Tezacaftor + Iivacaftor

Indications

Tezacaftor + Iivacaftor is used for: Cystic Fibrosis

Adult Dose

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 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

Child Dose

Renal Dose

Renal impairment Mild or moderate: No dose adjustment required Severe or ESRD: Caution recommended Not studied in moderate/severe impairment or ESRD

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)

Contra Indications

Precautions

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

Pregnancy-Lactation

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

Interactions

Coadministration with itraconazole, a strong CYP3A inhibitor, increased tezacaftor AUC by 4-fold and ivacaftor by 15.6-fold 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

Adverse Effects

Side effects of Tezacaftor + Iivacaftor : >10% Headache (15%) 1-10% Nausea (9%) Sinus congestion (4%) Dizziness (4%)

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