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Elexacaftor, Tezacaftor, And Ivacaftor (Monograph)

Brand name: Trikafta
Drug class: Cystic Fibrosis Transmembrane Conductance Regulator Correctors
VA class: RE000
Chemical name: N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1- yl]pyridine-3-carboxamide
Molecular formula: C26H34F3N7O4SC26H27F3N2O6C24H28N2O3
CAS number: 2216712-66-0

Medically reviewed by Drugs.com on Dec 24, 2022. Written by ASHP.

Introduction

Combination containing elexacaftor and tezacaftor (cystic fibrosis transmembrane conductance regulator [CFTR] correctors) and ivacaftor (CFTR potentiator).

Uses for Elexacaftor, Tezacaftor, And Ivacaftor

Cystic Fibrosis

Elexacaftor/tezacaftor/ivacaftor combination therapy: Treatment of cystic fibrosis in patients ≥6 years of age who have at least one F508del mutation in the CFTR gene or who have at least one mutation in the CFTR gene that is responsive to the combination drug regimen based on in vitro data.

Designated an orphan drug by FDA for this use.

If patient's genotype unknown, use FDA-approved cystic fibrosis mutation test to confirm presence of at least one F508del mutation or a mutation that is responsive based on in vitro data.

There are several approved therapies for specific subpopulations of cystic fibrosis patients; however, the treatment effect in some mutations (e.g. homozygous F508del) are modest. Elexacaftor/tezacaftor/ivacaftor provides a new therapeutic option for patients with mutations not covered by other approved CFTR modulators.

The 2018 Cystic Fibrosis Foundation pulmonary guideline specifically addresses the use of CFTR modulators in patients with cystic fibrosis. Elexacaftor/tezacaftor/ivacaftor was approved after publication of the guideline, and therefore is not addressed.

Elexacaftor, Tezacaftor, And Ivacaftor Dosage and Administration

General

Pretreatment Screening

Patient Monitoring

Administration

Oral Administration

Administer orally with fat-containing food (e.g., eggs, cheese, nuts, whole milk, meats, food prepared with butter or oils) to increase systemic absorption of the drug.

Swallow tablets whole.

If a dose of elexacaftor/tezacaftor/ivacaftor combination therapy is missed by ≤6 hours, the dose should be taken as soon as it is remembered and the original dosing schedule should be resumed.

If a morning dose is missed by >6 hours, the dose should be taken as soon as possible and the evening dose of single-entity ivacaftor should be omitted; the morning fixed-combination dose on the following day should be taken at the regularly scheduled time.

If an evening dose of single-entity ivacaftor is missed by >6 hours, the evening dose should be omitted and the next morning fixed-combination dose should be taken at the regularly scheduled time.

Do not take the morning and evening doses at the same time.

Dosage

Available as a kit consisting of 4 weekly blister cards of 14 tablets containing fixed combination tablets of elexacaftor 100 mg, tezacaftor 50 mg, and ivacaftor 75 mg copackaged with 7 tablets containing 150 mg of single-entity ivacaftor.

Also available as a kit consisting of 4 weekly blister cards of 14 tablets containing fixed combination tablets of elexacaftor 50 mg, tezacaftor 25 mg, and ivacaftor 37.5 mg copackaged with 7 tablets containing 75 mg of single-entity ivacaftor.

Pediatric Patients

Cystic Fibrosis
Oral

Children 6 to <12 years of age: Recommended dosage is weight-based. For patients <30 kg, recommended dosage is elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (administered as 2 fixed-combination tablets each containing elexacaftor 50 mg, tezacaftor 25 mg, and ivacaftor 37.5 mg) once daily in the morning and ivacaftor 75 mg (administered as a single-entity tablet) once daily in the evening approximately 12 hours apart. For patients ≥30 kg, recommended dosage is the same for children ≥12 years of age and adults.

Children ≥12 years of age: Elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg (administered as 2 fixed-combination tablets each containing elexacaftor 100 mg, tezacaftor 50 mg, and ivacaftor 75 mg) once daily in the morning and ivacaftor 150 mg (administered as a single-entity tablet) once daily in the evening approximately 12 hours apart.

Dosage adjustment necessary when used concomitantly with moderate or strong inhibitors of CYP3A. (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.)

