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  • CLASSES

    Protein Kinase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Oral selective epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TK1)
    FDA-approved for the treatment of locally advanced and metastatic non-small cell lung cancer
    FDA-approved in combination with gemcitabine for first-line treatment of unresectable or metastatic pancreatic cancer

    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.
    NOTE: Erlotinib is not recommended for use in combination with platinum-based chemotherapy as there is no clinical benefit.
    NOTE: 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 occurs. Avoid use with CYP1A2 and 3A4 inducers, and with strong CYP3A4 inhibitors if possible; a dosage adjustment may be necessary. The safety and efficacy of erlotinib has not been established in patients with NSCLC whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution mutations. Despite a high crossover rate (82%), erlotinib monotherapy (n = 86) improved the primary endpoint of progression-free survival (PFS) compared with platinum-based doublet chemotherapy (n = 88) 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; HR 0.34; p < 0.001); median overall survival (22.9 months vs. 19.5 months; 95% CI, 0.64 to 1.35) and overall response rate (65% vs. 16%) were also improved. Median PFS (2.8 months vs. 2.6 months; p < 0.0001) and OS (12 months vs. 11 months; p = 0.0088) were minimally but significantly improved with erlotinib (n = 438) compared with placebo (n = 451) when given as maintenance therapy after first-line treatment with platinum-based chemotherapy in a multicenter, placebo controlled clinical trial in a population that was 70% EGFR positive. 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 (n = 643). 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 therapy (n = 488) compared with placebo (n = 243) (6.7 months vs. 4.7 months; p < 0.001).

    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 up to 7 consecutive weeks, followed by 1 week of rest. After week 8, 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. Avoid use with CYP1A2 and 3A4 inducers, and with strong CYP3A4 inhibitors if possible; a dosage adjustment may be necessary. In a Phase III trial, the addition of erlotinib to gemcitabine improved survival 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. Further study is needed to define the benefit of erlotinib in the treatment of head and neck cancer. In a phase II 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 (p = 0.045). No difference in response was noted based upon HER1/EGFR expression.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    NSCLC: 150 mg PO daily; up to 300 mg daily with concurrent tobacco smoking; up to 450 mg PO daily if taken with a CYP3A4 inducer.
    Pancreatic Cancer: 100 mg PO daily; up to 300 mg daily with concurrent tobacco smoking; up to 450 mg PO daily if taken with a CYP3A4 inducer.

    Geriatric

    NSCLC: 150 mg PO daily; up to 300 mg daily with concurrent tobacco smoking; up to 450 mg PO daily if taken with a CYP3A4 inducer.
    Pancreatic Cancer: 100 mg PO daily; up to 300 mg daily with concurrent tobacco smoking; up to 450 mg PO daily if taken with a CYP3A4 inducer.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment
    Child-Pugh A, B, and C; total bilirubin above upper limit of normal (ULN): Closely monitor for adverse events, as erlotinib undergoes significant liver metabolism. Use increased monitoring in patients with total bilirubin more than 3 times ULN.
    Treatment-Related Hepatotoxicity
    Total bilirubin more than 3 times 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 grade 0 or 1 (bilirubin less than or equal to 1.5 times ULN, or AST/ALT less than or equal to 3 times ULN). 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 grade 0 or 1 (bilirubin less than or equal to 1.5 times ULN, or AST/ALT less than or equal to 3 times ULN). Discontinue erlotinib if resolution or significant improvement does not occur within 3 weeks.

    Renal Impairment

    Baseline Renal Impairment
    Less than 9% of a single dose of erlotinib is excreted in the urine; clinical studies have not been conducted in patients with renal impairment.
    Treatment-Induced Nephrotoxicity
    Grade 3 or 4 renal impairment (serum creatinine (SCr) more than 3 times baseline, or more than 3 to 6 times upper limit of normal (ULN)): Hold erlotinib therapy. When nephrotoxicity has resolved to grade 0 or 1 (SCr less than or equal to 1.5 times either baseline or ULN), 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 between meals. Do not administer with food. Administering with food increases the risk of side effects.

    STORAGE

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

    CONTRAINDICATIONS / PRECAUTIONS

    Chronic lung disease (CLD), pneumonitis, pulmonary disease, respiratory insufficiency

    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 or respiratory insufficiency 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. Symptoms may begin from 5 days to more than 9 months (median 39 days) after initiating erlotinib therapy. Use caution if erlotinib is used in patients with underlying or chronic lung disease (CLD) or pulmonary disease, as they may be at higher risk for adverse pulmonary reactions.

    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

    Corneal perforation or ulceration have been reported in patients receiving erlotinib; known risk factors such as decreased lacrimation, abnormal eyelash growth, keratoconjunctivitis, and keratitis have also occurred with erlotinib therapy. 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. Cautious use of erlotinib may be necessary in patients with pre-existing ocular disease.

    Corticosteroid therapy, diverticulitis, GI perforation, peptic ulcer disease

    Cases of gastrointestinal (GI) perforation, including some fatal cases, have been reported with the use of erlotinib. Permanently discontinue erlotinib if a GI perforation occurs. 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 GI perforation.

    Tobacco smoking

    Patients should avoid smoking tobacco while being treated with erlotinib. 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, geriatric, renal disease, renal failure, renal impairment

    Administration of erlotinib to a patient with dehydration or hepatic impairment may lead to renal failure, especially in patients with preexisting renal disease including renal impairment or renal failure, medical conditions or medications that may lead to renal disease, or other predisposing conditions including advanced age (geriatric). 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

    keratoconjunctivitis / Early / 12.0-12.0
    thrombosis / Delayed / 11.0-11.0
    ileus / Delayed / 0-5.0
    pancreatitis / Delayed / 0-5.0
    myocardial infarction / Delayed / 2.3-2.3
    stroke / Early / 2.3-2.3
    hemolytic anemia / Delayed / 0-1.4
    Stevens-Johnson syndrome / Delayed / 0.4-1.2
    toxic epidermal necrolysis / Delayed / 0.4-1.2
    uveitis / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 0-1.0
    hyperbilirubinemia / Delayed / 0-1.0
    hepatic failure / Delayed / 0-0.4
    GI perforation / Delayed / 0.2-0.4
    keratitis / Delayed / Incidence not known
    acute respiratory distress syndrome (ARDS) / Early / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    bronchiolitis obliterans / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    peptic ulcer / Delayed / Incidence not known
    hematemesis / Delayed / Incidence not known

    Moderate

    dyspnea / Early / 41.0-41.0
    edema / Delayed / 37.0-37.0
    constipation / Delayed / 31.0-31.0
    bone pain / Delayed / 25.0-25.0
    depression / Delayed / 19.0-19.0
    stomatitis / Delayed / 17.0-17.0
    oral ulceration / Delayed / 17.0-17.0
    peripheral neuropathy / Delayed / 13.0-13.0
    conjunctivitis / Delayed / 12.0-12.0
    thrombocytopenia / Delayed / 0-1.4
    ocular inflammation / Early / Incidence not known
    pneumonitis / Delayed / Incidence not known
    dehydration / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    bleeding / Early / Incidence not known
    prolonged bleeding time / Delayed / Incidence not known
    gastritis / Delayed / Incidence not known
    melena / Delayed / Incidence not known

