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  • CLASSES

    Protein Kinase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Oral epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)
    Used for first-line treatment of EGFR-positive metastatic NSCLC with exon 19 deletions or exon 21 (L858R) substitution mutation
    Serious adverse effects include interstitial lung disease, liver damage, gastrointestinal perforation, severe diarrhea, and ocular disorders; the most common side effects are diarrhea and skin reactions

    COMMON BRAND NAMES

    Iressa

    HOW SUPPLIED

    Iressa Oral Tab: 250mg

    DOSAGE & INDICATIONS

    For the first-line treatment of metastatic non-small cell lung cancer (NSCLC) in patients whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.
    NOTE: If EGFR exon 19 deletions or exon 21 (L858R) substitution mutations are not detected in a plasma specimen, test tumor tissue if available. Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.
    Oral dosage
    Adults

    250 mg PO once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, single-arm, open-label clinical trial, patients with metastatic EGFR mutation positive NSCLC who received gefitinib (n = 106) had an objective response rate (ORR) of 50% for a median duration of 6 months by blinded independent central review (BICR), and an ORR of 70% for a median duration of 8.3 months by investigator assessment; complete responses occurred in 0.9% and 1.9% of patients, respectively. The results of this study were supported by an exploratory analysis of a subset of EGFR positive patients (15%) with metastatic NSCLC (adenocarcinoma) from a multicenter, randomized, open-label clinical trial. In these patients, the median progression-free survival (PFS) by BICR was 10.9 months for a median duration of 9.6 months in patients receiving first-line treatment with gefitinib compared with PFS of 7.4 months for a median duration of 5.5 months in those who received carboplatin plus paclitaxel (HR 0.54; 95% CI, 0.38 to 0.79). The ORR was 67% versus 41%, respectively.[45935]

    For the treatment of recurrent or metastatic squamous-cell head and neck cancer†.
    Oral dosage
    Adults

    250 or 500 mg/day PO has been studied; survival is not improved with gefitinib in this population. In a randomized, phase 3 trial in 486 patients, median overall survival (OS) was not improved with a daily dose of 250 mg (5.6 months) or 500 mg (6 months) compared with methotrexate 40 or 60 mg/m2 IV weekly (6.7 months). Additionally, significantly worse OS was reported with both doses of gefitinib compared with methotrexate therapy in a subgroup of patients who had platinum-resistant disease. Grade 3 to 5 tumor hemorrhage was reported in 4 patients (2.5%) who received gefitinib 250 mg per day and in 2 patients (1.2%) who received gefitinib 500 mg per day.[44837]

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    250 mg per day PO.

    Geriatric

    250 mg per day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment:
    No dosage adjustment is necessary.
     
    Treatment-Related Hepatotoxicity:
    Grade 2 or higher increases in ALT or AST: Hold gefitinib treatment for up to 14 days. When symptoms resolve to grade 1 or less, resume therapy with gefitinib.
    Severe hepatic impairment: Permanently discontinue gefitinib.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    Gefitinib is given orally with or without food.
    For patients who have difficulty swallowing, drop a gefitinib tablet into 4 to 8 ounces of water. Do not crush the tablet. Stir until it is dispersed (approximately 15 minutes) and drink the liquid immediately. Rinse the glass with 4 to 8 ounces of water and immediately drink. The liquid can also be administered through a naso-gastric (NG) tube.
    Do not take a missed dose within 12 hours of the next dose.

    STORAGE

    Iressa:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Chronic lung disease (CLD), pneumonitis, pulmonary disease, pulmonary fibrosis

    Use gefitinib with caution in patients with a history of pulmonary disease or chronic lung disease (CLD). Interstitial lung disease (ILD) or ILD-like reactions including lung infiltration, pneumonitis, acute respiratory distress syndrome, or pulmonary fibrosis have occurred in patients treated with gefitinib across clinical trials, including 3 fatalities. Patients with a history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease were excluded from non-small cell lung cancer (NSCLC) clinical trials. An exploratory exposure response analysis showed an increase in the incidence of ILD with more than a 2-fold increase in gefitinib exposure. Hold gefitinib therapy in patients who develop acute or worsening pulmonary symptoms such as dyspnea, cough, and fever. Permanently discontinue therapy in patients with confirmed ILD.[45935]

    Hepatic disease

    Hepatotoxicity has been reported across clinical trials in patients treated with gefitinib, including fatal hepatotoxicity in 0.04%. Use gefitinib with caution in patients with baseline hepatic disease. Obtain periodic liver function tests. Gefitinib should be held for worsening liver function, and discontinued in patients with severe hepatic impairment.

