ATC Class:N05AX15

VA Class:CN709

AHFS Class:

• Atypical Antipsychotics 28:16.08.04

Generic Name(s):

• Cariprazine Hydrochloride

• Cariprazine Hydrochloride

Chemical Name:

• N '-[ trans -4-[2-[4-(2,3-Dichlorophenyl)-1-piperazinyl]ethyl]cyclohexyl]- N , N -dimethyl-urea

• N '-[ trans -4-[2-[4-(2,3-Dichlorophenyl)-1-piperazinyl]ethyl]cyclohexyl]- N , N -dimethyl-urea hydrochloride (1:1)

Molecular Formula:

• C₂₁H₃₂Cl₂N₄O

• C₂₁H₃₂Cl₂N₄O•HCl

Cariprazine hydrochloride is considered an atypical or second-generation antipsychotic agent.1,7,8,9,10

Schizophrenia

Cariprazine hydrochloride is used for the treatment of schizophrenia.1,2,3,11 Schizophrenia is a chronic major psychotic disorder that frequently has devastating effects on various aspects of the 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 Diagnostic criteria for schizophrenia also may include disorganized speech (e.g., frequent derailment or incoherence) or grossly disorganized or catatonic behavior.69

Short-term efficacy of cariprazine monotherapy in the treatment of schizophrenia has been established in 3 randomized, multicenter, double-blind, placebo-controlled studies of 6 weeks' duration (studies 1, 2, and 3) in adults who met DSM-IV-TR criteria for schizophrenia and were experiencing an acute exacerbation of psychotic symptoms.1,2,3,11 The primary and secondary efficacy end points in these studies were the change from baseline to week 6 on the Positive and Negative Syndrome Scale (PANSS) total score and the Clinical Global Impressions-Severity (CGI-S) score, respectively.1,2,3,11 Studies 1 and 2 included an active control arm (risperidone and aripiprazole, respectively) to assess assay sensitivity.1,2,11 Study 1 evaluated 3 fixed dosages of cariprazine (1.5, 3, or 4.5 mg daily), study 2 evaluated 2 fixed dosages of cariprazine (3 or 6 mg daily), and study 3 evaluated flexible dosages of cariprazine in the range of 3-6 or 6-9 mg daily.1,2,3,11 In all 3 studies, cariprazine was found to be more effective than placebo in improving the PANSS total score and CGI-S score at week 6.1,2,3,11 Antipsychotic efficacy was demonstrated at cariprazine dosages ranging from 1.5-9 mg daily, and a modest dose-response relationship for efficacy was observed.1,2,3,7,11 However, there was a dose-related increase in certain adverse effects, particularly at dosages above 6 mg daily; therefore, the manufacturer states that the maximum recommended dosage of cariprazine for the treatment of schizophrenia is 6 mg daily.1 An examination of population subgroups did not reveal any clear evidence of differential responsiveness to the drug based on age (there were few patients over 55 years of age), gender, or race.1

Efficacy and safety of cariprazine in the maintenance treatment of schizophrenia have been established in a randomized withdrawal study in adults with schizophrenia whose disease was clinically stable following 20 weeks of open-label cariprazine therapy at dosages of 3-9 mg daily.1 Patients were randomized to either continue cariprazine at their achieved stable dosage or to receive placebo for up to 72 weeks.1 The primary endpoint was time to relapse during the double-blind treatment phase.1 Patients continuing cariprazine therapy had a substantially longer time to relapse compared with those who were switched to placebo.1 Although efficacy of cariprazine was demonstrated at dosages ranging from 3 to 9 mg daily, dose-related increases in certain adverse effects were observed, particularly at dosages above 6 mg daily.1 Therefore, the maximum recommended dosage of cariprazine for the treatment of schizophrenia is 6 mg daily.1 (See Dosage under Dosage and Administration.)

Antipsychotic therapy is integral to the management of patients with 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 (including first psychotic episodes).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 be made in the context of shared decision-making, taking into consideration multiple patient- and drug-related factors, including adverse effect profiles, concurrent medical conditions or risk factors, potential for drug interactions, and potential pharmacogenomic considerations, as well as the 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

The APA recommends that patients with schizophrenia whose symptoms have improved with an antipsychotic agent continue to receive such therapy.28 The 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 used as part of a comprehensive, patient-centered treatment plan that includes evidence-based nonpharmacologic and pharmacologic treatments for schizophrenia.28,30 Clinicians may consult APA's Practice Guideline for the Treatment of Patients with Schizophrenia (available at [Web]) for additional information on the treatment of schizophrenia.28

For additional information on the symptomatic management of schizophrenia, including treatment recommendations, see Schizophrenia and Other Psychotic Disorders under Uses: Psychotic Disorders, in the Phenothiazines General Statement 28:16.08.24.

