Caplyta Drug Information

is indicated for: Treatment of schizophrenia in adults . Treatment of depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults, as monotherapy and as adjunctive therapy with lithium or valproate . Adjunctive therapy with antidepressants for the treatment of major depressive disorder (MDD) in adults. CAPLYTA is an atypical antipsychotic indicated for: Treatment of schizophrenia in adults. Treatment of depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults, as monotherapy and as adjunctive therapy with lithium or valproate.

Adjunctive therapy with antidepressants for the treatment of major depressive disorder (MDD) in adults.

Recommended Dosage

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

Dosage Recommendations for

Concomitant Use with Moderate or Strong CYP3A4 Inhibitors The recommended CAPLYTA dosage in patients who receive : Strong CYP3A4 inhibitors is 10.5 mg once daily. Moderate CYP3A4 inhibitors is 21 mg once daily.

Dosage Recommendations for Patients with Hepatic Impairment For patients with moderate hepatic

impairment (HI) (Child-Pugh class B) or severe HI (Child-Pugh class C), the recommended CAPLYTA dosage is 21 mg once daily . The recommended CAPLYTA dosage in patients with mild HI is the same as those with normal hepatic function.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of CAPLYTA has been evaluated in placebo-controlled clinical trials that included 3575 adult patients with schizophrenia, bipolar depression, or major depressive disorder, exposed to one or more CAPLYTA doses. A total of 852 CAPLYTA-treated patients had at least 6 months of treatment and 108 had at least 1 year of treatment with the 42-mg once daily dosage.

Adverse Reactions in Patients with Schizophrenia The following adverse reactions are based on the pooled short-term (4- to 6-week), placebo-controlled studies in adult patients with schizophrenia in which CAPLYTA was administered at a dosage of 42 mg once daily (N=406). There was no single adverse reaction that led to discontinuation that occurred at a rate of >2% in CAPLYTA-treated patients. The most common adverse reactions (incidence of at least 5% of CAPLYTA-treated patients and greater than twice the rate of placebo-treated patients) were somnolence/sedation and dry mouth. Adverse reactions (incidence of at least 2% in CAPLYTA-treated patients and greater than in placebo-treated patients) are shown in Table 2. Table 2: Adverse Reactions Reported in ≥2% of CAPLYTA-Treated Patients and Greater Incidence Than in Placebo-Treated Patients in 4- to 6-week Schizophrenia Trials CAPLYTA 42 mg (N=406) Placebo (N=412) Somnolence/Sedation 24% 10% Nausea 9% 5% Dry Mouth 6% 2% Dizziness 1 5% 3% Creatine Phosphokinase Increased 4% 1% Fatigue 3% 1% Vomiting 3% 2% Hepatic Transaminases Increased 2 2% 1% Decreased Appetite 2% 1% 1 Dizziness, dizziness postural 2 ALT, AST, “hepatic enzymes” increased, or liver function test abnormal Adverse Reactions in Patients with Bipolar Depression (CAPLYTA Monotherapy) The following adverse reactions are based on the pooled short-term (6-week), placebo-controlled monotherapy bipolar depression studies in adult patients treated with CAPLYTA 42 mg once daily (N=372) . There was no single adverse reaction leading to discontinuation that occurred at a rate of >2% in CAPLYTA-treated patients.

The most common adverse reactions (incidence of at least 5% of CAPLYTA-treated patients and greater than twice the rate in placebo-treated patients) were somnolence/sedation, dizziness, nausea, and dry mouth. Adverse reactions associated with CAPLYTA (incidence of at least 2% in CAPLYTA-treated patients and greater than placebo-treated patients) are shown in Table 3. Table 3: Adverse Reactions Reported in ≥2% of CAPLYTA-Treated Patients and Greater Incidence than in Placebo-Treated Patients in Pooled 6-week Monotherapy Bipolar Depression Trials CAPLYTA 42 mg (N=372) Placebo (N=374) Headache 14% 8% Somnolence/Sedation 13% 3% Dizziness 1 8% 4% Nausea 8% 3% Dry mouth 5% 1% Diarrhea 4% 2% Vomiting 4% 0% Abdominal pain 2 2% 1% Upper respiratory tract infection 2% 1% 1 Dizziness, dizziness postural 2 Abdominal discomfort, abdominal pain, abdominal pain upper and lower Adverse Reactions in Patients with Bipolar Depression (Concomitant Treatment with CAPLYTA and Lithium or Valproate) The adverse reactions below are based on a 6-week, placebo-controlled adjunctive therapy bipolar depression study in adult patients treated with CAPLYTA 42 mg once daily + lithium or valproate OR placebo + lithium or valproate (N=177). There was no single adverse reaction leading to discontinuation that occurred at a rate of >2% in patients in the CAPLYTA + lithium or valproate group. The most common adverse reactions (incidence of at least 5% in patients treated with CAPLYTA + lithium or valproate and greater than twice the rate of patients treated with placebo + lithium or valproate) were somnolence/sedation, dizziness, nausea, and dry mouth.

