Vraylar (cariprazine HCl)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Cariprazine hydrochloride is considered an atypical or second-generation antipsychotic agent.
Cariprazine hydrochloride is considered an atypical or second-generation antipsychotic agent. The exact mechanism of action of cariprazine in schizophrenia and bipolar disorder has not been fully elucidated but 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.
Cariprazine acts as a partial agonist at D2 and D3 receptors with high binding affinity and at 5-HT1A receptors in vitro. Cariprazine's partial agonist activity at D2 receptors is similar to that of aripiprazole (another atypical antipsychotic agent with D2 partial agonist activity) but cariprazine has shown approximately threefold to tenfold higher binding affinity at D3 receptors compared with D2 receptors; the clinical implications of the D3-receptor selectivity are not known. In addition, cariprazine is a partial agonist at 5-HT1A receptors; an antagonist at 5-HT2A and 5-HT2B receptors; and exhibits moderate to low binding affinity for histamine (H1) receptors, lower binding affinity for 5-HT2C and alpha1A-adrenergic receptors than aripiprazole, and no appreciable affinity for muscarinic receptors.
The pharmacologic activity of cariprazine is thought to be mediated by cariprazine and its 2 principal active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). DCAR and DDCAR, which pharmacologically are as potent as cariprazine, are present in mean plasma concentrations that are approximately 30 and 400% of cariprazine plasma concentrations at the end of 12 weeks, respectively. Therefore, at steady state, DDCAR is the major active moiety circulating in plasma; in a pharmacokinetic study, DDCAR accounted for about 70% of the total activity after 27 days of dosing.
Following oral administration of cariprazine capsules, peak plasma concentrations of cariprazine occur in approximately 3-6 hours. Administration of a single dose of cariprazine with a high-fat meal does not substantially affect peak plasma concentration or systemic exposure of cariprazine or DCAR. Steady-state mean plasma concentrations of cariprazine and DCAR are achieved within 1-2 weeks.
Steady-state plasma concentrations of DDCAR appear to approach steady state within about 4-8 weeks; however, the time varies and some patients did not reach steady-state DDCAR concentrations after 12 weeks of treatment. Cariprazine and its main metabolites are highly bound (91-97%) to plasma proteins. Cariprazine is extensively metabolized by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by CYP2D6 to DCAR and DDCAR.
DCAR is further metabolized to DDCAR by CYP3A4 and CYP2D6; DDCAR is then metabolized by CYP3A4 to a hydroxylated metabolite. Following administration of cariprazine 12.5 mg daily for 27 days, approximately 21% of the daily dose is recovered in urine, with approximately 1.2% of the dose excreted in urine as unchanged cariprazine. The elimination half-lives of cariprazine and DDCAR are estimated to be 2-4 days and approximately 1-3 weeks, respectively.
Following discontinuance of cariprazine, mean plasma concentrations of cariprazine and DCAR decrease by 50% in about 1 day and mean plasma concentrations of DDCAR decrease by about 50% in 1 week. CYP2D6 poor metabolizer status does not appear to affect the pharmacokinetics of cariprazine and its metabolites.
USES: This medication is used to treat certain mental/mood disorders (such as bipolar disorder, depression, schizophrenia). Cariprazine belongs to a class of drugs known as atypical antipsychotics. It works by helping to restore the balance of certain natural substances in the brain.
Generic name: cariprazine HCl
Pronunciation: (kar-IP-ra-zeen)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Vraylar
Indications
The following indications are listed for Vraylar:
- Depression Associated With Bipolar Disorder
- Major Depressive Disorder Treatment Adjunct
- Mania Associated With Bipolar Disorder
- Mixed Bipolar I Disorder
- Schizophrenia
Also known as: Adjunctive Treatment Of Major Depressive Disorder, Augmentation Therapy For Major Depressive Disorder, Bipolar Mania, Dementia Praecox, Depression Associated With Bipolar Affective Disorder, Depression Associated With Manic Depressive Disorder, Depressive Episode Associated With Bipolar Disorder, Depressive Phase Of Bipolar Disorder, Major Depressive Disorder Treatment Augmentation, Mania Associated With Bipolar Affective Disorder, Manic Episode Associated With Bipolar Disorder, Manic Phase Bipolar Mood Disorder, Manic Phase Of Bipolar Mood Disorder, Manic Phase Of Manic-Depression, Parergasia.
Dosing
Dosage of cariprazine hydrochloride is expressed in terms of cariprazine.
Because of the long half-life of cariprazine and its active metabolites, changes in dosage will not be fully reflected in plasma concentrations for several weeks (see Description). Therefore, patients receiving the drug should be monitored for adverse effects and clinical response for several weeks after initiation of therapy and after each dosage change. In addition, plasma concentrations of cariprazine and its active metabolites may not be immediately reflected in patients' clinical symptoms following discontinuance of the drug. Plasma concentrations of cariprazine and its active metabolites will decrease by 50% in approximately 1 week.
