ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 AvKARE, Inc. at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Adjuvant Colon Cancer Table shows the adverse reactions occurring in >=5% of patients from one phase trial in patients with Dukes colon cancer who received at least one dose of study medication and had at least one safety assessment. total of 995 patients were treated with 1250 mg/m twice day of capecitabine administered for weeks followed by 1-week rest period, and 974 patients were administered 5-FU and leucovorin (20 mg/m leucovorin IV followed by 425 mg/m IV bolus 5-FU on days to every 28 days). The median duration of treatment was 164 days for capecitabine-treated patients and 145 days for 5-FU/LV-treated patients. total of 112 (11%) and 73 (7%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions. total of 18 deaths due to all causes occurred either on study or within 28 days of receiving study drug: (0.8%) patients randomized to capecitabine and 10 (1%) randomized to 5-FU/LV. Table shows grade 3/4 laboratory abnormalities occurring in >=1% of patients from one phase trial in patients with Dukes colon cancer who received at least one dose of study medication and had at least one safety assessment. Table 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=1969) Capecitabine (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 47 Stomatitis 22 60 14 Vomiting 15 21 Abdominal Pain 14 16 Constipation - 11 <1 Upper Abdominal Pain <1 <1 Dyspepsia <1 - Skin and Subcutaneous Tissue Disorders Hand-and-Foot Syndrome 60 17 <1 Alopecia - 22 <1 Rash - - Erythema 1 <1 General Disorders and Administration Site Conditions Fatigue 16 <1 16 Pyrexia <1 <1 Asthenia 10 <1 10 Lethargy 10 <1 <1 Nervous System Disorders Dizziness <1 - Headache <1 <1 Dysgeusia - - Metabolism and Nutrition Disorders Anorexia <1 11 <1 Eye Disorders Conjunctivitis <1 <1 Blood and Lymphatic System Disorders Neutropenia <1 5 Respiratory Thoracic and Mediastinal Disorders Epistaxis - - Table Percent Incidence of Grade 3/4 Laboratory Abnormalities Reported in >=1% of Patients Receiving Capecitabine Monotherapy for Adjuvant Treatment of Colon Cancer (Safety Population) Adverse Event Capecitabine (n=995) Grade 3/4 IV 5-FU/LV (n=974) Grade 3/4 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 (May, 1994). In the NCIC-CTC Version 1, hyperbilirubinemia grade indicates bilirubin value of 1.5 to x upper limit of normal (ULN) range, and grade a value of 3 ULN. The NCI CTC Version and above define grade bilirubin value of >3 to 10 ULN, and grade values >10 ULN. Increased ALAT (SGPT) 1.6 0.6 Increased calcium 1.1 0.7 Decreased calcium 2.3 2.2 Decreased hemoglobin 1.2 Decreased lymphocytes 13 13 Decreased neutrophils 2.2 26.2 Decreased neutrophils/granulocytes 2.4 26.4 Decreased platelets 0.7 Increased bilirubin 20 6.3. 6.2 Metastatic Colorectal Cancer Monotherapy Table shows the adverse reactions occurring in >=5% of patients from pooling the two phase trials in first line metastatic colorectal cancer. total of 596 patients with metastatic colorectal cancer were treated with 1250 mg/m twice day of capecitabine administered for weeks followed by 1-week rest period, and 593 patients were administered 5-FU and leucovorin in the Mayo regimen (20 mg/m leucovorin IV followed by 425 mg/m IV bolus 5-FU, on days to 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. total of 78 (13%) and 63 (11%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions/intercurrent illness. 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 Pooled Phase Colorectal Trials: Percent Incidence of Adverse Reactions in >=5% of Patients Adverse Event Capecitabine (n=596) 5-FU/LV (n=593) Total Grade % Grade % Total Grade % Grade % Number of Patients With One Adverse Event 96 52 94 45 Body System/Adverse Event Not observed Excluding vertigo NA Not Applicable GI Diarrhea 55 13 61 10 Nausea 43 - 51 <1 Vomiting 27 <1 30 <1 Stomatitis 25 <1 62 14 Abdominal Pain 35 <1 31 - Gastrointestinal Motility Disorder 10 <1 7 <1 Constipation 14 <1 17 - Oral Discomfort 10 - 10 - Upper GI Inflammatory Disorders <1 10 - Gastrointestinal Hemorrhage 1 <1 1 Ileus 4 5 1 Skin and Subcutaneous Hand-and-Foot Syndrome 54 17 NA 1 NA Dermatitis 27 - 26 - Skin Discoloration <1 5 - Alopecia - 21 <1 General Fatigue/Weakness 42 - 46 - Pyrexia 18 - 21 - Edema 15 - 1 Pain 12 - 10 - Chest Pain 1 6 <1 Neurological Peripheral Sensory Neuropathy 10 - - Headache 10 - - Dizziness <1 8 <1 Insomnia - 7 - Taste Disturbance 1 11 <1 Metabolism Appetite Decreased 26 <1 31 <1 Dehydration 2 <1 3 Eye Eye Irritation 13 - 10 <1 Vision Abnormal - 2 - Respiratory Dyspnea 14 - 10 <1 Cough <1 8 - Pharyngeal Disorder - 5 - Epistaxis <1 6 - Sore Throat - 6 - Musculoskeletal Back Pain 10 - <1 Arthralgia 1 6 - Vascular Venous Thrombosis 3 <1 2 Psychiatric Mood Alteration - 6 <1 Depression - 4 <1 Infections Viral <1 5 <1 Blood and Lymphatic Anemia 80 <1 79 <1 Neutropenia 13 2 46 13 Hepatobiliary Hyperbilirubinemia 48 18 17 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 and Table 8. In the capecitabine and docetaxel combination arm the treatment was capecitabine administered orally 1250 mg/m twice daily as intermittent therapy (2 weeks of treatment followed by week without treatment) for at least weeks and docetaxel administered as 1-hour intravenous infusion at dose of 75 mg/m on the first day of each 3-week cycle for at least weeks. In the monotherapy arm docetaxel was administered as 1-hour intravenous infusion at dose of 100 mg/m on the first day of each 3-week cycle for at least weeks. The mean duration of treatment was 129 days in the combination arm and 98 days in the monotherapy arm. 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. Table Percent Incidence of Adverse Events Considered Related or Unrelated to Treatment in >=5% of Patients Participating in the Capecitabine and Docetaxel Combination vs Docetaxel Monotherapy Study Adverse Event Capecitabine 1250 mg/m /bid With Docetaxel 75 mg/m /3 weeks (n=251) Docetaxel 100 mg/m /3 weeks (n=255) Total Grade % Grade % Total Grade % Grade % Number of Patients With at Least One Adverse Event 99 76.5 29.1 97 57.6 31.8 Body System/Adverse Event Not observed NA Not Applicable GI Diarrhea 67 14 <1 48 <1 Stomatitis 67 17 <1 43 - Nausea 45 - 36 - Vomiting 35 1 24 - Constipation 20 - 18 - Abdominal Pain 30 <3 <1 24 - Dyspepsia 14 - 1 Dry Mouth <1 5 - Skin and Subcutaneous Hand-and-Foot Syndrome 63 24 NA 1 NA Alopecia 41 - 42 - Nail Disorder 14 - 15 - Dermatitis - 11 - Rash Erythematous <1 5 - Nail Discoloration - 4 <1 Onycholysis 1 5 - Pruritus - 5 - General Pyrexia 28 - 34 - Asthenia 26 <1 25 - Fatigue 22 - 27 - Weakness 16 - 11 - Pain in Limb 13 <1 13 - Lethargy - 6 - Pain <1 5 - Chest Pain (non-cardiac) <1 6 - Influenza-like Illness - 5 - Neurological Taste Disturbance 16 <1 14 <1 Headache 15 - 15 - Paresthesia 12 <1 16 - Dizziness 12 - <1 Insomnia - 10 <1 Peripheral Neuropathy - 10 - Hypoaesthesia <1 8 <1 Metabolism Anorexia 13 - 11 <1 Appetite Decreased 10 - - Weight Decreased - 5 - Dehydration 10 - <1 <1 Eye Lacrimation Increased 12 - <1 Conjunctivitis - 4 - Eye Irritation - 1 - Musculoskeletal Arthralgia 15 - 24 - Myalgia 15 - 25 - Back Pain 12 <1 11 - Bone Pain <1 10 - Cardiac Edema 33 <2 34 <3 Blood Neutropenic Fever 16 13 21 16 Respiratory Dyspnea 14 <1 16 - Cough 13 - 22 <1 Sore Throat 12 - 11 <1 Epistaxis <1 6 - Rhinorrhea - 3 - Pleural Effusion 1 7 - Infection Oral Candidiasis <1 8 <1 Urinary Tract Infection <1 4 - Upper Respiratory Tract - 5 - Vascular Flushing - 5 - Lymphoedema <1 5 - Psychiatric Depression - 5 - Table Percent of Patients With Laboratory Abnormalities Participating in the Capecitabine and Docetaxel Combination vs Docetaxel Monotherapy Study Adverse Event Capecitabine 1250 mg/m /bid With Docetaxel 75 mg/m /3 weeks (n=251) Docetaxel 100 mg/m /3 weeks (n=255) Body System/Adverse Event Total Grade % Grade % Total Grade % Grade % Hematologic Leukopenia 91 37 24 88 42 33 Neutropenia/Granulocytopenia 86 20 49 87 10 66 Thrombocytopenia 41 1 23 2 Anemia 80 3 83 <1 Lymphocytopenia 99 48 41 98 44 40 Hepatobiliary Hyperbilirubinemia 20 2 2 2Monotherapy The following data are shown for the study in stage IV breast cancer patients who received dose of 1250 mg/m administered twice daily for weeks followed by 1-week rest period. The mean duration of treatment was 114 days. total of 13 out of 162 patients (8%) discontinued treatment because of adverse reactions/intercurrent illness. Table Percent Incidence of Adverse Reactions 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 Trial in Stage IV Breast Cancer (n=162) Body System/Adverse Event Total Grade % Grade % Not observed NA Not Applicable GI Diarrhea 57 12 Nausea 53 - Vomiting 37 - Stomatitis 24 - Abdominal Pain 20 - Constipation 15 - Dyspepsia - Skin and Subcutaneous Hand-and-Foot Syndrome 57 11 NA Dermatitis 37 - Nail Disorder - General Fatigue 41 - Pyrexia 12 - Pain in Limb 1 Neurological Paresthesia 21 - Headache 1 Dizziness - Insomnia - Metabolism Anorexia 23 - Dehydration 4 Eye Eye Irritation 15 - Musculoskeletal Myalgia - Cardiac Edema 1 Blood Neutropenia 26 2 Thrombocytopenia 24 1 Anemia 72 1 Lymphopenia 94 44 15 Hepatobiliary Hyperbilirubinemia 22 2. 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 and 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%), 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, 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 Warning and Precautions (5.7)] persistent or severe hand-and-foot syndrome can eventually lead to loss of fingerprints [see Warnings and Precautions (5.7)] 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%) To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993; email drugsafetyavkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Enzymes convert capecitabine to 5-fluorouracil (5-FU) in vivo. Both normal and tumor cells metabolize 5-FU to 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor, 5-10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form covalently bound ternary complex. This binding inhibits the formation of thymidylate from 2-deoxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that deficiency of this compound can inhibit cell division. Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis. 12.3 Pharmacokinetics Absorption Following oral administration of 1255 mg/m BID to cancer patients, capecitabine reached peak blood levels in about 1.5 hours (T max) with peak 5-FU levels occurring slightly later, at hours. Food reduced both the rate and extent of absorption of capecitabine with mean max and AUC 0- decreased by 60% and 35%, respectively. The max and AUC 0- of 5-FU were also reduced by food by 43% and 21%, respectively. Food delayed max of both parent and 5-FU by 1.5 hours [see Warnings and Precautions (5) Dosage and Administration (2) and Drug-Food Interaction (7.2) ]. The pharmacokinetics of capecitabine and its metabolites have been evaluated in about 200 cancer patients over dosage range of 500 to 3500 mg/m 2/day. Over this range, the pharmacokinetics of capecitabine and its metabolite, 5-DFCR were dose proportional and did not change over time. The increases in the AUCs of 5-DFUR and 5-FU, however, were greater than proportional to the increase in dose and the AUC of 5-FU was 34% higher on day 14 than on day 1. The interpatient variability in the max and AUC of 5-FU was greater than 85%. Distribution Plasma protein binding of capecitabine and its metabolites is less than 60% and is not concentration-dependent. Capecitabine was primarily bound to human albumin (approximately 35%). Capecitabine has low potential for pharmacokinetic interactions related to plasma protein binding.Bioactivation and Metabolism Capecitabine is extensively metabolized enzymatically to 5-FU. In the liver, 60 kDa carboxylesterase hydrolyzes much of the compound to 5-deoxy-5-fluorocytidine (5-DFCR). Cytidine deaminase, an enzyme found in most tissues, including tumors, subsequently converts 5-DFCR to 5-DFUR. The enzyme, thymidine phosphorylase (dThdPase), then hydrolyzes 5-DFUR to the active drug 5-FU. Many tissues throughout the body express thymidine phosphorylase. Some human carcinomas express this enzyme in higher concentrations than surrounding normal tissues. Following oral administration of capecitabine days before surgery in patients with colorectal cancer, the median ratio of 5-FU concentration in colorectal tumors to adjacent tissues was 2.9 (range from 0.9 to 8). These ratios have not been evaluated in breast cancer patients or compared to 5-FU infusion.Metabolic Pathway of capecitabine to 5-FUThe enzyme dihydropyrimidine dehydrogenase hydrogenates 5-FU, the product of capecitabine metabolism, to the much less toxic 5-fluoro-5, 6-dihydro-fluorouracil (FUH 2). Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, -ureido-propionase cleaves FUPA to -fluoro--alanine (FBAL) which is cleared in the urine. In vitro enzymatic studies with human liver microsomes indicated that capecitabine and its metabolites (5DFUR, 5-DFCR, 5-FU, and FBAL) did not inhibit the metabolism of test substrates by cytochrome P450 isoenzymes 1A2, 2A6, 3A4, 2C19, 2D6, and 2E1. Excretion Capecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered capecitabine dose is recovered in urine. Fecal excretion is minimal (2.6%). The major metabolite excreted in urine is FBAL which represents 57% of the administered dose. About 3% of the administered dose is excreted in urine as unchanged drug. The elimination half-life of both parent capecitabine and 5-FU was about 0.75 hour.Effect of Age, Gender, and Race on the Pharmacokinetics of Capecitabine population analysis of pooled data from the two large controlled studies in patients with metastatic colorectal cancer (n=505) who were administered capecitabine at 1250 mg/m twice day indicated that gender (202 females and 303 males) and race (455 white/Caucasian patients, 22 black patients, and 28 patients of other race) have no influence on the pharmacokinetics of 5-DFUR, 5-FU and FBAL. Age has no significant influence on the pharmacokinetics of 5-DFUR and 5-FU over the range of 27 to 86 years. 20% increase in age results in 15% increase in AUC of FBAL [see Warnings and Precautions (5.11) and Dosage and Administration (2.4) ]. Following oral administration of 825 mg/m capecitabine twice daily for 14 days, Japanese patients (n=18) had about 36% lower max and 24% lower AUC for capecitabine than the Caucasian patients (n=22). Japanese patients had also about 25% lower max and 34% lower AUC for FBAL than the Caucasian patients. The clinical significance of these differences is unknown. No significant differences occurred in the exposure to other metabolites (5-DFCR, 5-DFUR, and 5-FU). Effect of Hepatic Insufficiency Capecitabine has been evaluated in 13 patients with mild to moderate hepatic dysfunction due to liver metastases defined by composite score including bilirubin, AST/ALT and alkaline phosphatase following single 1255 mg/m dose of capecitabine. Both AUC 0- and max of capecitabine increased by 60% in patients with hepatic dysfunction compared to patients with normal hepatic function (n=14). The AUC 0- and max of 5-FU were not affected. In patients with mild to moderate hepatic dysfunction due to liver metastases, caution should be exercised when capecitabine is administered. The effect of severe hepatic dysfunction on capecitabine is not known [see Warnings and Precautions (5.11) and Use in Special Populations (8.6) ]. Effect of Renal Insufficiency Following oral administration of 1250 mg/m capecitabine twice day to cancer patients with varying degrees of renal impairment, patients with moderate (creatinine clearance 30 to 50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment showed 85% and 258% higher systemic exposure to FBAL on day compared to normal renal function patients (creatinine clearance >80 mL/min). Systemic exposure to 5-DFUR was 42% and 71% greater in moderately and severely renal impaired patients, respectively, than in normal patients. Systemic exposure to capecitabine was about 25% greater in both moderately and severely renal impaired patients [see Dosage and Administration (2.4) Contraindications (4.1) Warnings and Precautions (5.5) and Use in Special Populations (8.7) ]. Effect of Capecitabine on the Pharmacokinetics of Warfarin In four patients with cancer, chronic administration of capecitabine (1250 mg/m bid) with single 20 mg dose of warfarin increased the mean AUC of S-warfarin by 57% and decreased its clearance by 37%. Baseline corrected AUC of INR in these patients increased by 2.8-fold, and the maximum observed mean INR value was increased by 91% [see Boxed Warning and Drug Interactions (7.1) ]. Effect of Antacids on the Pharmacokinetics of Capecitabine When Maalox (R) (20 mL), an aluminum hydroxide- and magnesium hydroxide-containing antacid, was administered immediately after capecitabine (1250 mg/m 2, n=12 cancer patients), AUC and max increased by 16% and 35%, respectively, for capecitabine and by 18% and 22%, respectively, for 5-DFCR. No effect was observed on the other three major metabolites (5-DFUR, 5-FU, FBAL) of capecitabine. Effect of Capecitabine on the Pharmacokinetics of Docetaxel and Vice Versa Phase study evaluated the effect of capecitabine on the pharmacokinetics of docetaxel (Taxotere (R)) and the effect of docetaxel on the pharmacokinetics of capecitabine was conducted in 26 patients with solid tumors. Capecitabine was found to have no effect on the pharmacokinetics of docetaxel (C max and AUC) and docetaxel has no effect on the pharmacokinetics of capecitabine and the 5-FU precursor 5-DFUR. 8649c6ce-figure-02.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1 Adjuvant Colon Cancer A multicenter randomized, controlled phase clinical trial in patients with Dukes colon cancer (X-ACT) provided data concerning the use of capecitabine for the adjuvant treatment of patients with colon cancer. The primary objective of the study was to compare disease-free survival (DFS) in patients receiving capecitabine to those receiving IV 5-FU/LV alone. In this trial, 1987 patients were randomized either to treatment with capecitabine 1250 mg/m orally twice daily for weeks followed by 1-week rest period, given as 3-week cycles for total of cycles (24 weeks) or IV bolus 5-FU 425 mg/m and 20 mg/m IV leucovorin on days to 5, given as 4-week cycles for total of cycles (24 weeks). Patients in the study were required to be between 18 and 75 years of age with histologically-confirmed Dukes stage colon cancer with at least one positive lymph node and to have undergone (within weeks prior to randomization) complete resection of the primary tumor without macroscopic or microscopic evidence of remaining tumor. Patients were also required to have no prior cytotoxic chemotherapy or immunotherapy (except steroids), and have an ECOG performance status of or (KPS >= 70%), ANC >= 1.5x10 9/L, platelets >= 100x10 9/L, serum creatinine <= 1.5 ULN, total bilirubin <= 1.5 ULN, AST/ALT <= 2.5 ULN and CEA within normal limits at time of randomization. The baseline demographics for capecitabine and 5-FU/LV patients are shown in Table 10. The baseline characteristics were well-balanced between arms. Table 10 Baseline Demographics Capecitabine (n=1004) 5-FU/LV (n=983) Age (median, years) 62 63 Range (25 to 80) (22 to 82) Gender Male (n, %) 542 (54) 532 (54) Female (n, %) 461 (46) 451 (46) ECOG PS (n, %) 849 (85) 830 (85) (n, %) 152 (15) 147 (15) Staging Primary Tumor PT1 (n, %) 12 (1) (0.6) PT2 (n, %) 90 (9) 92 (9) PT3 (n, %) 763 (76) 746 (76) PT4 (n, %) 138 (14) 139 (14) Other (n, %) (0.1) (0) Staging Lymph Node pN1 (n, %) 695 (69) 694 (71) pN2 (n, %) 305 (30) 288 (29) Other (n, %) (0.4) (0.1)All patients with normal renal function or mild renal impairment began treatment at the full starting dose of 1250 mg/m orally twice daily. The starting dose was reduced in patients with moderate renal impairment (calculated creatinine clearance 30 to 50 mL/min) at baseline [see Dosage and Administration (2.4) ]. Subsequently, for all patients, doses were adjusted when needed according to toxicity. Dose management for capecitabine included dose reductions, cycle delays and treatment interruptions (see Table 11). Table 11 Summary of Dose Modifications in X-ACT Study Capecitabine = 995 5-FU/LV = 974 Median relative dose intensity (%) 93 92 Patients completing full course of treatment (%) 83 87 Patients with treatment interruption (%) 15 Patients with cycle delay (%) 46 29 Patients with dose reduction (%) 42 44 Patients with treatment interruption, cycle delay, or dose reduction (%) 57 52The median follow-up at the time of the analysis was 83 months (6.9 years). The hazard ratio for DFS for capecitabine compared to 5-FU/LV was 0.88 (95% C.I. 0.77 to 1.01) (see Table 12 and Figure 1). Because the upper 2-sided 95% confidence limit of hazard ratio was less than 1.20, capecitabine was non-inferior to 5-FU/LV. The choice of the non-inferiority margin of 1.20 corresponds to the retention of approximately 75% of the 5-FU/LV effect on DFS. The hazard ratio for capecitabine compared to 5-FU/LV with respect to overall survival was 0.86 (95% C.I. 0.74 to 1.01). The 5-year overall survival rates were 71.4% for capecitabine and 68.4% for 5-FU/LV (see Figure 2). Table 12 Efficacy of Capecitabine vs 5-FU/LV in Adjuvant Treatment of Colon Cancera All Randomized Population Capecitabine (n=1004) 5-FU/LV (n=983) aApproximately 93.4% had 5-year DFS information bBased on Kaplan-Meier estimates cTest of superiority of capecitabine vs 5-FU/LV (Wald chi-square test) Median follow-up (months) 83 83 5-year Disease-free Survival Rates (%) 59.1 54.6 Hazard Ratio 0.88 (Capecitabine/5-FU/LV) (0.77 to 1.01) (95% C.I. for Hazard Ratio) p-value p 0.068Figure Kaplan-Meier Estimates of Disease-Free Survival (All Randomized Population)a aCapecitabine has been demonstrated to be non-inferior to 5-FU/LV. Figure Kaplan-Meier Estimates of Overall Survival (All Randomized Population). 8649c6ce-figure-03. 8649c6ce-figure-04. 14.2 Metastatic Colorectal Cancer General The recommended dose of capecitabine was determined in an open-label, randomized clinical study, exploring the efficacy and safety of continuous therapy with capecitabine (1331 mg/m 2/day in two divided doses, n=39), intermittent therapy with capecitabine (2510 mg/m 2/day in two divided doses, n=34), and intermittent therapy with capecitabine in combination with oral leucovorin (LV) (capecitabine 1657 mg/m 2/day in two divided doses, n=35; leucovorin 60 mg/day) in patients with advanced and/or metastatic colorectal carcinoma in the first-line metastatic setting. There was no apparent advantage in response rate to adding leucovorin to capecitabine; however, toxicity was increased. Capecitabine, 1250 mg/m twice daily for 14 days followed by 1-week rest, was selected for further clinical development based on the overall safety and efficacy profile of the three schedules studied. Monotherapy Data from two open-label, multicenter, randomized, controlled clinical trials involving 1207 patients support the use of capecitabine in the first-line treatment of patients with metastatic colorectal carcinoma. The two clinical studies were identical in design and were conducted in 120 centers in different countries. Study was conducted in the US, Canada, Mexico, and Brazil; Study was conducted in Europe, Israel, Australia, New Zealand, and Taiwan. Altogether, in both trials, 603 patients were randomized to treatment with capecitabine at dose of 1250 mg/m twice daily for weeks followed by 1-week rest period and given as 3-week cycles; 604 patients were randomized to treatment with 5-FU and leucovorin (20 mg/m leucovorin IV followed by 425 mg/m IV bolus 5-FU, on days to 5, every 28 days). In both trials, overall survival, time to progression and response rate (complete plus partial responses) were assessed. Responses were defined by the World Health Organization criteria and submitted to blinded independent review committee (IRC). Differences in assessments between the investigator and IRC were reconciled by the sponsor, blinded to treatment arm, according to specified algorithm. Survival was assessed based on non-inferiority analysis.The baseline demographics for capecitabine and 5-FU/LV patients are shown in Table 13. Table 13 Baseline Demographics of Controlled Colorectal Trials Study Study Capecitabine (n=302) 5-FU/LV (n=303) Capecitabine (n=301) 5-FU/LV (n=301) Age (median, years) 64 63 64 64 Range (23 to 86) (24 to 87) (29 to 84) (36 to 86) Gender Male (%) 181 (60) 197 (65) 172 (57) 173 (57) Female (%) 121 (40) 106 (35) 129 (43) 128 (43) Karnofsky PS (median) 90 90 90 90 Range (70 to 100) (70 to 100) (70 to 100) (70 to 100) Colon (%) 222 (74) 232 (77) 199 (66) 196 (65) Rectum (%) 79 (26) 70 (23) 101 (34) 105 (35) Prior radiation therapy (%) 52 (17) 62 (21) 42 (14) 42 (14) Prior adjuvant 5-FU (%) 84 (28) 110 (36) 56 (19) 41 (14)The efficacy endpoints for the two phase trials are shown in Table 14 and Table 15. Table 14 Efficacy of Capecitabine vs 5-FU/LV in Colorectal Cancer (Study 1) Capecitabine (n=302) 5-FU/LV (n=303) Overall Response Rate (%, 95% C.I.) 21 (16 to 26) 11 (8 to 15) p-value) 0.0014 Time to Progression (Median, days, 95% C.I.) 128 (120 to 136) 131 (105 to 153) Hazard Ratio (Capecitabine/5-FU/LV) 95% C.I. for Hazard Ratio 0.99 (0.84 to 1.17) Survival (Median, days, 95% C.I.) 380 (321 to 434) 407 (366 to 446) Hazard Ratio (Capecitabine/5-FU/LV) 95% C.I. for Hazard Ratio (0.84 to 1.18) Table 15 Efficacy of Capecitabine vs 5-FU/LV in Colorectal Cancer (Study 2) Capecitabine (n=301) 5-FU/LV (n=301) Overall Response Rate (%, 95% C.I.) 21 (16 to 26) 14 (10 to 18) p-value) 0.027 Time to Progression (Median, days, 95% C.I.) 137 (128 to 165) 131 (102 to 156) Hazard Ratio (Capecitabine/5-FU/LV) 95% C.I. for Hazard Ratio 0.97 (0.82 to 1.14) Survival (Median, days, 95% C.I.) 404 (367 to 452) 369 (338 to 430) Hazard Ratio (Capecitabine/5-FU/LV) 95% C.I. for Hazard Ratio 0.92 (0.78 to 1.09) Figure Kaplan-Meier Curve for Overall Survival of Pooled Data (Studies and 2)Capecitabine was superior to 5-FU/LV for objective response rate in Study and Study 2. The similarity of capecitabine and 5-FU/LV in these studies was assessed by examining the potential difference between the two treatments. In order to assure that capecitabine has clinically meaningful survival effect, statistical analyses were performed to determine the percent of the survival effect of 5-FU/LV that was retained by capecitabine. The estimate of the survival effect of 5-FU/LV was derived from meta-analysis of ten randomized studies from the published literature comparing 5-FU to regimens of 5-FU/LV that were similar to the control arms used in these Studies and 2. The method for comparing the treatments was to examine the worst case (95% confidence upper bound) for the difference between 5-FU/LV and capecitabine, and to show that loss of more than 50% of the 5-FU/LV survival effect was ruled out. It was demonstrated that the percent of the survival effect of 5-FU/LV maintained was at least 61% for Study and 10% for Study 1. The pooled result is consistent with retention of at least 50% of the effect of 5-FU/LV. It should be noted that these values for preserved effect are based on the upper bound of the 5-FU/LV vs capecitabine difference. These results do not exclude the possibility of true equivalence of capecitabine to 5-FU/LV (see Table 14 Table 15 and Figure 3). 8649c6ce-figure-05. 14.3 Breast Cancer Capecitabine has been evaluated in clinical trials in combination with docetaxel (Taxotere (R)) and as monotherapy. In Combination With Docetaxel The dose of capecitabine used in the phase clinical trial in combination with docetaxel was based on the results of phase study, where range of doses of docetaxel administered in 3-week cycles in combination with an intermittent regimen of capecitabine (14 days of treatment, followed by 7-day rest period) were evaluated. The combination dose regimen was selected based on the tolerability profile of the 75 mg/m administered in 3week cycles of docetaxel in combination with 1250 mg/m twice daily for 14 days of capecitabine administered in 3-week cycles. The approved dose of 100 mg/m of docetaxel administered in 3-week cycles was the control arm of the phase study. Capecitabine in combination with docetaxel was assessed in an open-label, multicenter, randomized trial in 75 centers in Europe, North America, South America, Asia, and Australia. total of 511 patients with metastatic breast cancer resistant to, or recurring during or after an anthracycline-containing therapy, or relapsing during or recurring within years of completing an anthracycline-containing adjuvant therapy were enrolled. Two hundred and fifty-five (255) patients were randomized to receive capecitabine 1250 mg/m twice daily for 14 days followed by week without treatment and docetaxel 75 mg/m as 1-hour intravenous infusion administered in 3-week cycles. In the monotherapy arm, 256 patients received docetaxel 100 mg/m as 1-hour intravenous infusion administered in 3-week cycles. Patient demographics are provided in Table 16. Table 16 Baseline Demographics and Clinical Characteristics Capecitabine and Docetaxel Combination vs Docetaxel in Breast Cancer Trial Capecitabine Docetaxel (n=255) Docetaxel (n=256) 1Includes 10 patients in combination and 18 