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  • CLASSES

    Cystic Fibrosis Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator
    Used for patients 2 years and older with CF 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 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 years and older

    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 2 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 2 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 years and older: 300 mg/day PO.
    2 to 5 years weighing 14 kg or more: 150 mg/day PO.
    2 to 5 years weighing less than 14 kg: 100 mg/day PO.
    Less than 2 years: Safety and efficacy have not been established.

    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, children, infants, neonates

    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 has not been established in neonates, infants, or children less than 2 years of age.

    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 (unspecified) / 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; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) Use caution when administering ivacaftor and dextromethorphan concurrently. Ivacaftor is an inhibitor of CYP3A, and dextromethorphan is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dextromethorphan, can theoretically increase dextromethorphan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Use caution when administering ivacaftor and dextromethorphan concurrently. Ivacaftor is an inhibitor of CYP3A, and dextromethorphan is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dextromethorphan, can theoretically increase dextromethorphan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Acetaminophen; Dextromethorphan: (Minor) Use caution when administering ivacaftor and dextromethorphan concurrently. Ivacaftor is an inhibitor of CYP3A, and dextromethorphan is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dextromethorphan, can theoretically increase dextromethorphan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Acetaminophen; Dextromethorphan; Doxylamine: (Minor) Use caution when administering ivacaftor and dextromethorphan concurrently. Ivacaftor is an inhibitor of CYP3A, and dextromethorphan is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dextromethorphan, can theoretically increase dextromethorphan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Use caution when administering ivacaftor and dextromethorphan concurrently. Ivacaftor is an inhibitor of CYP3A, and dextromethorphan is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dextromethorphan, can theoretically increase dextromethorphan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Minor) Use caution when administering ivacaftor and dextromethorphan concurrently. Ivacaftor is an inhibitor of CYP3A, and dextromethorphan is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dextromethorphan, can theoretically increase dextromethorphan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Minor) Use caution when administering ivacaftor and dextromethorphan concurrently. Ivacaftor is an inhibitor of CYP3A, and dextromethorphan is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dextromethorphan, can theoretically increase dextromethorphan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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: (Minor) Use caution when administering ivacaftor and hydrocodone concurrently. Ivacaftor is an inhibitor of CYP3A and hydrocodone is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as hydrocodone, can theoretically increase hydrocodone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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.
    Aldesleukin, IL-2: (Moderate) Use caution when administering ivacaftor and aldesleukin, IL-2 concurrently. Ivacaftor is a CYP3A substrate, and aldesleukin, IL-2 is a mild CYP3A inhibitor. Co-administration may lead to increased ivacaftor exposure; however, the clinical impact of this has not yet been determined.
    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.
    Alfuzosin: (Moderate) Use caution when administering ivacaftor and alfuzosin concurrently. Ivacaftor is an inhibitor of CYP3A, and alfuzosin is a CYP3A substrate. Co-administration may increase alfuzosin exposure leading to increased or prolonged therapeutic effects and adverse events.
    Aliskiren: (Moderate) Use caution when administering ivacaftor and aliskiren concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (P-gp). Co-administration of ivacaftor with CYP3A and P-gp substrates, such as aliskiren, can increase aliskiren exposure leading to increased or prolonged therapeutic effects and adverse events.
    Aliskiren; Amlodipine: (Moderate) Use caution when administering ivacaftor and aliskiren concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (P-gp). Co-administration of ivacaftor with CYP3A and P-gp substrates, such as aliskiren, can increase aliskiren exposure leading to increased or prolonged therapeutic effects and adverse events. (Moderate) Use caution when administering ivacaftor and amlodipine concurrently. Although there is a theoretical interaction, the clinical significance is not known. Ivacaftor is an inhibitor of CYP3A, and amlodipine is a CYP3A4 substrate. Co-administration may increase amlodipine exposure leading to increased or prolonged therapeutic effects and adverse events. However, coadministration of erythromycin, another CYP3A inhibitor, in healthy volunteers did not significantly change amlodipine systemic exposure.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Use caution when administering ivacaftor and aliskiren concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (P-gp). Co-administration of ivacaftor with CYP3A and P-gp substrates, such as aliskiren, can increase aliskiren exposure leading to increased or prolonged therapeutic effects and adverse events. (Moderate) Use caution when administering ivacaftor and amlodipine concurrently. Although there is a theoretical interaction, the clinical significance is not known. Ivacaftor is an inhibitor of CYP3A, and amlodipine is a CYP3A4 substrate. Co-administration may increase amlodipine exposure leading to increased or prolonged therapeutic effects and adverse events. However, coadministration of erythromycin, another CYP3A inhibitor, in healthy volunteers did not significantly change amlodipine systemic exposure.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Use caution when administering ivacaftor and aliskiren concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (P-gp). Co-administration of ivacaftor with CYP3A and P-gp substrates, such as aliskiren, can increase aliskiren exposure leading to increased or prolonged therapeutic effects and adverse events.
    Aliskiren; Valsartan: (Moderate) Use caution when administering ivacaftor and aliskiren concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (P-gp). Co-administration of ivacaftor with CYP3A and P-gp substrates, such as aliskiren, can increase aliskiren exposure leading to increased or prolonged therapeutic effects and adverse events.
    Almotriptan: (Minor) Use caution when administering ivacaftor and almotriptan concurrently. Ivacaftor is an inhibitor of CYP3A and almotriptan is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as almotriptan, can theoretically increase almotriptan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Alogliptin; Pioglitazone: (Moderate) Use caution when administering ivacaftor and pioglitazone concurrently; the clinical impact of this interaction has not yet been determined. Ivacaftor is an inhibitor of CYP3A, and pioglitazone is partially metabolized by CYP3A. Co-administration may increase pioglitazone exposure leading to increased or prolonged therapeutic effects and adverse events. In addition, ivacaftor is a CYP3A substrate and pioglitazone is a mild CYP3A inducer. Administration of ivacaftor with strong CYP3A inducers is not recommended because sub-therapeutic ivacaftor exposure could result; the impact of mild inducers is not known.
    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) Use caution when administering ivacaftor and amiodarone concurrently; increased monitoring and/or dose reduction of ivacaftor may be necessary. The manufacturer recommends administering ivacaftor at the usual recommended dose but reducing the frequency to once daily when used concurrently with a moderate CYP3A inhibitor. Ivacaftor is a CYP3A substrate, and amiodarone is a CYP3A inhibitor. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. Ivacaftor is also an inhibitor of CYP3A and amiodarone is partially metabolized by CYP3A. Coadministration may increase amiodarone exposure leading to increased or prolonged therapeutic effects and adverse events.
    Amitriptyline: (Moderate) Use caution when administering ivacaftor and amitriptyline concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as amitriptyline, can increase amitriptyline exposure leading to increased or prolonged therapeutic effects and adverse events.
    Amitriptyline; Chlordiazepoxide: (Moderate) Use caution when administering ivacaftor and amitriptyline concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as amitriptyline, can increase amitriptyline exposure leading to increased or prolonged therapeutic effects and adverse events.
    Amlodipine: (Moderate) Use caution when administering ivacaftor and amlodipine concurrently. Although there is a theoretical interaction, the clinical significance is not known. Ivacaftor is an inhibitor of CYP3A, and amlodipine is a CYP3A4 substrate. Co-administration may increase amlodipine exposure leading to increased or prolonged therapeutic effects and adverse events. However, coadministration of erythromycin, another CYP3A inhibitor, in healthy volunteers did not significantly change amlodipine systemic exposure.
    Amlodipine; Atorvastatin: (Moderate) Use caution when administering ivacaftor and amlodipine concurrently. Although there is a theoretical interaction, the clinical significance is not known. Ivacaftor is an inhibitor of CYP3A, and amlodipine is a CYP3A4 substrate. Co-administration may increase amlodipine exposure leading to increased or prolonged therapeutic effects and adverse events. However, coadministration of erythromycin, another CYP3A inhibitor, in healthy volunteers did not significantly change amlodipine systemic exposure. (Moderate) Use caution when administering ivacaftor and atorvastatin concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as atorvastatin, can increase atorvastatin exposure leading to increased or prolonged therapeutic effects and adverse events.
    Amlodipine; Benazepril: (Moderate) Use caution when administering ivacaftor and amlodipine concurrently. Although there is a theoretical interaction, the clinical significance is not known. Ivacaftor is an inhibitor of CYP3A, and amlodipine is a CYP3A4 substrate. Co-administration may increase amlodipine exposure leading to increased or prolonged therapeutic effects and adverse events. However, coadministration of erythromycin, another CYP3A inhibitor, in healthy volunteers did not significantly change amlodipine systemic exposure.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Use caution when administering ivacaftor and amlodipine concurrently. Although there is a theoretical interaction, the clinical significance is not known. Ivacaftor is an inhibitor of CYP3A, and amlodipine is a CYP3A4 substrate. Co-administration may increase amlodipine exposure leading to increased or prolonged therapeutic effects and adverse events. However, coadministration of erythromycin, another CYP3A inhibitor, in healthy volunteers did not significantly change amlodipine systemic exposure.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Use caution when administering ivacaftor and amlodipine concurrently. Although there is a theoretical interaction, the clinical significance is not known. Ivacaftor is an inhibitor of CYP3A, and amlodipine is a CYP3A4 substrate. Co-administration may increase amlodipine exposure leading to increased or prolonged therapeutic effects and adverse events. However, coadministration of erythromycin, another CYP3A inhibitor, in healthy volunteers did not significantly change amlodipine systemic exposure.
    Amlodipine; Olmesartan: (Moderate) Use caution when administering ivacaftor and amlodipine concurrently. Although there is a theoretical interaction, the clinical significance is not known. Ivacaftor is an inhibitor of CYP3A, and amlodipine is a CYP3A4 substrate. Co-administration may increase amlodipine exposure leading to increased or prolonged therapeutic effects and adverse events. However, coadministration of erythromycin, another CYP3A inhibitor, in healthy volunteers did not significantly change amlodipine systemic exposure.
    Amlodipine; Telmisartan: (Moderate) Use caution when administering ivacaftor and amlodipine concurrently. Although there is a theoretical interaction, the clinical significance is not known. Ivacaftor is an inhibitor of CYP3A, and amlodipine is a CYP3A4 substrate. Co-administration may increase amlodipine exposure leading to increased or prolonged therapeutic effects and adverse events. However, coadministration of erythromycin, another CYP3A inhibitor, in healthy volunteers did not significantly change amlodipine systemic exposure.
    Amlodipine; Valsartan: (Moderate) Use caution when administering ivacaftor and amlodipine concurrently. Although there is a theoretical interaction, the clinical significance is not known. Ivacaftor is an inhibitor of CYP3A, and amlodipine is a CYP3A4 substrate. Co-administration may increase amlodipine exposure leading to increased or prolonged therapeutic effects and adverse events. However, coadministration of erythromycin, another CYP3A inhibitor, in healthy volunteers did not significantly change amlodipine systemic exposure.
