Erlotinib

Usage

• Erlotinib is prescribed for the treatment of certain types of non-small cell lung cancer (NSCLC) and pancreatic cancer. Specifically, it’s used:
  • As maintenance therapy for locally advanced or metastatic NSCLC whose disease hasn’t progressed after first-line platinum-based chemotherapy.
  • To treat locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen.
  • As first-line treatment, in combination with gemcitabine, for locally advanced, unresectable, or metastatic pancreatic cancer.
• Pharmacological Classification: Erlotinib is a tyrosine kinase inhibitor (TKI), specifically an epidermal growth factor receptor (EGFR) inhibitor.
• Mechanism of Action: Erlotinib reversibly binds to the adenosine triphosphate (ATP)-binding site of the EGFR tyrosine kinase domain, inhibiting its autophosphorylation and downstream signaling pathways crucial for cancer cell growth, proliferation, and survival. It has highest activity against tumors with activating mutations in EGFR.

Alternate Names

• International Nonproprietary Name (INN): Erlotinib
• Brand Name: Tarceva

How It Works

• Pharmacodynamics: Erlotinib selectively targets EGFR tyrosine kinase in cancer cells, leading to inhibition of cell growth, proliferation, and angiogenesis, and promoting apoptosis.
• Pharmacokinetics:
  • Absorption: Administered orally, it is well absorbed with peak plasma concentrations reached after approximately 4 hours. Food may delay absorption.
  • Metabolism: Primarily metabolized in the liver by CYP3A4, with minor contributions from CYP1A2 and CYP1A1. An active metabolite, OSI-420, is formed.
  • Elimination: Primarily excreted in the feces (>90%), with a small portion (<9%) excreted in urine. The terminal half-life is approximately 36 hours.
• Mode of Action: Erlotinib competitively inhibits ATP binding to the intracellular tyrosine kinase domain of the EGFR, thereby blocking downstream signaling pathways involved in cancer cell growth and proliferation.
• Receptor Binding: Binds reversibly and highly selectively to the ATP-binding site of EGFR tyrosine kinase.
• Enzyme Inhibition: Inhibits EGFR tyrosine kinase activity.
• Elimination Pathways: Primarily hepatic metabolism via CYP3A4 followed by biliary excretion and elimination in feces.

Dosage

Standard Dosage

Adults:

• NSCLC: 150 mg orally once daily, taken on an empty stomach (at least 1 hour before or 2 hours after food).
• Pancreatic Cancer: 100 mg orally once daily, taken on an empty stomach, in combination with gemcitabine.

Children:

• Use and dose must be determined by a doctor experienced in pediatric oncology. Based on previous clinical trials, a dose of 85 mg/m²/day is recommended for recurrent pediatric solid tumors. Safety and efficacy have not been fully established in pediatric patients.

Special Cases:

• Elderly Patients: No dose adjustment is typically required.
• Patients with Renal Impairment: No dose adjustment required for mild to moderate impairment. Use with caution in severe renal impairment.
• Patients with Hepatic Dysfunction: Use with caution; dose reduction may be considered. Not recommended in severe hepatic dysfunction.
• Patients with Comorbid Conditions: Exercise caution in patients with pre-existing lung disease, cardiac conditions, or those taking medications known to interact with erlotinib.

Clinical Use Cases

• Erlotinib is not typically used in clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its primary role is in targeted therapy for specific cancers.

Dosage Adjustments

• Dose reductions (usually in 50 mg decrements) may be necessary for managing side effects like rash, diarrhea, or other adverse reactions.
• Consider dose adjustments for patients with moderate to severe hepatic impairment or those taking interacting medications.

Side Effects

Common Side Effects:

• Rash (acneiform)
• Diarrhea
• Fatigue
• Anorexia
• Nausea
• Vomiting
• Stomatitis
• Dry skin
• Infection
• Elevated liver enzymes

Rare but Serious Side Effects:

• Interstitial Lung Disease (ILD)
• Gastrointestinal perforation
• Severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis)
• Keratitis and corneal ulceration
• Hepatic failure

Long-Term Effects:

• Potential for chronic skin changes, pulmonary fibrosis, or liver damage with long-term use.

