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  • CLASSES

    Cystic Fibrosis Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Cystic fibrosis transmembrane conductance regulator (CFTR) modulator
    Used for treatment of CF in patients who are homozygous for F508del mutation in CFTR gene, the most common mutation associated with CF
    Liver function monitoring and eye exams (pediatric patients) required at baseline and periodically throughout therapy

    COMMON BRAND NAMES

    ORKAMBI

    HOW SUPPLIED

    Lumacaftor, Ivacaftor Oral Gran: 100-125mg, 150-188mg
    ORKAMBI Oral Tab: 100-125mg, 200-125mg

    DOSAGE & INDICATIONS

    For the treatment of cystic fibrosis (CF) in patients who are homozygous for the F508del mutation in the CFTR gene.
    Oral dosage (tablet)
    Adults

    2 tablets (each containing lumacaftor 200 mg and ivacaftor 125 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 12 years and older

    2 tablets (each containing lumacaftor 200 mg and ivacaftor 125 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 6 to 11 years

    2 tablets (each containing lumacaftor 100 mg and ivacaftor 125 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.

    Oral dosage (granules)
    Children 2 to 5 years weighing 14 kg or more

    One packet of oral granules (containing lumacaftor 150 mg and ivacaftor 188 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

    One packet of oral granules (containing lumacaftor 100 mg and ivacaftor 125 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

    4 tablets/day PO (total daily dose: lumacaftor 800 mg/ivacaftor 500 mg).

    Geriatric

    4 tablets/day PO (total daily dose: lumacaftor 800 mg/ivacaftor 500 mg).

    Adolescents

    4 tablets/day PO (total daily dose: lumacaftor 800 mg/ivacaftor 500 mg).

    Children

    12 years: 4 tablets/day PO (total daily dose: lumacaftor 800 mg/ivacaftor 500 mg).
    6 to 11 years: 4 tablets/day PO (total daily dose: lumacaftor 400 mg/ivacaftor 500 mg).
    2 to 5 years weighing 14 kg or more: 2 oral granule packets/day PO (total daily dose: lumacaftor 300 mg/ivacaftor 376 mg).
    2 to 5 years weighing less than 14 kg: 2 oral granule packets/day PO (total daily dose: lumacaftor 200 mg/ivacaftor 250 mg).
    younger 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): For patients 2 to 5 years, reduce the dosage to 1 packet of oral granules in the morning and 1 packet of oral granules every other day in the evening PO. For patients 6 years and older, reduce the dosage to 2 tablets in the morning and 1 tablet in the evening PO.
    Severe impairment (Child-Pugh Class C): For patients 2 to 5 years, reduce the dosage to 1 packet of oral granules once daily in the morning PO or less frequently. For patients 6 years and older, reduce the dosage to 1 tablet PO every 12 hours or less frequently. Use with caution; this drug has not been studied in patients with severe hepatic impairment.

    Renal Impairment

    CrCl more than 30 mL/minute: No dosage adjustment necessary.
    CrCl 30 mL/minute or less: Use 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, avocados, nuts, butter, peanut butter, cheese pizza, whole-milk dairy products).
    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 of oral granules with 5 mL of age-appropriate soft food (e.g., pureed fruits, flavored yogurt, or pudding) or liquid (e.g., milk or juice); the mixture should be completely consumed. Food should be at room temperature or below. Each packet is for single use only. Once mixed, the product is stable for 1 hour and should be consumed during that time.

    STORAGE

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

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    If a patient's genotype is unknown, an FDA-cleared CF mutation test should be performed to detect the presence of the F508del mutation on both alleles of the CFTR gene. The safety and efficacy of lumacaftor; ivacaftor in CF patients with other types of mutations has not been established.

    Hepatic disease, hepatic encephalopathy

    Use lumacaftor; ivacaftor with caution in patients with hepatic disease. Worsening of liver function, including hepatic encephalopathy, has been reported in some patients with advanced hepatic disease. In CF patients with pre-existing cirrhosis with portal hypertension, liver function decompensation, including liver failure leading to death, has been reported during lumacaftor; ivacaftor therapy. Use lumacaftor; ivacaftor in such patients only if the expected benefits outweigh the risks, and monitor patients closely. Dosage reduction is recommended in patients with moderate to severe hepatic impairment (Child-Pugh Class B or C). Lumacaftor; ivacaftor has been associated with elevated liver transaminases and, in some cases, concomitant elevations in total serum bilirubin. Monitor AST, ALT, and bilirubin 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 and/or bilirubin elevations. Patients who develop increased concentrations should be closely monitored until the abnormalities resolve. Temporarily discontinue lumacaftor; ivacaftor in patients with an ALT or AST more than 5 times the upper limit of normal when not associated with elevated bilirubin. Interrupt therapy in patients with an ALT or AST more than 3 times the upper limit of normal when associated with bilirubin elevations more than 2 times the upper limit of normal. Upon resolution, carefully consider the benefits and risks before resuming therapy.

    Severe lung dysfunction

    Monitor patients with severe lung dysfunction closely during lumacaftor; ivacaftor initiation. Clinical experience in patients with a ppFEV1 < 40 (FEV1 < 40% predicted) is limited; however, patients with significant airway obstruction may be at increased risk for adverse respiratory events. During clinical trials, respiratory events (e.g., chest discomfort, dyspnea, abnormal respirations) were observed more commonly in patients initiated on lumacaftor; ivacaftor than those receiving placebo. In a phase 3 trial of 29 patients, patients with ppFEV1 < 40 experienced a similar treatment effect as those with ppFEV1 >= 40.

    Renal disease, renal impairment

    Use lumacaftor; ivacaftor with caution in patients with severe renal impairment (CrCl <= 30 mL/minute) or end stage renal disease. Lumacaftor; 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 for children and adolescents initiating lumacaftor; ivacaftor treatment. Safety and efficacy have not been established in neonates, infants, or children less than 6 years of age.

    Pregnancy

    There are limited and incomplete human data from clinical trials and postmarketing reports on the use of lumacaftor; ivacaftor during human pregnancy to inform a drug-associated risk. It was not found to be teratogenic in animals at lumacaftor and ivacaftor doses approximately 5 to 8 times and 7 to 45 times the maximum recommended human dose (MRHD), respectively. No adequate and well-controlled studies have been performed in pregnant women.

    Breast-feeding

    There is no information regarding the presence of lumacaftor or ivacaftor in human milk, the effects on the breast-feeding infant, or the effects on milk production. Both lumacaftor and ivacaftor are excreted into the breast milk of lactating rats; however, due to species-specific differences in lactation physiology, animal lactation data may not reliably predict levels in human milk. No studies have been done to assess the effects of lumacaftor; 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.

    Organ transplant

    Lumacaftor; ivacaftor has not been studied in cystic fibrosis patients who have received an organ transplant. Use in transplanted patients is not recommended due to potential drug-drug interactions.

    ADVERSE REACTIONS

    Severe

    hepatic encephalopathy / Delayed / 0-1.0

    Moderate

    dyspnea / Early / 13.0-13.0
    hypertension / Early / 1.1-1.1
    hyperbilirubinemia / Delayed / 0-1.0
    hemoptysis / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 1.0
    cataracts / Delayed / Incidence not known

    Mild

    cough / Delayed / 17.5-17.5
    nasal congestion / Early / 16.5-16.5
    pharyngitis / Delayed / 13.0-13.0
    nausea / Early / 13.0-13.0
    abdominal pain / Early / 12.6-12.6
    headache / Early / 12.6-12.6
    diarrhea / Early / 12.0-12.0
    infection / Delayed / 0-10.0
    menstrual irregularity / Delayed / 10.0-10.0
    menorrhagia / Delayed / 10.0-10.0
    amenorrhea / Delayed / 10.0-10.0
    dysmenorrhea / Delayed / 10.0-10.0
    fatigue / Early / 9.0-9.0
    flatulence / Early / 7.0-7.0
    rash / Early / 7.0-7.0
    rhinorrhea / Early / 6.0-6.0
    influenza / Delayed / 5.0-5.0

