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  • CLASSES

    Protein Kinase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Oral epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)
    Used for the treatment of metastatic non-small cell lung cancer (NSCLC) with exon 19 deletions or exon 21 (L858R) substitution mutations as monotherapy, and for the treatment of locally advanced, unresectable, or metastatic pancreatic cancer with gemcitabine
    Periodically monitor liver function, renal function, and electrolytes during treatment

    COMMON BRAND NAMES

    Tarceva

    HOW SUPPLIED

    Tarceva Oral Tab: 25mg, 100mg, 150mg

    DOSAGE & INDICATIONS

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

    150 mg PO once daily on an empty stomach (i.e., at least 1 hour before or 2 hours after food) until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Despite a high crossover rate (82%), erlotinib monotherapy significantly improved progression-free survival (PFS) compared with platinum-based doublet chemotherapy in a randomized, multicenter, open label trial of patients with previously untreated metastatic NSCLC and EGFR exon 19 deletions or exon 21 (L858R) substitution mutations (10.4 months vs. 5.2 months). Median overall survival (22.9 months vs. 19.5 months) and overall response rate (65% vs. 16%) were also improved. In a separate trial, erlotinib maintenance therapy after first-line treatment with platinum-based chemotherapy for metastatic NSCLC minimally but significantly improved median PFS (2.8 months vs. 2.6 months) and OS (12 months vs. 11 months) compared with placebo in a population that was 70% EGFR positive. However, in a separate trial, erlotinib was not effective as maintenance therapy in patients without an EGFR exon 19 deletion or exon 21 (L858R) substitution mutation. In a final study of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen, OS was also significantly improved with erlotinib compared with placebo (6.7 months vs. 4.7 months). Erlotinib was not effective in patients with locally advanced or metastatic NSCLC when administered concurrently with platinum-based chemotherapy.

    For the first-line treatment of locally advanced, unresectable or metastatic pancreatic cancer in combination with gemcitabine.
    Oral dosage
    Adults

    100 mg PO once daily on an empty stomach (i.e., at least one hour before or two hours after food) in combination with gemcitabine 1,000 mg/m2 IV over 30 minutes once weekly for 7 consecutive weeks, followed by 1 week of rest. Beginning with week 9 (day 57), administer gemcitabine 1,000 mg/m2 IV over 30 minutes on days 1, 8, and 15, repeated every 28 days. Continue treatment until disease progression or unacceptable toxicity occurs. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a Phase 3 trial, the addition of erlotinib to gemcitabine significantly improved overall survival compared with gemcitabine plus placebo in patients with advanced pancreatic cancer.

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

    150 mg PO once daily has been studied. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Further study is needed to define the benefit of erlotinib in the treatment of head and neck cancer. In a phase 2 trial, 115 patients treated with erlotinib had an overall response rate (ORR) of 4.3% with disease stabilization in 38.3% for a median duration of 16.1 months. The median progression-free survival (PFS) was 9.6 weeks and the median overall survival (OS) was 6 months. Subgroup analysis revealed a significant difference in overall survival favoring patients who developed at least grade 2 skin rashes compared to those who did not. No difference in response was noted based upon HER1/EGFR expression.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    NSCLC: 150 mg PO daily.
    Pancreatic Cancer: 100 mg PO daily.

    Geriatric

    NSCLC: 150 mg PO daily.
    Pancreatic Cancer: 100 mg PO daily.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment
    No dosage adjustment is necessary.
    Treatment-Related Hepatotoxicity
    Total bilirubin more than 3 times the upper limit of normal (ULN) or AST/ALT more than 5 times ULN in patients WITHOUT baseline hepatic impairment: Hold erlotinib therapy. Resume erlotinib at a reduced dose (by 50 mg decrements) when liver function tests resolve to baseline or less than or equal to grade 1. Discontinue erlotinib if resolution or significant improvement does not occur within 3 weeks.
    Total bilirubin 2 times baseline or AST/ALT 3 times baseline in patients WITH pre-existing hepatic impairment, or biliary obstruction: Hold erlotinib therapy. Resume erlotinib at a reduced dose (by 50 mg decrements) when liver function tests resolve to baseline or less than or equal to grade 1. Discontinue erlotinib if resolution or significant improvement does not occur within 3 weeks.

    Renal Impairment

    Baseline Renal Impairment
    No dosage adjustments are necessary.
    Treatment-Induced Nephrotoxicity
    Grade 3 or 4 renal impairment: Hold erlotinib therapy. When nephrotoxicity has resolved to baseline or less than or equal to grade 1, therapy may be resumed at a reduced dose (by 50 mg decrements). Alternatively, consider discontinuation of erlotinib.

    ADMINISTRATION

    Oral Administration

    Erlotinib must be given orally on an empty stomach, 1 hour before or 2 hours after the ingestion of food. Administer at the same time each day.

    STORAGE

    Tarceva:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Chronic lung disease (CLD), pneumonitis, pulmonary disease

    Use erlotinib with caution in patients with underlying or chronic lung disease (CLD) or pre-existing pulmonary disease. Interstitial lung disease (ILD; pneumonitis), including fatal cases, has been reported with the use of erlotinib. Monitor patients for new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever. If symptoms develop, interrupt erlotinib therapy and evaluate; initiate treatment as appropriate. Permanently discontinue erlotinib if ILD is confirmed. In patients with ILD, symptoms began from 5 days to more than 9 months (median 39 days) after initiating erlotinib therapy in clinical trials.

    Biliary obstruction, hepatic disease, hepatotoxicity

    Hepatotoxicity, hepatic failure, and hepatorenal syndrome (including fatalities) has been reported with erlotinib therapy in patients with normal hepatic function; the risk is increased in patients with baseline hepatic disease. Periodically monitor liver function tests during treatment; monitor more frequently in patients with pre-existing hepatic impairment or biliary obstruction. In patients without baseline hepatic impairment, hold erlotinib therapy for total bilirubin greater than 3 times the upper limit of normal (ULN) or transaminases greater than 5 times ULN. In patients who have pre-existing hepatic impairment or biliary obstruction, hold erlotinib if the bilirubin doubles or transaminases triple over baseline. If liver function tests do not improve significantly or resolve within 3 weeks, discontinue erlotinib therapy.

    Keratitis, ocular disease

    Use erlotinib with caution in patients with pre-existing ocular disease, as decreased lacrimation, abnormal eyelash growth, keratoconjunctivitis, and keratitis have occurred with erlotinib therapy which can lead to corneal perforation or ulceration. Patients who develop an onset of new eye symptoms such as ocular pain should be evaluated and managed appropriately. Interrupt or discontinue erlotinib if patients present with acute or worsening ocular pain, grade 2 keratitis lasting for more than 2 weeks, or any grade 3 or 4 keratitis. Discontinue erlotinib for corneal perforation or severe ulceration.

