KALYDECO

CFTR Potentiators

Oral Administration

If a dose is missed within 6 hours of the time it is usually taken, the dose should be taken with fat-containing food as soon as possible. If more than 6 hours have passed since the dose is usually taken, skip that dose and resume with the usual dosing schedule.

Oral Solid Formulations

Swallow tablets whole.
Administer each dose with fat-containing food (e.g., eggs, butter, peanut butter, cheese pizza, whole-milk dairy products (such as whole milk, cheese, yogurt, breast milk, or infant formula)).[48524]

Other Oral Formulations

Oral granules
Mix the entire contents of packet with 5 mL of age-appropriate soft food or liquid (e.g., pureed fruits or vegetables, yogurt, applesauce, water, breast milk, infant formula, milk, juice) that is at or below room temperature.
Administer each dose immediately before or after ingestion of fat-containing food (e.g., eggs, butter, peanut butter, cheese pizza, whole-milk dairy products (such as whole milk, cheese, yogurt, breast milk, or infant formula)).
The mixture is stable for 1 hour and should be completely consumed within this time period.

Severe

anaphylactoid reactions / Rapid / Incidence not known

Moderate

elevated hepatic enzymes / Delayed / 2.0-15.0
hyperglycemia / Delayed / 4.0-7.0
wheezing / Rapid / 4.0-7.0
hypoglycemia / Early / Incidence not known
cataracts / Delayed / Incidence not known

Mild

headache / Early / 4.0-24.0
infection / Delayed / 16.0-22.0
nasal congestion / Early / 16.0-20.0
abdominal pain / Early / 16.0-16.0
pharyngitis / Delayed / 15.0-15.0
diarrhea / Early / 13.0-13.0
rash / Early / 10.0-13.0
nausea / Early / 10.0-12.0
dizziness / Early / 5.0-9.0
rhinitis / Early / 4.0-7.0
acne vulgaris / Delayed / 4.0-7.0
musculoskeletal pain / Early / 4.0-7.0
arthralgia / Delayed / 4.0-7.0
myalgia / Early / 4.0-7.0

Kalydeco

Rx

Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator
Used for cystic fibrosis in patients 1 month of age and older who have one mutation in the CFTR gene that is responsive to ivacaftor; not effective in patients who are homozygous for F508del mutation
Liver function test monitoring and eye exams required at baseline and periodically throughout therapy

For the treatment of cystic fibrosis in persons who have 1 mutation in the CFTR gene that is responsive to ivacaftor.
NOTE: If a patient's genotype is unknown, an FDA-cleared cystic fibrosis (CF) mutation test should be performed; some tests may require verification with bi-directional sequencing.
Oral dosage Adults

150 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Children and Adolescents 6 to 17 years

150 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Infants and Children 6 months to 5 years weighing 14 kg or more

75 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Infants and Children 6 months to 5 years weighing 7 to 13 kg

50 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Infants and Children 6 months to 5 years weighing 5 to 6 kg

25 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Infants 4 to 5 months weighing 5 kg or more

25 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided; review drug interactions.

Infants 2 to 3 months weighing 3 kg or more

13.4 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided; review drug interactions.

Infants 1 month weighing 3 kg or more

5.8 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided; review drug interactions.

Hepatic Impairment

Use is NOT recommended in patients younger than 6 months of age with hepatic impairment.
In patients 6 months of age and older:
Mild impairment (Child-Pugh Class A): No dosage adjustment necessary.
Moderate impairment (Child-Pugh Class B): Administer the usual recommended dose, but reduce the frequency to once daily (e.g., if the usual dosage is 150 mg PO twice daily, reduce to 150 mg PO once daily).
Severe impairment (Child-Pugh Class C): Administer the usual recommended dose, but reduce the frequency to once daily or less frequently after weighing the risks and benefits of treatment. Use with caution; ivacaftor has not been studied in patients with severe hepatic impairment.[48524]

Renal Impairment

CrCl more than 30 mL/minute: No dosage adjustment is recommended.
CrCl 30 mL/minute or less: Use ivacaftor with caution; specific guidelines for dosage adjustments are not available.

