Introduction

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

Uses for Tezacaftor and Ivacaftor

Cystic Fibrosis

Treatment of cystic fibrosis in patients ≥6 years of age who are homozygous for F508del mutation in the CFTR gene or have at least 1 mutation in the CFTR gene that is responsive to the combination drug regimen.

Designated an orphan drug by FDA for treatment of cystic fibrosis.

If the genotype of the patient is not known, use an FDA-approved cystic fibrosis mutation test to detect presence of CFTR mutations followed by verification with bidirectional sequencing when recommended by the mutation test instructions.

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

Tezacaftor and Ivacaftor Dosage and Administration

General

Pretreatment Screening

• Select patients for treatment with tezacaftor/ivacaftor based on whether they have 2 copies of the F508del mutation or at least one mutation in the CFTR gene that is responsive to tezacaftor/ivacaftor based on clinical and/or in vitro assay data. If the patient's genotype is unknown, use an FDA-approved cystic fibrosis mutation test to detect presence of a CFTR mutation followed by verification with bidirectional sequencing when recommended by the mutation test instructions.

• Obtain baseline serum ALT and AST concentrations.

• Baseline ophthalmologic examinations recommended in pediatric patients.

Patient Monitoring

• Assess serum ALT and AST concentrations every 3 months during the first year of therapy and annually thereafter. In patients with a history of ALT or AST elevations, consider more frequent monitoring. Closely monitor patients who develop increased ALT, AST, or bilirubin concentrations until abnormalities resolve.

• Follow-up ophthalmologic examinations recommended in pediatric patients.

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.

Dosage

Available as a kit containing 4 weekly blister cards of 7 tablets containing 100 mg of tezacaftor in fixed combination with 150 mg of ivacaftor copackaged with 7 tablets containing 150 mg of single-entity ivacaftor.

Also available as a kit containing 4 weekly blister cards of 7 tablets containing 50 mg of tezacaftor in fixed combination with 75 mg of ivacaftor copackaged with 7 tablets containing 75 mg of single-entity ivacaftor.

Pediatric Patients

Cystic Fibrosis

Oral

Children 6 to <12 years of age weighing <30 kg: Tezacaftor 50 mg/ivacaftor 75 mg once daily in the morning and single-entity ivacaftor 75 mg once daily in the evening (taken approximately 12 hours apart).

Children 6 to <12 years of age weighing ≥30 kg: Tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning and single-entity ivacaftor 150 mg once daily in the evening (taken approximately 12 hours apart).

Children ≥12 years of age: Tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning and single-entity ivacaftor 150 mg once daily in the evening (taken approximately 12 hours apart).

Dosage adjustment necessary when used concomitantly with moderate or strong inhibitors of CYP3A.

Dosage Modification for Concomitant Use of Moderate or Strong CYP3A Inhibitors

Oral

Pediatric patients 6 to <12 years of age weighing <30 kg receiving a moderate CYP3A inhibitor (e.g., erythromycin, fluconazole): administer tezacaftor 50 mg/ivacaftor 75 mg fixed-combination tablets once every other day and single-entity ivacaftor 75 mg once every other day, on alternate days in the morning. Do not administer the evening dose of single-entity ivacaftor 75 mg in such patients.

Pediatric patients 6 to <12 years of age weighing ≥30 kg receiving a moderate CYP3A inhibitor (e.g., erythromycin, fluconazole): administer 100 mg/ivacaftor 150 mg fixed-combination tablets once every other day and single-entity ivacaftor 150 mg once every other day, on alternate days in the morning. Do not administer the evening dose of single-entity ivacaftor 150 mg in such patients.

Pediatric patients ≥12 years of age receiving a moderate CYP3A inhibitor (e.g., erythromycin, fluconazole): administer tezacaftor 100 mg/ivacaftor 150 mg fixed-combination tablets once every other day and single-entity ivacaftor 150 mg once every other day, on alternate days in the morning. Do not administer the evening dose of single-entity ivacaftor 150 mg in such patients.