Adults

Cystic Fibrosis
Oral

Elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg (administered as 2 fixed-combination tablets each containing elexacaftor 100 mg, tezacaftor 50 mg, and ivacaftor 75 mg) once daily in the morning and ivacaftor 150 mg (administered as a single-entity tablet) once daily in the evening approximately 12 hours apart.

Dosage adjustment necessary when used concomitantly with moderate or strong inhibitors of CYP3A. (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.)

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Dosage adjustment not necessary.

Moderate hepatic impairment (Child-Pugh class B): Use with caution at a reduced dosage of 2 fixed-combination tablets in the morning on day 1 and one fixed-combination tablet in the morning on day 2; continue dosing with 2 elexacaftor/tezacaftor/ivacaftor tablets and one ivacaftor tablet on alternate days in the morning. Do not administer evening dose of ivacaftor in such patients.

Severe hepatic impairment (Child-Pugh class C): Use not recommended.

Renal Impairment

Mild to moderate renal impairment: Dosage adjustment not necessary.

Severe renal impairment (eGFR <30 mL/minute per 1.73 m2) or end-stage renal disease (ESRD): Caution advised.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Elexacaftor, Tezacaftor, And Ivacaftor

Contraindications

Warnings/Precautions

Hepatic Effects

Elevated aminotransferase (ALT or AST) and bilirubin concentrations reported.

Assess serum ALT, AST, and bilirubin concentrations prior to initiation of therapy, every 3 months during the first year of therapy, and annually thereafter. In patients with a history of hepatobiliary disease or liver function test elevations, consider more frequent monitoring.

Interrupt therapy in patients with ALT or AST elevations >5 times the ULN or in those with ALT or AST elevations >3 times the ULN when associated with elevated bilirubin concentrations >2 times the ULN; monitor patients closely until abnormalities resolve. Following resolution of liver function test elevations, consider benefits and risks of resuming therapy.

Interactions with CYP3A Inducers

Concomitant use of elexacaftor/tezacaftor/ivacaftor and potent CYP3A inducers (e.g., rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, St. John's wort [Hypericum perforatum]) substantially decreases systemic exposure of ivacaftor and may decrease exposure of elexacaftor and tezacaftor; decreased exposures may reduce therapeutic efficacy. Concomitant use with potent CYP3A inducers not recommended.

Interactions with CYP3A Inhibitors

Concomitant use of elexacaftor/tezacaftor/ivacaftor and strong or moderate CYP3A inhibitors (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, clarithromycin, fluconazole, erythromycin) increases systemic exposure of elexacaftor, tezacaftor, and ivacaftor. Reduce dosage of elexacaftor/tezacaftor/ivacaftor when used concomitantly with moderate or strong CYP3A inhibitors.

Ocular Effects

Ocular lens opacities (not congenital in nature) reported in pediatric patients receiving ivacaftor-containing drug regimens. Although other risk factors were present in some cases (e.g., corticosteroid use, radiation exposure), possible risk attributable to ivacaftor therapy cannot be excluded. Baseline and follow-up ophthalmologic examinations recommended in pediatric patients.

Specific Populations

Pregnancy

Limited data available regarding use of elexacaftor/tezacaftor/ivacaftor combination therapy or its individual components in pregnant women. Evidence of teratogenicity or adverse effects on fetal development not observed in animals receiving elexacaftor, tezacaftor, or ivacaftor. No animal data available with concomitant use of elexacaftor, tezacaftor, and ivacaftor. Placental transfer of individual components observed in animals.

Lactation

Distributed into milk in rats; not known whether distributed into human milk. Consider developmental and health benefits of breast-feeding and clinical importance of therapy to the woman when deciding whether to use caution or discontinue nursing. Effects of elexacaftor/tezacaftor/ivacaftor on nursing infants or milk production unknown.

Pediatric Use

Safety and efficacy not established in pediatric patients <6 years of age.

Geriatric Use

Clinical trials did not include any patients ≥65 years of age.

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Dosage adjustment not necessary. Monitor liver function tests closely.

Moderate hepatic impairment (Child-Pugh class B): Increased exposure; use with caution and at reduced dosage after weighing risks and benefits of therapy. Monitor liver function tests closely. In a clinical study of 11 subjects with moderate hepatic impairment (Child-Pugh class B), one subject developed total and direct bilirubin elevations >2 times the ULN and one subject developed direct bilirubin elevation >4.5 times the ULN.