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with lumacaftor; ivacaftor; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Dolutegravir is partially metabolized by CYP3A and, in vitro, is a substrate for the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggest lumacaftor; ivacaftor may also induce and/or inhibit P-gp.
    Abemaciclib: (Major) Avoid coadministration of lumacaftor; ivacaftor with abemaciclib due to decreased exposure to abemaciclib and its active metabolites, which may lead to reduced efficacy. Consider alternative treatments. Abemaciclib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 70% in healthy subjects.
    Abiraterone: (Major) Avoid coadministration of abiraterone with lumacaftor; ivacaftor if possible due to decreased plasma concentrations of abiraterone. If concomitant use is unavoidable, increase the dosing frequency of abiraterone to twice daily. Reduce the dose back to the previous dose and frequency if lumacaftor; ivacaftor is discontinued. Abiraterone is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased abiraterone exposure by 55%.
    Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and lumacaftor; ivacaftor. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Decreased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; lumacaftor is a strong CYP3A4 inducer. In healthy subjects, the Cmax and AUC values of acalabrutinib were decreased by 68% and 77%, respectively, when acalabrutinib was coadministered with another strong CYP3A4 inducer for 9 days.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with lumacaftor; ivacaftor can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with ivacaftor may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of ivacaftor could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Ivacaftor is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) Concomitant use of dihydrocodeine with lumacaftor; ivacaftor can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Lumacaftor; ivacaftor is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with lumacaftor; ivacaftor can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Acetaminophen; Diphenhydramine: (Minor) Concomitant use of diphenhydramine and lumacaftor; ivacaftor may alter diphenhydramine exposure; monitor for diphenhydramine efficacy and adverse events. Diphenhydramine is partially metabolized by CYP2C9 and CYP2C19. In vitro data suggest that lumacaftor; ivacaftor may induce CYP2C19 and induce and/or inhibit CYP2C9. Although induction of diphenhydramine through the CYP2C19 pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear. (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as diphenhydramine. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4. (Moderate) Concomitant use of hydrocodone with lumacaftor; ivacaftor can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ivacaftor is necessary. If ivacaftor is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like ivacaftor can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ivacaftor is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with lumacaftor; ivacaftor is necessary; consider increasing the dose of oxycodone as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Acetaminophen; Tramadol: (Moderate) Lumacaftor; ivacaftor may reduce the analgesic effect of tramadol by decreasing its systemic exposure. If used together, monitor patients closely for loss of tramadol efficacy; a tramadol dosage adjustment may be required to obtain the desired therapeutic effect. Do not exceed the maximum recommended dose. Tramadol preferentially undergoes N-demethylation, which is mediated by CYP3A4 and CYP2B6. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor may induce CYP2B6. (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: (Major) Avoid coadministration of afatinib with lumacaftor; ivacaftor if possible, due to unpredictability of clinical effect. Although the clinical significance of this interaction is unknown, concurrent use of afatinib and lumacaftor; ivacaftor may alter afatinib exposure; caution and close monitoring are advised if these drugs are used together. Afatinib is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected leading to either decreased efficacy of afatinib or increased or prolonged therapeutic effects and adverse events. FDA-approved labeling for afatinib recommends reducing the dose by 10 mg per day if the original dose is not tolerated when administered with P-gp inhibitors, and increasing the dose by 10 mg/day as tolerated when given with P-gp inducers. Administration of the 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. Pre-treatment with a strong P-gp inducer, rifampicin (600 mg daily for 7 days), decreased the afatinib AUC by 34% and the Cmax by 22%. (Moderate) If the concomitant use of ivacaftor and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of ivacaftor. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro. Ivacaftor and its M1 metabolite are weak P-gp inhibitors; coadministration may increase plasma concentrations of afatinib. Coadministration of ivacaftor with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Alfentanil: (Moderate) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of alfentanil. If used together, alfentanil dosages may need to be adjusted. Alfentanil is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer. In a crossover study in healthy males, plasma alfentanil concentration-time profiles significantly depended on CYP3A4 activity. In the presence of rifampin, another strong CYP3A inducer, alfentanil noncompartmental clearance increased from 5.3 +/- 2.3 mL/kg/minute to 14.6 +/- 3.8 mL/kg/minute and elimination half-life decreased from 58 +/- 13 minutes to 35 +/- 7 minutes. (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: (Minor) Lumacaftor; ivacaftor may reduce the efficacy of alfuzosin by decreasing its systemic exposure. If used together, monitor the patient for appropriate clinical effects. Alfuzosin is a CYP3A4 substrate. Lumacaftor is a strong CYP3A inducer.
    Aliskiren: (Moderate) Lumacaftor; ivacaftor may alter the systemic exposure of aliskiren. If used together, monitor blood pressure closely and adjust the aliskiren dosage as appropriate. Aliskiren is a substrate of CYP3A4 and the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggests lumacaftor; ivacaftor may also induce and/or inhibit P-gp. While the induction of aliskiren through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear.
    Aliskiren; Amlodipine: (Moderate) Lumacaftor; ivacaftor may alter the systemic exposure of aliskiren. If used together, monitor blood pressure closely and adjust the aliskiren dosage as appropriate. Aliskiren is a substrate of CYP3A4 and the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggests lumacaftor; ivacaftor may also induce and/or inhibit P-gp. While the induction of aliskiren through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. (Moderate) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of amlodipine. If used together, monitor blood pressure closely; the dosage requirements of amlodipine may be increased. Amlodipine is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Lumacaftor; ivacaftor may alter the systemic exposure of aliskiren. If used together, monitor blood pressure closely and adjust the aliskiren dosage as appropriate. Aliskiren is a substrate of CYP3A4 and the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggests lumacaftor; ivacaftor may also induce and/or inhibit P-gp. While the induction of aliskiren through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. (Moderate) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of amlodipine. If used together, monitor blood pressure closely; the dosage requirements of amlodipine may be increased. Amlodipine is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Lumacaftor; ivacaftor may alter the systemic exposure of aliskiren. If used together, monitor blood pressure closely and adjust the aliskiren dosage as appropriate. Aliskiren is a substrate of CYP3A4 and the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggests lumacaftor; ivacaftor may also induce and/or inhibit P-gp. While the induction of aliskiren through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear.
    Aliskiren; Valsartan: (Moderate) Lumacaftor; ivacaftor may alter the systemic exposure of aliskiren. If used together, monitor blood pressure closely and adjust the aliskiren dosage as appropriate. Aliskiren is a substrate of CYP3A4 and the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggests lumacaftor; ivacaftor may also induce and/or inhibit P-gp. While the induction of aliskiren through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear.
    Almotriptan: (Minor) Lumacaftor; ivacaftor may reduce the efficacy of almotriptan by decreasing its systemic exposure. If used together, monitor the patient for appropriate clinical effects. Almotriptan is partially metabolized by CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Alpelisib: (Major) Avoid coadministration of alpelisib with lumacaftor; ivacaftor due to decreased exposure to alpelisib which could decrease efficacy. Alpelisib is a CYP3A4 substrate; lumacaftor is a strong CYP3A4 inducer.
    Alprazolam: (Moderate) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of alprazolam. If used together, alprazolam dosages may need to be adjusted. Alprazolam is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer. When alprazolam (0.8 mg as a single dose) was given with carbamazepine (300 mg/day for 10 days), another strong CYP3A inducer, alprazolam clearance more than doubled and elimination half-life decreased from 17.1 +/- 4.9 hours to 7.7 +/- 1.7 hours. (Moderate) Use caution when administering ivacaftor and alprazolam concurrently because patients are at increased risk for adverse effects from alprazolam. Ivacaftor is a CYP3A inhibitor, and alprazolam is a CYP3A substrate. Co-administration of ivacaftor with midazolam, another CYP3A substrate, increased midazolam exposure by 1.5-fold.
    Amiodarone: (Major) If amiodarone and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Amitriptyline: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of amitriptyline by decreasing its systemic exposure. If used together, monitor patients closely for amitriptyline efficacy; an amitriptyline dosage adjustment may be required to obtain the desired therapeutic effect. Do not exceed recommended maximum doses. Amitriptyline is primarily metabolized by CYP2C19 (and CYP2D6) and is also a substrate of CYP3A4 and CYP2C9. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce CYP2C19 and induce and/or inhibit CYP2C9.
    Amitriptyline; Chlordiazepoxide: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of amitriptyline by decreasing its systemic exposure. If used together, monitor patients closely for amitriptyline efficacy; an amitriptyline dosage adjustment may be required to obtain the desired therapeutic effect. Do not exceed recommended maximum doses. Amitriptyline is primarily metabolized by CYP2C19 (and CYP2D6) and is also a substrate of CYP3A4 and CYP2C9. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce CYP2C19 and induce and/or inhibit CYP2C9. (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of chlordiazepoxide by decreasing its systemic exposure; a dosage increase of chlordiazepoxide may be necessary during co-administration of lumacaftor; ivacaftor. Do not exceed the maximum recommended dose. Chlordiazepoxide is a CYP3A4 substrate. Lumacaftor is a strong CYP3A inducer.
    Amlodipine: (Moderate) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of amlodipine. If used together, monitor blood pressure closely; the dosage requirements of amlodipine may be increased. Amlodipine is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer.
    Amlodipine; Atorvastatin: (Moderate) Lumacaftor; ivacaftor may alter the systemic exposure of atorvastatin; if used together, monitor serum lipid concentrations. Atorvastatin is a substrate of CYP3A4 and the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggests lumacaftor; ivacaftor may also induce and/or inhibit P-gp. While the induction of atorvastatin through the CYP3A pathway may lead to decreased plasma concentrations of atorvastatin, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. (Moderate) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of amlodipine. If used together, monitor blood pressure closely; the dosage requirements of amlodipine may be increased. Amlodipine is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer.
    Amlodipine; Benazepril: (Moderate) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of amlodipine. If used together, monitor blood pressure closely; the dosage requirements of amlodipine may be increased. Amlodipine is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of amlodipine. If used together, monitor blood pressure closely; the dosage requirements of amlodipine may be increased. Amlodipine is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of amlodipine. If used together, monitor blood pressure closely; the dosage requirements of amlodipine may be increased. Amlodipine is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer.
    Amlodipine; Olmesartan: (Moderate) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of amlodipine. If used together, monitor blood pressure closely; the dosage requirements of amlodipine may be increased. Amlodipine is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer.
    Amlodipine; Telmisartan: (Moderate) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of amlodipine. If used together, monitor blood pressure closely; the dosage requirements of amlodipine may be increased. Amlodipine is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer.
    Amlodipine; Valsartan: (Moderate) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of amlodipine. If used together, monitor blood pressure closely; the dosage requirements of amlodipine may be increased. Amlodipine is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration if possible; lumacaftor; ivacaftor may decrease the therapeutic efficacy of clarithromycin. If concomitant use is necessary, monitor microbiological activity and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when clarithromycin is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking clarithromycin, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking clarithromycin. Clarithromycin is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Increasing the metabolism of clarithromycin decreases plasma concentrations of clarithromycin, but increases plasma concentrations of 14-OH-clarithromycin (active metabolite); the microbiological activity of each is different for different bacteria. In addition, the inhibitory effects of clarithromycin may increase the systemic exposure of ivacaftor. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A inhibitor, increased ivacaftor exposure by 4.3-fold. However, because lumacaftor is a strong inducer of CYP3A, the net exposure of ivacaftor at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours). (Major) If clarithromycin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of lansoprazole by substantially decreasing its systemic exposure. If used together, a lansoprazole dosage adjustment may be necessary to obtain the desired therapeutic effect. Lansoprazole is a CYP3A4 and CYP2C19 substrate. Lumacaftor; ivacaftor is a strong inducer of CYP3A; in vitro data suggests is also has the potential to induce CYP2C19.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration if possible; lumacaftor; ivacaftor may decrease the therapeutic efficacy of clarithromycin. If concomitant use is necessary, monitor microbiological activity and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when clarithromycin is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking clarithromycin, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking clarithromycin. Clarithromycin is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Increasing the metabolism of clarithromycin decreases plasma concentrations of clarithromycin, but increases plasma concentrations of 14-OH-clarithromycin (active metabolite); the microbiological activity of each is different for different bacteria. In addition, the inhibitory effects of clarithromycin may increase the systemic exposure of ivacaftor. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A inhibitor, increased ivacaftor exposure by 4.3-fold. However, because lumacaftor is a strong inducer of CYP3A, the net exposure of ivacaftor at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours). (Major) If clarithromycin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of omeprazole by substantially decreasing its systemic exposure. If used together, an omeprazole dosage adjustment may be necessary to obtain the desired therapeutic effect. Omeprazole is a CYP3A4 and CYP2C19 substrate. Lumacaftor; ivacaftor is a strong inducer of CYP3A; in vitro data suggests is also has the potential to induce CYP2C19.
    Apalutamide: (Major) Coadministration of ivacaftor with apalutamide is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold.
    Apremilast: (Major) Coadministration of apremilast and lumacaftor; ivacaftor is not recommended due to the potential for decreased apremilast exposure and reduced efficacy. Lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration of another strong CYP450 inducer decreased the apremilast AUC and Cmax by 72% and 43%, respectively.
    Aprepitant, Fosaprepitant: (Major) Avoid coadministration of lumacaftor; ivacaftor and aprepitant, fosaprepitant, as substantially decreased exposure of aprepitant in patients taking a strong CYP3A4 inducer may decrease efficacy. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Aprepitant, fosaprepitant is primarily metabolized by CYP3A4, and lumacaftor is a strong CYP3A inducer. The AUC and mean terminal half-life of aprepitant decreased approximately 11-fold and 3-fold, respectively, when a single 375-mg dose of aprepitant was administered during a 14-day course of another strong CYP3A inducer. (Major) If multi-day regimens of aprepitant and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate, and aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. When administered as a single oral or single intravenous dose, the inhibitory effect of aprepitant on CYP3A4 is weak and did not result in a clinically significant increase in the AUC of a sensitive substrate.
    Aripiprazole: (Major) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of aripiprazole. Lumacaftor is a strong CYP3A inducer and aripiprazole is a partial CYP3A4 substrate. Coadministration of aripiprazole (30 mg daily) with carbamazepine (200 mg twice daily), another strong CYP3A inducer, resulted in a 70% decrease in Cmax and AUC values of both aripiprazole and its active metabolite. If used together, the oral aripiprazole dose should be doubled over 1 to 2 weeks. Monitor the patient closely for antipsychotic efficacy; additional dosage increases should be based on clinical evaluation. If lumacaftor; ivacaftor therapy is later withdrawn, the oral ariprazole dosage should be reduced to the original level over 1 to 2 weeks. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving Aristada with a strong CYP3A4 inducer, no dose adjustment is necessary for the 662 mg or the 882 mg dose; increase the 441 mg dose to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers.
    Artemether; Lumefantrine: (Severe) Concomitant use of lumacaftor; ivacaftor and artemether; lumefantrine is contraindicated. Coadministration is expected to result in subtherapeutic artemether; lumefantrine serum concentrations and a possible reduction in antimalarial activity. Artemether; lumefantrine is primarily metabolized by CYP3A4 and is also a substrate of CYP2B6, CYP2C9, and CYP2C19. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce CYP2B6 and CYP2C19, and induce and/or inhibit CYP2C9.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with lumacaftor; ivacaftor can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with ivacaftor may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of ivacaftor could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Ivacaftor is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) Concomitant use of dihydrocodeine with lumacaftor; ivacaftor can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Lumacaftor; ivacaftor is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Aspirin, ASA; Carisoprodol: (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. The formation of meprobamate (active metabolite of carisoprodol) is catalyzed by CYP2C19. In vitro data suggest that lumacaftor may induce CYP2C19. If these drugs are coadministered, the potential exists for increased metabolism of carisoprodol. Theoretically, carisoprodol plasma concentrations could be decreased, and meprobamate (active metabolite) plasma concentrations could be increased. The full pharmacological impact of these potential alterations of exposures in terms of either efficacy or safety of carisoprodol is unknown.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with lumacaftor; ivacaftor can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lumacaftor; ivacaftor is a strong CYP3A4 inducer. (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. The formation of meprobamate (active metabolite of carisoprodol) is catalyzed by CYP2C19. In vitro data suggest that lumacaftor may induce CYP2C19. If these drugs are coadministered, the potential exists for increased metabolism of carisoprodol. Theoretically, carisoprodol plasma concentrations could be decreased, and meprobamate (active metabolite) plasma concentrations could be increased. The full pharmacological impact of these potential alterations of exposures in terms of either efficacy or safety of carisoprodol is unknown.
    Aspirin, ASA; Omeprazole: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of omeprazole by substantially decreasing its systemic exposure. If used together, an omeprazole dosage adjustment may be necessary to obtain the desired therapeutic effect. Omeprazole is a CYP3A4 and CYP2C19 substrate. Lumacaftor; ivacaftor is a strong inducer of CYP3A; in vitro data suggests is also has the potential to induce CYP2C19.
    Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ivacaftor is necessary. If ivacaftor is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like ivacaftor can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ivacaftor is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with lumacaftor; ivacaftor is necessary; consider increasing the dose of oxycodone as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Atazanavir: (Major) If atazanavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor is expected to decrease the therapeutic efficacy of atazanavir; avoid concurrent use. If concomitant use cannot be avoided, consider limiting concurrent use to regimens in which atazanavir is boosted with ritonavir and monitor antiretroviral efficacy carefully. Lumacaftor; ivacaftor dosage adjustment is not required when atazanavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking atazanavir, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking atazanavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Atazanavir is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of atazanavir and decrease its therapeutic efficacy. Although atazanavir is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold.
    Atazanavir; Cobicistat: (Major) If atazanavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) If cobicistat and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor is expected to decrease the therapeutic efficacy of atazanavir; avoid concurrent use. If concomitant use cannot be avoided, consider limiting concurrent use to regimens in which atazanavir is boosted with ritonavir and monitor antiretroviral efficacy carefully. Lumacaftor; ivacaftor dosage adjustment is not required when atazanavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking atazanavir, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking atazanavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Atazanavir is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of atazanavir and decrease its therapeutic efficacy. Although atazanavir is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of cobicistat; avoid concurrent use if possible. If concomitant use of cobicistat is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when cobicistat is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking cobicistat, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking cobicistat. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Cobicistat is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of cobicistat and decrease its therapeutic efficacy. Although cobicistat is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold.
    Atorvastatin: (Moderate) Lumacaftor; ivacaftor may alter the systemic exposure of atorvastatin; if used together, monitor serum lipid concentrations. Atorvastatin is a substrate of CYP3A4 and the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggests lumacaftor; ivacaftor may also induce and/or inhibit P-gp. While the induction of atorvastatin through the CYP3A pathway may lead to decreased plasma concentrations of atorvastatin, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear.
