Gefitinib

1 INDICATIONS AND USAGE Gefitinib tablets are 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 [ see Clinical Studies (14) ]. Limitation of Use: Safety and efficacy of gefitinib tablets 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 [ see Clinical Studies (14) ]. Gefitinib tablets are 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. (1) Limitation of Use: Safety and efficacy of gefitinib tablets have not been established in patients whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution mutations. (1)

2 DOSAGE AND ADMINISTRATION Recommended dose is 250 mg orally, once daily with or without food. (2.2) 2.1 Patient Selection Select patients for the first-line treatment of metastatic NSCLC with gefitinib tablets based on the presence of EGFR exon 19 deletions or exon 21 L858R mutations in their tumor or plasma specimens[ see Indications and Usage (1) , Clinical Studies (14) ]. 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 . 2.2 Recommended Dose The recommended dose of gefitinib tablets 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. 2.3 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. 2.4 Dose Modification Dose Modifications for Adverse Drug Reactions Withhold gefitinib tablets (for up to 14 days) for any of the following: Acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever) [ see Warnings and Precautions (5.1) ] NCI CTCAE Grade 2 or higher in ALT and/or AST elevations [ see Warnings and Precautions (5.2) ] NCI CTCAE Grade 3 or higher diarrhea [ see Warnings and Precautions (5.4) ] Signs and symptoms of severe or worsening ocular disorders including keratitis [ see Warnings and Precautions (5.5) ] NCI CTCAE Grade 3 or higher skin reactions [ see Warnings and Precautions (5.6) ] Resume treatment with gefitinib tablets when the adverse reaction fully resolves or improves to NCI CTCAE Grade 1. Permanently discontinue gefitinib tablets for: Confirmed interstitial lung disease (ILD) [ see Warnings and Precautions (5.1) ] Severe hepatic impairment [ see Warnings and Precautions (5.2) ] Gastrointestinal perforation [ see Warnings and Precautions (5.3) ] Persistent ulcerative keratitis [ see Warnings and Precautions (5.5) ] Dose Modifications for Drug Interactions Strong CYP3A4 Inducers Increase gefitinib tablets to 500 mg daily in the absence of severe adverse drug reaction, and resume gefitinib tablets at 250 mg seven days after discontinuation of the strong CYP3A4 inducer [ see Drug Interactions (7) , Clinical Pharmacology (12.3) ].

4 CONTRAINDICATIONS None. None. (4)

Not available.

