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Ivacaftor (Monograph)

Brand name: Kalydeco
Drug class: Cystic Fibrosis Transmembrane Conductance Regulator Potentiators

Medically reviewed by Drugs.com on Mar 10, 2024. Written by ASHP.

Introduction

A cystic fibrosis transmembrane conductance regulator (CFTR) potentiator.1 2 4 5 8 10 11 12

Uses for Ivacaftor

Cystic Fibrosis

Treatment of cystic fibrosis in patients ≥1 month of age who have at least one mutation in the CFTR gene that is responsive to ivacaftor based on in vitro assay and/or clinical data.1

Use an FDA-approved cystic fibrosis mutation test to detect presence of a CFTR mutation if genotype of patient unknown.1

Designated an orphan drug by FDA for treatment of cystic fibrosis.3

The 2018 Cystic Fibrosis Foundation pulmonary guideline specifically addresses the use of CFTR modulators in patients with cystic fibrosis.201 For adults and children ≥6 years of age with cystic fibrosis due to gating mutations other than G551D or R117H, the guideline makes a conditional recommendation for use of ivacaftor.201 For patients with the R117H mutation, the guideline makes a conditional recommendation for ivacaftor use in adults ≥18 years of age and in children 6–17 years of age with an FEV1 <90% predicted.201

The Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline provides recommendations for identifying patients who are eligible and could benefit from ivacaftor treatment based on CFTR genotyping.202 For the most recent updates, consult the Clinical Pharmacogenetics Implementation Consortium (CPIC) website at [Web]

Ivacaftor Dosage and Administration

General

Pretreatment Screening

Patient Monitoring

Administration

Oral Administration

Commercially available as tablets (for administration in adults and pediatric patients ≥6 years of age) or oral granules (for administration in pediatric patients 1 month to less than 6 years of age).1

Tablets:Administer orally every 12 hours with fat-containing food (e.g., butter, cheese pizza, eggs, peanut butter, whole-milk dairy products [e.g., cheese, yogurt, whole milk, breast milk, or infant formula]) to increase systemic absorption of the drug.1 Typical diet recommended for patients with cystic fibrosis satisfies requirement for fat-containing food.1 Swallow tablets whole.1

Oral granules: Administer orally every 12 hours with age-appropriate soft food or liquid (e.g., pureed fruits or vegetables, breast milk or infant formula, juice, water, milk, yogurt).1 Each dose is administered just before or after consumption of fat-containing food.1

Preparation of oral granules: Mix entire contents of each packet of oral granules with one teaspoon (5 mL) of an age-appropriate soft food or liquid (e.g., pureed fruits or vegetables, yogurt, applesauce, water, breast milk, infant formula, milk, juice) and completely consume.1 Food or liquid should be at or below room temperature.1 Once mixed, the product has been shown to be stable for 1 hour, and therefore should be consumed during this period.1 Administer each dose just before or just after fat-containing food.1

If a dose of ivacaftor is missed within 6 hours of time of usual administration, take the dose with fat-containing food as soon as possible.1 If more than 6 hours have passed, missed dose should not be taken; take the dose at the next scheduled time.1

Dosage

Pediatric Patients

Cystic Fibrosis
Oral

Pediatric patients ≥6 years of age: 150 mg every 12 hours (total daily dosage of 300 mg) with fat-containing food.1

Oral

Pediatric patients 1 month to <6 years of age: weight-based dosing (see Table 1).1 Administer dose just before or after consumption of fat-containing food.1

Use of ivacaftor in pediatric patients 1 to <6 months born at a gestational age <37 weeks has not been evaluated.1

Table 1: Dosage of Ivacaftor Oral Granules by Body Weight in Pediatric Patients 1 Month to Less Than 6 Years of Age1

Age

Body Weight (kg)

