4.4%.

Food

Administration with a high-fat meal delays peak plasma concentrations by about 1 hour, decreases peak plasma concentration by 33%, and increases AUC by 9%. The drug was administered with food in the principal efficacy studies.

Special Populations

Renal impairment does not have clinically important effects on lumateperone pharmacokinetics.

In individuals with Child-Pugh class A, B, or C hepatic impairment, lumateperone exposures were 14, 137, or 80% higher, respectively, than in individuals with normal hepatic function.

Distribution

Plasma Protein Binding

97.4%.

Elimination

Metabolism

Extensively metabolized via multiple pathways, including CYP3A4, CYP2C8, and CYP1A2; uridine 5'-diphospho-glucuronosyltransferase (UGT) isoenzymes 1A1, 1A4, and 2B15; and aldo-keto reductase isoenzymes 1C1, 1B10, and 1C4. Over 20 metabolites identified, some possessing pharmacologic and/or toxicologic activity comparable to that of the parent drug.

Elimination Route

Following administration of a single radiolabeled dose, 58% of the dose recovered in urine (<1% excreted unchanged) and 29% recovered in feces.

Half-life

Approximately 18 hours following IV administration.

Special Populations

Age, gender, and race do not have clinically important effects on pharmacokinetics of lumateperone.

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).

Actions

• Atypical or second-generation antipsychotic agent.

• Exact mechanism of action in schizophrenia and bipolar depression unknown; efficacy may be mediated through antagonist activity at central serotonin type 2A (5-HT_2A) receptors and postsynaptic antagonist activity at dopamine type 2 (D₂) receptors.

• Exhibits high binding affinity for 5-HT_2A receptors and moderate binding affinity for D₂ receptors and serotonin transporters in vitro. Demonstrates approximately 60-fold higher binding affinity for 5-HT_2A receptors than for D₂ receptors.

• Exhibits moderate binding affinity for D₁ and D₄ receptors and α_1A- and α_1B-adrenergic receptors, and low binding affinity for 5-HT_2C, muscarinic, and histamine H₁ receptors.

Advice to Patients

• Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide).

• Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and instruct them to report such symptoms to their healthcare provider.

• Risk of neuroleptic malignant syndrome (NMS), which may be potentially life-threatening. Advise patients, family members, and caregivers to contact their clinician or seek emergency medical care if signs and symptoms of NMS develop (e.g., high fever, muscle stiffness, sweating, fast or irregular heart beat, change in BP, confusion, kidney damage).

• Inform patients and caregivers of the signs and symptoms of tardive dyskinesia and instruct them to contact their clinician if any abnormal movements occur.

• Advise patients and caregivers about the risk of metabolic changes with lumateperone and the need for specific monitoring, including blood glucose, lipids, and weight.

• Risk of leukopenia/neutropenia. Advise patients with a preexisting low WBC count or a history of drug-induced leukopenia/neutropenia that their CBC should be monitored during lumateperone therapy.

• Inform patients about the risk of orthostatic hypotension and syncope, especially when initiating or reinitiating treatment.

• Risk of somnolence and impairment of judgment, thinking, or motor skills. Advise patients to exercise caution when performing activities requiring mental alertness (e.g., driving, operating hazardous machinery) until they gain experience with the drug’s effects.

• Educate patients regarding appropriate care in avoiding overheating and dehydration.

• Advise patients to inform their clinicians of existing or contemplated therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Advise women to inform their clinicians if they are or plan to become pregnant. Advise patients that exposure to lumateperone during the third trimester may cause extrapyramidal and/or withdrawal symptoms in the neonate. Inform patients about the existence of a pregnancy registry that monitors pregnancy outcomes in women exposed to lumateperone during pregnancy.

• Advise women to avoid breast-feeding during therapy.

• Advise males and females of reproductive potential that lumateperone may impair fertility.

• Inform patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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