ADVERSE REACTIONS SECTION.

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)] 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 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 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 single agent were lymphopenia, anemia, diarrhea, hand-and-foot syndrome, nausea, fatigue, vomiting, and dermatitis. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-272-7901 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Most common adverse reactions in patients who received capecitabine tablets as 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 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 single agent were lymphopenia, anemia, diarrhea, hand-and-foot syndrome, nausea, fatigue, vomiting, and dermatitis. (6.1). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 CancerSingle AgentThe safety of capecitabine tablets as single agent was evaluated in patients with Stage III colon cancer in X-ACT [see Clinical Studies (14.1)]. Patients received capecitabine tablets 1,250 mg/m2 orally twice daily for the first 14 days of 21-day cycle (N=995) or leucovorin 20 mg/m2 intravenously followed by fluorouracil 425 mg/m2 as an intravenous bolus on days to 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 and summarize the adverse reactions and laboratory abnormalities in X-ACT.Table Adverse Reactions (>10%) in Patients Who Received Capecitabine Tablets for Adjuvant Treatment of Colon Cancer in X-ACT Adverse Reaction Capecitabine Tablets (N=995)Fluorouracil Leucovorin (N=974) All Grades (%)Grade or (%)All Grades(%)Grade or (%)Skin and Subcutaneous TissuePalmar-plantar erythrodysesthesia syndrome 60 17 <1 GastrointestinalDiarrhea 47 12 65 14 Nausea 34 47 Stomatitis 22 60 14 Vomiting 15 21 Abdominal pain 14 16 GeneralFatigue 16 <1 16 Asthenia 10 <1 10 Lethargy 10 <1 <1 Clinically relevant adverse reactions in <10% of patients are presented below:Eye: conjunctivitisGastrointestinal: constipation, upper abdominal pain, dyspepsiaGeneral: pyrexiaMetabolism and Nutrition: anorexiaNervous System: dizziness, dysgeusia, headacheSkin Subcutaneous Tissue: rash, alopecia, erythemaTable Grade or Laboratory Abnormalities (>1%) in Patients Who Received Capecitabine Tablets as Single Agent for Adjuvant Treatment of Colon Cancer in X- ACT Laboratory Abnormality CapecitabineTablets (N=995)Fluorouracil Leucovorin (N=974)Grade or 4(%)Grade or 4(%)Bilirubin increased 20 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 1.2 Platelets decreased 0.7 In Combination with Oxaliplatin-Containing RegimensThe safety of capecitabine tablets for the perioperative treatment of adults with Stage III colon cancer as component of 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 component of combination chemotherapy regimen was similar to those in patients treated with capecitabine tablets as single agent, with the exception of an increased incidence of neurosensory toxicity.Perioperative Treatment of Rectal CancerThe safety of capecitabine tablets for the perioperative treatment of adults with locally advanced rectal cancer as 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 component of chemoradiotherapy was similar to those in patients treated with capecitabine tablets as single agent, with the exception of an increased incidence of diarrhea. Metastatic Colorectal CancerSingle AgentThe safety of capecitabine tablets as single agent was evaluated in pooled metastatic colorectal cancer population (Study SO14695 and Study SO14796) [see Clinical Studies (14.1)]. Patients received capecitabine tablets 1,250 mg/m2 orally twice day for the first 14 days of 21-day cycle (N=596) or leucovorin 20 mg/m2 intravenously followed by fluorouracil 425 mg/m2 as an intravenous bolus on days to 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 shows the adverse reactions occurring in this pooled colorectal cancer population. Table Adverse Reactions (>10%) in Patients Who Received Capecitabine Tablets in Pooled Metastatic Colorectal Cancer Population (Study SO14695 and Study SO14796) Adverse Reaction Capecitabine Tablets (N=596)Fluorouracil Leucovorin(N=593)All Grades (%)Grade (%)Grade 4(%)All Grades (%)Grade 3(%)Grade 4(%)Blood and Lymphatic SystemAnemia 80 <1 79 <1 Neutropenia 13 2 46 13 GastrointestinalDiarrhea 55 13 61 10 Nausea 43 - 51 <1 Abdominal pain 35 <1 31 - Vomiting 27 <1 30 <1 Stomatitis 25 <1 62 14 Constipation 14 <1 17 - Gastrointestinal motility disorder 10 <1 7 <1 Oral discomfort 10 - 10 - Skin and Subcutaneous TissuePalmar-plantar erythrodysesthesia syndrome 54 17 NA 1 NA Dermatitis 27 - 26 - HepatobiliaryHyperbilirubinemia 48 18 17 3 GeneralFatigue 42 - 46 - Pyrexia 18 - 21 - Edema 15 - 1 Pain 12 - 10 - Metabolism and NutritionDecreased appetite 26 <1 31 <1 Respiratory Thoracic and MediastinalDyspnea 14 - 10 <1 EyeEye irritation 13 - 10 <1 Nervous SystemPeripheral sensory neuropathy 10 - - Headache 10 - - MusculoskeletalBack pain 10 - <1 - Not observedIncludes weakness NA Not ApplicableClinically relevant adverse reactions in <10% of patients are presented below: Eye: abnormal visionGastrointestinal: upper gastrointestinal tract inflammatory disorders, gastrointestinal hemorrhage, ileusGeneral: chest painInfections: viralMetabolism and Nutrition: dehydrationMusculoskeletal: arthralgiaNervous System: dizziness (excluding vertigo), insomnia, taste disturbancePsychiatric: mood alteration, depressionRespiratory, Thoracic, and Mediastinal: cough, pharyngeal disorder Skin and Subcutaneous Tissue: skin discoloration, alopecia Vascular: venous thrombosisIn Combination with Oxaliplatin The safety of capecitabine tablets for the treatment of patients with unresectable or metastatic colorectal cancer as component of combination chemotherapy regimen was derived from published literature [see Clinical Studies (14.1)]. The safety of capecitabine tablets for the treatment of patients with unresectable or metastatic colorectal cancer as component of combination chemotherapy regimen was similar to those in patients treated with capecitabine tablets as single agent, with the exception of an increased incidence of peripheral neuropathy.Metastatic Breast CancerIn Combination with DocetaxelThe safety of capecitabine tablets in combination with docetaxel was evaluated in patients with metastatic breast cancer in Study SO14999 [see Clinical Studies (14.2)]. Patients received capecitabine tablets 1,250 mg/m2 orally twice daily for the first 14 days of 21-day cycle with docetaxel 75 mg/m2 as 1- hour intravenous infusion on day of each 21-day cycle for at least weeks or docetaxel 100 mg/m2 as 1-hour intravenous infusion on day of each 21-day cycle for at least weeks. Among patients who received capecitabine tablets, the mean duration of treatment was 4.2 months.Permanent discontinuation due to an adverse reaction occurred in 26% of patients who received capecitabine tablets. Dosage interruptions due to an adverse reaction occurred in 79% of patients who received capecitabine tablets 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 summarizes the adverse reactions in Study SO14999.Table Adverse Reactions (>=10%) in Patients Who Received Capecitabine Tablets with