    Keratitis, ocular disease

    Ocular disorders including keratitis, corneal erosion, aberrant eyelash growth, conjunctivitis, blepharitis, and dry eye have been reported in patients receiving gefitinib treatment. Abnormal eyelash growth and keratitis are known risk factors for corneal perforation and ulceration. Use caution in patients with pre-existing ocular disease. Evaluate and manage any new or worsening vision impairment, eye pain, or other ocular disorders. An interruption of therapy may be necessary.

    Diarrhea, GI perforation

    Serious gastrointestinal toxicity has been reported with gefitinib use across clinical trials (n = 2,462), including severe diarrhea and GI perforation. Use gefitinib with caution in patients at risk for GI perforation. Patients with pre-existing diarrhea or dehydration should be treated prior to receiving gefitinib. Hold gefitinib therapy for severe or persistent diarrhea; an interruption or discontinuation of therapy may be necessary. Also, monitor patients for symptoms of GI perforation and permanently discontinue gefitinib if it occurs.[45935]

    Serious rash

    Serious rash has been reported with gefitinib therapy, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and erythema multiforme. Monitor patients for the development of severe cutaneous reactions; interrupt or discontinue therapy if the patient develops severe bullous, blistering, or exfoliating conditions.

    Pregnancy

    Although there are no adequate and well-controlled studies in pregnant women, gefitinib is considered a potential teratogen in humans because animal studies found gefitinib to be teratogenic at doses below those recommended for human use. Females of reproductive potential should use effective contraception during treatment with gefitinib and for at least 2 weeks after the last dose. Advise pregnant women of the potential hazard to the fetus or risk for pregnancy loss. Studies in rats showed that gefitinib crossed the placenta and led to a reduction in the number of live offspring at doses approximately 20% of the recommended human dose; at doses approximating the human dose on a mg/m2 bases, this effect was accompanied by high neonatal mortality. Reduced fetal weight has also been reported in rabbits at doses about twice the recommended human dose.

    Contraception requirements, infertility, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during gefitinib treatment. Gefitinib can be teratogenic if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and for at least 2 weeks after treatment with gefitinib. Females of reproductive potential should undergo pregnancy testing prior to initiation of gefitinib. Women who become pregnant while receiving gefitinib should be apprised of the potential hazard to the fetus. In addition, based on animal data, gefitinib may result in reduced fertility (infertility) in females of reproductive potential.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from gefitinib, advise women to discontinue breast-feeding during treatment. It is not known whether gefitinib is present in human milk, although many drugs are excreted in human milk.[45935]

    ADVERSE REACTIONS

    Severe

    elevated hepatic enzymes / Delayed / 2.0-5.1
    proteinuria / Delayed / 4.7-4.7
    diarrhea / Early / 3.0-3.0
    anorexia / Delayed / 2.3-2.3
    vomiting / Early / 1.2-1.2
    angioedema / Rapid / 0-1.1
    pneumonitis / Delayed / 0.7-0.7
    hyperbilirubinemia / Delayed / 0.7-0.7
    pulmonary embolism / Delayed / 0.5-0.5
    stomatitis / Delayed / 0.3-0.3
    corneal erosion / Delayed / 0-0.2
    keratitis / Delayed / 0.1-0.1
    GI perforation / Delayed / 0.1-0.1
    pancreatitis / Delayed / 0.1-0.1
    pulmonary fibrosis / Delayed / Incidence not known
    acute respiratory distress syndrome (ARDS) / Early / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    hemorrhagic cystitis / Delayed / Incidence not known

    Moderate

    conjunctivitis / Delayed / 0-6.7
    blepharitis / Early / 0-6.7
    bleeding / Early / 4.3-4.3
    dehydration / Delayed / 1.8-1.8
    dyspnea / Early / Incidence not known
    ocular inflammation / Early / Incidence not known
    erythema / Early / Incidence not known
    bullous rash / Early / Incidence not known
    oral ulceration / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known
    cystitis / Delayed / Incidence not known

