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  • CLASSES

    Protein Kinase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Oral selective epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI).
    Received accelerated approval for third-line treatment of advanced NSCLC (unselected for EGFR status) in 2003, and was later withdrawn from the market after subsequent clinical trials failed to verify clinical benefit. The current approval is for first-line treatment of EGFR mutation-positive metastatic NSCLC (exon 19 deletion or exon 21 (L858R) substitution mutation) after demonstrating an improvement in ORR in a multicenter, single-arm clinical trial. An unplanned subgroup analysis of another clinical trial found an improvement in PFS and duration of response with gefitinib treatment over carboplatin/paclitaxel.
    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: Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at http://www.fda.gov/CompanionDiagnostics.
    NOTE: The safety and efficacy of gefitinib have not been established in patients with metastatic NSCLC whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution mutations.
    Oral dosage
    Adults

    250 mg PO once daily until disease progression or unacceptable toxicity. In the absence of severe adverse drug reactions, increase the dose to 500 mg PO once daily in patients receiving concomitant strong CYP450 3A4 enzyme inducers. After a median treatment duration of 8 months, patients with EGFR mutation-positive metastatic NSCLC (n = 106) had an objective response rate (ORR) of 50% (95% CI, 41%—59%) with a median duration of response of 6 months (95% CI, 5.6—11.1 months) by blinded independent central review in a multicenter, single-arm, open-label clinical trial. Response rates were similar in patients whose tumors had EGFR exon 19 deletions and exon 21 L858R substitution mutations. An unplanned exploratory analysis of a randomized, multicenter, open-label clinical trial (n = 1217) found improved progression-free survival (PFS) (10.9 months vs. 7.4 months; HR 0.54; 95% CI, 0.38—0.79) and ORR (67% vs. 41%) in EGFR mutation-positive metastatic NSCLC treated with first-line gefitinib compared with carboplatin/paclitaxel.

    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 III trial in 486 patients, median overall survival (OS) (primary endpoint) times were not improved with 250 mg/day PO (5.6 months; hazard ratio (HR) = 1.22; 95% CI, 0.95—1.57; p = 0.12) or 500 mg/day PO (6 months; HR = 1.12; 95% CI, 0.87—1.43; p = 0.39) compared with methotrexate 40 or 60 mg/m2 IV weekly (6.7 months). Additionally, significantly worse OS was reported with 250 mg/day (HR = 1.62; 95% CI, 1.13—2.32; p = 0.01) or 500 mg/day (HR = 1.5; 95% CI, 1.06—2.13; p = 0.02) compared with methotrexate therapy in a subgroup of patients who had platinum-resistant disease. Grade 3—5 tumor hemorrhage was reported in 4 patients (2.5%) who received gefitinib 250 mg/day and 2 patients (1.2%) who received gefitinib 500 mg/day.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    500 mg/day PO.

    Elderly

    500 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    ALT or AST increased > 5 times the upper limit of normal (ULN) (>= Grade 2): Hold gefitinib treatment for up to 14 days. When symptoms resolve to <= grade 1, 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

    Asthma, chronic obstructive pulmonary disease (COPD), pneumonitis, pulmonary disease, pulmonary fibrosis, radiation therapy, respiratory insufficiency

    Interstitial pulmonary disease / interstitial lung disease (ILD) or ILD-like reactions including lung infiltration, pneumonitis, acute respiratory distress syndrome, or pulmonary fibrosis have occurred in 1.3% of patients treated with gefitinib across non-small cell lung cancer (NSCLC) clinical trials (n = 2462), including 3 fatalities; patients with a history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis (radiation therapy) requiring steroid treatment, or any evidence of clinically active interstitial lung disease were excluded from clinical trials. Patients with dyspnea at rest due to complications of advanced malignancy or co-morbidities (e.g. asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, or respiratory insufficiency) may be at increased risk of pulmonary toxicity. Additionally, an exploratory exposure response analysis showed an increase in the incidence of ILD with more than a 2-fold increase in gefitinib exposure. Signs and symptoms include dyspnea, cough, fatigue, fever, and pulmonary infiltrates; these events may or may not occur as sequelae of infusion reactions; hold gefitinib therapy in patients who develop acute or worsening pulmonary symptoms. Permanently discontinue therapy in patients with confirmed, treatment-related ILD.

    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, diverticulitis, GI obstruction, GI perforation, radiation exposure

    Gefitinib therapy has been associated with GI perforation; the typical presentation may include abdominal pain associated with symptoms such as constipation, fever, nausea, and vomiting. Risk factors include a history of ulcers or diverticulitis, radiation exposure, recent sigmoidoscopy or colonoscopy, and GI obstruction. Permanently discontinue gefitinib in patients who develop a GI perforation. Severe diarrhea has also been reported with gefitinib treatment across non-small cell lung cancer (NSCLC) clinical trials (n = 2462). Patients with pre-existing diarrhea or dehydration should be treated prior to receiving gefitinib. Hold gefitinib therapy for severe or persistent diarrhea. Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated or antibiotic therapy if they develop ileus or fever.

    Children

    The safe and effective use of gefitinib in children has not been established. In pediatric clinical trials of gefitinib alone or with radiation therapy for primary CNS tumors, CNS hemorrhage and death have been reported. A causal relationship has not been established due to the limited data available.

    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, pregnancy testing, 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

    According to the manufacturer, either gefitinib or breast-feeding should be discontinued because of the potential for serious adverse reactions in nursing infants from gefitinib. It is not known if gefitinib is excreted in human milk. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    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
    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
    keratitis / 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
    corneal erosion / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    GI perforation / Delayed / Incidence not known
    hemorrhagic cystitis / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known

