Source: FDA, National Drug Code (US) Revision Year: 2019
CAPLYTA is contraindicated in patients with history of hypersensitivity reaction to lumateperone. Reactions have included pruritus, rash (e.g. allergic dermatitis, papular rash, and generalized rash), and urticaria.
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in placebo-treated patients. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. CAPLYTA is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.2)].
In placebo-controlled trials in elderly subjects with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. CAPLYTA is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)].
Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, delirium, and autonomic instability. Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue CAPLYTA and provide intensive symptomatic treatment and monitoring.
Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. The risk appears to be highest among the elderly, especially elderly women, but it is not possible to predict which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
The risk of tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses. It may also occur after discontinuation of treatment.
Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of tardive dyskinesia is unknown.
Given these considerations, CAPLYTA should be prescribed in a manner most likely to reduce the risk of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: 1) who suffer from a chronic illness that is known to respond to antipsychotic drugs; and 2) for whom alternative, effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.
If signs and symptoms of tardive dyskinesia appear in a patient on CAPLYTA, drug discontinuation should be considered. However, some patients may require treatment with CAPLYTA despite the presence of the syndrome.
Antipsychotic drugs have caused metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. Although all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.
Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma or death, has been reported in patients treated with antipsychotics. There have been reports of hyperglycemia in patients treated with CAPLYTA. Assess fasting plasma glucose before or soon after initiation of antipsychotic medication and monitor periodically during long-term treatment.
In pooled data from short-term (4- to 6-week), placebo-controlled trials of adult patients with schizophrenia, mean changes from baseline and the proportion of patients with shifts from normal to greater than normal levels of fasting glucose in patients treated with CAPLYTA were similar to those in patients treated with placebo.
In an uncontrolled open-label trial of CAPLYTA for up to 1 year in patients with stable schizophrenia, the percentages of patients with shifts in fasting glucose and insulin values from normal to high were 8% and 12%, respectively. 4.7% of patients with normal hemoglobin A1c (<6.5%) at baseline developed elevated levels (≥6.5%) post-baseline.
Antipsychotics have caused adverse alterations in lipids. Before or soon after initiation of antipsychotic medications, obtain a fasting lipid profile at baseline and monitor periodically during treatment.
In pooled data from short-term (4- to 6-week), placebo-controlled trials of adult patients with schizophrenia, mean changes from baseline and the proportion of patients with shifts to higher levels of fasting total cholesterol and triglycerides were similar in patients treated with CAPLYTA and placebo.
In an uncontrolled open-label trial of CAPLYTA for up to 1 year in patients with stable schizophrenia, the percentages of patients with a shift from normal to high were 8%, 5%, and 4% for total cholesterol, triglycerides, and LDL cholesterol, respectively.
Weight gain has been observed with use of antipsychotics. Monitor weight at baseline and frequently thereafter. In pooled data from placebo-controlled trials of adult patients with schizophrenia, mean changes from baseline and the proportion of patients with an increase in weight ≥7% from baseline to end of study was similar in patients treated with CAPLYTA and placebo.
In an uncontrolled open-label trial of CAPLYTA for up to 1 year in patients with stable schizophrenia, the mean change in body weight was approximately -2 kg (SD 5.6) at Day 175 and approximately – 3.2 kg (SD 7.4) at Day 350.
Leukopenia and neutropenia have been reported during treatment with antipsychotic agents, including CAPLYTA. Agranulocytosis (including fatal cases) has been reported with other agents in the class.
Possible risk factors for leukopenia and neutropenia include pre-existing low white blood cell count (WBC) or absolute neutrophil count (ANC) and history of drug-induced leukopenia or neutropenia. In patients with a pre-existing low WBC or ANC or a history of drug-induced leukopenia or neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of CAPLYTA at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue CAPLYTA in patients with absolute neutrophil count <1000/mm³ and follow their WBC until recovery.
Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose administration. In these clinical trials the frequencies of orthostatic hypotension for CAPLYTA and placebo were 0.7% and 0%, respectively. The rates of syncope for CAPLYTA and placebo were 0.2% and 0.2%.
Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension (e.g., elderly patients, patients with dehydration, hypovolemia, and concomitant treatment with antihypertensive medications), patients with known cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. CAPLYTA has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease. Such patients were excluded from pre-marketing clinical trials.
Antipsychotics, including CAPLYTA, may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls and, consequently, fractures and other injuries. For patients with diseases, conditions or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and periodically during long-term treatment.
Like other antipsychotic drugs, CAPLYTA may cause seizures. The risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in older patients.
CAPLYTA, like other antipsychotics, may cause somnolence and has the potential to impair judgment, thinking, and motor skills. In short-term (i.e., 4- to 6-week) placebo-controlled clinical trials of patients with schizophrenia, somnolence and sedation were reported in 24% of CAPLYTA-treated patients, compared to 10% of placebo-treated patients.
Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with CAPLYTA does not affect them adversely.
Atypical antipsychotics may disrupt the body’s ability to reduce core body temperature. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use CAPLYTA with caution in patients who may experience these conditions.
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Antipsychotic drugs, including CAPLYTA, should be used cautiously in patients at risk for aspiration.
The following adverse reactions are discussed in detail in other sections of the labeling:
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 1724 adult patients with schizophrenia exposed to one or more doses. Of these patients, 811 participated in short-term (4- to 6-week), placebo-controlled trials with doses ranging from 14 to 84 mg/day. A total of 329 CAPLYTA-exposed patients had at least 6 months of exposure and 108 had at least 1 year of exposure to the 42-mg dose of CAPLYTA.
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 patients exposed to CAPLYTA and greater than twice the rate of placebo) are somnolence/sedation and dry mouth.
Adverse reactions associated with CAPLYTA (incidence of at least 2% in patients exposed to CAPLYTA and greater than placebo) are shown in Table 1. The following findings 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 daily dose of 42 mg (N=406).
Table 1. Adverse Reactions Reported in >2% of CAPLYTA-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% |
| Dizziness1 | 5% | 3% |
| Creatine Phosphokinase Increased | 4% | 1% |
| Fatigue | 3% | 1% |
| Vomiting | 3% | 2% |
| Hepatic Transaminases Increased2 | 2% | 1% |
| Decreased Appetite | 2% | 1% |
1 Dizziness, dizziness postural
2 ALT, AST, “hepatic enzymes” increased, or liver function test abnormal
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.
In the 4- to 6-week, placebo-controlled trials, the frequency of reported events related to extrapyramidal symptoms (EPS), 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 CAPLYTA and 6.3% for placebo.
In the 4- to 6-week trials, data were collected using 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). 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.
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 | |
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/.
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.
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.
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.
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.
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.
Based on findings from animal studies, lumateperone may impair male and female fertility [see Nonclinical Toxicology (13.1)].
Safety and effectiveness of CAPLYTA have not been established in pediatric patients.
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)].
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).
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