Erlotinib

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
Brands: Tarceva

Medically reviewed by Drugs.com on Jun 21, 2021. Written by ASHP.

Introduction

Antineoplastic agent; an 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.

Pancreatic Cancer

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

Erlotinib Dosage and Administration

General

Confirm presence of EGFR del19 or L858R substitution mutations in tumor or plasma specimens by an FDA-approved diagnostic test prior to initiating therapy for metastatic NSCLC. Patients with a negative plasma del19 or L858R result should be reevaluated for feasibility of biopsy.

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 or less. (See Pulmonary Toxicity under Cautions.)

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 or less, and then resume therapy at a reduced dosage. (See Renal Failure under Cautions.)

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 or less, and then resume therapy at a reduced dosage. (See Hepatic Toxicity under Cautions.)

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 or less, 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 or less, resume therapy at a reduced dosage. (See Diarrhea under Cautions.)

Permanently discontinue therapy if GI perforation occurs. (See GI Perforation under Cautions.)

Dermatologic Toxicity

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

Discontinue therapy if severe skin reactions (i.e., bullous, blistering, or exfoliative conditions) occur. (See Bullous and Exfoliative Skin Disorders under Cautions.)

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 or less, 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 or less, resume therapy at a reduced dosage.

Discontinue therapy if corneal perforation or severe corneal ulceration occurs. (See Corneal Ulceration or Perforation under Cautions.)

Special Populations

Hepatic Impairment

Consider interruption or discontinuance of therapy if abnormal liver function tests occur. (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations at this time. (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time. (See Geriatric Use under Cautions.)

Cautions for Erlotinib

Contraindications

No known contraindications according to manufacturer.

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. (See Pulmonary Toxicity under Dosage and Administration.)

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. (See Renal Toxicity under Dosage and Administration.)

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). (See Hepatic Impairment under Cautions.)

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. (See Hepatic Toxicity under Dosage and Administration.)

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. (See Dermatologic Toxicity under Dosage and Administration.)

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. (See Ocular Toxicity under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryolethality demonstrated in animals.

Avoid pregnancy during therapy. Women of childbearing potential should use effective contraception while receiving the drug and for 1 month after the last dose. (See Advice to Patients.) If used during pregnancy, apprise of potential fetal hazard or risk for loss of the pregnancy.

Dermatologic Effects

Rash reported frequently. Median time to onset is 8–15 days.

Hyperpigmentation or dry skin, with or without digital skin fissures, may occur. Rash may occur or worsen in sun-exposed areas of the skin. (See Advice to Patients.) If dermatologic reactions occur, dosage modification may be necessary. (See Dermatologic Toxicity under Dosage and Administration.)

Diarrhea

Diarrhea frequently reported, including grade 3/4 diarrhea. Median time to onset is 12–32 days.

Manage diarrhea with loperamide. If diarrhea becomes severe and is unresponsive to loperamide, temporary interruption of therapy and dosage reduction may be necessary. (See GI Toxicity under Dosage and Administration.)

Elevated INR and Bleeding

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

Specific Populations

Pregnancy

May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

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.

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. (See Special Populations under Pharmacokinetics.)

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. (See Hepatic Toxicity under Dosage and Administration.)

Renal Impairment

Safety and efficacy not established.

Common Adverse Effects

First-line therapy for NSCLC: Rash, diarrhea, cough, dyspnea, dry skin, back pain, chest pain, conjunctivitis, mucosal inflammation, pruritus, paronychia, arthralgia, musculoskeletal pain.

Second-line or subsequent therapy for NSCLC: Rash, diarrhea, anorexia, fatigue, dyspnea, nausea, infection, stomatitis, pruritus, dry skin, conjunctivitis, keratoconjunctivitis sicca.

Maintenance therapy for NSCLC: Rash, diarrhea.

Combination therapy with gemcitabine for pancreatic cancer: rash, diarrhea, decreased weight, infection, pyrexia, stomatitis, depression, cough, headache.

Interactions for Erlotinib

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. (See Specific Drugs and Foods under Interactions.)

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. (See Specific Drugs and Foods under Interactions.)

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. (See Specific Drugs and Foods under Interactions.)

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. (See Specific Drugs and Foods under Interactions.)

Drugs Affecting Gastric Acidity

Pharmacokinetic interaction (decreased solubility and reduced oral bioavailability of erlotinib) with drugs that increase pH of upper GI tract. (See Specific Drugs and Foods under Interactions.)

