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

• Obtain a baseline ophthalmologic examination in pediatric patients.

• Obtain liver function tests prior to initiation of therapy.

Patient Monitoring

• Perform follow-up ophthalmologic examinations in pediatric patients.

• Monitor liver function tests every 3 months during the first year of therapy and annually thereafter.

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.

Contraindications

• Manufacturer states none known.

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.

General

Pretreatment Screening

• Obtain a baseline ophthalmologic examination in pediatric patients.

• Obtain liver function tests prior to initiation of therapy.

Patient Monitoring

• Perform follow-up ophthalmologic examinations in pediatric patients.

• Monitor liver function tests every 3 months during the first year of therapy and annually thereafter.

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.

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