Adverse reactions associated with CAPLYTA + lithium or valproate (incidence of at least 2% in patients treated with CAPLYTA + lithium or valproate and greater than with patients treated with placebo + lithium or valproate) are shown in Table 4. Table 4: Adverse Reactions Reported in ≥2% of CAPLYTA-Treated Patients and that Occurred at Greater Incidence than in the Placebo-Treated Patients in a 6-Week Adjunctive Therapy Bipolar Depression Trial CAPLYTA 42 mg + lithium or valproate (N=177) Placebo + lithium or valproate (N=175) Somnolence/Sedation 13% 3% Dizziness 1 11% 2% Nausea 9% 4% Dry mouth 5% 1% Vomiting 4% 0% Diarrhea 3% 2% Upper respiratory tract infection 3% 1% Blurred vision 3% 1% Increased blood prolactin 2% 0% 1 Dizziness, dizziness postural Adverse Reactions in Studies for Adjunctive Treatment of Major Depressive Disorder The following adverse reactions are based on pooled short-term (6-week), placebo-controlled adjunctive therapy MDD studies in adult patients treated with CAPLYTA 42 mg orally once daily and background antidepressant therapy (ADT) or placebo and background ADT (N=483). There was no single adverse reaction leading to discontinuation that occurred at an incidence of >2% in patients treated with CAPLYTA and background ADT. The most common adverse reactions (incidence of at least 5% of patients treated with CAPLYTA and background ADT and greater than twice the incidence in patients treated with placebo and background ADT) were dizziness, dry mouth, somnolence/sedation, nausea, fatigue, and diarrhea. Adverse reactions in the adjunctive therapy MDD studies (incidence of at least 2% of patients treated with CAPLYTA and background ADT and greater than in patients treated with placebo and background ADT) are shown in Table 5. Table 5: Adverse Reactions Reported in ≥2% of Patients Treated with CAPLYTA + Background ADT and at Greater Incidence than in Patients Treated with Placebo + Background ADT in Pooled 6-Week Adjunctive MDD Trials CAPLYTA 42 mg + ADT (N=483) Placebo + ADT (N=481) Headache 1 19% 13% Dizziness 2 17% 5% Dry Mouth 13% 3% Somnolence/Sedation 12% 2% Nausea 9% 4% Fatigue 8% 2% Diarrhea 5% 1% Tremor 4% <1% Vomiting 3% 2% Vertigo 3% <1% Insomnia 3% 2% 1 Headache, migraine, tension headache 2 Dizziness, postural dizziness Additional Adverse Reactions Dystonia: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue.

Although these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Extrapyramidal Symptoms: In the short-term, placebo-controlled schizophrenia, bipolar depression, and adjunctive MDD studies, extrapyramidal (EPS) symptom data was objectively collected on the Simpson-Angus Scale (SAS) for EPS (total score ranges from 0 to 40), the Barnes Akathisia Rating Scale (BARS) for akathisia (total score ranges from 0 to 14), and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesia (total score ranges from 0 to 28). In the 4- to 6-week, placebo-controlled schizophrenia trials, the frequency of EPS-related reported events including akathisia, extrapyramidal disorder, muscle spasms, restlessness, musculoskeletal stiffness, dyskinesia, dystonia, muscle twitching, tardive dyskinesia, tremor, drooling, and involuntary muscle contractions was 6.7% for the CAPLYTA-treated patients and 6.3% for placebo-treated patients.

