elexacaftor/tezacaftor/ivacaftor

Drug-drug:

Strong CYP3A inducers, including carbamazepine, phenobarbital, phenytoin, rifabutin, and rifampin, may ↓ elexacaftor, tezacaftor, and ivacaftor levels and effectiveness; avoid concurrent use.
Strong CYP3A inhibitors, including clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole as well as moderate CYP3A inhibitors, including erythromycin and fluconazole may ↑ elexacaftor, tezacaftor, and ivacaftor levels and risk of toxicity; dose adjustment recommended.
May ↑ levels and risk of bleeding with warfarin; monitor INR closely.
May ↑ levels and risk of hypoglycemia with glimepiride or glipizide.
May ↑ levels of P-glycoprotein substrates, including cyclosporine, digoxin, everolimus, sirolimus, and tacrolimus.
May ↑ levels of glyburide, nateglinide, repaglinide, and statins.
Hormonal contraceptives may ↑ risk of rash.

Drug-Natural Products:

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

Drug-Food:

Grapefruit juice may ↑ elexacaftor, tezacaftor, and ivacaftor levels; avoid concurrent use.

Availability ⬆ ⬇

Tablets: elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg (combo) + ivacaftor 75 mg (separate tablets); elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (combo) + ivacaftor 150 mg (separate tablets)
Oral granules: elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg (combo) + ivacaftor 59.5 mg (separate oral granules); elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (combo) + ivacaftor 75 mg (separate oral granules)

Route/Dosage ⬆ ⬇

PO (Adults and Children ≥12 yr): Two elexacaftor 100-mg/tezacaftor 50-mg/ivacaftor 75-mg tablets in am and one ivacaftor 150-mg tablet in pm (approximately 12 hr apart) with fat-containing food. Concurrent use of strong CYP3A inhibitor: Two elexacaftor 100-mg/tezacaftor 50-mg/ivacaftor 75-mg tablets given twice weekly (3–4 days apart) in am. Do not give pm ivacaftor dose on any of the days. Concurrent use of moderate CYP3A inhibitor: Two elexacaftor 100-mg/tezacaftor 50-mg/ivacaftor 75-mg tablets in am on Day 1, then one ivacaftor 150-mg tablet in am on Day 2; continue this regimen on alternate days in am. Do not give pm ivacaftor dose on any of the days.
PO (Children 6–11 yr and ≥30 kg): Two elexacaftor 100-mg/tezacaftor 50-mg/ivacaftor 75-mg tablets in am and one ivacaftor 150-mg tablet in pm (approximately 12 hr apart) with fat-containing food. Concurrent use of strong CYP3A inhibitor: Two elexacaftor 100-mg/tezacaftor 50-mg/ivacaftor 75-mg tablets given twice weekly (3–4 days apart) in am. Do not give pm ivacaftor dose on any of the days. Concurrent use of moderate CYP3A inhibitor: Two elexacaftor 100-mg/tezacaftor 50-mg/ivacaftor 75-mg tablets in am on Day 1, then one ivacaftor 150-mg tablet in am on Day 2; continue this regimen on alternate days in am. Do not give pm ivacaftor dose on any of the days.
PO (Children 6–11 yr and <30 kg): Two elexacaftor 50-mg/tezacaftor 25-mg/ivacaftor 37.5-mg tablets in am and one ivacaftor 75-mg tablet in pm (approximately 12 hr apart) with fat-containing food. Concurrent use of strong CYP3A inhibitor: Two elexacaftor 50-mg/tezacaftor 25-mg/ivacaftor 37.5-mg tablets given twice weekly (3–4 days apart) in am. Do not give pm ivacaftor dose on any of the days. Concurrent use of moderate CYP3A inhibitor: Two elexacaftor 50-mg/tezacaftor 25-mg/ivacaftor 37.5-mg tablets in am on Day 1, then one ivacaftor 75-mg tablet in am on Day 2; continue this regimen on alternate days in am. Do not give pm ivacaftor dose on any of the days.
PO (Children 2–5 yr and ≥14 kg): One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg oral granules) in am and one packet (containing ivacaftor 75-mg oral granules) in pm (approximately 12 hr apart) with fat-containing food. Concurrent use of strong CYP3A inhibitor: One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg oral granules) twice weekly (given 3–4 days apart). Do not give pm ivacaftor dose on any of the days. Concurrent use of moderate CYP3A inhibitor: One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg oral granules) in am on Day 1, then one packet (containing ivacaftor 75-mg oral granules) in am on Day 2; continue this regimen on alternate days in am. Do not give pm ivacaftor dose on any of the days.
PO (Children 2–5 yr and <14 kg): One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg oral granules) in am and one packet (containing ivacaftor 59.5-mg oral granules) in pm (approximately 12 hr apart) with fat-containing food. Concurrent use of strong CYP3A inhibitor: One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg oral granules) twice weekly (given 3–4 days apart). Do not give pm ivacaftor dose on any of the days. Concurrent use of moderate CYP3A inhibitor: One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg oral granules) in am on Day 1, then one packet (containing ivacaftor 59.5-mg oral granules) in am on Day 2; continue this regimen on alternate days in am. Do not give pm ivacaftor dose on any of the days.

