Capecitabine

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Cardiotoxicity [see Warnings and Precautions (5.3) ] Diarrhea [see Warnings and Precautions (5.4) ] Dehydration [see Warnings and Precautions (5.5) ] Renal Toxicity [see Warnings and Precautions (5.6) ] Serious Skin Toxicities [see Warnings and Precautions (5.7) ] Palmar-Plantar Erythrodysesthesia Syndrome [see Warnings and Precautions (5.8) ] Myelosuppression [see Warnings and Precautions (5.9) ] Hyperbilirubinemia [see Warnings and Precautions (5.10) ] Most common adverse reactions in patients who received capecitabine as a single agent for the adjuvant treatment for colon cancer (>30%) were palmar-plantar erythrodysesthesia syndrome, diarrhea, and nausea. ( 6.1 ) Most common adverse reactions (>30%) in patients with metastatic colorectal cancer who received capecitabine as a single agent were anemia, diarrhea, palmar-plantar erythrodysesthesia syndrome, hyperbilirubinemia, nausea, fatigue, and abdominal pain. ( 6.1 ) Most common adverse reactions (>30%) in patients with metastatic breast cancer who received capecitabine with docetaxel were diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, nausea, alopecia, vomiting, edema, and abdominal pain. ( 6.1 ) Most common adverse reactions (>30%) in patients with metastatic breast cancer who received capecitabine as a single agent were lymphopenia, anemia, diarrhea, hand-and-foot syndrome, nausea, fatigue, vomiting, and dermatitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chartwell RX, LLC. at 1-845-232-1683 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adjuvant Treatment of Colon Cancer Single Agent The safety of capecitabine as a single agent was evaluated in patients with Stage III colon cancer in X-ACT [ see Clinical Studies (14.1 ) ]. Patients received capecitabine 1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle (N=995) or leucovorin 20 mg/m 2 intravenously followed by fluorouracil 425 mg/m 2 as an intravenous bolus on days 1 to 5 of each 28-day cycle (N=974). Among patients who received capecitabine, the median duration of treatment was 5.4 months. Deaths due to all causes occurred in 0.8% of patients who received capecitabine on study or within 28 days of receiving study drug. Permanent discontinuation due to an adverse reaction occurred in 11% of patients who received capecitabine. Most common adverse reactions (>30%) were palmar-plantar erythrodysesthesia syndrome, diarrhea, and nausea. Tables 2 and 3 summarize the adverse reactions and laboratory abnormalities in X-ACT. Table 2 Adverse Reactions (>10%) in Patients Who Received Capecitabine for Adjuvant Treatment of Colon Cancer in X-ACT Adverse Reaction Capecitabine (N=995) Fluorouracil + Leucovorin (N=974) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia syndrome 60 17 9 <1 Gastrointestinal Diarrhea 47 12 65 14 Nausea 34 2 47 2 Stomatitis 22 2 60 14 Vomiting 15 2 21 2 Abdominal pain 14 3 16 2 General Fatigue 16 <1 16 1 Asthenia 10 <1 10 1 Lethargy 10 <1 9 <1 Clinically relevant adverse reactions in <10% of patients are presented below: Eye: conjunctivitis Gastrointestinal: constipation, upper abdominal pain, dyspepsia General: pyrexia Metabolism and Nutrition: anorexia Nervous System: dizziness, dysgeusia, headache Skin & Subcutaneous Tissue: rash, alopecia, erythema Table 3 Grade 3 or 4 Laboratory Abnormalities (>1%) in Patients Who Received Capecitabine as a Single Agent for Adjuvant Treatment of Colon Cancer in XACT Laboratory Abnormality Capecitabine (N=995) Fluorouracil + Leucovorin (N=974) Grade 3 or 4 (%) Grade 3 or 4 (%) Bilirubin increased 20 6 Lymphocytes decreased 13 13 Neutrophils/granulocytes decreased 2.4 26 Calcium decreased 2.3 2.2 Neutrophils decreased 2.2 26 ALT increased 1.6 0.6 Calcium increased 1.1 0.7 Hemoglobin decreased 1 1.2 Platelets decreased 1 0.7 In Combination with Oxaliplatin-Containing Regimens The safety of capecitabine for the perioperative treatment of adults with Stage III colon cancer as a component of a combination chemotherapy regimen was derived from published literature [see Clinical Studies (14.1) ]. The safety of capecitabine for the adjuvant treatment of patients with Stage III colon cancer as a component of a combination chemotherapy regimen was similar to those in patients treated with capecitabine as a single agent, with the exception of an increased incidence of neurosensory toxicity. Perioperative Treatment of Rectal Cancer The safety of capecitabine for the perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy was derived from published literature [see Clinical Studies (14.1) ]. The safety of capecitabine for the perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy was similar to those in patients treated with capecitabine as a single agent, with the exception of an increased incidence of diarrhea. Metastatic Colorectal Cancer Single Agent The safety of capecitabine as a single agent was evaluated in a pooled metastatic colorectal cancer population (Study SO14695 and Study SO14796) [ see Clinical Studies (14.1) ]. Patients received capecitabine 1,250 mg/m 2 orally twice a day for the first 14 days of a 21-day cycle (N=596) or leucovorin 20 mg/m 2 intravenously followed by fluorouracil 425 mg/m 2 as an intravenous bolus on days 1 to 5 of each 28-day cycle (N=593). Among the patients who received capecitabine, the median duration of treatment was 4.6 months. Deaths due to all causes occurred in 8% of patients who received capecitabine on study or within 28 days of receiving study drug. Permanent discontinuation due to an adverse reaction or intercurrent illness occurred in 13% of patients who received capecitabine. Most common adverse reactions (>30%) were anemia, diarrhea, palmar-plantar erythrodysesthesia syndrome, hyperbilirubinemia, nausea, fatigue, and abdominal pain. Table 4 shows the adverse reactions occurring in this pooled colorectal cancer population. Table 4 Adverse Reactions (>10%) in Patients Who Received Capecitabine in Pooled Metastatic Colorectal Cancer Population (Study SO14695 and Study SO14796) Adverse Reaction Capecitabine (N=596) Fluorouracil + Leucovorin (N=593) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) G rade 4 (%) Blood and Lymphatic System Anemia 80 2 <1 79 1 <1 Neutropenia 13 1 2 46 8 13 Gastrointestinal Diarrhea 55 13 2 61 10 2 Nausea 43 4 - 51 3 <1 Abdominal pain 35 9 <1 31 5 - Vomiting 27 4 <1 30 4 <1 Stomatitis 25 2 <1 62 14 1 Constipation 14 1 <1 17 1 - Gastrointestinal motility disorder 10 <1 - 7 <1 - Oral discomfort 10 - - 10 - - Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia syndrome 54 17 NA 6 1 NA Dermatitis 27 1 - 26 1 - Hepatobiliary Hyperbilirubinemia 48 18 5 17 3 3 General Fatigue* 42 4 - 46 4 - Pyrexia 18 1 - 21 2 - Edema 15 1 - 9 1 - Pain 12 1 - 10 1 - Metabolism and Nutrition Decreased appetite 26 3 <1 31 2 <1 Respiratory Thoracic and Mediastinal Dyspnea 14 1 - 10 <1 1 Eye Eye irritation 13 - - 10 <1 - Nervous System Peripheral sensory neuropathy 10 - - 4 - - Headache 10 1 - 7 - - Musculoskeletal Back pain 10 2 - 9 <1 - – Not observed * Includes weakness NA = Not Applicable Clinically relevant adverse reactions in <10% of patients are presented below: Eye: abnormal vision Gastrointestinal: upper gastrointestinal tract inflammatory disorders, gastrointestinal hemorrhage, ileus General: chest pain Infections: viral Metabolism and Nutrition: dehydration Musculoskeletal: arthralgia Nervous System: dizziness (excluding vertigo), insomnia, taste disturbance Psychiatric: mood alteration, depression Respiratory, Thoracic, and Mediastinal: cough, pharyngeal disorder Skin and Subcutaneous Tissue: skin discoloration, alopecia Vascular: venous thrombosis In Combination with Oxaliplatin The safety of capecitabine for the treatment of patients with unresectable or metastatic colorectal cancer as a component of a combination chemotherapy regimen was derived from published literature [see Clinical Studies (14.1) ] . The safety of capecitabine for the treatment of patients with unresectable or metastatic colorectal cancer as a component of a combination chemotherapy regimen was similar to those in patients treated with capecitabine as a single agent, with the exception of an increased incidence of peripheral neuropathy. Metastatic Breast Cancer In Combination with Docetaxel The safety of capecitabine in combination with docetaxel was evaluated in patients with metastatic breast cancer in Study SO14999 [see Clinical Studies (14.2) ] . Patients received capecitabine 1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle with docetaxel 75 mg/m 2 as 1- hour intravenous infusion on day 1 of each 21-day cycle for at least 6 weeks or docetaxel 100 mg/m 2 as a 1-hour intravenous infusion on day 1 of each 21-day cycle for at least 6 weeks. Among patients who received capecitabine, the mean duration of treatment was 4.2 months. Permanent discontinuation due to an adverse reaction occurred in 26% of patients who received capecitabine. Dosage interruptions due to an adverse reaction occurred in 79% of patients who received capecitabine and dosage reductions due to an adverse reaction occurred in 65%. Most common adverse reactions (>30%) were diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, nausea, alopecia, vomiting, edema, and abdominal pain. Table 5 summarizes the adverse reactions in Study SO14999. Table 5 Adverse Reactions (≥10%) in Patients Who Received Capecitabine with Docetaxel for Metastatic Breast Cancer in Study SO14999 Adverse Reaction Capecitabine with Docetaxel (N=251) Docetaxel (N=255) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Gastrointestinal Diarrhea 67 14 <1 48 5 <1 Stomatitis 67 17 <1 43 5 - Nausea 45 7 - 36 2 - Vomiting 35 4 1 24 2 - Abdominal pain 30 3 <1 24 2 - Constipation 20 2 - 18 - - Dyspepsia 14 - - 8 1 - Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia syndrome 63 24 NA 8 1 NA Alopecia 41 6 - 42 7 - Nail disorder 14 2 - 15 - - Cardiac Edema 33 <2 - 34 <3 1 General Pyrexia 28 2 - 34 2 - Asthenia 26 4 <1 25 6 - Fatigue 22 4 - 27 6 - Weakness 16 2 - 11 2 - Pain in Limb 13 <1 - 13 2 - Blood and Lymphatic System Neutropenic fever 16 3 13 21 5 16 Nervous System Taste disturbance 16 <1 - 14 <1 - Headache 15 3 - 15 2 - Paresthesia 12 <1 - 16 1 - Dizziness 12 - - 8 <1 - Musculoskeletal and Connective Tissue Arthralgia 15 2 - 24 3 - Myalgia 15 2 - 25 2 - Back Pain 12 <1 - 11 3 - Respiratory, Thoracic and Mediastinal Dyspnea 14 2 <1 16 2 - Cough 13 1 - 22 <1 - Sore Throat 12 2 - 11 <1 - Metabolism and Nutrition Anorexia 13 <1 - 11 <1 - Appetite decreased 10 - - 5 - - Dehydration 10 2 - 7 <1 <1 Eye Lacrimation increased 12 - - 7 <1 - – Not observed NA = Not Applicable. Clinically relevant adverse reactions in <10% of patients are presented below: Blood and Lymphatic System: agranulocytosis, prothrombin decreased Cardiac: supraventricular tachycardia Eye: conjunctivitis, eye irritation Gastrointestinal: ileus, necrotizing enterocolitis, esophageal ulcer, hemorrhagic diarrhea, dry mouth General: chest pain (non-cardiac), lethargy, pain, influenza-like illness Hepatobiliary: jaundice, abnormal liver function tests, hepatic failure, hepatic coma, hepatotoxicity Immune System: hypersensitivity Infection: hypoesthesia, neutropenic sepsis, sepsis, bronchopneumonia, oral candidiasis, urinary tract infection Metabolism and Nutrition: weight decreased Musculoskeletal and Connective Tissue: bone pain Nervous System: insomnia, peripheral neuropathy, ataxia, syncope, taste loss, polyneuropathy, migraine Psychiatric: depression Renal and Urinary: renal failure Respiratory, Thoracic and Mediastinal: upper respiratory tract infection, pleural effusion, epistaxis, rhinorrhea Skin and Subcutaneous Tissue: pruritis, rash erythematous, dermatitis, nail discoloration, onycholysis Vascular: lymphedema, hypotension, venous phlebitis and thrombophlebitis, postural hypotension, flushing Table 6 summarizes the laboratory abnormalities in this trial. Table 6 Laboratory Abnormalities (≥20%) in Patients Who Received Capecitabine with Docetaxel for Metastatic Breast Cancer in Study SO14999 Laboratory Abnormality Capecitabine with Docetaxel (N=251) Docetaxel (N=255) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Hematologic Lymphocytopenia 99 48 41 98 44 40 Leukopenia 91 37 24 88 42 33 Neutropenia 86 20 49 87 10 66 Anemia 80 7 3 83 5 <1 Thrombocytopenia 41 2 1 23 1 2 Hepatobiliary Hyperbilirubinemia 20 7 2 6 2 2 Single Agent The safety of capecitabine as a single agent was evaluated in patients with metastatic breast cancer in Study SO14697 [see Clinical Studies (14.2) ] . Patients received capecitabine 1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle. The mean duration of treatment was 3.7 months. Permanent discontinuation due to an adverse reaction or intercurrent illness occurred in 8% of patients. Most common adverse reactions (>30%) were lymphopenia, anemia, diarrhea, hand-and-foot syndrome, nausea, fatigue, vomiting, and dermatitis. Table 7 summarizes the adverse reactions in Study SO14697. Table 7 Adverse Reactions (>10%) in Patients Who Received Capecitabine for Metastatic Breast Cancer in Study SO14697 Adverse Reaction Capecitabine (n=162) All Grades (%) Grade 3 (%) Grade 4 (%) Blood and Lymphatic System Lymphopenia 94 44 15 Anemia 72 3 1 Neutropenia 26 2 2 Thrombocytopenia 24 3 1 Gastrointestinal Diarrhea 57 12 3 Nausea 53 4 - Vomiting 37 4 - Stomatitis 24 7 - Abdominal pain 20 4 - Constipation 15 1 - Skin and Subcutaneous Tissue Hand-and-foot syndrome 57 11 NA Dermatitis 37 1 - General Fatigue 41 8 - Pyrexia 12 1 - Metabolism and Nutrition Anorexia 23 3 - Hepatobiliary Hyperbilirubinemia 22 9 2 Nervous System Paresthesia 21 1 - Eye Eye irritation 15 - - – = Not observed NA = Not Applicable Pooled Safety Population Clinically relevant adverse reactions in <10% of patients who received capecitabine as a single agent are presented below. Blood & Lymphatic System: leukopenia, coagulation disorder, bone marrow depression, pancytopenia Cardiac: tachycardia, bradycardia, atrial fibrillation, myocarditis, edema Ear: vertigo Eye: conjunctivitis Gastrointestinal: abdominal distension, dysphagia, proctalgia, gastric ulcer, ileus, gastroenteritis, dyspepsia General: chest pain, influenza-like illness, hot flushes, pain, thirst, fibrosis, hemorrhage, edema, pain in limb Hepatobiliary: hepatic fibrosis, hepatitis, cholestatic hepatitis, abnormal liver function tests Immune System: drug hypersensitivity Infections: bronchitis, pneumonia, keratoconjunctivitis, sepsis, fungal infections Metabolism and Nutrition: cachexia, hypertriglyceridemia, hypokalemia, hypomagnesemia, dehydration Musculoskeletal and Connective Tissue: myalgia, arthritis, muscle weakness Nervous System: insomnia, ataxia, tremor, dysphasia, encephalopathy, dysarthria, impaired balance, headache, dizziness Psychiatric: depression, confusion Renal and Urinary: renal impairment Respiratory, Mediastinal and Thoracic: cough, epistaxis, respiratory distress, dyspnea Skin and Subcutaneous Tissue: nail disorder, sweating increased, photosensitivity reaction, skin ulceration, pruritus, radiation recall syndrome Vascular: hypotension, hypertension, lymphedema, pulmonary embolism Unresectable or Metastatic Gastric, Esophageal, or Gastroesophageal Junction Cancer The safety of capecitabine for the treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy regimen was derived from published literature [see Clinical Studies (14.3) ]. The safety of capecitabine for the treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy regimen was consistent with the known safety profile of capecitabine. The safety of capecitabine for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease as a component of a combination regimen was derived from the published literature [see Clinical Studies (14.3) ]. The safety of capecitabine for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma was consistent with the known safety profile of capecitabine. Pancreatic Cancer The safety of capecitabine for the adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen was derived from the published literature [ see Clinical Studies (14.4) ]. The safety of capecitabine for the adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen was consistent with the known safety profile of capecitabine 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of capecitabine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Eye: lacrimal duct stenosis, corneal disorders including keratitis Hepatobiliary: hepatic failure Immune System Disorders: angioedema Nervous System: toxic leukoencephalopathy Renal & Urinary: acute renal failure secondary to dehydration including fatal outcome Skin & Subcutaneous Tissue: cutaneous lupus erythematosus, severe skin reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (TEN), persistent or severe PPES can eventually lead to loss of fingerprints

