Drug Interactions between copanlisib and ivacaftor / lumacaftor

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ivacaftor. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Elexacaftor and tezacaftor are also CYP450 3A4 substrates in vitro and may interact similarly with grapefruit juice, whereas lumacaftor is not expected to interact.

ADJUST DOSING INTERVAL: According to prescribing information, systemic exposure to ivacaftor increased approximately 2.5- to 4-fold, systemic exposure to elexacaftor increased approximately 1.9- to 2.5-fold, and systemic exposure to lumacaftor increased approximately 2-fold following administration with fat-containing foods relative to administration in a fasting state. Tezacaftor exposure is not significantly affected by administration of fat-containing foods.

MANAGEMENT: Patients treated with ivacaftor-containing medications should avoid consumption of grapefruit juice and any food that contains grapefruit or Seville oranges. All ivacaftor-containing medications should be administered with fat-containing foods such as eggs, avocados, nuts, meat, butter, peanut butter, cheese pizza, and whole-milk dairy products. A typical cystic fibrosis diet will satisfy this requirement.

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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.

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