FDA label 15601703-7442-48f3-89f4-44fef66b7514

WARNING XELODA Warfarin Interaction: Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. A clinically important XELODA-Warfarin drug interaction was demonstrated in a clinical pharmacology trial (see CLINICAL PHARMACOLOGY and PRECAUTIONS ). Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking XELODA concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. Postmarketing reports have shown clinically significant increases in prothrombin time (PT) and INR in patients who were stabilized on anticoagulants at the time XELODA was introduced. These events occurred within several days and up to several months after initiating XELODA therapy and, in a few cases, within 1 month after stopping XELODA. These events occurred in patients with and without liver metastases. Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.

WARNINGS Renal Insufficiency Patients with moderate renal impairment at baseline require dose reduction (see DOSAGE AND ADMINISTRATION ). Patients with mild and moderate renal impairment at baseline should be carefully monitored for adverse events. Prompt interruption of therapy with subsequent dose adjustments is recommended if a patient develops a grade 2 to 4 adverse event as outlined in Table 18 in DOSAGE AND ADMINISTRATION . Coagulopathy See Boxed WARNING . Diarrhea XELODA can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. In 875 patients with either metastatic breast or colorectal cancer who received XELODA monotherapy, the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range from 1 to 369 days). The median duration of grade 3 to 4 diarrhea was 5 days. National Cancer Institute of Canada (NCIC) grade 2 diarrhea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhea as an increase of 7 to 9 stools/day or incontinence and malabsorption, and grade 4 diarrhea as an increase of ≥10 stools/day or grossly bloody diarrhea or the need for parenteral support. If grade 2, 3 or 4 diarrhea occurs, administration of XELODA should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1. Following a reoccurrence of grade 2 diarrhea or occurrence of any grade 3 or 4 diarrhea, subsequent doses of XELODA should be decreased (see DOSAGE AND ADMINISTRATION ). Standard antidiarrheal treatments (eg, loperamide) are recommended. Necrotizing enterocolitis (typhlitis) has been reported. Geriatric Patients Patients ≥80 years old may experience a greater incidence of grade 3 or 4 adverse events (see PRECAUTIONS: Geriatric Use ). In 875 patients with either metastatic breast or colorectal cancer who received XELODA monotherapy, 62% of the 21 patients ≥80 years of age treated with XELODA experienced a treatment-related grade 3 or 4 adverse event: diarrhea in 6 (28.6%), nausea in 3 (14.3%), hand-and-foot syndrome in 3 (14.3%), and vomiting in 2 (9.5%) patients. Among the 10 patients 70 years of age and greater (no patients were >80 years of age) treated with XELODA in combination with docetaxel, 30% (3 out of 10) of patients experienced grade 3 or 4 diarrhea and stomatitis, and 40% (4 out of 10) experienced grade 3 hand-and-foot syndrome. Among the 67 patients ≥60 years of age receiving XELODA in combination with docetaxel, the incidence of grade 3 or 4 treatment-related adverse events, treatment-related serious adverse events, withdrawals due to adverse events, treatment discontinuations due to adverse events and treatment discontinuations within the first two treatment cycles was higher than in the <60 years of age patient group. In 995 patients receiving XELODA as adjuvant therapy for Dukes' C colon cancer after resection of the primary tumor, 41% of the 398 patients ≥65 years of age treated with XELODA experienced a treatment-related grade 3 or 4 adverse event: hand-and-foot syndrome in 75 (18.8%), diarrhea in 52 (13.1%), stomatitis in 12 (3.0%), neutropenia/granulocytopenia in 11 (2.8%), vomiting in 6 (1.5%), and nausea in 5 (1.3%) patients. In patients ≥65 years of age (all randomized population; capecitabine 188 patients, 5-FU/LV 208 patients) treated for Dukes' C colon cancer after resection of the primary tumor, the hazard ratios for disease-free survival and overall survival for XELODA compared to 5-FU/LV were 1.01 (95% C.I. 0.80 – 1.27) and 1.04 (95% C.I. 0.79 – 1.37), respectively. Pregnancy XELODA may cause fetal harm when given to a pregnant woman. Capecitabine at doses of 198 mg/kg/day during organogenesis caused malformations and embryo death in mice. In separate pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values about 0.2 times the corresponding values in patients administered the recommended daily dose. Malformations in mice included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail and dilation of cerebral ventricles. At doses of 90 mg/kg/day, capecitabine given to pregnant monkeys during organogenesis caused fetal death. This dose produced 5'-DFUR AUC values about 0.6 times the corresponding values in patients administered the recommended daily dose. There are no adequate and well-controlled studies in pregnant women using XELODA. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with XELODA.

