Dosing & Uses
Dosage Forms & Strengths
copackaged tablets
- Copackaged as a fixed dose combination tablet of tezacaftor 100mg and ivacaftor 150mg PLUS a separate ivacaftor 150mg tablet
Cystic Fibrosis
Indicated for cystic fibrosis (CF) in patients who are homozygous for the F508del mutation or who have at least 1 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence
Morning dose: One tezacaftor/ivacaftor 100-mg/150-mg fixed-dose tablet PO
Evening dose: One ivacaftor 150-mg tablet PO
Administer morning and evening doses ~12 hr apart
Dosage Modifications
Hepatic impairment
- Mild (Child-Pugh A): No dose adjustment required
-
Moderate (Child-Pugh B)
- Morning dose: One tablet of tezacaftor 100 mg/ivacaftor 150 mg PO qDay
- Evening dose: Omit evening ivacaftor 150-mg dose
-
Severe (Child-Pugh C)
- Morning dose: One tablet of tezacaftor 100 mg/ivacaftor 150 mg PO once daily or less frequently
- Evening dose: Omit evening ivacaftor 150-mg dose
Renal impairment
- Mild or moderate: No dose adjustment required
- Severe or ESRD: Caution recommended
- Not studied in moderate/severe impairment or ESRD
Coadministration with CYP3A inhibitors
- Avoid food or drink containing grapefruit or Seville oranges during treatment
-
Moderate CYP3A inhibitors
- Morning dose: Alternate dosing schedule (ie, day 1, administer tezacaftor 100 mg/ivacaftor 150 mg qDay; on day 2, administer ivacaftor 150 mg qDay; continue dosing schedule with tezacaftor 100 mg/ivacaftor 150 mg or ivacaftor 150 mg on alternate days)
- Evening dose: Do not administer
-
Strong CYP3A inhibitors
- Morning dose: Adjust dose to twice weekly, taken ~3-4 days apart (ie, on day 1, administer tezacaftor 100 mg/ivacaftor 150 mg qDay; do not administer any tablets on days 2 and 3; on day 4, administer tezacaftor 100 mg/ivacaftor 150 mg qDay; continue dosing with tezacaftor 100 mg/ivacaftor 150 mg twice a week, administered ~3 -4 days apart)
- Evening dose: Do not administer
Dosing Considerations
If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation, followed by verification with bidirectional sequencing when recommended by the mutation test instructions for use
Dosage Forms & Strengths
copackaged tablets
- Copackaged as a fixed-dose combination tablet of tezacaftor 50mg and ivacaftor 75mg PLUS a separate ivacaftor 75mg tablet
- Copackaged as a fixed dose combination tablet of tezacaftor 100mg and ivacaftor 150mg PLUS a separate ivacaftor 150mg tablet
Cystic Fibrosis
Indicated for cystic fibrosis in patients aged ≥6 yr who are homozygous for the F508del mutation or who have at least 1 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence
<6 years: Safety and efficacy not established
6 to <12 years weighing <30 kg
- Morning dose: One tezacaftor/ivacaftor 50-mg/75-mg fixed-dose tablet PO
- Evening dose: One ivacaftor 75-mg tablet PO
- Administer morning and evening doses ~12 hr apart
≥6 years weighing ≥30 kg
- Morning dose: One tezacaftor/ivacaftor 100-mg/150-mg fixed-dose tablet PO
- Evening dose: One ivacaftor 150-mg tablet PO
- Administer morning and evening doses ~12 hr apart
Dosage Modifications
Hepatic impairment for patients aged 6 to <12 years weighing <30 kg
- Mild (Child-Pugh A): No dose adjustment required
Moderate (Child-Pugh B)
- Morning dose: One tablet of tezacaftor 50 mg/ivacaftor 75 mg PO qDay
- Evening dose: Omit evening ivacaftor 75-mg dose
Severe (Child-Pugh C)
- Morning dose: One tablet of tezacaftor 50 mg/ivacaftor 75 mg PO qDay or less frequently
- Evening dose: Omit evening ivacaftor 75-mg dose
Hepatic impairment patients aged ≥6 years weighing ≥30 kg
- Mild (Child-Pugh A): No dose adjustment required
Moderate (Child-Pugh B)
- Morning dose: One tablet of tezacaftor 100 mg/ivacaftor 150 mg PO qDay
- Evening dose: Omit evening ivacaftor 150-mg dose
Severe (Child-Pugh C)