Severe hepatic impairment (Child-Pugh class C): Effect on pharmacokinetics not studied, but increased exposure expected. Use not recommended.

Renal Impairment

Mild or moderate renal impairment: Dosage adjustment not necessary.

Severe renal impairment (eGFR <30 mL/minute per 1.73 m2) or ESRD: Use with caution.

Severe Lung Dysfunction

Safety and efficacy in 18 patients with baseline FEV1 <40% of predicted receiving elexacaftor/tezacaftor/ivacaftor combination therapy in one of the principal efficacy studies was comparable to overall study population.

Common Adverse Effects

Adverse effects occurring in ≥5% of patients: Headache, upper respiratory tract infection, abdominal pain, diarrhea, rash, increased ALT concentrations, nasal congestion, increased CK concentrations, increased AST concentrations, rhinorrhea, rhinitis, influenza, sinusitis, increased bilirubin concentrations.

Drug Interactions

Elexacaftor is a substrate of CYP3A isoenzymes (e.g., CYP3A4, 3A5) and P-glycoprotein (P-gp) transport. In vitro, elexacaftor has shown low potential to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and P-gp. In vitro, elexacaftor and its M23 metabolite inhibit the uptake of organic anion transporting polypeptide (OATP) 1B1 and 1B3.

Tezacaftor is a substrate of CYP3A isoenzymes (e.g., CYP3A4, 3A5), P-gp transport, breast cancer resistance protein (BCRP), and OATP1B1. In vitro, tezacaftor has shown low potential to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, P-gp, BCRP, organic cation transporter (OCT) 2, organic anion transporter (OAT) 1, and OAT3.

Ivacaftor is a sensitive substrate of CYP3A (e.g., CYP3A4, 3A5). In vitro, ivacaftor has shown potential to inhibit CYP3A and P-gp, and also may inhibit CYP2C8 and CYP2C9.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Strong CYP3A inhibitors (e.g., clarithromycin, itraconazole, ketoconazole, posaconazole, telithromycin, voriconazole): Possible increased elexacaftor, tezacaftor, and ivacaftor exposures. Reduced dosage recommended. Administer the appropriate fixed-combination dose of elexacaftor/tezacaftor/ivacaftor (as 2 fixed-combination tablets) once daily in the morning twice weekly (approximately 3–4 days apart). Do not administer the evening dose of single-entity ivacaftor.

Moderate CYP3A inhibitors (e.g., fluconazole, erythromycin): Possible increased elexacaftor, tezacaftor, and ivacaftor exposures. Reduced dosage recommended. Administer the appropriate fixed-combination dose of elexacaftor/tezacaftor/ivacaftor (as 2 fixed-combination tablets) once daily in the morning on day 1 and appropriate ivacaftor dose (administered as a single-entity tablet) once daily in the morning on day 2; thereafter, continue dosing with 2 elexacaftor/tezacaftor/ivacaftor tablets and one ivacaftor tablet on alternate days. Do not administer the evening dose of single-entity ivacaftor.

Strong CYP3A inducers: Possible decreased ivacaftor exposure; decreased elexacaftor and tezacaftor exposure expected. Concomitant use not recommended.

Drugs Affected by P-glycoprotein Transport

P-gp substrates: Possible increased exposure, prolonged therapeutic effect, or increased risk of adverse effects of the substrate drug. Use P-gp substrates with narrow therapeutic index concomitantly with caution; monitor patients appropriately.

Drugs Affected by Organic Anion-transporting Polypeptide 1B1 and 1B3

Substrates of OATP1B1 and 1B3: Possible increased exposure, prolonged therapeutic effect, or increased risk of adverse effects of the substrate drug. Use substrates of these transporters concomitantly with caution; monitor patients appropriately.

