Capecitabine

INDICATIONS AND USAGE Capecitabine tablet 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 tablets are 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 tablets are indicated for the: • treatment of patients with advanced or metastatic breast cancer as a single agent if an anthracycline- or taxanecontaining 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 tablets are 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 tablets are indicated for the adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen.

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. ( 2.2) Perioperative Treatment of Rectal Cancer • With Concomitant Radiation Therapy: 825 mg/m 2 orally twice daily ( 2.2 ) • Without Radiation Therapy: 1,250 mg/m 2 orally twice daily ( 2.2 ) 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. ( 2.2 ) • 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/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. ( 2.3 ) • 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 ( 2.3 ) 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. ( 2.4 ) 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. ( 2.4 ) 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. ( 2.4 ) 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. ( 2.5 ) 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 Evaluation and Testing of DPD Deficiency Before Initiating Capecitabine Tablets Prior to initiating capecitabine tablets, test patients for genetic variants of the DPYD gene unless immediate treatment is necessary. An FDA-authorized test for the detection of the DPYD gene to identify patients at risk of serious adverse reactions with capecitabine tablets are not currently available. Currently available tests used to identify DPYD variants may vary in accuracy and design (e.g., which DPYD variant(s) they identify). Avoid use of capecitabine tablets in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency. No capecitabine tablets dose has been proven safe for patients with complete DPD deficiency. For patients with partial DPD deficiency, individualize the dosage and modify based on tolerability and intent of treatment [see Warnings and Precautions ( 5.1 )]. 2.2 Recommended Dosage for Colorectal Cancer Adjuvant Treatment of Colon Cancer Single Agent The recommended dosage of capecitabine tablets 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 tablets 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 tablets 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 tablets 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. 2.3 Recommended Dosage for Breast Cancer Advanced or Metastatic Breast Cancer Single Agent The recommended dosage of capecitabine tablets 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 tablets based on patient risk factors and adverse reactions. In Combination with Docetaxel The recommended dosage of capecitabine tablets 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. 2.4 Recommended Dosage for Gastric, Esophageal, or Gastroesophageal Junction Cancer The recommended dosage of capecitabine tablets 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 tablets based on patient risk factors and adverse reactions. The recommended dosage of capecitabine tablets 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. 2.5 Recommended Dosage for Pancreatic Cancer The recommended dosage of capecitabine tablets 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. 2.6 Dosage Modifications for Adverse Reactions Monitor patients for adverse reactions and modify dosages of capecitabine tablets as described in Table 1. Do not replace missed doses of capecitabine tablets; instead resume capecitabine tablets with the next planned dosage. When capecitabine tablets is administered with docetaxel, withhold capecitabine tablets and doceta