    Corticosteroid therapy, diverticulitis, GI perforation, peptic ulcer disease

    Use erlotinib with caution in patients with a history of peptic ulcer disease or diverticulitis or those receiving concomitant anti-angiogenic agents, corticosteroid therapy, NSAIDs, and/or taxane-based chemotherapy as they may be at an increased risk for development of gastrointestinal (GI) perforation. Cases of GI perforation, including some fatal cases, have been reported with the use of erlotinib. Permanently discontinue erlotinib if a GI perforation occurs.

    Tobacco smoking

    Patients should avoid smoking tobacco if possible while being treated with erlotinib; an erlotinib dosage adjustment may be necessary for patients who continue to smoke. Tobacco smoking reduces the effectiveness of erlotinib by increasing the plasma clearance by about 24% and decreasing erlotinib plasma trough concentrations by about 2-fold in current smokers as compared with values from former or never smokers. Further, erlotinib systemic exposure from time zero to infinity is about one-third the value obtained from either former smokers or never smokers. Sudden smoking cessation may result in a reduced clearance of erlotinib despite the initiation of nicotine replacement products, as the effect of tobacco on hepatic microsomal enzymes is not related to the nicotine component. Determine a patient's smoking status before erlotinib initiation. Inform patients of the importance of communicating a change in their smoking status to their health care professional.

    Dehydration, renal disease, renal failure, renal impairment

    Use erlotinib with caution in patients with pre-existing renal disease including renal impairment or renal failure, hepatic impairment, or dehydration. Hepatorenal syndrome, renal insufficiency, and acute renal failure (including fatal cases) can occur with erlotinib treatment; renal failure may be a result of exacerbation of underlying baseline hepatic impairment or severe dehydration. Periodically monitor renal function and serum electrolytes in patients treated with erlotinib, and maintain adequate hydration. Hold erlotinib therapy until resolution of toxicity if severe renal impairment develops, and consider discontinuation.

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during erlotinib treatment and for at least 1 month after the last dose. Although there are no adequately controlled studies in pregnant women, erlotinib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving erlotinib should be apprised of the potential hazard to the fetus. Erlotinib caused maternal toxicity resulting in embryo-fetal death and abortion in rabbits when given during organogenesis at exposures approximately 3 times those achieved with the recommended dose in humans. There was no increase in embryolethality or abortion in rabbits or rats when erlotinib was given during organogenesis at exposures approximately equal to those achieved with the recommended daily dose in humans. Teratogenicity was not observed with erlotinib administration during organogenesis at exposures up to 3 times the exposure with the recommended dose in humans in rabbits, and up to 0.7 times the exposure with the recommended dose in humans in rats.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from erlotinib, advise women to discontinue breast-feeding during treatment and for 2 weeks after the final dose. It is not known if erlotinib is excreted in human breast milk.

    Contraception requirements, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during erlotinib treatment. Erlotinib can cause fetal harm or death if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 1 month after treatment with erlotinib. Females of reproductive potential should undergo pregnancy testing prior to initiation of erlotinib. Women who become pregnant while receiving erlotinib should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of erlotinib on human fertility, fertility was not affected by erlotinib in either male or female rats.

    ADVERSE REACTIONS

    Severe

    dyspnea / Early / 8.0-28.0
    fatigue / Early / 0-18.0
    infection / Delayed / 4.0-16.0
    elevated hepatic enzymes / Delayed / 0-14.0
    rash / Early / 5.0-14.0
    keratoconjunctivitis / Early / 0-12.0
    hyperbilirubinemia / Delayed / 0-11.0
    thromboembolism / Delayed / 0-11.0
    anorexia / Delayed / 0-9.0
    diarrhea / Early / 0-7.0
    ileus / Delayed / 0-5.0
    arrhythmia exacerbation / Early / 0-5.0
    myocardial infarction / Delayed / 0-5.0
    thrombosis / Delayed / 0-4.0
    fever / Early / 0-3.0
    nausea / Early / 0-3.0
    stroke / Early / 0.6-2.5
    weight loss / Delayed / 0-2.0
    back pain / Delayed / 0-2.0
    depression / Delayed / 0-2.0
    hemolytic anemia / Delayed / 0-1.4
    Stevens-Johnson syndrome / Delayed / 0.4-1.2
    toxic epidermal necrolysis / Delayed / 0.4-1.2
    conjunctivitis / Delayed / 0-1.0
    cough / Delayed / 0-1.0
    xerosis / Delayed / 0-1.0
    pruritus / Rapid / 0-1.0
    arthralgia / Delayed / 0-1.0
    musculoskeletal pain / Early / 0-1.0
    chest pain (unspecified) / Early / 0-1.0
    headache / Early / 0-1.0
    hepatic failure / Delayed / 0.4-0.4
    GI perforation / Delayed / 0.2-0.4
    uveitis / Delayed / Incidence not known
    keratitis / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    peptic ulcer / Delayed / Incidence not known
    hematemesis / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known

    Moderate

    thrombocytopenia / Delayed / 0-1.4
    pneumonitis / Delayed / 1.1-1.1
    stomatitis / Delayed / 0-1.0
    ocular inflammation / Early / Incidence not known
    dehydration / Delayed / Incidence not known
    erythema / Early / Incidence not known
    skin ulcer / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
    gastritis / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    melena / Delayed / Incidence not known
    prolonged bleeding time / Delayed / Incidence not known
    myopathy / Delayed / Incidence not known

