Erlotinib

Approved Indications:

• Non-Small Cell Lung Cancer (NSCLC):
• First-line treatment of metastatic NSCLC with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.
• Maintenance treatment after first-line chemotherapy for locally advanced or metastatic NSCLC.
• Second- or third-line treatment for NSCLC after failure of at least one prior chemotherapy regimen.
• Pancreatic Cancer:
• In combination with gemcitabine, for the treatment of locally advanced, unresectable, or metastatic pancreatic cancer.

Clinically Accepted Off-Label Uses:

• Head and Neck Cancer: Investigated for recurrent/metastatic squamous cell carcinoma of the head and neck.
• Colorectal Cancer: In EGFR-overexpressing metastatic disease (investigational).
• Other Solid Tumors: EGFR-positive tumors, in experimental or compassionate-use settings.

General Administration:

• Administer orally at least 1 hour before or 2 hours after food.
• Dose modifications may be required based on toxicity or hepatic impairment.

Adult Dosage:

• NSCLC:
• 150 mg orally once daily until disease progression or unacceptable toxicity.
• Pancreatic Cancer:
• 100 mg orally once daily, combined with gemcitabine, until progression or unacceptable toxicity.

Pediatric Use:

• Not approved or well studied in pediatric populations; safety and efficacy have not been established.

Elderly:

• No specific dosage adjustment required based solely on age. Monitor closely for toxicity.

Renal Impairment:

• No initial dosage adjustment required. Use with caution; data are limited.

Hepatic Impairment:

• Use with caution in patients with hepatic impairment.
• Monitor liver function tests regularly.
• Consider dose reduction in cases of bilirubin >3x ULN or transaminases >5x ULN.

Dose Adjustments:

• Interrupt treatment or reduce dosage for:
• Grade 3/4 rash, diarrhea, or liver enzyme elevations.
• Interstitial lung disease (permanently discontinue).
• Reduce dose in CYP3A4 inhibitor or inducer coadministration scenarios.

Erlotinib is a reversible tyrosine kinase inhibitor (TKI) that specifically targets the intracellular domain of the epidermal growth factor receptor (EGFR). By binding competitively to the ATP-binding site of EGFR, it blocks EGFR autophosphorylation and downstream signaling cascades such as RAS-RAF-MEK-ERK and PI3K-AKT, which are essential for cancer cell proliferation, survival, angiogenesis, and metastasis. The drug is most effective in tumors with EGFR-activating mutations, which render cells dependent on this pathway for growth.

• Absorption: Peak plasma concentration achieved in ~4 hours. Food increases bioavailability by ~100%; must be taken on an empty stomach.
• Bioavailability: ~60% under fasting conditions.
• Distribution: Highly protein bound (~93%) mainly to albumin and alpha-1 acid glycoprotein.
• Metabolism: Extensively metabolized in the liver by CYP3A4, with minor contributions from CYP1A2, CYP1A1, and others.
• Active Metabolites: Several metabolites, but their activity is significantly lower than the parent compound.
• Elimination Half-Life: ~36 hours.
• Excretion: Primarily via feces (~90%), with minor renal excretion (~9%).

• Pregnancy: Category D (USA – historical). Not recommended during pregnancy due to potential risk of fetal harm. Animal studies have shown embryo-fetal toxicity.
• Lactation:
• Unknown if excreted in human milk; potential for serious adverse reactions in breastfed infants.
• Breastfeeding is not recommended during treatment and for at least 2 weeks after the last dose.

• Primary Class: Antineoplastic agent
• Subclass: Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor
• Generation: First-generation EGFR TKI

• Known hypersensitivity to erlotinib or any component of the formulation.
• Use in combination with strong CYP3A4 inducers (relative contraindication).
• Pregnancy, unless benefit outweighs risk.
• Severe or uncontrolled interstitial lung disease (ILD) or prior ILD attributed to EGFR inhibitors.

• Interstitial Lung Disease (ILD): Rare but potentially fatal. Permanently discontinue if confirmed.
• Hepatotoxicity: Monitor LFTs; dose modification or discontinuation may be required.
• Gastrointestinal Perforation: Rare events reported, especially in patients with risk factors (e.g., NSAID use, steroid use, ulcers).
• Severe Diarrhea & Dehydration: May require dose reduction, interruption, or supportive care.
• Ocular Disorders: Reports of keratitis, ulcerative keratitis; discontinue if severe symptoms occur.
• Dermatologic Toxicity: Rash is common and may be severe; topical or oral therapy may be required.
• Smoking: Decreases erlotinib plasma levels due to CYP1A1 induction; smokers may require higher doses.

Common (≥10%):

• Dermatologic: Acneiform rash, dry skin, pruritus
• Gastrointestinal: Diarrhea, nausea, vomiting, anorexia, stomatitis
• Ocular: Conjunctivitis, dry eyes
• Hepatic: Transaminase elevations

Serious / Rare:

• Interstitial Lung Disease (ILD)
• Hepatic failure
• Gastrointestinal perforation
• Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN)
• Keratitis or corneal ulceration
• Hemorrhage (especially with warfarin)

Onset & Severity:

• Most side effects appear within the first 1–2 weeks of treatment.
• Rash and diarrhea are dose-related and may require dose adjustment.

• CYP3A4 Inducers (e.g., rifampicin, phenytoin, carbamazepine, St. John’s wort): ↓ Erlotinib levels → reduced efficacy.
• CYP3A4 Inhibitors (e.g., ketoconazole, clarithromycin): ↑ Erlotinib levels → risk of toxicity.
• Smoking: Induces CYP1A1 → ↓ Erlotinib plasma concentration.
• Proton Pump Inhibitors (PPIs): ↓ Absorption due to higher gastric pH; avoid use or consider alternative acid suppression.
• Warfarin: Increased risk of bleeding; monitor INR frequently.
• Grapefruit Juice: May increase erlotinib plasma levels; avoid.

• FDA Label Update: Use restricted to patients with confirmed EGFR exon 19 deletions or L858R substitution mutations for NSCLC.
• NCCN Guidelines: Erlotinib has been deprioritized in favor of newer EGFR inhibitors like osimertinib for first-line NSCLC.
• EMA Guidance: Recommends molecular testing for EGFR mutations before use.
• No longer recommended as a broad first-line agent; now mainly reserved for specific EGFR-positive cancers.

• Store at 20°C to 25°C (68°F to 77°F).
• Allowable excursions between 15°C to 30°C.
• Protect from moisture and light.
• Keep in original container until use.
• Do not refrigerate or freeze.
• Handle with care; avoid crushing or breaking tablets unless directed by a healthcare professional.