    Mild

    rash (unspecified) / Early / 49.2-75.0
    diarrhea / Early / 20.3-54.0
    anorexia / Delayed / 9.2-52.0
    fatigue / Early / 9.0-52.0
    fever / Early / 36.0-36.0
    nausea / Early / 33.0-33.0
    cough / Delayed / 33.0-33.0
    infection / Delayed / 24.0-24.0
    vomiting / Early / 23.0-23.0
    myalgia / Early / 21.0-21.0
    dyspepsia / Early / 17.0-17.0
    insomnia / Early / 15.0-15.0
    headache / Early / 15.0-15.0
    dizziness / Early / 15.0-15.0
    alopecia / Delayed / 14.0-14.0
    flatulence / Early / 13.0-13.0
    pruritus / Rapid / 7.4-13.0
    anxiety / Delayed / 13.0-13.0
    xerosis / Delayed / 4.4-12.0
    abdominal pain / Early / 11.0-11.0
    lacrimation / Early / 1.0-10.0
    acne vulgaris / Delayed / 6.2-6.2
    syncope / Early / 0-5.0
    acneiform rash / Delayed / 4.6-4.6
    weight loss / Delayed / 3.9-3.9
    ocular pain / Early / Incidence not known
    hypertrichosis / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known
    hirsutism / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: (Major) Avoid the coadministration of erlotinib with butalbital 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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Butalbital is a CYP1A2 and 3A4 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. 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.
    Acetaminophen; Butalbital; Caffeine: (Major) Avoid the coadministration of erlotinib with butalbital 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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Butalbital is a CYP1A2 and 3A4 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. 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.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Avoid the coadministration of erlotinib with butalbital 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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Butalbital is a CYP1A2 and 3A4 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. 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.
    Aldesleukin, IL-2: (Moderate) Use caution if coadministration of erlotinib with aldesleukin, IL-2 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 aldesleukin, IL-2 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. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Aldesleukin, IL-2 increases IL-6 concentrations, and IL-6 is a weak CYP3A4 inhibitor; IL-2 has also been shown to inhibit CYP3A4 directly. 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 aldesleukin, IL-2 may also increase erlotinib exposure.
    Aliskiren; Amlodipine: (Moderate) Use caution if coadministration of erlotinib with amlodipine 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 amlodipine 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. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Amlodipine is a weak CYP3A4 inhibitor. 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 amlodipine may also increase erlotinib exposure.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Use caution if coadministration of erlotinib with amlodipine 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 amlodipine 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. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Amlodipine is a weak CYP3A4 inhibitor. 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 amlodipine may also increase erlotinib exposure.
    Alogliptin; Pioglitazone: (Major) Avoid the coadministration of erlotinib with pioglitazone if possible due to the risk of decreased erlotinib efficacy; if concomitant use is unavoidable, the manufacturer recommends increasing the dose of erlotinib by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Pioglitazone is a weak CYP3A4 inducer. The AUC and Cmax of another CYP3A4 substrate, midazolam, were each decreased by 26% when administered with pioglitazone. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with pioglitazone may also decrease erlotinib exposure.
    Aluminum Hydroxide: (Major) 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. No formal analysis has been performed to assess the impact of antacids on erlotinib pharmacokinetics; however, if coadministration is necessary, the manufacturer recommends separation of antacids and erlotinib by several hours.
    Aluminum Hydroxide; Magnesium Carbonate: (Major) 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. No formal analysis has been performed to assess the impact of antacids on erlotinib pharmacokinetics; however, if coadministration is necessary, the manufacturer recommends separation of antacids and erlotinib by several hours.
    Aluminum Hydroxide; Magnesium Hydroxide: (Major) 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. No formal analysis has been performed to assess the impact of antacids on erlotinib pharmacokinetics; however, if coadministration is necessary, the manufacturer recommends separation of antacids and erlotinib by several hours.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Major) 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. No formal analysis has been performed to assess the impact of antacids on erlotinib pharmacokinetics; however, if coadministration is necessary, the manufacturer recommends separation of antacids and erlotinib by several hours.
    Aluminum Hydroxide; Magnesium Trisilicate: (Major) 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. No formal analysis has been performed to assess the impact of antacids on erlotinib pharmacokinetics; however, if coadministration is necessary, the manufacturer recommends separation of antacids and erlotinib by several hours.
    Amiodarone: (Major) Avoid the coadministration of erlotinib with amiodarone 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Amiodarone is an inhibitor of CYP3A4 and 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 amiodarone may also increase erlotinib exposure.
    Amlodipine: (Moderate) Use caution if coadministration of erlotinib with amlodipine 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 amlodipine 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. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Amlodipine is a weak CYP3A4 inhibitor. 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 amlodipine may also increase erlotinib exposure.
    Amlodipine; Atorvastatin: (Moderate) Concomitant use of erlotinib and HMG-coA reductase inhibitors (statins) may increase the risk for statin-induced myopathy. Myopathy and rhabdomyolysis has been observed rarely with concurrent use of statins and erlotinib during post-market use. The mechanism for this interaction is not known. Use erlotinib and statins together with caution and monitor for signs or symptoms of statin-related adverse events including myopathy (e.g., muscle pain or weakness) and rhabdomyolysis (e.g., nausea/vomiting, dark colored urine). (Moderate) Use caution if coadministration of erlotinib with amlodipine 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 amlodipine 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. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Amlodipine is a weak CYP3A4 inhibitor. 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 amlodipine may also increase erlotinib exposure.
    Amlodipine; Benazepril: (Moderate) Use caution if coadministration of erlotinib with amlodipine 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 amlodipine 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. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Amlodipine is a weak CYP3A4 inhibitor. 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 amlodipine may also increase erlotinib exposure.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Use caution if coadministration of erlotinib with amlodipine 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 amlodipine 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. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Amlodipine is a weak CYP3A4 inhibitor. 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 amlodipine may also increase erlotinib exposure.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Use caution if coadministration of erlotinib with amlodipine 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 amlodipine 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. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Amlodipine is a weak CYP3A4 inhibitor. 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 amlodipine may also increase erlotinib exposure.
    Amlodipine; Olmesartan: (Moderate) Use caution if coadministration of erlotinib with amlodipine 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 amlodipine 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. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Amlodipine is a weak CYP3A4 inhibitor. 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 amlodipine may also increase erlotinib exposure.
    Amlodipine; Telmisartan: (Moderate) Use caution if coadministration of erlotinib with amlodipine 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 amlodipine 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. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Amlodipine is a weak CYP3A4 inhibitor. 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 amlodipine may also increase erlotinib exposure.
    Amlodipine; Valsartan: (Moderate) Use caution if coadministration of erlotinib with amlodipine 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 amlodipine 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. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Amlodipine is a weak CYP3A4 inhibitor. 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 amlodipine may also increase erlotinib exposure.
    Amobarbital: (Major) Avoid the coadministration of erlotinib with amobarbital 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, 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. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. 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.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of lansoprazole with erlotinib if possible due to the risk of decreased efficacy of erlotinib. 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, like proton pump inhibitors (PPIs), may decrease the absorption of erlotinib. Concomitant use of erlotinib and omeprazole, a PPI, decreased erlotinib AUC and Cmax by 46% and 61% respectively. Increasing the dose of erlotinib may not compensate for the loss of exposure. Proton-pump inhibitors exert their effect over an extended amount of time, as a result spacing of doses is also not expected to eliminate the interaction. Substitution of antacids, separated from the erlotinib dose by several hours, may be considered. No formal analysis has been performed to assess the impact of antacids on erlotinib pharmacokinetics. (Major) Avoid the coadministration of erlotinib with clarithromycin 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Clarithromycin is a strong CYP3A4 inhibitor. Clarithromycin increased the AUC of another CYP3A4 substrate, midazolam, by 174% after IV administration and by 600% after oral administration. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with clarithromycin may also increase erlotinib exposure.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid the coadministration of erlotinib with clarithromycin 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Clarithromycin is a strong CYP3A4 inhibitor. Clarithromycin increased the AUC of another CYP3A4 substrate, midazolam, by 174% after IV administration and by 600% after oral administration. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with clarithromycin may also increase erlotinib exposure. (Major) Avoid the coadministration of erlotinib with omeprazole if possible, as there are multiple issues with concomitant use. Erlotinib solubility is pH dependent, and solubility decreases as pH increase; increasing the dose may not compensate for this loss of exposure. Additionally, erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Omeprazole is a CYP1A2 inducer in vitro. The manufacturer recommends increasing the dose of erlotinib by 50 mg increments at 2-week intervals to a maximum of 300 mg when used with CYP1A2 inducers; however, this may not be effective due to the solubility issue. Omeprazole decreased the AUC and Cmax of erlotinib by 46% and 61%, respectively. In addition to the pharmacokinetic interaction, 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. Coadministration with omeprazole may also decrease erlotinib exposure.
    Antacids: (Major) 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. No formal analysis has been performed to assess the impact of antacids on erlotinib pharmacokinetics; however, if coadministration is necessary, the manufacturer recommends separation of antacids and erlotinib by several hours.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if erlotinib and aprepitant, fosaprepitant are used concurrently and monitor for an increase in erlotinib-related adverse effects for several days after administration of a multi-day aprepitant regimen. Avoid coadministration if possible if the patient is additionally taking a CYP1A2 inhibitor; if 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. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer which may result in a net increase of erlotinib plasma concentrations. Aprepitant has not been shown to alter plasma concentrations of CYP3A4 substrates when given as a single 40 mg dose for post-operative nausea and vomiting. Fosaprepitant is rapidly converted to aprepitant, but its effects on CYP3A4 after a single dose are not considered clinically important. Coadministration of erlotinib with ketoconazole, a strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%, while coadministration with ciprofloxacin, a moderate inhibitor of CYP3A4 and CYP1A2, increased the erlotinib AUC by 39% and the Cmax by 17%. A 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively.
    Armodafinil: (Major) Avoid the coadministration of erlotinib with armodafinil if possible due to the risk of decreased erlotinib efficacy; if concomitant use is unavoidable, the manufacturer recommends increasing the dose of erlotinib by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Armodafinil is a weak CYP3A4 inducer in vitro. It decreased the AUC of another CYP3A4 substrate, midazolam, by 32% after a single oral dose and by 17% after a single IV dose. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with armodafinil may also decrease erlotinib exposure.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid the coadministration of erlotinib with butalbital 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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Butalbital is a CYP1A2 and 3A4 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. 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.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Avoid the coadministration of erlotinib with butalbital 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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Butalbital is a CYP1A2 and 3A4 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. 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.
    Aspirin, ASA; Omeprazole: (Major) Avoid the coadministration of erlotinib with omeprazole if possible, as there are multiple issues with concomitant use. Erlotinib solubility is pH dependent, and solubility decreases as pH increase; increasing the dose may not compensate for this loss of exposure. Additionally, erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Omeprazole is a CYP1A2 inducer in vitro. The manufacturer recommends increasing the dose of erlotinib by 50 mg increments at 2-week intervals to a maximum of 300 mg when used with CYP1A2 inducers; however, this may not be effective due to the solubility issue. Omeprazole decreased the AUC and Cmax of erlotinib by 46% and 61%, respectively. In addition to the pharmacokinetic interaction, 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. Coadministration with omeprazole may also decrease erlotinib exposure.
    Aspirin, ASA; Pravastatin: (Moderate) Concomitant use of erlotinib and HMG-coA reductase inhibitors (statins) may increase the risk for statin-induced myopathy. Myopathy and rhabdomyolysis has been observed rarely with concurrent use of statins and erlotinib during post-market use. The mechanism for this interaction is not known. Use erlotinib and statins together with caution and monitor for signs or symptoms of statin-related adverse events including myopathy (e.g., muscle pain or weakness) and rhabdomyolysis (e.g., nausea/vomiting, dark colored urine).
    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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Atazanavir is a strong CYP3A4 inhibitor. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with atazanavir may also increase erlotinib exposure.
    Atazanavir; Cobicistat: (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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Atazanavir is a strong CYP3A4 inhibitor. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with atazanavir may also increase erlotinib exposure. (Moderate) Use caution if coadministration of erlotinib with cobicistat 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 cobicistat 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. Cobicistat is a moderate CYP3A4 inhibitor. 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 cobicistat may also increase erlotinib exposure.
    Atorvastatin: (Moderate) Concomitant use of erlotinib and HMG-coA reductase inhibitors (statins) may increase the risk for statin-induced myopathy. Myopathy and rhabdomyolysis has been observed rarely with concurrent use of statins and erlotinib during post-market use. The mechanism for this interaction is not known. Use erlotinib and statins together with caution and monitor for signs or symptoms of statin-related adverse events including myopathy (e.g., muscle pain or weakness) and rhabdomyolysis (e.g., nausea/vomiting, dark colored urine).
    Atorvastatin; Ezetimibe: (Moderate) Concomitant use of erlotinib and HMG-coA reductase inhibitors (statins) may increase the risk for statin-induced myopathy. Myopathy and rhabdomyolysis has been observed rarely with concurrent use of statins and erlotinib during post-market use. The mechanism for this interaction is not known. Use erlotinib and statins together with caution and monitor for signs or symptoms of statin-related adverse events including myopathy (e.g., muscle pain or weakness) and rhabdomyolysis (e.g., nausea/vomiting, dark colored urine).
