Capecitabine

WARNING: CAPECITABINE -WARFARIN INTERACTION Capecitabine 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 capecitabine -Warfarin drug interaction was demonstrated in a clinical pharmacology trial [see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7.1 )] . Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking capecitabine 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 capecitabine was introduced. These events occurred within several days and up to several months after initiating capecitabine therapy and, in a few cases, within 1 month after stopping capecitabine. 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. WARNING: CAPECITABINE -WARFARIN INTERACTION See full prescribing information for complete boxed warning . Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulants such as warfarin and phenprocoumon should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. Altered coagulation parameters and/or bleeding, including death, have been reported during concomitant use. Occurrence: Within several days and up to several months after initiating capecitabine therapy; may also be seen within 1 month after stopping capecitabine Predisposing factors: age>60 and diagnosis of cancer

5 WARNINGS AND PRECAUTIONS Coagulopathy: May result in bleeding, death. Monitor anticoagulant response (e.g., INR) and adjust anticoagulant dose accordingly. ( 5.1 ) Diarrhea : May be severe. Interrupt capecitabine treatment immediately until diarrhea resolves or decreases to grade 1. Recommend standard antidiarrheal treatments. ( 5.2 ) Cardiotoxicity: Common in patients with a prior history of coronary artery disease. ( 5.3 ) Increased Risk of Severe or Fatal Adverse Reactions in Patients with Low or Absent Dihydropyrimidine Dehydrogenase (DPD) Activity: Withhold or permanently discontinue capecitabine in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No capecitabine dose has been proven safe in patients with absent DPD activity. ( 5.4 ) Dehydration and Renal Failure: Interrupt capecitabine treatment until dehydration is corrected. Potential risk of acute renal failure secondary to dehydration. Monitor and correct dehydration. ( 5.5 ). Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 ) Mucocutaneous and Dermatologic Toxicity: Severe mucocutaneous reactions, Steven-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), have been reported. Capecitabine should be permanently discontinued in patients who experience a severe mucocutaneous reaction during treatment. Capecitabine may induce hand-and-foot syndrome. Persistent or severe hand-and-foot syndrome can lead to loss of fingerprints which could impact patient identification. Interrupt capecitabine treatment until the hand-and-foot syndrome event resolves or decreases in intensity. ( 5.7 ) Hyperbilirubinemia: Interrupt capecitabine treatment immediately until the hyperbilirubinemia resolves or decreases in intensity. ( 5.8 ) Hematologic: Do not treat patients with neutrophil counts <1.5 x 10 9 /L or thrombocyte counts <100 x 10 9 /L. If grade 3-4 neutropenia or thrombocytopenia occurs, stop therapy until condition resolves. ( 5.9 ) 5.1 Coagulopathy Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored closely with great frequency and the anticoagulant dose should be adjusted accordingly [ see Boxed Warning and Drug Interactions ( 7.1 ) ]. 5.2 Diarrhea Capecitabine 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 capecitabine 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 capecitabine should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1 [see Dosage and Administration ( 2.3 )] . Standard antidiarrheal treatments (e.g, loperamide) are recommended. Necrotizing enterocolitis (typhlitis) has been reported. 5.3 Cardiotoxicity The cardiotoxicity observed with capecitabine includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy. These adverse reactions may be more common in patients with a prior history of coronary artery disease. 5.4 Dihydropyrimidine Dehydrogenase Deficiency Based on postmarketing reports, patients with certain homozygous or certain compound heterozygous mutations in the DPD gene that result in complete or near complete absence of DPD activity are at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by capecitabine (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions caused by capecitabine. Withhold or permanently discontinue capecitabine based on clinical assessment of the onset, duration and severity of the observed toxicities in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No capecitabine dose has been proven safe for patients with complete absence of DPD activity. There is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by any specific test. 5.5 Dehydration and Renal Failure Dehydration has been observed and may cause acute renal failure which can be fatal. Patients with pre-existing compromised renal function or who are receiving concomitant capecitabine with known nephrotoxic agents are at higher risk. Patients with anorexia, asthenia, nausea, vomiting or diarrhea may rapidly become dehydrated. Monitor patients when capecitabine is administered to prevent and correct dehydration at the onset. If grade 2 (or higher) dehydration occurs, capecitabine treatment should be immediately interrupted and the dehydration corrected. Treatment should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled. Dose modifications should be applied for the precipitating adverse event as necessary [see Dosage and Administration ( 2.3 )]. Patients with moderate renal impairment at baseline require dose reduction [see Dosage and Administration ( 2.4 )] . Patients with mild and moderate renal impairment at baseline should be carefully monitored for adverse reactions. 