patients in monotherapy arms treated with an anthracenedione Age (median, years) 52 51 Karnofsky PS (median) 90 90 Site of Disease Lymph nodes 121 (47%) 125 (49%) Liver 116 (45%) 122 (48%) Bone 107 (42%) 119 (46%) Lung 95 (37%) 99 (39%) Skin 73 (29%) 73 (29%) Prior Chemotherapy Anthracycline 255 (100%) 256 (100%) 5-FU 196 (77%) 189 (74%) Paclitaxel 25 (10%) 22 (9%) Resistance to an Anthracycline No resistance 19 (7%) 19 (7%) Progression on anthracycline therapy 65 (26%) 73 (29%) Stable disease after cycles of anthracycline therapy 41 (16%) 40 (16%) Relapsed within years of completion of anthracycline-adjuvant therapy 78 (31%) 74 (29%) Experienced brief response to anthracycline therapy, with subsequent progression while on therapy or within 12 months after last dose 51 (20%) 50 (20%) No. of Prior Chemotherapy Regimens for Treatment of Metastatic Disease 89 (35%) 80 (31%) 123 (48%) 135 (53%) 43 (17%) 39 (15%) 0 (0%) (1%)Capecitabine in combination with docetaxel resulted in statistically significant improvement in time to disease progression, overall survival and objective response rate compared to monotherapy with docetaxel as shown in Table 17, Figure 4, and Figure 5. Table 17 Efficacy of Capecitabine and Docetaxel Combination vs Docetaxel Monotherapy Efficacy Parameter Combination Therapy Monotherapy p-value Hazard Ratio The response rate reported represents reconciliation of the investigator and IRC assessments performed by the sponsor according to predefined algorithm. NA Not Applicable Time to Disease Progression Median Days 186 128 0.0001 0.643 95% C.I. (165 to 198) (105 to 136) Overall Survival Median Days 442 352 0.0126 0.775 95% C.I. (375 to 497) (298 to 387) Response Rate 32% 22% 0.009 NA Figure Kaplan-Meier Estimates for Time to Disease Progression Capecitabine and Docetaxel vs Docetaxel Figure Kaplan-Meier Estimates of Survival Capecitabine and Docetaxel vs Docetaxel Monotherapy The antitumor activity of capecitabine as monotherapy was evaluated in an open-label single-arm trial conducted in 24 centers in the US and Canada. total of 162 patients with stage IV breast cancer were enrolled. The primary endpoint was tumor response rate in patients with measurable disease, with response defined as >=50% decrease in sum of the products of the perpendicular diameters of bidimensionally measurable disease for at least month. Capecitabine was administered at dose of 1255 mg/m twice daily for weeks followed by 1-week rest period and given as 3-week cycles. The baseline demographics and clinical characteristics for all patients (n=162) and those with measurable disease (n=135) are shown in Table 18. Resistance was defined as progressive disease while on treatment, with or without an initial response, or relapse within months of completing treatment with an anthracycline-containing adjuvant chemotherapy regimen. Table 18 Baseline Demographics and Clinical Characteristics Single-Arm Breast Cancer Trial Patients With Measurable Disease (n=135) All Patients (n=162) 1Lung, pleura, liver, peritoneum 2Includes patients treated with an anthracenedione Age (median, years) 55 56 Karnofsky PS 90 90 No. Disease Sites to 43 (32%) 60 (37%) to 63 (46%) 69 (43%) >5 29 (22%) 34 (21%) Dominant Site of Disease Visceral 101 (75%) 110 (68%) Soft Tissue 30 (22%) 35 (22%) Bone (3%) 17 (10%) Prior Chemotherapy Paclitaxel 135 (100%) 162 (100%) Anthracycline 122 (90%) 147 (91%) 5-FU 110 (81%) 133 (82%) Resistance to Paclitaxel 103 (76%) 124 (77%) Resistance to an Anthracycline 55 (41%) 67 (41%) Resistance to both Paclitaxel and an Anthracycline 43 (32%) 51 (31%)Antitumor responses for patients with disease resistant to both paclitaxel and an anthracycline are shown in Table 19. Table 19 Response Rates in Doubly-Resistant Patients Single-Arm Breast Cancer Trial Resistance to Both Paclitaxel and an Anthracycline (n=43) 1Includes patients treated with an anthracenedione 2From date of first response CR PR 11 CR PR 11 Response Rate (95% C.I.) 25.6% (13.5, 41.2) Duration of Response, Median in days (Range) 154 (63 to 233) For the subgroup of 43 patients who were doubly resistant, the median time to progression was 102 days and the median survival was 255 days. The objective response rate in this population was supported by response rate of 18.5% (1 CR, 24 PRs) in the overall population of 135 patients with measurable disease, who were less resistant to chemotherapy (see Table 18). The median time to progression was 90 days and the median survival was 306 days. 8649c6ce-figure-06. 8649c6ce-figure-07.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION Take capecitabine tablets with water within 30 min after meal 2.1) Monotherapy: 1250 mg/m twice daily orally for weeks followed by one week rest period in 3-week cycles 2.2) Adjuvant treatment is recommended for total of months (8 cycles) 2.2) In combination with docetaxel, the recommended dose of capecitabine tablets is 1250 mg/m twice daily for weeks followed by 7-day rest period, combined with docetaxel at 75 mg/m as 1-hour IV infusion every weeks 2.2) Capecitabine tablets dosage may need to be individualized to optimize patient management 2.3) Reduce the dose of capecitabine tablets by 25% in patients with moderate renal impairment (2.4) Take capecitabine tablets with water within 30 min after meal 2.1) Monotherapy: 1250 mg/m twice daily orally for weeks followed by one week rest period in 3-week cycles 2.2) Adjuvant treatment is recommended for total of months (8 cycles) 2.2) In combination with docetaxel, the recommended dose of capecitabine tablets is 1250 mg/m twice daily for weeks followed by 7-day rest period, combined with docetaxel at 75 mg/m as 1-hour IV infusion every weeks 2.2) Capecitabine tablets dosage may need to be individualized to optimize patient management 2.3) Reduce the dose of capecitabine tablets by 25% in patients with moderate renal impairment (2.4) 2.1 Important Administration Instructions Capecitabine tablets should be swallowed whole with water within 30 minutes after meal. Capecitabine tablets are cytotoxic drug. Follow applicable special handling and disposal procedures. If capecitabine tablets must be cut or crushed, this should be done by professional trained in safe handling of cytotoxic drugs using appropriate equipment and safety procedures. Capecitabine tablets dose is calculated according to body surface area. 2.2 Standard Starting Dose Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer) The recommended dose of capecitabine tablets is 1250 mg/m administered orally twice daily (morning and evening; equivalent to 2500 mg/m total daily dose) for weeks followed by 1-week rest period given as 3-week cycles (see Table 1). Adjuvant treatment in patients with Dukes colon cancer is recommended for total of months [ie, capecitabine tablets 1250 mg/m orally twice daily for weeks followed by 1-week rest period, given as 3-week cycles for total of cycles (24 weeks)]. Table Capecitabine Tablets Dose Calculation According to Body Surface Area Dose Level 1250 mg/m Twice Day Number of Tablets to be Taken at Each Dose (Morning and Evening) Surface Area (m ) Total Daily Dose (mg) 150 mg 500 mg Total Daily Dose divided by to allow equal morning and evening doses <= 1.25 3000 3 1.26 to 1.37 3300 3 1.38 to 1.51 3600 3 1.52 to 1.65 4000 4 1.66 to 1.77 4300 4 1.78 to 1.91 4600 4 1.92 to 2.05 5000 5 2.06 to 2.17 5300 5 >= 2.18 5600 5In Combination With Docetaxel (Metastatic Breast Cancer) In combination with docetaxel, the recommended dose of capecitabine tablets is 1250 mg/m twice daily for weeks followed by 1-week rest period, combined with docetaxel at 75 mg/m as 1-hour intravenous infusion every weeks. Pre-medication, according to the docetaxel labeling, should be started prior to docetaxel administration for patients receiving the capecitabine tablets plus docetaxel combination. Table displays the total daily dose of capecitabine tablets by body surface area and the number of tablets to be taken at each dose. 2.3 Dose Management Guidelines General Capecitabine tablets dosage may need to be individualized to optimize patient management. Patients should be carefully monitored for toxicity and doses of capecitabine tablets should be modified as necessary to accommodate individual patient tolerance to treatment [see Clinical Studies (14) ]. Toxicity due to capecitabine tablets administration may be managed by symptomatic treatment, dose interruptions and adjustment of capecitabine tablets dose. Once the dose has been reduced, it should not be increased at later time. Doses of capecitabine tablets omitted for toxicity are not replaced or restored; instead the patient should resume the planned treatment cycles. The dose of phenytoin and the dose of coumarin-derivative anticoagulants may need to be reduced when either drug is administered concomitantly with capecitabine tablets [see Drug Interactions (7.1) ]. Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer) Capecitabine tablets dose modification scheme as described below (see Table 2) is recommended for the management of adverse reactions. Table Recommended Dose Modifications of Capecitabine Tablets Toxicity NCIC Grades During Course of Therapy Dose Adjustment for Next Treatment (% of starting dose) National Cancer Institute of Canada Common Toxicity Criteria were used except for the hand-and-foot syndrome [see Warnings and Precautions (5) ]. Grade Maintain dose level Maintain dose level Grade -1st appearance Interrupt until resolved to grade to 100% -2nd appearance 75% -3rd appearance 50% -4th appearance Discontinue treatment permanently Grade -1st appearance Interrupt until resolved to grade to 75% -2nd appearance 50% -3rd appearance Discontinue treatment permanently Grade -1st appearance Discontinue permanently OR If physician deems it to be in the patients best interest to continue, interrupt until resolved to grade to 50%In Combination With Docetaxel (Metastatic Breast Cancer) Dose modifications of capecitabine tablets for toxicity should be made according to Table above for capecitabine tablets. At the beginning of treatment cycle, if treatment delay is indicated for either capecitabine tablets or docetaxel, then administration of both agents should be delayed until the requirements for restarting both drugs are met. The dose reduction schedule for docetaxel when used in combination with capecitabine tablets for the treatment of metastatic breast cancer is shown in Table 3. Table Docetaxel Dose Reduction Schedule in Combination with Capecitabine Tablets Toxicity NCIC Grades Grade Grade Grade National Cancer Institute of Canada Common Toxicity Criteria were used except for hand-and-foot syndrome [see Warnings and Precautions (5) ]. 