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  • CLASSES

    Cystic Fibrosis Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator
    Used for cystic fibrosis in patients 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

    COMMON BRAND NAMES

    KALYDECO

    HOW SUPPLIED

    KALYDECO Oral Gran: 50mg, 75mg
    KALYDECO Oral Tab: 150mg

    DOSAGE & INDICATIONS

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

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

    Children 1 to 5 years weighing 14 kg or more

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

    Children 1 to 5 years weighing less than 14 kg

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

    MAXIMUM DOSAGE

    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 less than 14 kg: 100 mg/day PO.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.

    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.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Administer each dose with fat-containing food (e.g. eggs, butter, peanut butter, cheese pizza).
    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 granules: Mix the entire contents of each packet with 5 mL of age-appropriate soft food or liquid (e.g., pureed fruits or vegetables, yogurt, applesauce, water, milk, juice). Food or liquid should be at or below room temperature. The mixture is stable for 1 hour and should be completely consumed within this time period. The mixture should be consumed just before or just after consuming fat-containing food.

    STORAGE

    KALYDECO:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Ivacaftor is not effective in patients with cystic fibrosis (CF) who are homozygous for the F508del mutation in the CFTR gene. Results from a double-blind, placebo-controlled trial in patients with CF who were homozygous for the F508del mutation showed no statistically significant difference in forced expiratory volume exhaled in one second (FEV1) over 16 weeks of treatment compared to placebo. Ivacaftor has not been studied in other patients with CF. If a patient's genotype is unknown, an FDA-cleared CF mutation test should be performed.

    Hepatic disease

    Use ivacaftor with caution in patients with hepatic disease. A dose reduction is required in patients with moderate or severe (Child-Pugh Class B or C) hepatic disease. Ivacaftor can cause elevated transaminases in patients with cystic fibrosis, and it is recommended that patients have AST and ALT assessed prior to initiating therapy, every 3 months during the first year of therapy, and annually thereafter. Consider more frequent monitoring in patients with a history of transaminase elevations. Patients who develop increased transaminase levels should be closely monitored until the abnormalities resolve. Temporarily discontinue ivacaftor in patients with an ALT or AST greater than 5 times the upper limit of normal. Upon resolution, ivacaftor therapy may be resumed after careful consideration of the benefits and risks of therapy.

    Renal disease, renal failure, renal impairment

    Use ivacaftor with caution in patients with severe renal impairment (CrCl 30 mL/minute or less) or end stage renal disease (renal failure). Ivacaftor has not been studied in patients with any degree of renal impairment or renal disease.

    Cataracts, infants

    Cases of non-congenital lens opacities/cataracts have been reported in pediatric patients treated with ivacaftor. Although other risk factors (e.g., corticosteroid use, radiation exposure) were present in some cases, a possible risk attributable to ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in children and adolescents initiating ivacaftor treatment. The safety and efficacy of ivacaftor have not been established in infants less than 12 months of age and use in this population is not recommended.[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.

    Breast-feeding

    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.