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 2 [see Dosage and Administration ( 2.3 ), Use in Specific Populations ( 8.7 ), and Clinical Pharmacology ( 12.3 )] . 5.6 Embryo-Fetal Toxicity Based on findings from animal reproduction studies and its mechanism of action, capecitabine may cause fetal harm when given to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . Limited available data are not sufficient to inform use of capecitabine in pregnant women. In animal reproduction studies, administration of capecitabine to pregnant animals during the period of organogenesis caused embryolethality and teratogenicity in mice and embryolethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving the recommended dose respectively [see Use in Specific Populations ( 8.1 )] . Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of capecitabine [see Use in Specific Populations ( 8.3 )] . 5.7 Mucocutaneous and Dermatologic Toxicity Severe mucocutaneous reactions, some with fatal outcome, such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis (TEN) can occur in patients treated with capecitabine [see Adverse Reactions ( 6.4 )] . Capecitabine should be permanently discontinued in patients who experience a severe mucocutaneous reaction possibly attributable to capecitabine treatment. Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) is a cutaneous toxicity. Median time to onset was 79 days (range from 11 to 360 days) with a severity range of grades 1 to 3 for patients receiving capecitabine monotherapy in the metastatic setting. Grade 1 is characterized by any of the following: numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt normal activities. Grade 2 hand-and-foot syndrome is defined as painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient's activities of daily living. Grade 3 hand-and-foot syndrome is defined as moist desquamation, ulceration, blistering or severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living. Persistent or severe hand-and-foot syndrome (grade 2 and above) can eventually lead to loss of fingerprints which could impact patient identification. If grade 2 or 3 hand-and-foot syndrome occurs, administration of capecitabine should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-and-foot syndrome, subsequent doses of capecitabine should be decreased [see Dosage and Administration ( 2.3 )] . 5.8 Hyperbilirubinemia In 875 patients with either metastatic breast or colorectal cancer who received at least one dose of capecitabine 1,250 mg/m 2 twice daily as monotherapy for 2 weeks followed by a 1-week rest period, grade 3 (1.5-3 x ULN) hyperbilirubinemia occurred in 15.2% (n=133) of patients and grade 4 (>3 x ULN) hyperbilirubinemia occurred in 3.9% (n=34) of patients. Of 566 patients who had hepatic metastases at baseline and 309 patients without hepatic metastases at baseline, grade 3 or 4 hyperbilirubinemia occurred in 22.8% and 12.3%, respectively. Of the 167 patients with grade 3 or 4 hyperbilirubinemia, 18.6% (n=31) also had postbaseline elevations (grades 1 to 4, without elevations at baseline) in alkaline phosphatase and 27.5% (n=46) had postbaseline elevations in transaminases at any time (not necessarily concurrent). The majority of these patients, 64.5% (n=20) and 71.7% (n=33), had liver metastases at baseline. In addition, 57.5% (n=96) and 35.3% (n=59) of the 167 patients had elevations (grades 1 to 4) at both prebaseline and postbaseline in alkaline phosphatase or transaminases, respectively. Only 7.8% (n=13) and 3.0% (n=5) had grade 3 or 4 elevations in alkaline phosphatase or transaminases. In the 596 patients treated with capecitabine as first-line therapy for metastatic colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was similar to the overall clinical trial safety database of capecitabine monotherapy. The median time to onset for grade 3 or 4 hyperbilirubinemia in the colorectal cancer population was 64 days and median total bilirubin increased from 8 μm/L at baseline to 13 μm/L during treatment with capecitabine. Of the 136 colorectal cancer patients with grade 3 or 4 hyperbilirubinemia, 49 patients had grade 3 or 4 hyperbilirubinemia as their last measured value, of which 46 had liver metastases at baseline. In 251 patients with metastatic breast cancer who received a combination of capecitabine and docetaxel, grade 3 (1.5 to 3 x ULN) hyperbilirubinemia occurred in 7% (n=17) and grade 4 (>3 x ULN) hyperbilirubinemia occurred in 2% (n=5). If drug-related grade 3 to 4 elevations in bilirubin occur, administration of capecitabine should be immediately interrupted until the hyperbilirubinemia decreases to ≤3.0 X ULN [ see recommended dose modifications under Dosage and Administration ( 2.3 )] . 