Erlotinib (Monograph)

Brand name: Tarceva
Drug class: Antineoplastic Agents
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
- Epidermal Growth Factor Receptor Inhibitors
- EGFR Inhibitors
- EGF Receptor Inhibitors
Chemical name: N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-quinazolinamine hydrochloride
Molecular formula: C₂₂H₂₃N₃O₄•HCl
CAS number: 183319-69-9

Medically reviewed by Drugs.com on Sep 19, 2024. Written by ASHP.

Introduction

Antineoplastic agent; epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor.¹

Uses for Erlotinib

Non-small Cell Lung Cancer (NSCLC)

First-line treatment or maintenance therapy of metastatic NSCLC in patients with tumors positive for 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); also used for second-line or subsequent treatment in such patients whose disease progressed following at least one prior chemotherapy regimen.¹ Information on FDA-approved companion diagnostic tests for the detection of EGFR mutations in NSCLC is available at [Web].¹

Combination regimen of erlotinib with platinum-based chemotherapy not effective for the treatment of locally advanced or metastatic NSCLC;^{1 4 5} use in this setting not recommended.¹

Safety and efficacy not established in patients with NSCLC whose tumors harbor EGFR mutations other than exon 19 deletions or exon 21 substitution mutations.¹

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

Pancreatic Cancer

Used in combination with gemcitabine for first-line treatment of locally advanced, unresectable or metastatic pancreatic cancer.¹

The 2020 ASCO 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

Other Uses

Has been used as monotherapy and in combination with bevacizumab (with or without imatinib) for treatment of advanced or metastatic renal cell carcinoma^{† [off-label]}.^{58 59 60 61 62}

Erlotinib Dosage and Administration

General

Pretreatment Screening

• Confirm presence of epidermal growth factor receptor (EGFR) exon 19 deletions (del19) or exon 21 (L858R) substitution mutations in tumor or plasma specimens of patients with metastatic non-small cell lung cancer (NSCLC) by an FDA-approved diagnostic test prior to initiating therapy with erlotinib.¹

Patient Monitoring

• Monitor liver function tests periodically during treatment; more frequent monitoring may be necessary in patients with preexisting hepatic impairment or biliary obstruction.¹

• Monitor for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever.¹

• Monitor renal function and serum electrolytes.¹

• Monitor for new onset of severe bullous, blistering, or exfoliating skin conditions.¹

• Monitor for acute or worsening ocular disorders.¹

• Monitor prothrombin time and international normalized ratio during erlotinib therapy in patients receiving concomitant warfarin or other coumarin derivatives.¹

Administration

Oral Administration

• Administer orally once daily on an empty stomach (e.g., at least 1 hour before or 2 hours after ingestion of food).¹

Dosage

Available as erlotinib hydrochloride; dosage expressed in terms of erlotinib.¹

Adults

Non-small Cell Lung Cancer

First-line or Subsequent Treatment of Metastatic NSCLC

Oral

150 mg once daily.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Maintenance Treatment of Metastatic NSCLC

Oral

150 mg once daily.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Pancreatic Cancer

First-line Therapy of Locally Advanced, Unresectable or Metastatic Pancreatic Cancer

Oral

100 mg 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]).¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Dosage Modification for Toxicity

Dosage interruption and/or reduction, or discontinuance of therapy may be necessary.¹ When dosage reduction is required, reduce dosage in 50-mg decrements.¹

Pulmonary Toxicity

Interrupt therapy pending diagnostic evaluation upon acute onset of new or progressive pulmonary manifestations.¹ Permanently discontinue if interstitial lung disease is diagnosed.¹ If interstitial lung disease is excluded, resume therapy at a reduced dosage when toxicity resolves completely or improves to ≤grade 1.¹

Renal Toxicity

If grade 3 or 4 renal toxicity occurs, consider discontinuance of therapy.¹ Alternatively, interrupt therapy until toxicity resolves completely or improves to ≤grade 1, and then resume therapy at a reduced dosage.¹

Hepatic Toxicity

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 therapy.¹ Alternatively, interrupt therapy until toxicity resolves completely or improves to ≤grade 1, and then resume therapy at a reduced dosage.¹