    Atorvastatin; Ezetimibe: (Moderate) Lumacaftor; ivacaftor may alter the systemic exposure of atorvastatin; if used together, monitor serum lipid concentrations. Atorvastatin is a substrate of CYP3A4 and the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggests lumacaftor; ivacaftor may also induce and/or inhibit P-gp. While the induction of atorvastatin through the CYP3A pathway may lead to decreased plasma concentrations of atorvastatin, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Coadministration of ivacaftor with phenobarbital is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold. Additionally, phenobarbital is a CYP2C9 substrate and ivacaftor may inhibit CYP2C9. Coadministration may increase exposure to phenobarbital leading to increased or prolonged therapeutic effects and adverse events. (Major) Concomitant use of phenobarbital and lumacaftor; ivacaftor is not recommended. Phenobarbital may decrease the therapeutic effect of lumacaftor; ivacaftor by significantly decreasing the systemic exposure of ivacaftor. Ivacaftor is a substrate of CYP3A, and phenobarbital is a potent CYP3A inducer. In a pharmacokinetic study, coadministration of lumacaftor; ivacaftor with rifampin, another potent CYP3A inducer, decreased ivacaftor exposure (AUC) by 57%, with minimal effect on the exposure of lumacaftor. In vitro studies suggest lumacaftor; ivacaftor has the potential to induce CYP2C9 and CYP2C19; inhibition CYP2C9 has also been observed. Because phenobarbital is a substrate of these enzymes, altered phenobarbital exposure may occur.
    Avanafil: (Major) Lumacaftor; ivacaftor may reduce the efficacy of avanafil by decreasing its systemic exposure; concomitant use is not recommended. Avanafil is a primary substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Axitinib: (Major) Avoid coadministration of axitinib with lumacaftor; ivacaftor, due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Bedaquiline: (Major) Lumacaftor; ivacaftor may reduce the efficacy of bedaquiline by decreasing its systemic exposure; avoid concomitant use. Bedaquiline is a primary substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Coadministration of ivacaftor with phenobarbital is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold. Additionally, phenobarbital is a CYP2C9 substrate and ivacaftor may inhibit CYP2C9. Coadministration may increase exposure to phenobarbital leading to increased or prolonged therapeutic effects and adverse events. (Major) Concomitant use of phenobarbital and lumacaftor; ivacaftor is not recommended. Phenobarbital may decrease the therapeutic effect of lumacaftor; ivacaftor by significantly decreasing the systemic exposure of ivacaftor. Ivacaftor is a substrate of CYP3A, and phenobarbital is a potent CYP3A inducer. In a pharmacokinetic study, coadministration of lumacaftor; ivacaftor with rifampin, another potent CYP3A inducer, decreased ivacaftor exposure (AUC) by 57%, with minimal effect on the exposure of lumacaftor. In vitro studies suggest lumacaftor; ivacaftor has the potential to induce CYP2C9 and CYP2C19; inhibition CYP2C9 has also been observed. Because phenobarbital is a substrate of these enzymes, altered phenobarbital exposure may occur. (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. (Minor) Lumacaftor; ivacaftor may reduce the efficacy of ergotamine by decreasing its systemic exposure; if used together, monitor patients closely for clinical efficacy. Ergotamine is a substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with ivacaftor may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of ivacaftor in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4. (Moderate) Concurrent use of benzhydrocodone with lumacaftor; ivacaftor may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If concomitant use is necessary, consider increasing the benzhydrocodone dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Discontinuation of lumacaftor; ivacaftor may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. If lumacaftor; ivacaftor is discontinued, consider a benzhydrocodone dosage reduction and monitor patients for respiratory depression and sedation at frequent intervals. Benzhydrocodone is a prodrug of hydrocodone. Lumacaftor is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone.
    Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving ivacaftor. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving ivacaftor. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; ivacaftor inhibits P-gp. (Major) Coadministration of betrixaban and lumacaftor; ivacaftor may alter betrixaban exposure resulting in increased or decreased plasma concentrations of betrixaban that may alter its intended therapeutic effect. Betrixaban is a P-glycoprotein (P-gp) substrate, ivacaftor is a weak P-gp inhibitor, and lumacaftor is both a P-gp inhibitor and P-gp inducer.
    Bexarotene: (Moderate) Use caution when administering ivacaftor and bexarotene concurrently; the clinical impact of this interaction has not yet been determined. Administration of ivacaftor with strong CYP3A inducers is not recommended because sub-therapeutic ivacaftor exposure could result. Ivacaftor is a CYP3A substrate and bexarotene is a moderate CYP3A inducer. Co-administration with a strong CYP3A inducer decreased the ivacaftor exposure by approximately 9-fold.
    Boceprevir: (Severe) Concomitant use of lumacaftor; ivacaftor and boceprevir is contraindicated due to the risk for reduced boceprevir efficacy. Boceprevir is a substrate of CYP3A, and lumacaftor is a strong CYP3A inducer. (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: (Major) Lumacaftor; ivacaftor may reduce the efficacy of bortezomib by decreasing its systemic exposure; avoid concurrent use. Bortezomib is primarily metabolized by CYP3A4 and is also a substrate of CYP2C19. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor may induce CYP2C19. Drug interaction studies suggest coadministration of bortezomib and rifampin, another strong CYP3A inducer, reduces bortezomib exposure by at least 45%.
    Bosentan: (Moderate) Concomitant use of bosentan and lumacaftor; ivacaftor may alter the therapeutic effects of bosentan; caution and close monitoring are advised if these drugs are used together. Bosentan is a CYP3A4 and CYP2C9 substrate, as well as a moderate CYP3A inducer. Ivacaftor is a sensitive CYP3A substrate and lumacaftor is a strong CYP3A inducer; in vitro data also suggest lumacaftor; ivacaftor may induce and/or inhibit CYP2C9. Although induction of bosentan through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear. Monitor the patient for decreased bosentan efficacy or increased adverse events. Coadministration of bosentan and rifampin, a strong CYP3A inducer, resulted in a 60% decrease in bosentan concentrations at steady-state. Although ivacaftor exposure could theoretically be further decreased when given with another CYP3A inducer, ivacaftor; lumacaftor dosage adjustments are not recommended with concomitant use of a moderate CYP3A inducer such as bosentan.
    Bosutinib: (Major) Lumacaftor; ivacaftor may reduce the efficacy of bosutinib by significantly decreasing its systemic exposure; avoid concomitant use. Bosutinib is a primary substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were decreased by 86% and 94%, respectively, after a single oral dose of bosutinib 500 mg administered after 6 days of another CYP3A inducer (oral rifampin 600 mg/day).
    Brexpiprazole: (Major) Lumacaftor; ivacaftor may reduce the efficacy of brexpiprazole by significantly decreasing its systemic exposure; if used together, gradually double the usual brexpiprazole dose over 1 to 2 weeks. If lumacaftor; ivacaftor is subsequently discontinued, reduce the brexpiprazole dose back to the original dose over 1 to 2 weeks. Brexpiprazole is a primary substrate of CYP3A4 (and CYP2D6). Lumacaftor is a strong CYP3A inducer.
    Brigatinib: (Major) Avoid coadministration of brigatinib with lumacaftor; ivacaftor due to decreased plasma exposure to brigatinib which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively. (Moderate) Monitor for a decrease in the efficacy of ivacaftor if coadministration with brigatinib is necessary. Ivacaftor is a sensitive CYP3A4 substrate. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates.
    Bromocriptine: (Moderate) Caution and close monitoring are advised if bromocriptine and lumacaftor; ivacaftor are used together. Concurrent use may decrease the plasma concentrations of bromocriptine resulting in loss of efficacy. Bromocriptine is extensively metabolized by the liver via CYP3A4; lumacaftor is a strong inducer of CYP3A4
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4. (Moderate) Concomitant use of hydrocodone with lumacaftor; ivacaftor can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4. (Moderate) Concomitant use of hydrocodone with lumacaftor; ivacaftor can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Budesonide: (Moderate) Concomitant use of budesonide and lumacaftor; ivacaftor may alter the therapeutic effects of budesonide; caution and close monitoring are advised if these drugs are used together. Budesonide is a primary substrate of CYP3A4 and a substrate of the P-glycoprotein (P-gp) efflux transporter. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest lumacaftor; ivacaftor may induce and/or inhibit P-gp. Although induction of budesonide through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. Monitor the patient for decreased corticosteroid efficacy or increased or prolonged therapeutic effects and adverse events. (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) Concomitant use of budesonide and lumacaftor; ivacaftor may alter the therapeutic effects of budesonide; caution and close monitoring are advised if these drugs are used together. Budesonide is a primary substrate of CYP3A4 and a substrate of the P-glycoprotein (P-gp) efflux transporter. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest lumacaftor; ivacaftor may induce and/or inhibit P-gp. Although induction of budesonide through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. Monitor the patient for decreased corticosteroid efficacy or increased or prolonged therapeutic effects and adverse events. (Moderate) Use caution when administering ivacaftor and budesonide concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as budesonide, can increase budesonide exposure leading to increased or prolonged therapeutic effects and adverse events.
    Buprenorphine: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of buprenorphine by decreasing its systemic exposure; use together with caution and consider buprenorphine dosage adjustment if necessary. Buprenorphine is a primary substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer. (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) Lumacaftor; ivacaftor may reduce the efficacy of buprenorphine by decreasing its systemic exposure; use together with caution and consider buprenorphine dosage adjustment if necessary. Buprenorphine is a primary substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer. (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.
    Bupropion: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of bupropion by decreasing its systemic exposure. If used together, monitor patients closely for loss of bupropion efficacy; a bupropion dosage adjustment may be required to obtain the desired therapeutic effect. Do not exceed the maximum recommended dose. Bupropion is a substrate of CYP2B6; in vitro data suggest that lumacaftor may induce this enzyme.
    Bupropion; Naltrexone: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of bupropion by decreasing its systemic exposure. If used together, monitor patients closely for loss of bupropion efficacy; a bupropion dosage adjustment may be required to obtain the desired therapeutic effect. Do not exceed the maximum recommended dose. Bupropion is a substrate of CYP2B6; in vitro data suggest that lumacaftor may induce this enzyme.
    Buspirone: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of buspirone by decreasing its systemic exposure. A buspirone dosage adjustment may be necessary to maintain anxiolytic activity. Lumacaftor is a strong CYP3A inducer. Buspirone has been shown in vitro to be metabolized via CYP3A4; this finding is consistent with in vivo interactions observed. When coadministered with rifampin, another strong CYP3A inducer, buspirone Cmax and AUC decreased by 84% and 90%, respectively.
    Cabozantinib: (Major) Avoid coadministration of cabozantinib with lumacaftor; ivacaftor due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with lumacaftor; ivacaftor 2 to 3 days after discontinuation of lumacaftor; ivacaftor. Cabozantinib is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased single-dose cabozantinib exposure by 77%.
    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. (Minor) Lumacaftor; ivacaftor may reduce the efficacy of ergotamine by decreasing its systemic exposure; if used together, monitor patients closely for clinical efficacy. Ergotamine is a substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer.
    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.
    Cannabidiol: (Moderate) Consider a dose increase of cannabidiol if coadministered with lumacaftor; ivacaftor. Coadministration may decrease cannabidiol plasma concentrations resulting in a decrease in efficacy. Cannabidiol is metabolized by CYP3A4; lumacaftor is a strong inducer of CYP3A4.
    Carbamazepine: (Major) Coadministration of ivacaftor with carbamazepine is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold. (Major) Concomitant use of carbamazepine and lumacaftor; ivacaftor is not recommended. Carbamazepine may decrease the therapeutic effect of lumacaftor; ivacaftor by significantly decreasing the systemic exposure of ivacaftor. Lumacaftor; ivacaftor may also decrease the therapeutic effect of carbamazepine. Carbamazepine is a substrate and potent inducer of CYP3A. Ivacaftor is a substrate of CYP3A and lumacaftor is a potent inducer of CYP3A. Although the enzyme induction effects of lumacaftor are already accounted for in fixed-combination dosing, ivacaftor exposure is further decreased when given together with other CYP3A inducers. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with rifampin, another potent CYP3A inducer, decreased ivacaftor exposure by 57%, with minimal effect on the exposure of lumacaftor.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Minor) Concomitant use of diphenhydramine and lumacaftor; ivacaftor may alter diphenhydramine exposure; monitor for diphenhydramine efficacy and adverse events. Diphenhydramine is partially metabolized by CYP2C9 and CYP2C19. In vitro data suggest that lumacaftor; ivacaftor may induce CYP2C19 and induce and/or inhibit CYP2C9. Although induction of diphenhydramine through the CYP2C19 pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear. (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as diphenhydramine. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4. (Moderate) Concomitant use of hydrocodone with lumacaftor; ivacaftor can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4. (Moderate) Concomitant use of hydrocodone with lumacaftor; ivacaftor can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Carisoprodol: (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. The formation of meprobamate (active metabolite of carisoprodol) is catalyzed by CYP2C19. In vitro data suggest that lumacaftor may induce CYP2C19. If these drugs are coadministered, the potential exists for increased metabolism of carisoprodol. Theoretically, carisoprodol plasma concentrations could be decreased, and meprobamate (active metabolite) plasma concentrations could be increased. The full pharmacological impact of these potential alterations of exposures in terms of either efficacy or safety of carisoprodol is unknown.
    Carvedilol: (Moderate) Concomitant use of carvedilol and lumacaftor; ivacaftor may alter the therapeutic effects of carvedilol; monitor blood pressure closely until the effects of using these drugs together are known. Carvedilol is partially metabolized by CYP3A4, CYP2C9, and CYP2C19, and is a substrate of the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce CYP2C19, and induce and/or inhibit CYP2C9 and P-gp. Although induction of carvedilol through the CYP3A and CYP2C19 pathways may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism and P-gp transport is not clear. (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) Although the clinical significance of this interaction is unknown, concurrent use of celecoxib and lumacaftor; ivacaftor may alter celecoxib exposure; caution and close monitoring are advised if these drugs are used together. Celecoxib is a substrate of CYP2C9; in vitro data suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C9. The net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear, but CYP2C9 substrate exposure may be affected. (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 ceritinib with lumacaftor; ivacaftor due to decreased ceritinib exposure, resulting in decreased efficacy of treatment. Ceritinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of ceritinib by 70% and 44%, respectively. (Major) If ceritinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and ceritinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
    Cevimeline: (Minor) Lumacaftor; ivacaftor may reduce the efficacy of cevimeline by decreasing its systemic exposure; if used together, monitor patients for adequate muscarinic response. Cevimeline is a substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Chloramphenicol: (Major) If chloramphenicol and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and chloramphenicol is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Use caution with the concomitant use of lumacaftor; ivacaftor and chloramphenicol as the exposure of ivacaftor may be increased. Lumacaftor; ivacaftor dosage adjustment is not required when chloramphenicol is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking chloramphenicol, reduce the dosage of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking chloramphenicol. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Chloramphenicol is a strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Although chloramphenicol is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold.
    Chlordiazepoxide: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of chlordiazepoxide by decreasing its systemic exposure; a dosage increase of chlordiazepoxide may be necessary during co-administration of lumacaftor; ivacaftor. Do not exceed the maximum recommended dose. Chlordiazepoxide is a CYP3A4 substrate. Lumacaftor is a strong CYP3A inducer.
    Chlordiazepoxide; Clidinium: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of chlordiazepoxide by decreasing its systemic exposure; a dosage increase of chlordiazepoxide may be necessary during co-administration of lumacaftor; ivacaftor. Do not exceed the maximum recommended dose. Chlordiazepoxide is a CYP3A4 substrate. Lumacaftor is a strong CYP3A inducer.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with lumacaftor; ivacaftor can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with ivacaftor may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of ivacaftor could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Ivacaftor is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) Concomitant use of dihydrocodeine with lumacaftor; ivacaftor can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Lumacaftor; ivacaftor is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with ivacaftor may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of ivacaftor could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Ivacaftor is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) Concomitant use of dihydrocodeine with lumacaftor; ivacaftor can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Lumacaftor; ivacaftor is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4. (Moderate) Concomitant use of hydrocodone with lumacaftor; ivacaftor can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4. (Moderate) Concomitant use of hydrocodone with lumacaftor; ivacaftor can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4. (Moderate) Concomitant use of hydrocodone with lumacaftor; ivacaftor can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4. (Moderate) Concomitant use of hydrocodone with lumacaftor; ivacaftor can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Chlorpropamide: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of chlorpropamide by decreasing its systemic exposure. If used together, monitor blood glucose concentrations closely; a chlorpropamide dosage adjustment may be required to obtain the desired therapeutic effect. Chlorpropamide is a CYP2C9 substrate; in vitro studies suggest lumacaftor; ivacaftor has the potential to induce and inhibit CYP2C9.
    Cilostazol: (Major) Lumacaftor; ivacaftor may reduce the efficacy of cilostazol by decreasing its systemic exposure; caution and close monitoring are advised if these drugs are used together. Cilostazol is extensively metabolized by CYP3A4 and, to a lesser extent, CYP2C19. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest lumacaftor; ivacaftor may induce CYP2C19.
    Cinacalcet: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of cinacalcet by decreasing its systemic exposure; if used together, monitor intact parathyroid hormone (iPTH), serum calcium, and serum phosphorus concentrations. Cinacalcet is partially metabolized by CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Cisapride: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of cisapride by decreasing its systemic exposure; use together with caution and consider cisapride dosage adjustment if necessary. Do not exceed recommended dosages. Cisapride is a CYP3A4 substrate. Lumacaftor is a strong CYP3A inducer.
    Citalopram: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of citalopram by decreasing its systemic exposure. If used together, a higher dose of citalopram may be required to obtain the desired therapeutic effect. Do not exceed the recommended maximum dose. Citalopram is a CYP3A and CYP2C19 substrate. Lumacaftor; ivacaftor is a strong inducer of CYP3A and has the potential to induce CYP2C19.
    Clarithromycin: (Major) Avoid coadministration if possible; lumacaftor; ivacaftor may decrease the therapeutic efficacy of clarithromycin. If concomitant use is necessary, monitor microbiological activity and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when clarithromycin is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking clarithromycin, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking clarithromycin. Clarithromycin is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Increasing the metabolism of clarithromycin decreases plasma concentrations of clarithromycin, but increases plasma concentrations of 14-OH-clarithromycin (active metabolite); the microbiological activity of each is different for different bacteria. In addition, the inhibitory effects of clarithromycin may increase the systemic exposure of ivacaftor. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A inhibitor, increased ivacaftor exposure by 4.3-fold. However, because lumacaftor is a strong inducer of CYP3A, the net exposure of ivacaftor at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours). (Major) If clarithromycin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
    Clindamycin: (Moderate) Concomitant use of clindamycin and lumacaftor; ivacaftor may increase clindamycin clearance and result in loss of efficacy of clindamycin. Clindamycin is a CYP3A4 substrate; lumacaftor is a strong inducer of CYP3A4. Caution and close monitoring are advised if these drugs are used together.
    Clobazam: (Moderate) Although the clinical significance of this interaction is unknown, lumacaftor; ivacaftor may reduce the efficacy of clobazam by decreasing its systemic exposure; a dosage increase of clobazam may be necessary during co-administration of lumacaftor; ivacaftor. Do not exceed the maximum recommended dose. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and in vitro data suggest that lumacaftor may induce CYP2C19. Clobazam and its active metabolite are also substrates of the drug transporter P-glycoprotein (P-gp) and in vitro data suggest that lumacaftor; ivacaftor may inhibit and/or induce P-gp. The net effect on P-gp substrates is not clear, but their exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events.
    Clomipramine: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of clomipramine by decreasing its systemic exposure. If used together, monitor patients closely for clomipramine efficacy; a clomipramine dosage adjustment may be required to obtain the desired therapeutic effect. Do not exceed the recommended maximum dosage. Clomipramine is primarily metabolized by CYP3A4 (and CYP2D6) and is also a substrate of CYP2C19. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may also induce CYP2C19.
    Clonazepam: (Moderate) Lumacaftor may induce the metabolism of clonazepam thereby decreasing the systemic exposure and therapeutic effect. Clonazepam concentration decreases of approximately 38% have been reported when clonazepam is used with strong CYP3A4 inducers. Clonazepam is a CYP3A4 substrate. Lumacaftor is a strong CYP3A4 inducer.
    Clorazepate: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of clorazepate by decreasing the systemic exposure of its active metabolite. If used together, monitor patients closely for clorazepate efficacy; a clorazepate dosage adjustment may be required to obtain the desired therapeutic effect. Clorazepate is a prodrug converted to N-desmethyldiazepam in the GI tract; N-desmethyldiazepam is metabolized by CYP3A4 and CYP2C19. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor may induce CYP2C19.