5.9 Hematologic In 875 patients with either metastatic breast or colorectal cancer who received a dose of 1,250 mg/m 2 administered twice daily as monotherapy for 2 weeks followed by a 1-week rest period, 3.2%, 1.7%, and 2.4% of patients had grade 3 or 4 neutropenia, thrombocytopenia or decreases in hemoglobin, respectively. In 251 patients with metastatic breast cancer who received a dose of capecitabine in combination with docetaxel, 68% had grade 3 or 4 neutropenia, 2.8% had grade 3 or 4 thrombocytopenia, and 9.6% had grade 3 or 4 anemia. Patients with baseline neutrophil counts of <1.5 x 10 9 /L and/or thrombocyte counts of <100 x 10 9 /L should not be treated with capecitabine. If unscheduled laboratory assessments during a treatment cycle show grade 3 or 4 hematologic toxicity, treatment with capecitabine should be interrupted. 5.10 Geriatric Patients Patients ≥80 years old may experience a greater incidence of grade 3 or 4 adverse reactions. In 875 patients with either metastatic breast or colorectal cancer who received capecitabine monotherapy, 62% of the 21 patients ≥80 years of age treated with capecitabine 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 capecitabine 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 capecitabine in combination with docetaxel, the incidence of grade 3 or 4 treatment-related adverse reactions, treatment-related serious adverse reactions, withdrawals due to adverse reactions, treatment discontinuations due to adverse reactions and treatment discontinuations within the first two treatment cycles was higher than in the <60 years of age patient group. In 995 patients receiving capecitabine 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 capecitabine 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%), 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 capecitabine 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. 5.11 Hepatic Insufficiency Patients with mild to moderate hepatic dysfunction due to liver metastases should be carefully monitored when capecitabine is administered. The effect of severe hepatic dysfunction on the disposition of capecitabine is not known [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )] . 5.12 Combination With Other Drugs Use of capecitabine in combination with irinotecan has not been adequately studied.

6 ADVERSE REACTIONS 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. Most common adverse reactions (≥30%) were diarrhea, hand-and-foot syndrome, nausea, vomiting, abdominal pain, fatigue/weakness, and hyperbilirubinemia. Other adverse reactions, including serious adverse reactions, have been reported. ( 6) To report SUSPECTED ADVERSE REACTIONS, contact Cipla Limited, at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Adjuvant Colon Cancer Table 4 shows the adverse reactions 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 1,250 mg/m2 twice a day of capecitabine administered for 2 weeks followed by a 1-week rest period, and 974 patients were administered 5-FU and leucovorin (20 mg/m2 leucovorin IV followed by 425 mg/m2 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 reactions. 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 capecitabine and 10 (1%) randomized to 5-FU/LV. Table 5 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 4 Percent Incidence of Adverse Reactions Reported in ≥5% of Patients Treated With Capecitabine or 5-FU/LV for Colon Cancer in the Adjuvant Setting (Safety Population) Adjuvant Treatment for Colon Cancer (N=1,969) Capecitabine ( N=995) 5-FU/LV ( N=974) B o d y System/Adverse Event All Grades Grade 3/4 All Grades Grade 3/4 Gastrointestinal Disorders Diarrhea Nausea Stomatitis Vomiting Abdominal Pain Constipation Upper Abdominal Pain Dyspepsia 47 34 22 15 14 9 7 6 12 2 2 2 3 - <1 <1 65 47 60 21 16 11 7 5 14 2 14 2 2 <1 <1 - S kin and Subcutaneous T issue Disorders Hand-and-Foot Syndrome Alopecia Rash Erythema 60 6 7 6 17 - - 1 9 22 8 5 <1 <1 - <1 General Disorders and Administration Site Conditions Fatigue Pyrexia Asthenia Lethargy 16 7 10 10 <1 <1 <1 <1 16 9 10 9 1 <1 1 <1 Nervous System Disorders Dizziness Headache Dysgeusia 6 5 6 <1 <1 - 6 6 9 - <1 - M e tabolism and Nutrition Disorders Anorexia 9 <1 11 <1 E y e Disorders Conjunctivitis 5 <1 6 <1 Blood and Lymphatic System Disorders Neutropenia 2 <1 8 5 R e s piratory Thoracic and Mediastinal Disorders Epistaxis 2 - 5 - Table 5 Percent Incidence of Grade 3/4 Laboratory Abnormalities Reported in ≥1% of Patients Receiving Capecitabine Monotherapy for Adjuvant Treatment of Colon Cancer (Safety Population) *The incidence of grade 3/4 white blood cell abnormalities was 1.3% in the capecitabine arm and 4.9% in the IV 5-FU/LV arm. **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. Adverse Event Capecitabine ( n = 995) Grade 3/4 % I V 5-FU/LV ( n = 974) 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* 2.2 26.2 Decreased