Drug Interaction Report

GENERALLY AVOID: Coadministration with potent or moderate inducers of CYP450 3A4 may significantly decrease the plasma concentrations of vanzacaftor, tezacaftor, and deutivacaftor, drugs primarily metabolized by the isoenzyme. Physiologically based pharmacokinetic (PBPK) simulations suggest that coadministration with the potent CYP450 3A4 inducer rifampin may decrease vanzacaftor peak plasma concentration (Cmax) and systemic exposure (AUC) by 78% and 82%, respectively, and may decrease deutivacaftor Cmax and AUC by 80% and 90%, respectively. Similarly, the moderate CYP450 3A4 inducer efavirenz is predicted to decrease vanzacaftor Cmax and AUC by 65% and 69%, respectively; and may decrease deutivacaftor Cmax and AUC by 56% and 73%, respectively. No pharmacokinetic data are available for tezacaftor, but decreased exposures are expected according to prescribing information.

MANAGEMENT: Concomitant use of vanzacaftor, tezacaftor, and deutivacaftor containing medications with potent CYP450 3A4 inducers is not recommended.

GENERALLY AVOID: Coadministration with potent or moderate inducers of CYP450 3A4 may significantly decrease the plasma concentrations of vanzacaftor, tezacaftor, and deutivacaftor, drugs primarily metabolized by the isoenzyme. Physiologically based pharmacokinetic (PBPK) simulations suggest that coadministration with the potent CYP450 3A4 inducer rifampin may decrease vanzacaftor peak plasma concentration (Cmax) and systemic exposure (AUC) by 78% and 82%, respectively, and may decrease deutivacaftor Cmax and AUC by 80% and 90%, respectively. Similarly, the moderate CYP450 3A4 inducer efavirenz is predicted to decrease vanzacaftor Cmax and AUC by 65% and 69%, respectively; and may decrease deutivacaftor Cmax and AUC by 56% and 73%, respectively. No pharmacokinetic data are available for tezacaftor, but decreased exposures are expected according to prescribing information.

MANAGEMENT: Concomitant use of vanzacaftor, tezacaftor, and deutivacaftor containing medications with potent CYP450 3A4 inducers is not recommended.

GENERALLY AVOID: Coadministration with potent or moderate inducers of CYP450 3A4 may significantly decrease the plasma concentrations of vanzacaftor, tezacaftor, and deutivacaftor, drugs primarily metabolized by the isoenzyme. Physiologically based pharmacokinetic (PBPK) simulations suggest that coadministration with the potent CYP450 3A4 inducer rifampin may decrease vanzacaftor peak plasma concentration (Cmax) and systemic exposure (AUC) by 78% and 82%, respectively, and may decrease deutivacaftor Cmax and AUC by 80% and 90%, respectively. Similarly, the moderate CYP450 3A4 inducer efavirenz is predicted to decrease vanzacaftor Cmax and AUC by 65% and 69%, respectively; and may decrease deutivacaftor Cmax and AUC by 56% and 73%, respectively. No pharmacokinetic data are available for tezacaftor, but decreased exposures are expected according to prescribing information.

MANAGEMENT: Concomitant use of vanzacaftor, tezacaftor, and deutivacaftor containing medications with potent CYP450 3A4 inducers is not recommended.

GENERALLY AVOID: Concurrent use of rifampin in patients who ingest alcohol daily may result in an increased incidence of hepatotoxicity. The increase in hepatotoxicity may be due to an additive risk as both alcohol and rifampin are individually associated with this adverse reaction. However, the exact mechanism has not been established.

ADJUST DOSING INTERVAL: Administration with food may reduce oral rifampin absorption, increasing the risk of therapeutic failure or resistance. In a randomized, four-period crossover phase I study of 14 healthy male and female volunteers, the pharmacokinetics of single dose rifampin 600 mg were evaluated under fasting conditions and with a high-fat meal. Researchers observed that administration of rifampin with a high-fat meal reduced rifampin peak plasma concentration (Cmax) by 36%, nearly doubled the time to reach peak plasma concentration (Tmax) but reduced overall exposure (AUC) by only 6%.

MANAGEMENT: The manufacturer of oral forms of rifampin recommends administration on an empty stomach, 30 minutes before or 2 hours after meals. Patients should be encouraged to avoid alcohol or strictly limit their intake. Patients who use alcohol and rifampin concurrently or have a history of alcohol use disorder may require additional monitoring of their liver function during treatment with rifampin.

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.

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.

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.