Drug Interaction Report

MONITOR: Coadministration with ibrutinib may increase the plasma concentrations of drugs that are substrates of the P-glycoprotein (P-gp) efflux transporter. In vitro studies indicate that ibrutinib is not a substrate for P-gp, and systemic ibrutinib is unlikely to be an inhibitor of P-gp at clinical doses. However, it may have an effect on P-gp substrates in the gastrointestinal tract due to higher local concentrations after an oral dose.

MANAGEMENT: Caution is advised if ibrutinib is prescribed in combination with orally administered P-gp substrates, particularly those with a narrow therapeutic range. Dosage reduction and/or dosage interval adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ibrutinib is added to or withdrawn from therapy. Some authorities recommend that narrow therapeutic range P-gp substrates, such as digoxin, should be administered at least 6 hours before or after ibrutinib.

GENERALLY AVOID: Coadministration with grapefruit, grapefruit juice, or Seville oranges may significantly increase the plasma concentrations of ibrutinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Pharmacokinetic modeling suggests that other moderate CYP450 3A4 inhibitors such as diltiazem and erythromycin may increase ibrutinib systemic exposure (AUC) by 6- to 9-fold under fasting condition. The safety and efficacy of these exposures are unknown. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 to 1400 mg) given for 28 days, which yielded single dose AUC values that were approximately 50% greater than steady-state exposures seen at the highest indicated dose of 560 mg.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of ibrutinib. The mechanism of interaction is unknown. According to the product labeling, administration with food increases ibrutinib exposure approximately 2-fold compared to administration after overnight fasting.

MANAGEMENT: Patients treated with ibrutinib should avoid consumption of Seville oranges, grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Ibrutinib should be taken once daily at approximately the same time each day.

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of orally administered everolimus. The mechanism is inhibition of CYP450 3A4 and P-glycoprotein activity in the gut wall by certain compounds present in grapefruit.

MANAGEMENT: Patients treated with everolimus should avoid consumption of grapefruit and grapefruit juice.