1st appearance Delay treatment until resolved to grade to 1; Resume treatment with original dose of 75 mg/m docetaxel Delay treatment until resolved to grade to 1; Resume treatment at 55 mg/m of docetaxel. Discontinue treatment with docetaxel 2nd appearance Delay treatment until resolved to grade to 1; Resume treatment at 55 mg/m of docetaxel. Discontinue treatment with docetaxel 3rd appearance Discontinue treatment with docetaxel -. 2.4 Adjustment of Starting Dose in Special Populations Renal Impairment No adjustment to the starting dose of capecitabine tablets is recommended in patients with mild renal impairment (creatinine clearance 51 to 80 mL/min [Cockroft and Gault, as shown below]). In patients with moderate renal impairment (baseline creatinine clearance 30 to 50 mL/min), dose reduction to 75% of the capecitabine tablets starting dose when used as monotherapy or in combination with docetaxel (from 1250 mg/m to 950 mg/m twice daily) is recommended [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ]. Subsequent dose adjustment is recommended as outlined in Table and Table (depending on the regimen) if patient develops grade to adverse event [see Warnings and Precautions (5.5) ]. The starting dose adjustment recommendations for patients with moderate renal impairment apply to both capecitabine tablets monotherapy and capecitabine tablets in combination use with docetaxel. Cockroft and Gault Equation: (140 age [yrs]) (body wt [kg]) Creatinine clearance for males -------------------------- (72) (serum creatinine [mg/dL]) Creatinine clearance for females 0.85 male value Geriatrics Physicians should exercise caution in monitoring the effects of capecitabine tablets, USP in the elderly. Insufficient data are available to provide dosage recommendation.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE Capecitabine tablets are nucleoside metabolic inhibitor with antineoplastic activity indicated for:Adjuvant Colon Cancer(1.1)Patients with Dukes colon cancerMetastatic Colorectal Cancer (1.1) First-line as monotherapy when treatment with fluoropyrimidine therapy alone is preferredMetastatic Breast Cancer (1.2) In combination with docetaxel after failure of prior anthracycline-containing therapyAs monotherapy in patients resistant to both paclitaxel and an anthracycline-containing regimen. Adjuvant Colon Cancer(1.1)Patients with Dukes colon cancer. Patients with Dukes colon cancer. Metastatic Colorectal Cancer (1.1) First-line as monotherapy when treatment with fluoropyrimidine therapy alone is preferred. First-line as monotherapy when treatment with fluoropyrimidine therapy alone is preferred. Metastatic Breast Cancer (1.2) In combination with docetaxel after failure of prior anthracycline-containing therapyAs monotherapy in patients resistant to both paclitaxel and an anthracycline-containing regimen. In combination with docetaxel after failure of prior anthracycline-containing therapy. As monotherapy in patients resistant to both paclitaxel and an anthracycline-containing regimen. 1.1 Colorectal Cancer. Capecitabine tablets are indicated as single agent for adjuvant treatment in patients with Dukes colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. Capecitabine tablets were non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Physicians should consider results of combination chemotherapy trials, which have shown improvement in DFS and OS, when prescribing single-agent capecitabine tablets in the adjuvant treatment of Dukes colon cancer.Capecitabine tablets are indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown survival benefit compared to 5-FU/LV alone. survival benefit over 5-FU/LV has not been demonstrated with capecitabine tablets monotherapy. Use of capecitabine tablets instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.. Capecitabine tablets are indicated as single agent for adjuvant treatment in patients with Dukes colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. Capecitabine tablets were non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Physicians should consider results of combination chemotherapy trials, which have shown improvement in DFS and OS, when prescribing single-agent capecitabine tablets in the adjuvant treatment of Dukes colon cancer.. Capecitabine tablets are indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown survival benefit compared to 5-FU/LV alone. survival benefit over 5-FU/LV has not been demonstrated with capecitabine tablets monotherapy. Use of capecitabine tablets instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.. 1.2 Breast Cancer. Capecitabine tablets in combination with docetaxel are indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.Capecitabine tablets monotherapy is also indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated (e.g., patients who have received cumulative doses of 400 mg/m of doxorubicin or doxorubicin equivalents). Resistance is defined as progressive disease while on treatment, with or without an initial response, or relapse within months of completing treatment with an anthracycline-containing adjuvant regimen. Capecitabine tablets in combination with docetaxel are indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.. Capecitabine tablets monotherapy is also indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated (e.g., patients who have received cumulative doses of 400 mg/m of doxorubicin or doxorubicin equivalents). Resistance is defined as progressive disease while on treatment, with or without an initial response, or relapse within months of completing treatment with an anthracycline-containing adjuvant regimen.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Patients and patients caregivers should be informed of the expected adverse effects of capecitabine, particularly nausea, vomiting, diarrhea, and hand-and-foot syndrome, and should be made aware that patient-specific dose adaptations during therapy are expected and necessary [see Dosage and Administration (2.3) ]. As described below, patients taking capecitabine should be informed of the need to interrupt treatment and to call their physician immediately if moderate or severe toxicity occurs. Patients should be encouraged to recognize the common grade toxicities associated with capecitabine treatment. See FDA-approved patient labeling Patient Information). Dihydropyrimidine Dehydrogenase Deficiency Patients should be advised to notify their healthcare provider if they have known DPD deficiency. Advise patients if they have complete or near complete absence of DPD activity they are at an increased risk of acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by capecitabine (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity) [see Warnings and Precautions (5.4)] Diarrhea Patients experiencing grade diarrhea (an increase of to stools/day or nocturnal stools) or greater or experiencing severe bloody diarrhea with severe abdominal pain and fever should be instructed to stop taking capecitabine and call their physician immediately. Standard antidiarrheal treatments (eg, loperamide) are recommended.DehydrationPatients experiencing grade or higher dehydration should be instructed to stop taking capecitabine immediately and the dehydration corrected. Treatment should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled.Nausea Patients experiencing grade nausea (food intake significantly decreased but able to eat intermittently) or greater should be instructed to stop taking capecitabine immediately. Initiation of symptomatic treatment is recommended.Vomiting Patients experiencing grade vomiting (2 to episodes in 24-hour period) or greater should be instructed to stop taking capecitabine immediately. Initiation of symptomatic treatment is recommended.Hand-and-Foot Syndrome Patients experiencing grade hand-and-foot syndrome (painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patients activities of daily living) or greater should be instructed to stop taking capecitabine immediately. Initiation of symptomatic treatment is recommended. Hand-and-foot syndrome can lead to loss of fingerprints which could impact your identification.Stomatitis Patients experiencing grade stomatitis (painful erythema, edema or ulcers of the mouth or tongue, but able to eat) or greater should be instructed to stop taking capecitabine immediately and to call their physician. Initiation of symptomatic treatment is recommended.Fever and Neutropenia Patients who develop fever of 100.5F or greater or other evidence of potential infection should be instructed to call their physician immediately.Embryo-Fetal Toxicity Advise females of reproductive potential of the potential risk to fetus and to use effective contraception during treatment with capecitabine and for months after the last dose. Advise females to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.6), Use in Specific Populations (8.1 and 8.3)] Advise male patients with female partners of reproductive potential to use effective contraception during treatment with capecitabine and for months after the last dose [see Use in Specific Populations (8.3)] Lactation Advise females not to breastfeed during treatment with capecitabine and for weeks after the last dose [see Use in Specific Populations (8.2)] Manufactured for: AvKARE, Inc. Pulaski, TN 38478 Mfg. Rev. 12-2016-00AV 03/18 (P) AvPAK.