Schizophrenia 
Lumateperone is used for the treatment of schizophrenia in adults.1,2,3
Clinical Experience
Efficacy and safety of lumateperone for the treatment of schizophrenia have been established in 2 randomized, double-blind, placebo-controlled, multicenter studies of 4 weeks' duration (studies 1 and 2) in adults who met DSM-IV-TR or DSM-5 criteria for schizophrenia.1,2,3 In study 1 (NCT01499563), patients were randomized in a 1:1:1:1 ratio to receive lumateperone 42 mg once daily, lumateperone 84 mg once daily, risperidone 4 mg once daily, or placebo once daily.1,2 In study 2 (NCT02282761), patients were randomized in a 1:1:1 ratio to receive lumateperone 28 mg once daily, lumateperone 42 mg once daily, or placebo.1,3 The primary efficacy end point in both studies was the change from baseline to week 4 on the Positive and Negative Syndrome Scale (PANSS) total score.1,2,3 The PANSS is a 30-item scale used to measure symptoms of schizophrenia, with higher scores reflecting greater overall symptom severity.1 In both studies, patients receiving lumateperone 42 mg daily had statistically significant reductions in the PANSS total score compared with patients who received placebo.1,2,3 These differences were observed by week 1 and were maintained through week 4.1,2,3 Patients receiving the 28- and 84-mg daily dosages of lumateperone did not experience substantial reductions in the PANSS total score compared with those receiving placebo.1,2,3 An analysis of subgroups did not reveal any clear evidence of differential response to the drug based on sex or race; the studies did not include any patients ≥65 years of age.1
Clinical Perspective
Schizophrenia is a chronic major psychotic disorder that can affect various aspects of a patient's life and is associated with an increased risk of suicide and increased overall mortality.28,30,69 The principal manifestations of schizophrenia usually are described in terms of positive, negative, and cognitive symptoms.28,33,34 Positive (i.e., psychotic) symptoms include hallucinations and delusions, while negative symptoms include decreases in emotional expression, initiation of goal-directed behavior (avolition), speech productivity (alogia), ability to experience pleasure from external stimuli (anhedonia), and apparent interest in social interactions (asociality).28,30,34 Cognitive symptoms include impairments in attention, concentration, and memory.30,33,34
Antipsychotic therapy is integral to the management of schizophrenia,28,29,31 both for management of acute psychotic symptoms and for maintenance treatment to prevent symptom recurrence.28,29,30,31,32 The American Psychiatric Association (APA) and other experts consider antipsychotic agents (i.e., first- and second-generation antipsychotic agents) to be first-line drugs for the management of schizophrenia.28,29,31,32 The APA states that, with the possible exception of clozapine for the management of treatment-resistant symptoms, there currently is no definitive evidence that one antipsychotic agent will have superior efficacy compared with another agent, although meaningful differences in response may be observed in individual patients.28 Therefore, initial choice of an antipsychotic agent should be individualized, and generally made in the context of shared decision-making, taking into consideration multiple patient- and drug-related factors, including adverse effect profiles, concurrent medical conditions, potential drug interactions, pharmacogenomic considerations, patient's preferences, prior responses to treatment, available formulations, and cost.28,29,30,31,32 Patient response and tolerance to antipsychotic agents are variable, and patients who do not respond to or tolerate one drug may be successfully treated with another drug with different receptor binding or adverse effect profile.28,70,71,72
APA recommends that patients with schizophrenia whose symptoms have improved with an antipsychotic agent continue to receive such therapy.28 APA also suggests that patients whose symptoms have improved with an antipsychotic agent continue to be treated with the same antipsychotic agent; however, some circumstances (e.g., patient preferences, drug availability, adverse effects) may necessitate a change in antipsychotic agent.28 Drug therapy should be part of a comprehensive, patient-centered treatment plan that includes evidence-based nonpharmacologic and pharmacologic treatments for schizophrenia.28,30
Bipolar Disorder
Lumateperone is used for the treatment of depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults; the drug is indicated for use as monotherapy or as adjunctive therapy with lithium or valproate.1,8
Clinical Experience
