Erlotinib

Pronunciation: er-LOE-ti-nib
Class: Epidermal growth factor receptor inhibitor

Trade Names

Tarceva
- Tablets 25 mg
- Tablets 100 mg
- Tablets 150 mg

Pharmacology

Inhibits intracellular phosphorylation of tyrosine kinase associated with epidermal growth factor receptor.

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

Approximately 60% after oral administration; increased to almost 100% by food. T max is 4 h. Steady state is reached in 7 to 8 days.

Distribution

Approximately 93% protein bound to albumin and alpha-1 acid glycoprotein. Apparent Vd is 232 L.

Metabolism

Metabolized primarily by CYP3A4 and, to a lesser degree, by CYP1A2 and the extrahepatic isoform CYP1A1.

Elimination

Eliminated by hepatic metabolism and biliary excretion. Approximately 83% excreted in feces and 8% in urine. The half-life is approximately 36 h.

Special Populations

Renal Function Impairment

Less than 9% is excreted in the urine.

Hepatic Function Impairment

Primarily cleared by the liver. Use with caution in patients with total bilirubin levels 3 times the ULN.

Gender

No significant change in Cl related to gender was observed.

Age

No significant change in Cl related to age was observed.

Body weight

No significant change in Cl related to body weight was observed.

Cigarette smoking

Smokers had a 24% higher rate of erlotinib Cl.

Indications and Usage

As monotherapy for the treatment of locally advanced or metastatic non–small cell lung cancer after failure of at least 1 prior chemotherapy regimen; as monotherapy for the maintenance of patients with locally advanced or metastatic non–small cell lung cancer whose disease has not progressed after 4 cycles of platinum-based first-line chemotherapy; in combination with gemcitabine as first-line treatment of locally advanced, unresectable or metastatic pancreatic cancer.

Unlabeled Uses

Treatment of squamous cell head and neck cancer.

Contraindications

None well documented.

Dosage and Administration

Non–Small Cell Lung Cancer
Adults

PO 150 mg daily at least 1 h before or 2 h after food. Continue treatment until disease progression or unacceptable toxicity occurs.

Pancreatic Cancer
Adults

PO 100 mg daily at least 1 h before or 2 h after food, in combination with gemcitabine. Continue treatment until disease progression or unacceptable toxicity occurs.

Dose Modifications
Adults

PO When dose reduction is necessary, reduce the dose in 50 mg increments. In patients who develop an acute onset of new or progressive pulmonary symptoms (eg, cough, dyspnea, fever), interrupt treatment pending diagnostic evaluation. If interstitial lung disease is diagnosed, discontinue erlotinib and institute appropriate treatment. Discontinue erlotinib for hepatic failure or GI perforation. Patients with dehydration who are at risk for renal failure, patients who develop severe skin reactions, patients who develop severe diarrhea unresponsive to loperamide or who become dehydrated, or patients with acute/worsening ocular disorders may require dose reduction or temporary interruption of therapy.

CYP-450 therapy

In patients receiving a strong CYP3A4 inhibitor or an inhibitor of both CYP3A4 and CYP1A2, consider a dose reduction. In patients receiving CYP3A4 inducers, alternative treatment lacking CYP3A4-inducing activity is strongly recommended. If an alternative is unavailable, consider increasing the dose of erlotinib, as tolerated, at 2-wk intervals. Reduce the erlotinib dose immediately after discontinuing the CYP3A4 inducer.

Cigarette smoking

Advise patients to stop smoking. In patients who continue to smoke during erlotinib administration, a cautious increase in the dose of erlotinib, not exceeding 300 mg, may be considered. Reduce dose of erlotinib immediately after cessation of smoking.

Storage/Stability

Store tablets at 59° to 86°F.

Drug Interactions

Cigarette smoking

Cigarette smoking may reduce erlotinib exposure. Advise patients to stop smoking. If a patient continues to smoke, consider cautiously increasing the erlotinib dose, not exceeding 300 mg, while monitoring the patient. Safety and efficacy of doses higher than the recommended starting dose have not been established in patients who continue to smoke for more than 14 days. If the erlotinib dose is adjusted upward, reduce the dose immediately to the indicated starting dose upon cessation of smoking.

CYP inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John's wort)

May reduce erlotinib plasma concentrations, decreasing the therapeutic effect and necessitating dosage adjustments or changes in therapy. If alternative treatment is unavailable, consider a dose increase of erlotinib if coadministered with a potent CYP3A4 inducer. If the erlotinib dose is adjusted upward, the dose should be reduced immediately to the indicated starting dose when the CYP3A4 inducer is discontinued.

Drugs that alter upper GI tract pH (eg, antacids, H 2 receptor antagonists [eg, ranitidine], proton pump inhibitors [eg, omeprazole])

Avoid coadministration of erlotinib and proton pump inhibitors. Separate erlotinib and antacid dosing by several hours. Administer erlotinib 10 h after the H 2 receptor antagonist and at least 2 h before the next H 2 antagonist dose.