    Mild

    syncope / Early / 0-5.0
    asthenia / Delayed / 30.0
    lacrimation / Early / Incidence not known
    hypertrichosis / Delayed / Incidence not known
    photosensitivity / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    acneiform rash / Delayed / Incidence not known
    folliculitis / Delayed / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with butalbital; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Butalbital is a CYP3A4 and 1A2 inducer. Coadministration may decrease plasma concentrations of erlotinib.
    Acetaminophen; Butalbital; Caffeine: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with butalbital; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Butalbital is a CYP3A4 and 1A2 inducer. Coadministration may decrease plasma concentrations of erlotinib.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with butalbital; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Butalbital is a CYP3A4 and 1A2 inducer. Coadministration may decrease plasma concentrations of erlotinib.
    Aluminum Hydroxide: (Major) Separate administration by several hours if concomitant use of erlotinib and antacids is necessary. Erlotinib displays pH-dependent solubility with decreased solubility at a higher pH; the increased gastric pH resulting from antacid therapy may reduce the bioavailability of erlotinib. Increasing the dose of erlotinib without modifying the administration schedule is unlikely to compensate for loss of exposure. The effects of antacids on erlotinib pharmacokinetics has not been evaluated.
    Aluminum Hydroxide; Magnesium Carbonate: (Major) Separate administration by several hours if concomitant use of erlotinib and antacids is necessary. Erlotinib displays pH-dependent solubility with decreased solubility at a higher pH; the increased gastric pH resulting from antacid therapy may reduce the bioavailability of erlotinib. Increasing the dose of erlotinib without modifying the administration schedule is unlikely to compensate for loss of exposure. The effects of antacids on erlotinib pharmacokinetics has not been evaluated.
    Aluminum Hydroxide; Magnesium Hydroxide: (Major) Separate administration by several hours if concomitant use of erlotinib and antacids is necessary. Erlotinib displays pH-dependent solubility with decreased solubility at a higher pH; the increased gastric pH resulting from antacid therapy may reduce the bioavailability of erlotinib. Increasing the dose of erlotinib without modifying the administration schedule is unlikely to compensate for loss of exposure. The effects of antacids on erlotinib pharmacokinetics has not been evaluated.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Major) Separate administration by several hours if concomitant use of erlotinib and antacids is necessary. Erlotinib displays pH-dependent solubility with decreased solubility at a higher pH; the increased gastric pH resulting from antacid therapy may reduce the bioavailability of erlotinib. Increasing the dose of erlotinib without modifying the administration schedule is unlikely to compensate for loss of exposure. The effects of antacids on erlotinib pharmacokinetics has not been evaluated.
    Aluminum Hydroxide; Magnesium Trisilicate: (Major) Separate administration by several hours if concomitant use of erlotinib and antacids is necessary. Erlotinib displays pH-dependent solubility with decreased solubility at a higher pH; the increased gastric pH resulting from antacid therapy may reduce the bioavailability of erlotinib. Increasing the dose of erlotinib without modifying the administration schedule is unlikely to compensate for loss of exposure. The effects of antacids on erlotinib pharmacokinetics has not been evaluated.
    Amiodarone: (Major) Avoid coadministration of erlotinib with amiodarone if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP1A2. amiodarone is a CYP3A4 and CYP1A2 inhibitor. Coadministration with another moderate CYP3A4/CYP1A2 inhibitor increased erlotinib exposure by 39% and increased the erlotinib Cmax by 17%.
    Amobarbital: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with amobarbital; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Amobarbital is a CYP3A4 and 1A2 inducer. Coadministration may decrease plasma concentrations of erlotinib.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of erlotinib with clarithromycin if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%. (Major) Avoid coadministration of erlotinib with lansoprazole if possible due to decreases in erlotinib plasma concentrations. Erlotinib solubility is pH dependent and solubility decreases as pH increases. Coadministration of erlotinib with medications that increase the pH of the upper gastrointestinal tract may decrease the absorption of erlotinib. Separation of doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI tract for an extended period of time. Increasing the dose of erlotinib is also not likely to compensate for the loss of exposure. Coadministration with another proton pump inhibitor decreased erlotinib exposure by 46% and the erlotinib Cmax by 61%.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of erlotinib with clarithromycin if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%. (Major) Avoid coadministration of erlotinib with omeprazole if possible due to decreases in erlotinib plasma concentrations. Erlotinib solubility is pH dependent and solubility decreases as pH increases. Coadministration of erlotinib with medications that increase the pH of the upper gastrointestinal tract may decrease the absorption of erlotinib. Separation of doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI tract for an extended period of time. Increasing the dose of erlotinib is also not likely to compensate for the loss of exposure. Coadministration with omeprazole decreased erlotinib exposure by 46% and the erlotinib Cmax by 61%.
    Antacids: (Major) Separate administration by several hours if concomitant use of erlotinib and antacids is necessary. Erlotinib displays pH-dependent solubility with decreased solubility at a higher pH; the increased gastric pH resulting from antacid therapy may reduce the bioavailability of erlotinib. Increasing the dose of erlotinib without modifying the administration schedule is unlikely to compensate for loss of exposure. The effects of antacids on erlotinib pharmacokinetics has not been evaluated.
    Apalutamide: (Major) Avoid coadministration of erlotinib with apalutamide if possible due to decreased plasma concentrations of erlotinib. If concomitant use is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals as tolerated (maximum dose, 450 mg). Erlotinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased erlotinib exposure by 58% to 80%.
    Armodafinil: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with armodafinil; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate, and armodafinil is a CYP3A4 inducer.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with butalbital; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Butalbital is a CYP3A4 and 1A2 inducer. Coadministration may decrease plasma concentrations of erlotinib.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with butalbital; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Butalbital is a CYP3A4 and 1A2 inducer. Coadministration may decrease plasma concentrations of erlotinib.
    Aspirin, ASA; Omeprazole: (Major) Avoid coadministration of erlotinib with omeprazole if possible due to decreases in erlotinib plasma concentrations. Erlotinib solubility is pH dependent and solubility decreases as pH increases. Coadministration of erlotinib with medications that increase the pH of the upper gastrointestinal tract may decrease the absorption of erlotinib. Separation of doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI tract for an extended period of time. Increasing the dose of erlotinib is also not likely to compensate for the loss of exposure. Coadministration with omeprazole decreased erlotinib exposure by 46% and the erlotinib Cmax by 61%.
    Atazanavir: (Major) Avoid the coadministration of erlotinib with atazanavir due to the risk of increased erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration of erlotinib with another strong CYP3A4 inhibitor increased the erlotinib AUC by 67%.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of erlotinib with cobicistat if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%. (Major) Avoid the coadministration of erlotinib with atazanavir due to the risk of increased erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration of erlotinib with another strong CYP3A4 inhibitor increased the erlotinib AUC by 67%.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid coadministration of erlotinib with phenobarbital if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals as tolerated (maximum dose, 450 mg). Erlotinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased erlotinib exposure by 58% to 80%.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of erlotinib with phenobarbital if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals as tolerated (maximum dose, 450 mg). Erlotinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased erlotinib exposure by 58% to 80%.
    Bexarotene: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with bexarotene; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate, and bexarotene is a moderate CYP3A4 inducer.
    Bosentan: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with bosentan; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate, and bosentan is a moderate CYP3A4 inducer.
    Brigatinib: (Major) Avoid the coadministration of erlotinib with brigatinib if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate and brigatinib is a moderate CYP3A4 inducer. Coadministration may decrease plasma concentrations of erlotinib.
    Budesonide: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with budesonide is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases; patients receiving concomitant budesonide may be at increased risk.
