Erlotinib hydrochloride, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is an antineoplastic agent.1
Erlotinib hydrochloride is used for the first-line or maintenance treatment of metastatic non-small cell lung cancer (NSCLC) in patients whose tumors harbor epidermal growth factor receptor ( EGFR ) exon 19 deletions (del19) or exon 21 (L858R) substitution mutations as detected by an FDA-approved diagnostic test (e.g., cobas® EGFR Mutation Test); the drug also is used for second-line or subsequent treatment in such patients whose disease progressed following at least one chemotherapy regimen.1 Information on FDA-approved companion diagnostic tests for the detection of EGFR mutations in NSCLC is available at [Web].1
Data from 2 multicenter, randomized, placebo-controlled studies in over 1000 patients did not demonstrate any clinical benefit from concurrent administration of erlotinib with carboplatin and paclitaxel or with gemcitabine and cisplatin in the first-line setting.1, 4, 5 Therefore, the manufacturer states that use of erlotinib in combination with platinum-based chemotherapy is not recommended.1
The manufacturer states that the safety and efficacy of erlotinib have not been established in patients with NSCLC whose tumors harbor EGFR mutations other than exon 19 deletions or exon 21 substitution mutations.1
First-line Treatment of Metastatic Non-small Cell Lung Cancer
The current indication for erlotinib in the first-line treatment of metastatic NSCLC is based principally on the results of a randomized, multicenter, open-label phase 3 study (EURTAC) in adults with newly diagnosed locally advanced or metastatic NSCLC.1, 11 In this study, 174 patients were randomized (stratified by type of EGFR mutation and Eastern Cooperative Oncology Group [ECOG] performance status) in a 1:1 ratio to receive either erlotinib (150 mg orally once daily until disease progression occurred) or investigator's choice of platinum-based chemotherapy (cisplatin 75 mg/m2 and docetaxel 75 mg/m2 on day 1 of each 3-week cycle for 4 cycles; gemcitabine 1.25 g/m2 on days 1 and 8 and cisplatin 75 mg/m2 on day 1 of each 3-week cycle for 4 cycles; carboplatin at the dose required to obtain AUC of 6 mg/mL per minute and docetaxel 75 mg/m2 on day 1 of each 3-week cycle for 4 cycles; gemcitabine 1 g/m2 on days 1 and 8 and carboplatin at the dose required to obtain an AUC of 5 mg/mL per minute on day 1 of each 3-week cycle for 4 cycles).1, 11 The primary measure of efficacy was progression-free survival.1 The median age of patients was 65 years (range: 24-82 years); most patients (99%) were Caucasian, 93% had metastatic disease, 93% had adenocarcinoma histology, 72% were female, 86% had a baseline ECOG performance status of 0 or 1, 69% had never smoked, 20% were former smokers, and 11% were current smokers.1, 11 The majority (66%) of patients had exon 19 deletions and 34% of patients had L858R substitution mutations as determined by a clinical trial assay.1 The majority (84%) of patients randomized to investigator's choice of platinum-based chemotherapy received at least one subsequent therapy; 97% of these patients received an EGFR tyrosine kinase inhibitor.1 Approximately 66% of patients randomized to erlotinib received at least one subsequent therapy.1
In the EURTAC study, patients receiving erlotinib had longer median progression-free survival compared with patients receiving platinum-based chemotherapy (10.4 versus 5.2 months; hazard ratio of 0.34).1 Effects of erlotinib on investigator-assessed progression-free survival and progression-free survival as assessed by an independent review committee were comparable.1 Patients receiving erlotinib also had a higher objective response rate compared with those receiving platinum-based chemotherapy (65 versus 16%).1 At the time of analysis, no significant difference in overall survival was observed between patients receiving erlotinib and those receiving platinum-based chemotherapy.1 An exploratory subgroup analysis based on EGFR mutation (del19 or L858R substitution mutations) indicated that the magnitude of progression-free survival benefit from erlotinib was greater in patients with exon 19 deletions than in those with L858R substitution mutations (hazard ratio: 0.27 and 0.52, respectively); however, an overall survival benefit for the drug in patients with exon 19 deletions or L858R substitution mutations was not apparent.1 Subgroup analysis suggested that erlotinib had a greater effect on progression-free survival relative to platinum-based chemotherapy in patients who had never smoked than in those who were current smokers (hazard ratio: 0.24 and 0.56, respectively) and in those who had not received prior surgery or radiation therapy than in those who had previously undergone surgery (hazard ratio: 0.32 and 0.61, respectively) or radiation therapy (hazard ratio: 0.31 and 0.79, respectively); a progression-free survival benefit for the drug versus platinum-based chemotherapy was not apparent in patients who were former smokers or those who previously received chemotherapy.11