Docetaxel for Metastatic Breast Cancer in Study SO14999 Adverse Reaction Capecitabine Tablets with Docetaxel (N=251)Docetaxel (N=255)All Grades (%)Grade (%)Grade (%)All Grades (%)Grade (%)Grade (%)GastrointestinalDiarrhea 67 14 <1 48 <1 Stomatitis 67 17 <1 43 - Nausea 45 - 36 - Vomiting 35 1 24 - Abdominal pain 30 <1 24 - Constipation 20 - 18 - Dyspepsia 14 - 1 Skin and Subcutaneous TissuePalmar-plantar erythrodysesthesia syndrome 63 24 NA 1 NA Alopecia 41 - 42 - Nail disorder 14 - 15 - CardiacEdema 33 <2 34 <3 GeneralPyrexia 28 - 34 - Asthenia 26 <1 25 - Fatigue 22 - 27 - Weakness 16 - 11 - Pain in Limb 13 <1 13 - Blood and Lymphatic SystemNeutropenic fever 16 13 21 16 Nervous SystemTaste disturbance 16 <1 14 <1 Headache 15 - 15 - Paresthesia 12 <1 16 - Dizziness 12 - <1 Musculoskeletal and Connective TissueArthralgia 15 - 24 - Myalgia 15 - 25 - Back Pain 12 <1 11 - Respiratory, Thoracic and MediastinalDyspnea 14 <1 16 - Cough 13 - 22 <1 Sore Throat 12 - 11 <1 Metabolism and NutritionAnorexia 13 <1 11 <1 Appetite decreased 10 - - Dehydration 10 - <1 <1 EyeLacrimation increased 12 - <1 - Not observedNA Not ApplicableClinically relevant adverse reactions in <10% of patients are presented below: Blood and Lymphatic System: agranulocytosis, prothrombin decreased Cardiac: supraventricular tachycardiaEye: conjunctivitis, eye irritationGastrointestinal: ileus, necrotizing enterocolitis, esophageal ulcer, hemorrhagic diarrhea, dry mouthGeneral: chest pain (non-cardiac), lethargy, pain, influenza-like illnessHepatobiliary: jaundice, abnormal liver function tests, hepatic failure, hepatic coma, hepatotoxicityImmune System: hypersensitivityInfection: hypoesthesia, neutropenic sepsis, sepsis, bronchopneumonia, oral candidiasis, urinary tract infectionMetabolism and Nutrition: weight decreasedMusculoskeletal and Connective Tissue: bone painNervous System: insomnia, peripheral neuropathy, ataxia, syncope, taste loss, polyneuropathy, migrainePsychiatric: depressionRenal and Urinary: renal failureRespiratory, Thoracic and Mediastinal: upper respiratory tract infection, pleural effusion, epistaxis, rhinorrheaSkin and Subcutaneous Tissue: pruritis, rash erythematous, dermatitis, nail discoloration, onycholysisVascular: lymphedema, hypotension, venous phlebitis and thrombophlebitis, postural hypotension, flushingTable summarizes the laboratory abnormalities in this trial.Table Laboratory Abnormalities (>=20%) in Patients Who Received Capecitabine Tablets with Docetaxel for Metastatic Breast Cancer in Study SO14999 Laboratory Abnormality Capecitabine Tablets with Docetaxel (N=251)Docetaxel (N=255)All Grades (%)Grade (%)Grade (%)All Grades (%)Grade (%)Grade (%)HematologicLymphocytopenia 99 48 41 98 44 40 Leukopenia 91 37 24 88 42 33 Neutropenia 86 20 49 87 10 66 Anemia 80 3 83 <1 Thrombocytopenia 41 1 23 2 HepatobiliaryHyperbilirubinemia 20 2 2 Single AgentThe safety of capecitabine tablets as single agent was evaluated in patients with metastatic breast cancer in Study SO14697 [see Clinical Studies (14.2)]. Patients received capecitabine tablets 1,250 mg/m2 orally twice daily for the first 14 days of 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 summarizes the adverse reactions in Study SO14697.Table Adverse Reactions (>10%) in Patients Who Received Capecitabine Tablets for Metastatic Breast Cancer in Study SO14697 Adverse Reaction Capecitabine Tablets (n=162)All Grades(%)Grade 3(%)Grade 4(%)Blood and Lymphatic SystemLymphopenia 94 44 15 Anemia 72 1 Neutropenia 26 2 Thrombocytopenia 24 1 GastrointestinalDiarrhea 57 12 Nausea 53 - Vomiting 37 - Stomatitis 24 - Abdominal pain 20 - Constipation 15 - Skin and Subcutaneous TissueHand-and-foot syndrome 57 11 NA Dermatitis 37 - GeneralFatigue 41 - Pyrexia 12 - Metabolism and NutritionAnorexia 23 - HepatobiliaryHyperbilirubinemia 22 2 Nervous SystemParesthesia 21 - EyeEye irritation 15 - = Not observed NA Not ApplicablePooled Safety PopulationClinically relevant adverse reactions in <10% of patients who received capecitabine tablets as single agent are presented below.Blood Lymphatic System: leukopenia, coagulation disorder, bone marrow depression, pancytopeniaCardiac: tachycardia, bradycardia, atrial fibrillation, myocarditis, edemaEar: vertigoEye: conjunctivitisGastrointestinal: abdominal distension, dysphagia, proctalgia, gastric ulcer, ileus, gastroenteritis, dyspepsiaGeneral: chest pain, influenza-like illness, hot flushes, pain, thirst, fibrosis, hemorrhage, edema, pain in limbHepatobiliary: hepatic fibrosis, hepatitis, cholestatic hepatitis, abnormal liver function testsImmune System: drug hypersensitivity Infections: bronchitis, pneumonia, keratoconjunctivitis, sepsis, fungal infectionsMetabolism and Nutrition: cachexia, hypertriglyceridemia, hypokalemia, hypomagnesemia, dehydrationMusculoskeletal and Connective Tissue: myalgia, arthritis, muscle weaknessNervous System: insomnia, ataxia, tremor, dysphasia, encephalopathy, dysarthria, impaired balance, headache, dizzinessPsychiatric: depression, confusionRenal and Urinary: renal impairmentRespiratory, Mediastinal and Thoracic: cough, epistaxis, respiratory distress, dyspneaSkin and Subcutaneous Tissue: nail disorder, sweating increased, photosensitivity reaction, skin ulceration, pruritus, radiation recall syndromeVascular: hypotension, hypertension, lymphedema, pulmonary embolismUnresectable or Metastatic Gastric, Esophageal, or Gastroesophageal Junction Cancer The safety of capecitabine tablets for the treatment of adults with unresectable or metastatic gastric,esophageal, or gastroesophageal junction cancer as component of combination chemotherapy regimen was derived from published literature [see Clinical Studies (14.3)]. The safety of capecitabine tablets for the treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as component of combination chemotherapy regimen was consistent with the known safety profile of capecitabine tablets.The safety of capecitabine tablets for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease as component of combination regimen was derived from the published literature [see Clinical Studies (14.3)]. The safety of capecitabine tablets for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma was consistent with the known safety profile of capecitabine tablets. Pancreatic CancerThe safety of capecitabine tablets for the adjuvant treatment of adults with pancreatic adenocarcinoma as component of combination chemotherapy regimen was derived from the published literature [see Clinical Studies (14.4)]. The safety of capecitabine tablets for the adjuvant treatment of adults with pancreatic adenocarcinoma as component of combination chemotherapy regimen was consistent with the known safety profile of capecitabine tablets. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of capecitabine tablets. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Eye: lacrimal duct stenosis, corneal disorders including keratitisHepatobiliary: hepatic failureImmune System Disorders: angioedemaNervous System: toxic leukoencephalopathyRenal Urinary: acute renal failure secondary to dehydration including fatal outcomeSkin 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.