WARNINGS AND PRECAUTIONS • Cardiotoxicity : May be more common in patients with a prior history of coronary artery disease. Withhold capecitabine tablets for cardiotoxicity as appropriate. The safety of resumption of capecitabine tablets in patients with cardiotoxicity that has resolved has not been established. ( 2.5 , 5.3 ) • Diarrhea : Withhold capecitabine tablets and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence. ( 2.5 , 5.4 ) • Dehydration : Optimize hydration before starting capecitabine tablets. Monitor hydration status and kidney function at baseline and as clinically indicated. Withhold capecitabine tablets and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence. ( 2.5 , 5.5 ) • Renal Toxicity : Monitor renal function at baseline and as clinically indicated. Optimize hydration before starting capecitabine tablets. Withhold capecitabine tablets and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence. ( 2.5 , 5.6 ) • Serious Skin Toxicities : Monitor for new or worsening serious skin reactions. Permanently discontinue capecitabine tablets in patients who experience a severe cutaneous adverse reaction. ( 5.7 ) • Palmar-Plantar Erythrodysesthesia Syndrome : Withhold capecitabine tablets then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence. ( 2.5 , 5.8 ) • Myelosuppression : Monitor complete blood count at baseline and before each cycle. capecitabine tablets is not recommended in patients with baseline neutrophil counts <1.5 x 10 9 /L or platelet counts <100 x 10 9 /L. For grade 3 or 4 myelosuppression, withhold capecitabine tablets and then resume at same or reduced dose, or permanently discontinue, based on occurrence. ( 2.5 , 5.9 ) • Hyperbilirubinemia : Patients with Grade 3-4 hyperbilirubinemia may resume treatment once the event is Grade 2 or less (<3 x ULN), using the percent of current dose as shown in column 3 of Table 1 ( 2.5 , 5.10 ) ] • Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.11 , 8.1 , 8.3 ) 5.1 Serious Adverse Reactions or Death from Dihydropyrimidine Dehydrogenase (DPD) Deficiency Patients with certain homozygous or compound heterozygous variants in the DPYD gene known to result in complete or near complete absence of DPD activity (complete DPD deficiency) are at increased risk for acute early-onset toxicity and serious, including fatal, adverse reactions due to capecitabine tablets (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity (partial DPD deficiency) may also have increased risk of serious, or fatal, adverse reactions. Prior to initiating capecitabine tablets, test patients for genetic variants of the DPYD gene unlessimmediate treatment is necessary [see Clinical Pharmacology (12.5)]. Serious adverse reactions may still occur even if no DPYD variants are identified. Avoid use of capecitabine tablets in patients with certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency. Withhold or permanently discontinue capecitabine tablets based on clinical assessment of the onset, duration, and severity of adverse reactions in patients with evidence of acute early-onset orunusually severe reactions. No capecitabine tablets dose has been proven safe for patients with complete DPD deficiency. For patients with partial DPD deficiency, individualize the dosage and modify based on tolerability and intent of treatment. An FDA-authorized test for the detection of genetic variants of the DPYD gene to identifypatients at risk of serious adverse reactions with capecitabine tablets treatment is not currently available. Currently available tests used to identify DPYD variants may vary in accuracy and design (e.g., which DPYD variant(s) they identify). 5.2 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 tablets concomitantly with vitamin K antagonists, such as warfarin. Clinically significant increases in PT and INR have been reported in patients who were on stable doses of oral vitamin K antagonists at the time capecitabine tablets was introduced. These events occurred within several days and up to several months after initiating capecitabine tablets and, in a few cases, within 1 month after stopping capecitabine tablets. 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 (7.1) ]. 5.3 Cardiotoxicity Cardiotoxicity can occur with capecitabine tablets. Myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy have been reported with capecitabine tablets. These adverse reactions may be more common in patients with a prior history of coronary artery disease. Withhold capecitabine tablets for cardiotoxicity as appropriate [see Dosage and Administration ( 2.5 )]. The safety of resumption of capecitabine tablets in patients with cardiotoxicity that has resolved have not been established. 5.4 Diarrhea Diarrhea, sometimes severe, can occur with capecitabine tablets. In 875 patients with metastatic breast or colorectal cancer who received capecitabine tablets as a single agent, the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range: 1 day to 1 year). The median duration of grade 3 to 4 diarrhea was 5 days.Withhold capecitabine tablets and then resume at same or reduced dose or permanently discontinue based on severity and occurrence [see Dosage and Administration ( 2.5 ) ]. 5.5 Dehydration Dehydration can occur with capecitabine tablets. Patients with anorexia, asthenia, nausea, vomiting, or diarrhea may be at an increased risk of developing dehydration with capecitabine tablets. Optimize hydration before startingcapecitabine tablets. Monitor hydration status and kidney function at baseline and as clinically indicated. Withhold capecitabine tablets and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence [see Dosage and Administration (2.5) ]. 5.6 Renal Toxicity Serious renal failure, sometimes fatal, can occur with capecitabine tablets. Renal impairment or coadministration of capecitabine tablets with other products known to cause renal toxicity may increase the risk of renal toxicity [see Drug Interactions (7.3)]. Monitor renal function at baseline and as clinically indicated. Optimize hydration before starting capecitabine tablets. Withhold capecitabine tablets and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence [see Dosage and Administration ( 2.5 )]. 5.7 Serious Skin Toxicities Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson Syndrome and toxic epidermal necrolysis (TEN), which can be fatal, can occur with capecitabine tablets [see Adverse Reactions ( 6.2 )]. Monitor for new or worsening serious skin reactions. Permanently discontinue capecitabine tablets for severe cutaneous adverse reactions. 5.8 Palmar-Plantar Erythrodysesthesia Syndrome Palmar-plantar erythrodysesthesia syndrome (PPES) can occur with capecitabine tablets. In patients with metastatic breast or colorectal cancer who received capecitabine tablets as a single agent, the median time to onset of grades 1 to 3 PPES was 2.6 months (range: 11 days to 1 year). Withhold capecitabine tablets and then resume at same or reduced dose or permanently discontinue based on severity and occurrence [see Dosage and Administration ( 2.5 ) ]. 5.9 Myelosuppression Myelosuppression can occur with capecitabine tablets. In the 875 patients with me