    Mild

    fever / Early / 9.0-9.0
    xerophthalmia / Early / 0-6.7
    alopecia / Delayed / 4.7-4.7
    xerostomia / Early / 2.0-2.0
    urticaria / Rapid / 0-1.1
    cough / Delayed / Incidence not known
    ocular irritation / Rapid / Incidence not known
    ocular pruritus / Rapid / Incidence not known
    rash / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    maculopapular rash / Early / Incidence not known
    vesicular rash / Delayed / Incidence not known
    folliculitis / Delayed / Incidence not known
    acne vulgaris / Delayed / Incidence not known
    onycholysis / Delayed / Incidence not known
    xerosis / Delayed / Incidence not known
    acneiform rash / Delayed / Incidence not known
    cheilitis / Delayed / Incidence not known
    epistaxis / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abiraterone: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with abiraterone is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and abiraterone is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Acetaminophen; Diphenhydramine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and diphenhydramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; diphenhydramine is a CYP2D6 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with CYP2D6 inhibitors, in patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated. Additionally, at high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of diphenhydramine. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); however, the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated.
    Acetaminophen; Oxycodone: (Moderate) Monitor for an increased incidence of oxycodone-related adverse effects if gefitinib and oxycodone are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of oxycodone. As < 15% of the total administered dose is metabolized by CYP2D6 to oxymorphone, concurrent use of some agents that inhibit CYP2D6 has not been shown to result in clinically significant interactions. However, potent inhibitors of CYP2D6, such as ritonavir, may potentially increase the effects of oxycodone. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated such as oxycodone.
    Aluminum Hydroxide: (Major) Avoid coadministration of antacids with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next antacid dose. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Aluminum Hydroxide; Magnesium Carbonate: (Major) Avoid coadministration of antacids with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next antacid dose. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Aluminum Hydroxide; Magnesium Hydroxide: (Major) Avoid coadministration of antacids with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next antacid dose. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Major) Avoid coadministration of antacids with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next antacid dose. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Aluminum Hydroxide; Magnesium Trisilicate: (Major) Avoid coadministration of antacids with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next antacid dose. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of lansoprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of lansoprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%. (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with clarithromycin is necessary. Gefitinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of omeprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of omeprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%. (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with clarithromycin is necessary. Gefitinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Antacids: (Major) Avoid coadministration of antacids with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next antacid dose. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Apalutamide: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with apalutamide is necessary. If apalutamide is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
    Aripiprazole: (Moderate) Because aripiprazole is partially metabolized by CYP2D6, patients should be carefully monitored for aripiprazole-related adverse reactions during concurrent use of a CYP2D6 inhibitor such as gefitinib. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 inhibitor.
    Aspirin, ASA; Omeprazole: (Major) Avoid coadministration of omeprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of omeprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Aspirin, ASA; Oxycodone: (Moderate) Monitor for an increased incidence of oxycodone-related adverse effects if gefitinib and oxycodone are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of oxycodone. As < 15% of the total administered dose is metabolized by CYP2D6 to oxymorphone, concurrent use of some agents that inhibit CYP2D6 has not been shown to result in clinically significant interactions. However, potent inhibitors of CYP2D6, such as ritonavir, may potentially increase the effects of oxycodone. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated such as oxycodone.
    Atazanavir: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with atazanavir is necessary. Gefitinib is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Atazanavir; Cobicistat: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with atazanavir is necessary. Gefitinib is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%. (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with cobicistat is necessary. Gefitinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with phenobarbital is necessary. If phenobarbital is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with phenobarbital is necessary. If phenobarbital is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
    Bupropion: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with bupropion is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and bupropion is a strong CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Bupropion; Naltrexone: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with bupropion is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and bupropion is a strong CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Calcium Carbonate: (Major) Avoid coadministration of calcium carbonate with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of calcium carbonate. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Calcium Carbonate; Magnesium Hydroxide: (Major) Avoid coadministration of antacids with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next antacid dose. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%. (Major) Avoid coadministration of calcium carbonate with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of calcium carbonate. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Calcium Carbonate; Risedronate: (Major) Avoid coadministration of calcium carbonate with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of calcium carbonate. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Calcium; Vitamin D: (Major) Avoid coadministration of calcium carbonate with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of calcium carbonate. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Carbamazepine: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with carbamazepine is necessary. If carbamazepine is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and diphenhydramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; diphenhydramine is a CYP2D6 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with CYP2D6 inhibitors, in patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated. Additionally, at high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of diphenhydramine. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); however, the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated.
    Ceritinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with ceritinib is necessary. Gefitinib is a CYP3A4 substrate and ceritinib is a CYP3A4 inhibitor, although the strength of inhibition is unknown. Coadministration with a strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Chloramphenicol: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with chloramphenicol is necessary. Gefitinib is a CYP3A4 substrate and chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Cimetidine: (Major) Avoid coadministration of cimetidine with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of cimetidine. Gefitinib exposure is affected by gastric pH. Coadministration with high doses of another H2-blocker to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Cinacalcet: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with cinacalcet is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and cinacalcet is a strong CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Clarithromycin: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with clarithromycin is necessary. Gefitinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Cobicistat: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with cobicistat is necessary. Gefitinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with cobicistat is necessary. Gefitinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with cobicistat is necessary. Gefitinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Codeine; Phenylephrine; Promethazine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and promethazine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; promethazine is a moderate CYP2D6 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with CYP2D6 inhibitors, in patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated. Additionally, at high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of promethazine. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); however, the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated.
