Captabine

1 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: •…

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. ( 2.2) 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…

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.

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…

4 CONTRAINDICATIONS Capecitabine tablets are 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)

5 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…

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…