ADVERSE REACTIONS Adjuvant Colon Cancer Table 11 shows the adverse events occurring in ≥5% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment. A total of 995 patients were treated with 1250 mg/m 2 twice a day of XELODA administered for 2 weeks followed by a 1-week rest period, and 974 patients were administered 5-FU and leucovorin (20 mg/m 2 leucovorin IV followed by 425 mg/m 2 IV bolus 5-FU, on days 1-5, every 28 days). The median duration of treatment was 164 days for capecitabine-treated patients and 145 days for 5-FU/LV-treated patients. A total of 112 (11%) and 73 (7%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse events. A total of 18 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 8 (0.8%) patients randomized to XELODA and 10 (1.0%) randomized to 5-FU/LV. Table 12 shows grade 3/4 laboratory abnormalities occurring in ≥1% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment. Table 11 Percent Incidence of Adverse Events Reported in ≥5% of Patients Treated With XELODA or 5-FU/LV for Colon Cancer in the Adjuvant Setting (Safety Population) Adjuvant Treatment for Colon Cancer (N=1969) XELODA (N=995) 5-FU/LV (N=974) Body System/ Adverse Event All Grades Grade 3/4 All Grades Grade 3/4 Gastrointestinal Disorders Diarrhea 47 12 65 14 Nausea 34 2 47 2 Stomatitis 22 2 60 14 Vomiting 15 2 21 2 Abdominal Pain 14 3 16 2 Constipation 9 - 11 <1 Upper Abdominal Pain 7 <1 7 <1 Dyspepsia 6 <1 5 - Skin and Subcutaneous Tissue Disorders Hand-and-Foot Syndrome 60 17 9 <1 Alopecia 6 - 22 <1 Rash 7 - 8 - Erythema 6 1 5 <1 General Disorders and Administration Site Conditions Fatigue 16 <1 16 1 Pyrexia 7 <1 9 <1 Asthenia 10 <1 10 1 Lethargy 10 <1 9 <1 Nervous System Disorders Dizziness 6 <1 6 - Headache 5 <1 6 <1 Dysgeusia 6 - 9 - Metabolism and Nutrition Disorders Anorexia 9 <1 11 <1 Eye Disorders Conjunctivitis 5 <1 6 <1 Blood and Lymphatic System Disorders Neutropenia 2 <1 8 5 Respiratory Thoracic and Mediastinal Disorders Epistaxis 2 - 5 - Table 12 Percent Incidence of Grade 3/4 Laboratory Abnormalities Reported in ≥1% of Patients Receiving XELODA Monotherapy for Adjuvant Treatment of Colon Cancer (Safety Population) Adverse Event XELODA (n=995) IV 5-FU/LV (n=974) Grade 3/4 % Grade 3/4 % Increased ALAT (SGPT) 1.6 0.6 Increased calcium 1.1 0.7 Decreased calcium 2.3 2.2 Decreased hemoglobin 1.0 1.2 Decreased lymphocytes 13.0 13.0 Decreased neutrophils The incidence of grade 3/4 white blood cell abnormalities was 1.3% in the XELODA arm and 4.9% in the IV 5-FU/LV arm. 2.2 26.2 Decreased neutrophils/granulocytes 2.4 26.4 Decreased platelets 1.0 0.7 Increased bilirubin It should be noted that grading was according to NCIC CTC Version 1 (May, 1994). In the NCIC-CTC Version 1, hyperbilirubinemia grade 3 indicates a bilirubin value of 1.5 to 3.0 × upper limit of normal (ULN) range, and grade 4 a value of > 3.0 × ULN. The NCI CTC Version 2 and above define a grade 3 bilirubin value of >3.0 to 10.0 × ULN, and grade 4 values >10.0 × ULN. 20 6.3 Metastatic Colorectal Cancer Table 13 shows the adverse events occurring in ≥5% of patients from pooling the two phase 3 trials in first line metastatic colorectal cancer. A total of 596 patients with metastatic colorectal cancer were treated with 1250 mg/m 2 twice a day of XELODA administered for 2 weeks followed by a 1-week rest period, and 593 patients were administered 5-FU and leucovorin in the Mayo regimen (20 mg/m 2 leucovorin IV followed by 425 mg/m 2 IV bolus 5-FU, on days 1-5, every 28 days). In the pooled colorectal database the median duration of treatment was 139 days for capecitabine-treated patients and 140 days for 5-FU/LV-treated patients. A total of 78 (13%) and 63 (11%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse events/intercurrent illness. A total of 82 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 50 (8.4%) patients randomized to XELODA and 32 (5.4%) randomized to 5-FU/LV. Table 13 Pooled Phase 3 Colorectal Trials: Percent Incidence of Adverse Events in ≥5% of Patients Adverse Event XELODA (n=596) 5-FU/LV (n=593) Total % Grade 3 % Grade 4 % Total % Grade 3 % Grade 4 % – Not observed NA = Not Applicable Number of Patients With > One Adverse Event 96 52 9 94 45 9 Body System/Adverse Event GI Diarrhea 55 13 2 61 10 2 Nausea 43 4 – 51 3 <1 Vomiting 27 4 <1 30 4 <1 Stomatitis 25 2 <1 62 14 1 Abdominal Pain 35 9 <1 31 5 – Gastrointestinal Motility Disorder 10 <1 – 7 <1 – Constipation 14 1 <1 17 1 – Oral Discomfort 10 – – 10 – – Upper GI Inflammatory Disorders 8 <1 – 10 1 – Gastrointestinal Hemorrhage 6 1 <1 3 1 – Ileus 6 4 1 5 2 1 Skin and Subcutaneous Hand-and-Foot Syndrome 54 17 NA 6 1 NA Dermatitis 27 1 – 26 1 – Skin Discoloration 7 <1 – 5 – – Alopecia 6 – – 21 <1 – General Fatigue/Weakness 42 4 – 46 4 – Pyrexia 18 1 – 21 2 – Edema 15 1 – 9 1 – Pain 12 1 – 10 1 – Chest Pain 6 1 – 6 1 <1 Neurological Peripheral Sensory Neuropathy 10 – – 4 – – Headache 10 1 – 7 – – Dizziness Excluding vertigo 8 <1 – 8 <1 – Insomnia 7 – – 7 – – Taste Disturbance 6 1 – 11 <1 1 Metabolism Appetite Decreased 26 3 <1 31 2 <1 Dehydration 7 2 <1 