ERLOTINIB — 150 mg film‑coated tablets

Erlotinib is a first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that revolutionized the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). It was first approved by the U.S. FDA in 2004 for locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. Subsequently, its indication was refined to require the presence of EGFR activating mutations (exon 19 deletions or exon 21 L858R substitution mutations) based on pivotal trials demonstrating superior efficacy in this molecularly selected population. Erlotinib is also approved for first-line treatment of locally advanced, unresectable, or metastatic pancreatic cancer in combination with gemcitabine.

Mechanism of action: Erlotinib reversibly and competitively inhibits the intracellular tyrosine kinase domain of the epidermal growth factor receptor (EGFR), also known as HER1/ErbB1. By binding to the ATP-binding site of the receptor, it blocks autophosphorylation and downstream signaling through pathways such as RAS/RAF/MEK/ERK and PI3K/AKT, which are critical for tumor cell proliferation, survival, angiogenesis, and metastasis. Erlotinib is most effective in tumors harboring specific EGFR-activating mutations (exon 19 deletions and exon 21 L858R), which confer constitutive activation of the receptor and hypersensitivity to EGFR TKIs.

Clinical efficacy: In the pivotal phase 3 EURTAC trial, erlotinib significantly improved progression-free survival (PFS) compared to platinum-based chemotherapy in first-line treatment of patients with EGFR-mutant NSCLC (median PFS 9.7 vs 5.2 months). Similar results were observed in the OPTIMAL and ENSURE studies. For pancreatic cancer, the phase 3 NCIC CTG PA.3 trial demonstrated that the addition of erlotinib to gemcitabine resulted in a modest but statistically significant improvement in overall survival (median 6.24 vs 5.91 months) and 1-year survival (23% vs 17%) compared to gemcitabine alone.

Pharmacokinetics: Erlotinib is well absorbed after oral administration, with peak plasma concentrations reached in approximately 4 hours. Bioavailability is significantly increased by food (to almost 100%), which is why it must be taken on an empty stomach. It is extensively metabolized in the liver, primarily by CYP3A4, with minor contributions from CYP1A2 and CYP1A1. The elimination half-life is approximately 36 hours, allowing once-daily dosing. Excretion is predominantly via feces (83%) and urine (8%).

• None. Erlotinib has no absolute contraindications listed in the prescribing information. However, use is not recommended in patients with hypersensitivity to erlotinib or any component of the formulation.

• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, voriconazole, clarithromycin, ritonavir, atazanavir, indinavir, nelfinavir, saquinavir, telithromycin, troleandomycin, nefazodone): May increase erlotinib plasma concentrations (AUC increased by 60-86%). Avoid concomitant use if possible. If unavoidable, reduce erlotinib dose by 50 mg decrements and monitor for toxicity.
• Combined CYP3A4 and CYP1A2 inhibitors (ciprofloxacin): May increase erlotinib AUC by 39%. Reduce erlotinib dose by 50 mg decrements.
• Strong CYP3A4 inducers (rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, St. John’s wort): May decrease erlotinib plasma concentrations (rifampin decreases AUC by 58-80%). Avoid concomitant use if possible. If unavoidable, increase erlotinib dose by 50 mg increments at 2-week intervals, not exceeding 450 mg.
• Drugs that increase gastric pH (proton pump inhibitors, H2-receptor antagonists, antacids): May decrease erlotinib solubility and absorption. For PPIs, avoid concomitant use if possible. For H2-receptor antagonists, take erlotinib 10 hours after H2 antagonist dosing and at least 2 hours before next H2 antagonist dose. For antacids, separate dosing by several hours (take erlotinib at least 4 hours before or 2 hours after antacids).
• Cigarette smoking (CYP1A2 inducer): Decreases erlotinib plasma concentrations by 50-64%. Avoid smoking. If smoking unavoidable, increase erlotinib dose as recommended for CYP3A4 inducers.
• Warfarin: Increased INR and bleeding risk. Monitor INR regularly.
• Statins (especially simvastatin): Erlotinib may increase statin levels via CYP3A4 inhibition; case reports of myopathy and rhabdomyolysis. Monitor for muscle symptoms.

• Pregnancy: FDA Category D. Can cause fetal harm based on animal data and mechanism of action. Women of reproductive potential should use effective contraception during treatment and for 1 month after last dose.
• Lactation: It is not known whether erlotinib is excreted in human milk. Advise women not to breastfeed during treatment and for 2 weeks after last dose due to potential risk of serious adverse reactions in nursing infants.
• Pediatric use: Safety and efficacy not established in pediatric patients. Not indicated for pediatric use.
• Geriatric use: No overall differences in safety or efficacy observed between elderly and younger patients, but greater sensitivity cannot be ruled out. Patients >65 years may be at increased risk of toxicity, particularly rash and diarrhea.
• Hepatic impairment: Patients with moderate to severe hepatic impairment (Child-Pugh B or C) should be monitored closely. Dose reduction or interruption may be required. Consider starting at lower dose (e.g., 75 mg for NSCLC) with careful monitoring. In pharmacokinetic study in 15 patients with moderate hepatic impairment (Child-Pugh B) with significant liver tumor burden, 10 died within 30 days of last dose.
• Renal impairment: No dedicated studies in severe renal impairment. Use with caution and monitor renal function, especially in patients at risk of dehydration.

• Non-Small Cell Lung Cancer (NSCLC): 150 mg orally once daily on an empty stomach (at least 1 hour before or 2 hours after food). Continue until disease progression or unacceptable toxicity.
• Pancreatic cancer: 100 mg orally once daily on an empty stomach, in combination with gemcitabine. Continue until disease progression or unacceptable toxicity.
• Dose modifications:
  • For adverse reactions (ILD, hepatotoxicity, renal toxicity, diarrhea, rash, ocular disorders): withhold erlotinib until resolved to baseline or grade ≤1, then restart at reduced dose (reduce by 50 mg decrements).
  • For severe bullous/exfoliative skin conditions, GI perforation, corneal perforation: permanently discontinue.
  • For concomitant strong CYP3A4 inhibitors: reduce dose by 50 mg decrements.
  • For concomitant strong CYP3A4 inducers: increase dose by 50 mg increments at 2-week intervals, not exceeding 450 mg.
  • For smokers: increase dose as recommended for CYP3A4 inducers (not exceeding 450 mg). Upon smoking cessation, reduce dose accordingly.
• Administration: Take on an empty stomach. Swallow tablets whole with water. Do not crush or chew. If a dose is missed, do not make up the missed dose; take the next dose as scheduled.

• Symptoms: Single oral doses up to 1000 mg in healthy adults were tolerated; repeated doses of 200 mg BID resulted in increased incidence of adverse reactions (diarrhea, rash). Overdose may result in severe adverse reactions including severe diarrhea, rash, hepatotoxicity, and ILD. [citation:1]
• Management: No specific antidote. Discontinue erlotinib, provide supportive care, monitor vital signs, and manage symptoms. In case of suspected overdose, contact a healthcare provider immediately.