    Budesonide; Formoterol: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with budesonide is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases; patients receiving concomitant budesonide may be at increased risk.
    Butabarbital: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with butabarbital; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Butabarbital is a CYP3A4 and 1A2 inducer. Coadministration may decrease plasma concentrations of erlotinib.
    Cabazitaxel: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with a taxane (i.e., cabazitaxel, docetaxel, paclitaxel) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases; patients receiving concomitant taxanes may be at increased risk.
    Calcium Carbonate: (Major) Separate administration by several hours if concomitant use of erlotinib with calcium carbonate is necessary. Erlotinib displays pH-dependent solubility with decreased solubility at a higher pH; the increased gastric pH resulting from calcium carbonate therapy may reduce the bioavailability of erlotinib. Increasing the dose of erlotinib without modifying the administration schedule is unlikely to compensate for loss of exposure. The effects of antacids on erlotinib pharmacokinetics has not been evaluated.
    Calcium Carbonate; Magnesium Hydroxide: (Major) Separate administration by several hours if concomitant use of erlotinib and antacids is necessary. Erlotinib displays pH-dependent solubility with decreased solubility at a higher pH; the increased gastric pH resulting from antacid therapy may reduce the bioavailability of erlotinib. Increasing the dose of erlotinib without modifying the administration schedule is unlikely to compensate for loss of exposure. The effects of antacids on erlotinib pharmacokinetics has not been evaluated. (Major) Separate administration by several hours if concomitant use of erlotinib with calcium carbonate is necessary. Erlotinib displays pH-dependent solubility with decreased solubility at a higher pH; the increased gastric pH resulting from calcium carbonate therapy may reduce the bioavailability of erlotinib. Increasing the dose of erlotinib without modifying the administration schedule is unlikely to compensate for loss of exposure. The effects of antacids on erlotinib pharmacokinetics has not been evaluated.
    Calcium Carbonate; Risedronate: (Major) Separate administration by several hours if concomitant use of erlotinib with calcium carbonate is necessary. Erlotinib displays pH-dependent solubility with decreased solubility at a higher pH; the increased gastric pH resulting from calcium carbonate therapy may reduce the bioavailability of erlotinib. Increasing the dose of erlotinib without modifying the administration schedule is unlikely to compensate for loss of exposure. The effects of antacids on erlotinib pharmacokinetics has not been evaluated.
    Calcium; Vitamin D: (Major) Separate administration by several hours if concomitant use of erlotinib with calcium carbonate is necessary. Erlotinib displays pH-dependent solubility with decreased solubility at a higher pH; the increased gastric pH resulting from calcium carbonate therapy may reduce the bioavailability of erlotinib. Increasing the dose of erlotinib without modifying the administration schedule is unlikely to compensate for loss of exposure. The effects of antacids on erlotinib pharmacokinetics has not been evaluated.
    Carbamazepine: (Major) Avoid coadministration of erlotinib with carbamazepine if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals as tolerated (maximum dose, 450 mg). Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Carbamazepine is a strong CYP3A4 inducer as well as a CYP1A2 inducer. Coadministration with another strong CYP3A4 inducer decreased erlotinib exposure by 58% to 80%.
    Celecoxib: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Chloramphenicol: (Major) Avoid coadministration of erlotinib with chloramphenicol if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Cimetidine: (Major) Avoid coadministration of erlotinib with cimetidine if possible due to altered plasma concentrations of erlotinib. If concomitant use is unavoidable, separate dosing is required, as the solubility of erlotinib is pH dependent, decreasing as the pH increases. Erlotinib must be taken 10 hours after the last dose of cimetidine and at least 2 hours before the next dose. Additionally, monitor for erlotinib-related adverse reactions; a dose reduction may be necessary for severe reactions. Coadministration of erlotinib with medications that increase the pH of the upper gastrointestinal tract may decrease the absorption of erlotinib. Erlotinib exposure was decreased by 33% and the Cmax by 54% when erlotinib was administered 2 hours after a single dose of an H2-antagonist. When administered at least 10 hours after an evening dose of an H2-antagonist and 2 hours before the morning dose, erlotinib exposure was decreased by 15% and Cmax by 17%. Increasing the dose of erlotinib is not likely to compensate for the loss of exposure. Erlotinib is also primarily metabolized by CYP3A4 and to a lesser extent by CYP1A2. Cimetidine is a weak CYP3A4 and CYP1A2 inhibitor.
    Ciprofloxacin: (Major) Avoid coadministration of erlotinib with ciprofloxacin if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP1A2. Ciprofloxacin is a CYP3A4 and CYP1A2 inhibitor. Coadministration with ciprofloxacin increased erlotinib exposure by 39% and increased the erlotinib Cmax by 17%.
    Clarithromycin: (Major) Avoid coadministration of erlotinib with clarithromycin if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Cobicistat: (Major) Avoid coadministration of erlotinib with cobicistat if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of erlotinib with cobicistat if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of erlotinib with cobicistat if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Conivaptan: (Major) Avoid coadministration of erlotinib with conivaptan if possible due to the increased risk of erlotinib-related adverse reactions; treatment with erlotinib should be initiated no sooner than 1 week after completion of conivaptan therapy. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and conivaptan is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Cortisone: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with cortisone is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases; patients receiving concomitant cortisone may be at increased risk.
    Dabrafenib: (Major) There may be a risk of reduced erlotinib efficacy when coadministered with dabrafenib; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate, and dabrafenib is a moderate CYP3A4 inducer.
    Dalfopristin; Quinupristin: (Major) Avoid coadministration of erlotinib with dalfopristin; quinupristin if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and quinupristin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Darunavir: (Major) Avoid coadministration of erlotinib with darunavir if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Darunavir; Cobicistat: (Major) Avoid coadministration of erlotinib with cobicistat if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%. (Major) Avoid coadministration of erlotinib with darunavir if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of erlotinib with ritonavir if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Deflazacort: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with deflazacort is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases; patients receiving concomitant deflazacort may be at increased risk.
    Delavirdine: (Major) Avoid coadministration of erlotinib with delavirdine if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and delavirdine is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Dexamethasone: (Major) Avoid the coadministration of erlotinib with dexamethasone if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Also, monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting); permanently discontinue erlotinib in patients who develop GI perforation. Erlotinib is a CYP3A4 substrate and dexamethasone is a moderate CYP3A4 inducer. Coadministration may decrease plasma concentrations of erlotinib. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases; patients receiving concomitant dexamethasone may be at increased risk.
    Dexlansoprazole: (Major) Avoid coadministration of erlotinib with dexlansoprazole if possible due to decreases in erlotinib plasma concentrations. Erlotinib solubility is pH dependent and solubility decreases as pH increases. Coadministration of erlotinib with medications that increase the pH of the upper gastrointestinal tract may decrease the absorption of erlotinib. Separation of doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI tract for an extended period of time. Increasing the dose of erlotinib is also not likely to compensate for the loss of exposure. Coadministration with another proton pump inhibitor decreased erlotinib exposure by 46% and the erlotinib Cmax by 61%.
    Diclofenac: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Diclofenac; Misoprostol: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Diflunisal: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Diphenhydramine; Ibuprofen: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Diphenhydramine; Naproxen: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Docetaxel: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with a taxane (i.e., cabazitaxel, docetaxel, paclitaxel) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases; patients receiving concomitant taxanes may be at increased risk.
    Efavirenz: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with efavirenz; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate, and efavirenz is a moderate CYP3A4 inducer.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with efavirenz; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate, and efavirenz is a moderate CYP3A4 inducer.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with efavirenz; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate, and efavirenz is a moderate CYP3A4 inducer.