Pediatric patients 6 to <12 years of age weighing <30 kg receiving a strong CYP3A inhibitor (e.g., clarithromycin, itraconazole, ketoconazole, posaconazole, telithromycin, voriconazole): administer tezacaftor 50 mg/ivacaftor 75 mg fixed-combination tablets twice weekly, approximately 3–4 days apart. Do not administer the evening dose of single-entity ivacaftor 75 mg in such patients.

Pediatric patients 6 to <12 years of age weighing ≥30 kg receiving a strong CYP3A inhibitor (e.g., clarithromycin, itraconazole, ketoconazole, posaconazole, telithromycin, voriconazole): administer tezacaftor 100 mg/ivacaftor 150 mg fixed-combination tablets twice weekly, approximately 3–4 days apart. Do not administer the evening dose of single-entity ivacaftor 150 mg in such patients.

Pediatric patients ≥12 years of age receiving a strong CYP3A inhibitor (e.g., clarithromycin, itraconazole, ketoconazole, posaconazole, telithromycin, voriconazole): administer tezacaftor 100 mg/ivacaftor 150 mg fixed-combination tablets twice weekly, approximately 3–4 days apart. Do not administer the evening dose of single-entity ivacaftor 150 mg in such patients.

Adults

Cystic Fibrosis

Oral

Tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning and single-entity ivacaftor 150 mg once daily in the evening (taken approximately 12 hours apart).

Dosage adjustment necessary when used concomitantly with moderate or strong inhibitors of CYP3A.

Dosage Modification for Concomitant Use of Moderate or Strong CYP3A Inhibitors

Oral

Concomitant use of a moderate CYP3A inhibitor (e.g., erythromycin, fluconazole): administer tezacaftor 100 mg/ivacaftor 150 mg fixed-combination tablets once every other day and single-entity ivacaftor 150 mg once every other day, given on alternate days in the morning. Do not administer the evening dose of single-entity ivacaftor 150 mg.

Concomitant use of a strong CYP3A inhibitor (e.g., clarithromycin, itraconazole, ketoconazole, posaconazole, telithromycin, voriconazole): administer tezacaftor 100 mg/ivacaftor 150 mg fixed-combination tablets twice weekly, approximately 3–4 days apart. Do not administer the evening dose of single-entity ivacaftor 150 mg.

Special Populations

Hepatic Impairment

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

Patients 6 to <12 years of age weighing <30 kg with moderate hepatic impairment (Child-Pugh class B): tezacaftor 50 mg/ivacaftor 75 mg once daily in the morning. Do not administer the evening dose of single-entity ivacaftor 75 mg in such patients.

Patients 6 to <12 years of age weighing ≥30 kg with moderate hepatic impairment (Child-Pugh class B): tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning. Do not administer the evening dose of single-entity ivacaftor 150 mg in such patients.

Patients ≥12 years of age with moderate hepatic impairment (Child-Pugh class B): tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning. Do not administer the evening dose of single-entity ivacaftor 150 mg in such patients.

Patients 6 to <12 years of age weighing <30 kg with severe hepatic impairment (Child-Pugh class C): tezacaftor 50 mg/ivacaftor 75 mg once daily in the morning or less frequently. Do not administer the evening dose of single-entity ivacaftor 75 mg in such patients.

Patients 6 to <12 years of age weighing ≥30 kg with severe hepatic impairment (Child-Pugh class C): tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning or less frequently. Do not administer the evening dose of single-entity ivacaftor 150 mg in such patients.

Patients ≥12 years of age with severe hepatic impairment (Child-Pugh class C): tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning or less frequently. Do not administer the evening dose of single-entity ivacaftor 150 mg in such patients.

Renal Impairment

Mild to moderate renal impairment: Dosage adjustment not necessary.

Severe renal impairment or end-stage renal disease (ESRD): Caution advised.

