Erlotinib

Class: Antineoplastic Agents
Chemical Name: N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-quinazolinamine hydrochloride
Molecular Formula: C₂₂H₂₃N₃O₄•HCl
CAS Number: 183319-69-9
Brands: Tarceva

Introduction

Antineoplastic agent; a kinase inhibitor.¹

Uses for Erlotinib

Non-small Cell Lung Cancer

Treatment of locally advanced or metastatic non-small cell lung cancer that is refractory to at least one prior chemotherapy regimen.¹

Combination regimen of erlotinib with carboplatin and paclitaxel or with gemcitabine and cisplatin not effective as first-line therapy† for the treatment of locally advanced or metastatic non-small cell lung cancer;^{1 4 5} use in this setting not recommended.¹

Pancreatic Cancer

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

Erlotinib Dosage and Administration

Administration

Oral Administration

Administer orally once daily, 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

Second-line or Subsequent Treatment of Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Oral

150 mg once daily.¹ Continue therapy until disease progression or unacceptable toxicity occurs; once disease progression occurs, there is no evidence that continued therapy is beneficial.¹ In principal efficacy study, therapy was continued for a median of 9.6 weeks.²

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

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 Discontinue if interstitial lung disease is diagnosed.¹ (See Pulmonary Toxicity under Cautions.)

Dehydration and/or Renal Toxicity

Interrupt therapy and take appropriate measures to intensively rehydrate patient if dehydration occurs, particularly in patients at risk for renal failure.¹ (See Renal Failure under Cautions.)

Hepatic Toxicity

Consider interruption of therapy or dosage reduction with frequent monitoring of liver function tests if worsening of liver function test results occurs; consider such action before severe changes in test results occur.¹

Interrupt or discontinue therapy if severe changes in liver function test results occur in patients with normal hepatic function prior to treatment.^{1 8} (See Hepatic Toxicity under Cautions.)

Discontinue therapy if hepatic failure occurs.¹

GI Toxicity

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

Consider dosage reduction or temporary interruption of therapy if severe diarrhea (unresponsive to loperamide or resulting in dehydration) occurs.¹

Dermatologic Toxicity

Interrupt or discontinue therapy if severe bullous, blistering, or exfoliative reaction occurs.^{1 10}

Ocular Toxicity

Interrupt or discontinue therapy if acute or worsening ocular toxicity (e.g., eye pain) occurs.^{1 10}

Special Populations

Hepatic Impairment

Consider interruption or discontinuance of therapy if severe adverse effects occur.¹ (See Hepatic Impairment under Cautions.)

Geriatric Patients

No dosage adjustment required.¹

Cautions for Erlotinib

Contraindications

• No known contraindications according to manufacturer.¹

Warnings/Precautions

Pulmonary Toxicity

Serious, sometimes fatal, interstitial lung disease-like events reported, usually developing between 5 days to >9 months (median: 39 days) after initiating therapy.¹ Often associated with concomitant or prior chemotherapy, prior radiotherapy, preexisting parenchymal lung disease, metastatic lung disease, or pulmonary infections.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, discontinue erlotinib and institute appropriate treatment.¹

Renal Failure

Hepatorenal syndrome or acute renal failure, sometimes fatal, and renal insufficiency, with or without hypokalemia, have been reported.¹ Risk factors include baseline hepatic impairment; severe dehydration caused by diarrhea, vomiting, and/or anorexia; and concurrent chemotherapy.¹

If dehydration occurs, interrupt erlotinib therapy and initiate intensive rehydration measures, particularly in patients at risk for renal failure (e.g., those with preexisting renal disease, medical conditions or drugs that may lead to renal disease, or other predisposing conditions such as advanced age).¹

Periodically monitor renal function and serum electrolytes in patients at risk of dehydration.¹

Hepatic Toxicity

Hepatic failure and hepatorenal syndrome, sometimes fatal, have occurred, particularly in patients with hepatic impairment prior to treatment.¹ (See Hepatic Impairment under Cautions.)

