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Tezacaftor and Ivacaftor

Class: Cystic Fibrosis Transmembrane Conductance Regulator Correctors
Chemical Name: 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)indol-5-yl]cyclopropane-1-carboxamide
Molecular Formula: C26H27F3N2O6C24H28N2O3
CAS Number: 1152311-62-0
Brands: Symdeko

Medically reviewed by Drugs.com. Last updated on Feb 8, 2021.

Introduction

Combination containing tezacaftor (cystic fibrosis transmembrane conductance regulator [CFTR] corrector) and ivacaftor (CFTR potentiator).1 3 4 6

Uses for Tezacaftor and Ivacaftor

Cystic Fibrosis

Tezacaftor/ivacaftor combination therapy: Treatment of cystic fibrosis in patients homozygous for F508del mutation in the CFTR gene or having at least 1 mutation in the CFTR gene that is responsive to the combination drug regimen (i.e., E56K, P67L, R74W, D110E, D110H, R117C, E193K, L206W, R347H, R352Q, A455E, D579G, 711+3A→G, E831X, S945L, S977F, F1052V, K1060T, A1067T, R1070W, F1074L, D1152H, D1270N, 2789+5G→A, 3272-26A→G, 3849+10kbC→T).1 3 4

Designated an orphan drug by FDA for this use.2

Use 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.1

Tezacaftor and Ivacaftor Dosage and Administration

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.1 (See Food under Pharmacokinetics.)

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.1

Pediatric Patients

Cystic Fibrosis
Oral

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 (approximately 12 hours apart).1

Dosage adjustment necessary when used concomitantly with moderate or potent inhibitors of CYP3A.1 (See Interactions.)

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 (approximately 12 hours apart).1

Dosage adjustment necessary when used concomitantly with moderate or potent inhibitors of CYP3A.1 (See Interactions.)

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Dosage adjustment not necessary.1

Moderate hepatic impairment (Child-Pugh class B): Tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning.1 Do not administer the evening dose of ivacaftor 150 mg in such patients.1

Severe hepatic impairment (Child-Pugh class C): Use with caution and at a dosage of tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning or less, after weighing risks and benefits of therapy.1 Do not administer the evening dose of ivacaftor 150 mg in such patients.1

Renal Impairment

Mild to moderate renal impairment: Dosage adjustment not necessary.1

Severe renal impairment or end-stage renal disease (ESRD): Caution advised.1

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Cautions for Tezacaftor and Ivacaftor

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Hepatic Effects

Elevated ALT or AST concentrations reported.1

Assess serum ALT and AST concentrations prior to initiation of therapy, every 3 months during the first year, and annually thereafter.1 In patients with a history of AST or ALT elevations, consider more frequent monitoring.1 Closely monitor patients who develop increased ALT, AST, or bilirubin concentrations until abnormalities resolve.1

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.1 Following resolution of ALT or AST elevations, consider benefits and risks of resuming therapy.1

Interactions with CYP3A Inducers

Concomitant use with potent CYP3A inducers substantially decreases systemic exposure of ivacaftor and may decrease exposure of tezacaftor; decreased exposures may reduce therapeutic efficacy.1 Concomitant use with potent CYP3A inducers not recommended.1 (See Interactions.)

Ocular Effects

Ocular lens opacities (not congenital in nature) reported in pediatric patients receiving tezacaftor/ivacaftor combination therapy or ivacaftor monotherapy.1 Baseline and follow-up ophthalmologic examinations recommended in pediatric patients.1

Specific Populations

Pregnancy

Limited data available regarding use of tezacaftor/ivacaftor combination therapy or its individual components in pregnant women.1 Evidence of teratogenicity or adverse effects on fetal development not observed in animals receiving tezacaftor or ivacaftor.1 No animal data available with concomitant use of tezacaftor and ivacaftor.1 Placental transfer of tezacaftor observed in pregnant rats; placental transfer of ivacaftor observed in pregnant rats and rabbits.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 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.1 Effects of tezacaftor/ivacaftor in fixed combination on nursing infants or milk production unknown.1

Pediatric Use

Safety and efficacy not established in pediatric patients <12 years of age.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Effect on pharmacokinetics not studied; dosage adjustment not necessary.1 (See Special Populations under Pharmacokinetics.)

