Gefitinib is a tyrosine kinase inhibitor indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.
Limitation of Use: Safety and efficacy of Gefitinib have not been established in patients whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution mutations.
Gefitinib is a kinase inhibitor. The epidermal growth factor receptor (EGFR) is expressed on the cell surface of both normal and cancer cells and plays a role in the processes of cell growth and proliferation. Some EGFR activating mutations (exon 19 deletions or exon 21 point mutation L858R) within non-small cell lung cancer (NSCLC) cells have been identified as contributing to the promotion of tumor cell growth, blocking of apoptosis, increasing the production of angiogenic factors and facilitating the processes of metastasis.
Gefitinib reversibly inhibits the kinase activity of wild-type and certain activating mutations of EGFR, preventing autophosphorylation of tyrosine residues associated with the receptor, thereby inhibiting further downstream signalling and blocking EGFR-dependent proliferation.
Gefitinib binding affinity for EGFR exon 19 deletion or exon 21 point mutation L858R mutations is higher than its affinity for the wild-type EGFR. Gefitinib also inhibits IGF and PDGF-mediated signalling at clinically relevant concentrations; inhibition of other tyrosine kinase receptors has not been fully characterized.
Gefitinib inhibits the epidermal growth factor receptor (EGFR) tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme. Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited; and malignant cells are inhibited. Gefitinib is the first selective inhibitor of the EGFR tyrosine kinase which is also referred to as Her1 or ErbB-1. EGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers. Overexpression leads to inappropriate activation of the apoptotic Ras signal transduction cascade, eventually leading to uncontrolled cell proliferation.
Dosage & Administration
The recommended dose of Gefitinib is 250 mg orally once daily with or without food until disease progression or unacceptable toxicity. Do not take a missed dose within 12 hours of the next dose.
Concomitant use with CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, barbiturates) may reduce serum gefitinib levels. Plasma concentrations may be increased with potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole). Increased INR or bleeding events with warfarin. May increase plasma levels of metoprolol. May exacerbate vinorelbine-induced neutropenia. Decreased plasma levels and potential reduction in efficacy with drugs that affect gastric pH (e.g. PPIs, H2-receptor antagonists).
Common side effects are pruritus, rash, angioedema, urticaria, epistaxis, haematuria, alopecia, dry mouth and skin, nausea, vomiting, anorexia, stomatitis, diarrhoea, nail disorders, asthenia, pyrexia, proteinuria, eye pain, corneal erosion or ulcer, aberrant eyelash growth and elevations in blood creatinine. Rarely, pancreatitis, erythema multiforme, toxic epidermal necrolysis, corneal membrane sloughing, ocular ischemia, or ocular haemorrhage.
Pregnancy & Lactation
Pregnancy 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).
Precautions & Warnings
Interstitial lung disease (ILD): ILD occurred in patients taking Gefitinib. Gefitinib should be withheld for worsening of respiratory symptoms. It should be discontinued if ILD is confirmed.
Hepatotoxicity: Periodic liver function testing should be performed. Gefitinib should be withheld for Grade 2 or higher for ALT and/or AST elevations. It should be discontinued for severe hepatic impairment.
Gastrointestinal perforation: Gefitinib should be discontinued for gastrointestinal perforation.
Diarrhea: Gefitinib should be withheld for Grade 3 or higher diarrhea.
Ocular Disorders including Keratitis: Gefitinib should be withheld for signs and symptoms of severe or worsening ocular disorders including keratitis. It should be discontinued for persistent ulcerative keratitis.
Bullous and Exfoliative Skin Disorders: Gefitinib should be withheld for Grade 3 or higher skin reactions or exfoliative conditions.
Embryo-fetal Toxicity: Gefitinib can cause fetal harm. Potential risk of Gefitinib to a fetus should be advised and effective contraception should be used.
Use in Special Populations
Pediatric Use: The safety and effectiveness of Gefitinib in pediatric patients have not been established.
Geriatric Use: No overall differences in safety were observed between patients 65 years and older and those younger than 65 years. There is insufficient information to assess for differences in efficacy between older and younger patients.
Administration to patients who have difficulty swallowing solids: Immerse Gefitinib tablets in 4 to 8 ounces of water by dropping the tablet in water, and stir for approximately 15 minutes. Immediately drink the liquid or administer through a naso-gastric tube. Rinse the container with 4 to 8 ounces of water and immediately drink or administer through the naso-gastric tube.
Targeted Cancer Therapy
Store between 20-25° C.
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