Bipolar Disorder

Manic or Mixed Episodes associated with Bipolar Disorder

Cariprazine hydrochloride is used for the acute treatment of manic or mixed episodes associated with bipolar I disorder.1,4,5,6

Efficacy of cariprazine in the acute treatment of bipolar mania was established in 3 double-blind, placebo-controlled studies of 3 weeks' duration (studies 1, 2, and 3) in adults who met DSM-IV-TR criteria for bipolar I disorder with manic or mixed episodes with or without psychotic features.1,4,5,6 The principal rating instrument used for assessing psychiatric signs and symptoms in these studies was the Young Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology in a range from 0 (no manic features) to 60 (maximum score).1,4,5,6 The main secondary rating instrument used in these trials was the CGI-S scale.1,4,5,6 The primary and secondary end points in these studies was the change from baseline to the end of week 3 on the YMRS and the CGI-S scores, respectively.1,4,5,6

Study 1 evaluated flexible dosages of cariprazine in the ranges of 3-6 and 6-12 mg daily; studies 2 and 3 evaluated flexible dosages of cariprazine in the range of 3-12 mg daily.1,4,5,6 In all 3 studies, cariprazine was found to be more effective than placebo on the primary and secondary end points.1,4,5,6 Efficacy was demonstrated at daily cariprazine dosages ranging from 3-12 mg; however, no additional benefit was demonstrated at dosages above 6 mg daily and there was a dose-related increase in certain adverse effects.1,4,5,6 Therefore, the maximum recommended dosage of cariprazine in the acute treatment of manic or mixed episodes associated with bipolar I disorder is 6 mg daily.1 An examination of population subgroups did not reveal any clear evidence of differential responsiveness to the drug based on age (there were few patients over 55 years of age), gender, or race.1

Depressive Episodes associated with Bipolar Disorder

Cariprazine hydrochloride is used for the treatment of depressive episodes associated with bipolar I disorder (bipolar depression).1

Efficacy of cariprazine in the treatment of bipolar depression was established in 3 placebo-controlled studies of at least 6 weeks' duration (studies 7, 8, and 9) in adults with depressive episodes associated with bipolar I disorder according to DSM-IV-TR or DSM-5 criteria.1 The primary endpoint in each study was change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score at the end of week 6.1 The secondary endpoint was change from baseline to week 6 in CGI-S.1 In all 3 studies, cariprazine 1.5 mg daily was found to be superior to placebo in reduction of MADRS total scores at the end of week 6.1 In one of the studies, cariprazine 3 mg daily also was superior to placebo in reduction of MADRS total score at the end of week 6.1 In addition, cariprazine 1.5 mg daily substantially improved CGI-S at the end of week 6 compared with placebo in 2 of the studies.1 An examination of population subgroups did not reveal any clear evidence of differential responsiveness to the drug based on age (there were few patients over 55 years of age), gender, or race.1

Administration

Cariprazine hydrochloride is commercially available as capsules, which are administered orally once daily without regard to meals.1 (See Description.)

Patients receiving cariprazine should be monitored for possible worsening of depression and emergence of suicidal thoughts or behaviors, especially at the beginning of therapy or during periods of dosage adjustments.1 (See Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults under Cautions.)

Dosage

Dosage of cariprazine hydrochloride is expressed in terms of cariprazine.1

Because of the long half-life of cariprazine and its active metabolites, changes in dosage will not be fully reflected in plasma concentrations for several weeks (see Description).1 Therefore, patients receiving the drug should be monitored for adverse effects and clinical response for several weeks after initiation of therapy and after each dosage change.1 In addition, plasma concentrations of cariprazine and its active metabolites may not be immediately reflected in patients' clinical symptoms following discontinuance of the drug.1 Plasma concentrations of cariprazine and its active metabolites will decrease by 50% in approximately 1 week.1

There are no systematically collected data to specifically address switching patients from cariprazine to other antipsychotic agents or concerning concomitant administration of cariprazine with other antipsychotic agents.1