neutrophils/granulocytes 2.4 26.4 Decreased platelets 1.0 0.7 Increased bilirubin** 20 6.3 6.2 Metastatic Colorectal Cancer Monotherapy Table 6 shows the adverse reactions 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 1,250 mg/m 2 twice a day of capecitabine 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 reactions/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 capecitabine and 32 (5.4%) randomized to 5-FU/LV. Table 6 Pooled Phase 3 Colorectal Trials: Percent Incidence of Adverse Reactions in ≥5% of Patients – Not observed * Excluding vertigo NA = Not Applicable Ad v er s e Event Capecitabine (n=596) 5-FU/LV (n=593) Total % Gr ade 3 % Gr ade 4 % Total % Gr ade 3 % Gr ade 4 % Nu m b e r of Patients With ˃ One Ad v er s e Event 96 52 9 94 45 9 B o d y System/Adverse Event GI Diarrhea Nausea Vomiting Stomatitis Abdominal Pain Gastrointestinal Motility Disorder Constipation Oral Discomfort Upper GI Inflammatory Disorders Gastrointestinal Hemorrhage Ileus 55 43 27 25 35 10 14 10 8 6 6 13 4 4 2 9 ˂1 1 – ˂1 1 4 2 – ˂1 ˂1 ˂1 – ˂1 – – ˂1 1 61 51 30 62 31 7 17 10 10 3 5 10 3 4 14 5 ˂1 1 – 1 1 2 2 ˂1 ˂1 1 – – – – – – 1 S kin 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 – G e n e r al 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 N e ur ological Peripheral Sensory Neuropathy 10 – – 4 – – Headache 10 1 – 7 – – Dizziness* 8 ˂1 – 8 ˂1 – Insomnia 7 – – 7 – – Taste Disturbance 6 1 – 11 ˂1 1 M et abolism Appetite Decreased 26 3 ˂1 31 2 ˂1 Dehydration 7 2 ˂1 8 3 1 E y e 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 – – Mus c u l oskeletal Back Pain 10 2 – 9 ˂1 – Arthralgia 8 1 – 6 1 – V ascular Venous Thrombosis 8 3 ˂1 6 2 – P s yc h i atric Mood Alteration 5 – – 6 ˂1 – Depression 5 – – 4 ˂1 – In fections Viral 5 ˂1 – 5 ˂1 – Blood and Lymphatic Anemia 80 2 ˂1 79 1 ˂1 Neutropenia 13 1 2 46 8 13 He patobiliary Hyperbilirubinemia 48 18 5 17 3 3 6.3 Breast Cancer In Combination with Docetaxel The following data are shown for the combination study with capecitabine and docetaxel in patients with metastatic breast cancer in Table 7 and Table 8. In the capecitabine and docetaxel combination arm the treatment was capecitabine administered orally 1,250 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 reactions. The percentage of patients requiring dose reductions due to adverse reactions was 65% in the combination arm and 36% in the monotherapy arm. The percentage of patients requiring treatment interruptions due to adverse reactions 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. 6.4 Clinically Relevant Adverse Events in <5% of Patients Clinically relevant adverse events reported in <5% of patients treated with capecitabine either as monotherapy or in combination with docetaxel that were considered at least remotely related to treatment are shown below; occurrences of each grade 3 and 4 adverse event are provided in parentheses. Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer Gastrointestinal : abdominal distension, dysphagia, proctalgia, ascites (0.1%), gastric ulcer (0.1%), ileus (0.3%), toxic dilation of intestine, gastroenteritis (0.1%) Skin & Subcutan. : 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%), 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 & Lymphatic : leukopenia (0.2%), coagulation disorder (0.1%), bone marrow depression (0.1%), idiopathic thrombocytopenia purpura (1%), pancytopenia (0.1%) Vascular : hypotension (0.2%), hypertension (0.1%), lymphedema (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%) Capecitabine In Combination With Docetaxel (Metastatic Breast Cancer) Gastrointestinal : ileus (0.4%), necrotizing enterocolitis (0.4%), esophageal ulcer (0.4%), hemorrhagic diarrhea (0.8%) Neurological : ataxia (0.4%), syncope (1.2%), taste loss (0.8%), polyneuropathy (0.4%), migraine (0.4%) Cardiac : supraventricular tachycardia (0.4%) Infection : neutropenic sepsis (2.4%), sepsis (0.4%), bronchopneumonia (0.4%) Blood & Lymphatic : agranulocytosis (0.4%), prothrombin decreased (0.4%) Vascular : hypotension (1.2%), venous phlebitis and thrombophlebitis (0.4%), postural hypotension (0.8%) Renal : renal failure (0.4%) Hepatobiliary : jaundice (0.4%), abnormal liver function tests (0.4%), hepatic failure (0.4%), hepatic coma (0.4%), hepatotoxicity (0.4%) Immune System : hypersensitivity (1.2%) 6.5 Postmarketing Experience The following adverse reactions have been observed in the postmarketing setting: hepatic failure, lacrimal duct stenosis, acute renal failure secondary to dehydration including fatal outcome [see Warnings and Precautions ( 5.5 )] , cutaneous lupus erythematosus, corneal disorders including keratitis, toxic leukoencephalopathy, severe skin reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (TEN) [see Warnings and Precautions ( 5.7 )], persistent or severe hand-and-foot syndrome can eventually lead to loss of fingerprints [ see Warnings and Precautions ( 5.7 ) ] In instances of exposure to crushed capecitabine tablets, the following adverse reactions have been reported: eye irritation and swelling, skin rash, diarrhea, paresthesia, headache, gastric irritation, vomiting, and nausea.