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid the 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 by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Phenobarbital is a strong CYP3A4 inducer and a moderate inducer of CYP1A2. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. 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. Coadministration with phenobarbital may also decrease erlotinib exposure.
    Basiliximab: (Moderate) Use caution if coadministration of erlotinib with basiliximab 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 basiliximab 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. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Basiliximab acts as an IL-2 receptor antagonist. Binding of basiliximab to the IL-2 receptors on activated T cells may allow circulating IL-2 to bind to IL-2 receptors on hepatic and intestinal cells, which may cause a down-regulation of CYP3A4 enzyme activity. Reduced CYP3A4 activity may increase concentrations of CYP3A4 substrates such as erlotinib. 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 basiliximab may also increase erlotinib exposure.
    Belinostat: (Moderate) Erlotinib inhibits UGT1A1 in vitro; belinostat is primarily metabolized by UGT1A1. Use caution if coadministration of belinostat with erlotinib is necessary, as increased belinostat concentrations and toxicities may occur.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid the 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 by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Phenobarbital is a strong CYP3A4 inducer and a moderate inducer of CYP1A2. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. 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. Coadministration with phenobarbital may also decrease erlotinib exposure.
    Bexarotene: (Major) Avoid the coadministration of erlotinib with bexarotene 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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Bexarotene is a CYP3A4 inducer. Exposure to atorvastatin, a CYP3A4 substrate, decreased by half when administered with erlotinib. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with bexarotene may also decrease erlotinib exposure.
    Boceprevir: (Major) Avoid the coadministration of erlotinib with boceprevir 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Boceprevir is a strong CYP3A4 inhibitor. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with boceprevir may also increase erlotinib exposure.
    Bosentan: (Major) Avoid the coadministration of erlotinib with bosentan 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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Bosentan is a CYP3A4 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with bosentan may also decrease erlotinib exposure.
    Brigatinib: (Major) Avoid coadministration of brigatinib with erlotinib if possible due to decreased plasma exposure to erlotinib which may result in decreased efficacy. If concomitant use is unavoidable, increase erlotinib doses by 50-mg increments at 2-week intervals as tolerated to a maximum dose of 450 mg. Erlotinib is a CYP3A4 substrate and brigatinib is a CYP3A4 inducer in vitro. Coadministration with a strong CYP3A inducer decreased the AUC of erlotinib by 58% to 80%.
    Butabarbital: (Major) Avoid the coadministration of erlotinib with butabarbital 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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Butabarbital is a CYP1A2 and 3A4 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. 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.
    Cabozantinib: (Moderate) Use caution if coadministration of erlotinib with cabozantinib 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 cabozantinib 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. Cabozantinib is a weak 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 cabozantinib may also increase erlotinib exposure.
    Calcium Carbonate: (Major) 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. No formal analysis has been performed to assess the impact of antacids on erlotinib pharmacokinetics; however, if coadministration is necessary, the manufacturer recommends separation of antacids and erlotinib by several hours.
    Calcium Carbonate; Magnesium Hydroxide: (Major) 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. No formal analysis has been performed to assess the impact of antacids on erlotinib pharmacokinetics; however, if coadministration is necessary, the manufacturer recommends separation of antacids and erlotinib by several hours.
    Calcium Carbonate; Risedronate: (Major) 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. No formal analysis has been performed to assess the impact of antacids on erlotinib pharmacokinetics; however, if coadministration is necessary, the manufacturer recommends separation of antacids and erlotinib by several hours.
    Calcium; Vitamin D: (Major) 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. No formal analysis has been performed to assess the impact of antacids on erlotinib pharmacokinetics; however, if coadministration is necessary, the manufacturer recommends separation of antacids and erlotinib by several hours.
    Carbamazepine: (Major) Avoid the 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 by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Carbamazepine is a strong inducer of CYP1A2 and 3A4. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. 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.
    Celecoxib: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Chloramphenicol: (Major) Avoid the coadministration of erlotinib with chloramphenicol 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Chloramphenicol is a strong CYP3A4 inhibitor. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with chloramphenicol may also increase erlotinib exposure.
    Cimetidine: (Major) Avoid the coadministration of erlotinib with cimetidine 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; additionally, cimetidine must be given approximately 10 hours before and at least 2 hours after the erlotinib dose. Erlotinib displays pH-dependent solubility with decreased solubility at a higher pH; the increased gastric pH resulting from cimetidine therapy may reduce the bioavailability of erlotinib. Higher erlotinib exposure resulting from the pharmacokinetic interaction between erlotinib and cimetidine is unlikely to compensate for the decrease in bioavailability. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Cimetidine is a moderate CYP3A4 and 1A2 inhibitor. 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 cimetidine may also increase erlotinib exposure.
    Ciprofloxacin: (Major) Avoid the coadministration of erlotinib with ciprofloxacin 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Ciprofloxacin is a moderate CYP1A2 inhibitor, and a weak inhibitor of CYP3A4 in vitro. In vivo data regarding CYP3A4 inhibition with ciprofloxacin are conflicting, with one study postulating that the in vivo concentrations reached with routine dosing may be below the inhibitory constant for CYP3A4 activity. Coadministration of erlotinib with ciprofloxacin increased the erlotinib AUC by 39% and the Cmax by 17%.
    Clarithromycin: (Major) Avoid the coadministration of erlotinib with clarithromycin 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Clarithromycin is a strong CYP3A4 inhibitor. Clarithromycin increased the AUC of another CYP3A4 substrate, midazolam, by 174% after IV administration and by 600% after oral administration. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with clarithromycin may also increase erlotinib exposure.
    Clobazam: (Major) Avoid the coadministration of erlotinib with clobazam if possible due to the risk of decreased erlotinib efficacy; if concomitant use is unavoidable, the manufacturer recommends increasing the dose of erlotinib by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Clobazam is a weak CYP3A4 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with clobazam may also decrease erlotinib exposure.
    Cobicistat: (Moderate) Use caution if coadministration of erlotinib with cobicistat 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 cobicistat 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. Cobicistat is a moderate CYP3A4 inhibitor. 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 cobicistat may also increase erlotinib exposure.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Use caution if coadministration of erlotinib with cobicistat 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 cobicistat 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. Cobicistat is a moderate CYP3A4 inhibitor. 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 cobicistat may also increase erlotinib exposure.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Use caution if coadministration of erlotinib with cobicistat 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 cobicistat 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. Cobicistat is a moderate CYP3A4 inhibitor. 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 cobicistat may also increase erlotinib exposure.
    Conivaptan: (Major) Avoid the coadministration of erlotinib with conivaptan due to the risk of increased erlotinib-related adverse reactions. According to the manufacturer of conivaptan, treatment with erlotinib may be initiated no sooner than 1 week after completion of conivaptan therapy. The manufacturer of erlotinib suggests that if concomitant use is unavoidable and severe reactions occur, the dose of erlotinib should be reduced by 50 mg decrements. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Conivaptan is a strong CYP3A4 inhibitor. Conivaptan has increased the mean AUC of another CYP3A4 substrate, midazolam, by 2- to 3-fold. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with conivaptan may also increase erlotinib exposure.
    Cyclosporine: (Moderate) Use caution if coadministration of erlotinib with cyclosporine 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 cyclosporine 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. Cyclosporine is a moderate CYP3A4 inhibitor. 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 cyclosporine may also increase erlotinib exposure.
    Dabrafenib: (Major) Avoid the coadministration of erlotinib with dabrafenib 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, to a maximum of 450 mg. Dabrafenib is a CYP3A4 inducer. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Dabrafenib decreased the AUC of another CYP3A4 substrate, midazolam, by 74%. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with dabrafenib may also decrease erlotinib exposure.
    Dalfopristin; Quinupristin: (Major) Avoid the coadministration of erlotinib with streptogramins such as dalfopristin; quinupristin 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Quinupristin is a strong CYP3A4 inhibitor. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with quinupristin may also increase erlotinib exposure.
    Darunavir: (Major) Avoid the coadministration of erlotinib with darunavir 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Darunavir is a strong CYP3A4 inhibitor. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with darunavir may also increase erlotinib exposure.
    Darunavir; Cobicistat: (Major) Avoid the coadministration of erlotinib with darunavir 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Darunavir is a strong CYP3A4 inhibitor. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with darunavir may also increase erlotinib exposure. (Moderate) Use caution if coadministration of erlotinib with cobicistat 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 cobicistat 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. Cobicistat is a moderate CYP3A4 inhibitor. 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 cobicistat may also increase erlotinib exposure.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid the coadministration of erlotinib with ritonavir due to the risk of increased erlotinib-related adverse reactions and possibly decreased efficacy of erlotinib; 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. Ritonavir is a strong CYP3A4 inhibitor, and may also induce CYP1A2. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. 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.
    Dasatinib: (Moderate) Use caution if coadministration of erlotinib with dasatinib 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 dasatinib 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. Dasatinib is a weak CYP3A4 inhibitor. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. A single dose of dasatinib increased the Cmax and AUC of another CYP3A4 substrate, simvastatin, by 37% and 20%, respectively. Coadministration of erlotinib with ketoconazole, a strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. When administered with ciprofloxacin, a moderate inhibitor of both CYP3A4 and 1A2, the erlotinib AUC increased by 39% and the Cmax by 17%; coadministration with dasatinib may also increase erlotinib exposure.
    Deferasirox: (Major) Avoid the coadministration of erlotinib with deferasirox due to an unpredictable effect on the efficacy and toxicity of erlotinib. Deferasirox is a moderate CYP3A4 inducer and a CYP1A2 inhibitor. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Deferasirox decreased the AUC and Cmax of another CYP3A4 substrate, midazolam, by 17% and 23%, respectively; in the clinical setting, this effect may be more pronounced. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. The AUC and elimination half-life of the CYP1A2 substrate, theophylline, approximately doubled when administered with deferasirox. Data are not available on the effect of CYP1A2 inhibition on erlotinib exposure; however, coadministration with ciprofloxacin, a moderate inhibitor of both CYP3A4 and CYP1A2, increased the erlotinib AUC by 39% and the Cmax by 17%.
    Delavirdine: (Major) Avoid the coadministration of erlotinib with delavirdine 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Delavirdine is a strong CYP3A4 inhibitor; the inhibition of CYP3A activity by delavirdine is reversible within 1 week of discontinuation. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with delavirdine may also increase erlotinib exposure.
    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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Dexamethasone is a CYP3A4 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with dexamethasone may also decrease erlotinib exposure.
    Dexlansoprazole: (Major) Avoid coadministration of dexlansoprazole with erlotinib if possible due to the risk of decreased efficacy of erlotinib. 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, like proton pump inhibitors (PPIs), may decrease the absorption of erlotinib. Concomitant use of erlotinib and omeprazole, a PPI, decreased erlotinib AUC and Cmax by 46% and 61% respectively. Increasing the dose of erlotinib may not compensate for the loss of exposure. Proton-pump inhibitors exert their effect over an extended amount of time, as a result spacing of doses is also not expected to eliminate the interaction. Substitution of antacids, separated from the erlotinib dose by several hours, may be considered. No formal analysis has been performed to assess the impact of antacids on erlotinib pharmacokinetics.
    Diclofenac: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Diclofenac; Misoprostol: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Diflunisal: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Diltiazem: (Moderate) Use caution if coadministration of erlotinib with diltiazem 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 diltiazem 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. Diltiazem is a moderate CYP3A4 inhibitor. 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 diltiazem may also increase erlotinib exposure.
    Diphenhydramine; Ibuprofen: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Diphenhydramine; Naproxen: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Dronedarone: (Moderate) Use caution if coadministration of erlotinib with dronedarone 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 dronedarone 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. Dronedarone is a moderate CYP3A4 inhibitor. 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 dronedarone may also increase erlotinib exposure.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Efavirenz: (Major) Avoid the coadministration of erlotinib with efavirenz 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, to a maximum of 450 mg. Efavirenz is a CYP3A4 inducer. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Efavirenz decreased the Cmax and AUC of another CYP3A4 substrate, simvastatin, by 72% and 68%, respectively. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with efavirenz may also decrease erlotinib exposure.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Avoid the coadministration of erlotinib with efavirenz 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, to a maximum of 450 mg. Efavirenz is a CYP3A4 inducer. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Efavirenz decreased the Cmax and AUC of another CYP3A4 substrate, simvastatin, by 72% and 68%, respectively. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with efavirenz may also decrease erlotinib exposure.
    Elbasvir; Grazoprevir: (Moderate) Use caution if coadministration of erlotinib with grazoprevir 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 grazoprevir 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. Grazoprevir is a weak CYP3A4 inhibitor. 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 grazoprevir may also increase erlotinib exposure.
    Eluxadoline: (Moderate) Use caution if coadministration of erlotinib with eluxadoline 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 eluxadoline 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. Eluxadoline is a weak CYP3A4 inhibitor. 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 eluxadoline may also increase erlotinib exposure.
    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%.
    Erythromycin: (Moderate) Use caution if coadministration of erlotinib with erythromycin 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 erythromycin 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. Erythromycin is a moderate CYP3A4 inhibitor. 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 erythromycin may also increase erlotinib exposure.