Schizophrenia

For the management of schizophrenia in adults, the recommended dosage range of cariprazine is 1.5-6 mg orally once daily.1 Therapy should be initiated at 1.5 mg once daily and may be increased to 3 mg once daily on day 2.1 Based on clinical response and tolerability, further dosage adjustments can be made in increments of 1.5 or 3 mg once daily.1 The maximum recommended dosage of cariprazine is 6 mg daily.1 In short-term controlled studies, cariprazine dosages exceeding 6 mg daily did not provide increased efficacy sufficient to outweigh the risk of dose-related adverse effects.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 specific goals and needs.28,29,30,32

Bipolar Disorder

Manic or Mixed Episodes associated with Bipolar Disorder

For the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults, the recommended dosage range of cariprazine is 3-6 mg orally once daily.1 Therapy should be initiated at 1.5 mg once daily and increased to 3 mg once daily on day 2.1 Based on clinical response and tolerability, further dosage adjustments can be made in increments of 1.5 or 3 mg once daily.1 The maximum recommended dosage of cariprazine for the treatment of manic or mixed episodes associated with bipolar disorder is 6 mg daily.1 In short-term controlled studies, cariprazine dosages exceeding 6 mg daily did not provide increased efficacy sufficient to outweigh the risk of dose-related adverse effects.1

Depressive Episodes associated with Bipolar Disorder

For the treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults, the recommended dosage of cariprazine is 1.5 or 3 mg orally once daily.1 Therapy should be initiated at 1.5 mg once daily and, depending on clinical response and tolerability, dosage may be increased to 3 mg once daily on day 15.1 The maximum recommended dosage of cariprazine for the treatment of bipolar depression is 3 mg daily.1

Special Populations

Dosage adjustment is not necessary in patients with mild to moderate renal impairment (creatinine clearance of 30 mL/minute or more).1 Cariprazine has not been studied in patients with severe renal impairment (creatinine clearance less than 30 mL/minute); use of the drug is not recommended in this patient population.1 (See Renal Impairment under Cautions.)

Dosage adjustment is not necessary in patients with mild to moderate hepatic impairment (Child-Pugh score 5-9).1 Cariprazine is not recommended in patients with severe hepatic impairment (Child-Pugh score 10-15); the drug has not been studied in this patient population.1 (See Hepatic Impairment under Cautions.)

In geriatric patients, the manufacturer states that dosage selection of cariprazine should be cautious, usually starting at the lower end of the recommended dosage range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function; concomitant illnesses; and other drug therapy in this population.1 (See Geriatric Use under Cautions.)

Dosage adjustment is not required based on gender, race, or smoking status.1

Drugs Affecting Hepatic Microsomal Enzymes

In patients receiving a stable dosage of cariprazine and in whom a potent inhibitor of cytochrome P-450 (CYP) isoenzyme 3A4 (e.g., itraconazole, ketoconazole) will be added to therapy, cariprazine dosage should be reduced to 50% of the current dosage.1 For patients taking 4.5 mg of cariprazine daily, the dosage should be reduced to 1.5 or 3 mg daily; for patients taking 1.5 mg daily, the dosing frequency should be reduced to every other day.1 Similarly, if cariprazine is initiated in patients already receiving a potent CYP3A4 inhibitor, the recommended initial dosage of cariprazine is 1.5 mg daily on days 1 and 3 (skipping day 2).1 From day 4 onward, the cariprazine dosage should be 1.5 mg daily; then, the dosage should be subsequently increased up to a maximum dosage of 3 mg daily.1 When the potent CYP3A4 inhibitor is withdrawn from combined therapy, the cariprazine dosage may need to be increased.1 (See Drugs Affecting Hepatic Microsomal Enzymes under Drug Interactions.)

Concomitant use of cariprazine and CYP3A4 inducers has not been evaluated and is not recommended.1 (See Drugs Affecting Hepatic Microsomal Enzymes under Drug Interactions.)

Pharmacogenomics and CYP2D6 Poor Metabolizer Phenotype

CYP2D6 poor metabolizer phenotype does not have a clinically important effect on the pharmacokinetics of cariprazine and its metabolites; therefore, dosage adjustment is unlikely to be necessary in patients who are CYP2D6 poor metabolizers.1

Contraindications

Known hypersensitivity to cariprazine.1 Hypersensitivity reactions, including rash, pruritus, urticaria, and manifestations of possible angioedema (e.g., swollen tongue, lip swelling, facial edema and swelling, pharyngeal edema), have been reported in patients receiving cariprazine.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 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 cariprazine is not approved for the treatment of patients with dementia-related psychosis.1 (See Adverse Cerebrovascular Events, including Stroke, in Geriatric Patients with Dementia-related Psychosis and also see Geriatric Use under Cautions.)

