Capecitabine

Boxed Warning (12/2022) Indications and Usage, Colorectal Cancer ( 1.1 ) (12/2022) Indications and Usage, Breast Cancer ( 1.2 ) (12/2022) Indications and Usage, Gastric, Esophageal, or Gastroesophageal Junction Cancer ( 1.3 ) (12/2022) Indications and Usage, Pancreatic Cancer ( 1.4 ) (12/2022) Dosage and Administration ( 2.1 - 2.7 ) (12/2022) Contraindications ( 4 ) (12/2022) Warnings and Precautions ( 5.1 - 5.12 ) (12/2022)

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 tablets, USP 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 USP are 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 tablets USP 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 USP are indicated for the adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen.

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 tablets are 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 …

3 DOSAGE FORMS AND STRENGTHS 150 mg Tablets Capecitabine tablets, USP are supplied as light peach to peach colored, oblong shaped, biconvex film coated tablets, debossed with "C" on one side and "150"on other side for oral administration. Each light peach to peach colored tablet contains 150 mg of capecitabine, USP. 500 mg Tablets Capecitabine tablets, USP are supplied as light peach to peach colored, oblong shaped, biconvex film coated tablets, debossed with "C" on one side and "500"on other side for oral administration. Each light peach to peach colored tablet contains 500 mg of capecitabine, USP. Tablets: 150 mg and 500 mg ( 3 )

4 CONTRAINDICATIONS Severe Renal Impairment ( 4.1 ) Hypersensitivity ( 4.2 ) 4.1 Severe Renal Impairment Capecitabine is 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 is contraindicated in patients with known hypersensitivity to capecitabine or to any of its components. Capecitabine is contraindicated in patients who have a known hypersensitivity to 5-fluorouracil.

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 Teva at 1-888-838-2872 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%) in Patients Who Received Capecitabine as a Single Agent for Adjuvant Treatment of Colon Cancer in X-ACT 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 saf …

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).

For full Taxotere prescribing information, please refer to Taxotere Package Insert. All trade names drug products are the property of their respective owners. Manufactured By: Intas Pharmaceuticals Limited, Ahmedabad – 380 054, India. For BluePoint Laboratories Issued 03/23

8 USE IN SPECIFIC POPULATIONS Lactation : Advise women not to breastfeed. ( 8.2 ) Females and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of capecitabine. Advise males with female partners of reproductive potential to use effective contraception. ( 8.3 ) Geriatric : Greater incidence of adverse reactions. Monitoring required. ( 8.5 ) Hepatic Impairment : Monitoring is recommended in patients with mild to moderate hepatic impairment. ( 8.6 ) Renal Impairment : Reduce capecitabine starting dose in patients with moderate renal impairment ( 2.4 , 8.7 , 12.3 ) 8.1 Pregnancy Risk Summary Based on findings in animal reproduction studies and its mechanism of action, capecitabine can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )]. Limited available human data are not sufficient to inform the drug-associated risk during pregnancy. In animal reproduction studies, administration of capecitabine to pregnant animals during the period of organogenesis caused embryo lethality and teratogenicity in mice and embryo lethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving the recommended dose respectively [see Data ] . Apprise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Oral administration of capecitabine to pregnant mice during the period of organogenesis at 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 in human milk, or on its effects on milk production or the breast-fed infant. Capecitabine metabolites were present in the milk of lactating mice [ see Data ]. Because of the potential for serious adverse reactions from capecitabine exposure in breast-fed infants, advise women not to breastfeed during treatment with capecitabine and for 2 weeks after the final 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 Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential prior to initiating capecitabine. Contraception Females Capecitabine can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )]. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the final dose of capecitabine. Males Based on genetic toxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months following the last dose of Capecitabine [see Nonclinical Toxicology ( 13.1 )]. Infertility Based on animal studies, capacetabine 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. No clinical benefit was demonstrated in two si …

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.

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 C15H22FN3O6 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 oval, biconvex, film-coated tablets for oral administration. Each light peach colored tablets debossed with ‘150’ on one side and plain on other side contains 150 mg of capecitabine USP and each peach colored tablet debossed with ‘500’ on one side and plain on other side contains 500 mg of capecitabine USP. The inactive ingredients in capecitabine tablets include: microcrystalline cellulose, croscarmellose sodium, hypromellose, anhydrous lactose, talc and magnesium stearate. The peach or light peach film coating contains hypromellose, titanium dioxide, lactose monohydrate, polyethylene glycol, red iron oxide and yellow iron oxide. Chemical Structure

10 OVERDOSAGE The manifestations of acute overdose would include nausea, vomiting, diarrhea, gastrointestinal irritation and bleeding, and bone marrow depression. Medical management of overdose should include customary supportive medical interventions aimed at correcting the presenting clinical manifestations. 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. Single doses of capecitabine were not lethal to mice, rats, and monkeys at doses up to 2,000 mg/kg (2.4, 4.8, and 9.6 times the recommended human daily dose on a mg/m 2 basis).

16 HOW SUPPLIED/STORAGE AND HANDLING Capecitabine tablets, USP are available as follows: 150 mg - Light peach colored, oval, biconvex, film coated tablets debossed with ‘150’ on one side and plain on other side. Bottles of 60 with Child Resistant Cap....................NDC 62756-238-86 Bottles of 100 with Child Resistant Cap..................NDC 62756-238-88 Bottles of 1000 ..............NDC 62756-238-18 500 mg - Peach colored, oval, biconvex, film coated tablets debossed with ‘500’ on one side and plain on other side. Bottles of 30with Child Resistant Cap.....................NDC 62756-239-83 Bottles of 120 with Child Resistant Cap....................NDC 62756-239-20 Bottles of 1000 ................NDC 62756-239-18 Storage and Handling Store capecitabine tablets at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature]. KEEP TIGHTLY CLOSED. Capecitabine is a hazardous drug. Follow applicable special handling and disposal procedures. 1