    Erythromycin; Sulfisoxazole: (Moderate) Use caution if coadministration of erlotinib with erythromycin 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 erythromycin 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. Erythromycin is a moderate CYP3A4 inhibitor. 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 erythromycin may also increase erlotinib exposure.
    Eslicarbazepine: (Major) Avoid the coadministration of erlotinib with eslicarbazepine 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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Eslicarbazepine is a CYP3A4 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with eslicarbazepine may also decrease erlotinib exposure.
    Esomeprazole: (Major) Avoid coadministration of esomeprazole with erlotinib if possible due to the risk of decreased efficacy of erlotinib. 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, like proton pump inhibitors (PPIs), may decrease the absorption of erlotinib. Concomitant use of erlotinib and omeprazole, a PPI, decreased erlotinib AUC and Cmax by 46% and 61% respectively. Increasing the dose of erlotinib may not compensate for the loss of exposure. Proton-pump inhibitors exert their effect over an extended amount of time, as a result spacing of doses is also not expected to eliminate the interaction. Substitution of antacids, separated from the erlotinib dose by several hours, may be considered. No formal analysis has been performed to assess the impact of antacids on erlotinib pharmacokinetics.
    Esomeprazole; Naproxen: (Major) Avoid coadministration of esomeprazole with erlotinib if possible due to the risk of decreased efficacy of erlotinib. 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, like proton pump inhibitors (PPIs), may decrease the absorption of erlotinib. Concomitant use of erlotinib and omeprazole, a PPI, decreased erlotinib AUC and Cmax by 46% and 61% respectively. Increasing the dose of erlotinib may not compensate for the loss of exposure. Proton-pump inhibitors exert their effect over an extended amount of time, as a result spacing of doses is also not expected to eliminate the interaction. Substitution of antacids, separated from the erlotinib dose by several hours, may be considered. No formal analysis has been performed to assess the impact of antacids on erlotinib pharmacokinetics. (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Ethanol: (Major) Avoid the coadministration of erlotinib with alcohol (ethanol) if possible due to a potential risk of decreased erlotinib efficacy. If co-use is not avoidable, it may be necessary to increase the adult dose of erlotinib by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Alcohol is a moderate CYP3A4 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. It is not yet clear how oadministration with alcohol might affect erlotinib exposure.
    Ethotoin: (Major) Avoid the coadministration of erlotinib with hydantoins (e.g., phenytoin, fosphenytoin, ethotoin) 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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Phenytoin (and fosphenytoin) is a strong CYP3A4 inducer as well as a moderate inducer of CYP1A2. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. 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. Coadministration with phenytoin / fosphenytoin may also decrease erlotinib exposure.
    Etodolac: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Etravirine: (Major) Avoid the coadministration of erlotinib with etravirine 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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Etravirine is a CYP3A4 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with etravirine may also decrease erlotinib exposure.
    Ezetimibe; Simvastatin: (Moderate) Concomitant use of erlotinib and HMG-coA reductase inhibitors (statins) may increase the risk for statin-induced myopathy. Myopathy and rhabdomyolysis has been observed rarely with concurrent use of statins and erlotinib during post-market use. The mechanism for this interaction is not known. Use erlotinib and statins together with caution and monitor for signs or symptoms of statin-related adverse events including myopathy (e.g., muscle pain or weakness) and rhabdomyolysis (e.g., nausea/vomiting, dark colored urine).
    Famotidine: (Major) If concomitant use of erlotinib with famotidine is necessary, administer famotidine approximately 10 hours before and at least 2 hours after the erlotinib 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.
    Famotidine; Ibuprofen: (Major) If concomitant use of erlotinib with famotidine is necessary, administer famotidine approximately 10 hours before and at least 2 hours after the erlotinib 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. (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    Felbamate: (Major) Avoid the coadministration of erlotinib with felbamate if possible due to the risk of decreased erlotinib efficacy; if concomitant use is unavoidable, the manufacturer recommends increasing the dose of erlotinib by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Felbamate is a weak CYP3A4 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with felbamate may also decrease erlotinib exposure.
    Fenoprofen: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Fluconazole: (Moderate) Use caution if coadministration of erlotinib with fluconazole 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 fluconazole 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. Fluconazole is a moderate CYP3A4 inhibitor. 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 fluconazole may also increase erlotinib exposure.
    Fluoxetine: (Moderate) Use caution if coadministration of erlotinib with fluoxetine 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 fluoxetine 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. Fluoxetine is a weak CYP3A4 inhibitor, but its active metabolite, norfluoxetine, is a moderate inhibitor of CYP3A4. 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 fluoxetine may also increase erlotinib exposure.
    Fluoxetine; Olanzapine: (Moderate) Use caution if coadministration of erlotinib with fluoxetine 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 fluoxetine 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. Fluoxetine is a weak CYP3A4 inhibitor, but its active metabolite, norfluoxetine, is a moderate inhibitor of CYP3A4. 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 fluoxetine may also increase erlotinib exposure.
    Flurbiprofen: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Flutamide: (Major) Avoid the coadministration of erlotinib with flutamide 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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Flutamide is a CYP3A4 inducer in vitro. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with flutamide may also decrease erlotinib exposure.
    Fluvastatin: (Moderate) Concomitant use of erlotinib and HMG-coA reductase inhibitors (statins) may increase the risk for statin-induced myopathy. Myopathy and rhabdomyolysis has been observed rarely with concurrent use of statins and erlotinib during post-market use. The mechanism for this interaction is not known. Use erlotinib and statins together with caution and monitor for signs or symptoms of statin-related adverse events including myopathy (e.g., muscle pain or weakness) and rhabdomyolysis (e.g., nausea/vomiting, dark colored urine).
    Fluvoxamine: (Major) Coadministration of erlotinib with fluvoxamine may increase the risk of erlotinib-related adverse reactions. Erlotinib is a primary CYP3A4 substrate and is metabolized by CYP1A2 to a lesser extent; fluvoxamine is a moderate CYP3A4 inhibitor and a strong inhibitor of CYP1A2. Coadministration of erlotinib with ciprofloxacin, a moderate inhibitor of CYP3A4 and CYP1A2, increased the erlotinib AUC by 39% and the Cmax by 17%.
    Fosamprenavir: (Major) Avoid the coadministration of erlotinib with fosamprenavir due to the risk of increased erlotinib-related adverse reactions and possibly decreased efficacy of erlotinib; 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. Fosamprenavir is a strong CYP3A4 inhibitor with the potential to also induce CYP3A4. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with fosamprenavir may also increase erlotinib exposure.
    Fosphenytoin: (Major) Avoid the coadministration of erlotinib with hydantoins (e.g., phenytoin, fosphenytoin, ethotoin) 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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Phenytoin (and fosphenytoin) is a strong CYP3A4 inducer as well as a moderate inducer of CYP1A2. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. 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. Coadministration with phenytoin / fosphenytoin may also decrease erlotinib exposure.
    Glimepiride; Pioglitazone: (Major) Avoid the coadministration of erlotinib with pioglitazone if possible due to the risk of decreased erlotinib efficacy; if concomitant use is unavoidable, the manufacturer recommends increasing the dose of erlotinib by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Pioglitazone is a weak CYP3A4 inducer. The AUC and Cmax of another CYP3A4 substrate, midazolam, were each decreased by 26% when administered with pioglitazone. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with pioglitazone may also decrease erlotinib exposure.
    Grapefruit juice: (Major) Avoid the coadministration of erlotinib with grapefruit juice or grapefruit products 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Grapefruit juice is a strong CYP3A4 inhibitor. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with grapefruit juice may also increase erlotinib exposure.
    Griseofulvin: (Major) Avoid the coadministration of erlotinib with griseofulvin 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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Griseofulvin is a CYP3A4 inducer in vitro. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with griseofulvin may also decrease erlotinib exposure.
    HMG-CoA reductase inhibitors: (Moderate) Concomitant use of erlotinib and HMG-coA reductase inhibitors (statins) may increase the risk for statin-induced myopathy. Myopathy and rhabdomyolysis has been observed rarely with concurrent use of statins and erlotinib during post-market use. The mechanism for this interaction is not known. Use erlotinib and statins together with caution and monitor for signs or symptoms of statin-related adverse events including myopathy (e.g., muscle pain or weakness) and rhabdomyolysis (e.g., nausea/vomiting, dark colored urine).
    Hydantoins: (Major) Avoid the coadministration of erlotinib with hydantoins (e.g., phenytoin, fosphenytoin, ethotoin) 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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Phenytoin (and fosphenytoin) is a strong CYP3A4 inducer as well as a moderate inducer of CYP1A2. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. 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. Coadministration with phenytoin / fosphenytoin may also decrease erlotinib exposure.
    Hydrocodone; Ibuprofen: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Ibuprofen: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Ibuprofen; Oxycodone: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Ibuprofen; Pseudoephedrine: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Idelalisib: (Major) Avoid the coadministration of erlotinib with idelalisib due to the risk of increased erlotinib-related adverse reactions. According the manufacturer of erlotinib, 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. Idelalisib is a strong CYP3A4 inhibitor. Idelalisib increased the Cmax and AUC of another CYP3A4 substrate, midazolam, by 2.4-fold and 5.4-fold, respectively. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with idelalisib may also increase erlotinib exposure.
    Imatinib: (Moderate) Use caution if coadministration of erlotinib with imatinib 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 imatinib 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. Imatinib is a moderate CYP3A4 inhibitor. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Imatinib increased the Cmax and AUC of another CYP3A4 substrate, simvastatin, by 2-fold and 3.5-fold, respectively. 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 imatinib may also increase erlotinib exposure.
    Indinavir: (Major) Avoid the coadministration of erlotinib with indinavir 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Indinavir is a strong CYP3A4 inhibitor. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with indinavir may also increase erlotinib exposure.
    Indomethacin: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Isavuconazonium: (Moderate) Use caution if coadministration of erlotinib with isavuconazonium 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 isavuconazonium 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. Isavuconazonium is a moderate CYP3A4 inhibitor. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Isavuconazonium increased by AUC of sensitive CYP3A4 substrates (midazolam, sirolimus, and tacrolimus) by approximately 2-fold. Coadministration of erlotinib with ketoconazole, a strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. Coadministration of erlotinib with ciprofloxacin, a moderate inhibitor of CYP3A4 and CYP1A2, increased the erlotinib AUC by 39% and the Cmax by 17%; coadministration with isavuconazonium may also increase erlotinib exposure.
    Isoniazid, INH: (Moderate) Use caution if coadministration of erlotinib with isoniazid, INH 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 isoniazid 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. Isoniazid is a moderate CYP3A4 inhibitor. 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 isoniazid may also increase erlotinib exposure.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the 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 by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Rifampin is a strong CYP3A4 inducer and a moderate inducer of CYP1A2. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin for 7 to 11 days. (Moderate) Use caution if coadministration of erlotinib with isoniazid, INH 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 isoniazid 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. Isoniazid is a moderate CYP3A4 inhibitor. 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 isoniazid may also increase erlotinib exposure.
    Isoniazid, INH; Rifampin: (Major) Avoid the 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 by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Rifampin is a strong CYP3A4 inducer and a moderate inducer of CYP1A2. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin for 7 to 11 days. (Moderate) Use caution if coadministration of erlotinib with isoniazid, INH 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 isoniazid 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. Isoniazid is a moderate CYP3A4 inhibitor. 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 isoniazid may also increase erlotinib exposure.
    Itraconazole: (Major) Avoid the coadministration of erlotinib with itraconazole 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Itraconazole is a strong CYP3A4 inhibitor. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with itraconazole may also increase erlotinib exposure.
    Ivacaftor: (Moderate) Use caution if coadministration of erlotinib with ivacaftor is necessary due to the risk of increased erlotinib-related adverse reactions, and avoid coadministration with erlotinib if the patient is additionally taking a CYP1A2 inhibitor. If the patient is taking both ivacaftor and a CYP1A2 inhibitor and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements; the manufacturer of erlotinib makes the same recommendations for toxicity-related dose reductions in patients taking strong CYP3A4 inhibitors without concomitant CYP1A2 inhibitors. Ivacaftor is a weak CYP3A4 inhibitor. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Ivacaftor increased the AUC of another CYP3A4 substrate, midazolam, by 1.5-fold. Coadministration of erlotinib with ketoconazole, a strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. Coadministration of erlotinib with ciprofloxacin, a moderate inhibitor of CYP3A4 and CYP1A2, increased the erlotinib AUC by 39% and the Cmax by 17%; coadministration with ivacaftor may also increase erlotinib exposure.
    Ketoconazole: (Major) Avoid the coadministration of erlotinib with ketoconazole 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Ketoconazole is a strong CYP3A4 inhibitor. Coadministration of erlotinib with ketoconazole increased the erlotinib AUC by 67%.
    Ketoprofen: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Ketorolac: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Lansoprazole: (Major) Avoid coadministration of lansoprazole with erlotinib if possible due to the risk of decreased efficacy of erlotinib. 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, like proton pump inhibitors (PPIs), may decrease the absorption of erlotinib. Concomitant use of erlotinib and omeprazole, a PPI, decreased erlotinib AUC and Cmax by 46% and 61% respectively. Increasing the dose of erlotinib may not compensate for the loss of exposure. Proton-pump inhibitors exert their effect over an extended amount of time, as a result spacing of doses is also not expected to eliminate the interaction. Substitution of antacids, separated from the erlotinib dose by several hours, may be considered. No formal analysis has been performed to assess the impact of antacids on erlotinib pharmacokinetics.
    Lansoprazole; Naproxen: (Major) Avoid coadministration of lansoprazole with erlotinib if possible due to the risk of decreased efficacy of erlotinib. 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, like proton pump inhibitors (PPIs), may decrease the absorption of erlotinib. Concomitant use of erlotinib and omeprazole, a PPI, decreased erlotinib AUC and Cmax by 46% and 61% respectively. Increasing the dose of erlotinib may not compensate for the loss of exposure. Proton-pump inhibitors exert their effect over an extended amount of time, as a result spacing of doses is also not expected to eliminate the interaction. Substitution of antacids, separated from the erlotinib dose by several hours, may be considered. No formal analysis has been performed to assess the impact of antacids on erlotinib pharmacokinetics. (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Lapatinib: (Moderate) Use caution if coadministration of erlotinib with lapatinib 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 lapatinib 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. Lapatinib is a weak CYP3A4 inhibitor. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Lapatinib increased the AUC of oral midazolam, another CYP3A4 substrate, by 45%; the AUC of IV midazolam was increased by 22%. 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 lapatinib may also increase erlotinib exposure.
