Drug-Drug Interactions

Drug-Drug Interactions Associated With KALYDECO®1

KALYDECO is supplied as tablets (150 mg) for patients 6 years and older and as oral granules (50 mg and 75 mg packets) for patients who are 1 to less than 6 years of age.

Choose metabolic type:

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CYP3A substrate
Moderate CYP3A inhibitor
Strong CYP3A inhibitor
Strong CYP3A inducer
CYP2C8 substrate
CYP2C9 substrate
CYP2D6 substrate
P-gp substrate
Metabolic
types
Generic name
Common brand name(s)
Potential effect
on drug exposure
KALYDECO dosing and administration
Recommendations
CYP3A substrate
Alprazolam
Xanax®, Niravam®
Increased exposure of alprazolam
One dose every 12 hours
Caution and monitoring for benzodiazepine-related side effects
Strong CYP3A inducer
Carbamazepine
Tegretol®, Equetro®, Carbatrol®
Decreased KALYDECO exposure
Co-administration with KALYDECO is not recommended
Ciprofloxacina
Cipro®
No effect on KALYDECO
One dose every 12 hours
No dose adjustment
Strong CYP3A inhibitor
Clarithromycin
Biaxin®
Increased KALYDECO exposure
One dose twice a week
Dose adjustment
CYP3A and P-gp substrate
Cyclosporine
Sandimmune®
Increased exposure of cyclosporine
One dose every 12 hours
Caution and appropriate monitoring for cyclosporine
CYP2D6 substrate
Desipraminea
Norpramin®
No effect on desipramine
One dose every 12 hours
No dose adjustment
CYP3A substrate
Diazepam
Valium®
Increased exposure of diazepam
One dose every 12 hours
Caution and monitoring for benzodiazepine-related side effects
P-gp substrate
Digoxinb
Lanoxin®
Increased exposure of digoxinb
One dose every 12 hours
Caution and appropriate monitoring for digoxin
Moderate CYP3A inhibitor
Erythromycin
E-Mycin®, Eryc®, Ery-Tab®, PCE®, Ilosone®
Increased KALYDECO exposure
One dose once daily
Dose adjustment
Moderate CYP3A inhibitor
Fluconazolea,c
Diflucan®
Increased KALYDECO exposurec
One dose once daily
Dose adjustment
Strong CYP3A inhibitor
Itraconazole
Sporanox®
Increased KALYDECO exposure
One dose twice a week
Dose adjustment
Strong CYP3A inhibitor
Ketoconazolea,d
Nizoral®, Extina®, Xolegel®, KuricTM
Increased KALYDECO exposured
One dose twice a week
Dose adjustment
CYP3A substrate
Midazolama,e
Versed®
Increased exposure of midazolame
One dose every 12 hours
Caution and monitoring for benzodiazepine-related side effects
CYP3A substrate
Oral contraceptivea
Numerous brand names available
No effect on oral contraceptive or KALYDECO
One dose every 12 hours
No dose adjustment
Strong CYP3A inducer
Phenobarbital
Donnatal®
Decreased KALYDECO exposure
Co-administration with KALYDECO is not recommended
Strong CYP3A inducer
Phenytoin
Dilantin®
Decreased KALYDECO exposure
Co-administration with KALYDECO is not recommended
Strong CYP3A inhibitor
Posaconazole
Noxafil®
Increased KALYDECO exposure
One dose twice a week
Dose adjustment
Strong CYP3A inducer
Rifabutin
Mycobutin®
Decreased KALYDECO exposure
Co-administration with KALYDECO is not recommended
Strong CYP3A inducer
Rifampina,f
Rifadin®
Decreased KALYDECO exposuref
Co-administration with KALYDECO is not recommended
CYP2C8 substrate
Rosiglitazonea
Avandia®
No effect on rosiglitazone
One dose every 12 hours
No dose adjustment
Strong CYP3A inducer
St. John's wort
Decreased KALYDECO exposure
Co-administration with KALYDECO is not recommended
CYP3A substrate
Tacrolimus
Prograf®
Increased exposure of tacrolimus
One dose every 12 hours
Caution and appropriate monitoring for tacrolimus
Strong CYP3A inhibitor
Telithromycin
Ketek®
Increased KALYDECO exposure
One dose twice a week
Dose adjustment
CYP3A substrate
Triazolam
Halcion®
Increased exposure of triazolam
One dose every 12 hours
Caution and monitoring for benzodiazepine-related side effects
Strong CYP3A inhibitor
Voriconazole
Vfend®
Increased KALYDECO exposure
One dose twice a week
Dose adjustment
CYP2C9 substrate
Warfarin
Coumadin®, Jantoven®
Increased exposure of warfarin
One dose every 12 hours
Caution and monitoring of INR is recommended

This is a representative list of drugs and common brand names and is not intended to be exhaustive.
Dose=one tablet or one packet of oral granules.

aThese interactions have been studied.
bCo-administration with digoxin increased digoxin exposure by 1.3-fold.
cCo-administration with fluconazole increased KALYDECO exposure (AUC) by 3-fold.
dCo-administration with ketoconazole significantly increased KALYDECO exposure (AUC) by 8.5-fold.
eKALYDECO increased midazolam exposure by 1.5-fold.
fCo-administration with rifampin significantly decreased KALYDECO exposure (AUC) by approximately 9-fold.

AUC, area under the curve; INR, international normalized ratio.

Drug Interactions

Potential for other drugs to affect KALYDECO

Inhibitors of CYP3A

  • Ivacaftor is a sensitive CYP3A substrate. Co-administration with ketoconazole, a strong CYP3A inhibitor, significantly increased ivacaftor exposure [measured as area under the curve (AUC)] by 8.5-fold. Based on simulations of these results, a reduction of the KALYDECO dose is recommended when co-administered with strong CYP3A inhibitors, such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin, as follows: in patients 6 years and older reduce dose to one 150 mg tablet twice a week; in patients 2 to less than 6 years with body weight less than 14 kg, reduce dose to one 50 mg packet of granules twice a week; and in patients 2 to less than 6 years with body weight 14 kg or greater, reduce dose to one 75 mg packet of granules twice a week1
  • Co-administration with fluconazole, a moderate inhibitor of CYP3A, increased ivacaftor exposure by 3-fold. Therefore, a reduction of the KALYDECO dose is recommended for patients taking concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin, as follows: in patients 6 years and older reduce dose to one 150 mg tablet once daily; in patients 2 to less than 6 years with body weight less than 14 kg, reduce dose to one 50 mg packet of granules once daily; and in patients 2 to less than 6 years with body weight 14 kg or greater, reduce dose to one 75 mg packet of granules once daily1
  • Co-administration of KALYDECO with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of ivacaftor. Therefore, food containing grapefruit or Seville oranges should be avoided during treatment with KALYDECO1

Inducers of CYP3A

Co-administration with rifampin, a strong CYP3A inducer, significantly decreased ivacaftor exposure (AUC) by approximately 9-fold. Therefore, co-administration with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John’s wort is not recommended.1

Ciprofloxacin

Co-administration of KALYDECO with ciprofloxacin had no effect on the exposure of ivacaftor. Therefore, no dose adjustment is necessary during concomitant administration of KALYDECO with ciprofloxacin.1

Potential for KALYDECO to affect other drugs

CYP3A and/or P-gp substrates

Ivacaftor and its M1 metabolite have the potential to inhibit CYP3A and P-gp. Co-administration with midazolam, a sensitive CYP3A substrate, increased midazolam exposure 1.5-fold, consistent with weak inhibition of CYP3A by ivacaftor. Co-administration with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold, consistent with weak inhibition of P-gp by ivacaftor. Administration of KALYDECO may increase systemic exposure of drugs that are substrates of CYP3A and/or P-gp, which may increase or prolong their therapeutic effect and adverse events. Therefore, caution and appropriate monitoring are recommended when co-administering KALYDECO with sensitive CYP3A and/or P-gp substrates, such as digoxin, cyclosporine, and tacrolimus.1

ISI-Tray

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Important Safety Information

Transaminase (ALT or AST) Elevations

  • Elevated transaminases have been reported in patients with CF receiving KALYDECO. Transaminase elevations were more common in patients with a history of transaminase elevations or in patients who had abnormal transaminases

Indications and Usage

KALYDECO® (ivacaftor) is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator indicated for the treatment of cystic fibrosis (CF) in patients age 12 months and older who have one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or in vitro assay data.

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Indications and Usage

KALYDECO® (ivacaftor) is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator indicated for the treatment of cystic fibrosis (CF) in patients age 12 months and older who have one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or in vitro assay data.

If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use.

Important Safety Information

Transaminase (ALT or AST) Elevations

  • Elevated transaminases have been reported in patients with CF receiving KALYDECO. Transaminase elevations were more common in patients with a history of transaminase elevations or in patients who had abnormal transaminases at baseline. It is recommended that ALT and AST be assessed prior to initiating KALYDECO, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of transaminase elevations, more frequent monitoring of liver function tests should be considered
  • Patients who develop increased transaminase levels should be closely monitored until the abnormalities resolve. Dosing should be interrupted in patients with ALT or AST of greater than 5 times the upper limit of normal (ULN). Following resolution of transaminase elevations, consider the benefits and risks of resuming KALYDECO dosing

Concomitant Use With CYP3A Inducers

  • Use of KALYDECO with strong CYP3A inducers, such as rifampin, substantially decreases the exposure of ivacaftor, which may reduce the therapeutic effectiveness of KALYDECO. Co-administration of KALYDECO with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John’s wort is not recommended

Cataracts

  • Cases of non-congenital lens opacities/cataracts have been reported in pediatric patients treated with KALYDECO. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating KALYDECO treatment

Pediatric Use

  • The safety and efficacy of KALYDECO in patients with CF younger than 12 months of age have not been studied. The use of KALYDECO in children under the age of 12 months is not recommended

Serious Adverse Reactions

  • Serious adverse reactions, whether considered drug-related or not by the investigators, which occurred more frequently in patients treated with KALYDECO included abdominal pain, increased hepatic enzymes, and hypoglycemia

