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.

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. Information on FDA-approved companion diagnostic tests for the detection of EGFR mutations in NSCLC is available at [Web].

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

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

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.

Pancreatic Cancer

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

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.

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]}.

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.

Patient Monitoring

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

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

• Monitor renal function and serum electrolytes.

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

• Monitor for acute or worsening ocular disorders.

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

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).

Dosage

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

Adults

Non-small Cell Lung Cancer

First-line or Subsequent Treatment of Metastatic NSCLC

Oral

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

Maintenance Treatment of Metastatic NSCLC

Oral

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

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

Dosage Modification for Toxicity

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

Pulmonary Toxicity

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

Renal Toxicity

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

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

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

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

GI Toxicity

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

Permanently discontinue therapy if GI perforation occurs.

Dermatologic Toxicity

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

Discontinue therapy if severe skin reactions (i.e., bullous, blistering, or exfoliative conditions) occur.

Ocular Toxicity

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

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

Discontinue therapy if corneal perforation or severe corneal ulceration occurs.

Special Populations

Hepatic Impairment

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

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Erlotinib

Contraindications

• None.

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.

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

Renal Failure

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

Periodically monitor renal function and serum electrolytes.

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

Hepatic Toxicity

Hepatic failure and hepatorenal syndrome, sometimes fatal, have occurred, particularly in patients with hepatic impairment prior to treatment. 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).

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. In patients with worsening liver function test results, interruption of therapy, dosage reduction, or discontinuance of therapy may be necessary.

GI Perforation

GI perforation, sometimes fatal, has occurred. Often associated with history of peptic ulcer disease or diverticulitis and concomitant therapy with antiangiogenesis drugs, corticosteroids, NSAIAs, and/or taxane-based chemotherapy. If GI perforation occurs, permanently discontinue therapy.

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. If severe dermatologic reactions occur, interrupt or discontinue therapy.

Cerebrovascular Accident

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

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.

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.

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

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. If ocular toxicity (e.g., eye pain) occurs, interrupt or discontinue therapy.

Elevated INR and Bleeding

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

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryolethality demonstrated in animals.

Avoid pregnancy during therapy. (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.

Specific Populations

Pregnancy

May cause fetal harm.

Lactation

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

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.

Pediatric Use

Safety and efficacy not established in pediatric patients.

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

Geriatric Use

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

Hepatic Impairment

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

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. 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.

Renal Impairment

Safety and efficacy not established.

Common Adverse Effects

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

Drug Interactions

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

Drugs and Foods Affecting Hepatic Microsomal Enzymes

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

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

Inducers of CYP3A4: Potential pharmacokinetic interaction (decreased erlotinib exposure). Avoid concomitant use. 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.

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

Drugs Affecting Gastric Acidity

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

Specific Drugs and Foods

Erlotinib Pharmacokinetics

Absorption

Bioavailability

Approximately 60% absorbed from the GI tract.

Peak plasma concentrations occur at 4 hours following oral administration.

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

Food

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

Specific Populations

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

Distribution

Plasma Protein Binding

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

Elimination

Metabolism

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

Elimination Route

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

Half-life

Approximately 36 hours.

Special Populations

Clearance rate is approximately 24% higher in smokers.

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).

Stability

Storage

Oral

Tablets

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

Actions

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

• EGFR (HER1/ErbB1) is expressed on the cell surface of both normal and cancer cells and plays a role in cell growth and proliferation. 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.

• Reversibly inhibits phosphorylation and downregulates EGFR signaling.

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

Advice to Patients

• Risk of skin rash, bullous and exfoliative skin disorders. 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. 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. Advise patients9 to immediately seek medical attention if a severe skin reaction occurs.

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

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

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

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

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

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

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

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

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

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

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

• 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.

• 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

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