Erlotinib also has been used in combination with ramucirumab† in patients with EGFR mutation positive metastatic NSCLC.50, 51 In a randomized, double-blind, placebo-controlled trial (RELAY), 449 previously untreated patients ≥18 years of age with stage IV NSCLC with an EGFR exon 19 deletion or exon 21 substitution mutation were randomized to receive either erlotinib (150 mg once daily orally) with IV ramucirumab (10 mg/kg once every 2 weeks) or erlotinib plus placebo.50 At a median follow-up of 20.7 months, median progression-free survival was substantially improved in patients receiving erlotinib in combination with ramucirumab compared with those receiving erlotinib alone (19.4 versus 12.4 months, respectively; hazard ratio of 0.59).50
Erlotinib also has been used in combination with bevacizumab† in patients with advanced EGFR mutation-positive NSCLC.52, 53 In an open-label, randomized trial (NEJ026) conducted in Japan, 224 patients with stage IIIB or IV EGFR mutation-positive NSCLC or recurrent EGFR mutation-positive NSCLC were randomized to receive erlotinib 150 mg once daily plus IV bevacizumab 15 mg/kg once every 21 days or erlotinib monotherapy.52, 53 At a prespecified interim analysis, progression-free survival was 16.9 months in patients receiving erlotinib in combination with bevacizumab versus 13.3 months in those receiving erlotinib monotherapy (hazard ratio: 0.605).52 At a median follow-up of 39.2 months, median overall survival with combination therapy was 50.7 months compared to 46.2 months with erlotinib alone (hazard ratio: 1.007).53
Second-line or Subsequent Treatment of Metastatic Non-small Cell Lung Cancer
Safety and efficacy of erlotinib in the second-line or subsequent treatment of patients with metastatic NSCLC were established in a randomized, double-blind, placebo-controlled study in 731 patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen.1, 3 In this study, patients were randomized on a 2:1 basis to receive either erlotinib (150 mg) or placebo, respectively, orally once daily until disease progression or unacceptable toxicity occurred;1, 3 therapy was continued for a median of 9.6 weeks.2 The objective response rate was higher in patients receiving erlotinib (8.9%) than in those receiving placebo (0.9%).1 In addition, median overall survival and progression-free survival were longer in patients receiving erlotinib (6.7 and 2.3 months, respectively) than in those receiving placebo (4.7 and 1.8 months, respectively).1
The current indication for maintenance therapy with erlotinib is based principally on the results of a randomized, double-blind, placebo-controlled phase 3 study (Sequential Tarceva® in Unresectable NSCLC [SATURN]) in adults with metastatic NSCLC who did not experience disease progression following prior platinum-based chemotherapy.1, 16 In this study, 889 patients were randomized in a 1:1 ratio to receive either erlotinib (150 mg orally once daily) or placebo until disease progression or unacceptable toxicity occurred.1 The primary measure of efficacy was progression-free survival.1, 16 The median age of patients was 60 years (range: 30-83 years); most patients (84%) were Caucasian, 74% were male, 55% were current smokers, 27% were former smokers, 17% had never smoked, and 15% of patients were of Asian ancestry.1 The majority (75%) of patients had metastatic disease and 25% of patients had stage IIIB disease with pleural effusion; approximately one-half (45%) of patients had adenocarcinoma/bronchoalveolar carcinoma, 40% had squamous histology, and 5% had large cell carcinoma.1 The majority (70%) of patients had positive EGFR expression as detected by an immunohistochemistry assay; 14% of patients had negative EGFR expression.1
In the SATURN study, the risk of disease progression or death was reduced by 29 or 19%, respectively, in patients receiving erlotinib maintenance therapy compared with those receiving placebo.1 Progression-free survival and overall survival benefits were observed in the overall study population and in patients with positive EGFR expression.16 Results of a subgroup analysis (based on age, gender, ethnicity, ECOG performance status, disease stage, histology) suggested that the effect of erlotinib on progression-free survival and overall survival was evident across all subgroups.16
Efficacy and safety of erlotinib have not been established in patients with NSCLC whose tumors harbor EGFR mutations other than exon 19 deletions or exon 21 substitution mutations.1 In a multicenter, randomized, placebo-controlled study, clinical benefit was not demonstrated in 643 patients with advanced NSCLC without exon 19 deletions or exon 21 (L858R) substitution mutations who received erlotinib maintenance therapy.1, 17
EGFR-activating mutations are present in approximately 15-22% of NSCLC cases in North America and Europe and are present in up to 30-50% of cases in patients of East Asian descent.24, 27, 28 The majority of EGFR mutations are exon 19 deletions and an L858R substitution in exon 21, which together account for about 90% of EGFR mutations in patients with NSCLC.24, 29 Patients with this form of lung cancer typically are nonsmokers (49.3%), female (43.7%), and have adenocarcinoma histology (38%).55
First-line Therapy for Metastatic Non-small Cell Lung Cancer
