cariprazine (Rx)

>10%

Schizophrenia

• Extrapyramidal symptoms, all (24-33%)
• Extrapyramidal symptoms, excluding akathisia/restlessness (15-20%)
• Parkinsonism (13-18%)
• Headache (9-18%)
• Akathisia (9-14%)
• Insomnia (11-13%)

Bipolar mania

• Extrapyramidal symptoms, all (41-45%)
• Extrapyramidal symptoms, excluding akathisia/restlessness (26-29%)
• Parkinsonism (21-26%)
• Akathisia (20-21%)
• Headache (13-14%)
• Nausea (11-13%)
• Constipation (6-11%)

Bipolar depression

• Extrapyramidal symptoms, all (10-19%)

1-10%

Decreased appetite (>1%)

Schizophrenia

• Constipation (6-10%)
• Somnolence (5-10%)
• Nausea (5-8%)
• Abdominal pain (3-7%)
• Restlessness (4-6%)
• Anxiety (3-6%)
• Toothache (3-6%)
• Hypertension (2-7%)
• Dyspepsia (4-5%)
• Vomiting (4-5%)
• Dizziness (3-5%)
• Agitation (3-5%)
• Diarrhea (1-5%)
• Pain in extremity (2-4%)
• Cough (1-4%)
• Tachycardia (2-3%)
• Increased weight (2-3%)
• Decreased appetite (1-3%)
• Dry mouth (1-3%)
• Fatigue (1-3%)
• Increased CPK (1-3%)
• Musculoskeletal stiffness (<3%)
• Back pain (1-3%)
• Dystonia (2%)
• Tachycardia (1-2%)
• Arthralgia (1-2%)
• Hepatic enzyme increased (1-2%)
• Nasopharyngitis (1-2%)
• Urinary tract infections (1-2%)
• Rash (1-2%)

Bipolar mania

• Vomiting (8-10%)
• Insomnia (8-9%)
• Dyspepsia (7-9%)
• Somnolence (7-8%)
• Abdominal pain (6-8%)
• Restlessness (7%)
• Dizziness (6-7%)
• Diarrhea (5-6%)
• Hypertension (4-5%)
• Fatigue (4-5%)
• Dystonia (3-5%)
• Blurred vision (4%)
• Decreased appetite (3-4%)
• Toothache (3-4%)
• Pain in extremity (2-4%)
• Pyrexia (1-4%)
• Weight increased (2-3%)
• Increased CPK (2-3%)
• Dry mouth (2-3%)
• Oropharyngeal pain (1-3%)
• Back pain (1-3%)
• Hepatic enzymes increased (1-3%)
• Musculoskeletal stiffness (2%)
• Tachycardia (1-2%)

Bipolar depression

• Insomnia (7-10%)
• Akathisia (6-10%)
• Nausea (7%)
• Somnolence (6-7%)
• Restlessness (2-7%)
• Extrapyramidal symptoms, excluding akathisia/restlessness (4-6%)
• Dizziness (3-4%)
• Fatigue (3-4%)
• Parkinsonism (3-4%)
• Increased appetite (3%)
• Increased weight (2%)
• Musculoskeletal stiffness (≤1%)

<1%

Gastroesophageal reflux disease (0.1-1%)

Gastritis (0.1-1%)

Suicide attempts (0.1-1%)

Suicide ideation (0.1-1%)

Hyponatremia (0.1-1%)

Pollakiuria (0.1-1%)

Hyperhidrosis (0.1-1%)

Rhabdomyolysis (0.1%)

Ischemic stroke (0.1%)

Completed suicide (0.1%)

Hepatitis (0.1%)

Bipolar disorder

• Tardive dyskinesia (<1%)
• Dystonia (<1%)

Postmarketing Reports

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome

Contraindications

Hypersensitivity to cariprazine

Cautions

Antipsychotic drugs increase the all-cause risk of death in elderly patients with dementia-related psychosis; a higher incidence of stroke and TIA, including fatal stroke, was also observed (see Black Box Warnings)

Hypersensitivity reactions reported ranging fom rash, pruritus, urticaria, and events suggestive of angioedema (eg, swollen, tongue, lip swelling, face edema, pharyngeal edema, facial swelling)

Neuroleptic malignant syndrome reported; monitor for hyperpyrexia, muscle rigidity, delirium, and autonomic instability; other signs include increased CPK, myoglobinuria (rhabdomyolysis), and acute renal failure; if NMS is suspected, immediately discontinue treatment

Tardive dyskinesia, a potentially irreversible, involuntary, dyskinetic movement syndrome, may develop in patients treated with antipsychotics

