Lumateperone Receptor Pharmacology

Lumateperone is thought to have a pharmacological profile that includes the modulation of serotonergic and dopaminergic receptors and may contribute to indirect activation of glutamatergic AMPA and NMDA receptors. The mechanism of action of lumateperone is unknown. Lumateperone acts as an antagonist at serotonin 2A receptors, binding with high affinity and a high occupancy at this receptor of over 80%. Lumateperone also binds to the serotonin transporter, also known as SERT, with moderate binding affinity. Inhibition of SERT contributes to increased serotonin in the synapse. Lumateperone also has moderate binding affinity for dopamine D2 receptors. Although its mechanism of action is unknown, it is thought to include partial agonist activity in these receptors. Partial agonists have a lower intrinsic activity at receptors than full agonists, allowing them to act either as functional agonists or functional antagonists, depending on the surrounding levels of the neurotransmitter.

There are published preclinical studies of lumateperone examining its potential activity at the D2 receptor as a presynaptic partial agonist and potentially as a postsynaptic antagonist. Lumateperone binds to D2 receptors with a moderate binding affinity and a receptor occupancy of up to 39%. When there are high levels of occupancy at the D2 receptor, which is defined as greater than or equal to 80%, risks of extrapyramidal symptoms and elevated prolactin levels may be increased. The molecule has moderate binding affinity to dopamine D1 receptors. This binding may contribute to indirect activation of the glutamatergic AMPA and NMDA receptors. Lumateperone has low binding affinity for off-target receptors, such as histaminergic and muscarinic receptors.

INDICATIONS. CAPLYTA® (lumateperone) is indicated in adults for adjunctive therapy along with antidepressants for the treatment of major depressive disorder (MDD); the treatment of depressive episodes associated with bipolar I or II disorder (bipolar depression) as monotherapy and as adjunctive therapy with lithium or valproate; and the treatment of schizophrenia.

IMPORTANT SAFETY INFORMATION

BOXED WARNINGS. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. CAPLYTA® is not approved for the treatment of patients with dementia-related psychosis. Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening and for the emergence of suicidal thoughts and behaviors. The safety and effectiveness of CAPLYTA® have not been established in pediatric patients.

Contraindications. CAPLYTA® is contraindicated in patients with a history of hypersensitivity to lumateperone or any components of CAPLYTA®. Reactions have included pruritus, rash, for example, allergic dermatitis, papular rash, generalized rash, and urticaria.

WARNINGS AND PRECAUTIONS. Antipsychotic drugs have been reported to cause cerebrovascular adverse reactions in elderly patients with dementia-related psychosis, including stroke and transient ischemic attack. See Boxed WARNING above.

Neuroleptic malignant syndrome, which is a potentially fatal reaction. Signs and symptoms include hyperpyrexia, muscle rigidity, delirium, autonomic instability, elevated creatinine phosphokinase, myoglobinuria, and/or rhabdomyolysis, and acute renal failure. Manage with immediate discontinuation of CAPLYTA® and provided intensive symptomatic treatment and monitoring.

Tardive dyskinesia (TD) may develop in patients treated with antipsychotic drugs, including CAPLYTA®. TD can develop after a relatively brief treatment period, even at low doses, or after treatment discontinuation. The TD risk appears to be highest in elderly women. The likelihood that TD will become irreversible increases with the duration of the antipsychotic drug treatment and cumulative dose. If signs and symptoms of TD appear, consider discontinuing CAPLYTA® if clinically appropriate.

Metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma or death, has been reported in patients treated with antipsychotics. Measure weight and assess fasting plasma glucose and lipids when initiating CAPLYTA® and monitor periodically during long-term treatment.

Leukopenia, neutropenia, and agranulocytosis (including fatal cases). Perform complete blood counts in patients with pre-existing low white blood cell count (WBC) or history of leukopenia or neutropenia. Consider discontinuing CAPLYTA® if a clinically significant decline in WBC occurs in absence of other causative factors. Discontinue CAPLYTA® in patients with clinically significant neutropenia or an absolute neutrophil count less than 1,000 per cubic millimeter and monitor closely until neutropenia resolves.

Orthostatic hypotension and syncope. Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease. Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension.

Falls. CAPLYTA® may cause somnolence, postural hypotension, and motor and/or sensory instability, which may lead to falls and, consequently, fractures and other injuries. Assess patients for fall risk when initiating treatment and periodically during long-term treatment.

Seizures. Use CAPLYTA® cautiously in patients with a history of seizures or with conditions that lower seizure threshold.

Potential for cognitive and motor impairment. Advise patients to use caution when operating machinery or motor vehicles until they know how CAPLYTA® affects them.

Body temperature dysregulation. Use CAPLYTA® with caution in patients who may experience conditions that may increase core body temperatures, such as strenuous exercise, extreme heat, dehydration, or concomitant anticholinergics.

Dysphagia. Use CAPLYTA® with caution in patients at risk for aspiration.

DRUG INTERACTIONS. Avoid concomitant use with CYP3A4 inducers. Reduce dose for concomitant use with strong CYP3A4 inhibitors, 10.5 milligrams, or with moderate CYP3A4 inhibitors, 21 milligrams. Increased monitoring for serotonin reuptake inhibitor (SRI)-associated adverse reactions is recommended when used with SRIs, including in geriatric patients who may be at greater risk for clinically significant hyponatremia.

SPECIAL POPULATIONS. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Reduced dose for patients with moderate Child-Pugh Class B, or severe Child-Pugh Class C hepatic impairment, 21 milligrams.

ADVERSE REACTIONS. The most common adverse reactions in clinical trials (greater than or equal to 5% and greater than twice placebo with CAPLYTA® versus placebo) were:

Major depressive disorder (adjunctive therapy). Dizziness, 17% versus 5%, dry mouth, 13% versus 3%, somnolence/sedation, 12% versus 2%, nausea, 9% versus 4%, fatigue, 8% versus 2%, and diarrhea, 5% versus 1%.

Bipolar depression, monotherapy, adjunctive therapy. Somnolence/sedation, 13% versus 3%, 13% versus 3%. Dizziness, 8% versus 4%, 11% versus 2%. Nausea, 8% versus 3%, 9% versus 4%, and dry mouth, 5% versus 1%, 5% versus 1%.

Schizophrenia. Somnolence/sedation 24% versus 10% and dry mouth 6% versus 2%.

CAPLYTA® is available in 42 milligram, 21 milligram, and 10.5 milligram capsules.

Please see full Prescribing Information, including Boxed WARNINGS for CAPLYTA®, available at CAPLYTAhcp.com.

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