Hepatic Impairment

(Adults and Children ≥12 yr): Moderate hepatic impairment: Two elexacaftor 100-mg/tezacaftor 50-mg/ivacaftor 75-mg tablets in am on Day 1, then one elexacaftor 100-mg/tezacaftor 50-mg/ivacaftor 75-mg tablet in am on Day 2. Continue this regimen on alternate days in am. Do not give ivacaftor 150-mg tablet in pm on any day.

Hepatic Impairment

(Adults and Children 6–11 yr and ≥30 kg): Moderate hepatic impairment: Two elexacaftor 100-mg/tezacaftor 50-mg/ivacaftor 75-mg tablets in am on Day 1, then one elexacaftor 100-mg/tezacaftor 50-mg/ivacaftor 75-mg tablet in am on Day 2. Continue this regimen on alternate days in am. Do not give ivacaftor 150-mg tablet in pm on any day.

Hepatic Impairment

(Adults and Children 6–11 yr and <30 kg): Moderate hepatic impairment: Two elexacaftor 50-mg/tezacaftor 25-mg/ivacaftor 37.5-mg tablets in am on Day 1, then one elexacaftor 50-mg/tezacaftor 25-mg/ivacaftor 37.5-mg tablet in am on Day 2. Continue this regimen on alternate days in am. Do not give ivacaftor 75-mg tablet in pm on any day.

Hepatic Impairment

(Adults and Children 2–5 yr and ≥14 kg): Moderate hepatic impairment: One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg oral granules) in am on Days 1–3. No dose on Day 4. One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg oral granules) in am on Days 5 and 6. No dose on Day 7. Continue this weekly dosing schedule in am. Do not give pm ivacaftor dose on any day of weekly dosing schedule.

Hepatic Impairment

(Adults and Children 2–5 yr and <14 kg): Moderate hepatic impairment: One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg oral granules) in am on Days 1–3. No dose on Day 4. One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg oral granules) in am on Days 5 and 6. No dose on Day 7. Continue this weekly dosing schedule in am. Do not give pm ivacaftor dose on any day of weekly dosing schedule.

US Brand Names ⬆ ⬇

Action ⬆ ⬇

Elexacaftor and tezacaftor: facilitate the cellular processing and trafficking of F508del-CFTR to increase the amount of mature CFTR protein delivered to the cell surface. 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).

Therapeutic effects:

Improved lung function.

Classifications ⬆ ⬇

Therapeutic Classification: cystic fibrosis therapy adjuncts

Pharmacologic Classification: transmembrane conductance regulator potentiators

Pharmacokinetics ⬆ ⬇

Elexacaftor

Absorption: Well absorbed (88%) following oral administration; absorption is enhanced 2-fold by moderate-fat-containing foods.

Distribution: Well distributed to tissues.

Protein Binding: >99%.

Metabolism/Excretion: Primarily metabolized in liver via the CYP3A4 and CYP3A5 isoenzymes; one metabolite (M23) is pharmacologically active; 87% excreted in feces (primarily as metabolite); <1% excreted in urine.

Half-Life: 30 hr.

Tezacaftor

Absorption: Some absorption following 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 following 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
Elexacaftor (PO)	unknown	6 hr	24 hr
Tezacaftor (PO)	unknown	4 hr	12 hr
Ivacaftor (PO)	unknown	6 hr	12 hr

Patient/Family Teaching ⬆ ⬇

Instruct patient to take as directed with a fat-containing meal to increase absorption. Fat-containing foods include eggs, butter, peanut better, cheese pizza. Take missed doses within 6 hr of missed dose. If >6 hr since missed morning dose, take missed dose as soon as possible and omit the evening dose. Take next scheduled morning dose at usual time. If missed evening dose, omit the missed dose. Take next scheduled morning dose at usual time. Do not take morning and evening doses at same time. Advise patient to read Patient Information before starting therapy and with each Rx refill in case of changes.
Advise patient to avoid eating grapefruit or drinking grapefruit juice during therapy.
May cause dizziness. Advise patient to avoid driving and other activities requiring alertness until response to medication is known.
Advise patient to notify health care professional immediately 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.
Emphasize the importance of blood tests to monitor liver function and eye examinations.

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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 ⬆