    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 (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg 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. Ivacaftor is also an inhibitor of CYP3A; clarithromycin is metabolized by CYP3A. Coadministration may increase clarithromycin exposure leading to increased or prolonged therapeutic effects and adverse events. (Minor) Use caution when administering ivacaftor and lansoprazole concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as lansoprazole, can increase lansoprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) If clarithromycin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg 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. Ivacaftor is also an inhibitor of CYP3A; clarithromycin is metabolized by CYP3A. Coadministration may increase clarithromycin exposure leading to increased or prolonged therapeutic effects and adverse events. (Minor) Use caution when administering ivacaftor and omeprazole concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as omeprazole, can increase omeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Aprepitant, Fosaprepitant: (Moderate) 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.
    Aripiprazole: (Moderate) Use caution when administering ivacaftor and aripiprazole concurrently. Ivacaftor is an inhibitor of CYP3A, and aripiprazole is a CYP3A substrate. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. Because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada during use of a mild to moderate CYP3A4 inhibitor.
    Artemether; Lumefantrine: (Moderate) Use caution when administering ivacaftor and artemether; lumefantrine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as artemether; lumefantrine, can increase artemether; lumefantrine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Aspirin, ASA; Omeprazole: (Minor) Use caution when administering ivacaftor and omeprazole concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as omeprazole, can increase omeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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 (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg twice weekly). Ivacaftor is a CYP3A substrate, and atazanavir 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 atazanavir is metabolized by CYP3A. Coadministration may increase atazanavir exposure leading to increased or prolonged therapeutic effects and adverse events.
    Atazanavir; Cobicistat: (Major) If atazanavir 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 atazanavir 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 atazanavir is metabolized by CYP3A. Coadministration may increase atazanavir exposure leading to increased or prolonged therapeutic effects and adverse events. (Major) If cobicistat and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg once daily). Ivacaftor is a CYP3A substrate, and cobicistat is a CYP3A inhibitor. Co-administration with fluconazole, another moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. Ivacaftor is also an inhibitor of CYP3A and cobicistat is metabolized by CYP3A. Coadministration may increase cobicistat exposure leading to increased adverse events.
    Atorvastatin: (Moderate) Use caution when administering ivacaftor and atorvastatin concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as atorvastatin, can increase atorvastatin exposure leading to increased or prolonged therapeutic effects and adverse events.
    Atorvastatin; Ezetimibe: (Moderate) Use caution when administering ivacaftor and atorvastatin concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as atorvastatin, can increase atorvastatin exposure leading to increased or prolonged therapeutic effects and adverse events.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Administration of ivacaftor with strong CYP3A inducers, such as phenobarbital, 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 CYP2C9 and phenobarbital is partially metabolized by CYP2C9. Co-administration may increase phenobarbital exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Axitinib: (Moderate) Use caution if coadministration of axitinib with ivacaftor is necessary, due to the risk of increased axitinib-related adverse reactions. Axitinib is a CYP3A4 substrate and ivacaftor is a weak CYP3A4 inhibitor. Ivacaftor increased the AUC of another CYP3A4 substrate, midazolam, by 1.5-fold. Coadministration with a strong CYP3A4/5 inhibitor, ketoconazole, significantly increased the plasma exposure of axitinib in healthy volunteers. The manufacturer of axitinib recommends a dose reduction in patients receiving strong CYP3A4 inhibitors, but recommendations are not available for moderate or weak CYP3A4 inhibitors.
    Azithromycin: (Moderate) Use caution when administering ivacaftor and azithromycin concurrently. Ivacaftor is an inhibitor of P-glycoprotein (Pgp). Co-administration of ivacaftor with Pgp substrates, such as azithromycin, may increase azithromycin exposure leading to increased or prolonged therapeutic effects and adverse events.
    Basiliximab: (Moderate) Use caution when administering ivacaftor and basiliximab concurrently. Ivacaftor is a CYP3A substrate, and basiliximab is a mild CYP3A inhibitor. Co-administration may lead to increased ivacaftor exposure; however, the clinical impact of this has not yet been determined.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Administration of ivacaftor with strong CYP3A inducers, such as phenobarbital, 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 CYP2C9 and phenobarbital is partially metabolized by CYP2C9. Co-administration may increase phenobarbital exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined. (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.
    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 CYP3A inducer. Co-administration with rifampin, a strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold. Ivacaftor is also an inhibitor of CYP3A and bexarotene is metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as bexarotene, may increase bexarotene exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    Bortezomib: (Moderate) Use caution when administering ivacaftor and bortezomib concurrently. Ivacaftor is an inhibitor of CYP3A and bortezomib is primarily metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as bortezomib, can theoretically increase bortezomib exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Bosentan: (Major) Use caution when administering ivacaftor and bosentan concurrently; the clinical impact of this interaction has not yet been determined but interactions may be significant. Administration of ivacaftor with strong CYP3A inducers is not recommended because sub-therapeutic ivacaftor exposure could result. Ivacaftor is a CYP3A substrate and bosentan is a CYP3A inducer. Co-administration with rifampin, a strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold. Ivacaftor is also an inhibitor of CYP3A and CYP2C9; bosentan is metabolized by CYP3A and CYP2C9. Co-administration may increase bosentan exposure leading to increased or prolonged therapeutic effects and adverse events. According to the manufacturer of bosentan, coadministration of bosentan with a potent CYP2C9 inhibitor plus a CYP3A4 inhibitor is not recommended; large increases in bosentan plasma concentrations are expected with such combinations.
    Brentuximab vedotin: (Minor) Use caution when administering ivacaftor and brentuximab vedotin concurrently. Ivacaftor is an inhibitor of CYP3A and monomethyl auristatin E (MMAE), which is one of the 3 components released from brentuximab vedotin, is metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as brentuximab vedotin, can theoretically increase brentuximab vedotin exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Brigatinib: (Moderate) Monitor for decreased efficacy of if coadministration is necessary. Ivacaftor is a CYP3A substrate and brigatinib induces CYP3A in vitro. Coadministration with a strong CYP3A4 inducer decreased the AUC of ivacaftor by approximately 9-fold; brigatinib may also decrease ivacaftor exposure.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Minor) Use caution when administering ivacaftor and dextromethorphan concurrently. Ivacaftor is an inhibitor of CYP3A, and dextromethorphan is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dextromethorphan, can theoretically increase dextromethorphan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Brompheniramine; Guaifenesin; Hydrocodone: (Minor) Use caution when administering ivacaftor and hydrocodone concurrently. Ivacaftor is an inhibitor of CYP3A and hydrocodone is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as hydrocodone, can theoretically increase hydrocodone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Minor) Use caution when administering ivacaftor and hydrocodone concurrently. Ivacaftor is an inhibitor of CYP3A and hydrocodone is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as hydrocodone, can theoretically increase hydrocodone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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.
    Bupivacaine Liposomal: (Moderate) Use caution when administering ivacaftor and bupivacaine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as bupivacaine, can increase bupivacaine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Bupivacaine: (Moderate) Use caution when administering ivacaftor and bupivacaine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as bupivacaine, can increase bupivacaine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Bupivacaine; Lidocaine: (Moderate) Use caution when administering ivacaftor and bupivacaine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as bupivacaine, can increase bupivacaine exposure leading to increased or prolonged therapeutic effects and adverse events. (Minor) Use caution when administering ivacaftor and lidocaine concurrently. Ivacaftor is an inhibitor of CYP3A and lidocaine is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as lidocaine, can theoretically increase lidocaine exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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.
    Buspirone: (Moderate) Use caution when administering ivacaftor and buspirone concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as buspirone, can increase buspirone 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.
    Canagliflozin: (Moderate) Canagliflozin is a substrate of drug transporter P glycoprotein (P-gp). Ivacaftor is a PGP inhibitor and may theoretically increase concentrations of canagliflozin. Patients should be monitored for changes in glycemic control.
    Canagliflozin; Metformin: (Moderate) Canagliflozin is a substrate of drug transporter P glycoprotein (P-gp). Ivacaftor is a PGP inhibitor and may theoretically increase concentrations of canagliflozin. Patients should be monitored for changes in glycemic control.
    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) Administration of ivacaftor with strong CYP3A inducers, such as carbamazepine, 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 carbamazepine is metabolized by CYP3A. Co-administration may increase carbamazepine exposure leading to increased or prolonged therapeutic effects and adverse events.
    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; Dextromethorphan; Pseudoephedrine: (Minor) Use caution when administering ivacaftor and dextromethorphan concurrently. Ivacaftor is an inhibitor of CYP3A, and dextromethorphan is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dextromethorphan, can theoretically increase dextromethorphan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Minor) Use caution when administering ivacaftor and hydrocodone concurrently. Ivacaftor is an inhibitor of CYP3A and hydrocodone is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as hydrocodone, can theoretically increase hydrocodone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Minor) Use caution when administering ivacaftor and hydrocodone concurrently. Ivacaftor is an inhibitor of CYP3A and hydrocodone is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as hydrocodone, can theoretically increase hydrocodone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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) Avoid coadministration of ivacaftor and ceritinib due to the potential for increased exposure to ivacaftor. Ceritinib inhibits CYP3A4; the manufacturer of ivacaftor recommends a reduced dose when coadministered with moderate and strong CYP3A4 inhibitors. Because the strength of inhibition of CYP3A4 by ceritinib is not known, specific dosage reduction recommendations for ivacaftor during concurrent use are unavailable.
    Cevimeline: (Minor) Use caution when administering ivacaftor and cevimeline concurrently. Ivacaftor is an inhibitor of CYP3A and cevimeline is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as cevimeline, can theoretically increase cevimeline exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Chloramphenicol: (Major) If chloramphenicol 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 chloramphenicol is a strong CYP3A inhibitor. Coadministration with ketoconazole, another strong CYP3A inhibitor, increased ivacaftor exposure by 8.5-fold.
    Chlorpheniramine; Dextromethorphan: (Minor) Use caution when administering ivacaftor and dextromethorphan concurrently. Ivacaftor is an inhibitor of CYP3A, and dextromethorphan is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dextromethorphan, can theoretically increase dextromethorphan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) Use caution when administering ivacaftor and dextromethorphan concurrently. Ivacaftor is an inhibitor of CYP3A, and dextromethorphan is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dextromethorphan, can theoretically increase dextromethorphan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Minor) Use caution when administering ivacaftor and hydrocodone concurrently. Ivacaftor is an inhibitor of CYP3A and hydrocodone is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as hydrocodone, can theoretically increase hydrocodone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Chlorpheniramine; Hydrocodone: (Minor) Use caution when administering ivacaftor and hydrocodone concurrently. Ivacaftor is an inhibitor of CYP3A and hydrocodone is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as hydrocodone, can theoretically increase hydrocodone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Minor) Use caution when administering ivacaftor and hydrocodone concurrently. Ivacaftor is an inhibitor of CYP3A and hydrocodone is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as hydrocodone, can theoretically increase hydrocodone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Minor) Use caution when administering ivacaftor and hydrocodone concurrently. Ivacaftor is an inhibitor of CYP3A and hydrocodone is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as hydrocodone, can theoretically increase hydrocodone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Cilostazol: (Minor) Use caution when administering ivacaftor and cilostazol concurrently. Ivacaftor is an inhibitor of CYP3A and cilostazol is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as cilostazol, can theoretically increase cilostazol exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Cimetidine: (Moderate) Use caution when administering ivacaftor and cimetidine concurrently. Ivacaftor is a CYP3A substrate, and cimetidine is a mild CYP3A inhibitor. Co-administration may lead to increased ivacaftor exposure; however, the clinical impact of this has not yet been determined.
