Drug Interaction Report

MONITOR: Coadministration with moderate or potent inhibitors of CYP450 2C9, 2C19, 2D6, and/or 2E1 may increase the plasma concentrations of pirfenidone, especially when used in addition to a moderate or potent CYP450 1A2 inhibitor. Pirfenidone is primarily (70% to 80%) metabolized by CYP450 1A2, with minor contribution from CYP450 2C9, 2C19, 2D6, and 2E1. In 25 healthy nonsmokers and 25 smokers who were administered a single dose of pirfenidone with the potent CYP450 1A2 inhibitor fluvoxamine (50 mg at bedtime for 3 days; 50 mg twice a day for 3 days; then 50 mg in the morning and 100 mg at bedtime for 4 days), pirfenidone systemic exposure (AUC) increased approximately 4-fold in nonsmoking subjects and 7-fold in smoking subjects. Fluvoxamine also inhibits CYP450 2C9, 2C19 and 2D6, although the extent to which these effects contribute to the interaction has not been established. The interaction has not been studied with specific inhibitors of other isoenzymes involved in the metabolism of pirfenidone.

MANAGEMENT: Concomitant use of pirfenidone with moderate or potent inhibitors of CYP450 2C9, 2C19, 2D6, and/or 2E1 in addition to a moderate or potent inhibitor of CYP450 1A2 (e.g., certain fluoroquinolones, oral contraceptives, deferasirox, methoxsalen, mexiletine, thiabendazole, ticlopidine, zileuton) should be avoided. No particular precaution is necessary if pirfenidone and CYP450 2C9, 2C19, 2D6, and/or 2E1 inhibitors are coadministered without a moderate or potent CYP450 1A2 inhibitor. However, a prolonged duration of monitoring for adverse effects may be required depending on the elimination half-life of the concomitant drug. For example, it should be noted that rolapitant, a moderate CYP450 2D6 inhibitor, may increase plasma concentrations and the risk of adverse effects of pirfenidone for at least 28 days after administration of rolapitant.

MONITOR: Coadministration with ribociclib may increase the plasma concentrations and pharmacologic effects of drugs that are substrates of CYP450 3A4. The proposed mechanism is decreased clearance due to ribociclib-mediated inhibition of CYP450 3A4 metabolism. In healthy study subjects, administration of midazolam, a sensitive CYP450 3A4 substrate, with multiple 400 mg daily doses of ribociclib increased the midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.1-fold and 3.8-fold, respectively, compared to midazolam administered alone. When given at a clinically relevant dose of 600 mg daily, ribociclib is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.

MANAGEMENT: Caution is advised when ribociclib is used concomitantly with drugs that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

ADJUST DOSING INTERVAL: Food significantly slows the rate but only modestly reduces the extent of absorption of pirfenidone. In healthy, older adult volunteers aged 50 to 66 years, administration of a single 801 mg oral dose of pirfenidone in the fed state resulted in an approximately 50% reduction in peak plasma concentration (Cmax) and a 15% to 20% reduction in systemic exposure (AUC) compared to administration in the fasted state. Median time to reach peak concentration (Tmax) increased from 0.5 hours to 3 hours with food. Less nausea and dizziness were observed in fed subjects compared to fasted subjects.

GENERALLY AVOID: Consumption of grapefruit juice is associated with inhibition of CYP450 1A2 and may increase the plasma concentrations of pirfenidone, which is primarily metabolized by the isoenzyme.

GENERALLY AVOID: Cigarette smoking may reduce pirfenidone exposure due to induction of CYP450 1A2, the isoenzyme primarily responsible for the metabolic clearance of pirfenidone. Following a single 801 mg oral dose of pirfenidone in 25 smokers and 25 healthy nonsmokers, the Cmax and AUC of pirfenidone in smokers were 68% and 46% of those in nonsmokers, respectively.

MANAGEMENT: Pirfenidone should be administered with food to reduce the likelihood of dizziness and gastrointestinal side effects such as nausea, diarrhea, dyspepsia, and vomiting. Patients who experience intolerance to therapy due to these adverse events should be reminded to take pirfenidone with food. If symptoms do not improve, or they worsen in severity, a dosage reduction or discontinuation of therapy may be warranted. Patients should be advised to avoid consumption of grapefruit and grapefruit juice during treatment with pirfenidone. Cigarette smoking should also be avoided during therapy to prevent reduced exposure to pirfenidone.

GENERALLY AVOID: Pomegranates and grapefruit may increase the systemic exposure to ribociclib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in these fruits. Increased exposure to ribociclib may increase the risk of adverse effects such as infections, neutropenia, leukopenia, anemia, thrombocytopenia, anorexia, nausea, vomiting, diarrhea, stomatitis, alopecia, fatigue, headache, and abnormal liver function may be increased.

MANAGEMENT: Patients receiving ribociclib should avoid consumption of pomegranates or pomegranate juice and grapefruit or grapefruit juice during treatment.