Drug Interactions between amoxicillin / clarithromycin / vonoprazan and isavuconazonium

CONTRAINDICATED: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of isavuconazole, which is primarily metabolized by CYP450 3A4 and 3A5 and subsequently by uridine diphosphate glucuronosyltransferases (UGT). When a single dose of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) was administered to healthy volunteers following multiple dosing of the potent CYP450 3A4 inhibitor ketoconazole (200 mg twice daily for 24 days), isavuconazole peak plasma concentration (Cmax) increased by 9% and systemic exposure (AUC) increased by 422%.

MANAGEMENT: Concomitant use of isavuconazonium sulfate with potent CYP450 3A4 inhibitors is considered contraindicated. Ritonavir given at low dosages as a pharmacokinetic booster may be used with caution, but is contraindicated at high dosages (e.g., 400 mg every 12 hours).

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of isavuconazole, which is primarily metabolized by CYP450 3A4 and 3A5 and subsequently by uridine diphosphate glucuronosyltransferases (UGT). When a single dose of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) was administered to healthy volunteers following multiple dosing of the potent CYP450 3A4 inhibitor ketoconazole (200 mg twice daily for 24 days), isavuconazole peak plasma concentration (Cmax) increased by 9% and systemic exposure (AUC) increased by 422%. Lopinavir-ritonavir (400 mg-100 mg twice daily) increased the Cmax and AUC of isavuconazole by 74% and 96%, respectively.

MANAGEMENT: Caution is advised when isavuconazonium sulfate is prescribed with CYP450 3A4 inhibitors. Patients should be monitored for adverse effects such as nausea, vomiting, diarrhea, peripheral edema, hypokalemia, hypomagnesemia, and hepatotoxicity. In addition, many CYP450 3A4 inhibitors are also substrates of the isoenzyme, thus pharmacologic response to these agents should also be monitored, as isavuconazole itself is reportedly a moderate CYP450 3A4 inhibitor.

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.