Oral Locally advanced, unresectable or metastatic pancreatic cancer
Adult: In combination with gemcitabine: 100 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs. Re-assess treatment within 4-8 weeks. Dosing interruption or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).
Adult: In patients with EGFR-activating mutations: 150 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs. Dosing interruption or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).
Special Patient Group
Patients taking CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, barbiturates, St. John’s wort): Increase dose in increments of 50 mg at 2-week intervals up to a Max 450 mg as tolerated.
Patients taking inhibitors of CYP3A4 (e.g. ketoconazole, voriconazole, ritonavir, saquinavir erythromycin, clarithromycin, grapefruit juice) or CYP1A2 (e.g. ciprofloxacin): Reduce dose in decrements of 50 mg if necessary.
Active cigarette smokers or patient taking CYP1A2 inducers: Increase dose in increments of 50 mg at 2-week intervals to a Max of 300 mg.
Pharmacogenomics:
Erlotinib potently inhibits the intracellular phosphorylation of EGFR leading to blockage of downstream signalling and cell death. EGFR is expressed on the cell surface of normal cells and cancer cells. The presence of activating EGFR mutations is an important factor in the use of biomarker-based treatment strategies including tyrosine kinase inhibitor (TKI) therapy. EGFR mutation testing is required prior to therapy to determine the suitability of Erlotinib as first-line treatment or maintenance for locally advanced or metastatic NSCLC.
EGFR exon 19 deletion and exon 21 L858R mutation
According to studies, exon 19 deletion and exon 21 L858R mutation constituted most of EGFR mutations. Erlotinib has high binding affinity for EGFR exon 19 deletion and exon 21 L858R mutations. The prevalence of EGFR mutations in Asians and Caucasians are approx 30% and 8%, respectively. Patients with EGFR mutation-positive advanced NSCLC have longer progression-free survival (PFS) time with erlotinib as first-line therapy compared to standard chemotherapy. Improved overall survival (OS), longer PFS and higher response rate with TKI therapy were associated in exon 19 deletion than in exon 21 L858R mutation. However, erlotinib treatment lacks prolongation of OS in both mutations. A significant association between EGFR mutation types and age or smoking status may also be considered in selecting appropriate therapy.
Renal Impairment
Severe: Not recommended.
Hepatic Impairment
Severe: Not recommended.
Administration
Should be taken on an empty stomach.
Contraindications
Lactation.
Special Precautions
Patient with history of peptic ulceration or diverticular disease; risk factors for of developing interstitial lung disease (e.g. previous radiotherapy, pre-existing parenchymal lung disease, metastatic lung disease, pulmonary infections); history of keratitis, ulcerative keratitis or severe dry eye; low expression levels of UGT1A1 or genetic glucuronidation disorders (e.g. Gilbert’s disease). Patients taking CYP3A4 and CY1A2 inducers or inhibitors. Cigarette smokers. Renal and hepatic impairment. Pregnancy.
Determine EGFR mutation status prior to non-small cell lung carcinoma (NSCLC) treatment. Perform ophthalmologic exam at baseline and reassess for toxicities at 4-8 week of treatment. Monitor LFT, renal function, serum electrolytes, signs and symptoms of dehydration, pulmonary toxicity, and dermatologic toxicity.
Overdosage
Symptoms: Severe adverse reactions including diarrhoea, rash, increased activity of liver aminotransferases. Management: Symptomatic treatment.
Drug Interactions
Increased serum concentration with inhibitors of CYP1A2 (e.g. ciprofloxacin, fluvoxamine) or CYP3A4 (e.g. ketoconazole, voriconazole, ritonavir, saquinavir, erythromycin, clarithromycin), and capecitabine. Decreased serum concentrations with inducers of CYP3A4 (e.g. rifampicin, phenytoin, carbamazepine, barbiturates) or CYP1A2 (e.g. teriflunomide) and pH-altering agents including antacids, PPI (e.g. omeprazole), and H2-receptor antagonists (e.g. ranitidine). Increased risk of bleeding events and increased INR with coumarin-derived anticoagulants (e.g. warfarin). May increase the risk of adverse effects (e.g. rhabdomyolysis) of statins. Altered distribution and/or elimination of erlotinib with concomitant use of P-gp inhibitors (e.g. ciclosporin, verapamil). Increased platinum concentrations with concomitant use of carboplatin and paclitaxel. Increased risk of gastrointestinal perforation with anti-angiogenic agents, corticosteroids, NSAIDs or taxane-based chemotherapy.
Food Interaction
Increased bioavailability with food. Decreased serum concentrations with St. John’s wort. Increased serum concentration with grapefruit or grapefruit juice.
Action
Description: Mechanism of Action: Erlotinib is a human epidermal growth factor receptor type 1/epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor. It reversibly inhibits the intracellular phosphorylation of tyrosine kinase associated with EGFR, thereby preventing further downstream signalling and resulting in cell death. Pharmacokinetics: Absorption: Absorbed from the gastrointestinal tract. Bioavailability: Approx 100% (with food); approx 60% (without food). Time to peak plasma concentration: Approx 4 hours. Distribution: Crosses the placenta. Volume of distribution: 232 L. Plasma protein binding: Approx 93%. Metabolism: Metabolised in the liver mainly by CYP3A4 and to a lesser extent by CYP1A1, CYP1A2 and CYP1C. Metabolic pathways include demethylation, oxidation and aromatic hydroxylation. Excretion: Via faeces (83%; 1% as unchanged drug), urine (8%; 0.3% as unchanged drug). Elimination half-life: 36.2 hours.
Chemical Structure
Erlotinib Source: National Center for Biotechnology Information. PubChem Database. Erlotinib, CID=176870, https://pubchem.ncbi.nlm.nih.gov/compound/Erlotinib (accessed on Jan. 22, 2020)
L01EB02 - erlotinib ; Belongs to the class of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Used in the treatment of cancer.
References
Caicun Zhou, Yi-long Wu, Gongyan Chen, et al. Erlotinib Versus Chemotherapy as First-line Treatment for Patients with Advanced EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Multicentre, Open-label, Randomised, Phase 3 Study. The Lancet Oncology. 2011 Aug;12:735-742. doi: 10.1016/S1470-2045(11)70184-X. Accessed 08/10/2019. PMID: 21783417Sheng M, Wang F, Zhao Y et al. Comparison of Clinical Outcomes of Patients with Non-Small Cell Lung Cancer Harbouring Epidermal Growth Factor Receptor Exon 19 or Exon 21 Mutations After Tyrosine Kinase Inhibitors Treatment: A Meta-Analysis. Eur J Clin Pharmacol. 2015 Oct. doi: 10.1007/s00228-015-1966-0. Accessed 08/10/2019Anon. Erlotinib. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 08/10/2019.Anon. Erlotinib. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 17/03/2014.Buckingham R (ed). Erlotinib Hydrochloride. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 08/10/2019.Clinical Annotation for Erlotinib (EGFR). Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 08/10/2019.Erlotinib Tablet (Teva Pharmaceuticals USA, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 08/10/2019.McEvoy GK, Snow EK, Miller J et al (eds). Erlotinib. AHFS Drug Information (AHFS DI) [online]. American Society of Health-System Pharmacists (ASHP). https://www.medicinescomplete.com. Accessed 17/03/2014.Tarceva (Genentech Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 17/03/2014.Tarceva Tablets. U.S. FDA. https://www.fda.gov/. Accessed 17/03/2014.
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