tezacaftor/ivacaftor

Drug-drug:

Strong CYP3A inducers, including carbamazepine, phenobarbital, phenytoin, rifabutin, and rifampin, may ↓ tezacaftor and ivacaftor levels and effectiveness; avoid concurrent use.
Moderate and strong CYP3A inhibitors, including clarithromycin, erythromycin, fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole, may ↑ tezacaftor and ivacaftor levels; dose adjustment recommended.
May ↑ levels of P-glycoprotein substrates, including cyclosporine, digoxin, everolimus, sirolimus, and tacrolimus.
May ↑ levels and risk of bleeding of warfarin; monitor INR closely.
May ↑ levels and risk of toxicity of CYP2C9 substrates, including glimepiride and glipizide.

Drug-Natural Products:

St. John's wort may ↓ tezacaftor and ivacaftor levels and effectiveness; avoid concurrent use.

Drug-Food:

Grapefruit juice or Seville oranges may ↑ tezacaftor and ivacaftor levels; avoid concurrent use.

Availability ⬆ ⬇

Tablets: tezacaftor 50 mg/ivacaftor 75 mg (combo) + ivacaftor 75 mg (separate tablets); tezacaftor 100 mg/ivacaftor 150 mg (combo) + ivacaftor 150 mg (separate tablets)

Route/Dosage ⬆ ⬇

PO (Adults and Children ≥12 yr): One tezacaftor 100-mg/ivacaftor 150-mg tablet in AM and one ivacaftor 150-mg tablet in PM (approximately 12 hr apart) with fat-containing food.Concurrent use of strong CYP3A inhibitor: One tezacaftor 100-mg/ivacaftor 150-mg tablet in AM given twice weekly (3–4 days apart). Do not give ivacaftor 150-mg tablet in PM. Concurrent use of moderate CYP3A inhibitor: One tezacaftor 100-mg/ivacaftor 150-mg tablet or one ivacaftor 150-mg tablet on alternate days in the AM. Do not give ivacaftor 150-mg tablet in PM.
PO (Children 6–<12 yr and ≥30 kg): One tezacaftor 100-mg/ivacaftor 150-mg tablet in AM and one ivacaftor 150-mg tablet in PM (approximately 12 hr apart) with fat-containing food.Concurrent use of strong CYP3A inhibitor: One tezacaftor 100-mg/ivacaftor 150-mg tablet in AM given twice weekly (3–4 days apart). Do not give ivacaftor 150-mg tablet in PM. Concurrent use of moderate CYP3A inhibitor: One tezacaftor 100-mg/ivacaftor 150-mg tablet or one ivacaftor 150-mg tablet on alternate days in the AM. Do not give ivacaftor 150-mg tablet in PM.
PO (Children 6–<12 yr and <30 kg): One tezacaftor 50-mg/ivacaftor 75-mg tablet in AM and one ivacaftor 75-mg tablet in PM (approximately 12 hr apart) with fat-containing food.Concurrent use of strong CYP3A inhibitor: One tezacaftor 50-mg/ivacaftor 75-mg tablet in AM given twice weekly (3–4 days apart). Do not give ivacaftor 75-mg tablet in PM. Concurrent use of moderate CYP3A inhibitor: One tezacaftor 50-mg/ivacaftor 75-mg tablet or one ivacaftor 75-mg tablet on alternate days in the AM. Do not give ivacaftor 75-mg tablet in PM.

Hepatic Impairment

(Adults and Children ≥12 yr): Moderate hepatic impairment: One tezacaftor 100-mg/ivacaftor 150-mg tablet every AM. Do not give ivacaftor 150-mg tablet in PM. Severe hepatic impairment: One tezacaftor 100-mg/ivacaftor 150-mg tablet every AM (or less frequently). Do not give ivacaftor 150-mg tablet in PM.