Specific Drugs

Drug

Interaction

Comments

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Possible decreased elexacaftor, tezacaftor, and ivacaftor exposures and reduced efficacy of elexacaftor/tezacaftor/ivacaftor

Concomitant use not recommended

Antidiabetic agents, sulfonylureas (glimepiride, glipizide, glyburide, nateglinide, repaglinide)

Possible increased exposures of glimepiride, glipizide, glyburide, nateglinide, repaglinide

Use concomitantly with caution and monitor patients appropriately

Antifungals, azoles (fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole)

Itraconazole: Concomitant use with tezacaftor/ivacaftor results in 4- and 15.6-fold increased tezacaftor and ivacaftor AUCs, respectively; concomitant use with single doses of elexacaftor and tezacaftor increased AUCs of elexacaftor and tezacaftor by 2.8- and 4- to 4.5-fold, respectively

Ketoconazole: Concomitant use with a single 150-mg dose of ivacaftor results in 8.5-fold increased AUC of ivacaftor

Fluconazole: Concomitant use with ivacaftor results in 2.9-fold increased AUC of ivacaftor; concomitant use with elexacaftor and tezacaftor may increase AUCs of elexacaftor and tezacaftor by 1.9- to 2.3- and 2.1-fold, respectively

Itraconazole, ketoconazole, posaconazole, voriconazole: Reduced dosage of elexacaftor/tezacaftor/ivacaftor recommended (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.)

Anti-infective agents, macrolides (clarithromycin, erythromycin)

Possible increased elexacaftor, tezacaftor, and ivacaftor exposures

Clarithromycin, erythromycin, telithromycin: Reduced dosage of elexacaftor/tezacaftor/ivacaftor recommended (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.)

Antilipemic agents, hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (i.e., statins)

Possible increased statin exposure

Use concomitantly with caution and monitor patients appropriately

Antimycobacterials (rifabutin, rifampin)

Rifabutin: Possible decreased elexacaftor, tezacaftor, and ivacaftor exposures and reduced efficacy of elexacaftor/tezacaftor/ivacaftor

Rifampin: Decreased ivacaftor exposure by 89%, and decreased elexacaftor and tezacaftor exposure also expected; possible reduced efficacy of elexacaftor/tezacaftor/ivacaftor

Concomitant use not recommended

Ciprofloxacin

No clinically important effect on elexacaftor, tezacaftor, or ivacaftor exposures expected

Dosage adjustment not needed

Digoxin

Increased digoxin exposure; possible prolonged therapeutic effect of digoxin or increased risk of digoxin-associated adverse effects

Use concomitantly with caution and appropriately monitor

Estrogens and progestins

Ethinyl estradiol and levonorgestrel: No substantial effect on exposures of ethinyl estradiol or levonorgestrel

Hormonal contraceptives: Concomitant use not expected to affect efficacy of hormonal contraceptives

Concomitant hormonal contraceptives may play role in rash associated with elexacaftor/tezacaftor/ivacaftor therapy

Consider interruption of elexacaftor/tezacaftor/ivacaftor in patients receiving hormonal contraceptives who develop a rash; once rash resolved, consider resuming elexacaftor/tezacaftor/ivacaftor without the hormonal contraceptive; if rash does not recur, consider resuming hormonal contraceptive

Grapefruit or grapefruit juice

Possible increased elexacaftor, tezacaftor, and ivacaftor exposures

Avoid concomitant use

Immunosuppressants (cyclosporine, everolimus, sirolimus, tacrolimus)

Possible increased immunosuppressant exposures, prolonged therapeutic effect, or increased risk of immunosuppressant-associated adverse effects

Use concomitantly with caution; monitor patients appropriately

St. John’s wort (Hypericum perforatum)

Possible decreased elexacaftor, tezacaftor, and ivacaftor exposures and reduced efficacy of elexacaftor/tezacaftor/ivacaftor

Concomitant use not recommended

Warfarin

Possible increased warfarin exposure

Monitor INR and adjust warfarin dose if needed

Elexacaftor, Tezacaftor, And Ivacaftor Pharmacokinetics

Absorption

Bioavailability

Elexacaftor: Absolute bioavailability 80%.

Tezacaftor and ivacaftor: Oral bioavailability not determined.

Peak plasma concentrations of elexacaftor, tezacaftor, and ivacaftor achieved approximately 6, 3, and 4 hours, respectively, following oral administration in the fed state.

Systemic exposure increases with accumulation ratio of approximately 2.2, 2.1, and 2.4 for elexacaftor, tezacaftor, and ivacaftor, respectively.