In these trials, the mean changes from baseline for CAPLYTA-treated patients and placebo-treated patients were 0.1 and 0 for the SAS, -0.1 and 0 for the BARS, and 0.1 and 0 for the AIMS, respectively. In the 6-week, monotherapy bipolar depression trials, the frequency of reported EPS-related reactions including muscle spasms, dyskinesia, extrapyramidal disorder, movement disorder, tremor, restlessness, and akathisia was 1.3% for CAPLYTA-treated patients and 1.1% for placebo-treated patients. In these trials, the mean changes from baseline for CAPLYTA-treated patients and placebo-treated patients were 0 and 0 for the SAS, -0.1 and -0.1 for the BARS, and 0 and 0 for the AIMS, respectively.

In a 6-week, adjunctive therapy bipolar depression trial, the frequency of reported EPS-related reactions, including tremor, muscle spasms, akathisia, extrapyramidal disorder, gait disturbance, and restlessness was 4% for CAPLYTA-treated patients and 2.3% for placebo-treated patients. In the 6-week, monotherapy bipolar depression trials, the mean changes from baseline for CAPLYTA-treated patients and placebo-treated patients were 0 and 0 for the SAS, -0.1 and -0.1 for the BARS, and 0 and 0 for the AIMS, respectively. In this trial, the mean changes from baseline for CAPLYTA-treated patients and placebo-treated patients were 0 and 0 for the SAS, 0 and -0.1 for the BARS, and 0 and 0 for the AIMS, respectively.

In the 6-week, adjunctive MDD trials, the frequency of reported EPS-related adverse reactions (tremor, bradykinesia, muscle spasms, gait disturbance, tongue spasm, muscle tightness and dyskinesia), excluding akathisia and restlessness, was 5% for CAPLYTA-treated patients and 0.8% for placebo-treated patients. The combined incidence of akathisia and restlessness was 1% for CAPLYTA-treated patients and 0.8% for placebo-treated patients. In these trials, the mean changes from baseline for CAPLYTA-treated patients and placebo-treated patients were 0 and 0 for the SAS, 0 and -0.1 for the BARS, and 0 and 0 for the AIMS, respectively.

Postmarketing Experience

The following adverse reaction has been identified during post-approval use of CAPLYTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. Central and Peripheral Nervous System Disorders : burning sensation, including skin burning sensation

Drugs Having Clinically Important Interactions with

CAPLYTA Clinically important drug interactions with CAPLYTA are presented in Table 6. Table 6: Clinically Important Drug Interactions with CAPLYTA CYP3A4 Inducers* Prevention or Management Avoid concomitant use of CAPLYTA with CYP3A4 inducers. Clinical Impact Concomitant use of CAPLYTA with CYP3A4 inducers decreases the exposure of lumateperone. Moderate or Strong CYP3A4 Inhibitors* Prevention or Management Reduce the CAPLYTA dosage when used concomitantly with 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. Serotonin Reuptake Inhibitors Prevention or Management Increased monitoring for SRI- associated adverse reactions is recommended. Clinical Impact Although no clinically significant drug interactions with adjunctive SSRI/SNRIs in MDD were observed in CAPLYTA clinical trials, CAPLYTA’s moderate serotonin transporter (SERT) activity may increase the risk of SRI-associated adverse reactions (e.g., serotonin syndrome, hyponatremia). * See www.fda.gov/CYPandTransporterInteractingDrugs for examples of CYP3A4 Inducers and Moderate or Strong CYP3A4 Inhibitors

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 advise patients to register by calling the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/research/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/m 2 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/m 2 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/m 2 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/m 2 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.

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.

is contraindicated in patients with history of hypersensitivity reaction to lumateperone or any components of CAPLYTA. Reactions have included pruritus, rash (e.g. allergic dermatitis, papular rash, and generalized rash), and urticaria. CAPLYTA is contraindicated in patients with history of hypersensitivity reaction to lumateperone or any components of CAPLYTA.

No specific antidotes for CAPLYTA are known. In managing a CAPLYTA overdose, provide supportive care, including close medical supervision and monitoring and consider the possibility of multiple drug involvement. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.