4 CONTRAINDICATIONS Capecitabine is contraindicated in patients with history of severe hypersensitivity reaction to fluorouracil or capecitabine [ see Adverse Reactions (6.1) ] . History of severe hypersensitivity reactions to fluorouracil or capecitabine ( 4 )

11 DESCRIPTION Capecitabine is a nucleoside metabolic inhibitor. The chemical name is 5’-deoxy-5-fluoro-N- [(pentyloxy) carbonyl]-cytidine and has a molecular formula of C 15 H 22 FN 3 O 6 and a molecular weight of 359.35. Capecitabine has the following structural formula: Capecitabine is a white to off-white crystalline powder with an aqueous solubility of 26 mg/mL at 20ºC. Capecitabine Tablets, USP are supplied as biconvex, oblong film-coated tablets for oral use. Each light peach- colored tablet debossed with ‘C150’ on one side and plain on other side contains 150 mg of capecitabine USP and each peach colored tablet debossed with ‘C500’ on one side and plain on other side contains 500 mg of capecitabine USP. The inactive ingredients in capecitabine include: anhydrous lactose, croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate. The peach or light peach film coating contains hydroxypropyl methylcellulose, polyethylene glycol, red iron oxides, synthetic yellow, talc and titanium dioxide. Cape

2 DOSAGE AND ADMINISTRATION Adjuvant Treatment of Colon Cancer Single agent: 1,250 mg/m 2 twice daily orally for the first 14 days of each 21-day cycle for a maximum of 8 cycles. ( 2.1 ) In combination with Oxaliplatin-Containing Regimens: 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle for a maximum of 8 cycles in combination with oxaliplatin 130 mg/m 2 administered intravenously on day 1 of each cycle. ( 2.1 ) Perioperative Treatment of Rectal Cancer With Concomitant Radiation Therapy: 825 mg/m 2 orally twice daily ( 2.1 ) Without Radiation Therapy: 1,250 mg/m 2 orally twice daily ( 2.1 ) Unresectable or Metastatic Colorectal Cancer Single agent: 1,250 mg/m 2 twice daily orally for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity. ( 2.1 ) In Combination with Oxaliplatin: 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with oxaliplatin 130 mg/m2 administered intravenously on day 1 of each cycle. ( 2.1 ) Advanced or Metastatic Breast Cancer: Single agent: 1,000 mg/m 2 or 1,250 mg/m 2 twice daily orally for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity. ( 2.2 ) In combination with docetaxel: 1,000 mg/m 2 or 1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle, until disease progression or unacceptable toxicity in combination with docetaxel at 75 mg/m 2 administered intravenously on day 1 of each cycle ( 2.2 ) Advanced or Metastatic Breast Cancer: Single agent: 1,000 mg/m 2 or 1,250 mg/m 2 twice daily orally for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity. ( 2.2 ) In combination with docetaxel: 1,000 mg/m 2 or 1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle, until disease progression or unacceptable toxicity in combination with docetaxel at 75 mg/m 2 administered intravenously on day 1 of each cycle ( 2.2 ) Unresectable or Metastatic Gastric, Esophageal, or Gastroesophageal Junction Cancer 625 mg/m 2 orally twice daily on days 1 to 21 of each 21-day cycle for a maximum of 8 cycles in combination with platinum-containing chemotherapy. ( 2.3 ) OR 850 mg/m 2 or 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with oxaliplatin 130 mg/m 2 administered intravenously on day 1 of each cycle. ( 2.3 ) HER2-overexpressing metastatic adenocarcinoma of the gastroesophageal junction or stomach 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with cisplatin and trastuzumab. ( 2.3 ) Pancreatic cancer 830 mg/m 2 orally twice daily for the first 21 days of each 28-day cycle for maximum of 6 cycles in combination with gemcitabine 1,000 mg/m 2 administered intravenously on days 1, 8, and 15 of each cycle. ( 2.4 ) Refer to Sections 2.5 and 2.6 for information related to dosage modifications for adverse reactions and renal impairment ( 2.5 and 2.6 ). 2.1 Recommended Dosage for Colorectal Cancer Adjuvant Treatment of Colon Cancer Single Agent The recommended dosage of capecitabine is 1,250 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle for a maximum of 8 cycles. In Combination with Oxaliplatin-Containing Regimens The recommended dosage of capecitabine is 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle for a maximum of 8 cycles in combination with oxaliplatin 130 mg/m 2 administered intravenously on day 1 of each cycle. Refer to the oxaliplatin prescribing information for additional dosing information as appropriate. Perioperative Treatment of Rectal Cancer The recommended dosage of capecitabine is 825 mg/m 2 orally twice daily when administered with concomitant radiation therapy and 1,250 mg/m 2 orally twice daily when administered without radiation therapy as part of a peri-operative combination regimen. Unresectable or Metastatic Colorectal Cancer Single Agent The recommended dosage of capecitabine is 1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle until disease progression or unacceptable toxicity. In Combination with Oxaliplatin The recommended dosage of capecitabine is 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with oxaliplatin 130 mg/m 2 administered intravenously on day 1 of each cycle. Refer to the Prescribing Information for oxaliplatin for additional dosing information as appropriate. 2.2 Recommended Dosage for Breast Cancer Advanced or Metastatic Breast Cancer Single Agent The recommended dosage of capecitabine is 1,000 mg/m 2 or 1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle until disease progression or unacceptable toxicity. Individualize the dose and dosing schedule of capecitabine based on patient risk factors and adverse reactions. In Combination with Docetaxel The recommended dosage of capecitabine is 1,000 mg/m 2 or 1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle until disease progression or unacceptable toxicity in combination with docetaxel 75 mg/m 2 administered intravenously on day 1 of each cycle. Refer to the Prescribing Information for docetaxel for additional dosing information as appropriate. 2.3 Recommended Dosage for Gastric, Esophageal, or Gastroesophageal Junction Cancer The recommended dosage of capecitabine for unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer is: 625 mg/m 2 orally twice daily on days 1 to 21 of each 21-day cycle for a maximum of 8 cycles in combination with platinum-containing chemotherapy. OR 850 mg/m 2 or 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with oxaliplatin 130 mg/m 2 administered intravenously on day 1 of each cycle. Individualize the dose and dosing schedule of capecitabine based on patient risk factors and adverse reactions. The recommended dosage of capecitabine for HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma is 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with cisplatin and trastuzumab. Refer to the Prescribing Information for agents used in combination for additional dosing information as appropriate. 2.4 Recommended Dosage for Pancreatic Cancer The recommended dosage of capecitabine is 830 mg/m 2 orally twice daily for the first 21 days of each 28-day cycle until disease progression, unacceptable toxicity, or for a maximum 6 cycles in combination with gemcitabine 1,000 mg/m 2 administered intravenously on days 1, 8, and 15 of each cycle. Refer to Prescribing Information for gemcitabine for additional dosing information as appropriate. 2.5 Dosage Modifications for Adverse Reactions Monitor patients for adverse reactions and modify dosages of capecitabine as described in Table 1. Do not replace missed doses of capecitabine; instead resume capecitabine with the next planned dosage. When capecitabine is administered with docetaxel, withhold capecitabine and docetaxel until the requirements for resuming both capecitabine and docetaxel are met. Refer to the Prescribing Information for docetaxel for additional dosing information as appropriate. Table 1 Recommended Dosage Modifications for Adverse Reactions Severity Dosage Modification Resume at Same or Reduced Dose (Percent of Current Dose) Grade 2 1 st appearance Withhold until resolved to grade 0-1. 100% 2 nd appearance 75% 3 rd appearance 50% 4 th appearance Permanently discontinue. - Grade 3 1 st appearance Withhold until resolved to grade 0-1. 75% 2 nd appearance 50% 3 rd appearance Permanently discontinue. - Grade 4 1 st appearance Permanently discontinue OR Withhold until resolved to grade 0-1. 50% Hyperbilirubinemia Patients with Grade 3-4 hyperbilirubinemia may resume treatment once the event is Grade 2 or less (less than three times the upper limit of normal), using the percent of current dose as shown in column 3 of Table 1 [see Warnings and Precautions (5.10) ]. 2.6 Dosage Modification For Renal Impairment Reduce the dose of capecitabine by 25% for patients with creatinine clearance (CLcr) of 30 to 50 mL/min as determined by Cockcroft-Gault equation. A dosage has not been established in patients with severe renal impairment (CLcr <30 mL/min) [ see Use in Specific Populations (8.6) ]. 2.7 Administration Round the recommended dosage for patients to the nearest 150 mg dose to provide whole capecitabine tablets. Swallow capecitabine tablets whole with water within 30 minutes after a meal. Do not chew, cut, or crush capecitabine tablets [see Warnings and Precautions (5.12) ]. Take capecitabine at the same time each day approximately 12 hours apart. Do not take an additional dose after vomiting and continue with the next scheduled dose. Do not take a missed dose and continue with the next scheduled dose. Capecitabine is a hazardous drug. Follow applicable special handling and disposal procedures. 1

1 INDICATIONS AND USAGE Capecitabine is a nucleoside metabolic inhibitor indicated for: Colorectal Cancer adjuvant treatment of patients with Stage III colon cancer as a single agent or as a component of a combination chemotherapy regimen. ( 1.1 ) perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy. ( 1.1 ) treatment of patients with unresectable or metastatic colorectal cancer as a single agent or as a component of a combination chemotherapy regimen. ( 1.1 ) Breast Cancer treatment of patients with advanced or metastatic breast cancer as a single agent if an anthracycline-or taxane-containing chemotherapy is not indicated. ( 1.2 ) treatment of patients with advanced or metastatic breast cancer in combination with docetaxel after disease progression on prior anthracycline-containing chemotherapy. ( 1.2 ) Gastric, Esophageal, or Gastroesophageal Junction Cancer treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy regimen. ( 1.3 ) treatment of adults with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease as a component of a combination regimen. ( 1.3 ) Pancreatic Cancer adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen. ( 1.4 ) 1.1 Colorectal Cancer Capecitabine is indicated for the: adjuvant treatment of patients with Stage III colon cancer as a single agent or as a component of a combination chemotherapy regimen. perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy. treatment of patients with unresectable or metastatic colorectal cancer as a single agent or as a component of a combination chemotherapy regimen. 1.2 Breast Cancer Capecitabine is indicated for the: treatment of patients with advanced or metastatic breast cancer as a single agent if an anthracycline- or taxane-containing chemotherapy is not indicated. treatment of patients with advanced or metastatic breast cancer in combination with docetaxel after disease progression on prior anthracycline-containing chemotherapy. 1.3 Gastric, Esophageal, or Gastroesophageal Junction Cancer Capecitabine is indicated for the: treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy regimen. treatment of adults with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease as a component of a combination regimen. 1.4 Pancreatic Cancer Capecitabine is indicated for the adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen.

