Elexacaftor + Tezacaftor + Ivacaftor

Indications

Elexacaftor + Tezacaftor + Ivacaftor is used for: Cystic Fibrosis

Adult Dose

Cystic Fibrosis Indicated for cystic fibrosis in patients who have at least 1 F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is estimated to represent 90% of the cystic fibrosis population 2 fixed-dose tablets (elexacaftor 100 mg, tezacaftor 50 mg, and ivacaftor 75 mg) PO qAM and 1 ivacaftor 150-mg tablet PO qPM; ~12 hr apart Hepatic impairment Mild (Child-Pugh A): No dosage adjustment required Moderate (Child-Pugh B): Not recommended unless benefit exceeds risk; reduce dose by omitting evening ivacaftor 150-mg tab; monitor liver function tests Severe (Child-Pugh C): Do not use

Child Dose

Cystic Fibrosis Indicated for cystic fibrosis in children aged ?12 years who have at least 1 F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is estimated to represent 90% of the cystic fibrosis population 2 fixed-dose tablets (elexacaftor 100 mg, tezacaftor 50 mg, and ivacaftor 75 mg) PO qAM and 1 ivacaftor 150-mg tablet PO qPM; ~12 hr apart

Renal Dose

Renal impairment Mild or moderate (eGFR 30 to <90 mL/min/1.73 m2): No dosage adjustment required Severe (eGFR <30 mL/min/1.73 m2) or ESRD: Use caution

Administration

Swallow tablets whole; do not chew, crush, or split Take with fat-containing food (eg, meals or snacks prepared with butter or oils or those containing eggs, cheeses, nuts, whole milk, or meats)

Contra Indications

Precautions

Elevated liver transaminases and bilirubin levels observed; measure levels before initiating, q3Months during first year, and annually thereafter; consider more frequent monitoring for those with history of hepatic disease; interrupt dosing for significant elevations Noncongenital lens opacities reported with ivacaftor-containing regimens; other risk factors were present in some cases (eg, corticosteroid use, radiation exposure); a possible risk attributable to treatment with ivacaftor cannot be excluded

Pregnancy-Lactation

Pregnancy Human data are limited and incomplete from clinical trials on the use of elexacaftor/tezacaftor/ivacaftor or its individual components in pregnant women to inform a drug-associated risk Although there are no animal reproduction studies with the concomitant administration of elexacaftor, tezacaftor, and ivacaftor, separate reproductive and developmental studies were conducted with each active component in pregnant rats and rabbits Animal data In animal embryofetal development studies, oral administration of elexacaftor to pregnant rats and rabbits during organogenesis demonstrated no teratogenicity or adverse developmental effects at doses that produced maternal exposures up to ~2 times the exposure at the maximum recommended human dose (MRHD) in rats and 4 times the MRHD in rabbits Lactation No data are available regarding the presence of elexacaftor, tezacaftor, or ivacaftor in human milk, the effects on the breastfed infant, or the effects on milk production. Elexacaftor, tezacaftor, and ivacaftor are excreted into the milk of lactating rats

Interactions

CYP3A inhibitors or inducers Coadministration with moderate or strong CYP3A inhibitors increases systemic exposure of elexacaftor/tezacaftor/ivacaftor; dosage adjustment is required if coadministered Coadministration with strong CYP3A inducers is not recommended; ivacaftor systemic exposure is significantly decreased and exposure to elexacaftor and tezacaftor are expected to decrease if coadministered with a strong CYP3A inducer Potential for elexacaftor/tezacaftor/ivacaftor to affect other drugs Ivacaftor may inhibit CYP2C9; monitor INR if coadministered with warfarin; caution with other CYP2C9 substrates (eg, glimepiride, glipizide) Coadministration of ivacaftor or tezacaftor/ivacaftor with digoxin, a sensitive P-gp substrate, increased digoxin AUC by 1.3-fold, consistent with weak inhibition of P-gp by ivacaftor Elexacaftor and its active metabolite (M23-ELX) inhibit uptake by OATP1B1 and OATP1B3 in vitro; coadministration may increase exposures of drugs that are substrates of these transporters (eg, statins, glyburide, nateglinide, repaglinide)

Side Effects

Side effects of Elexacaftor + Tezacaftor + Ivacaftor : >10% Headache (17%) Upper respiratory tract infection (16%) Abdominal pain (14%) Diarrhea (13%) 1-10% Rash (10%) Increased ALT (10%) Increased AST (9%) Increased BUN (9%) Nasal congestion (9%) Rhinorrhea (8%) Rhinitis (7%) Influenza (7%) Sinusitis (5%) Increased bilirubin (5%) 2 to <5% Flatulence Abdominal distension Conjunctivitis Pharyngitis Respiratory tract infection Tonsillitis Urinary tract infection Increased C-reactive protein Hypoglycemia Dizziness Dysmenorrhea Acne Eczema Pruritus

Mode of Action

Elexacaftor and tezacaftor bind to different sites on the cystic fibrosis transmembrane conductance regulator (CFTR) protein and have an additive effect in facilitating the cellular processing and trafficking of F508del-CFTR to increase the amount of CFTR protein delivered to the cell surface compared with either molecule alone Ivacaftor potentiates the channel open probability (or gating) of the CFTR protein at the cell surface