CLINICAL PHARMACOLOGY SECTION.

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, N5-10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form 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 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 positive association between AUC of fluorouracil and grade to hyperbilirubinemia.. 12.3 Pharmacokinetics. The AUC of capecitabine and its metabolite 5-DFCR increases proportionally over dosage range of 500 mg/m2/day to 3,500 mg/m2/day (0.2 to 1.4 times the approved recommended dosage). The AUC of capecitabines metabolites 5-DFUR and fluorouracil increased greater than proportional to the dose. The interpatient variability in the Cmax and AUC of fluorouracil was greater than 85%.AbsorptionFollowing oral administration of capecitabine tablets 1,255 mg/m2 orally twice daily (the recommended dosage when used as single agent), the median Tmax of capecitabine and its metabolite fluorouracil was approximately 1.5 hours and hours, respectively.Effect of FoodFollowing administration of meal (breakfast medium-rich in fat and carbohydrates), the mean Cmax and AUC0-INF of capecitabine was decreased by 60% and 34%, respectively. The mean Cmax and AUC0-INF of fluorouracil were also decreased by 37 and 12%, respectively. The Tmax of both capecitabine and fluorouracil was delayed by 1.5 hours.DistributionPlasma 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 tablets 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).EliminationThe elimination half-lives of capecitabine and fluorouracil were approximately 0.75 hour.MetabolismCapecitabine 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 (FUH2). The pyrimidine ring of FUH2 is cleaved by dihydropyrimidinase to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, FUPA is cleaved by -ureido-propionase to -fluoro--alanine (FBAL).ExcretionFollowing 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 PopulationsFollowing therapeutic doses of capecitabine tablets, 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 20% increase in age. Racial or Ethnic GroupsFollowing administration of capecitabine tablets 825 mg/m2 orally twice daily for 14 days (0.66 times the recommended dosage), the Cmax and AUC of capecitabine decreased by 36% and 24%, respectively in Japanese patients (n=18) compared to White patients (n=22). The Cmax 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 Effect of Renal Impairment on the Pharmacokinetics of Capecitabine, 5-DFUR, and FBAL Renal Impairmenta Changes in AUCb Capecitabine5-DFURc FBALc 5-FUCLcr 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% Compared to patients with CLcr >80 mL/min Following administration of capecitabine tablets 1,250 mg/m2 orally twice daily; day observations Capecitabine metaboliteCLcr= Creatine Clearance, AUC= Area under the plasma concentration-time curve Patients with Hepatic ImpairmentAUC0-INF and Cmax of capecitabines active principle, fluorouracil, were not affected in patients with mild or moderate hepatic impairment compared to patients with normal hepatic function. The AUC0-INF and Cmax of capecitabine increased by 60%. The effect of severe hepatic impairment on the pharmacokinetics of capecitabine and its metabolites are unknown.Drug Interaction StudiesClinical Studies Effect of Capecitabine on Warfarin: In four patients with cancer, chronic administration of capecitabine tablets 1,250 mg/m2 twice daily with 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 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 tablets 1,000 mg/m2 twice daily for 14 days) increased celecoxib (sensitive CYP2C9 substrate) AUC by 28%, Cmax by 24% and Ctrough by 30%.Effect of Antacids on Capecitabine: When an aluminum hydroxide- and magnesium hydroxide- containing antacid was administered immediately after capecitabine tablets dose of 1,250 mg/m2 in patients with cancer, AUC and Cmax 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 tablets.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 tablets had no effect on the pharmacokinetics of docetaxel (Cmax and AUC) and docetaxel has no effect on the pharmacokinetics of capecitabine and the fluorouracil precursor 5-DFUR.In Vitro StudiesCytochrome 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 to 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 DPD enzyme activity) or are compound heterozygous for no function DPYD variant plus 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 with capecitabine tablets. Partial DPD deficiency can result from the presence of either two decreased function DPYD variants or one normal function plus either decreased function or no function DPYD variant. Patients with partial DPD deficiency may also be at an increased risk for toxicity from capecitabine tablets.Several DPYD variants observed with variable frequency across populations have been associated with reduced or no DPD activity, especially when present as homozygous or compound heterozygous variants. These include c.1905+1G>A (DPYD 2A), c.1679T>G (DPYD 13), c.2846A>T, c.1129-5923C>G (Haplotype B3), and c557A>G. DPYD2A and DPYD13 are no function variants, and c.2846A>T, c.1129-5923C>G, and c557A>G are decreased function variants. This is not complete listing of all DPYD variants that may result in DPD deficiency [see Warnings and Precautions (5.1)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Colorectal Cancer. Adjuvant Treatment of Colon CancerSingle AgentThe efficacy of capecitabine tablets was evaluated in X-ACT (NCT00009737), multicenter, randomized, controlled clinical trial. Eligible patients were between 18 and 75 years of age with histologically-confirmed Dukes Stage colon cancer with at least one positive lymph node and to have undergone (within 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 or (KPS >70%), ANC >1.5x109/L, platelets >100x109/L, serum creatinine <1.5 ULN, total bilirubin <1.5 ULN, AST/ALT <2.5 ULN and CEA within normal limits at time of randomization.Patients (n=1,987) were randomized to capecitabine tablets 1,250 mg/m2 orally twice daily for the first 14 days of 21-day cycle for total of cycles or fluorouracil 425 mg/m2 and leucovorin 20 mg/m2 intravenously on days to of each 28-day cycle for total of cycles. The capecitabine tablets 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 Baseline Demographics in X-ACT Capecitabine Tablets (N=1,004)Fluorouracil Leucovorin (N=983)Age (median, years) 62 63 Range (25 to 80) (22 to 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 PT3, 76 76 PT4, 14 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 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 tablets 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 tablets 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 tablets and 68% for fluorouracil leucovorin.Table 10 Efficacy Results in X-ACTa (All Randomized Population) Efficacy Parameters Capecitabine Tablets (N=1,004)Fluorouracil Leucovorin(N=983)5-year Disease-free Survival Rateb 59% 55% Hazard Ratio 0.88 (95% CI) (0.77, 1.01) p-valuec = 0.068 aApproximately 93.4 had 5-year DFS informationb Based on Kaplan-Meier estimatesc Wald chi-square test Figure Kaplan-Meier Estimates of Disease-Free Survival in X-ACT (All Randomized Population) Figure Kaplan-Meier Estimates of Overall Survival in X-ACT (All Randomized Population) In Combination with Oxaliplatin-Containing RegimensThe efficacy of capecitabine tablets in combination with oxaliplatin for the adjuvant