Drug Interaction Report

GENERALLY AVOID: Coadministration with inducers of CYP450 3A4 is expected to alter the pharmacokinetics of cariprazine and its major active metabolites. However, the interaction has not been studied; therefore, the net effect on active drug and metabolites is unclear. Cariprazine is primarily metabolized by CYP450 3A4 and, to a lesser extent, by CYP450 2D6 to desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). DCAR is further metabolized to DDCAR by CYP450 3A4 and 2D6, and DDCAR is then metabolized by CYP450 3A4 to a hydroxylated metabolite. Both DCAR and DDCAR have in vitro receptor binding profiles similar to the parent drug and are considered pharmacologically equipotent to cariprazine.

MANAGEMENT: Concomitant use of cariprazine with CYP450 3A4 inducers has not been evaluated and is not recommended.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of cariprazine. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of cariprazine by certain compounds present in grapefruit. When cariprazine (0.5 mg/day) was coadministered with the potent CYP450 3A4 inhibitor, ketoconazole (400 mg/day), cariprazine peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 3.5- and 4-fold, respectively, while Cmax and AUC of DDCAR increased by approximately 1.5-fold each. The Cmax and AUC of another active metabolite, desmethyl cariprazine (DCAR), decreased by approximately one-third. The interaction has not been studied with grapefruit juice. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to cariprazine may increase the risk of adverse effects such as extrapyramidal symptoms, cognitive and motor impairment, hyperglycemia, dyslipidemia, weight gain, orthostatic hypotension, leucopenia, neutropenia, seizures, and dysphagia.

MANAGEMENT: Patients should avoid the consumption of grapefruit and grapefruit juice during treatment with cariprazine.