Capecitabine

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.

1 INDICATIONS AND USAGE Capecitabine tablets 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: • tr

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/m 2 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 ) 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 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. 2.2 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 reaction 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 Pre

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 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 neu

7 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).