    Moderate

    bleeding / Early / 4.3-4.3
    dyspnea / Early / 2.0-2.0
    dehydration / Delayed / 1.8-1.8
    ocular inflammation / Early / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    blepharitis / Early / Incidence not known
    bullous rash / Early / Incidence not known
    erythema / 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 / 6.7-6.7
    alopecia / Delayed / 4.7-4.7
    xerostomia / Early / 2.0-2.0
    cough / Delayed / Incidence not known
    ocular pain / Early / Incidence not known
    ocular pruritus / Rapid / Incidence not known
    ocular irritation / Rapid / Incidence not known
    rash / Early / Incidence not known
    acneiform rash / Delayed / Incidence not known
    acne vulgaris / Delayed / Incidence not known
    xerosis / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    vesicular rash / Delayed / Incidence not known
    folliculitis / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    onycholysis / Delayed / Incidence not known
    cheilitis / Delayed / Incidence not known
    epistaxis / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Moderate) Abciximab is contraindicated for use in patients with a platelet count of less than 100,000 cells/microliter. Patients with thrombocytopenia are at increased risk of bleeding complications. Thus, antineoplastic agents that cause clinically significant thrombocytopenia could increase the bleeding risk associated with abciximab. An additive risk of bleeding may occur when abciximab is used with agents that cause clinically significant thrombocytopenia.
    Abiraterone: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and abiraterone are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; abiraterone 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.
    Acetaminophen; Butalbital: (Major) Monitor for clinical response of gefitinib if used concomitantly with butalbital. Gefitinib is metabolized significantly by CYP3A4 and butalbital 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%.
    Acetaminophen; Butalbital; Caffeine: (Major) Monitor for clinical response of gefitinib if used concomitantly with butalbital. Gefitinib is metabolized significantly by CYP3A4 and butalbital 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%.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Monitor for clinical response of gefitinib if used concomitantly with butalbital. Gefitinib is metabolized significantly by CYP3A4 and butalbital 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%. (Moderate) Monitor for decreased efficacy of codeine if gefitinib and codeine are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of codeine to morphine. 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 such as codeine.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of a potent CYP2D6 inhibitor like gefitinib with dihydrocodeine-containing products may decrease the metabolism of dihydrocodeine to dihydromorphine.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and chlorpheniramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; chlorpheniramine 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. (Minor) Monitor for an increased incidence of dextromethorphan-related adverse effects if gefitinib and dextromethorphan are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of dextromethorphan. 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; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and chlorpheniramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; chlorpheniramine 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. (Minor) Monitor for an increased incidence of dextromethorphan-related adverse effects if gefitinib and dextromethorphan are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of dextromethorphan. 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; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and chlorpheniramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; chlorpheniramine 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.
    Acetaminophen; Codeine: (Moderate) Monitor for decreased efficacy of codeine if gefitinib and codeine are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of codeine to morphine. 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 such as codeine.
    Acetaminophen; Dextromethorphan: (Minor) Monitor for an increased incidence of dextromethorphan-related adverse effects if gefitinib and dextromethorphan are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of dextromethorphan. 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; Dextromethorphan; Doxylamine: (Minor) Monitor for an increased incidence of dextromethorphan-related adverse effects if gefitinib and dextromethorphan are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of dextromethorphan. 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; Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Monitor for an increased incidence of dextromethorphan-related adverse effects if gefitinib and dextromethorphan are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of dextromethorphan. 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; Dextromethorphan; Phenylephrine: (Minor) Monitor for an increased incidence of dextromethorphan-related adverse effects if gefitinib and dextromethorphan are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of dextromethorphan. 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; Dextromethorphan; Pseudoephedrine: (Minor) Monitor for an increased incidence of dextromethorphan-related adverse effects if gefitinib and dextromethorphan are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of dextromethorphan. 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; 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; Hydrocodone: (Minor) Monitor for a decrease in the efficacy of hydrocodone if gefitinib and hydrocodone are used concomitantly. The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. At high concentrations, gefitinib is an inhibitor of CYP2D6. 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 hydromorphone.
    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.
    Acetaminophen; Propoxyphene: (Moderate) Propoxyphene is a substrate and an inhibitor of CYP2D6. Increased serum concentrations of propoxyphene would be expected from concurrent use of a CYP2D6 inhibitor, such as gefitinib. A reduced dosage of propoxyphene may be needed. Monitor patients for CNS and respiratory depression.
    Acetaminophen; Tramadol: (Major) Monitor for an increased incidence of tramadol-related adverse effects as well as changes in the efficacy of tramadol if given concurrently with gefitinib. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of tramadol. 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 analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6; therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of CYP2D6 is expected to result in reduced metabolic clearance of tramadol, which in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures; serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. 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 tramadol.
    Aldesleukin, IL-2: (Minor) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and aldesleukin, IL-2 are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and aldesleukin, IL-2 is a weak CYP3A4 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 weak CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Alpha interferons: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Aluminum Hydroxide: (Moderate) If possible, avoid the concomitant use of gefitinib with antacids. If coadministration is necessary, give gefitinib 6 hours after the last dose or 6 hours before the next dose of antacid. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Aluminum Hydroxide; Magnesium Carbonate: (Moderate) If possible, avoid the concomitant use of gefitinib with antacids. If coadministration is necessary, give gefitinib 6 hours after the last dose or 6 hours before the next dose of antacid. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) If possible, avoid the concomitant use of gefitinib with antacids. If coadministration is necessary, give gefitinib 6 hours after the last dose or 6 hours before the next dose of antacid. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) If possible, avoid the concomitant use of gefitinib with antacids. If coadministration is necessary, give gefitinib 6 hours after the last dose or 6 hours before the next dose of antacid. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) If possible, avoid the concomitant use of gefitinib with antacids. If coadministration is necessary, give gefitinib 6 hours after the last dose or 6 hours before the next dose of antacid. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Amiodarone: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and amiodarone are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; amiodarone is a CYP3A4 inhibitor and a mild inhibitor of CYP2D6. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. 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.
    Amitriptyline: (Major) 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.
    Amitriptyline; Chlordiazepoxide: (Major) 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.
    Amobarbital: (Major) Monitor for clinical response of gefitinib if used concomitantly with amobarbital. Gefitinib is metabolized significantly by CYP3A4 and amobarbital, like other barbiturates, 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%.
    Amoxapine: (Major) Monitor for an increased incidence of amoxapine-related adverse effects if gefitinib and amoxapine are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of amoxapine. 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 amoxapine.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and clarithromycin are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. (Moderate) If possible, avoid the concomitant use of gefitinib with lansoprazole. If coadministration is necessary, give gefitinib 12 hours after the last dose or 12 hours before the next dose of lansoprazole. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and clarithromycin are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. (Moderate) If possible, avoid the concomitant use of gefitinib with omeprazole. If coadministration is necessary, give gefitinib 12 hours after the last dose or 12 hours before the next dose of omeprazole. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Amprenavir: (Moderate) Substances that are potent inhibitors of cytochrome P450 3A4 activity, such as amprenavir, decrease the metabolism of gefitinib and increase gefitinib concentrations. This increase may be clinically relevant as adverse reactions to gefitinib are related to dose and exposure; therefore caution should be used when administering CYP3A4 inhibitors with gefitinib.
    Anagrelide: (Minor) Anagrelide inhibits platelet aggregation at high doses. Patients with thrombocytopenia are at increased risk of bleeding complications. An increased risk of bleeding may occur when anagrelide is used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Antacids: (Moderate) If possible, avoid the concomitant use of gefitinib with antacids. If coadministration is necessary, give gefitinib 6 hours after the last dose or 6 hours before the next dose of antacid. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Antithrombin III: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Antithymocyte Globulin: (Moderate) Because antithymocyte globulin is an immunosuppressant, additive affects may be seen with other immunosuppressives or antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk of infection or other side effects.
    Apalutamide: (Major) Increase the dose of gefitinib to 500 mg PO once daily in patients taking gefitinib concurrently with apalutamide; monitor carefully for adverse effects of gefitinib. Resume gefitinib 250 mg PO daily 7 days after discontinuation of apalutamide. Gefitinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased gefitinib exposure by 83%.
    Aprepitant, Fosaprepitant: (Major) Use caution if gefitinib and aprepitant, fosaprepitant are used concurrently and monitor for an increase in gefitinib-related adverse effects for several days after administration of a multi-day aprepitant regimen. Gefitinib is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of gefitinib. While the manufacturer of gefitinib has provided no guidance regarding its' use with weak or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. The AUC of a single dose of another CYP3A4 substrate, midazolam, increased by 2.3-fold on day 1 and by 3.3-fold on day 5 when coadministered with a 5-day oral aprepitant regimen. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    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.
    Armodafinil: (Moderate) Monitor for clinical response of gefitinib if used concomitantly with armodafinil. Gefitinib is metabolized significantly by CYP3A4 and in vitro, armodafinil is a weak 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 resulted in reduced mean AUC of gefitinib by 83%.
    Asenapine: (Minor) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and asenapine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; in vitro, asenapine is a weak 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.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Monitor for clinical response of gefitinib if used concomitantly with butalbital. Gefitinib is metabolized significantly by CYP3A4 and butalbital 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%.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Monitor for clinical response of gefitinib if used concomitantly with butalbital. Gefitinib is metabolized significantly by CYP3A4 and butalbital 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%. (Moderate) Monitor for decreased efficacy of codeine if gefitinib and codeine are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of codeine to morphine. 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 such as codeine.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of a potent CYP2D6 inhibitor like gefitinib with dihydrocodeine-containing products may decrease the metabolism of dihydrocodeine to dihydromorphine.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Monitor for decreased efficacy of codeine if gefitinib and codeine are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of codeine to morphine. 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 such as codeine.
    Aspirin, ASA; Dipyridamole: (Moderate) Concurrent use of dipyridamole and gefitinib may lead to an increased risk of bleeding.
    Aspirin, ASA; Omeprazole: (Moderate) If possible, avoid the concomitant use of gefitinib with omeprazole. If coadministration is necessary, give gefitinib 12 hours after the last dose or 12 hours before the next dose of omeprazole. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC 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: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and atazanavir are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and atazanavir is a strong CYP3A4 inhibitor; additionally, cobicistat is a CYP3A4 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. Gefitinib is metabolized to a smaller extent by CYP2D6 and cobicistat is a CYP2D6 inhibitor. 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.
    Atazanavir; Cobicistat: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and atazanavir are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and atazanavir is a strong CYP3A4 inhibitor; additionally, cobicistat is a CYP3A4 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. Gefitinib is metabolized to a smaller extent by CYP2D6 and cobicistat is a CYP2D6 inhibitor. 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. (Moderate) Caution is warranted when cobicistat is administered with gefitinib as there is a potential for elevated gefitinib and cobicistat concentrations. Gefitinib is a CYP3A4 substrate and CYP2D6 inhibitor. Cobicistat is an inhibitor of CYP3A4 and a substrate/inhibitor of CYP2D6.
    Atomoxetine: (Moderate) Monitor for an increased incidence of atomoxetine-related adverse effects including dizziness, drowsiness, nervousness, insomnia, and cardiac effects (e.g., hypertension, increased pulse rate, QT prolongation) if gefitinib and atomoxetine are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of atomoxetine. 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.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Increase the dose of gefitinib to 500 mg PO once daily in patients taking gefitinib concurrently with phenobarbital; monitor carefully for adverse effects of gefitinib. Resume gefitinib 250 mg PO daily 7 days after discontinuation of phenobarbital. Gefitinib is metabolized significantly by CYP3A4 and phenobarbital is a strong CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. Administration of a single 500 mg gefitinib dose with another strong CYP3A4 inducer (rifampin) reduced the gefitinib mean AUC by 83%.
    Bacillus Calmette-Guerin Vaccine, BCG: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Increase the dose of gefitinib to 500 mg PO once daily in patients taking gefitinib concurrently with phenobarbital; monitor carefully for adverse effects of gefitinib. Resume gefitinib 250 mg PO daily 7 days after discontinuation of phenobarbital. Gefitinib is metabolized significantly by CYP3A4 and phenobarbital is a strong CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. Administration of a single 500 mg gefitinib dose with another strong CYP3A4 inducer (rifampin) reduced the gefitinib mean AUC by 83%.
    Bexarotene: (Major) Monitor for clinical response of gefitinib if used concomitantly with bexarotene. Gefitinib is metabolized significantly by CYP3A4 and bexarotene 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%.
    Boceprevir: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and boceprevir are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and boceprevir is a strong CYP3A4 inhibitor; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Bosentan: (Major) Monitor for clinical response of gefitinib if used concomitantly with bosentan. Gefitinib is metabolized significantly by CYP3A4 and bosentan 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%.
    Brigatinib: (Moderate) Monitor for decreased efficacy of gefitinib if coadministration with brigatinib is necessary. Gefitinib is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of gefitinib may decrease. Concomitant administration with a strong inducer of CYP3A4 reduced mean AUC of gefitinib by 83%.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Minor) Monitor for an increased incidence of dextromethorphan-related adverse effects if gefitinib and dextromethorphan are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of dextromethorphan. 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.
    Brompheniramine; Guaifenesin; Hydrocodone: (Minor) Monitor for a decrease in the efficacy of hydrocodone if gefitinib and hydrocodone are used concomitantly. The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. At high concentrations, gefitinib is an inhibitor of CYP2D6. 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 hydromorphone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Minor) Monitor for a decrease in the efficacy of hydrocodone if gefitinib and hydrocodone are used concomitantly. The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. At high concentrations, gefitinib is an inhibitor of CYP2D6. 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 hydromorphone.
    Bupropion: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and bupropion are used concomitantly; this also applies to combination products containing bupropion, such as bupropion; naltrexone. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; in vitro, bupriopion is a weak 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.