Drugs that inhibit both CYP1A2 and CYP3A4 (eg, ciprofloxacin)

Use with caution. Erlotinib plasma concentrations may be elevated, increasing the risk of adverse reactions and necessitating dosage reduction.

Food

The bioavailability of erlotinib is substantially increased by food to almost 100%. Administer erlotinib at least 1 h before or 2 h after food.

Midazolam

Midazolam AUC is decreased by erlotinib. Observe the clinical response of the patient and adjust the midazolam dose as needed.

Strong CYP3A4 inhibitors (eg, atazanavir, clarithromycin, grapefruit or grapefruit juice, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole)

Use with caution. Erlotinib plasma concentrations may be elevated, increasing the risk of adverse reactions and necessitating dosage reduction.

Warfarin

INR elevations and bleeding have been reported with erlotinib coadministration. Monitor PT and INR and adjust the warfarin dose as needed.

Adverse Reactions

CNS

Fatigue (52%).

Dermatologic

Rash (75%); pruritus (13%); dry skin (12%); acne (6%); dermatitis acneiform (5%); bullous, blistering, and exfoliative skin conditions (including cases of Stevens-Johnson syndrome/TEN).

EENT

Conjunctivitis, keratoconjunctivitis (12%); brittle and loose nails, corneal ulcerations or perforations, epistaxis, excessive growth and thickening of the eyelashes, hair and nail disorders including alopecia, hirsutism, ingrowing eyelashes.

GI

Diarrhea (54%); anorexia (52%); nausea (33%); vomiting (23%); stomatitis (17%); abdominal pain (11%); weight decreased (4%); GI bleeding, GI perforations.

Genitourinary

Acute renal failure or renal insufficiency (including fatalities) with or without hypokalemia.

Hepatic

Hepatic failure.

Lab Tests

Elevated bilirubin (4%); elevated ALT (2%).

Respiratory

Dyspnea (41%); cough (33%).

Miscellaneous

Infection (24%); paronychia (4%).

Precautions

Monitor

Monitor patient for dermatologic, GI, ophthalmic, respiratory, and general body adverse reactions. Periodic LFTs are recommended. Periodic monitoring of renal function and serum electrolytes is recommended in patients at risk of dehydration. Monitor patient for acute onset or progression of pulmonary symptoms (eg, cough, dyspnea, fever). Monitor PT and INR regularly in patients taking warfarin or other coumarin-derivative anticoagulants.


Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Hepatic Function

Use with caution, especially in patients with total bilirubin more than 3 times the ULN or Child-Pugh score A, B, and C. Consider erlotinib dose reduction (in 50 mg increments), interruption, or discontinuation of therapy if severe changes in hepatic function develop.

CV effects

MI, ischemia, and cerebrovascular accident, including fatalities, have been reported.

Dermatologic effects

Bullous, blistering, and exfoliative skin conditions have been reported, including cases of Stevens-Johnson syndrome/TEN, which were fatal in some cases.

GI perforation

Has been reported. Permanently discontinue erlotinib in patients who develop GI perforation.

Hematologic effects

Microangiopathic hemolytic anemia with thrombocytopenia has been reported.

Hepatotoxicity

Hepatic failure and hepatorenal syndrome (including fatalities) have been reported, particularly in patients with baseline hepatic impairment.

Ophthalmic effects

Corneal perforation, corneal ulceration, abnormal eyelash growth, keratoconjunctivitis sicca, and keratitis have been reported.

Pulmonary toxicity

Serious, sometimes fatal, interstitial lung disease has been reported. If diagnostic evaluation indicates interstitial lung disease, discontinue erlotinib and be prepared to institute appropriate treatment.

Renal failure

Hepatorenal syndrome, acute renal failure (including fatalities), and renal insufficiency have been reported, in some cases associated with severe dehydration due to diarrhea, vomiting, and/or anorexia, or concomitant chemotherapy.

Overdosage

Symptoms

Diarrhea, liver transaminase elevations, rash.

Patient Information

  • Explain name, action, and potential adverse reactions of the treatment regimen. Review the treatment regimen, including dosing schedule, duration of treatment, and monitoring that will be required.
  • Advise patient to take prescribed dose once daily, at least 1 h before or 2 h after meals or snacks.
  • Advise patient or caregiver to immediately report noted or significant adverse reactions to health care provider, including any of the following: eye irritation; new onset or worsening of unexplained shortness of breath or cough; onset or worsening of skin rash; severe or persistent diarrhea, nausea, appetite loss, or vomiting.
  • Caution woman of childbearing potential to avoid becoming pregnant during therapy. Advise patient to use effective contraceptive methods during and for 2 wk following completion of therapy.
  • Advise smokers to stop smoking during therapy.
  • Advise patients to use sunscreen during sun exposure or avoid sun exposure altogether.

Copyright © 2009 Wolters Kluwer Health.

Hide
(web4)