    Lesinurad: (Major) Avoid the coadministration of erlotinib with lesinurad if possible due to the risk of decreased erlotinib efficacy; if concomitant use is unavoidable, the manufacturer recommends increasing the dose of erlotinib by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Lesinurad is a weak CYP3A4 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with lesinurad may also decrease erlotinib exposure.
    Lesinurad; Allopurinol: (Major) Avoid the coadministration of erlotinib with lesinurad if possible due to the risk of decreased erlotinib efficacy; if concomitant use is unavoidable, the manufacturer recommends increasing the dose of erlotinib by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Lesinurad is a weak CYP3A4 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with lesinurad may also decrease erlotinib exposure.
    Lopinavir; Ritonavir: (Major) Avoid the coadministration of erlotinib with lopinavir 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Lopinavir is a strong CYP3A4 inhibitor. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with lopinavir may also increase erlotinib exposure. (Major) Avoid the coadministration of erlotinib with ritonavir due to the risk of increased erlotinib-related adverse reactions and possibly decreased efficacy of erlotinib; 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. Ritonavir is a strong CYP3A4 inhibitor, and may also induce CYP1A2. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. 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.
    Lovastatin: (Moderate) Concomitant use of erlotinib and HMG-coA reductase inhibitors (statins) may increase the risk for statin-induced myopathy. Myopathy and rhabdomyolysis has been observed rarely with concurrent use of statins and erlotinib during post-market use. The mechanism for this interaction is not known. Use erlotinib and statins together with caution and monitor for signs or symptoms of statin-related adverse events including myopathy (e.g., muscle pain or weakness) and rhabdomyolysis (e.g., nausea/vomiting, dark colored urine).
    Lovastatin; Niacin: (Moderate) Concomitant use of erlotinib and HMG-coA reductase inhibitors (statins) may increase the risk for statin-induced myopathy. Myopathy and rhabdomyolysis has been observed rarely with concurrent use of statins and erlotinib during post-market use. The mechanism for this interaction is not known. Use erlotinib and statins together with caution and monitor for signs or symptoms of statin-related adverse events including myopathy (e.g., muscle pain or weakness) and rhabdomyolysis (e.g., nausea/vomiting, dark colored urine).
    Lumacaftor; Ivacaftor: (Major) Avoid the 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 by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Lumacaftor is a strong CYP3A4 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with lumacaftor may also decrease erlotinib exposure.
    Lumacaftor; Ivacaftor: (Moderate) Use caution if coadministration of erlotinib with ivacaftor is necessary due to the risk of increased erlotinib-related adverse reactions, and avoid coadministration with erlotinib if the patient is additionally taking a CYP1A2 inhibitor. If the patient is taking both ivacaftor and a CYP1A2 inhibitor and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements; the manufacturer of erlotinib makes the same recommendations for toxicity-related dose reductions in patients taking strong CYP3A4 inhibitors without concomitant CYP1A2 inhibitors. Ivacaftor is a weak CYP3A4 inhibitor. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Ivacaftor increased the AUC of another CYP3A4 substrate, midazolam, by 1.5-fold. Coadministration of erlotinib with ketoconazole, a strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. Coadministration of erlotinib with ciprofloxacin, a moderate inhibitor of CYP3A4 and CYP1A2, increased the erlotinib AUC by 39% and the Cmax by 17%; coadministration with ivacaftor may also increase erlotinib exposure.
    Magnesium Hydroxide: (Major) 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. No formal analysis has been performed to assess the impact of antacids on erlotinib pharmacokinetics; however, if coadministration is necessary, the manufacturer recommends separation of antacids and erlotinib by several hours.
    Meclofenamate Sodium: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Mefenamic Acid: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Meloxicam: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Mephobarbital: (Major) Avoid the 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 by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Mephobarbital is metabolized to phenobarbital, a strong CYP3A4 inducer and a moderate inducer of CYP1A2. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. 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.
    Metformin; Pioglitazone: (Major) Avoid the coadministration of erlotinib with pioglitazone if possible due to the risk of decreased erlotinib efficacy; if concomitant use is unavoidable, the manufacturer recommends increasing the dose of erlotinib by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Pioglitazone is a weak CYP3A4 inducer. The AUC and Cmax of another CYP3A4 substrate, midazolam, were each decreased by 26% when administered with pioglitazone. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with pioglitazone may also decrease erlotinib exposure.
    Methohexital: (Major) Avoid the coadministration of erlotinib with methohexital 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, 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. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. 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. Coadministration with methohexital may also decrease erlotinib exposure.
    Metyrapone: (Major) Avoid the coadministration of erlotinib with metyrapone 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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Metyrapone is a CYP3A4 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with metyrapone may also decrease erlotinib exposure.
    Mifepristone, RU-486: (Moderate) Use caution if coadministration of erlotinib with mifepristone, RU-486 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 mifepristone 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. Mifepristone is a moderate CYP3A4 inhibitor in vitro. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown. 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 mifepristone may also increase erlotinib exposure.
    Mirabegron: (Moderate) Use caution if coadministration of erlotinib with mirabegron 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 mirabegron 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. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Mirabegron is a weak CYP3A4 inhibitor. 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 mirabegron may also increase erlotinib exposure.
    Mitotane: (Major) Avoid the 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 by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Mitotane is a CYP3A4 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with mitotane may also decrease erlotinib exposure.
    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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Modafinil is a moderate CYP3A4 inducer and a weak inducer of CYP1A2. In a clinical study, concomitant administration of armodafinil resulted in a reduction in the AUC of another CYP3A4 substrate, midazolam by 32% after a single oral dose and by 17% after a single IV dose. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. 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. Coadministration with modafinil may also decrease erlotinib exposure.
    Nabumetone: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Nafcillin is a CYP3A4 inducer in vitro. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with nafcillin may also decrease erlotinib exposure.
    Naproxen: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Naproxen; Pseudoephedrine: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Naproxen; Sumatriptan: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Nefazodone: (Major) Avoid the coadministration of erlotinib with nefazodone 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Nefazodone is a strong CYP3A4 inhibitor. Nefazodone increased the Cmax and AUC of another CYP3A4 substrate, triazolam, by 1.7-fold and 4-fold, respectively. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with nefazodone may also increase erlotinib exposure.
    Nelfinavir: (Major) Avoid the coadministration of erlotinib with nelfinavir 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Nelfinavir is a strong CYP3A4 inhibitor. Nelfinavir increased the Cmax and AUC of another CYP3A4 substrate, simvastatin, by 517% and 505%, respectively. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with nelfinavir may also increase erlotinib exposure.
    Netupitant; Palonosetron: (Moderate) Use caution if coadministration of erlotinib with netupitant 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 netupitant 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. Netupitant is a moderate CYP3A4 inhibitor. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Netupitant increased the mean Cmax and AUC of another CYP3A4 substrate, midazolam, by 36% and 126%, respectively. 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 netupitant may also increase erlotinib exposure.
    Nevirapine: (Major) Avoid the coadministration of erlotinib with nevirapine 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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Nevirapine is a CYP3A4 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with nevirapine may also decrease erlotinib exposure.
    Niacin; Simvastatin: (Moderate) Concomitant use of erlotinib and HMG-coA reductase inhibitors (statins) may increase the risk for statin-induced myopathy. Myopathy and rhabdomyolysis has been observed rarely with concurrent use of statins and erlotinib during post-market use. The mechanism for this interaction is not known. Use erlotinib and statins together with caution and monitor for signs or symptoms of statin-related adverse events including myopathy (e.g., muscle pain or weakness) and rhabdomyolysis (e.g., nausea/vomiting, dark colored urine).
    Nicardipine: (Moderate) Use caution if coadministration of erlotinib with nicardipine 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 nicardipine 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. Nicardipine 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 nicardipine may also increase erlotinib exposure.
    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, administer nizatidine approximately 10 hours before and at least 2 hours after the erlotinib 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.
    Nonsteroidal antiinflammatory drugs: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Octreotide: (Moderate) Use caution if coadministration of erlotinib with octreotide 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 octreotide 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. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Octreotide decreases growth hormone secretion, which in turn may inhibit CYP3A4 enzyme function. 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 octreotide may also increase erlotinib exposure.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid the coadministration of erlotinib with ritonavir due to the risk of increased erlotinib-related adverse reactions and possibly decreased efficacy of erlotinib; 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. Ritonavir is a strong CYP3A4 inhibitor, and may also induce CYP1A2. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. 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.
    Omeprazole: (Major) Avoid the coadministration of erlotinib with omeprazole if possible, as there are multiple issues with concomitant use. Erlotinib solubility is pH dependent, and solubility decreases as pH increase; increasing the dose may not compensate for this loss of exposure. Additionally, erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Omeprazole is a CYP1A2 inducer in vitro. The manufacturer recommends increasing the dose of erlotinib by 50 mg increments at 2-week intervals to a maximum of 300 mg when used with CYP1A2 inducers; however, this may not be effective due to the solubility issue. Omeprazole decreased the AUC and Cmax of erlotinib by 46% and 61%, respectively. In addition to the pharmacokinetic interaction, 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. Coadministration with omeprazole may also decrease erlotinib exposure.
    Omeprazole; Sodium Bicarbonate: (Major) Avoid the coadministration of erlotinib with omeprazole if possible, as there are multiple issues with concomitant use. Erlotinib solubility is pH dependent, and solubility decreases as pH increase; increasing the dose may not compensate for this loss of exposure. Additionally, erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Omeprazole is a CYP1A2 inducer in vitro. The manufacturer recommends increasing the dose of erlotinib by 50 mg increments at 2-week intervals to a maximum of 300 mg when used with CYP1A2 inducers; however, this may not be effective due to the solubility issue. Omeprazole decreased the AUC and Cmax of erlotinib by 46% and 61%, respectively. In addition to the pharmacokinetic interaction, 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. Coadministration with omeprazole may also decrease erlotinib exposure. (Major) 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. No formal analysis has been performed to assess the impact of antacids on erlotinib pharmacokinetics; however, if coadministration is necessary, the manufacturer recommends separation of antacids and erlotinib by several hours.
    Oritavancin: (Major) Avoid the coadministration of erlotinib with oritavancin if possible due to the risk of decreased erlotinib efficacy; if concomitant use is unavoidable, the manufacturer recommends increasing the dose of erlotinib by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Oritavancin is a weak CYP3A4 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with oritavancin may also decrease erlotinib exposure.
    Oxaprozin: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Oxcarbazepine: (Major) Avoid the coadministration of erlotinib with oxcarbazepine 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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Oxcarbazepine is a CYP3A4 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with oxcarbazepine may also decrease erlotinib exposure.
    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 pantoprazole with erlotinib if possible due to the risk of decreased efficacy of erlotinib. 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, like proton pump inhibitors (PPIs), may decrease the absorption of erlotinib. Concomitant use of erlotinib and omeprazole, a PPI, decreased erlotinib AUC and Cmax by 46% and 61% respectively. Increasing the dose of erlotinib may not compensate for the loss of exposure. Proton-pump inhibitors exert their effect over an extended amount of time, as a result spacing of doses is also not expected to eliminate the interaction. Substitution of antacids, separated from the erlotinib dose by several hours, may be considered. No formal analysis has been performed to assess the impact of antacids on erlotinib pharmacokinetics.
    Pazopanib: (Moderate) Use caution if coadministration of erlotinib with pazopanib 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 pazopanib 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. Pazopanib is a weak CYP3A4 inhibitor. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Pazopanib increased the Cmax and AUC of another CYP3A4 substrate, midazolam, by approximately 30%. 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 pazopanib may also increase erlotinib exposure.
    Peginterferon Alfa-2b: (Major) Monitor for adverse effects, such as GI or CNS effects, associated with increased exposure to erlotinib if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP1A2 inhibitor, while erlotinib is partially metabolized by CYP1A2.
    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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Pentobarbital is a CYP3A4 and 1A2 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. 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.
    Perampanel: (Major) Avoid the coadministration of erlotinib with perampanel if possible due to the risk of decreased erlotinib efficacy; if concomitant use is unavoidable, the manufacturer recommends increasing the dose of erlotinib by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Perampanel is a weak CYP3A4 inducer in vitro. In healthy subjects, perampanel decreased the Cmax and AUC of another CYP3A4 substrate, midazolam, by 15% and 13%, respectively. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with perampanel may also decrease erlotinib exposure.
    Perindopril; Amlodipine: (Moderate) Use caution if coadministration of erlotinib with amlodipine 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 amlodipine 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. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Amlodipine is a weak CYP3A4 inhibitor. 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 amlodipine may also increase erlotinib exposure.
    Phenobarbital: (Major) Avoid the 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 by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Phenobarbital is a strong CYP3A4 inducer and a moderate inducer of CYP1A2. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. 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. Coadministration with phenobarbital may also decrease erlotinib exposure.