There are no systematically collected data to specifically address switching patients from cariprazine to other antipsychotic agents or concerning concomitant administration of cariprazine with other antipsychotic agents.
Cariprazine hydrochloride is commercially available as capsules, which are administered orally once daily without regard to meals. (See Description.)
Patients receiving cariprazine should be monitored for possible worsening of depression and emergence of suicidal thoughts or behaviors, especially at the beginning of therapy or during periods of dosage adjustments. (See Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults under Cautions.)
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
Cariprazine is metabolized primarily by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, CYP2D6 to its major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). (See Description.)
In vitro studies indicate that cariprazine and its major active metabolites are not substrates of P-glycoprotein (P-gp), organic anion transport proteins (OATP) 1B1 and 1B3, or breast cancer resistance protein (BCRP).
Based on in vitro studies, cariprazine is not expected to cause clinically important pharmacokinetic drug interactions with substrates of CYP isoenzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E, or 3A4; OATP1B1 and OATP1B3; BCRP; organic cation transporter (OCT) 2; or organic anion transporters (OAT) 1 and 3.
Cariprazine's major active metabolites possess little or no inhibitory effects on P-gp; however, cariprazine probably inhibits P-gp.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
Known hypersensitivity to cariprazine. Hypersensitivity reactions, including rash, pruritus, urticaria, and manifestations of possible angioedema (e.g., swollen tongue, lip swelling, facial edema and swelling, pharyngeal edema), have been reported in patients receiving cariprazine.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
Adverse effects occurring in 5% or more of patients receiving cariprazine for schizophrenia and at a frequency at least twice that reported with placebo in short-term clinical studies include extrapyramidal symptoms (e.g., parkinsonism, dystonia, dyskinesia, tardive dyskinesia) and akathisia.
Adverse effects occurring in 5% or more of patients receiving cariprazine for bipolar mania and at a frequency at least twice that reported with placebo in short-term clinical studies include extrapyramidal symptoms (e.g., parkinsonism, dystonia, dyskinesia, tardive dyskinesia), akathisia, dyspepsia, vomiting, somnolence, and restlessness.
Adverse effects occurring in 5% or more of patients receiving cariprazine for bipolar depression and at a frequency at least twice that reported with placebo in short-term clinical studies include nausea, akathisia, restlessness, and extrapyramidal symptoms.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
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Safety and effectiveness of cariprazine in pediatric patients have not been established. The manufacturer states that pediatric clinical studies with cariprazine have not been conducted to date.
Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients. (See Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults under Cautions.)
There are no adequate and well-controlled studies to date of cariprazine use in pregnant women. The principal active metabolite of cariprazine, didesmethyl cariprazine (DDCAR), has been detected in adult patients up to 12 weeks following discontinuance of cariprazine. Based on animal findings, cariprazine may cause fetal harm. Fetal developmental toxicity (including reduced body weight, skeletal and external malformations, lower pup survival, and developmental delays) was observed when cariprazine was administered to pregnant rats at dosages 0.2-3.5 times the maximum recommended human dosage.
Neonates exposed to antipsychotic agents during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Symptoms reported to date have included agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder. Neonates exhibiting such symptoms should be monitored. The complications have varied in severity; some neonates recovered within hours to days without specific treatment while others have required intensive care unit support and prolonged hospitalization.
National Pregnancy Registry for Atypical Antipsychotics: 866-961-2388 and http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregis try/atypicalantipsychotic/.
It is not known whether cariprazine is distributed into milk in humans. The drug is distributed into milk in rats. The effects of the drug on breastfed infants or on milk production are not known. The benefits of cariprazine therapy to the woman as well as the benefits of breast-feeding to the infant should be weighed against the potential risk of infant exposure to the drug or from the underlying maternal condition.
Clinical trial experience with cariprazine in the treatment of schizophrenia and bipolar mania did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults.
Age did not have a clinically important effect on the pharmacokinetics of cariprazine and its principal metabolites (desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR)). The manufacturer states that dosage selection in geriatric patients should be cautious, usually starting at the lower end of the dosage range, reflecting the greater incidence of decreased hepatic, renal, and cardiac function; concomitant illnesses; and other drug therapy in this population.
Geriatric patients with dementia-related psychosis treated with cariprazine are at an increased risk of death compared with those treated with placebo. In addition, an increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies. The manufacturer of cariprazine states that the drug is not approved for the treatment of patients with dementia-related psychosis (see Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Cautions). For additional information on the use of antipsychotic agents in the management of dementia-related psychosis, see Geriatric Considerations under Uses: Psychotic Disorders, in the Phenothiazines General Statement 28:16.08.24.
ICD codes
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Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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