FDA label 6cbc3eaa-637b-301a-e053-2a91aa0af624

5 WARNINGS AND PRECAUTIONS Interstitial Lung Disease (ILD): Occurs in 1.1% of patients. Withhold TARCEVA for acute onset of new or progressive unexplained pulmonary symptoms, such as dyspnea, cough and fever. Discontinue TARCEVA if ILD is diagnosed. ( 5.1 ) Renal Failure: Monitor renal function and electrolytes, particularly in patients at risk of dehydration. Withhold TARCEVA for severe renal toxicity. ( 5.2 ) Hepatotoxicity with or without hepatic impairment including hepatic failure and hepatorenal syndrome: Monitor periodic liver testing. Withhold or discontinue TARCEVA for severe or worsening liver tests. ( 5.3 ) Gastrointestinal perforations: Discontinue TARCEVA. ( 5.4 ) Bullous and exfoliative skin disorders: Discontinue TARCEVA. ( 5.5 ) Myocardial infarction (MI)/ischemia: The risk of MI is increased in patients with pancreatic cancer. ( 5.6 ) Cerebrovascular accident (CVA): The risk of CVA is increased in patients with pancreatic cancer. ( 5.7 ) Microangiopathic hemolytic anemia (MAHA): The risk of MAHA is increased in patients with pancreatic cancer. ( 5.8 ) Ocular disorders: Discontinue TARCEVA for corneal perforation, ulceration or persistent severe keratitis. ( 5.9 ) Hemorrhage in patients taking warfarin: Regularly monitor INR in patients taking warfarin or other coumarin-derivative anticoagulants. ( 5.10 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to the fetus and to use highly effective contraception ( 5.11 , 8.6 ) 5.1 Interstitial Lung Disease (ILD) Cases of serious ILD, including fatal cases, can occur with TARCEVA treatment. The overall incidence of ILD in approximately 32,000 TARCEVA-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 TARCEVA therapy. Withhold TARCEVA 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 TARCEVA [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 TARCEVA 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 TARCEVA arms and 0.8% in the control arms. The incidence of renal impairment in the pancreatic cancer study was 1.4% in the TARCEVA plus gemcitabine arm and 0.4% in the control arm. Withhold TARCEVA in patients developing severe renal impairment until renal toxicity is resolved. Perform periodic monitoring of renal function and serum electrolytes during TARCEVA 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 TARCEVA 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 TARCEVA arms and 0% in the control arms. The incidence of hepatic failure in the pancreatic cancer study was 0.4% in the TARCEVA 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 TARCEVA 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 TARCEVA. Increased frequency of monitoring of liver function is required for patients with pre-existing hepatic impairment or biliary obstruction. Withhold TARCEVA 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 TARCEVA in patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases values over baseline. Discontinue TARCEVA 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 TARCEVA 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 TARCEVA arms and 0.1% in the control arms. The incidence of gastrointestinal perforation in the pancreatic cancer study was 0.4% in the TARCEVA plus gemcitabine arm and 0% in the control arm. Permanently discontinue TARCEVA 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 TARCEVA 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 TARCEVA 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 TARCEVA plus gemcitabine arm and 0% in the control arm. Discontinue TARCEVA treatment if the patient develops severe bullous, blistering or exfoliating conditions [see Dosage and Administration ( 2.4 )] . 5.6 Myocardial Infarction/Ischemia In the pancreatic carcinoma trial, six patients (incidence of 2.1%) in the TARCEVA/gemcitabine group developed myocardial infarction/ischemia. One of these patients died due to myocardial infarction. In comparison, 3 patients in the placebo/gemcitabine group developed myocardial infarction (incidence 1.1%), and one died due to myocardial infarction. The pooled incidence of myocardial infarction/ischemia in the 3 monotherapy lung cancer studies was 0.2% in the TARCEVA arms and 0.4% in the control arms. 5.7 Cerebrovascular Accident In the pancreatic carcinoma trial, seven patients in the TARCEVA/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 TARCEVA arms and 0.9% in the control arms. 5.8 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 TARCEVA 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 TARCEVA plus gemcitabine arm and 0% in the control arm. 5.9 Ocular Disorders Decreased tear production, abnormal eyelash growth, keratoconjunctivitis sicca or keratitis can occur with TARCEVA 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 TARCEVA arms and 4% in the control arms. The incidence of ocular disorders in the pancreatic cancer study was 12.8% in the TARCEVA plus gemcitabine arm and 11.4% in the control arm. Interrupt or discontinue TARCEVA therapy if patients present with acute or worsening ocular disorders such as eye pain [see Dosage and Administration ( 2.4 )] . 5.10 Hemorrhage in Patients Taking Warfarin Severe and fatal hemorrhage associated with International Normalized Ratio (INR) elevations can occur when TARCEVA and warfarin are administered concurrently. Regularly monitor prothrombin time and INR during TARCEVA treatment in patients taking warfarin or other coumarin-derivative anticoagulants [see Adverse Reactions ( 6.1 ) and Drug Interactions ( 7 )] . 5.11 Embryo-Fetal Toxicity Based on its mechanism of action, TARCEVA 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 doses approximately 3 times the recommended human daily dose of 150 mg. If TARCEVA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 2 weeks after the last dose of TARCEVA. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TARCEVA [see Use in Specific Populations ( 8.1 ) and ( 8.6 )] .