8 3 1 Eye Eye Irritation 13 – – 10 <1 – Vision Abnormal 5 – – 2 – – Respiratory Dyspnea 14 1 – 10 <1 1 Cough 7 <1 1 8 – – Pharyngeal Disorder 5 – – 5 – – Epistaxis 3 <1 – 6 – – Sore Throat 2 – – 6 – – Musculoskeletal Back Pain 10 2 – 9 <1 – Arthralgia 8 1 – 6 1 – Vascular Venous Thrombosis 8 3 <1 6 2 – Psychiatric Mood Alteration 5 – – 6 <1 – Depression 5 – – 4 <1 – Infections Viral 5 <1 – 5 <1 – Blood and Lymphatic Anemia 80 2 <1 79 1 <1 Neutropenia 13 1 2 46 8 13 Hepatobiliary Hyperbilirubinemia 48 18 5 17 3 3 Breast Cancer Combination The following data are shown for the combination study with XELODA and docetaxel in patients with metastatic breast cancer in Table 14 and Table 15 . In the XELODA and docetaxel combination arm the treatment was XELODA administered orally 1250 mg/m 2 twice daily as intermittent therapy (2 weeks of treatment followed by 1 week without treatment) for at least 6 weeks and docetaxel administered as a 1-hour intravenous infusion at a dose of 75 mg/m 2 on the first day of each 3-week cycle for at least 6 weeks. In the monotherapy arm docetaxel was administered as a 1-hour intravenous infusion at a dose of 100 mg/m 2 on the first day of each 3-week cycle for at least 6 weeks. The mean duration of treatment was 129 days in the combination arm and 98 days in the monotherapy arm. A total of 66 patients (26%) in the combination arm and 49 (19%) in the monotherapy arm withdrew from the study because of adverse events. The percentage of patients requiring dose reductions due to adverse events was 65% in the combination arm and 36% in the monotherapy arm. The percentage of patients requiring treatment interruptions due to adverse events in the combination arm was 79%. Treatment interruptions were part of the dose modification scheme for the combination therapy arm but not for the docetaxel monotherapy-treated patients. Table 14 Percent Incidence of Adverse Events Considered Related or Unrelated to Treatment in ≥5% of Patients Participating in the XELODA and Docetaxel Combination vs Docetaxel Monotherapy Study Adverse Event XELODA 1250 mg/m 2 /bid With Docetaxel 75 mg/m 2 /3 weeks Docetaxel 100 mg/m 2 /3 weeks (n=251) (n=255) Total % Grade 3 % Grade 4 % Total % Grade 3 % Grade 4 % – Not observed NA = Not Applicable Number of Patients With at Least One Adverse Event 99 76.5 29.1 97 57.6 31.8 Body System/Adverse Event GI Diarrhea 67 14 <1 48 5 <1 Stomatitis 67 17 <1 43 5 – Nausea 45 7 – 36 2 – Vomiting 35 4 1 24 2 – Constipation 20 2 – 18 – – Abdominal Pain 30 <3 <1 24 2 – Dyspepsia 14 – – 8 1 – Dry Mouth 6 <1 – 5 – – Skin and Subcutaneous Hand-and-Foot Syndrome 63 24 NA 8 1 NA Alopecia 41 6 – 42 7 – Nail Disorder 14 2 – 15 – – Dermatitis 8 – – 11 1 – Rash Erythematous 9 <1 – 5 – – Nail Discoloration 6 – – 4 <1 – Onycholysis 5 1 – 5 1 – Pruritus 4 – – 5 – – General Pyrexia 28 2 – 34 2 – Asthenia 26 4 <1 25 6 – Fatigue 22 4 – 27 6 – Weakness 16 2 – 11 2 – Pain in Limb 13 <1 – 13 2 – Lethargy 7 – – 6 2 – Pain 7 <1 – 5 1 – Chest Pain (non-cardiac) 4 <1 – 6 2 – Influenza-like Illness 5 – – 5 – – Neurological Taste Disturbance 16 <1 – 14 <1 – Headache 15 3 – 15 2 – Paresthesia 12 <1 – 16 1 – Dizziness 12 – – 8 <1 – Insomnia 8 – – 10 <1 – Peripheral Neuropathy 6 – – 10 1 – Hypoaesthesia 4 <1 – 8 <1 – Metabolism Anorexia 13 1 – 11 <1 – Appetite Decreased 10 – – 5 – – Weight Decreased 7 – – 5 – – Dehydration 10 2 – 7 <1 <1 Eye Lacrimation Increased 12 – – 7 <1 – Conjunctivitis 5 – – 4 – – Eye Irritation 5 – – 1 – – Musculoskeletal Arthralgia 15 2 – 24 3 – Myalgia 15 2 – 25 2 – Back Pain 12 <1 – 11 3 – Bone Pain 8 <1 – 10 2 – Cardiac Edema 33 <2 – 34 <3 1 Blood Neutropenic Fever 16 3 13 21 5 16 Respiratory Dyspnea 14 2 <1 16 2 – Cough 13 1 – 22 <1 – Sore Throat 12 2 – 11 <1 – Epistaxis 7 <1 – 6 – – Rhinorrhea 5 – – 3 – – Pleural Effusion 2 1 – 7 4 – Infection Oral Candidiasis 7 <1 – 8 <1 – Urinary Tract Infection 6 <1 – 4 – – Upper Respiratory Tract 4 – – 5 1 – Vascular Flushing 5 – – 5 – – Lymphoedema 3 <1 – 5 1 – Psychiatric Depression 5 – – 5 1 – Table 15 Percent of Patients With Laboratory Abnormalities Participating in the XELODA and Docetaxel Combination vs Docetaxel Monotherapy Study Adverse Event XELODA 1250 mg/m 2 /bid With Docetaxel 75 mg/m 2 /3 weeks Docetaxel 100 mg/m 2 /3 weeks (n=251) (n=255) Body System/Adverse Event Total % Grade 3 % Grade 4 % Total % Grade 3 % Grade 4 % Hematologic Leukopenia 91 37 24 88 42 33 Neutropenia/Granulocytopenia 86 20 49 87 10 66 Thrombocytopenia 41 2 1 23 1 2 Anemia 80 7 3 83 5 <1 Lymphocytopenia 99 48 41 98 44 40 Hepatobiliary Hyperbilirubinemia 20 7 2 6 2 2 Breast Cancer XELODA Monotherapy The following data are shown for the study in stage IV breast cancer patients who received a dose of 1250 mg/m 2 administered twice daily for 2 weeks followed by a 1-week rest period. The mean duration of treatment was 114 days. A total of 13 out of 162 patients (8%) discontinued treatment because of adverse events/intercurrent illness. Table 16 Percent Incidence of Adverse Events Considered Remotely, Possibly or Probably Related to Treatment in ≥5% of