10 OVERDOSAGE Administer uridine triacetate within 96 hours for management of capecitabine overdose. Although no clinical experience using dialysis as a treatment for capecitabine overdose has been reported, dialysis may be of benefit in reducing circulating concentrations of 5’-DFUR, a low–molecular-weight metabolite of the parent compound.

7 DRUG INTERACTIONS Allopurinol: Avoid concomitant use of allopurinol with capecitabine. ( 7.1 ) Leucovorin: Closely monitor for toxicities when capecitabine is coadministered with leucovorin. ( 7.1 ) CYP2C9 substrates: Closely monitor for adverse reactions when CYP2C9 substrates are coadministered with capecitabine. ( 7.2 ) Vitamin K antagonists: Monitor INR more frequently and dose adjust oral vitamin K antagonist as appropriate Phenytoin: Closely monitor phenytoin levels in patients taking capecitabine concomitantly with phenytoin and adjust the phenytoin dose as appropriate. ( 7.2 ) Nephrotoxic drugs : Closely monitor for signs of renal toxicity when capecitabine is used concomitantly with nephrotoxic drugs. ( 7.3 ) 7.1 Effect of Other Drugs on Capecitabine Allopurinol Concomitant use with allopurinol may decrease concentration of capecitabine’s active metabolites [see Clinical Pharmacology (12.3) ] , which may decrease efficacy. Avoid concomitant use of allopurinol with capecitabine. Leucovorin The concentration of fluorouracil is increased and its toxicity may be enhanced by leucovorin, folic acid, or folate analog products. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil. Instruct patients not to take products containing folic acid or folate analog products unless directed to do so by their healthcare provider. 7.2 Effect of Capecitabine on Other Drugs CYP2C9 Substrates Capecitabine increased exposure of CYP2C9 substrates [ see Clinical Pharmacology (12.3) ], which may increase the risk of adverse reactions related to these substrates. Closely monitor for adverse reactions of CYP2C9 substrates where minimal concentration changes may lead to serious adverse reactions when used concomitantly with capecitabine (e.g., anticoagulants, antidiabetic drugs). Vitamin K Antagonists Capecitabine increases exposure of vitamin K antagonist [ see Clinical Pharmacology (12.3) ], which may alter coagulation parameters and/or bleeding and could result in death [ see Warning and Precautions (5.1) ]. These events may occur within days of treatment initiation and up to 1 month after discontinuation of capecitabine. Monitor INR more frequently and refer to the prescribing information of oral vitamin K antagonist for dosage adjustment, as appropriate, when capecitabine is used concomitantly with vitamin K antagonist. Phenytoin Capecitabine may increases exposure of phenytoin, which may increase the risk of adverse reactions related to phenytoin. Closely monitor phenytoin levels and refer to the prescribing information of phenytoin for dosage adjustment, as appropriate, when capecitabine is used concomitantly with phenytoin. 7.3 Nephrotoxic Drugs Due of the additive pharmacologic effect, concomitant use of capecitabine with other drugs known to cause renal toxicity may increase the risk of renal toxicity [ see Warnings and Precautions (5.6) ]. Closely monitor for signs of renal toxicity when capecitabine is used concomitantly with nephrotoxic drugs (e.g. platinum salts, irinotecan, methotrexate, intravenous bisphosphonates).

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Capecitabine is metabolized to fluorouracil in vivo . Both normal and tumor cells metabolize fluorouracil 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, N 5-10 -methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a 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 a 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. 12.2 Pharmacodynamics Population-based exposure-effect analyses demonstrated a positive association between AUC of fluorouracil and grade 3-4 hyperbilirubinemia. 12.3 Pharmacokinetics The AUC of capecitabine and its metabolite 5’-DFCR increases proportionally over a dosage range of 500 mg/m 2 /day to 3,500 mg/m 2 /day (0.2 to 1.4 times the approved recommended dosage).The AUC of capecitabine’s metabolites 5’-DFUR and fluorouracil increased greater than proportional to the dose. The interpatient variability in the C max and AUC of fluorouracil was greater than 85%. Absorption Following oral administration of capecitabine 1,255 mg/m 2 orally twice daily (the recommended dosage when used as single agent), the median T max of capecitabine and its metabolite fluorouracil was approximately 1.5 hours and 2 hours, respectively. Effect of Food Following administration of a meal (breakfast medium-rich in fat and carbohydrates), the mean C max and AUC 0-INF of capecitabine was decreased by 60% and 34%, respectively. The mean C max and AUC 0-INF of fluorouracil were also decreased by 37% and 12%, respectively. The T max of both capecitabine and fluorouracil was delayed by1.5 hours. 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%). Following oral administration of capecitabine 7 days before surgery in patients with colorectal cancer, the median ratio of concentration for the active metabolite fluorouracil in colorectal tumors to adjacent tissues was 2.9 (range: 0.9 to 8.0). Elimination The elimination half-lives of capecitabine and fluorouracil were approximately0.75 hour. Metabolism Capecitabine undergoes metabolism by carboxylesterase and is hydrolyzed to 5’-DFCR. 5’- DFCR is subsequently converted to 5’-DFUR by cytidine deaminase. 5’-DFUR is then hydrolized by thymidine phosphorylase (dThdPase) enzymes to the active metabolite fluorouracil. Fluorouracil is subsequently metabolized by dihydropyrimidine dehydrogenase to 5-fluoro-5,6- dihydro-fluorouracil (FUH 2 ). The pyrimidine ring of FUH 2 is cleaved by dihydropyrimidinase to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, FUPA is cleaved by β-ureido-propionase to α-fluoro-β-alanine (FBAL). Excretion Following administration of radiolabeled capecitabine,96% of the administered capecitabine dose was recovered in urine (3% unchanged and 57% as metabolite FBAL) and 2.6% in feces. Specific Populations Following therapeutic doses of capecitabine, no clinically meaningful difference in the pharmacokinetics of 5’-DFUR, fluorouracil or FBAL were observed based on sex (202 females and 303 males) and race (455 White, 22 Black, and 28 Other). No clinically meaningful difference on the pharmacokinetics of 5’-DFUR and fluorouracil were observed based on age (range: 27 to 86 years); however, the AUC of FBAL increased by 15% following a 20% increase in age. Racial or Ethnic Groups Following administration of capecitabine 825 mg/m 2 orally twice daily for 14 days (0.66 times the recommended dosage), the C max and AUC of capecitabine decreased by 36% and 24%, respectively in Japanese patients (n=18) compared to White patients (n=22). The C max and AUC of FBAL decreased by approximately 25% and 34%, respectively in Japanese patients compared to White patients; however, the clinical significance of these differences is unknown. No clinically significant differences in the pharmacokinetics of 5’-DFCR, 5’-DFUR or fluorouracil were observed. Patients with Renal Impairment Table 8 Effect of Renal Impairment on the Pharmacokinetics of Capecitabine, 5’-DFUR, and FBAL Renal Impairment a Changes in AUC b Capecitabine 5’-DFUR c FBAL c 5-FU Lcr 30 to 50 mL/min Increased by 25% Increased by 42% Increased by 85% No relevant change CLcr <30 mL/min Increased by 25% Increased by 71% Increased by 258% Increased by 24% a Compared to patients with CLcr >80 mL/min b Following administration of capecitabine 1,250 mg/ m 2 orally twice daily; day 1 observations c Capecitabine metabolite CLcr=Creatine Clearance, AUC= Area under the plasma concentration-time curve Patients with Hepatic Impairment AUC 0-INF and C max of capecitabine’s active principle, fluorouracil, were not affected in patients with mild or moderate hepatic impairment compared to patients with normal hepatic function. The AUC 0-INF and C max of capecitabine increased by 60%. The effect of severe hepatic impairment on the pharmacokinetics of capecitabine and its metabolites are unknown. Drug Interaction Studies Clinical Studies Effect of Capecitabine on Warfarin: In four patients with cancer, chronic administration of capecitabine 1,250 mg/m 2 twice daily with a single dose of warfarin 20 mg increased the mean AUC of S-warfarin by 57% and decreased its clearance by 37%. Baseline corrected AUC of INR in these 4 patients increased by 2.8-fold, and the maximum observed mean INR value was increased by 91%. Effect of Capecitabine on Celecoxib: Concomitant administration of multiple doses of capecitabine (capecitabine 1,000 mg/m 2 twice daily for 14 days) increased celecoxib (sensitive CYP2C9 substrate) AUC by 28%, C max by 24% and C trough by 30%. Effect of Antacids on Capecitabine: When an aluminum hydroxide- and magnesium hydroxide containing antacid was administered immediately after a capecitabine dose of 1,250 mg/m 2 in patients with cancer, AUC and C 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, fluorouracil, FBAL) of capecitabine Effect of Allopurinol on Capecitabine: Concomitant use with allopurinol may decrease conversion of capecitabine to the active metabolites, FdUMP and FUTP. Effect of Capecitabine on Docetaxel and Effect of Docetaxel on Capecitabine: Capecitabine had no effect on the pharmacokinetics of docetaxel (C max and AUC) and docetaxel has no effect on the pharmacokinetics of capecitabine and the fluorouracil precursor 5’-DFUR. In Vitro Studies Cytochrome P450 (CYP) Enzymes: Capecitabine and its metabolites (5’-DFUR, 5’-DFCR, fluorouracil, and FBAL) did not inhibit CYP1A2, CYP2A6, CYP3A4, CYP2C19, CYP2D6, or CYP2E1 in vitro. 12.5 Pharmacogenomics The DPYD gene encodes the enzyme DPD, which is responsible for the catabolism of >80% of fluorouracil. Approximately 3-5% of White populations have partial DPD deficiency and 0.2% of White populations have complete DPD deficiency, which may be due to certain genetic no function or decreased function variants in DPYD resulting in partial to complete or near complete absence of enzyme activity. DPD deficiency is estimated to be more prevalent in Black or African American populations compared to White populations. Insufficient information is available to estimate the prevalence of DPD deficiency in other populations. Patients who are homozygous or compound heterozygous for no function DPYD variants (i.e., carry two no function DPYD variants) or are compound heterozygous for a no function DPYD variant plus a decreased function DPYD variant have complete DPD deficiency and are at increased risk for acute early-onset of toxicity and serious life-threatening, or fatal adverse reactions due to increased systemic exposure to capecitabine. Partial DPD deficiency can result from the presence of either two decreased function DPYD variants or one normal function plus either a decreased function or a no function DPYD variant. Patients with partial DPD deficiency may also be at an increased risk for toxicity from capecitabine. Four DPYD variants have been associated with impaired DPD activity in White populations, especially when present as homozygous or compound heterozygous variants: c.1905+1G>A ( DPYD *2A), c.1679T>G ( DPYD *13), c.2846A>T, and c.1129-5923C>G (Haplotype B3). DPYD *2A and DPYD *13 are no function variants, and c.2846A>T and c.1129-5923C > G are decreased function variants. The decreased function DPYD variant c.557A>G is observed in individuals of African ancestry. This is not a complete listing of all DPYD variants that may result in DPD deficiency [ see Warnings and Precautions (5.2) ].