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 )] Myocardial Infarction/Ischemia [see Warnings and Precautions ( 5.6 )] Cerebrovascular Accident [see Warnings and Precautions ( 5.7 )] Microangiopathic Hemolytic Anemia with Thrombocytopenia [see Warnings and Precautions ( 5.8 )] Ocular Disorders [see Warnings and Precautions ( 5.9 )] Hemorrhage in Patients Taking Warfarin [see Warnings and Precautions ( 5.10 )] The most common adverse reactions (≥ 20%) with TARCEVA from a pooled analysis of Studies 1-4 were rash, diarrhea, anorexia, fatigue, dyspnea, cough, nausea, and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact OSI Pharmaceuticals, LLC, at 1-800-572-1932 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 TARCEVA is based on more than 1200 cancer patients who received TARCEVA as monotherapy, more than 300 patients who received TARCEVA 100 or 150 mg plus gemcitabine, and 1228 patients who received TARCEVA concurrently with other chemotherapies. The most common adverse reactions with TARCEVA are rash and diarrhea usually with onset during the first month of treatment. The incidences of rash and diarrhea from clinical studies of TARCEVA 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 TARCEVA-treated patients were diarrhea, asthenia, rash, cough, dyspnea and decreased appetite. In TARCEVA-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 TARCEVA-treated patients were rash and diarrhea. Dose interruptions or reductions due to adverse reactions occurred in 37% of TARCEVA-treated patients, and 14.3% of TARCEVA-treated patients discontinued therapy due to adverse reactions. In TARCEVA-treated patients, the most frequently reported adverse reactions leading to dose modification were rash (13%), diarrhea (10%), and asthenia (3.6%). Selected, common adverse reactions in Study 4, occurring in at least 10% of patients who received TARCEVA or chemotherapy and an increase in ≥ 5% in the TARCEVA treated group, are summarized by NCI-CTC (version 3.0) Grade in Table 1 . The median duration of TARCEVA treatment was 9.6 months in Study 4. Table 1: Selected Adverse Reactions with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the TARCEVA-treated Group (Study 4) TARCEVA N = 84 Chemotherapy Platinum based doublet chemotherapy (cisplatin or carboplatin with gemcitabine or docetaxel) N = 83 MedDRA Preferred Term All Grades % Grades 3-4 % All Grades % Grades 3-4 % Rash Rash as a composite term includes : rash, acne, folliculitis, erythema, dermatitis acneiform, dermatitis, palmar-plantar erythrodysaesthesia syndrome, exfoliative rash, rash erythematous, rash pruritic, skin toxicity, eczema, rash follicular, 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 TARCEVA-treated patient experienced fatal hepatic failure and four additional patients experienced grade 3-4 liver test abnormalities in Study 4 [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 TARCEVA 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-CTC (version 3.0) Grade in Table 2 . The most common adverse reactions in patients receiving single-agent TARCEVA 150 mg were rash and diarrhea. Grade 3-4 rash and diarrhea occurred in 9% and 2%, respectively, in TARCEVA-treated patients. Rash and diarrhea resulted in study discontinuation in 1% and 0.5% of TARCEVA-treated patients, respectively. Dose reduction or interruption for rash and diarrhea was needed in 5% and 3% of patients, respectively. In TARCEVA-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: Selected Adverse Reactions Occurring with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the Single-Agent TARCEVA Group compared to the Placebo Group (Study 3) TARCEVA N = 433 PLACEBO N = 445 NCI-CTC Grade Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 MedDRA Preferred Term % % % % % % Rash Rash as a composite term includes: rash, acne, dermatitis acneiform, skin fissures, erythema, rash papular, rash generalized, rash pruritic, skin exfoliation, urticaria, dermatitis, eczema, exfoliative rash, dermatitis exfoliative, furuncle, rash macular, rash pustular, 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 TARCEVA-treated patients and 1% of placebo-treated patients. Grade 2 and above bilirubin elevations were observed in 5% of TARCEVA-treated patients and in < 1% in the placebo group [see Dosage and Administration ( 2.4 ) and Warnings and Precaution ( 5.3 )] . Second/Third Line Treatment Adverse reactions, regardless of causality, that occurred in at least 10% of patients treated with single-agent TARCEVA 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 (version 2.0) 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 TARCEVA-treated patients. Rash and diarrhea each resulted in study discontinuation in 1% of TARCEVA-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 2nd/3rd Line Study: Selected Adverse Reactions Occurring with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the Single-Agent TARCEVA Group compared to the Placebo Group (Study 1) TARCEVA 150 mg N=485 Placebo N=242 NCI-CTC