    Bupropion; Naltrexone: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and bupropion are used concomitantly; this also applies to combination products containing bupropion, such as bupropion; naltrexone. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; in vitro, bupriopion is a weak 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.
    Calcium Carbonate: (Moderate) If possible, avoid the concomitant use of gefitinib with antacids. If coadministration is necessary, give gefitinib 6 hours after the last dose or 6 hours before the next dose of antacid. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Calcium Carbonate; Magnesium Hydroxide: (Moderate) If possible, avoid the concomitant use of gefitinib with antacids. If coadministration is necessary, give gefitinib 6 hours after the last dose or 6 hours before the next dose of antacid. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Calcium Carbonate; Risedronate: (Moderate) If possible, avoid the concomitant use of gefitinib with antacids. If coadministration is necessary, give gefitinib 6 hours after the last dose or 6 hours before the next dose of antacid. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Calcium; Vitamin D: (Moderate) If possible, avoid the concomitant use of gefitinib with antacids. If coadministration is necessary, give gefitinib 6 hours after the last dose or 6 hours before the next dose of antacid. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Carbamazepine: (Major) Increase the dose of gefitinib to 500 mg PO once daily in patients taking gefitinib concurrently with carbamazepine; monitor carefully for adverse effects of gefitinib. Resume gefitinib 250 mg PO daily 7 days after discontinuation of carbamazepine. Gefitinib is metabolized significantly by CYP3A4 and carbamazepine is a strong CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. Administration of a single 500 mg gefitinib dose with another strong CYP3A4 inducer (rifampin) reduced the gefitinib mean AUC by 83%. Additionally, at high concentrations gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of carbamazepine. 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 carbamazepine.
    Carbetapentane; Chlorpheniramine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and chlorpheniramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; chlorpheniramine 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.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and chlorpheniramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; chlorpheniramine 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.
    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.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Minor) Monitor for an increased incidence of dextromethorphan-related adverse effects if gefitinib and dextromethorphan are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of dextromethorphan. 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.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Minor) Monitor for a decrease in the efficacy of hydrocodone if gefitinib and hydrocodone are used concomitantly. The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. At high concentrations, gefitinib is an inhibitor of CYP2D6. 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 hydromorphone.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Minor) Monitor for a decrease in the efficacy of hydrocodone if gefitinib and hydrocodone are used concomitantly. The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. At high concentrations, gefitinib is an inhibitor of CYP2D6. 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 hydromorphone.
    Carvedilol: (Moderate) Monitor for an increased incidence of carvedilol-related adverse effects if gefitinib and carvedilol are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of carvedilol. 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); additionally, coadministration of cimetidine, a CYP2D6 inhibitor, with carvedilol increased carvedilol steady-state AUC by 30%. 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 carvedilol.
    Ceritinib: (Moderate) Monitor for gefitinib-related adverse reactions if coadministration with ceritinib is necessary. Ceritinib is a CYP3A4 inhibitor and gefitinib is metabolized by CYP3A4. Coadministration with a strong CYP3A4 inhibitor increased the gefitinib AUC by 80%; the degree of CYP3A4 inhibition by ceritinib is unknown.
    Cevimeline: (Moderate) Cevimeline is partially metabolized by CYP2D6. Inhibitors of this isoenzyme, like gefitinib, would be expected to lead to an increase in cevimeline plasma concentrations.
    Chloramphenicol: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and chloramphenicol are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and chloramphenicol is a strong CYP3A4 inhibitor; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Chlorpheniramine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and chlorpheniramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; chlorpheniramine 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.
    Chlorpheniramine; Codeine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and chlorpheniramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; chlorpheniramine 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. (Moderate) Monitor for decreased efficacy of codeine if gefitinib and codeine are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of codeine to morphine. 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 such as codeine.
    Chlorpheniramine; Dextromethorphan: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and chlorpheniramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; chlorpheniramine 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. (Minor) Monitor for an increased incidence of dextromethorphan-related adverse effects if gefitinib and dextromethorphan are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of dextromethorphan. 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.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and chlorpheniramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; chlorpheniramine 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. (Minor) Monitor for an increased incidence of dextromethorphan-related adverse effects if gefitinib and dextromethorphan are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of dextromethorphan. 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.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and chlorpheniramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; chlorpheniramine 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. (Moderate) Concomitant use of a potent CYP2D6 inhibitor like gefitinib with dihydrocodeine-containing products may decrease the metabolism of dihydrocodeine to dihydromorphine.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and chlorpheniramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; chlorpheniramine 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. (Moderate) Concomitant use of a potent CYP2D6 inhibitor like gefitinib with dihydrocodeine-containing products may decrease the metabolism of dihydrocodeine to dihydromorphine.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and chlorpheniramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; chlorpheniramine 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. (Minor) Monitor for a decrease in the efficacy of hydrocodone if gefitinib and hydrocodone are used concomitantly. The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. At high concentrations, gefitinib is an inhibitor of CYP2D6. 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 hydromorphone.
    Chlorpheniramine; Hydrocodone: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and chlorpheniramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; chlorpheniramine 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. (Minor) Monitor for a decrease in the efficacy of hydrocodone if gefitinib and hydrocodone are used concomitantly. The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. At high concentrations, gefitinib is an inhibitor of CYP2D6. 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 hydromorphone.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and chlorpheniramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; chlorpheniramine 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. (Minor) Monitor for a decrease in the efficacy of hydrocodone if gefitinib and hydrocodone are used concomitantly. The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. At high concentrations, gefitinib is an inhibitor of CYP2D6. 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 hydromorphone.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and chlorpheniramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; chlorpheniramine 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. (Minor) Monitor for a decrease in the efficacy of hydrocodone if gefitinib and hydrocodone are used concomitantly. The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. At high concentrations, gefitinib is an inhibitor of CYP2D6. 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 hydromorphone.
    Chlorpheniramine; Phenylephrine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and chlorpheniramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; chlorpheniramine 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.
    Chlorpheniramine; Pseudoephedrine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and chlorpheniramine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; chlorpheniramine 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.
    Chlorpromazine: (Minor) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and chlorpromazine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; in vitro, chlorpromazine is a weak 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 chlorpromazine. 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.
    Cimetidine: (Moderate) If possible, avoid the concomitant use of gefitinib with cimetidine. If coadministration is necessary, give gefitinib 6 hours after the last dose or 6 hours before the next dose of cimetidine and monitor for an increased incidence of gefitinib-related adverse effects. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%. Additionally, gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; cimetidine is a weak CYP3A4 and 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 mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. 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.
    Cinacalcet: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and cinacalcet are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; cinacalcet is a strong 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.
    Citalopram: (Major) Do not exceed 20 mg/day of citalopram in patients receiving gefitinib. Monitor for a potential increase in side effects or toxicity, including QT prolongation. Citalopram causes dose-dependent QT interval prolongation. Gefitinib is an inhibitor of CYP2C19 and may increase citalopram exposure increasing the risk of citalopram-induced QT prolongation.
    Clarithromycin: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and clarithromycin are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Clomipramine: (Moderate) Monitor for an increased incidence of clomipramine-related adverse effects if gefitinib and clomipramine are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of clomipramine. 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 clomipramine.
    Clopidogrel: (Major) Gefitinib may reduce the antiplatelet activity of clopidogrel by inhibiting clopidogrel's metabolism to its active metabolite. Use clopidogrel and gefitinib together with caution and monitor for reduced efficacy of clopidogrel. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps; the CYP2C19 isoenzyme is involved in both steps. Gefitinib is an inhibitor of CYP2C19. In addition, because clopidogrel inhibits platelet aggregation, a potential additive risk for bleeding exists if clopidogrel is given in combination with other drugs that affect hemostasis. Clopidogrel should be used cautiously in patients with thrombocytopenia following the administration of myelosuppressive antineoplastic agents or other drugs that cause significant thrombocytopenia due to the increased risk of bleeding. Monitor for reduced efficacy of clopidogrel and for increased bleeding.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist. Additionally, at high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of clozapine. 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 clozapine.
    Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with gefitinib as there is a potential for elevated gefitinib and cobicistat concentrations. Gefitinib is a CYP3A4 substrate and CYP2D6 inhibitor. Cobicistat is an inhibitor of CYP3A4 and a substrate/inhibitor of CYP2D6.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with gefitinib as there is a potential for elevated gefitinib and cobicistat concentrations. Gefitinib is a CYP3A4 substrate and CYP2D6 inhibitor. Cobicistat is an inhibitor of CYP3A4 and a substrate/inhibitor of CYP2D6.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with gefitinib as there is a potential for elevated gefitinib and cobicistat concentrations. Gefitinib is a CYP3A4 substrate and CYP2D6 inhibitor. Cobicistat is an inhibitor of CYP3A4 and a substrate/inhibitor of CYP2D6.
    Codeine: (Moderate) Monitor for decreased efficacy of codeine if gefitinib and codeine are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of codeine to morphine. 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 such as codeine.
    Codeine; Guaifenesin: (Moderate) Monitor for decreased efficacy of codeine if gefitinib and codeine are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of codeine to morphine. 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 such as codeine.
    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. (Moderate) Monitor for decreased efficacy of codeine if gefitinib and codeine are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of codeine to morphine. 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 such as codeine.
    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. (Moderate) Monitor for decreased efficacy of codeine if gefitinib and codeine are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of codeine to morphine. 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 such as codeine.
    Conivaptan: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as gefitinib, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with gefitinib. Treatment with gefitinib may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Cyclosporine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and cyclosporine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and cyclosporine is a moderate CYP3A4 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 mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Dabrafenib: (Major) Monitor for clinical response of gefitinib if used concomitantly with dabrafenib. Gefitinib is metabolized significantly by CYP3A4 and dabrafenib 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%.
    Dalfopristin; Quinupristin: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and dalfopristin; quinupristin are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and quinupristin is a strong CYP3A4 inhibitor; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Dalteparin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Danazol: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and danazol are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and danazol is a moderate CYP3A4 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 mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Darifenacin: (Moderate) Clinicians should monitor patients for increased anticholinergic effects when CYP2D6 inhibitors, such as gefitinib, are coadministered with darifenacin; the dosage of darifenacin should be adjusted, if necessary.
    Darunavir: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and darunavir are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and is darunavir is a strong CYP3A4 inhibitor; additionally, cobicistat is a CYP3A4 inhibitor. Coadministration with darunavir or darunavir; cobicistat may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. Gefitinib is metabolized to a smaller extent by CYP2D6 and cobicistat is a CYP2D6 inhibitor. 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.
    Darunavir; Cobicistat: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and darunavir are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and is darunavir is a strong CYP3A4 inhibitor; additionally, cobicistat is a CYP3A4 inhibitor. Coadministration with darunavir or darunavir; cobicistat may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. Gefitinib is metabolized to a smaller extent by CYP2D6 and cobicistat is a CYP2D6 inhibitor. 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. (Moderate) Caution is warranted when cobicistat is administered with gefitinib as there is a potential for elevated gefitinib and cobicistat concentrations. Gefitinib is a CYP3A4 substrate and CYP2D6 inhibitor. Cobicistat is an inhibitor of CYP3A4 and a substrate/inhibitor of CYP2D6.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib is used concomitantly with either lopinavir or ritonavir. Gefitinib is metabolized significantly by CYP3A4 and both lopinavir and ritonavir are strong CYP3A4 inhibitors; gefitinib is metabolized to a lesser extent by CYP2D6, and ritonavir inhibits CYP2D6 in vitro. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. 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.
    Deferasirox: (Major) Monitor for clinical response of gefitinib if used concomitantly with deferasirox. Gefitinib is metabolized significantly by CYP3A4 and deferasirox 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%.
    Delavirdine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and delavirdine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; delavirdine is a strong CYP3A4 inhibitor and in vitro, also inhibits CYP2D6. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. 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.
    Desipramine: (Major) Monitor for an increased incidence of desipramine-related adverse effects if gefitinib and desipramine are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of desipramine. 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 such as desipramine.
    Desirudin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Desvenlafaxine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and desvenlafaxine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6. Desvenlafaxine is a CYP2D6 inhibitor; however, clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 inhibition at doses of 100 mg/day. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer of gefitinib has provided no guidance regarding its use 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. The manufacturer of desvenlafaxine recommends that the dose of primary substrates of CYP2D6 be reduced when coadministered with Pristiq 400 mg/day; however, CYP2D6 is not the primary route of metabolism for gefitinib.
    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%.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Monitor for an increased incidence of dextromethorphan-related adverse effects if gefitinib and dextromethorphan are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of dextromethorphan. 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.
