nail cutting [30:<1000/mm 3 ) 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 Interactions for Cariprazine Hydrochloride Metabolized principally by CYP3A4 and, to a lesser extent, by CYP2D6. 1 (See Metabolism under Pharmacokinetics.) In vitro, cariprazine and its major active metabolites are weak inhibitors of CYP isoenzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 and do not induce CYP1A2 and CYP3A4. 1 Cariprazine and its major active metabolites possess little or no inhibitory effects on organic anion transport proteins (OATP) 1B1 and 1B3, breast cancer resistance protein (BCRP), organic cation transporter (OCT) 2, and organic anion transporters (OAT) 1 and 3 in vitro. 1 Clinically important interactions between cariprazine and substrates of these enzymes or transporters unlikely. 1 In vitro, cariprazine and its major active metabolites are not substrates of P-glycoprotein (P-gp), OATP 1B1 and 1B3, or BCRP. 1 Cariprazine's major active metabolites possess little or no inhibitory effects on P-gp; however, the drug probably inhibits P-gp. 1 Drugs Affecting Hepatic Microsomal Enzymes Potent CYP3A4 inhibitors: Potential increased exposure to cariprazine and didesmethyl cariprazine (DDCAR); reduce cariprazine dosage during concurrent use. 1 Reduce cariprazine dosage to 50% of the current dosage if a potent CYP3A4 inhibitor is initiated in patients receiving a stable cariprazine dosage. 1 For patients taking 4.5 mg of cariprazine daily, reduce dosage to 1.5 or 3 mg daily. 1 For patients taking 1.5 mg of cariprazine daily, reduce dosing frequency to every other day. 1 If initiating cariprazine in patients already receiving a potent CYP3A4 inhibitor, administer cariprazine 1.5 mg on day 1 and on day 3 (skipping day 2), then give 1.5 mg daily from day 4 onward; increase dosage up to a maximum dosage of 3 mg daily. 1 When the potent CYP3A4 inhibitor is withdrawn, cariprazine dosage increase may be needed. 1 Moderate CYP3A4 inhibitors: Effects on pharmacokinetics of cariprazine and its metabolites not studied. 1 CYP3A4 inducers: Potential pharmacokinetic interaction; effects not studied. 1 Concomitant use not recommended. 1 CYP2D6 inhibitors: Clinically important pharmacokinetic interaction unlikely. 1 Specific Drugs Drug Interaction Comments Anticholinergic agents Possible disruption of body temperature regulation 1 Use with caution 1 Antifungals, azoles (e.g., itraconazole, ketoconazole) Potent CYP3A4 inhibitors: Possible increased exposure to cariprazine and DDCAR 1 Ketoconazole (potent CYP3A4 inhibitor) increased cariprazine peak concentration and AUC by about 3.5-fold and fourfold, respectively; increased DDCAR peak concentration and AUC by about 1.5-fold; and decreased desmethyl cariprazine (DCAR) peak concentration and AUC by about one-third 1 If initiating therapy with a potent CYP3A4 inhibitor, reduce current cariprazine dosage by 50% 1 For patients taking 4.5 mg of cariprazine daily, reduce dosage to 1.5 or 3 mg daily; for patients taking cariprazine 1.5 mg daily, reduce dosing frequency to every other day 1 If initiating cariprazine in patients receiving a potent CYP3A4 inhibitor, initiate cariprazine therapy at a dosage of 1.5 mg daily on days 1 and 3, administer 1.5 mg daily from day 4 onward, then increase dosage up to a maximum dosage of 3 mg daily 1 When the potent CYP3A4 inhibitor is withdrawn, an increase in cariprazine dosage may be necessary 1 Carbamazepine Potential pharmacokinetic interaction with carbamazepine (potent CYP3A4 inducer); not studied 1 Concomitant use not recommended 1 Hypotensive agents Possible additive hypotensive effects; may result in orthostatic hypotension and syncope 1 Monitor orthostatic vital signs 1 Rifampin Potential pharmacokinetic interaction with rifampin (potent CYP3A4 inducer); not studied 1 Concomitant use not recommended 1 Smoking Cariprazine is not a substrate for CYP1A2; smoking unlikely to alter cariprazine pharmacokinetics 1 Cariprazine Hydrochloride Pharmacokinetics Absorption Bioavailability Peak plasma concentrations of cariprazine achieved within approximately 3 6 hours following oral administration. 1 Mean steady-state concentrations of cariprazine and DCAR achieved within about 1 2 weeks. 1 Mean steady-state concentration of DDCAR achieved within about 4 8 weeks; however, time varies and may take> 12 weeks in some patients. 