For elevated total bilirubin concentrations >3 times the ULN or serum aminotransferase concentrations >5 times the ULN in patients without preexisting hepatic impairment, consider discontinuance of therapy.¹ Alternatively, interrupt therapy until toxicity resolves completely or improves to ≤grade 1, and then resume therapy at a reduced dosage.¹

Discontinue therapy if severe hepatotoxicity occurs and does not improve substantially or resolve within 3 weeks.¹

GI Toxicity

If severe and persistent diarrhea unresponsive to medical management (e.g., loperamide) occurs, interrupt therapy.¹ When toxicity resolves completely or improves to ≤grade 1, resume therapy at a reduced dosage.¹

Permanently discontinue therapy if GI perforation occurs.^{1 10}

Dermatologic Toxicity

If severe rash unresponsive to medical management occurs, interrupt therapy.¹ When toxicity resolves completely or improves to ≤grade 1, resume therapy at a reduced dosage.¹

Discontinue therapy if severe skin reactions (i.e., bullous, blistering, or exfoliative conditions) occur.^{1 10}

Ocular Toxicity

If acute or worsening ocular toxicity (e.g., eye pain) occurs, consider discontinuance of therapy.^{1 10} Alternatively, interrupt therapy until toxicity resolves completely or improves to ≤grade 1, and then resume therapy at a reduced dosage.¹

If grade 3 or 4 keratitis or persistent (lasting >2 weeks) grade 2 keratitis occurs, interrupt therapy.¹ When toxicity resolves completely or improves to ≤grade 1, resume therapy at a reduced dosage.¹

Discontinue therapy if corneal perforation or severe corneal ulceration occurs.¹

Special Populations

Hepatic Impairment

Consider interruption or discontinuance of therapy if abnormal liver function tests occur.¹

Renal Impairment

No specific dosage recommendations at this time.¹

Geriatric Patients

No specific dosage recommendations at this time.¹

Cautions for Erlotinib

Contraindications

• None.¹

Warnings/Precautions

Pulmonary Toxicity

Serious, sometimes fatal, interstitial lung disease reported, usually developing between 5 days to >9 months (median: 39 days) after initiating therapy.¹

If acute onset of new or progressive pulmonary manifestations (e.g., dyspnea, cough, fever) occurs, interrupt therapy pending diagnostic evaluation.¹ If interstitial lung disease is diagnosed, permanently discontinue erlotinib.¹ If interstitial lung disease is excluded, dosage reduction may be necessary.¹

Renal Failure

Hepatorenal syndrome or acute renal failure, sometimes fatal, and renal insufficiency reported.¹ Risk factors include baseline hepatic impairment and severe dehydration.¹

Periodically monitor renal function and serum electrolytes.¹

If renal impairment occurs, dosage reduction, temporary interruption, or discontinuance of therapy may be necessary.¹

Hepatic Toxicity

Hepatic failure and hepatorenal syndrome, sometimes fatal, have occurred, particularly in patients with hepatic impairment prior to treatment.¹ Fatality has been reported within 30 days of the last dose of erlotinib in patients with substantial tumor burden in the liver and moderate hepatic impairment (Child-Pugh class B).¹

Periodically monitor liver function tests (i.e., serum aminotransferases, bilirubin, and alkaline phosphatase concentrations) during therapy and more frequently in patients with preexisting hepatic impairment (e.g., total bilirubin concentrations >3 times the ULN) or biliary obstruction.¹ In patients with worsening liver function test results, interruption of therapy, dosage reduction, or discontinuance of therapy may be necessary.¹

GI Perforation

GI perforation, sometimes fatal, has occurred.^{1 10} Often associated with history of peptic ulcer disease or diverticulitis and concomitant therapy with antiangiogenesis drugs, corticosteroids, NSAIAs, and/or taxane-based chemotherapy.^{1 10} If GI perforation occurs, permanently discontinue 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 occurred; sometimes fatal.^{1 10} If severe dermatologic reactions occur, interrupt or discontinue therapy.^{1 10}

Cerebrovascular Accident

Among patients receiving erlotinib monotherapy for NSCLC in clinical studies, 0.6% of patients experienced cerebrovascular accident.¹