Efficacy and safety of lumateperone for this indication have been established in two randomized, double-blind, placebo-controlled studies in adults who met DSM-5 criteria for depressive episodes associated with bipolar I or bipolar II disorder; study 3 (NCT03249376) evaluated the drug as monotherapy and study 4 (NCT02600507) evaluated the drug as adjunctive therapy with lithium or valproate.1,7 In both studies, the primary efficacy measure was the change from baseline in the Montgomery-Asberg Depression Rating scale (MADRS) total score at week 6.1,7 The MADRS total score ranges from 0-60 with higher scores reflecting greater symptoms.1 Lumateperone at a dosage of 42 mg daily improved depression symptoms at 6 weeks compared with placebo and was generally well tolerated.1,7 Patients receiving lumateperone demonstrated a statistically significant, but modest, improvement from baseline in the MADRS total score at 43 days compared with placebo (least squares mean difference of -4.6 in study 3 and -2.4 in study 4).1,7,8 In both studies, patients who received lumateperone also had significant improvements from baseline in a key secondary endpoint (clinical global impression of bipolar severity of illness).1 Subgroup analysis did not suggest any differences in response based on age, sex, and race.1
Clinical Perspective
Pharmacologic treatments for bipolar depression include mood stabilizers (e.g., lithium, valproate, lamotrigine) and/or antipsychotic agents.8,9,10,11,12,13 Choice of therapy should be individualized, taking into account current and prior drugs used and response, personal preference, safety and tolerability of each agent, and specific clinical features.12 Lumateperone may offer an additional treatment option for patients with major depressive episodes associated with bipolar I or bipolar II disorder; however, it is not known how the drug compares to other second-generation antipsychotics with longer established efficacy for this use.7,8
General
Pretreatment Screening
- Monitor fasting blood glucose concentrations before or soon after initiation of lumateperone therapy.1
- Obtain a fasting lipid profile at baseline (prior to or soon after initiation of lumateperone).1
- Complete a fall risk assessment when initiating antipsychotic therapy in patients with diseases/conditions or receiving other drugs that could exacerbate the risk of a fall and repeat such testing periodically during long-term therapy.1
- Obtain baseline body weight.1
Patient Monitoring
- Closely monitor all patients receiving antidepressants for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments. for worsening and emergence of suicidal thoughts and behaviors.1
- Assess patients for abnormal involuntary movements at baseline and at each follow-up visit using a structured instrument.28 APA recommends assessments at least every 6 months in patients at high risk for tardive dyskinesia and at least every 12 months in other patients and whenever new onset or exacerbation of preexisting movements is observed.28
- Monitor fasting blood glucose concentrations periodically during long-term therapy.1
- Monitor fasting lipid profile periodically during therapy.1
- Monitor patient's body weight frequently during therapy.1
- Monitor CBC frequently during the first few months of therapy in patients with risk factors for leukopenia and neutropenia.1
- Monitor orthostatic vital signs in patients susceptible to hypotension (e.g., geriatric patients, patients with dehydration or hypovolemia, patients receiving concomitant antihypertensive therapy), patients with known cardiovascular disease (e.g., history of MI, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease.1
Administration
Administer orally once daily with or without food.1
Dosage
Dosage of lumateperone tosylate is expressed in terms of lumateperone.1
Schizophrenia
For the management of schizophrenia in adults, the recommended dosage of lumateperone is 42 mg orally once daily.1 Dosage titration is not required.1
In patients with schizophrenia whose symptoms have improved with an antipsychotic agent, continued treatment (i.e., maintenance therapy) with an antipsychotic agent is recommended to reduce the risk of relapse.28,29,30,31 The APA suggests that such patients continue to be treated with the same antipsychotic agent that was effective during acute treatment.28 Some experts have recommended maintenance antipsychotic therapy for at least 1-2 years after the first psychotic episode29,30,31 and for 2-5 years or longer following recurrent episodes.30,31,32 Indefinite maintenance antipsychotic treatment may be necessary in many cases; however, the benefits and risks of continued antipsychotic therapy should be assessed periodically in the context of shared decision-making, taking into consideration each patient's risk of relapse, drug-associated adverse effects, course of disease, and the specific goals and needs of each patient.28,29,30,32
Dosage Adjustments for Concomitant Therapy
Concomitant administration with strong CYP3A4 inhibitors: In patients receiving a strong CYP3A4 inhibitor, the recommended dosage of lumateperone is 10.5 mg once daily.1
Concomitant administration with moderate CYP3A4 inhibitors: In patients receiving a moderate CYP3A4 inhibitor, the recommended dosage of lumateperone is 21 mg once daily.1
Bipolar Disorder