treatment of patients with Stage III colon cancer as component of combination chemotherapy regimen was derived from studies in the published literature, including NO16968 [NCT00069121], multicenter, open-label, randomized trial, where the major efficacy outcome measure was disease free survival.Perioperative Treatment of Rectal CancerThe efficacy of capecitabine tablets for the perioperative treatment of adults with locally advanced rectal cancer as component of chemoradiotherapy was derived from studies in the published literature, including Rektum-III [NCT01500993], randomized, open-label, multicenter, non- inferiority trial, where the major efficacy outcome measure was overall survival.Metastatic Colorectal CancerThe efficacy of capecitabine tablets as 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 tablets 1,250 mg/m2 twice daily for first 14 days of 21-day cycle or leucovorin 20 mg/m2 intravenously followed by fluorouracil 425 mg/m2 as an intravenous bolus on days to 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 blinded independent review committee (IRC). Differences in assessments between the investigator and IRC were reconciled by the sponsor, blinded to treatment arm, according to specified algorithm. Survival was assessed based on non- inferiority analysis.The baseline demographics are shown in Table 11.Table 11 Baseline Demographics for Study SO14695 and Study SO14796 Study SO14695Study SO14796Capecitabine Tablets (N=302)Fluorouracil Leucovorin (N=303)Capecitabine Tablets (N=301)Fluorouracil Leucovorin (N=301)Age (median, years) 64 63 64 64 Range (23 to 86) (24 to 87) (29 to 84) (36 to 86) Sex Male, 60 65 57 57 Female, 40 35 43 43 Karnofsky PS (median) 90 90 90 90 Range (70 to 100) (70 to 100) (70 to 100) (70 to 100) Colon, 74 77 66 65 Rectum, 26 23 34 35 Prior radiation therapy, 17 21 14 14 Prior adjuvant 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 Tablets (N=302)Fluorouracil Leucovorin (N=303)Overall Response Rate% (95% CI) 21 (16, 26) 11 (8, 15) p-value0.0014 Time to ProgressionMedian, 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 SurvivalMedian, 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 Tablets (N=301)Fluorouracil Leucovorin (N=301)Overall Response Rate% (95% CI) 21 (16, 26) 14 (10, 18) p-value 0.027 Time to ProgressionMedian, 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 SurvivalMedian, 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 tablets. The estimate of the survival effect of fluorouracil leucovorin was derived from 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 tablets, 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 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 tablets difference. Figure Kaplan-Meier Curve for Overall Survival of Pooled Data (Studies SO14695 and SO14796)In Combination with OxaliplatinThe efficacy of capecitabine tablets for the treatment of patients with unresectable or metastatic colorectal cancer as component of combination chemotherapy regimen was derived from studies in the published literature, including NO16966 [NCT00069095], randomized, non-inferiority, 2x2 factorial trial, where the major efficacy outcome measure was progression free survival.. capecitabine-fig-1. capecitabine-fig-2. capecitabine-fig-3. 14.2 Metastatic Breast Cancer. In Combination With DocetaxelThe efficacy of capecitabine tablets 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 years of completing an anthracycline-containing adjuvant therapy were enrolled. Patients were randomized to capecitabine tablets 1,250 mg/m2 twice daily for the first 14 days of 21-day cycle and docetaxel 75 mg/m2 as 1-hour intravenous infusion on day of day of 21- day cycle or docetaxel 100 mg/m2 as 1-hour intravenous infusion on day of 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 Tablets +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 Anthracycline1, 100 100 Fluorouracil, 77 74 Paclitaxel, 10 Resistance to an Anthracycline No resistance, 7 Progression on anthracycline therapy, 26 29 Stable disease after cycles of anthracycline therapy, 16 16 Relapsed within years of completion of anthracycline-adjuvant therapy, 31 29 Experienced 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 1Includes 10 patients in combination and 18 patients in single agent arms treated with an anthracenedioneEfficacy results are shown in Table 15, Figure and Figure 5.Table 15 Efficacy Results in Metastatic Breast Cancer (Study SO14999) Efficacy ParameterCapecitabine Tablets Docetaxel(N=255)Docetaxel(N=256)Time to Disease ProgressionMedian, months 6.1 4.2 95% CI (5.4, 6.5) (3.5, 4.5) Hazard Ratio 0.643 p-value 0.0001 Overall SurvivalMedian, months 14.5 11.6 95% CI (12.3, 16.3) (9.8, 12.7) Hazard Ratio 0.775 p-value 0.0126 Response Rate132% 22% The response rate reported represents reconciliation of the investigator and IRC assessments performed by the sponsor according to predefined algorithm. Figure Kaplan-Meier Estimates for Time to Disease Progression in Metastatic Breast Cancer (Study SO14999) Figure Kaplan-Meier Estimates of Survival in Metastatic Breast Cancer (Study SO14999)Single AgentThe efficacy of capecitabine tablets as 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/m2 of doxorubicin or doxorubicin equivalents). Resistance was defined as progressive disease while on treatment, with or without an initial response, or relapse within months of completing treatment with an anthracycline-containing adjuvant chemotherapy regimen. Patients received capecitabine tablets 1,255 mg/m2 orally twice daily for first 14-days of 21-day treatment cycle. The major efficacy outcome measure was tumor response rate in patients with measurable disease, with response defined as >=50% decrease in sum of the products of the perpendicular diameters of bidimensionally measurable disease for at least 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 to 2, 32 37 to 4, 46 43 >5, 22 21 Dominant Site of Disease Visceral1, 75 68 Soft Tissue, 22 22 Bone, 3 10 Prior Chemotherapy Paclitaxel, 100 100 Anthracycline2, 90 91 Fluorouracil, 81 82 Resistance to Paclitaxel, 76 77 Resistance to an Anthracycline2, 41 41 Resistance to both Paclitaxel and an Anthracycline2, 32 31 1Lung, pleura, liver, peritoneum2Includes patients treated with an anthracenedioneEfficacy 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 Rate1(95% CI)25.6%(13.5, 41.2) Complete Response 0% Partial Response1 11% Duration of Response1Median, months2 (Range) 5.1 (2.1 to 7.7) Includes patients treated with an anthracenedione2 From date of first responseFor 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 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.. capecitabine-fig-4. capecitabine-fig-5. 14.3 Gastric, Esophageal, or Gastroesophageal Junction Cancer. The efficacy of capecitabine tablets for treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as component of combination chemotherapy regimen was derived from studies in the published literature. Capecitabine tablets were evaluated in REAL- 2, 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 tablets for the treatment of adults with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease as component of combination regimen was derived from studies in the published literature. Capecitabine tablets were evaluated in the ToGA trial [NCT01041404], an open-label, multicenter, randomized trial where the primary efficacy measure was overall survival.. 