Ivacaftor Dosage

1 month to <2 months

≥3

One 5.8 mg packet every 12 hours

2 months to <4 months

≥3

One 13.4 mg packet every 12 hours

4 months to <6 months

≥5

One 25 mg packet every 12 hours

≥6 months to <6 years

5 to <7

One 25 mg packet every 12 hours

≥6 months to <6 years

7 to <14

One 50 mg packet every 12 hours

≥6 months to <6 years

≥14

One 75 mg packet every 12 hours

Adults

Cystic Fibrosis
Oral

150 mg every 12 hours (total daily dosage of 300 mg) with fat-containing food.1

Dosage Modification for Concomitant Use of CYP3A Inhibitors in Patients ≥6 Months of Age

When coadministered with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin) reduce dosage of ivacaftor to one tablet or one packet of oral granules twice weekly.1

When co-administered with moderate CYP3A inhibitors (e.g., fluconazole, erythromycin), reduce dosage of ivacaftor to one tablet or one packet of granules once daily.1

Concomitant use of moderate or strong CYP3A inhibitors not recommended in patients <6 months of age.1

Dosage Modification for Toxicity

Hepatic Toxicity

Interrupt ivacaftor dosing if elevation in serum ALT or AST concentrations exceeding 5 times the ULN occurs.1 Consider benefits versus risks of resuming ivacaftor after resolution of aminotransferase levels to baseline.1

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Not recommended in patients <6 months of age.1 Dosage adjustment not necessary in patients ≥6 months of age.1

Moderate hepatic impairment (Child-Pugh class B) Not recommended in patients <6 months of age.1 In patients 6 months to <6 years of age, recommended dose is one packet of granules (containing 25 mg, 50 mg, or 75 mg ivacaftor, based on dosing recommended for weight in Table 1) once daily.1 For patients ≥6 years of age, recommended dose is 150 mg orally once daily.1

Severe hepatic impairment (Child-Pugh class C) Not recommended in patients <6 months of age.1 Use with caution and at a reduced dosage after weighing risks and benefits of therapy in patients ≥6 months of age.1 In patients 6 months to <6 years of age, recommended dosage is one packet of oral granules (containing 25 mg, 50 mg, or 75 mg ivacaftor, based on dosing recommended for weight in Table 1) once daily or less frequently.1 For patients ≥6 years of age, recommended dosage is 150 mg orally once daily or less frequently.1

Renal Impairment

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

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

Geriatric Patients

No specific dosage recommendations.1

Cautions for Ivacaftor

Contraindications

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 first year of therapy, and annually thereafter as clinically indicated.1

Closely monitor patients who develop increased ALT or AST concentrations until abnormalities resolve.1

Interrupt therapy in patients with ALT or AST elevations >5 times ULN.1 Following resolution, consider benefits and risks of resuming therapy.1

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, reported.1

Discontinue ivacaftor if serious hypersensitivity reactions develop and institute appropriate therapy.1 Consider benefits and risks for the individual patient to determine whether to resume treatment.1

Concomitant Use with CYP3A Inducers

Concomitant use with strong CYP3A inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John’s wort [Hypericum perforatum]) substantially decreases systemic exposure of ivacaftor, possibly reducing efficacy of the drug.1 Concomitant use not recommended.1

Cataracts

Non-congenital lens opacities and cataracts reported in pediatric patients.1

Ophthalmological examinations recommended in pediatric patients at baseline and follow-up during treatment as clinically indicated.1

Specific Populations

Pregnancy

Limited human data from clinical trials and postmarketing reports of ivacaftor use in pregnant women.1

Ivacaftor administration in animal studies did not reveal teratogenicity or adverse effects on fetal development.1

Lactation

Distributed into milk in rats; likely distributed into human milk.1 Use with caution in breastfeeding women.1

Pediatric Use

Safety and efficacy established in pediatric patients 1 month to 17 years of age with cystic fibrosis and one mutation in the CFTR gene that is responsive to ivacaftor based on clinical and/or in vitro assay data.1

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

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; cystic fibrosis is generally a disease of children and young adults.1

Hepatic Impairment

Effect of mild hepatic impairment (Child-Pugh class A) on pharmacokinetics not studied but minimal effects expected; dosage adjustment not necessary in patients >6 months of age.1

Increased AUC in patients with moderate hepatic impairment (Child-Pugh class B); dosage reduction recommended in patients >6 months of age.1