Grade Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 MedDRA Preferred Term % % % % % % Rash Rash as a composite term includes: rash, palmar-plantar erythrodysaesthesia syndrome, acne, skin disorder, pigmentation disorder, erythema, skin ulcer, dermatitis exfoliative, rash papular, 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 TARCEVA 150 mg. These elevations were mainly transient or associated with liver metastases. Grade 2 (> 2.5 – 5.0 x ULN) ALT elevations occurred in 4% and < 1% of TARCEVA and placebo treated patients, respectively. Grade 3 (> 5.0 – 20.0 x ULN) elevations were not observed in TARCEVA-treated patients. TARCEVA dosing should be interrupted or discontinued if changes in liver function are severe [see Dosage and Administration ( 2.4 )] . Pancreatic Cancer - TARCEVA Administered Concurrently with Gemcitabine This was a randomized, double blind placebo-controlled study of TARCEVA (150 mg or 100 mg daily) or placebo plus gemcitabine (1000 mg/m 2 IV) in patients with locally advanced, unresectable or metastatic pancreatic cancer (Study 2). 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 TARCEVA 100 mg plus gemcitabine in the randomized trial of patients with pancreatic cancer (Study 2) are summarized by NCI-CTC (version 2.0) Grade in Table 4 . The most common adverse reactions in pancreatic cancer patients receiving TARCEVA 100 mg plus gemcitabine were fatigue, rash, nausea, anorexia and diarrhea. In the TARCEVA 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 TARCEVA plus gemcitabine. Severe adverse reactions (≥ Grade 3 NCI-CTC) in the TARCEVA 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: Selected Adverse Reactions Occurring with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in TARCEVA-treated Pancreatic Cancer Patients: 100 mg cohort (Study 2) * Includes all MedDRA preferred terms in the Infections and Infestations System Organ Class † Rash as a composite term includes: rash, palmar-plantar erythrodysaesthesia syndrome, pigmentation disorder, dermatitis acneiform, folliculitis, photosensitivity reaction, Stevens-Johnson syndrome, urticaria, erythematous rash, skin disorder, skin ulcer. TARCEVA + Gemcitabine 1000 mg/m 2 IV N=259 Placebo + Gemcitabine 1000 mg/m 2 IV N=256 NCI-CTC Grade Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 MedDRA Preferred Term % % % % % % Rash † 70 5 0 30 1 0 Diarrhea 48 5 <1 36 2 0 Weight decreased 39 2 0 29 <1 0 Infection* 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 TARCEVA/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 TARCEVA plus gemcitabine and 9% for placebo plus gemcitabine. The incidences of liver test abnormalities (≥ Grade 2) in Study 2 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 2) TARCEVA + Gemcitabine 1000 mg/m 2 IV N=259 Placebo + Gemcitabine 1000 mg/m 2 IV N=256 NCI-CTC Grade 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 ( 5.10 ) 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 TARCEVA. 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="_Ref356383898" width="100%"> <caption>Table 1: Selected Adverse Reactions with an Incidence Rate &#x2265; 10% and an Increase of &#x2265; 5% in the TARCEVA-treated Group (Study 4)</caption> <col width="27%"/> <col width="24%"/> <col width="16%"/> <col width="17%"/> <col width="16%"/> <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">TARCEVA</content> <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="_Ref356383609">Platinum based doublet 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="bottom"> <paragraph> <content styleCode="bold">MedDRA Preferred Term</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="_Ref356383646">Rash as a composite term includes : rash, acne, folliculitis, erythema, dermatitis acneiform, dermatitis, palmar-plantar erythrodysaesthesia syndrome, exfoliative rash, rash erythematous, rash pruritic, skin toxicity, eczema, rash follicular, 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="_Ref356380633" width="100%"> <caption>Table 2: NSCLC Maintenance Study: Selected Adverse Reactions Occurring with an Incidence Rate &#x2265; 10% and an Increase of &#x2265; 5% in the Single-Agent TARCEVA Group compared to the Placebo Group (Study 3)</caption> <col width="28%"/> <col width="14%"/> <col width="11%"/> <col width="11%"/> <col width="14%"/> <col width="11%"/> <col width="11%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="middle"/> <td align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">TARCEVA</content> </paragraph> <paragraph> <content styleCode="bold">N = 433</content> </paragraph> </td> <td align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">PLACEBO</content> </paragraph> <paragraph> <content styleCode="bold">N = 445</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="bold">NCI-CTC Grade</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> <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 styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="bold">MedDRA Preferred Term</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> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="bold">%</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>Rash <footnote ID="_Ref356223472">Rash as a composite term includes: rash, acne, dermatitis acneiform, skin fissures, erythema, rash papular, rash generalized, rash pruritic, skin exfoliation, urticaria, dermatitis, eczema, exfoliative rash, dermatitis exfoliative, furuncle, rash macular, rash pustular, skin hyperpigmentation, skin reaction, skin ulcer.