Adverse Reactions

  • The most common adverse reactions in patients with a G551D mutation in the CFTR gene (Trials 1 and 2) with an incidence of ≥8% and at a higher incidence for patients treated with KALYDECO (N=109) than for placebo (N=104) were headache, oropharyngeal pain, upper respiratory tract infection, nasal congestion, abdominal pain, nasopharyngitis, diarrhea, rash, nausea, and dizziness
  • The safety profiles for patients with additional approved mutations enrolled in Trials 4, 5, and 7; and for patients ages 2 to less than 6 years enrolled in Trial 6; and for patients aged 12 months to less than 24 months enrolled in Trial 8; were similar to that observed in Trials 1 and 2

Click here to access full Prescribing Information for KALYDECO (ivacaftor).

References: 1. KALYDECO (ivacaftor) [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; August 2018. 2. Zielenski J. Genotype and phenotype in cystic fibrosis. Respiration. 2000;67(2):117-133. 3. Welsh MJ, Ramsey BW, Accurso F, Cutting GR. Cystic fibrosis: membrane transport disorders. In: Valle D, Beaudet A, Vogelstein B, et al, eds. The Online Metabolic & Molecular Bases of Inherited Disease. The McGraw-Hill Companies, Inc; 2004:part 21, chap 201. https://ommbid.mhmedical.com/content.aspx?bookid=971&sectionid=62656007. Accessed July 5, 2018. 4. Bombieri C, Seia M, Castellani C. Genotypes and phenotypes in cystic fibrosis and cystic fibrosis transmembrane regulator-related disorders. Semin Respir Crit Care Med. 2015;36(2):180-193. 5. Nick JA, Nichols DP. Diagnosis of adult patients with cystic fibrosis. Clin Chest Med. 2016;37(1):47-57. 6. Welsh MJ, Smith AE. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell. 1993;73(7):1251-1254. 7. Yu H, Burton B, Huang C-J, et al. Ivacaftor potentiation of multiple CFTR channels with gating mutations. J Cyst Fibros. 2012;11(3):237-245. 8. Sheppard DN, Rich DP, Ostedgaard LS, Gregory RJ, Smith AE, Welsh MJ. Mutations in CFTR associated with mild-disease-form Cl channels with altered pore properties. Nature. 1993;362(6416):160-164. 9. Van Goor F, Yu H, Burton B, Hoffman BJ. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014;13(1):29-36. 10. Pettit RS. Cystic fibrosis transmembrane conductance regulator-modifying medications: the future of cystic fibrosis treatment. Ann Pharmacother. 2012;46(7-8):1065-1075. 11. Clain J, Fritsch J, Lehrmann-Che J, et al. Two mild cystic fibrosis-associated mutations result in severe cystic fibrosis when combined in cis and reveal a residue important for cystic fibrosis transmembrane conductance regulator processing and function. J Biol Chem. 2001;276(12):9045-9049. 12. Selvadurai HC, McKay KO, Blimkie CJ, Cooper PH, Mellis CM, Van Asperen PP. The relationship between genotype and exercise tolerance in children with cystic fibrosis. Am J Respir Crit Care Med. 2002;165(6):762-765. 13. Berwouts S, Morris MA, Girodon E, Schwarz M, Stuhrmann M, Dequeker E. Mutation nomenclature in practice: findings and recommendations from the cystic fibrosis external quality assessment scheme. Hum Mutat. 2011;32(11):1197-1203. 14. Ramsey BW, Davies J, McElvaney NG, et al; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663-1672. 15. Davies JC, Wainwright CE, Canny GJ, et al; VX08-770-103 (ENVISION) Study Group. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med. 2013;187(11):1219-1225. 16. Elborn JS. Cystic fibrosis. Lancet. 2016;388(10059):2519-2531. 17. Sosnay P, et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013;45(10):1160-1167. 18. Davis P, et al. Cystic fibrosis. Am J Respir Crit Care Med. 1996;154(5):1229-1256. 19. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VXR-HQ-88-00079(3); 2017. 20. Quittner AL, Modi AC, Wainwright C, Otto K, Kirihara J, Montgomery AB. Determination of the minimal clinically important difference scores for the Cystic Fibrosis Questionnaire-Revised respiratory symptom scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. Chest. 2009;135(6):1610-1618. 21. Rosenfeld M, Wainwright CE, Higgins M, et al. Ivacaftor treatment of cystic fibrosis in children aged 12 to <24 months and with a CFTR gating mutation (ARRIVAL): a phase 3 single-arm study. Lancet Respir Med. 2018. http://dx.doi.org/10.1016/S2213-2600(18)30202-9. 22. Rosenfeld M, Wainwright CE, Higgins M, et al. Ivacaftor treatment of cystic fibrosis in children aged 12 to <24 months and with a CFTR gating mutation (ARRIVAL): a phase 3 single-arm study. Lancet Respir Med. 2018 (suppl1-11). http://dx.doi.org/10.1016/S2213-2600(18)30202-9. 23. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VX15770124; 2017.

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