Gefitinib

5 WARNINGS AND PRECAUTIONS Interstitial lung disease (ILD): ILD occurred in patients taking gefitinib tablets. Withhold gefitinib tablets for worsening of respiratory symptoms. Discontinue gefitinib tablets if ILD is confirmed. ( 2.4 , 5.1 ) Hepatotoxicity: Obtain periodic liver function testing. Withhold gefitinib tablets for Grade 2 or higher for ALT and/or AST elevations. Discontinue for severe hepatic impairment. ( 2.4 , 5.2 ) Gastrointestinal perforation: Discontinue gefitinib tablets for gastrointestinal perforation. ( 2.4 , 5.3 ) Diarrhea: Withhold gefitinib tablets for Grade 3 or higher diarrhea. ( 2.4 , 5.4 ) Ocular Disorders including Keratitis: Withhold gefitinib tablets 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 gefitinib tablets 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 gefitinib tablets across clinical trials; of these, 0.7% were Grade 3 or higher and 3 cases were fatal. Withhold gefitinib tablets and promptly investigate for ILD in any patient who presents with worsening of respiratory symptoms such as dyspnea, cough and fever. Permanently discontinue gefitinib tablets if ILD is confirmed [see Dosage and Administration (2.4) , Adverse Reactions (6.1) ] . 5.2 Hepatotoxicity In patients who received gefitinib tablets 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 gefitinib tablets 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 gefitinib tablets-treated patients across clinical trials [see Adverse Reactions (6.1) ] . Permanently discontinue gefitinib tablets 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 gefitinib tablets-treated patients across clinical trials. Withhold gefitinib tablets 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, blephritis and dry eye (6.7%)] occurred in the 2462 gefitinib tablets-treated patients across clinical trials. The incidence of Grade 3 ocular disorders was 0.1% [see Adverse Reactions (6.1) ] . Interrupt or discontinue gefitinib tablets 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 gefitinib tablets. Erythema multiforme and dermatitis bullous have been reported in two patients (0.08%) across NSCLC trials (Study 2, Study 3 and Study 4). Gefitinib tablets 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 gefitinib tablets 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 gefitinib tablets 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 Teva at 1-888-838-2872 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 are 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 greater than 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 Adverse Reaction Percentage (%) of patients Gefitinib Tablets (N=1126) Placebo (N=562) All Grades Grade 3 and 4 All Grades Grade 3 and 4 Skin and subcutaneous tissue disorders Skin reactions 1 47% 2% 17% 0.4% Nail disorders 2 5% 0.1% 0.7% 0% Gastrointestinal disorders Diarrhea 3 29% 3% 10% 1% Vomiting 14% 1.2% 10% 0.4% Stomatitis 4 7% 0.3% 4% 0.2% Metabolism and nutrition disorders Decreased appetite 17% 2.3% 14% 2.0% Eye disorders Conjunctivitis/blepharitis/ dry eye 5 6% 0% 3.2% 0% 1 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 2 Includes Ingrowing nail, Nail bed infection, Nail disorder, Nail infection, Onychoclasis, Onycholysis, Paronychia 3 Includes Diarrhea, Feces soft, Frequent bowel movements 4 Includes Aphthous stomatitis, Cheilitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oral mucosal blistering, Stomatitis, Tongue disorder, Tongue ulceration 5 Includes Blepharitis, Conjunctival hyperemia, Conjunctivitis, Dry eye, Eye irritation, Eye pruritus, Eye swelling, Eyelid irritation, Eyelid edema, Eyelids pruritus Table 2 – Treatment Emergent Laboratory Abnormalities Occurring More Frequently in Gefitinib Tablets-Treated Patients in Study 3 Gefitinib T ablets Placebo Adverse Reaction All Grades % Grade 3 and 4 % All Grades % Grade 3 and 4 % Alanine aminotransferase increased 1 38% 2 2.4% 23% 2 1.4% 4 Aspartate aminotransferase increased 1 40% 3 2.0% 25% 3 1.3% 5 Proteinuria 35% 4.7% 31% 3.3% 1 Patients were allowed to enter the clinical study with lab values of ALT or AST CTCAE grade 1 or 2 2 14% gefitinib patients and 10% placebo patients were CTC grade 1 or 2 ALT at baseline 3 15% gefitinib patients and 12% placebo patients were CTC grade 1 or 2 AST at baseline 4 0.2% of placebo patients were CTC grade 3 at baseline 5 0.4% of placebo patients were CTC grade 3 at baseline 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

