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Vraylar

Generic Name: Cariprazine
Class: Atypical Antipsychotics
Chemical Name: 3-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-1,1-dimethylurea
Molecular Formula: C21H32Cl2N4O
CAS Number: 839712-12-8

Warning(s)

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

See full prescribing information for complete boxed warning.

  • Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.1

  • Cariprazine is not approved for the treatment of patients with dementia-related psychosis.1

Introduction

Cariprazine is an atypical antipsychotic agent.

Uses for Vraylar

Cariprazine has the following uses:

Cariprazine is an atypical antipsychotic indicated for the treatment of schizophrenia.1

Cariprazine also is indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder.1

Vraylar Dosage and Administration

General

Cariprazine is available in the following dosage form(s) and strength(s):

Capsules: 1.5 mg, 3 mg, 4.5 mg, and 6 mg.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • Administer cariprazine once daily with or without food.1

Starting Dose

Recommended Dose

Schizophrenia

1.5 mg/day

1.5 mg to 6 mg/day

Bipolar Mania

1.5 mg/day

3 mg to 6 mg/day

  • Doses above 6 mg daily do not confer significant benefit but increased the risk of dose-related adverse reactions. 1

Cautions for Vraylar

Contraindications

Known hypersensitivity to cariprazine.1

Warnings/Precautions

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Antipsychotic drugs increase the all-cause risk of death in elderly patients with dementia-related psychosis. Analyses of 17 dementia-related psychosis placebo-controlled trials (modal duration of 10 weeks and largely in patients taking atypical antipsychotic drugs) revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in placebo-treated patients. 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. Cariprazine is not approved for the treatment of patients with dementia-related psychosis. 1

Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis

In placebo-controlled trials in elderly subjects with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. Cariprazine is not approved for the treatment of patients with dementia-related psychosis. 1

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal symptom complex, has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, delirium, and autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. 1

If NMS is suspected, immediately discontinue cariprazine and provide intensive symptomatic treatment and monitoring.1

Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs, including cariprazine. The risk appears to be highest among the elderly, especially elderly women, but it is not possible to predict which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.1

The risk of tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses. It may also occur after discontinuation of treatment. 1

There is no known treatment for tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of tardive dyskinesia is unknown. 1

Given these considerations, cariprazine should be prescribed in a manner most likely to reduce the risk of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: 1) who suffer from a chronic illness that is known to respond to antipsychotic drugs; and 2) for whom alternative, effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. Periodically reassess the need for continued treatment.1

If signs and symptoms of tardive dyskinesia appear in a patient on cariprazine, drug discontinuation should be considered. However, some patients may require treatment with cariprazine despite the presence of the syndrome.1

Late-Occurring Adverse Reactions

Adverse events may first appear several weeks after the initiation of cariprazine treatment, probably because plasma levels of cariprazine and its major metabolites accumulate over time. As a result, the incidence of adverse reactions in short-term trials may not reflect the rates after longer term exposures.1

Monitor for adverse reactions, including EPS or akathisia, and patient response for several weeks after a patient has begun cariprazine and after each dosage increase. Consider reducing the dose or discontinuing the drug.1

Metabolic Changes

Atypical antipsychotic drugs, including cariprazine, have caused metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. Although all of the drugs in the class to date have been shown to produce some metabolic changes, each drug has its own specific risk profile.1

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assess fasting plasma glucose before or soon after initiation of antipsychotic medication, and monitor periodically during long-term treatment. 1

In the 6-week, placebo-controlled trials of adult patients with schizophrenia, the proportion of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) and borderline (≥100 and <126 mg/dL) to high were similar in patients treated with cariprazine and placebo. In the long-term, open-label schizophrenia studies, 4% of patients with normal hemoglobin A1c baseline values developed elevated levels ( ≥6.5%).1

In the 3-week, placebo-controlled trials of adult patients with bipolar disorder, the proportion of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) and borderline (≥100 and <126 mg/dL) to high were similar in patients treated with cariprazine and placebo. In the long-term, open-label bipolar disorder studies, 4% of patients with normal hemoglobin A1c baseline values developed elevated levels (≥6.5%).1

Dyslipidemia

Atypical antipsychotics cause adverse alterations in lipids. Before or soon after initiation of antipsychotic medication, obtain a fasting lipid profile at baseline and monitor periodically during treatment. 1

In the 6-week, placebo-controlled trials of adult patients with schizophrenia, the proportions of patients with shifts in fasting total cholesterol, LDL, HDL and triglycerides were similar in patients treated with cariprazine and placebo.1

In the 3-week, placebo-controlled trials of adult patients with bipolar disorder, the proportions of patients with shifts in fasting total cholesterol, LDL, HDL and triglycerides were similar in patients treated with cariprazine and placebo.1

Weight Gain

Weight gain has been observed with use of atypical antipsychotics, including cariprazine. Monitor weight at baseline and frequently thereafter. Tables 1 and 2 show the change in body weight occurring from baseline to endpoint in 6-week schizophrenia and 3-week bipolar mania trials. 1

Data shown by modal daily dose, defined as most frequently administered dose per patient.