12.3 Pharmacokinetics The AUC of capecitabine and its metabolite 5’-DFCR increases proportionally over a dosage range of 500 mg/m 2 /day to 3,500 mg/m 2 /day (0.2 to 1.4 times the approved recommended dosage).The AUC of capecitabine’s metabolites 5’-DFUR and fluorouracil increased greater than proportional to the dose. The interpatient variability in the C max and AUC of fluorouracil was greater than 85%. Absorption Following oral administration of capecitabine 1,255 mg/m 2 orally twice daily (the recommended dosage when used as single agent), the median T max of capecitabine and its metabolite fluorouracil was approximately 1.5 hours and 2 hours, respectively. Effect of Food Following administration of a meal (breakfast medium-rich in fat and carbohydrates), the mean C max and AUC 0-INF of capecitabine was decreased by 60% and 34%, respectively. The mean C max and AUC 0-INF of fluorouracil were also decreased by 37% and 12%, respectively. The T max of both capecitabine and fluorouracil was delayed by1.5 hours. 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%). Following oral administration of capecitabine 7 days before surgery in patients with colorectal cancer, the median ratio of concentration for the active metabolite fluorouracil in colorectal tumors to adjacent tissues was 2.9 (range: 0.9 to 8.0). Elimination The elimination half-lives of capecitabine and fluorouracil were approximately0.75 hour. Metabolism Capecitabine undergoes metabolism by carboxylesterase and is hydrolyzed to 5’-DFCR. 5’- DFCR is subsequently converted to 5’-DFUR by cytidine deaminase. 5’-DFUR is then hydrolized by thymidine phosphorylase (dThdPase) enzymes to the active metabolite fluorouracil. Fluorouracil is subsequently metabolized by dihydropyrimidine dehydrogenase to 5-fluoro-5,6- dihydro-fluorouracil (FUH 2 ). The pyrimidine ring of FUH 2 is cleaved by dihydropyrimidinase to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, FUPA is cleaved by β-ureido-propionase to α-fluoro-β-alanine (FBAL). Excretion Following administration of radiolabeled capecitabine,96% of the administered capecitabine dose was recovered in urine (3% unchanged and 57% as metabolite FBAL) and 2.6% in feces. Specific Populations Following therapeutic doses of capecitabine, no clinically meaningful difference in the pharmacokinetics of 5’-DFUR, fluorouracil or FBAL were observed based on sex (202 females and 303 males) and race (455 White, 22 Black, and 28 Other). No clinically meaningful difference on the pharmacokinetics of 5’-DFUR and fluorouracil were observed based on age (range: 27 to 86 years); however, the AUC of FBAL increased by 15% following a 20% increase in age. Racial or Ethnic Groups Following administration of capecitabine 825 mg/m 2 orally twice daily for 14 days (0.66 times the recommended dosage), the C max and AUC of capecitabine decreased by 36% and 24%, respectively in Japanese patients (n=18) compared to White patients (n=22). The C max and AUC of FBAL decreased by approximately 25% and 34%, respectively in Japanese patients compared to White patients; however, the clinical significance of these differences is unknown. No clinically significant differences in the pharmacokinetics of 5’-DFCR, 5’-DFUR or fluorouracil were observed. Patients with Renal Impairment Table 8 Effect of Renal Impairment on the Pharmacokinetics of Capecitabine, 5’-DFUR, and FBAL Renal Impairment a Changes in AUC b Capecitabine 5’-DFUR c FBAL c 5-FU Lcr 30 to 50 mL/min Increased by 25% Increased by 42% Increased by 85% No relevant change CLcr <30 mL/min Increased by 25% Increased by 71% Increased by 258% Increased by 24% a Compared to patients with CLcr >80 mL/min b Following administration of capecitabine 1,250 mg/ m 2 orally twice daily; day 1 observations c Capecitabine metabolite CLcr=Creatine Clearance, AUC= Area under the plasma concentration-time curve Patients with Hepatic Impairment AUC 0-INF and C max of capecitabine’s active principle, fluorouracil, were not affected in patients with mild or moderate hepatic impairment compared to patients with normal hepatic function. The AUC 0-INF and C max of capecitabine increased by 60%. The effect of severe hepatic impairment on the pharmacokinetics of capecitabine and its metabolites are unknown. Drug Interaction Studies Clinical Studies Effect of Capecitabine on Warfarin: In four patients with cancer, chronic administration of capecitabine 1,250 mg/m 2 twice daily with a single dose of warfarin 20 mg increased the mean AUC of S-warfarin by 57% and decreased its clearance by 37%. Baseline corrected AUC of INR in these 4 patients increased by 2.8-fold, and the maximum observed mean INR value was increased by 91%. Effect of Capecitabine on Celecoxib: Concomitant administration of multiple doses of capecitabine (capecitabine 1,000 mg/m 2 twice daily for 14 days) increased celecoxib (sensitive CYP2C9 substrate) AUC by 28%, C max by 24% and C trough by 30%. Effect of Antacids on Capecitabine: When an aluminum hydroxide- and magnesium hydroxide containing antacid was administered immediately after a capecitabine dose of 1,250 mg/m 2 in patients with cancer, AUC and C 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, fluorouracil, FBAL) of capecitabine Effect of Allopurinol on Capecitabine: Concomitant use with allopurinol may decrease conversion of capecitabine to the active metabolites, FdUMP and FUTP. Effect of Capecitabine on Docetaxel and Effect of Docetaxel on Capecitabine: Capecitabine had no effect on the pharmacokinetics of docetaxel (C max and AUC) and docetaxel has no effect on the pharmacokinetics of capecitabine and the fluorouracil precursor 5’-DFUR. In Vitro Studies Cytochrome P450 (CYP) Enzymes: Capecitabine and its metabolites (5’-DFUR, 5’-DFCR, fluorouracil, and FBAL) did not inhibit CYP1A2, CYP2A6, CYP3A4, CYP2C19, CYP2D6, or CYP2E1 in vitro.

20231024

1

3 DOSAGE FORMS AND STRENGTHS Tablets, film-coated: 150 mg: biconvex, oblong, light-peach colored, with C150 on one side and plain on the other 500 mg: biconvex, oblong, peach colored, with C500 on one side and plain on the other Tablets: 150 mg and 500 mg ( 3 )

Capecitabine Capecitabine CROSCARMELLOSE SODIUM ANHYDROUS LACTOSE MAGNESIUM STEARATE TALC TITANIUM DIOXIDE FERRIC OXIDE RED FERRIC OXIDE YELLOW POLYETHYLENE GLYCOL, UNSPECIFIED HYPROMELLOSE 2910 (6 MPA.S) HYPROMELLOSE 2208 (3 MPA.S) MICROCRYSTALLINE CELLULOSE CAPECITABINE CAPECITABINE Light Peach oblong C150 Capecitabine Capecitabine CROSCARMELLOSE SODIUM ANHYDROUS LACTOSE MAGNESIUM STEARATE TALC TITANIUM DIOXIDE FERRIC OXIDE RED FERRIC OXIDE YELLOW POLYETHYLENE GLYCOL, UNSPECIFIED HYPROMELLOSE 2910 (6 MPA.S) HYPROMELLOSE 2208 (3 MPA.S) MICROCRYSTALLINE CELLULOSE CAPECITABINE CAPECITABINE Peach Oblong C500

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Adequate studies investigating the carcinogenic potential of capecitabine have not been conducted. Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). Capecitabine was clastogenic in vitro to human peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow (micronucleus test). Fluorouracil causes mutations in bacteria and yeast. Fluorouracil also causes chromosomal abnormalities in the mouse micronucleus test in vivo . In studies of fertility and general reproductive performance in female mice, oral capecitabine doses of 760 mg/kg/day (about 2300 mg/m 2 /day) disturbed estrus and consequently caused a decrease in fertility. In mice that became pregnant, no fetuses survived this dose. The disturbance in estrus was reversible. In males, this dose caused degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids. In separate pharmacokinetic studies, this dose in mice produced 5’-DFUR AUC values about 0.7 times the corresponding values in patients administered the recommended daily dose.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Adequate studies investigating the carcinogenic potential of capecitabine have not been conducted. Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). Capecitabine was clastogenic in vitro to human peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow (micronucleus test). Fluorouracil causes mutations in bacteria and yeast. Fluorouracil also causes chromosomal abnormalities in the mouse micronucleus test in vivo . In studies of fertility and general reproductive performance in female mice, oral capecitabine doses of 760 mg/kg/day (about 2300 mg/m 2 /day) disturbed estrus and consequently caused a decrease in fertility. In mice that became pregnant, no fetuses survived this dose. The disturbance in estrus was reversible. In males, this dose caused degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids. In separate pharmacokinetic studies, this dose in mice produced 5’-DFUR AUC values about 0.7 times the corresponding values in patients administered the recommended daily dose.