<table ID="ID360" width="84%" styleCode="Noautorules"><caption> Table 4 Percent Incidence of Adverse Reactions Reported in &#x2265;5% of Patients Treated With Capecitabine or 5-FU/LV for Colon Cancer in the Adjuvant Setting (Safety Population) </caption><col width="32%"/><col width="17%"/><col width="15%"/><col width="17%"/><col width="17%"/><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule"/><td colspan="4" valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Adjuvant Treatment for Colon Cancer (N=1,969)</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule"/><td colspan="2" valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Capecitabine</content> <content styleCode="bold"> (</content><content styleCode="bold"> N=995)</content> </td><td colspan="2" valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> 5-FU/LV </content> <content styleCode="bold"> (</content><content styleCode="bold"> N=974)</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> B</content><content styleCode="bold"> o</content><content styleCode="bold"> d</content><content styleCode="bold"> y System/Adverse Event </content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> All Grades</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Grade 3/4</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> All Grades</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Grade 3/4</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"><content styleCode="italics">Gastrointestinal Disorders</content></content> Diarrhea Nausea Stomatitis Vomiting Abdominal Pain Constipation Upper Abdominal Pain Dyspepsia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 47 34 22 15 14 9 7 6 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 12 2 2 2 3 - &lt;1 &lt;1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 65 47 60 21 16 11 7 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 14 2 14 2 2 &lt;1 &lt;1 - </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"><content styleCode="italics">S</content></content><content styleCode="bold"><content styleCode="italics">kin and Subcutaneous</content></content> <content styleCode="bold"><content styleCode="italics">T</content></content><content styleCode="bold"><content styleCode="italics">issue Disorders </content></content> Hand-and-Foot Syndrome Alopecia Rash Erythema </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 60 6 7 6 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 17 - - 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9 22 8 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &lt;1 &lt;1 - &lt;1 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"><content styleCode="italics">General Disorders and Administration Site Conditions</content></content> Fatigue Pyrexia Asthenia Lethargy </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 16 7 10 10 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &lt;1 &lt;1 &lt;1 &lt;1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 16 9 10 9 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 &lt;1 1 &lt;1 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"><content styleCode="italics">Nervous System Disorders </content></content> Dizziness Headache Dysgeusia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 5 6 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &lt;1 &lt;1 - </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 6 9 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> - &lt;1 - </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"><content styleCode="italics">M</content></content><content styleCode="bold"><content styleCode="italics">e</content></content><content styleCode="bold"><content styleCode="italics">tabolism and</content></content><content styleCode="bold"><content styleCode="italics">Nutrition Disorders</content></content> Anorexia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &lt;1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 11 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &lt;1 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"><content styleCode="italics">E</content></content><content styleCode="bold"><content styleCode="italics">y</content></content><content styleCode="bold"><content styleCode="italics">e Disorders </content></content> Conjunctivitis </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &lt;1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &lt;1 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"><content styleCode="italics">Blood and Lymphatic System Disorders</content></content> Neutropenia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &lt;1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"><content styleCode="italics">R</content></content><content styleCode="bold"><content styleCode="italics">e</content></content><content styleCode="bold"><content styleCode="italics">s</content></content><content styleCode="bold"><content styleCode="italics">piratory Thoracic and Mediastinal Disorders</content></content> Epistaxis </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> - </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> - </td></tr></tbody></table>

<table ID="ID361" width="75%" styleCode="Noautorules"><caption> Table 5 Percent Incidence of Grade 3/4 Laboratory Abnormalities Reported in &#x2265;1% of Patients Receiving Capecitabine Monotherapy for Adjuvant Treatment of Colon Cancer (Safety Population) </caption><col width="43%"/><col width="28%"/><col width="28%"/><tfoot><tr><td align="left" colspan="3"><paragraph styleCode="Footnote">*The incidence of grade 3/4 white blood cell abnormalities was 1.3% in the capecitabine arm and 4.9% in the IV 5-FU/LV arm.</paragraph></td></tr><tr><td align="left" colspan="3"><paragraph styleCode="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</paragraph></td></tr><tr><td align="left" colspan="3"><paragraph styleCode="Footnote">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</paragraph></td></tr><tr><td align="left" colspan="3"><paragraph styleCode="Footnote">bilirubin value of &gt;3.0 to 10.0 &#xD7; ULN, and grade 4 values &gt;10.0 &#xD7; ULN.