Moderate hepatic impairment (Child-Pugh class B): Increased exposure; dosage reduction recommended.1 (See Hepatic Impairment under Dosage and Administration and Special Populations under Pharmacokinetics.)

Severe hepatic impairment (Child-Pugh class C): Effect on pharmacokinetics not studied, but increased exposure expected.1 Use with caution and at reduced dosage after weighing risks and benefits of therapy.1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Not studied in patients with moderate or severe renal impairment or in those with ESRD.1

Mild or moderate renal impairment: Dosage adjustment not necessary.1

Severe renal impairment (Clcr ≤30 mL/minute) or ESRD: Use with caution.1

Common Adverse Effects

Headache,1 3 4 nausea,1 nasopharyngitis,3 4 increased sputum production,4 sinus congestion,1 diarrhea,4 dizziness,1 increased CPK concentrations.4

Interactions for Tezacaftor and Ivacaftor

Tezacaftor is a substrate of CYP3A isoenzymes (e.g., CYP3A4, 3A5), P-glycoprotein (P-gp) transport, breast cancer resistance protein (BCRP), and organic anion transporting polypeptide (OATP) 1B1.1

Ivacaftor is a sensitive substrate of CYP3A.1 In vitro, ivacaftor has potential to inhibit CYP3A and P-gp, and also may inhibit CYP2C9.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP3A substrates: No dosage adjustment needed.1

Potent CYP3A inhibitors: Pharmacokinetic interaction (possible increased tezacaftor and ivacaftor exposures).1 Reduce dosage to tezacaftor 100 mg/ivacaftor 150 mg in fixed combination twice weekly, approximately 3–4 days apart.1 Do not administer single-entity ivacaftor 150 mg.1

Moderate CYP3A inhibitors: Pharmacokinetic interaction (possible increased tezacaftor and ivacaftor exposures).1 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.1

Potent CYP3A inducers: Pharmacokinetic interaction (decreased ivacaftor exposure; decreased tezacaftor exposure expected).1 Concomitant use not recommended.1

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).1 Use P-gp substrates with narrow therapeutic index concomitantly with caution; monitor patients appropriately.1

Specific Drugs

Drug or Food

Interaction

Comments

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Possible decreased tezacaftor and ivacaftor exposures and reduced efficacy of tezacaftor/ivacaftor1

Concomitant use not recommended1

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, respectively1

Fluconazole: Concomitant use with ivacaftor results in threefold increased ivacaftor AUC;1 concomitant use with tezacaftor may increase tezacaftor exposures approximately twofold1

Itraconazole, ketoconazole, posaconazole, voriconazole: Reduce dosage to tezacaftor 100 mg/ivacaftor 150 mg twice weekly, approximately 3–4 days apart1

Fluconazole: Reduce dosage to tezacaftor 100 mg/ivacaftor 150 mg once every other day and single-entity ivacaftor 150 mg once every other day, given on alternate days1

Antimycobacterials (rifabutin, rifampin)

Rifabutin: Possible decreased tezacaftor and ivacaftor exposures and reduced efficacy of tezacaftor/ivacaftor1

Rifampin: Decreased ivacaftor exposure by 89%; decreased tezacaftor exposure also expected; possible reduced efficacy of tezacaftor/ivacaftor1

Concomitant use not recommended1

Ciprofloxacin

No clinically important effect on tezacaftor or ivacaftor exposures1

Dosage adjustment not needed1

Digoxin

Increased digoxin exposure;1 possible prolonged therapeutic effect of digoxin or increased risk of digoxin-associated adverse effects1

Use concomitantly with caution and appropriately monitor1

Erythromycin

Possible increased tezacaftor and ivacaftor exposures1

Reduce dosage to tezacaftor 100 mg/ivacaftor 150 mg once every other day and single-entity ivacaftor 150 mg once every other day, given on alternate days1

Estrogens and progestins

Ethinyl estradiol and norethindrone: No substantial effect on exposures of ethinyl estradiol, norethindrone, tezacaftor, or ivacaftor1

Hormonal contraceptives: Concomitant use not expected to affect efficacy of hormonal contraceptives1

Grapefruit or grapefruit juice

Possible increased tezacaftor and ivacaftor exposures1

Avoid concomitant use1

Immunosuppressants (cyclosporine, everolimus, sirolimus, tacrolimus)