Adverse effects may first appear several weeks after initiating treatment, as drug and metabolite levels accumulate; monitor for extrapyramidal symptoms or akathisia

Leukopenia and neutropenia reported; agranulocytosis (including fatal cases) reported with other atypical antipsychotics; discontinue cariprazine in patients with absolute neutrophil count <1000/mm³ and follow WBC until recovery

May cause orthostatic hypotension and syncope; caution in patients vulnerable to hypotension (eg, elderly, dehydration, hypovolemia, concomitant antihypertensive drugs, cardiovascular or cerebrovascular disease)

May cause seizures; risk is greatest with history of seizures or conditions that lower seizure threshold

May cause cognitive and motor impairment

Body temperature dysregulation reported; may disrupt ability to reduce core body temperature; caution with strenuous exercise, exposure to extreme heat, dehydration, and coadministration with anticholinergic medications

Esophageal dysmotility and aspiration reported with antipsychotic drug use

May cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries; for patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy

Drug interactions overview

• Coadministration with a strong CYP3A4 inhibitor increases the exposures of cariprazine and its major active metabolite, didesmethylcariprazine (DDCAR), compared to use of cariprazine alone (see Dosage Modifications)
• Effect of CYP3A4 inducers on the exposure of cariprazine has not been evaluated, and net effect is unclear

Metabolic changes

• Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, reported; assess fasting plasma glucose before or soon after initiation of antipsychotic medication, and monitor periodically
• Lipids alteration has occurred; obtain a fasting lipid profile at baseline and monitor periodically during treatment before or soon after initiation of antipsychotic medication
• Weight gain observed; monitor weight at baseline and frequently thereafter

Suicidal thoughts or behaviors

• Pooled analyses of placebo-controlled trials of antidepressive drugs showed an increased risk of suicidal thoughts or behavior in patients aged ≤24 yr taking these drugs for any indication; monitor for emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior
• Inform patients, their caregivers, and families of the increase the risk of suicidal thoughts and behavior; advise to be alert for the emergence or worsening of signs and symptoms

Pregnancy

Neonates exposed to antipsychotic drugs during third trimester of pregnancy are at risk for extrapyramidal symptoms or withdrawal symptoms after delivery; these complications vary in severity, with some being self-limited and others requiring ICU support and prolonged hospitalization

Pregnancy exposure registry

• Report exposure during pregnancy to the National Pregnancy Registry for Atypical Antipsychotics 1-866-961-2388 OR, http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/

Animal data

• Administration in pregnant rats during organogenesis at doses 0.2 to 3.5 times maximum recommended human dose caused fetal developmental toxicity at all doses, including reduced body weight, decreased male anogenital distance, and skeletal malformations of bent limb bones, scapula, and humerus
• Decreased postnatal survival, birth weight, and post-weaning body weight was also observed

Lactation

Unknown if distributed in human breast milk

Present in rat milk

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Precise mechanism by which cariprazine works for schizophrenia or bipolar disorder is unknown

Efficacy could be mediated through a combination of partial agonist activity at central dopamine (D2) and serotonin 5-HT1A receptors

Forms 2 major metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), that have in vitro receptor binding profiles similar to the parent drug

Absorption

Peak plasma time: 3-6 hr (cariprazine)

Mean concentrations of DCAR and DDCAR are ~30% and 400%, respectively, of cariprazine concentrations by the end of 12-week treatment

Distribution

Protein bound: 91-97% (parent drug and metabolites)

Metabolism

Active metabolites: Desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR) are pharmacologically equipotent to cariprazine

Extensively metabolized by CYP3A4 to DCAR and DDCAR

Metabolized to a lesser extent by CYP2D6 to DCAR and DDCAR

DDCAR is metabolized by CYP3A4 to a hydroxylated metabolite

Elimination

Half-life: 2-4 days (cariprazine); 1-3 weeks (DDCAR)

Excretion, cariprazine 12.5 mg/day: Urine (21%); [1.2% unchanged]

Instructions

Take orally with or without food

Discontinuation

• Decline in plasma concentrations of active drug and metabolites may not be immediately reflected in patients’ clinical symptoms
• Plasma concentration declines by 50% in ~1 week
• There are no systematically collected data to address switching patients from cariprazine to other antipsychotics or concomitant administration with other antipsychotics

Storage

Store at controlled room temperature (20-25ºC [68-77ºF]); excursions permitted between 15-30ºC (59-86ºF)

Protect 3- and 4.5-mg capsules from light to prevent potential color fading