Periodically monitor liver function tests (i.e., serum transaminase, bilirubin, and alkaline phosphatase concentrations).¹ In patients with worsening liver function test results, consider interruption of therapy or dosage reduction with frequent monitoring of liver function tests before changes become severe.¹ If liver function changes are severe (e.g., total bilirubin >3 times ULN and/or serum aminotransferase concentrations >5 times ULN in patients with normal pretreatment values), interrupt or discontinue therapy.¹ If hepatic failure occurs, discontinue therapy.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 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 such reactions are severe, interrupt or discontinue therapy.^{1 10}

Myocardial Infarction/Ischemia

Among patients receiving erlotinib and gemcitabine for pancreatic cancer in a randomized trial, 6 patients (2.3%) experienced myocardial infarction/ischemia; one of these patients died.¹

Cerebrovascular Accident

Among patients receiving erlotinib and gemcitabine for pancreatic cancer in a randomized trial, 6 patients (2.3%) experienced cerebrovascular accidents, including one fatal hemorrhagic stroke.¹

Microangiopathic Hemolytic Anemia with Thrombocytopenia

Among patients receiving erlotinib and gemcitabine for pancreatic cancer in a randomized trial, 2 patients (0.8%) developed microangiopathic hemolytic anemia with thrombocytopenia.¹

Corneal Ulceration or Perforation

Corneal ulceration and perforation reported.^{1 10} Abnormal eyelash growth (e.g., ingrowing eyelashes, excessive growth, thickening of eyelashes), keratoconjunctivitis sicca (i.e., dry eye), and keratitis also reported and are potential risk factors for corneal ulceration or perforation.^{1 10} If acute or worsening ocular toxicity (e.g., eye pain) occurs, interrupt or discontinue therapy.^{1 10}

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryolethality demonstrated in animals.¹ Avoid pregnancy during therapy.¹ (See Advice to Patients.) If used during pregnancy, apprise of potential fetal hazard or risk for loss of the pregnancy.¹

Rash

Rash reported frequently.¹ Median time to onset is 8–10 days.¹ Typically is erythematous and maculopapular; may resemble acne with follicular pustules but is histopathologically different.¹ Commonly occurs on the face, upper chest, and back, but may be more generalized or severe (grade 3 or 4) with desquamation.¹ (See Bullous and Exfoliative Skin Disorders under Cautions.)

Based on severity, management may include use of topical corticosteroids or topical anti-infectives with anti-inflammatory properties.¹ (See Advice to Patients.) Dosage reduction or drug discontinuance required in some patients.¹

Diarrhea

Diarrhea frequently reported, including grade 3/4 diarrhea.¹ Median time to onset is 12–15 days.¹

Manage diarrhea with loperamide.¹ If diarrhea becomes severe and is unresponsive to loperamide or results in dehydration, consider reducing erlotinib dosage or temporarily interrupting therapy.¹

Elevated INR and Bleeding

Increased INR and infrequent bleeding (including GI and non-GI bleeding) reported; some of these patients were receiving concomitant warfarin or NSAIA therapy.¹ (See Interactions.)

Therapy Monitoring

Periodically monitor liver function tests (i.e., serum transaminases, bilirubin, and alkaline phosphatase).¹

Periodically monitor renal function and serum electrolytes in patients at risk of dehydration.¹

Specific Populations

Pregnancy

Category D.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether distributed into milk.¹ Discontinue nursing or the drug because of potential risk to nursing infants.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.^{1 2}

Geriatric Use

In clinical trial of erlotinib monotherapy for non-small cell lung cancer, no overall differences in safety and efficacy relative to younger adults.¹

In clinical trial for pancreatic cancer, survival benefit for erlotinib/gemcitabine versus placebo/gemcitabine was less clear in geriatric patients; no meaningful differences in safety or pharmacokinetics relative to younger adults.¹

Hepatic Impairment

Use with caution since erlotinib undergoes hepatic metabolism and biliary excretion;¹ extreme caution advised in patients with severe hepatic impairment (total bilirubin >3 times ULN).^{1 8} Close monitoring required in patients with total bilirubin exceeding ULN or Child-Pugh class A, B, or C.^{1 8} (See Special Populations under Pharmacokinetics.)