Possible increased immunosuppressant exposures, prolonged therapeutic effect, or increased risk of immunosuppressant-associated adverse effects1

Use concomitantly with caution; monitor patients appropriately 1

Seville oranges

Possible increased tezacaftor and ivacaftor exposures1

Avoid concomitant use1

St. John’s wort (Hypericum perforatum)

Possible decreased tezacaftor and ivacaftor exposures and reduced efficacy of tezacaftor/ivacaftor1

Concomitant use not recommended1

Tezacaftor and Ivacaftor Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations of tezacaftor and ivacaftor achieved approximately 4 and 6 hours, respectively, after oral administration in the fed state.1

Systemic exposure increases with accumulation ratio of approximately 1.5 (for tezacaftor) and approximately 2.2 (for ivacaftor).1

Steady-state concentrations of tezacaftor (once daily) and ivacaftor (twice daily) achieved within 8 and 3–5 days, respectively.1

Food

Administration of single dose of fixed combination of tezacaftor/ivacaftor with fat-containing food resulted in systemic exposures of ivacaftor approximately threefold higher when compared with administration in fasting state;1 systemic exposures of tezacaftor similar to those observed with administration in fasting state.1

Special Populations

Mild hepatic impairment (Child-Pugh class A): Effect on pharmacokinetics not studied.1

Moderate hepatic impairment (Child-Pugh class B): AUCs and peak plasma concentrations of tezacaftor and ivacaftor increased by 36 and 50%, respectively, when compared with healthy individuals.1 In a separate study, a twofold increased AUC observed when compared with healthy individuals, but peak plasma concentrations similar between the 2 groups.1

Severe hepatic impairment (Child-Pugh class C): Effect on pharmacokinetics not studied.1 Systemic exposures expected to be higher than that observed in patients with moderate hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration.)

Renal impairment: Not studied in patients with moderate or severe renal impairment or in those with ESRD.1 Population pharmacokinetic data indicate that mild or moderate renal impairment does not substantially affect clearance of tezacaftor.1 (See Renal Impairment under Cautions.)

Pediatric patients 12 to <18 years of age: Based on population pharmacokinetic analyses, exposures of tezacaftor and ivacaftor similar to those observed in adults.1

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

Tezacaftor: Approximately 99% (mainly albumin).1

Ivacaftor: Approximately 99% (mainly α1-acid glycoprotein, albumin).1

Elimination

Metabolism

Tezacaftor: Extensively metabolized principally by CYP3A4 and 3A5 to 3 major circulating metabolites (M1, M2, M5).1 M1 has similar potency to the parent drug and is pharmacologically active; M2 has less pharmacologic activity than M1; M5 is inactive.1 M3 is a minor metabolite resulting from direct glucuronidation.1

Ivacaftor: Extensively metabolized principally by CYP3A4 and 3A5 to 2 major metabolites (M1, M6).1 M1 has approximately one-sixth the potency of ivacaftor; M6 is inactive.1

Elimination Route

Tezacaftor: Mainly excreted unchanged in feces (72% as unchanged drug or M2 metabolite);1 14% excreted in urine (mainly as M2 metabolite).1

Ivacaftor: Mainly excreted in feces (87.8%) after metabolic conversion.1 Ivacaftor and metabolites minimally excreted in urine (6.6%).1

Half-life

Tezacaftor: 15 hours in patients with cystic fibrosis.1

Ivacaftor: 13.7 hours in patients with cystic fibrosis.1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Actions

  • Tezacaftor/ivacaftor combination therapy contains 2 drugs acting directly on CFTR protein, a chloride channel present at epithelial cell surface in multiple organs involved in salt and fluid transport.1 6 7 8 Tezacaftor is a CFTR corrector; ivacaftor is a CFTR potentiator.1 3

  • Mutations in the gene encoding CFTR affect quantity or function of this protein at the cell surface resulting in cystic fibrosis.5 6 7 8

  • Tezacaftor facilitates processing and trafficking of normal and select mutant forms of CFTR protein to cell surface.1 6 7

  • Ivacaftor facilitates increased chloride transport by potentiating probability of channel opening (or gating) of the CFTR protein at cell surface.1 7