The American Society of Clinical Oncology (ASCO) and Ontario Health (OH; formerly known as Cancer Care Ontario) 2021 joint guideline specifically addresses treatment of stage IV NSCLC harboring driver alterations such as EGFR mutations.35 For patients with previously untreated stage IV NSCLC harboring sensitizing EGFR mutations (L858R/exon 19 deletion) and a performance status of 0 to 2, ASCO/OH states that afatinib monotherapy or the combination of erlotinib with a vascular endothelial growth factor (VEGF) inhibitor† (e.g., bevacizumab, ramucirumab) may be used when first-line treatment with osimertinib, dacomitinib, or gefitinib in combination with carboplatin and pemetrexed are not treatment options.35 Although progression-free survival benefit has been demonstrated with afatinib monotherapy or combination erlotinib therapy†, overall survival benefit has not been demonstrated compared with first-generation EGFR tyrosine kinase inhibitors alone.35 For patients with previously untreated stage IV NSCLC harboring sensitizing EGFR mutations (L858R/exon 19 deletion) and a performance status of 3, monotherapy with an EGFR tyrosine kinase inhibitor may be offered based on access and toxicity.35
A 2021 Cochrane review on first-line treatment options for patients with EGFR mutation-positive NSCLC concluded that erlotinib, gefitinib, afatinib, and icotinib (not commercially available in the US market) demonstrate increased tumor response, prolonged progression-free survival, less toxicity, and greater quality of life compared to cytotoxic chemotherapy.36 The analysis also states that single agent tyrosine kinase inhibitor therapy remains the standard of care and the benefit of combining a tyrosine kinase inhibitor with chemotherapy remains uncertain.36 Cytotoxic chemotherapy is less effective for the treatment of NSCLC harboring EGFR mutations compared with erlotinib, gefitinib, afatinib or icotinib, and is associated with greater toxicity.36
Erlotinib is used in combination with gemcitabine for the first-line treatment of locally advanced, unresectable or metastatic pancreatic cancer.1 Efficacy and safety of this treatment combination is supported by a randomized placebo-controlled trial.1, 6 Guidelines generally support the use of erlotinib in the treatment of pancreatic cancer for patients unable to receive more intensive therapy.63
Efficacy and safety of erlotinib in combination with gemcitabine as first-line therapy for locally advanced, unresectable or metastatic pancreatic cancer have been evaluated in a randomized, double-blind, placebo-controlled trial in 569 patients.1, 6 Patients received either erlotinib (100 mg or 150 mg) or placebo orally once daily in combination with gemcitabine 1 g/m2 IV once weekly (for 7 consecutive weeks of an 8-week cycle and thereafter for 3 consecutive weeks of a 4-week cycle) until disease progression or unacceptable toxicity.1 Because of the small number of patients receiving erlotinib 150 mg or placebo (24 patients in each group), efficacy and safety results are reported only for the patients receiving erlotinib 100 mg (261 patients) or placebo (260 patients).1 These groups were comparable except there were more females in the group receiving erlotinib 100 mg (51%) than in the group receiving placebo (44%).1 Upon entry to the study, most of the patients (about 76%) had metastatic disease as the initial manifestation of pancreatic cancer.1
Patients receiving erlotinib plus gemcitabine had longer median overall survival (6.5 versus 6 months) and median progression-free survival (3.8 versus 3.6 months) than those receiving placebo and gemcitabine as first-line therapy for locally advanced, unresectable or metastatic pancreatic cancer.1 The objective response rate was 8.6 or 7.9% in patients receiving erlotinib plus gemcitabine or placebo plus gemcitabine, respectively.1 Among the most common adverse effects, rash (70 versus 30%) and diarrhea (48 versus 36%) occurred more frequently in patients receiving erlotinib and gemcitabine than in those receiving gemcitabine alone.1
The 2020 American Society of Clinical Oncology (ASCO) guideline specifically addresses treatment of metastatic pancreatic cancer.63 The guideline states that gemcitabine-based combination therapy such as the combination of gemcitabine and erlotinib may be considered in selected patients with metastatic pancreatic adenocarcinoma, with proactive dose and schedule adjustments to minimize toxicities.63
Erlotinib also has been used as monotherapy and in combination with bevacizumab (with or without imatinib) for the treatment of advanced or metastatic renal cell carcinoma†.58, 59, 60, 61, 62
Administer erlotinib orally once daily.1 The drug should be administered on an empty stomach (e.g., at least 1 hour before or 2 hours after ingestion of food).1
Store erlotinib tablets at 25°C (excursions permitted between 15-30°C).1
Dosage of erlotinib hydrochloride is expressed in terms of erlotinib.1
For the first-line or subsequent treatment or maintenance treatment of metastatic NSCLC in patients whose tumors harbor EGFR del19 or L858R substitution mutations and progressed following at least one chemotherapy regimen, the usual adult dosage of erlotinib is 150 mg once daily.1 Treatment should be continued until disease progression or unacceptable toxicity occurs.1