Table 1. Change in Body Weight (kg) in 6-Week Schizophrenia Trials

Cariprazine

Placebo (N=573)

1.5 - 3 mg/day (N=512)

4.5 - 6 mg/day (N=570)

9 - 12 mg/day (N=203)

Mean Change at Endpoint

+0.3

+0.8

+1

+1

Proportion of Patients with Weight Increase (≥ 7% )

5%

8%

8%

17%

Data shown by modal daily dose, defined as most frequently administered dose per patient.

Table 2. Change in Body Weight (kg) in 3-Week Bipolar Mania Trials

Cariprazine

Placebo (N=439)

3 - 6 mg/day (N=259)

9 - 12 mg/day (N=360)

Mean Change at Endpoint

+0.2

+0.5

+0.6

Proportion of Patients with Weight Increase (≥ 7% )

2%

1%

3%

In long-term, uncontrolled trials with cariprazine in schizophrenia, the mean changes from baseline in weight at 12, 24, and 48 weeks were 1.2 kg, 1.7 kg, and 2.5 kg, respectively.1

Leukopenia, Neutropenia, and Agranulocytosis

Leukopenia and neutropenia have been reported during treatment with antipsychotic agents, including cariprazine. Agranulocytosis (including fatal cases) has been reported with other agents in the class.1

Possible risk factors for leukopenia and neutropenia include pre-existing low white blood cell count (WBC) or absolute neutrophil count (ANC) and history of drug-induced leukopenia or neutropenia. In patients with a pre-existing low WBC or ANC or a history of drug-induced leukopenia or neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of cariprazine at the first sign of a clinically significant decline in WBC in the absence of other causative factors.1

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue cariprazine in patients with absolute neutrophil count < 1000/mm3 and follow their WBC until recovery. 1

Orthostatic Hypotension and Syncope

Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose titration and when increasing the dose. Symptomatic orthostatic hypotension was infrequent in trials of cariprazine and was not more frequent on cariprazine than placebo. Syncope was not observed.1

Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension (e.g., elderly patients, patients with dehydration, hypovolemia, and concomitant treatment with antihypertensive medications), patients with known cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. Cariprazine has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease. Such patients were excluded from pre-marketing clinical trials.1

Seizures

Like other antipsychotic drugs, cariprazine may cause seizures. This risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in older patients.1

Potential for Cognitive and Motor Impairment

Cariprazine, like other antipsychotics, has the potential to impair judgment, thinking, or motor skills.1

In 6-week schizophrenia trials, somnolence (hypersomnia, sedation, and somnolence) was reported in 7% of cariprazine-treated patients compared to 6% of placebo-treated patients. In 3-week bipolar mania trials, somnolence was reported in 8% of cariprazine-treated patients compared to 4% of placebo-treated patients.1

Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with cariprazine does not affect them adversely.1

Body Temperature Dysregulation

Atypical antipsychotics may disrupt the body's ability to reduce core body temperature. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use cariprazine with caution in patient who may experience these conditions.1

Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Dysphagia has been reported with cariprazine. Cariprazine and other antipsychotic drugs should be used cautiously in patients at risk for aspiration.1

Specific Populations

Pregnancy

Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to cariprazine during pregnancy. For more information, contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit . 1

Risk Summary: Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There are no available data on cariprazine use in pregnant women to inform any drug-associated risks for birth defects or miscarriage. Based on animal data, cariprazine may cause fetal harm. Administration of cariprazine to rats during the period of organogenesis caused malformations, lower pup survival, and developmental delays at drug exposures less than the human exposure at the maximum recommended human dose (MRHD) of 6 mg/day. However, cariprazine was not teratogenic in rabbits at doses up to 4.6 times the MRHD of 6 mg/day. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus. 1

Fetal/Neonatal Adverse Reactions: Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates whose mothers were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. 1

Animal Data

Administration of cariprazine to pregnant rats during the period of organogenesis at oral doses of 0.5, 2.5, and 7.5 mg/kg/day which are 0.2 to 3.5 times the maximum recommended human dose (MRHD) of 6 mg/day based on AUC of total cariprazine (i.e., sum of cariprazine, desmethyl cariprazine [DCAR], and didesmethyl cariprazine [DDCAR]) caused fetal developmental toxicity at all doses which included reduced body weight, decreased male anogenital distance and skeletal malformations of bent limb bones, scapula and humerus. These effects occurred in the absence or presence of maternal toxicity. Maternal toxicity, observed as a reduction in body weight and food consumption, occurred at doses 1.2 and 3.5 times the MRHD of 6 mg/kg/day based on AUC of total cariprazine. At these doses, cariprazine caused fetal external malformations (localized fetal thoracic edema), visceral variations (undeveloped/underdeveloped renal papillae and/or distended urethrae), and skeletal developmental variations (bent ribs, unossified sternebrae). Cariprazine had no effect on fetal survival. 1