    Phentermine; Topiramate: (Major) Avoid the coadministration of erlotinib with topiramate if possible due to the risk of decreased erlotinib efficacy; if concomitant use is unavoidable, the manufacturer recommends increasing the dose of erlotinib by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Topiramate is a weak CYP3A4 inducer. Coadministration with topiramate decreased the AUC and Cmax of another CYP3A4 substrate, diltiazem, by 25% and 10%, respectively. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with topiramate may also decrease erlotinib exposure.
    Phenytoin: (Major) Avoid the coadministration of erlotinib with hydantoins (e.g., phenytoin, fosphenytoin, ethotoin) 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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Phenytoin (and fosphenytoin) is a strong CYP3A4 inducer as well as a moderate inducer of CYP1A2. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. 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. Coadministration with phenytoin / fosphenytoin may also decrease erlotinib exposure.
    Pioglitazone: (Major) Avoid the coadministration of erlotinib with pioglitazone if possible due to the risk of decreased erlotinib efficacy; if concomitant use is unavoidable, the manufacturer recommends increasing the dose of erlotinib by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Pioglitazone is a weak CYP3A4 inducer. The AUC and Cmax of another CYP3A4 substrate, midazolam, were each decreased by 26% when administered with pioglitazone. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with pioglitazone may also decrease erlotinib exposure.
    Pirfenidone: (Major) Avoid the coadministration of erlotinib with pirfenidone 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Pirfenidone is a weak concentration-dependent inhibitor of CYP3A4 and CYP1A2 in vitro. At a concentration of 1000 microM, pirfenidone inhibits the activity of these enzymes by 9.6% and 34.1%, respectively. 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 pirfenidone may also increase erlotinib exposure.
    Piroxicam: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Posaconazole: (Major) Avoid the coadministration of erlotinib with posaconazole 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Posaconazole is a strong CYP3A4 inhibitor. It increased the Cmax and AUC of IV midazolam, another CYP3A4 substrate, by 30% and 362%, while increasing the Cmax and AUC of oral midazolam by 169% and 470%, respectively. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with posaconazole may also increase erlotinib exposure.
    Pravastatin: (Moderate) Concomitant use of erlotinib and HMG-coA reductase inhibitors (statins) may increase the risk for statin-induced myopathy. Myopathy and rhabdomyolysis has been observed rarely with concurrent use of statins and erlotinib during post-market use. The mechanism for this interaction is not known. Use erlotinib and statins together with caution and monitor for signs or symptoms of statin-related adverse events including myopathy (e.g., muscle pain or weakness) and rhabdomyolysis (e.g., nausea/vomiting, dark colored urine).
    Primidone: (Major) Avoid the 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 by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Primidone is a strong CYP3A4 inducer and a moderate inducer of CYP1A2. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. 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.
    Quinine: (Major) Avoid the coadministration of erlotinib with quinine due to an unpredictable effect on the efficacy and toxicity of erlotinib. Quinine is a CYP3A4 inhibitor and a CYP1A2 inducer; it also may induce CYP3A4 in vitro. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. 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. Coadministration of erlotinib with ketoconazole, a strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with quinine may also increase erlotinib exposure.
    Rabeprazole: (Major) Avoid coadministration of rabeprazole with erlotinib if possible due to the risk of decreased efficacy of erlotinib. 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, like proton pump inhibitors (PPIs), may decrease the absorption of erlotinib. Concomitant use of erlotinib and omeprazole, a PPI, decreased erlotinib AUC and Cmax by 46% and 61% respectively. Increasing the dose of erlotinib may not compensate for the loss of exposure. Proton-pump inhibitors exert their effect over an extended amount of time, as a result spacing of doses is also not expected to eliminate the interaction. Substitution of antacids, separated from the erlotinib dose by several hours, may be considered. No formal analysis has been performed to assess the impact of antacids on erlotinib pharmacokinetics.
    Ranitidine: (Major) If concomitant use of erlotinib with ranitidine is necessary, administer ranitidine approximately 10 hours before and at least 2 hours after the erlotinib 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.
    Ranolazine: (Moderate) Use caution if coadministration of erlotinib with ranolazine 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 ranolazine 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. Ranolazine is a weak CYP3A4 inhibitor in vitro. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Ranolazine increased plasma levels of another CYP3A4 substrate, simvastatin, by 100% in healthy volunteers; however, the pharmacokinetics of the CYP3A4 substrate diltiazem were not affected by ranolazine. 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 ranolazine may also increase erlotinib exposure.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with erlotinib is necessary, as the systemic exposure of erlotinib may be increased resulting in increase in treatment-related adverse reactions; avoid coadministration if the patient is additionally taking a CYP1A2 inhibitor. If the patient is taking ribociclib, erlotinib, and a CYP1A2 inhibitor and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Ribociclib is a moderate CYP3A4 inhibitor. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Coadministration with a moderate inhibitor of CYP3A4 and CYP1A2 increased the erlotinib AUC by 39% and the Cmax by 17%.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with erlotinib is necessary, as the systemic exposure of erlotinib may be increased resulting in increase in treatment-related adverse reactions; avoid coadministration if the patient is additionally taking a CYP1A2 inhibitor. If the patient is taking ribociclib, erlotinib, and a CYP1A2 inhibitor and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Ribociclib is a moderate CYP3A4 inhibitor. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Coadministration with a moderate inhibitor of CYP3A4 and CYP1A2 increased the erlotinib AUC by 39% and the 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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Rifabutin is a CYP3A4 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with rifabutin may also decrease erlotinib exposure.
    Rifampin: (Major) Avoid the 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 by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Rifampin is a strong CYP3A4 inducer and a moderate inducer of CYP1A2. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin for 7 to 11 days.
    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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Rifapentine is a CYP3A4 inducer. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with rifapentine may also decrease erlotinib exposure.
    Rifaximin: (Moderate) Use caution if coadministration of erlotinib with rifaximin is necessary due to the risk of decreased erlotinib efficacy. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Rifaximin is a CYP3A4 inducer in vitro; the manufacturer of erlotinib recommends avoiding coadministration with CYP3A4 inducers, and increasing the dose if avoidance is not possible. However, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of erlotinib in patients with reduced liver function who may have elevated rifaximin concentrations. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with rifaximin in certain patient populations may also decrease erlotinib exposure.
    Ritonavir: (Major) Avoid the coadministration of erlotinib with ritonavir due to the risk of increased erlotinib-related adverse reactions and possibly decreased efficacy of erlotinib; 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. Ritonavir is a strong CYP3A4 inhibitor, and may also induce CYP1A2. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. 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.
    Rofecoxib: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Rosuvastatin: (Moderate) Concomitant use of erlotinib and HMG-coA reductase inhibitors (statins) may increase the risk for statin-induced myopathy. Myopathy and rhabdomyolysis has been observed rarely with concurrent use of statins and erlotinib during post-market use. The mechanism for this interaction is not known. Use erlotinib and statins together with caution and monitor for signs or symptoms of statin-related adverse events including myopathy (e.g., muscle pain or weakness) and rhabdomyolysis (e.g., nausea/vomiting, dark colored urine).
    Saquinavir: (Major) Avoid the coadministration of erlotinib with saquinavir 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Saquinavir is a strong CYP3A4 inhibitor. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with saquinavir may also increase erlotinib exposure.
    Secobarbital: (Major) Avoid the coadministration of erlotinib with secobarbital 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, 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. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. 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.
    Simeprevir: (Major) Avoid the coadministration of erlotinib with simeprevir 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Simeprevir is a weak CYP3A4 and 1A2 inhibitor. 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 simeprevir may also increase erlotinib exposure.
    Simvastatin: (Moderate) Concomitant use of erlotinib and HMG-coA reductase inhibitors (statins) may increase the risk for statin-induced myopathy. Myopathy and rhabdomyolysis has been observed rarely with concurrent use of statins and erlotinib during post-market use. The mechanism for this interaction is not known. Use erlotinib and statins together with caution and monitor for signs or symptoms of statin-related adverse events including myopathy (e.g., muscle pain or weakness) and rhabdomyolysis (e.g., nausea/vomiting, dark colored urine).
    Simvastatin; Sitagliptin: (Moderate) Concomitant use of erlotinib and HMG-coA reductase inhibitors (statins) may increase the risk for statin-induced myopathy. Myopathy and rhabdomyolysis has been observed rarely with concurrent use of statins and erlotinib during post-market use. The mechanism for this interaction is not known. Use erlotinib and statins together with caution and monitor for signs or symptoms of statin-related adverse events including myopathy (e.g., muscle pain or weakness) and rhabdomyolysis (e.g., nausea/vomiting, dark colored urine).
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and antineoplastic agents should be avoided. Concurrent administration of antineoplastic agents with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving antineoplastic agents may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of antineoplastic agents prior to initiating therapy with sipuleucel-T.
    Sodium Bicarbonate: (Major) 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. No formal analysis has been performed to assess the impact of antacids on erlotinib pharmacokinetics; however, if coadministration is necessary, the manufacturer recommends separation of antacids and erlotinib by several hours.
    St. John's Wort, Hypericum perforatum: (Major) Avoid the coadministration of erlotinib with St. John's Wort, Hypericum perforatum 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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. St. John's Wort is a strong CYP3A4 inducer and a moderate inducer of CYP1A2 in vitro. The amount of individual constituents in various products may alter the inducing effects, making drug interactions unpredictable. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. 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. Coadministration with St. John's Wort may also decrease erlotinib exposure.
    Streptogramins: (Major) Avoid the coadministration of erlotinib with streptogramins such as dalfopristin; quinupristin 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Quinupristin is a strong CYP3A4 inhibitor. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with quinupristin may also increase erlotinib exposure.
    Sulindac: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Telithromycin: (Major) Avoid the coadministration of erlotinib with telithromycin 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Telithromycin is a strong CYP3A4 inhibitor. Telithromycin increased the AUC of another CYP3A4 substrate, midazolam, by 2-fold (IV) and 6-fold (PO). Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with telithromycin may also increase erlotinib exposure.
    Telotristat Ethyl: (Major) Avoid the coadministration of erlotinib with telotristat ethyl 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. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Teriflunomide: (Major) Avoid the coadministration of erlotinib with teriflunomide if possible; if concomitant use is unavoidable, increase the dose of erlotinib by 50 mg increments at 2-week intervals to a maximum of 300 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Teriflunomide is a weak 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. Coadministration with teriflunomide may also decrease erlotinib exposure.
    Thiopental: (Major) Avoid the coadministration of erlotinib with thiopental 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, 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. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. 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.
    Ticagrelor: (Moderate) Use caution if coadministration of erlotinib with ticagrelor 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 ticagrelor 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. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Ticagrelor is a weak CYP3A4 inhibitor. 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 ticagrelor may also increase erlotinib exposure.
    Tipranavir: (Major) Avoid the coadministration of erlotinib with tipranavir 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Tipranavir is a strong CYP3A4 inhibitor. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with tipranavir may also increase erlotinib exposure.
    Tobacco: (Major) Avoid tobacco smoking while taking erlotinib if possible; if concomitant use is unavoidable, increase the dose of erlotinib by 50 mg increments at 2-week intervals to a maximum of 300 mg. 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) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Topiramate: (Major) Avoid the coadministration of erlotinib with topiramate if possible due to the risk of decreased erlotinib efficacy; if concomitant use is unavoidable, the manufacturer recommends increasing the dose of erlotinib by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Topiramate is a weak CYP3A4 inducer. Coadministration with topiramate decreased the AUC and Cmax of another CYP3A4 substrate, diltiazem, by 25% and 10%, respectively. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with topiramate may also decrease erlotinib exposure.
    Trandolapril; Verapamil: (Major) Avoid the coadministration of erlotinib with verapamil 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Verapamil is a moderate CYP3A4 inhibitor and a weak inhibitor of 1A2. 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 verapamil may also increase erlotinib exposure.
    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) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Valproic Acid, Divalproex Sodium: (Major) Avoid the coadministration of erlotinib with valproic acid due to an unpredictable effect on the efficacy and toxicity of erlotinib. Valproic acid is a weak CYP3A4 inhibitor as well as a weak inducer of CYP3A4 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 with Valproic Acid may also increase erlotinib exposure. However, the AUC of erlotinib was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days.
    Vemurafenib: (Moderate) Concomitant use of vemurafenib and erlotinib may result in altered concentrations of erlotinib. Vemurafenib is an inhibitor of CYP1A2 and an inducer of CYP3A4. Erlotinib is a substrate of CYP1A2 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    Verapamil: (Major) Avoid the coadministration of erlotinib with verapamil 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Verapamil is a moderate CYP3A4 inhibitor and a weak inhibitor of 1A2. 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 verapamil may also increase erlotinib exposure.
    Voriconazole: (Moderate) Use caution if coadministration of erlotinib with voriconazole 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 voriconazole 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. Voriconazole is a moderate CYP3A4 inhibitor. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. In a randomized crossover study in healthy volunteers, voriconazole decreased the clearance of another CYP3A4 substrate, midazolam (IV) by 72% and increased the elimination half-life to about 8 hours. It also increased the Cmax and AUC of oral midazolam by 3.8-fold and 10.3-fold, respectively, as well as a 31% to 84% increase in the bioavailability of oral midazolam. 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 voriconazole may also increase erlotinib exposure.
    Warfarin: (Major) International Normalized Ratio (INR) elevations and bleeding events including gastrointestinal and non-gastrointestinal bleeds (some cases fatal) have been reported with concomitant use of erlotinib and warfarin. Some reports of bleeding were associated with erlotinib and concomitant nonsteroidal antiinflammatory drugs (NSAIDs) usage. Patients taking warfarin or other coumarin-derivative anticoagulants should be monitored regularly for changes in prothrombin time or INR.
    Zafirlukast: (Major) Avoid the coadministration of erlotinib with zafirlukast 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Zafirlukast is a moderate CYP1A2 inhibitor in vitro and a weak in vitro inhibitor of CYP3A4. 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 zafirlukast may also increase erlotinib exposure.