</paragraph></td></tr></tfoot><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule" align="left"><content styleCode="bold"> Adverse Event</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Capecitabine</content> <content styleCode="bold"> (</content><content styleCode="bold"> n</content><content styleCode="bold"> =</content><content styleCode="bold"> 995)</content> <content styleCode="bold"> Grade 3/4 %</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> I</content><content styleCode="bold"> V 5-FU/LV </content> <content styleCode="bold"> (</content><content styleCode="bold"> n</content><content styleCode="bold"> =</content><content styleCode="bold"> 974)</content> <content styleCode="bold"> Grade 3/4 %</content> </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Increased ALAT (SGPT) </td><td valign="top" styleCode=" Rrule" align="center"> 1.6 </td><td valign="top" styleCode=" Rrule" align="center"> 0.6 </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Increased calcium </td><td valign="top" styleCode=" Rrule" align="center"> 1.1 </td><td valign="top" styleCode=" Rrule" align="center"> 0.7 </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Decreased calcium </td><td valign="top" styleCode=" Rrule" align="center"> 2.3 </td><td valign="top" styleCode=" Rrule" align="center"> 2.2 </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Decreased hemoglobin </td><td valign="top" styleCode=" Rrule" align="center"> 1.0 </td><td valign="top" styleCode=" Rrule" align="center"> 1.2 </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Decreased lymphocytes </td><td valign="top" styleCode=" Rrule" align="center"> 13.0 </td><td valign="top" styleCode=" Rrule" align="center"> 13.0 </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Decreased neutrophils* </td><td valign="top" styleCode=" Rrule" align="center"> 2.2 </td><td valign="top" styleCode=" Rrule" align="center"> 26.2 </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Decreased neutrophils/granulocytes </td><td valign="top" styleCode=" Rrule" align="center"> 2.4 </td><td valign="top" styleCode=" Rrule" align="center"> 26.4 </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Decreased platelets </td><td valign="top" styleCode=" Rrule" align="center"> 1.0 </td><td valign="top" styleCode=" Rrule" align="center"> 0.7 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Increased bilirubin** </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 20 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6.3 </td></tr></tbody></table>

<table ID="ID364" width="614"><caption> Table 6 Pooled Phase 3 Colorectal Trials: Percent Incidence of Adverse Reactions in &#x2265;5% of Patients </caption><col width="205"/><col width="85"/><col width="60"/><col width="54"/><col width="78"/><col width="72"/><col width="60"/><tfoot><tr><td align="left" colspan="7"><paragraph styleCode="Footnote">&#x2013; Not observed</paragraph></td></tr><tr><td align="left" colspan="7"><paragraph styleCode="Footnote">* Excluding vertigo</paragraph></td></tr><tr><td align="left" colspan="7"><paragraph styleCode="Footnote">NA = Not Applicable</paragraph></td></tr></tfoot><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule" align="left"><content styleCode="bold"> Ad</content><content styleCode="bold"> v</content><content styleCode="bold"> er</content><content styleCode="bold"> s</content><content styleCode="bold"> e Event</content> </td><td colspan="3" valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Capecitabine</content> <content styleCode="bold"> (n=596)</content> </td><td colspan="3" valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> 5-FU/LV</content> <content styleCode="bold"> (n=593)</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule" align="left"><content styleCode="bold"> Total</content> <content styleCode="bold"> %</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Gr</content><content styleCode="bold"> ade 3</content> <content styleCode="bold"> %</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Gr</content><content styleCode="bold"> ade 4</content> <content styleCode="bold"> %</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Total</content> <content styleCode="bold"> %</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Gr</content><content styleCode="bold"> ade 3</content> <content styleCode="bold"> %</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Gr</content><content styleCode="bold"> ade 4</content> <content styleCode="bold"> %</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Nu</content><content styleCode="bold"> m</content><content styleCode="bold"> b</content><content styleCode="bold"> e</content><content styleCode="bold"> r of Patients With </content> &#x2C3; <content styleCode="bold"> One </content> <content styleCode="bold"> Ad</content><content styleCode="bold"> v</content><content styleCode="bold"> er</content><content styleCode="bold"> s</content><content styleCode="bold"> e Event</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 96 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 52 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 94 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 45 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> B</content><content styleCode="bold"> o</content><content styleCode="bold"> d</content><content styleCode="bold"> y System/Adverse Event </content> </td><td valign="top" styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"><content styleCode="bold"><content styleCode="italics">GI</content></content> </td><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Diarrhea Nausea Vomiting Stomatitis Abdominal Pain Gastrointestinal Motility Disorder Constipation Oral Discomfort Upper GI Inflammatory Disorders Gastrointestinal Hemorrhage Ileus </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 55 43 27 25 35 10 14 10 8 6 6 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 13 4 4 2 9 &#x2C2;1 1 &#x2013; &#x2C2;1 1 4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 &#x2013; &#x2C2;1 &#x2C2;1 &#x2C2;1 &#x2013; &#x2C2;1 &#x2013; &#x2013; &#x2C2;1 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 