DRUG INTERACTIONS-

Drugs Having Clinically Important Interactions with CAPLYTA Table 2. Clinically Important Drug Interactions with CAPLYTA

Moderate or Strong CYP3A4 Inhibitors -                                                                 Clinical Impact Concomitant use of CAPLYTA with moderate or strong CYP3A4 inhibitors increases lumateperone exposure [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions.

Intervention Avoid concomitant use of CAPLYTA with moderate or strong CYP3A4 inhibitors [see Dosage and Administration (2.2)].

Examples Moderate inhibitors Amprenavir, ciprofloxacin, cyclosporine, diltiazem, erythromycin, fluconazole, fluvoxamine, verapamil Strong inhibitors Clarithromycin, grapefruit juice, itraconazole, voriconazole, nefazodone, ritonavir, nelfinavir CYP3A4 Inducers Clinical Impact Concomitant use of CAPLYTA with CYP3A4 inducers decreases the exposure of lumateperone [see Clinical Pharmacology (12.3)]. Intervention

Avoid concomitant use of CAPLYTA with CYP3A4 inducers [see Dosage and Administration (2.2)].

Examples Carbamazepine, phenytoin, rifampin, St. John’s wort, bosentan, efavirenz, etravirine, modafinil, nafcillin, aprepitant, armodafinil, pioglitazone, prednisone UGT Inhibitors

Clinical Impact Concomitant use of CAPLYTA with UGT inhibitors may increase the exposure of lumateperone and/or its metabolites. Intervention Avoid concomitant use of CAPLYTA with UGT inhibitors. Examples Valproic acid, probenecid

BRIEF SUMMARY

TUMATEPERONE- (Dec 2019)

Indn-    To treat Schizophrenia

Comp-    Capsules: 42 mg.  The recommended dosage of CAPLYTA is 42 mg once daily.

ADR-

CI-    Known hypersensitivity to lumateperone or any components of CAPLYTA. 

WARNINGS -

 Cerebrovascular Adverse Reactions in Elderly Patients with DementiaRelated Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke and transient ischemic attack)

Pat Inform-

Neuroleptic Malignant Syndrome- Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS), that has been reported with administration of antipsychotic drugs.

Advise patients, family members, or caregivers to contact the healthcare provider or to report to the emergency room if they experience signs and symptoms of NMS.

CONTRAINDICATIONS-

 Known hypersensitivity to lumateperone or any components of CAPLYTA. 

WARNINGS AND PRECAUTIONS-

 Cerebrovascular Adverse Reactions in Elderly Patients with DementiaRelated Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke and transient ischemic attack). 

Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring. 

Tardive Dyskinesia: Discontinue treatment if clinically appropriate. (5.4) ? Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain. (5.5) ? Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts (CBC) in patients with pre-existing low white blood cell count (WBC) or history of leukopenia or neutropenia. Consider discontinuing CAPLYTA if clinically significant decline in WBC occurs in absence of other causative factors. (5.6) ? Orthostatic Hypotension and Syncope: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope. (5.7) ? Seizures: Use cautiously in patients with a history of seizure or with conditions that lower seizure threshold. (5.9) ? Potential for Cognitive and Motor Impairment: Use caution when operating machinery. (5.10) -------------------------------ADVERSE REACTIONS------------------------------ Most common adverse reactions in clinical trials (incidence > 5% and greater than twice placebo) were somnolence/sedation and dry mouth. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Intra-Cellular Therapies, Inc. at 1-888-611-4824 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------------------DRUG INTERACTIONS------------------------------ ? CYP3A4 inducers: Avoid concomitant use. (2.2, 7.1) ? Moderate or strong CYP3A4 inhibitors: Avoid concomitant use. (2.2, 7.1) ------------------------USE IN SPECIFIC POPULATIONS----------------------- ? Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. (8.1) ? Lactation: Breastfeeding not recommended. (8.2) ? Moderate or severe hepatic impairment: Avoid use. (2.3, 8.6) See 17 for PATIENT COUNSELING INFORMATION

PATIENT COUNSELING INFORMATION

Physicians should discuss all relevant safety information with patients, including, but not limited to, the following:

Neuroleptic Malignant Syndrome- Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS), that has been reported with administration of antipsychotic drugs.

Advise patients, family members, or caregivers to contact the healthcare provider or to report to the emergency room if they experience signs and symptoms of NMS [see Warnings and Precautions (5.3)].

Tardive Dyskinesia Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [see Warnings and Precautions (5.4)].

Metabolic Changes Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.5)].

Leukopenia/Neutropenia Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/ neutropenia that they should have their CBC monitored while taking CAPLYTA [see Warnings and Precautions (5.6)].

Orthostatic Hypotension and Syncope Educate patients about the risk of orthostatic hypotension and syncope, especially early in treatment, and also at times of re-initiating treatment [see Warnings and Precautions (5.7)].

Interference with Cognitive and Motor Performance Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that CAPLYTA therapy does not affect them adversely [see Warnings and Precautions (5.10)].

Heat Exposure and Dehydration Educate patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.11)].

Concomitant Medications Advise patients to inform their health care providers of any changes to their current prescription or over-the-counter medications because there is a potential for interactions [see Drug Interactions (7.1)].

Pregnancy Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with CAPLYTA.

Advise patients that CAPLYTA used during the third trimester may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in the neonate.

Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to CAPLYTA during pregnancy [see Use in Specific Populations (8.1)]. Reference ID: 4537407

Lactation -                                                                                                                       Advise females not to breastfeed during treatment with lumateperone [see Use in Specific Populations 8.2].

Infertility Advise males and females of reproductive potential that CAPLYTA may impair fertility [see Use in Specific Populations (8.3)].