    Codeine; Promethazine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and promethazine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; promethazine is a moderate CYP2D6 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with CYP2D6 inhibitors, in patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated. Additionally, at high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of promethazine. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); however, the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated.
    Conivaptan: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with conivaptan is necessary. Gefitinib is a CYP3A4 substrate and conivaptan is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Dalfopristin; Quinupristin: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with dalfopristin; quinupristin is necessary. Gefitinib is a CYP3A4 substrate and quinupristin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Darunavir: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with darunavir is necessary. Gefitinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Darunavir; Cobicistat: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with cobicistat is necessary. Gefitinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%. (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with darunavir is necessary. Gefitinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with cobicistat is necessary. Gefitinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%. (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with darunavir is necessary. Gefitinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with ritonavir is necessary. Gefitinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Delavirdine: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with delavirdine is necessary; the risk is increased in CYP2D6 poor metabolizers. Gefitinib is a CYP3A4 substrate and delavirdine is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%. Based on in vitro data, gefitinib is also metabolized to O-desmethyl gefitinib by CYP2D6 and delavirdine is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends additional precautions based on exposure in patients with poor CYP2D6 metabolism.
    Dexamethasone: (Moderate) Monitor for clinical response of gefitinib if used concomitantly with dexamethasone. Gefitinib is metabolized significantly by CYP3A4 and dexamethasone is a CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inducers, administration of a single 500 mg gefitinib dose with a concurrent strong CYP3A4 inducer (rifampin) resulted in reduced mean AUC of gefitinib by 83%.
    Dexlansoprazole: (Major) Avoid coadministration of dexlansoprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of dexlansoprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and diphenhydramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; diphenhydramine is a CYP2D6 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with CYP2D6 inhibitors, in patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated. Additionally, at high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of diphenhydramine. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); however, the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated.
    Dextromethorphan; Promethazine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and promethazine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; promethazine is a moderate CYP2D6 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with CYP2D6 inhibitors, in patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated. Additionally, at high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of promethazine. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); however, the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated.
    Dextromethorphan; Quinidine: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with quinidine is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and quinidine is strong CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Diphenhydramine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and diphenhydramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; diphenhydramine is a CYP2D6 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with CYP2D6 inhibitors, in patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated. Additionally, at high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of diphenhydramine. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); however, the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and diphenhydramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; diphenhydramine is a CYP2D6 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with CYP2D6 inhibitors, in patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated. Additionally, at high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of diphenhydramine. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); however, the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated.
    Diphenhydramine; Ibuprofen: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and diphenhydramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; diphenhydramine is a CYP2D6 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with CYP2D6 inhibitors, in patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated. Additionally, at high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of diphenhydramine. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); however, the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated.
    Diphenhydramine; Naproxen: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and diphenhydramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; diphenhydramine is a CYP2D6 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with CYP2D6 inhibitors, in patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated. Additionally, at high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of diphenhydramine. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); however, the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated.
    Diphenhydramine; Phenylephrine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and diphenhydramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; diphenhydramine is a CYP2D6 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with CYP2D6 inhibitors, in patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated. Additionally, at high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of diphenhydramine. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); however, the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated.
    Dronedarone: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with dronedarone is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and dronedarone is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Duloxetine: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with duloxetine is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and duloxetine is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Eliglustat: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with eliglustat is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and eliglustat is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Enzalutamide: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with enzalutamide is necessary. If enzalutamide is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
    Escitalopram: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with escitalopram is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and escitalopram is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Esomeprazole: (Major) Avoid coadministration of esomeprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of esomeprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Esomeprazole; Naproxen: (Major) Avoid coadministration of esomeprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of esomeprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Famotidine: (Major) Avoid coadministration of famotidine with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of famotidine. Gefitinib exposure is affected by gastric pH. Coadministration with high doses of another H2-blocker to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Famotidine; Ibuprofen: (Major) Avoid coadministration of famotidine with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of famotidine. Gefitinib exposure is affected by gastric pH. Coadministration with high doses of another H2-blocker to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Fluoxetine: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with fluoxetine is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and fluoxetine is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Fluoxetine; Olanzapine: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with fluoxetine is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and fluoxetine is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Fosamprenavir: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with fosamprenavir is necessary. Gefitinib is a CYP3A4 substrate and fosamprenavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Fosphenytoin: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with fosphenytoin is necessary. If fosphenytoin is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