14.4Pancreatic Cancer. The efficacy of capecitabine tablets for the adjuvant treatment of adults with pancreatic adenocarcinoma as component of combination chemotherapy regimen was derived from study in the published literature. Capecitabine tablets were evaluated in ESPAC-4 trial, two-group, open-label, multicenter, randomized trial, where the major efficacy outcome measure was overall survival.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Adjuvant Treatment of Colon CancerSingle agent: 1,250 mg/m2 twice daily orally for the first 14 days of each 21-day cycle for maximum of cycles. (2.1) In combination with Oxaliplatin-Containing Regimens: 1,000 mg/m2 orally twice daily for the first 14 days of each 21-day cycle for maximum of cycles in combination with oxaliplatin 130 mg/m2 administered intravenously on day of each cycle. (2.2)Perioperative Treatment of Rectal CancerWith Concomitant Radiation Therapy: 825 mg/m2 orally twice daily (2.2)Without Radiation Therapy: 1,250 mg/m2 orally twice daily (2.2)Unresectable or Metastatic Colorectal Cancer:Single agent: 1,250 mg/m2 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/m2 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 of each cycle. (2.2)Advanced or Metastatic Breast Cancer:Single agent: 1,000 mg/m2 or 1,250 mg/m2 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/m2 or 1,250 mg/m2 orally twice daily for the first 14 days of 21-day cycle, until disease progression or unacceptable toxicity in combination with docetaxel at 75 mg/m2 administered intravenously on day of each cycle (2.3)Unresectable or Metastatic Gastric, Esophageal, or Gastroesophageal Junction Cancer625 mg/m2 orally twice daily on days to 21 of each 21-day cycle for maximum of cycles in combination with platinum-containing chemotherapy. (2.4)OR850 mg/m2 or 1,000 mg/m2 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 of each cycle. (2.4)HER2-overexpressing metastatic adenocarcinoma of the gastroesophageal junction or stomach1,000 mg/m2 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 cancer830 mg/m2 orally twice daily for the first 21 days of each 28-day cycle for maximum of cycles in combination with gemcitabine 1,000 mg/m2 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).. Single agent: 1,250 mg/m2 twice daily orally for the first 14 days of each 21-day cycle for maximum of cycles. (2.1) In combination with Oxaliplatin-Containing Regimens: 1,000 mg/m2 orally twice daily for the first 14 days of each 21-day cycle for maximum of cycles in combination with oxaliplatin 130 mg/m2 administered intravenously on day of each cycle. (2.2). With Concomitant Radiation Therapy: 825 mg/m2 orally twice daily (2.2). Without Radiation Therapy: 1,250 mg/m2 orally twice daily (2.2). Single agent: 1,250 mg/m2 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/m2 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 of each cycle. (2.2). Single agent: 1,000 mg/m2 or 1,250 mg/m2 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/m2 or 1,250 mg/m2 orally twice daily for the first 14 days of 21-day cycle, until disease progression or unacceptable toxicity in combination with docetaxel at 75 mg/m2 administered intravenously on day of each cycle (2.3). 625 mg/m2 orally twice daily on days to 21 of each 21-day cycle for maximum of cycles in combination with platinum-containing chemotherapy. (2.4)OR. 850 mg/m2 or 1,000 mg/m2 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 of each cycle. (2.4). 1,000 mg/m2 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). 830 mg/m2 orally twice daily for the first 21 days of each 28-day cycle for maximum of cycles in combination with gemcitabine 1,000 mg/m2 administered intravenously on days 1, 8, and 15 of each cycle. (2.5). 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 tablet 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). 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 CancerSingle AgentThe recommended dosage of capecitabine tablet is 1,250 mg/m2 orally twice daily for the first 14 days of each 21-day cycle for maximum of cycles.In Combination with Oxaliplatin-Containing RegimensThe recommended dosage of capecitabine tablet is 1,000 mg/m2 orally twice daily for the first 14 days of each 21-day cycle for maximum of cycles in combination with oxaliplatin 130 mg/m2 administered intravenously on day 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/m2 orally twice daily when administered with concomitant radiation therapy and 1,250 mg/m2 orally twice daily when administered without radiation therapy as part of peri-operative combination regimen.Unresectable or Metastatic Colorectal CancerSingle AgentThe recommended dosage of capecitabine tablet is 1,250 mg/m2 orally twice daily for the first 14 days of 21-day cycle until disease progression or unacceptable toxicity.In Combination with OxaliplatinThe recommended dosage of capecitabine tablet is 1,000 mg/m2 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 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 CancerSingle AgentThe recommended dosage of capecitabine tablet is 1,000 mg/m2 or 1,250 mg/m2 orally twice daily for the first 14 days of 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 DocetaxelThe recommended dosage of capecitabine tablet is 1,000 mg/m2 or 1,250 mg/m2 orally twice daily for the first 14 days of 21-day cycle until disease progression or unacceptable toxicity in combination with docetaxel 75 mg/m2 administered intravenously on day 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/m2 orally twice daily on days to 21 of each 21-day cycle for maximum of cycles in combination with platinum-containing chemotherapy.OR850 mg/m2 or 1,000 mg/m2 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 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/m2 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.. 625 mg/m2 orally twice daily on days to 21 of each 21-day cycle for maximum of cycles in combination with platinum-containing chemotherapy.. 850 mg/m2 or 1,000 mg/m2 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 of each cycle. Individualize the dose and dosing schedule of capecitabine tablets based on patient risk factors and adverse reactions.. 2.5 Recommended Dosage for Pancreatic Cancer. The recommended dosage of capecitabine tablet is 830 mg/m2 orally twice daily for the first 21 days of each 28-day cycle until disease progression, unacceptable toxicity, or for maximum cycles in combination with gemcitabine 1,000 mg/m2 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 are administered with docetaxel, withhold capecitabine tablets and docetaxel until the requirements for resuming both capecitabine tablets and docetaxel are met. Refer to the Prescribing Information for docetaxel for additional dosing information as appropriate.Table Recommended Dosage Modifications for Adverse Reactions SeverityDosage ModificationResume at Same or Reduced Dose(Percent of Current Dose)Grade 21st appearance Withhold until resolved to grade to 1. 100% 2nd appearance 75% 3rd appearance 50% 4th appearance Permanently discontinue. Grade 31st appearance Withhold until resolved to grade to 1. 75% 2nd appearance 50% 3rd appearance Permanently discontinue. Grade 41st appearance Permanently discontinue OR Withhold until resolved to grade to 1. 50% HyperbilirubinemiaPatients with Grade to hyperbilirubinemia may resume treatment once the event is Grade or less (less than three times the upper limit of normal), using the percent of current dose as shown in column of Table [see Warnings and Precautions (5.10)]. 