For the treatment of depressive episodes associated with bipolar I or II disorder in adults, the recommended dosage of lumateperone is 42 mg orally once daily, either as monotherapy or as adjunctive therapy with lithium or valproate.1 Dosage titration of lumateperone is not required.1
Dosage Adjustments for Concomitant Therapy
Concomitant administration with strong CYP3A4 inhibitors: In patients receiving a strong CYP3A4 inhibitor, the recommended dosage of lumateperone is 10.5 mg once daily.1
Concomitant administration with moderate CYP3A4 inhibitors: In patients receiving a moderate CYP3A4 inhibitor, the recommended dosage of lumateperone is 21 mg once daily.1
Special Populations
Hepatic Impairment
Dosage adjustment is not necessary in patients with mild hepatic impairment (Child-Pugh class A).1
In patients with moderate or severe hepatic impairment (Child-Pugh class B or C), the recommended dosage of lumateperone is 21 mg once daily.1
Renal Impairment
Dosage adjustment is not necessary in patients with renal impairment.6
Geriatric Patients
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Contraindications
- Known hypersensitivity to lumateperone or any components in the formulation.1 Hypersensitivity reactions, including pruritus, rash (e.g. allergic dermatitis, papular rash, generalized rash), and urticaria, reported.1
Warnings/Precautions
Warnings
Increased Mortality in Geriatric Patients with Dementia-related Psychosis
Geriatric patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.1 A boxed warning about this risk has been included in the prescribing information for lumateperone.1 Analyses of 17 placebo-controlled trials (modal duration of 10 weeks) revealed a 1.6- to 1.7-fold increase in mortality among geriatric patients who were mainly receiving atypical antipsychotic drugs (i.e., aripiprazole, olanzapine, quetiapine, risperidone) compared with that observed in patients receiving placebo.1 Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with a rate of about 2.6% in the placebo group.1 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.1 The manufacturer states that lumateperone is not approved for the treatment of patients with dementia-related psychosis.1
Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults
Antidepressants may increase the risk of suicidal thoughts and behaviors in children, adolescents, and young adults.1 A boxed warning about this risk has been included in the prescribing information for lumateperone.1 Pooled analyses of short-term, placebo-controlled studies of antidepressants (i.e., selective serotonin-reuptake inhibitors [SSRIs] and other antidepressants) have shown an increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults (24 years of age or younger) receiving antidepressants for major depressive disorder and other indications.1 Although the risk varied considerably between drugs, an increased risk was identified for most antidepressants studied.1 Differences in absolute risk of suicidal thoughts and behaviors were seen across the different indications, with the highest incidence in patients with major depressive disorder.1 An increased risk of suicidal thoughts and behaviors was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age, and a reduced risk was observed in adults 65 years of age or older.1 Because the studies analyzed were short-term, it is not known whether the increased risk of suicidal thoughts or behaviors in such patients continues with longer-term antidepressant treatment (i.e., beyond 4 months).1 However, substantial evidence from placebo-controlled maintenance studies in adults with major depressive disorder indicates that antidepressants delay the recurrence of depression.1 Lumateperone is not approved for use in pediatric patients.1
All patients being treated with antidepressants for any indication should be closely monitored for worsening of depression and emergence of suicidal thoughts and behaviors, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.1 Family members and caregivers of patients being treated with antidepressants also should be advised to monitor patients for changes in behavior and to alert a health-care provider if such changes occur.1 Consideration should be given to changing the therapeutic regimen or discontinuing therapy in patients whose depression is persistently worse or who are experiencing emergent suicidal thoughts or behaviors.1
Other Warnings and Precautions
Adverse Cerebrovascular Events, including Stroke, in Geriatric Patients with Dementia-related Psychosis
An increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies.1 The manufacturer states that lumateperone is not approved for the treatment of patients with dementia-related psychosis.1
Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome characterized by hyperpyrexia, muscle rigidity, delirium, and autonomic instability, has been reported with antipsychotic agents.1 If NMS is suspected, antipsychotic therapy should be immediately discontinued and intensive symptomatic treatment and monitoring should be provided.1
Tardive Dyskinesia