    Grapefruit juice: (Moderate) Instruct patients they may experience increased side effects from gefitinib if they regularly consume grapefruit juice. Gefitinib is a CYP3A4 substrate and grapefruit juice is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Halofantrine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and halofantrine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; halofantrine is a CYP2D6 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with CYP2D6 inhibitors, in patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated.
    Hydroxychloroquine: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with hydroxychloroquine is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and hydroxychloroquine is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Ibuprofen; Oxycodone: (Moderate) Monitor for an increased incidence of oxycodone-related adverse effects if gefitinib and oxycodone are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of oxycodone. As < 15% of the total administered dose is metabolized by CYP2D6 to oxymorphone, concurrent use of some agents that inhibit CYP2D6 has not been shown to result in clinically significant interactions. However, potent inhibitors of CYP2D6, such as ritonavir, may potentially increase the effects of oxycodone. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated such as oxycodone.
    Idelalisib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with idelalisib is necessary. Gefitinib is a CYP3A4 substrate and idelalisib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Indinavir: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with indinavir is necessary. Gefitinib is a CYP3A4 substrate and indinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with rifampin is necessary. If rifampin is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin reduced gefitinib exposure by 83%.
    Isoniazid, INH; Rifampin: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with rifampin is necessary. If rifampin is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin reduced gefitinib exposure by 83%.
    Itraconazole: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with itraconazole is necessary. Gefitinib is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole increased gefitinib exposure by 80%.
    Ketoconazole: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with ketoconazole is necessary. Gefitinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Lansoprazole: (Major) Avoid coadministration of lansoprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of lansoprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Lansoprazole; Naproxen: (Major) Avoid coadministration of lansoprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of lansoprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Letermovir: (Moderate) A clinically relevant increase in the plasma concentration of gefitinib may occur if given with letermovir. Closely monitor for gefitinib-related adverse reactions in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. Gefitinib is predominately metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A4 inhibitor increased mean exposure of gefitinib by 80%.
    Lopinavir; Ritonavir: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with lopinavir; ritonavir is necessary. Gefitinib is a CYP3A4 substrate and lopinavir; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%. (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with ritonavir is necessary. Gefitinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Lumacaftor; Ivacaftor: (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%.
    Lumacaftor; Ivacaftor: (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%.
    Magnesium Hydroxide: (Major) Avoid coadministration of antacids with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next antacid dose. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Meperidine; Promethazine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and promethazine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; promethazine is a moderate CYP2D6 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with CYP2D6 inhibitors, in patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated. Additionally, at high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of promethazine. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); however, the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated.
    Mephobarbital: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with mephobarbital is necessary. If mephobarbital is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and mephobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
    Mifepristone: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with chronic mifepristone therapy is necessary. Gefitinib is a CYP3A4 substrate and mifepristone is a strong CYP3A4 inhibitor. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Mirabegron: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with mirabegron is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and mirabegron is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Mitotane: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with mitotane is necessary. If mitotane is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
    Nefazodone: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with nefazodone is necessary. Gefitinib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Nelfinavir: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with nelfinavir is necessary. Gefitinib is a CYP3A4 substrate and nelfinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Nizatidine: (Major) Avoid coadministration of nizatidine with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of nizatidine. Gefitinib exposure is affected by gastric pH. Coadministration with high doses of an H2-blocker to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with ritonavir is necessary. Gefitinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Omeprazole: (Major) Avoid coadministration of omeprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of omeprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Omeprazole; Sodium Bicarbonate: (Major) Avoid coadministration of omeprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of omeprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%. (Major) Avoid coadministration of sodium bicarbonate with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of sodium bicarbonate. Gefitinib exposure is affected by gastric pH. Coadministration with high doses of ranitidine with sodium bicarbonate to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Oxycodone: (Moderate) Monitor for an increased incidence of oxycodone-related adverse effects if gefitinib and oxycodone are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of oxycodone. As < 15% of the total administered dose is metabolized by CYP2D6 to oxymorphone, concurrent use of some agents that inhibit CYP2D6 has not been shown to result in clinically significant interactions. However, potent inhibitors of CYP2D6, such as ritonavir, may potentially increase the effects of oxycodone. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated such as oxycodone.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Panobinostat: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with panobinostat is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and panobinostat is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Pantoprazole: (Moderate) Avoid coadministration of pantoprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of pantoprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Paroxetine: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with paroxetine is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and paroxetine is a strong CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentosan: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Perphenazine: (Moderate) Monitor for an increased incidence of gefitinib- and perphenazine-related adverse effects if gefitinib and perphenazine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; in vitro, perphenazine is a moderate CYP2D6 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with CYP2D6 inhibitors, in patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated. Additionally, at high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of perphenazine. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated such as perphenazine.