    Clozapine: (Major) Lumacaftor; ivacaftor may reduce the efficacy of clozapine by decreasing its systemic exposure; concomitant use is not recommended. If coadministration cannot be avoided, monitor for a lack of antipsychotic efficacy and consider increasing the clozapine dosage if necessary. Upon discontinuation of lumacaftor; ivacaftor, reduce the clozapine dosage based on clinical response. Clozapine is primarily metabolized by CYP3A4, CYP1A2, and CYP2D6. Lumacaftor is a strong CYP3A inducer. (Moderate) Use caution when administering ivacaftor and clozapine concurrently. Ivacaftor is an inhibitor of CYP3A and clozapine is partially metabolized by CYP3A. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Cobicistat: (Major) If cobicistat and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of cobicistat; avoid concurrent use if possible. If concomitant use of cobicistat is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when cobicistat is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking cobicistat, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking cobicistat. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Cobicistat is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of cobicistat and decrease its therapeutic efficacy. Although cobicistat is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold.
    Codeine: (Moderate) Concomitant use of codeine with lumacaftor; ivacaftor can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with lumacaftor; ivacaftor can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with lumacaftor; ivacaftor can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with lumacaftor; ivacaftor can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Colchicine: (Major) Avoid concomitant use of colchicine and lumacaftor; ivacaftor if possible. If concurrent use cannot be avoided, monitor the patient closely for both colchicine toxicity and therapeutic efficacy. Colchicine is a substrate of CYP3A4 and the P-glycoprotein (P-gp) efflux transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggests lumacaftor; ivacaftor may also induce and/or inhibit P-gp. While the induction of colchicine through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. Caution is warranted as coadministration of P-gp inhibitors and colchicine have been reported to lead to colchicine toxicity. (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.
    Colchicine; Probenecid: (Major) Avoid concomitant use of colchicine and lumacaftor; ivacaftor if possible. If concurrent use cannot be avoided, monitor the patient closely for both colchicine toxicity and therapeutic efficacy. Colchicine is a substrate of CYP3A4 and the P-glycoprotein (P-gp) efflux transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggests lumacaftor; ivacaftor may also induce and/or inhibit P-gp. While the induction of colchicine through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. Caution is warranted as coadministration of P-gp inhibitors and colchicine have been reported to lead to colchicine toxicity. (Major) Use caution when administering ivacaftor and colchicine concurrently; increased monitoring and/or dose adjustment of colchine may be necessary. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as colchicine, can increase colchicine exposure leading to increased or prolonged therapeutic effects and adverse events. Fatal colchicine toxicity has been reported when given with strong CYP3A4 and Pgp inhibitors.
    Conivaptan: (Major) If conivaptan and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and conivaptan is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of conivaptan; avoid concurrent use if possible. If concomitant use of conivaptan is necessary, monitor efficacy and adjust therapy as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when conivaptan is used in a patient already taking lumacaftor; ivacaftor. If a patient is already receiving conivaptan therapy, waiting at least 1 week after the last conivaptan dose before starting lumacaftor; ivacaftor would simplify treatment initiation. However, if the decision is made to begin lumacaftor; ivacaftor in a patient already receiving conivaptan, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking conivaptan. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Conivaptan is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of conivaptan and decrease its therapeutic efficacy. Although conivaptan is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold.
    Conjugated Estrogens; Medroxyprogesterone: (Major) Avoid concomitant use of medroxyprogesterone and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease medroxyprogesterone, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative and/or additional methods of birth control. In addition, concomitant use of hormonal contraceptives and lumacaftor; ivacaftor may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia). Patients taking medroxyprogesterone for other indications should be monitored for clinical efficacy of the progestin. Medroxyprogesterone is primarily metabolized in vitro via CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Copanlisib: (Major) Avoid the concomitant use of copanlisib and lumacaftor; ivacaftor; decreased copanlisib exposure and loss of efficacy may occur. Copanlisib is a CYP3A substrate; lumacaftor is a strong CYP3A inducer. The AUC and Cmax values of copanlisib decreased by 60% and 12%, respectively, when a single IV dose of copanlisib 60 mg was administered following 12 days of another strong CYP3A4 inducer in a drug interaction study in patients with cancer.
    Crizotinib: (Major) Avoid coadministration of crizotinib with lumacaftor; ivacaftor due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively. (Major) If crizotinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Cyclophosphamide: (Minor) Lumacaftor; ivacaftor may increase the clinical and/or toxic effects of cyclophosphamide due to a potential for increased conversion of cyclophosphamide to its metabolites. If used together, monitor patients closely for cyclophosphamide efficacy and/or toxicity. The extensive P-450 catalyzed metabolism of cyclophosphamide yields both therapeutically active (N-hydroxylated) and therapeutically inactive but neurotoxic (N-dechlorethylated) metabolites. It is not yet completely clear what effect inducers of the CYP450 isoenzymes have on the activation and/or toxicity of cyclophosphamide. Cyclophosphamide is primarily metabolized by CYP2B6, and to a lesser extent by CYP3A4, CYP2C9, and CYP2C19. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce CYP2B6 and CYP2C19, and induce and/or inhibit CYP2C9. It is not yet completely clear what effect inducers of the CYP450 isoenzymes have on the activation and/or toxicity of cyclophosphamide. Chronic administration of high doses of phenobarbital, another strong CYP3A inducer, has been reported to increase the rate of metabolism and the leukopenic activity of cyclophosphamide.
    Cyclosporine: (Major) Concomitant use of cyclosporine and lumacaftor; ivacaftor is not recommended. If concurrent use cannot be avoided, monitor cyclosporine serum concentrations closely and adjust the dose accordingly. Lumacaftor; ivacaftor may decrease the systemic exposure of cyclosporine. In return, cyclosporine may increase ivacaftor exposure, although the clinical significance of this interaction is unclear. Cyclosporine is a substrate and moderate inhibitor of CYP3A. Lumacaftor is a strong inducer of CYP3A, and ivacaftor is CYP3A substrate. In addition, the exposure of cyclosporine may be altered via P-glycoprotein (P-gp) transport. Cyclosporine is P-gp substrate; in vitro studies suggest lumacaftor; ivacaftor has the potential to induce and inhibit P-gp. (Major) If cyclosporine and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration may increase exposure to both drugs leading to increased or prolonged therapeutic effects and adverse events. More careful monitoring of cyclosporine blood concentrations may be warranted. Ivacaftor is a CYP3A substrate and cyclosporine is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. In addition, ivacaftor is an inhibitor of CYP3A and P-glycoprotein (P-gp); cyclosporine is a sensitive CYP3A and P-gp substrate.
    Dabigatran: (Major) Concomitant use of dabigatran and lumacaftor; ivacaftor may alter dabigatran exposure; avoid coadministration if possible. Dabigatran is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected. FDA-approved labeling for dabigatran recommends, in general, to avoid coadministration with P-gp inducers. Concomitant administration of dabigatran and rifampin, another P-gp inducer, resulted in a significant decrease in dabigatran AUC and Cmax. Labeling also recommends to avoid coadministration with P-gp inhibitors in patients with a CrCl less than 50 mL/minute when used for treatment or reduction in risk of deep vein thrombosis (DVT) or pulmonary embolism or prophylaxis of DVT or PE following hip replacement surgery and in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. (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) Avoid the concomitant administration of dabrafenib and lumacaftor; ivacaftor. If concomitant use is unavoidable, monitor patients closely for loss of dabrafenib efficacy. Dabrafenib is primarily metabolized by CYP3A4 and CYP2C8. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor may induce and/or inhibit CYP2C8.
    Danazol: (Major) If danazol and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and danazol is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Dapagliflozin; Saxagliptin: (Moderate) Lumacaftor; ivacaftor may alter the systemic exposure of saxagliptin; if used together, monitor blood glucose concentrations closely. Saxagliptin is a substrate of CYP3A (primary) and the P-glycoprotein (P-gp) efflux transporter. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest lumacaftor; ivacaftor may induce and/or inhibit P-gp. Although induction of saxagliptin metabolism through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear.
    Dapsone: (Major) If dapsone and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and dapsone is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. (Moderate) Monitor for an increase in hemolysis if coadministration of dapsone with lumacaftor; ivacaftor is necessary; dapsone efficacy may also be compromised. Dapsone is a CYP3A4 metabolite and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Strong CYP3A4 inducers may increase the formation of dapsone hydroxylamine, a metabolite associated with hemolysis. Coadministration with another strong CYP3A4 inducer decreased dapsone levels by 7-fold to 10-fold; in leprosy, this reduction has not required a change in dosage.
    Darifenacin: (Minor) Lumacaftor; ivacaftor may reduce the efficacy of darifenacin by decreasing its systemic exposure; if used together, monitor patients for clinical efficacy and increase the darifenacin dosage if needed. Darifenacin is a substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Darolutamide: (Major) Avoid coadministration of darolutamide with lumacaftor; ivacaftor due to the risk of decreased darolutamide plasma concentrations which may decrease efficacy. Lumacaftor is a P-glycoprotein (P-gp) inducer and a strong inducer of CYP3A4; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp and strong CYP3A4 inducer decreased the mean AUC and Cmax of darolutamide by 72% and 52%, respectively.
    Darunavir: (Major) If darunavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of darunavir; avoid concurrent use if possible. If concomitant use of darunavir is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when darunavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking darunavir, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking darunavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Darunavir is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of darunavir and decrease its therapeutic efficacy. Although darunavir is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold.
    Darunavir; Cobicistat: (Major) If cobicistat and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) If darunavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of cobicistat; avoid concurrent use if possible. If concomitant use of cobicistat is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when cobicistat is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking cobicistat, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking cobicistat. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Cobicistat is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of cobicistat and decrease its therapeutic efficacy. Although cobicistat is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of darunavir; avoid concurrent use if possible. If concomitant use of darunavir is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when darunavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking darunavir, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking darunavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Darunavir is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of darunavir and decrease its therapeutic efficacy. Although darunavir is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) If cobicistat and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) If darunavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of cobicistat; avoid concurrent use if possible. If concomitant use of cobicistat is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when cobicistat is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking cobicistat, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking cobicistat. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Cobicistat is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of cobicistat and decrease its therapeutic efficacy. Although cobicistat is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of darunavir; avoid concurrent use if possible. If concomitant use of darunavir is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when darunavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking darunavir, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking darunavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Darunavir is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of darunavir and decrease its therapeutic efficacy. Although darunavir is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Severe) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir and lumacaftor; ivacaftor is contraindicated due to the potential for hepatitis C treatment failure. Dasabuvir is a 2C8 and 3A (minor) substrate; ombitasvir is a P-gp substrate; paritaprevir is a 3A4 substrate and P-gp substrate; ritonavir is a substrate of CYP3A4 and P-gp. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C8 and P-gp. (Major) If ritonavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and ritonavir is a CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of ritonavir; avoid concurrent use if possible. If concomitant use of ritonavir is necessary, monitor antiretroviral efficacy and adjust therapy as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when ritonavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking ritonavir, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking ritonavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Ritonavir is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of ritonavir and decrease its therapeutic efficacy. Although ritonavir is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold. Lastly, ritonavir is also a substrate of the drug transporter P-glycoprotein (P-gp), and lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect on P-gp substrates is not clear, but their exposure may be affected.
    Dasatinib: (Major) Avoid coadministration of dasatinib and lumacaftor; ivacaftor due to the potential for decreased dasatinib exposure and reduced efficacy. Consider an alternative to lumacaftor; ivacaftor with less potential for enzyme induction. If coadministration cannot be avoided, consider an increased dose of dasatinib and monitor for toxicity. Dasatinib is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Concurrent use of another strong CYP3A4 inducer decreased the mean Cmax and AUC of dasatinib by 81% and 82%, respectively.
    Daunorubicin Liposomal: (Minor) Although the clinical significance of this interaction is unknown, concurrent use of daunorubicin liposomal and lumacaftor; ivacaftor may alter daunorubicin liposomal exposure; caution and close monitoring are advised if these drugs are used together. Daunorubicin is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events.
    Daunorubicin Liposomal; Cytarabine Liposomal: (Minor) Although the clinical significance of this interaction is unknown, concurrent use of daunorubicin liposomal and lumacaftor; ivacaftor may alter daunorubicin liposomal exposure; caution and close monitoring are advised if these drugs are used together. Daunorubicin is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events.
    Deflazacort: (Major) Avoid concomitant use of deflazacort and lumacaftor; ivacaftor. Concurrent use may significantly decrease concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in loss of efficacy. Deflazacort is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong inducer of CYP3A4. Administration of deflazacort with multiple doses of rifampin (a strong CYP3A4 inducer) resulted in geometric mean exposures that were approximately 95% lower compared to administration alone.
    Delavirdine: (Major) If delavirdine and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and delavirdine is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of delavirdine; avoid concurrent use if possible. If concomitant use of delavirdine is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when delavirdine is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking delavirdine, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking delavirdine. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Delavirdine is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of delavirdine and decrease its therapeutic efficacy. Although delavirdine is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold.
    Dexamethasone: (Moderate) Concomitant use of dexamethasone and lumacaftor; ivacaftor may alter dexamethasone exposure. If used together, dexamethasone dosages may need to be adjusted to achieve desired therapeutic effects. Dexamethasone is a substrate and moderate inducer of CYP3A and a substrate of the P-glycoprotein (P-gp) drug transporter. Ivacaftor is a sensitive CYP3A substrate and lumacaftor is a strong CYP3A inducer; in vitro data suggests lumacaftor; ivacaftor may also induce and/or inhibit P-gp. Although induction of dexamethasone through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. Monitor the patient for decreased corticosteroid efficacy or increased or prolonged therapeutic effects and adverse events. Additionally, ivacaftor exposure could theoretically be further decreased when given with another CYP3A inducer; however, ivacaftor; lumacaftor dosage adjustments are not recommended with concomitant use of a moderate CYP3A inducer such as dexamethasone.
    Dexlansoprazole: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of dexlansoprazole by decreasing its systemic exposure. If used together, monitor for dexlansoprazole efficacy. Dexlansoprazole is a CYP3A4 and CYP2C19 substrate. Lumacaftor; ivacaftor is a strong inducer of CYP3A; in vitro data suggests lumacaftor may also induce CYP2C19.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Minor) Concomitant use of diphenhydramine and lumacaftor; ivacaftor may alter diphenhydramine exposure; monitor for diphenhydramine efficacy and adverse events. Diphenhydramine is partially metabolized by CYP2C9 and CYP2C19. In vitro data suggest that lumacaftor; ivacaftor may induce CYP2C19 and induce and/or inhibit CYP2C9. Although induction of diphenhydramine through the CYP2C19 pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear. (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.
    Dextromethorphan; Quinidine: (Major) Lumacaftor; ivacaftor may alter the therapeutic effects of quinidine. Use these agents together with caution; monitor quinidine concentrations and adjust the dosage as needed to attain antiarrhythmic efficacy endpoints. Quinidine is a substrate of CYP3A and the P-glycoprotein (P-gp) efflux transporter. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest lumacaftor; ivacaftor may induce and/or inhibit P-gp. Although induction of quinidine metabolism through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. Monitor the patient for decreased antiarrhythmic efficacy or increased or prolonged therapeutic effects and adverse events.
    Diazepam: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of diazepam by decreasing its systemic exposure. If used together, monitor patients closely for loss of diazepam efficacy; a diazepam dosage adjustment may be required to obtain the desired therapeutic effect. Diazepam is primarily metabolized by CYP2C19 and CYP3A4, and to a lesser extent by CYP2B6 and CYP2C9. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce CYP2B6 and CYP2C19, and induce and/or inhibit CYP2C9. (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. (Minor) Concomitant use of diclofenac and lumacaftor; ivacaftor may alter diclofenac exposure; monitor for diclofenac efficacy and adverse events. Diclofenac metabolism is primarily mediated by CYP2C9, with CYP3A4 and possibly CYP2C8 playing a lesser role. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C9 and CYP2C8. Although induction of diclofenac's metabolism through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9- and CYP2C8-mediated metabolism is not clear.
    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. (Minor) Concomitant use of diclofenac and lumacaftor; ivacaftor may alter diclofenac exposure; monitor for diclofenac efficacy and adverse events. Diclofenac metabolism is primarily mediated by CYP2C9, with CYP3A4 and possibly CYP2C8 playing a lesser role. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C9 and CYP2C8. Although induction of diclofenac's metabolism through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9- and CYP2C8-mediated metabolism is not clear.
    Dienogest; Estradiol valerate: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    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. (Moderate) Concomitant use of digoxin and lumacaftor; ivacaftor may alter digoxin exposure. Monitor digoxin serum concentrations closely and titrate the dosage to achieve the desired therapeutic effect. Digoxin is a substrate for the P-glycoprotein (P-gp) efflux transporter. In vitro studies suggest lumacaftor; ivacaftor has the potential to both inhibit and induce P-gp.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with ivacaftor may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of ivacaftor could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Ivacaftor is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) Concomitant use of dihydrocodeine with lumacaftor; ivacaftor can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Lumacaftor; ivacaftor is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Dihydroergotamine: (Moderate) Use caution when administering ivacaftor and dihydroergotamine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as dihydroergotamine, can increase dihydroergotamine exposure leading to increased or prolonged therapeutic effects and adverse events, including the risk for ergot toxicity. (Minor) Lumacaftor; ivacaftor may reduce the efficacy of dihydroergotamine by decreasing its systemic exposure; if used together, monitor patients closely for clinical efficacy. Dihydroergotamine is a substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Diltiazem: (Major) Avoid concomitant use and consider alternative therapy when possible. Lumacaftor; ivacaftor may reduce the efficacy of diltiazem by decreasing its systemic exposure. Monitor cardiovascular effects (e.g., heart rate, chest pain, blood pressure) closely and adjust the diltiazem dosage as appropriate. Diltiazem is a substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer. Coadministration of diltiazem and a strong CYP3A inducer resulted in undetectable diltiazem plasma concentrations. (Major) If diltiazem and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Diphenhydramine: (Minor) Concomitant use of diphenhydramine and lumacaftor; ivacaftor may alter diphenhydramine exposure; monitor for diphenhydramine efficacy and adverse events. Diphenhydramine is partially metabolized by CYP2C9 and CYP2C19. In vitro data suggest that lumacaftor; ivacaftor may induce CYP2C19 and induce and/or inhibit CYP2C9. Although induction of diphenhydramine through the CYP2C19 pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear. (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as diphenhydramine. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4. (Moderate) Concomitant use of hydrocodone with lumacaftor; ivacaftor can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. (Minor) Concomitant use of diphenhydramine and lumacaftor; ivacaftor may alter diphenhydramine exposure; monitor for diphenhydramine efficacy and adverse events. Diphenhydramine is partially metabolized by CYP2C9 and CYP2C19. In vitro data suggest that lumacaftor; ivacaftor may induce CYP2C19 and induce and/or inhibit CYP2C9. Although induction of diphenhydramine through the CYP2C19 pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear. (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as diphenhydramine. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
