Gefitinib is a kinase inhibitor. The chemical name of gefitinib is 4-Quinazolinamine N -(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl) propoxy] and the following structural formula: Gefitinib has the molecular formula C 22 H 24 ClFN 4 O 3 , a relative molecular mass of 446.9 daltons and is a white-colored powder. Gefitinib is a free base. The molecule has pK a s of 5.4 and 7.2. Gefitinib can be defined as sparingly soluble at pH 1, but is practically insoluble above pH 7, with the solubility decreasing sharply between pH 4 and pH 6. In non-aqueous solvents, gefitinib is freely soluble in glacial acetic acid and dimethyl sulfoxide, soluble in pyridine, sparingly soluble in tetrahydrofuran, and slightly soluble in methanol, ethanol (99.5%), ethyl acetate, propan-2-ol and acetonitrile. IRESSA ® (gefitinib) tablets are available as brown film-coated tablets, containing 250 mg of gefitinib, for oral administration. The inactive ingredients of the tablet core of IRESSA tablets are lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulfate and magnesium stearate. The tablet coating is composed of hypromellose, polyethylene glycol 300, titanium dioxide, red ferric oxide and yellow ferric oxide. structural formula for 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. Limitation of Use: Safety and efficacy of IRESSA have not been established in patients whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution mutations.

250 mg tablets: round, biconvex, brown film-coated, debossed with "IRESSA 250" on one side and plain on the other side. Tablets: 250 mg.

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

Recommended Dose The recommended dose of IRESSA 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

Administration to Patients Who Have Difficulty Swallowing Solids Immerse IRESSA 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

Dose Modification Dose Modifications for Adverse Drug Reactions Withhold IRESSA (for up to 14 days) for any of the following: • Acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever) • NCI CTCAE Grade 2 or higher in ALT and/or AST elevations • NCI CTCAE Grade 3 or higher diarrhea • Signs and symptoms of severe or worsening ocular disorders including keratitis • NCI CTCAE Grade 3 or higher skin reactions Resume treatment with IRESSA when the adverse reaction fully resolves or improves to NCI CTCAE Grade 1. Permanently discontinue IRESSA for: • Confirmed interstitial lung disease (ILD) • Severe hepatic impairment • Gastrointestinal perforation • Persistent ulcerative keratitis Dose Modifications for Drug Interactions Strong CYP3A4 Inducers Increase IRESSA to 500 mg daily in the absence of severe adverse drug reaction, and resume IRESSA at 250 mg seven days after discontinuation of the strong CYP3A4 inducer .

• 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. Advise of potential risk to a fetus and use of effective contraception. ( 5.7 , 8.1 , 8.3 ) 5.1 Interstitial Lung Disease (ILD) ILD or ILD-like adverse drug reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or pulmonary fibrosis) occurred in 1.3% of the 2462 patients who received IRESSA across clinical trials; of these, 0.7% were Grade 3 or higher and 3 cases were fatal. Withhold IRESSA and promptly investigate for ILD in any patient who presents with worsening of respiratory symptoms such as dyspnea, cough and fever. Permanently discontinue IRESSA if ILD is confirmed

Hepatotoxicity In patients who received IRESSA across clinical trials, 11.4% of patients had increased alanine aminotransferase (ALT), 7.9% of patients had increased aspartate aminotransferase (AST), and 2.7% of patients had increased bilirubin. Grade 3 or higher liver test abnormalities occurred in 5.1% (ALT), 3.0% (AST), and 0.7% (bilirubin) of patients. The incidence of fatal hepatotoxicity was 0.04%. Obtain periodic liver function testing. Withhold IRESSA in patients with worsening liver function and discontinue in patients with severe hepatic impairment

Gastrointestinal Perforation Gastrointestinal perforation occurred in three (0.1%) of the 2462 IRESSA-treated patients across clinical trials . Permanently discontinue IRESSA in patients who develop gastrointestinal perforation

Severe or Persistent Diarrhea Grade 3 or 4 diarrhea occurred in 3% of 2462 IRESSA-treated patients across clinical trials. Withhold IRESSA for severe or persistent (up to 14 days) diarrhea

Ocular Disorders including Keratitis Ocular disorders [keratitis (0.1%), corneal erosion and aberrant eyelash growth (0.2%), conjunctivitis, blepharitis and dry eye (6.7%)] occurred in the 2462 IRESSA-treated patients across clinical trials. The incidence of Grade 3 ocular disorders was 0.1% . Interrupt or discontinue IRESSA for severe, or worsening ocular disorders

Bullous and Exfoliative Skin Disorders Bullous conditions including toxic epidermal necrolysis, Stevens Johnson syndrome and erythema multiforme have been reported from treatment with IRESSA. Erythema multiforme and dermatitis bullous have been reported in two patients (0.08%) across NSCLC trials (Study 2, Study 3 and Study 4). IRESSA treatment should be interrupted or discontinued if the patient develops severe bullous, blistering or exfoliating conditions

Embryo-fetal Toxicity Based on its mechanism of action and data from animal reproduction studies IRESSA can cause fetal harm when administered to a pregnant woman. In animal reproductive studies, oral administration of gefitinib from organogenesis through weaning resulted in fetotoxicity and neonatal death at doses below the recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IRESSA and for at least two weeks following completion of therapy .

• 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

Drugs Affecting Gefitinib Exposure CYP3A4 Inducer Drugs that are strong inducers of CYP3A4 increase the metabolism of gefitinib and decrease gefitinib plasma concentrations. Increase IRESSA to 500 mg daily in patients receiving a strong CYP3A4 inducer (e.g., rifampicin, phenytoin, or tricyclic antidepressant) and resume IRESSA at 250 mg 7 days after discontinuation of the strong inducer . CYP3A4 Inhibitor Drugs that are strong inhibitors of CYP3A4 (e.g., ketoconazole and itraconazole) decrease gefitinib metabolism and increase gefitinib plasma concentrations. Monitor adverse reactions when administering strong CYP3A4 inhibitors with IRESSA. Drugs Affecting Gastric pH Drugs that elevate gastric pH (e.g., proton pump inhibitors, histamine H 2 -receptor antagonists, and antacids) may reduce plasma concentrations of gefitinib. Avoid concomitant use of IRESSA with proton pump inhibitors, if possible. If treatment with a proton-pump inhibitor is required, take IRESSA 12 hours after the last dose or 12 hours before the next dose of the proton-pump inhibitor. Take IRESSA 6 hours after or 6 hours before an H 2 -receptor antagonist or an antacid

Hemorrhage in Patients taking Warfarin International Normalized Ratio (INR) elevations and/or hemorrhage 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.