    Perphenazine; Amitriptyline: (Moderate) Monitor for an increased incidence of gefitinib- and perphenazine-related adverse effects if gefitinib and perphenazine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; in vitro, perphenazine is a moderate CYP2D6 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with CYP2D6 inhibitors, in patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated. Additionally, at high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of perphenazine. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated such as perphenazine.
    Phenobarbital: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with phenobarbital is necessary. If phenobarbital is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
    Phentermine; Topiramate: (Moderate) Monitor for clinical response of gefitinib if used concomitantly with topiramate. Gefitinib is metabolized significantly by CYP3A4 and topiramate is a weak CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. This also applies to combination products containing topiramate, such as phentermine; topiramate. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inducers, administration of a single 500 mg gefitinib dose with a concurrent strong CYP3A4 inducer (rifampin) resulted in reduced mean AUC of gefitinib by 83%.
    Phenylephrine; Promethazine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and promethazine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; promethazine is a moderate CYP2D6 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with CYP2D6 inhibitors, in patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated. Additionally, at high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of promethazine. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); however, the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated.
    Phenytoin: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with phenytoin is necessary. If phenytoin is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
    Pimozide: (Moderate) Monitor for an increase in pimozide-related adverse reactions if coadministration with gefitinib is necessary. Pimozide is a CYP2D6 substrate with a narrow therapeutic range and gefitinib is a CYP2D6 inhibitor. While the manufacturer has provided no guidance regarding pimozide use with mild or moderate CYP2D6 inhibitors, concurrent use of the drug with more potent inhibitors of CYP2D6 is contraindicated. Elevated concentrations of pimozide can lead to QT prolongation, ventricular arrhythmias, and sudden death.
    Posaconazole: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with posaconazole is necessary. Gefitinib is a CYP3A4 substrate and posaconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Primidone: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with primidone is necessary. If primidone is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
    Promethazine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and promethazine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; promethazine is a moderate CYP2D6 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with CYP2D6 inhibitors, in patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated. Additionally, at high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of promethazine. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); however, the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated.
    Propafenone: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with propafenone is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and propafenone is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Quinidine: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with quinidine is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and quinidine is strong CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Quinine: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with quinine is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and quinine is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Rabeprazole: (Major) Avoid coadministration of rabeprazole with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 12 hours after the last dose or 12 hours before the next dose of rabeprazole. Gefitinib exposure is affected by gastric pH. Coadministration with another drug to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Ranitidine: (Major) Avoid coadministration of ranitidine with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of ranitidine. Gefitinib exposure is affected by gastric pH. Coadministration of high doses of ranitidine with sodium bicarbonate to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Ranolazine: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with ranolazine is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and ranolazine is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Ribociclib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with ribociclib is necessary. Gefitinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Ribociclib; Letrozole: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with ribociclib is necessary. Gefitinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Rifampin: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with rifampin is necessary. If rifampin is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin reduced gefitinib exposure by 83%.
    Ritonavir: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with ritonavir is necessary. Gefitinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Rolapitant: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with rolapitant is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and rolapitant is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Saquinavir: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with saquinavir is necessary. Gefitinib is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Sodium Bicarbonate: (Major) Avoid coadministration of sodium bicarbonate with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of sodium bicarbonate. Gefitinib exposure is affected by gastric pH. Coadministration with high doses of ranitidine with sodium bicarbonate to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    St. John's Wort, Hypericum perforatum: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with St John's Wort is necessary. If St John's Wort is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and St John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
    Streptogramins: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with dalfopristin; quinupristin is necessary. Gefitinib is a CYP3A4 substrate and quinupristin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Telithromycin: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with telithromycin is necessary. Gefitinib is a CYP3A4 substrate and telithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Terbinafine: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with terbinafine is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and terbinafine is a strong CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Thioridazine: (Severe) The concomitant use of gefitinib and thioridazine is contraindicated; exposure to gefitinib may also increase. Thioridazine is a CYP2D6 substrate and gefitinib is a weak-to-moderate CYP2D6 inhibitor. Concomitant use may increase the risk of serious, potentially fatal, cardiac arrhythmias, such as torsades de pointes (TdP)-type arrhythmias. Additionally, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and thioridazine is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Tipranavir: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with tipranavir is necessary; the risk is increased in CYP2D6 poor metabolizers. Gefitinib is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%. Based on in vitro data, gefitinib is also metabolized to O-desmethyl gefitinib by CYP2D6 and tipranavir is a strong CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Topiramate: (Moderate) Monitor for clinical response of gefitinib if used concomitantly with topiramate. Gefitinib is metabolized significantly by CYP3A4 and topiramate is a weak CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. This also applies to combination products containing topiramate, such as phentermine; topiramate. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inducers, administration of a single 500 mg gefitinib dose with a concurrent strong CYP3A4 inducer (rifampin) resulted in reduced mean AUC of gefitinib by 83%.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Voriconazole: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with voriconazole is necessary. Gefitinib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Warfarin: (Moderate) Regularly monitor INR regularly and watch carefully for signs and symptoms of bleeding if gefitinib and warfarin are used concomitantly. Elevated INR and/or hemorrhage have been reported in some patients taking warfarin while on gefitinib therapy.

