Cariprazine Hydrochloride

Atypical or second-generation antipsychotic agent.1 7 8 9 10

Administration

Oral Administration

Administer capsules orally once daily without regard to meals.1

Dosage

Available as cariprazine hydrochloride; dosage expressed in terms of cariprazine.1

Because of the long half-life of cariprazine and its active metabolites, dosage changes will not be fully reflected in plasma for several weeks.1 Monitor patients for adverse effects and treatment 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. (See Pharmacokinetics.)

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

If used with a potent CYP3A4 inhibitor, dosage adjustment is recommended; avoid concurrent use with CYP3A4 inducers.1 (See Interactions.)

Adults

Schizophrenia Oral

Initially, 1.5 mg once daily; may increase to 3 mg once daily on day 2.1 May make further dosage adjustments in 1.5- or 3-mg increments based on clinical response and tolerability.1 Recommended dosage range is 1.5–6 mg once daily.1

In patients with remitted first or multiple episodes, APA recommends either indefinite maintenance therapy or gradual discontinuance of the antipsychotic with close follow-up and a plan to reinstitute treatment upon symptom recurrence.28 Consider antipsychotic therapy discontinuance only after ≥1 year of symptom remission or optimal response while receiving the drug.28 Indefinite maintenance treatment recommended if patient has experienced multiple previous psychotic episodes or 2 episodes within 5 years.28

Bipolar Disorder Manic or Mixed Episodes Oral

Initially, 1.5 mg once daily; increase to 3 mg once daily on day 2.1 May make further dosage adjustments in 1.5- or 3-mg increments based on clinical response and tolerability.1 Recommended dosage range is 3–6 mg once daily.1

Prescribing Limits

Adults

Schizophrenia Oral

Maximum 6 mg daily.1 Increased efficacy of higher dosages not sufficient to outweigh risk of dose-related adverse effects.1

Bipolar Disorder Manic or Mixed Episodes Oral

Maximum 6 mg daily.1 Increased efficacy of higher dosages not sufficient to outweigh risk of dose-related adverse effects.1

Special Populations

Hepatic Impairment

Mild to moderate hepatic impairment (Child-Pugh score 5–9): Dosage adjustment not necessary.1

Severe hepatic impairment (Child-Pugh score 10–15): Not studied; use not recommended.1

Renal Impairment

Mild to moderate renal impairment (Clcr ≥30 mL/minute): Dosage adjustment not necessary.1

Severe renal impairment (Clcr <30 mL/minute): Not studied; use not recommended.1 (See Renal Impairment under Cautions.)

Geriatric Patients

Cautious dosage selection recommended, 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

Gender, Race, or Smoking Status

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

Contraindications

• Known hypersensitivity to cariprazine.1 Rash, pruritus, urticaria, and manifestations of possible angioedema (e.g., swollen tongue, lip swelling, facial edema and swelling, pharyngeal edema) reported.1

Warnings/Precautions

Warnings

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Increased risk of death with use of either conventional (first-generation) or atypical (second-generation) antipsychotics in geriatric patients with dementia-related psychosis.1 39 73

Antipsychotic agents, including cariprazine, are not approved for the treatment of dementia-related psychosis.1 39 73 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning; Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions; and also see Dysphagia under Cautions.)

Other Warnings and Precautions

Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis

Increased incidence of adverse cerebrovascular events (cerebrovascular accidents and TIAs), including fatalities, observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies.1 Cariprazine is not approved for the treatment of patients with dementia-related psychosis.1 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability, reported with antipsychotic agents.1

If NMS is suspected, immediately discontinue therapy and initiate intensive symptomatic treatment and monitoring.1

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary dyskinetic movements, reported with use of antipsychotic agents, including cariprazine.1

Reserve long-term antipsychotic treatment for patients with chronic illness 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 requiring chronic treatment, use smallest dosage and shortest duration of treatment producing a satisfactory clinical response; periodically reassess need for continued therapy.1