    Dexlansoprazole: (Moderate) If possible, avoid the concomitant use of gefitinib with dexlansoprazole. If coadministration is necessary, give gefitinib 12 hours after the last dose or 12 hours before the next dose of dexlansoprazole. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Dextromethorphan: (Minor) Monitor for an increased incidence of dextromethorphan-related adverse effects if gefitinib and dextromethorphan are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of dextromethorphan. 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; 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. (Minor) Monitor for an increased incidence of dextromethorphan-related adverse effects if gefitinib and dextromethorphan are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of dextromethorphan. 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; Guaifenesin: (Minor) Monitor for an increased incidence of dextromethorphan-related adverse effects if gefitinib and dextromethorphan are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of dextromethorphan. 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; Guaifenesin; Phenylephrine: (Minor) Monitor for an increased incidence of dextromethorphan-related adverse effects if gefitinib and dextromethorphan are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of dextromethorphan. 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; Guaifenesin; Potassium Guaiacolsulfonate: (Minor) Monitor for an increased incidence of dextromethorphan-related adverse effects if gefitinib and dextromethorphan are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of dextromethorphan. 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; Guaifenesin; Pseudoephedrine: (Minor) Monitor for an increased incidence of dextromethorphan-related adverse effects if gefitinib and dextromethorphan are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of dextromethorphan. 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. (Minor) Monitor for an increased incidence of dextromethorphan-related adverse effects if gefitinib and dextromethorphan are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of dextromethorphan. 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: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and quinidine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; quinidine is a strong 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. (Minor) Monitor for an increased incidence of dextromethorphan-related adverse effects if gefitinib and dextromethorphan are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of dextromethorphan. 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.
    Diclofenac: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Diclofenac; Misoprostol: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of a potent CYP2D6 inhibitor like gefitinib with dihydrocodeine-containing products may decrease the metabolism of dihydrocodeine to dihydromorphine.
    Diltiazem: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and diltiazem are used concomitantly; this also applies to the combination product, diltiazem; enalapril. Gefitinib is metabolized significantly by CYP3A4 and diltiazem is a moderate CYP3A4 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 mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    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. (Minor) Monitor for a decrease in the efficacy of hydrocodone if gefitinib and hydrocodone are used concomitantly. The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. At high concentrations, gefitinib is an inhibitor of CYP2D6. 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 hydromorphone.
    Diphenhydramine; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. (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. (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    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.
    Dipyridamole: (Moderate) Concurrent use of dipyridamole and gefitinib may lead to an increased risk of bleeding.
    Dolasetron: (Major) Monitor for an increased incidence of dolasetron-related adverse effects if gefitinib and dolasetron are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of dolasetron. 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.
    Donepezil: (Moderate) Monitor for an increased incidence of donepezil-related adverse effects if gefitinib and donepezil are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of donepezil. 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 donepezil.
    Donepezil; Memantine: (Moderate) Monitor for an increased incidence of donepezil-related adverse effects if gefitinib and donepezil are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of donepezil. 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 donepezil.
    Doxepin: (Major) Monitor for an increased incidence of doxepin-related adverse effects if gefitinib and doxepin are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of doxepin. 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 doxepin.
    Doxercalciferol: (Moderate) CYP450 enzyme inhibitors, like gefitinib, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if CYP450 inhibitors are coadministered with doxercalciferol.
    Doxorubicin: (Major) Monitor for an increased incidence of doxorubicin-related adverse effects if gefitinib and doxorubicin are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of doxorubicin. 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: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and dronedarone are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; dronedarone is a moderate CYP3A4 and 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 mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. 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.
    Duloxetine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and duloxetine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; duloxetine 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.
    Dutasteride; Tamsulosin: (Moderate) Use caution when administering tamsulosin with a moderate CYP2D6 inhibitor such as gefitinib. Tamsulosin is extensively metabolized by CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP2D6 inhibitor resulted in increases in tamsulosin exposure; interactions with moderate CYP2D6 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Efavirenz: (Moderate) Monitor for clinical response of gefitinib if used concomitantly with efavirenz. Gefitinib is metabolized significantly by CYP3A4 and efavirenz 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%.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Monitor for clinical response of gefitinib if used concomitantly with efavirenz. Gefitinib is metabolized significantly by CYP3A4 and efavirenz 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%.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for clinical response of gefitinib if used concomitantly with efavirenz. Gefitinib is metabolized significantly by CYP3A4 and efavirenz 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%.
    Elbasvir; Grazoprevir: (Major) Administering gefitinib with grazoprevir may result in elevated gefitinib plasma concentrations. Gefitinib is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eliglustat: (Major) In extensive or intermediate CYP2D6 metabolizers (EMs or IMs), coadministration of gefitinib and eliglustat requires dosage reduction of eliglustat to 84 mg PO once daily; however, coadministration of eliglustat with both gefitinib and a strong or moderate CYP3A inhibitor is contraindicated. Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and eliglustat are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; eliglustat is a CYP2D6 inhibitor. Additionally, at high concentrations, gefitinib is an inhibitor of CYP2D6; eliglustat is a CYP2D6 and CYP3A substrate. 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. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations, and may also increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias). 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.
    Encainide: (Major) Encainide is significantly metabolized by CYP2D6 isoenzymes. Caution is recommended when administering encainide with CYP2D6 inhibitors, such as gefitinib, since encainide exhibits a narrow therapeutic range and large increases in serum concentrations may be associated with severe adverse reactions.
    Enoxaparin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Enzalutamide: (Major) Increase the dose of gefitinib to 500 mg PO once daily in patients taking gefitinib concurrently with enzalutamide; monitor carefully for adverse effects of gefitinib. Resume gefitinib 250 mg PO daily 7 days after discontinuation of enzalutamide. Gefitinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased gefitinib exposure by 83%.
    Eptifibatide: (Moderate) Patients with thrombocytopenia are at increased risk of bleeding complications. An increased risk of bleeding may occur when eptifibatide is used concomitantly with agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Erythromycin: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and erythromycin are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and erythromycin is a moderate CYP3A4 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 mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor increased the mean AUC of gefitinib by 80%.
    Erythromycin; Sulfisoxazole: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and erythromycin are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and erythromycin is a moderate CYP3A4 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 mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor increased the mean AUC of gefitinib by 80%.
    Escitalopram: (Minor) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and escitalopram are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; escitalopram is a weak 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.
    Eslicarbazepine: (Major) Monitor for clinical response of gefitinib if used concomitantly with eslicarbazepine. Gefitinib is metabolized significantly by CYP3A4 and eslicarbazepine 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%.
    Esomeprazole: (Moderate) If possible, avoid the concomitant use of gefitinib with esomeprazole; this also applies to combination products, such as esomeprazole; naproxen. If coadministration is necessary, give gefitinib 12 hours after the last dose or 12 hours before the next dose of esomeprazole. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Esomeprazole; Naproxen: (Moderate) If possible, avoid the concomitant use of gefitinib with esomeprazole; this also applies to combination products, such as esomeprazole; naproxen. If coadministration is necessary, give gefitinib 12 hours after the last dose or 12 hours before the next dose of esomeprazole. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%. (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ethotoin: (Major) Increase the dose of gefitinib to 500 mg PO once daily in patients taking gefitinib concurrently with phenytoin or fosphenytoin (and possibly ethotoin); monitor carefully for adverse effects of gefitinib. Resume gefitinib 250 mg PO daily 7 days after discontinuation of phenytoin / fosphenytoin. Gefitinib is metabolized significantly by CYP3A4 and both phenytoin and fosphenytoin are strong CYP3A4 inducers; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. Administration of a single 500 mg gefitinib dose with another strong CYP3A4 inducer (rifampin) reduced the gefitinib mean AUC by 83%.
    Etodolac: (Minor) An increased risk of bleeding may occur when NSAIDs, such as etodolac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Etravirine: (Major) Monitor for clinical response of gefitinib if used concomitantly with etravirine. Gefitinib is metabolized significantly by CYP3A4 and etravirine 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%.
    Famotidine: (Moderate) If possible, avoid the concomitant use of gefitinib with famotidine. If coadministration is necessary, give gefitinib 6 hours after the last dose or 6 hours before the next dose of famotidine. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Famotidine; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. (Moderate) If possible, avoid the concomitant use of gefitinib with famotidine. If coadministration is necessary, give gefitinib 6 hours after the last dose or 6 hours before the next dose of famotidine. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Felbamate: (Moderate) Monitor for clinical response of gefitinib if used concomitantly with felbamate. Gefitinib is metabolized significantly by CYP3A4 and felbamate is a weak 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%.
    Flecainide: (Major) Flecainide is significantly metabolized by CYP2D6 isoenzymes. Caution is recommended when administering flecainide with CYP2D6 inhibitors, such as gefitinib; flecainide exhibits a narrow therapeutic range and large increases in serum concentrations may be associated with severe adverse reactions.
    Fluconazole: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and fluconazole are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and fluconazole is a moderate CYP3A4 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 mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Fluoxetine; Olanzapine: (Moderate) Monitor for an increased incidence of olanzapine-related adverse effects if gefitinib and olanzapine are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of olanzapine. 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 olanzapine.
    Fluphenazine: (Moderate) Monitor for an increased incidence of gefitinib- and fluphenazine-related adverse effects, including QT prolongation, if gefitinib and fluphenazine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; in vitro, fluphenazine is a weak 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 fluphenazine. 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 fluphenazine.
    Flurbiprofen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as flurbiprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Flutamide: (Major) Monitor for clinical response of gefitinib if used concomitantly with flutamide. Gefitinib is metabolized significantly by CYP3A4 and in vitro, flutamide 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%.
    Fondaparinux: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Fosamprenavir: (Major) Monitor for clinical response of gefitinib and an increased incidence of gefitinib-related adverse effects if gefitinib and fosamprenavir are used concomitantly. Gefitinib is metabolized significantly by CYP3A4; fosamprenavir is a strong inhibitor and moderate inducer of CYP3A4. Coadministration may alter gefitinib serum concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%; administration of a single dose of gefitinib with a strong CYP3A4 inducer (rifampin) decreased mean AUC by 83%.
    Fosphenytoin: (Major) Increase the dose of gefitinib to 500 mg PO once daily in patients taking gefitinib concurrently with phenytoin or fosphenytoin (and possibly ethotoin); monitor carefully for adverse effects of gefitinib. Resume gefitinib 250 mg PO daily 7 days after discontinuation of phenytoin / fosphenytoin. Gefitinib is metabolized significantly by CYP3A4 and both phenytoin and fosphenytoin are strong CYP3A4 inducers; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. Administration of a single 500 mg gefitinib dose with another strong CYP3A4 inducer (rifampin) reduced the gefitinib mean AUC by 83%.
    Grapefruit juice: (Moderate) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib is taken with grapefruit juice. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; grapefruit juice is a strong CYP3A4 inhibitor and in vitro, also inhibits CYP2D6; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. 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.
    Guaifenesin; Hydrocodone: (Minor) Monitor for a decrease in the efficacy of hydrocodone if gefitinib and hydrocodone are used concomitantly. The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. At high concentrations, gefitinib is an inhibitor of CYP2D6. 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 hydromorphone.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Minor) Monitor for a decrease in the efficacy of hydrocodone if gefitinib and hydrocodone are used concomitantly. The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. At high concentrations, gefitinib is an inhibitor of CYP2D6. 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 hydromorphone.
    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.
    Haloperidol: (Moderate) Gefitinib is an inhibitor of CYP2D6, the primary isoenzyme responsible for the metabolism of haloperidol. Mild to moderate increases in haloperidol plasma concentrations have been reported during concurrent use of haloperidol and inhibitors of CYP2D6. Until more data are available, it is advisable to closely monitor for adverse events when these medications are co-administered.
    Heparin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Homatropine; Hydrocodone: (Minor) Monitor for a decrease in the efficacy of hydrocodone if gefitinib and hydrocodone are used concomitantly. The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. At high concentrations, gefitinib is an inhibitor of CYP2D6. 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 hydromorphone.
    Hydantoins: (Major) Increase the dose of gefitinib to 500 mg PO once daily in patients taking gefitinib concurrently with phenytoin or fosphenytoin (and possibly ethotoin); monitor carefully for adverse effects of gefitinib. Resume gefitinib 250 mg PO daily 7 days after discontinuation of phenytoin / fosphenytoin. Gefitinib is metabolized significantly by CYP3A4 and both phenytoin and fosphenytoin are strong CYP3A4 inducers; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. Administration of a single 500 mg gefitinib dose with another strong CYP3A4 inducer (rifampin) reduced the gefitinib mean AUC by 83%.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Monitor for an increased incidence of metoprolol-related adverse effects if gefitinib and metoprolol are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of metoprolol. In patients with solid tumors, exposure to metoprolol 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 metoprolol.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Monitor for an increased incidence of propranolol-related adverse effects if gefitinib and propranolol are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is primarily responsible for the metabolism of propranolol. 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 propranolol.
    Hydrocodone: (Minor) Monitor for a decrease in the efficacy of hydrocodone if gefitinib and hydrocodone are used concomitantly. The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. At high concentrations, gefitinib is an inhibitor of CYP2D6. 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 hydromorphone.
    Hydrocodone; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. (Minor) Monitor for a decrease in the efficacy of hydrocodone if gefitinib and hydrocodone are used concomitantly. The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. At high concentrations, gefitinib is an inhibitor of CYP2D6. 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 hydromorphone.
    Hydrocodone; Phenylephrine: (Minor) Monitor for a decrease in the efficacy of hydrocodone if gefitinib and hydrocodone are used concomitantly. The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. At high concentrations, gefitinib is an inhibitor of CYP2D6. 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 hydromorphone.