Adverse Drug Reactions (ADR):

• ILD, GI perforation, severe skin reactions, and hepatic failure require immediate intervention.

Contraindications

• Hypersensitivity to erlotinib.
• Concurrent use of strong CYP3A4 inducers.
• Severe hepatic dysfunction.

Drug Interactions

• CYP3A4 Inducers (e.g., rifampin, phenytoin, St. John’s Wort): Decrease erlotinib concentrations.
• CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole, clarithromycin): Increase erlotinib concentrations.
• Proton Pump Inhibitors (e.g., omeprazole, lansoprazole): Reduce erlotinib absorption.
• Warfarin: Increased risk of bleeding.
• Statins: Possible increased risk of statin-related myopathy.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: D (FDA classification). Erlotinib can cause fetal harm. Advise effective contraception during and for at least 2 weeks after therapy.
• Fetal Risks: Embryo-fetal lethality, abortion, growth restriction.
• Breastfeeding: Erlotinib is present in breast milk. Breastfeeding is contraindicated during and for 2 weeks after treatment.

Drug Profile Summary

• Mechanism of Action: EGFR tyrosine kinase inhibitor.
• Side Effects: Rash, diarrhea, fatigue, ILD (rare), GI perforation (rare).
• Contraindications: Hypersensitivity, strong CYP3A4 inducers, pregnancy, breastfeeding.
• Drug Interactions: CYP3A4 inducers/inhibitors, proton pump inhibitors, warfarin.
• Pregnancy & Breastfeeding: Contraindicated.
• Dosage: NSCLC: 150mg daily; Pancreatic Cancer: 100mg daily with gemcitabine.
• Monitoring Parameters: Monitor for rash, diarrhea, pulmonary symptoms, liver function tests, complete blood counts.

Popular Combinations

• Gemcitabine: For pancreatic cancer.

Precautions

• General Precautions: Evaluate pulmonary function, liver function, and complete blood count before and during treatment.
• Specific Populations: Avoid in pregnancy and breastfeeding. Use with caution in patients with hepatic impairment.
• Lifestyle Considerations: Advise patients to quit smoking.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Erlotinib?

A: For NSCLC, 150 mg orally once daily on an empty stomach. For pancreatic cancer, 100 mg orally once daily on an empty stomach, in combination with gemcitabine. Pediatric dosing needs individual assessment.

Q2: What are the most common side effects of Erlotinib?

A: Rash, diarrhea, fatigue, anorexia, nausea, and vomiting are among the most common side effects.

Q3: How does Erlotinib interact with other medications?

A: Erlotinib interacts with CYP3A4 inducers and inhibitors, proton pump inhibitors, and warfarin, among others. Consult a comprehensive drug interaction resource before co-prescribing.

Q4: Can Erlotinib be used during pregnancy or breastfeeding?

A: No, Erlotinib is contraindicated during pregnancy and breastfeeding due to potential fetal harm.

Q5: What are the warning signs of serious side effects associated with Erlotinib?

A: New or worsening respiratory symptoms (cough, shortness of breath, fever) may indicate ILD. Severe abdominal pain may suggest GI perforation. Any signs of severe skin reactions warrant immediate attention.

Q6: How should Erlotinib be administered?

A: Orally, on an empty stomach (at least 1 hour before or 2 hours after food).

Q7: What is the role of EGFR mutation testing in Erlotinib therapy?

A: EGFR mutation testing is crucial for predicting the likelihood of response to Erlotinib in NSCLC. Patients with activating EGFR mutations are more likely to benefit.

Q8: How does smoking affect Erlotinib therapy?

A: Smoking reduces erlotinib plasma concentrations. Patients should be strongly advised to quit smoking.

Q9: How are Erlotinib-related adverse events managed?

A: Dose reductions may be necessary. Loperamide can be used for diarrhea. Supportive care measures are essential for managing side effects. Severe adverse reactions may require discontinuation of therapy.