    Enzalutamide: (Major) Avoid coadministration of erlotinib with enzalutamide if possible due to decreased plasma concentrations of erlotinib. If concomitant use is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals as tolerated (maximum dose, 450 mg). Coadministration with another strong CYP3A4 inducer decreased erlotinib exposure by 58% to 80%.
    Eslicarbazepine: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with eslicarbazepine; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate, and eslicarbazepine is a moderate CYP3A4 inducer.
    Esomeprazole: (Major) Avoid coadministration of erlotinib with esomeprazole if possible due to decreases in erlotinib plasma concentrations. Erlotinib solubility is pH dependent and solubility decreases as pH increases. Coadministration of erlotinib with medications that increase the pH of the upper gastrointestinal tract may decrease the absorption of erlotinib. Separation of doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI tract for an extended period of time. Increasing the dose of erlotinib is also not likely to compensate for the loss of exposure. Coadministration with another proton pump inhibitor decreased erlotinib exposure by 46% and the erlotinib Cmax by 61%.
    Esomeprazole; Naproxen: (Major) Avoid coadministration of erlotinib with esomeprazole if possible due to decreases in erlotinib plasma concentrations. Erlotinib solubility is pH dependent and solubility decreases as pH increases. Coadministration of erlotinib with medications that increase the pH of the upper gastrointestinal tract may decrease the absorption of erlotinib. Separation of doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI tract for an extended period of time. Increasing the dose of erlotinib is also not likely to compensate for the loss of exposure. Coadministration with another proton pump inhibitor decreased erlotinib exposure by 46% and the erlotinib Cmax by 61%. (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Etodolac: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Etravirine: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with etravirine; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate, and etravirine is a moderate CYP3A4 inducer.
    Famotidine: (Major) If concomitant use of erlotinib with famotidine is necessary, erlotinib must be taken 10 hours after the last dose of famotidine and at least 2 hours before the next dose. Erlotinib displays pH-dependent solubility with decreased solubility at a higher pH; the increased gastric pH resulting from famotidine therapy may reduce the bioavailability of erlotinib. Increasing the dose of erlotinib without modifying the administration schedule is unlikely to compensate for loss of exposure. Erlotinib exposure was decreased by 33% and the Cmax by 54% when erlotinib was administered 2 hours after a single dose of an H2-antagonist. When administered at least 10 hours after an evening dose of an H2-antagonist and 2 hours before the morning dose, erlotinib exposure was decreased by 15% and Cmax by 17%.
    Famotidine; Ibuprofen: (Major) If concomitant use of erlotinib with famotidine is necessary, erlotinib must be taken 10 hours after the last dose of famotidine and at least 2 hours before the next dose. Erlotinib displays pH-dependent solubility with decreased solubility at a higher pH; the increased gastric pH resulting from famotidine therapy may reduce the bioavailability of erlotinib. Increasing the dose of erlotinib without modifying the administration schedule is unlikely to compensate for loss of exposure. Erlotinib exposure was decreased by 33% and the Cmax by 54% when erlotinib was administered 2 hours after a single dose of an H2-antagonist. When administered at least 10 hours after an evening dose of an H2-antagonist and 2 hours before the morning dose, erlotinib exposure was decreased by 15% and Cmax by 17%. (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Fenoprofen: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Fludrocortisone: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with fludrocortisone is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases; patients receiving concomitant fludrocortisone may be at increased risk.
    Flurbiprofen: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Fluvoxamine: (Major) Avoid coadministration of erlotinib with fluvoxamine if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP1A2. Fluvoxamine is a CYP3A4 and CYP1A2 inhibitor. Coadministration with another moderate CYP3A4/CYP1A2 inhibitor increased erlotinib exposure by 39% and increased the erlotinib Cmax by 17%.
    Fosamprenavir: (Major) Avoid coadministration of erlotinib with fosamprenavir if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and fosamprenavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Fosphenytoin: (Major) Avoid coadministration of erlotinib with fosphenytoin if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals as tolerated (maximum dose, 450 mg). Erlotinib is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased erlotinib exposure by 58% to 80%.
    Grapefruit juice: (Major) Have patients avoid grapefruit or grapefruit juice during erlotinib treatment due to the increased risk of erlotinib-related adverse reactions. Erlotinib is a CYP3A4 substrate and grapefruit juice is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Hydrocodone; Ibuprofen: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Hydrocortisone: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with hydrocortisone is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases; patients receiving concomitant hydrocortisone may be at increased risk.
    Ibuprofen: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Ibuprofen; Oxycodone: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Ibuprofen; Pseudoephedrine: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Idelalisib: (Major) Avoid coadministration of erlotinib with idelalisib if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and idelalisib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Indinavir: (Major) Avoid coadministration of erlotinib with indinavir if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and indinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Indomethacin: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of erlotinib with rifampin if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals as tolerated (maximum dose, 450 mg). Erlotinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased erlotinib exposure by 58% to 80%.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of erlotinib with rifampin if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals as tolerated (maximum dose, 450 mg). Erlotinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased erlotinib exposure by 58% to 80%.
    Itraconazole: (Major) Avoid coadministration of erlotinib with itraconazole if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment; the decline in plasma concentrations may be more gradual In patients with cirrhosis or receiving other CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Ketoconazole: (Major) Avoid coadministration of erlotinib with ketoconazole if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased erlotinib exposure by 67%.
    Ketoprofen: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Ketorolac: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Lansoprazole: (Major) Avoid coadministration of erlotinib with lansoprazole if possible due to decreases in erlotinib plasma concentrations. Erlotinib solubility is pH dependent and solubility decreases as pH increases. Coadministration of erlotinib with medications that increase the pH of the upper gastrointestinal tract may decrease the absorption of erlotinib. Separation of doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI tract for an extended period of time. Increasing the dose of erlotinib is also not likely to compensate for the loss of exposure. Coadministration with another proton pump inhibitor decreased erlotinib exposure by 46% and the erlotinib Cmax by 61%.
    Lansoprazole; Naproxen: (Major) Avoid coadministration of erlotinib with lansoprazole if possible due to decreases in erlotinib plasma concentrations. Erlotinib solubility is pH dependent and solubility decreases as pH increases. Coadministration of erlotinib with medications that increase the pH of the upper gastrointestinal tract may decrease the absorption of erlotinib. Separation of doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI tract for an extended period of time. Increasing the dose of erlotinib is also not likely to compensate for the loss of exposure. Coadministration with another proton pump inhibitor decreased erlotinib exposure by 46% and the erlotinib Cmax by 61%. (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Letermovir: (Moderate) An increase in the plasma concentration of erlotinib may occur if given with letermovir. Avoid coadministration in patients also receiving cyclosporine, because the magnitude of the interaction may be amplified. If erlotinib must be coadministered with both letermovir and cyclosporine and the patient experiences a severe reaction, reduce the erlotinib dose by 50 mg decrements. Erlotinib 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 erlotinib exposure by 67%.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of erlotinib with lopinavir; ritonavir if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and lopinavir; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%. (Major) Avoid coadministration of erlotinib with ritonavir if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of erlotinib with lumacaftor; ivacaftor if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals as tolerated (maximum dose, 450 mg). Erlotinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased erlotinib exposure by 58% to 80%.