Patients Participating in the Single Arm Trial in Stage IV Breast Cancer Adverse Event Phase 2 Trial in Stage IV Breast Cancer (n=162) Body System/Adverse Event Total % Grade 3 % Grade 4 % – Not observed NA = Not Applicable GI Diarrhea 57 12 3 Nausea 53 4 – Vomiting 37 4 – Stomatitis 24 7 – Abdominal Pain 20 4 – Constipation 15 1 – Dyspepsia 8 – – Skin and Subcutaneous Hand-and-Foot Syndrome 57 11 NA Dermatitis 37 1 – Nail Disorder 7 – – General Fatigue 41 8 – Pyrexia 12 1 – Pain in Limb 6 1 – Neurological Paresthesia 21 1 – Headache 9 1 – Dizziness 8 – – Insomnia 8 – – Metabolism Anorexia 23 3 – Dehydration 7 4 1 Eye Eye Irritation 15 – – Musculoskeletal Myalgia 9 – – Cardiac Edema 9 1 – Blood Neutropenia 26 2 2 Thrombocytopenia 24 3 1 Anemia 72 3 1 Lymphopenia 94 44 15 Hepatobiliary Hyperbilirubinemia 22 9 2 XELODA and Docetaxel in Combination Shown below by body system are the clinically relevant adverse events in <5% of patients in the overall clinical trial safety database of 251 patients (Study Details) reported as related to the administration of XELODA in combination with docetaxel and that were clinically at least remotely relevant. In parentheses is the incidence of grade 3 and 4 occurrences of each adverse event. It is anticipated that the same types of adverse events observed in the XELODA monotherapy studies may be observed in patients treated with the combination of XELODA plus docetaxel. Gastrointestinal: ileus (0.39), necrotizing enterocolitis (0.39), esophageal ulcer (0.39), hemorrhagic diarrhea (0.80) Neurological: ataxia (0.39), syncope (1.20), taste loss (0.80), polyneuropathy (0.39), migraine (0.39) Cardiac: supraventricular tachycardia (0.39) Infection: neutropenic sepsis (2.39), sepsis (0.39), bronchopneumonia (0.39) Blood and Lymphatic: agranulocytosis (0.39), prothrombin decreased (0.39) Vascular: hypotension (1.20), venous phlebitis and thrombophlebitis (0.39), postural hypotension (0.80) Renal: renal failure (0.39) Hepatobiliary: jaundice (0.39), abnormal liver function tests (0.39), hepatic failure (0.39), hepatic coma (0.39), hepatotoxicity (0.39) Immune System: hypersensitivity (1.20) XELODA Monotherapy Metastatic Breast and Colorectal Cancer Shown below by body system are the clinically relevant adverse events in <5% of patients in the overall clinical trial safety database of 875 patients (phase 3 colorectal studies — 596 patients, phase 2 colorectal study — 34 patients, phase 2 breast cancer studies — 245 patients) reported as related to the administration of XELODA and that were clinically at least remotely relevant. In parentheses is the incidence of grade 3 or 4 occurrences of each adverse event. Gastrointestinal: abdominal distension, dysphagia, proctalgia, ascites (0.1), gastric ulcer (0.1), ileus (0.3), toxic dilation of intestine, gastroenteritis (0.1) Skin and Subcutaneous: nail disorder (0.1), sweating increased (0.1), photosensitivity reaction (0.1), skin ulceration, pruritus, radiation recall syndrome (0.2) General: chest pain (0.2), influenza-like illness, hot flushes, pain (0.1), hoarseness, irritability, difficulty in walking, thirst, chest mass, collapse, fibrosis (0.1), hemorrhage, edema, sedation Neurological: insomnia, ataxia (0.5), tremor, dysphasia, encephalopathy (0.1), abnormal coordination, dysarthria, loss of consciousness (0.2), impaired balance Metabolism: increased weight, cachexia (0.4), hypertriglyceridemia (0.1), hypokalemia, hypomagnesemia Eye: conjunctivitis Respiratory: cough (0.1), epistaxis (0.1), asthma (0.2), hemoptysis, respiratory distress (0.1), dyspnea Cardiac: tachycardia (0.1), bradycardia, atrial fibrillation, ventricular extrasystoles, extrasystoles, myocarditis (0.1), pericardial effusion Infections: laryngitis (1.0), bronchitis (0.2), pneumonia (0.2), bronchopneumonia (0.2), keratoconjunctivitis, sepsis (0.3), fungal infections (including candidiasis) (0.2) Musculoskeletal: myalgia, bone pain (0.1), arthritis (0.1), muscle weakness Blood and Lymphatic: leukopenia (0.2), coagulation disorder (0.1), bone marrow depression (0.1), idiopathic thrombocytopenia purpura (1.0), pancytopenia (0.1) Vascular: hypotension (0.2), hypertension (0.1), lymphoedema (0.1), pulmonary embolism (0.2), cerebrovascular accident (0.1) Psychiatric: depression, confusion (0.1) Renal: renal impairment (0.6) Ear: vertigo Hepatobiliary: hepatic fibrosis (0.1), hepatitis (0.1), cholestatic hepatitis (0.1), abnormal liver function tests Immune System: drug hypersensitivity (0.1) Postmarketing: hepatic failure, lacrimal duct stenosis