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information. Capecitabine (KAP-e-SYE-ta-been) Tablets USP, Film-CoatedWhat is the most important information should know about capecitabine tabletsCapecitabine tablets can cause serious side effects, including:Capecitabine tablets can interact with blood thinner medicines, such as warfarin (COUMADIN (R)). Taking capecitabine tablets with these medicines can cause changes in how fast your blood clots, and can cause bleeding that can lead to death. This can happen as soon as few days after you start taking capecitabine tablets, or later during treatment, and possibly even within month after you stop taking capecitabine tablets. Your risk may be higher because you have cancer, and if you are over 60 years of age. Before taking capecitabine tablets, tell your doctor if you are taking warfarin (COUMADIN) or another blood thinner medicine.If you take warfarin (COUMADIN) or another blood thinner that is like warfarin (COUMADIN) during treatment with capecitabine tablets, your doctor should do blood tests often, to check how fast your blood clots during and after you stop treatment with capecitabine tablets. Your doctor may change your dose of the blood thinner medicine if needed. See What are the possible side effects of capecitabine tablets for more information about side effects. What are capecitabine tablets Capecitabine tablets are prescription medicine used to treat people with:cancer of the colon that has spread to lymph nodes in the area close to the colon (Dukes stage), after they have surgery.cancer of the colon or rectum (colorectal) that has spread to other parts of the body (metastatic ).breast cancer that has spread to other parts of the body (metastatic) together with another medicine called docetaxel after treatment with certain other anti-cancer medicines have not worked.breast cancer that has spread to other parts of the body and has not improved after treatment with paclitaxel and certain other anti-cancer medicines, or who cannot receive any more treatment with certain anti-cancer medicines.It is not known if capecitabine tablets are safe and effective in children.Who should not take capecitabine tabletsDo not take capecitabine tablets if you:have severe kidney problems.are allergic to capecitabine, 5-fluorouracil or to any of the ingredients in capecitabine tablets. See the end of this leaflet for complete list of ingredients in capecitabine tablets.Talk to your doctor before taking capecitabine tablets if you are not sure if you have any of the conditions listed above.What should tell my doctor before taking capecitabine tabletsSee What is the most important information should know about capecitabine tablets Before you take capecitabine tablets, tell your doctor if you:have had heart problems.have kidney or liver problems.have been told that you lack the enzyme DPD (dihydropyrimidine dehydrogenase)have any other medical conditions.are pregnant or plan to become pregnant. Capecitabine tablets may harm your unborn baby. You should not become pregnant during treatment with capecitabine tablets. Talk to your doctor about birth control choices that may be right for you during treatment with capecitabine tablets.are breastfeeding or plan to breastfeed. It is not known if capecitabine passes into your breast milk. Do not breastfeed during treatment with capecitabine tablets.Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Capecitabine tablets may affect the way other medicines work, and other medicines may affect the way capecitabine tablets work.Know the medicines you take. Keep list of them to show your doctor and pharmacist when you get new medicine.How should take capecitabine tablets Take capecitabine tablets exactly as your doctor tells you to take it.Your doctor will tell you how much capecitabine tablets to take and when to take it.Take capecitabine tablets times day, time in the morning and time in the evening.Take capecitabine tablets within 30 minutes after finishing meal. Swallow capecitabine tablets whole with water. Do not crush or cut capecitabine tablets.Ask your healthcare provider or pharmacist how to safely throw away any unused capecitabine tablets.If you have side effects with capecitabine tablets, if needed your doctor may decide to: change your dose of capecitabine tabletstreat you with capecitabine tablets less oftentell you to stop taking capecitabine tablets until certain side effects get better or go awaystop your treatment with capecitabine tablets if you have certain side effects and they are severe If you take too much capecitabine tablets, call your doctor or go to the nearest emergency room right away.What are the possible side effects of capecitabine tablets Capecitabine tablets may cause serious side effects including:See What is the most important information should know about capecitabine tablets diarrhea. Diarrhea is common with capecitabine tablets and can sometimes be severe. Stop taking capecitabine tablets and call your doctor right away if the number of bowel movements you have in day increases by or more than is usual for you. Ask your doctor about what medicines you can take to treat your diarrhea. If you have severe bloody diarrhea with severe abdominal pain and fever, call your doctor or go to the nearest emergency room right away. heart problems. Capecitabine tablets can cause heart problems including: heart attack and decreased blood flow to the heart, chest pain, irregular heartbeats, changes in the electrical activity of your heart seen on an electrocardiogram (ECG), problems with your heart muscle, heart failure, and sudden death. Stop taking capecitabine tablets and call your doctor right away if you get any of the following symptoms: unexplained tirednessloss of too much body fluid (dehydration) and kidney failure. Dehydration can happen with capecitabine tablets and may cause sudden kidney failure that can lead to death. You are at higher risk if you have kidney problems before taking capecitabine tablets and also take other medicines that can cause kidney problems. Nausea, and vomiting are common with capecitabine tablets. If you lose your appetite, feel weak, and have nausea, vomiting, or diarrhea, you can quickly become dehydrated.Stop taking capecitabine tablets and call your doctor right away if you:vomit or more times in day.are only able to eat or drink little now and then, or not at all due to nausea.have diarrhea. See diarrhea above.serious skin and mouth reactions.Capecitabine tablets can cause serious skin reactions that may lead to death. Tell your doctor right away if you develop skin rash, blisters and peeling of your skin. Your doctor may tell you to stop taking capecitabine tablets if you have serious skin reaction. Do not take capecitabine tablets again if this happens.Capecitabine tablets can also cause hand and foot syndrome. Hand and foot syndrome is common with capecitabine tablets and can cause you to have numbness and changes in sensation in your hands and feet, or cause redness, pain, swelling of your hands and feet. Stop taking capecitabine tablets and call your doctor right away if you have any of these symptoms and you are not able to do your usual activities. Hand and foot syndrome can lead to loss of fingerprints which could impact your identification.you may get sores in your mouth or on your tongue when taking capecitabine tablets. Stop taking capecitabine tablets and call your doctor if you get painful redness, swelling, or ulcers in your mouth and tongue, or if you are having problems eating. Tell your doctor if you have any side effect that bothers you or that does not go away.increased level of bilirubin in your blood and liver problems. Increased bilirubin in your blood is common with capecitabine tablets. Your doctor will check you for these problems during treatment with capecitabine tablets. decreased white blood cells, platelets, and red blood cell counts. Your doctor will do blood tests during treatment with capecitabine tablets to check your blood cell counts. If your white blood cell count is very low, you are at increased risk for infection. Call your doctor right away if you develop fever of 100.5F or greater or have other signs and symptoms of infection.People 80 years of age or older may be more likely to develop severe or serious side effects with capecitabine tablets.The most common side effects of capecitabine tabletsinclude:diarrheahand and foot syndromenauseavomitingstomach-area (abdominal) paintirednessweaknessincreased amounts of red blood cell breakdown products (bilirubin) in your bloodThese are not all the possible side effects of capecitabine tablets. For more information, ask your doctor or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store capecitabine tabletsStore capecitabine tablets at room temperature between 68F to 77F (20C to 25C).Keep capecitabine tablets in tightly closed container.Keep capecitabine tablets and all medicines out of the reach of children.General information about the safe and effective use of capecitabine tablets.Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use capecitabine tablets for condition for which it was not prescribed. Do not give capecitabine tablets to other people, even if they have the same symptoms you have. It may harm them.You can ask your pharmacist or doctor for information about capecitabine tablets that is written for health professionals.For more information, go to www.avkare.com or 1-855-361-3993.What are the ingredients in capecitabine tabletsActive ingredient: capecitabine, USPInactive ingredients: anhydrous lactose, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose and purified water. The peach or light peach film-coating contains iron oxide red, iron oxide yellow, macrogol, polyvinyl alcohol, talc and titanium dioxide.XELODA (R) is registered trademark of Hoffmann-La Roche Inc. For full TAXOTERE prescribing information, please refer to TAXOTERE Package Insert.This Patient Information has been approved by the U.S. Food and Drug Administration.All trade names drug products are the property of their respective owners.Manufactured for: AvKARE, Inc. Pulaski, TN 38478 Mfg. Rev. 03-2017-01AV 03/18 (P) AvPAK Capecitabine tablets can interact with blood thinner medicines, such as warfarin (COUMADIN (R)). Taking capecitabine tablets with these medicines can cause changes in how fast your blood clots, and can cause bleeding that can lead to death. This can happen as soon as few days after you start taking capecitabine tablets, or later during treatment, and possibly even within month after you stop taking capecitabine tablets. Your risk may be higher because you have cancer, and if you are over 60 years of age. Before taking capecitabine tablets, tell your doctor if you are taking warfarin (COUMADIN) or another blood thinner medicine.If you take warfarin (COUMADIN) or another blood thinner that is like warfarin (COUMADIN) during treatment with capecitabine tablets, your doctor should do blood tests often, to check how fast your blood clots during and after you stop treatment with capecitabine tablets. Your doctor may change your dose of the blood thinner medicine if needed. Before taking capecitabine tablets, tell your doctor if you are taking warfarin (COUMADIN) or another blood thinner medicine.. If you take warfarin (COUMADIN) or another blood thinner that is like warfarin (COUMADIN) during treatment with capecitabine tablets, your doctor should do blood tests often, to check how fast your blood clots during and after you stop treatment with capecitabine tablets. Your doctor may change your dose of the blood thinner medicine if needed.. cancer of the colon that has spread to lymph nodes in the area close to the colon (Dukes stage), after they have surgery.. cancer of the colon or rectum (colorectal) that has spread to other parts of the body (metastatic ).. breast cancer that has spread to other parts of the body (metastatic) together with another medicine called docetaxel after treatment with certain other anti-cancer medicines have not worked.. breast cancer that has spread to other parts of the body and has not improved after treatment with paclitaxel and certain other anti-cancer medicines, or who cannot receive any more treatment with certain anti-cancer medicines.. have severe kidney problems.. are allergic to capecitabine, 5-fluorouracil or to any of the ingredients in capecitabine tablets. See the end of this leaflet for complete list of ingredients in capecitabine tablets.. have had heart problems.. have kidney or liver problems.. have been told that you lack the enzyme DPD (dihydropyrimidine dehydrogenase). have any other medical conditions.. are pregnant or plan to become pregnant. Capecitabine tablets may harm your unborn baby. You should not become pregnant during treatment with capecitabine tablets. Talk to your doctor about birth control choices that may be right for you during treatment with capecitabine tablets.. are breastfeeding or plan to breastfeed. It is not known if capecitabine passes into your breast milk. Do not breastfeed during treatment with capecitabine tablets.. Take capecitabine tablets exactly as your doctor tells you to take it.. Your doctor will tell you how much capecitabine tablets to take and when to take it.. Take capecitabine tablets times day, time in the morning and time in the evening.. Take capecitabine tablets within 30 minutes after finishing meal. Swallow capecitabine tablets whole with water. Do not crush or cut capecitabine tablets.. Ask your healthcare provider or pharmacist how to safely throw away any unused capecitabine tablets.. If you have side effects with capecitabine tablets, if needed your doctor may decide to: change your dose of capecitabine tabletstreat you with capecitabine tablets less oftentell you to stop taking capecitabine tablets until certain side effects get better or go awaystop your treatment with capecitabine tablets if you have certain side effects and they are severe change your dose of capecitabine tablets. treat you with capecitabine tablets less often. tell you to stop taking capecitabine tablets until certain side effects get better or go away. stop your treatment with capecitabine tablets if you have certain side effects and they are severe. If you take too much capecitabine tablets, call your doctor or go to the nearest emergency room right away.. diarrhea. Diarrhea is common with capecitabine tablets and can sometimes be severe. Stop taking capecitabine tablets and call your doctor right away if the number of bowel movements you have in day increases by or more than is usual for you. Ask your doctor about what medicines you can take to treat your diarrhea. If you have severe bloody diarrhea with severe abdominal pain and fever, call your doctor or go to the nearest emergency room right away. heart problems. Capecitabine tablets can cause heart problems including: heart attack and decreased blood flow to the heart, chest pain, irregular heartbeats, changes in the electrical activity of your heart seen on an electrocardiogram (ECG), problems with your heart muscle, heart failure, and sudden death. Stop taking capecitabine tablets and call your doctor right away if you get any of the following symptoms: unexplained tiredness. loss of too much body fluid (dehydration) and kidney failure. Dehydration can happen with capecitabine tablets and may cause sudden kidney failure that can lead to death. You are at higher risk if you have kidney problems before taking capecitabine tablets and also take other medicines that can cause kidney problems. vomit or more times in day.. are only able to eat or drink little now and then, or not at all due to nausea.. have diarrhea. See diarrhea above.. serious skin and mouth reactions.. Capecitabine tablets can cause serious skin reactions that may lead to death. Tell your doctor right away if you develop skin rash, blisters and peeling of your skin. Your doctor may tell you to stop taking capecitabine tablets if you have serious skin reaction. Do not take capecitabine tablets again if this happens.. Capecitabine tablets can also cause hand and foot syndrome. Hand and foot syndrome is common with capecitabine tablets and can cause you to have numbness and changes in sensation in your hands and feet, or cause redness, pain, swelling of your hands and feet. Stop taking capecitabine tablets and call your doctor right away if you have any of these symptoms and you are not able to do your usual activities. Hand and foot syndrome can lead to loss of fingerprints which could impact your identification.. you may get sores in your mouth or on your tongue when taking capecitabine tablets. Stop taking capecitabine tablets and call your doctor if you get painful redness, swelling, or ulcers in your mouth and tongue, or if you are having problems eating. Tell your doctor if you have any side effect that bothers you or that does not go away.. increased level of bilirubin in your blood and liver problems. Increased bilirubin in your blood is common with capecitabine tablets. Your doctor will check you for these problems during treatment with capecitabine tablets. decreased white blood cells, platelets, and red blood cell counts. Your doctor will do blood tests during treatment with capecitabine tablets to check your blood cell counts. diarrhea. hand and foot syndrome. nausea. vomiting. stomach-area (abdominal) pain. tiredness. weakness. increased amounts of red blood cell breakdown products (bilirubin) in your blood. Store capecitabine tablets at room temperature between 68F to 77F (20C to 25C).. Keep capecitabine tablets in tightly closed container.. Keep capecitabine tablets and all medicines out of the reach of children.