    Magnesium Hydroxide: (Major) Separate administration by several hours if concomitant use of erlotinib and antacids is necessary. Erlotinib displays pH-dependent solubility with decreased solubility at a higher pH; the increased gastric pH resulting from antacid therapy may reduce the bioavailability of erlotinib. Increasing the dose of erlotinib without modifying the administration schedule is unlikely to compensate for loss of exposure. The effects of antacids on erlotinib pharmacokinetics has not been evaluated.
    Meclofenamate Sodium: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Mefenamic Acid: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Meloxicam: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Mephobarbital: (Major) Avoid coadministration of erlotinib with mephobarbital if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals as tolerated (maximum dose, 450 mg). Erlotinib is a CYP3A4 substrate and mephobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased erlotinib exposure by 58% to 80%.
    Methohexital: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with methohexital; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Methohexital is a CYP3A4 and 1A2 inducer. Coadministration may decrease plasma concentrations of erlotinib.
    Methylprednisolone: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with methylprednisolone is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases; patients receiving concomitant methylprednisolone may be at increased risk.
    Mifepristone: (Major) Avoid coadministration of erlotinib with chronic mifepristone use if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown. Erlotinib is a CYP3A4 substrate and mifepristone is a strong CYP3A4 inhibitor. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Mitotane: (Major) Avoid coadministration of erlotinib with mitotane if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals as tolerated (maximum dose, 450 mg). Erlotinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased erlotinib exposure by 58% to 80%.
    Modafinil: (Major) Avoid the coadministration of erlotinib with modafinil if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. Coadministration may decrease plasma concentrations of erlotinib.
    Nabumetone: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Nafcillin: (Major) Avoid the coadministration of erlotinib with nafcillin if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Coadministration may decrease plasma concentrations of erlotinib.
    Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with a taxane (i.e., cabazitaxel, docetaxel, paclitaxel) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases; patients receiving concomitant taxanes may be at increased risk.
    Naproxen: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Naproxen; Pseudoephedrine: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Naproxen; Sumatriptan: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Nefazodone: (Major) Avoid coadministration of erlotinib with nefazodone if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Nelfinavir: (Major) Avoid coadministration of erlotinib with nelfinavir if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and nelfinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Nevirapine: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with nevirapine; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate, and nevirapine is a moderate CYP3A4 inducer.
    Nilotinib: (Moderate) Use caution if coadministration of erlotinib with nilotinib is necessary due to the risk of increased erlotinib-related adverse reactions, and avoid coadministration with erlotinib if the patient is additionally taking a CYP1A2 inhibitor. If the patient is taking both nilotinib and a CYP1A2 inhibitor and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements; the manufacturer of erlotinib makes the same recommendations for toxicity-related dose reductions in patients taking strong CYP3A4 inhibitors without concomitant CYP1A2 inhibitors. Nilotinib is a moderate CYP3A4 inhibitor in vitro. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Coadministration of erlotinib with ketoconazole, a strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. Coadministration of erlotinib with ciprofloxacin, a moderate inhibitor of CYP3A4 and CYP1A2, increased the erlotinib AUC by 39% and the Cmax by 17%; coadministration with nilotinib may also increase erlotinib exposure.
    Nizatidine: (Major) If concomitant use of erlotinib with nizatidine is necessary, erlotinib must be taken 10 hours after the last dose of nizatidine and at least 2 hours before the next dose. Erlotinib displays pH-dependent solubility with decreased solubility at a higher pH; the increased gastric pH resulting from nizatidine therapy may reduce the bioavailability of erlotinib. Increasing the dose of erlotinib without modifying the administration schedule is unlikely to compensate for loss of exposure. Erlotinib exposure was decreased by 33% and the Cmax by 54% when erlotinib was administered 2 hours after a single dose of an H2-antagonist. When administered at least 10 hours after an evening dose of an H2-antagonist and 2 hours before the morning dose, erlotinib exposure was decreased by 15% and Cmax by 17%.
    Nonsteroidal antiinflammatory drugs: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of erlotinib with ritonavir if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Omeprazole: (Major) Avoid coadministration of erlotinib with omeprazole if possible due to decreases in erlotinib plasma concentrations. Erlotinib solubility is pH dependent and solubility decreases as pH increases. Coadministration of erlotinib with medications that increase the pH of the upper gastrointestinal tract may decrease the absorption of erlotinib. Separation of doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI tract for an extended period of time. Increasing the dose of erlotinib is also not likely to compensate for the loss of exposure. Coadministration with omeprazole decreased erlotinib exposure by 46% and the erlotinib Cmax by 61%.
    Omeprazole; Sodium Bicarbonate: (Major) Avoid coadministration of erlotinib with omeprazole if possible due to decreases in erlotinib plasma concentrations. Erlotinib solubility is pH dependent and solubility decreases as pH increases. Coadministration of erlotinib with medications that increase the pH of the upper gastrointestinal tract may decrease the absorption of erlotinib. Separation of doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI tract for an extended period of time. Increasing the dose of erlotinib is also not likely to compensate for the loss of exposure. Coadministration with omeprazole decreased erlotinib exposure by 46% and the erlotinib Cmax by 61%. (Major) Separate administration by several hours if concomitant use of erlotinib with sodium bicarbonate is necessary. Erlotinib displays pH-dependent solubility with decreased solubility at a higher pH; the increased gastric pH resulting from sodium bicarbonate therapy may reduce the bioavailability of erlotinib. Increasing the dose of erlotinib without modifying the administration schedule is unlikely to compensate for loss of exposure. The effects of antacids on erlotinib pharmacokinetics has not been evaluated.
    Oxaprozin: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Oxcarbazepine: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with oxcarbazepine; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate, and oxcarbazepine is a moderate CYP3A4 inducer.
    Paclitaxel: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with a taxane (i.e., cabazitaxel, docetaxel, paclitaxel) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases; patients receiving concomitant taxanes may be at increased risk.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Pantoprazole: (Major) Avoid coadministration of erlotinib with pantoprazole if possible due to decreases in erlotinib plasma concentrations. Erlotinib solubility is pH dependent and solubility decreases as pH increases. Coadministration of erlotinib with medications that increase the pH of the upper gastrointestinal tract may decrease the absorption of erlotinib. Separation of doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI tract for an extended period of time. Increasing the dose of erlotinib is also not likely to compensate for the loss of exposure. Coadministration with another proton pump inhibitor decreased erlotinib exposure by 46% and the erlotinib Cmax by 61%.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentobarbital: (Major) Avoid the coadministration of erlotinib with pentobarbital if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Pentobarbital is a CYP3A4 and CYP1A2 inducer. Coadministration may decrease plasma concentrations of erlotinib.
    Phenobarbital: (Major) Avoid coadministration of erlotinib with phenobarbital if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals as tolerated (maximum dose, 450 mg). Erlotinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased erlotinib exposure by 58% to 80%.
    Phenytoin: (Major) Avoid coadministration of erlotinib with phenytoin if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals as tolerated (maximum dose, 450 mg). Erlotinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased erlotinib exposure by 58% to 80%.
    Piroxicam: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Posaconazole: (Major) Avoid coadministration of erlotinib with posaconazole if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and posaconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Prednisolone: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with prednisolone is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases; patients receiving concomitant prednisolone may be at increased risk.
    Prednisone: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with prednisone is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases; patients receiving concomitant prednisone may be at increased risk.