<table ID="t11" width="80%"> <caption>Table 11 Percent Incidence of Adverse Events Reported in &#x2265;5% of Patients Treated With XELODA or 5-FU/LV for Colon Cancer in the Adjuvant Setting (Safety Population)</caption> <col align="left" width="24%" valign="middle"/> <col align="center" width="19%" valign="middle"/> <col align="center" width="19%" valign="middle"/> <col align="center" width="19%" valign="middle"/> <col align="center" width="19%" valign="middle"/> <thead> <tr> <th styleCode="Lrule"/> <th colspan="4" styleCode="Lrule Rrule">Adjuvant Treatment for Colon Cancer (N=1969)</th> </tr> <tr> <th styleCode="Lrule Toprule"/> <th colspan="2" styleCode="Lrule Toprule">XELODA (N=995)</th> <th colspan="2" styleCode="Lrule Toprule Rrule">5-FU/LV (N=974)</th> </tr> <tr> <th styleCode="Lrule Toprule">Body System/ Adverse Event</th> <th styleCode="Lrule Toprule" valign="top">All Grades</th> <th styleCode="Lrule Toprule" valign="top">Grade 3/4</th> <th styleCode="Lrule Toprule" valign="top">All Grades</th> <th styleCode="Lrule Toprule Rrule" valign="top">Grade 3/4</th> </tr> </thead> <tbody> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold"> <content styleCode="italics">Gastrointestinal Disorders</content> </content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Diarrhea</td> <td styleCode="Rrule">47</td> <td styleCode="Rrule">12</td> <td styleCode="Rrule">65</td> <td styleCode="Rrule">14</td> </tr> <tr> <td styleCode="Lrule Rrule"> Nausea</td> <td styleCode="Rrule">34</td> <td styleCode="Rrule">2</td> <td styleCode="Rrule">47</td> <td styleCode="Rrule">2</td> </tr> <tr> <td styleCode="Lrule Rrule"> Stomatitis</td> <td styleCode="Rrule">22</td> <td styleCode="Rrule">2</td> <td styleCode="Rrule">60</td> <td styleCode="Rrule">14</td> </tr> <tr> <td styleCode="Lrule Rrule"> Vomiting</td> <td styleCode="Rrule">15</td> <td styleCode="Rrule">2</td> <td styleCode="Rrule">21</td> <td styleCode="Rrule">2</td> </tr> <tr> <td styleCode="Lrule Rrule"> Abdominal Pain</td> <td styleCode="Rrule" valign="top">14</td> <td styleCode="Rrule" valign="top">3</td> <td styleCode="Rrule" valign="top">16</td> <td styleCode="Rrule" valign="top">2</td> </tr> <tr> <td styleCode="Lrule Rrule"> Constipation</td> <td styleCode="Rrule">9</td> <td styleCode="Rrule">-</td> <td styleCode="Rrule">11</td> <td styleCode="Rrule">&lt;1</td> </tr> <tr> <td styleCode="Lrule Rrule"> Upper Abdominal Pain</td> <td styleCode="Rrule" valign="top">7</td> <td styleCode="Rrule" valign="top">&lt;1</td> <td styleCode="Rrule" valign="top">7</td> <td styleCode="Rrule" valign="top">&lt;1</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Dyspepsia</td> <td styleCode="Rrule">6</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">5</td> <td styleCode="Rrule">- </td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold"> <content styleCode="italics">Skin and Subcutaneous Tissue Disorders</content> </content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Hand-and-Foot Syndrome</td> <td styleCode="Rrule" valign="top">60</td> <td styleCode="Rrule" valign="top">17</td> <td styleCode="Rrule" valign="top">9</td> <td styleCode="Rrule" valign="top">&lt;1</td> </tr> <tr> <td styleCode="Lrule Rrule"> Alopecia</td> <td styleCode="Rrule">6</td> <td styleCode="Rrule">-</td> <td styleCode="Rrule">22</td> <td styleCode="Rrule">&lt;1</td> </tr> <tr> <td styleCode="Lrule Rrule"> Rash</td> <td styleCode="Rrule">7</td> <td styleCode="Rrule">-</td> <td styleCode="Rrule">8</td> <td styleCode="Rrule">-</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Erythema</td> <td styleCode="Rrule">6</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">5</td> <td styleCode="Rrule">&lt;1</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold"> <content styleCode="italics">General Disorders and Administration Site Conditions</content> </content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Fatigue</td> <td styleCode="Rrule">16</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">16</td> <td styleCode="Rrule">1</td> </tr> <tr> <td styleCode="Lrule Rrule"> Pyrexia</td> <td styleCode="Rrule">7</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">9</td> <td styleCode="Rrule">&lt;1</td> </tr> <tr> <td styleCode="Lrule Rrule"> Asthenia</td> <td styleCode="Rrule">10</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">10</td> <td styleCode="Rrule">1</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Lethargy</td> <td styleCode="Rrule">10</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">9</td> <td styleCode="Rrule">&lt;1</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold"> <content styleCode="italics">Nervous System Disorders</content> </content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Dizziness</td> <td styleCode="Rrule">6</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">6</td> <td styleCode="Rrule">-</td> </tr> <tr> <td styleCode="Lrule Rrule"> Headache</td> <td styleCode="Rrule">5</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">6</td> <td styleCode="Rrule">&lt;1</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Dysgeusia</td> <td styleCode="Rrule">6</td> <td styleCode="Rrule">-</td> <td styleCode="Rrule">9</td> <td styleCode="Rrule">-</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold"> <content styleCode="italics">Metabolism and Nutrition Disorders</content> </content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Anorexia</td> <td styleCode="Rrule">9</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">11</td> <td styleCode="Rrule">&lt;1</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold"> <content