61 51 30 62 31 7 17 10 10 3 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 10 3 4 14 5 &#x2C2;1 1 &#x2013; 1 1 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 &#x2C2;1 &#x2C2;1 1 &#x2013; &#x2013; &#x2013; &#x2013; &#x2013; &#x2013; 1 </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"><content styleCode="bold"><content styleCode="italics">S</content></content><content styleCode="bold"><content styleCode="italics">kin and Subcutaneous</content></content> </td><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Hand-and-Foot Syndrome </td><td valign="top" styleCode=" Rrule" align="center"> 54 </td><td valign="top" styleCode=" Rrule" align="center"> 17 </td><td valign="top" styleCode=" Rrule" align="center"> NA </td><td valign="top" styleCode=" Rrule" align="center"> 6 </td><td valign="top" styleCode=" Rrule" align="center"> 1 </td><td valign="top" styleCode=" Rrule" align="center"> NA </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Dermatitis </td><td valign="top" styleCode=" Rrule" align="center"> 27 </td><td valign="top" styleCode=" Rrule" align="center"> 1 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> 26 </td><td valign="top" styleCode=" Rrule" align="center"> 1 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Skin Discoloration </td><td valign="top" styleCode=" Rrule" align="center"> 7 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2C2;1 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> 5 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Alopecia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 21 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2C2;1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2013; </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"><content styleCode="bold"><content styleCode="italics">G</content></content><content styleCode="bold"><content styleCode="italics">e</content></content><content styleCode="bold"><content styleCode="italics">n</content></content><content styleCode="bold"><content styleCode="italics">e</content></content><content styleCode="bold"><content styleCode="italics">r</content></content><content styleCode="bold"><content styleCode="italics">al</content></content> </td><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Fatigue/Weakness </td><td valign="top" styleCode=" Rrule" align="center"> 42 </td><td valign="top" styleCode=" Rrule" align="center"> 4 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> 46 </td><td valign="top" styleCode=" Rrule" align="center"> 4 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Pyrexia </td><td valign="top" styleCode=" Rrule" align="center"> 18 </td><td valign="top" styleCode=" Rrule" align="center"> 1 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> 21 </td><td valign="top" styleCode=" Rrule" align="center"> 2 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Edema </td><td valign="top" styleCode=" Rrule" align="center"> 15 </td><td valign="top" styleCode=" Rrule" align="center"> 1 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> 9 </td><td valign="top" styleCode=" Rrule" align="center"> 1 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Pain </td><td valign="top" styleCode=" Rrule" align="center"> 12 </td><td valign="top" styleCode=" Rrule" align="center"> 1 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> 10 </td><td valign="top" styleCode=" Rrule" align="center"> 1 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Chest Pain </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2C2;1 </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"><content styleCode="bold"><content styleCode="italics">N</content></content><content styleCode="bold"><content styleCode="italics">e</content></content><content styleCode="bold"><content styleCode="italics">ur</content></content><content styleCode="bold"><content styleCode="italics">ological</content></content> </td><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Peripheral Sensory Neuropathy </td><td valign="top" styleCode=" Rrule" align="center"> 10 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> 4 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Headache </td><td valign="top" styleCode=" Rrule" align="center"> 10 </td><td valign="top" styleCode=" Rrule" align="center"> 1 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> 7 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Dizziness* </td><td valign="top" styleCode=" Rrule" align="center"> 8 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2C2;1 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> 8 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2C2;1 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Insomnia </td><td valign="top" styleCode=" Rrule" align="center"> 7 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> 7 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Taste Disturbance </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 11 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2C2;1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"><content styleCode="bold"><content styleCode="italics">M</content></content><content styleCode="bold"><content styleCode="italics">et</content></content><content styleCode="bold"><content styleCode="italics">abolism</content></content> </td><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Appetite Decreased </td><td valign="top" styleCode=" Rrule" align="center"> 26 </td><td valign="top" styleCode=" Rrule" align="center"> 3 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2C2;1 </td><td valign="top" styleCode=" Rrule" align="center"> 31 </td><td valign="top" styleCode=" Rrule" align="center"> 2 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2C2;1 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Dehydration </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2C2;1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"><content styleCode="bold"><content styleCode="italics">E</content></content><content styleCode="bold"><content styleCode="italics">y</content></content><content styleCode="bold"><content