Acetaminophen; Aspirin; Diphenhydramine: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as diphenhydramine. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with ivacaftor may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of ivacaftor could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Ivacaftor is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Diphenhydramine: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as diphenhydramine. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ivacaftor is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ivacaftor can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ivacaftor is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Ibuprofen: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as ibuprofen. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ivacaftor is necessary. If ivacaftor is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like ivacaftor can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ivacaftor is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Adagrasib: (Major) If adagrasib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Afatinib: (Moderate) If the concomitant use of ivacaftor and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of ivacaftor. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro. Ivacaftor and its M1 metabolite are weak P-gp inhibitors; coadministration may increase plasma concentrations of afatinib. Coadministration of ivacaftor with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
Albuterol; Budesonide: (Moderate) Use caution when administering ivacaftor and budesonide concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as budesonide, can increase budesonide exposure leading to increased or prolonged therapeutic effects and adverse events.
Alfentanil: (Moderate) Use caution when administering ivacaftor and alfentanil concurrently. Ivacaftor is an inhibitor of CYP3A, and alfentanil is a CYP3A substrate. Co-administration can increase alfentanil exposure leading to increased or prolonged therapeutic effects and adverse events.
Alprazolam: (Major) Avoid coadministration of alprazolam and ivacaftor due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with ivacaftor, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and ivacaftor is a weak CYP3A4 inhibitor. Coadministration with another weak CYP3A4 inhibitor increased alprazolam maximum concentration by 82%, decreased clearance by 42%, and increased half-life by 16%.
Amiodarone: (Major) If amiodarone and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Amlodipine; Celecoxib: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as celecoxib. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Amoxicillin; Clarithromycin; Omeprazole: (Major) If clarithromycin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Apalutamide: (Major) Coadministration of ivacaftor with apalutamide is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold.
Aprepitant, Fosaprepitant: (Major) If aprepitant/fosaprepitant and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and aprepitant/fosaprepitant is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Aripiprazole: (Moderate) Monitor for aripiprazole-related adverse reactions during concomitant use of ivacaftor. Patients receiving both a CYP2D6 inhibitor plus ivacaftor may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form, CYP2D6 inhibitor strength, and CYP2D6 metabolizer status. See prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is a CYP3A and CYP2D6 substrate; ivacaftor is a weak CYP3A inhibitor.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ivacaftor is necessary. If ivacaftor is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like ivacaftor can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ivacaftor is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Atazanavir: (Major) If atazanavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Atazanavir; Cobicistat: (Major) If atazanavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) If cobicistat and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with ivacaftor may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of ivacaftor in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4.
Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking ivacaftor. Additionally, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Concurrent use may increase the exposure of both drugs and the risk of adverse effects. Berotralstat is a P-gp substrate and moderate CYP3A inhibitor; ivacaftor is a CYP3A substrate and P-gp inhibitor. Coadministration with another P-gp inhibitor increased berotralstat exposure by 69% while coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving ivacaftor. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving ivacaftor. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; ivacaftor inhibits P-gp.
Bexarotene: (Moderate) Use caution when administering ivacaftor and bexarotene concurrently; the clinical impact of this interaction has not yet been determined. Administration of ivacaftor with strong CYP3A inducers is not recommended because sub-therapeutic ivacaftor exposure could result. Ivacaftor is a CYP3A substrate and bexarotene is a moderate CYP3A inducer. Co-administration with a strong CYP3A inducer decreased the ivacaftor exposure by approximately 9-fold.
Budesonide: (Moderate) Use caution when administering ivacaftor and budesonide concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as budesonide, can increase budesonide exposure leading to increased or prolonged therapeutic effects and adverse events.
Budesonide; Formoterol: (Moderate) Use caution when administering ivacaftor and budesonide concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as budesonide, can increase budesonide exposure leading to increased or prolonged therapeutic effects and adverse events.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Use caution when administering ivacaftor and budesonide concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as budesonide, can increase budesonide exposure leading to increased or prolonged therapeutic effects and adverse events.
Bupivacaine; Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with ivacaftor is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and ivacaftor is a weak CYP2C9 inhibitor.
Buprenorphine: (Moderate) Use caution when administering ivacaftor and buprenorphine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as buprenorphine, can increase buprenorphine exposure leading to increased or prolonged therapeutic effects and adverse events.
Buprenorphine; Naloxone: (Moderate) Use caution when administering ivacaftor and buprenorphine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as buprenorphine, can increase buprenorphine exposure leading to increased or prolonged therapeutic effects and adverse events.
Candesartan: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as candesartan. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Candesartan; Hydrochlorothiazide, HCTZ: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as candesartan. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Carbamazepine: (Major) Coadministration of ivacaftor with carbamazepine is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold.
Carvedilol: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as carvedilol. Ivacaftor is an inhibitor of CYP3A, P-glycoprotein (Pgp) and a weak inhibitor of CYP2C9; carvedilol is partially metabolized by CYP3A, CYP2C9 and is a substrate of Pgp. Co-administration of ivacaftor with CYP3A, CYP2C9, and Pgp substrates,such as carvedilol, can theoretically increase carvedilol exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Celecoxib: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as celecoxib. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Celecoxib; Tramadol: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as celecoxib. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined. (Minor) Use caution when administering ivacaftor and tramadol concurrently. Ivacaftor is an inhibitor of CYP3A and tramadol is partially metabolized by CYP3A. Co-administration can theoretically increase tramadol exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Ceritinib: (Major) If ceritinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and ceritinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Chloramphenicol: (Major) If chloramphenicol and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and chloramphenicol is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with ivacaftor may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of ivacaftor could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Ivacaftor is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ivacaftor is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ivacaftor can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ivacaftor is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as ibuprofen. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Ciprofloxacin: (Major) If ciprofloxacin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and ciprofloxacin is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Clarithromycin: (Major) If clarithromycin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Clozapine: (Moderate) Use caution when administering ivacaftor and clozapine concurrently. Ivacaftor is an inhibitor of CYP3A and clozapine is partially metabolized by CYP3A. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Cobicistat: (Major) If cobicistat and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Colchicine: (Major) Avoid concomitant use of colchicine and ivacaftor due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a P-gp substrate and ivacaftor is a P-gp inhibitor.
