FDA label b4dc994e-d507-2fc0-e053-2a95a90ae131

5 WARNINGS AND PRECAUTIONS Interstitial lung disease (ILD): Occurs in 1.1% of patients. Withhold erlotinib for acute onset of new or progressive unexplained pulmonary symptoms, such as dyspnea, cough and fever. Discontinue erlotinib if ILD is diagnosed. ( 5.1 ) Renal failure: Monitor renal function and electrolytes, particularly in patients at risk of dehydration. Withhold erlotinib for severe renal toxicity. ( 5.2 ) Hepatotoxicity: Occurs with or without hepatic impairment, including hepatic failure and hepatorenal syndrome: Monitor periodic liver testing. Withhold or discontinue erlotinib for severe or worsening liver tests. ( 5.3 ) Gastrointestinal perforations: Discontinue erlotinib. ( 5.4 ) Bullous and exfoliative skin disorders: Discontinue erlotinib. ( 5.5 ) Cerebrovascular accident (CVA): The risk of CVA is increased in patients with pancreatic cancer. ( 5.6 ) Microangiopathic hemolytic anemia (MAHA): The risk of MAHA is increased in patients with pancreatic cancer. ( 5.7 ) Ocular disorders: Discontinue erlotinib for corneal perforation, ulceration or persistent severe keratitis. ( 5.8 ) Hemorrhage in patients taking warfarin: Regularly monitor INR in patients taking warfarin or other coumarin-derivative anticoagulants. ( 5.9 ) Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. ( 5.10 , 8.1 , 8.3 ) 5.1 Interstitial Lung Disease (ILD) Cases of serious ILD, including fatal cases, can occur with erlotinib treatment. The overall incidence of ILD in approximately 32,000 erlotinib-treated patients in uncontrolled studies and studies with concurrent chemotherapy was approximately 1.1%. In patients with ILD, the onset of symptoms was between 5 days to more than 9 months (median 39 days) after initiating erlotinib therapy. Withhold erlotinib for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever pending diagnostic evaluation. If ILD is confirmed, permanently discontinue erlotinib [see Dosage and Administration (2.4) ] . 5.2 Renal Failure Hepatorenal syndrome, severe acute renal failure including fatal cases, and renal insufficiency can occur with erlotinib treatment. Renal failure may arise from exacerbation of underlying baseline hepatic impairment or severe dehydration. The pooled incidence of severe renal impairment in the 3 monotherapy lung cancer studies was 0.5% in the erlotinib arms and 0.8% in the control arms. The incidence of renal impairment in the pancreatic cancer study was 1.4% in the erlotinib plus gemcitabine arm and 0.4% in the control arm. Withhold erlotinib in patients developing severe renal impairment until renal toxicity is resolved. Perform periodic monitoring of renal function and serum electrolytes during erlotinib treatment [see Adverse Reactions (6.1) and Dosage and Administration (2.4) ] . 5.3 Hepatotoxicity with or without Hepatic Impairment Hepatic failure and hepatorenal syndrome, including fatal cases, can occur with erlotinib treatment in patients with normal hepatic function; the risk of hepatic toxicity is increased in patients with baseline hepatic impairment. In clinical studies where patients with moderate to severe hepatic impairment were excluded, the pooled incidence of hepatic failure in the 3 monotherapy lung cancer studies was 0.4% in the erlotinib arms and 0% in the control arms. The incidence of hepatic failure in the pancreatic cancer study was 0.4% in the erlotinib plus gemcitabine arm and 0.4% in the control arm. In a pharmacokinetic study in 15 patients with moderate hepatic impairment (Child-Pugh B) associated with significant liver tumor burden, 10 of these 15 patients died within 30 days of the last erlotinib dose. One patient died from hepatorenal syndrome, 1 patient died from rapidly progressing liver failure and the remaining 8 patients died from progressive disease. Six out of the 10 patients who died had baseline total bilirubin > 3 x ULN. Perform periodic liver testing (transaminases, bilirubin, and alkaline phosphatase) during treatment with erlotinib. Increased frequency of monitoring of liver function is required for patients with pre-existing hepatic impairment or biliary obstruction. Withhold erlotinib in patients without pre-existing hepatic impairment for total bilirubin levels greater than 3 times the upper limit of normal or transaminases greater than 5 times the upper limit of normal. Withhold erlotinib in patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases values over baseline. Discontinue erlotinib in patients whose abnormal liver tests meeting the above criteria do not improve significantly or resolve within three weeks [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ]. 