styleCode="italics">Eye Disorders</content> </content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Conjunctivitis</td> <td styleCode="Rrule">5</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">6</td> <td styleCode="Rrule">&lt;1</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold"> <content styleCode="italics">Blood and Lymphatic System Disorders</content> </content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Neutropenia</td> <td styleCode="Rrule">2</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">8</td> <td styleCode="Rrule">5</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold"> <content styleCode="italics">Respiratory Thoracic and Mediastinal Disorders</content> </content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Epistaxis</td> <td styleCode="Rrule">2</td> <td styleCode="Rrule">-</td> <td styleCode="Rrule">5</td> <td styleCode="Rrule">-</td> </tr> </tbody> </table>

<table ID="t12" width="70%"> <caption>Table 12 Percent Incidence of Grade 3/4 Laboratory Abnormalities Reported in &#x2265;1% of Patients Receiving XELODA Monotherapy for Adjuvant Treatment of Colon Cancer (Safety Population)</caption> <col align="left" width="50%" valign="middle"/> <col align="center" width="25%" valign="middle"/> <col align="center" width="25%" valign="middle"/> <thead> <tr> <th rowspan="2" styleCode="Lrule" valign="bottom">Adverse Event</th> <th styleCode="Lrule">XELODA (n=995)</th> <th styleCode="Lrule Rrule">IV 5-FU/LV (n=974)</th> </tr> <tr> <th align="center" styleCode="Lrule">Grade 3/4 %</th> <th styleCode="Lrule Rrule">Grade 3/4 %</th> </tr> </thead> <tbody> <tr> <td styleCode="Lrule Rrule"> Increased ALAT (SGPT)</td> <td styleCode="Rrule">1.6</td> <td styleCode="Rrule">0.6</td> </tr> <tr> <td styleCode="Lrule Rrule"> Increased calcium </td> <td styleCode="Rrule">1.1</td> <td styleCode="Rrule">0.7</td> </tr> <tr> <td styleCode="Lrule Rrule"> Decreased calcium</td> <td styleCode="Rrule">2.3</td> <td styleCode="Rrule">2.2</td> </tr> <tr> <td styleCode="Lrule Rrule"> Decreased hemoglobin</td> <td styleCode="Rrule">1.0</td> <td styleCode="Rrule">1.2</td> </tr> <tr> <td styleCode="Lrule Rrule"> Decreased lymphocytes</td> <td styleCode="Rrule">13.0</td> <td styleCode="Rrule">13.0</td> </tr> <tr> <td styleCode="Lrule Rrule"> Decreased neutrophils<footnote>The incidence of grade 3/4 white blood cell abnormalities was 1.3% in the XELODA arm and 4.9% in the IV 5-FU/LV arm.</footnote> </td> <td styleCode="Rrule">2.2</td> <td styleCode="Rrule">26.2</td> </tr> <tr> <td styleCode="Lrule Rrule"> Decreased neutrophils/granulocytes</td> <td styleCode="Rrule">2.4</td> <td styleCode="Rrule">26.4</td> </tr> <tr> <td styleCode="Lrule Rrule"> Decreased platelets</td> <td styleCode="Rrule">1.0</td> <td styleCode="Rrule">0.7</td> </tr> <tr> <td styleCode="Lrule Rrule"> Increased bilirubin<footnote>It should be noted that grading was according to NCIC CTC Version 1 (May, 1994). In the NCIC-CTC Version 1, hyperbilirubinemia grade 3 indicates a bilirubin value of 1.5 to 3.0 &#xD7; upper limit of normal (ULN) range, and grade 4 a value of &gt; 3.0 &#xD7; ULN. The NCI CTC Version 2 and above define a grade 3 bilirubin value of &gt;3.0 to 10.0 &#xD7; ULN, and grade 4 values &gt;10.0 &#xD7; ULN.</footnote> </td> <td styleCode="Rrule">20</td> <td styleCode="Rrule">6.3</td> </tr> </tbody> </table>

<table ID="t13" width="85%"> <caption>Table 13 Pooled Phase 3 Colorectal Trials: Percent Incidence of Adverse Events in &#x2265;5% of Patients</caption> <col align="left" width="34%" valign="middle"/> <col align="center" width="11%" valign="middle"/> <col align="center" width="11%" valign="middle"/> <col align="center" width="11%" valign="middle"/> <col align="center" width="11%" valign="middle"/> <col align="center" width="11%" valign="middle"/> <col align="center" width="11%" valign="middle"/> <thead> <tr> <th styleCode="Lrule" valign="top">Adverse Event</th> <th colspan="3" styleCode="Lrule">XELODA (n=596)</th> <th colspan="3" styleCode="Lrule Botrule Rrule">5-FU/LV (n=593)</th> </tr> <tr> <th styleCode="Lrule Toprule"/> <th styleCode="Lrule Toprule">Total %</th> <th styleCode="Lrule Toprule">Grade 3 %</th> <th styleCode="Lrule Toprule">Grade 4 %</th> <th styleCode="Lrule Toprule">Total %</th> <th styleCode="Lrule Toprule">Grade 3 %</th> <th styleCode="Lrule Toprule Rrule">Grade 4 %</th> </tr> </thead> <tfoot> <tr> <td colspan="7" align="left">&#x2013; Not observed</td> </tr> <tr> <td colspan="7" align="left">NA = Not Applicable</td> </tr> </tfoot> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Number of Patients With </content> <content styleCode="bold">&gt;</content> <content styleCode="bold"> One Adverse Event</content> </td> <td styleCode="Rrule">96</td> <td styleCode="Rrule">52</td> <td styleCode="Rrule">9</td> <td styleCode="Rrule">94</td> <td styleCode="Rrule">45</td> <td styleCode="Rrule">9</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Body System/Adverse Event</content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold"> <content