Among patients receiving erlotinib and gemcitabine for pancreatic cancer in a randomized trial, 7 patients (2.5%) experienced cerebrovascular accidents, including one fatal hemorrhagic stroke.¹

Microangiopathic Hemolytic Anemia with Thrombocytopenia

Among patients receiving erlotinib monotherapy for NSCLC in clinical studies, none of the patients experienced microangiopathic hemolytic anemia with thrombocytopenia.¹

Among patients receiving erlotinib and gemcitabine for pancreatic cancer in a randomized trial, 1.4% of patients developed microangiopathic hemolytic anemia with thrombocytopenia.¹

Corneal Ulceration or Perforation

Abnormal eyelash growth, keratoconjunctivitis sicca (i.e., dry eye), keratitis, and decreased lacrimation reported and are potential risk factors for corneal ulceration or perforation.^{1 10} If ocular toxicity (e.g., eye pain) occurs, interrupt or discontinue therapy.^{1 10}

Elevated INR and Bleeding

Increased INR and hemorrhagic events, sometimes fatal, reported; some of these patients were receiving concomitant warfarin or NSAIA therapy.¹

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryolethality demonstrated in animals.¹

Avoid pregnancy during therapy.¹ (See Females and Males of Reproductive Potential under Cautions.) If used during pregnancy, apprise of potential fetal hazard or risk for loss of the pregnancy.¹

Specific Populations

Pregnancy

May cause fetal harm.¹

Lactation

Not known whether erlotinib distributes into milk or affects milk production or the nursing infant.¹ Discontinue nursing during therapy and for 2 weeks after the last dose.¹

Females and Males of Reproductive Potential

Advise females of childbearing potential to use effective contraception while receiving erlotinib and for 1 month after the last dose of the drug.¹

Pediatric Use

Safety and efficacy not established in pediatric patients.^{1 2}

Age (range of 2–21 years) does not appear to substantially affect erlotinib clearance normalized to BSA.¹

Geriatric Use

In clinical studies in patients with NSCLC or pancreatic cancer, no overall differences in safety and efficacy relative to younger adults.¹

Hepatic Impairment

Use with caution since erlotinib undergoes hepatic metabolism and biliary excretion.¹ Close monitoring required in patients with total bilirubin exceeding ULN or Child-Pugh class A, B, or C;^{1 8} monitor patients with biliary obstruction or total bilirubin concentrations >3 times the ULN more frequently.¹

If worsening of liver dysfunction occurs, interruption of therapy or dosage reduction accompanied by frequent monitoring of liver function tests before changes in liver function become severe may be necessary.¹ If severe changes in liver function test results (e.g., doubling of bilirubin, tripling of serum aminotransferase concentrations) occur in patients with hepatic dysfunction prior to treatment, interrupt or discontinue therapy.^{1 8}

Renal Impairment

Safety and efficacy not established.¹

Common Adverse Effects

Adverse effects (≥20%): rash, diarrhea, anorexia, fatigue, dyspnea, cough, nausea, vomiting.¹

Drug Interactions

Extensively metabolized by CYP isoenzymes, principally CYP3A4 and, to a lesser extent, CYP1A1 and CYP1A2.¹

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased erlotinib exposure).¹ Avoid concomitant use with potent CYP3A4 inhibitors.¹ If concomitant use cannot be avoided, reduce erlotinib dosage in 50-mg decrements.¹

Combined inhibitors of CYP3A4 and CYP1A2: Potential pharmacokinetic interaction (increased erlotinib exposure).¹ Avoid concomitant use.¹ If concomitant use cannot be avoided, reduce erlotinib dosage in 50-mg decrements.¹

Inducers of CYP3A4: Potential pharmacokinetic interaction (decreased erlotinib exposure).¹ Avoid concomitant use.¹ If concomitant use cannot be avoided, increase erlotinib dosage in 50-mg increments (not to exceed 450 mg daily) as tolerated at 2-week intervals.¹

Inducers of CYP1A2: Potential pharmacokinetic interaction (decreased erlotinib exposure).¹ Avoid concomitant use with moderate CYP1A2 inducers.¹ If concomitant use cannot be avoided, increase erlotinib dosage.¹