ANDA211724

Capecitabine

Capecitabine

62135-784

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Capecitabine Tablets, USP 150 mg - NDC 62135-783-60 - 60's Bottle Label Capecitabine Tablets, USP 500 mg - NDC 62135-784-12 - 120's Bottle Label image description image description

Manufactured For: Chartwell RX, LLC. Congers, NY 10920 Manufactured by: Reliance Life Sciences Pvt. Ltd. Navi Mumbai - 400 701, INDIA L71747 Rev. 10/2023 Print Patient Information at: www.chartwellpharma.com/our-products/ Print Patient Information at: www.chartwellpharma.com/our-products/

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information ). Increased Risk of Bleeding with Concomitant Use of Vitamin K Antagonists Advise patients on vitamin K antagonists, such as warfarin, that they are at an increased risk of severe bleeding while taking capecitabine. Advise these patients that INR should be monitored more frequently, and dosage modifications of the vitamin K antagonist may be required, while taking and after discontinuation of capecitabine. Advise these patients to immediately contact their healthcare provider if signs or symptoms of bleeding occur [ see Warnings and Precautions (5.1) ]. Serious Adverse Reactions from Dihydropyrimidine Dehydrogenase (DPD) Deficiency Inform patients of the potential for serious and life-threatening adverse reactions due to DPD deficiency and discuss with your patient whether they should be tested for genetic variants of DPYD that are associated with an increased risk of serious adverse reactions from the use of capecitabine. Advise patients to immediately contact their healthcare provider if symptoms of severe mucositis, diarrhea, neutropenia, and neurotoxicity occur [ see Warnings and Precautions (5.2) and Clinical Pharmacology (12.5) ]. Cardiotoxicity Advise patients of the risk of cardiotoxicity and to immediately contact their healthcare provider for new onset of chest pain, shortness of breath, dizziness, or lightheadedness [ see Warnings and Precautions (5.3 ) ]. Diarrhea Inform patients experiencing grade 2 diarrhea (an increase of 4 to 6 stools/day or nocturnal stools) or greater or experiencing severe bloody diarrhea with severe abdominal pain and fever to stop taking capecitabine. Advise patients on the use of antidiarrheal treatments (e.g., loperamide) to manage diarrhea [see Warnings and Precautions (5.4) ]. Dehydration Instruct patients experiencing grade 2 or higher dehydration (IV fluids indicated < 24 hours) to stop taking capecitabine immediately and to contact their healthcare provider to correct the dehydration. Advise patients to not restart capecitabine until rehydrated and any precipitating causes have been corrected or controlled [see Warnings and Precautions (5.5) ] Renal Toxicity Instruct patients experiencing decreased urinary output or other signs and symptoms of renal toxicity to immediately contact their healthcare provider [ see Warnings and Precautions (5.6) ]. Serious Skin Toxicities Instruct patients skin rash, blistering, or peeling to immediately contact their healthcare provider [ see Warnings and Precautions (5.7) ]. Palmar-Plantar Erythrodysesthesia Syndrome Instruct patients experiencing grade 2 palmar-plantar erythrodysesthesia syndrome or greater to stop taking capecitabine immediately and to contact their healthcare provider. Inform patients that initiation of symptomatic treatment is recommended and hand-and-foot syndrome can lead to loss of fingerprints which could impact personal identification [ see Warnings and Precautions (5.8) ]. Myelosuppression Inform patients who develop a fever of 100.5°F or greater or other evidence of potential infection to immediately contact their healthcare provider [ see Warnings and Precautions (5.9 ) ]. Hyperbilirubinemia Inform patients who develop jaundice or icterus to immediately contact their healthcare provider [ see Warnings and Precautions (5.10) ]. Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [ see Warnings and Precautions (5.11) , Use in Specific Populations (8.1) ]. Advise females of reproductive potential to use effective contraception during treatment with capecitabine and for 6 months after the last dose [ see Use in Specific Populations (8.3) ]. Advise males with female partners of reproductive potential to use effective contraception during treatment with capecitabine and for 3 months after the last dose [ see Use in Specific Populations (8.3 ) ]. Lactation Advise females not to breastfeed during treatment with capecitabine and for 1 week after the last dose [ see Use in Specific Populations (8.2) ]. Infertility Advise males and females of reproductive potential that capecitabine may impair fertility [ see Use in Specific Populations (8.3) ]. Hypersensitivity and Angioedema Advise patients that capecitabine may cause severe hypersensitivity reactions and angioedema. Advise patients who have known hypersensitivity to capecitabine or 5-fluorouracil to inform their healthcare provider [see Contraindications (4) ]. Instruct patients who develop hypersensitivity reactions or mucocutaneous symptoms (e.g., urticaria, rash, erythema, pruritus, or swelling of the face, lips, tongue or throat which make it difficult to swallow or breathe) to stop taking capecitabine and immediately contact their healthcare provider or to go to an emergency room . [see Adverse Reactions (6) ]. Nausea and Vomiting Instruct patients experiencing grade 2 nausea (food intake significantly decreased but able to eat intermittently) or greater to stop taking capecitabine and to immediately contact their healthcare provider for management of nausea [see Adverse Reactions (6.1) ]. Instruct patients experiencing grade 2 vomiting (2 to 5 episodes in a 24-hour period) or greater to stop taking capecitabine immediately and to contact their healthcare provider for management of vomiting [see Adverse Reactions (6.1) ]. Stomatitis Inform patients experiencing grade 2 stomatitis (painful erythema, edema or ulcers of the mouth or tongue, but able to eat) or greater to stop taking capecitabine immediately and to contact their healthcare provider [see Adverse Reactions (6.1) ]. Important Administration Instructions Advise patients to swallow capecitabine tablets whole with water within 30 minutes after a meal. Advise patients and caregivers not to chew, crush, or cut capecitabine tablets. Advise patients if they cannot swallow capecitabine tablets whole to inform their healthcare provider [ see Dosage and Administration (2.7) , Warnings and Precautions (5.12 ) ]. Drug interactions Instruct patients not to take products containing folic acid or folate analog products (e.g., leucovorin, levoleucovorin) unless directed to do so by their healthcare provider. Advise patients to inform their healthcare provider of all prescription or nonprescription medications, vitamins or herbal products [ see Drug Interactions (7.1 , 7.2 , 7.3) ].