    Primidone: (Major) Avoid coadministration of erlotinib with primidone if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals as tolerated (maximum dose, 450 mg). Erlotinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased erlotinib exposure by 58% to 80%.
    Quinine: (Major) Avoid coadministration of erlotinib with quinine if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib by 50 mg increments at 2-week intervals as tolerated, to a maximum of 300 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Quinine is a CYP1A2 inducer. Coadministration may decrease plasma concentrations of erlotinib.
    Rabeprazole: (Major) Avoid coadministration of erlotinib with rabeprazole if possible due to decreases in erlotinib plasma concentrations. Erlotinib solubility is pH dependent and solubility decreases as pH increases. Coadministration of erlotinib with medications that increase the pH of the upper gastrointestinal tract may decrease the absorption of erlotinib. Separation of doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI tract for an extended period of time. Increasing the dose of erlotinib is also not likely to compensate for the loss of exposure. Coadministration with another proton pump inhibitor decreased erlotinib exposure by 46% and the erlotinib Cmax by 61%.
    Ranitidine: (Major) If concomitant use of erlotinib with ranitidine is necessary, erlotinib must be taken 10 hours after the last dose of ranitidine and at least 2 hours before the next dose. Erlotinib displays pH-dependent solubility with decreased solubility at a higher pH; the increased gastric pH resulting from ranitidine therapy may reduce the bioavailability of erlotinib. Increasing the dose of erlotinib without modifying the administration schedule is unlikely to compensate for loss of exposure. Erlotinib exposure was decreased by 33% and the Cmax by 54% when erlotinib was administered 2 hours after a 300-mg dose of ranitidine. When administered at least 10 hours after an evening dose of ranitidine and 2 hours before the morning dose, erlotinib exposure was decreased by 15% and Cmax by 17%.
    Rifabutin: (Major) Avoid the coadministration of erlotinib with rifabutin if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate and rifabutin is a CYP3A4 inducer. Coadministration may decrease plasma concentrations of erlotinib.
    Rifampin: (Major) Avoid coadministration of erlotinib with rifampin if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals as tolerated (maximum dose, 450 mg). Erlotinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased erlotinib exposure by 58% to 80%.
    Rifapentine: (Major) Avoid the coadministration of erlotinib with rifapentine if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate and rifapentine is a CYP3A4 inducer. Coadministration may decrease plasma concentrations of erlotinib.
    Ritonavir: (Major) Avoid coadministration of erlotinib with ritonavir if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Rofecoxib: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Saquinavir: (Major) Avoid coadministration of erlotinib with saquinavir if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Secobarbital: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with secobarbital; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Secobarbital is a CYP3A4 and 1A2 inducer. Coadministration may decrease plasma concentrations of erlotinib.
    Simeprevir: (Major) Avoid coadministration of erlotinib with simeprevir if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP1A2. Simeprevir is a CYP3A4 and CYP1A2 inhibitor. Coadministration with another moderate CYP3A4/CYP1A2 inhibitor increased erlotinib exposure by 39% and increased the erlotinib Cmax by 17%.
    Sodium Bicarbonate: (Major) Separate administration by several hours if concomitant use of erlotinib with sodium bicarbonate is necessary. Erlotinib displays pH-dependent solubility with decreased solubility at a higher pH; the increased gastric pH resulting from sodium bicarbonate therapy may reduce the bioavailability of erlotinib. Increasing the dose of erlotinib without modifying the administration schedule is unlikely to compensate for loss of exposure. The effects of antacids on erlotinib pharmacokinetics has not been evaluated.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of erlotinib with St. John's Wort if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals as tolerated (maximum dose, 450 mg). Erlotinib is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer, although the amount of individual constituents in various products may alter the inducing effects, making drug interactions unpredictable. Coadministration with another strong CYP3A4 inducer decreased erlotinib exposure by 58% to 80%.
    Streptogramins: (Major) Avoid coadministration of erlotinib with dalfopristin; quinupristin if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and quinupristin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Sulindac: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Taxanes: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with a taxane (i.e., cabazitaxel, docetaxel, paclitaxel) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases; patients receiving concomitant taxanes may be at increased risk.
    Telithromycin: (Major) Avoid coadministration of erlotinib with telithromycin if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and telithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Thiopental: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with thiopental; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Thiopental is a CYP3A4 and 1A2 inducer. Coadministration may decrease plasma concentrations of erlotinib.
    Tipranavir: (Major) Avoid coadministration of erlotinib with tipranavir if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Tobacco: (Major) Advise patients to avoid tobacco smoking while taking erlotinib if possible. Patients should communicate to their prescriber any changes in smoking status during erlotinib treatment. If the patient continues to smoke or begins to smoke and concomitant use is unavoidable, increase the dose of erlotinib by 50 mg increments at 2-week intervals to a maximum of 300 mg/day. Immediately reduce the dose of erlotinib to the recommended dose upon cessation of smoking. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Tobacco smoke is a CYP1A2 inducer. In a single-dose pharmacokinetics trial in healthy volunteers, cigarette smoking (moderate CYP1A2 inducer) decreased the AUC of erlotinib by 64% (95% CI, 46% to 76%) in current smokers compared with former/never smokers. Steady-state trough concentrations of erlotinib were approximately 2-fold less in current smokers compared with former/never smokers in a separate study of patients with NSCLC.
    Tolmetin: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Trandolapril; Verapamil: (Major) Avoid coadministration of erlotinib with verapamil if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP1A2. Verapamil is a CYP3A4 and CYP1A2 inhibitor. Coadministration with another moderate CYP3A4/CYP1A2 inhibitor increased erlotinib exposure by 39% and increased the erlotinib Cmax by 17%.
    Triamcinolone: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with systemic triamcinolone is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases; patients receiving concomitant triamcinolone may be at increased risk.
    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.
    Valdecoxib: (Moderate) Monitor for symptoms of gastrointestinal (GI) perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with nonsteroidal antiinflammatory drugs (NSAIDs) is necessary. Permanently discontinue erlotinib in patients who develop GI perforation. The pooled incidence of GI perforation clinical trials of erlotinib ranged from 0.1% to 0.4%, including fatal cases. Patients receiving concomitant NSAIDs may be at increased risk of perforation.
    Verapamil: (Major) Avoid coadministration of erlotinib with verapamil if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP1A2. Verapamil is a CYP3A4 and CYP1A2 inhibitor. Coadministration with another moderate CYP3A4/CYP1A2 inhibitor increased erlotinib exposure by 39% and increased the erlotinib Cmax by 17%.
    Voriconazole: (Major) Avoid coadministration of erlotinib with voriconazole if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Warfarin: (Major) Regularly monitor prothrombin time (PT) or INR in patients taking warfarin. Increased INR and bleeding adverse reactions, in some cases fatal, have been reported in patients receiving concomitant therapy. Dose modifications of erlotinib are not recommended.
    Zafirlukast: (Major) Avoid coadministration of erlotinib with zafirlukast if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP1A2. Zafirlukast is a CYP3A4 and CYP1A2 inhibitor. Coadministration with a moderate CYP3A4/CYP1A2 inhibitor increased erlotinib exposure by 39% and increased the erlotinib Cmax by 17%.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during erlotinib treatment and for at least 1 month after the last dose. Although there are no adequately controlled studies in pregnant women, erlotinib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving erlotinib should be apprised of the potential hazard to the fetus. Erlotinib caused maternal toxicity resulting in embryo-fetal death and abortion in rabbits when given during organogenesis at exposures approximately 3 times those achieved with the recommended dose in humans. There was no increase in embryolethality or abortion in rabbits or rats when erlotinib was given during organogenesis at exposures approximately equal to those achieved with the recommended daily dose in humans. Teratogenicity was not observed with erlotinib administration during organogenesis at exposures up to 3 times the exposure with the recommended dose in humans in rabbits, and up to 0.7 times the exposure with the recommended dose in humans in rats.