Conivaptan: (Major) If conivaptan and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Crizotinib: (Major) If crizotinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Cyclosporine: (Major) If cyclosporine and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. More careful monitoring of cyclosporine blood concentrations may be warranted. Coadministration may increase exposure to both drugs leading to increased or prolonged therapeutic effects and adverse events. Ivacaftor is a CYP3A substrate and cyclosporine is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. In addition, ivacaftor is an inhibitor of CYP3A and P-gp; cyclosporine is a CYP3A and P-gp substrate.
Dabigatran: (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with ivacaftor is necessary in patients with creatinine clearance (CrCl) greater than 50 mL/min. Avoid coadministration in patients with CrCl less than 50 mL/min when dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery. Avoid coadministration in patients with CrCl less than 30 mL/min in patients with non-valvular atrial fibrillation. Serum concentrations of dabigatran are expected to be higher in patients with renal impairment compared to patients with normal renal function. Dabigatran is a P-glycoprotein substrate and ivacaftor is a P-gp inhibitor.
Danazol: (Major) If danazol and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and danazol is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Dapsone: (Major) If dapsone and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and dapsone is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Darunavir: (Major) If darunavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Darunavir; Cobicistat: (Major) If cobicistat and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) If darunavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) If cobicistat and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) If darunavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Delavirdine: (Major) If delavirdine and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and delavirdine is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as diphenhydramine. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Diazepam: (Moderate) Use caution when administering ivacaftor and diazepam concurrently because patients may be at increased risk for adverse effects from diazepam. Ivacaftor is a CYP3A inhibitor, and diazepam is a CYP3A substrate. Diazepam is also metabolized by CYP2C19, which is not affected by ivacaftor. Co-administration of ivacaftor with midazolam, another CYP3A substrate, increased midazolam exposure by 1.5-fold.
Diclofenac: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with diclofenac. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; diclofenac is metabolized by CYP3A and CYP2C9. Co-administration can theoretically increase diclofenac exposure leading to increased or prolonged therapeutic effects and adverse events. Do not exceed a total daily diclofenac dose of 100 mg.
Diclofenac; Misoprostol: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with diclofenac. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; diclofenac is metabolized by CYP3A and CYP2C9. Co-administration can theoretically increase diclofenac exposure leading to increased or prolonged therapeutic effects and adverse events. Do not exceed a total daily diclofenac dose of 100 mg.
Digoxin: (Moderate) Coadministration of ivacaftor with digoxin may increase digoxin exposure leading to increased or prolonged therapeutic effects and adverse events. Digoxin is a substrate for P-glycoprotein (P-gp). Ivacaftor is an inhibitor of P-glycoprotein (P-gp). Use caution when administering ivacaftor and digoxin concurrently.
Diltiazem: (Major) If diltiazem and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Diphenhydramine: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as diphenhydramine. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Diphenhydramine; Ibuprofen: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as diphenhydramine. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined. (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as ibuprofen. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Diphenhydramine; Naproxen: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as diphenhydramine. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined. (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as naproxen. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Diphenhydramine; Phenylephrine: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as diphenhydramine. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Disopyramide: (Moderate) Use caution when administering ivacaftor and disopyramide concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as disopyramide, can increase disopyramide exposure leading to increased or prolonged therapeutic effects and adverse events.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ivacaftor. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Doxepin: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as doxepin. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Doxorubicin Liposomal: (Major) Ivacaftor is a mild inhibitor of CYP3A and P-glycoprotein (P-gp); doxorubicin is a major CYP3A4 and P-gp substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4 and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ivacaftor and doxorubicin if possible. If avoidance is not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
Doxorubicin: (Major) Ivacaftor is a mild inhibitor of CYP3A and P-glycoprotein (P-gp); doxorubicin is a major CYP3A4 and P-gp substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4 and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ivacaftor and doxorubicin if possible. If avoidance is not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
Dronabinol: (Minor) Use caution if coadministration of dronabinol with ivacaftor is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; ivacaftor is a weak inhibitor of CYP3A4 and a weak CYP2C9 inhibitor in vitro. Concomitant use may result in elevated plasma concentrations of dronabinol.
Dronedarone: (Major) If dronedarone and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and dronedarone is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Duvelisib: (Major) If duvelisib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and duvelisib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ivacaftor. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ivacaftor. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Eletriptan: (Moderate) Use caution when administering ivacaftor and eletriptan concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as eletriptan, can increase eletriptan exposure leading to increased or prolonged therapeutic effects and adverse events.
Eliglustat: (Major) In poor CYP2D6 metabolizers (PMs), coadministration of ivacaftor and eliglustat is not recommended. In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. Ivacaftor and its primary metabolite M1 are considered weak CYP3A inhibitors; eliglustat is a CYP3A and CYP2D6 substrate. Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration of eliglustat with CYP3A inhibitors may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias) in these patients.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) If cobicistat and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) If cobicistat and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ivacaftor. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ivacaftor. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ivacaftor. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Encorafenib: (Major) Coadministration of encorafenib with ivacaftor may result in increased toxicity or decreased efficacy of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Enzalutamide: (Major) Coadministration of ivacaftor with enzalutamide is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold.