Because use of antipsychotic agents, including lumateperone, may be associated with tardive dyskinesia (a syndrome of potentially irreversible, involuntary, dyskinetic movements), lumateperone should be prescribed in a manner that is most likely to minimize the occurrence of this syndrome.1 Chronic antipsychotic treatment generally should be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic agents, and for whom alternative, effective, but potentially less harmful treatments are not available or appropriate.1 In patients who do require chronic treatment, the lowest dosage and the shortest duration of treatment producing a satisfactory clinical response should be sought, and the need for continued treatment should be reassessed periodically.1
The American Psychiatric Association (APA) currently recommends that patients with schizophrenia who are receiving antipsychotic agents be assessed clinically for abnormal involuntary movements at baseline and at each follow-up visit and that assessment with a structured instrument (e.g., the Abnormal Involuntary Movement Scale [AIMS], Dyskinesia Identification System: Condensed User Scale [DISCUS]) occur at least every 6 months in patients considered at high risk for tardive dyskinesia (including patients older than 55 years of a women; individuals with a mood disorder, substance use disorder, intellectual disability, or CNS injury; individuals with high cumulative exposure to antipsychotic medications, particularly high-potency dopamine D2 receptor antagonists; and patients who experience acute dystonic reactions, clinically significant parkinsonism, or akathisia) or at least every 12 months in other patients as well as if a new onset or exacerbation of preexisting movements is observed at any follow-up visit.28 In some jurisdictions, the frequency of monitoring for involuntary movements in individuals receiving antipsychotic agents may also be subject to local regulations.28
If signs and symptoms of tardive dyskinesia appear in a lumateperone-treated patient, lumateperone discontinuance should be considered; however, some patients may require continued treatment with the drug despite the presence of the syndrome.1
APA recommends that patients who have moderate to severe or disabling tardive dyskinesia associated with antipsychotic therapy be treated with a vesicular monoamine transporter 2 (VMAT2) inhibitor (e.g., deutetrabenazine, valbenazine, tetrabenazine); such treatment may also be considered for patients with mild tardive dyskinesia based on factors such as patient preference, associated impairment, and effect on psychosocial functioning.28
Metabolic Changes
Atypical antipsychotic agents have been associated with metabolic changes, including hyperglycemia and diabetes mellitus, dyslipidemia, and body weight gain.1 While all of these drugs produce some metabolic changes, each drug has its own specific risk profile.1
Hyperglycemia and Diabetes Mellitus
Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients receiving antipsychotic agents, including lumateperone.1
In short-term, controlled trials in patients with schizophrenia, changes from baseline in fasting glucose concentrations were similar between patients receiving lumateperone and placebo.1 In a longer-term, open-label trial of up to 1 year in duration, shifts from normal to high in fasting glucose and insulin concentrations occurred in 8 and 12%, respectively, of patients treated with lumateperone, and a shift from normal to elevated (i.e., 6.5% or higher) glycosylated hemoglobin (hemoglobin A1c; HbA1c) concentrations occurred in 4.7% of patients receiving the drug.1
In short-term controlled trials in patients with bipolar depression, mean changes from baseline and the proportion of patients with a shift from normal to elevated levels of fasting glucose and insulin in patients treated with lumateperone were similar to those in patients treated with placebo.1
Fasting blood glucose concentrations should be monitored before or soon after initiation of lumateperone and periodically during long-term therapy.1
Dyslipidemia
Antipsychotic agents have been associated with undesirable changes in lipid parameters.1
In short-term, controlled trials in patients with schizophrenia, changes from baseline in fasting total cholesterol and triglyceride concentrations and the proportion of patients with shifts to higher levels of these lipid parameters were similar between patients receiving lumateperone and placebo.1 In a longer-term, open-label trial of up to 1 year in duration, a shift from normal to high in total cholesterol, triglyceride, and LDL-cholesterol concentrations occurred in 8, 5, and 4%, respectively, of lumateperone-treated patients.1
In short-term, controlled trials in patients with bipolar depression, mean changes from baseline and the proportion of patients with a shift to higher levels of fasting total cholesterol and triglycerides were similar in patients treated with lumateperone and placebo.1 In an uncontrolled open-label trial of lumateperone for up to 6 months in patients with bipolar depression, the proportion of patients with a shift from normal to high total cholesterol, triglyceride, and LDL cholesterol concentrations were 10, 5, and 2%, respectively.1
