Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 3A4 and P-glycoprotein (P-gp) may increase the plasma concentrations of copanlisib, which is a substrate of both the isoenzyme and efflux transporter. When a single 60 mg intravenous dose of copanlisib was administered to cancer patients in combination with the potent CYP450 3A4 and P-gp inhibitor, itraconazole (200 mg once daily for 10 days), mean copanlisib peak plasma concentration (Cmax) did not change but systemic exposure (AUC) increased by 53%.

MANAGEMENT: Caution is advised when copanlisib is used with CYP450 3A4 inhibitors. Patients should be monitored for potentially increased adverse effects such as nausea, vomiting, diarrhea, stomatitis, hyperglycemia, hypertension, noninfectious pneumonitis, cutaneous reactions (e.g., exfoliative dermatitis, maculopapular rash), anemia, neutropenia, thrombocytopenia, and infections. Dosage adjustments for copanlisib may be necessary and should be done in accordance with the product labeling.

GENERALLY AVOID: Coadministration of imatinib with strong CYP450 3A4 inhibitors such as grapefruit juice, may significantly increase the plasma concentrations of imatinib, a known substrate of CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of imatinib by certain compounds present in grapefruits. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). 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. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict. In a single-dose study, coadministration of imatinib with ketoconazole (a strong CYP450 3A4 inhibitor) increased imatinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 26% and 40%, respectively.

MANAGEMENT: Patients treated with imatinib should preferably avoid the consumption of grapefruit or grapefruit juice. If coadministration is unavoidable, monitor for prolonged and/or increased pharmacologic effects of imatinib, including edema, hematologic toxicity and immunosuppression.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of copanlisib. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of copanlisib by certain compounds present in grapefruit. When a single 60 mg intravenous dose of copanlisib was administered to cancer patients in combination with the potent CYP450 3A4 and P-gp inhibitor, itraconazole (200 mg once daily for 10 days), mean copanlisib peak plasma concentration (Cmax) did not change but systemic exposure (AUC) increased by 53%. 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 copanlisib may increase the risk of adverse effects such as nausea, vomiting, diarrhea, stomatitis, hyperglycemia, hypertension, noninfectious pneumonitis, cutaneous reactions (e.g., exfoliative dermatitis, maculopapular rash), anemia, neutropenia, thrombocytopenia, and infections.

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