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Antacids	Effect of antacids on erlotinib disposition not established	Although effects on erlotinib not established, antacids may be considered as an alternative to histamine H₂-receptor antagonists or proton-pump inhibitors; if use is necessary, separate antacid dose and erlotinib dose by several hours
Antifungals, azoles (e.g., itraconazole, ketoconazole, posaconazole, voriconazole)	Possible increased plasma erlotinib concentrations; ketoconazole increased erlotinib AUC	Potent CYP3A4 inhibitors: Avoid concomitant use; if concomitant use cannot be avoided, reduce erlotinib dosage in 50-mg decrements
Antimycobacterials, rifamycins (rifabutin, rifampin, rifapentine)	Possible decreased plasma erlotinib concentrations Rifampin decreased AUC of erlotinib by 58–80%	Avoid concomitant use; if concomitant use cannot be avoided, increase erlotinib dosage in 50-mg increments (maximum 450 mg daily) as tolerated at 2-week intervals
Capecitabine	Pharmacokinetic interaction unlikely
Carbamazepine	Possible decreased plasma erlotinib concentrations	Avoid concomitant use; if concomitant use cannot be avoided, increase erlotinib dosage in 50-mg increments (maximum 450 mg daily) as tolerated at 2-week intervals
Carboplatin	Pharmacokinetic interaction unlikely
Cigarette smoking	Decreased AUC of erlotinib by approximately 64% Increased clearance of erlotinib by 24%, decreased steady-state plasma trough concentrations of erlotinib by approximately twofold	Advise patients to stop smoking If patient continues to smoke, consider increasing erlotinib dosage in 50-mg increments (maximum 300 mg daily) at 2-week intervals Upon cessation of smoking, immediately reduce erlotinib dosage to recommended starting dosage
Ciprofloxacin	Increased peak plasma erlotinib concentrations and AUC by 17 and 39%, respectively	Avoid concomitant use; if concomitant use cannot be avoided, reduce erlotinib dosage in 50-mg decrements
Cisplatin	Pharmacokinetic interaction unlikely
Clarithromycin	Possible increased plasma erlotinib concentrations	Avoid concomitant use; if concomitant use cannot be avoided, reduce erlotinib dosage in 50-mg decrements
Conivaptan	Possible increased plasma erlotinib concentrations	Avoid concomitant use; if concomitant use cannot be avoided, reduce erlotinib dosage in 50-mg decrements
Crizotinib	Increased AUC of erlotinib by 1.5- to 1.8-fold
Docetaxel	Pharmacokinetic interaction unlikely
Gemcitabine	Pharmacokinetic interaction unlikely
Grapefruit or grapefruit juice	Possible increased plasma erlotinib concentrations	Avoid concomitant use; if concomitant use cannot be avoided, reduce erlotinib dosage in 50-mg decrements
Histamine H₂-receptor antagonists (e.g., ranitidine)	Decreased solubility and oral bioavailability of erlotinib Ranitidine (300 mg) administered 2 hours before erlotinib decreased peak plasma concentration and AUC of erlotinib by 54 and 33%, respectively; however, ranitidine (150 mg twice daily) administered at least 10 hours before or 2 hours after erlotinib decreased peak plasma concentration and AUC of erlotinib by 17 and 15%, respectively	Antacids may be considered as an alternative, but effect on erlotinib disposition not studied (see antacids entry in table) If concomitant use is necessary, administer H₂-receptor antagonist 10 hours before or >2 hours after erlotinib
HIV protease inhibitors (e.g., atazanavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir)	Possible increased plasma erlotinib concentrations	Potent CYP3A4 inhibitors: Avoid concomitant use; if concomitant use cannot be avoided, reduce erlotinib dosage in 50-mg decrements
Midazolam	Decreased systemic exposure to midazolam
Nefazodone	Possible increased plasma erlotinib concentrations	Avoid concomitant use; if concomitant use cannot be avoided, reduce erlotinib dosage in 50-mg decrements
Paclitaxel	Pharmacokinetic interaction unlikely
Phenobarbital	Possible decreased plasma erlotinib concentrations	Avoid concomitant use; if concomitant use cannot be avoided, increase erlotinib dosage in 50-mg increments (maximum 450 mg daily) as tolerated at 2-week intervals
Phenytoin	Possible decreased plasma erlotinib concentrations	Avoid concomitant use; if concomitant use cannot be avoided, increase erlotinib dosage in 50-mg increments (maximum 450 mg daily) as tolerated at 2-week intervals
Proton-pump inhibitors (e.g., omeprazole)	Decreased solubility and oral bioavailability of erlotinib Omeprazole decreased peak plasma concentration and AUC of erlotinib by 61 and 46%, respectively	If possible, avoid concomitant use Increasing erlotinib dosage is not likely to compensate for the decrease in systemic exposure; separation of doses may not eliminate the interaction because of prolonged effect of proton-pump inhibitors on gastric pH Antacids may be considered as an alternative, but effect on erlotinib disposition not studied (see antacids entry in table)
St. John’s wort (Hypericum perforatum)	Possible decreased plasma erlotinib concentrations	Avoid concomitant use; if concomitant use cannot be avoided, increase erlotinib dosage in 50-mg increments (maximum 450 mg daily) as tolerated at 2-week intervals
Telithromycin	Possible increased plasma erlotinib concentrations	Avoid concomitant use; if concomitant use cannot be avoided, reduce erlotinib dosage in 50-mg decrements
Teriflunomide	Possible decreased erlotinib exposure	Avoid concomitant use; if concomitant use cannot be avoided, increase erlotinib dosage
Warfarin or other coumarin-derivative anticoagulants	Increased INR and possible bleeding	Monitor PT or INR regularly Dosage adjustment of erlotinib not necessary

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 (may be exposed to 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

Importance of skin care (e.g., alcohol-free emollient cream, use of sunscreen or avoidance of sun exposure), to minimize the risk of skin reactions.
Risk of serious dermatologic reactions. Importance of immediately informing clinician if severe dermatologic reactions occur.
Risk of diarrhea. 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.
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. (See Specific Drugs and Foods under Interactions.)
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.