Brands, Medical Use, Clinical Data
- Antineoplastic Agents
- Protein Kinase Inhibitors
Brands / Synonyms
Gefitinib [USAN]; Iressa; Irressat
For the continued treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of either platinum-based or docetaxel chemotherapies.
Gefitinib inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the epidermal growth factor receptor (EGFR-TK). EGFR is expressed on the cell surface of many normal cells and cancer cells.
Mechanism of Action
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.
Absorbed slowly after oral administration with mean bioavailability of 60%.
Biotrnasformation / Drug Metabolism
Primarily hepatic via CYP3A4. Three sites of biotransformation have been identified: metabolism of the N-propoxymorpholino-group, demethylation of the methoxy-substituent on the quinazoline, and oxidative defluorination of the halogenated phenyl group.
IRESSA is contraindicated in patients with severe hypersensitivity to gefitinib or to any other component of
Substances that are inducers of CYP3A4 activity increase the metabolism of gefitinib and decrease its plasma
concentrations. In patients receiving a potent CYP3A4 inducer such as rifampicin or phenytoin, a dose increase to 500
mg daily should be considered in the absence of severe adverse drug reaction, and clinical response and adverse
events should be carefully monitored (see CLINICAL PHARMACOLOGY-Pharmacokinetics-Drug-Drug Interactions and
DOSAGE AND ADMINISTRATION-Dosage Adjustment sections).
International Normalized Ratio (INR) elevations and/or bleeding events have been reported in some patients taking
warfarin while on IRESSA therapy. Patients taking warfarin should be monitored regularly for changes in prothrombin
time or INR.
Substances that are potent inhibitors of CYP3A4 activity (eg, ketoconazole and itraconazole) decrease gefitinib
metabolism and increase gefitinib plasma concentrations. This increase may be clinically relevant as adverse
experiences are related to dose and exposure; therefore, caution should be used when administering CYP3A4 inhibitors
Drugs that cause significant sustained elevation in gastric pH (histamine H2-receptor antagonists such
as ranitidine or cimetidine) may reduce plasma concentrations of IRESSA and therefore potentially may reduce
Phase II clinical trial data, where IRESSA and vinorelbine have been used concomitantly, indicate that IRESSA may
exacerbate the neutropenic effect of vinorelbine.