If worsening of liver dysfunction occurs, consider interruption of therapy or dosage reduction accompanied by frequent monitoring of liver function tests before changes in liver function become severe.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

Erlotinib monotherapy for non-small cell lung cancer: Rash,¹ diarrhea,¹ anorexia,¹ fatigue,¹ dyspnea,¹ cough,¹ nausea,¹ infection,¹ vomiting,¹ stomatitis,¹ pruritus,¹ dry skin,¹ conjunctivitis,¹ keratoconjunctivitis sicca,¹ abdominal pain.¹

Erlotinib and gemcitabine for pancreatic cancer: Fatigue,¹ rash,¹ nausea,¹ anorexia,¹ diarrhea,¹ abdominal pain,¹ vomiting,¹ decreased weight,¹ infection,¹ edema,¹ pyrexia,¹ constipation.¹

Interactions for Erlotinib

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 plasma erlotinib concentrations).¹ Caution when used concomitantly with potent CYP3A4 inhibitors.¹ Consider reducing erlotinib dosage if severe adverse effects occur.¹ (See Specific Drugs and Foods under Interactions.)

Inhibitors of CYP3A4 and CYP1A2: Potential pharmacokinetic interaction (increased plasma erlotinib concentrations).¹ Consider reducing erlotinib dosage if severe adverse effects occur.¹ (See Specific Drugs and Foods under Interactions.)

Inducers of CYP3A4: Potential pharmacokinetic interaction (increased erlotinib clearance, resulting in decreased plasma erlotinib concentrations).¹ Avoid concomitant use.¹ If concomitant use cannot be avoided, consider increasing erlotinib dosage as tolerated at 2-week intervals with close monitoring; if the CYP3A4 inducer is discontinued, immediately reduce erlotinib dosage to the recommended starting dosage.¹ (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 (e.g., proton-pump inhibitors, histamine H₂-receptor antagonists).¹ (See Specific Drugs and Foods under Interactions.)

