Drug Interaction Report

MONITOR: Coadministration with ivacaftor may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme and/or P-glycoprotein (P-gp) efflux transporter. The mechanism is decreased clearance via these pathways due to inhibition by ivacaftor and its pharmacologically active M1 metabolite. The interaction has been studied with midazolam and digoxin, probe substrates for CYP450 3A4 ad P-gp, respectively. In study subjects, midazolam systemic exposure (AUC) increased by 1.5-fold when it was administered with ivacaftor, suggesting weak inhibition of CYP450 3A4 by ivacaftor. Likewise, digoxin AUC increased by 1.3-fold with ivacaftor, which is also consistent with weak inhibition of P-gp by ivacaftor.

MANAGEMENT: Caution is advised when ivacaftor is used with drugs that are substrates of CYP450 3A4 and/or P-gp, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ivacaftor is added to or withdrawn from therapy.

GENERALLY AVOID: In a small, randomized, crossover study, the administration of quinidine with grapefruit juice (compared to water) to healthy volunteers significantly prolonged the time to reach peak plasma quinidine concentrations and decreased the plasma concentrations of its major metabolite, 3-hydroxyquinidine. These changes were associated pharmacodynamically with both a delay and a reduction in the maximal effect on QTc interval. The proposed mechanism is delay of gastric emptying as well as inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruits.

MANAGEMENT: Given the drug's narrow therapeutic index, patients receiving quinidine therapy should avoid the consumption of grapefruits and grapefruit juice to prevent any undue fluctuations in plasma drug levels.

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.