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed. (8.2) Females and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of capecitabine. Advise males with female partners of reproductive potential to use effective contraception. (8.3) Geriatric: Greater incidence of adverse reactions. Monitoring required. (8.5) Hepatic Impairment: Monitoring is recommended in patients with mild to moderate hepatic impairment. (8.6) Renal Impairment: Reduce capecitabine starting dose in patients with moderate renal impairment (2.3, 8.7, 12.3) See 17 for PATIENT COUNSELING INFORMATION AND FDA-approved patient labeling. Revised: 03/2018. Lactation: Advise women not to breastfeed. (8.2) Females and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of capecitabine. Advise males with female partners of reproductive potential to use effective contraception. (8.3) Geriatric: Greater incidence of adverse reactions. Monitoring required. (8.5) Hepatic Impairment: Monitoring is recommended in patients with mild to moderate hepatic impairment. (8.6) Renal Impairment: Reduce capecitabine starting dose in patients with moderate renal impairment (2.3, 8.7, 12.3) 8.1 Pregnancy. Risk Summary Based on findings in animal reproduction studies and its mechanism of action, capecitabine can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)] Limited available human data are not sufficient to inform the drug-associated risk during pregnancy. In animal reproduction studies, administration of capecitabine to pregnant animals during the period of organogenesis caused embryo lethality and teratogenicity in mice and embryo lethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving the recommended dose respectively [see Data]. Apprise pregnant women of the potential risk to fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Oral administration of capecitabine to pregnant mice during the period of organogenesis at dose of 198 mg/kg/day caused malformations and embryo lethality. In separate pharmacokinetic studies, this dose in mice produced 5-DFUR AUC values that were approximately 0.2 times the AUC 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. Oral administration of capecitabine to pregnant monkeys during the period of organogenesis at dose of 90 mg/kg/day, caused fetal lethality. This dose produced 5-DFUR AUC values that were approximately 0.6 times the AUC values in patients administered the recommended daily dose.. 8.2 Lactation. Risk Summary There is no information regarding the presence of capecitabine in human milk, or on its effects on milk production or the breast-fed infant. Capecitabine metabolites were present in the milk of lactating mice [see Data]. Because of the potential for serious adverse reactions from capecitabine exposure in breast-fed infants, advise women not to breastfeed during treatment with capecitabine and for weeks after the final dose. Data Lactating mice given single oral dose of capecitabine excreted significant amounts of capecitabine metabolites into the milk. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential prior to initiating capecitabine. Contraception Females Capecitabine can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)] Advise females of reproductive potential to use effective contraception during treatment and for months following the final dose of capecitabine. Males Based on genetic toxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for months following the last dose of capecitabine [see Nonclinical Toxicology (13.1)] Infertility Based on animal studies, capecitabine may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)] . 8.4 Pediatric Use The safety and effectiveness of capecitabine in pediatric patients have not been established.Additional information from the two clinical studies in which efficacy was not demonstrated in certain pediatric patients is approved for Hoffmann La Roches Xeloda (capecitabine) tablets. However, due to Hoffman La Roches marketing exclusivity rights, this product is not labeled with that information. 8.5 Geriatric Use Physicians should pay particular attention to monitoring the adverse effects of capecitabine in the elderly [see Warnings and Precautions (5.11) ]. 8.6 Hepatic Insufficiency Exercise caution when patients with mild to moderate hepatic dysfunction due to liver metastases are treated with capecitabine. The effect of severe hepatic dysfunction on capecitabine is not known [see Warnings and Precautions (5.12) and Clinical Pharmacology (12.3) ]. 8.7 Renal Insufficiency Patients with moderate (creatinine clearance 30 to 50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment showed higher exposure for capecitabine, 5-DFUR, and FBAL than in those with normal renal function [see Contraindications (4.1) Warnings and Precautions (5.5) Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ].

WARNINGS AND PRECAUTIONS SECTION.

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 prior history of coronary artery disease. (5.3) Increased Risk of Severe or Fatal Adverse Reactions in Patients with Lo 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 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 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 10 9/L or thrombocyte counts <100 10 9/L. If grade to neutropenia or thrombocytopenia occurs, stop therapy until condition resolves. (5.9) 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 prior history of coronary artery disease. (5.3) Increased Risk of Severe or Fatal Adverse Reactions in Patients with Lo 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 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 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 10 9/L or thrombocyte counts <100 10 9/L. If grade to 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 to diarrhea was 34 days (range from to 369 days). The median duration of grade to diarrhea was days. National Cancer Institute of Canada (NCIC) grade diarrhea is defined as an increase of to stools/day or nocturnal stools, grade diarrhea as an increase of to stools/day or incontinence and malabsorption, and grade diarrhea as an increase of >=10 stools/day or grossly bloody diarrhea or the need for parenteral support. If grade 2, or diarrhea occurs, administration of capecitabine should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade [see Dosage and Administration (2.3)] Standard antidiarrheal treatments (eg, 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 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 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 (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 patient develops grade to adverse event as outlined in Table [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 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 fetus. Advise females of reproductive potential to use effective contraception during treatment and for 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 severe mucocutaneous reaction possibly attributable to capecitabine treatment. Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) is cutaneous toxicity. Median time to onset was 79 days (range from 11 to 360 days) with severity range of grades to for patients receiving capecitabine monotherapy in the metastatic setting. Grade 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 hand-and-foot syndrome is defined as painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patients activities of daily living. Grade 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 and above) can eventually lead to loss of fingerprints which could impact patient identification. If grade or hand-and-foot syndrome occurs, administration of capecitabine should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 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 1250 mg/m twice daily as monotherapy for weeks followed by 1-week rest period, grade (1.5 to x ULN) hyperbilirubinemia occurred in 15.2% (n=133) of patients and grade (>3 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 or hyperbilirubinemia occurred in 22.8% and 12.3%, respectively. Of the 167 patients with grade or hyperbilirubinemia, 18.6% (n=31) also had postbaseline elevations (grades 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 to 4) at both prebaseline and postbaseline in alkaline phosphatase or transaminases, respectively. Only 7.8% (n=13) and 3% (n=5) had grade or 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 or hyperbilirubinemia was similar to the overall clinical trial safety database of capecitabine monotherapy. The median time to onset for grade or hyperbilirubinemia in the colorectal cancer population was 64 days and median total bilirubin increased from um/L at baseline to 13 um/L during treatment with capecitabine. Of the 136 colorectal cancer patients with grade or hyperbilirubinemia, 49 patients had grade or hyperbilirubinemia as their last measured value, of which 46 had liver metastases at baseline.In 251 patients with metastatic breast cancer who received combination of capecitabine and docetaxel, grade (1.5 to x ULN) hyperbilirubinemia occurred in 7% (n=17) and grade (>3 ULN) hyperbilirubinemia occurred in 2% (n=5).If drug-related grade to elevations in bilirubin occur, administration of capecitabine should be immediately interrupted until the hyperbilirubinemia decreases to <=3 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 dose of 1250 mg/m administered twice daily as monotherapy for weeks followed by 1-week rest period, 3.2%, 1.7%, and 2.4% of patients had grade or neutropenia, thrombocytopenia or decreases in hemoglobin, respectively. In 251 patients with metastatic breast cancer who received dose of capecitabine in combination with docetaxel, 68% had grade or neutropenia, 2.8% had grade or thrombocytopenia, and 9.6% had grade or anemia. Patients with baseline neutrophil counts of <1.5 10 9/L and/or thrombocyte counts of <100 10 9/L should not be treated with capecitabine. If unscheduled laboratory assessments during treatment cycle show grade or hematologic toxicity, treatment with capecitabine should be interrupted. 5.10 Geriatric Patients Patients >=80 years old may experience greater incidence of grade or 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 treatment-related grade or adverse event: diarrhea in (28.6%), nausea in (14.3%), hand-and-foot syndrome in (14.3%), and vomiting in (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 or diarrhea and stomatitis, and 40% (4 out of 10) experienced grade hand-and-foot syndrome.Among the 67 patients >=60 years of age receiving capecitabine in combination with docetaxel, the incidence of grade or 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 colon cancer after resection of the primary tumor, 41% of the 398 patients >=65 years of age treated with capecitabine experienced treatment-related grade or 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 (1.5%), and nausea in (1.3%) patients. In patients >=65 years of age (all randomized population; capecitabine 188 patients, 5-FU/LV 208 patients) treated for Dukes 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 to 1.27) and 1.04 (95% C.I. 0.79 to 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.