APA recommends assessing patients receiving atypical antipsychotic agents for abnormal involuntary movements every 12 months; for patients at increased risk for tardive dyskinesia, assess every 6 months.28 Consider discontinuance of cariprazine if signs and symptoms of tardive dyskinesia appear.1 However, some patients may require treatment despite presence of the syndrome.1

Late-occurring Adverse Effects

Adverse effects may first appear several weeks after initiation of cariprazine, probably because plasma concentrations of cariprazine and its principal metabolites accumulate over time (see Bioavailability under Pharmacokinetics).1 Therefore, incidence of adverse effects reported in short-term clinical trials may not reflect the incidence after longer-term exposure to the drug.1

Monitor for adverse effects, including adverse extrapyramidal effects and akathisia, for several weeks after initiation of therapy and after each dosage increase.1 (See Dosage under Dosage and Administration.)

Metabolic Changes

Atypical antipsychotic agents are associated with metabolic changes that may increase cardiovascular and cerebrovascular risk (e.g., hyperglycemia, dyslipidemia, weight gain).1 While all atypical antipsychotics 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, reported in patients receiving atypical antipsychotic agents.1 In short-term controlled trials, clinically important differences between cariprazine and placebo in shifts from normal or borderline to high fasting glucose concentrations not observed.1 In longer-term studies, 4% of cariprazine-treated patients experienced a shift from normal to elevated HbA1c concentrations.1

Monitor fasting glucose concentration before or soon after initiation of cariprazine and periodically during long-term therapy.1

Dyslipidemia

Undesirable changes in lipid parameters observed in patients treated with some atypical antipsychotics.1 However, clinically important effects of cariprazine on serum total cholesterol, LDL, HDL, and triglycerides not observed in short-term clinical studies.1

Manufacturer recommends baseline and periodic follow-up lipid evaluations in patients receiving cariprazine.1

Weight Gain

Weight gain observed with atypical antipsychotic therapy, including cariprazine.1

Manufacturer recommends baseline and frequent monitoring of weight during therapy.1

Leukopenia, Neutropenia, and Agranulocytosis

Leukopenia and neutropenia reported during treatment with antipsychotic agents, including cariprazine.1 78 Agranulocytosis (including fatal cases) also reported with other antipsychotic agents.1

Possible risk factors for leukopenia and neutropenia include preexisting low WBC count and a history of drug-induced leukopenia or neutropenia.1 78 Monitor CBC frequently during the first few months of therapy in patients with such risk factors.1 Discontinue cariprazine at the first sign of a decline in WBC count in the absence of other causative factors.1

Carefully monitor patients with neutropenia for signs and symptoms of infection (e.g., fever) and treat promptly if they occur.1 Discontinue cariprazine if severe neutropenia (ANC <1000/mm3) occurs; monitor WBC until recovery occurs.1

Orthostatic Hypotension and Syncope

Risk of orthostatic hypotension and syncope reported with atypical antipsychotics, particularly during initial dosage titration and when dosage is increased.1

In clinical trials, incidence of symptomatic orthostatic hypotension with cariprazine was infrequent and not higher than that reported with placebo; syncope not observed.1

Monitor orthostatic vital signs in patients who are susceptible to hypotension (e.g., geriatric patients, patients with dehydration or hypovolemia, patients concomitantly receiving antihypertensive therapy), patients with cardiovascular disease (e.g., history of MI, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease.1

Falls

May cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries.1

In patients with diseases, conditions, or other drugs that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic therapy and repeat such testing periodically during long-term antipsychotic therapy.1

Seizures

Cariprazine may cause seizures.1 Higher risk of seizures in patients with a history of seizures or with conditions that lower the seizure threshold; conditions that lower seizure threshold may be more prevalent in older patients.1

Cognitive and Motor Impairment

Judgment, thinking, or motor skills may be impaired.1 Somnolence (including hypersomnia and sedation) reported in 7 and 8% of cariprazine-treated patients in short-term schizophrenia and bipolar mania clinical trials, respectively.1 (See Advice to Patients.)