    ADVERSE REACTIONS

    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

    DRUG INTERACTIONS

    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) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4.
    Acetaminophen; Oxycodone: (Minor) Use caution when administering ivacaftor and oxycodone concurrently. Ivacaftor is an inhibitor of CYP3A and oxycodone is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as oxycodone, can theoretically increase oxycodone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Acetaminophen; 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.
    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.
    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: (Moderate) Use caution when administering ivacaftor and alprazolam concurrently because patients are at increased risk for adverse effects from alprazolam. Ivacaftor is a CYP3A inhibitor, and alprazolam is a CYP3A substrate. Co-administration of ivacaftor with midazolam, another CYP3A substrate, increased midazolam exposure by 1.5-fold.
    Amiodarone: (Major) If amiodarone 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 amiodarone is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) If clarithromycin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. 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.
    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. 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 multi-day regimens of aprepitant 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 aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. When administered as a single oral or single intravenous dose, the inhibitory effect of aprepitant on CYP3A4 is weak and did not result in a clinically significant increase in the AUC of a sensitive substrate.
    Aspirin, ASA; 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.
    Aspirin, ASA; Oxycodone: (Minor) Use caution when administering ivacaftor and oxycodone concurrently. Ivacaftor is an inhibitor of CYP3A and oxycodone is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as oxycodone, can theoretically increase oxycodone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Atazanavir: (Major) If atazanavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. 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. 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. 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.
    Atropine; Hyoscyamine; Phenobarbital; 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.
    Belladonna Alkaloids; Ergotamine; 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. (Moderate) Use caution when administering ivacaftor and ergotamine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as ergotamine, can increase ergotamine exposure leading to increased or prolonged therapeutic effects and adverse events, including the risk for ergot toxicity.
    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.
    Boceprevir: (Major) If boceprevir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg twice weekly). Ivacaftor is a CYP3A substrate, and boceprevir is a strong CYP3A inhibitor. Coadministration with ketoconazole, another strong CYP3A inhibitor, increased ivacaftor exposure by 8.5-fold. Ivacaftor is also an inhibitor of CYP3A and P-glycoprotein (P-gp); boceprevir is metabolized by CYP3A4 and is a substrate of P-gp. Coadministration may increase boceprevir exposure leading to increased or prolonged therapeutic effects and adverse events.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4.
    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.
    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.
    Caffeine; Ergotamine: (Moderate) Use caution when administering ivacaftor and ergotamine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as ergotamine, can increase ergotamine exposure leading to increased or prolonged therapeutic effects and adverse events, including the risk for ergot toxicity.
    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.
    Carbetapentane; 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.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4.
    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.
    Ceritinib: (Major) If ceritinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but consider reducing the frequency to once daily. Ivacaftor is a CYP3A substrate and in vitro studies suggest ceritinib is a CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Chloramphenicol: (Major) If chloramphenicol and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. 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; Dihydrocodeine; Pseudoephedrine: (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; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4.
    Clarithromycin: (Major) If clarithromycin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. 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. 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.
    Cobicistat; Elvitegravir; 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. 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.
    Cobicistat; Elvitegravir; 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. 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.
    Colchicine: (Major) Use caution when administering ivacaftor and colchicine concurrently; increased monitoring and/or dose adjustment of colchine may be necessary. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as colchicine, can increase colchicine exposure leading to increased or prolonged therapeutic effects and adverse events. Fatal colchicine toxicity has been reported when given with strong CYP3A4 and Pgp inhibitors.
    Conivaptan: (Major) If conivaptan and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and conivaptan is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
    Crizotinib: (Major) If crizotinib 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 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 may increase exposure to both drugs leading to increased or prolonged therapeutic effects and adverse events. More careful monitoring of cyclosporine blood concentrations may be warranted. 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-glycoprotein (P-gp); cyclosporine is a sensitive CYP3A and P-gp substrate.
    Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with ivacaftor, a mild P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. 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 with P-gp inhibitors like ivacaftor in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation andsevere renal impairment (CrCl less than 30 mL/minute), avoid coadministration with ivacaftor, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Dalfopristin; Quinupristin: (Major) If dalfopristin; quinupristin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate, dalfopristin; quinupristin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
    Danazol: (Major) If danazol 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 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. 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. 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. 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. 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. 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.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) If ritonavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and ritonavir is a 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. 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.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (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.
    Dihydroergotamine: (Moderate) Use caution when administering ivacaftor and dihydroergotamine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dihydroergotamine, can increase dihydroergotamine exposure leading to increased or prolonged therapeutic effects and adverse events, including the risk for ergot toxicity.
    Diltiazem: (Major) If diltiazem 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 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; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4. (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: (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. 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) Administer ivacaftor at the usual recommended dose but reduce the frequency to once daily if coadministered with duvelisib. Ivacaftor is a sensitive CYP3A substrate and duvelisib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Efavirenz; Emtricitabine; Tenofovir: (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.
    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.
    Enalapril; 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.
    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.
    Ergotamine: (Moderate) Use caution when administering ivacaftor and ergotamine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as ergotamine, can increase ergotamine exposure leading to increased or prolonged therapeutic effects and adverse events, including the risk for ergot toxicity.
    Erythromycin: (Major) If erythromcyin 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 erythromcyin is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Erythromycin; Sulfisoxazole: (Major) If erythromcyin 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 erythromcyin is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Esomeprazole; 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.
    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.
    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.
    Famotidine; 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.
    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) Use caution when administering ivacaftor and fentanyl concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as fentanyl, can increase fentanyl exposure leading to increased or prolonged therapeutic effects and adverse events.