1 The principal active metabolites, DCAR and DDCAR, are present at mean plasma concentrations approximately 30 and 400% of plasma cariprazine concentrations after 12 weeks, respectively. 1 Food High-fat meal did not substantially affect peak plasma concentration or AUC of cariprazine or DCAR. 1 Special Populations In patients with mild or moderate hepatic impairment, cariprazine exposure is approximately 25% higher and DCAR and DDCAR exposure is approximately 45% lower than in individuals with normal hepatic function. 1 Distribution Extent Cariprazine distributes into milk in rats; not known if drug or metabolites distribute into human milk. 1 Plasma Protein Binding Cariprazine and its principal active metabolites: 91 97% bound. 1 Elimination Metabolism Extensively metabolized by CYP3A4 and, to a lesser extent, CYP2D6 to DCAR and DDCAR, which are pharmacologically active with similar potency to cariprazine. 1 DCAR metabolized by CYP3A4 and CYP2D6 to DDCAR. 1 DDCAR metabolized by CYP3A4 to a hydroxylated metabolite. 1 Elimination Route Following chronic administration of cariprazine, approximately 21% of daily dose recovered in urine; approximately 1.2% of dose excreted in urine as unchanged cariprazine. 1 Half-life Cariprazine: 2 4 days. 1 DDCAR: Approximately 1 3 weeks. 1 Following discontinuance, mean plasma concentrations of cariprazine and DCAR decrease by about 50% in about 1 day and mean plasma concentrations of DDCAR decrease by about 50% after 1 week. 1 Special Populations Pharmacokinetic analyses indicate no substantial relationship between clearance of the drug and its metabolites and Cl cr . 1 Not studied in severe renal impairment. 1 Age, gender, and race do not have clinically important effects on pharmacokinetics of cariprazine, DCAR, or DDCAR. 1 CYP2D6 poor metabolizer status also does not appear to affect the pharmacokinetics of cariprazine and its metabolites. 1 Stability Storage Oral Capsules 20 25 C (may be exposed to 15 30 C). 1 Protect 3- and 4.5-mg capsules from light to prevent potential color fading. 1 Actions 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 (D 2 ) and serotonin type 1 (5-hydroxytryptamine [5-HT 1A ]) receptors and antagonist activity at serotonin type 2 (5-HT 2A ) receptors. 1 7 8 9 10 Demonstrates partial agonist activity at D 2 and D 3 receptors and 5-HT 1A receptors and antagonist activity at 5-HT 2A and 5-HT 2B receptors. 1 7 8 9 10 Exhibits approximately 3- to 10-fold higher binding affinity at D 3 compared with D 2 receptors; clinical implications of D 3 receptor selectivity not known. 1 7 8 9 10 Exhibits moderate to low binding affinity for histamine (H 1 ) receptors, lower affinity for 5-HT 2C and α 1A -adrenergic receptors than aripiprazole, and no appreciable affinity for muscarinic receptors. 1 8 9 Advice to Patients 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.) Preparations Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details. Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations. Cariprazine Hydrochloride Routes Dosage Forms Strengths Brand Names Manufacturer Oral Capsules 1.5 mg (of cariprazine) Vraylar Allergan 3 mg (of cariprazine) Vraylar Allergan 4.5 mg (of cariprazine) Vraylar Allergan 6 mg (of cariprazine) Vraylar Allergan Titration Pack 1 Capsule, 1.5 mg (of cariprazine) (Vraylar ) 6 Capsules, 3 mg (of cariprazine) (Vraylar ) Vraylar Titration Pack Allergan AHFS DI Essentials. Copyright 2017, Selected Revisions June 12, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814. References 1. Allergan USA, Inc. Vraylar (cariprazine hydrochloride) capsules prescribing information. Irvine, CA; 2017 Feb. 2. Durgam S, Starace A, Li D et al. An evaluation of the safety and efficacy of cariprazine in patients with acute exacerbation of schizophrenia: a phase II, randomized clinical trial. Schizophr Res . 2014; 152:450-7. [PubMed 24412468] 3. Kane JM, Zukin S, Wang Y et al. Efficacy and safety of cariprazine in acute exacerbation of schizophrenia: results from an international, phase III clinical trial. J Clin Psychopharmacol . 2015; 35:367-73. [PubMed 26075487] 4. Calabrese JR, Keck PE, Starace A et al. Efficacy and safety of low- and high-dose cariprazine in acute and mixed mania associated with bipolar I disorder: a double-blind, placebo-controlled study. J Clin Psychiatry . 