<table width="800px"><caption>Table 1 &#x2013; Selected Adverse Drug Reactions Occurring with an Incidence Rate &#x2265;5% and an Increase of &gt;2% of Gefitinib Tablets-Treated Patients in Study 3</caption><col/><col/><col/><col/><col/><tbody><tr><td valign="bottom" rowspan="3" styleCode=" Toprule Lrule Rrule"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" colspan="4" styleCode=" Toprule Lrule Rrule"> <content styleCode="bold">Percentage (%) of patients</content></td></tr><tr><td align="center" colspan="2" styleCode=" Toprule Lrule Rrule"> <content styleCode="bold">Gefitinib Tablets (N=1126)</content></td><td colspan="2" styleCode=" Toprule Lrule Rrule"> <content styleCode="bold">Placebo (N=562)</content></td></tr><tr><td align="center" styleCode=" Toprule Lrule Rrule"> <content styleCode="bold">All Grades</content></td><td align="center" styleCode=" Toprule Lrule Rrule"> <content styleCode="bold">Grade 3 and 4</content></td><td align="center" styleCode=" Toprule Lrule Rrule"> <content styleCode="bold">All Grades</content></td><td align="center" styleCode=" Toprule Lrule Rrule"> <content styleCode="bold">Grade 3 and 4</content></td></tr><tr><td colspan="5" styleCode=" Toprule Lrule Rrule"> <content styleCode="bold">Skin and subcutaneous tissue disorders</content></td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Skin reactions<content styleCode="italics">¹</content></td><td align="center" styleCode=" Toprule Lrule Rrule"> 47%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 2%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 17%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 0.4%</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Nail disorders<content styleCode="italics">²</content></td><td align="center" styleCode=" Toprule Lrule Rrule"> 5%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 0.1%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 0.7%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 0%</td></tr><tr><td colspan="5" styleCode=" Toprule Lrule Rrule"> <content styleCode="bold">Gastrointestinal disorders</content></td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Diarrhea<content styleCode="italics">³</content></td><td align="center" styleCode=" Toprule Lrule Rrule"> 29%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 3%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 10%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 1%</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Vomiting</td><td align="center" styleCode=" Toprule Lrule Rrule"> 14%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 1.2%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 10%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 0.4%</td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Stomatitis<content styleCode="italics">⁴</content></td><td align="center" styleCode=" Toprule Lrule Rrule"> 7%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 0.3%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 4%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 0.2%</td></tr><tr><td colspan="5" styleCode=" Toprule Lrule Rrule"> <content styleCode="bold">Metabolism and nutrition disorders</content></td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Decreased appetite</td><td align="center" styleCode=" Toprule Lrule Rrule"> 17%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 2.3%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 14%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 2.0%</td></tr><tr><td colspan="5" styleCode=" Toprule Lrule Rrule"> <content styleCode="bold">Eye disorders</content></td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Conjunctivitis/blepharitis/ dry eye<content styleCode="italics">⁵</content></td><td align="center" styleCode=" Toprule Lrule Rrule"> 6%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 0%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 3.2%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 0%</td></tr><tr><td colspan="5" styleCode=" Toprule"> ¹Includes 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 ²Includes Ingrowing nail, Nail bed infection, Nail disorder, Nail infection, Onychoclasis, Onycholysis, Paronychia ³Includes Diarrhea, Feces soft, Frequent bowel movements ⁴Includes Aphthous stomatitis, Cheilitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oral mucosal blistering, Stomatitis, Tongue disorder, Tongue ulceration ⁵Includes Blepharitis, Conjunctival hyperemia, Conjunctivitis, Dry eye, Eye irritation, Eye pruritus, Eye swelling, Eyelid irritation, Eyelid edema, Eyelids pruritus </td></tr></tbody></table>

<table width="800px"><caption>Table 2 &#x2013; Treatment Emergent Laboratory Abnormalities Occurring More Frequently in Gefitinib Tablets-Treated Patients in Study 3</caption><col/><col/><col/><col/><col/><tbody><tr><td styleCode=" Toprule Lrule Rrule"> </td><td align="center" colspan="2" styleCode=" Toprule Lrule Rrule"> <content styleCode="bold">Gefitinib</content> <content styleCode="bold">T</content><content styleCode="bold">ablets</content></td><td align="center" colspan="2" styleCode=" Toprule Lrule Rrule"> <content styleCode="bold">Placebo</content></td></tr><tr><td styleCode=" Lrule Rrule"> <content styleCode="bold">Adverse Reaction</content></td><td align="center" styleCode=" Toprule Lrule Rrule"> <content styleCode="bold">All Grades </content> <content styleCode="bold">%</content></td><td align="center" styleCode=" Toprule Lrule Rrule"> <content styleCode="bold">Grade 3 and 4 </content> <content styleCode="bold">%</content></td><td align="center" styleCode=" Toprule Lrule Rrule"> <content styleCode="bold">All Grades </content> <content styleCode="bold">%</content></td><td align="center" valign="bottom" styleCode=" Toprule Lrule Rrule"> <content styleCode="bold">Grade 3 and 4</content> <content styleCode="bold">%</content></td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Alanine aminotransferase increased<content styleCode="italics">¹</content></td><td align="center" styleCode=" Toprule Lrule Rrule"> 38%<content styleCode="italics">²</content></td><td align="center" styleCode=" Toprule Lrule Rrule"> 2.4%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 23%<content styleCode="italics">²</content></td><td align="center" styleCode=" Toprule Lrule Rrule"> 1.4%<content styleCode="italics">⁴</content></td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Aspartate aminotransferase increased<content styleCode="italics">¹</content></td><td align="center" styleCode=" Toprule Lrule Rrule"> 40%<content styleCode="italics">³</content></td><td align="center" styleCode=" Toprule Lrule Rrule"> 2.0%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 25%<content styleCode="italics">³</content></td><td align="center" styleCode=" Toprule Lrule Rrule"> 1.3%<content styleCode="italics">⁵</content></td></tr><tr><td styleCode=" Toprule Lrule Rrule"> Proteinuria</td><td align="center" styleCode=" Toprule Lrule Rrule"> 35%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 4.7%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 31%</td><td align="center" styleCode=" Toprule Lrule Rrule"> 3.3%</td></tr><tr><td colspan="5" styleCode=" Toprule">¹ Patients were allowed to enter the clinical study with lab values of ALT or AST CTCAE grade 1 or 2 ²14% gefitinib patients and 10% placebo patients were CTC grade 1 or 2 ALT at baseline ³ 15% gefitinib patients and 12% placebo patients were CTC grade 1 or 2 AST at baseline ⁴ 0.2% of placebo patients were CTC grade 3 at baseline ⁵ 0.4% of placebo patients were CTC grade 3 at baseline</td></tr></tbody></table>