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>60 </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>9</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>9</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 Botrule Lrule " valign="middle"> <paragraph>Diarrhea</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="middle"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="middle"> <paragraph>2</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>4</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>0</paragraph> </td> </tr> </tbody> </table>

<table ID="_Ref356388660" width="100%"> <caption>Table 3: NSCLC 2nd/3rd Line Study: Selected Adverse Reactions Occurring with an Incidence Rate &#x2265; 10% and an Increase of &#x2265; 5% in the Single-Agent TARCEVA Group compared to the Placebo Group (Study 1)</caption> <col width="28%"/> <col width="13%"/> <col width="12%"/> <col width="11%"/> <col width="13%"/> <col width="12%"/> <col width="11%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"/> <td align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">TARCEVA 150 mg</content> </paragraph> <paragraph> <content styleCode="bold">N=485</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=242</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">NCI-CTC Grade</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> <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 styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">MedDRA Preferred Term</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> <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="_Ref356388675">Rash as a composite term includes: rash, palmar-plantar erythrodysaesthesia syndrome, acne, skin disorder, pigmentation disorder, erythema, skin ulcer, dermatitis exfoliative, rash papular, skin desquamation.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>75</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>&lt;1</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</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>54</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>&lt;1</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>&lt;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>Anorexia</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>52</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>1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>38</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>&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="middle"> <paragraph>52</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>4</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>16</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>Dyspnea</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>41</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>11</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>35</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <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="middle"> <paragraph>33</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>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>24</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>Infection</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>24</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</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>15</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>Stomatitis</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>&lt;1</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>3</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>Pruritus</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>&lt;1</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>5</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>Dry skin</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> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>0</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</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>12</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>&lt;1</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>2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph>&lt;1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <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="middle"> <paragraph>12</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>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="middle"> <paragraph>3</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>0</paragraph> </td> </tr> </tbody> </table>