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.

ADJUST DOSING INTERVAL: Fat-rich food enhances the absorption of mitotane. One study evaluated blood levels of mitotane (o,p'-DDD) after subjects ingested a single dose of 2 g administered using various delivery vehicles (e.g., tablets, granules, milk, chocolate or oil emulsion). Mitotane plasma levels were significantly higher for milk, chocolate, and oil emulsion when compared to those who received tablets or granules alone. In the same study, mitotane levels were evaluated in subjects following long-term treatment (total dose of 200 g over 30 to 60 days) in tablet, oil emulsion, or milk formulations. Significantly higher mean plasma levels were recorded in subjects who received mitotane as an oil emulsion or mixed in milk, when compared to tablets alone. Additionally, the recovery of o,p'-DDD from the feces was about 5 times higher in subjects who received tablets alone, suggesting absorption was reduced when compared to subjects who received mitotane mixed with a fat-rich vehicle (e.g., oil emulsion or milk).

GENERALLY AVOID: Concomitant use of mitotane with central nervous system (CNS) depressants, including alcohol, may potentiate adverse effects such as somnolence and sedation.

MANAGEMENT: According to product labeling, mitotane tablets should be taken during meals containing fat-rich food (e.g., milk, chocolate, or oil) and with a full glass of water. Patients should be advised to avoid or limit consumption of alcohol and to avoid activities requiring mental alertness such as driving or operating hazardous machinery until they know how the medication affects them.

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.