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 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 Safety and efficacy of cariprazine have not been established 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 cariprazine is not approved for the treatment of patients with dementia-related psychosis.1 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis and also see Geriatric Use under Cautions.)

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 (See Advice to Patients.) For additional information on NMS, see Neuroleptic Malignant Syndrome under Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.

Tardive Dyskinesia

Because use of antipsychotic agents, including cariprazine, may be associated with tardive dyskinesia (a syndrome of potentially irreversible, involuntary, dyskinetic movements), cariprazine 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, equally 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 type 2 [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 cariprazine-treated patient, cariprazine 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 (See Deutetrabenazine 28:56, Tetrabenazine 28:56, and Valbenazine 28:56.)

For additional information on tardive dyskinesia, see Tardive Dyskinesia under Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.

Late-occurring Adverse Effects

Adverse effects may first appear several weeks after initiation of cariprazine therapy, probably because plasma concentrations of cariprazine and its principal metabolites accumulate over time (see Description).1 Therefore, the incidence of adverse effects reported with cariprazine in short-term clinical trials may not reflect the incidence after longer-term exposure to the drug.1 Patients should therefore be monitored for adverse effects, including adverse extrapyramidal effects and akathisia, for several weeks after initiation of cariprazine therapy and after each dosage increase.1 (See Dosage under Dosage and Administration.)

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 (See Hyperglycemia and Diabetes Mellitus, see Dyslipidemia, and also see Weight Gain under Cautions.)

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients receiving atypical antipsychotic agents.1 In short-term controlled trials in patients with schizophrenia or bipolar disorder, clinically important differences between cariprazine and placebo in the proportion of patients with shifts from normal or borderline to high fasting glucose concentrations were not observed.1 In longer-term, open-label studies, 4% of cariprazine-treated patients experienced a shift from normal to elevated (6.5% or higher) glycosylated hemoglobin (hemoglobin A_1c; HbA_1c) concentrations.1

The manufacturer states that patients should undergo fasting blood glucose testing before or soon after initiation of cariprazine and periodically during long-term therapy.1

Dyslipidemia

Undesirable changes in lipid parameters have been observed in patients treated with some atypical antipsychotic agents; however, cariprazine generally does not appear to adversely affect the lipid profile in patients receiving short-term therapy with the drug.1 In short-term, placebo-controlled studies in patients with schizophrenia or bipolar disorder, clinically important differences between cariprazine and placebo in the proportion of patients with shifts in fasting total cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, and triglyceride concentrations were not observed.1

The manufacturer recommends baseline and periodic follow-up lipid evaluations in patients receiving cariprazine therapy.1

Weight Gain

Weight gain has been observed with atypical antipsychotic therapy, including cariprazine.1 Mean weight gain during short-term studies in patients receiving cariprazine for schizophrenia or bipolar mania was 0.5-1 kg compared with 0.2-0.3 kg in those receiving placebo.1 In the 6-week schizophrenia studies, 8 and 17% of patients receiving cariprazine daily dosages of 1.5-6 mg and 9-12 mg, respectively, gained 7% or more of their baseline body weight compared with 5% of placebo recipients.1 In longer-term, uncontrolled trials with cariprazine in schizophrenia, mean weight gain from baseline at 12, 24, and 48 weeks was 1.2, 1.7, and 2.5 kg, respectively.1

The manufacturer recommends baseline and frequent monitoring of weight in patients receiving cariprazine.1

Leukopenia, Neutropenia, and Agranulocytosis

Leukopenia and neutropenia have been reported with antipsychotic agents, including cariprazine.1,78 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.1,78 Patients with a preexisting low leukocyte count or a history of drug-induced leukopenia or neutropenia should have their complete blood count monitored frequently during the first few months of therapy.1 Cariprazine should be discontinued 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 or 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), cariprazine should be discontinued and the leukocyte count monitored until recovery occurs.1 Lithium reportedly has been used successfully in the treatment of several cases of leukopenia associated with aripiprazole, clozapine, and some other drugs; however, further clinical experience is needed to confirm these anecdotal findings.78

Orthostatic Hypotension and Syncope

Atypical antipsychotic agents can cause orthostatic hypotension and syncope.1 The risk is usually the greatest during initial dosage titration and when dosage is increased.1 In clinical trials with cariprazine, the incidence of symptomatic orthostatic hypotension was infrequent and was not higher in cariprazine-treated patients compared with those receiving placebo; syncope was not observed in patients receiving the drug.1