Effect of severe hepatic impairment (Child-Pugh class C) on pharmacokinetics not studied but increased AUC expected; use with caution and at reduced dosage after weighing risks and benefits of therapy at a reduced dosage in patients >6 months of age.1

Not recommended in patients 1 to <6 months of age with any level of hepatic impairment.1

Renal Impairment

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

Dosage adjustment not necessary in patients with mild or moderate renal impairment because of minimal urinary excretion of drug and metabolites.1

Use with caution in patients with severe renal impairment (Clcr ≤30 mL/minute) or in those with ESRD.1

Common Adverse Effects

Most common (≥8%) adverse effects include headache, oropharyngeal pain, upper respiratory tract infection, nasal congestion, abdominal pain, nasopharyngitis, diarrhea, rash, nausea, dizziness.1

Drug Interactions

Principally metabolized by CYP3A.1

Ivacaftor and its M1 metabolite are substrates of CYP3A (i.e., 3A4, 3A5).1

Ivacaftor is a weak inhibitor of CYP3A, has potential to inhibit P-glycoprotein (P-gp) at therapeutic concentrations, and may inhibit CYP2C9.1 M1 metabolite (but not M6) has potential to inhibit CYP3A and P-gp.1

Ivacaftor and its M1 and M6 metabolites are not CYP inducers.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes or Transport Proteins

Strong CYP3A inhibitors: Pharmacokinetic interaction (substantially increased AUC of ivacaftor).1 If used concomitantly, reduce dosage of ivacaftor in patients ≥6 months of age.1 Use not recommended in patients <6 months of age.1

Moderate CYP3A inhibitors: Pharmacokinetic interaction (increased AUC of ivacaftor).1 7 If used concomitantly, reduce dosage of ivacaftor in patients ≥6 months of age.1 Use not recommended in patients <6 months of age.

Strong CYP3A inducers: Pharmacokinetic interaction (substantially decreased AUC and possible reduced efficacy of ivacaftor).1 Concomitant use not recommended.1

Substrates of CYP3A and/or P-gp: Potential pharmacokinetic interaction (increased systemic exposure; possible increased or prolonged therapeutic and adverse effects of substrate).1 Use with caution and appropriate monitoring.1 7

Substrates of CYP2C9: Potential pharmacokinetic interaction (increased systemic exposure; possible increased or prolonged therapeutic and adverse effects of substrate).1 7 Appropriate monitoring recommended.1 7

Specific Drugs

Drug

Interaction

Comments

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Potential decreased AUC and efficacy of ivacaftor1

Concomitant use not recommended1

Azole antifungals (e.g., fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole)

Concomitant administration with ketoconazole, a potent CYP3A inhibitor, substantially increased AUC of ivacaftor 1

Concomitant administration with fluconazole, a moderate CYP3A inhibitor, also increased AUC of ivacaftor, but a lesser extent1

Reduce dosage of ivacaftor when used concomitantly1

Use not recommended for patients <6 months of age.1

Benzodiazepines (alprazolam, diazepam, midazolam, triazolam)

Concomitant administration of ivacaftor with midazolam, a sensitive CYP3A substrate, increased systemic exposure of midazolam1

Caution and adequate monitoring for benzodiazepine-related adverse effects (e.g., prolonged or increased sedation or respiratory depression) is recommended when ivacaftor is used concomitantly with alprazolam, diazepam, midazolam, or triazolam1

Ciprofloxacin

No effect on ivacaftor exposure1

No dose adjustment is necessary1

Cyclosporine

Possible increased systemic exposure of cyclosporine1

Caution advised with concomitant use; appropriate monitoring recommended1

Digoxin

Possible increased systemic exposure of digoxin1

Caution advised with concomitant use; appropriate monitoring recommended1

Glimepiride

Possible increased systemic exposure of glimepiride1

Use concomitantly with caution1

Glipizide

Possible increased systemic exposure of glipizide1

Use concomitantly with caution1

Grapefruit juice

Possible increased systemic exposure of ivacaftor1

Avoid use of grapefruit juice or foods containing grapefruit1

Macrolide antibiotics (clarithromycin, erythromycin)