Erythromycin: (Major) If erythromycin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and erythromycin is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Estazolam: (Moderate) Use caution when administering ivacaftor and estazolam concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as estazolam, can increase estazolam exposure leading to increased or prolonged therapeutic effects and adverse events.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with ivacaftor is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and ivacaftor is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
Ezetimibe; Simvastatin: (Minor) Use caution when administering ivacaftor and simvastatin concurrently. Coadministration of ivacaftor with simvastatin may increase simvastatin exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined. Simvastatin is a sensitive CYP3A4 substrate; ivacaftor is a weak CYP3A4 inhibitor.
Fedratinib: (Major) If fedratinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Felodipine: (Moderate) Use caution when administering ivacaftor and felodipine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as felodipine, can increase felodipine exposure leading to increased or prolonged therapeutic effects and adverse events.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of ivacaftor is necessary. If ivacaftor is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ivacaftor can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If ivacaftor is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or ivacaftor; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and ivacaftor is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased overall exposure to finerenone by 21%.
Flibanserin: (Moderate) The concomitant use of flibanserin and multiple weak CYP3A4 inhibitors, including ivacaftor, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the risks of combination therapy with multiple weak CYP3A4 inhibitors and flibanserin should be discussed with the patient.
Fluconazole: (Major) If fluconazole and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold.
Fluoxetine: (Minor) Although an interaction between ivacaftor and fluoxetine is possible, the clinical impact of this interaction has not yet been determined. Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates. Fluoxetine is partially metabolized by CYP2C9, but it is also a substrate for at least 2 other enzymes. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may possibly lead to increased exposure to fluoxetine; however, because fluoxetine has multiple metabolic pathways, the clinical impact of this inhibition is not clear. In addition, ivacaftor is a CYP3A substrate, and fluoxetine is a mild CYP3A inhibitor. Co-administration may lead to increased ivacaftor exposure.
Flurbiprofen: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as flurbiprofen. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Fluvastatin: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as fluvastatin. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Fluvoxamine: (Major) If fluvoxamine and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Fosamprenavir: (Major) If fosamprenavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and fosamprenavir is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Fosphenytoin: (Major) Coadministration of ivacaftor with fosphenytoin is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and ivacaftor as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of P-glycoprotein (P-gp); ivacaftor is a P-gp inhibitor.
Glimepiride: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as glimepiride. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Glipizide: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as glipizide. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Glipizide; Metformin: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as glipizide. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Glyburide: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as glyburide. Ivacaftor is an inhibitor of P-glycoprotein (Pgp) and a weak inhibitor of CYP2C9; glyburide is metabolized by CYP2C9 and is substrate of Pgp. Co-administration of ivacaftor with Pgp and CYP2C9 substrates, such as glyburide, can theoretically increase glyburide exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Glyburide; Metformin: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as glyburide. Ivacaftor is an inhibitor of P-glycoprotein (Pgp) and a weak inhibitor of CYP2C9; glyburide is metabolized by CYP2C9 and is substrate of Pgp. Co-administration of ivacaftor with Pgp and CYP2C9 substrates, such as glyburide, can theoretically increase glyburide exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Grapefruit juice: (Major) The manufacturer recommends avoiding grapefruit or Seville oranges during ivacaftor therapy because ivacaftor exposure may be increased. Ivacaftor is a CYP3A substrate. Grapefruit juice and Seville oranges contain components that inhibit CYP3A, and therefore, may reduce ivacaftor metabolism.
Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ivacaftor is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ivacaftor can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ivacaftor is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ivacaftor is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ivacaftor can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ivacaftor is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ivacaftor is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ivacaftor can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ivacaftor is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ivacaftor is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ivacaftor can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ivacaftor is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as ibuprofen. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ivacaftor is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ivacaftor can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ivacaftor is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Ibuprofen: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as ibuprofen. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Ibuprofen; Famotidine: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as ibuprofen. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ivacaftor is necessary. If ivacaftor is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like ivacaftor can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ivacaftor is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as ibuprofen. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Ibuprofen; Pseudoephedrine: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as ibuprofen. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Idelalisib: (Major) If idelalisib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and idelalisib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Imatinib: (Major) If imatinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and imatinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Indinavir: (Major) If indinavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and indinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Indomethacin: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as indomethacin. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Isavuconazonium: (Major) If isavuconazonium and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and isavuconazonium is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Coadministration of ivacaftor with rifampin is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin significantly decreased ivacaftor exposure by approximately 9-fold.
Isoniazid, INH; Rifampin: (Major) Coadministration of ivacaftor with rifampin is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin significantly decreased ivacaftor exposure by approximately 9-fold.
Itraconazole: (Major) If itraconazole and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and itraconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Ivosidenib: (Moderate) Monitor for loss of efficacy of ivacaftor during coadministration of ivosidenib; a ivacaftor dose adjustment may be necessary. Ivacaftor is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased ivacaft

