brand vraylar 1.5 mg capsule

Uses

Psychotic Disorders

Drug therapy is integral to the management of acute psychotic episodes in patients with schizophrenia and generally is required for long-term stabilization to sustain symptom remission or control and to minimize the risk of relapse. Antipsychotic agents are the principal class of drugs used for the management of all phases of schizophrenia. 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 an agent from a different class or with a different adverse effect profile.

Schizophrenia

Cariprazine hydrochloride is an atypical antipsychotic that is administered orally in the treatment of schizophrenia. Schizophrenia is a major psychotic disorder that frequently has devastating effects on various aspects of the patient's life and carries a high risk of suicide and other life-threatening behaviors. Manifestations of schizophrenia involve multiple psychologic processes, including perception (e.g., hallucinations), ideation, reality testing (e.g., delusions), emotion (e.g., flatness, inappropriate affect), thought processes (e.g., loose associations), behavior (e.g., catatonia, disorganization), attention, concentration, motivation (e.g., avolition, impaired intention and planning), and judgment. The principal manifestations of this disorder usually are described in terms of positive and negative (deficit) symptoms and, more recently, disorganized symptoms. Positive symptoms include hallucinations, delusions, bizarre behavior, hostility, uncooperativeness, and paranoid ideation, while negative symptoms include restricted range and intensity of emotional expression (affective flattening), reduced thought and speech productivity (alogia), anhedonia, apathy, and decreased initiation of goal-directed behavior (avolition). Disorganized symptoms include disorganized speech (thought disorder) and behavior and poor attention.

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. 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. Studies 1 and 2 included an active control arm (risperidone and aripiprazole, respectively) to assess assay sensitivity. 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. 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. Antipsychotic efficacy was demonstrated at cariprazine dosages ranging from 1.5-9 mg daily, and a modest dose-response relationship for efficacy was observed. 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. 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.

The American Psychiatric Association (APA) considers most atypical antipsychotic agents first-line drugs for the management of the acute phase of schizophrenia (including first psychotic episodes), principally because of the decreased risk of adverse extrapyramidal effects and tardive dyskinesia, with the understanding that the relative advantages, disadvantages, and cost-effectiveness of conventional and atypical antipsychotic agents remain controversial. 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 atypical antipsychotic agent will have superior efficacy compared with another agent in the class, although meaningful differences in response may be observed in individual patients. Conventional antipsychotic agents also may be an appropriate first-line option for some patients, including those who have been treated successfully in the past with or who prefer conventional agents. The choice of an antipsychotic agent should be individualized, considering past response to therapy, current symptomatology, concurrent medical conditions, other medications and treatments, adverse effect profile, and the patient's preference for a specific drug, including route of administration.

For additional information on the symptomatic management of schizophrenia, including treatment recommendations, .

Bipolar Disorder

Cariprazine hydrochloride is used orally for the acute treatment of manic or mixed episodes associated with bipolar I disorder.

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. 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). The main secondary rating instrument used in these trials was the CGI-S scale. 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.

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. In all 3 studies, cariprazine was found to be more effective than placebo on the primary and secondary end points. 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. 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. 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.

Dosage and Administration

Administration

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

Dosage

Dosage of cariprazine hydrochloride is expressed in terms of cariprazine.

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). 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. In addition, plasma concentrations of cariprazine and its active metabolites may not be immediately reflected in patients' clinical symptoms following discontinuance of the drug. Plasma concentrations of cariprazine and its active metabolites will decrease by 50% in approximately 1 week.

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.

Schizophrenia

For the management of schizophrenia in adults, the recommended dosage range of cariprazine is 1.5-6 mg orally once daily. Therapy should be initiated at 1.5 mg once daily and may be increased to 3 mg once daily on day 2. Based on clinical response and tolerability, further dosage adjustments can be made in increments of 1.5 or 3 mg once daily. The maximum recommended dosage of cariprazine is 6 mg daily. 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.

The American Psychiatric Association (APA) states that prudent long-term treatment options in patients with schizophrenia with remitted first or multiple episodes include either indefinite maintenance therapy or gradual discontinuance of the antipsychotic agent with close follow-up and a plan to reinstitute treatment upon symptom recurrence. Discontinuance of antipsychotic therapy should be considered only after a period of at least 1 year of symptom remission or optimal response while receiving the antipsychotic agent. In patients who have had multiple previous psychotic episodes or 2 psychotic episodes within 5 years, indefinite maintenance antipsychotic treatment is recommended.

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. Therapy should be initiated at 1.5 mg once daily and increased to 3 mg once daily on day 2. Based on clinical response and tolerability, further dosage adjustments can be made in increments of 1.5 or 3 mg once daily. The maximum recommended dosage of cariprazine is 6 mg daily. 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.

Special Populations

Dosage adjustment is not necessary in patients with mild to moderate renal impairment (creatinine clearance of 30 mL/minute or more). 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.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Dosage adjustment is not necessary in patients with mild to moderate hepatic impairment (Child-Pugh score 5-9). 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.(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in 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.(See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

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

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. 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. 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). 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. When the potent CYP3A4 inhibitor is withdrawn from combined therapy, the cariprazine dosage may need to be increased.(See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

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

CYP2D6 poor metabolizer status 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 poor metabolizers of CYP2D6 substrates.

Cautions

Contraindications

Known hypersensitivity to cariprazine. 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.