Orthostatic vital signs should be monitored in patients receiving cariprazine 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 myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease.1

Falls

Cariprazine therapy 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, conditions, or other drugs that could exacerbate these effects, fall risk assessments should be completed when initiating antipsychotic treatment and periodically during long-term antipsychotic therapy.1

Seizures

As with other antipsychotic agents, cariprazine 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, cariprazine potentially may impair judgment, thinking, or motor skills.1 In short-term schizophrenia trials, somnolence (including hypersomnia and sedation) was reported in 7% of patients receiving cariprazine compared with 6% of patients receiving placebo.1 In short-term bipolar mania clinical trials, somnolence was reported in 8% of patients receiving cariprazine compared with 4% of placebo recipients.1 (See Advice to Patients.)

Body Temperature Dysregulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents.1 The manufacturer recommends appropriate caution when cariprazine is used in patients who will be experiencing conditions that may contribute to an elevation in core body temperature (e.g., strenuous exercise, extreme heat, dehydration, concomitant use of agents with anticholinergic activity).1 (See Advice to Patients.)

Dysphagia

Esophageal dysmotility and aspiration have been associated with the use of antipsychotic agents.1 Dysphagia has been reported in patients receiving cariprazine.1 Cariprazine and other antipsychotic agents should be used with caution in patients at risk for aspiration.1

Specific Populations

Pregnancy

There are no adequate and well-controlled studies to date of cariprazine use in pregnant women.1 The principal active metabolite of cariprazine, didesmethyl cariprazine (DDCAR), has been detected in adult patients up to 12 weeks following discontinuance of cariprazine.1 Based on animal findings, cariprazine may cause fetal harm.1 Fetal developmental toxicity (including reduced body weight, skeletal and external malformations, lower pup survival, and developmental delays) was observed when cariprazine was administered to pregnant rats at dosages 0.2-3.5 times the maximum recommended human dosage.1

Neonates exposed to antipsychotic agents during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.1,79,80,81 Symptoms reported to date have included agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder.1,79,80,81 Neonates exhibiting such symptoms should be monitored.81 The complications have varied in severity; some neonates recovered within hours to days without specific treatment while others have required intensive care unit support and prolonged hospitalization.1,79,80,81

National Pregnancy Registry for Atypical Antipsychotics: 866-961-2388 and [Web].1

Lactation

It is not known whether cariprazine is distributed into milk in humans.1 The drug is distributed into milk in rats.1 The effects of the drug on breastfed infants or on milk production are not known.1 The benefits of cariprazine therapy to the woman as well as the benefits of breast-feeding to the infant should be weighed against the potential risk of infant exposure to the drug or from the underlying maternal condition.1

Pediatric Use

Safety and effectiveness of cariprazine in pediatric patients have not been established.1 The manufacturer states that pediatric clinical studies with cariprazine have not been conducted to date.1

Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients.1 (See Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults under Cautions.)

Geriatric Use

Clinical trial experience with cariprazine in the treatment of schizophrenia and bipolar mania did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults.1

Age did not have a clinically important effect on the pharmacokinetics of cariprazine and its principal metabolites (desmethyl cariprazine [DCAR] and didesmethyl cariprazine [DDCAR]).1 The manufacturer states that dosage selection in geriatric patients should be cautious, usually starting at the lower end of the dosage range, reflecting the greater incidence of decreased hepatic, renal, and cardiac function; concomitant illnesses; and other drug therapy in this population.1

Geriatric patients with dementia-related psychosis treated with cariprazine are at an increased risk of death compared with those treated with placebo.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 The manufacturer of cariprazine states that the drug is not approved for the treatment of patients with dementia-related psychosis (see Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Cautions).1 For additional information on the use of antipsychotic agents in the management of dementia-related psychosis, see Geriatric Considerations under Uses: Psychotic Disorders, in the Phenothiazines General Statement 28:16.08.24.

