Erlotinib

Uses

Locally advanced or metastatic non-small cell lung carcinoma, Locally advanced, unresectable or metastatic pancreatic cancer.

Erlotinib is also used to associated treatment for these conditions: Locally Advanced Non-Small Cell Lung Cancer, Locally Advanced Pancreatic Cancer, Metastatic Non-Small Cell Lung Cancer, Non-Small Cell Lung Carcinoma (NSCLC), Pancreatic Cancer Metastatic

How Erlotinib works

The mechanism of clinical antitumor action of erlotinib is not fully characterized. Erlotinib inhibits the intracellular phosphorylation of tyrosine kinase associated with the epidermal growth factor receptor (EGFR). Specificity of inhibition with regard to other tyrosine kinase receptors has not been fully characterized. EGFR is expressed on the cell surface of normal cells and cancer cells.

Dosage

Erlotinib dosage

Oral (Adult)-

Locally advanced or metastatic non-small cell lung carcinoma:150 mg once daily until disease progression or unacceptable toxicity. Reduce dose in decrements of 50 mg when necessary.

Locally advanced, unresectable or metastatic pancreatic cancer:As 1st-line treatment with gemcitabine: 100 mg once daily, reduce dose in decrements of 50 mg when necessary.

Patient on CYP3A4 or CYP1A2 inhibitor: Reduce dose in decrements of 50 mg when necessary.

Smokers or patient on CYP3A4 inducer: Increase dose as tolerated in increments of 50 mg at 2-wk intervals.

Should be taken on an empty stomach. Take at least 1 hr before or 2 hr after meals.

Side Effects

Rash manifests as a mild or moderate erythematous and papulopustular rash. Bullous, blistering, and exfoliative skin conditions, diarrhoea, nausea, vomiting, stomatitis, GI bleeding, abdominal pain, anorexia, alopecia, pruritus, dry skin, paronychia, conjunctivitis, epistaxis, fatigue, alterations in LFT, abnormal eyelash growth, bilateral eardrum perforation, keratoconjunctivitis sicca or keratitis.

Toxicity

Symptoms of overdose include diarrhea, rash, and liver transaminase elevation. The most common adverse reactions (>50%) in NSCLC are rash, diarrhea, anorexia and fatigue. The most common adverse reactions (>50%) in pancreatic cancer are fatigue, rash, nausea and anorexia.

Precaution

Hepatic and renal impairment. Interrupt or discontinue therapy if patient develops unexplained pulmonary symptoms (e.g. dyspnoea, cough, fever), GI perforation, severe bullous, skin or ocular disorders, if dehydration occurs (esp in at-risk patients). Pregnancy and lactation. LFT (e.g. serum transaminase, bilirubin, alkaline phosphatase) should be periodically monitored. Renal function and electrolytes should be monitored periodically in patients at risk of dehydration.

Interaction

Increased serum levels with potent CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, atazanavir). CYP3A4 inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital) may reduce exposure of erlotinib. Increased serum levels with potent inhibitors of CYP1A2 (e.g. ciprofloxacin) or capecitabine. Use with P-glycoprotein inhibitors (e.g. ciclosporin, verapamil) may cause altered distribution or elimination of erlotinib. Drugs that increase the pH of the GI tract (e.g. antacids, H2-receptor antagonists, or PPIs) may reduce the solubility of erlotinib thus lowering its bioavailability. Concomitant use with warfarin or other coumarin derivates may increase INR and bleeding events.

Food Interaction

• Exercise caution with grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of erlotinib.
• Exercise caution with St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum concentration of erlotinib.
• Take on an empty stomach. Food increases erlotinib bioavailability, therefore administer at least 1 hour before or 2 hours after meals.

[Moderate] GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of erlotinib.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

ADJUST DOSING INTERVAL: Food enhances the oral absorption and bioavailability of erlotinib.

According to product labeling, administration with food increased the oral bioavailability of erlotinib from approximately 60% to almost 100% compared to administration in the fasting state.

MANAGEMENT: Patients treated with erlotinib should preferably avoid consumption of grapefruit or grapefruit juice.

Erlotinib should be administered at least one hour before or two hours after the ingestion of food.

Erlotinib Drug Interaction

Unknown: acetaminophen / diphenhydramine, acetaminophen / diphenhydramine, aspirin, aspirin, bevacizumab, bevacizumab, carboplatin, carboplatin, ethanol, ethanol, gemcitabine, gemcitabine, acetaminophen, acetaminophen, acetylcarbromal, acetylcarbromal, tramadol, tramadol, cyanocobalamin, cyanocobalamin

Erlotinib Disease Interaction

Major: dermatologic toxicities, GI disorders, ocular disorders, pulmonary toxicity, hepatic/renal impairment

Volume of Distribution

Apparent volume of distribution = 232 L

Elimination Route

Erlotinib is about 60% absorbed after oral administration and its bioavailability is substantially increased by food to almost 100%. Peak plasma levels occur 4 hours after dosing. The solubility of erlotinib is pH dependent. Solubility decreases pH increases. Smoking also decrease the exposure of erlotinib.

Half Life

Median half-life of 36.2 hours.

Clearance

Smokers have a 24% higher rate of erlotinib clearance.

Elimination Route

Following a 100 mg oral dose, 91% of the dose was recovered in which 83% was in feces (1% of the dose as unchanged parent compound) and 8% in urine (0.3% of the dose as unchanged parent compound).

Pregnancy & Breastfeeding use

Category D: There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

Contraindicated in pregnancy, hypersensitivity

Acute Overdose

Symptoms: Diarrhoea, rash, and liver transaminase elevation.

Management: Symptomatic and supportive treatment.

Storage Condition

Store between 15-30°C.

Innovators Monograph

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