Potential for substantially increased AUC of ivacaftor1

Reduce dosage of ivacaftor when used concomitantly1

Use not recommended for patients <6 months of age.1

Oral contraceptives

Concomitant administration with an oral contraceptive containing ethinyl estradiol and norethindrone did not affect systemic exposures of ivacaftor or its metabolites, ethinyl estradiol, or norethindrone1

Dosage adjustment of ivacaftor or oral contraceptives not necessary1

Rifabutin

Potential decreased AUC and efficacy of ivacaftor1

Concomitant use not recommended1

Rifampin

Concomitant administration with rifampin, a potent CYP3A inducer, substantially decreased AUC of ivacaftor; potential reduced efficacy of ivacaftor1

Concomitant use not recommended1

St. John's wort (Hypericum perforatum)

Potential decreased AUC and efficacy of ivacaftor1

Concomitant use not recommended1

Tacrolimus

Possible increased systemic exposure of tacrolimus1

Caution advised with concomitant use; appropriate monitoring recommended1

Warfarin

Possible increase systemic exposure of warfarin1

Use concomitantly with caution with INR monitoring1

Ivacaftor Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations achieved at approximately 4 hours following oral administration in the fed state.1

Steady-state plasma concentrations attained within 3–5 days.1

Food

Systemic exposure increased approximately two- to four-fold when administered with food containing fat.1 Effect of food is similar for tablets and granules.1

Special Populations

Mild hepatic impairment (Child-Pugh class A): Effect on pharmacokinetics not studied; increase in AUC expected to be less than two-fold.1

Moderate hepatic impairment (Child-Pugh class B): Similar peak plasma concentrations, but an approximately two-fold increase in AUC, compared with healthy individuals matched for demographics.1

Severe hepatic impairment (Child-Pugh class C): Effect on pharmacokinetics not studied; magnitude of increase in systemic exposure unknown but expected to be substantially higher than that observed in patients with moderate hepatic impairment.1

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

Distribution

Extent

Distributed into milk in rats; likely distributed into human milk.1

Plasma Protein Binding

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

Does not bind to human RBCs.1

Elimination

Metabolism

Extensively metabolized in humans, principally by CYP3A.1

Two major metabolites are M1 and M6.1 M1 considered pharmacologically active (approximately one-sixth the potency of ivacaftor).1 M6 not considered pharmacologically active (<one-fiftieth the potency of ivacaftor).1

Ivacaftor and its M1 metabolite are substrates of CYP3A (i.e., 3A4, 3A5).1 Ivacaftor is a weak inhibitor of CYP3A, has potential to inhibit P-gp at therapeutic concentrations, and may inhibit CYP2C8 and 2C9.1 M1 metabolite (but not M6) has potential to inhibit CYP3A and P-gp.1

Ivacaftor and its M1 and M6 metabolites are not CYP inducers.1

Elimination Route

Mainly excreted in feces (87.8%) after metabolic conversion.1 Approximately 65% of total dose excreted as M1 (22%) and M6 (43%) metabolites.1

Ivacaftor and metabolites minimally excreted in urine (6.6% of total radioactivity recovered); negligible amounts of unchanged drug excreted in urine.1

Half-life

Apparent terminal half-life: Approximately 12 hours.1

Stability

Storage

Oral

Tablets

Store at 20–25°C (excursions permitted between 15–30°C).1

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.

Ivacaftor is available only from designated specialty distributors and pharmacies.19 The manufacturer should be contacted for additional information.19

Ivacaftor

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

150 mg

Kalydeco

Vertex

Oral granules

5.8 mg per packet

Kalydeco

Vertex

13.4 mg per packet

Kalydeco

Vertex

25 mg per packet

Kalydeco

Vertex

50 mg per packet

Kalydeco

Vertex

75 mg per packet

Kalydeco

Vertex

AHFS DI Essentials™. © Copyright 2024, Selected Revisions March 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Vertex Pharmaceuticals Incorporated. Kalydeco (ivacaftor) tablets prescribing information. Boston, MA; 2023 Aug.

2. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 203188Orig1s000: Summary review. From FDA website. Accessed 2012 Oct 4. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203188Orig1s000SumR.pdf

3. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Rockville, MD. From FDA website. Accessed 2012 Oct 4. http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm

4. Ramsey BW, Davies J, McElvaney NG et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011; 365:1663-72. http://www.ncbi.nlm.nih.gov/pubmed/22047557?dopt=AbstractPlus

5. Flume PA, Liou TG, Borowitz DS et al. Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest. 2012; 142:718-24. http://www.ncbi.nlm.nih.gov/pubmed/22383668?dopt=AbstractPlus

6. Vertex Pharmaceuticals Incorporated, Cambridge, MA: Personal communication.

7. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 203188Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. Accessed 2012 Oct 15. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203188Orig1s000ClinPharmR.pdf

8. Van Goor F, Hadida S, Grootenhuis PD et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci U S A. 2009; 106:18825-30. http://www.ncbi.nlm.nih.gov/pubmed/19846789?dopt=AbstractPlus

9. Jones AM, Helm JM. Emerging treatments in cystic fibrosis. Drugs. 2009; 69:1903-10. http://www.ncbi.nlm.nih.gov/pubmed/19747007?dopt=AbstractPlus

10. O'Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009; 373:1891-904. http://www.ncbi.nlm.nih.gov/pubmed/19403164?dopt=AbstractPlus

11. Pettit RS. Cystic fibrosis transmembrane conductance regulator-modifying medications: the future of cystic fibrosis treatment. Ann Pharmacother. 2012 Jul-Aug; 46:1065-75.

12. Accurso FJ, Rowe SM, Clancy JP et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med. 2010; 363:1991-2003. http://www.ncbi.nlm.nih.gov/pubmed/21083385?dopt=AbstractPlus

13. Food and Drug Administration. Consumer Health Information. Grapefruit juice and medicine may not mix. From FDA website. Accessed 2012 Nov 15. http://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/ucm292839.pdf

14. Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med. 2017;377(21):2024-2035. http://www.ncbi.nlm.nih.gov/pubmed/29099333?dopt=AbstractPlus

15. De Boeck K, Munck A, Walker S, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cyst Fibros. 2014;13(6):674-680. http://www.ncbi.nlm.nih.gov/pubmed/25266159?dopt=AbstractPlus

16. Moss RB, Flume PA, Elborn JS, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial. Lancet Respir Med. 2015;3(7):524-533.

17. Davies JC, Cunningham S, Harris WT, et al. Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study [published correction appears in Lancet Respir Med. 2016 Dec;4(12 ):e57]. Lancet Respir Med. 2016;4(2):107-115. http://www.ncbi.nlm.nih.gov/pubmed/26803277?dopt=AbstractPlus

18. Davies JC, Wainwright CE, Sawicki GS, et al. Ivacaftor in infants aged 4 to <12 months with cystic fibrosis and a gating mutation. Results of a two-part phase 3 clinical trial. Am J Respir Crit Care Med. 2021;203(5):585-593. http://www.ncbi.nlm.nih.gov/pubmed/33023304?dopt=AbstractPlus

19. Vertex Pharmaceuticals. Authorized Specialty Pharmacies and Distributors. Accessed 2022 Mar 24. From Vertex Pharmaceuticals website. https://www.vrtx.com/authorized-distributors/

200. Dickinson KM, Collaco JM. Cystic Fibrosis. Pediatr Rev. 2021 Feb;42(2):55-67. http://www.ncbi.nlm.nih.gov/pubmed/33526571?dopt=AbstractPlus

201. Ren CL, Morgan RL, Oermann C, et al. Cystic Fibrosis Foundation pulmonary guidelines. Use of cystic fibrosis transmembrane conductance regulator modulator therapy in patients with cystic fibrosis. Ann Am Thorac Soc. 2018;15(3):271-280. http://www.ncbi.nlm.nih.gov/pubmed/29342367?dopt=AbstractPlus

202. Clancy JP, Johnson SG, Yee SW et al Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for ivacaftor therapy in the context of CFTR genotype. Clin Pharmacol Ther. 2014 Jun;95(6):592-7. Epub 2014 Mar 5. http://www.ncbi.nlm.nih.gov/pubmed/24598717?dopt=AbstractPlus

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