    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. 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.
    Fluoxetine; Olanzapine: (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. 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: (Moderate) Use caution when administering ivacaftor and fosamprenavir concurrently; the clinical effect of this interaction is unknown. Ivacaftor is a CYP3A substrate, and fosamprenavir is a CYP3A inhibitor and can also act as an inducer. Co-administration may lead to altered ivacaftor exposure. Ivacaftor is also an inhibitor of CYP3A , CYP2C9, and P-glycoprotein (Pgp); fosamprenavir is metabolized by CYP3A and CYP2C9 and is a substrate of Pgp. Co-administration may increase fosamprenavir exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    Glimepiride; Pioglitazone: (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.
    Glimepiride; Rosiglitazone: (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) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4.
    Hydrochlorothiazide, HCTZ; 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.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4. (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; Phenylephrine: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4.
    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; 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. (Minor) Use caution when administering ivacaftor and oxycodone concurrently. Ivacaftor is an inhibitor of CYP3A and oxycodone is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as oxycodone, can theoretically increase oxycodone exposure leading to increased or prolonged therapeutic effects and adverse events; 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. Ivacaftor is a CYP3A substrate and idelalisib is a 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. 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. 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. Ivacaftor is a CYP3A substrate and isavuconazole, the active moiety of 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. 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 ivacaftor concentrations.
    Ixabepilone: (Moderate) Frequently monitor peripheral blood counts between cycles of ixabepilone, and for other acute ixabepilone-related adverse reactions if coadministration with ivacaftor is necessary; consider the use of an alternative agent to ivacaftor that does not inhibit CYP3A4. Ixabepilone is a CYP3A4 substrate and ivacaftor is a weak CYP3A4 inhibitor. The effect of weak CYP3A4 inhibitors on exposure to ixabepilone has not been studied.
    Ketoconazole: (Major) If ketoconazole and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate. Coadministration with ketoconazole, a strong CYP3A inhibitor, 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; 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.
    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. Ivacaftor is a CYP3A substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with other moderate and strong CYP3A inhibitors increased ivacaftor exposure by 3- and 8.5-fold, respectively.
    Lopinavir; Ritonavir: (Major) If ritonavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and ritonavir is a 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.
    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.
    Lovastatin; Niacin: (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) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as meloxicam. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; meloxicam is metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates,such as meloxicam, can theoretically increase meloxicam exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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. 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.
    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; 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.
    Naproxen; Sumatriptan: (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. 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. 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; palonosetron 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 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. 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%.
    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.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) If ritonavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and ritonavir is a CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
    Oxycodone: (Minor) Use caution when administering ivacaftor and oxycodone concurrently. Ivacaftor is an inhibitor of CYP3A and oxycodone is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as oxycodone, can theoretically increase oxycodone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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.
    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.
    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. Ivacaftor is a CYP3A substrate, and posaconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
    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.
    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.
    Ribociclib: (Major) If ribociclib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and ribociclib is a strong CYP3A4 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. Ivacaftor is a CYP3A substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
    Rifabutin: (Major) Administration of ivacaftor with strong CYP3A inducers, such as rifabutin, is not recommended because sub-therapeutic ivacaftor exposure could result. Ivacaftor is a CYP3A substrate. Co-administration with rifampin, another strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold. Ivacaftor is also an inhibitor of CYP3A, and rifabutin is metabolized by CYP3A. Co-administration may increase rifabutin exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    Rifaximin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and ivacaftor, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin. In addition, rifaximin was shown to induce CYP3A in in vitro models; however, absorption after oral administration is low and in patients with normal liver function, rifaximin is not expected to induce CYP3A4.
    Ritonavir: (Major) If ritonavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and ritonavir is a 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. Ivacaftor is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. 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.
    Simvastatin; Sitagliptin: (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) Use caution when administering ivacaftor and sirolimus concurrently; careful monitoring of sirolimus blood concentrations is warranted. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as sirolimus, can increase sirolimus exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    Streptogramins: (Major) If dalfopristin; quinupristin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate, dalfopristin; quinupristin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
    Sufentanil: (Moderate) Use caution when administering ivacaftor and sufentanil concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as sufentanil, can increase sufentanil exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    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-glycoprotein (P-gp) substrate and ivacaftor is a P-gp inhibitor. Coadministration with other P-gp inhibitors increased talazoparib exposure by 8% to 45%.
    Telithromycin: (Major) If telithromycin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and telithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
    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, PMPA: (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. Ivacaftor is a CYP3A substrate and tipranavir is a CYP3A inhibitor. 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.
    Tolvaptan: (Moderate) Use caution when administering ivacaftor and tolvaptan concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as tolvaptan, can increase tolvaptan exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    Trandolapril; Verapamil: (Major) If verapamil 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 verapamil is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Triazolam: (Moderate) Monitor for serious adverse events, such as prolonged hypnotic and/or sedative effects during coadministration of ivacaftor and triazolam. Ivacaftor is a weak CYP3A inhibitor, and triazolam is a sensitive CYP3A substrate. Coadministration of ivacaftor with another sensitive CYP3A substrate increased exposure by 1.5-fold.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and ivacaftor. Venetoclax is a CYP3A4 and P-glycoprotein substrate and ivacaftor is a weak inhibitor of CYP3A and P-gp. Consider alternative agents. Consider alternative agents. If concomitant use of these drugs is required, reduce the venetoclax dosage by at least 50% (maximum dose of 200 mg/day). If ivacaftor is discontinued, wait 2 to 3 days and then resume the recommended venetoclax dosage (or prior dosage if less). Monitor patients for signs and symptoms of venetoclax toxicity such as hematologic toxicity, GI toxicity, and tumor lysis syndrome. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were increased by 106% and 78%, respectively, when a P-gp inhibitor was co-administered in healthy subjects.
    Verapamil: (Major) If verapamil 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 verapamil is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Voriconazole: (Major) If voriconazole and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. 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.
    Warfarin: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as warfarin. 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.

    PREGNANCY AND LACTATION

    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.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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]