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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ivacaftor is added to or withdrawn from therapy.

MONITOR: Concomitant use of hormonal contraceptives and ivacaftor/tezacaftor/elexacaftor (IVA/TEZ/ELX) or vanzacaftor, tezacaftor, and deutivacaftor may increase the risk for rash events. In one clinical study, the overall incidence of rash events was 10.9% in IVA/TEZ/ELX-treated and 6.5% in placebo-treated patients. The incidence of rash events was 16.3% in females and 5.8% in males for IVA/TEZ/ELX-treated patients and 8.3% in females and 4.8% in males for placebo-treated patients. For IVA/TEZ/ELX-treated patients, the incidence of rash events was 20.5% in females taking a hormonal contraceptive and 13.6% in females not taking a hormonal contraceptive. In other studies, the incidence of rash was 11% in vanzacaftor, tezacaftor, and deutivacaftor treated patients and 7.7% in IVA/TEZ/ELX-treated patients. The incidence of rash was 9.4% in males and 13% in females with vanzacaftor, tezacaftor, and deutivacaftor treatment and 7.6% in males and 7.9% in females with IVA/TEZ/ELX treatment. Rash events were generally mild to moderate in severity with either treatment. The mechanism of this interaction is unknown.

MANAGEMENT: Monitor for rash in patients taking hormonal contraceptives and IVA/TEZ/ELX or vanzacaftor, tezacaftor, and deutivacaftor. Consider interrupting IVA/TEZ/ELX or vanzacaftor, tezacaftor, and deutivacaftor and hormonal contraceptives in patients who develop rash. Once the rash clears, IVA/TEZ/ELX or vanzacaftor, tezacaftor, and deutivacaftor may be restarted without the hormonal contraceptives. If rash does not recur, resumption of hormonal contraceptives can be considered.

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.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of tezacaftor, deutivacaftor, and vanzacaftor. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. 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. The risk and/or severity of serious side effects such as liver damage may be increased.

ADJUST DOSING INTERVAL: Administration with fat-containing food may increase the oral bioavailability of vanzacaftor and deutivacaftor. Administration with a fat containing meal increased vanzacaftor systemic exposure (AUC) by 4- (low-fat meal) to 6- (high-fat meal) fold. While deutivacaftor AUC increased approximately 3- (low-fat meal) to 4- (high-fat meal) fold, relative to administration in a fasting state. Tezacaftor exposure is not significantly affected by administration of fat-containing foods.

MANAGEMENT: Patients treated with tezacaftor, deutivacaftor, vanzacaftor -containing medications should avoid consumption of grapefruit juice and any food that contains grapefruit. To improve absorption, patients should be advised to take vanzacaftor and/or deutivacaftor containing medications with fat-containing foods such as eggs, avocados, nuts, meat, butter, peanut butter, cheese pizza, and whole-milk dairy products at approximately the same time of the day. A typical cystic fibrosis diet will satisfy this requirement.

MONITOR: Coadministration of ethinyl estradiol may increase the plasma concentrations of drugs that are primarily metabolized by CYP450 1A2. In a study of 30 healthy volunteers administered the CYP450 1A2 substrate tizanidine, the systemic exposure (AUC) of tizanidine was 3.9 times greater in women using an oral contraceptive containing ethinyl estradiol.

MANAGEMENT: Patients should be monitored for increased adverse effects of the CYP450 1A2 substrate during concomitant use with ethinyl estradiol. Product labeling for the specific CYP450 1A2 substrate should be consulted for additional recommendations.

Coadministration with grapefruit juice may increase the bioavailability of oral estrogens. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruits. In a small, randomized, crossover study, the administration of ethinyl estradiol with grapefruit juice (compared to herbal tea) increased peak plasma drug concentration (Cmax) by 37% and area under the concentration-time curve (AUC) by 28%. Based on these findings, grapefruit juice is unlikely to affect the overall safety profile of ethinyl estradiol. However, as with other drug interactions involving grapefruit juice, the pharmacokinetic alterations are subject to a high degree of interpatient variability. Also, the effect on other estrogens has not been studied.

The central nervous system effects and blood levels of ethanol may be increased in patients taking oral contraceptives, although data are lacking and reports are contradictory. The mechanism may be due to enzyme inhibition. Consider counseling women about this interaction which is unpredictable.