    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 is a selective inhibitor of the epidermal growth factor receptor-tyrosine kinase (EGFR-TK). The EGFR (ErbB1, HER1) receptor is closely related to the Her2/neu (ErbB2), Her3 (ErbB3), and Her4 (ErbB4) receptors. Erlotinib shows minimal activity against other tyrosine kinases such as HER2/neu, KDR, c-flt, or serine/threonine kinases including protein kinase C, MEK-1, and ERK. The activity of protein tyrosine kinases is tightly regulated since they function as mediators of cell growth, differentiation, and death. Numerous protein kinase genes have been identified as oncogenes associated with transforming retroviruses or human tumors. Stimulation of EGFR occurs by various ligands including transforming growth factor-alpha, amphiregulin, epiregulin, heparin-binding EGF-like growth factor, and ß-cellulin. Upon active binding, EGFR undergoes dimerization with either another EGFR or with erbB2 (HER2/neu), erbB3 (HER3), or erb4 (HER4). In addition, EGFR may also be activated by other receptors such as G-protein coupled proteins. Up-regulation or overexpression of EGFR in cancer cells has been associated with increased cell proliferation (alters cell cycle regulation), cell survival (blocks apoptosis), increased motility and invasive capacity (associated with metastases), and promotion of angiogenesis.
     