    Cinacalcet: (Minor) Use caution when administering ivacaftor and cinacalcet concurrently. Ivacaftor is an inhibitor of CYP3A and cinacalcet is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as cinacalcet, can theoretically increase cinacalcet exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Ciprofloxacin: (Moderate) If ciprofloxacin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose, but reduce the frequency to once daily (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg once daily). Ivacaftor is a CYP3A4 substrate, and ciprofloxacin is a moderate inhibitor of this enzyme. Coadministration with another moderate CYP3A4 inhibitor, increased ivacaftor exposure by 3-fold.
    Cisapride: (Major) Do not use ivacaftor and cisapride concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as cisapride, can increase cisapride exposure leading to toxicity, specifically an increased risk for QT prolongation.
    Citalopram: (Minor) Use caution when administering ivacaftor and citalopram concurrently. Ivacaftor is an inhibitor of CYP3A and citalopram is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as citalopram, can theoretically increase citalopram exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Clarithromycin: (Major) If clarithromycin 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 clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. Ivacaftor is also an inhibitor of CYP3A; clarithromycin is metabolized by CYP3A. Coadministration may increase clarithromycin exposure leading to increased or prolonged therapeutic effects and adverse events.
    Clonazepam: (Moderate) Use caution when administering ivacaftor and clonazepam concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as clonazepam, can increase clonazepam exposure leading to increased or prolonged therapeutic effects and adverse events.
    Clopidogrel: (Minor) Use caution when administering ivacaftor and clopidogrel concurrently. Ivacaftor is an inhibitor of CYP3A and clopidogrel is partially metabolized by CYP3A. Co-administration may theoretically increase clopidogrel exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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 once daily (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg once daily). Ivacaftor is a CYP3A substrate, and cobicistat is a CYP3A inhibitor. Co-administration with fluconazole, another moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. Ivacaftor is also an inhibitor of CYP3A and cobicistat is metabolized by CYP3A. Coadministration may increase cobicistat exposure leading to increased adverse events.
    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 once daily (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg once daily). Ivacaftor is a CYP3A substrate, and cobicistat is a CYP3A inhibitor. Co-administration with fluconazole, another moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. Ivacaftor is also an inhibitor of CYP3A and cobicistat is metabolized by CYP3A. Coadministration may increase cobicistat exposure leading to increased adverse events.
    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 once daily (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg once daily). Ivacaftor is a CYP3A substrate, and cobicistat is a CYP3A inhibitor. Co-administration with fluconazole, another moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. Ivacaftor is also an inhibitor of CYP3A and cobicistat is metabolized by CYP3A. Coadministration may increase cobicistat exposure leading to increased adverse events. (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.
    Cobimetinib: (Moderate) If concurrent use of cobimetinib and ivacaftor is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro as well as a P-glycoprotein (P-gp) substrate; ivacaftor is a weak inhibitor of both CYP3A and P-gp. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
    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) Avoid concurrent use of conivaptan and ivacaftor. The manufacturer of conivaptan recommends subsequent treatment with drugs metabolized primarily via CYP3A-mediated metabolism, such as ivacaftor, may be initiated or resumed no sooner than 1 week after the infusion of conivaptan is complete. When used with a strong CYP3A inhibitor, such as conivaptan, the manufacturer of ivacaftor recommends administering ivacaftor at the usual recommended dose, but reducing the frequency to twice weekly. Ivacaftor is a CYP3A substrate, and conivaptan is a strong CYP3A inhibitor. Ivacaftor is also a weak inhibitor of CYP3A, and conivaptan is metabolized by CYP3A. Coadministration may increase both conivaptan and ivacaftor exposure leading to increased or prolonged therapeutic effects and adverse events.
    Crizotinib: (Major) If crizotinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Monitor for an increase in ivacaftor-related adverse reactions. Ivacaftor is a CYP3A substrate, and crizotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Cyclobenzaprine: (Minor) Use caution when administering ivacaftor and cyclobenzaprine concurrently. Ivacaftor is an inhibitor of CYP3A and cyclobenzaprine is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as cyclobenzaprine, can theoretically increase cyclobenzaprine exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Cyclosporine: (Major) Use caution when administering ivacaftor and cyclosporine concurrently. Ivacaftor is a substrate of CYP3A, and an inhibitor of CYP3A and P-glycoprotein (P-gp). Cyclosporine is a CYP3A and P-glycoprotein (P-gp) substrate and inhibitor. If these agents are given together, the manufacturer of ivacaftor recommends administering ivacaftor at the usual recommended dose but reducing the frequency to once daily (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg once daily). Coadministration of ivacaftor with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. In addition, coadministration of ivacaftor with CYP3A and P-gp substrates, such as cyclosporine, can increase cyclosporine exposure leading to increased or prolonged therapeutic effects and adverse events. More careful monitoring of cyclosporine blood concentrations may be warranted.
    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.
    Dabrafenib: (Major) The concomitant use of dabrafenib and ivacaftor may lead to decreased ivacaftor concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of ivacaftor efficacy. Dabrafenib is a moderate CYP3A4 inducer and ivacaftor is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 74%.
    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 (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg twice weekly). Ivacaftor is a CYP3A substrate, dalfopristin; quinupristin is a strong CYP3A inhibitor. Coadministration with ketoconazole, another strong CYP3A inhibitor, increased ivacaftor exposure by 8.5-fold.
    Danazol: (Major) Use caution when administering ivacaftor and danazol concurrently; increased monitoring and/or dose reduction of ivacaftor may be necessary. The manufacturer recommends administering ivacaftor at the usual recommended dose but reducing the frequency to once daily when used concurrently with a moderate CYP3A inhibitor. Ivacaftor is a CYP3A substrate, and danazol is a CYP3A inhibitor. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold.
    Dapsone: (Moderate) Use caution when administering ivacaftor and dapsone concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dapsone, can increase dapsone exposure leading to increased or prolonged therapeutic effects and adverse events.
    Darifenacin: (Minor) Use caution when administering ivacaftor and darifenacin concurrently. Ivacaftor is an inhibitor of CYP3A and darifenacin is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as darifenacin, can theoretically increase darifenacin exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Darunavir: (Major) If darunavir 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 darunavir 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 darunavir is metabolized by CYP3A. Coadministration may increase darunavir exposure leading to increased or prolonged therapeutic effects and adverse events.
    Darunavir; Cobicistat: (Major) If cobicistat and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg once daily). Ivacaftor is a CYP3A substrate, and cobicistat is a CYP3A inhibitor. Co-administration with fluconazole, another moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. Ivacaftor is also an inhibitor of CYP3A and cobicistat is metabolized by CYP3A. Coadministration may increase cobicistat exposure leading to increased adverse events. (Major) If darunavir 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 darunavir 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 darunavir is metabolized by CYP3A. Coadministration may increase darunavir exposure leading to increased or prolonged therapeutic effects and adverse events.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Concurrent administration of ivacaftor with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of all 5 drugs. If these drugs are taken concurrently, reduce the ivacaftor dose to 150 mg twice weekly and monitor of adverse effects associated with any of the drugs. Ivacaftor is a substrate and inhibitor of CYP3A4, and an inhibitor of the drug transporter P-glycoprotein (P-gp). Ritonavir is an inhibitor of CYP3A4, and ritonavir, paritaprevir and dasabuvir (minor) are CYP3A4 substrates. In addition, dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. Caution and close monitoring are advised if these drugs are administered together. (Major) If ritonavir 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 ritonavir is a 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); ritonavir is metabolized by CYP3A and is a substrate of P-gp. Coadministration may increase ritonavir exposure leading to increased or prolonged therapeutic effects and adverse events.
    Dasatinib: (Major) Use caution when administering ivacaftor and dasatinib concurrently; increased monitoring and/or dose reduction may be necessary. Ivacaftor is a CYP3A substrate, and dasatinib is a weak CYP3A inhibitor; the manufacturer of ivacaftor does not recommend dose reduction for weak inhibition of CYP3A. Ivacaftor is also an inhibitor of CYP3A, and dasatinib is metabolized by CYP3A. Coadministration may increase dasatinib exposure leading to increased or prolonged therapeutic effects and adverse events.
    Daunorubicin: (Moderate) Use caution when administering ivacaftor and daunorubicin concurrently. Ivacaftor is an inhibitor of P-glycoprotein (Pgp). Co-administration of ivacaftor with Pgp substrates, such as daunorubicin, may increase daunorubicin exposure leading to increased or prolonged therapeutic effects and adverse events.
    Delavirdine: (Major) If delavirdine 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 delavirdine is a strong CYP3A inhibitor. Ivacaftor is also an inhibitor of CYP3A and delavirdine is partially metabolized by CYP3A. Coadministration may increase delavirdine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Desloratadine: (Minor) Use caution when administering ivacaftor and desloratadine concurrently. Ivacaftor is an inhibitor of P-glycoprotein (Pgp). Co-administration of ivacaftor with Pgp substrates, such as desloratadine, can increase desloratadine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Desloratadine; Pseudoephedrine: (Minor) Use caution when administering ivacaftor and desloratadine concurrently. Ivacaftor is an inhibitor of P-glycoprotein (Pgp). Co-administration of ivacaftor with Pgp substrates, such as desloratadine, can increase desloratadine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Dexamethasone: (Moderate) Use caution when administering ivacaftor and dexamethasone 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 dexamethasone is a CYP3A inducer. Co-administration with rifampin, a strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold. Ivacaftor is also an inhibitor of CYP3A and P-glycoprotein (Pgp); dexamethasone is metabolized by CYP3A and is a substrate of Pgp. Co-administration may increase dexamethasone exposure leading to increased or prolonged therapeutic effects and adverse events.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Use caution when administering ivacaftor and dextromethorphan concurrently. Ivacaftor is an inhibitor of CYP3A, and dextromethorphan is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dextromethorphan, can theoretically increase dextromethorphan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Dexlansoprazole: (Minor) Use caution when administering ivacaftor and dexlansoprazole concurrently. Ivacaftor is an inhibitor of CYP3A and dexlansoprazole is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dexlansoprazole, can theoretically increase dexlansoprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Dextromethorphan: (Minor) Use caution when administering ivacaftor and dextromethorphan concurrently. Ivacaftor is an inhibitor of CYP3A, and dextromethorphan is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dextromethorphan, can theoretically increase dextromethorphan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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. (Minor) Use caution when administering ivacaftor and dextromethorphan concurrently. Ivacaftor is an inhibitor of CYP3A, and dextromethorphan is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dextromethorphan, can theoretically increase dextromethorphan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Dextromethorphan; Guaifenesin: (Minor) Use caution when administering ivacaftor and dextromethorphan concurrently. Ivacaftor is an inhibitor of CYP3A, and dextromethorphan is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dextromethorphan, can theoretically increase dextromethorphan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Use caution when administering ivacaftor and dextromethorphan concurrently. Ivacaftor is an inhibitor of CYP3A, and dextromethorphan is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dextromethorphan, can theoretically increase dextromethorphan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Minor) Use caution when administering ivacaftor and dextromethorphan concurrently. Ivacaftor is an inhibitor of CYP3A, and dextromethorphan is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dextromethorphan, can theoretically increase dextromethorphan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Minor) Use caution when administering ivacaftor and dextromethorphan concurrently. Ivacaftor is an inhibitor of CYP3A, and dextromethorphan is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dextromethorphan, can theoretically increase dextromethorphan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Dextromethorphan; Promethazine: (Minor) Use caution when administering ivacaftor and dextromethorphan concurrently. Ivacaftor is an inhibitor of CYP3A, and dextromethorphan is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dextromethorphan, can theoretically increase dextromethorphan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Dextromethorphan; Quinidine: (Minor) Use caution when administering ivacaftor and dextromethorphan concurrently. Ivacaftor is an inhibitor of CYP3A, and dextromethorphan is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dextromethorphan, can theoretically increase dextromethorphan exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined. (Minor) Use caution when administering ivacaftor and quinidine concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (P-gp). Coadministration of ivacaftor with CYP3A and P-gp substrates, such as quinidine, can increase quinidine exposure leading to increased or prolonged therapeutic effects and adverse events; 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.
