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 (5.8 mg, 13.4 mg, 25 mg, 50 mg, and 75 mg packets) for patients aged 1 month to <6 years.

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

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
-	Ciprofloxacin^a 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	Desipramine^a 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	Digoxin^b LANOXIN^®	Increased exposure of digoxin^b	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	Fluconazole^a,c DIFLUCAN^®	Increased KALYDECO exposure^c	One dose once daily	Dose adjustment
Strong CYP3A inhibitor	Itraconazole SPORANOX^®	Increased KALYDECO exposure	One dose twice a week	Dose adjustment
Strong CYP3A inhibitor	Ketoconazole^a,d EXTINA^®, XOLEGEL^®	Increased KALYDECO exposure^d	One dose twice a week	Dose adjustment
CYP3A substrate	Midazolam^a,e	Increased exposure of midazolam^e	One dose every 12 hours	Caution and monitoring for benzodiazepine -related side effects
CYP3A substrate^2,4	Oral contraceptive^a 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	Rifampin^a,f RIFADIN^®	Decreased KALYDECO exposure^f	Co-administration with KALYDECO is not recommended
CYP2C8 substrate²	Rosiglitazone^a 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, telithromycin, and 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 or drink 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 therapeutic products for which exposure may be increased by KALYDECO include glimepiride and glipizide; these therapeutic 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 oral 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.

View the safety profile of KALYDECO

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Important Safety Information

Warnings and Precautions

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 indicated for the treatment of cystic fibrosis (CF) in patients age 1 month and older who have at least 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.

Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions, including cases of anaphylaxis, have been reported in the postmarketing setting. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue KALYDECO and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with 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 treatment with KALYDECO

ADVERSE REACTIONS

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 the 221 patients treated with KALYDECO were headache (17%), upper respiratory tract infection (16%), nasal congestion (16%), nausea (10%), rash (10%), rhinitis (6%), dizziness (5%), arthralgia (5%), and bacteria in sputum (5%)
The safety profile for the CF patients enrolled in clinical trials (Trials 3-8) was similar to that observed in the 48-week, placebo-controlled trials (Trials 1 and 2)

USE IN SPECIFIC POPULATIONS

Pediatric Use

The safety and effectiveness of KALYDECO in patients with CF younger than 1 month of age have not been established. The use of KALYDECO in children under the age of 1 month is not recommended
Use of KALYDECO in patients aged 1 to less than 6 months born at a gestational age less than 37 weeks has not been evaluated

Click here to access full Prescribing Information.

Reference:

1. KALYDECO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; August 2023. 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.

Important Safety Information and Indication

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COLLAPSE

Indications and Usage

Important Safety Information

Warnings and Precautions

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

Important Safety Information

Warnings and Precautions

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

Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions, including cases of anaphylaxis, have been reported in the postmarketing setting. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue KALYDECO and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with 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 treatment with KALYDECO

ADVERSE REACTIONS

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 the 221 patients treated with KALYDECO were headache (17%), upper respiratory tract infection (16%), nasal congestion (16%), nausea (10%), rash (10%), rhinitis (6%), dizziness (5%), arthralgia (5%), and bacteria in sputum (5%)
The safety profile for the CF patients enrolled in clinical trials (Trials 3-8) was similar to that observed in the 48-week, placebo-controlled trials (Trials 1 and 2)

USE IN SPECIFIC POPULATIONS

Pediatric Use

The safety and effectiveness of KALYDECO in patients with CF younger than 1 month of age have not been established. The use of KALYDECO in children under the age of 1 month is not recommended
Use of KALYDECO in patients aged 1 to less than 6 months born at a gestational age less than 37 weeks has not been evaluated

Click here to access full Prescribing Information.

Reference:

Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions, including cases of anaphylaxis, have been reported in the postmarketing setting. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue KALYDECO and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with 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 treatment with KALYDECO

ADVERSE REACTIONS

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 the 221 patients treated with KALYDECO were headache (17%), upper respiratory tract infection (16%), nasal congestion (16%), nausea (10%), rash (10%), rhinitis (6%), dizziness (5%), arthralgia (5%), and bacteria in sputum (5%)
The safety profile for the CF patients enrolled in clinical trials (Trials 3-8) was similar to that observed in the 48-week, placebo-controlled trials (Trials 1 and 2)

USE IN SPECIFIC POPULATIONS

Pediatric Use

The safety and effectiveness of KALYDECO in patients with CF younger than 1 month of age have not been established. The use of KALYDECO in children under the age of 1 month is not recommended
Use of KALYDECO in patients aged 1 to less than 6 months born at a gestational age less than 37 weeks has not been evaluated

Click here to access full Prescribing Information.

Reference:

1. KALYDECO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; August 2023. 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.

Drug Interactions with KALYDECO® (ivacaftor)

Drug Interactions with KALYDECO^® (ivacaftor)