Geriatric Patients

No specific dosage recommendations at this time.

Contraindications

• None.

Warnings/Precautions

Hepatic Effects

Elevated ALT or AST concentrations reported.

Assess serum ALT and AST concentrations prior to initiation of therapy, every 3 months during the first year, and annually thereafter. In patients with a history of ALT or AST elevations, consider more frequent monitoring. Closely monitor patients who develop increased ALT, AST, or bilirubin concentrations until abnormalities resolve.

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. Following resolution of ALT or AST elevations, consider benefits and risks of resuming therapy.

Interactions with CYP3A Inducers

Concomitant use with strong CYP3A inducers substantially decreases systemic exposure of ivacaftor and may decrease exposure of tezacaftor; decreased exposures may reduce therapeutic efficacy. Concomitant use with strong CYP3A inducers not recommended. (See Interactions.)

Ocular Effects

Ocular lens opacities (not congenital in nature) reported in pediatric patients receiving tezacaftor/ivacaftor combination therapy or ivacaftor monotherapy. Baseline and follow-up ophthalmologic examinations recommended in pediatric patients.

Specific Populations

Pregnancy

Limited data available regarding use of 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 tezacaftor or ivacaftor. No animal data available with concomitant use of tezacaftor and ivacaftor. Placental transfer of tezacaftor observed in pregnant rats; placental transfer of ivacaftor observed in pregnant rats and rabbits.

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 tezacaftor/ivacaftor in fixed combination on nursing infants or milk production unknown.

Pediatric Use

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

Efficacy in patients 6 to <12 years of age extrapolated from efficacy results in patients ≥12 years of age with support from population pharmacokinetic analyses demonstrating similar drug exposures in patients 6 to <12 years of age and those ≥12 years of age. Safety profile in patients 6 to <12 years of age similar to that observed in patients ≥12 years of age.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.

Hepatic Impairment

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

Moderate hepatic impairment (Child-Pugh class B): Increased exposure; dosage reduction recommended.

Severe hepatic impairment (Child-Pugh class C): Effect on pharmacokinetics not studied, but increased exposure expected. Use with caution and at reduced dosage after weighing risks and benefits of therapy.

Renal Impairment

Not studied in patients with moderate or severe renal impairment or in those with ESRD.

Mild or moderate renal impairment: Dosage adjustment not necessary.

Severe renal impairment (Cl_cr ≤30 mL/minute) or ESRD: Use with caution.

Common Adverse Effects

Adverse effects (≥3% of patients): headache, nausea, sinus congestion, dizziness.

General

Pretreatment Screening

• Select patients for treatment with tezacaftor/ivacaftor based on whether they have 2 copies of the F508del mutation or at least one mutation in the CFTR gene that is responsive to tezacaftor/ivacaftor based on clinical and/or in vitro assay data. If the patient's genotype is unknown, use an FDA-approved cystic fibrosis mutation test to detect presence of a CFTR mutation followed by verification with bidirectional sequencing when recommended by the mutation test instructions.

• Obtain baseline serum ALT and AST concentrations.

• Baseline ophthalmologic examinations recommended in pediatric patients.

Patient Monitoring

• Assess serum ALT and AST concentrations every 3 months during the first year of therapy and annually thereafter. In patients with a history of ALT or AST elevations, consider more frequent monitoring. Closely monitor patients who develop increased ALT, AST, or bilirubin concentrations until abnormalities resolve.

• Follow-up ophthalmologic examinations recommended in pediatric patients.

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.

Dosage

Available as a kit containing 4 weekly blister cards of 7 tablets containing 100 mg of tezacaftor in fixed combination with 150 mg of ivacaftor copackaged with 7 tablets containing 150 mg of single-entity ivacaftor.

Also available as a kit containing 4 weekly blister cards of 7 tablets containing 50 mg of tezacaftor in fixed combination with 75 mg of ivacaftor copackaged with 7 tablets containing 75 mg of single-entity ivacaftor.

