Cariprazine (Vraylar, Allergan)
Indication and Clinical Profile7,8
Cariprazine is a new atypical antipsychotic approved for the treatment of schizophrenia and for the acute treatment of manic or mixed episodes associated with bipolar I disorder. Annually, schizophrenia affects about 1% of the U.S. population aged ≥18 years. The disorder is characterized by three symptom types: positive (abnormal behavior), negative (inability to perform daily activities), and cognitive (inability to make decisions). Patients with schizophrenia experience symptoms including multiple forms of hallucinations, paranoia, and social withdrawal. Bipolar disorder is a psychological condition characterized by alternating periods of mania and depression resulting in unusual shifts in mood, energy, and daily level of activity.
FDA approval of cariprazine for schizophrenia was based on results of three 6-week, randomized, placebo-controlled trials involving 1,754 patients with schizophrenia. The primary efficacy endpoint was symptom improvement from baseline measured by the Positive and Negative Syndrome Scale (PANSS). In all three trials, cariprazine over the dosage range of 1.5 to 9 mg per day was superior to placebo based on the PANSS total score (mean change –8.3 vs. placebo); however, there was a dose-related increase in certain adverse reactions, noted particularly at doses exceeding 6 mg.
FDA approval of cariprazine for manic or mixed episodes associated with bipolar I disorder was based on results of three 3-week placebo-controlled trials including 1,037 patients with bipolar I disorder with manic or mixed episodes with or without psychotic features. The primary efficacy endpoint was symptom improvement from baseline measured by the Young Mania Rating Scale (YMRS). In all three trials, cariprazine over the dosage range of 1.5 to 9 mg per day was superior to placebo based on the YMRS total score (mean change –5.6 vs. placebo); however, there was a dose-related increase in certain adverse reactions, noted particularly at doses exceeding 6 mg.
Pharmacology and Pharmacokinetics7,8
Cariprazine, which is a cyclohexylurea derivative of aripiprazole, acts as a partial agonist at central dopamine D2 and serotonin 5-HT1A receptors, and it has antagonist activity at serotonin 5-HT2A receptors (Figure 2). Its exact mechanism of action in schizophrenia and bipolar I disorder is unknown, but is thought to be related to its ability as a partial agonist to antagonize dopamine receptors when dopamine levels are elevated (as is hypothesized in schizophrenic patients). Also, because of its activity as a partial agonist, this drug acts as an agonist when dopamine levels are low.
The bioavailability of cariprazine is 52%, and absorption is not affected by high-fat meals. Peak plasma concentrations are reached between 3 and 6 hours, and the drug is >90% bound by plasma proteins. Cariprazine undergoes extensive hepatic oxidation primarily by CYP3A4 and some CYP2D6, yielding the active metabolites desmethyl cariprazine and didesmethyl cariprazine (DDCAR). DDCAR undergoes further CYP3A4 hydroxylation to an inactive metabolite. The half-lives of cariprazine and DDCAR are 2 to 4 days and 1 to 3 weeks, respectively. Cariprazine is excreted primarily as metabolites.
Adverse Reactions and Drug Interactions7,8
The most common adverse reactions reported by patients receiving cariprazine in clinical trials included extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness. All atypical antipsychotics carry a black box warning alerting prescribers to an increased risk of death associated with off-label use to treat behavioral problems in older people with dementiarelated psychosis. Like many atypical antipsychotics, cariprazine comes with warnings for cerebrovascular adverse effects, including stroke, neuroleptic malignant syndrome, tardive dyskinesia, metabolic changes, and orthostatic hypotension. Cariprazine should be used with caution in pregnant women because neonates exposed to the drug during the third trimester of pregnancy have experienced extrapyramidal and/or withdrawal symptoms.
Drug interactions with cariprazine are limited to those that are due to its metabolism by CYP3A4. If cariprazine is administered with a strong CYP3A4 inhibitor (e.g., clarithromycin, azole antifungals, protease inhibitors), the dose should be reduced to 75 mg. The use of cariprazine in patients taking a strong CYP3A4 inducer (e.g., rifampin, carbamazepine) should be avoided.
Dosage and Administration7,8
Cariprazine is supplied as 1.5-, 3-, 4.5-, and 6-mg capsules for oral administration once daily with or without food. The recommended starting dosage for both indications is 1.5 mg daily, which may be increased to 3 mg on day 2 of therapy. The recommended dosage range for schizophrenia and bipolar disorder is 1.5 to 6 mg per day and 3 to 6 mg per day, respectively, with a maximum recommended dosage of 6 mg. Safety and effectiveness have not been established in pediatric patients. No dose adjustments of cariprazine are required in patients with mild-to-moderate hepatic impairment (Child-Pugh score 5–9) or mild-to-moderate renal impairment (creatinine clearance ≥30 mL/min). Cariprazine should not be used in patients with severe renal or hepatic impairment, as the drug has not been adequately studied in this patient population.
US Pharmacist. 2016;41(10):30-36. © 2016 Jobson Publishing