Administration of cariprazine to pregnant rats during pregnancy and lactation at oral doses of 0.1, 0.3, and 1 mg/kg/day which are 0.03 to 0.4 times the MRHD of 6 mg/day based on AUC of total cariprazine caused a decrease in postnatal survival, birth weight, and post-weaning body weight of first generation pups at the dose that is 0.4 times the MRHD of 6 mg/day based on AUC of total cariprazine in absence of maternal toxicity. First generation pups also had pale, cold bodies and developmental delays (renal papillae not developed or underdeveloped and decreased auditory startle response in males). Reproductive performance of the first generation pups was unaffected; however, the second generation pups had clinical signs and lower body weight similar to these of the first generation pups. 1

Administration of cariprazine to pregnant rabbits during the period of organogenesis at oral doses of 0.1, 1, and 5 mg/kg/day, which are 0.02 to 4.6 times the MRHD of 6 mg/day based on AUC of total cariprazine was not teratogenic. Maternal body weight and food consumption were decreased at 4.6 times the MRHD of 6 mg/day based on AUC of total cariprazine; however, no adverse effects were observed on pregnancy parameters or reproductive organs. 1

Lactation

Lactation studies have not been conducted to assess the presence of cariprazine in human milk, the effects on the breastfed infant, or the effects on milk production. Cariprazine is present in rat milk. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for cariprazine and any potential adverse effects on the breastfed infant from cariprazine or from the underlying maternal condition.1

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Pediatric studies of cariprazine have not been conducted. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.1

Geriatric Use

Clinical trials of cariprazine in the treatment of schizophrenia and bipolar mania did not include sufficient numbers of patients aged 65 and older to determine whether or not they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 1

Elderly patients with dementia-related psychosis treated with cariprazine are at an increased risk of death compared to placebo. Cariprazine is not approved for the treatment of patients with dementia-related psychosis. 1

Hepatic Impairment

No dosage adjustment for cariprazine is required in patients with mild to moderate hepatic impairment (Child-Pugh score between 5 and 9). Usage of cariprazine is not recommended in patients with severe hepatic impairment (Child-Pugh score between 10 and 15). Cariprazine has not been evaluated in this patient population.1

Renal Impairment

No dosage adjustment for cariprazine is required in patients with mild to moderate (CrCL ≥ 30 mL/minute) renal impairment. 1

Usage of cariprazine is not recommended in patients with severe renal impairment (CrCL < 30 mL/minute). Cariprazine has not been evaluated in this patient population.1

Smoking

No dosage adjustment for cariprazine is needed for patients who smoke. Cariprazine is not a substrate for CYP1A2; smoking is not expected to have an effect on the pharmacokinetics of cariprazine.1

Other Specific Populations

No dosage adjustment is required based on patient's age, sex, or race. These factors do not affect the pharmacokinetics of cariprazine. 1

Common Adverse Effects

Most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) were:

  • Schizophrenia: extrapyramidal symptoms and akathisia.1

  • Bipolar mania: extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Strong CYP3A4 inhibitors: reduce cariprazine dosage by half.1

  • CYP3A4 inducers: do not recommend use with cariprazine.1

Actions

Mechanism of Action

The mechanism of action of cariprazine in schizophrenia and bipolar I disorder is unknown. However, the efficacy of cariprazine could be mediated through a combination of partial agonist activity at central dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors. Cariprazine forms two major metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), that have in vitro receptor binding profiles similar to the parent drug. 1

Advice to Patients

Physicians are advised to discuss with patients for whom they prescribe cariprazine all relevant safety information including, but not limited to, the following:

Dosage and Administration

Advise patients that cariprazine can be taken with or without food. Counsel them on the importance of following dosage escalation instructions.1

Neuroleptic Malignant Syndrome

Counsel patients about a potentially fatal adverse reaction, neuroleptic malignant syndrome (NMS), that has been reported in association with administration of antipsychotic drugs. 1

Tardive Dyskinesia

Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur.1

Metabolic Changes

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight. 1

Leukopenia/Neutropenia

Advise patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia that they should have their CBC monitored while taking cariprazine. 1

Orthostatic Hypotension

Counsel patients on the risk of orthostatic hypotension and syncope, especially early in treatment, and also at times of re-initiating treatment or increases in dose. 1

Interference with Cognitive and Motor Performance

Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that cariprazine therapy does not affect them adversely. 1

Heat Exposure and Dehydration

Educate patients regarding appropriate care in avoiding overheating and dehydration. 1

Concomitant Medications

Advise patients to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs since there is a potential for interactions.1

Pregnancy

Advise patients that third trimester use of cariprazine may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients to notify their healthcare provider with a known or suspected pregnancy.1

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to cariprazine during pregnancy. 1

Additional Information

AHFS First Release. For additional information 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 uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Cariprazine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsule, Gelatin Coated

1.5 mg

Vraylar

Actavis Pharma Inc.

3 mg

Vraylar

Actavis Pharma Inc.

4.5 mg

Vraylar

Actavis Pharma Inc.

6 mg

Vraylar

Actavis Pharma Inc.

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Date published: September 08, 2016
Last reviewed: September 08, 2016
Date modified: October 12, 2016

References

1. Actavis Pharma, Inc. . Vraylar (cariprazine) ORAL prescribing information. 2015 Sep.

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