Drug Interaction Report

GENERALLY AVOID: Coadministration with potent or moderate 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.

MONITOR CLOSELY: Central nervous system depressant or toxic effects may be additively or synergistically increased in patients taking cariprazine with certain other drugs (such as other CNS-active agents or efavirenz) that cause these effects, especially in elderly or debilitated patients.

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

ADJUST DOSING INTERVAL: Fat-rich food enhances the absorption of mitotane. One study evaluated blood levels of mitotane (o,p'-DDD) after subjects ingested a single dose of 2 g administered using various delivery vehicles (e.g., tablets, granules, milk, chocolate or oil emulsion). Mitotane plasma levels were significantly higher for milk, chocolate, and oil emulsion when compared to those who received tablets or granules alone. In the same study, mitotane levels were evaluated in subjects following long-term treatment (total dose of 200 g over 30 to 60 days) in tablet, oil emulsion, or milk formulations. Significantly higher mean plasma levels were recorded in subjects who received mitotane as an oil emulsion or mixed in milk, when compared to tablets alone. Additionally, the recovery of o,p'-DDD from the feces was about 5 times higher in subjects who received tablets alone, suggesting absorption was reduced when compared to subjects who received mitotane mixed with a fat-rich vehicle (e.g., oil emulsion or milk).

GENERALLY AVOID: Concomitant use of mitotane with central nervous system (CNS) depressants, including alcohol, may potentiate adverse effects such as somnolence and sedation.

MANAGEMENT: According to product labeling, mitotane tablets should be taken during meals containing fat-rich food (e.g., milk, chocolate, or oil) and with a full glass of water. Patients should be advised to avoid or limit consumption of alcohol and to avoid activities requiring mental alertness such as driving or operating hazardous machinery until they know how the medication affects them.

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.