Drug Interaction Report

ADJUST DOSE: Coadministration with potent or moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of vanzacaftor, tezacaftor and deutivacaftor, which are primarily metabolized by the isoenzyme. In clinical studies, itraconazole, a potent CYP450 3A4 inhibitor increased vanzacaftor systemic exposure (AUC) by 6.4-fold, tezacaftor AUC by 4 to 4.5-fold and deutivacaftor AUC by 11.1-fold. Erythromycin, a moderate CYP450 3A4 inhibitor, is predicted to increase vanzacaftor peak plasma concentration (Cmax) and AUC by 3.2- and 3.3-fold, respectively, and deutivacaftor Cmax and AUC by 2.9- and 4.1-fold, respectively. Likewise, fluconazole, another moderate CYP450 3A4 inhibitor, is predicted to increase vanzacaftor and deutivacaftor Cmax and AUC by 2.6- and 2.5-fold; and 3.1- and 2.3-fold, respectively. The risk and/or severity of serious side effects such as liver damage may be increased.

MANAGEMENT: Please consult manufacturer's product labeling for complete dosing information.
For vanzacaftor/tezacaftor/deutivacaftor:
- For patients 6 to less than 12 years old, weighing less than 40 kg:
Potent CYP450 3A4 inhibitors: The dose should be reduced to two tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg once a week (total dose of vanzacaftor 8 mg/tezacaftor 40 mg/deutivacaftor 100mg).
Moderate CYP450 3A4 inhibitors: The dose should be reduced to two tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg every other day (total dose of vanzacaftor 8 mg/tezacaftor 40 mg/deutivacaftor 100 mg).

- For patients 6 years old to less than 12 years old, weighing 40 kg or more:
Potent CYP450 3A4 inhibitors: The dose should be reduced to one tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg once a week.
Moderate CYP450 3A4 inhibitors: The dose should be reduced to one tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every other day.

-For patients 12 years old and older:
Potent CYP450 3A4 inhibitors: The dose should be reduced to one tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg once a week
Moderate CYP450 3A4 inhibitors: The dose should be reduced to one tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every other day.

For tezacaftor/ivacaftor:
- The morning dose of tezacaftor/ivacaftor should be reduced to one tablet twice a week, approximately 3 to 4 days apart, and the evening ivacaftor dose should not be taken during treatment with potent CYP450 3A4 inhibitors. The frequency of dosing should be reduced to a single morning dose of one tezacaftor/ivacaftor tablet alternating with one ivacaftor tablet every other morning during treatment with moderate CYP450 3A4 inhibitors. The evening dose of ivacaftor should not be taken.

For elexacaftor/tezacaftor/ivacaftor:
- The morning dose of 2 elexacaftor/tezacaftor/ivacaftor tablets once a day should be reduced to 2 tablets twice a week, approximately 3 to 4 days apart, and the evening ivacaftor dose should not be taken during treatment with potent CYP450 3A4 inhibitors. The frequency of dosing should be reduced to a single morning dose of two elexacaftor /tezacaftor /ivacaftor tablets alternating with one ivacaftor tablet every other day during treatment with moderate CYP450 3A4 inhibitors. The evening dose of ivacaftor should not be taken.

ADJUST DOSE: Coadministration with potent or moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of vanzacaftor, tezacaftor and deutivacaftor, which are primarily metabolized by the isoenzyme. In clinical studies, itraconazole, a potent CYP450 3A4 inhibitor increased vanzacaftor systemic exposure (AUC) by 6.4-fold, tezacaftor AUC by 4 to 4.5-fold and deutivacaftor AUC by 11.1-fold. Erythromycin, a moderate CYP450 3A4 inhibitor, is predicted to increase vanzacaftor peak plasma concentration (Cmax) and AUC by 3.2- and 3.3-fold, respectively, and deutivacaftor Cmax and AUC by 2.9- and 4.1-fold, respectively. Likewise, fluconazole, another moderate CYP450 3A4 inhibitor, is predicted to increase vanzacaftor and deutivacaftor Cmax and AUC by 2.6- and 2.5-fold; and 3.1- and 2.3-fold, respectively. The risk and/or severity of serious side effects such as liver damage may be increased.

MANAGEMENT: Please consult manufacturer's product labeling for complete dosing information.
For vanzacaftor/tezacaftor/deutivacaftor:
- For patients 6 to less than 12 years old, weighing less than 40 kg:
Potent CYP450 3A4 inhibitors: The dose should be reduced to two tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg once a week (total dose of vanzacaftor 8 mg/tezacaftor 40 mg/deutivacaftor 100mg).
Moderate CYP450 3A4 inhibitors: The dose should be reduced to two tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg every other day (total dose of vanzacaftor 8 mg/tezacaftor 40 mg/deutivacaftor 100 mg).

- For patients 6 years old to less than 12 years old, weighing 40 kg or more:
Potent CYP450 3A4 inhibitors: The dose should be reduced to one tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg once a week.
Moderate CYP450 3A4 inhibitors: The dose should be reduced to one tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every other day.

-For patients 12 years old and older:
Potent CYP450 3A4 inhibitors: The dose should be reduced to one tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg once a week
Moderate CYP450 3A4 inhibitors: The dose should be reduced to one tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every other day.