styleCode="italics">e</content></content> </td><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Eye Irritation </td><td valign="top" styleCode=" Rrule" align="center"> 13 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> 10 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2C2;1 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Vision Abnormal </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2013; </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"><content styleCode="bold"><content styleCode="italics">Respiratory </content></content> </td><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Dyspnea </td><td valign="top" styleCode=" Rrule" align="center"> 14 </td><td valign="top" styleCode=" Rrule" align="center"> 1 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> 10 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2C2;1 </td><td valign="top" styleCode=" Rrule" align="center"> 1 </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Cough </td><td valign="top" styleCode=" Rrule" align="center"> 7 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2C2;1 </td><td valign="top" styleCode=" Rrule" align="center"> 1 </td><td valign="top" styleCode=" Rrule" align="center"> 8 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Pharyngeal Disorder </td><td valign="top" styleCode=" Rrule" align="center"> 5 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> 5 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Epistaxis </td><td valign="top" styleCode=" Rrule" align="center"> 3 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2C2;1 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> 6 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Sore Throat </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2013; </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"><content styleCode="bold"><content styleCode="italics">Mus</content></content><content styleCode="bold"><content styleCode="italics">c</content></content><content styleCode="bold"><content styleCode="italics">u</content></content><content styleCode="bold"><content styleCode="italics">l</content></content><content styleCode="bold"><content styleCode="italics">oskeletal </content></content> </td><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"><content styleCode="bold"><content styleCode="italics"> </content></content> Back Pain </td><td valign="top" styleCode=" Rrule" align="center"> 10 </td><td valign="top" styleCode=" Rrule" align="center"> 2 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> 9 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2C2;1 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Arthralgia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2013; </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"><content styleCode="bold"><content styleCode="italics">V</content></content><content styleCode="bold"><content styleCode="italics">ascular</content></content> </td><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Venous Thrombosis </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2C2;1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2013; </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"><content styleCode="bold"><content styleCode="italics">P</content></content><content styleCode="bold"><content styleCode="italics">s</content></content><content styleCode="bold"><content styleCode="italics">yc</content></content><content styleCode="bold"><content styleCode="italics">h</content></content><content styleCode="bold"><content styleCode="italics">i</content></content><content styleCode="bold"><content styleCode="italics">atric</content></content> </td><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Mood Alteration </td><td valign="top" styleCode=" Rrule" align="center"> 5 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Rrule" align="center"> 6 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2C2;1 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2013; </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Depression </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2C2;1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2013; </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"><content styleCode="bold"><content styleCode="italics">In</content></content><content styleCode="bold"><content styleCode="italics">fections</content></content> </td><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Viral </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2C2;1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2013; </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2C2;1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &#x2013; </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"><content styleCode="bold"><content styleCode="italics">Blood and Lymphatic</content></content> </td><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"> Anemia </td><td valign="top" styleCode=" Rrule" align="center"> 80 </td><td valign="top" styleCode=" Rrule" align="center"> 2 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2C2;1 </td><td valign="top" styleCode=" Rrule" align="center"> 79 </td><td valign="top" styleCode=" Rrule" align="center"> 1 </td><td valign="top" styleCode=" Rrule" align="center"> &#x2C2;1 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Neutropenia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 13 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 46 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 13 </td></tr><tr><td valign="top" styleCode=" Lrule Rrule" align="left"><content styleCode="bold"><content styleCode="italics">He</content></content><content styleCode="bold"><content styleCode="italics">patobiliary</content></content> </td><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/><td valign="top" styleCode=" Rrule"/></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hyperbilirubinemia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 48 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 18 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 17 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td></tr></tbody></table>