  • Combined effect of tezacaftor and ivacaftor increases quantity and function of CFTR at cell surface, resulting in increased chloride transport.1

  • In vitro, tezacaftor/ivacaftor increased chloride transport by at least 10% compared with baseline in Fisher rat thyroid (FRT) cells expressing certain CFTR mutations.1 In clinical studies, tezacaftor/ivacaftor improved lung function and decreased sweat chloride concentrations in patients homozygous or heterozygous for F508del mutation.1 3 4 7

  • Patients expected to be responsive to tezacaftor/ivacaftor if they possess homozygous CFTR genotype with F508del mutation or if they have at least 1 copy of a responsive CFTR mutation (i.e., E56K, P67L, R74W, D110E, D110H, R117C, E193K, L206W, R347H, R352Q, A455E, D579G, 711+3A→G, E831X, S945L, S977F, F1052V, K1060T, A1067T, R1070W, F1074L, D1152H, D1270N, 2789+5G→A, 3272-26A→G, 3849+10kbC→T).1

  • With the exception of homozygous F508del genotype, CFTR gene mutations not responsive to ivacaftor monotherapy not expected to respond to tezacaftor/ivacaftor.1

Advice to Patients

  • Importance of advising patients to read the manufacturer's patient information.1

  • Importance of taking tezacaftor/ivacaftor with fat-containing food (e.g., eggs, butter, peanut butter, cheese pizza, whole milk dairy products) to increase systemic absorption of the drug.1

  • If a dose of tezacaftor/ivacaftor is missed by ≤6 hours, take the dose with fat-containing food as soon as it is remembered.1 If a dose is missed by >6 hours, omit the dose and take the next dose at the regularly scheduled time.1 Do not take a double dose to make up for a missed dose.1

  • Importance of dosage reduction in patients with moderate hepatic impairment (Child-Pugh class B).1 Importance of considering risks and benefits of tezacaftor/ivacaftor in patients with severe hepatic impairment (Child-Pugh class C) prior to initiating therapy; importance of dosage reduction in such patients.1

  • Risk of elevated liver function test results.1 Importance of monitoring liver function tests prior to initiation of tezacaftor/ivacaftor, every 3 months during the first year of therapy, and annually thereafter.1

  • Ocular lens opacities (cataracts) observed in some pediatric patients.1 Importance of baseline and follow-up ophthalmologic examinations in pediatric patients receiving tezacaftor/ivacaftor.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, vitamins, and herbal supplements, as well as any concomitant illnesses (e.g., hepatic impairment).1 Concomitant use of tezacaftor/ivacaftor with sensitive CYP3A inhibitors and inducers requires particular attention.1 (See Interactions.)

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

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.

Tezacaftor and Ivacaftor

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Kit

Tezacaftor 100 mg and Ivacaftor 150 mg (28 film-coated tablets)

Ivacaftor 150 mg (28 film-coated tablets)

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

Vertex

AHFS DI Essentials™. © Copyright 2021, Selected Revisions February 18, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Vertex Pharmaceuticals Incorporated. Symdeko (tezacaftor and ivacaftor) tablets; (ivacaftor) tablets prescribing information. Boston, MA; 2018 Feb.

2. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2018 Aug 14. http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm

3. Taylor-Cousar J, Munck A, McKone E et al. Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Engl J Med. 2017; 377:2013-23.

4. Rowe S, Daines C, Ringshausen F et al. Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med. 2017; 377:2024-35.

5. Fanen P, Wohlhuter-Haddad A, Hinzpeter A et al. Genetics of cystic fibrosis: CFTR mutation classifications toward genotype-based CF therapies. Int J Biochem Cell B. 2014; 52:94-102.

6. Sala M, Jain M et al. Tezacaftor for the treatment of cystic fibrosis. Expert Rev Resp Med. 2018;

7. Donaldson S, Pilewski J, Griese M et al. Tezacaftor/ivacaftor in subjects with cystic fibrosis and F508del/F508del-CFTR or F508del/G551D-CFTR. N Am J Respir Crit Care Med. 2018; 197:214-224.

8. Southern K, Patel S, Sinha I et al. Correctors (specific therapies for class II CFTR mutations) for cystic fibrosis (review). Cochrane Database of Systematic Reviews. 2018;

Frequently asked questions