2.7 Dosage Modification For Renal Impairment. Reduce the dose of capecitabine tablets by 25% for patients with creatinine clearance (CLcr) of 30 to 50 mL/min as determined by Cockcroft-Gault equation. dosage has not been established in patients with severe renal impairment (CLcr <30 mL/min) [see Use in Specific Populations (8.6)].. 2.8 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 meal. Do not chew, cut, or crush capecitabine tablets [see Warnings and Precautions (5.12)]. Take capecitabine tablets 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 missed dose and continue with the next scheduled dose.Capecitabine tablets are hazardous drug. Follow applicable special handling and disposal procedures.1.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Allopurinol: Avoid concomitant use of allopurinol with capecitabine tablets. (7.1)Leucovorin: Closely monitor for toxicities when capecitabine tablets are coadministered with leucovorin. (7.1)CYP2C9 substrates: Closely monitor for adverse reactions when CYP2C9 substrates are coadministered with capecitabine tablets. (7.2) Vitamin antagonists: Monitor INR more frequently and dose adjust oral vitamin antagonist as appropriatePhenytoin: 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 are used concomitantly with nephrotoxic drugs. (7.3). Allopurinol: Avoid concomitant use of allopurinol with capecitabine tablets. (7.1). Leucovorin: Closely monitor for toxicities when capecitabine tablets are coadministered with leucovorin. (7.1). CYP2C9 substrates: Closely monitor for adverse reactions when CYP2C9 substrates are coadministered with capecitabine tablets. (7.2). Vitamin antagonists: Monitor INR more frequently and dose adjust oral vitamin 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 are used concomitantly with nephrotoxic drugs. (7.3). 7.1 Effect of Other Drugs on Capecitabine Tablets. AllopurinolConcomitant use with allopurinol may decrease concentration of capecitabines active metabolites [see Clinical Pharmacology (12.3)], which may decrease efficacy. Avoid concomitant use of allopurinol with capecitabine tablets.LeucovorinThe 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 SubstratesCapecitabine 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 AntagonistsCapecitabine tablets increases exposure of vitamin 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 month after discontinuation of capecitabine tablets.Monitor INR more frequently and refer to the prescribing information of oral vitamin antagonist for dosage adjustment, as appropriate, when capecitabine tablets are used concomitantly with vitamin antagonist.PhenytoinCapecitabine 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 are used concomitantly with phenytoin.. 7.3Nephrotoxic 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 are used concomitantly with nephrotoxic drugs (e.g. platinum salts, irinotecan, methotrexate, intravenous bisphosphonates).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Capecitabine tablets are nucleoside metabolic inhibitor indicated for:Colorectal Canceradjuvant treatment of patients with Stage III colon cancer as single agent or as component of combination chemotherapy regimen. (1.1)perioperative treatment of adults with locally advanced rectal cancer as component of chemoradiotherapy. (1.1) treatment of patients with unresectable or metastatic colorectal cancer as single agent or as component of combination chemotherapy regimen. (1.1)Breast Cancertreatment of patients with advanced or metastatic breast cancer as 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 component of 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 component of combination regimen. (1.3)Pancreatic Cancer adjuvant treatment of adults with pancreatic adenocarcinoma as component of combination chemotherapy regimen. (1.4). adjuvant treatment of patients with Stage III colon cancer as single agent or as component of combination chemotherapy regimen. (1.1). perioperative treatment of adults with locally advanced rectal cancer as component of chemoradiotherapy. (1.1). treatment of patients with unresectable or metastatic colorectal cancer as single agent or as component of combination chemotherapy regimen. (1.1). treatment of patients with advanced or metastatic breast cancer as 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). treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as component of 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 component of combination regimen. (1.3). adjuvant treatment of adults with pancreatic adenocarcinoma as component of 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 single agent or as component of combination chemotherapy regimen.perioperative treatment of adults with locally advanced rectal cancer as component of chemoradiotherapy.treatment of patients with unresectable or metastatic colorectal cancer as single agent or as component of combination chemotherapy regimen.. adjuvant treatment of patients with Stage III colon cancer as single agent or as component of combination chemotherapy regimen.. perioperative treatment of adults with locally advanced rectal cancer as component of chemoradiotherapy.. treatment of patients with unresectable or metastatic colorectal cancer as single agent or as component of combination chemotherapy regimen.. 1.2 Breast Cancer. Capecitabine tablets are indicated for the:treatment of patients with advanced or metastatic breast cancer as 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.. treatment of patients with advanced or metastatic breast cancer as 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.. 1.3Gastric, 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 component of 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 component of combination regimen.. treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as component of 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 component of combination regimen.. 1.4Pancreatic Cancer. Capecitabine tablets are indicated for the adjuvant treatment of adults with pancreatic adenocarcinoma as component of combination chemotherapy regimen.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).Serious Adverse Reactions or Death from Dihydropyrimidine Dehydrogenase (DPD) Deficiency Prior to initiating capecitabine tablets treatment, inform patients of the potential for serious or fatal adverse reactions due to DPD deficiency and testing for genetic variants of DPYD. Advise patients to immediately contact their healthcare provider if symptoms of severe mucositis, diarrhea, neutropenia, and neurotoxicity occur [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.5)]. Increased Risk of Bleeding with Concomitant Use of Vitamin AntagonistsAdvise patients on vitamin antagonists, such as warfarin, that they are at an increased risk of severe bleeding while taking capecitabine tablets. Advise these patients that INR should be monitored more frequently, and dosage modifications of the vitamin antagonist may be required, while taking and after discontinuation of capecitabine tablets. Advise these patients to immediately contact their healthcare provider if signs or symptoms of bleeding occur [see Warnings and Precautions (5.2)]. CardiotoxicityAdvise 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)].DiarrheaInform patients experiencing grade diarrhea (an increase of to stools/day or