Pediatric Patients

Cystic Fibrosis

Oral

Children 6 to <12 years of age weighing <30 kg: Tezacaftor 50 mg/ivacaftor 75 mg once daily in the morning and single-entity ivacaftor 75 mg once daily in the evening (taken approximately 12 hours apart).

Children 6 to <12 years of age weighing ≥30 kg: Tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning and single-entity ivacaftor 150 mg once daily in the evening (taken approximately 12 hours apart).

Children ≥12 years of age: Tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning and single-entity ivacaftor 150 mg once daily in the evening (taken approximately 12 hours apart).

Dosage adjustment necessary when used concomitantly with moderate or strong inhibitors of CYP3A.

Dosage Modification for Concomitant Use of Moderate or Strong CYP3A Inhibitors

Oral

Pediatric patients 6 to <12 years of age weighing <30 kg receiving a moderate CYP3A inhibitor (e.g., erythromycin, fluconazole): administer tezacaftor 50 mg/ivacaftor 75 mg fixed-combination tablets once every other day and single-entity ivacaftor 75 mg once every other day, on alternate days in the morning. Do not administer the evening dose of single-entity ivacaftor 75 mg in such patients.

Pediatric patients 6 to <12 years of age weighing ≥30 kg receiving a moderate CYP3A inhibitor (e.g., erythromycin, fluconazole): administer 100 mg/ivacaftor 150 mg fixed-combination tablets once every other day and single-entity ivacaftor 150 mg once every other day, on alternate days in the morning. Do not administer the evening dose of single-entity ivacaftor 150 mg in such patients.

Pediatric patients ≥12 years of age receiving a moderate CYP3A inhibitor (e.g., erythromycin, fluconazole): administer tezacaftor 100 mg/ivacaftor 150 mg fixed-combination tablets once every other day and single-entity ivacaftor 150 mg once every other day, on alternate days in the morning. Do not administer the evening dose of single-entity ivacaftor 150 mg in such patients.

Pediatric patients 6 to <12 years of age weighing <30 kg receiving a strong CYP3A inhibitor (e.g., clarithromycin, itraconazole, ketoconazole, posaconazole, telithromycin, voriconazole): administer tezacaftor 50 mg/ivacaftor 75 mg fixed-combination tablets twice weekly, approximately 3–4 days apart. Do not administer the evening dose of single-entity ivacaftor 75 mg in such patients.

Pediatric patients 6 to <12 years of age weighing ≥30 kg receiving a strong CYP3A inhibitor (e.g., clarithromycin, itraconazole, ketoconazole, posaconazole, telithromycin, voriconazole): administer tezacaftor 100 mg/ivacaftor 150 mg fixed-combination tablets twice weekly, approximately 3–4 days apart. Do not administer the evening dose of single-entity ivacaftor 150 mg in such patients.

Pediatric patients ≥12 years of age receiving a strong CYP3A inhibitor (e.g., clarithromycin, itraconazole, ketoconazole, posaconazole, telithromycin, voriconazole): administer tezacaftor 100 mg/ivacaftor 150 mg fixed-combination tablets twice weekly, approximately 3–4 days apart. Do not administer the evening dose of single-entity ivacaftor 150 mg in such patients.

Adults

Cystic Fibrosis

Oral

Tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning and single-entity ivacaftor 150 mg once daily in the evening (taken approximately 12 hours apart).

Dosage adjustment necessary when used concomitantly with moderate or strong inhibitors of CYP3A.

Dosage Modification for Concomitant Use of Moderate or Strong CYP3A Inhibitors

Oral

Concomitant use of a moderate CYP3A inhibitor (e.g., erythromycin, fluconazole): administer tezacaftor 100 mg/ivacaftor 150 mg fixed-combination tablets once every other day and single-entity ivacaftor 150 mg once every other day, given on alternate days in the morning. Do not administer the evening dose of single-entity ivacaftor 150 mg.