or concentrations.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of ivacaftor is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and ivacaftor a weak CYP3A inhibitor.
Ketoconazole: (Major) If ketoconazole and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration increased ivacaftor exposure by 8.5-fold.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ivacaftor. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) If clarithromycin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Lapatinib: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with ivacaftor is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and ivacaftor is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
Lefamulin: (Major) Avoid coadministration of ivacaftor with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; ivacaftor may be administered with intravenous lefamulin. If lefamulin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Lefamulin is a P-gp substrate and a moderate CYP3A inhibitor, and ivacaftor is a P-gp inhibitor and a CYP3A substrate. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Lemborexant: (Major) Limit the dose of lemborexant to a maximum of 5 mg PO once daily if coadministered with ivacaftor as concurrent use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; ivacaftor is a weak CYP3A4 inhibitor. Coadministration of lemborexant with a weak CYP3A4 inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
Lenacapavir: (Major) If lenacapavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and lenacapavir is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Letermovir: (Major) If letermovir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. In patients also receiving cyclosporine, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly, because the magnitude of the interaction may be increased. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate. Letermovir is a moderate CYP3A inhibitor; however, when given with cyclosporine, the combined effect on CYP3A substrates may be similar to a strong CYP3A inhibitor. Coadministration with other moderate and strong CYP3A inhibitors increased ivacaftor exposure by 3- and 8.5-fold, respectively.
Levoketoconazole: (Major) If ketoconazole and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration increased ivacaftor exposure by 8.5-fold.
Lonafarnib: (Major) Avoid concomitant use of lonafarnib and ivacaftor due to the risk of increased exposure and adverse effects from both drugs. If coadministration is unavoidable, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly and reduce to or continue lonafarnib at a dosage or 115 mg/m2. Coadministration is not recommended in patients younger than 6 months. Lonafarnib is a CYP2C9 and CYP3A substrate and strong CYP3A inhibitor; ivacaftor is a CYP3A substrate and CYP2C9 and weak CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Loperamide: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with ivacaftor. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and ivacaftor is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Loperamide; Simethicone: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with ivacaftor. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and ivacaftor is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Lopinavir; Ritonavir: (Major) If ritonavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Losartan: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as losartan. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; losartan is metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates,such as losartan, can theoretically increase losartan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as losartan. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; losartan is metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates,such as losartan, can theoretically increase losartan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Lovastatin: (Moderate) Monitoring for lovastatin-related adverse events (i.e., myopathy, rhabdomyolysis) is recommended if administered concurrently with ivacaftor. Coadministration can increase lovastatin exposure leading to increased or prolonged therapeutic effects and adverse events. Lovastatin is a CYP3A4 substrate; ivacaftor is a weak CYP3A4 inhibitor.
Maraviroc: (Minor) Use caution if coadministration of maraviroc with ivacaftor is necessary, due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A and P-glycoprotein (Pgp) substrate and ivacaftor is a weak CYP3A4/Pgp inhibitor. Monitor for an increase in adverse effects with concomitant use.
Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with ivacaftor is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and ivacaftor is a weak CYP2C9 inhibitor.
Methadone: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as methadone. Ivacaftor is an inhibitor of CYP3A, P-glycoprotein (Pgp), and a weak inhibitor of CYP2C9; methadone is metabolized by CYP3A4, CYP2C9, and is a substrate of Pgp. Co-administration of ivacaftor with CYP3A, CYP2C9, and Pgp substrates,such as methadone may increase methadone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Midazolam: (Moderate) Use caution when administering ivacaftor and midazolam concurrently because patients are at increased risk for adverse effects from midazolam. Ivacaftor is a CYP3A inhibitor, and midazolam is a CYP3A substrate. When administered with ivacaftor, midazolam exposure was increased by 1.5-fold.
Mifepristone: (Major) If mifepristone and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and mifepristone is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Mitotane: (Major) Coadministration of ivacaftor with mitotane is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold.
Morphine: (Moderate) Use caution when administering ivacaftor and morphine concurrently. Ivacaftor is an inhibitor of P-glycoprotein (P-gp). Coadministration of ivacaftor with P-gp substrates, such as morphine, can increase morphine exposure leading to increased or prolonged therapeutic effects and adverse events.
Morphine; Naltrexone: (Moderate) Use caution when administering ivacaftor and morphine concurrently. Ivacaftor is an inhibitor of P-glycoprotein (P-gp). Coadministration of ivacaftor with P-gp substrates, such as morphine, can increase morphine exposure leading to increased or prolonged therapeutic effects and adverse events.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and ivacaftor. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and ivacaftor is a weak CYP3A and P-gp inhibitor.
Naproxen: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as naproxen. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Naproxen; Esomeprazole: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as naproxen. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Naproxen; Pseudoephedrine: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as naproxen. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Nateglinide: (Moderate) Monitor blood glucose and for signs of hypoglycemia. Ivacaftor is a weak inhibitor of CYP2C9; nateglinide is metabolized by CYP2C9. Use of ivacaftor with nateglinide can theoretically increase nateglinide exposure leading to increased or prolonged therapeutic effects; however, the clinical impact of this potential interaction has not yet been determined.
Nefazodone: (Major) If nefazodone and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Nelfinavir: (Major) If nelfinavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and nelfinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Netupitant, Fosnetupitant; Palonosetron: (Major) If netupitant and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Niacin; Simvastatin: (Minor) Use caution when administering ivacaftor and simvastatin concurrently. Coadministration of ivacaftor with simvastatin may increase simvastatin exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined. Simvastatin is a sensitive CYP3A4 substrate; ivacaftor is a weak CYP3A4 inhibitor.