    Diphenhydramine; Ibuprofen: (Minor) Concomitant use of diphenhydramine and lumacaftor; ivacaftor may alter diphenhydramine exposure; monitor for diphenhydramine efficacy and adverse events. Diphenhydramine is partially metabolized by CYP2C9 and CYP2C19. In vitro data suggest that lumacaftor; ivacaftor may induce CYP2C19 and induce and/or inhibit CYP2C9. Although induction of diphenhydramine through the CYP2C19 pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear. (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. (Minor) Lumacaftor; ivacaftor may alter the systemic exposure of ibuprofen. If used together, a dose adjustment of ibuprofen may be required to obtain the desired therapeutic effect and/or avoid adverse effects. Do not exceed the recommended maximum dose. Ibuprofen is a CYP2C9 substrate, and in vitro studies suggest that lumacaftor; ivacaftor has the potential to induce or inhibit CYP2C9.
    Diphenhydramine; Naproxen: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of naproxen and lumacaftor; ivacaftor may alter naproxen exposure; caution and monitoring are advised if these drugs are administered together. Naproxen is a substrate of CYP2C9 (primary) and CYP2C8. In vitro data suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C8 and CYP2C9. The net effect on these substrates is not clear, but their exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events. (Minor) Concomitant use of diphenhydramine and lumacaftor; ivacaftor may alter diphenhydramine exposure; monitor for diphenhydramine efficacy and adverse events. Diphenhydramine is partially metabolized by CYP2C9 and CYP2C19. In vitro data suggest that lumacaftor; ivacaftor may induce CYP2C19 and induce and/or inhibit CYP2C9. Although induction of diphenhydramine through the CYP2C19 pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear. (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) Concomitant use of diphenhydramine and lumacaftor; ivacaftor may alter diphenhydramine exposure; monitor for diphenhydramine efficacy and adverse events. Diphenhydramine is partially metabolized by CYP2C9 and CYP2C19. In vitro data suggest that lumacaftor; ivacaftor may induce CYP2C19 and induce and/or inhibit CYP2C9. Although induction of diphenhydramine through the CYP2C19 pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear. (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) Lumacaftor; ivacaftor may reduce the efficacy of disopyramide by significantly decreasing its systemic exposure. If used together, monitor disopyramide plasma concentrations and adjust the dose as appropriate. Disopyramide is a CYP3A4 substrate. Lumacaftor is a strong inducer of CYP3A. (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) Lumacaftor; ivacaftor may reduce the efficacy of disulfiram by decreasing its systemic exposure. If used together, monitor patients closely for loss of disulfiram efficacy; a disulfiram dosage adjustment may be required to obtain the desired therapeutic effect. Do not exceed the maximum recommended dose. Disulfiram is primarily metabolized by CYP3A4 and is also a substrate of CYP2B6. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor may induce CYP2B6.
    Docetaxel: (Major) Avoid coadministration of docetaxel with lumacaftor; ivacaftor due to decreased plasma concentrations of docetaxel. Docetaxel is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Concomitant use with other strong CYP3A4 inducers increased docetaxel metabolism by 2.6-fold to 32-fold.
    Dolasetron: (Minor) Lumacaftor; ivacaftor may reduce the efficacy of dolasetron by decreasing its systemic exposure. Dolasetron is partially metabolized by CYP3A4. Lumacaftor is a strong inducer of CYP3A. When oral dolasetron was administered with rifampin, another strong CYP3A inducer, for 7 days, the AUC and Cmax of hydrodolasetron decreased by 28% and 17%, respectively. Of note, rifampin is also a weak inducer of CYP2D6, the primary substrate of dolasetron, but lumacaftor; ivacaftor does not affect CYP2D6.
    Dolutegravir: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with lumacaftor; ivacaftor; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Dolutegravir is partially metabolized by CYP3A and, in vitro, is a substrate for the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggest lumacaftor; ivacaftor may also induce and/or inhibit P-gp.
    Dolutegravir; Lamivudine: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with lumacaftor; ivacaftor; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Dolutegravir is partially metabolized by CYP3A and, in vitro, is a substrate for the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggest lumacaftor; ivacaftor may also induce and/or inhibit P-gp.
    Dolutegravir; Rilpivirine: (Severe) Concomitant use of lumacaftor; ivacaftor and rilpivirine is contraindicated, as significant decreases in rilpivirine plasma concentrations may occur. This may result in loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Rilpivirine is primarily metabolize by CYP3A, and lumacaftor is a strong CYP3A inducer. (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with lumacaftor; ivacaftor; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Dolutegravir is partially metabolized by CYP3A and, in vitro, is a substrate for the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggest lumacaftor; ivacaftor may also induce and/or inhibit P-gp.
    Donepezil: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of donepezil by decreasing its systemic exposure. Donepezil is a primary substrate of CYP3A4. Lumacaftor is a strong inducer of CYP3A.
    Donepezil; Memantine: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of donepezil by decreasing its systemic exposure. Donepezil is a primary substrate of CYP3A4. Lumacaftor is a strong inducer of CYP3A.
    Doravirine: (Severe) Concurrent administration of doravirine and lumacaftor; ivacaftor is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; lumacaftor is a strong CYP3A4 inducer.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Severe) Concurrent administration of doravirine and lumacaftor; ivacaftor is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; lumacaftor is a strong CYP3A4 inducer. (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) Although the clinical significance of this interaction is unknown, concurrent use of tenofovir, PMPA and lumacaftor; ivacaftor may alter tenofovir exposure; caution and close monitoring are advised if these drugs are used together. Tenofovir is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events.
    Doxepin: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of doxepin by decreasing its systemic exposure. If used together, monitor patients for doxepin efficacy; a doxepin dosage adjustment may be required to obtain the desired therapeutic effect. Do not exceed the recommended maximum dosage. CYP2C19 and CYP2C9 both play a role in doxepin's metabolism. In vitro data suggest that lumacaftor; ivacaftor may induce CYP2C19 and induce and/or inhibit CYP2C9. (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) Concomitant administration of doxorubicin and lumacaftor; ivacaftor may alter the exposure of doxorubicin; avoid concurrent use. Doxorubicin is a major substrate of CYP3A4 and P-glycoprotein (P-gp). Lumacaftor is a strong CYP3A inducer; in vitro data also suggest lumacaftor; ivacaftor may induce and/or inhibit P-gp. (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: (Moderate) Use caution if coadministration of dronabinol with lumacaftor; ivacaftor is necessary, and monitor for changes in the efficacy or adverse effect profile of dronabinol (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, while lumacaftor is a strong CYP3A4 inducer. Concomitant use may result in altered plasma concentrations of dronabinol. (Minor) Use caution if coadministration of dronabinol with ivacaftor is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; ivacaftor is a weak inhibitor of CYP3A4 and a weak CYP2C9 inhibitor in vitro. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Dronedarone: (Major) If dronedarone and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and dronedarone is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. (Major) Lumacaftor; ivacaftor may reduce the efficacy of dronedarone by decreasing its systemic exposure; avoid concomitant use. Dronedarone is a substrate and moderate inhibitor of CYP3A. Ivacaftor is a sensitive CYP3A substrate and lumacaftor is a strong CYP3A inducer. Induction of dronedarone through the CYP3A pathway may lead to decreased drug efficacy. Although ivacaftor exposure may increase when given with a CYP3A inhibitor, ivacaftor; lumacaftor dosage adjustments are not recommended with concomitant use of a moderate CYP3A inducer such as dronedarone.
    Drospirenone: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Drospirenone; Estradiol: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Drospirenone; Ethinyl Estradiol: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Duvelisib: (Major) Administer ivacaftor at the usual recommended dose but reduce the frequency to once daily if coadministered with duvelisib. Ivacaftor is a sensitive CYP3A substrate and duvelisib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. (Major) Avoid coadministration of duvelisib with lumacaftor; ivacaftor. Coadministration may decrease the exposure of duvelisib, which may reduce the efficacy of duvelisib. Duvelisib is a CYP3A substrate; lumacaftor; ivacaftor is a strong CYP3A inducer. In drug interaction studies, coadministration of duvelisib with another strong CYP3A inducer for 7 days decreased duvelisib Cmax and AUC by 66% and 82%, respectively.
    Efavirenz: (Major) Lumacaftor; ivacaftor can reduce the efficacy of efavirenz by decreasing its systemic exposure. If these agents must be used together, monitor efavirenz plasma concentrations; an efavirenz dosage adjustment may be required to obtain the desired therapeutic effect. Efavirenz is a substrate of CYP3A4 and CYP2B6. Lumacaftor is a strong CYP3A inducer, and in vitro data suggest that lumacaftor may also induce CYP2B6. When efavirenz is coadministered with rifampin, a strong CYP3A4 and CYP2B6 inducer, it is recommended to increase efavirenz from 600 mg/day to 800 mg/day (patients >= 50 kg).
    Efavirenz; Emtricitabine; Tenofovir: (Major) Lumacaftor; ivacaftor can reduce the efficacy of efavirenz by decreasing its systemic exposure. If these agents must be used together, monitor efavirenz plasma concentrations; an efavirenz dosage adjustment may be required to obtain the desired therapeutic effect. Efavirenz is a substrate of CYP3A4 and CYP2B6. Lumacaftor is a strong CYP3A inducer, and in vitro data suggest that lumacaftor may also induce CYP2B6. When efavirenz is coadministered with rifampin, a strong CYP3A4 and CYP2B6 inducer, it is recommended to increase efavirenz from 600 mg/day to 800 mg/day (patients >= 50 kg). (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) Although the clinical significance of this interaction is unknown, concurrent use of tenofovir, PMPA and lumacaftor; ivacaftor may alter tenofovir exposure; caution and close monitoring are advised if these drugs are used together. Tenofovir is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Lumacaftor; ivacaftor can reduce the efficacy of efavirenz by decreasing its systemic exposure. If these agents must be used together, monitor efavirenz plasma concentrations; an efavirenz dosage adjustment may be required to obtain the desired therapeutic effect. Efavirenz is a substrate of CYP3A4 and CYP2B6. Lumacaftor is a strong CYP3A inducer, and in vitro data suggest that lumacaftor may also induce CYP2B6. When efavirenz is coadministered with rifampin, a strong CYP3A4 and CYP2B6 inducer, it is recommended to increase efavirenz from 600 mg/day to 800 mg/day (patients >= 50 kg). (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) Although the clinical significance of this interaction is unknown, concurrent use of tenofovir, PMPA and lumacaftor; ivacaftor may alter tenofovir exposure; caution and close monitoring are advised if these drugs are used together. Tenofovir is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events.
    Elagolix: (Moderate) Concomitant use of elagolix and lumacaftor; ivacaftor may result in decreased concentrations of elagolix; monitor for decreased efficacy with coadministration. Elagolix is a CYP3A substrate; lumacaftor; ivacaftor is a strong inducer of CYP3A.
    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. (Minor) Lumacaftor; ivacaftor may alter the systemic exposure of eletriptan. Eletriptan is a primarily metabolized by CYP3A4 and is a P-glycoprotein (P-gp) substrate. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest lumacaftor; ivacaftor may induce and/or inhibit P-gp. Although induction of eletriptan through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. Monitor the patient for decreased eletriptan efficacy or increased or prolonged therapeutic effects and adverse events.
    Eliglustat: (Major) Coadministration of eliglustat and lumacaftor; ivacaftor significantly decreases eliglustat exposure; coadministration is not recommended in patients of any metabolizer status. Lumacaftor is a strong CYP3A inducer, and eliglustat is a CYP3A substrate. During clinical trials, systemic exposures (Cmax and AUC) of eliglustat decreased by approximately 90% in EMs and IMs after coadministration of eliglustat 127 mg PO twice daily with another strong CYP3A inducer, rifampin 600 mg PO once daily. Of note, the only FDA-approved dose of eliglustat is 84 mg. Additionally, systemic exposures decreased by approximately 95% after coadministration of eliglustat 84 mg PO twice daily with rifampin 600 mg PO once daily in PMs. Eliglustat is also a substrate of the drug transporter P-glycoprotein (P-gp), and in vitro data suggests lumacaftor; ivacaftor may induce and/or inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear. (Major) In poor CYP2D6 metabolizers (PMs), coadministration of ivacaftor and eliglustat is not recommended. In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. Ivacaftor and its primary metabolite M1 are considered weak CYP3A inhibitors; eliglustat is a CYP3A and CYP2D6 substrate. Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration of eliglustat with CYP3A inhibitors may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias) in these patients.
    Elvitegravir: (Major) Concomitant use of lumacaftor; ivacaftor and elvitegravir is not recommended, as significant decreases in elvitegravir plasma concentrations may occur. This may result in loss of virologic response and possible resistance. Elvitegravir is metabolized by CYP3A, and lumacaftor is a strong CYP3A inducer.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Concomitant use of lumacaftor; ivacaftor and elvitegravir is not recommended, as significant decreases in elvitegravir plasma concentrations may occur. This may result in loss of virologic response and possible resistance. Elvitegravir is metabolized by CYP3A, and lumacaftor is a strong CYP3A inducer. (Major) If cobicistat and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of cobicistat; avoid concurrent use if possible. If concomitant use of cobicistat is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when cobicistat is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking cobicistat, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking cobicistat. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Cobicistat is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of cobicistat and decrease its therapeutic efficacy. Although cobicistat is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Concomitant use of lumacaftor; ivacaftor and elvitegravir is not recommended, as significant decreases in elvitegravir plasma concentrations may occur. This may result in loss of virologic response and possible resistance. Elvitegravir is metabolized by CYP3A, and lumacaftor is a strong CYP3A inducer. (Major) If cobicistat and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of cobicistat; avoid concurrent use if possible. If concomitant use of cobicistat is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when cobicistat is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking cobicistat, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking cobicistat. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Cobicistat is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of cobicistat and decrease its therapeutic efficacy. Although cobicistat is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ivacaftor. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (Minor) Although the clinical significance of this interaction is unknown, concurrent use of tenofovir, PMPA and lumacaftor; ivacaftor may alter tenofovir exposure; caution and close monitoring are advised if these drugs are used together. Tenofovir is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Severe) Concomitant use of lumacaftor; ivacaftor and rilpivirine is contraindicated, as significant decreases in rilpivirine plasma concentrations may occur. This may result in loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Rilpivirine is primarily metabolize by CYP3A, and lumacaftor is a strong CYP3A inducer.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Severe) Concomitant use of lumacaftor; ivacaftor and rilpivirine is contraindicated, as significant decreases in rilpivirine plasma concentrations may occur. This may result in loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Rilpivirine is primarily metabolize by CYP3A, and lumacaftor is a strong CYP3A inducer. (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) Although the clinical significance of this interaction is unknown, concurrent use of tenofovir, PMPA and lumacaftor; ivacaftor may alter tenofovir exposure; caution and close monitoring are advised if these drugs are used together. Tenofovir is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected leading to decreased efficacy or 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. (Minor) Although the clinical significance of this interaction is unknown, concurrent use of tenofovir, PMPA and lumacaftor; ivacaftor may alter tenofovir exposure; caution and close monitoring are advised if these drugs are used together. Tenofovir is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events.
    Enalapril; Felodipine: (Moderate) Concomitant use of felodipine and lumacaftor; ivacaftor may decrease the exposure and therapeutic efficacy of felodipine. If used together, monitor blood pressure closely; the dosage requirements of felodipine may be increased. Felodipine is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer. (Moderate) Use caution when administering ivacaftor and felodipine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as felodipine, can increase felodipine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Encorafenib: (Major) Avoid coadministration of encorafenib and lumacaftor; ivacaftor due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; lumacaftor is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction. (Major) Coadministration of encorafenib with ivacaftor may result in increased toxicity or decreased efficacy of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Entrectinib: (Major) Avoid coadministration of entrectinib with lumacaftor; ivacaftor due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
    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. (Major) Coadministration of lumacaftor; ivacaftor with enzalutamide is not recommended due to decreased plasma concentrations of both enzalutamide and ivacaftor, which may compromise efficacy. Enzalutamide is a CYP3A4 substrate and strong inducer; ivacaftor is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%. Coadministration with a strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold.
    Eplerenone: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of eplerenone by decreasing its systemic exposure. If used together, monitor blood pressure closely. Eplerenone is a CYP3A4 substrate. Lumacaftor is a strong CYP3A inducer.
    Eravacycline: (Major) Increase the dose of eravacycline to 1.5 mg/kg IV every 12 hours when coadministered with a strong CYP3A4 inducer, such as lumacaftor. Concomitant use of strong CYP3A4 inducers decreases the exposure of eravacycline, which may reduce its efficacy. When eravacycline was administered with a strong CYP3A4/3A5 inducer, the eravacycline AUC was decreased by 35% and its clearance was increased by 54%.
    Erdafitinib: (Major) Avoid coadministration of erdafitinib and lumacaftor; ivacaftor due to the risk of decreased plasma concentrations of erdafitinib resulting in decreased efficacy. Erdafitinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer.
    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. (Minor) Lumacaftor; ivacaftor may reduce the efficacy of ergotamine by decreasing its systemic exposure; if used together, monitor patients closely for clinical efficacy. Ergotamine is a substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Erlotinib: (Major) Avoid coadministration of erlotinib with lumacaftor; ivacaftor if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals as tolerated (maximum dose, 450 mg). Erlotinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased erlotinib exposure by 58% to 80%.
    Erythromycin: (Major) If erythromcyin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and erythromcyin is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of erythromycin; avoid concurrent use if possible. If concomitant use of erythromycin is necessary, monitor for microbiological activity and signs and symptoms of lumacaftor; ivacaftor toxicity. Erythromycin is a substrate and inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. The enzyme induction effects of lumacaftor may decrease the systemic exposure of erythromycin and decrease its therapeutic efficacy. In addition, the inhibitory effects of erythromycin may increase the systemic exposure of ivacaftor, although no dosage adjustment is recommended for moderate CYP3A inhibition.
    Erythromycin; Sulfisoxazole: (Major) If erythromcyin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and erythromcyin is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of erythromycin; avoid concurrent use if possible. If concomitant use of erythromycin is necessary, monitor for microbiological activity and signs and symptoms of lumacaftor; ivacaftor toxicity. Erythromycin is a substrate and inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. The enzyme induction effects of lumacaftor may decrease the systemic exposure of erythromycin and decrease its therapeutic efficacy. In addition, the inhibitory effects of erythromycin may increase the systemic exposure of ivacaftor, although no dosage adjustment is recommended for moderate CYP3A inhibition.
    Escitalopram: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of escitalopram by decreasing its systemic exposure. If used together, a higher dose of escitalopram may be required to obtain the desired therapeutic effect. Do not exceed the recommended maximum dose. Escitalopram is a CYP3A and CYP2C19 substrate. Lumacaftor; ivacaftor is a strong inducer of CYP3A and has the potential to induce CYP2C19.
    Esomeprazole: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of esomeprazole by substantially decreasing its systemic exposure. If used together, an esomeprazole dosage adjustment may be necessary to obtain the desired therapeutic effect. Esomeprazole is a CYP3A4 and CYP2C19 substrate. Lumacaftor; ivacaftor is a strong inducer of CYP3A; in vitro data suggests is also has the potential to induce CYP2C19.
    Esomeprazole; Naproxen: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of naproxen and lumacaftor; ivacaftor may alter naproxen exposure; caution and monitoring are advised if these drugs are administered together. Naproxen is a substrate of CYP2C9 (primary) and CYP2C8. In vitro data suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C8 and CYP2C9. The net effect on these substrates is not clear, but their exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events. (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of esomeprazole by substantially decreasing its systemic exposure. If used together, an esomeprazole dosage adjustment may be necessary to obtain the desired therapeutic effect. Esomeprazole is a CYP3A4 and CYP2C19 substrate. Lumacaftor; ivacaftor is a strong inducer of CYP3A; in vitro data suggests is also has the potential to induce CYP2C19. (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as naproxen. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
    Estazolam: (Moderate) Use caution when administering ivacaftor and estazolam concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as estazolam, can increase estazolam exposure leading to increased or prolonged therapeutic effects and adverse events. (Minor) Lumacaftor; ivacaftor is expected to decrease the systemic exposure of estazolam. If used together, monitor for clinical efficacy. In vitro, estazolam is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer.
