Dosing and uses of Vraylar (cariprazine)
Adult dosage forms and strengths
capsule
- 1.5mg
- 3mg
- 4.5mg
- 6mg
Schizophrenia
Starting dose: 1.5 mg PO qDay
Dose may be increased to 3 mg on Day 2
Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5 to 3-mg increments
Dosage range: 1.5-6 mg PO qDay
Bipolar Disorder
Indicated for manic or mixed episodes associated with bipolar I disorder
Starting dose: 1.5 mg PO qDay
Dose should be increased to 3 mg on Day 2
Depending on clinical response and tolerability, further dose adjustments can be made in 1.5 to 3-mg increments
Dosage range: 3-6 mg PO qDay
Dosage modifications
Initiating a strong CYP3A4 inhibitor while on stable dose of cariprazine
- Reduce current cariprazine dose by 50%
- For patients taking cariprazine 4.5 mg/day, the dose should be reduced to 1.5 mg or 3 mg daily
- For patients taking 1.5 mg daily, the dosing regimen should be adjusted to every other day
- When the CYP3A4 inhibitor is discontinued, cariprazine dosage may need to be increased
Initiating cariprazine while already on a strong CYP3A4 inhibitor
- Cariprazine 1.5 mg PO on Days 1 and 3 (no dose on Day 2)
- From Day 4 onward, the dose should be administered at 1.5 mg PO qDay, then increased to a maximum of 3 mg/day
- When CYP3A4 inhibitor is discontinued, cariprazine dosage may need to be increased
Coadministration with CYP3A4 inducers
- Concomitant administration has not been evaluated and is not recommended because the net effect on active drug and metabolites is unclear
Hepatic impairment
- Mild-to-moderate (Child-Pugh score 5-9): No dosage adjustment required
- Severe (Child-Pugh score 10-15): Not recommended
Renal impairment
- Mild-to-moderate (CrCl ≥30 mL/min) No dosage adjustment required
- Severe (CrCl <30 mL/min): Not evaluated
Dosing Considerations
Because of the long half-life of cariprazine and its active metabolites, changes in dose will not be fully reflected in plasma for several weeks
Prescribers should monitor patients for adverse effects and treatment response for several weeks after initiating the drug and after each dosage change
Pediatric dosage forms and strengths
Safety and efficacy not established
Vraylar (cariprazine) adverse (side) effects
>10% (Schizophrenia)
Extrapyramidal symptoms, all (24-33%)
Parkinsonism (13-18%)
Headache (9-18%)
Akathisia (9-14%)
Insomnia (11-13%)
>10% (Bipolar Disorder)
Extrapyramidal symptoms, all (41-45%)
Parkinsonism (21-26%)
Akathisia (20-21%)
Headache (13-14%)
Nausea (11-13%)
Constipation (6-11%)
1-10% (Schizophrenia)
Constipation (6-10%)
Somnolence (5-10%)
Nausea (5-8%)
Abdominal pain (3-7%)
Restlessness (4-6%)
Anxiety (3-6%)
Toothache (3-6%)
Hypertension (2-6%)
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 (1-3%)
Back pain (1-3%)
Dystonia (2%)
Tachycardia (1-2%)
Arthralgia (1-2%)
Increased LFTs (1-2%)
Nasopharyngitis (1-2%)
Urinary tract infections (1-2%)
Rash (1-2%)
1-10% (Bipolar Disorder)
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%)
Increased LFTs (1-3%)
Musculoskeletal stiffness (2%)
Warnings
Black box warnings
Elderly patients with dementia-related psychosis treatment with antipsychotic drugs are at an increased risk of death
Not approved for treatment of patients with dementia-related psychosis
Contraindications
History of hypersensitivity to cariprazine
Hypersensitivity reactions have ranged from rash, pruritus, urticaria, and events suggestive of angioedema (eg, swollen, tongue, lip swelling, face edema, pharyngeal edema, facial swelling)
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)
Neuroleptic malignant syndrome reported; monitor for hyperpyrexia, muscle rigidity, delirium, and autonomic instability; other signs include increased CPK, myoglobinuria (rhabdomyolysis), and acute renal failure
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
Metabolic changes associated with atypical antipsychotics include hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain; extreme hyperglycemia associated with ketoacidosis or hyperosmolar coma or death have been reported with atypical antipsychotics
Leukopenia and neutropenia reported with cariprazine; agranulocytosis (including fatal cases) reported with other atypical antipsychotics
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
Coadministration with CYP3A4 inhibitors requires dosage adjustment; not recommended with concomitant CYP3A4 inducers (see Dosage modifications)
Pregnancy
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, https://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.
Pharmacology of Vraylar (cariprazine)
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
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: 21% urine (1.2% unchanged)
Administration
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 (20-25°C [68-77°F]); excursions permitted between 15-30°C (59-86°F)
Protect 3- and 4.5-mg capsules from light to prevent potential color fading