Steady-state concentrations of elexacaftor (once daily), tezacaftor (once daily), and ivacaftor (twice daily) achieved within 7, 8, and 3–5 days, respectively.

Food

Administration of single dose of fixed combination elexacaftor/tezacaftor/ivacaftor with fat-containing food resulted in systemic exposures of elexacaftor and ivacaftor about 1.9- to 2.5-fold and 2.5- to 4-fold, respectively, higher when compared with administration in fasting state; systemic exposures of tezacaftor similar to those observed with administration in fasting state.

Special Populations

Mild hepatic impairment (Child-Pugh class A): Effect on pharmacokinetics not studied.

Moderate hepatic impairment (Child-Pugh class B): Increases in AUCs of 25, 73, and 36% and in peak plasma concentrations of 12, 70, and 24% for elexacaftor, the active M23 metabolite of elexacaftor, and elexacaftor and the active M23 metabolite of elexacaftor combined, respectively. A 1.5-fold increase in AUC and a 10% increase in peak plasma concentrations reported for ivacaftor; tezacaftor AUC increases by 20%, and tezacaftor peak plasma concentrations not affected.

Severe hepatic impairment (Child-Pugh class C): Effect on pharmacokinetics not studied. Systemic exposures expected to be higher than that observed in patients with moderate hepatic impairment.

Renal impairment: Not studied in patients with severe renal impairment or in those with ESRD. Population pharmacokinetic data indicate that mild or moderate renal impairment does not substantially affect the clearance of elexacaftor or tezacaftor. Renal excretion of elexacaftor, tezacaftor, and ivacaftor is minimal.

Pediatric patients 12 to <18 years of age: Based on population pharmacokinetic analyses, exposures of elexacaftor, tezacaftor, and ivacaftor similar to those observed in adults.

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.

Plasma Protein Binding

Elexacaftor: >99% (mainly albumin).

Tezacaftor: Approximately 99% (mainly albumin).

Ivacaftor: Approximately 99% (mainly α1-acid glycoprotein, albumin, human γ-globulin).

Elimination

Metabolism

Elexacaftor: Extensively metabolized principally by CYP3A4 and 3A5 to metabolites including M23, which has similar potency to the parent drug.

Tezacaftor: Extensively metabolized principally by CYP3A4 and 3A5 to metabolites including M1, which has similar potency to the parent drug.

Ivacaftor: Extensively metabolized principally by CYP3A4 and 3A5 to metabolites including M1, which has approximately one-sixth the potency of ivacaftor.

Elimination Route

Elexacaftor: Mainly excreted unchanged in feces (87.3%, primarily as metabolites); 0.23% excreted in urine.

Tezacaftor: Mainly excreted unchanged in feces (72% as unchanged drug or M2 metabolite); 14% excreted in urine (0.79% unchanged).

Ivacaftor: Mainly excreted in feces (87.8%); 6.6% excreted in urine.

Half-life

Elexacaftor: 27.4 hours (effective) and 24.7 hours (terminal) in patients with cystic fibrosis.

Tezacaftor: 25.1 hours (effective) and 60.3 hours (terminal) in patients with cystic fibrosis.

Ivacaftor: 15 hours (effective) and 13.1 hours (terminal) in patients with cystic fibrosis.

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted between 15–30°C).

Actions

Advice to Patients

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

The fixed combination of elexacaftor/tezacaftor/ivacaftor can only be obtained through select specialty pharmacies and distributors.

Elexacaftor, Tezacaftor, and Ivacaftor

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Kit

Elexacaftor 50 mg, Tezacaftor 25 mg, and Ivacaftor 37.5 mg (56 film-coated tablets); Ivacaftor 75 mg (28 film-coated tablets)

Trikafta (available as blister cards containing 14 fixed-combination tablets and 7 single-entity tablets)

Vertex Pharmaceuticals

Elexacaftor 100 mg, Tezacaftor 50 mg, and Ivacaftor 75 mg (56 film-coated tablets); Ivacaftor 150 mg (28 film-coated tablets)

Trikafta (available as blister cards containing 14 fixed-combination tablets and 7 single-entity tablets)

Vertex Pharmaceuticals

AHFS DI Essentials™. © Copyright 2024, Selected Revisions December 24, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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