    Hydrocodone; Potassium Guaiacolsulfonate: (Minor) Monitor for a decrease in the efficacy of hydrocodone if gefitinib and hydrocodone are used concomitantly. The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. At high concentrations, gefitinib is an inhibitor of CYP2D6. 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 hydromorphone.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Minor) Monitor for a decrease in the efficacy of hydrocodone if gefitinib and hydrocodone are used concomitantly. The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. At high concentrations, gefitinib is an inhibitor of CYP2D6. 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 hydromorphone.
    Hydrocodone; Pseudoephedrine: (Minor) Monitor for a decrease in the efficacy of hydrocodone if gefitinib and hydrocodone are used concomitantly. The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. At high concentrations, gefitinib is an inhibitor of CYP2D6. 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 hydromorphone.
    Hydroxychloroquine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and hydroxychloroquine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; hydroxychloroquine 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.
    Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ibuprofen; Oxycodone: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. (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.
    Ibuprofen; Pseudoephedrine: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Idelalisib: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and idelalisib are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and idelalisib is a strong CYP3A4 inhibitor; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Imatinib: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and imatinib, STI-571 are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; imatinib is a moderate CYP3A4 and 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 mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. 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.
    Imipramine: (Major) Monitor for an increased incidence of imipramine-related adverse effects if gefitinib and imipramine are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of imipramine. 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 imipramine.
    Indinavir: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and indinavir are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and indinavir is a strong CYP3A4 inhibitor; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Indomethacin: (Major) An increased risk of bleeding may occur when NSAIDs, such as indomethacin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Interferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b; Ribavirin: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfacon-1: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-n3: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Intranasal Influenza Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Isavuconazonium: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and isavuconazonium are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and isavuconazonium is a moderate CYP3A4 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 mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Isoniazid, INH: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and isoniazid, INH are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and isoniazid is a moderate CYP3A4 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 mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Increase the dose of gefitinib to 500 mg PO once daily in patients taking gefitinib concurrently rifampin; monitor carefully for adverse effects of gefitinib. Resume gefitinib 250 mg PO daily 7 days after discontinuation of rifampin. Gefitinib is metabolized significantly by CYP3A4 and rifampin is a strong CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. Administration of a single 500 mg gefitinib dose with concurrent rifampin therapy reduced the gefitinib mean AUC by 83%. (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and isoniazid, INH are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and isoniazid is a moderate CYP3A4 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 mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Isoniazid, INH; Rifampin: (Major) Increase the dose of gefitinib to 500 mg PO once daily in patients taking gefitinib concurrently rifampin; monitor carefully for adverse effects of gefitinib. Resume gefitinib 250 mg PO daily 7 days after discontinuation of rifampin. Gefitinib is metabolized significantly by CYP3A4 and rifampin is a strong CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. Administration of a single 500 mg gefitinib dose with concurrent rifampin therapy reduced the gefitinib mean AUC by 83%. (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and isoniazid, INH are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and isoniazid is a moderate CYP3A4 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 mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Itraconazole: (Moderate) Substances that are potent inhibitors of cytochrome P450 3A4 activity, such as itraconazole, decrease the metabolism of gefitinib and increase gefitinib concentrations. This increase may be clinically relevant as adverse reactions to gefitinib are related to dose and exposure; therefore, caution should be used when administering CYP3A4 inhibitors with gefitinib.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and gefitinib concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as gefitinib, can increase gefitinib exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ketoconazole: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and ketoconazole are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and ketoconazole is a strong CYP3A4 inhibitor; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Ketoprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ketoprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ketorolac: (Major) An increased risk of bleeding may occur when NSAIDs, such as ketorolac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Lansoprazole: (Moderate) If possible, avoid the concomitant use of gefitinib with lansoprazole. If coadministration is necessary, give gefitinib 12 hours after the last dose or 12 hours before the next dose of lansoprazole. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Lansoprazole; Naproxen: (Moderate) If possible, avoid the concomitant use of gefitinib with lansoprazole. If coadministration is necessary, give gefitinib 12 hours after the last dose or 12 hours before the next dose of lansoprazole. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%. (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Lapatinib: (Minor) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and lapatinib are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and lapatinib is a weak CYP3A4 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 weak CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    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%.
    Live Vaccines: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Lopinavir; Ritonavir: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib is used concomitantly with either lopinavir or ritonavir. Gefitinib is metabolized significantly by CYP3A4 and both lopinavir and ritonavir are strong CYP3A4 inhibitors; gefitinib is metabolized to a lesser extent by CYP2D6, and ritonavir inhibits CYP2D6 in vitro. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. 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.
    Lumacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and gefitinib concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as gefitinib, can increase gefitinib exposure leading to increased or prolonged therapeutic effects and adverse events.
    Magnesium Hydroxide: (Moderate) If possible, avoid the concomitant use of gefitinib with antacids. If coadministration is necessary, give gefitinib 6 hours after the last dose or 6 hours before the next dose of antacid. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Maprotiline: (Moderate) Gefitinib may inhibit cytochrome P450 2D6 at clinical doses. Caution is recommended when administering gefitinib with other CYP2D6 substrates, such as maprotiline, that have a narrow therapeutic range or where large increases in serum concentrations may be associated with severe adverse reactions.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles/Mumps/Rubella Vaccines, MMR: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Meclofenamate Sodium: (Major) An increased risk of bleeding may occur when NSAIDs, such as meclofenamate sodium, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Mefenamic Acid: (Major) An increased risk of bleeding may occur when NSAIDs, such as mefenamic acid, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Meloxicam: (Minor) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. However, meloxicam may be associated with less risk than other NSAIDs due to its relative minimal platelet inhibitory effects and gastric ulceration or hemorrhagic potential. Monitor closely for bleeding.
    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 in patients taking gefitinib concurrently with phenobarbital; monitor carefully for adverse effects of gefitinib. Resume gefitinib 250 mg PO daily 7 days after discontinuation of phenobarbital. This also applies to drugs that are metabolized to phenobarbital, such as mephobarbital. Gefitinib is metabolized significantly by CYP3A4 and phenobarbital is a strong CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. Administration of a single 500 mg gefitinib dose with another strong CYP3A4 inducer (rifampin) reduced the gefitinib mean AUC by 83%.
    Methadone: (Moderate) Gefitinib may inhibit cytochrome P450 2D6 at clinical doses. Caution is recommended when administering gefitinib with other CYP2D6 substrates, such as methadone; however, CYP2D6 is not the primary route of methadone metabolism. The clinical significance of this interaction is not known.
    Methamphetamine: (Moderate) Monitor for an increased incidence of methamphetamine-related adverse effects if gefitinib and methamphetamine are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of methamphetamine. 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.
    Methohexital: (Moderate) Monitor for clinical response of gefitinib if used concomitantly with methohexital. Gefitinib is metabolized significantly by CYP3A4 and methohexital, like other barbiturates, 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%. The clinical relevance of this interaction may be low due to the short-term use of methohexital in clinical practice.
    Metoclopramide: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and metoclopramide are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; in vitro, metoclopramide 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.
    Metoprolol: (Moderate) Monitor for an increased incidence of metoprolol-related adverse effects if gefitinib and metoprolol are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of metoprolol. In patients with solid tumors, exposure to metoprolol 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 metoprolol.
    Mexiletine: (Major) Monitor for an increased incidence of mexiletine-related adverse effects if gefitinib and mexiletine are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of mexiletine. 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 such as mexiletine.
    Mifepristone: (Moderate) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and mifepristone are used concomitantly. When mifepristone is used in the treatment of Cushing's syndrome and coadministered with drugs that inhibit CYP3A4, limit the dose of mifepristone to 300 mg/day. Gefitinib is metabolized significantly by CYP3A4 and in vitro, mifepristone is a moderate CYP3A4 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 mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Mirabegron: (Moderate) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and mirabegron are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6. Mirabegron is a moderate inhibitor of CYP2D6. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. 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.
    Mitotane: (Major) Increase the dose of gefitinib to 500 mg PO once daily in patients taking gefitinib concurrently mitotane; monitor carefully for adverse effects of gefitinib. Resume gefitinib 250 mg PO daily 7 days after discontinuation of mitotane. Gefitinib is metabolized significantly by CYP3A4 and mitotane is a strong CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. Administration of a single 500 mg gefitinib dose with concurrent rifampin therapy (another strong CYP3A inducer) reduced the gefitinib mean AUC by 83%.
    Modafinil: (Major) Monitor for clinical response of gefitinib if used concomitantly with modafinil. Gefitinib is metabolized significantly by CYP3A4 and modafinil 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%.
    Nabumetone: (Minor) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. However, nabumetone may be associated with less risk than other NSAIDs due to its relative minimal platelet inhibitory effects and gastric ulceration or hemorrhagic potential. Monitor closely for bleeding.
    Nafcillin: (Major) Monitor for clinical response of gefitinib if used concomitantly with nafcillin. Gefitinib is metabolized significantly by CYP3A4 and in vitro, nafcillin 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%.
    Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Naproxen; Pseudoephedrine: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Naproxen; Sumatriptan: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Nefazodone: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and nefazodone are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and nefazodone is a strong CYP3A4 inhibitor; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Nelfinavir: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and nelfinavir are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and nelfinavir is a strong CYP3A4 inhibitor; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and netupitant; palonosetron are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and netupitant is a moderate CYP3A4 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 mild or moderate CYP3A4 inhibitor, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. Additionally, at high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of palonosetron. 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.
    Nevirapine: (Major) Monitor for clinical response of gefitinib if used concomitantly with nevirapine. Gefitinib is metabolized significantly by CYP3A4 and nevirapine 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%.
    Nilotinib: (Moderate) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and gefitinib, a CYP3A4 substrate, may result in increased gefitinib levels. A gefitinib dose reduction may be necessary if these drugs are used together.
    Nizatidine: (Moderate) If possible, avoid the concomitant use of gefitinib with nizatidine. If coadministration is necessary, give gefitinib 6 hours after the last dose or 6 hours before the next dose of nizatidine. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Nortriptyline: (Major) Monitor for an increased incidence of nortriptyline-related adverse effects if gefitinib and nortriptyline are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of nortriptyline. 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 nortriptyline.
    Octreotide: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and octreotide are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and octreotide is a moderate CYP3A4 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 mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Olanzapine: (Moderate) Monitor for an increased incidence of olanzapine-related adverse effects if gefitinib and olanzapine are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of olanzapine. 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 olanzapine.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib is used concomitantly with either lopinavir or ritonavir. Gefitinib is metabolized significantly by CYP3A4 and both lopinavir and ritonavir are strong CYP3A4 inhibitors; gefitinib is metabolized to a lesser extent by CYP2D6, and ritonavir inhibits CYP2D6 in vitro. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. 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.
    Omeprazole: (Moderate) If possible, avoid the concomitant use of gefitinib with omeprazole. If coadministration is necessary, give gefitinib 12 hours after the last dose or 12 hours before the next dose of omeprazole. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Omeprazole; Sodium Bicarbonate: (Moderate) If possible, avoid the concomitant use of gefitinib with antacids. If coadministration is necessary, give gefitinib 6 hours after the last dose or 6 hours before the next dose of antacid. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%. (Moderate) If possible, avoid the concomitant use of gefitinib with omeprazole. If coadministration is necessary, give gefitinib 12 hours after the last dose or 12 hours before the next dose of omeprazole. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Oritavancin: (Moderate) Monitor for clinical response of gefitinib if used concomitantly with oritavancin. Gefitinib is metabolized significantly by CYP3A4 and oritavancin is a weak 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%.
    Oxaprozin: (Minor) An increased risk of bleeding may occur when NSAIDs, such as oxaprozin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Oxcarbazepine: (Major) Monitor for clinical response of gefitinib if used concomitantly with oxcarbazepine. Gefitinib is metabolized significantly by CYP3A4 and oxcarbazepine 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%.
    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: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and panobinostat are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; panobinostat 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.
    Pantoprazole: (Moderate) If possible, avoid the concomitant use of gefitinib with pantoprazole. If coadministration is necessary, give gefitinib 12 hours after the last dose or 12 hours before the next dose of pantoprazole. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Paroxetine: (Moderate) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and paroxetine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; paroxetine is a strong 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 paroxetine. 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.
    Pazopanib: (Minor) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and pazopanib are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; pazopanib is a weak CYP3A4 and 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 mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. 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.
    Peginterferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Peginterferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentobarbital: (Major) Monitor for clinical response of gefitinib if used concomitantly with pentobarbital. Gefitinib is metabolized significantly by CYP3A4 and pentobarbital, like other barbiturates, 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%.
    Pentosan: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Perampanel: (Moderate) Monitor for clinical response of gefitinib if used concomitantly with perampanel. Gefitinib is metabolized significantly by CYP3A4 and perampanel is a weak 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%.
