LUMATEPERONE TOSYLATE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for LUMATEPERONE TOSYLATE (LUMATEPERONE TOSYLATE).
Lumateperone tosylate is an atypical antipsychotic with a unique mechanism of action involving antagonism of serotonin 5-HT2A receptors, partial agonism of serotonin 5-HT1A receptors, and antagonism of dopamine D2 receptors; it also modulates glutamate via phosphorylation of GluN2B subunits and inhibits serotonin reuptake.
| Metabolism | Primarily metabolized by CYP3A4 and CYP2D6; minor contributions from CYP1A2, CYP2C19, and CYP2C9. |
| Excretion | Approximately 60% excreted in urine as metabolites (unchanged drug negligible) and 30% in feces via biliary elimination. |
| Half-life | Terminal elimination half-life is approximately 24-29 hours, allowing once-daily dosing. Steady-state reached in about 5 days. |
| Protein binding | Approximately 99% bound to serum proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Volume of distribution is approximately 4-6 L/kg, indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is approximately 20-30% due to first-pass metabolism; increased by 2-fold with high-fat meal. |
| Onset of Action | Oral: Clinical onset of antipsychotic effect occurs within 1-2 weeks of initiating therapy. |
| Duration of Action | Duration of action supports once-daily dosing due to long half-life. Clinical effect persists with regular administration. |
42 mg orally once daily
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment; not studied in severe renal impairment (CrCl <30 mL/min). |
| Liver impairment | Child-Pugh Class A: no adjustment; Child-Pugh Class B: reduce to 21 mg once daily; Child-Pugh Class C: not recommended. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | No specific dose adjustment; use with caution due to increased risk of adverse effects (e.g., hypotension, sedation). |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for LUMATEPERONE TOSYLATE (LUMATEPERONE TOSYLATE).
| Breastfeeding | Unknown if excreted in human milk. M/P ratio not determined. Due to potential for serious adverse reactions (e.g., sedation, extrapyramidal effects) in breastfed infants, advise against breastfeeding during treatment and for 1–2 weeks after last dose. |
| Teratogenic Risk | Pregnancy category N. Limited human data; animal studies show no teratogenicity at clinically relevant doses, but fetal toxicity (reduced weight, delayed ossification) occurred at multiples of MRHD. Avoid in first trimester unless benefit outweighs risk; use in third trimester may cause extrapyramidal symptoms or withdrawal in neonates. |
■ FDA Black Box Warning
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death; lumateperone is not approved for the treatment of dementia-related psychosis.
| Serious Effects |
Concomitant use with strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's wort) due to risk of reduced efficacy.
| Precautions | Cerebrovascular adverse events in elderly patients with dementia; neuroleptic malignant syndrome; tardive dyskinesia; metabolic changes (hyperglycemia, dyslipidemia, weight gain); leukopenia/neutropenia; orthostatic hypotension; seizures; body temperature dysregulation; dysphagia; cognitive/motor impairment; and interactions with strong CYP3A4 inhibitors/inducers. |
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| Fetal Monitoring | Monitor maternal weight, glucose, lipids, and prolactin at baseline and periodically. Assess for extrapyramidal symptoms, tardive dyskinesia, and neuroleptic malignant syndrome. Fetal monitoring: ultrasound for growth restriction if exposure in third trimester; neonatal monitoring for extrapyramidal symptoms, respiratory depression, feeding difficulties, and sedation after delivery. |
| Fertility Effects | Hyperprolactinemia may occur, potentially impairing fertility via suppression of GnRH and gonadal steroidogenesis. In males: decreased libido, erectile dysfunction, gynecomastia. In females: menstrual irregularities, amenorrhea. Reversible upon dose reduction or discontinuation. |