    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) Use caution when administering ivacaftor and diltiazem concurrently; increased monitoring and/or dose reduction of ivacaftor may be necessary. The manufacturer recommends administering ivacaftor at the usual recommended dose but reducing the frequency to once daily when used concurrently with a moderate CYP3A inhibitor. Ivacaftor is a CYP3A substrate, and diltiazem is a CYP3A inhibitor. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. Ivacaftor is also an inhibitor of CYP3A and P-glycoprotein (P-gp); diltiazem is metabolized by CYP3A and is a substrate of P-gp. Coadministration may increase diltiazem exposure leading to increased or prolonged therapeutic effects and adverse events.
    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: (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) Use caution when administering ivacaftor and hydrocodone concurrently. Ivacaftor is an inhibitor of CYP3A and hydrocodone is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as hydrocodone, can theoretically increase hydrocodone exposure leading to increased or prolonged therapeutic effects and adverse events; 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.
    Disulfiram: (Moderate) Use caution when administering ivacaftor and disulfiram concurrently. Ivacaftor is an inhibitor of CYP3A and disulfiram is primarily metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as disulfiram, can theoretically increase disulfiram exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Docetaxel: (Moderate) Use caution when administering ivacaftor and docetaxel concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as docetaxel, can increase docetaxel exposure leading to increased or prolonged therapeutic effects and adverse events.
    Dolasetron: (Minor) Use caution when administering ivacaftor and dolasetron concurrently. Ivacaftor is an inhibitor of CYP3A and dolasetron is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dolasetron, can theoretically increase dolasetron exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Dolutegravir; Rilpivirine: (Minor) Use caution when administering ivacaftor and rilpivirine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as rilpivirine, can increase rilpivirine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Donepezil: (Moderate) Use caution when administering ivacaftor and donepezil concurrently. Ivacaftor is an inhibitor of CYP3A and donepezil is primarily metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as donepezil, can theoretically increase donepezil exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Donepezil; Memantine: (Moderate) Use caution when administering ivacaftor and donepezil concurrently. Ivacaftor is an inhibitor of CYP3A and donepezil is primarily metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as donepezil, can theoretically increase donepezil exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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, THC: (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) Avoid the concomitant use of ivacaftor and dronedarone if possible. If the combination must be used, an ivacaftor dosage reduction may be necessary and increased monitoring is needed. The manufacturer recommends administering ivacaftor at the usual recommended dose but reducing the frequency to once daily when used concurrently with a moderate CYP3A inhibitor. Ivacaftor is a CYP3A substrate, and dronedarone is a CYP3A inhibitor. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. Ivacaftor is also an inhibitor of CYP3A; dronedarone is metabolized by CYP3A. Coadministration of ivacaftor may increase dronedarone exposure leading to increased or prolonged therapeutic effects and adverse events.
    Droperidol: (Moderate) Use caution when administering ivacaftor and droperidol concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as droperidol, can increase droperidol exposure leading to increased or prolonged therapeutic effects and adverse events.
    Dutasteride: (Moderate) Use caution when administering ivacaftor and dutasteride concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dutasteride, can increase dutasteride exposure leading to increased or prolonged therapeutic effects and adverse events.
    Dutasteride; Tamsulosin: (Moderate) Use caution when administering ivacaftor and dutasteride concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dutasteride, can increase dutasteride exposure leading to increased or prolonged therapeutic effects and adverse events. (Minor) Use caution when administering ivacaftor and tamsulosin concurrently. Ivacaftor is an inhibitor of CYP3A and tamsulosin is partially metabolized by CYP3A. Co-administration can theoretically increase tamsulosin exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Edoxaban: (Moderate) Coadministration of edoxaban and ivacaftor may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and ivacaftor is a mild P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of ivacaftor; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Efavirenz: (Moderate) Use caution when administering ivacaftor and efavirenz concurrently; the clinical effect of this interaction is unknown. Ivacaftor is a CYP3A substrate, and efavirenz is a CYP3A inducer and may also act as an inhibitor. Co-administration may lead to altered ivacaftor exposure. Ivacaftor is also an inhibitor of CYP3A and efavirenz is partially metabolized by CYP3A. Co-administration may increase efavirenz exposure leading to increased or prolonged therapeutic effects and adverse events.
    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. (Moderate) Use caution when administering ivacaftor and efavirenz concurrently; the clinical effect of this interaction is unknown. Ivacaftor is a CYP3A substrate, and efavirenz is a CYP3A inducer and may also act as an inhibitor. Co-administration may lead to altered ivacaftor exposure. Ivacaftor is also an inhibitor of CYP3A and efavirenz is partially metabolized by CYP3A. Co-administration may increase efavirenz exposure leading to increased or prolonged therapeutic effects and adverse events.
    Elbasvir; Grazoprevir: (Moderate) Administering elbasvir; grazoprevir with ivacaftor may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ivacaftor is a substrate and mild inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
    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. 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 alafenamide: (Minor) Use caution when administering ivacaftor and rilpivirine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as rilpivirine, can increase rilpivirine exposure leading to increased or prolonged therapeutic effects and adverse events.
    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. (Minor) Use caution when administering ivacaftor and rilpivirine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as rilpivirine, can increase rilpivirine exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    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.
    Erlotinib: (Moderate) Use caution if coadministration of erlotinib with ivacaftor is necessary due to the risk of increased erlotinib-related adverse reactions, and avoid coadministration with erlotinib if the patient is additionally taking a CYP1A2 inhibitor. If the patient is taking both ivacaftor and a CYP1A2 inhibitor and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements; the manufacturer of erlotinib makes the same recommendations for toxicity-related dose reductions in patients taking strong CYP3A4 inhibitors without concomitant CYP1A2 inhibitors. Ivacaftor is a weak CYP3A4 inhibitor. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Ivacaftor increased the AUC of another CYP3A4 substrate, midazolam, by 1.5-fold. Coadministration of erlotinib with ketoconazole, a strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. Coadministration of erlotinib with ciprofloxacin, a moderate inhibitor of CYP3A4 and CYP1A2, increased the erlotinib AUC by 39% and the Cmax by 17%; coadministration with ivacaftor may also increase erlotinib exposure.
    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 erythromycin is a moderate CYP3A inhibitor. Coadministration with fluconazole, another moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. Ivacaftor is also an inhibitor of CYP3A and P-glycoprotein (P-gp); erythromycin is metabolized by CYP3A and is a substrate of P-gp. Coadministration may increase erythromycin exposure leading to increased or prolonged therapeutic effects and adverse events.
    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 erythromycin is a moderate CYP3A inhibitor. Coadministration with fluconazole, another moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. Ivacaftor is also an inhibitor of CYP3A and P-glycoprotein (P-gp); erythromycin is metabolized by CYP3A and is a substrate of P-gp. Coadministration may increase erythromycin exposure leading to increased or prolonged therapeutic effects and adverse events.
    Escitalopram: (Minor) Use caution when administering ivacaftor and escitalopram concurrently. Ivacaftor is an inhibitor of CYP3A and escitalopram is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as escitalopram, can theoretically increase escitalopram exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Esomeprazole: (Minor) Use caution when administering ivacaftor and esomeprazole concurrently. Ivacaftor is an inhibitor of CYP3A, and esomeprazole is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as esomeprazole, can theoretically increase esomeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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. (Minor) Use caution when administering ivacaftor and esomeprazole concurrently. Ivacaftor is an inhibitor of CYP3A, and esomeprazole is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as esomeprazole, can theoretically increase esomeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; 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.
    Eszopiclone: (Moderate) Use caution when administering ivacaftor and eszopiclone concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as eszopiclone, can increase eszopiclone exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ethosuximide: (Moderate) Use caution when administering ivacaftor and ethosuximide concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as ethosuximide, can increase ethosuximide exposure leading to increased or prolonged therapeutic effects and adverse events.
    Etoposide, VP-16: (Minor) Use caution when administering ivacaftor and etoposide, VP-16 concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as etoposide, VP-16, can increase etoposide, VP-16 exposure leading to increased or prolonged therapeutic effects and adverse events.
    Etravirine: (Moderate) Use caution when administering ivacaftor and etravirine 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 etravirine is a CYP3A inducer. Co-administration with rifampin, a strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold. Ivacaftor is also an inhibitor of CYP3A and CYP2C9; etravirine is metabolized by CYP3A and CYP2C9. Co-administration may increase etravirine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ezetimibe; Simvastatin: (Moderate) Use caution when administering ivacaftor and simvastatin concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as simvastatin, can increase simvastatin exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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.
    Fexofenadine: (Minor) Use caution when administering ivacaftor and fexofenadine concurrently. Ivacaftor is an inhibitor of P-glycoprotein (Pgp). Co-administration of ivacaftor with Pgp substrates, such as fexofenadine, can increase fexofenadine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Fexofenadine; Pseudoephedrine: (Minor) Use caution when administering ivacaftor and fexofenadine concurrently. Ivacaftor is an inhibitor of P-glycoprotein (Pgp). Co-administration of ivacaftor with Pgp substrates, such as fexofenadine, can increase fexofenadine 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 (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg 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.
    Flurazepam: (Moderate) Use caution when administering ivacaftor and flurazepam concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as flurazepam, can increase flurazepam exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    Flutamide: (Moderate) Use caution when administering ivacaftor and flutamide 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 flutamide is a CYP3A inducer. Co-administration with rifampin, a strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold. Ivacaftor is also an inhibitor of CYP3A, and flutamide is partially metabolized by CYP3A. Theoretically, co-administration may increase flutamide exposure; however, CYP3A is thought to be a minor pathway of metabolism.
