cariprazine (Rx)

Brand and Other Names:Vraylar
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule

  • 1.5mg
  • 3mg
  • 4.5mg
  • 6mg

Schizophrenia

Treatment of schizophrenia in adults

Starting dose: 1.5 mg PO qDay

Dose may be increased to 3 mg/day 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 I Disorder

Manic or mixed episodes

  • Indicated for acute treatment of manic or mixed episodes associated with bipolar I disorder
  • Starting dose: 1.5 mg PO qDay
  • Dose should be increased to 3 mg/day 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; not to exceed 6 mg/day

Depressive episodes

  • Indicated for treatment of depressive episodes associated with bipolar I disorder
  • Starting dose: 1.5 mg PO qDay
  • Depending upon clinical response and tolerability, dosage can be increased to 3 mg qDay on Day 15
  • Not to exceed 3 mg 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 recommended; safety and efficacy has not been established

Dosing Considerations

Following discontinuation of cariprazine, decline in plasma concentrations of active drug and metabolites may not be immediately reflected in patients’ clinical symptoms; plasma concentration of cariprazine and its active metabolites will decline by 50% in ~1 week

Prescribers should monitor patients for adverse effects and treatment response for several weeks after initiating the drug and after each dosage change

Safety and efficacy not established

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Interactions

Interaction Checker

and cariprazine

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    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse 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%)

            Postmarketing Reports

            Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome

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            Warnings

            Black Box Warnings

            Increased mortality in elderly patients with dementia-related psychosis

            • 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

            Suicidal thoughts and behaviors

            • Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies
            • Closely monitor all antidepressant-treated patients for clinical worsening, and for the emergence of suicidal thoughts and behaviors
            • Safety and effectiveness of cariprazine has not been established in pediatric patients

            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
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            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, 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.

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            Pharmacology

            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]

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            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

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.