For the first-line treatment of locally advanced, unresectable or metastatic pancreatic cancer, erlotinib 100 mg once daily, is used in combination with gemcitabine.1 In the randomized trial, patients received erlotinib in combination with gemcitabine 1 g/m2 IV once weekly (for 7 consecutive weeks of an 8-week cycle and thereafter for 3 consecutive weeks of a 4-week cycle).1 Treatment should be continued until disease progression or unacceptable toxicity occurs.1
Dosage interruption and/or reduction, or discontinuance of erlotinib therapy, may be necessary based on severity of adverse reactions.1 When dosage reduction is required, reduce the dose of erlotinib by 50-mg decrements.1
In patients who experience acute onset of new or progressive pulmonary manifestations (e.g., dyspnea, cough, fever), interrupt treatment with erlotinib pending diagnostic evaluation.1 If interstitial lung disease is diagnosed, permanently discontinue erlotinib.1 If interstitial lung disease is excluded, erlotinib may be resumed at a reduced dosage when pulmonary manifestations resolve completely or improve to ≤grade 1.1
If severe (grade 3 or 4) renal toxicity occurs, consider discontinuance of erlotinib therapy.1 Alternatively, erlotinib therapy may be interrupted; when the toxicity resolves completely or improves to ≤grade 1, erlotinib may be resumed at a reduced dosage.1
If total bilirubin concentrations increase to 2 times baseline values or serum aminotransferase concentrations increase to 3 times baseline values in patients with preexisting hepatic impairment or biliary obstruction, consider discontinuance of erlotinib therapy.1 Alternatively, erlotinib therapy may be interrupted; when hepatic impairment resolves or improves to ≤grade 1, erlotinib may be resumed at a reduced dosage.1
If elevated total bilirubin concentrations greater than 3 times the upper limit of normal (ULN) or serum aminotransferase concentrations greater than 5 times the ULN occur in patients without preexisting hepatic impairment, consider discontinuance of erlotinib therapy.1 Alternatively, erlotinib therapy may be interrupted; when hepatic impairment resolves or improves to ≤grade 1, erlotinib may be resumed at a reduced dosage.1
If severe hepatotoxicity occurs and does not improve substantially or resolve within 3 weeks, discontinue erlotinib therapy.1
In patients with severe and persistent diarrhea that is unresponsive to medical management (e.g., loperamide), interrupt erlotinib therapy.1 When the toxicity resolves completely or improves to ≤grade 1, erlotinib may be resumed at a reduced dosage.1
If GI perforation occurs, permanently discontinue erlotinib therapy.1, 10
If severe rash unresponsive to medical management occurs, interrupt erlotinib therapy.1 When the rash resolves completely or improves to ≤grade 1, erlotinib may be resumed at a reduced dosage.1
In patients with severe skin reactions, such as severe bullous, blistering, or exfoliative conditions, discontinue erlotinib therapy.1, 10
In patients who experience acute or worsening ocular toxicity, such as eye pain, consider discontinuance of erlotinib therapy.1, 10 Alternatively, erlotinib therapy may be interrupted; when the toxicity resolves completely or improves to ≤grade 1, erlotinib may be resumed at a reduced dosage.1
If grade 3 or 4 keratitis or persistent (lasting longer than 2 weeks) grade 2 keratitis occurs, interrupt erlotinib therapy.1 When toxicity resolves completely or improves to ≤grade 1, erlotinib may be resumed at a reduced dosage.1
In patients who experience corneal perforation or severe corneal ulceration, discontinue erlotinib therapy.1
Concomitant Use with Drugs and Foods Affecting Hepatic Microsomal Enzymes
Concomitant use with potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4 (e.g., atazanavir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole) or combined inhibitors of CYP3A4 and CYP1A2 (e.g., ciprofloxacin) should be avoided.1 If concomitant use cannot be avoided, the manufacturer recommends reducing the dosage of erlotinib in 50-mg decrements.1
Concomitant use with an inducer of CYP3A4 (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John's wort [ Hypericum perforatum ]) should be avoided.1 If concomitant use cannot be avoided, the manufacturer recommends increasing the dosage of erlotinib in 50-mg increments (not to exceed 450 mg daily) as tolerated at 2-week intervals.1
Concomitant use with moderate inducers of CYP1A2 (e.g., phenytoin, rifampin, teriflunomide) should be avoided.1 If concomitant use cannot be avoided, the manufacturer recommends increasing the dosage of erlotinib.1
Because cigarette smoking reduces systemic exposure to erlotinib, patients should be advised to stop smoking.1 In patients who continue to smoke, the manufacturer recommends increasing the dosage of erlotinib in 50-mg increments (not to exceed 300 mg daily) at 2-week intervals.1 Upon cessation of smoking, the erlotinib dose should be reduced immediately to the recommended starting dose.1
Drugs Affecting Gastric Acidity