    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) Use caution when administering ivacaftor and fluvoxamine concurrently; increased monitoring and/or dose reduction of ivacaftor may be necessary. The manufacturer recommends administering ivacaftor at the usual recommended dose but reducing the frequency to twice weekly when used concurrenlty with a strong CYP3A inhibitor or reducing the frequency to once daily when used concurrently with a moderate CYP3A inhibitor. Ivacaftor is a CYP3A substrate, and fluvoxamine is a CYP3A inhibitor. Although it has not been definitively demonstrated that fluvoxamine is a potent CYP3A inhibitor, FDA-approved product labeling states that is likely to be, based on substantial interaction with alprazolam. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. Coadministration with ketoconazole, a strong CYP3A inhibitor, increased ivacaftor exposure by 8.5-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) Administration of ivacaftor with strong CYP3A inducers, such as phenytoin or fosphenytoin, 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 CYP2C9 and phenytoin is partially metabolized by CYP2C9. Co-administration may increase phenytoin exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Gefitinib: (Moderate) Use caution when administering ivacaftor and gefitinib concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as gefitinib, can increase gefitinib exposure leading to increased or prolonged therapeutic effects and adverse events.
    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. (Moderate) Caution is advised with the coadministration of pibrentasvir and ivacaftor as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of P-glycoprotein (P-gp); ivacaftor is an inhibitor of P-gp.
    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: (Moderate) Use caution when administering ivacaftor and pioglitazone concurrently; the clinical impact of this interaction has not yet been determined. Ivacaftor is an inhibitor of CYP3A, and pioglitazone is partially metabolized by CYP3A. Co-administration may increase pioglitazone exposure leading to increased or prolonged therapeutic effects and adverse events. In addition, ivacaftor is a CYP3A substrate and pioglitazone is a mild CYP3A inducer. Administration of ivacaftor with strong CYP3A inducers is not recommended because sub-therapeutic ivacaftor exposure could result; the impact of mild inducers is not known. (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.
    Granisetron: (Moderate) Use caution when administering ivacaftor and granisetron concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as granisetron, can increase granisetron exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    Griseofulvin: (Moderate) Use caution when administering ivacaftor and griseofulvin 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 griseofulvin is a CYP3A inducer. Co-administration with rifampin, a strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold.
    Guaifenesin; Hydrocodone: (Minor) Use caution when administering ivacaftor and hydrocodone concurrently. Ivacaftor is an inhibitor of CYP3A and hydrocodone is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as hydrocodone, can theoretically increase hydrocodone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Minor) Use caution when administering ivacaftor and hydrocodone concurrently. Ivacaftor is an inhibitor of CYP3A and hydrocodone is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as hydrocodone, can theoretically increase hydrocodone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Haloperidol: (Moderate) Use caution when administering ivacaftor and haloperidol concurrently. Ivacaftor is an inhibitor of CYP3A and haloperidol is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as haloperidol, can theoretically increase haloperidol exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Homatropine; Hydrocodone: (Minor) Use caution when administering ivacaftor and hydrocodone concurrently. Ivacaftor is an inhibitor of CYP3A and hydrocodone is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as hydrocodone, can theoretically increase hydrocodone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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: (Minor) Use caution when administering ivacaftor and hydrocodone concurrently. Ivacaftor is an inhibitor of CYP3A and hydrocodone is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as hydrocodone, can theoretically increase hydrocodone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Hydrocodone; Ibuprofen: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as ibuprofen. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined. (Minor) Use caution when administering ivacaftor and hydrocodone concurrently. Ivacaftor is an inhibitor of CYP3A and hydrocodone is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as hydrocodone, can theoretically increase hydrocodone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Hydrocodone; Phenylephrine: (Minor) Use caution when administering ivacaftor and hydrocodone concurrently. Ivacaftor is an inhibitor of CYP3A and hydrocodone is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as hydrocodone, can theoretically increase hydrocodone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Hydrocodone; Potassium Guaiacolsulfonate: (Minor) Use caution when administering ivacaftor and hydrocodone concurrently. Ivacaftor is an inhibitor of CYP3A and hydrocodone is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as hydrocodone, can theoretically increase hydrocodone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Minor) Use caution when administering ivacaftor and hydrocodone concurrently. Ivacaftor is an inhibitor of CYP3A and hydrocodone is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as hydrocodone, can theoretically increase hydrocodone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Hydrocodone; Pseudoephedrine: (Minor) Use caution when administering ivacaftor and hydrocodone concurrently. Ivacaftor is an inhibitor of CYP3A and hydrocodone is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as hydrocodone, can theoretically increase hydrocodone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Hydroxyprogesterone: (Moderate) Use caution when administering ivacaftor and hydroxyprogesterone concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as hydroxyprogesterone, can increase hydroxyprogesterone exposure leading to increased or prolonged therapeutic effects and adverse events.
    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) Avoid concurrent use of idelalisib and ivacaftor. Ivacaftor is a CYP3A substrate, and idelalisib is a strong CYP3A inhibitor. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when idelalisib was given concurrently; hence the manufacturer of idelasib recommends against coadministration of sensitive CYP3A substrates. The manufacturer of ivacaftor recommends administering ivacaftor at the usual recommended dose, but reducing the frequency to twice weekly when used with a strong CYP3A inhibitor, such as idelalisib. Ivacaftor is also a weak inhibitor of CYP3A, and idelalisib is metabolized by CYP3A. Coadministration may increase both idelalisib and ivacaftor exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ifosfamide: (Minor) Use caution when administering ivacaftor and ifosfamide concurrently; the clinical significance of this interaction is unclear. Ivacaftor is an inhibitor of CYP3A, and ifosfamide is a CYP3A4 substrate. Theoretically, co-administration of ivacaftor and ifosfamide could increase ifosfamide exposure leading to increased or prolonged therapeutic effects and adverse events. However, one pharmacokinetic trial found that ketoconazole, a potent CYP3A inhibitor, did not cause a clinically significant interaction with ifosfamide.
    Imatinib: (Major) Use caution when administering ivacaftor and imatinib, STI-571 concurrently; increased monitoring and/or dose reduction of ivacaftor may be necessary. The manufacturer recommends administering ivacaftor at the usual recommended dose but reducing the frequency to once daily when used concurrently with a moderate CYP3A inhibitor. Ivacaftor is a CYP3A substrate, and imatinib, STI-571 is a CYP3A inhibitor. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. Ivacaftor is also an inhibitor of CYP3A, CYP2C9, and P-glycoprotein (P-gp); imatinib, STI-571 is metabolized by CYP3A, CYP2C9, and is a substrate of P-gp. Coadministration may increase imatinib, STI-571 exposure leading to increased or prolonged therapeutic effects and adverse events.
    Imipramine: (Moderate) Use caution when administering ivacaftor and imipramine concurrently. Ivacaftor is an inhibitor of CYP3A and imipramine is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as imipramine, can theoretically increase imipramine exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Indacaterol: (Moderate) Use caution when administering ivacaftor and indacaterol concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as indacaterol, can increase indacaterol exposure leading to increased or prolonged therapeutic effects and adverse events.
    Indacaterol; Glycopyrrolate: (Moderate) Use caution when administering ivacaftor and indacaterol concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as indacaterol, can increase indacaterol exposure leading to increased or prolonged therapeutic effects and adverse events.
    Indinavir: (Major) If indinavir 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 indinavir is a strong CYP3A inhibitor. Ivacaftor is also an inhibitor of CYP3A and P-glycoprotein (P-gp); indinavir is metabolized by CYP3A and is a substrate of P-gp. Coadministration may increase indinavir exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    Irinotecan Liposomal: (Moderate) Use caution if irinotecan liposomal is coadministered with ivacaftor, a weak CYP3A4 inhibitor, due to a possible increased risk of irinotecan-related toxicity. The metabolism of liposomal irinotecan has not been evaluated; however, coadministration of ketoconazole, a strong CYP3A4 and UGT1A1 inhibitor, with non-liposomal irinotecan HCl resulted in increased exposure to both irinotecan and its active metabolite, SN-38.
    Irinotecan: (Moderate) Use caution when administering ivacaftor and irinotecan concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (P-gp). Co-administration of ivacaftor with CYP3A and P-gp substrates, such as irinotecan, can increase irinotecan exposure leading to increased or prolonged therapeutic effects and adverse events. If concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Isavuconazonium: (Moderate) If isavuconazonium and ivacaftor are taken together, administer ivacaftor at the usual recommended dose, but reduce the frequency to once daily (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg once daily). Ivacaftor is a CYP3A4 substrate, and isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Coadministration with fluconazole, another moderate CYP3A4 inhibitor, increased ivacaftor exposure by 3-fold. Ivacaftor is also an inhibitor of CYP3A4 and isavuconazole is a substrate of CYP3A4. Coadministration may increase isavuconazole exposure leading to increased adverse events.
    Isoniazid, INH: (Major) If isoniazid, INH 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 isoniazid is a strong CYP3A inhibitor. Coadministration with ketoconazole, another strong CYP3A inhibitor, increased ivacaftor exposure by 8.5-fold.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Administration of ivacaftor with strong CYP3A inducers, such as rifampin, is not recommended because sub-therapeutic ivacaftor exposure could result. Ivacaftor is a CYP3A substrate. Co-administration with rifampin, a strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold. Ivacaftor is also an inhibitor of P-glycoprotein (Pgp), and rifampin is a substrate of Pgp. Co-administration may increase rifampin exposure leading to increased or prolonged therapeutic effects and adverse events. (Major) If isoniazid, INH 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 isoniazid is a strong CYP3A inhibitor. Coadministration with ketoconazole, another strong CYP3A inhibitor, increased ivacaftor exposure by 8.5-fold.
    Isoniazid, INH; Rifampin: (Major) Administration of ivacaftor with strong CYP3A inducers, such as rifampin, is not recommended because sub-therapeutic ivacaftor exposure could result. Ivacaftor is a CYP3A substrate. Co-administration with rifampin, a strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold. Ivacaftor is also an inhibitor of P-glycoprotein (Pgp), and rifampin is a substrate of Pgp. Co-administration may increase rifampin exposure leading to increased or prolonged therapeutic effects and adverse events. (Major) If isoniazid, INH 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 isoniazid is a strong CYP3A inhibitor. Coadministration with ketoconazole, another strong CYP3A inhibitor, increased ivacaftor exposure by 8.5-fold.
    Isradipine: (Moderate) Use caution when administering ivacaftor and isradipine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as isradipine, can increase isradipine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Itraconazole: (Major) If itraconazole 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 itraconazole is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor, increased ivacaftor exposure by 8.5-fold. Ivacaftor is also an inhibitor of CYP3A and P-glycoprotein (P-gp); itraconazole is metabolized by CYP3A4 and is a substrate of P-gp. Coadministration may increase itraconazole exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ivabradine: (Moderate) Use caution during coadministration of ivabradine and ivacaftor as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; ivacaftor is a weak inhibitor of CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Ixabepilone: (Moderate) Use caution when administering ivacaftor and ixabepilone concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as ixabepilone, can increase ixabepilone exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ketoconazole: (Major) If ketoconazole 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. Coadministration with ketoconazole, a strong CYP3A inhibitor, increased ivacaftor exposure by 8.5-fold. Ivacaftor is also an inhibitor of CYP3A; ketoconazole is metabolized by CYP3A4. Coadministration may increase ketoconazole exposure leading to increased or prolonged therapeutic effects and adverse events.