Hepatic Impairment

Following multiple doses of cariprazine in individuals with mild or moderate hepatic impairment (Child-Pugh score 5-9), cariprazine exposure was approximately 25% higher and exposure to the drug's principal active metabolites, DCAR and DDCAR, was approximately 20-30% lower than in individuals with normal hepatic function.1 Dosage adjustment of cariprazine is not necessary in patients with mild to moderate hepatic impairment.1

Cariprazine has not been studied in patients with severe hepatic impairment (Child-Pugh score 10-15), and use of the drug is not recommended in such patients.1

Renal Impairment

Cariprazine and its principal active metabolites are minimally excreted in urine.1 Pharmacokinetic analyses indicate no substantial relationship between clearance of the drug and its metabolites and creatinine clearance.1 Dosage adjustment is not necessary for patients with mild to moderate renal impairment (creatinine clearance of 30 mL/minute or more).1 Cariprazine has not been studied in patients with severe renal impairment (creatinine clearance less than 30 mL/minute), and use of the drug is not recommended in such patients.1

Common Adverse Effects

Adverse effects occurring in 5% or more of patients receiving cariprazine for schizophrenia and at a frequency at least twice that reported with placebo in short-term clinical studies include extrapyramidal symptoms (e.g., parkinsonism, dystonia, dyskinesia, tardive dyskinesia)1,2,3 and akathisia.1,2,3,11

Adverse effects occurring in 5% or more of patients receiving cariprazine for bipolar mania and at a frequency at least twice that reported with placebo in short-term clinical studies include extrapyramidal symptoms (e.g., parkinsonism, dystonia, dyskinesia, tardive dyskinesia),1,4,5,6 akathisia,1,4,5,6 dyspepsia,1,5,6 vomiting,1,4,6 somnolence,1,6 and restlessness.1,4,5,6

Adverse effects occurring in 5% or more of patients receiving cariprazine for bipolar depression and at a frequency at least twice that reported with placebo in short-term clinical studies include nausea, akathisia, restlessness, and extrapyramidal symptoms.1

Cariprazine is metabolized primarily by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, CYP2D6 to its major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR).1 (See Description.)

In vitro studies indicate that cariprazine and its major active metabolites are not substrates of P-glycoprotein (P-gp), organic anion transport proteins (OATP) 1B1 and 1B3, or breast cancer resistance protein (BCRP).1

Based on in vitro studies, cariprazine is not expected to cause clinically important pharmacokinetic drug interactions with substrates of CYP isoenzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E, or 3A4; OATP1B1 and OATP1B3; BCRP; organic cation transporter (OCT) 2; or organic anion transporters (OAT) 1 and 3.1

Cariprazine's major active metabolites possess little or no inhibitory effects on P-gp; however, cariprazine probably inhibits P-gp.1

Drugs Affecting Hepatic Microsomal Enzymes

Clinically important pharmacokinetic interactions with cariprazine and its active metabolites DCAR and DDCAR are possible with drugs that inhibit or induce CYP3A4.1 CYP2D6 inhibitors are not expected to substantially affect the pharmacokinetics of cariprazine or its active metabolites.1

CYP3A4 Inhibitors

Concomitant use of cariprazine with a potent CYP3A4 inhibitor (e.g., itraconazole, ketoconazole) may result in increased systemic exposure to cariprazine and its major active metabolite, DDCAR.1 Cariprazine dosage should therefore be reduced when used concurrently with a potent CYP3A4 inhibitor.1 (See Special Populations under Dosage and Administration.)

The effect of moderate CYP3A4 inhibitors on the pharmacokinetics of cariprazine and its metabolites has not been studied to date.1

Ketoconazole

Concomitant administration of ketoconazole (400 mg daily; a potent CYP3A4 inhibitor) and cariprazine (0.5 mg daily) increased peak plasma concentrations and AUC of cariprazine by approximately 3.5-fold and fourfold, respectively; increased peak concentrations and AUC of DDCAR by about 1.5-fold; and decreased peak concentrations and AUC of DCAR by about one-third.1

CYP3A4 Inducers

CYP3A4 is responsible for the formation and elimination of the active metabolites of cariprazine (see Description).1 The effect of CYP3A4 inducers on the pharmacokinetics of cariprazine and its active metabolites has not been studied to date, and the net effect is not known.1 Therefore, concomitant use of cariprazine with a CYP3A4 inducer (e.g., carbamazepine, rifampin) is not recommended.1

CYP2D6 Inhibitors

Based on observations in CYP2D6 poor metabolizers, CYP2D6 inhibitors are not likely to substantially affect the pharmacokinetics of cariprazine, DCAR, or DDCAR.1

Anticholinergic Agents

Potential pharmacologic interaction (possible disruption of body temperature regulation); use cariprazine with caution in patients concurrently receiving drugs with anticholinergic activity.1 (See Body Temperature Dysregulation under Cautions.)

