IRESSA

5 WARNINGS AND PRECAUTIONS • Interstitial lung disease (ILD): ILD occurred in patients taking IRESSA. Withhold IRESSA for worsening of respiratory symptoms. Discontinue IRESSA if ILD is confirmed. ( 2.4 , 5.1 ) • Hepatotoxicity: Obtain periodic liver function testing. Withhold IRESSA for Grade 2 or higher for ALT and/or AST elevations. Discontinue for severe hepatic impairment. ( 2.4 , 5.2 ) • Gastrointestinal perforation: Discontinue IRESSA for gastrointestinal perforation. ( 2.4 , 5.3 ) • Diarrhea: Withhold IRESSA for Grade 3 or higher diarrhea. ( 2.4 , 5.4 ) • Ocular Disorders including Keratitis: Withhold IRESSA for signs and symptoms of severe or worsening ocular disorders including keratitis. Discontinue for persistent ulcerative keratitis. ( 2.4 , 5.5 ) • Bullous and Exfoliative Skin Disorders: Withhold IRESSA for Grade 3 or higher skin reactions or exfoliative conditions. ( 2.4 , 5.6 ) • 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 [see Dosage and Administration (2.4) , Adverse Reactions (6.1) ] . 5.2 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 [see Dosage and Administration (2.4) , Adverse Reactions (6.1) , Use in Specific Populations (8.7) ] . 5.3 Gastrointestinal Perforation Gastrointestinal perforation occurred in three (0.1%) of the 2462 IRESSA-treated patients across clinical trials [see Adverse Reactions (6.1) ] . Permanently discontinue IRESSA in patients who develop gastrointestinal perforation [see Dosage and Administration (2.4) ] . 5.4 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 [see Dosage and Administration (2.4) , Adverse Reactions (6.1) ] . 5.5 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% [see Adverse Reactions (6.1) ] . Interrupt or discontinue IRESSA for severe, or worsening ocular disorders [see Dosage and Administration (2.4) ] . 5.6 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. 5.7 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 [see Use in Specific Populations ( 8.1 , 8.3 )] .

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 AstraZeneca at 1-800-236-9933 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 IRESSA is based on the data from 2462 patients with NSCLC who received IRESSA 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 IRESSA 250 mg daily and 589 patients received carboplatin/paclitaxel. The median duration of treatment with IRESSA 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 IRESSA 250 mg daily and 562 patients received placebo. The median duration of treatment with IRESSA 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 IRESSA 250 mg daily and 715 patients received docetaxel. The median duration of treatment with IRESSA 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 IRESSA-treated patients were skin reactions (47%) and diarrhea (29%). The most frequent fatal adverse reactions in IRESSA-treated patients were respiratory failure (0.9%), pneumonia (0.8%), and pulmonary embolism (0.5%). Approximately 5% of IRESSA-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 IRESSA 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 IRESSA-treated Patients in Study 3 Adverse Reaction Percentage (%) of patients IRESSA (N=1126) Placebo (N=562) 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 IRESSA-Treated Patients in Study 3 Adverse Reaction IRESSA Placebo 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 IRESSA 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 IRESSA. 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

<table ID="_RefID0EZHAE" width="100%"><caption>Table 1 - Selected Adverse Drug Reactions Occurring with an Incidence Rate &#x2265;5% and an Increase of &gt;2% of IRESSA-treated Patients in Study 3</caption><col width="33%"/><col width="15%"/><col width="19%"/><col width="15%"/><col width="19%"/><tbody><tr><td rowspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" colspan="4" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Percentage (%) of patients</content></paragraph></td></tr><tr><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">IRESSA (N=1126)</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Placebo (N=562)</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">All Grades</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Grade 3 and 4</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">All Grades</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Grade 3 and 4</content></paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Skin and subcutaneous tissue disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Skin reactions<footnote ID="_Ref523749595">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</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>47%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>17%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0.4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nail disorders<footnote ID="_Ref413761388">Includes Ingrowing nail, Nail bed infection, Nail disorder, Nail infection, Onychoclasis, Onycholysis, Paronychia</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0.1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0.7%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0%</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Diarrhea<footnote ID="_Ref413761407">Includes Diarrhea, Feces soft, Frequent bowel movements</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>29%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Vomiting</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>14%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1.2%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0.4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Stomatitis<footnote ID="_Ref413761481">Includes Aphthous stomatitis, Cheilitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oral mucosal blistering, Stomatitis, Tongue disorder, Tongue ulceration</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>7%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0.3%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>4%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0.2%</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolism and nutrition disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Decreased appetite</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>17%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>2.3%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>14%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>2.0%</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Eye disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Conjunctivitis/blepharitis/dry eye<footnote ID="_Ref413761540">Includes Blepharitis, Conjunctival hyperemia, Conjunctivitis, Dry eye, Eye irritation, Eye pruritus, Eye swelling, Eyelid irritation, Eyelid edema, Eyelids pruritus</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>6%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>0%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>3.2%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>0%</paragraph></td></tr></tbody></table>

<table width="100%"><caption>Table 2 - Treatment Emergent Laboratory Abnormalities Occurring More Frequently in IRESSA-Treated Patients in Study 3</caption><col width="39%"/><col width="14%"/><col width="17%"/><col width="14%"/><col width="17%"/><tbody><tr><td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">IRESSA</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Placebo</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">All Grades</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Grade 3 and 4</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">All Grades</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Grade 3 and 4</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Alanine aminotransferase increased<footnote ID="_Ref523749700">Patients were allowed to enter the clinical study with lab values of ALT or AST CTCAE grade 1 or 2</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>38%<footnote ID="_Ref523749808">14% gefitinib patients and 10% placebo patients were CTC grade 1 or 2 ALT at baseline</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2.4%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>23%<footnoteRef IDREF="_Ref523749808"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.4%<footnote ID="_Ref523749830">0.2% of placebo patients were CTC grade 3 at baseline</footnote></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Aspartate aminotransferase increased<footnoteRef IDREF="_Ref523749700"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>40%<footnote ID="_Ref523749839">15% gefitinib patients and 12% placebo patients were CTC grade 1 or 2 AST at baseline</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2.0%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>25%<footnoteRef IDREF="_Ref523749839"/></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.3%<footnote ID="_Ref523749860">0.4% of placebo patients were CTC grade 3 at baseline</footnote></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Proteinuria</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>35%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>4.7%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>31%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>3.3%</paragraph></td></tr></tbody></table>