14 CLINICAL STUDIES 14.1 Colorectal Cancer Adjuvant Treatment of Colon Cancer Single Agent The efficacy of capecitabine was evaluated in X-ACT( NCT00009737 ), a multicenter, randomized, controlled clinical trial. Eligible patients were between 18 and 75 years of age with histologically-confirmed Dukes’ Stage C colon cancer with at least one positive lymph node and to have undergone (within 8 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 0 or 1 (KPS ≥70%), ANC ≥1.5x10 9 /L,platelets ≥100x10 9 /L,serum creatinine ≤1.5ULN, total bilirubin ≤1.5 ULN,AST/ALT≤2.5 ULN and CEA within normal limits at time of randomization. Patients (n=1987) were randomized to capecitabine1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle for a total of 8 cycles or fluorouracil 425 mg/m 2 and leucovorin 20 mg/m 2 intravenously on days 1 to 5 of each 28-day cycle for a total of 6 cycles. The capecitabine dose was reduced in patients with baseline CLcr of 30 to 50 mL/min. The major efficacy outcome measure was disease-free survival (DFS). The baseline demographics are shown in Table 9.The baseline characteristics were well balanced between arms. Table 9 Baseline Demographics in X-ACT Capecitabine (N=1004) Fluorouracil+Leucovorin (N=983) Age (median, years) 62 63 Range (25-80) (22-82) Sex Male,% 54 54 Female,% 46 46 ECOG Performance Status 0,% 85 85 1,% 15 15 Staging–Primary Tumor PT1,% 1 0.6 PT2,% 9 9 PT3,% 76 76 PT4,% 14 0 Other,% 0.1 14 Staging–Lymph Node pN1,% 69 71 pN2, % 30 29 Other,% 0.4 0.1 Efficacy results are summarized in Table 10 and Figures 1 and 2. The median follow-up at the time of the analysis was 6.9 years. Because the upper 2-sided 95% confidence limit of hazard ratio for DFS was less than 1.20, capecitabine was non-inferior to fluorouracil + leucovorin. The choice of the non-inferiority margin of 1.20 corresponds to the retention of approximately 75% of the fluorouracil + leucovorin effect on DFS. The hazard ratio for capecitabine compared to fluorouracil + leucovorin with respect to overall survival was 0.86 (95% CI 0.74,1.01). The 5- year overall survival rates were 71% for capecitabine and 68% for fluorouracil + leucovorin. Table 10 Efficacy Results in X-ACT a (All Randomized Population) Efficacy Parameters Capecitabine (N=1004) Fluorouracil+Leucovorin(N=983) 5-year Disease-free Survival Rate b 59% 55% Hazard Ratio 0.88 (95%CI) (0.77,1.01) p-value c p=0.068 a Approximately 93.4% had 5-year DFS information b Based on Kaplan-Meier estimates c Wald chi-square test In Combination with Oxaliplatin-Containing Regimens The efficacy of capecitabine in combination with oxaliplatin for the adjuvant treatment of patients with Stage III colon cancer as a component of a combination chemotherapy regimen was derived from studies in the published literature, including NO16968 [ NCT00069121 ], a multicenter, open-label, randomized trial, where the major efficacy outcome measure was disease free survival. Perioperative Treatment of Rectal Cancer The efficacy of capecitabine for the perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy was derived from studies in the published literature, including Rektum-III [ NCT01500993 ], a randomized, open-label, multicenter, non-inferiority trial, where the major efficacy outcome measure was overall survival. Metastatic Colorectal Cancer The efficacy of capecitabine as a single agent was evaluated in two open-label, multicenter, randomized, controlled clinical trials (Study SO14695 and Study SO14796). Eligible patients received first-line treatment for metastatic colorectal cancer. Patients were randomized to capecitabine 1,250 mg/m 2 twice daily for first 14 days of a 21-day cycle or leucovorin 20 mg/m 2 intravenously followed by fluorouracil 425 mg/m 2 as an intravenous bolus on days 1 to 5 of each 28-day cycle. The efficacy outcome measures were overall survival, time to progression and response rate (complete plus partial responses). Responses were defined by the World Health Organization criteria and submitted to a blinded independent review committee (IRC). Differences in assessments between the investigator and IRC were reconciled by the sponsor, blinded to treatment arm, according to a specified algorithm. Survival was assessed based on a non-inferiority analysis. The baseline demographics are shown in Table 11. Table 11 Baseline Demographics for Study SO14695 and Study SO14796 Study SO14695 Study SO14796 Capecitabine (N=302) Fluorouracil + Leucovorin (N=303) Capecitabine (N=301) Fluorouracil + Leucovorin (N=301) Age (median, years) 64 63 64 64 Range (23-86) (24-87) (29-84) (36-86) Sex Male, % 60 65 57 57 Female, % 40 35 43 43 Karnofsky PS (median) 90 90 90 90 Range (70-100) (70-100) (70-100) (70-100) Colon,% 74 77 66 65 Rectum,% 26 23 34 35 Prior radiation therapy,% 17 21 14 14 Prioradjuvant fluorouracil,% 28 36 19 14 Efficacy results for Study SO14695 and Study SO14796 are shown in Table 12 and Table 13. Table 12 Efficacy Results for First-Line Treatment of Metastatic Colorectal Cancer (Study SO14695) Capecitabine (N=302) Fluorouracil +Leucovorin(N=303) Overall Response Rate %(95% CI) 21(16, 26) 11(8, 15) p-value 0.0014 Time to Progression Median, months(95%CI) 4.2(3.9, 4.5) 4.3(3.4, 5.0) Hazard Ratio 0.99 95% CI (0.84, 1.17) Overall Survival Median, months(95%CI) 12.5(10.5, 14.3) 13.4(12.0, 14.7) Hazard Ratio 1.00 95% CI (0.84, 1.18) Table 13 Efficacy Results for First-Line Treatment of Metastatic Colorectal Cancer (Study SO14796) Capecitabine(N=301) Fluorouracil+Leucovorin(N=301) Overall Response Rate %(95% CI) 21(16, 26) 14(10, 18) p-value 0.027 Time to Progression Median, months (95% CI) 4.5 (4.2, 5.5) 4.3 (3.4, 5.1) Hazard Ratio 0.97 95%CI (0.82,1.14) Overall Survival Median, months(95%CI) 13.3 (12.1, 14.8) 12.1 (11.1,14.1) Hazard Ratio 0.92 95% CI (0.78, 1.09) Efficacy results of the pooled population from Study SO14695 and Study SO14796 are shown in Figure 3. Statistical analyses were performed to determine the percent of the survival effect of fluorouracil +leucovorin that was retained by capecitabine. The estimate of the survival effect of fluorouracil + leucovorin was derived from a meta-analysis of ten randomized studies from the published literature comparing fluorouracil to regimens of fluorouracil + leucovorin that were similar to the control arms used in these Studies SO14695 and SO14796. The method for comparing the treatments was to examine the worst case (95% confidence upper bound) for the difference between fluorouracil + leucovorin and capecitabine, and to show that loss of more than 50% of the fluorouracil + leucovorin survival effect was ruled out. It was demonstrated that the percent of the survival effect of fluorouracil + leucovorin maintained was at least 61% for Study SO14796 and 10% for Study SO14695. The pooled result is consistent with a retention of at least 50% of the effect of fluorouracil + leucovorin. It should be noted that these values for preserved effect are based on the upper bound of the fluorouracil +leucovorin vs capecitabine difference. In Combination with Oxaliplatin. The efficacy of capecitabine for the treatment of patients with unresectable or metastatic colorectal cancer as a component of a combination chemotherapy regimen was derived from studies in the published literature, including NO16966 [ NCT00069095 ], a randomized, non-inferiority, 2x2 factorial trial, where the major efficacy outcome measure was progression free survival. Figure-1 Figure-2 Figure-3 14.2 Metastatic Breast Cancer In Combination With Docetaxel The efficacy of capecitabine in combination with docetaxel was evaluated in an open-label, multicenter, randomized trial (Study SO14999). Eligible patients had metastatic breast cancer resistant to, or recurring during or after an anthracycline-containing therapy, or relapsing during or recurring within 2 years of completing an anthracycline-containing adjuvant therapy were enrolled. Patients were randomized to capecitabine 1,250 mg/m 2 twice daily for the first 14 days of a 21-day cycle and docetaxel 75 mg/m2 as a 1-hour intravenous infusion on day 1 of day of a 21- day cycle or docetaxel 100 mg/m 2 as a 1-hour intravenous infusion on day 1 of a 21-day cycle. The efficacy outcome measures were time to disease progression, overall survival, and response rate. Patient demographics are provided in Table 14. Table 14 Baseline Demographics in Metastatic Breast Cancer (Study SO14999) Capecitabine + Docetaxel (N=255) Docetaxel (N=256) Age (median, years) 52 51 Karnofsky Performance Status (median) 90 90 Site of Disease Lymph nodes, % 47 49 Liver, % 45 48 Bone, % 42 46 Lung, % 37 39 Skin, % 29 29 Prior Chemotherapy Anthracycline 1 , % 100 100 Fluorouracil, % 77 74 Paclitaxel, % 10 9 Resistance to an Anthracycline No resistance, % 7 7 Progression on anthracycline therapy, % 26 29 Stable disease after 4 cycles of anthracycline therapy, % 16 16 Relapsed within 2 years of completion of anthracycline-adjuvant therapy, % 31 29 Experienced a brief response to anthracycline therapy, with subsequent progression while on therapy or within 12 months after last dose, % 20 20 No. of Prior Chemotherapy Regimens for Treatment of Metastatic Disease 0, % 35 31 1, % 48 53 2, % 17 15 3, % 0 1 1 Includes 10 patients in combination and 18 patients in single agent arms treated with an anthracenedione Efficacy results are shown in Table 15, Figure 4 and Figure 5. Table 15 Efficacy Results in Metastatic Breast Cancer (Study SO14999) Efficacy Parameter Capecitabine + Docetaxel (N=255) Docetaxel (N=256) Time to Disease Progression Median, months 6.1 4.2 95% CI (5.4, 6.5) (3.5, 4.5) Hazard Ratio 0.643 p-value 0.0001 Overall Survival Median, months 14.5 11.6 95% CI (12.3, 16.3) (9.8, 12.7) Hazard Ratio 0.775 p-value 0.0126 Response Rate 1 32% 22% 1 The response rate reported represents a reconciliation of the investigator and IRC assessments performed by the sponsor according to a predefined algorithm. Single Agent The efficacy of capecitabine as a single agent was evaluated in an open-label single-arm trial (Study SO14697). Eligible patients had 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 2 of doxorubicin or doxorubicin equivalents). Resistance was defined as progressive disease while on treatment, with or without an initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant chemotherapy regimen. Patients received capecitabine 1,255 mg/m 2 orally twice daily for first 14-days of a 21-day treatment cycle. The major efficacy outcome measure was tumor response rate in patients with measurable disease, with response defined as a ≥50% decrease in sum of the products of the perpendicular diameters of bidimensionally measurable disease for at least 1 month. The baseline demographics are shown in Table 16. Table 16 Baseline Demographics in Metastatic Breast Cancer (Study SO14697) Patients With Measurable Disease (N=135) All Patients (N=162) Age (median, years) 55 56 Karnofsky Performance Status 90 90 No. Disease Sites 1-2, % 32 37 3-4, % 46 43 >5, % 22 21 Dominant Site of Disease Visceral 1 , % 75 68 Soft Tissue, % 22 22 Bone, % 3 10 Prior Chemotherapy Paclitaxel, % 100 100 Anthracycline 2 , % 90 91 Fluorouracil, % 81 82 Resistance to Paclitaxel, % 76 77 Resistance to an Anthracycline 2 , % 41 41 Resistance to both Paclitaxel and an Anthracycline 2 , % 32 31 1 Lung, pleura, liver, peritoneum 2 Includes 2 patients treated with an anthracenedione Efficacy for Study SO14697 are shown in Table 17. Table 17 Efficacy Results in Metastatic Breast Cancer (Study SO14697) Efficacy Parameter Resistance to Both Paclitaxel and an Anthracycline (N=43) Response Rate 1 (95% CI) 25.6% (13.5, 41.2) Complete Response 0% Partial Response 1 11% Duration of Response 1 Median, months 2 (Range) 5.1 (2.1-7.7) 1 Includes 2 patients treated with an anthracenedione 2 From date of first response For the subgroup of 43 patients who were doubly resistant, the median time to progression was 3.4 months and the median survival was 8.4 months. The objective response rate in this population was supported by a 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 15 ). The median time to progression was 3.0 months and the median survival was 10.1 months. Figure-4 Figure-5 14.3 Gastric, Esophageal, or Gastroesophageal Junction Cancer The efficacy of capecitabine for treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy regimen was derived from studies in the published literature. capecitabine was evaluated in REAL-2, a randomized non-inferiority, 2x2 factorial trial, where the major efficacy outcome measure was overall survival, and an additional randomized trial conducted by the North Central Cancer Treatment Group, where the major efficacy outcome measure was objective response rate. The efficacy of capecitabine for the treatment of adults with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease as a component of a combination regimen was derived from studies in the published literature. Capecitabine was evaluated in the ToGA trial [ NCT01041404 ], an open-label, multicenter, randomized trial where the primary efficacy measure was overall survival. 14.4 Pancreatic Cancer The efficacy of capecitabine for the adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen was derived from a study in the published literature. Capecitabine was evaluated in ESPAC-4 trial, a two-group, open-label, multicenter, randomized trial, where the major efficacy outcome measure was overall survival.