5.4 Gastrointestinal Perforation Gastrointestinal perforation, including fatal cases, can occur with erlotinib treatment. Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, or taxane-based chemotherapy, or who have prior history of peptic ulceration or diverticular disease may be at increased risk of perforation [see Adverse Reactions (6.1 , 6.2) ] . The pooled incidence of gastrointestinal perforation in the 3 monotherapy lung cancer studies was 0.2% in the erlotinib arms and 0.1% in the control arms. The incidence of gastrointestinal perforation in the pancreatic cancer study was 0.4% in the erlotinib plus gemcitabine arm and 0% in the control arm. Permanently discontinue erlotinib in patients who develop gastrointestinal perforation [see Dosage and Administration (2.4) ] . 5.5 Bullous and Exfoliative Skin Disorders Bullous, blistering and exfoliative skin conditions, including cases suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis, which in some cases were fatal, can occur with erlotinib treatment [see Adverse Reactions (6.1 , 6.2) ] . The pooled incidence of bullous and exfoliative skin disorders in the 3 monotherapy lung cancer studies was 1.2% in the erlotinib arms and 0% in the control arms. The incidence of bullous and exfoliative skin disorders in the pancreatic cancer study was 0.4% in the erlotinib plus gemcitabine arm and 0% in the control arm. Discontinue erlotinib treatment if the patient develops severe bullous, blistering or exfoliating conditions [see Dosage and Administration (2.4) ] . 5.6 Cerebrovascular Accident In the pancreatic carcinoma trial, seven patients in the erlotinib/gemcitabine group developed cerebrovascular accidents (incidence: 2.5%). One of these was hemorrhagic and was the only fatal event. In comparison, in the placebo/gemcitabine group there were no cerebrovascular accidents. The pooled incidence of cerebrovascular accident in the 3 monotherapy lung cancer studies was 0.6% in the erlotinib arms and not higher than that observed in the control arms. 5.7 Microangiopathic Hemolytic Anemia with Thrombocytopenia The pooled incidence of microangiopathic hemolytic anemia with thrombocytopenia in the 3 monotherapy lung cancer studies was 0% in the erlotinib arms and 0.1% in the control arms. The incidence of microangiopathic hemolytic anemia with thrombocytopenia in the pancreatic cancer study was 1.4% in the erlotinib plus gemcitabine arm and 0% in the control arm. 5.8 Ocular Disorders Decreased tear production, abnormal eyelash growth, keratoconjunctivitis sicca or keratitis can occur with erlotinib treatment and can lead to corneal perforation or ulceration [see Adverse Reactions (6.1) and (6.2) ] . The pooled incidence of ocular disorders in the 3 monotherapy lung cancer studies was 17.8% in the erlotinib arms and 4% in the control arms. The incidence of ocular disorders in the pancreatic cancer study was 12.8% in the erlotinib plus gemcitabine arm and 11.4% in the control arm. Interrupt or discontinue erlotinib therapy if patients present with acute or worsening ocular disorders such as eye pain [see Dosage and Administration (2.4) ] . 5.9 Hemorrhage in Patients Taking Warfarin Severe and fatal hemorrhage associated with International Normalized Ratio (INR) elevations can occur when erlotinib and warfarin are administered concurrently. Regularly monitor prothrombin time and INR during erlotinib treatment in patients taking warfarin or other coumarin-derivative anticoagulants [see Adverse Reactions (6.1) and Drug Interactions (7) ] . 5.10 Embryo-Fetal Toxicity Based on animal data and its mechanism of action, erlotinib can cause fetal harm when administered to a pregnant woman. When given during organogenesis, erlotinib administration resulted in embryo-fetal lethality and abortion in rabbits at exposures approximately 3 times the exposure at the recommended human daily dose of 150 mg. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during therapy and for one month after the last dose of erlotinib [see Use in Specific Populations (8.1) and (8.3) , Clinical Pharmacology (12.1) ] .