6 ADVERSE REACTIONS The following adverse drug reactions are discussed in more detail in other sections of the labeling: • Interstitial Lung Disease [ see Warnings and Precautions (5.1) ] • Hepatotoxicity [ see Warnings and Precautions (5.2) ] • Gastrointestinal Perforation [ see Warnings and Precautions (5.3) ] • Severe or Persistent Diarrhea [ see Warnings and Precautions (5.4) ] • Ocular Disorders including Keratitis [ see Warnings and Precautions (5.5) ] • Bullous and Exfoliative Skin Disorders [ see Warning and Precautions (5.6) ] 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ingenus Pharmaceuticals, LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of gefitinib tablets is based on the data from 2462 patients with NSCLC who received gefitinib tablets 250 mg daily monotherapy in three randomized clinical studies (Study 2, Study 3 and Study 4). Patients with a history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis that required steroid treatment or any evidence of clinically active interstitial lung disease were excluded from these studies. Controlled Studies: Study 2 was a randomized, multicenter, open-label trial in which 1217 patients were randomized to receive first-line treatment for metastatic NSCLC; 607 patients received gefitinib tablets 250 mg daily and 589 patients received carboplatin/paclitaxel. The median duration of treatment with gefitinib tablets was 5.9 months. The study population characteristics were: median age 57 years, age less than 65 years (73%), female (79%), Asian (100%), NSCLC adenocarcinoma histology (100%), never smoker (94%), light ex-smoker (6%), ECOG PS 0 or 1 (90%). Study 3 was a randomized, multicenter, double-blind, placebo-controlled trial in which 1692 patients were randomized to receive second- or third-line treatment for metastatic NSCLC; of which 1126 patients received gefitinib tablets 250 mg daily and 562 patients received placebo. The median duration of treatment with gefitinib tablets was 2.9 months. The study population characteristics were: median age 62 years, age less than 65 years (60%), female (33%), Caucasian (75%), Asian (21%), NSCLC adenocarcinoma histology (48%), never smoker (22%), ECOG PS 0 or 1 (65%), PS 2 (29%), PS 3 (5%) and two or more prior therapies (51%). Study 4 was a randomized, multicenter, open-label trial in which 1466 patients were randomized to receive second-line treatment for metastatic NSCLC; 729 patients received gefitinib tablets 250 mg daily and 715 patients received docetaxel. The median duration of treatment with gefitinib tablets was 2.4 months. The study population characteristics were: median age 61 years, age less than 65 years (61%), female (36%), Caucasian (79%), Asian (21%), NSCLC adenocarcinoma histology (54%), never smoker (20%), ECOG PS 0 or 1 (88%) and two or more prior therapies (16%). The pooled safety database from the three randomized trials was used to evaluate for serious and uncommon adverse drug reactions. Common adverse reactions were evaluated in Study 3. The most frequent adverse reactions in Study 3 (incidence of >20% and greater than placebo) reported in gefitinib tablets-treated patients were skin reactions (47%) and diarrhea (29%). The most frequent fatal adverse reactions in gefitinib tablets-treated patients were respiratory failure (0.9%), pneumonia (0.8%), and pulmonary embolism (0.5%). Approximately 5% of gefitinib tablets-treated patients and 2.3% of placebo-treated patients discontinued treatment due to an adverse event. The most frequent adverse reactions that led to discontinuation in patients treated with gefitinib tablets were nausea (0.5%), vomiting (0.5%) and diarrhea (0.4%). Table 1 - Selected Adverse Drug Reactions Occurring with an Incidence Rate ≥ 5% and an Increase of >2% of Gefitinib Tablets-treated Patients in Study 3 Percentage (%) of patients Gefitinib Tablets (N=1126) Placebo (N=562) Adverse Reaction All Grades Grade 3 and 4 All Grades Grade 3 and 4 Skin and subcutaneous tissue disorders Skin reactions Includes Acne, Acne pustular, Dermatitis, Dermatitis acneiform, Dermatitis exfoliative, Drug eruption, Dry skin, Erythema, Exfoliative rash, Folliculitis, Pruritus, Pruritus generalized, Rash, Rash erythematous, Rash generalized, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, Rash pustular, Rash vesicular, Skin exfoliation, Skin toxicity, Xeroderma 47% 2% 17% 0.4% Nail disorders Includes Ingrowing nail, Nail bed infection, Nail disorder, Nail infection, Onychoclasis, Onycholysis, Paronychia 5% 0.1% 0.7% 0% Gastrointestinal disorders Diarrhea Includes Diarrhea, Feces soft, Frequent bowel movements 29% 3% 10% 1% Vomiting 14% 1.2% 10% 0.4% Stomatitis Includes Aphthous stomatitis, Cheilitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oral mucosal blistering, Stomatitis, Tongue disorder, Tongue ulceration 7% 0.3% 4% 0.2% Metabolism and nutrition disorders Decreased appetite 17% 2.3% 14% 2.0% Eye disorders Conjunctivitis/blepharitis/dry eye Includes Blepharitis, Conjunctival hyperemia, Conjunctivitis, Dry eye, Eye irritation, Eye pruritus, Eye swelling, Eyelid irritation, Eyelid edema, Eyelids pruritus 6% 0% 3.2% 0% Table 2 - Treatment Emergent Laboratory Abnormalities Occurring More Frequently in Gefitinib Tablets-Treated Patients in Study 3 Gefitinib Tablets Placebo Adverse Reaction All Grades % Grade 3 and 4 % All Grades % Grade 3 and 4 % Alanine aminotransferase increased Patients were allowed to enter the clinical study with lab values of ALT or AST CTCAE grade 1 or 2 38% 14% gefitinib patients and 10% placebo patients were CTC grade 1 or 2 ALT at baseline 2.4% 23% 1.4% 0.2% of placebo patients were CTC grade 3 at baseline Aspartate aminotransferase increased 40% 15% gefitinib patients and 12% placebo patients were CTC grade 1 or 2 AST at baseline 2.0% 25% 1.3% 0.4% of placebo patients were CTC grade 3 at baseline Proteinuria 35% 4.7% 31% 3.3% The following adverse reactions have been reported with gefitinib tablets across NSCLC trials (Study 2, Study 3 and Study 4) and are not listed elsewhere in Section 6: nausea (18%), asthenia (17%), pyrexia (9%), alopecia (4.7%), hemorrhage (including epistaxis and hematuria) (4.3%), dry mouth (2%), dehydration (1.8%), elevations in blood creatinine (1.5%), allergic reactions including angioedema and urticaria (1.1%), palmar-plantar erythrodysesthesia syndrome (0.2%) and pancreatitis (0.1%). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of gefitinib tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Renal and urinary disorders : cystitis, hemorrhagic cystitis Skin and subcutaneous tissue disorders : cutaneous vasculitis