Nifedipine: (Moderate) Use caution when administering ivacaftor and nifedipine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as nifedipine, can increase nifedipine exposure leading to increased or prolonged therapeutic effects and adverse events.
Nilotinib: (Major) If nilotinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Nintedanib: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as ivacaftor, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Ivacaftor is a mild inhibitor of both P-glycoprotein (P-gp) and CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
Nirmatrelvir; Ritonavir: (Major) If ritonavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with ivacaftor due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and ivacaftor is a CYP3A4 inhibitor.
Olanzapine; Fluoxetine: (Minor) Although an interaction between ivacaftor and fluoxetine is possible, the clinical impact of this interaction has not yet been determined. Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates. Fluoxetine is partially metabolized by CYP2C9, but it is also a substrate for at least 2 other enzymes. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may possibly lead to increased exposure to fluoxetine; however, because fluoxetine has multiple metabolic pathways, the clinical impact of this inhibition is not clear. In addition, ivacaftor is a CYP3A substrate, and fluoxetine is a mild CYP3A inhibitor. Co-administration may lead to increased ivacaftor exposure.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ivacaftor is necessary. If ivacaftor is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like ivacaftor can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ivacaftor is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Phenobarbital: (Major) Coadministration of ivacaftor with phenobarbital is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold. Additionally, phenobarbital is a CYP2C9 substrate and ivacaftor may inhibit CYP2C9. Coadministration may increase exposure to phenobarbital leading to increased or prolonged therapeutic effects and adverse events.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Coadministration of ivacaftor with phenobarbital is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold. Additionally, phenobarbital is a CYP2C9 substrate and ivacaftor may inhibit CYP2C9. Coadministration may increase exposure to phenobarbital leading to increased or prolonged therapeutic effects and adverse events.
Phenytoin: (Major) Coadministration of ivacaftor with phenytoin is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold.
Pimozide: (Minor) Use caution when administering ivacaftor and pimozide concurrently. Ivacaftor is an inhibitor of CYP3A and pimozide is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as pimozide, can theoretically increase pimozide exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Pioglitazone; Glimepiride: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as glimepiride. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Piroxicam: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as piroxicam. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Posaconazole: (Major) If posaconazole and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Additionally, monitor for an increase in posaconazole-related adverse reactions. Ivacaftor is a CYP3A substrate and a P-gp inhibitor, and posaconazole is a strong CYP3A inhibitor and a P-gp substrate. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Pralsetinib: (Major) Avoid concomitant use of ivacaftor with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a P-gp substrate and ivacaftor is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased the overall exposure of pralsetinib by 81%.
Prasugrel: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as prasugrel. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; prasugrel is metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates, such as prasugrel, can theoretically increase prasugrel exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Prednisolone: (Moderate) Use caution when administering ivacaftor and prednisone concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp); prednisone is a substrate of Pgp and it's active metabolite, prednisolone, is metabolized by CYP3A. Co-administration can increase prednisone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Primidone: (Major) Coadministration of ivacaftor with primidone is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold. Additionally, primidone is a CYP2C9 substrate and ivacaftor may inhibit CYP2C9. Coadministration may increase exposure to primidone leading to increased or prolonged therapeutic effects and adverse events.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and ivacaftor due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a P-gp substrate and ivacaftor is a P-gp inhibitor.
Quetiapine: (Moderate) Use caution when administering ivacaftor and quetiapine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as quetiapine, can increase quetiapine exposure leading to increased or prolonged therapeutic effects and adverse events.
Quinine: (Major) If quinine and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and quinine is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Ramelteon: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as ramelteon. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; ramelteon is partially metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates, such as ramelteon, can theoretically increase ramelteon exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Relugolix: (Major) Avoid concomitant use of relugolix and oral ivacaftor. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer ivacaftor at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and ivacaftor is a P-gp inhibitor.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral ivacaftor. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer ivacaftor at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and ivacaftor is a P-gp inhibitor.
Ribociclib: (Major) If ribociclib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Ribociclib; Letrozole: (Major) If ribociclib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Rifampin: (Major) Coadministration of ivacaftor with rifampin is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin significantly decreased ivacaftor exposure by approximately 9-fold.
Rifapentine: (Major) Coadministration of ivacaftor with rifapentine is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with ivacaftor is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and ivacaftor is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with ivacaftor; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and ivacaftor is a P-gp inhibitor.