    Lansoprazole: (Minor) Use caution when administering ivacaftor and lansoprazole concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as lansoprazole, can increase lansoprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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. (Minor) Use caution when administering ivacaftor and lansoprazole concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as lansoprazole, can increase lansoprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Lapatinib: (Major) Use caution when administering ivacaftor and lapatinib concurrently; increased monitoring and/or dose reduction may be necessary. Ivacaftor is a CYP3A substrate, and lapatinib is a weak CYP3A inhibitor; the manufacturer of ivacaftor does not recommend dose reduction for weak inhibition of CYP3A. Ivacaftor is also an inhibitor of CYP3A and P-glycoprotein (P-gp); lapatinib is metabolized by CYP3A and is a substrate of P-gp. Coadministration may increase lapatinib exposure leading to increased or prolonged therapeutic effects and adverse events.
    Lesinurad: (Moderate) Use lesinurad and ivacaftor together with caution; ivacaftor may increase the systemic exposure of lesinurad. Ivacaftor is a mild inhibitor of CYP2C9 in vitro and lesinurad is a CYP2C9 substrate. In addition, lesinurad may decrease the systemic exposure and therapeutic efficacy of ivacaftor; monitor for potential reduction in efficacy. Ivactafor is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Use lesinurad and ivacaftor together with caution; ivacaftor may increase the systemic exposure of lesinurad. Ivacaftor is a mild inhibitor of CYP2C9 in vitro and lesinurad is a CYP2C9 substrate. In addition, lesinurad may decrease the systemic exposure and therapeutic efficacy of ivacaftor; monitor for potential reduction in efficacy. Ivactafor is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lidocaine: (Minor) Use caution when administering ivacaftor and lidocaine concurrently. Ivacaftor is an inhibitor of CYP3A and lidocaine is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as lidocaine, can theoretically increase lidocaine exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Loperamide: (Moderate) The plasma concentration of loperamide, a CYP3A4 and P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with ivacaftor, a weak inhibitor of CYP3A4 and P-gp. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a CYP3A4 and P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with ivacaftor, a weak inhibitor of CYP3A4 and P-gp. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: (Major) If ritonavir 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 ritonavir is a 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); ritonavir is metabolized by CYP3A and is a substrate of P-gp. Coadministration may increase ritonavir exposure leading to increased or prolonged therapeutic effects and adverse events.
    Loratadine: (Minor) Use caution when administering ivacaftor and loratadine concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as loratadine, can increase loratadine exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Loratadine; Pseudoephedrine: (Minor) Use caution when administering ivacaftor and loratadine concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as loratadine, can increase loratadine exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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) Use caution when administering ivacaftor and lovastatin concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as lovastatin, can increase lovastatin exposure leading to increased or prolonged therapeutic effects and adverse events.
    Lovastatin; Niacin: (Moderate) Use caution when administering ivacaftor and lovastatin concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as lovastatin, can increase lovastatin exposure leading to increased or prolonged therapeutic effects and adverse events.
    Lurasidone: (Moderate) Use caution when administering ivacaftor and lurasidone concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as lurasidone, can increase lurasidone exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    Mefloquine: (Moderate) Use caution when administering ivacaftor and mefloquine concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as mefloquine, can increase mefloquine exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    Metformin; Pioglitazone: (Moderate) Use caution when administering ivacaftor and pioglitazone concurrently; the clinical impact of this interaction has not yet been determined. Ivacaftor is an inhibitor of CYP3A, and pioglitazone is partially metabolized by CYP3A. Co-administration may increase pioglitazone exposure leading to increased or prolonged therapeutic effects and adverse events. In addition, ivacaftor is a CYP3A substrate and pioglitazone is a mild CYP3A inducer. Administration of ivacaftor with strong CYP3A inducers is not recommended because sub-therapeutic ivacaftor exposure could result; the impact of mild inducers is not known.
    Metformin; Repaglinide: (Minor) Use caution when administering ivacaftor and repaglinide concurrently. Ivacaftor is an inhibitor of CYP3A and repaglinide is partially metabolized by CYP3A. Co-administration can theoretically increase repaglinide 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.
    Methylprednisolone: (Moderate) Use caution when administering ivacaftor and methylprednisolone concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as methylprednisolone, can increase methylprednisolone exposure leading to increased or prolonged therapeutic effects and adverse events.
    Metyrapone: (Moderate) Use caution when administering ivacaftor and metyrapone 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 metyrapone is a CYP3A inducer. Co-administration with rifampin, a strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold.
    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, RU-486: (Major) Use caution when administering ivacaftor and mifepristone, RU-486 concurrently; increased monitoring and/or dose reduction of ivacaftor may be necessary. The manufacturer recommends administering ivacaftor at the usual recommended dose but reducing the frequency to once daily when used concurrently with a moderate CYP3A inhibitor. Ivacaftor is a CYP3A substrate, and mifepristone, RU-486 is a CYP3A inhibitor. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. Ivacaftor is also an inhibitor of CYP3A; mifepristone, RU-486 is metabolized by CYP3A. Coadministration may increase mifepristone, RU-486 exposure leading to increased or prolonged therapeutic effects and adverse events.
    Mirtazapine: (Minor) Use caution when administering ivacaftor and mirtazapine concurrently. Ivacaftor is an inhibitor of CYP3A and mirtazapine is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as mirtazapine, can theoretically increase mirtazapine exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Mitomycin: (Moderate) Use caution when administering ivacaftor and mitomycin concurrently. Ivacaftor is an inhibitor of P-glycoprotein (Pgp). Co-administration of ivacaftor with Pgp substrates, such as mitomycin, can increase mitomycin exposure leading to increased or prolonged therapeutic effects and adverse events.
    Mitotane: (Major) The concomitant use of mitotane with ivacaftor is not recommended; if coadministration cannot be avoided, monitor for decreased efficacy of ivacaftor. Mitotane is a strong CYP3A4 inducer and ivacaftor is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of ivacaftor. Coadministration of ivacaftor with rifampin, another strong CYP3A inducer, decreased ivacaftor exposure by approximately 9-fold.
    Modafinil: (Moderate) Use caution when administering ivacaftor and modafinil 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 modafinil is a CYP3A inducer. Co-administration with rifampin, a strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold. Ivacaftor is also an inhibitor of CYP3A and modafinil is metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as modafinil, may increase modafinil exposure leading to increased or prolonged therapeutic effects and adverse events.
    Montelukast: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as montelukast. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; montelukast is metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates, such as montelukast, can theoretically increase montelukast exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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.
    Nafcillin: (Moderate) Use caution when administering ivacaftor and nafcillin 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 nafcillin may induce CYP3A. Co-administration with rifampin, a strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold.
    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) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as nateglinide. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; nateglinide is metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates, such as nateglinide, can theoretically increase nateglinide exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this 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 (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg twice weekly). Ivacaftor is a CYP3A substrate, and nefazodone 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 nefazodone is metabolized by CYP3A. Coadministration may increase nefazodone exposure leading to increased or prolonged therapeutic effects and adverse events.
    Nelfinavir: (Major) If nelfinavir 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 nelfinavir 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); nelfinavir is partially metabolized by CYP3A and is a substrate of P-gp. Coadministration may increase nelfinavir exposure leading to increased or prolonged therapeutic effects and adverse events.
    Netupitant; Palonosetron: (Major) Use caution when administering netupitant; palonosetron and ivacaftor concurrently. Ivacaftor is a substrate and weak inhibitor of CYP3A. Netupitant is a substrate and weak inhibitor of CYP3A. Inhibition of CYP3A by netupitant can result in increased plasma concentrations of the concomitant drug for at least 4 days or longer. If these agents are given together, the manufacturer of ivacaftor recommends administering ivacaftor at the usual recommended dose but reducing the frequency to once daily (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg once daily). Coadministration of ivacaftor with fluconazole, another moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. In addition, coadministration of ivacaftor with a CYP3A substrate, such as netupitant; palonosetron, can increase netupitant; palonosetron exposure leading to increased or prolonged therapeutic effects and adverse events.
    Nevirapine: (Moderate) Use caution when administering ivacaftor and nevirapine 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 nevirapine is a CYP3A inducer. Co-administration with rifampin, a strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold. Ivacaftor is also an inhibitor of CYP3A and nevirapine is partially metabolized by CYP3A. Co-administration may increase nevirapine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Niacin; Simvastatin: (Moderate) Use caution when administering ivacaftor and simvastatin concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as simvastatin, can increase simvastatin exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Nicardipine: (Major) Use caution when administering ivacaftor and nicardipine concurrently; increased monitoring and/or dose reduction of ivacaftor may be necessary. The manufacturer recommends administering ivacaftor at the usual recommended dose but reducing the frequency to once daily when used concurrently with a moderate CYP3A inhibitor. Ivacaftor is a CYP3A substrate, and nicardipine is a CYP3A inhibitor. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold.
    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.
    Nimodipine: (Moderate) Use caution when administering ivacaftor and nimodipine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as nimodipine, can increase nimodipine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Nintedanib: (Moderate) Ivacaftor is a mild inhibitor of both P-glycoprotein (P-gp) and CYP3A4; nintedanib is a P-gp substrate as well as a minor substrate of CYP3A4. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of ivacaftor and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Nisoldipine: (Moderate) Use caution when administering ivacaftor and nisoldipine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as nisoldipine, can increase nisoldipine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Nortriptyline: (Moderate) Use caution when administering ivacaftor and nortriptyline concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as nortriptyline, can increase nortriptyline exposure leading to increased or prolonged therapeutic effects and adverse events.
    Octreotide: (Major) Use caution when administering ivacaftor and octreotide concurrently; increased monitoring and/or dose reduction of ivacaftor may be necessary. The manufacturer recommends administering ivacaftor at the usual recommended dose but reducing the frequency to once daily when used concurrently with a moderate CYP3A inhibitor. Ivacaftor is a CYP3A substrate, and octreotide is a CYP3A inhibitor. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Concurrent administration of ivacaftor with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of all 5 drugs. If these drugs are taken concurrently, reduce the ivacaftor dose to 150 mg twice weekly and monitor of adverse effects associated with any of the drugs. Ivacaftor is a substrate and inhibitor of CYP3A4, and an inhibitor of the drug transporter P-glycoprotein (P-gp). Ritonavir is an inhibitor of CYP3A4, and ritonavir, paritaprevir and dasabuvir (minor) are CYP3A4 substrates. In addition, dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. Caution and close monitoring are advised if these drugs are administered together. (Major) If ritonavir 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 ritonavir is a 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); ritonavir is metabolized by CYP3A and is a substrate of P-gp. Coadministration may increase ritonavir exposure leading to increased or prolonged therapeutic effects and adverse events.