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Antacids	Effect of antacids on erlotinib disposition not established1	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 hours1
Antifungals, azoles (e.g., itraconazole, ketoconazole, voriconazole)	Possible increased plasma erlotinib concentrations; ketoconazole increased erlotinib AUC1	Use concomitantly with caution; consider reducing erlotinib dosage if severe adverse effects occur1
Antimycobacterials, rifamycins (e.g., rifabutin, rifampin, rifapentine)	Possible decreased plasma erlotinib concentrations1 Rifampin increased erlotinib clearance, resulting in decreased plasma erlotinib concentrations1	Avoid concomitant use; if concomitant use cannot be avoided, consider increasing erlotinib dosage as tolerated at 2-week intervals with close monitoring; if the rifamycin is discontinued, immediately reduce erlotinib dosage to recommended starting dosage1 Maximum erlotinib dose studied in combination with rifampin: 450 mg1
Carbamazepine	Possible decreased plasma erlotinib concentrations1	Avoid concomitant use; if concomitant use cannot be avoided, consider increasing erlotinib dosage as tolerated at 2-week intervals with close monitoring; if carbamazepine is discontinued, immediately reduce erlotinib dosage to recommended starting dosage1
Cigarette smoking	Decreased systemic exposure to erlotinib1	Advise patients to stop smoking1 If patient continues to smoke, consider increasing erlotinib dose (maximum 300 mg) with close monitoring; efficacy and safety of dosages exceeding the recommended starting dosage not established in smokers beyond 14 days1 Upon cessation of smoking, immediately reduce erlotinib dosage to recommended starting dosage1
Ciprofloxacin	Increased plasma erlotinib concentrations1	Use concomitantly with caution; consider reducing erlotinib dosage if severe adverse effects occur1
Clarithromycin	Possible increased plasma erlotinib concentrations1	Use concomitantly with caution; consider reducing erlotinib dosage if severe adverse effects occur1
Gemcitabine	Pharmacokinetic interaction unlikely1
Grapefruit or grapefruit juice	Possible increased plasma erlotinib concentrations1	Use concomitantly with caution; consider reducing erlotinib dosage if severe adverse effects occur1
Histamine H2-receptor antagonists	Decreased solubility and oral bioavailability of erlotinib1	Antacids may be considered as an alternative, but effect on erlotinib disposition not studied1 (see antacids entry in table)
HIV protease inhibitors (e.g., atazanavir, indinavir, nelfinavir, ritonavir, saquinavir)	Possible increased plasma erlotinib concentrations1	Use concomitantly with caution; consider reducing erlotinib dosage if severe adverse effects occur1
Midazolam	Decreased systemic exposure to midazolam1
Nefazodone	Possible increased plasma erlotinib concentrations1	Use concomitantly with caution; consider reducing erlotinib dosage if severe adverse effects occur1
Phenobarbital	Possible decreased plasma erlotinib concentrations1	Avoid concomitant use; if concomitant use cannot be avoided, consider increasing erlotinib dosage as tolerated at 2-week intervals with close monitoring; if phenobarbital is discontinued, immediately reduce erlotinib dosage to recommended starting dosage1
Phenytoin	Possible decreased plasma erlotinib concentrations1	Avoid concomitant use; if concomitant use cannot be avoided, consider increasing erlotinib dosage as tolerated at 2-week intervals with close monitoring; if phenytoin is discontinued, immediately reduce erlotinib dosage to recommended starting dosage1
Proton-pump inhibitors	Decreased solubility and oral bioavailability of erlotinib1	If possible, avoid concomitant use1 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 pH1 Antacids may be considered as an alternative, but effect on erlotinib disposition not studied1 (see antacids entry in table)
St. John’s wort (Hypericum perforatum)	Possible decreased plasma erlotinib concentrations1	Avoid concomitant use; if concomitant use cannot be avoided, consider increasing erlotinib dosage as tolerated at 2-week intervals with close monitoring; if St. John’s wort is discontinued, immediately reduce erlotinib dosage to recommended starting dosage1
Telithromycin	Possible increased plasma erlotinib concentrations1	Use concomitantly with caution; consider reducing erlotinib dosage if severe adverse effects occur1
Troleandomycin	Possible increased plasma erlotinib concentrations1	Use concomitantly with caution; consider reducing erlotinib dosage if severe adverse effects occur1
Warfarin or other coumarin-derivative anticoagulants	Increased INR and possible bleeding (including GI and non-GI bleeding)1 2	Monitor PT or INR regularly1

Erlotinib Pharmacokinetics

Absorption

Bioavailability

Approximately 60% absorbed from the GI tract.¹

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

Food

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

Distribution

Plasma Protein Binding

Approximately 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 (may be exposed to 15–30°C).¹

Actions

• Antineoplastic agent; a kinase inhibitor.¹

• Exact mechanism of antineoplastic activity not fully elucidated.¹ Appears to inhibit intracellular phosphorylation of tyrosine kinase associated with epidermal growth factor receptor (EGFR), which is expressed on the surface of normal and cancer cells.¹ Specificity with regard to other tyrosine kinase receptors not fully characterized.¹

Advice to Patients

• Risk of adverse pulmonary, dermatologic, GI, or ocular effects.¹ Importance of seeking medical advice promptly if the following manifestations occur: new onset or exacerbation of unexplained shortness of breath or cough; onset or exacerbation of rash; severe or persistent diarrhea, nausea, anorexia, or vomiting; or ocular pain or irritation.¹

• 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; avoidance of acne preparations with drying properties, which may aggravate dry skin and erythema.¹

• Advise smokers to stop smoking; smoking may reduce efficacy of erlotinib.¹ (See Specific Drugs and Foods under Interactions.)

• Importance of women using an effective method of contraception during and for at least 2 weeks 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 informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs 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.

Erlotinib Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	25 mg (of erlotinib)	Tarceva	Genentech
		100 mg (of erlotinib)	Tarceva	Genentech
		150 mg (of erlotinib)	Tarceva	Genentech