Drugs Affecting Gastric Acidity

Pharmacokinetic interaction (decreased solubility and reduced oral bioavailability of erlotinib) with drugs that increase pH of upper GI tract.¹

Specific Drugs and Foods

Erlotinib Pharmacokinetics

Absorption

Bioavailability

Approximately 60% absorbed from the GI tract.¹

Peak plasma concentrations occur at 4 hours following oral administration.¹

Steady-state concentrations are achieved within 7–8 days.¹

Food

Presence of food in the GI tract increases oral bioavailability to almost 100%.¹

Specific Populations

Age, body weight, and gender do not substantially affect systemic exposure.¹

Distribution

Plasma Protein Binding

93% (mainly to albumin and α₁-acid glycoprotein).¹

Elimination

Metabolism

Extensively metabolized by CYP isoenzymes, principally CYP3A4 and, to a lesser extent, CYP1A1 and CYP1A2.¹

Elimination Route

Excreted mainly as metabolites in feces (83%) via biliary excretion and in urine (8%).¹

Half-life

Approximately 36 hours.¹

Special Populations

Clearance rate is approximately 24% higher in smokers.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

Stability

Storage

Oral

Tablets

25°C (excursions permitted between 15–30°C).¹

Actions

• Reversible inhibitor of EGFR, including mutated EGFR (i.e., del19, L858R mutations), tyrosine kinases.¹

• EGFR (HER1/ErbB1) is expressed on the cell surface of both normal and cancer cells and plays a role in cell growth and proliferation.^{1 12 13 14 15} Some EGFR-activating mutations (del19 or L858R substitution mutations) within NSCLC cells can promote tumor cell growth, block apoptosis, increase production of angiogenic factors, and facilitate metastasis.¹⁵

• Reversibly inhibits phosphorylation and downregulates EGFR signaling.¹

• Exhibits greater binding affinity for cell lines expressing del19 or L858R mutations than for wild-type EGFR.¹ Specificity with regard to other tyrosine kinase receptors not fully characterized.¹

Advice to Patients

• Risk of skin rash, bullous and exfoliative skin disorders.¹ Importance of proper skin care (e.g., alcohol-free emollient cream, use of sunscreen or avoidance of sun exposure), to minimize the risk of skin reactions.¹ Advise patients that hyperpigmentation or dry skin, with or without digital skin fissures, have been reported and in the majority of cases were associated with rash.¹ Advise patients9 to immediately seek medical attention if a severe skin reaction occurs.¹

• Risk of diarrhea.¹ Diarrhea can usually be managed with loperamide.¹ Importance of informing clinician if severe or persistent diarrhea occurs.¹

• Risk of interstitial lung disease.¹ Importance of immediately informing clinician if new or worsening respiratory symptoms (e.g., dyspnea, cough) occur.¹

• Risk of renal failure and importance of periodic monitoring of kidney function and electrolytes.¹

• Risk of hepatotoxicity and importance of periodic liver function test monitoring.¹ Importance of reporting any manifestations of hepatotoxicity.¹

• Risk of GI perforation.¹ Importance of advising patients to seek immediate medical attention if they experience symptoms of GI perforation (e.g., severe abdominal pain).¹

• Risk of cerebrovascular accident.¹ Importance of advising patients to seek immediate medical attention if they experience symptoms of cerebrovascular accident.¹

• Risk of ocular disorders.¹ Importance of promptly informing clinician if ocular problems (e.g., lacrimation, sensitivity to light, eye pain, redness, blurred vision, other vision changes) occur.¹

• Risk of hair or nail disorders (e.g., hirsutism, brittle or loose nails).¹

• Advise smokers to stop smoking; smoking may reduce efficacy of erlotinib.¹

• Importance of women using an effective method of contraception during and for one month after discontinuance of therapy.¹ If pregnancy occurs, advise patient of risk to the fetus.¹

• Importance of women informing clinicians if they plan to breast-feed.¹ Importance of advising women to avoid breast-feeding while receiving erlotinib and for 2 weeks after discontinuance of therapy.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., warfarin) and herbal supplements, as well as any concomitant illnesses.¹

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

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.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Frequently asked questions

• How does erlotinib work (mechanism of action)?
• Can Tarceva (erlotinib) cure lung cancer?

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