If possible, avoid concomitant use of erlotinib and proton-pump inhibitors.1
If use of a histamine H2-receptor antagonist is necessary, erlotinib must be taken 10 hours after the H2-receptor antagonist and at least 2 hours before the next dose of the H2-receptor antagonist.1
If use of an antacid is necessary, separate the antacid dose and erlotinib dose by several hours.1
Avoid concomitant use of erlotinib with grapefruit or grapefruit juice, a potent inhibitor of CYP3A4.1 If concomitant use cannot be avoided, the manufacturer recommends reducing the dosage of erlotinib in 50-mg decrements.1
Consider dosage interruption or discontinuance of erlotinib therapy if abnormal liver function tests occur in patients with preexisting hepatic impairment.1
The manufacturer currently makes no special dosage recommendations for patients with renal impairment.1
The manufacturer currently makes no special dosage recommendations for geriatric patients.1
Serious, sometimes fatal, interstitial lung disease has occurred in patients receiving erlotinib.1, 7 Interstitial lung disease has been reported in approximately 1.1% of patients receiving erlotinib in controlled and uncontrolled studies.1 Onset of manifestations occurred from 5 days to more than 9 months (median: 39 days) after initiating erlotinib therapy.1
Interruption or discontinuance of erlotinib therapy may be required in patients experiencing pulmonary toxicity.1
Hepatorenal syndrome or acute renal failure, sometimes fatal, and renal insufficiency have been reported in patients receiving erlotinib.1 Factors contributing to these adverse renal effects included baseline hepatic impairment and severe dehydration.1 In clinical studies for non-small cell lung cancer (NSCLC), severe renal impairment occurred in 0.5% of patients receiving erlotinib monotherapy compared with 0.8% of those assigned to the control groups.1 In the principal efficacy study for pancreatic cancer, renal impairment occurred in 1.4% of patients receiving erlotinib and gemcitabine versus 0.4% of those receiving placebo and gemcitabine.1
Renal function and serum electrolytes should be monitored periodically.1
If severe (grade 3 or 4) renal impairment occurs, interrupt or discontinue erlotinib therapy.1
Hepatic failure and hepatorenal syndrome, sometimes fatal, have occurred in patients receiving erlotinib, particularly in patients with hepatic impairment prior to treatment.1 In clinical studies for NSCLC, which excluded patients with baseline moderate to severe hepatic impairment, hepatic failure occurred in 0.4% of patients receiving erlotinib monotherapy compared with none of those assigned to the control groups.1 In the principal efficacy study for pancreatic cancer, the reported incidence of hepatic failure (0.4%) was similar between patients receiving erlotinib and gemcitabine and those receiving placebo and gemcitabine.1
In a small subset of 15 patients with substantial tumor burden in the liver and moderate hepatic impairment (Child-Pugh class B), 10 patients died within 30 days of the last dose of erlotinib; 6 of the 10 patients had baseline total bilirubin concentrations greater than 3 times the upper limit of normal (ULN).1 Hepatorenal syndrome and rapidly progressing hepatic failure were the cause of death in 2 patients; the remaining 8 patients died from disease progression.1
Monitor liver function tests (i.e., serum concentrations of aminotransferases, bilirubin, and alkaline phosphatase) periodically during therapy and more frequently in patients with preexisting hepatic impairment (e.g., total bilirubin concentrations greater than 3 times the ULN) or biliary obstruction.1 Interrupt or discontinue erlotinib therapy if changes in liver function are severe.1
GI perforation, sometimes fatal, has been reported in patients receiving erlotinib.1, 10 Patients with a history of peptic ulcer disease or diverticulitis and those who are receiving concomitant therapy with antiangiogenesis drugs, corticosteroids, nonsteroidal anti-inflammatory agents (NSAIAs), and/or taxane-based chemotherapy are at increased risk for perforation while receiving erlotinib therapy.1, 10 In clinical studies for NSCLC, GI perforation occurred in 0.2% of patients receiving erlotinib monotherapy compared with 0.1% of those assigned to the control groups.1 In the principal efficacy study for pancreatic cancer, GI perforation occurred in 0.4% of patients receiving erlotinib and gemcitabine compared with none of those receiving placebo and gemcitabine.1 If GI perforation occurs, permanently discontinue erlotinib therapy.1, 10
Bullous and Exfoliative Skin Disorders
Bullous, blistering, and exfoliative skin reactions, including cases suggestive of Stevens-Johnson syndrome or toxic epidermal necrolysis, have been reported in patients receiving erlotinib therapy; some cases have been fatal.1, 10 In clinical studies for NSCLC, bullous and exfoliative skin reactions occurred in 1.2% of patients receiving erlotinib monotherapy compared with none of those assigned to the control groups.1 In the principal efficacy study for pancreatic cancer, GI perforation occurred in 0.4% of patients receiving erlotinib and gemcitabine compared with none of those receiving placebo and gemcitabine.1