    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: (Major) 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. (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 in patients taking gefitinib concurrently with phenobarbital; monitor carefully for adverse effects of gefitinib. Resume gefitinib 250 mg PO daily 7 days after discontinuation of phenobarbital. Gefitinib is metabolized significantly by CYP3A4 and phenobarbital is a strong CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. Administration of a single 500 mg gefitinib dose with another strong CYP3A4 inducer (rifampin) reduced the gefitinib mean AUC 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 in patients taking gefitinib concurrently with phenytoin or fosphenytoin (and possibly ethotoin); monitor carefully for adverse effects of gefitinib. Resume gefitinib 250 mg PO daily 7 days after discontinuation of phenytoin / fosphenytoin. Gefitinib is metabolized significantly by CYP3A4 and both phenytoin and fosphenytoin are strong CYP3A4 inducers; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. Administration of a single 500 mg gefitinib dose with another strong CYP3A4 inducer (rifampin) reduced the gefitinib mean AUC by 83%.
    Pimozide: (Major) Caution is advisable during concurrent use of pimozide and CYP2D6 inhibitors such as gefitinib. Pimozide is metabolized primarily through CYP3A4, and to a lesser extent CYP1A2 and CYP2D6. 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.
    Pirfenidone: (Minor) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and pirfenidone are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; in vitro, pirfenidone is a weak CYP3A4 and 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 mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. 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.
    Piroxicam: (Minor) An increased risk of bleeding may occur when NSAIDs, such as piroxicam, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Posaconazole: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and posaconazole are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and posaconazole is a strong CYP3A4 inhibitor; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Prednisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Primidone: (Major) Increase the dose of gefitinib to 500 mg PO once daily in patients taking gefitinib concurrently with primidone; monitor carefully for adverse effects of gefitinib. Resume gefitinib 250 mg PO daily 7 days after discontinuation of primidone. Gefitinib is metabolized significantly by CYP3A4 and primidone is a strong CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. Administration of a single 500 mg gefitinib dose with another strong CYP3A4 inducer (rifampin) reduced the gefitinib mean AUC 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: (Major) Monitor for an increased incidence of gefitinib- and propafenone-related adverse effects if gefitinib and propafenone are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; propafenone 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 propafenone. 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 propafenone.
    Propoxyphene: (Moderate) Propoxyphene is a substrate and an inhibitor of CYP2D6. Increased serum concentrations of propoxyphene would be expected from concurrent use of a CYP2D6 inhibitor, such as gefitinib. A reduced dosage of propoxyphene may be needed. Monitor patients for CNS and respiratory depression.
    Propranolol: (Moderate) Monitor for an increased incidence of propranolol-related adverse effects if gefitinib and propranolol are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is primarily responsible for the metabolism of propranolol. 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 propranolol.
    Protriptyline: (Major) Monitor for an increased incidence of protriptyline-related adverse effects if gefitinib and protriptyline are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of protriptyline. 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 protriptyline.
    Quinidine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and quinidine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; quinidine is a strong 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.
    Quinine: (Major) Monitor for clinical response of gefitinib and an increased incidence of gefitinib-related adverse effects if gefitinib and quinine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent, by CYP2D6; quinine is a moderate inhibitor of both CYP3A4 and CYP2D6, as well as a moderate CYP3A4 inducer in vitro. Coadministration may alter gefitinib serum concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inhibitors or inducers, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%; administration of a single dose of gefitinib with a strong CYP3A4 inducer (rifampin) decreased mean AUC by 83%.
    Rabeprazole: (Moderate) If possible, avoid the concomitant use of gefitinib with rabeprazole. If coadministration is necessary, give gefitinib 12 hours after the last dose or 12 hours before the next dose of rabeprazole. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Ranitidine: (Moderate) If possible, avoid the concomitant use of gefitinib with ranitidine; this also applies to products containing ranitidine such as ranitidine bismuth citrate. If coadministration is necessary, give gefitinib 6 hours after the last dose or 6 hours before the next dose of ranitidine. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Ranolazine: (Minor) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and ranolazine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; ranolazine is a weak CYP3A4 inhibitor in vitro and a moderate inhibitor of CYP2D6. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. 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.
    Regorafenib: (Minor) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and regorafenib are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; in vitro, regorafenib is a weak CYP3A4 inhibitor and its active metabolite, M-2, is a weak inhibitor of CYP2D6. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. 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.
    Ribociclib: (Moderate) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and ribociclib are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and ribociclib is a moderate CYP3A4 inhibitor; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations.
    Ribociclib; Letrozole: (Moderate) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and ribociclib are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and ribociclib is a moderate CYP3A4 inhibitor; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations.
    Rifabutin: (Major) Monitor for clinical response of gefitinib if used concomitantly with rifabutin. Gefitinib is metabolized significantly by CYP3A4 and rifabutin 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%.
    Rifampin: (Major) Increase the dose of gefitinib to 500 mg PO once daily in patients taking gefitinib concurrently rifampin; monitor carefully for adverse effects of gefitinib. Resume gefitinib 250 mg PO daily 7 days after discontinuation of rifampin. Gefitinib is metabolized significantly by CYP3A4 and rifampin is a strong CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. Administration of a single 500 mg gefitinib dose with concurrent rifampin therapy reduced the gefitinib mean AUC by 83%.
    Rifapentine: (Major) Monitor for clinical response of gefitinib if used concomitantly with rifapentine. Gefitinib is metabolized significantly by CYP3A4 and rifapentine 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%.
    Rifaximin: (Major) Monitor for clinical response of gefitinib if used concomitantly with rifaximin. Gefitinib is metabolized significantly by CYP3A4 and in vitro, rifaximin is a CYP3A4 inducer; however, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin 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%.
    Ritonavir: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib is used concomitantly with either lopinavir or ritonavir. Gefitinib is metabolized significantly by CYP3A4 and both lopinavir and ritonavir are strong CYP3A4 inhibitors; gefitinib is metabolized to a lesser extent by CYP2D6, and ritonavir inhibits CYP2D6 in vitro. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. 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.
    Rolapitant: (Major) Monitor for gefitinib-related adverse effects, including QT prolongation, if coadministered with rolapitant. Increased exposure to gefitinib may occur. Gefitinib is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Rotavirus Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rubella Virus Vaccine Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rufinamide: (Minor) Rufinamide is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as gefitinib, may occur during concurrent use with rufinamide.
    Saquinavir: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and saquinavir are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and saquinavir is a strong CYP3A4 inhibitor; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Sertraline: (Moderate) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and sertraline are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; sertraline is a weak 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 partially responsible for the metabolism of sertraline in vitro. 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.
    Simeprevir: (Minor) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and simeprevir are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and simeprevir is a weak CYP3A4 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 weak CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Smallpox Vaccine, Vaccinia Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Sodium Bicarbonate: (Moderate) If possible, avoid the concomitant use of gefitinib with antacids. If coadministration is necessary, give gefitinib 6 hours after the last dose or 6 hours before the next dose of antacid. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    St. John's Wort, Hypericum perforatum: (Major) Increase the dose of gefitinib to 500 mg PO once daily in patients taking gefitinib concurrently with St. John's Wort, hypericum perforatum; monitor carefully for adverse effects of gefitinib. Resume gefitinib 250 mg PO daily 7 days after discontinuation of St. John's Wort; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. Gefitinib is metabolized significantly by CYP3A4 and St. John's Wort is a strong CYP3A4 inducer. Administration of a single 500 mg gefitinib dose with another strong CYP3A4 inducer (rifampin) reduced the gefitinib mean AUC by 83%.
    Streptogramins: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and dalfopristin; quinupristin are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and quinupristin is a strong CYP3A4 inhibitor; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Sulindac: (Minor) An increased risk of bleeding may occur when NSAIDs, such as sulindac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Tamsulosin: (Moderate) Use caution when administering tamsulosin with a moderate CYP2D6 inhibitor such as gefitinib. Tamsulosin is extensively metabolized by CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP2D6 inhibitor resulted in increases in tamsulosin exposure; interactions with moderate CYP2D6 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering gefitinib with telaprevir due to an increased potential for gefitinib-related adverse events. If gefitinib dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of gefitinib. Gefitinib is metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated gefitinib plasma concentrations.
    Telithromycin: (Moderate) Concentrations of gefitinib may be increased with concomitant use of telithromycin. Gefitinib is a CYP3A4 substrate and telithromycin is a strong CYP3A4 inhibitor. Caution is warranted if these drugs are coadministered.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and gefitinib is necessary, as the systemic exposure of gefitinib may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of gefitinib; consider increasing the dose of gefitinib if necessary. Gefitinib is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Terbinafine: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and terbinafine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; terbinafine 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.
    Teriflunomide: (Moderate) In vitro studies indicate that teriflunomide is a substrate of ABCG2 (breast cancer resistance protein, BCRP). Drugs that are inhibitors of BCRP, such as gefitinib, may cause increases in teriflunomide plasma concentrations. Monitor patients for adverse effects, including symptoms serious liver injury and immunosuppression.
    Tetrabenazine: (Moderate) Monitor for an increased incidence of tetrabenazine-related adverse effects if gefitinib and tetrabenazine are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of tetrabenazine. 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.
    Tezacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and gefitinib concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as gefitinib, can increase gefitinib exposure leading to increased or prolonged therapeutic effects and adverse events.
    Thioridazine: (Severe) The use of these drugs concurrently is not recommended. Monitor for an increased incidence of gefitinib- and thioridazine-related adverse effects if gefitinib and thioridazine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; in vitro, thioridazine 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 thioridazine. 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 thioridazine. Since this may lead to QT prolongation, the use of these drugs concurrently is not recommended.
    Thiothixene: (Minor) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and thiothixene are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; in vitro, thiothixene is a weak 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.
    Ticagrelor: (Minor) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and ticagrelor are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and ticagrelor is a weak CYP3A4 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 weak CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Ticlopidine: (Moderate) Ticlopidine therapy is contraindicated in patients with hematopoietic disorders including myelosuppression and thrombocytopenia. Ticlopidine should be used cautiously, if at all, in patients with thrombocytopenia following the administration of myelosuppressive antineoplastic agents.
    Tinzaparin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Tipranavir: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and tipranavir are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; tipranavir is a strong CYP3A4 and CYP2D6 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. 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.
    Tirofiban: (Moderate) Patients with thrombocytopenia are at increased risk of bleeding complications. An increased risk of bleeding may occur when tirofiban is used in with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with antineoplastic agents.
    Tolmetin: (Minor) An increased risk of bleeding may occur when NSAIDs, such as tolmetin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Tolterodine: (Moderate) Monitor for an increased incidence of tolterodine-related adverse effects if gefitinib and tolterodine are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of tolterodine. 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.
    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%.
    Topotecan: (Major) Avoid the concomitant use of gefitinib, a breast cancer resistance protein (BCRP) inhibitor, with oral topotecan, a BCRP substrate; the effect of gefitinib on intravenous topotecan is unknown. If coadministration of gefitinib and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea. When oral topotecan was administered concomitantly with escalating doses of a dual inhibitor of BCRP and P-glycoprotein, exposure to both total topotecan and topotecan lactone increased by approximately 2.5-fold compared with control.
    Tramadol: (Major) Monitor for an increased incidence of tramadol-related adverse effects as well as changes in the efficacy of tramadol if given concurrently with gefitinib. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of tramadol. 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 analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6; therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of CYP2D6 is expected to result in reduced metabolic clearance of tramadol, which in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures; serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. 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 tramadol.
    Trandolapril; Verapamil: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and verapamil are used concomitantly; this also applies to trandolapril; verapamil. Gefitinib is metabolized significantly by CYP3A4 and verapamil is a moderate CYP3A4 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 mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Trimipramine: (Major) Monitor for an increased incidence of trimipramine-related adverse effects if gefitinib and trimipramine are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of trimipramine. 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 trimipramine.
    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.
    Typhoid Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Valproic Acid, Divalproex Sodium: (Moderate) Monitor for clinical response of gefitinib and an increased incidence of gefitinib-related adverse effects if gefitinib and valproic acid, divalproex sodium are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and valproic acid is a weak inhibitor and weak in vitro inducer of CYP3A4. Coadministration may alter gefitinib serum concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inhibitors or inducers, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%; administration of a single dose of gefitinib with a strong CYP3A4 inducer (rifampin) decreased mean AUC by 83%.
    Varicella-Zoster Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Vemurafenib: (Major) Monitor for clinical response of gefitinib if used concomitantly with vemurafenib. Gefitinib is metabolized significantly by CYP3A4 and vemurafenib 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%.
    Venlafaxine: (Moderate) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and venlafaxine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; venlafaxine is a weak 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 venlafaxine. 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 venlafaxine.
    Verapamil: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and verapamil are used concomitantly; this also applies to trandolapril; verapamil. Gefitinib is metabolized significantly by CYP3A4 and verapamil is a moderate CYP3A4 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 mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Voriconazole: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and voriconazole are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and voriconazole is a moderate CYP3A4 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 mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Warfarin: (Major) 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. At high concentrations, gefitinib is an inhibitor of CYP2D6 and CYP2C19, which are partially responsible for the metabolism of warfarin. 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).
    Yellow Fever Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Zafirlukast: (Minor) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and zafirlukast are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and zafirlukast is a weak CYP3A4 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 weak CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.