    PREGNANCY AND LACTATION

    Pregnancy

    Although there are no adequate and well-controlled studies in pregnant women, gefitinib is considered a potential teratogen in humans because animal studies found gefitinib to be teratogenic at doses below those recommended for human use. Females of reproductive potential should use effective contraception during treatment with gefitinib and for at least 2 weeks after the last dose. Advise pregnant women of the potential hazard to the fetus or risk for pregnancy loss. Studies in rats showed that gefitinib crossed the placenta and led to a reduction in the number of live offspring at doses approximately 20% of the recommended human dose; at doses approximating the human dose on a mg/m2 bases, this effect was accompanied by high neonatal mortality. Reduced fetal weight has also been reported in rabbits at doses about twice the recommended human dose.

    Due to the potential for serious adverse reactions in nursing infants from gefitinib, advise women to discontinue breast-feeding during treatment. It is not known whether gefitinib is present in human milk, although many drugs are excreted in human milk.[45935]

    MECHANISM OF ACTION

    Gefitinib is a synthetic anilinoquinazoline that is a selective inhibitor of the epidermal growth factor receptor-tyrosine kinase (EGFR-TK). The activity of protein tyrosine kinases is tightly regulated since they function as mediators of cell growth, differentiation, and death. Exon 19 deletion and exon 21 (L858R) substitution mutation are activating mutations within NSCLC cells, and have been identified as contributing to the promotion of tumor cell growth, blocking of apoptosis, increasing the production of angiogenic factors, and facilitating the process of metastasis. The binding affinity of gefitinib for EGFR exon 19 deletion or exon 21 (L858R) substitution mutations is higher than its affinity for wild-type EGFR. Gefitinib also inhibits IGF and PDGF-mediated signaling at clinically relevant concentrations. The effect of gefitinib on other tyrosine kinase receptors has not been fully characterized.[45935]
    Gefitinib reversibly binds to the ATP-binding site and completely inhibits autophosphorylation by EGFR-TK. This results in blockage of downstream EGFR signal transduction pathways, cell cycle arrest, and inhibition of angiogenesis.[45935] The skin rash adverse reaction commonly seen with gefitinib is thought to be a result of inhibition of EGRF-positive epidermal keratinocytes and other skin cells that are dependent upon EGFR for normal cellular growth and activity; the appearance of skin rash appears to correlate with clinical activity of the drug.[59976] [59977]