Hepatic Impairment

(Children 6–12 yr and ≥30 kg): Moderate hepatic impairment: One tezacaftor 100-mg/ivacaftor 150-mg tablet every AM. Do not give ivacaftor 150-mg tablet in PM. Severe hepatic impairment: One tezacaftor 100-mg/ivacaftor 150-mg tablet every AM (or less frequently). Do not give ivacaftor 150-mg tablet in PM.

Hepatic Impairment

(Children 6–12 yr and <30 kg): Moderate hepatic impairment: One tezacaftor 50 mg/ivacaftor 75-mg tablet every AM. Do not give ivacaftor 75-mg tablet in PM. Severe hepatic impairment: One tezacaftor 50-mg/ivacaftor 75-mg tablet every AM (or less frequently). Do not give ivacaftor 75-mg tablet in PM.

US Brand Names ⬆ ⬇

Action ⬆ ⬇

Ivacaftor: acts as a potentiator of the CFTR protein (a chloride channel on the surface of endothelial cells) facilitating chloride transport by increasing the channel-open probability (gating). Tezacaftor: facilitates the cellular processing and trafficking of normal and select mutant forms of CFTR (including F508del-CFTR) to increase the amount of mature CFTR protein delivered to the cell surface.

Therapeutic effects:

Improved lung function.

Classifications ⬆ ⬇

Therapeutic Classification: cystic fibrosis therapy adjuncts

Pharmacologic Classification: transmembrane conductance regulator potentiators

Pharmacokinetics ⬆ ⬇

Tezacaftor

Absorption: Some absorption follows oral administration.

Distribution: Widely distributed to tissues.

Protein Binding: >99%.

Metabolism/Excretion: Primarily metabolized in liver via the CYP3A4 and CYP3A5 isoenzymes; one metabolite (M1) is pharmacologically active; 72% excreted in feces as unchanged drug or metabolite; 14% excreted in urine (primarily as metabolite).

Half-Life: 15 hr.

Ivacaftor

Absorption: Some absorption follows oral administration; absorption is enhanced 3-fold by fat-containing foods.

Distribution: Widely distributed to tissues.

Protein Binding: >99%.

Metabolism/Excretion: Primarily metabolized in liver via the CYP3A4 and CYP3A5 isoenzymes; one metabolite (M1) is pharmacologically active; 87.8% eliminated in feces; negligible urinary elimination.

Half-Life: 14 hr.

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
Tezacaftor (PO)	unknown	4 hr	12 hr
Ivacaftor (PO)	unknown	6 hr	12 hr

Patient/Family Teaching ⬆ ⬇

Instruct patient to take medication as directed with a fat-containing meal to increase absorption. Fat-containing foods include eggs, butter, peanut better, and cheese pizza. If a dose is missed and ≤6 hr since the missed morning or evening dose, take missed dose as soon as possible and continue on the original schedule. If >6 hr since the missed morning or evening dose, omit dose and take next scheduled dose at usual time. Do not double doses.
Advise patient to avoid eating Seville oranges and grapefruit and drinking grapefruit juice during therapy.
Advise patient to notify health care professional if symptoms of liver problems (pain or discomfort in right abdominal area, yellowing of skin or whites of eyes, loss of appetite, nausea, vomiting, dark amber-colored urine) occur.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications, especially St. John's wort.
Rep: Advise females of reproductive potential to notify health care professional if pregnancy is planned or suspected or if breastfeeding.

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Indications ⬇

Contraind./Precautions ⬆ ⬇

Adv. Reactions/Side Effects ⬆ ⬇

Interactions ⬆ ⬇

Availability ⬆ ⬇

Route/Dosage ⬆ ⬇

US Brand Names ⬆ ⬇

Action ⬆ ⬇

Classifications ⬆ ⬇

Pharmacokinetics ⬆ ⬇

Time/Action Profile ⬆ ⬇

Patient/Family Teaching ⬆ ⬇

Pronunciation ⬆