Hypotensive Agents

The manufacturer states that patients receiving cariprazine may be at increased risk of orthostatic hypotension and syncope.1 Therefore, monitoring of orthostatic vital signs is recommended in patients receiving cariprazine and antihypertensive agents concomitantly.1 (See Orthostatic Hypotension and Syncope under Cautions and see also Advice to Patients.)

Pantoprazole

Concomitant administration of pantoprazole (40 mg daily) and cariprazine (6 mg daily) for 15 days in patients with schizophrenia did not substantially affect the exposure to cariprazine, DCAR, or DDCAR at steady state.1

Smoking

Cariprazine is not a substrate for CYP1A2; therefore, smoking should not alter the pharmacokinetics of the drug.1 Dosage adjustment of cariprazine in patients who smoke is not necessary.1

Description

Cariprazine hydrochloride is considered an atypical or second-generation antipsychotic agent.1,7,8,9,10 The exact mechanism of action of cariprazine in schizophrenia and bipolar disorder has not been fully elucidated but may be mediated through a combination of partial agonist activity at central dopamine type 2 (D₂) and serotonin type 1 (5-hydroxytryptamine [5-HT_1A]) receptors and antagonist activity at serotonin type 2 (5-HT_2A) receptors.1,7,8,9,10

Cariprazine acts as a partial agonist at D₂ and D₃ receptors with high binding affinity and at 5-HT_1A receptors in vitro.1,7,8,9,10 Cariprazine's partial agonist activity at D₂ receptors is similar to that of aripiprazole (another atypical antipsychotic agent with D₂ partial agonist activity)9 but cariprazine has shown approximately threefold to tenfold higher binding affinity at D₃ receptors compared with D₂ receptors; the clinical implications of the D₃-receptor selectivity are not known.1,7,8,9,10 In addition, cariprazine is a partial agonist at 5-HT_1A receptors; an antagonist at 5-HT_2A and 5-HT_2B receptors; and exhibits moderate to low binding affinity for histamine (H₁) receptors, lower binding affinity for 5-HT_2C and α_1A-adrenergic receptors than aripiprazole, and no appreciable affinity for muscarinic receptors.1,8,9

The pharmacologic activity of cariprazine is thought to be mediated by cariprazine and its 2 principal active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR).1 DCAR and DDCAR, which pharmacologically are as potent as cariprazine, are present in mean plasma concentrations that are approximately 30 and 400% of cariprazine plasma concentrations at the end of 12 weeks, respectively.1 Therefore, at steady state, DDCAR is the major active moiety circulating in plasma; in a pharmacokinetic study, DDCAR accounted for about 70% of the total activity after 27 days of dosing.1,7

Following oral administration of cariprazine capsules, peak plasma concentrations of cariprazine occur in approximately 3-6 hours.1 Administration of a single dose of cariprazine with a high-fat meal does not substantially affect peak plasma concentration or systemic exposure of cariprazine or DCAR.1 Steady-state mean plasma concentrations of cariprazine and DCAR are achieved within 1-2 weeks.1 Steady-state plasma concentrations of DDCAR appear to approach steady state within about 4-8 weeks; however, the time varies and some patients did not reach steady-state DDCAR concentrations after 12 weeks of treatment.1 Cariprazine and its main metabolites are highly bound (91-97%) to plasma proteins.1 Cariprazine is extensively metabolized by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by CYP2D6 to DCAR and DDCAR.1 DCAR is further metabolized to DDCAR by CYP3A4 and CYP2D6; DDCAR is then metabolized by CYP3A4 to a hydroxylated metabolite.1 Following administration of cariprazine 12.5 mg daily for 27 days, approximately 21% of the daily dose is recovered in urine, with approximately 1.2% of the dose excreted in urine as unchanged cariprazine.1 The elimination half-lives of cariprazine and DDCAR are estimated to be 2-4 days and approximately 1-3 weeks, respectively.1 Following discontinuance of cariprazine, mean plasma concentrations of cariprazine and DCAR decrease by 50% in about 1 day and mean plasma concentrations of DDCAR decrease by about 50% in 1 week.1 CYP2D6 poor metabolizer status does not appear to affect the pharmacokinetics of cariprazine and its metabolites.1

Advice to Patients

Importance of advising patients and/or caregivers to read the patient information (medication guide).1

Importance of advising patients and caregivers that geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.1 Patients and caregivers also should be informed that cariprazine is not approved for treating geriatric patients with dementia-related psychosis.1

Risk of suicidal thoughts and behaviors; importance of patients, family, and caregivers being alert to and reporting emergence of suicidality, especially during the first few months of therapy or during periods of dosage adjustment.1 (See Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults under Cautions.)