If severe dermatologic reactions occur, interrupt or discontinue erlotinib therapy.1, 10
In the principal efficacy study for pancreatic cancer, cerebrovascular accidents occurred in 7 patients (2.5%) receiving erlotinib and gemcitabine compared with none of those receiving placebo and gemcitabine; one of these events was a hemorrhagic stroke and the patient died.1 In clinical studies for NSCLC, cerebrovascular accident occurred in 0.6% of patients receiving erlotinib monotherapy.1
Microangiopathic Hemolytic Anemia with Thrombocytopenia
In clinical studies for NSCLC, microangiopathic hemolytic anemia with thrombocytopenia occurred in none of the patients receiving erlotinib monotherapy compared with 0.1% of those assigned to the control groups.1 In the principal efficacy study for pancreatic cancer, microangiopathic hemolytic anemia with thrombocytopenia occurred in 1.4% of patients receiving erlotinib and gemcitabine compared with none of those receiving placebo and gemcitabine.1
Corneal Ulceration or Perforation
Abnormal eyelash growth, keratoconjunctivitis sicca (i.e., dry eye), keratitis, and decreased lacrimation may occur in patients receiving erlotinib and are considered risk factors for corneal ulceration or perforation.1, 10 In clinical studies for NSCLC, ocular disorders occurred in 17.8% of patients receiving erlotinib monotherapy compared with 4% of those assigned to the control groups.1 In the principal efficacy study for pancreatic cancer, ocular disorders occurred in 12.8% of patients receiving erlotinib and gemcitabine compared with 11.4% of those receiving placebo and gemcitabine.1
If patients experience ocular toxicity, interrupt or discontinue erlotinib therapy.1, 10
Elevated International Normalized Ratio (INR) and Bleeding
Increased INR and hemorrhagic events, sometimes fatal, have been reported in clinical studies; some of these patients were receiving erlotinib concomitantly with warfarin or a nonsteroidal anti-inflammatory agent (NSAIA).1 GI bleeding included peptic ulcer bleeding (gastritis, gastroduodenal ulcers), hematemesis, hematochezia, melena, and hemorrhage from possible colitis.1
Fetal/Neonatal Morbidity and Mortality
Erlotinib may cause fetal harm in humans based on its mechanism of action and animal findings; the drug has been shown to be embryotoxic and fetotoxic in animals.1 Limited data are available regarding use of erlotinib in pregnant women; data are insufficient to inform a drug-associated risk of adverse developmental outcomes or miscarriage.1 Embryofetal toxicity (e.g., embryofetal lethality, abortion) has been demonstrated in animals receiving the drug at exposure levels equivalent to approximately 3 times the human exposure at the recommended erlotinib dosage of 150 mg daily.1 In a fertility study, increased early resorptions were observed in animals receiving the drug at exposure levels equivalent to 0.3 or 0.7 times the human exposure at the recommended daily dosage.1
Pregnancy should be avoided during erlotinib therapy.1 (See Females and Males of Reproductive Potential under Cautions.) Patients should be apprised of the potential fetal hazard or potential risk for loss of the pregnancy if erlotinib is used during pregnancy.1
Erlotinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
It is not known whether erlotinib is distributed into human milk or if the drug or its metabolites have any effect on milk production or the nursing infant.1 Because of the potential for serious adverse reactions to erlotinib in nursing infants, women should be advised not to breast-feed while receiving the drug and for 2 weeks after the last dose of the drug.1
Females and Males of Reproductive Potential
Females of childbearing potential should be advised to use effective contraception while receiving erlotinib and for 1 month after the last dose of the drug.1
Safety and efficacy of erlotinib have not been established in pediatric patients.1, 2
In a clinical trial, 25 patients 3-20 years of age with recurrent or refractory ependymoma received erlotinib (85 mg/m2 orally daily).1 No overall difference in safety relative to adults was observed.1
Among patients 2-21 years of age, age did not appear to substantially affect erlotinib clearance normalized to body surface area in a population pharmacokinetic analysis.1
In clinical studies in patients with NSCLC or pancreatic cancer, 40% of patients receiving erlotinib were ≥65 years of age and 10% were ≥75 years of age.1 No overall differences in safety and efficacy relative to younger adults were observed.1