    Estradiol Cypionate; Medroxyprogesterone: (Major) Avoid concomitant use of medroxyprogesterone and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease medroxyprogesterone, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative and/or additional methods of birth control. In addition, concomitant use of hormonal contraceptives and lumacaftor; ivacaftor may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia). Patients taking medroxyprogesterone for other indications should be monitored for clinical efficacy of the progestin. Medroxyprogesterone is primarily metabolized in vitro via CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Estradiol; Levonorgestrel: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Estradiol; Norethindrone: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Estradiol; Norgestimate: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Eszopiclone: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of eszopiclone by decreasing its systemic exposure. If used together, monitor for efficacy and consider increasing the eszopiclone dosage as appropriate. Eszopiclone is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer. Coadministration of racemic zopiclone and rifampicin, another strong CYP3A inducer, decreased the exposure of zopiclone by 80%; a similar effect would be expected with eszopiclone.
    Ethinyl Estradiol: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Ethinyl Estradiol; Desogestrel: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Ethinyl Estradiol; Ethynodiol Diacetate: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Ethinyl Estradiol; Etonogestrel: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Ethinyl Estradiol; Levonorgestrel: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Ethinyl Estradiol; Norelgestromin: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Ethinyl Estradiol; Norethindrone: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Ethinyl Estradiol; Norgestimate: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Ethinyl Estradiol; Norgestrel: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Ethosuximide: (Major) Concomitant use of ethosuximide and lumacaftor; ivacaftor is not recommended. Lumacaftor; ivacaftor may decrease the systemic exposure of ethosuximide, a narrow therapeutic index drug. Ethosuxamide is a substrate of CYP3A, and lumacaftor; ivacaftor is a potent CYP3A inducer.
    Etonogestrel: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Etoposide, VP-16: (Moderate) Concomitant use of etoposide, VP-16 and lumacaftor; ivacaftor may alter the therapeutic effects of etoposide; caution and close monitoring are advised if these drugs are used together. Etoposide is a substrate of CYP3A4 and the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest lumacaftor; ivacaftor may induce and/or inhibit P-gp. Although induction of etoposide through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. Monitor the patient closely for chemotherapeutic efficacy and adverse effects.
    Etravirine: (Major) Lumacaftor; ivacaftor may reduce the efficacy of etravirine by significantly decreasing its systemic exposure; avoid concurrent use if possible. If concomitant use of etravirine is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust drug dosages as necessary. Etravirine is a substrate of CYP3A4, CYP2C9, and CYP2C19 and a moderate inducer of CYP3A4. Ivacaftor is a sensitive CYP3A substrate and lumacaftor is a strong CYP3A inducer; in vitro data also suggest lumacaftor; ivacaftor may induce CYP2C19 and induce and/or inhibit CYP2C9. Although induction of etravirine through the CYP3A and CYP2C19 pathways may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear. Although ivacaftor exposure could theoretically be further decreased when given with another CYP3A inducer, ivacaftor; lumacaftor dosage adjustments are not recommended with concomitant use of a moderate CYP3A inducer such as etravirine.
    Everolimus: (Major) Depending on the indication, coadministration of lumacaftor; ivacaftor with everolimus may need to be avoided or an everolimus dose adjustment may be necessary due to decreased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), avoid concomitant use where alternatives exist. If concurrent use cannot be avoided, double the daily dose of everolimus using increments of 5 mg or less. Resume the previous dose after the inducer has been discontinued for 5 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial seizures, double the daily dose of everolimus using increments of 5 mg or less; multiple increments may be required. Addition of a second strong CYP3A4 inducer may not require additional dosage modifications. Assess trough concentrations when initiating and discontinuing the inducer. Subsequent dosing should be guided by therapeutic drug monitoring. Resume the previous dose of everolimus once all inducers are discontinued for 5 days. Coadministration of lumacaftor; ivacaftor with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. (Moderate) Monitor for increased everolimus adverse reactions if coadministered with ivacaftor as concurrent use may increase everolimus exposure. Everolimus is a substrate of CYP3A4 and P-gp with a narrow therapeutic index; ivacaftor is an inhibitor of CYP3A4 and P-gp.
    Exemestane: (Major) If coadministration of exemestane with lumacaftor; ivacaftor is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exemestane exposure by 54%.
    Ezetimibe; Simvastatin: (Moderate) Monitor for reduced efficacy of simvastatin if coadministered with lumacaftor; ivacaftor. Lumacaftor; ivacaftor may reduce the systemic exposure of simvastatin. Simvastatin is a sensitive substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer. (Minor) Use caution when administering ivacaftor and simvastatin concurrently. Coadministration of ivacaftor with simvastatin may increase simvastatin exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined. Simvastatin is a sensitive CYP3A4 substrate; ivacaftor is a weak CYP3A4 inhibitor.
    Famotidine; Ibuprofen: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as ibuprofen. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined. (Minor) Lumacaftor; ivacaftor may alter the systemic exposure of ibuprofen. If used together, a dose adjustment of ibuprofen may be required to obtain the desired therapeutic effect and/or avoid adverse effects. Do not exceed the recommended maximum dose. Ibuprofen is a CYP2C9 substrate, and in vitro studies suggest that lumacaftor; ivacaftor has the potential to induce or inhibit CYP2C9.
    Fedratinib: (Major) Avoid coadministration of fedratinib with lumacaftor; ivacaftor as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. The coadministration of fedratinib with a strong CYP3A4 inducer has not been evaluated. (Major) If fedratinib 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 fedratinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Felodipine: (Moderate) Concomitant use of felodipine and lumacaftor; ivacaftor may decrease the exposure and therapeutic efficacy of felodipine. If used together, monitor blood pressure closely; the dosage requirements of felodipine may be increased. Felodipine is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer. (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) Lumacaftor; ivacaftor may induce the metabolism of fentanyl, which could result in lack of therapeutic efficacy or the development of an abstinence syndrome in patients who are physically dependent on opioids. If coadministration is necessary, monitor the patient closely at frequent intervals for appropriate pain control and signs of opioid withdrawal. Consider fentanyl dosage adjustments until stable drug effects are achieved. If lumacaftor; ivacaftor is subsequently discontinued, fentanyl plasma concentrations will increase. Monitor the patient closely at frequent intervals for oversedation and respiratory depression and reduce the fentanyl dosage as appropriate. Fentanyl is a substrate of CYP3A4 and P-glycoprotein (P-gp). Lumacaftor is a strong CYP3A inducer; in vitro data also suggestion lumacaftor; ivacaftor may induce and/or inhibit P-gp. Although induction of fentanyl through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. (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) Although the clinical significance of this interaction is unknown, concurrent use of fexofenadine and lumacaftor; ivacaftor may alter fexofenadine exposure. Fexofenadine is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events.
    Fexofenadine; Pseudoephedrine: (Minor) Although the clinical significance of this interaction is unknown, concurrent use of fexofenadine and lumacaftor; ivacaftor may alter fexofenadine exposure. Fexofenadine is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events.
    Flibanserin: (Moderate) The concomitant use of flibanserin and multiple weak CYP3A4 inhibitors, including ivacaftor, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the risks of combination therapy with multiple weak CYP3A4 inhibitors and flibanserin should be discussed with the patient.
    Fluconazole: (Major) If fluconazole and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate. Coadministration with fluconazole, a moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold.
    Fluoxetine: (Minor) Although an interaction between ivacaftor and fluoxetine is possible, the clinical impact of this interaction has not yet been determined. Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates. Fluoxetine is partially metabolized by CYP2C9, but it is also a substrate for at least 2 other enzymes. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may possibly lead to increased exposure to fluoxetine; however, because fluoxetine has multiple metabolic pathways, the clinical impact of this inhibition is not clear. In addition, ivacaftor is a CYP3A substrate, and fluoxetine is a mild CYP3A inhibitor. Co-administration may lead to increased ivacaftor exposure. (Minor) Concomitant use of fluoxetine and lumacaftor; ivacaftor may alter fluoxetine exposure; caution and close monitoring are advised if these drugs are used together. Fluoxetine is a substrate of CYP2C9 and CYP2C19. In vitro data suggest that lumacaftor; ivacaftor may induce CYP2C19 and induce and/or inhibit CYP2C9. Although induction of fluoxetine through the CYP2C19 pathway could potentially lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear. Monitor the patient for decreased fluoxetine efficacy or increased or prolonged therapeutic effects and adverse events. Of note, norfluoxetine, the active metabolite of fluoxetine, is a moderate CYP3A inhibitor. Although lumacaftor; ivacaftor is a primary substrate of CYP3A, lumacaftor; ivacaftor dosage adjustment is not required.
    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. (Minor) Concomitant use of fluoxetine and lumacaftor; ivacaftor may alter fluoxetine exposure; caution and close monitoring are advised if these drugs are used together. Fluoxetine is a substrate of CYP2C9 and CYP2C19. In vitro data suggest that lumacaftor; ivacaftor may induce CYP2C19 and induce and/or inhibit CYP2C9. Although induction of fluoxetine through the CYP2C19 pathway could potentially lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear. Monitor the patient for decreased fluoxetine efficacy or increased or prolonged therapeutic effects and adverse events. Of note, norfluoxetine, the active metabolite of fluoxetine, is a moderate CYP3A inhibitor. Although lumacaftor; ivacaftor is a primary substrate of CYP3A, lumacaftor; ivacaftor dosage adjustment is not required.
    Flurazepam: (Minor) Lumacaftor; ivacaftor is expected to decrease the systemic exposure of flurazepam. If used together, monitor for clinical efficacy. Flurazepam is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer.
    Flurbiprofen: (Minor) Although the clinical significance of this interaction is unknown, concurrent use of flurbiprofen and lumacaftor; ivacaftor may alter flurbiprofen exposure; caution and monitoring are advised if these drugs are used together. Flurbiprofen is a substrate of CYP2C9. In vitro data suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C9. The net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear, but CYP2C9 substrate exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events. (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.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Lumacaftor; ivacaftor may alter the exposure of umeclidinium; vilanterol. In vitro data suggest vilanterol is a primary substrate of CYP3A4; both vilanterol and umeclidinium are substrates for P-glycoprotein (P-gp). Lumacaftor is a strong CYP3A inducer; in vitro data suggest lumacaftor; ivacaftor may also induce and/or inhibit P-gp. Although induction of vilanterol metabolism through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport and its effect on umeclidinium; vilanterol is not clear. Monitor the patient for decreased beta-agonist efficacy or increased or prolonged beta-agonist and/or anticholinergic effects and adverse events. (Minor) Lumacaftor; ivacaftor may alter the exposure of umeclidinium. Umeclidinium is a substrate for P-glycoprotein (P-gp); in vitro data suggest lumacaftor; ivacaftor may induce and/or inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport and its effect on umeclidinium is not clear. Monitor the patient for therapeutic efficacy and increased or prolonged anticholinergic effects.
    Fluticasone; Vilanterol: (Moderate) Lumacaftor; ivacaftor may alter the exposure of umeclidinium; vilanterol. In vitro data suggest vilanterol is a primary substrate of CYP3A4; both vilanterol and umeclidinium are substrates for P-glycoprotein (P-gp). Lumacaftor is a strong CYP3A inducer; in vitro data suggest lumacaftor; ivacaftor may also induce and/or inhibit P-gp. Although induction of vilanterol metabolism through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport and its effect on umeclidinium; vilanterol is not clear. Monitor the patient for decreased beta-agonist efficacy or increased or prolonged beta-agonist and/or anticholinergic effects and adverse events.
    Fluvastatin: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as fluvastatin. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
    Fluvoxamine: (Major) If fluvoxamine and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Fosamprenavir: (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of fosamprenavir; avoid concurrent use if possible. If concomitant use of fosamprenavir is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when fosamprenavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking fosamprenavir, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking fosamprenavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Fosamprenavir is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of fosamprenavir and decrease its therapeutic efficacy. Although fosamprenavir is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold. Lastly, fosamprenavir is also a substrate of CYP2C9 and the drug transporter P-glycoprotein (P-gp), and lumacaftor; ivacaftor has the potential to both induce and inhibit CYP2C9 and P-gp. The net effect on CYP2C9 and P-gp substrates is not clear, but their exposure may be affected. (Moderate) Use caution when administering ivacaftor and fosamprenavir concurrently; the clinical effect of this interaction is unknown. Ivacaftor is a CYP3A substrate, and fosamprenavir is a CYP3A inhibitor and can also act as an inducer. Co-administration may lead to altered ivacaftor exposure. Ivacaftor is also an inhibitor of CYP3A , CYP2C9, and P-glycoprotein (Pgp); fosamprenavir is metabolized by CYP3A and CYP2C9 and is a substrate of Pgp. Co-administration may increase fosamprenavir exposure leading to increased or prolonged therapeutic effects and adverse events.
    Fosphenytoin: (Major) Coadministration of ivacaftor with fosphenytoin is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold. (Major) Concomitant use of phenytoin or fosphenytoin and lumacaftor; ivacaftor is not recommended. Phenytoin may decrease the therapeutic effect of lumacaftor; ivacaftor by significantly decreasing the systemic exposure of ivacaftor. Ivacaftor is a substrate of CYP3A, and phenytoin is a potent CYP3A inducer. In a pharmacokinetic study, coadministration of lumacaftor; ivacaftor with rifampin, another potent CYP3A inducer, decreased ivacaftor exposure by 57%, with minimal effect on the exposure of lumacaftor. In vitro studies suggest lumacaftor; ivacaftor has the potential to induce CYP2C9 and CYP2C19; inhibition CYP2C9 has also been observed. Because phenytoin is a substrate of these enzymes, altered phenytoin exposure may occur.
    Fostamatinib: (Major) Avoid the concomitant use of fostamatinib with lumacaftor; ivacaftor. Concomitant use of fostamatinib with a strong CYP3A4 inducer decreases exposure to the major active metabolite, R406. R406 is extensively metabolized by CYP3A4; lumacaftor is a strong CYP3A4 inducer. Concomitant use of fostamatinib with another strong CYP3A4 inducer decreased R406 AUC by 75% and Cmax by 59%.
    Galantamine: (Minor) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of galantamine. Galantamine is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer.
    Gefitinib: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with lumacaftor; ivacaftor is necessary. If lumacaftor; ivacaftor is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
    Gilteritinib: (Major) Avoid coadministration of gilteritinib and lumacaftor; ivacaftor due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; lumacaftor; ivacaftor is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
    Glasdegib: (Major) Avoid coadministration of glasdegib and lumacaftor; ivacaftor due to the potential for decreased glasdegib exposure and risk of decreased efficacy. Glasdegib is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the glasdegib AUC by 70% in a drug interaction study.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with coadministration of glecaprevir and lumacaftor; ivacaftor as decreased plasma concentrations of glecaprevir may occur resulting in the potential loss of efficacy of glecaprevir. Glecaprevir is a substrate of CYP3A4 and P-glycoprotein (P-gp); lumacaftor is a CYP3A4 inducer as well as an inhibitor and inducer of P-gp. The net effect on P-gp substrates is unknown. (Moderate) Caution is advised with coadministration of pibrentasvir and lumacaftor; ivacaftor as altered plasma concentrations of pibrentasvir may occur resulting in the potential loss of efficacy of pibrentasvir and/or increased adverse effects. Pibrentasvir is a substrate of P-glycoprotein (P-gp); lumacaftor is an inhibitor and inducer of P-gp. The net effect on P-gp substrates is unknown. (Moderate) Caution is advised with the coadministration of glecaprevir and ivacaftor as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of P-glycoprotein (P-gp); ivacaftor is a P-gp inhibitor.
    Glimepiride: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of glimepiride by decreasing its systemic exposure. If used together, monitor blood glucose concentrations closely; a glimepiride dosage adjustment may be required to obtain the desired therapeutic effect. Glimepiride is a CYP2C9 substrate; in vitro studies suggest lumacaftor; ivacaftor has the potential to induce and inhibit CYP2C9. (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) Lumacaftor; ivacaftor may reduce the efficacy of glimepiride by decreasing its systemic exposure. If used together, monitor blood glucose concentrations closely; a glimepiride dosage adjustment may be required to obtain the desired therapeutic effect. Glimepiride is a CYP2C9 substrate; in vitro studies suggest lumacaftor; ivacaftor has the potential to induce and inhibit CYP2C9. (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: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rosiglitazone and lumacaftor; ivacaftor may alter the therapeutic effects of rosiglitazone; caution and close monitoring of blood glucose are advised if these drugs are administered together. Rosiglitazone is a substrate of CYP2C8 and CYP2C9. In vitro data suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C8 and CYP2C9. The net effect on these substrates is not clear, but their exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events. (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of glimepiride by decreasing its systemic exposure. If used together, monitor blood glucose concentrations closely; a glimepiride dosage adjustment may be required to obtain the desired therapeutic effect. Glimepiride is a CYP2C9 substrate; in vitro studies suggest lumacaftor; ivacaftor has the potential to induce and inhibit CYP2C9. (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: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of glipizide by decreasing glipizide's systemic exposure. If used together, monitor blood glucose concentrations closely; the antidiabetic agent may require a dosage adjustment to obtain the desired therapeutic effect. Glipizide is a CYP2C9 substrate; in vitro studies suggest lumacaftor; ivacaftor has the potential to induce and inhibit CYP2C9. Of note, the metabolism of metformin is not affected. (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: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of glipizide by decreasing glipizide's systemic exposure. If used together, monitor blood glucose concentrations closely; the antidiabetic agent may require a dosage adjustment to obtain the desired therapeutic effect. Glipizide is a CYP2C9 substrate; in vitro studies suggest lumacaftor; ivacaftor has the potential to induce and inhibit CYP2C9. Of note, the metabolism of metformin is not affected. (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. (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of glyburide by decreasing glyburide's systemic exposure. If used together, monitor blood glucose concentrations closely; the antidiabetic agent may require a dosage adjustment to obtain the desired therapeutic effect. Glyburide is a CYP2C9 substrate; in vitro studies suggest lumacaftor; ivacaftor has the potential to induce and inhibit CYP2C9. Of note, the metabolism of metformin is not affected.
    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. (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of glyburide by decreasing glyburide's systemic exposure. If used together, monitor blood glucose concentrations closely; the antidiabetic agent may require a dosage adjustment to obtain the desired therapeutic effect. Glyburide is a CYP2C9 substrate; in vitro studies suggest lumacaftor; ivacaftor has the potential to induce and inhibit CYP2C9. Of note, the metabolism of metformin is not affected.
    Grapefruit juice: (Major) It may be prudent to avoid consumption of grapefruit or grapefruit juice with lumacaftor; ivacaftor if possible. If a patient has taken lumacaftor; ivacaftor uninterrupted for more than 1 week, grapefruit consumption may be acceptable. However, when initiating lumacaftor; ivacaftor, avoid consumption of grapefruit and/or its juice for a minimum of 1 week. If lumacaftor; ivacaftor therapy is interrupted for more than 1 week, consumption of grapefruit and/or its juice should be avoided until lumacaftor; ivacaftor therapy is reinstated for a minimum of 1 week. The 1-week lead-in period allows for lumacaftor's induction of CYP3A to reach steady state. Grapefruit is a potent CYP3A inhibitor, ivacaftor is a CYP3A substrate, and lumacaftor is a potent CYP3A inducer. The inhibitory effects of grapefruit and its juice may increase the systemic exposure of ivacaftor. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with once-daily itraconazole, a strong CYP3A inhibitor, increased ivacaftor exposure by 4.3-fold. However, because lumacaftor is a strong inducer of CYP3A, the net exposure of ivacaftor at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours). (Major) The manufacturer recommends avoiding grapefruit or Seville oranges during ivacaftor therapy because ivacaftor exposure may be increased. Ivacaftor is a CYP3A substrate. Grapefruit juice and Seville oranges contain components that inhibit CYP3A, and therefore, may reduce ivacaftor metabolism.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4. (Moderate) Concomitant use of hydrocodone with lumacaftor; ivacaftor can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4. (Moderate) Concomitant use of hydrocodone with lumacaftor; ivacaftor can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Guanfacine: (Major) Lumacaftor; ivacaftor may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if lumacaftor; ivacaftor is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If lumacaftor; ivacaftor is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and lumacaftor is a strong CYP3A4 inducer.
    Haloperidol: (Moderate) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of haloperidol with prolonged (1 to 2 weeks) coadministration. Carefully monitor clinical status when lumacaftor; ivacaftor is administered or discontinued in haloperidol-treated patients. Haloperidol may require dosage adjustment to achieve the desired clinical response. If lumacaftor; ivacaftor is subsequently discontinued, it may be necessary to reduce the haloperidol dosage. Haloperidol is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer. Coadministration of haloperidol and rifampin, another strong CYP3A inducer, resulted in a 70% decrease in haloperidol plasma concentrations in 12 schizophrenic patients; correspondingly, Brief Psychiatric Rating Scale scores increased from baseline. In 5 other schizophrenic patients also treated with haloperidol and rifampin, antibiotic discontinuation resulted in a 3.3-fold increase in haloperidol concentrations.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4. (Moderate) Concomitant use of hydrocodone with lumacaftor; ivacaftor can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Concomitant use of losartan and lumacaftor; ivacaftor may alter the therapeutic effects of losartan; caution and close monitoring of blood pressure are advised if these drugs are used together. Losartan is primarily metabolized by CYP2C9 and is also a substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer; in vitro data suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C9. Although induction of losartan through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear. Monitor the patient for decreased losartan efficacy or increased or prolonged therapeutic effects and adverse events. (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.