nocturnal stools) or greater or experiencing severe bloody diarrhea with severe abdominal pain and fever to stop taking capecitabine tablets. Advise patients on the use of antidiarrheal treatments (e.g., loperamide) to manage diarrhea [see Warnings and Precautions (5.4)].DehydrationInstruct patients experiencing grade or higher dehydration to stop taking capecitabine tablets immediately and to contact their healthcare provider. Advise patients to not restart capecitabine tablets until rehydrated and any precipitating causes have been corrected or controlled [see Warnings and Precautions (5.5)].Renal ToxicityInstruct 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 ToxicitiesInstruct patients skin rash, blistering, or peeling to immediately contact their healthcare provider[see Warnings and Precautions (5.7)]. Palmar-Plantar Erythrodysesthesia SyndromeInstruct patients experiencing grade palmar-plantar erythrodysesthesia syndrome or greater to stop taking capecitabine tablets 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)].MyelosuppressionInform patients who develop fever of 100.5F or greater or other evidence of potential infection to immediately contact their healthcare provider [see Warnings and Precautions (5.9)].HyperbilirubinemiaInform patients who develop jaundice or icterus to immediately contact their healthcare provider [see Warnings and Precautions (5.10)]. Embryo-Fetal ToxicityAdvise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of 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 tablets and for 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 tablets and for months after the last dose [see Use in Specific Populations (8.3)].LactationAdvise females not to breastfeed during treatment with capecitabine tablets and for week after the last dose [see Use in Specific Populations (8.2)].InfertilityAdvise males and females of reproductive potential that capecitabine tablets may impair fertility [see Use in Specific Populations (8.3)].Hypersensitivity and AngioedemaAdvise patients that capecitabine tablets 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 tablets and immediately contact their healthcare provider or to go to an emergency room. [see Adverse Reactions (6)].Nausea and VomitingInstruct patients experiencing grade nausea (food intake significantly decreased but able to eat intermittently) or greater to stop taking capecitabine tablets and to immediately contact their healthcare provider for management of nausea [see Adverse Reactions (6.1)].Instruct patients experiencing grade vomiting (2 to episodes in 24-hour period) or greater to stop taking capecitabine tablets immediately and to contact their healthcare provider for management of vomiting [see Adverse Reactions (6.1)].StomatitisInform patients experiencing grade stomatitis (painful erythema, edema or ulcers of the mouth or tongue, but able to eat) or greater to stop taking capecitabine tablets immediately and to contact their healthcare provider [see Adverse Reactions (6.1)].Important Administration InstructionsAdvise patients to swallow capecitabine tablets whole with water within 30 minutes after 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 interactionsInstruct 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)]. Manufactured by: Alkem Laboratories Ltd., Mumbai 400 013, INDIA. Distributed by: Ascend Laboratories, LLC Bedminster, NJ 07921 Trademarks are the property of their respective owners. Revised: October 2025.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The AUC of capecitabine and its metabolite 5-DFCR increases proportionally over dosage range of 500 mg/m2/day to 3,500 mg/m2/day (0.2 to 1.4 times the approved recommended dosage). The AUC of capecitabines metabolites 5-DFUR and fluorouracil increased greater than proportional to the dose. The interpatient variability in the Cmax and AUC of fluorouracil was greater than 85%.AbsorptionFollowing oral administration of capecitabine tablets 1,255 mg/m2 orally twice daily (the recommended dosage when used as single agent), the median Tmax of capecitabine and its metabolite fluorouracil was approximately 1.5 hours and hours, respectively.Effect of FoodFollowing administration of meal (breakfast medium-rich in fat and carbohydrates), the mean Cmax and AUC0-INF of capecitabine was decreased by 60% and 34%, respectively. The mean Cmax and AUC0-INF of fluorouracil were also decreased by 37 and 12%, respectively. The Tmax of both capecitabine and fluorouracil was delayed by 1.5 hours.DistributionPlasma 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 tablets 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).EliminationThe elimination half-lives of capecitabine and fluorouracil were approximately 0.75 hour.MetabolismCapecitabine 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 (FUH2). The pyrimidine ring of FUH2 is cleaved by dihydropyrimidinase to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, FUPA is cleaved by -ureido-propionase to -fluoro--alanine (FBAL).ExcretionFollowing 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 PopulationsFollowing therapeutic doses of capecitabine tablets, 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 20% increase in age. Racial or Ethnic GroupsFollowing administration of capecitabine tablets 825 mg/m2 orally twice daily for 14 days (0.66 times the recommended dosage), the Cmax and AUC of capecitabine decreased by 36% and 24%, respectively in Japanese patients (n=18) compared to White patients (n=22). The Cmax 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 Effect of Renal Impairment on the Pharmacokinetics of Capecitabine, 5-DFUR, and FBAL Renal Impairmenta Changes in AUCb Capecitabine5-DFURc FBALc 5-FUCLcr 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% Compared to patients with CLcr >80 mL/min Following administration of capecitabine tablets 1,250 mg/m2 orally twice daily; day observations Capecitabine metaboliteCLcr= Creatine Clearance, AUC= Area under the plasma concentration-time curve Patients with Hepatic ImpairmentAUC0-INF and Cmax of capecitabines active principle, fluorouracil, were not affected in patients with mild or moderate hepatic impairment compared to patients with normal hepatic function. The AUC0-INF and Cmax of capecitabine increased by 60%. The effect of severe hepatic impairment on the pharmacokinetics of capecitabine and its metabolites are unknown.Drug Interaction StudiesClinical Studies Effect of Capecitabine on Warfarin: In four patients with cancer, chronic administration of capecitabine tablets 1,250 mg/m2 twice daily with 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 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 tablets 1,000 mg/m2 twice daily for 14 days) increased celecoxib (sensitive CYP2C9 substrate) AUC by 28%, Cmax by 24% and Ctrough by 30%.Effect of Antacids on Capecitabine: When an aluminum hydroxide- and magnesium hydroxide- containing antacid was administered immediately after capecitabine tablets dose of 1,250 mg/m2 in patients with cancer, AUC and Cmax 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 tablets.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 tablets had no effect on the pharmacokinetics of docetaxel (Cmax and AUC) and docetaxel has no effect on the pharmacokinetics of capecitabine and the fluorouracil precursor 5-DFUR.In Vitro StudiesCytochrome 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.

USE IN SPECIFIC POPULATIONS SECTION.

