lumateperone (Rx)

>10%

Schizophrenia

• Somnolence/sedation (24%)

Bipolar disorder (adjunctive therapy)

• Somnolence/sedation (13%)
• Dizziness (11%)

Bipolar disorder (monotherapy)

• Headache (14%)
• Somnolence/sedation (13%)

1-10%

Schizophrenia

• Nausea (9%)
• Extrapyramidal symptoms (6.7%)
• Dry mouth (6%)
• Dizziness (5%)
• Creatine phosphokinase increased (4%)
• Fatigue (3%)
• Vomiting (3%)
• Hepatic transaminases increased (2%)
• Decreased appetite (2%)

Bipolar disorder (adjunctive therapy)

• Nausea (9%)
• Dry mouth (5%)
• Vomiting (4%) Extrapyramidal symptoms, adjunctive therapy (4%)
• Diarrhea (3%)
• Upper respiratory tract infection (3%)
• Blurred vision (3%)
• Increased blood prolactin (2%)
• Extrapyramidal symptoms, monotherapy (1.3%)

Bipolar disorder (monotherapy)

• Dizziness (8%)
• Nausea (8%)
• Dry mouth (5%)
• Diarrhea (4%)
• Vomiting (4%)
• Abdominal pain (2%)
• Upper respiratory tract infection (2%)

Frequency Not Defined

Dystonia

Contraindications

History of hypersensitivity; reactions have included pruritus, rash (eg, allergic dermatitis, papular rash, and generalized rash), and urticaria

Cautions

Geriatric patients with dementia-related psychosis who are treated with antipsychotic drugs are at increased risk of death

Geriatric patients with dementia who were treated with antipsychotics had a higher incidence of stroke and transient ischemic attacks, including fatal stroke

Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during initial few months of drug therapy, and at times of dosage changes; counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider; consider changing therapeutic regimen, including possibly discontinuing therapy, in patients whose depression is persistently worse, or who are experiencing suicidal thoughts or behaviors

Neuroleptic malignant syndrome (NMS), a potentially fatal symptom complex, reported with administration of antipsychotic drugs; if NMS suspected, immediately discontinue lumateperone and provide intensive symptomatic treatment and monitoring

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs; risk appears to be highest among elderly individuals, especially women, but it is not possible to predict which patients are likely to develop the syndrome

May cause metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain

Leukopenia and neutropenia reported with antipsychotic agents, including lumateperone; agranulocytosis reported with other agents in the class

May cause orthostatic hypotension and syncope; risk is greatest during initial dose administration

Antipsychotics, including lumateperone, may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls and, consequently, fractures and other injuries

May cause seizures; risk is greatest with history of seizures or with conditions that lower seizure threshold

May cause somnolence and has the potential to impair judgment, thinking, and motor skills

May disrupt the body’s ability to reduce core body temperature; strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevated core body temperature

Esophageal dysmotility and aspiration reported with antipsychotic drug use

Drug interaction overview

• CYP3A4 inhibitors or inducers

  • Moderate or strong inhibitors: Avoid coadministration
  • Inducers: Avoid coadministration

• UGT inhibitors

  • Coadministration may increase lumateperone and/or its metabolites
  • Avoid coadministration

Pregnancy

Neonates exposed to antipsychotic drugs during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery

Available data from case reports on use in pregnant women are insufficient to establish any drug-associated risks for birth defects, miscarriage, or adverse maternal or fetal outcomes

Register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/

Animal studies

• No malformations were observed with oral administration of lumateperone to pregnant rats and rabbits during organogenesis at doses up to 2.4 and 9.7 times, respectively, the maximum recommended human dose (MRHD) of 42 mg/day on a mg/m² basis
• When pregnant rats were administered lumateperone during organogenesis through lactation, the number of perinatal deaths of pups was increased at 4.9 times the MRHD, with no adverse effects on pups at 2.4 times the MRHD

Clinical considerations

• There is risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide
• Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth; unknown if this is a direct result of the illness or other comorbid factors

Infertility

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

Lactation

Data are not available regarding presence of lumateperone or its metabolites in human milk, effect on breastfed infants, or effect on milk production

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

The mechanism of action of lumateperone in the treatment of schizophrenia is unknown; however, efficacy could be mediated through a combination of antagonist activity at central serotonin 5-HT2A receptors and postsynaptic antagonist activity at central dopamine D2 receptors

Absorption

Bioavailability: 4.4%

Peak plasma time: 1-2 hr

Ingestion with high-fat meal

• Lowers lumateperone mean peak plasma concentration by 33% and increases mean AUC by 9%
• Median peak plasma time delayed ~1 hr (from 1 hr at fasted state to 2 hr in the presence of food)

Distribution

Protein bound: 97.4%

Vd: 4.1 L/kg

Metabolism

Extensively metabolized with >20 metabolites identified in vivo

Multiple enzymes, including but not limited to uridine 5’-diphospho- glucuronosyltransferases (UDP-glucuronosyltransferase, UGT) 1A1, 1A4, and 2B15, aldoketoreductase (AKR)1C1, 1B10, and 1C4, and cytochrome P450 (CYP) 3A4, 2C8, and 1A2, are involved in the metabolism of lumateperone

Elimination

Half-life: ~18 hr (IV administration)

Clearance: 27.9 L/hr

Excretion: Feces: 29%; urine 58%

Oral Administration

Administer with food

Storage

Store at controlled room temperature 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)