    Hydrochlorothiazide, HCTZ; Propranolol: (Minor) Concomitant use of propranolol and lumacaftor; ivacaftor may decrease the systemic exposure of propranolol; caution and monitoring of blood pressure and other therapeutic effects are advised if these drugs are used together. Propranolol is partially metabolized by CYP2C19; in vitro data suggest that lumacaftor may induce CYP2C19.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4. (Moderate) Concomitant use of hydrocodone with lumacaftor; ivacaftor can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4. (Moderate) Concomitant use of hydrocodone with lumacaftor; ivacaftor can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. (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) Lumacaftor; ivacaftor may alter the systemic exposure of ibuprofen. If used together, a dose adjustment of ibuprofen may be required to obtain the desired therapeutic effect and/or avoid adverse effects. Do not exceed the recommended maximum dose. Ibuprofen is a CYP2C9 substrate, and in vitro studies suggest that lumacaftor; ivacaftor has the potential to induce or inhibit CYP2C9.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4. (Moderate) Concomitant use of hydrocodone with lumacaftor; ivacaftor can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4. (Moderate) Concomitant use of hydrocodone with lumacaftor; ivacaftor can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4. (Moderate) Concomitant use of hydrocodone with lumacaftor; ivacaftor can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4. (Moderate) Concomitant use of hydrocodone with lumacaftor; ivacaftor can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Ibrutinib: (Major) Avoid the concomitant use of ibrutinib and lumacaftor; ivacaftor; ibrutinib plasma concentrations may decrease. Ibrutinib is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
    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) Lumacaftor; ivacaftor may alter the systemic exposure of ibuprofen. If used together, a dose adjustment of ibuprofen may be required to obtain the desired therapeutic effect and/or avoid adverse effects. Do not exceed the recommended maximum dose. Ibuprofen is a CYP2C9 substrate, and in vitro studies suggest that lumacaftor; ivacaftor has the potential to induce or inhibit CYP2C9.
    Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ivacaftor is necessary. If ivacaftor is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like ivacaftor can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ivacaftor is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with lumacaftor; ivacaftor is necessary; consider increasing the dose of oxycodone as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. (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) Lumacaftor; ivacaftor may alter the systemic exposure of ibuprofen. If used together, a dose adjustment of ibuprofen may be required to obtain the desired therapeutic effect and/or avoid adverse effects. Do not exceed the recommended maximum dose. Ibuprofen is a CYP2C9 substrate, and in vitro studies suggest that lumacaftor; ivacaftor has the potential to induce or inhibit CYP2C9.
    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. (Minor) Lumacaftor; ivacaftor may alter the systemic exposure of ibuprofen. If used together, a dose adjustment of ibuprofen may be required to obtain the desired therapeutic effect and/or avoid adverse effects. Do not exceed the recommended maximum dose. Ibuprofen is a CYP2C9 substrate, and in vitro studies suggest that lumacaftor; ivacaftor has the potential to induce or inhibit CYP2C9.
    Idelalisib: (Major) Avoid concomitant use of idelalisib and lumacaftor; ivacaftor as idelalisib exposure may be significantly reduced and efficacy compromised. Additionally, the exposure of ivacaftor may be increased. Lumacaftor; ivacaftor dosage adjustment is not required when idelalisib is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking idelalisib, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking idelalisib. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Idelalisib is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of idelalisib and decrease its therapeutic efficacy. Although idelalisib is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold. (Major) If idelalisib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and idelalisib is a CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
    Ifosfamide: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with lumacaftor; ivacaftor is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; lumacaftor is a strong CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Iloperidone: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of iloperidone by decreasing its systemic exposure. If used together, monitor the patient for appropriate clinical effects. Iloperidone is a CYP3A substrate. Lumacaftor is a strong inducer of CYP3A.
    Imatinib: (Major) Concomitant use of lumacaftor; ivacaftor and imatinib should be avoided; if coadministration is necessary, increase the imatinib dosage by at least 50% and monitor clinical response closely. The net effect of lumacaftor; ivacaftor is strong CYP3A induction; imatinib is a CYP3A4 substrate and a moderate CYP3A4 inhibitor. Dosage adjustment of lumacaftor; ivacaftor is not required. Coadministration of other strong CYP3A inducers have decreased imatinib exposure (AUC) by 73% and 30%, respectively. (Major) If imatinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and imatinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Imipramine: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of imipramine by decreasing its systemic exposure. If used together, monitor patients closely for imipramine efficacy; an imipramine dosage adjustment may be required to obtain the desired therapeutic effect. Although imipramine is a primary substrate of CYP2D6, CYP3A4 and CYP2C19 also contribute to its metabolism. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor may induce CYP2C19.
    Indacaterol: (Moderate) Lumacaftor; ivacaftor may alter the systemic exposure of indacaterol; use together with caution. Indacaterol is a substrate of CYP3A4 and the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggests lumacaftor; ivacaftor may also induce and/or inhibit P-gp. While the induction of indacaterol through the CYP3A pathway may lead to decreased plasma concentrations of indacaterol, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear.
    Indacaterol; Glycopyrrolate: (Moderate) Lumacaftor; ivacaftor may alter the systemic exposure of indacaterol; use together with caution. Indacaterol is a substrate of CYP3A4 and the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggests lumacaftor; ivacaftor may also induce and/or inhibit P-gp. While the induction of indacaterol through the CYP3A pathway may lead to decreased plasma concentrations of indacaterol, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear.
    Indinavir: (Major) If indinavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and indinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of indinavir; avoid concurrent use if possible. If concomitant use of indinavir is necessary, monitor antiretroviral efficacy, consider therapeutic drug monitoring, and adjust therapy as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when indinavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking indinavir, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking indinavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Indinavir is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of indinavir and decrease its therapeutic efficacy. Although indinavir is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold. Lastly, indinavir is also a substrate of the drug transporter P-glycoprotein (P-gp), and lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect on P-gp substrates is not clear, but their exposure may be affected.
    Indomethacin: (Minor) Although the clinical significance of this interaction is unknown, concurrent use of indomethacin and lumacaftor; ivacaftor may alter indomethacin exposure; caution and close monitoring are advised if these drugs are used together. Indomethacin is a substrate of CYP2C9. In vitro data suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C9. The net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear, but CYP2C9 substrate exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events. (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: (Major) Avoid administration of lumacaftor; ivacaftor during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Irinotecan: (Major) Avoid administration of lumacaftor; ivacaftor during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Exposure to irinotecan or its active metabolite, SN-38, was substantially reduced in patients treated with other strong CYP3A4 inducers. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
    Isavuconazonium: (Major) Concomitant use of isavuconazonium and lumacaftor; ivacaftor is not recommended because lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic effectiveness of isavuconazonium. If concurrent use cannot be avoided, monitor closely for antifungal efficacy and adjust the dose accordingly. Isavuconazole, the active moiety of isavuconazonium, is a sensitive CYP3A4 substrate, and lumacaftor is a strong CYP3A inducer. (Major) If isavuconazonium and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and isavuconazole, the active moiety of isavuconazonium, is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Coadministration of ivacaftor with rifampin is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin significantly decreased ivacaftor exposure by approximately 9-fold. (Major) Concomitant use of rifampin and lumacaftor; ivacaftor is not recommended. Rifampin may decrease the therapeutic effect of lumacaftor; ivacaftor by significantly decreasing ivacaftor exposure. Ivacaftor is a sensitive substrate of CYP3A, and rifampin is a potent CYP3A inducer. In a pharmacokinetic study, coadministration of lumacaftor; ivacaftor with rifampin decreased ivacaftor exposure (AUC) by 57%, with minimal effect on the exposure of lumacaftor.
    Isoniazid, INH; Rifampin: (Major) Coadministration of ivacaftor with rifampin is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin significantly decreased ivacaftor exposure by approximately 9-fold. (Major) Concomitant use of rifampin and lumacaftor; ivacaftor is not recommended. Rifampin may decrease the therapeutic effect of lumacaftor; ivacaftor by significantly decreasing ivacaftor exposure. Ivacaftor is a sensitive substrate of CYP3A, and rifampin is a potent CYP3A inducer. In a pharmacokinetic study, coadministration of lumacaftor; ivacaftor with rifampin decreased ivacaftor exposure (AUC) by 57%, with minimal effect on the exposure of lumacaftor.
    Isradipine: (Moderate) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of isradipine. If used together, monitor blood pressure closely; the dosage requirements of isradipine may be increased. Isradipine is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer.
    Istradefylline: (Major) Avoid coadministration of istradefylline with lumacaftor; ivacaftor as istradefylline exposure and efficacy may be reduced. Lumacaftor; ivacaftor is a strong inducer. Istradefylline exposure was decreased by 81% when administered with a strong inducer in a drug interaction study.
    Itraconazole: (Major) Avoid lumacaftor; ivacaftor use during and for up to 2 weeks before and after itraconazole treatment. Lumacaftor; ivacaftor may decrease the therapeutic efficacy of itraconazole. Consider alternative antifungals such as fluconazole. If concomitant use of itraconazole is necessary, monitor for antifungal efficacy and adjust the dosage as appropriate. Lumacaftor; ivacaftor dosage adjustment is not required when itraconazole is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking itraconazole, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking itraconazole. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Itraconazole is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of itraconazole and decrease its therapeutic efficacy. Although itraconazole is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with itraconazole increased ivacaftor exposure by 4.3-fold. Lastly, itraconazole is also a substrate for P-glycoprotein (P-gp) efflux, and lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect on P-gp substrates is not clear, but their exposure may be affected. (Major) If itraconazole and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and itraconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
    Ivabradine: (Major) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of ivabradine; avoid concurrent use. Ivabradine is primarily metabolized by CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with lumacaftor; ivacaftor due to decreased plasma concentrations of ivosidenib. Ivosidenib is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer is predicted to decrease ivosidenib exposure at steady-state by 33%. (Moderate) Monitor for loss of efficacy of ivacaftor during coadministration of ivosidenib; a ivacaftor dose adjustment may be necessary. Ivacaftor is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased ivacaftor concentrations.
    Ixabepilone: (Major) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of ixabepilone; avoid concurrent use if possible. Ixabepilone is primarily metabolized by CYP3A4, and lumacaftor is a strong CYP3A inducer. If coadministration is necessary and appropriate alternative agents are not available, FDA-approved labeling for ixabepilone suggests to gradually increase the ixabepilone dose from 40 mg/m2 to 60 mg/m2 depending on tolerance once the patient is maintained on lumacaftor; ivacaftor. If the ixabepilone dose is increased, it should be given as a 4-hour infusion and the patient monitored closely for toxicity. If lumacaftor; ivacaftor is subsequently discontinued, the ixabepilone dose should be reduced to the dose used prior to its initiation. It should be noted that this recommendation is based on extrapolation from a drug interaction study with rifampin; there is not clinical data with this dosage adjustment in patients receiving other strong CYP3A inducers. Coadministration of ixabepilone with rifampin, another strong CYP3A inducer, decreased ixabepilone AUC by 43%. Ixabepilone is also a substrate of the P-glycoprotein (P-gp) drug transporter; in vitro data suggests lumacaftor; ivacaftor may induce and/or inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear. (Moderate) Frequently monitor peripheral blood counts between cycles of ixabepilone, and for other acute ixabepilone-related adverse reactions if coadministration with ivacaftor is necessary; consider the use of an alternative agent to ivacaftor that does not inhibit CYP3A4. Ixabepilone is a CYP3A4 substrate and ivacaftor is a weak CYP3A4 inhibitor. The effect of weak CYP3A4 inhibitors on exposure to ixabepilone has not been studied.
    Ketoconazole: (Major) If ketoconazole and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate. Coadministration with ketoconazole, a strong CYP3A inhibitor, increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of ketoconazole; avoid concomitant use if possible. Consider alternative antifungals such as fluconazole. If concomitant use of ketoconazole is necessary, monitor for antifungal efficacy and adjust the dosage as appropriate. Lumacaftor; ivacaftor dosage adjustment is not required when ketoconazole is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking ketoconazole, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking ketoconazole. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Ketoconazole is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of ketoconazole and decrease its therapeutic efficacy. Although ketoconazole is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ivacaftor. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (Minor) Although the clinical significance of this interaction is unknown, concurrent use of tenofovir, PMPA and lumacaftor; ivacaftor may alter tenofovir exposure; caution and close monitoring are advised if these drugs are used together. Tenofovir is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events.
    Lansoprazole: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of lansoprazole by substantially decreasing its systemic exposure. If used together, a lansoprazole dosage adjustment may be necessary to obtain the desired therapeutic effect. Lansoprazole is a CYP3A4 and CYP2C19 substrate. Lumacaftor; ivacaftor is a strong inducer of CYP3A; in vitro data suggests is also has the potential to induce CYP2C19.
    Lansoprazole; Naproxen: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of naproxen and lumacaftor; ivacaftor may alter naproxen exposure; caution and monitoring are advised if these drugs are administered together. Naproxen is a substrate of CYP2C9 (primary) and CYP2C8. In vitro data suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C8 and CYP2C9. The net effect on these substrates is not clear, but their exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events. (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of lansoprazole by substantially decreasing its systemic exposure. If used together, a lansoprazole dosage adjustment may be necessary to obtain the desired therapeutic effect. Lansoprazole is a CYP3A4 and CYP2C19 substrate. Lumacaftor; ivacaftor is a strong inducer of CYP3A; in vitro data suggests is also has the potential to induce CYP2C19. (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.
    Lapatinib: (Major) Avoid coadministration of lapatinib with lumacaftor; ivacaftor due to decreased plasma concentrations of lapatinib. If concomitant use is unavoidable, gradually titrate the dose of lapatinib from 1,250 mg per day to 4,500 mg per day in patients receiving concomitant capecitabine (HER2-positive metastatic breast cancer), and from 1,500 mg per day to 5,500 mg per day in patients receiving concomitant aromatase inhibitor therapy (HR-positive, HER2-positive breast cancer) based on tolerability. If lumacaftor; ivacaftor is discontinued, reduce lapatinib to the indicated dose. Lapatinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased lapatinib exposure by 72%. (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with ivacaftor is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and ivacaftor is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    Larotrectinib: (Major) Avoid coadministration of larotrectinib with lumacaftor; ivacaftor due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If lumacaftor; ivacaftor is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of lumacaftor; ivacaftor. Larotrectinib is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
    Ledipasvir; Sofosbuvir: (Minor) Although the clinical significance of this interaction is unknown, concurrent use of ledipasvir; sofosbuvir and lumacaftor; ivacaftor may alter ledipasvir; sofosbuvir exposure; avoid concurrent use. Both ledipasvir and sofosbuvir are substrates of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected. FDA-approved labeling for ledipasvir; sofosbuvir recommends to avoid coadministration with P-gp inducers. (Minor) Although the clinical significance of this interaction is unknown, concurrent use of sofosbuvir and lumacaftor; ivacaftor may alter sofosbuvir exposure; caution and close monitoring are advised if these drugs are used together. Sofosbuvir is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events. FDA-approved labeling for sofosbuvir recommends to avoid coadministration with potent P-gp inducers.
    Lefamulin: (Major) Avoid coadministration of lefamulin with lumacaftor; ivacaftor unless the benefits outweigh the risks due to unpredictable lefamulin exposure. Lefamulin is a CYP3A4 and P-gp substrate; lumacaftor; ivacaftor is both a strong inducer of CYP3A4 as well as a P-gp inhibitor and inducer. The net effect on lefamulin concentrations is unclear. (Major) If oral lefamulin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Additionally, monitor for lefamulin-related adverse effects as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Ivacaftor is a CYP3A substrate and P-gp inhibitor. Oral lefamulin is a CYP3A4 and P-gp substrate and moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Letermovir: (Major) Concurrent administration of letermovir and lumacaftor; ivacaftor is not recommended. Use of these drugs together may alter letermovir plasma concentrations; decreased letermovir exposure may result in potential loss of letermovir efficacy. Letermovir is a substrate of the drug transporter P-glycoprotein (P-gp). Lumacaftor; ivacaftor has potential to both inhibit and induce P-gp. Also, concurrent use may increase ivacaftor plasma concentrations. Ivacaftor is a CYP3A substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with other moderate and strong CYP3A inhibitors increased ivacaftor exposure by 3- and 8.5-fold, respectively. (Major) If letermovir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. In patients also receiving cyclosporine, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly, because the magnitude of the interaction may be increased. Ivacaftor is a CYP3A substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with other moderate and strong CYP3A inhibitors increased ivacaftor exposure by 3- and 8.5-fold, respectively.
    Leuprolide; Norethindrone: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Levonorgestrel: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Lomitapide: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of lomitapide by decreasing its systemic exposure. If used together, monitor patients closely for loss of lomitapide efficacy; a lomitapide dosage adjustment may be required to obtain the desired therapeutic effect. Lomitapide is a substrate of CYP3A4; lumacaftor; ivacaftor is a strong CYP3A inducer.
    Loperamide: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of loperamide by decreasing its systemic exposure. If used together, monitor for loss of loperamide efficacy; a loperamide dosage adjustment may be required to obtain the desired therapeutic effect. Do not exceed the maximum recommended dose. Loperamide is primarily metabolized by CYP3A4 and CYP2C8; CYP2B6 also plays a minor role. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor may induce CYP2B6 and induce and/or inhibit CYP2C8. (Moderate) The plasma concentration of loperamide, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with ivacaftor, an inhibitor of 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) Lumacaftor; ivacaftor may reduce the efficacy of loperamide by decreasing its systemic exposure. If used together, monitor for loss of loperamide efficacy; a loperamide dosage adjustment may be required to obtain the desired therapeutic effect. Do not exceed the maximum recommended dose. Loperamide is primarily metabolized by CYP3A4 and CYP2C8; CYP2B6 also plays a minor role. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor may induce CYP2B6 and induce and/or inhibit CYP2C8. (Moderate) The plasma concentration of loperamide, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with ivacaftor, an inhibitor of 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. Ivacaftor is a CYP3A substrate and ritonavir is a CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of lopinavir; ritonavir; avoid concurrent use if possible. If concomitant use of lopinavir; ritonavir is necessary, monitor antiretroviral efficacy and adjust therapy as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when lopinavir; ritonavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking lopinavir; ritonavir, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking lopinavir; ritonavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Lopinavir; ritonavir is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of lopinavir; ritonavir and decrease its therapeutic efficacy. Although lopinavir; ritonavir is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of ritonavir; avoid concurrent use if possible. If concomitant use of ritonavir is necessary, monitor antiretroviral efficacy and adjust therapy as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when ritonavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking ritonavir, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking ritonavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Ritonavir is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of ritonavir and decrease its therapeutic efficacy. Although ritonavir is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold. Lastly, ritonavir is also a substrate of the drug transporter P-glycoprotein (P-gp), and lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect on P-gp substrates is not clear, but their exposure may be affected.
    Lorlatinib: (Severe) Coadministration of lorlatinib with lumacaftor; ivacaftor is contraindicated due to the potential for serious hepatotoxicity; the efficacy of lorlatinib may also be decreased. Discontinue lumacaftor; ivacaftor for 3 plasma half-lives of lumacaftor prior to initiating lorlatinib. Lorlatinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Severe hepatotoxicity indicated by increased AST/ALT (grade 2, 8%; grade 3 or 4, 83%) occurred in healthy subjects receiving a single 100-mg dose of lorlatinib with multiple daily doses of another strong CYP3A4 inducer (n = 12); ALT and AST returned to normal limits after a median of 15 days. Additionally, the mean AUC and Cmax of lorlatinib were decreased by 85% and 76%, respectively.