6 ADVERSE REACTIONS The following serious adverse reactions, which may include fatalities, are discussed in greater detail in other sections of the labeling: Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.1) ] Renal Failure [see Warnings and Precautions (5.2) ] Hepatotoxicity with or without Hepatic Impairment [see Warnings and Precautions (5.3) ] Gastrointestinal Perforation [see Warnings and Precautions (5.4) ] Bullous and Exfoliative Skin Disorders [see Warnings and Precautions (5.5) ] Cerebrovascular Accident [see Warnings and Precautions (5.6) ] Microangiopathic Hemolytic Anemia with Thrombocytopenia [see Warnings and Precautions (5.7) ] Ocular Disorders [see Warnings and Precautions (5.8) ] Hemorrhage in Patients Taking Warfarin [see Warnings and Precautions (5.9) ] The most common adverse reactions (≥ 20%) with erlotinib from a pooled analysis in patients with NSCLC across all approved lines of therapy, with and without EGFR mutations, and in patients with pancreatic cancer were rash, diarrhea, anorexia, fatigue, dyspnea, cough, nausea, and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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. Safety evaluation of erlotinib is based on more than 1200 cancer patients who received erlotinib as monotherapy, more than 300 patients who received erlotinib 100 or 150 mg plus gemcitabine, and 1228 patients who received erlotinib concurrently with other chemotherapies. The most common adverse reactions with erlotinib are rash and diarrhea usually with onset during the first month of treatment. The incidences of rash and diarrhea from clinical studies of erlotinib for the treatment of NSCLC and pancreatic cancer were 70% for rash and 42% for diarrhea. Non-Small Cell Lung Cancer First-Line Treatment of Patients with EGFR Mutations The most frequent (≥ 30%) adverse reactions in erlotinib-treated patients were diarrhea, asthenia, rash, cough, dyspnea, and decreased appetite. In erlotinib-treated patients the median time to onset of rash was 15 days and the median time to onset of diarrhea was 32 days. The most frequent Grade 3-4 adverse reactions in erlotinib-treated patients were rash and diarrhea. Dose interruptions or reductions due to adverse reactions occurred in 37% of erlotinib-treated patients, and 14.3% of erlotinib-treated patients discontinued therapy due to adverse reactions. In erlotinib-treated patients, the most frequently reported adverse reactions leading to dose modification were rash (13%), diarrhea (10%), and asthenia (3.6%). Common adverse reactions in Study 1, occurring in at least 10% of patients who received erlotinib or chemotherapy and an increase in ≥ 5% in the erlotinib-treated group, are graded by National Cancer Institute Common Toxicity Criteria for Adverse Events version 3.0 (NCI-CTCAE v3.0) Grade in Table 1. The median duration of erlotinib treatment was 9.6 months in Study 1. Table 1: Adverse Reactions with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the Erlotinib-Treated Group (Study 1) Erlotinib N = 84 Chemotherapy Platinum-based chemotherapy (cisplatin or carboplatin with gemcitabine or docetaxel). N = 83 Adverse Reaction All Grades % Grades 3-4 % All Grades % Grades 3-4 % Rash Rash as a composite term includes rash, acne, folliculitis, erythema, acneiform dermatitis, dermatitis, palmar-plantar erythrodysesthesia syndrome, exfoliative rash, erythematous rash, rash pruritic, skin toxicity, eczema, follicular rash, skin ulcer. 85 14 5 0 Diarrhea 62 5 21 1 Cough 48 1 40 0 Dyspnea 45 8 30 4 Dry skin 21 1 2 0 Back pain 19 2 5 0 Chest pain 18 1 12 0 Conjunctivitis 18 0 0 0 Mucosal inflammation 18 1 6 0 Pruritus 16 0 1 0 Paronychia 14 0 0 0 Arthralgia 13 1 6 1 Musculoskeletal pain 11 1 1 0 Hepatic Toxicity One erlotinib-treated patient experienced fatal hepatic failure and four additional patients experienced grade 3-4 liver test abnormalities in Study 1 [see Warnings and Precautions (5.3) ] . Maintenance Treatment Adverse reactions, regardless of causality, that occurred in at least 3% of patients treated with single-agent erlotinib at 150 mg and at least 3% more often than in the placebo group in the randomized maintenance trial (Study 