Although erlotinib is eliminated mainly by the liver, systemic exposure was not substantially altered in patients with Child-Pugh class B hepatic impairment relative to those with adequate hepatic function (including individuals with primary liver cancer or hepatic metastases);1 however, because hepatic failure and hepatorenal syndrome, sometimes fatal, have been reported in patients with normal hepatic function, the risk of hepatotoxicity is increased in patients with preexisting hepatic impairment.1 Close monitoring is required during erlotinib therapy in patients with hepatic impairment (total bilirubin concentrations greater than the upper limit of normal [ULN] or Child-Pugh class A, B, or C);1, 8 patients with biliary obstruction or total bilirubin concentrations greater than 3 times the ULN should be monitored more frequently.1 If worsening of liver dysfunction occurs, interruption of erlotinib therapy or reduction of erlotinib dosage accompanied by frequent monitoring of liver function tests should be considered before changes in liver function become severe.1 If severe changes in liver function test results, such as doubling of total bilirubin and/or tripling of serum aminotransferase concentrations, occur in patients with hepatic dysfunction prior to treatment, erlotinib therapy should be interrupted or discontinued.1, 8
Safety and efficacy of erlotinib have not been established in patients with renal impairment.1
Adverse effects occurring in ≥20% of patients receiving erlotinib in a pooled analysis of data from patients with NSCLC across all approved lines of therapy, with and without EGFR mutations, and in patients with pancreatic cancer were rash, diarrhea, anorexia, fatigue, dyspnea, cough, nausea, and vomiting.1
Erlotinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, CYP1A1 and CYP1A2.1
Drugs and Foods Affecting Hepatic Microsomal Enzymes
Concomitant use of erlotinib with potent inhibitors of CYP3A4 may result in increased erlotinib exposure.1 When the potent CYP3A4 inhibitor ketoconazole was administered concomitantly with erlotinib, the area under the concentration-time curve (AUC) of erlotinib was increased by 67%.1 Concomitant use of erlotinib with potent CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit or grapefruit juice) should be avoided.1 If concomitant use cannot be avoided, the manufacturer recommends reducing the dosage of erlotinib in 50-mg decrements.1
Combined Inhibitors of CYP3A4 and 1A2
Concomitant use of erlotinib with combined inhibitors of CYP3A4 and 1A2 may result in increased peak plasma concentrations and systemic exposure of erlotinib.1 When the combined CYP3A4 and CYP1A2 inhibitor ciprofloxacin was administered concomitantly with erlotinib, the peak plasma concentration and AUC of erlotinib was increased by 17 and 39%, respectively.1 Concomitant use of erlotinib with combined CYP3A4 and CYP1A2 inhibitors (e.g., ciprofloxacin) should be avoided.1 If concomitant use cannot be avoided, the manufacturer recommends reducing the dosage of erlotinib in 50-mg decrements.1
Concomitant use of erlotinib with inducers of CYP3A4 may result in decreased erlotinib exposure.1 When the CYP3A4 inducer rifampin was administered 7-11 days prior to erlotinib, the AUC of erlotinib was decreased by 58-80%.1 Concomitant use of erlotinib with CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John's wort [ Hypericum perforatum ]) should be avoided.1 If concomitant use with these agents cannot be avoided, the manufacturer recommends increasing the dosage of erlotinib in 50-mg increments (not to exceed 450 mg daily) as tolerated at 2-week intervals.1
Concomitant use of erlotinib with moderate inducers of CYP1A2 may result in decreased erlotinib exposure.1 Concomitant use with moderate CYP1A2 inducers (e.g., phenytoin, rifampin, teriflunomide) should be avoided.1 If concomitant use with these agents cannot be avoided, the manufacturer recommends increasing the dosage of erlotinib.1
Because cigarette smoking moderately induces CYP1A2, concomitant cigarette smoking may result in decreased systemic exposure to erlotinib.1 Patients should be advised to stop smoking.1 Cigarette smoking decreases the AUC of erlotinib by approximately 64%.1 In a clinical trial, clearance of erlotinib was increased by 24% resulting in steady-state plasma trough concentrations of erlotinib approximately twofold less in current smokers compared with those who never smoked or were former smokers.1 In a pharmacokinetic analysis in current smokers, steady-state exposure of erlotinib increased in a dose-proportional manner following an increase in erlotinib dosage from 150 to 300 mg.1
If patients continue to smoke, the manufacturer recommends increasing the dosage of erlotinib in 50-mg increments (not to exceed 300 mg daily) at 2-week intervals.1 Upon cessation of smoking, the erlotinib dose should be reduced immediately to the recommended starting dose.1
Drugs Affecting Gastric Acidity
Drugs that increase the pH of the upper GI tract decrease the solubility of erlotinib and reduce its bioavailability.1 Concomitant administration of omeprazole, a proton-pump inhibitor, decreased the peak plasma concentration and AUC of erlotinib by 61 and 46%, respectively.1 In another small study, concomitant administration of pantoprazole and erlotinib decreased AUC and peak plasma concentrations of erlotinib by 50% compared to patients who received erlotinib alone; however, when erlotinib was administered concomitantly with famotidine, a H2-receptor antagonist, no clinically important change in peak plasma concentrations of erlotinib was observed.56 Increasing the dose level of erlotinib is not likely to compensate for the loss of exposure, and separation of doses may not eliminate the interaction because proton-pump inhibitors have an extended effect on the pH of the upper GI tract.1 If possible, concomitant use of erlotinib and proton-pump inhibitors should be avoided.1