For tezacaftor/ivacaftor:
- The morning dose of tezacaftor/ivacaftor should be reduced to one tablet twice a week, approximately 3 to 4 days apart, and the evening ivacaftor dose should not be taken during treatment with potent CYP450 3A4 inhibitors. The frequency of dosing should be reduced to a single morning dose of one tezacaftor/ivacaftor tablet alternating with one ivacaftor tablet every other morning during treatment with moderate CYP450 3A4 inhibitors. The evening dose of ivacaftor should not be taken.

For elexacaftor/tezacaftor/ivacaftor:
- The morning dose of 2 elexacaftor/tezacaftor/ivacaftor tablets once a day should be reduced to 2 tablets twice a week, approximately 3 to 4 days apart, and the evening ivacaftor dose should not be taken during treatment with potent CYP450 3A4 inhibitors. The frequency of dosing should be reduced to a single morning dose of two elexacaftor /tezacaftor /ivacaftor tablets alternating with one ivacaftor tablet every other day during treatment with moderate CYP450 3A4 inhibitors. The evening dose of ivacaftor should not be taken.

ADJUST DOSE: Coadministration with potent or moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of vanzacaftor, tezacaftor and deutivacaftor, which are primarily metabolized by the isoenzyme. In clinical studies, itraconazole, a potent CYP450 3A4 inhibitor increased vanzacaftor systemic exposure (AUC) by 6.4-fold, tezacaftor AUC by 4 to 4.5-fold and deutivacaftor AUC by 11.1-fold. Erythromycin, a moderate CYP450 3A4 inhibitor, is predicted to increase vanzacaftor peak plasma concentration (Cmax) and AUC by 3.2- and 3.3-fold, respectively, and deutivacaftor Cmax and AUC by 2.9- and 4.1-fold, respectively. Likewise, fluconazole, another moderate CYP450 3A4 inhibitor, is predicted to increase vanzacaftor and deutivacaftor Cmax and AUC by 2.6- and 2.5-fold; and 3.1- and 2.3-fold, respectively. The risk and/or severity of serious side effects such as liver damage may be increased.

MANAGEMENT: Please consult manufacturer's product labeling for complete dosing information.
For vanzacaftor/tezacaftor/deutivacaftor:
- For patients 6 to less than 12 years old, weighing less than 40 kg:
Potent CYP450 3A4 inhibitors: The dose should be reduced to two tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg once a week (total dose of vanzacaftor 8 mg/tezacaftor 40 mg/deutivacaftor 100mg).
Moderate CYP450 3A4 inhibitors: The dose should be reduced to two tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg every other day (total dose of vanzacaftor 8 mg/tezacaftor 40 mg/deutivacaftor 100 mg).

- For patients 6 years old to less than 12 years old, weighing 40 kg or more:
Potent CYP450 3A4 inhibitors: The dose should be reduced to one tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg once a week.
Moderate CYP450 3A4 inhibitors: The dose should be reduced to one tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every other day.

-For patients 12 years old and older:
Potent CYP450 3A4 inhibitors: The dose should be reduced to one tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg once a week
Moderate CYP450 3A4 inhibitors: The dose should be reduced to one tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every other day.

For tezacaftor/ivacaftor:
- The morning dose of tezacaftor/ivacaftor should be reduced to one tablet twice a week, approximately 3 to 4 days apart, and the evening ivacaftor dose should not be taken during treatment with potent CYP450 3A4 inhibitors. The frequency of dosing should be reduced to a single morning dose of one tezacaftor/ivacaftor tablet alternating with one ivacaftor tablet every other morning during treatment with moderate CYP450 3A4 inhibitors. The evening dose of ivacaftor should not be taken.

For elexacaftor/tezacaftor/ivacaftor:
- The morning dose of 2 elexacaftor/tezacaftor/ivacaftor tablets once a day should be reduced to 2 tablets twice a week, approximately 3 to 4 days apart, and the evening ivacaftor dose should not be taken during treatment with potent CYP450 3A4 inhibitors. The frequency of dosing should be reduced to a single morning dose of two elexacaftor /tezacaftor /ivacaftor tablets alternating with one ivacaftor tablet every other day during treatment with moderate CYP450 3A4 inhibitors. The evening dose of ivacaftor should not be taken.

GENERALLY AVOID: Administration with a high-fat meal may decrease the oral bioavailability of amprenavir. The mechanism is unknown. In healthy volunteers, consumption of a standardized high-fat meal decreased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of amprenavir (1200 mg single oral dose) by 36% and 21%, respectively, compared to administration in the fasted state. The time to reach Cmax (Tmax) was increased 44% following a high-fat meal.

Grapefruit juice does not appear to significantly affect the pharmacokinetics of amprenavir. In 12 healthy volunteers, administration with grapefruit juice (200 mL) decreased the mean peak plasma concentration (Cmax) of amprenavir (1200 mg single oral dose) by 22% compared to water. The median time to reach Cmax (Tmax) was prolonged from 0.75 to 1.13 hours. These pharmacokinetic changes are not thought to be clinically significant, since antiretroviral response is more closely associated with systemic exposure (AUC) and trough plasma concentration (Cmin), which were not affected in the study.

MANAGEMENT: Amprenavir may be taken with or without food, but should not be taken with a high-fat meal.

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.