Ritlecitinib: (Major) If ritlecitinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Ritonavir: (Major) If ritonavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Rivaroxaban: (Minor) The coadministration of rivaroxaban and ivacaftor should be undertaken with caution in patients with renal impairment; it is unclear whether a clinically significant interaction occurs when these two drugs are coadministered to patients with normal renal function. Ivacaftor is a combined mild CYP3A4 inhibitor and mild P-glycoprotein (P-gp) inhibitor. Rivaroxaban is a substrate of CYP3A4/5 and the P-gp transporter. Coadministration in patients with renal impairment may result in increased exposure to rivaroxaban compared with patients with normal renal function and no inhibitor use since both pathways of elimination are affected. While an increase in exposure to rivaroxaban may be expected, results from an analysis of the ROCKET-AF trial which allowed concomitant administration of rivaroxaban and a combined P-gp inhibitor and weak or moderate CYP3A4 inhibitor did not show an increased risk of bleeding in patients with CrCl 30 to < 50 ml/min [HR (95% CI): 1.05 (0.77, 1.42)].
Saquinavir: (Major) If saquinavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Additionally, monitor for an increase in saquinavir-related adverse reactions if coadministration with ivacaftor is necessary as concomitant use may increase saquinavir exposure. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and a P-gp inhibitor, and saquinavir is a strong CYP3A inhibitor and a P-gp substrate. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Sertraline: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as sertraline. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; sertraline is metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates, such as sertraline, can theoretically increase sertraline exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Sildenafil: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as sildenafil. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; sildenafil is metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates, such as sildenafil, can theoretically increase sildenafil exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Simvastatin: (Minor) Use caution when administering ivacaftor and simvastatin concurrently. Coadministration of ivacaftor with simvastatin may increase simvastatin exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined. Simvastatin is a sensitive CYP3A4 substrate; ivacaftor is a weak CYP3A4 inhibitor.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of ivacaftor. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and ivacaftor is a weak CYP3A and P-gp inhibitor.
Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with ivacaftor. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); ivacaftor is a weak inhibitor of P-gp. Ivacaftor is also a weak inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with ivacaftor. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); ivacaftor is a weak inhibitor of P-gp. Ivacaftor is also a weak inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
St. John's Wort, Hypericum perforatum: (Major) Coadministration of ivacaftor with St. John's Wort is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if ivacaftor must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of ivacaftor is necessary. If ivacaftor is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like ivacaftor can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If ivacaftor is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as sulfamethoxazole; trimethoprim, SMX-TMP. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Sumatriptan; Naproxen: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as naproxen. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Tacrolimus: (Major) Use caution when administering ivacaftor and tacrolimus concurrently; careful tacrolimus blood concentrations is warranted. Ivacaftor is an inhibitor of CYP3A, and tacrolimus is a CYP3A substrate. Co-administration can increase tacrolimus exposure leading to increased or prolonged therapeutic effects and adverse events.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with ivacaftor is necessary. Talazoparib is a P-gp substrate and ivacaftor is a P-gp inhibitor.
Temsirolimus: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with ivacaftor is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate. Both ivacaftor and its M1 metabolite have the potential to inhibit P-gp. Concomitant use is likely to lead to increased concentrations of temsirolimus.
Tenofovir Alafenamide: (Minor) Use caution when administering ivacaftor and tenofovir alafenamide concurrently. Ivacaftor is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Concurrent use can increase tenofovir exposure leading to adverse events. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ivacaftor. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering ivacaftor. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C9 and CYP3A4; ivacaftor is an inhibitor of these enzymes. Monitor patients for adverse reactions if these drugs are coadministered.
Ticagrelor: (Minor) Coadministration of ticagrelor and ivacaftor may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and ivacaftor is a mild P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
Tipranavir: (Major) If tipranavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Additionally, monitor for an increase in tipranavir-related adverse reactions if coadministration with ivacaftor is necessary. Concomitant use may increase tipranavir exposure. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and a P-gp inhibitor, and tipranavir is a strong CYP3A inhibitor and a P-gp substrate. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Tolbutamide: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as tolbutamide. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Topotecan: (Major) Avoid coadministration of ivacaftor with oral topotecan due to increased topotecan exposure; ivacaftor may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and ivacaftor is a weak P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
Torsemide: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as torsemide. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Tramadol: (Minor) Use caution when administering ivacaftor and tramadol concurrently. Ivacaftor is an inhibitor of CYP3A and tramadol is partially metabolized by CYP3A. Co-administration can theoretically increase tramadol exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Tramadol; Acetaminophen: (Minor) Use caution when administering ivacaftor and tramadol concurrently. Ivacaftor is an inhibitor of CYP3A and tramadol is partially metabolized by CYP3A. Co-administration can theoretically increase tramadol exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Trandolapril; Verapamil: (Major) If verapamil and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with ivacaftor and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A substrate and ivacaftor is a weak CYP3A inhibitor.
Tucatinib: (Major) If tucatinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with ivacaftor. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 and P-gp substrate; ivacaftor is a weak CYP3A4 inhibitor and a P-gp inhibitor.
Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with ivacaftor due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of ivacaftor. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; ivacaftor is a CYP3A4 (weak) and P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
Verapamil: (Major) If verapamil and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) If clarithromycin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Voriconazole: (Major) If voriconazole and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Voxelotor: (Major) If voxelotor and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with ivacaftor is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Ivacaftor is a weak CYP3A4 inhibitor and the R-enantiomer is a CYP3A4 substrate. Ivacaftor is also a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9/CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.