    Erlotinib reversibly binds to the ATP-binding site and completely inhibits autophosphorylation by EGFR-TK. This results in blockage of downstream EGFR signal transduction pathways, cell cycle arrest, and inhibition of angiogenesis. Preclinical trials have demonstrated additive or synergistic effects when erlotinib was added to chemotherapy. The inhibition of EGFR occurs at erlotinib concentrations readily achievable with oral dosing (median 50% inhibitory concentration 0.786 ng/mL). The skin rash adverse reaction commonly seen with erlotinib is thought to be a result of inhibition of EGFR-positive epidermal keratinocytes and other skin cells that are dependent upon EGFR for normal cellular growth and activity; the appearance of skin rash appears to correlate with clinical activity of the drug.

    PHARMACOKINETICS

    Erlotinib is administered orally. Binding to plasma proteins, primarily albumin and alpha-1-acid glycoprotein, is 93%. Time to reach steady state plasma concentration is 7—8 days. 
     
    Erlotinib undergoes significant hepatic metabolism, predominantly via the cytochrome P450 isoenzyme 3A4 (CYP3A4) and to a lesser extent by CYP1A2 and the extrahepatic isoform CYP1A1. Concurrent administration of drugs that affect this enzyme could affect exposure. The elimination half-life is approximately 36 hours. Excretion is predominantly via the feces (83%), with renal elimination of the drug and metabolites accounting for 8% of the administered dose.
     
    Affected cytochrome P450 isoenzymes: CYP3A4, CYP1A2, CYP1A1
     

    Oral Route

    Erlotinib is slowly absorbed with peak plasma levels occurring 3—4 hours after dosing with a mean bioavailability of 60%. Bioavailability is significantly improved by administration with food (to approximately 100%) with the mean AUC increasing by approximately 33% when given with food. The increase in bioavailability from administration with food is substantial and increases the risk of drug-related side effects; therefore, erlotinib should be given on an empty stomach. Following continuous daily administration of a 150 mg oral dose, the peak concentration of erlotinib is 2690 ng/mL, and the AUC is 38.4 mcg hour/mL with significant inter- and intra-patient variability.