    PHARMACOKINETICS

    Gefitinib is administered orally. In vitro binding to plasma proteins, primarily albumin and alpha-1-acid glycoprotein, is 90% and independent of drug concentrations. Gefitinib is cleared primarily by the liver, with total plasma clearance and elimination half-life of 48 hours after intravenous administration. Steady-state plasma concentrations are achieved within 10 days after daily dosing. Excretion is predominantly via the feces (86%), with renal elimination of the drug and metabolites accounting for less than 4% of the administered dose.[45935]
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2D6
    Gefitinib undergoes significant hepatic metabolism, predominantly via the cytochrome P450 isoenzyme 3A4 (CYP3A4). Three sites of biotransformation have been identified: metabolism of the N-propoxymorpholino group, demethylation of the methoxy-substituent on the quinazoline, and oxidative defluorination of the halogenated phenyl group. A dose adjustment is necessary in patients receiving strong CYP3A4 inducers, with extra monitoring in place for patients receiving strong CYP3A4 inhibitors. Additionally, in vitro CYP2D6 metabolizes gefitinib to its major (14%) active metabolite, O-desmethyl gefitinib, which has similar EGFR-tyrosine kinase activity to gefitinib, but only 1/14 of the potency in a cell-based assay. Eight metabolites have been identified in human plasma, with only O-desmethyl gefitinib having exposure comparable to gefitinib; five metabolites have been fully identified in fecal extracts. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and the mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers; this may be relevant as some adverse drug reactions are related to higher exposure of gefitinib. Monitor known CYP2D6 poor metabolizers for an increased incidence of adverse effects; however, a dose adjustment is not recommended by the manufacturer. The impact of drugs that inhibit CYP2D6 has not been studied, but similar precautions should be in place.[45935]
    In human liver microsome studies, gefitinib inhibited CYP2C19 by 24% and CYP2D6 by 43% at the highest concentration studied (5,000 ng/mL).[45935] In another pharmacokinetic study, gefitinib administration at twice the recommended dose increased the AUC of metoprolol, a CYP2D6 substrate, by 35% which was not statistically significant. The investigators concluded that gefitinib is a weak inhibitor of CYP2D6 that is unlikely to exert a clinically relevant effect on CYP2D6 substrates; however, the potential should be considered in CYP2D6 substrates that have a narrow therapeutic index or are individually dose titrated.[59966] The manufacturer of gefitinib does not recommend precautions in patients receiving CYP2D6 substrates. No inhibitory effects were seen on CYP1A2, CYP2C9, or CYP3A4 at concentrations ranging from 2,000 to 5,000 ng/mL. Gefitinib is a P-glycoprotein (P-gp) substrate, but it is unlikely to influence gefitinib absorption as P-gp is saturated at higher concentrations.[45935]

    Oral Route

    Gefitinib is slowly absorbed with peak plasma levels occurring 3 to 7 hours after dosing with a mean bioavailability of 60%; bioavailability is not meaningfully altered by food. However, the mean AUC of gefitinib was decreased by 47% in healthy subjects when coadministered with high doses of ranitidine and sodium bicarbonate to maintain the gastric pH above 5. Administration of gefitinib with proton pump inhibitors, H2-blockers, and antacids should be avoided if possible. If concomitant use is unavoidable, administration should be separated by 6 hours for antacids and H2-blockers and by 12 hours for proton pump inhibitors. Inter-subject variability (coefficient of variation) for AUC in healthy subjects was 67%. Daily oral administration of gefitinib to cancer patients resulted in a 2-fold accumulation compared to single dose administration.[45935]

    Intravenous Route

    Gefitinib is extensively distributed throughout the body, with a mean steady state volume of distribution of 1,400 liters after intravenous administration.