Concomitant use of a strong CYP3A inhibitor (e.g., clarithromycin, itraconazole, ketoconazole, posaconazole, telithromycin, voriconazole): administer tezacaftor 100 mg/ivacaftor 150 mg fixed-combination tablets twice weekly, approximately 3–4 days apart. Do not administer the evening dose of single-entity ivacaftor 150 mg.

Special Populations

Hepatic Impairment

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

Patients 6 to <12 years of age weighing <30 kg with moderate hepatic impairment (Child-Pugh class B): tezacaftor 50 mg/ivacaftor 75 mg once daily in the morning. Do not administer the evening dose of single-entity ivacaftor 75 mg in such patients.

Patients 6 to <12 years of age weighing ≥30 kg with moderate hepatic impairment (Child-Pugh class B): tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning. Do not administer the evening dose of single-entity ivacaftor 150 mg in such patients.

Patients ≥12 years of age with moderate hepatic impairment (Child-Pugh class B): tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning. Do not administer the evening dose of single-entity ivacaftor 150 mg in such patients.

Patients 6 to <12 years of age weighing <30 kg with severe hepatic impairment (Child-Pugh class C): tezacaftor 50 mg/ivacaftor 75 mg once daily in the morning or less frequently. Do not administer the evening dose of single-entity ivacaftor 75 mg in such patients.

Patients 6 to <12 years of age weighing ≥30 kg with severe hepatic impairment (Child-Pugh class C): tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning or less frequently. Do not administer the evening dose of single-entity ivacaftor 150 mg in such patients.

Patients ≥12 years of age with severe hepatic impairment (Child-Pugh class C): tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning or less frequently. Do not administer the evening dose of single-entity ivacaftor 150 mg in such patients.

Renal Impairment

Mild to moderate renal impairment: Dosage adjustment not necessary.

Severe renal impairment or end-stage renal disease (ESRD): Caution advised.

Geriatric Patients

No specific dosage recommendations at this time.

Tezacaftor is a substrate of CYP3A isoenzymes (e.g., CYP3A4, CYP3A5), P-glycoprotein (P-gp) transport, breast cancer resistance protein (BCRP), and organic anion transporting polypeptide (OATP) 1B1.

Ivacaftor is a sensitive substrate of CYP3A. In vitro, ivacaftor has potential to inhibit CYP3A and P-gp, and also may inhibit CYP2C9.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP3A substrates: No dosage adjustment needed.

Strong CYP3A inhibitors: Pharmacokinetic interaction (possible increased tezacaftor and ivacaftor exposures). Reduce dosage to tezacaftor 100 mg/ivacaftor 150 mg in fixed combination twice weekly, approximately 3–4 days apart. Do not administer single-entity ivacaftor 150 mg.

Moderate CYP3A inhibitors: Pharmacokinetic interaction (possible increased tezacaftor and ivacaftor exposures). In adults, children ≥12 years of age, and children 6 to <12 years of age weighing ≥30 kg, reduce dosage to tezacaftor 100 mg/ivacaftor 150 mg in fixed combination once every other day in combination with single-entity ivacaftor 150 mg once every other day, given on alternate days. Do not administer the evening dose of single-entity ivacaftor 150 mg in such patients. In children 6 to <12 years of age weighing <30 kg, reduce dosage to tezacaftor 50 mg/ivacaftor 75 mg in fixed combination once every other day in combination with single-entity ivacaftor 75 mg once every other day, given on alternate days. Do not administer the evening dose of single-entity ivacaftor 75 mg in such patients.

Strong CYP3A inducers: Pharmacokinetic interaction (decreased ivacaftor exposure; decreased tezacaftor exposure expected). Concomitant use not recommended.

Drugs Affected by P-glycoprotein Transport

P-gp substrates: Pharmacokinetic interaction (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.

Specific Drugs