2015; 76:284-92. [PubMed 25562205] 5. Durgam S, Starace A, Li D et al. The efficacy and tolerability of cariprazine in acute mania associated with bipolar I disorder: a phase II trial. Bipolar Disord . 2015; 17:63-75. [PubMed 25056368] 6. Sachs GS, Greenberg WM, Starace A et al. Cariprazine in the treatment of acute mania in bipolar I disorder: a double-blind, placebo-controlled, phase III trial. J Affect Disord . 2015; 174:296-302. [PubMed 25532076] 7. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number 204370Orig1Orig2s000: Summary Review. 2015 Sep 17. From FDA website. 8. Kiss B, Horváth A, Némethy Z et al. Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile. J Pharmacol Exp Ther . 2010; 333:328-40. [PubMed 20093397] 9. Citrome L. Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability. Expert Opin Drug Metab Toxicol . 2013; 9:193-206. [PubMed 23320989] 10. Citrome L. Cariprazine in schizophrenia: clinical efficacy, tolerability, and place in therapy. Adv Ther . 2013; 30:114-26. [PubMed 23361833] 11. Durgam S, Cutler AJ, Lu K et al. Cariprazine in acute exacerbation of schizophrenia: a fixed-dose, phase 3, randomized, double-blind, placebo- and active-controlled trial. J Clin Psychiatry . 2015; 76:1574-82. 13. Dixon L, Perkins D, Calmes C. Guideline watch (September 2009): practice guideline for the treatment of patients with schizophrenia. American Psychiatric Association. Arlington, VA; 2009 Sep. From the American Psychiatric Association website. 14. Allergan, Inc. Vraylar (cariprazine hydrochloride) patient information. 2016 Feb. From Vraylar website 28. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry . 2004; 161(2 Suppl):1-56. 39. US Food and Drug Administration. Information for Healthcare Professionals: Conventional antipsychotics. Rockville, MD; 2008 Jun 16. From the FDA website. 68. American Psychiatric Association. DSM-IV : diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994:273-86. 70. Volavka J, Citrome L. Oral antipsychotics for the treatment of schizophrenia: heterogeneity in efficacy and tolerability should drive decision-making. Expert Opin Pharmacother . 2009; 10:1917-28. [PubMed 19558339] 71. Lieberman JA. Atypical antipsychotic drugs as a first-line treatment of schizophrenia: a rationale and hypothesis. J Clin Psychiatry . 1996; 57(Suppl 11):68-71. [PubMed 8941173] 72. Lahti AC, Tamminga CA. Recent developments in the neuropharmacology of schizophrenia. Am J Health-Syst Pharm . 1995; 52(Suppl 1):S5-8. [PubMed 7749964] 73. US Food and Drug Administration. Public health advisory: Deaths with antipsychotics in elderly patients with behavioral disturbances. Rockville, MD; 2005 Apr 11. From the FDA website. 78. Qureshi SU, Rubin E. Risperidone- and aripiprazole-induced leukopenia: a case report. Prim Care Companion J Clin Psychiatry . 2008; 10:482-3. [PubMed 19287562] 79. Sexson WR, Barak Y. Withdrawal emergent syndrome in an infant associated with maternal haloperidol therapy. J Perinatol . 1989; 9:170-2. [PubMed 2738729] 80. Coppola D, Russo LJ, Kwarta RF Jr. et al. Evaluating the postmarketing experience of risperidone use during pregnancy: pregnancy and neonatal outcomes. Drug Saf . 2007; 30:247-64. [PubMed 17343431] 81. US Food and Drug Administration. FDA drug safety communication: Antipsychotic drug labels updated in use during pregnancy and risk of abnormal muscle movements and withdrawal symptoms in newborns. Rockville, MD; 2011 Feb 22. From the FDA website. Next Interactions Print this page Add to My Med List More about cariprazine Side Effects During Pregnancy Dosage Information Drug Interactions Support Group En Español 92 Reviews Add your own review/rating Drug class: atypical antipsychotics Consumer resources Cariprazine Cariprazine (Advanced Reading) Professional resources Cariprazine (Wolters Kluwer) Other brands: Vraylar Related treatment guides Bipolar Disorder Schizophrenia ]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only N/A CSA Schedule Not a controlled drug Approval History Drug history at FDA Drug Class Atypical antipsychotics Related Drugs Bipolar Disorder Seroquel , lithium , quetiapine , lamotrigine , Abilify , Lamictal , Depakote , risperidone , carbamazepine , olanzapine , divalproex sodium , Risperdal , More... 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