Importance of advising patients that cariprazine hydrochloride capsules can be taken with or without food.1 Importance of advising patients to follow the dosage titration instructions for the drug.1

Importance of informing patients and caregivers about the risk of neuroleptic malignant syndrome (NMS), a rare but potentially life-threatening syndrome that can cause high fever, stiff muscles, confusion, sweating, or changes in respiration, heart rate, or blood pressure.1,14 Importance of immediately contacting clinician or seeking emergency medical attention if signs and symptoms of this syndrome develop.1,14

Importance of informing patients of the signs and symptoms of tardive dyskinesia.1,14 Importance of advising patients to report any abnormal movements to a healthcare professional.1,14

Importance of informing patients that, because plasma concentrations of cariprazine and its metabolites accumulate over time, adverse effects may not appear until several weeks after the initiation of therapy.1

Importance of informing patients and caregivers about the risk of metabolic changes (e.g., hyperglycemia and diabetes mellitus, dyslipidemia, weight gain) with cariprazine and the need for specific monitoring, including blood glucose, lipids, and weight, for such changes during therapy.1,14 Importance of patients and caregivers being aware of the symptoms of hyperglycemia and diabetes mellitus (e.g., increased thirst, increased urination, increased appetite, weakness).1,14

Risk of leukopenia/neutropenia.1 Importance of advising patients with a preexisting low leukocyte count or a history of drug-induced leukopenia/neutropenia that they should have their complete blood count (CBC) monitored during cariprazine therapy.1

Importance of informing patients about the risk of orthostatic hypotension and syncope, especially when initiating or reinitiating treatment or increasing the dosage.1

Because somnolence and impairment of judgment, thinking, or motor skills may be associated with cariprazine, patients should be cautioned about performing activities requiring mental alertness, such as driving or operating hazardous machinery, while taking the drug until they gain experience with the drug's effects.1

Importance of avoiding overheating or dehydration.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (see Drug Interactions) and OTC drugs or herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular disease, diabetes mellitus, seizures).1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1,14,81 Importance of clinicians informing patients about the benefits and risks of taking antipsychotics during pregnancy (see Pregnancy under Cautions).1,14,81 Importance of advising patients not to stop taking cariprazine if they become pregnant without consulting their clinician; abruptly stopping antipsychotic agents may cause complications.81

Importance of informing patients of other important precautionary information.1,14 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Allergan USA, Inc. Vraylar^® (cariprazine hydrochloride) capsules prescribing information. Madison, NJ; 2019 May.

2. Durgam S, Starace A, Li D et al. An evaluation of the safety and efficacy of cariprazine in patients with acute exacerbation of schizophrenia: a phase II, randomized clinical trial. Schizophr Res . 2014; 152:450-7. [PubMed 24412468]

3. Kane JM, Zukin S, Wang Y et al. Efficacy and safety of cariprazine in acute exacerbation of schizophrenia: results from an international, phase III clinical trial. J Clin Psychopharmacol . 2015; 35:367-73. [PubMed 26075487]

4. Calabrese JR, Keck PE, Starace A et al. Efficacy and safety of low- and high-dose cariprazine in acute and mixed mania associated with bipolar I disorder: a double-blind, placebo-controlled study. J Clin Psychiatry . 2015; 76:284-92. [PubMed 25562205]

5. Durgam S, Starace A, Li D et al. The efficacy and tolerability of cariprazine in acute mania associated with bipolar I disorder: a phase II trial. Bipolar Disord . 2015; 17:63-75. [PubMed 25056368]

6. Sachs GS, Greenberg WM, Starace A et al. Cariprazine in the treatment of acute mania in bipolar I disorder: a double-blind, placebo-controlled, phase III trial. J Affect Disord . 2015; 174:296-302. [PubMed 25532076]

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9. Citrome L. Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability. Expert Opin Drug Metab Toxicol . 2013; 9:193-206. [PubMed 23320989]

10. Citrome L. Cariprazine in schizophrenia: clinical efficacy, tolerability, and place in therapy. Adv Ther . 2013; 30:114-26. [PubMed 23361833]

11. Durgam S, Cutler AJ, Lu K et al. Cariprazine in acute exacerbation of schizophrenia: a fixed-dose, phase 3, randomized, double-blind, placebo- and active-controlled trial. J Clin Psychiatry . 2015; 76:1574-82.

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28. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia. 3rd ed. American Psychiatric Association Publishing. Washington, DC; 2021.

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