The manufacturer recommends baseline (prior to or soon after initiation of lumateperone) and periodic follow-up fasting lipid evaluations in patients receiving lumateperone therapy.1
Weight Gain
Antipsychotic agents have been associated with weight gain.1
In short-term, controlled trials in patients with schizophrenia, changes from baseline body weight and the proportion of patients with an increase in weight of ≥7% were similar between patients receiving lumateperone and placebo.1 In a longer-term, open-label trial of up to 1 year in duration, patients with schizophrenia receiving lumateperone had a mean decrease in body weight of 2 and 3.2 kg at days 175 and 350, respectively.1
In short-term, controlled trials in patients with bipolar depression, mean changes from baseline and the proportion of patients with an increase in weight ≥7% from baseline were similar in patients treated with lumateperone and placebo.1 In an uncontrolled open-label trial of lumateperone for up to 6 months in patients with bipolar depression, the mean change in body weight was approximately -0.01 kg at day 175.1
The manufacturer recommends baseline and frequent monitoring of weight in patients receiving lumateperone.1
Leukopenia, Neutropenia, and Agranulocytosis
Leukopenia and neutropenia have been reported with antipsychotic agents, including lumateperone.1 Agranulocytosis (including fatal cases) also has been reported with other antipsychotic agents.1
Possible risk factors for leukopenia and neutropenia include preexisting low leukocyte or absolute neutrophil count (ANC) and a history of drug-induced leukopenia or neutropenia.1 Patients with these risk factors should have their complete blood count monitored frequently during the first few months of therapy; discontinuance of lumateperone should be considered at the first sign of a clinically important decline in leukocyte count in the absence of other causative factors.1
Patients with neutropenia should be carefully monitored for fever and other signs or symptoms of infection and promptly treated if such signs and symptoms occur.1 In patients with severe neutropenia (ANC less than 1000/mm3), lumateperone should be discontinued and the leukocyte count monitored until recovery occurs.1
Orthostatic Hypotension and Syncope
Atypical antipsychotic agents can cause orthostatic hypotension and syncope.1 The risk is usually the greatest during initiation of therapy.1
In short-term, controlled clinical trials in patients with schizophrenia, the incidence of orthostatic hypotension was 0.7% in patients receiving lumateperone compared with 0% in placebo recipients; the incidence of syncope was 0.2% in both groups of patients.1
In short-term, controlled clinical trials in patients with bipolar depression, orthostatic hypotension occurred in no patients treated with lumateperone or placebo.1 Syncope was reported in 0.3% or 0.5% of patients receiving the drug or placebo, respectively in the monotherapy trials, and there were no reports of syncope in either treatment group in the adjunctive therapy trial.1
Orthostatic vital signs should be monitored in patients receiving lumateperone who are susceptible to hypotension (e.g., geriatric patients, patients with dehydration or hypovolemia, patients concomitantly receiving antihypertensive therapy), patients with cardiovascular disease (e.g., history of MI, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease.1
Lumateperone has not been evaluated in patients with a recent history of MI or unstable cardiovascular disease; such patients were excluded from premarketing clinical trials.1
Falls
Antipsychotic agents, including lumateperone, may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls; as a consequence, fractures or other injuries may occur.1 For patients with diseases or conditions or receiving other drugs that could exacerbate these effects, fall risk assessments should be completed when initiating antipsychotic treatment and periodically during long-term therapy.1
Seizures
Antipsychotic agents, including lumateperone, may cause seizures.1 The risk of seizures is greatest in patients with a history of seizures or with conditions that lower the seizure threshold; such conditions may be more prevalent in older patients.1
Cognitive and Motor Impairment
Like other antipsychotic agents, lumateperone may cause somnolence and potentially may impair judgment, thinking, or motor skills.1
In short-term, controlled schizophrenia trials, somnolence and sedation were reported in 24% of patients receiving lumateperone compared with 10% of patients receiving placebo.1
In short-term, controlled bipolar depression trials, somnolence and sedation were reported in 13% of lumateperone-treated patients compared to 3% of placebo-treated patients.1
Body Temperature Dysregulation