    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.

    According to the manufacturer, either gefitinib or breast-feeding should be discontinued because of the potential for serious adverse reactions in nursing infants from gefitinib. It is not known if gefitinib is excreted in human milk. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Gefitinib is a synthetic anilinoquinazoline that is a selective inhibitor of the epidermal growth factor receptor-tyrosine kinase (EGFR-TK). The EGFR (ErbB1, HER1) receptor is closely related to the Her2/neu (ErbB2), Her3 (ErbB3), and Her4 (ErbB4) receptors. Gefitinib shows minimal activity against other tyrosine kinases such as HER2/neu, KDR, c-flt, or serine/threonine kinases including protein kinase C, MEK-1, and ERK. The activity of protein tyrosine kinases is tightly regulated since they function as mediators of cell growth, differentiation, and death. Numerous protein kinase genes have been identified as oncogenes associated with transforming retroviruses or human tumors. Stimulation of EGFR occurs by various ligands including transforming growth factor-alpha, amphiregulin, epiregulin, heparin-binding EGF-like growth factor, and ß-cellulin. Upon active binding, EGRF undergoes dimerization with either another EGFR or with erbB2 (HER2/neu), erbB3 (HER3), or erb4 (HER4). In addition EGRF may also be activated by other receptors such as G-protein coupled proteins.
    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.
    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. 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.