Ivacaftor/Kalydeco Oral Gran: 5.8mg, 13.4mg, 25mg, 50mg, 75mg
Kalydeco Oral Tab: 150mg

Adults

300 mg/day PO.

Geriatric

300 mg/day PO.

Adolescents

300 mg/day PO.

Children

6 to 12 years: 300 mg/day PO.
1 to 5 years weighing 14 kg or more: 150 mg/day PO.
1 to 5 years weighing 7 to 13 kg: 100 mg/day PO.
1 to 5 years weighing 5 to 6 kg: 50 mg/day PO.

Infants

6 to 11 months weighing 14 kg or more: 150 mg/day PO.
6 to 11 months weighing 7 to 13 kg: 100 mg/day PO.
6 to 11 months weighing 5 to 6 kg: 50 mg/day PO.
4 to 5 months weighing 5 kg or more: 50 mg/day PO.
2 to 3 months weighing 3 kg or more: 26.8 mg/day PO.
1 month weighing 3 kg or more: 11.6 mg/day PO.
Younger than 1 month: Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

Ivacaftor is a potentiator of the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel present at the surface of epithelial cells in multiple organs. Ivacaftor increases chloride transport by potentiating the channel-open probability of the CFTR protein. In clinical trials, patients with one of the following mutations in the CFTR gene had statistically significant reductions in sweat chloride concentrations after receiving ivacaftor: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H. Evidence of clinical efficacy exists for other mutations in the CFTR gene that are responsive to ivacaftor, including some splice mutations. Ivacaftor is not effective in patients with CF who are homozygous for the F508del mutation.

Ivacaftor is administered orally. It is approximately 99% bound to proteins, primarily alpha1-acid glycoprotein and albumin. Mean apparent Vd is 353 +/- 122 L at steady state. Ivacaftor is extensively metabolized, primarily by CYP3A, to the major metabolites M1 (pharmacologically active; one-sixth the potency of parent drug) and M6 (pharmacologically inactive). Ivacaftor is primarily eliminated in the feces (88%), with M1 and M6 accounting for approximately 65% of the total dose eliminated; negligible amounts of the parent drug are eliminated in the urine. Mean clearance is 17 +/- 8 L/hour with a terminal half-life of approximately 12 hours.[48524]
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A, CYP2C9, and P-gp
Ivacaftor is metabolized by the cytochrome P450 (CYP450) enzyme group, primarily CYP3A. Dosage adjustments are recommended when ivacaftor is co-administered with moderate or strong CYP3A inhibitors; concurrent use with strong CYP3A inducers is not recommended. Ivacaftor and the M1 metabolite are considered weak inhibitors of CYP3A, CYP2C9, and P-glycoprotein (P-gp) transport. Increased monitoring is recommended when ivacaftor is administered concurrently with CYP3A, CYP2C9, or P-gp substrates.[48524]

Oral Route

Peak plasma concentrations (768 +/- 233 ng/mL) were obtained approximately 4 hours (range: 3 to 6 hours) after oral administration of a single 150-mg dose (fed state) during clinical trials. Under these same conditions, AUC was 10,600 +/- 5,260 ng x hour/mL. In adult patients receiving one 150-mg tablet every 12 hours, mean AUC at steady state was 10,700 +/- 4,100 ng x hour/mL, which was similar to exposure achieved in most pediatric populations studied. After every 12-hour dosing, steady state plasma concentrations were obtained within 3 to 5 days. Administration of ivacaftor with fat-containing foods increased exposure by 2 to 4 fold during clinical studies; hence, administration with fat-containing foods is recommended. The bioavailability of ivacaftor tablets and granules is similar.[48524]

Pregnancy

No adequate and well-controlled studies have been performed with ivacaftor use during human pregnancy. The drug was not found to be teratogenic in animals at doses 6 to 12 times the maximum recommended human dose (MRHD). Because animal reproductive studies are not always predictive of human response, ivacaftor should only be used in pregnancy if clearly needed.

Ivacaftor should be used cautiously in a breast-feeding woman. Ivacaftor is excreted into the breast milk of lactating rats. According to the manufacturer, excretion into human milk is probable; however, the drug is approximately 99% protein bound, which should limit the amount of drug available in breast milk. No studies have been done to assess the effects of ivacaftor on a nursing infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.