CONTRAINDICATIONS Severe Renal Impairment (4.1) Hypersensitivity (4.2) 4.1 Severe Renal Impairment Capecitabine tablets are contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min [Cockroft and Gault]) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] . 4.2 Hypersensitivity Capecitabine tablets are contraindicated in patients with known hypersensitivity to capecitabine or to any of its components. Capecitabine tablets are contraindicated in patients who have a known hypersensitivity to 5-fluorouracil.

DRUG INTERACTIONS • Allopurinol: Avoid concomitant use of allopurinol with capecitabine tablets. ( 7.1 ) • Leucovorin : Closely monitor for toxicities when capecitabine tablets is coadministered with leucovorin. ( 7.1 ) • CYP2C9 substrates : Closely monitor for adverse reactions when CYP2C9 substrates are coadministered with capecitabine tablets. ( 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 tablets concomitantly with phenytoin and adjust the phenytoin dose as appropriate. ( 7.2 ) • Nephrotoxic drugs : Closely monitor for signs of renal toxicity when capecitabine tablets is used concomitantly with nephrotoxic drugs. ( 7.3 ) 7.1 Effect of Other Drugs on Capecitabine Tablets 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 tablets. 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 Tablets on Other Drugs CYP2C9 Substrates Capecitabine tablets 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 tablets (e.g., anticoagulants, antidiabetic drugs). Vitamin K Antagonists Capecitabine tablets 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 tablets. Monitor INR more frequently and refer to the prescribing information of oral vitamin K antagonist for dosage adjustment, as appropriate, when capecitabine tablets is used concomitantly with vitamin K antagonist. Phenytoin Capecitabine tablets 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 tablets is used concomitantly with phenytoin. 7.3 Nephrotoxic Drugs Due of the additive pharmacologic effect, concomitant use of capecitabine tablets 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 tablets is used concomitantly with nephrotoxic drugs (e.g. platinum salts, irinotecan, methotrexate, intravenous bisphosphonates).

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 tablets 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 tablets 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 tablets 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 tablets as a single agent were lymphopenia, anemia, diarrhea, handand- foot syndrome, nausea, fatigue, vomiting, and dermatitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories Inc., at 1-888-375-3784 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 tablets as a single agent was evaluated in patients with Stage III colon cancer in X-ACT [see Clinical Studies (14.1)]. Patients receivedcapecitabine tablets 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 tablets, the median duration of treatment was 5.4 months. Deaths due to all causes occurred in 0.8% of patients who received capecitabine tablets 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 tablets. 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 tablets for Adjuvant Treatment of Colon Cancer in X-ACT Adverse Reaction C apecitabine Tablets (N=995) Fluorouracil + Leucovorin (N=974) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesiasyndrome 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:d izziness, dysgeusia, headache Skin & Subcutaneous Tissue: rash, alopecia, erythema Table 3 Grade 3 or 4 Laboratory Abnormalities (>1%) in Patients Who Received Capecitabine tablets as a Single Agent for Adjuvant Treatment of Colon Cancer in X- ACT Laboratory Abnormality C apecitabine tablets (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 tablets 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 tablets 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 tablets as a single agent, with the exception of an increased incidence of neurosensory toxicity. Perioperative Treatment of RectalCancer The safety of capecitabine tablets 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 tablets 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 tablets as a single agent, with the exception of an increased incidence of diarrhea. Metastatic Colorectal Cancer Single Agent The safety of capecitabine tablets 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 tablets 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 tablets, the median duration of treatment was 4.6 months. Deaths due to all causes occurred in 8% of patients who received capecitabine tablets 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 tablets. 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 tablets in Pooled Metastatic Colorectal Cancer Population (Study SO14695 and Study SO14796) Adverse Reaction C apecitabine tablets (N=596) Fluorouracil + Leucovorin (N=593) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 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 be

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 500mg/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 theC max and AUC of fluorouracil was greater than 85%. Absorption Following oral administration of capecitabine1,255 mg/m 2 orally twice daily (the recommended dosage when used as single agent), the medianT 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’-DFURc FBAL c 5-FU CLcr 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/m2 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%. E ffect 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 DPYD variants that results in no D