If use of a histamine H2-receptor antagonist (e.g., ranitidine) is necessary, erlotinib must be taken 10 hours after the H2-receptor antagonist and at least 2 hours before the next dose of the H2-receptor antagonist.1 Concomitant administration of ranitidine (300 mg) administered 2 hours prior to erlotinib decreased the peak plasma concentration and AUC of erlotinib by 54 and 33%, respectively; however, when ranitidine (150 mg twice daily) was administered at least 10 hours before or 2 hours after erlotinib, the peak plasma concentration and AUC of erlotinib decreased by 17 and 15%, respectively.1
The effect of antacids on the pharmacokinetics of erlotinib has not been studied.1 If use of an antacid is necessary, the antacid dose and the erlotinib dose should be separated by several hours.1
Concomitant use of erlotinib with gemcitabine did not affect the clearance of erlotinib.1
Concomitant use of erlotinib with paclitaxel and carboplatin in patients with cancers other than non-small cell lung cancer (NSCLC) did not substantially alter the pharmacokinetics of these antineoplastic agents.30
Concomitant use of erlotinib with gemcitabine and cisplatin in patients with cancers other than NSCLC did not substantially alter the pharmacokinetics of these antineoplastic agents.30
Concomitant use of erlotinib with capecitabine and docetaxel in patients with cancers other than NSCLC did not substantially alter the pharmacokinetics of these antineoplastic agents.30
Concomitant use of erlotinib with docetaxel in patients with cancers other than NSCLC did not substantially alter the pharmacokinetics of either drug.30
Concomitant use of erlotinib with capecitabine in patients with pancreatic cancer did not substantially alter the pharmacokinetics of either drug.30
Concomitant use of erlotinib with crizotinib 150 or 200 mg twice daily in patients with NSCLC increased the AUC of erlotinib by 1.5- or 1.8-fold, respectively.30
Increased international normalized ratio (INR) and hemorrhagic events, sometimes fatal, have been reported in patients receiving erlotinib concomitantly with warfarin.1, 2 Prothrombin time (PT) or INR should be monitored regularly in patients receiving erlotinib concomitantly with warfarin or other coumarin-derivative anticoagulants.1 Dosage adjustment of erlotinib is not necessary.1
Erlotinib, a reversible inhibitor of epidermal growth factor receptor (EGFR/human epidermal growth factor receptor type 1 [HER1]/ErbB1) and mutated EGFR (e.g., exon 19 deletion [del19], exon 21 substitution [L858R]) tyrosine kinases, is an antineoplastic agent.1 EGFR is expressed on the cell surface of many cancer cells, as well as many normal cells;1, 15 activation of EGFR tyrosine kinase is thought to initiate a cascade of intracellular signaling events leading to cell proliferation and influencing processes critical to cell survival and tumor progression (e.g., angiogenesis, apoptosis, metastasis).12, 13, 14 Some EGFR -activating mutations, such as exon 19 deletion (del19) and exon 21 (L858R) substitution mutation, contribute to increased cell proliferation and survival in non-small cell lung cancer (NSCLC) cells harboring these mutations.15 The drug binds to the kinase domains of EGFR and reversibly inhibits tyrosine kinase phosphorylation, resulting in downregulation of EGFR signaling.1 Erlotinib has demonstrated a greater affinity for cell lines expressing del19 or L858R mutations than for wild-type EGFR.1 Specificity with regard to other tyrosine kinase receptors has not been fully characterized.1
Approximately 60% of an oral dose of erlotinib is absorbed from the GI tract; presence of food in the GI tract increases oral bioavailability to approximately 100%.1 Peak plasma concentrations of erlotinib occur at 4 hours following oral administration.1 Steady-state concentrations of erlotinib are achieved within 7-8 days.1 Erlotinib is 93% bound to plasma proteins (mainly to albumin and α1-acid glycoprotein).1 Erlotinib is extensively metabolized via the cytochrome P-450 (CYP) enzyme system, mainly by CYP3A4 and, to a lesser extent, by CYP1A1 (principally an extrahepatic enzyme) and CYP1A2.1 The half-life of erlotinib is approximately 36 hours; the clearance is approximately 24% higher in smokers.1 Following a 100-mg oral dose, erlotinib is excreted mainly as metabolites in feces (83%) and urine (8%).1
Systemic exposure of erlotinib does not appear to be affected substantially by age, body weight, or gender in patients receiving the drug as a single agent for maintenance or second- or third-line therapy in NSCLC or in combination with gemcitabine for the treatment of pancreatic cancer.1
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 25 mg (of erlotinib)* | Erlotinib Hydrochloride Tablets | |
100 mg (of erlotinib)* | Erlotinib Hydrochloride Tablets | |||
Tarceva® | Genentech | |||
150 mg (of erlotinib)* | Erlotinib Hydrochloride Tablets | |||
Tarceva® | Genentech |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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