    Losartan: (Moderate) Concomitant use of losartan and lumacaftor; ivacaftor may alter the therapeutic effects of losartan; caution and close monitoring of blood pressure are advised if these drugs are used together. Losartan is primarily metabolized by CYP2C9 and is also a substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer; in vitro data suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C9. Although induction of losartan through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear. Monitor the patient for decreased losartan efficacy or increased or prolonged therapeutic effects and adverse events. (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) Lumacaftor; ivacaftor may decrease the systemic exposure of lovastatin; if used together, monitor serum lipid concentrations. Lovastatin is a substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer. (Moderate) Monitoring for lovastatin-related adverse events (i.e., myopathy, rhabdomyolysis) is recommended if administered concurrently with ivacaftor. Coadministration can increase lovastatin exposure leading to increased or prolonged therapeutic effects and adverse events. Lovastatin is a CYP3A4 substrate; ivacaftor is a weak CYP3A4 inhibitor.
    Lovastatin; Niacin: (Moderate) Lumacaftor; ivacaftor may decrease the systemic exposure of lovastatin; if used together, monitor serum lipid concentrations. Lovastatin is a substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer. (Moderate) Monitoring for lovastatin-related adverse events (i.e., myopathy, rhabdomyolysis) is recommended if administered concurrently with ivacaftor. Coadministration can increase lovastatin exposure leading to increased or prolonged therapeutic effects and adverse events. Lovastatin is a CYP3A4 substrate; ivacaftor is a weak CYP3A4 inhibitor.
    Lurasidone: (Severe) Concomitant use of lumacaftor; ivacaftor and lurasidone is contraindicated. Lurasidone is predominantly metabolized via CYP3A4. Lumacaftor is a strong CYP3A inducer. During pharmacokinetic trials, the Cmax and AUC of lurasidone decreased to one-seventh and one-fifth, respectively, of lurasidone alone when a single 40 mg dose was coadministered with rifampin (600 mg/day for 8 days), another strong CYP3A inducer.
    Macimorelin: (Major) Discontinue lumacaftor; ivacaftor and allow a sufficient washout period to pass before administering macimorelin. Use of these drugs together can decrease macimorelin plasma concentrations, and may result in a false positive test for growth hormone deficiency. Drug interaction studies involving macimorelin have not been conducted; however, macimorelin is primarily metabolized by CYP3A4 and lumacaftor is a strong CYP3A4 inducer. In a drug interaction study, concurrent administration of lumacaftor with a sensitive CYP3A substrate decreased exposure of that substrate by 80%.
    Macitentan: (Major) Lumacaftor; ivacaftor may reduce the efficacy of macitentan by significantly decreasing its systemic exposure; avoid concomitant use. Macitentan is primarily metabolized via CYP3A4, with a minor contribution from CYP2C19. Lumacaftor is a strong CYP3A inducer; in vitro data suggest lumacaftor; ivacaftor may also induce CYP2C19.
    Maraviroc: (Major) Coadministration of maraviroc, a CYP3A substrate, and lumacaftor; ivacaftor, a strong CYP3A inducer, without a concomitant strong CYP3A inhibitor may decrease maraviroc concentrations, therefore, the adult maraviroc dose should be increased to 600 mg PO twice daily when coadministered with lumacaftor; ivacaftor without a concomitant strong CYP3A inhibitor. Coadministration of maraviroc and lumacaftor; ivacaftor is contraindicated in patients with CrCl less than 30 mL/min. For pediatric patients, concomitant use of maraviroc with a strong CYP3A inducer, without a strong CYP3A inhibitor, is not recommended. If the patient's medication regimen also contains a strong CYP3A inhibitor, the CYP3A inhibitor's actions are expected to exceed that of the inducer; overall, increased maraviroc concentrations are expected. (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.
    Medroxyprogesterone: (Major) Avoid concomitant use of medroxyprogesterone and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease medroxyprogesterone, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative and/or additional methods of birth control. In addition, concomitant use of hormonal contraceptives and lumacaftor; ivacaftor may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia). Patients taking medroxyprogesterone for other indications should be monitored for clinical efficacy of the progestin. Medroxyprogesterone is primarily metabolized in vitro via CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Mefloquine: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of mefloquine by decreasing its systemic exposure; caution and close monitoring are advised if these drugs are used together. Mefloquine is a substrate of CYP3A (in vivo) and P-glycoprotein (P-gp) (in vitro). Lumacaftor is a strong CYP3A inducer; in vitro data also suggest lumacaftor; ivacaftor may induce and/or inhibit P-gp. Although induction of mefloquine through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. Coadministration of mefloquine and rifampin , another strong CYP3A inducer, resulted in a 19% and 68% decrease in mean Cmax and AUC, respectively; mefloquine half-life decreased from 305 hours to 113 hours.
    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. (Minor) Concomitant use of meloxicam and lumacaftor; ivacaftor may alter meloxicam exposure; caution and close monitoring are advised if these drugs are used together. Meloxicam is primarily metabolized by CYP2C9 and is also a substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C9. Although induction of meloxicam through the secondary CYP3A pathway may lead to minor decreases in drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear. Monitor the patient for decreased meloxicam efficacy or increased or prolonged therapeutic effects and adverse events.
    Mestranol; Norethindrone: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Metformin; Repaglinide: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of repaglinide by decreasing its systemic exposure. If used together, monitor blood glucose concentrations closely; a repaglinide dosage adjustment may be required to obtain the desired therapeutic effect. Repaglinide is metabolized by CYP3A and CYP2C8. Lumacaftor; ivacaftor is a strong inducer of CYP3A; in vitro studies suggest lumacaftor also has the potential to induce and inhibit CYP2C8.
    Metformin; Rosiglitazone: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rosiglitazone and lumacaftor; ivacaftor may alter the therapeutic effects of rosiglitazone; caution and close monitoring of blood glucose are advised if these drugs are administered together. Rosiglitazone is a substrate of CYP2C8 and CYP2C9. In vitro data suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C8 and CYP2C9. The net effect on these substrates is not clear, but their exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events.
    Metformin; Saxagliptin: (Moderate) Lumacaftor; ivacaftor may alter the systemic exposure of saxagliptin; if used together, monitor blood glucose concentrations closely. Saxagliptin is a substrate of CYP3A (primary) and the P-glycoprotein (P-gp) efflux transporter. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest lumacaftor; ivacaftor may induce and/or inhibit P-gp. Although induction of saxagliptin metabolism through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear.
    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. (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of methadone by decreasing its systemic exposure. If used together, monitor patients closely for loss of methadone efficacy; a methadone dosage adjustment may be required to obtain the desired therapeutic effect. Methadone is a substrate of CYP3A4 (primary), CYP2B6, CYP2C9, and CYP2C19. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor may induce CYP2B6 and CYP2C19 and induce and/or inhibit CYP2C9.
    Methylprednisolone: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of methylprednisolone by decreasing systemic exposure of the corticosteroid. If used together, a higher systemic corticosteroid dose may be required to obtain the desired therapeutic effect. Methylprednisolone is a CYP3A4 substrate. Lumacaftor is a strong CYP3A inducer.
    Midazolam: (Major) Concomitant use of midazolam and lumacaftor; ivacaftor is not recommended; if sedation or anxiolysis is needed, consider alternative therapy. Lumacaftor; ivacaftor may decrease the therapeutic effect of midazolam by decreasing systemic exposure. Lumacaftor; ivacaftor is a strong inducer of CYP3A, and midazolam is a CYP3A substrate. (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.
    Midostaurin: (Major) Avoid the concomitant use of midostaurin and lumacaftor; ivacaftor as significantly decreased exposure of midostaurin and its active metabolites may occur resulting in decreased efficacy. Midostaurin is a CYP3A4 substrate; lumacaftor is a strong CYP3A4 inducer. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 decreased by 96%, 92%, and 59%, respectively, when midostaurin was administered with another strong CYP3A4 inducer in a drug interaction study.
    Mifepristone: (Major) If mifepristone and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate, and mifepristone is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of mifepristone; avoid concurrent use if possible. If coadministration is necessary, monitor efficacy and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when mifepristone is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking mifepristone, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking mifepristone. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Mifepristone is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of mifepristone and decrease its therapeutic efficacy. Although mifepristone is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold.
    Mirtazapine: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of mirtazapine by decreasing its systemic exposure; if used together, it may be necessary to increase the mirtazapine dose to achieve clinical efficacy. If lumacaftor; ivacaftor is subsequently discontinued, consider mirtazapine dosage reduction. Mirtazapine is a substrate of CYP3A. Lumacaftor is a strong CYP3A inducer. At steady state, carbamazepine and phenytoin, both strong inducers of CYP3A, increased mirtazapine clearance approximately 2-fold, resulting in respective decreases of 60% and 45% in average plasma mirtazapine concentrations.
    Mitomycin: (Minor) Although the clinical significance of this interaction is unknown, concurrent use of mitomycin and lumacaftor; ivacaftor may alter mitomycin exposure; caution and close monitoring are advised if these drugs are used together. Mitomycin is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events.
    Mitotane: (Major) Coadministration of ivacaftor with mitotane is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold.
    Montelukast: (Minor) Lumacaftor; ivacaftor may reduce the systemic exposure of montelukast. However, dosage adjustment is not likely to be needed. If used together, the manufacturer recommends monitoring for proper montelukast effectiveness as a precaution. Lumacaftor is a strong CYP3A inducer, and in vitro studies suggest lumacaftor; ivacaftor has the potential to induce CYP2C8 and CYP2C9. Montelukast is metabolized by CYP2C8 (primary), and also CYP2C9 and CYP3A4.
    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. (Minor) Although the clinical significance of this interaction is unknown, concurrent use of morphine and lumacaftor; ivacaftor may alter morphine exposure; caution and close monitoring are advised if these drugs are used together. Morphine is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected leading to decreased efficacy or 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. (Minor) Although the clinical significance of this interaction is unknown, concurrent use of morphine and lumacaftor; ivacaftor may alter morphine exposure; caution and close monitoring are advised if these drugs are used together. Morphine is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events.
    Naldemedine: (Major) Avoid coadministration of naldemedine with strong CYP3A4 inducers. Naldemedine is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inducers, such as lumacaftor, significantly decrease plasma naldemedine concentrations and may decrease the efficacy of naldemedine treatment.
    Naloxegol: (Major) Coadministration of naloxegol with lumacaftor; ivacaftor is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased naloxegol exposure by 89%.
    Naproxen: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of naproxen and lumacaftor; ivacaftor may alter naproxen exposure; caution and monitoring are advised if these drugs are administered together. Naproxen is a substrate of CYP2C9 (primary) and CYP2C8. In vitro data suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C8 and CYP2C9. The net effect on these substrates is not clear, but their exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events. (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: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of naproxen and lumacaftor; ivacaftor may alter naproxen exposure; caution and monitoring are advised if these drugs are administered together. Naproxen is a substrate of CYP2C9 (primary) and CYP2C8. In vitro data suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C8 and CYP2C9. The net effect on these substrates is not clear, but their exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events. (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: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of naproxen and lumacaftor; ivacaftor may alter naproxen exposure; caution and monitoring are advised if these drugs are administered together. Naproxen is a substrate of CYP2C9 (primary) and CYP2C8. In vitro data suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C8 and CYP2C9. The net effect on these substrates is not clear, but their exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events. (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) Lumacaftor; ivacaftor may alter the therapeutic effects of nateglinide; caution and close monitoring of blood glucose are advised if these drugs are used together. Nateglinide is primarily metabolized by CYP2C9. In vitro data suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C9. The net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear. Monitor the patient for decreased nateglinide efficacy or increased or prolonged therapeutic effects, including hypoglycemia and adverse events. (Moderate) Monitor blood glucose and for signs of hypoglycemia. Ivacaftor is a weak inhibitor of CYP2C9; nateglinide is metabolized by CYP2C9. Use of ivacaftor with nateglinide can theoretically increase nateglinide exposure leading to increased or prolonged therapeutic effects; however, the clinical impact of this potential interaction has not yet been determined.
    Nefazodone: (Major) If nefazodone and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate, and nefazodone is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of nefazodone; avoid concurrent use if possible. If concomitant use of nefazodone is necessary, monitor for efficacy and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when nefazodone is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking nefazodone, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other dayfor the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking nefazodone. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Nefazodone is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of nefazodone and decrease its therapeutic efficacy. Although nefazodone is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold.
    Nelfinavir: (Major) If nelfinavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate, and nelfinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of nelfinavir; avoid concurrent use if possible. If concomitant use of nelfinavir is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust therapy as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when nelfinavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking nelfinavir, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking nelfinavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Nelfinavir is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of nelfinavir and decrease its therapeutic efficacy. Although nelfinavir is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold. Lastly, nelfinavir is also a substrate of CYP2C19 and the drug transporter P-glycoprotein (P-gp), and lumacaftor; ivacaftor has the potential to induce CYP2C19 and both induce and inhibit P-gp.
    Neratinib: (Major) Avoid concomitant use of lumacaftor; ivacaftor with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased neratinib exposure by 87%, while exposure to active metabolites M6 and M7 were reduced by 37% to 49%. Concomitant use with other strong inducers of CYP3A4 may also decrease neratinib concentrations.
    Netupitant, Fosnetupitant; Palonosetron: (Major) Avoid concomitant use of netupitant; palonosetron in patients who are taking ivacaftor; lumacaftor. Lumacaftor; ivacaftor may reduce the antiemetic efficacy of netupitant; palonosetron by significantly decreasing the systemic exposure of netupitant. Netupitant is extensively metabolized primarily by CYP3A4, and lumacaftor is a strong CYP3A inducer. Palonosetron is also partially metabolized via CYP3A4, although in vitro studies suggest this is not its primary metabolic pathway. In addition, netupitant is a moderate inhibitor of CYP3A. Because ivacaftor is primarily metabolized by CYP3A, systemic exposure could theoretically increase when given with a CYP3A inhibitor; however, intermittent single-dose use of netupitant; palonosetron and the CYP3A induction effects of lumacaftor on ivacaftor make the clinical relevance of this interaction unlikely. Lumacaftor; ivacaftor dosage adjustments are not recommended with concomitant use of a moderate CYP3A inhibitor such as netupitant. (Major) If netupitant; palonosetron and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Nevirapine: (Major) Lumacaftor; ivacaftor can decrease the therapeutic efficacy of nevirapine; avoid concomitant use if possible. If concomitant use of nevirapine is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust drug dosages as necessary. Do not exceed the maximum recommended dose. Nevirapine is a substrate of CYP3A4 and CYP2B6. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor may induce CYP2B6.
    Niacin; Simvastatin: (Moderate) Monitor for reduced efficacy of simvastatin if coadministered with lumacaftor; ivacaftor. Lumacaftor; ivacaftor may reduce the systemic exposure of simvastatin. Simvastatin is a sensitive substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer. (Minor) Use caution when administering ivacaftor and simvastatin concurrently. Coadministration of ivacaftor with simvastatin may increase simvastatin exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined. Simvastatin is a sensitive CYP3A4 substrate; ivacaftor is a weak CYP3A4 inhibitor.
    Nifedipine: (Major) Avoid coadministration of nifedipine and lumacaftor; ivacaftor and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%. (Moderate) Use caution when administering ivacaftor and nifedipine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as nifedipine, can increase nifedipine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib and lumacaftor; ivacaftor because significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%. (Major) If nilotinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Nimodipine: (Major) Concomitant use of lumacaftor; ivacaftor and nimodipine should generally be avoided, as the systemic exposure and therapeutic efficacy of nimodipine may be significantly reduced. If coadministration is necessary, monitor patients closely and increase the nimodipine dosage as appropriate. Nimodipine is a CYP3A4 substrate and lumacaftor is a strong CYP3A inducer.
    Nintedanib: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as ivacaftor, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Ivacaftor is a mild inhibitor of both P-glycoprotein (P-gp) and CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with ivacaftor due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and ivacaftor is a CYP3A4 inhibitor. (Major) Avoid coadministration of nisoldipine with lumacaftor; ivacaftor due to decreased plasma concentrations of nisoldipine. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer lowered nisoldipine plasma concentrations to undetectable levels.
    Non-oral combination contraceptives: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Norethindrone: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Norgestrel: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Olaparib: (Major) Avoid the coadministration of olaparib with lumacaftor; ivacaftor due to the risk of decreased olaparib efficacy. Olaparib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC of olaparib by 87%.
    Ombitasvir; Paritaprevir; Ritonavir: (Severe) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir and lumacaftor; ivacaftor is contraindicated due to the potential for hepatitis C treatment failure. Dasabuvir is a 2C8 and 3A (minor) substrate; ombitasvir is a P-gp substrate; paritaprevir is a 3A4 substrate and P-gp substrate; ritonavir is a substrate of CYP3A4 and P-gp. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C8 and P-gp. (Major) If ritonavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and ritonavir is a CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of ritonavir; avoid concurrent use if possible. If concomitant use of ritonavir is necessary, monitor antiretroviral efficacy and adjust therapy as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when ritonavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking ritonavir, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking ritonavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Ritonavir is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of ritonavir and decrease its therapeutic efficacy. Although ritonavir is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold. Lastly, ritonavir is also a substrate of the drug transporter P-glycoprotein (P-gp), and lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect on P-gp substrates is not clear, but their exposure may be affected.
    Omeprazole: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of omeprazole by substantially decreasing its systemic exposure. If used together, an omeprazole dosage adjustment may be necessary to obtain the desired therapeutic effect. Omeprazole is a CYP3A4 and CYP2C19 substrate. Lumacaftor; ivacaftor is a strong inducer of CYP3A; in vitro data suggests is also has the potential to induce CYP2C19.
    Omeprazole; Sodium Bicarbonate: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of omeprazole by substantially decreasing its systemic exposure. If used together, an omeprazole dosage adjustment may be necessary to obtain the desired therapeutic effect. Omeprazole is a CYP3A4 and CYP2C19 substrate. Lumacaftor; ivacaftor is a strong inducer of CYP3A; in vitro data suggests is also has the potential to induce CYP2C19.
    Ondansetron: (Minor) Lumacaftor; ivacaftor may reduce the efficacy of ondansetron by decreasing its systemic exposure; however, based on available data, no ondansetron dosage adjustment is recommended. If used together, monitor patients for antiemetic efficacy. Lumacaftor is a strong CYP3A inducer. Ondansetron is a substrate for CY1A2, CYP2D6, and CYP3A4, with CYP3A4 playing a predominant role in ondansetron turnover. During pharmacokinetic studies, patients treated with strong CYP3A inducers (i.e., phenytoin, carbamazepine, rifampin) and ondansetron had significantly increased ondansetron clearance, resulting in significant reductions in AUC, Cmax, and half-life. However, these changes in ondansetron exposure are not thought to be clinically relevant.
    Oral Contraceptives: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Osimertinib: (Major) Avoid coadministration of lumacaftor; ivacaftor with osimertinib due to decreased plasma concentrations of osimertinib which may lead to reduced efficacy. If concomitant use is unavoidable, increase the dose of osimertinib to 160 mg once daily. If lumacaftor; ivacaftor is discontinued, reduce the dose of osimertinib to 80 mg once daily after a washout period of 3 weeks. Osimertinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased osimertinib exposure by 78%.
    Oxcarbazepine: (Moderate) Monitor MHD, the active metabolite of oxcarbazepine, concentrations during oxcarbazepine dosage titration if oxcarbazepine and lumacaftor are used concurrently. A dose adjustment of oxcarbazepine may be required after initiation, dosage modification, or discontinuation of lumacaftor. Lumacaftor is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased plasma concentrations of MHD by 25% to 40%.
    Oxybutynin: (Minor) Lumacaftor; ivacaftor may reduce the efficacy of oxybutynin by decreasing its systemic exposure; if used together, monitor patients for anticholinergic efficacy. Oxybutynin is a substrate of CYP3A4, and lumacaftor is a strong CYP3A inducer.
    Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitorin