Drug Interactions with KALYDECO® (ivacaftor)

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Drug-Drug interaction profiles1

KALYDECO is supplied as tablets (150 mg) for patients 6 years and older and as oral granules (25-mg, 50-mg, and 75-mg packets) for patients age 4 months to less than 6 years

Concomitant use of strong or moderate CYP3A inhibitors is not recommended for patients age 4 to <6 months.1

Choose metabolic type:
Metabolic types Generic name Common brand name(s) Potential effect on drug exposure KALYDECO dosing and administration Recommendations

CYP3A substrate2

Alprazolam XANAX®

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

CYP2D6 substrate3

Desipraminea NORPRAMIN®

No effect on desipramine

One dose every 12 hours

No dose adjustment

CYP3A substrate2

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 ERYC®, ERY-TAB®

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®

Increased KALYDECO exposured

One dose twice a week

Dose adjustment

CYP3A substrate

Midazolama,e

Increased exposure of midazolame

One dose every 12 hours

Caution and monitoring for benzodiazepine -related side effects

CYP3A substrate2,4

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

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 inhibitor

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 substrate2

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

Increased KALYDECO exposure

One dose twice a week

Dose adjustment

CYP3A substrate2

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 substrate2

Warfarin 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.

Potential drug interactions with KALYDECO

Inhibitors of CYP3A1

  • 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, telithromycinand clarithromycin
  • 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
  • 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 should be avoided during treatment with KALYDECO

Inducers of CYP3A1

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.

Ciprofloxacin1

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.

Potential for KALYDECO to affect other drugs1

CYP2C9 Substrates

Ivacaftor may inhibit CYP2C9; therefore, monitoring of the international normalized ratio (INR) during co-administration of KALYDECO with warfarin is recommended. Other medicinal products for which exposure may be increased by KALYDECO include glimepiride and glipizide; these medicinal products should be used with caution.

CYP3A and/or P-gp substrates1

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.

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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 at baseline. ALT and AST should 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, consider more frequent monitoring of liver function tests
  • 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

Indications and Usage

KALYDECO is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator indicated for the treatment of cystic fibrosis (CF) in patients age 4 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.

Indications and Usage

KALYDECO is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator indicated for the treatment of cystic fibrosis (CF) in patients age 4 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. ALT and AST should 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, consider more frequent monitoring of liver function tests
  • 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

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 effectiveness of KALYDECO in patients with CF younger than 4 months of age have not been studied. The use of KALYDECO in children under the age of 4 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

Most Common 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 aged 2 to less than 6 years enrolled in Trial 6; and for patients aged 4 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.

References:
1
. KALYDECO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; December 2020. 2. Data on File. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-10745; 2021. 3. Norpramin [prescribing information]. Bridgewater, NJ: Sanofi-Aventis Incorporated; 2012. 4. Belle DJ, Callaghan JT, Gorski JC, et al. The effects of an oral contraceptive containing ethinyl estradiol and norgestrel on CYP3A activity. J Clin Pharmacol. 2002;53:67-74.