    Omeprazole: (Minor) Use caution when administering ivacaftor and omeprazole concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as omeprazole, can increase omeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Omeprazole; Sodium Bicarbonate: (Minor) Use caution when administering ivacaftor and omeprazole concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as omeprazole, can increase omeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Ondansetron: (Minor) Use caution when administering ivacaftor and ondansetron concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and P-gp substrates, such as ondansetron, can increase ondansetron exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Oritavancin: (Moderate) Ivacaftor is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Use caution when administering ivacaftor and oritavancin 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. Co-administration with rifampin, a strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold.
    Oxcarbazepine: (Moderate) Use caution when administering ivacaftor and oxcarbazepine 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 oxcarbazepine is a CYP3A inducer. Co-administration with rifampin, a strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold.
    Oxybutynin: (Moderate) Use caution when administering ivacaftor and oxybutynin concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as oxybutynin, can increase oxybutynin exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    Paclitaxel: (Moderate) Use caution when administering ivacaftor and paclitaxel concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as paclitaxel, can increase paclitaxel exposure leading to increased or prolonged therapeutic effects and adverse events.
    Pantoprazole: (Major) Use caution when administering ivacaftor and pantoprazole concurrently; increased monitoring and/or dose reduction of ivacaftor may be necessary. The manufacturer recommends administering ivacaftor at the usual recommended dose but reducing the frequency to once daily when used concurrently with a moderate CYP3A inhibitor. Ivacaftor is a CYP3A substrate, and pantoprazole is a CYP3A inhibitor. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. Ivacaftor is also an inhibitor of CYP3A and P-glycoprotein (P-gp); pantoprazole is partially metabolized by CYP3A and is a substrate of P-gp. Coadministration may increase pantoprazole exposure leading to increased or prolonged therapeutic effects and adverse events.
    Paricalcitol: (Moderate) Use caution when administering ivacaftor and paricalcitol concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as paricalcitol, can increase paricalcitol exposure leading to increased or prolonged therapeutic effects and adverse events.
    Perindopril; Amlodipine: (Moderate) Use caution when administering ivacaftor and amlodipine concurrently. Although there is a theoretical interaction, the clinical significance is not known. Ivacaftor is an inhibitor of CYP3A, and amlodipine is a CYP3A4 substrate. Co-administration may increase amlodipine exposure leading to increased or prolonged therapeutic effects and adverse events. However, coadministration of erythromycin, another CYP3A inhibitor, in healthy volunteers did not significantly change amlodipine systemic exposure.
    Perphenazine; Amitriptyline: (Moderate) Use caution when administering ivacaftor and amitriptyline concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as amitriptyline, can increase amitriptyline exposure leading to increased or prolonged therapeutic effects and adverse events.
    Phenobarbital: (Major) Administration of ivacaftor with strong CYP3A inducers, such as phenobarbital, 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 CYP2C9 and phenobarbital is partially metabolized by CYP2C9. Co-administration may increase phenobarbital exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Phentermine; Topiramate: (Moderate) Use caution when administering ivacaftor and topiramate concurrently; the clinical impact of this interaction has not yet been determined. Ivacaftor is a CYP3A substrate and topiramate is a weak CYP3A inducer. Administration of ivacaftor with strong CYP3A inducers is not recommended because sub-therapeutic ivacaftor exposure could result; the impact of mild inducers is not known.
    Phenytoin: (Major) Administration of ivacaftor with strong CYP3A inducers, such as phenytoin, 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 CYP2C9 and phenytoin is partially metabolized by CYP2C9. Co-administration may increase phenytoin exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Pimozide: (Minor) Use caution when administering ivacaftor and pimozide concurrently. Ivacaftor is an inhibitor of CYP3A and pimozide is partially metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as pimozide, can theoretically increase pimozide exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Pioglitazone: (Moderate) Use caution when administering ivacaftor and pioglitazone concurrently; the clinical impact of this interaction has not yet been determined. Ivacaftor is an inhibitor of CYP3A, and pioglitazone is partially metabolized by CYP3A. Co-administration may increase pioglitazone exposure leading to increased or prolonged therapeutic effects and adverse events. In addition, ivacaftor is a CYP3A substrate and pioglitazone is a mild CYP3A inducer. Administration of ivacaftor with strong CYP3A inducers is not recommended because sub-therapeutic ivacaftor exposure could result; the impact of mild inducers is not known.
    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 (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg twice weekly). Ivacaftor is a CYP3A substrate, and posaconazole 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 P-glycoprotein (P-gp); posaconazole is a substrate of P-gp. Coadministration may increase posaconazole exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    Prednisone: (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: (Moderate) Use caution when administering ivacaftor and primidone 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 primidone is a CYP3A inducer. Co-administration with rifampin, a strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold.
    Propafenone: (Minor) Use caution when administering ivacaftor and propafenone concurrently. Ivacaftor is an inhibitor of CYP3A and propafenone is partially metabolized by CYP3A. Co-administration can theoretically increase propafenone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Quazepam: (Moderate) Use caution when administering ivacaftor and quazepam concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as quazepam, can increase quazepam exposure 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.
    Quinidine: (Minor) Use caution when administering ivacaftor and quinidine concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (P-gp). Coadministration of ivacaftor with CYP3A and P-gp substrates, such as quinidine, can increase quinidine exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Quinine: (Moderate) Use caution when administering ivacaftor and quinine concurrently; the clinical effect of this interaction is unknown. Ivacaftor is a CYP3A substrate, and quinine 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); quinine is partially metabolized by CYP3A, CYP2C9 and is a substrate of Pgp. Co-administration may increase quinine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Rabeprazole: (Minor) Use caution when administering ivacaftor and rabeprazole concurrently. Ivacaftor is an inhibitor of CYP3A and rabeprazole is partially metabolized by CYP3A. Co-administration can theoretically increase rabeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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.
    Ranolazine: (Major) Avoid the concomitant use of ivacaftor and ranolazine if possible. Ivacaftor is a CYP3A substrate, and ranolazine is a mild CYP3A inhibitor. Co-administration may lead to increased ivacaftor exposure; however, the clinical impact of this has not yet been determined. Ivacaftor is also an inhibitor of CYP3A and P-glycoprotein (Pgp); ranolazine is partially metabolized by CYP3A and is a substrate of Pgp. Co-administration may increase ranolazine exposure leading to increased or prolonged therapeutic effects and adverse events, specifically an increased risk for QT prolongation.
    Repaglinide: (Minor) Use caution when administering ivacaftor and repaglinide concurrently. Ivacaftor is an inhibitor of CYP3A and repaglinide is partially metabolized by CYP3A. Co-administration can theoretically increase repaglinide 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 once daily. Monitor for an increase in ivacaftor-related adverse reactions. Exposure to ribociclib may also increase, increasing in ribociclib-related adverse reactions (e.g., neutropenia, QT prolongation). Ribociclib is a moderate CYP3A4 inhibitor and ivacaftor is a CYP3A4 substrate. Ribociclib is also extensively metabolized by CYP3A4 and ivacaftor is a weak CYP3A4 inhibitor.
    Ribociclib; Letrozole: (Major) If ribociclib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Monitor for an increase in ivacaftor-related adverse reactions. Exposure to ribociclib may also increase, increasing in ribociclib-related adverse reactions (e.g., neutropenia, QT prolongation). Ribociclib is a moderate CYP3A4 inhibitor and ivacaftor is a CYP3A4 substrate. Ribociclib is also extensively metabolized by CYP3A4 and ivacaftor is a weak CYP3A4 inhibitor.
    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) Administration of ivacaftor with strong CYP3A inducers, such as rifampin, is not recommended because sub-therapeutic ivacaftor exposure could result. Ivacaftor is a CYP3A substrate. Co-administration with rifampin, a strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold. Ivacaftor is also an inhibitor of P-glycoprotein (Pgp), and rifampin is a substrate of Pgp. Co-administration may increase rifampin exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    Rilpivirine: (Minor) Use caution when administering ivacaftor and rilpivirine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as rilpivirine, can increase rilpivirine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Risperidone: (Minor) Use caution when administering ivacaftor and risperidone concurrently. Ivacaftor is an inhibitor of CYP3A; risperidone is partially metabolized by CYP3A. Co-administration may increase risperidone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Ritonavir: (Major) If ritonavir 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 ritonavir is a 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); ritonavir is metabolized by CYP3A and is a substrate of P-gp. Coadministration may increase ritonavir exposure leading to increased or prolonged therapeutic effects and adverse events.
    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)].
    Ropivacaine: (Minor) Use caution when administering ivacaftor and ropivacaine concurrently. Ivacaftor is an inhibitor of CYP3A; ropivacaine is partially metabolized by CYP3A. Co-administration may increase ropivacaine exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Saquinavir: (Major) If saquinavir 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 saquinavir 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); saquinavir is metabolized by CYP3A4 and is a substrate of P-gp. Coadministration may increase saquinavir exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    Silodosin: (Moderate) Use caution when administering ivacaftor and silodosin concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as silodosin, can increase silodosin exposure leading to increased or prolonged therapeutic effects and adverse events.
    Simvastatin: (Moderate) Use caution when administering ivacaftor and simvastatin concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as simvastatin, can 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; Sitagliptin: (Moderate) Use caution when administering ivacaftor and simvastatin concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as simvastatin, can increase simvastatin exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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.
    Solifenacin: (Moderate) Use caution when administering ivacaftor and solifenacin concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as solifenacin, can increase solifenacin exposure leading to increased or prolonged therapeutic effects and adverse events.
    St. John's Wort, Hypericum perforatum: (Major) Administration of ivacaftor with strong CYP3A inducers, such as St. John's wort, Hypericum perforatum, 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.
    Streptogramins: (Major) If dalfopristin; quinupristin 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, dalfopristin; quinupristin is a strong CYP3A inhibitor. Coadministration with ketoconazole, 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.
    Sunitinib: (Moderate) Use caution when administering ivacaftor and sunitinib concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as sunitinib, can increase sunitinib exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    Tadalafil: (Moderate) Use caution when administering ivacaftor and tadalafil concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as tadalafil, can increase tadalafil exposure leading to increased or prolonged therapeutic effects and adverse events.
    Tamoxifen: (Major) Use caution when administering ivacaftor and tamoxifen concurrently; monitor for changes in the therapeutic efficacy of tamoxifen. Ivacaftor is a weak CYP3A4 inhibitor, as well as in vitro, a CYP2C9 inhibitor; tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Ivacaftor may affect the metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen; the clinical significance of these potential changes is not known.
    Tamsulosin: (Minor) Use caution when administering ivacaftor and tamsulosin concurrently. Ivacaftor is an inhibitor of CYP3A and tamsulosin is partially metabolized by CYP3A. Co-administration can theoretically increase tamsulosin exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Telaprevir: (Major) If telaprevir 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 telaprevir is a strong CYP3A inhibitor. Ivacaftor is also an inhibitor of CYP3A and P-glycoprotein (P-gp); telaprevir is partially metabolized by CYP3A and is a substrate of P-gp. Coadministration may increase telaprevir exposure leading to increased or prolonged therapeutic effects and adverse events.