3) are summarized by NCI-CTCAE v3.0 Grade in Table 2. The most common adverse reactions in patients receiving single-agent erlotinib 150 mg were rash and diarrhea. Grade 3-4 rash and diarrhea occurred in 9% and 2%, respectively, in erlotinib-treated patients. Rash and diarrhea resulted in study discontinuation in 1% and 0.5% of erlotinib-treated patients, respectively. Dose reduction or interruption for rash and diarrhea was needed in 5% and 3% of patients, respectively. In erlotinib-treated patients the median time to onset of rash was 10 days, and the median time to onset of diarrhea was 15 days. Table 2: NSCLC Maintenance Study: Adverse Reactions Occurring with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the Single-Agent Erlotinib Group compared to the Placebo Group (Study 3) Adverse Reaction Erlotinib N = 433 Placebo N = 445 Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 % % % % % % Rash Rash as a composite term includes: rash, acne, acneiform dermatitis, skin fissures, erythema, papular rash, rash generalized, pruritic rash, skin exfoliation, urticaria, dermatitis, eczema, exfoliative rash, exfoliative dermatitis, furuncle, macular rash, pustular rash, skin hyperpigmentation, skin reaction, skin ulcer. 60 9 0 9 0 0 Diarrhea 20 2 0 4 0 0 Liver test abnormalities including ALT elevations were observed at Grade 2 or greater severity in 3% of erlotinib-treated patients and 1% of placebo-treated patients. Grade 2 and above bilirubin elevations were observed in 5% of erlotinib-treated patients and in < 1% in the placebo group [see Dosage and Administration (2.4) and Warnings and Precautions (5.3) ] . Second/Third Line Treatment Adverse reactions, regardless of causality, that occurred in at least 10% of patients treated with single-agent erlotinib at 150 mg and at least 5% more often than in the placebo group in the randomized trial of patients with NSCLC are summarized by NCI-CTC v2.0 Grade in Table 3. The most common adverse reactions in this patient population were rash and diarrhea. Grade 3-4 rash and diarrhea occurred in 9% and 6%, respectively, in erlotinib-treated patients. Rash and diarrhea each resulted in study discontinuation in 1% of erlotinib-treated patients. Six percent and 1% of patients needed dose reduction for rash and diarrhea, respectively. The median time to onset of rash was 8 days, and the median time to onset of diarrhea was 12 days. Table 3: NSCLC 2 nd /3 rd Line Study: Adverse Reactions Occurring with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the Single-Agent Erlotinib Group Compared to the Placebo Group (Study 4) Adverse Reaction Erlotinib 150 mg N = 485 Placebo N = 242 Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 % % % % % % Rash Rash as a composite term includes: rash, palmar-plantar erythrodysesthesia syndrome, acne, skin disorder, pigmentation disorder, erythema, skin ulcer, exfoliative dermatitis, papular rash, skin desquamation. 75 8 < 1 17 0 0 Diarrhea 54 6 < 1 18 < 1 0 Anorexia 52 8 1 38 5 < 1 Fatigue 52 14 4 45 16 4 Dyspnea 41 17 11 35 15 11 Nausea 33 3 0 24 2 0 Infection 24 4 0 15 2 0 Stomatitis 17 < 1 0 3 0 0 Pruritus 13 < 1 0 5 0 0 Dry skin 12 0 0 4 0 0 Conjunctivitis 12 < 1 0 2 < 1 0 Keratoconjunctivitis sicca 12 0 0 3 0 0 Liver function test abnormalities [including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin] were observed in patients receiving single-agent erlotinib 150 mg. These elevations were mainly transient or associated with liver metastases. Grade 2 [> 2.5 – 5.0 x upper limit of normal (ULN)] ALT elevations occurred in 4% and < 1% of erlotinib and placebo-treated patients, respectively. Grade 3 (> 5.0 - 20.0 x ULN) elevations were not observed in erlotinib-treated patients. Erlotinib dosing should be interrupted or discontinued if changes in liver function are severe [see Dosage and Administration (2.4) ] . Pancreatic Cancer - Erlotinib Administered Concurrently with Gemcitabine This was a randomized, double-blind, placebo-controlled study of erlotinib (150 mg or 100 mg daily) or placebo plus gemcitabine (1000 mg/m 2 by intravenous infusion) in patients with locally advanced, unresectable or metastatic pancreatic cancer (Study 