Disruption of the body's ability to reduce core body temperature has been attributed to atypical antipsychotics.1 Lumateperone should be used with caution in patients who may experience conditions that can contribute to an elevation in core body temperature (e.g., strenuous exercise, extreme heat, dehydration, concomitant use of agents with anticholinergic activity).1
Dysphagia
Esophageal dysmotility and aspiration have been associated with the use of antipsychotic agents.1 Antipsychotic agents, including lumateperone, should be used with caution in patients at risk for aspiration.1
Specific Populations
Pregnancy
There are insufficient data on use of lumateperone in pregnant women to date.1 In animals, lumateperone was not teratogenic but increased perinatal death in pups at dosages 4.9 times higher than the maximum recommended human dosage.1
Risk for extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, feeding disorder) in neonates exposed to antipsychotic agents during the third trimester; monitor neonates exhibiting such symptoms.1 Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive support and prolonged hospitalization.1
Neonates exposed to antipsychotic agents during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.1 Symptoms reported to date have included agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder.1 The complications have varied in severity; some neonates recovered within hours to days without specific treatment while others have required prolonged hospitalization.1 Neonates should be monitored for extrapyramidal and/or withdrawal symptoms and neonates exhibiting such symptoms should be managed as appropriate.1
National Pregnancy Registry for Atypical Antipsychotics: 866-961-2388 and [Web].1
Lactation
It is not known whether lumateperone and its metabolites are distributed into milk in humans or animals; it is also not known if they have any effects on milk production or the nursing infant.1 In animals, formation of aniline metabolites of lumateperone has been associated with toxicity.1 Although aniline metabolites were not present in adult humans at quantifiable concentrations, it is not known whether infants exposed to lumateperone will exhibit comparable lumateperone metabolism and elimination pathways as adults.1 In addition, sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) have been reported in infants exposed to antipsychotics through breast milk.1
Based on findings of toxicity in animal studies and the potential for serious adverse reactions to lumateperone in nursing infants, breast-feeding is not recommended during treatment with lumateperone.1
Females and Males of Reproductive Potential
Based on findings from animal studies, lumateperone may impair male and female fertility.1 In female rats, estrus cycle irregularities were observed at lumateperone dosages equivalent to or higher than approximately twice the maximum recommended dosage in humans, and other irregularities (i.e., decreased number of corpora lutea and implantation sites and increased number of non-gravid uteruses) were observed at higher dosages.1 In male rats, decreased sperm motility, changes in sperm morphology, reduced epididymal counts, and adverse histopathologic changes in testes and epididymides were observed at dosages equivalent to approximately 5 or 10 times the maximum recommended dosage in humans.1
Pediatric Use
Safety and efficacy of lumateperone have not been established in pediatric patients.1
Geriatric Use
Clinical efficacy trials of lumateperone did not include any patients ≥65 years of age to determine whether they respond differently than younger adults.1
Age does not have a clinically important effect on the pharmacokinetics of lumateperone.1
Geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.1 In addition, an increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies.1 Lumateperone is not approved for the treatment of patients with dementia-related psychosis.1
Hepatic Impairment
Systemic exposure to lumateperone is increased in individuals with hepatic impairment (14, 137, or 80% higher in individuals with Child-Pugh class A, B, or C, respectively) compared with individuals with normal hepatic function.1,6
Dosage reduction of lumateperone is recommended in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).1 Dosage adjustment is not necessary in patients with mild hepatic impairment (Child-Pugh class A).1
Renal Impairment
Renal impairment does not have any clinically important effects on the pharmacokinetics of lumateperone.1,6 Dosage adjustment is not necessary in patients with renal impairment.6
Common Adverse Effects
Adverse effects occurring in ≥5% of patients receiving lumateperone for schizophrenia include somnolence/sedation and dry mouth.1
Adverse effects occurring in ≥5% of patients receiving lumateperone for bipolar disorder include somnolence/sedation, dizziness, nausea, and dry mouth.1
Lumateperone is extensively metabolized via multiple pathways, including cytochrome P450 (CYP) isoenzymes 3A4, 2C8, and 1A2; uridine 5'-diphospho-glucuronosyltransferase (UGT) isoenzymes 1A1, 1A4, and 2B15; and aldo-keto reductase isoenzymes 1C1, 1B10, and 1C4.1 (See Description.)
