consider more frequent monitoring for those with history of hepatic disease; interrupt dosing for significant elevations Drug interaction overview 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) 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 ratsPregnancy 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. Mechanism 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 Absorption Absolute bioavailability Elexacaftor: 80% Tezacaftor: Not determined Ivacaftor: Not determined Peak plasma time Elexacaftor: 6 hr Tezacaftor: 3 hr Ivacaftor: 4 hr Peak plasma concentration Elexacaftor: 8.7 mcg/ml Tezacaftor: 6.8 mcg/mL Ivacaftor: 1.2 mcg/mL AUC Elexacaftor: 162 mcg⋅h/mL Tezacaftor: 94.5 mcg⋅h/mL Ivacaftor: 11.7 mcg⋅h/mL Time to steady-state Elexacaftor: Within 14 days Tezacaftor: Within 8 days Ivacaftor: Within 3-5 days Distribution Protein bound Elexacaftor: >99% Tezacaftor: ~99% Ivacaftor: ~99% Vd Elexacaftor: 53.7 L Tezacaftor: 82 L Ivacaftor: 293 L Metabolism Elexacaftor Primary pathway: CYP3A4/5 Active metabolite: M23-ELX Metabolite potency relative to parent: Similar Tezacaftor Primary pathway: CYP3A4/5 Active metabolite: M1-TEZ Metabolite potency relative to parent: Similar Ivacaftor Primary pathway: CYP3A4/5 Active metabolite: M1-IVA Metabolite potency relative to parent: ~1/6 Elimination Half-life Elexacaftor: 29.8 hr Tezacaftor: 17.4 hr Ivacaftor: 15 hr Clearance Elexacaftor: 1.18 L/hr Tezacaftor: 0.79 L/hr Ivacaftor: 10.2 L/hr Excretion Elexacaftor: Feces (87.3%; primarily as metabolites); urine (0.23%) Tezacaftor: Feces (72%; unchanged or as M2-TEZ); urine (14%; 0.79% unchanged) Ivacaftor: Feces (87.8%); urine (6.6%) Pharmacogenomics CFTR gene mutations that produce CFTR protein and are responsive to ivacaftor 3141del9, 546insCTA A46D, A120T, A234D, A349V, A455E, A1006E, A1067T D110E, D110H, D192G, D443Y, D4437;G576A;R668C, D579G, D614G, D836Y, D924N, D979V, D1152H, D1270N E56K, E60K, E92K, E116K, E193K, E403D, E588V, E822K F191V, F311del, F311L, F508C, F508C;S1251N, F508del, F575Y, F1016S, F1052V, F1074L, F1099L G27R, G85E, G126D, G178E, G178R, G194R, G194V, G314E, G463V, G480C, G551D, G551S, G576A, G576A;R668C, G970D, G1061R, G1069R, G1244E, G1249R, G1349D H939R, H199Y, H939R, H1054D, H1085P, H1085R, H1375P I148T, I175V, I336K, I502T, I601F, I618T I807M, I980K, I1027T, I1139V, I1269N, I1366N K1060T L15P, L165S, L206W, L320V, L346P, L453S, L967S, L997F, L1077P, L1324P, L1335P, L1480P M152V, M265R, M952I, M952T, M1101K P5L, P67L, P205S, P574H Q98R, Q237E, Q237H, Q359R, Q1291R R31L, R74W, R74W;D1270N, R74W;V201M, R74W;V201M;D127N, R75Q, R117C, R117G, R117H, R117L, R117P, R170H, R258G, R334L, R334Q, R347H, R347L, R347P, R352Q, R352W, R553Q, R668C, R751L, R792G, R933G, R1066H, R1070Q, R1070W, R1162L, R1283M, R1283S S13F, S341P, S364P, S492F S549N, S549R, S737F, S589N, S737F, S912L, S945L, S977F, S1159F, S1159P, S1251N, S1255P T338I, T1036N, T1053I V201M, V232D, V456F, V562I, V754M, V1153E, V1240G, V1293G W361R, W1098C, W1282R Y109N, Y161D, Y161S, Y563N, Y1014C, Y1032C Oral 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) Missed dose ≤6 hr since missing a morning or evening dose: Take missed dose as soon as possible and continue on the original schedule >6 hr since a missed morning dose: Take missed dose as soon as possible and NOT take the evening dose; the next scheduled morning dose should be taken at the usual time >6 hr since a missed evening dose: Do NOT take the missed dose; the next scheduled morning dose should be taken at the usual time Morning and evening doses should not be taken at the same time Oral granules Administer each dose immediately before or after ingestion of fat containing food Mix entire contents of each packet of oral granules with 1 teaspoon (5 mL) of age-appropriate soft food or liquid (eg, pureed fruits or vegetables, yogurt, applesauce, water, milk, juice) that is at or below room temperature Once mixed, consume product completely within 1 hour Storage Tablets: Store at 68-77ºF (20-25ºC); excursions permitted to 59-86ºF (15-30ºC) Oral granules Store at 68-77ºF (20-25ºC); excursions permitted to 59-86ºF (15-30ºC) Use within 1 hr of mixing No images available for this drug. No images available for this drug.A Patient Handout is not currently available for this monograph.Print FormularyPatient DiscountsAdding plans allows you to compare formulary status to other drugs in the same class.To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.Create Your List of PlansAdding plans allows you to:View the formulary and any restrictions for each plan.Manage and view all your plans together – even plans in different states.Compare formulary status to other drugs in the same class.Access your plan list on any device – mobile or desktop. The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information. View explanations for tiers and restrictions Tier Description 1 This drug is available at the lowest co-pay. 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