    Telithromycin: (Major) If telithromycin 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 telithromycin is a strong CYP3A inhibitor. Coadministration with ketoconazole, another strong CYP3A inhibitor, increased ivacaftor exposure by 8.5-fold.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and ivacaftor is necessary, as the systemic exposure of ivacaftor may be decreased resulting in reduced efficacy; exposure to telotristat ethyl may also be increased. If these drugs are used together, monitor patients for suboptimal efficacy of ivacaftor as well as an increase in adverse reactions related to telotristat ethyl. Consider increasing the dose of ivacaftor if necessary. Ivacaftor is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Additionally, the active metabolite of telotristat ethyl, telotristat, is a substrate of P-glycoprotein (P-gp) and ivacaftor is a weak P-gp inhibitor. Exposure to telotristat ethyl may increase.
    Teniposide: (Moderate) Use caution when administering ivacaftor and teniposide concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as teniposide, can increase teniposide exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    Testosterone: (Minor) Use caution when administering ivacaftor and testosterone concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as testosterone, can increase testosterone exposure leading to increased or prolonged therapeutic effects and adverse events.
    Theophylline, Aminophylline: (Minor) Use caution when administering ivacaftor and theophylline, aminophylline concurrently. Ivacaftor is an inhibitor of CYP3A and theophylline and aminophylline are partially metabolized by CYP3A. Co-administration can theoretically increase theophylline or aminophylline exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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.
    Tinidazole: (Minor) Use caution when administering ivacaftor and tinidazole concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as tinidazole, can increase tinidazole exposure leading to increased or prolonged therapeutic effects and adverse events.
    Tipranavir: (Major) Use caution when administering ivacaftor and tipranavir concurrently; increased monitoring and/or dose reduction of ivacaftor may be necessary. The manufacturer recommends reducing the ivacaftor dose to 150 mg twice weekly when used concurrently with a strong CYP3A inhibitor and reducing the ivacaftor dose to 150 mg once daily when used concurrently with a moderate CYP3A inhibitor. Ivacaftor is a CYP3A substrate, and tipranavir is a CYP3A inhibitor. Ivacaftor is also an inhibitor of CYP3A and P-glycoprotein (Pgp); tipranavir is metabolized by CYP3A4 and is a substrate of Pgp. Co-administration may increase tipranavir exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    Tolterodine: (Minor) Use caution when administering ivacaftor and tolterodine concurrently. Ivacaftor is an inhibitor of CYP3A and tolterodine is partially metabolized by CYP3A. Co-administration can theoretically increase tolterodine exposure leading to increased or prolonged therapeutic effects and adverse events; 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.
    Topiramate: (Moderate) Use caution when administering ivacaftor and topiramate concurrently; the clinical impact of this interaction has not yet been determined. Ivacaftor is a CYP3A substrate and topiramate is a weak CYP3A inducer. Administration of ivacaftor with strong CYP3A inducers is not recommended because sub-therapeutic ivacaftor exposure could result; the impact of mild inducers is not known.
    Topotecan: (Major) Avoid the concomitant use of ivacaftor, a P-glycoprotein (P-gp) inhibitor, with oral topotecan, a P-gp substrate; P-gp inhibitors have less of an effect on intravenous topotecan and these may be coadministered with caution. If coadministration of ivacaftor and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea. In a pharmacokinetic cohort study, coadministration of oral topotecan with a potent P-gp inhibitor (n = 8) increased the Cmax and AUC of topotecan by 2 to 3 fold (p = 0.008); coadministration with intravenous topotecan (n = 8) increased total topotecan exposure by 1.2-fold (p = 0.02) and topotecan lactone by 1.1-fold (not significant).
    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.
    Trabectedin: (Moderate) Use caution if coadministration of trabectedin and ivacaftor is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and ivacaftor is a weak CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    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) Use caution when administering ivacaftor and verapamil concurrently; increased monitoring and/or dose reduction of ivacaftor may be necessary. The manufacturer recommends administering ivacaftor at the usual recommended dose but reducing the frequency to once daily when used concurrently with a moderate CYP3A inhibitor. Ivacaftor is a CYP3A substrate, and verapamil is a CYP3A inhibitor. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. Ivacaftor is also an inhibitor of CYP3A, CYP2C9, and P-glycoprotein (P-gp); verapamil is partially metabolized by CYP3A, CYP2C9, and is a substrate of P-gp. Coadministration may increase verapamil exposure leading to increased or prolonged therapeutic effects and adverse events.
    Trazodone: (Minor) Use caution when administering ivacaftor and trazodone concurrently. Ivacaftor is an inhibitor of CYP3A and trazodone is partially metabolized by CYP3A. Co-administration can theoretically increase trazodone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Triazolam: (Moderate) Use caution when administering ivacaftor and triazolam concurrently because patients are at increased risk for adverse effects from triazolam. Ivacaftor is a CYP3A inhibitor, and triazolam is a CYP3A substrate. Co-administration of ivacaftor with midazolam, another CYP3A substrate, increased midazolam exposure by 1.5-fold.
    Vardenafil: (Moderate) Use caution when administering ivacaftor and vardenafil concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as vardenafil, can increase vardenafil exposure leading to increased or prolonged therapeutic effects and adverse events.
    Vemurafenib: (Moderate) Use caution when administering ivacaftor and vemurafenib 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 vemurafenib is a CYP3A inducer. Co-administration with rifampin, a strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold. Ivacaftor is also an inhibitor of CYP3A and P-glycoprotein (Pgp); vemurafenib is metabolized by CYP3A and is a substrate of Pgp. Co-administration may increase vemurafenib exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    Venlafaxine: (Minor) Use caution when administering ivacaftor and venlafaxine concurrently. Ivacaftor is an inhibitor of CYP3A and venlafaxine is partially metabolized by CYP3A. Venlafaxine is likely metabolized to a minor, less active metabolite by CYP3A4 and, normally, the potential for clinically significant drug interactions between CYP3A4 inhibitors and venlafaxine is small.
    Verapamil: (Major) Use caution when administering ivacaftor and verapamil concurrently; increased monitoring and/or dose reduction of ivacaftor may be necessary. The manufacturer recommends administering ivacaftor at the usual recommended dose but reducing the frequency to once daily when used concurrently with a moderate CYP3A inhibitor. Ivacaftor is a CYP3A substrate, and verapamil is a CYP3A inhibitor. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. Ivacaftor is also an inhibitor of CYP3A, CYP2C9, and P-glycoprotein (P-gp); verapamil is partially metabolized by CYP3A, CYP2C9, and is a substrate of P-gp. Coadministration may increase verapamil exposure leading to increased or prolonged therapeutic effects and adverse events.
    Vinblastine: (Moderate) Use caution when administering ivacaftor and vinblastine concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as vinblastine, can increase vinblastine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Vincristine Liposomal: (Moderate) Use caution when administering ivacaftor and vincristine concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as vincristine, can increase vincristine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Vincristine: (Moderate) Use caution when administering ivacaftor and vincristine concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as vincristine, can increase vincristine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Vinorelbine: (Moderate) Use caution with concurrent use of ivacaftor, a weak CYP3A4 inhibitor, and vinorelbine, a CYP3A4 substrate, as the metabolism of vinorelbine may be decreased. Monitor patients for an earlier onset and/or an increased severity of adverse effects including neurotoxicity and myelosuppression.
    Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and ivacaftor. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with ivacaftor, a mild CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Voriconazole: (Major) If voriconazole 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 voriconazole 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 CYP2C9; voriconazole is metabolized by CYP3A4 and CYP2C9. Coadministration may increase voriconazole exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    Zafirlukast: (Major) Use caution when administering ivacaftor and zafirlukast concurrently; increased monitoring and/or dose reduction of ivacaftor may be necessary. The manufacturer recommends administering ivacaftor at the usual recommended dose but reducing the frequency to once daily when used concurrently with a moderate CYP3A inhibitor. Ivacaftor is a CYP3A substrate, and zafirlukast is a CYP3A inhibitor. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. Ivacaftor is also an inhibitor of CYP2C9; zafirlukast is metabolized by CYP2C9. Coadministration may increase zafirlukast exposure leading to increased or prolonged therapeutic effects and adverse events.
    Zileuton: (Moderate) Use caution when administering ivacaftor and zileuton concurrently. Ivacaftor is an inhibitor of CYP3A; zileuton is partially metabolized by CYP3A. Coadministration may increase zileuton exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ziprasidone: (Moderate) Use caution when administering ivacaftor and ziprasidone concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as ziprasidone, can increase ziprasidone exposure leading to increased or prolonged therapeutic effects and adverse events.
    Zolpidem: (Moderate) Use caution when administering ivacaftor and zolpidem concurrently. Ivacaftor is an inhibitor of CYP3A and zolpidem is primarily metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as zolpidem, can theoretically increase zolpidem exposure leading to increased or prolonged therapeutic effects and adverse events.

    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. The pharmacokinetics are similar in healthy subjects and in patients with cystic fibrosis. Ivacaftor is approximately 99% protein bound. The mean +/- SD apparent volume of distribution after administration of 150 mg every 12 hours to healthy volunteers in the fed state was 353 +/- 122 L. Ivacaftor is extensively metabolized, primarily by CYP3A, to two major metabolites, one of which is considered pharmacologically active. Ivacaftor is primarily eliminated in the feces; negligible amounts of the parent drug are eliminated in the urine. The terminal half-life was approximately 12 hours after a single dose.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A, CYP2C9, and P-gp
    Ivacaftor is metabolized by the cytochrome P450 (CYP450) enzyme group, primarily CYP3A4 and CYP3A5. Dosage adjustments are recommended when ivacaftor is coadministered with moderate or strong CYP3A inhibitors; concurrent use with strong CYP3A inducers is not recommended. Ivacaftor is a weak inhibitor of CYP3A and P-glycoprotein (P-gp) transport. Ivacaftor may also inhibit CYP2C9. This inhibition may result in unexpectedly high plasma concentrations of other drugs that are metabolized by these CYP450 enzymes or are substrates of P-gp. The manufacturer recommends increased monitoring when ivacaftor is administered concurrently with CYP3A, CYP2C9, or P-gp substrates.

    Oral Route

    Peak plasma concentration occurred approximately 4 hours after oral administration. Steady-state plasma concentrations were reached approximately 3—5 days after initiating every 12 hour dosing. The mean +/- SD AUC and Cmax for ivacaftor were 10,600 +/- 5260 ng x hr/mL and 768 +/- 233 ng/mL, respectively, after a single 150 mg dose. Mean AUC at steady state was 10,700 +/- 4100 ng x hr/mL. Administration of ivacaftor with fat-containing foods increased exposure by 2—4 fold; hence, administration with fat-containing foods is recommended. The bioavailability of ivacaftor tablets and granules is similar.