- Morning dose: One tablet of tezacaftor 100 mg/ivacaftor 150 mg PO qDay or less frequently
- Evening dose: Omit evening ivacaftor 150-mg dose
Renal impairment
- Mild or moderate: No dose adjustment required
- Severe or ESRD: Not studied, caution recommended
- Not studied in moderate/severe impairment or ESRD
Coadministration with CYP3A inhibitors for patients aged 6 to <12 years weighing <30 kg
- Avoid food or drink containing grapefruit or Seville oranges during treatment
Moderate CYP3A inhibitors
- Morning dose: Alternate dosing schedule (ie, day 1, administer tezacaftor 50 mg/ivacaftor 75 mg qDay; on day 2, administer ivacaftor 75 mg qDay; continue dosing schedule with tezacaftor 50 mg/ivacaftor 75 mg or ivacaftor 75 mg on alternate days)
- Evening dose: Do not administer
Strong CYP3A inhibitors
- Morning dose: Adjust dose to twice weekly, taken ~3-4 days apart (ie, on day 1, administer tezacaftor 50 mg/ivacaftor 75 mg qDay; do not administer any tablets on days 2 and 3; on day 4, administer tezacaftor 50 mg/ivacaftor 75 mg qDay; continue dosing with tezacaftor 50 mg/ivacaftor 75 mg twice a week, administered ~3 -4 days apart)
- Evening dose: Do not administer
Coadministration with CYP3A inhibitors for patients aged ≥6 years weighing ≥30 kg
- Avoid food or drink containing grapefruit or Seville oranges during treatment
Moderate CYP3A inhibitors
- Morning dose: Alternate dosing schedule (ie, day 1, administer tezacaftor 100 mg/ivacaftor 150 mg qDay; on day 2, administer ivacaftor 150 mg qDay; continue dosing schedule with tezacaftor 100 mg/ivacaftor 150 mg or ivacaftor 150 mg on alternate days)
- Evening dose: Do not administer
Strong CYP3A inhibitors
- Morning dose: Adjust dose to twice weekly, taken ~3-4 days apart (ie, on day 1, administer tezacaftor 100 mg/ivacaftor 150 mg qDay; do not administer any tablets on days 2 and 3; on day 4, administer tezacaftor 100 mg/ivacaftor 150 mg qDay; continue dosing with tezacaftor 100 mg/ivacaftor 150 mg twice a week, administered ~3 -4 days apart)
- Evening dose: Do not administer
Dosing Considerations
If the patient’s genotype is unknown, an FDA-cleared cystic fibrosis mutation test should be used to detect the presence of a CFTR mutation, followed by verification with bidirectional sequencing when recommended by the mutation test instructions for use
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>10%
Headache (15%)
1-10%
Nausea (9%)
Sinus congestion (4%)
Dizziness (4%)
Warnings
Contraindications
None
Cautions
Ivacaftor may elevate liver transaminases; assess ALT and AST before initiating, q3months during first year, and annually thereafter; monitor more frequently in patients with history of elevated transaminases; when transaminases are significantly elevated (eg, ALT/AST >5x ULN, ALT/AST >3x ULN with bilirubin >2x ULN), interrupt dosing and closely monitor until the abnormalities resolve
Noncongenital lens opacities reported in pediatric patients with ivacaftor; baseline and follow-up ophthalmological examinations are recommended before initiating
Drug interaction overview
CYP3A inducers
- Avoid coadministration with strong CYP3A inducers
- Coadministration with strong CYP3A inducers is not recommended, owing to significantly decreased systemic exposure to ivacaftor, which may reduce therapeutic effectiveness (eg, rifampin decreases ivacaftor AUC by 89%)
- Tezacaftor exposures can also be expected to decrease significantly
CYP3A inhibitors
- Also see Dosage Modifications
- Strong and moderate CYP3A inhibitors significantly increase tezacaftor and ivacaftor systemic exposure; dosage regimen modifications are required if coadministered
- Coadministration with itraconazole, a strong CYP3A inhibitor, increased tezacaftor AUC by 4-fold and ivacaftor by 15.6-fold
P-gp substrates
- Coadministration with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold, consistent with weak inhibition of P-gp by ivacaftor
