Lumateperoneside effects

The following adverse reactions are discussed in detail in other sections of the labeling: Increased Mortality in Elderly Patients with Dementia-Related Psychosis Suicidal Thoughts and Behaviors Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-related Psychosis Neuroleptic Malignant Syndrome Tardive Dyskinesia Metabolic Changes Leukopenia, Neutropenia, and Agranulocytosis Orthostatic Hypotension and Syncope Falls Seizures Potential for Cognitive and Motor Impairment Body Temperature Dysregulation Dysphagia Most common adverse reactions in clinical trials (incidence ≥ 5% and greater than twice placebo) were: Schizophrenia: somnolence/sedation and dry mouth.

Bipolar depression: somnolence/sedation, dizziness, nausea, dry mouth.

MDD: dizziness, dry mouth, somnolence/sedation, nausea, fatigue, diarrhea. To report SUSPECTED ADVERSE REACTIONS, contact Intra-Cellular Therapies, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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.

6.2 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