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. 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. 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. 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. Observational studies suggest that, similar to atypical antipsychotics, treatment with conventional (first-generation) antipsychotics may increase mortality; the extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients remains unclear. The manufacturer states that cariprazine is not approved for the treatment of patients with dementia-related psychosis. (See Adverse Cerebrovascular Events, including Stroke, in Geriatric Patients with Dementia-related Psychosis and see Dysphagia under Warnings/Precautions: Other Warnings and Precautions, in Cautions, and also see Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

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. The manufacturer states that cariprazine is not approved for the treatment of patients with dementia-related psychosis. (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Warnings/Precautions: Warnings, and also see Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported in patients receiving antipsychotic agents.(See Advice to Patients.) For additional information on NMS,

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. 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. 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.

The American Psychiatric Association (APA) recommends that patients receiving atypical antipsychotic agents be assessed clinically for abnormal involuntary movements every 12 months and that patients considered to be at increased risk for tardive dyskinesia be assessed every 6 months. 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. For additional information on tardive dyskinesia,

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). 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. 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.(See Dosage and Administration: Dosage.)

Metabolic Changes

Atypical antipsychotic agents have been associated with metabolic changes, including hyperglycemia and diabetes mellitus, dyslipidemia, and body weight gain. While all of these drugs produce some metabolic changes, each drug has its own specific risk profile. (See Hyperglycemia and Diabetes Mellitus, see Dyslipidemia, and also see Weight Gain under Warnings/Precautions: Other Warnings and Precautions, in 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. In short-term controlled trials in patients with schizophrenia or bipolar mania, 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. 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.

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

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. In short-term, placebo-controlled studies in patients with schizophrenia or bipolar mania, 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.

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

Weight Gain

Weight gain has been observed with atypical antipsychotic therapy, including cariprazine. 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. 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. 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.

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

Leukopenia, Neutropenia, and Agranulocytosis

Leukopenia and neutropenia have been reported with antipsychotic agents, including cariprazine. Agranulocytosis (including fatal cases) also has been reported with other antipsychotic agents.

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. 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. Cariprazine should be discontinued at the first sign of a clinically important decline in leukocyte count in the absence of other causative factors.

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. In patients with severe neutropenia (ANC less than 1000/mm), cariprazine should be discontinued and the leukocyte count monitored until recovery occurs. 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.

Orthostatic Hypotension and Syncope

Atypical antipsychotic agents can cause orthostatic hypotension and syncope. The risk is usually the greatest during initial dosage titration and when dosage is increased. 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.

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.

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. 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.

Seizures

As with other antipsychotic agents, cariprazine may cause seizures. 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.

Cognitive and Motor Impairment

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

Body Temperature Dysregulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. 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).(See Advice to Patients.)

Dysphagia

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

Specific Populations

Pregnancy

There are no adequate and well-controlled studies to date of cariprazine use in pregnant women. 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.

Neonates exposed to antipsychotic agents during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Symptoms reported to date have included agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder. Neonates exhibiting such symptoms should be monitored. 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.

National Pregnancy Registry for Atypical Antipsychotics: 866-961-2388 and http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/atypicalantipsychotic/.

Lactation

It is not known whether cariprazine is distributed into milk in humans. The drug is distributed into milk in rats. The effects of the drug on breastfed infants or on milk production are not known. 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.

Pediatric Use

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

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.

Age did not have a clinically important effect on the pharmacokinetics of cariprazine and its principal metabolites (desmethyl cariprazine [DCAR] and didesmethyl cariprazine [DDCAR]). 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.

Geriatric patients with dementia-related psychosis treated with cariprazine are at an increased risk of death compared with those treated with placebo. 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. 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 Warnings/Precautions: Warnings, in Cautions and see Dysphagia under Warnings/Precautions: Other Warnings and Precautions, in Cautions). For additional information on the use of antipsychotic agents in the management of dementia-related psychosis, .

Hepatic Impairment

Following single or 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 45% lower than in individuals with normal hepatic function. Dosage adjustment of cariprazine is not necessary in patients with mild to moderate hepatic impairment.

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.

Renal Impairment

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

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) and akathisia.

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), akathisia, dyspepsia, vomiting, somnolence, and restlessness.

Drug Interactions

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).(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).

In vitro studies indicate that cariprazine and its major active metabolites are weak inhibitors of CYP isoenzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 and do not induce CYP1A2 and CYP3A4. Cariprazine and its major active metabolites possess little or no inhibitory effects on OATP1B1, OATP1B3, BCRP, organic cation transporter (OCT) 2, and organic anion transporters (OAT) 1 and 3 in vitro. Clinically important interactions between cariprazine and substrates of these enzymes or transporters are unlikely.

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

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. CYP2D6 inhibitors are not expected to substantially affect the pharmacokinetics of cariprazine or its active metabolites.

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. Cariprazine dosage should therefore be reduced when used concurrently with a potent CYP3A4 inhibitor.(See Dosage and Administration: Special Populations.)

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

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.

CYP3A4 Inducers

CYP3A4 is responsible for the formation and elimination of the active metabolites of cariprazine (see Description). 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. Therefore, concomitant use of cariprazine with a CYP3A4 inducer (e.g., carbamazepine, rifampin) is not recommended.

CYP2D6 Inhibitors

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

Anticholinergic Agents

Potential pharmacologic interaction (possible disruption of body temperature regulation); use cariprazine with caution in patients concurrently receiving drugs with anticholinergic activity.(See Body Temperature Dysregulation under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Hypotensive Agents

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

Smoking

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