    Due to the potential for serious adverse reactions in nursing infants from erlotinib, advise women to discontinue breast-feeding during treatment and for 2 weeks after the final dose. It is not known if erlotinib is excreted in human breast milk.

    MECHANISM OF ACTION

    Erlotinib is a synthetic quinazolinamine that reversibly inhibits the kinase activity of the epidermal growth factor receptor (EGFR), preventing autophosphorylation of tyrosine residues associated with the receptor and thereby inhibiting further downstream signaling. EGFR is expressed on cell surfaces of both normal and cancer cells. In some tumor cells, signaling through this receptor plays a role in tumor cell survival and proliferation irrespective of EGFR mutation status. Erlotinib has a higher binding affinity for EGFR exon 19 deletion or exon 21 (L858R) substitution mutations compared to its affinity for the wild-type receptor; inhibition of other tyrosine kinase receptors by erlotinib has not been fully characterized.

    PHARMACOKINETICS

    Erlotinib is administered orally. Binding to plasma proteins, primarily albumin and alpha-1-acid glycoprotein, is 93%. The apparent volume of distribution (Vd) is 232 liters. The median elimination half-life of erlotinib when given as second- or third-line monotherapy is 36.2 hours; the time to reach steady state plasma concentration is 7 to 8 days. Excretion is predominantly (83%) via the feces, with only 1% of a dose recovered as intact parent drug; renal elimination of erlotinib accounts for 8% of the administered dose (0.3% as intact parent drug).
     
    Affected cytochrome P450 isoenzymes: CYP3A4, CYP1A2, CYP1A1
    Erlotinib undergoes significant hepatic metabolism, predominantly by CYP3A4 and to a lesser extent by CYP1A2 and the extrahepatic isoform CYP1A1. Coadministration with strong CYP3A4 inhibitors or inducers are expected to affect erlotinib exposure. Cigarette smoking (moderate CYP1A2 inducer) also significantly increases erlotinib clearance compared to former smokers or never smokers.

    Oral Route

    Peak plasma levels of erlotinib occur 4 hours after dosing with a mean bioavailability of 60%. Bioavailability increases by 100% with the administration of food. Following continuous daily administration of a 150 mg oral dose, the peak concentration of erlotinib is 2,690 ng/mL, and the AUC is 38.4 mcg*hour/mL with significant inter- and intra-patient variability.
     
    The solubility of erlotinib is pH-dependent and decreases as the pH increases. Coadministration with medications that increase gastric pH decrease erlotinib exposure.