Lumateperone demonstrates little to no inhibition of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, or 3A4/5 and no induction of CYP isoenzymes 1A2, 2B6, or 3A4 in vitro.1 Lumateperone is not a substrate of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) and demonstrates little to no inhibition of organic cation transporter (OCT) 2, organic anion transporters (OAT) 1 or 3, or organic anion transport proteins (OATP) 1B1 or 1B3.1
Drugs Affecting Hepatic Microsomal Enzymes
CYP3A4 Inhibitors
Concomitant use of lumateperone and moderate or strong CYP3A4 inhibitors may result in increased systemic exposure to lumateperone and increased risk of lumateperone adverse effects.1 Dosage of lumateperone should be reduced when used concomitantly with a moderate or strong CYP3A4 inhibitor.1
Effects of a weak CYP3A inhibitor on the exposure of lumateperone are not expected to be clinically important;6 dosage adjustment of lumateperone is not necessary when used concomitantly with a weak CYP3A inhibitor.6
Diltiazem
Concomitant administration of lumateperone (single 14-mg dose) and the moderate CYP3A4 inhibitor diltiazem (250 mg daily) in patients with schizophrenia resulted in approximately twofold increased lumateperone exposure.1,6
Itraconazole
Concomitant administration of lumateperone (single 14-mg dose) and the strong CYP3A4 inhibitor itraconazole (200 mg daily) in patients with schizophrenia resulted in approximately fourfold increased lumateperone exposure.1,6
CYP3A4 Inducers
Concomitant use of lumateperone and CYP3A4 inducers may result in decreased systemic exposure to lumateperone.1 Concomitant use of lumateperone with CYP3A4 inducers should be avoided.1
Rifampin
Concomitant administration of lumateperone (single 28-mg dose) and the potent CYP3A4 inducer rifampin (600 mg daily) in healthy individuals decreased peak plasma concentration and AUC of lumateperone by 92.3 and 97.9%, respectively.6
Drugs Metabolized by Hepatic Microsomal Enzymes
CYP3A4 Substrates
Coadministration of lumateperone (single and multiple doses) and the CYP3A4 substrate midazolam did not result in clinically important effects on the pharmacokinetics of midazolam or its metabolite 1-hydroxymidazolam.1
Anticholinergic Agents
Lumateperone should be used with caution in patients concurrently receiving drugs with anticholinergic activity because of possible disruption of body temperature regulation.1
Hypotensive Agents
The manufacturer states that patients receiving lumateperone may be at increased risk of orthostatic hypotension and syncope.1 Therefore, monitoring of orthostatic vital signs is recommended in patients receiving lumateperone and antihypertensive agents concomitantly.1
1. Intra-Cellular Therapies, Inc. Caplyta® (lumateperone tosylate) capsules prescribing information. New York, NY; 2022 Apr.
2. Lieberman JA, Davis RE, Correll CU et al. ITI-007 for the Treatment of Schizophrenia: A 4-Week Randomized, Double-Blind, Controlled Trial. Biol Psychiatry . 2016; 79:952-61. [PubMed 26444072]
3. Correll CU, Davis RE, Weingart M et al. Efficacy and Safety of Lumateperone for Treatment of Schizophrenia: A Randomized Clinical Trial. JAMA Psychiatry . 2020; 77:349-358. [PubMedCentral][PubMed 31913424]
4. Davis RE, Correll CU. ITI-007 in the treatment of schizophrenia: from novel pharmacology to clinical outcomes. Expert Rev Neurother . 2016; 16:601-14. [PubMedCentral][PubMed 27042868]
5. Snyder GL, Vanover KE, Zhu H et al. Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission. Psychopharmacology (Berl) . 2015; 232:605-21. [PubMedCentral][PubMed 25120104]
6. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number 209500Orig1s000: Multi-discipline Review. From FDA website. [Web]
7. Calabrese JR, Durgam S, Satlin A, et al. Efficacy and Safety of Lumateperone for Major Depressive Episodes Associated With Bipolar I or Bipolar II Disorder: A Phase 3 Randomized Placebo-Controlled Trial. Am J Psychiatry. 2021 Dec;178(12):1098-1106. Epub 2021 Sep 23. [PubMed 34551584]
8. Lumateperone (Caplyta) for bipolar depression. Med Lett Drugs Ther. 2022 Aug 8;64(1656):126-128. [PubMed 35921078]
9. Geddes JR, Miklowitz DJ. Treatment of bipolar disorder. Lancet. 2013 May 11;381(9878):1672-82. [PubMedCentral][PubMed 23663953]
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