    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.
    The elimination half-life is roughly 48 hours. 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. Excretion is predominantly via the feces (86%), with renal elimination of the drug and metabolites accounting for < 4% of the administered dose.
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2D6, CYP2C19
    Gefitinib undergoes significant hepatic metabolism, predominantly via the cytochrome P450 isoenzyme 3A4 (CYP3A4). Additionally, in vitro CYP2D6 metabolizes gefitinib to an 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. Of 5 metabolites identified in fecal extracts, O-desmethyl gefitinib accounted for 14% of the dose. Eight metabolites were identified in human plasma, with only O-desmethyl gefitinib having exposure comparable to gefitinib. In poor CYP2D6 metabolizers, the concentration of O-desmethyl gefitinib was not measurable and the mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. Monitor known poor 2D6 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.
    In human liver microsome studies, gefitinib inhibited CYP2C19 by 24% and CYP2D6 by 43% at the highest concentration studied (5000 ng/mL). The effect of gefitinib on CYP2D6 substrates is only likely to be clinically relevant for drugs with a narrow therapeutic index or those that are individually titrated. No inhibitory effects were seen on CYP1A2, CYP2C9, or CYP3A4 at concentrations ranging from 2—5000 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.

    Oral Route

    Gefitinib is slowly absorbed with peak plasma levels occurring 3—7 hours after dosing with a mean bioavailability of 60%. Bioavailability is not significantly altered by food. In phase I studies, the mean plasma concentrations of gefitinib following doses of 225 mg/day and 400 mg/day were 160—307 ng/ml and 478—621 ng/ml, respectively, with significant interpatient variability.

    Intravenous Route

    Gefitinib is extensively distributed throughout the body, with a mean steady state volume of distribution of 1400 liters after intravenous administration.