Manufactured for ITI, Limited. Hamilton, Bermuda Distributed by Intra-Cellular Therapies, Inc. New York, NY 10016 CAPLYTA is a registered trademark of Intra-Cellular Therapies, Inc. © 2019 Intra-Cellular Therapies, Inc. All rights reserved

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of action of lumateperone in the treatment of schizophrenia is unknown. However, the efficacy of lumateperone could be mediated through a combination of antagonist activity at central serotonin 5-HT2A receptors and postsynaptic antagonist activity at central dopamine D2 receptors. Reference ID: 4537407

Pharmacodynamics Lumateperone has high binding affinity for serotonin 5-HT2A receptors (Ki = 0.54 nM) and moderate binding affinity for dopamine D2 (Ki = 32 nM) receptors. Lumateperone has moderate binding affinity for serotonin transporters (Ki = 33 nM). Lumateperone also has moderate binding affinity for dopamine D1 (41 nM) and D4 and adrenergic alpha1A and alpha1B receptors (Ki projected at < 100 nM) but has low binding affinity (less than 50% inhibition at 100 nM) for muscarinic and histaminergic receptors.

Cardiac Electrophysiology QTcF interval was evaluated in a randomized, placebo- and active- (moxifloxacin 400 mg) controlled, four-arm crossover study utilizing concentration-QTc effect modeling in 33 patients with schizophrenia.

The placebocorrected change from baseline QTcF (90% two-sided upper confidence interval) values of 4.9 (8.9) and 15.8 (19.8) ms for the 42 mg and the supratherapeutic dose of 126 mg (three times the recommended daily dosage) CAPLYTA, respectively, administered orally once daily for 5 days.

Pharmacokinetics Following once daily oral administration of CAPLYTA, lumateperone steady state is reached in about 5 days. Increase in steady-state exposure is approximately dose-proportional in the range of 21 mg to 56 mg. A large intersubject variability in lumateperone PK parameters was observed, with coefficients of variation for Cmax (peak plasma concentration) and AUC (area under the concentration vs time curve) ranging from 68% to 97% at steady state.

Absorption The absolute bioavailability of lumateperone capsules is about 4.4%. Cmax of lumateperone is reached approximately 1-2 hours after CAPLYTA dosing.

Effect of Food Ingestion of a high-fat meal with CAPLYTA lowers lumateperone mean Cmax by 33% and increases mean AUC by 9%. Median Tmax was delayed about 1 hour (from 1 hour at fasted state to 2 hours in the presence of food).

Distribution Protein binding of lumateperone is 97.4% at 5 µM (about 70-fold higher than therapeutic concentrations) in human plasma. The volume of distribution of lumateperone following intravenous administration is about 4.1 L/kg.

Elimination The clearance of lumateperone is approximately 27.9 L/hour and the terminal half-life is about 18 hours after intravenous administration.

Metabolism Lumateperone is extensively metabolized with more than twenty metabolites identified in vivo. After a single 14Clabeled oral dose, lumateperone and glucuronidated metabolites represent about 2.8% and 51% of the total plasma radioactivity, respectively. In vitro studies show that 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.

Excretion In a human mass-balance study, 58% and 29% of the radioactive dose was recovered in the urine and feces, respectively. Less than 1% of the dose was excreted as unchanged lumateperone in the urine.

Specific Populations Effects of hepatic or renal impairment on lumateperone exposure are presented in Figure 1. No clinically significant differences in the pharmacokinetics of lumateperone were observed based on age, sex, or race. Reference ID: 4537407 Figure

1: Effects of Intrinsic Factors on Lumateperone Pharmacokinetics Drug Interaction Studies Clinical Studies The effects of other drugs on the exposures of lumateperone are presented in Figure 2.

Figure 2: Effects of Other Drugs on Lumateperone Pharmacokinetics CYP3A4 substrates: No clinically significant differences in the pharmacokinetics of midazolam (CYP3A4 substrate) or its metabolite 1-hydroxymidazolam were observed when used concomitantly with single or multiple doses of lumateperone in patients with schizophrenia. In Vitro Studies Reference ID: 4537407

Lumateperone showed little to no inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5. It showed no induction of CYP1A2, CYP2B6, or CYP3A4. Lumateperone did not appear to be a P-gp or BCRP substrate. It showed little to no inhibition of OCT2, OAT1, OAT3, OATP1B3, or OATP1B1.

 USE IN SPECIFIC POPULATIONS-

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. Reference ID: 4537407

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 There are no available data on the presence of lumateperone or its metabolites in human milk or animal milk, the effects on the breastfed infant, or the effects on milk production. Toxicity in animals has been linked to the formation of aniline metabolites of lumateperone [see Nonclinical Toxicology (13.2)].

Although aniline metabolites were not present in (adult) humans at quantifiable levels, it is unknown whether infants exposed to lumateperone will exhibit comparable lumateperone metabolism and elimination pathways as adults. In addition, there are published reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to antipsychotics. Based on findings of toxicity in animal studies and the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended during treatment with lumateperone.

8.3 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)]. Reference ID: 4537407

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

8.5 Geriatric Use Controlled clinical studies of CAPLYTA did not include any patients aged 65 or older 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. CALYPTA is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.1) and (5.2)]

8.6 Hepatic Impairment Use of CAPLYTA is not recommended for patients with moderate (Child-Pugh class B) to severe hepatic impairment (Child-Pugh class C). Patients with moderate and severe hepatic impairment experienced higher exposure to lumateperone [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. No dosage adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A).

10 OVERDOSAGE No specific antidotes for CAPLYTA are known. In managing overdose, provide supportive care, including close medical supervision and monitoring and consider the possibility of multiple drug involvement. In case of overdose, consult a Certified Poison Control Center (1-800-222-1222 or www.poison.org).