Body Temperature Dysregulation

Antipsychotic agents may disrupt ability to regulate core body temperature.1

Use appropriate caution 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

Dysphagia

Esophageal dysmotility and aspiration associated with the use of antipsychotic agents.1 Dysphagia reported with cariprazine.1 Use with caution in patients at risk for aspiration.1

Specific Populations

Pregnancy

No adequate and well-controlled studies to date in pregnant women.1 Fetal developmental toxicity (e.g., reduced body weight, skeletal and external malformations, lower pup survival, developmental delays) observed in animals.1

Risk for extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, feeding disorder) in neonates exposed to antipsychotic agents during the third trimester; monitor neonates exhibiting such symptoms.1 79 80 81 Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive support and prolonged hospitalization.1 79 80 81

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

Lactation

Cariprazine distributes into milk in rats; not known whether cariprazine distributes into human milk.1 Effects of the drug on nursing infants and on milk production not known.1

Weigh benefit of cariprazine therapy to the woman and benefits of breast-feeding against potential risk of infant exposure to the drug or from the underlying maternal condition.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1 Pediatric clinical studies with cariprazine have not been conducted to date.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1 (See Geriatric Patients under Dosage and Administration and also see Elimination: Special Populations, under Pharmacokinetics.)

Geriatric patients with dementia-related psychosis treated with either conventional or atypical antipsychotic agents are at an increased risk of death;1 39 73 increased incidence of cerebrovascular events also observed with certain atypical antipsychotic agents.1 Cariprazine is not approved for the treatment of patients with dementia-related psychosis.1 (See Boxed Warning and also see Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions.)

Hepatic Impairment

Dosage adjustment not necessary in patients with mild to moderate hepatic impairment (Child-Pugh score 5–9).1 (See Absorption: Special Populations, under Pharmacokinetics.)

Not studied in patients with severe hepatic impairment (Child-Pugh score 10–15); use not recommended.1

Renal Impairment

Renal impairment unlikely to substantially alter the pharmacokinetics of cariprazine; the drug and its active metabolites are minimally excreted in urine.1 (See Renal Impairment under Dosage and Administration and also see Elimination: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Schizophrenia: Extrapyramidal symptoms (e.g., parkinsonian symptoms, dystonia, dyskinesia, tardive dyskinesia),1 2 3 akathisia.1 2 3 11

Bipolar mania: 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 restlessness.1 4 5 6

• Exact mechanism of action in schizophrenia and bipolar mania unknown; efficacy may be mediated through a combination of partial agonist activity at central dopamine type 2 (D2) and serotonin type 1 (5-hydroxytryptamine [5-HT1A]) receptors and antagonist activity at serotonin type 2 (5-HT2A) receptors.1 7 8 9 10

• Demonstrates partial agonist activity at D2 and D3 receptors and 5-HT1A receptors and antagonist activity at 5-HT2A and 5-HT2B receptors.1 7 8 9 10

• Exhibits approximately 3- to 10-fold higher binding affinity at D3 compared with D2 receptors; clinical implications of D3 receptor selectivity not known.1 7 8 9 10

• Exhibits moderate to low binding affinity for histamine (H1) receptors, lower affinity for 5-HT2C and α1A-adrenergic receptors than aripiprazole, and no appreciable affinity for muscarinic receptors.1 8 9

• 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 39 73 Inform patients and caregivers that cariprazine is not approved for treating geriatric patients with dementia-related psychosis.1 73

• Importance of advising patients that 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 NMS, which can cause high fever, stiff muscles, sweating, fast or irregular heart beat, change in BP, confusion, and kidney damage.1 14 Importance of immediately contacting clinician if signs and symptoms of this syndrome develop.14

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

• 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 WBC count or history of drug-induced leukopenia/neutropenia that their CBC should be monitored during cariprazine therapy.1

• Risk of orthostatic hypotension and syncope, especially when initiating or reinitiating treatment or increasing the dosage.1

• Risk of somnolence and impairment of judgment, thinking, or motor skills.1 Importance of advising patients to exercise caution when performing activities requiring mental alertness (e.g., driving, operating hazardous machinery) until they gain experience with the drug’s effects.1

• Importance of avoiding overheating and dehydration.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (see 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.)