5). The safety population comprised 282 patients in the erlotinib group (259 in the 100 mg cohort and 23 in the 150 mg cohort) and 280 patients in the placebo group (256 in the 100 mg cohort and 24 in the 150 mg cohort). Adverse reactions that occurred in at least 10% of patients treated with erlotinib 100 mg plus gemcitabine in the randomized trial of patients with pancreatic cancer (Study 5) were graded according to NCI-CTC v2.0 in Table 4. The most common adverse reactions in pancreatic cancer patients receiving erlotinib 100 mg plus gemcitabine were fatigue, rash, nausea, anorexia and diarrhea. In the erlotinib plus gemcitabine arm, Grade 3-4 rash and diarrhea were each reported in 5% of patients. The median time to onset of rash and diarrhea was 10 days and 15 days, respectively. Rash and diarrhea each resulted in dose reductions in 2% of patients, and resulted in study discontinuation in up to 1% of patients receiving erlotinib plus gemcitabine. Severe adverse reactions (≥ Grade 3 NCI-CTC) in the erlotinib plus gemcitabine group with incidences < 5% included syncope, arrhythmias, ileus, pancreatitis, hemolytic anemia including microangiopathic hemolytic anemia with thrombocytopenia, myocardial infarction/ischemia, cerebrovascular accidents including cerebral hemorrhage, and renal insufficiency [see Warnings and Precautions (5) ] . The 150 mg cohort was associated with a higher rate of certain class-specific adverse reactions including rash and required more frequent dose reduction or interruption. Table 4: Adverse Reactions Occurring with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in Erlotinib-Treated Pancreatic Cancer Patients: 100 mg Cohort (Study 5) Adverse Reaction Erlotinib + Gemcitabine 1000 mg/m 2 IV N = 259 Placebo + Gemcitabine 1000 mg/m 2 IV N = 256 Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 % % % % % % Rash Rash as a composite term includes: rash, palmar-plantar erythrodysesthesia syndrome, pigmentation disorder, acneiform dermatitis, folliculitis, photosensitivity reaction, Stevens-Johnson syndrome, urticaria, erythematous rash, skin disorder, skin ulcer. 70 5 0 30 1 0 Diarrhea 48 5 < 1 36 2 0 Decreased weight 39 2 0 29 < 1 0 Infection Infections as a composite term include infections with unspecified pathogens as well as bacterial (including chlamydial, rickettsial, mycobacterial and mycoplasmal), parasitic (including helminthic, ectoparasitic and protozoal), viral and fungal infectious disorders. 39 13 3 30 9 2 Pyrexia 36 3 0 30 4 0 Stomatitis 22 < 1 0 12 0 0 Depression 19 2 0 14 < 1 0 Cough 16 0 0 11 0 0 Headache 15 < 1 0 10 0 0 Ten patients (4%) in the erlotinib/gemcitabine group and three patients (1%) in the placebo/gemcitabine group developed deep venous thrombosis. The overall incidence of grade 3 or 4 thrombotic events, including deep venous thrombosis was 11% for erlotinib plus gemcitabine and 9% for placebo plus gemcitabine. The incidences of liver test abnormalities (≥ Grade 2) in Study 5 are provided in Table 5 [see Dosage and Administration (2.4) and Warnings and Precautions (5.3) ] . Table 5: Liver Test Abnormalities in Pancreatic Cancer Patients: 100 mg Cohort (Study 5) Erlotinib + Gemcitabine 1000 mg/m 2 IV N = 259 Placebo + Gemcitabine 1000 mg/m 2 IV N = 256 Grade 2 Grade 3 Grade 4 Grade 2 Grade 3 Grade 4 Bilirubin 17% 10% < 1% 11% 10% 3% ALT 31% 13% < 1% 22% 9% 0% AST 24% 10% < 1% 19% 9% 0% NSCLC and Pancreatic Indications Selected Low Frequency Adverse Reactions Gastrointestinal Disorders Cases of gastrointestinal bleeding (including fatalities) have been reported, some associated with concomitant warfarin or NSAID administration [see Warnings and Precautions (5.9) and Drug Interactions (7) ] . These adverse reactions were reported as peptic ulcer bleeding (gastritis, gastroduodenal ulcers), hematemesis, hematochezia, melena and hemorrhage from possible colitis. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post approval use of erlotinib. 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. Musculoskeletal and Connective Tissue Disorders: Myopathy, including rhabdomyolysis, in combination with statin therapy. Eye Disorders: Ocular inflammation including uveitis.

