Caplyta

Recommended Dosage

The recommended dosage of CAPLYTA is 42 mg administered orally once daily with or without food. Dose titration is not required.

Dosage Recommendations for Concomitant Use with Moderate or Strong CYP3A4Inhibitors

Coadministration with Strong CYP3A4 Inhibitors

The recommended dosage for patients receiving strong CYP3A4 inhibitors is CAPLYTA 10.5 mg once daily [see  Drug Interactions (7.1)].

Coadministration with Moderate CYP3A4 Inhibitors

The recommended dosage for patients receiving moderate CYP3A4 inhibitors is CAPLYTA 21 mg once daily [see  Drug Interactions (7.1)].

Dosage Recommendations for Patients with HepaticImpairment

For patients with moderate or severe hepatic impairment (Child-Pugh class B or C), the recommended dosage of CAPLYTA is 21 mg once daily [see Use in Specific Populations (8.6)].

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including CAPLYTA, during pregnancy. Healthcare providers are encouraged to 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/.

Risk Summary

Neonates exposed to antipsychotic drugs during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). Available data from case reports on CAPLYTA use in pregnant women are insufficient to establish any drug associated risks for birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including CAPLYTA, during pregnancy (see Clinical Considerations). In animal reproduction 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 the period of 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 (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease associated maternal and/or embryo/fetal risk

 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. It is not known if this is a direct result of the illness or other comorbid factors.

Fetal/neonatal adverse reactions

 Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Data

Animal Data

Pregnant rats were treated with oral doses of 3.5, 10.5, 21, and 63 mg/kg/day lumateperone (0.8, 2.4, 4.9, and 14.6 times the MRHD on a mg/m2 basis) during the period of organogenesis. No malformations were observed with lumateperone at doses up to 2.4 times the MRHD. Findings of decreased body weight were observed in fetuses at 4.9 and 14.6 times the MRHD. Findings of incomplete ossification and increased incidences of visceral and skeletal variations were recorded in fetuses at 14.6 times the MRHD, a dose that induced maternal toxicity.

Pregnant rabbits were treated with oral doses of 2.1, 7, and 21 mg/kg/day lumateperone (1.0, 3.2, and 9.7 times the MRHD on a mg/m2 basis) during the period of organogenesis. Lumateperone did not cause adverse developmental effects at doses up to 9.7 times the MRHD.

In a study in which pregnant rats were administered oral doses of 3.5, 10.5, and 21 mg/kg/day lumateperone (0.8, 2.4, and 4.9 times the MRHD on a mg/m2 basis) during the period of organogenesis and through lactation, the number of live-born pups was decreased at 2.4 and 4.9 times the MRHD, and early postnatal deaths increased at a dose 4.9 times the MRHD. Impaired nursing and decreased body weight gain in pups were observed at 4.9 times, but not at 2.4 times, the MRHD.

Pregnant rats were treated with a human metabolite of lumateperone (reduced ketone metabolite) at oral doses of 15, 60, and 100 mg/kg/day (1.2, 19, and 27 times the exposure to this metabolite at the MRHD of lumateperone based on AUC plasma exposure) during the period of organogenesis. This metabolite did not cause adverse developmental effects at a dose 1.2 times the exposure at the MRHD of lumateperone; however, it caused an increase in visceral malformations (cleft palate) at 27 times and skeletal malformations at 19 times the exposure at the MRHD of lumateperone, a dose that induced maternal toxicity.

Lactation

Risk Summary

Lumateperone and its metabolites are present in human breast milk in low amounts. In a clinical lactation study, lumateperone was detected in human milk at an estimated daily infant dose 0.0004 mg/kg, with a relative infant dose (RID) of 0.06% the maternal weight-adjusted dosage. Several major circulating metabolites were similarly detected in breast milk in low amounts; however, aniline metabolites were not present in milk or maternal plasma at quantifiable levels (see Data). There are no data on the effects of lumateperone on the breastfed infant or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CAPLYTA and any potential adverse effects on the breastfed child from CAPLYTA or from the underlying maternal condition.

Data

A lactation study in 17 lactating women evaluated the concentrations of lumateperone and its metabolites in plasma and mature breast milk following a single dose of 42 mg CAPLYTA. The estimated daily infant dose of lumateperone in human milk was 0.0004 mg/kg/day (with assumed average milk consumption of 200 ml/kg/day). The mean relative infant dose (RID) (with assumed mean milk consumption of 200 mL/kg/day and average maternal weight of 71 kg) was 0.06% of the maternal weight-adjusted dosage. Several major circulating metabolites were also present in breast milk at estimated daily infant dose of 0.0004 mg/kg/day. Aniline metabolites were not present in milk or maternal plasma at quantifiable levels.

Females and Males of Reproductive Potential

Infertility

Based on findings from animal studies, lumateperone may impair male and female fertility [see Nonclinical Toxicology (13.1)].

Pediatric Use

Safety and effectiveness of CAPLYTA have not been established in pediatric patients.

Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning, Warnings and Precautions (5.2)].

Geriatric Use

Controlled clinical studies of CAPLYTA in the treatment of schizophrenia did not include any patients aged 65 or older to determine whether or not they respond differently from younger patients. Controlled clinical studies of CAPLYTA in the treatment of bipolar depression included patients aged 65 or older; the number of patients was not sufficient to determine whether or not they respond differently from younger patients.

Antipsychotic drugs increase the risk of death in elderly patients with dementia-related psychosis. CAPLYTA is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.1) and (5.3 )].

Hepatic Impairment

Patients with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment generally had higher exposure to lumateperone than patients with normal hepatic function; therefore, a dosage reduction of CAPLYTA is recommended in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

No dosage adjustment is recommended for patients with mild hepatic impairment (Child-Pugh class A).