DRUG INTERACTIONS 

Having Clinically Important Interactions with CAPLYTA

 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, which may increase the risk of adverse reactions.

Intervention- Avoid concomitant use of CAPLYTA with moderate or strong CYP3A4 inhibitors .

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 

Intervention Avoid concomitant use of CAPLYTA with CYP3A4 inducers 

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

ADVERSE REACTIONS

 Most common adverse reactions in clinical trials (incidence > 5% and greater than twice placebo) were somnolence/sedation and dry mouth. 

 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 

Tardive Dyskinesia                                                                                                   Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur  

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 

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 

 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 

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 

Heat Exposure and Dehydration                                                                               Educate patients regarding appropriate care in avoiding overheating and dehydration 

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 

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 

Lactation                                                                                                                     Advise females not to breastfeed during treatment with lumateperone 

Infertility                                                                                                                           Advise males and females of reproductive potential that CAPLYTA may impair fertility 

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

 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.

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.                                                                          

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.

No clinically significant differences in the pharmacokinetics of lumateperone were observed based on age, sex, or race.

Pharmacokinetics- Drug Interaction Studies Clinical Studies                                      he effects of other drugs on the exposures of lumateperone are presented.

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. 

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.

13 NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Lifetime carcinogenicity studies were conducted in rats and mice, and results showed no carcinogenic potential in either species. In Sprague-Dawley rats,

USE IN SPECIFIC POPULATIONS

1.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 

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. 

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. 

2.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.

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.

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

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

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 

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 

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

 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).