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 . 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 SummaryBased on findings in animal reproduction studies and its mechanism of action [see Clinical Pharmacology (12.1)], capecitabine tablets can cause fetal harm when administered to pregnant woman. Available human data with capecitabine tablets 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/m2 twice daily, respectively (see Data). Advise pregnant women of the potential risk to fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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.DataAnimal DataOral administration of capecitabine to pregnant mice during the period of organogenesis at 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 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 SummaryThere 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 breastfed child, advise women not to breastfeed during treatment with capecitabine tablets and for week after the last dose.DataLactating mice given single oral dose of capecitabine excreted significant amounts of capecitabine metabolites into the milk.. 8.3 Females and Males of Reproductive Potential. Capecitabine tablets can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating capecitabine tablets. Contraception FemalesAdvise females of reproductive potential to use effective contraception during treatment with capecitabine tablets and for months after the last dose.MalesBased on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with capecitabine tablets and for months after the last dose [see Nonclinical Toxicology (13.1)]. InfertilityBased on animal studies, capecitabine tablets 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 tablets 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 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 5,580 cGy in 180 cGy fractions). The relative bioavailability of the investigational formulation to capecitabine tablets 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 7,938 patients with colorectal cancer who were treated with capecitabine tablets, 33% were older than 65 years. Of the 4,536 patients with metastatic breast cancer who were treated with capecitabine tablets, 18% were older than 65 years.Of 1,951 patients with gastric, esophageal, or gastrointestinal junction cancer who were treated with capecitabine tablets, 26% were older than 65 years.Of 364 patients with pancreatic cancer who received adjuvant treatment with capecitabine tablets, 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 tablets 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 tablets in patients with CLcr <30 mL/min, and dosage has not been established in those patients. If no treatment alternative exists, capecitabine tablets could be administered to such patients on an individual basis applying reduced starting dose, close monitoring of patients 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 tablets are unknown [see Clinical Pharmacology (12.3)]. Monitor patients with hepatic impairment more frequently for adverse reactions.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Cardiotoxicity: May be more common in patients with 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 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 are not recommended in patients with baseline neutrophil counts <1.5 109/L or platelet counts <100 109/L. For grade or 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 to hyperbilirubinemia may resume treatment once the event is Grade or less (<3 ULN), using the percent of current dose as shown in column of Table (2.5,5.10)Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to fetus and to use effective contraception. (5.11,8.1,8.3). Cardiotoxicity: May be more common in patients with 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 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 are not recommended in patients with baseline neutrophil counts <1.5 109/L or platelet counts <100 109/L. For grade or 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 to hyperbilirubinemia may resume treatment once the event is Grade or less (<3 ULN), using the percent of current dose as shown in column of Table (2.5,5.10). Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to fetus and to use effective contraception. (5.11,8.1,8.3). 5.1Serious 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 unless immediate 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 or unusually 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 identify patients 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). 5.2Increased Risk of Bleeding With Concomitant Use of Vitamin Antagonists. Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking capecitabine tablets concomitantly with vitamin antagonists, such as warfarin.Clinically significant increases in PT and INR have been reported in patients who were on stable doses of oral vitamin 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 few cases, within 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 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 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 single agent, the median time to first occurrence of grade to diarrhea was 34 days (range: day to year). The median duration of grade to diarrhea was 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 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 [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 single agent, the median time to onset of grades to PPES was 2.6 months (range: 11 days to 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 metastatic breast or colorectal cancer who received capecitabine tablets as single agent, 3.2% had grade or neutropenia, 1.7% had grade or thrombocytopenia, and 2.4% had grade or anemia.In the 251 patients with metastatic breast cancer who received capecitabine tablets with docetaxel, 68% had grade or neutropenia, 2.8% had grade or thrombocytopenia, and 10% had grade or anemia.Necrotizing enterocolitis (typhlitis) has been reported. Consider typhlitis in patients with fever, neutropenia and abdominal pain.Monitor complete blood count at baseline and before each cycle. Capecitabine tablets are not recommended if baseline neutrophil count <1.5 109/L or platelet count <100 109/L. For grade to myelosuppression, withhold capecitabine tablets and then resume at same or reduced dose, or permanently discontinue, based on occurrence [see Dosage and Administration (2.5)].. 5.10 Hyperbilirubinemia. Hyperbilirubinemia can occur with capecitabine tablets. In the 875 patients with metastatic breast or colorectal cancer who received capecitabine tablets as single agent, grade hyperbilirubinemia occurred in 15% of patients and grade hyperbilirubinemia occurred in 3.9%. Of the 566 patients who had hepatic metastases at baseline and the 309 patients without hepatic metastases at baseline, grade or hyperbilirubinemia occurred in 23% and 12%, respectively. Of these 167 patients with grade or hyperbilirubinemia, 19% had postbaseline increased alkaline phosphatase and 28% had postbaseline increased transaminases at any time (not necessarily concurrent). The majority of these patients with increased transaminases or alkaline phosphatase had liver metastases at baseline. In addition, 58% and 35% of the 167 patients with grade or hyperbilirubinemia had pre- and postbaseline increased alkaline phosphatase or transaminases (grades to 4), respectively. Only 8% (n=13) and 3% (n=5) had grade or increased alkaline phosphatase or transaminases. In the 596 patients who received capecitabine tablets for metastatic colorectal cancer, the incidence of grade or hyperbilirubinemia was similar to that observed for the pooled population of patients with metastatic breast and colorectal cancer. The median time to onset for grade or hyperbilirubinemia was 64 days and median total bilirubin increased from um/L at baseline to 13 um/L during treatment with capecitabine tablets. Of the 136 patients with grade or hyperbilirubinemia, 49 patients had grade or hyperbilirubinemia as their last measured value, of which 46 had liver metastases at baseline.In the 251 patients with metastatic breast cancer who received capecitabine tablets with docetaxel, grade hyperbilirubinemia occurred in 7% and grade hyperbilirubinemia occurred in 2%.Withhold capecitabine tablets and then resume at same or reduced dose, or permanently discontinue, based on occurrence [see Dosage and Administration (2.5)]. Patients with Grade to hyperbilirubinemia may resume treatment once the event is Grade or less than three times the upper limit of normal, using the percent of current dose as shown in Table [see Dosage and Administration (2.5)].. 5.11 Embryo-Fetal Toxicity. Based on findings from animal reproduction studies and its mechanism of action, capecitabine tablets can cause fetal harm when administered to pregnant woman. Insufficient data is available on capecitabine tablets use in pregnant women to evaluate 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 human exposure (AUC) in patients who received dosage of 1,250 mg/m2 twice daily, respectively.Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with capecitabine tablets and for months following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with capecitabine tablets and for months following the last dose [see Use in Specific Populations (8.1, 8.3)].. 5.12 Eye Irritation, Skin Rash and Other Adverse Reactions from Exposure to Crushed Tablets. In instances of exposure to crushed capecitabine tablets, the following adverse reactions have been reported: eye irritation and swelling, skin rash, diarrhea, paresthesia, headache, gastric irritation, vomiting and nausea. Advise patients not to cut or crush tablets.If capecitabine tablets must be cut or crushed, this should be done by professional trained in safe handling of cytotoxic drugs using appropriate equipment and safety procedures [see Dosage and Administration (2.7)]. The safety and effectiveness have not been established for the administration of crushed capecitabine tablets.