Drug Interactions between amoxicillin / clarithromycin / vonoprazan and cariprazine

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of cariprazine and its major active metabolite, didesmethyl cariprazine (DDCAR), both of which are primarily metabolized by the isoenzyme. 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.

MANAGEMENT: The dosage of cariprazine should be reduced in the presence of a potent CYP450 3A4 inhibitor. When initiating a potent CYP450 3A4 inhibitor during stable treatment with cariprazine, the manufacturer recommends reducing the current dosage of cariprazine by one-half. For patients taking 4.5 mg daily, the dosage should be reduced to 1.5 mg or 3 mg daily. For patients taking 1.5 mg daily, the dosing interval should be adjusted to every other day. Conversely, if cariprazine therapy is initiated during treatment with a potent CYP450 3A4 inhibitor, the recommended starting dosage of cariprazine is 1.5 mg on day 1 and day 3, with no dose administered on day 2. From day 4 onward, the dosage should be 1.5 mg daily, then increased to a maximum dosage of 3 mg daily. Following withdrawal of the CYP450 3A4 inhibitor, the dosage of cariprazine may need to be increased.

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of cariprazine and its major active metabolite, didesmethyl cariprazine (DDCAR), both of which are primarily metabolized by the isoenzyme. 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 extent to which other, less potent inhibitors of CYP450 3A4 may interact with cariprazine and its metabolites is unknown.

MANAGEMENT: Caution is advised when cariprazine is prescribed with CYP450 3A4 inhibitors. Patients should be monitored for adverse effects such as extrapyramidal symptoms, cognitive and motor impairment, hyperglycemia, dyslipidemia, weight gain, orthostatic hypotension, leucopenia, neutropenia, seizures and dysphagia, and the dosage of cariprazine adjusted as necessary in accordance with the product labeling.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.