Drug Interactions With KALYDECO® (ivacaftor)

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 6 months to less than 6 years

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

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
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,dNizoral®,
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 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.

 

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, telithromycin, and clarithromycin, as follows: in patients 6 years and older reduce dose to one 150-mg tablet twice a week; in patients 6 months to less than 6 years with body weight 5-kg to less than 7-kg, reduce dose to one   25-mg packet of granules twice a week; in patients 6 months to less than 6 years with body weight 7 kg to less than 14-kg, reduce dose to one 50-mg packet of granules twice a week; and in patients 6 months to less than 6 years with body weight 14-kg or greater, reduce dose to one 75-mg packet of granules twice a week
  • 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 6 months to less than 6 years with body weight 5-kg to less than 7-kg, reduce dose to one 25-mg packet of granules once daily; in patients 6 months to less than 6 years with body weight 7-kg to less than 14-kg, reduce dose to one 50-mg packet of granules once daily; and in patients 6 months to less than 6 years with body weight 14-kg or greater, reduce dose to one 75-mg packet of granules once daily
  • 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 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

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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