Gefitinib

IRESSA is 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 IRESSA have not been established in patients with metastatic NSCLC whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution mutations. IRESSA 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.

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 deletion or exon 21 point mutation L858R) within 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 signaling 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.

Recommended dose is 250 mg orally, once daily with or without food. Patient Selection Select patients for the first-line treatment of metastatic NSCLC with IRESSA based on the presence of EGFR exon 19 deletions or exon 21 L858R mutations in their tumor or plasma specimens. If these mutations are not detected in a plasma specimen, test tumor tissue if feasible. Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.

None. None.

• Interstitial lung disease (ILD): ILD occurred in patients taking IRESSA. Withhold IRESSA for worsening of respiratory symptoms. Discontinue IRESSA if ILD is confirmed. • Hepatotoxicity: Obtain periodic liver function testing. Withhold IRESSA for Grade 2 or higher for ALT and/or AST elevations. Discontinue for severe hepatic impairment. • Gastrointestinal perforation: Discontinue IRESSA for gastrointestinal perforation. • Diarrhea: Withhold IRESSA for Grade 3 or higher diarrhea. • Ocular Disorders including Keratitis: Withhold IRESSA for signs and symptoms of severe or worsening ocular disorders including keratitis. Discontinue for persistent ulcerative keratitis. • Bullous and Exfoliative Skin Disorders: Withhold IRESSA for Grade 3 or higher skin reactions or exfoliative conditions. • Embryo-fetal Toxicity: Can cause fetal harm.

The following adverse drug reactions are discussed in more detail in other sections of the labeling: • Interstitial Lung Disease • Hepatotoxicity • Gastrointestinal Perforation • Severe or Persistent Diarrhea • Ocular Disorders including Keratitis • Bullous and Exfoliative Skin Disorders The most commonly reported adverse drug reactions (ADRs), reported in more than 20% of the patients and greater than placebo were skin reactions and diarrhea.

• CYP3A4 Inducer: Increase IRESSA to 500 mg daily in patients receiving a strong CYP3A4 inducer. • CYP3A4 Inhibitor: Monitor adverse reactions if concomitant use with IRESSA. • Drugs Affecting Gastric pH: Avoid concomitant use of IRESSA with proton pump inhibitors, if possible. • Hemorrhage in patients taking warfarin: Monitor changes in prothrombin time or INR.

Store at controlled room temperature 20°C-25°C (68°F-77°F).