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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 29, 2022. 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

Patient Monitoring

Administration

Oral Administration

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

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

Drug or Food

Interaction

Comments

Antacids

Effect of antacids on erlotinib disposition 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., famotidine, 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

No clinically important change in peak plasma concentrations of erlotinib observed following concomitant administration with famotidine

If concomitant use is necessary, administer erlotinib 10 hours after the H2-receptor antagonist and ≥2 hours before the next dose of the H2-receptor antagonist

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, pantoprazole)

Decreased solubility and oral bioavailability of erlotinib

Omeprazole decreased peak plasma concentration and AUC of erlotinib by 61 and 46%, respectively

Concomitant administration of pantoprazole and erlotinib decreased AUC and peak plasma concentrations of erlotinib by 50%

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

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

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 (excursions permitted between 15–30°C).

Actions

Advice to Patients

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

Erlotinib Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

25 mg (of erlotinib)*

Erlotinib Hydrochloride Tablets

Tarceva

Genentech

100 mg (of erlotinib)*

Erlotinib Hydrochloride Tablets

Tarceva

Genentech

150 mg (of erlotinib)*

Erlotinib Hydrochloride Tablets

Tarceva

Genentech

AHFS DI Essentials™. © Copyright 2024, Selected Revisions September 29, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

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Frequently asked questions