- When used concomitantly with digoxin or other substrates of P-gp with a narrow therapeutic index (eg, cyclosporine, everolimus, sirolimus, tacrolimus), appropriate monitoring should be used
Pregnancy
Pregnancy
There are limited and incomplete human data from clinical trials and postmarketing reports on the use of tezacaftor and ivacaftor in pregnant women to inform a drug-associated risk
Lactation
Unknown if distributed in human breast milk
Both tezacaftor and ivacaftor are excreted into the milk of lactating rats
Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Tezacaftor: CFTR corrector; increases amount of mature CFTR protein at the cell surface by targeting the processing and trafficking defect of the F508del CFTR protein
Ivacaftor: CFTR potentiator; enhances function of the CFTR protein once it reaches the cell surface
Absorption
Peak plasma time, median at fed state: 4 hr (tezacaftor); 6 hr (ivacaftor)
Peak plasma concentration: 5.95 mcg/mL (tezacaftor); 1.17 mcg/mL (ivacaftor)
AUC: 84.5 mcg·h/mL (tezacaftor); 11.3 mcg·h/mL (ivacaftor)
When administered with fat-containing foods, tezacaftor exposure was similar and ivacaftor exposure was approximately 3 times higher than when taken in a fasting state
Distribution
Protein bound: 99%, primarily to albumin (tezacaftor); 99%, primarily to alpha 1-acid glycoprotein and albumin (ivacaftor)
Vd: 271 L (tezacaftor); 206 L (ivacaftor)
Metabolism
Both tezacaftor and ivacaftor are extensively metabolized in humans, mainly by CYP3A4 and CYP3A5
Elimination
Half-life: 15 hr (tezacaftor); 13.7 hr (ivacaftor)
Clearance: 1.31 L/hr (tezacaftor); 15.7 L/hr (ivacaftor)
Excretion
- Feces: 72% (tezacaftor); 87.8% (ivacaftor)
- Urine: 14% (tezacaftor); 6.6% (ivacaftor)
Pharmacogenomics
CFTR gene mutations that produce CFTR protein and are responsive to ivacaftor
- 546insCTA, 711+3A→G, 2789+5G→A, 3272-26A→G, 3849+10κβC→T
- A120T, A234D, A349V, A455E, A554E, A1006E, A1067T
- D110E, D110H, D192G, D443Y, D4437;G576A;R668C, D579G, D614G, D836Y, D924N, D979V, D1152H, D1270N
- E56K, E60K, E92K, E116K, E193K, E403D, E588V, E822K, E831X
- F191V, F311del, F311L, F508C, F508C;S1251N, F508del, F575Y, F1016S, F1052V, F1074L, F1099L
- G126D, G178E, G178R, G194R, G194V, G314E, G551D, G551S, G576A, G970D, G1069R, G1244E, G1249R, G1349D, G576A, G576A;R668C, G622D, G970D, G1069R, G1244E, G1249R, G1349D
- H939R, H1054D, H1375P
- I148T, I175V, I336K, I601F, I618T I807M, I980K, I1027T, I1139V, I1269N, I1366N
- K1060T
- L206W, L320V, L346P, L967S, L997F, L1324P, L1335P, L1480P
- M152V, M265R, M952I, M952T
- P5L, P67L
- Q237E, Q237H, Q359R, Q1291R R31L, R74W, R74W;D1270N, R74W;V201M, R74W;V201M;D127N, R75Q, R117C, R117G, R117H, R117L, R117P, R170H, R334L, R334Q, R347H, R347L, R347P, R352Q, R553Q, R668C, R792G, R933G, R1070Q, R1070W, R1162L, R1283M, R1283S
- S549N, S549R, S589N, S737F, S945L, S977F, S1159F, S1159P, S1251N, S1255P
- T338I, T1036N, T1053I
- V201M, V232D, V562I, V754M, V1293G
- W1282R
- Y109N, Y161S, Y1014C, Y1032C
Administration
Oral Administration
Swallow tablet whole; do not crush, chew, or split
Take at approximately the same time each day about 12 hr apart
Take with fat-containing food (eg, food prepared with butter or oils; food containing eggs, cheeses, nuts, whole milk, or meats)
Missed dose
- If ≤6 hr have passed since missed morning or evening dose, take missed dose as soon as possible and continue on the original schedule
- If >6 hr have passed since missed dose, do not take missed dose; resume taking next scheduled dose at usual time
- Do not take more than one dose at the same time
Storage
Store at controlled room temperature (20-25ºC [68-77ºF]); excursions permitted to 15-30ºC (59-86ºF)
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Patient Handout
Formulary
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