styleCode="italics">GI</content> </content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Diarrhea</td> <td styleCode="Rrule">55</td> <td styleCode="Rrule">13</td> <td styleCode="Rrule">2</td> <td styleCode="Rrule">61</td> <td styleCode="Rrule">10</td> <td styleCode="Rrule">2</td> </tr> <tr> <td styleCode="Lrule Rrule"> Nausea</td> <td styleCode="Rrule">43</td> <td styleCode="Rrule">4</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">51</td> <td styleCode="Rrule">3</td> <td styleCode="Rrule">&lt;1</td> </tr> <tr> <td styleCode="Lrule Rrule"> Vomiting</td> <td styleCode="Rrule">27</td> <td styleCode="Rrule">4</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">30</td> <td styleCode="Rrule">4</td> <td styleCode="Rrule">&lt;1</td> </tr> <tr> <td styleCode="Lrule Rrule"> Stomatitis</td> <td styleCode="Rrule">25</td> <td styleCode="Rrule">2</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">62</td> <td styleCode="Rrule">14</td> <td styleCode="Rrule">1</td> </tr> <tr> <td styleCode="Lrule Rrule"> Abdominal Pain</td> <td styleCode="Rrule">35</td> <td styleCode="Rrule">9</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">31</td> <td styleCode="Rrule">5</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr> <td styleCode="Lrule Rrule"> Gastrointestinal Motility Disorder</td> <td styleCode="Rrule">10</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">7</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr> <td styleCode="Lrule Rrule"> Constipation</td> <td styleCode="Rrule">14</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">17</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr> <td styleCode="Lrule Rrule"> Oral Discomfort</td> <td styleCode="Rrule">10</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">10</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr> <td styleCode="Lrule Rrule"> Upper GI Inflammatory Disorders</td> <td styleCode="Rrule">8</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">10</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr> <td styleCode="Lrule Rrule"> Gastrointestinal Hemorrhage</td> <td styleCode="Rrule">6</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">3</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Ileus</td> <td styleCode="Rrule">6</td> <td styleCode="Rrule">4</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">5</td> <td styleCode="Rrule">2</td> <td styleCode="Rrule">1</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold"> <content styleCode="italics">Skin and Subcutaneous</content> </content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Hand-and-Foot Syndrome</td> <td styleCode="Rrule">54</td> <td styleCode="Rrule">17</td> <td styleCode="Rrule">NA</td> <td styleCode="Rrule">6</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">NA</td> </tr> <tr> <td styleCode="Lrule Rrule"> Dermatitis</td> <td styleCode="Rrule">27</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">26</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr> <td styleCode="Lrule Rrule"> Skin Discoloration</td> <td styleCode="Rrule">7</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">5</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Alopecia</td> <td styleCode="Rrule">6</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">21</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold"> <content styleCode="italics">General</content> </content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Fatigue/Weakness</td> <td styleCode="Rrule">42</td> <td styleCode="Rrule">4</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">46</td> <td styleCode="Rrule">4</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr> <td styleCode="Lrule Rrule"> Pyrexia</td> <td styleCode="Rrule">18</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">21</td> <td styleCode="Rrule">2</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr> <td styleCode="Lrule Rrule"> Edema</td> <td styleCode="Rrule">15</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">9</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr> <td styleCode="Lrule Rrule"> Pain</td> <td styleCode="Rrule">12</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">10</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Chest Pain</td> <td styleCode="Rrule">6</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">6</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">&lt;1</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold"> <content styleCode="italics">Neurological</content> </content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Peripheral Sensory Neuropathy</td> <td styleCode="Rrule">10</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">4</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr> <td styleCode="Lrule Rrule"> Headache</td> <td styleCode="Rrule">10</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">7</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr> <td styleCode="Lrule Rrule"> Dizziness<footnote>Excluding vertigo</footnote> </td> <td styleCode="Rrule">8</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">8</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr> <td