<table ID="_RefID0EGGAG" width="100%"><caption>Table 1: Adverse Reactions with an Incidence Rate &#x2265; 10% and an Increase of &#x2265; 5% in the Erlotinib-Treated Group (Study 1)</caption><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Erlotinib </content></paragraph><paragraph><content styleCode="bold">N = 84</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Chemotherapy</content><footnote ID="_Ref535330079">Platinum-based chemotherapy (cisplatin or carboplatin with gemcitabine or docetaxel).</footnote></paragraph><paragraph><content styleCode="bold">N = 83</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">All Grades</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Grades 3-4</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">All Grades</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Grades 3-4</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Rash <footnote ID="_Ref535330089">Rash as a composite term includes rash, acne, folliculitis, erythema, acneiform dermatitis, dermatitis, palmar-plantar erythrodysesthesia syndrome, exfoliative rash, erythematous rash, rash pruritic, skin toxicity, eczema, follicular rash, skin ulcer.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>85</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>5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>62</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>21</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> Cough</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>48</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>40</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Dyspnea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>45</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>30</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Dry skin</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>21</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1</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>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Back pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>19</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>5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Chest pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Conjunctivitis</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Mucosal inflammation</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pruritus</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Paronychia</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>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Arthralgia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Musculoskeletal pain</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>0</paragraph></td></tr></tbody></table>

<table ID="_RefID0ESUAG" width="100%"><caption>Table 2: NSCLC Maintenance Study: Adverse Reactions Occurring with an Incidence Rate &#x2265; 10% and an Increase of &#x2265; 5% in the Single-Agent Erlotinib Group compared to the Placebo Group (Study 3)</caption><col width="14%"/><col width="14%"/><col width="14%"/><col width="14%"/><col width="14%"/><col width="14%"/><col width="14%"/><tbody><tr><td rowspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Erlotinib </content> <content styleCode="bold">N = 433</content></paragraph></td><td align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">N = 445</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Any Grade</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Grade 3</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Grade 4</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Any Grade</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Grade 3</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Grade 4</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Rash <footnote ID="_Ref535488867">Rash as a composite term includes: rash, acne, acneiform dermatitis, skin fissures, erythema, papular rash, rash generalized, pruritic rash, skin exfoliation, urticaria, dermatitis, eczema, exfoliative rash, exfoliative dermatitis, furuncle, macular rash, pustular rash, skin hyperpigmentation, skin reaction, skin ulcer.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>60</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>20</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>0</paragraph></td></tr></tbody></table>

<table ID="_RefID0E42AG" width="100%"><caption>Table 3: NSCLC 2 ^nd/3 ^rd Line Study: Adverse Reactions Occurring with an Incidence Rate &#x2265; 10% and an Increase of &#x2265; 5% in the Single-Agent Erlotinib Group Compared to the Placebo Group (Study 4) </caption><col width="20%"/><col width="20%"/><col width="19%"/><col width="18%"/><col width="8%"/><col width="8%"/><col width="8%"/><tbody><tr><td rowspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Erlotinib 150 mg</content></paragraph><paragraph><content styleCode="bold">N = 485</content></paragraph></td><td align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">N = 242</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Any Grade</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Grade 3</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Grade 4</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Any Grade</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Grade 3</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Grade 4</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Rash <footnote ID="_Ref535489062">Rash as a composite term includes: rash, palmar-plantar erythrodysesthesia syndrome, acne, skin disorder, pigmentation disorder, erythema, skin ulcer, exfoliative dermatitis, papular rash, skin desquamation.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>75</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt; 1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>54</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt; 1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt; 1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Anorexia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>52</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>38</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt; 1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Fatigue</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>52</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>45</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dyspnea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>41</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>35</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>33</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Infection</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Stomatitis</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt; 1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Pruritus </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt; 1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dry skin</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Conjunctivitis</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt; 1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt; 1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Keratoconjunctivitis sicca</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>0</paragraph></td></tr></tbody></table>