15 REFERENCES 1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html .

8.5 Geriatric Use Of 7938 patients with colorectal cancer who were treated with capecitabine, 33% were older than 65 years. Of the 4536 patients with metastatic breast cancer who were treated with capecitabine, 18% were older than 65 years. Of 1951 patients with gastric, esophageal, or gastrointestinal junction cancer who were treated with capecitabine, 26% were older than 65 years. Of 364 patients with pancreatic cancer who received adjuvant treatment with capecitabine, 47% were 65 years or older. No overall differences in efficacy were observed comparing older versus younger patients with colorectal cancer, gastric, esophageal or gastrointestinal junction cancer, or pancreatic cancer using the approved recommended dosages and treatment regimens. Older patients experience increased gastrointestinal toxicity due to capecitabine compared to younger patients. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil [see Drug Interactions (7.1) ].

8.4 Pediatric Use The safety and effectiveness of capecitabine in pediatric patients have not been established. Safety and effectiveness were assessed, but not established in two single arm studies in 56 pediatric patients aged 3 months to <17 years with newly diagnosed gliomas. In both trials, pediatric patients received an investigational pediatric formulation of capecitabine concomitantly with and following completion of radiation therapy (total dose of 5580 cGy in 180 cGy fractions). The relative bioavailability of the investigational formulation to capecitabine was similar. The adverse reaction profile was consistent with that of adults, with the exception of laboratory abnormalities which occurred more commonly in pediatric patients. The most frequently reported laboratory abnormalities (per-patient incidence ≥ 40%) were increased ALT (75%), lymphocytopenia (73%), hypokalemia (68%), thrombocytopenia (57%), hypoalbuminemia (55%), neutropenia (50%), low hematocrit (50%), hypocalcemia (48%), hypophosphatemia (45%) and hyponatremia (45%).

8.1 Pregnancy Risk Summary Based on findings in animal reproduction studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , capecitabine can cause fetal harm when administered to a pregnant woman. Available human data with capecitabine use in pregnant women is not sufficient to inform the drug-associated risk. 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 of 1,250 mg/m 2 twice daily, respectively (see Data) . Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 a 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 a 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 USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed. ( 8.2 ) Hepatic Impairment : Monitor patients with hepatic impairment more frequently for adverse reactions. ( 8.7 ) 8.1 Pregnancy Risk Summary Based on findings in animal reproduction studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , capecitabine can cause fetal harm when administered to a pregnant woman. Available human data with capecitabine use in pregnant women is not sufficient to inform the drug-associated risk. 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 of 1,250 mg/m 2 twice daily, respectively (see Data) . Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 a 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 a 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 or its metabolites in human milk, or on its effects on milk production or the breastfed child. Capecitabine metabolites were present in the milk of lactating mice (see Data) . Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with capecitabine and for 1 week after the last dose. Data Lactating mice given a single oral dose of capecitabine excreted significant amounts of capecitabine metabolites into the milk. 8.3 Females and Males of Reproductive Potential Capecitabine can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating capecitabine. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with capecitabine and for 6 months after the last dose. Males Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with capecitabine and for 3 months after the last dose [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. Safety and effectiveness were assessed, but not established in two single arm studies in 56 pediatric patients aged 3 months to <17 years with newly diagnosed gliomas. In both trials, pediatric patients received an investigational pediatric formulation of capecitabine concomitantly with and following completion of radiation therapy (total dose of 5580 cGy in 180 cGy fractions). The relative bioavailability of the investigational formulation to capecitabine was similar. The adverse reaction profile was consistent with that of adults, with the exception of laboratory abnormalities which occurred more commonly in pediatric patients. The most frequently reported laboratory abnormalities (per-patient incidence ≥ 40%) were increased ALT (75%), lymphocytopenia (73%), hypokalemia (68%), thrombocytopenia (57%), hypoalbuminemia (55%), neutropenia (50%), low hematocrit (50%), hypocalcemia (48%), hypophosphatemia (45%) and hyponatremia (45%). 8.5 Geriatric Use Of 7938 patients with colorectal cancer who were treated with capecitabine, 33% were older than 65 years. Of the 4536 patients with metastatic breast cancer who were treated with capecitabine, 18% were older than 65 years. Of 1951 patients with gastric, esophageal, or gastrointestinal junction cancer who were treated with capecitabine, 26% were older than 65 years. Of 364 patients with pancreatic cancer who received adjuvant treatment with capecitabine, 47% were 65 years or older. No overall differences in efficacy were observed comparing older versus younger patients with colorectal cancer, gastric, esophageal or gastrointestinal junction cancer, or pancreatic cancer using the approved recommended dosages and treatment regimens. Older patients experience increased gastrointestinal toxicity due to capecitabine compared to younger patients. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil [see Drug Interactions (7.1) ]. 8.6 Renal Impairment The exposure of capecitabine and its inactive metabolites (5-DFUR and FBAL) increases in patients with CLcr <50 mL/min as determined by Cockcroft-Gault [see Clinical Pharmacology (12.3) ]. Reduce the dosage for patients with CLcr of 30 to 50 mL/min [ see Dosage and Administration (2.6) ]. There is limited experience with capecitabine in patients with CLcr <30 mL/min, and a dosage has not been established in those patients. If no treatment alternative exists, capecitabine could be administered to such patients on an individual basis applying a reduced starting dose, close monitoring of a patient's clinical and biochemical data and dose modifications guided by observed adverse reactions. 8.7 Hepatic Impairment The exposure of capecitabine increases in patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the safety and pharmacokinetics of capecitabine is unknown [ see Clinical Pharmacology (12.3) ] . Monitor patients with hepatic impairment more frequently for adverse reactions.

16 HOW SUPPLIED/STORAGE AND HANDLING Capecitabine Tablets, USP are available as follows: 150 mg Color: Light peach Engraving: C150 on one side and plain on the other 150 mg tablets are packaged in bottles of 60 (NDC 62135-783-60). 500 mg Color: Peach Engraving: C500 on one side and plain on the other 500 mg tablets are packaged in bottles of 120 (NDC 62135-784-12). Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature]. Keep tightly closed. Capecitabine is a cytotoxic drug. Follow applicable special handling and disposal procedures 1 .

Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature]. Keep tightly closed. Capecitabine is a cytotoxic drug. Follow applicable special handling and disposal procedures 1 .

WARNING: INCREASED RISK OF BLEEDING WITH CONCOMITANT USE OF VITAMIN K ANTAGONISTS Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking capecitabine concomitantly with oral vitamin K antagonists, such as warfarin [see Warnings and Precautions (5.1) , Drug Interactions (7.2) ]. Clinically significant increases in prothrombin time (PT) and international normalized ratio (INR) have been reported in patients who were on stable doses of a vitamin K antagonist at the time capecitabine was introduced. These events occurred within several days and up to several months after initiating capecitabine and, in a few cases, within 1 month after stopping capecitabine. These events occurred in patients with and without liver metastases. Monitor INR more frequently and adjust the dose of the vitamin K antagonist as appropriate [see Drug Interactions (7.2) ]. INCREASED RISK OF BLEEDING WITH CONCOMITANT USE OF VITAMIN K ANTAGONISTS See full prescribing information for complete boxed warning. Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking capecitabine concomitantly with oral vitamin K antagonists. ( 5.1 , 7.2 ) Monitor international normalized ratio (INR) more frequently and adjust the dose of the vitamin K antagonist as appropriate. ( 7.2 )