styleCode="Lrule Rrule"> Insomnia</td> <td styleCode="Rrule">7</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">7</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Taste Disturbance</td> <td styleCode="Rrule">6</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">11</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">1</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold"> <content styleCode="italics">Metabolism</content> </content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Appetite Decreased</td> <td styleCode="Rrule">26</td> <td styleCode="Rrule">3</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">31</td> <td styleCode="Rrule">2</td> <td styleCode="Rrule">&lt;1</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Dehydration</td> <td styleCode="Rrule">7</td> <td styleCode="Rrule">2</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">8</td> <td styleCode="Rrule">3</td> <td styleCode="Rrule">1</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold"> <content styleCode="italics">Eye</content> </content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Eye Irritation</td> <td styleCode="Rrule">13</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">10</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Vision Abnormal</td> <td styleCode="Rrule">5</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">2</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold"> <content styleCode="italics">Respiratory</content> </content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Dyspnea</td> <td styleCode="Rrule">14</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">10</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">1</td> </tr> <tr> <td styleCode="Lrule Rrule"> Cough</td> <td styleCode="Rrule">7</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">8</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr> <td styleCode="Lrule Rrule"> Pharyngeal Disorder</td> <td styleCode="Rrule">5</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">5</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr> <td styleCode="Lrule Rrule"> Epistaxis</td> <td styleCode="Rrule">3</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">6</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Sore Throat</td> <td styleCode="Rrule">2</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">6</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold"> <content styleCode="italics">Musculoskeletal</content> </content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Back Pain</td> <td styleCode="Rrule">10</td> <td styleCode="Rrule">2</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">9</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Arthralgia</td> <td styleCode="Rrule">8</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">6</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold"> <content styleCode="italics">Vascular</content> </content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Venous Thrombosis</td> <td styleCode="Rrule">8</td> <td styleCode="Rrule">3</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">6</td> <td styleCode="Rrule">2</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold"> <content styleCode="italics">Psychiatric</content> </content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Mood Alteration</td> <td styleCode="Rrule">5</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">6</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Depression</td> <td styleCode="Rrule">5</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">4</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold"> <content styleCode="italics">Infections</content> </content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Viral</td> <td styleCode="Rrule">5</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">&#x2013;</td> <td styleCode="Rrule">5</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">&#x2013;</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold"> <content styleCode="italics">Blood and Lymphatic</content> </content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Anemia</td> <td styleCode="Rrule">80</td> <td styleCode="Rrule">2</td> <td styleCode="Rrule">&lt;1</td> <td styleCode="Rrule">79</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">&lt;1</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Neutropenia</td> <td styleCode="Rrule">13</td> <td styleCode="Rrule">1</td> <td styleCode="Rrule">2</td> <td styleCode="Rrule">46</td> <td styleCode="Rrule">8</td> <td styleCode="Rrule">13</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="bold"> <content styleCode="italics">Hepatobiliary</content> </content> </td> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> <td styleCode="Rrule"/> </tr> <tr> <td styleCode="Lrule Rrule"> Hyperbilirubinemia</td> <td styleCode="Rrule">48</td> <td styleCode="Rrule">18</td> <td styleCode="Rrule">5</td> <td styleCode="Rrule">17</td> <td styleCode="Rrule">3</td> <td styleCode="Rrule">3</td> </tr> </tbody> </table>