INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).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. 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.Advise these patients to immediately contact their healthcare provider if signs or symptoms of bleeding occur[see Warnings and Precautions 5.1)]. Serious Adverse Reactions from Dihydropyrimidine Dehydrogenase (DPD) DeficiencyInform patients of the potential for serious and life-threatening adverse reactions due to DPD deficiency and discuss with your patient whether they should be tested for genetic variants of DPYD that are associated with an increased risk of serious adverse reactions from the use of capecitabine. Advise patients to immediately contact their healthcare provider if symptoms of severe mucositis, diarrhea, neutropenia, and neurotoxicity occur [see Warnings and Precautions 5.2) and Clinical Pharmacology 12.5)] 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. 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 immediately and to contact their healthcare provider. Advise patients to not restart capecitabine 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 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 impactpersonal 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 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 and for months after the last dose [see Use in Specific Populations 8.3)] LactationAdvise females not to breastfeed during treatment with capecitabine and for week after the last dose [see Use in Specific Populations 8.2)] InfertilityAdvise males and females of reproductive potential that capecitabine may impair fertility [see Use in Specific Populations 8.3)] Hypersensitivity and AngioedemaAdvise patients that capecitabine 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 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 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 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 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)]. For full Taxotere prescribing information, please refer to Taxotere Package Insert.All trade names drug products are the property of their respective owners.Manufactured By:Intas Pharmaceuticals Limited, Ahmedabad 380 054, India. For BluePoint LaboratoriesIssued 03/23.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling:o Cardiotoxicity [see Warnings and Precautions 5.3)] Diarrhea [see Warnings and Precautions 5.4)] Dehydration [see Warnings and Precautions 5.5)] Renal Toxicity [see Warnings and Precautions 5.6)] Serious Skin Toxicities [see Warnings and Precautions 5.7)] Palmar-Plantar Erythrodysesthesia Syndrome [see Warnings and Precautions 5.8)] Myelosuppression [see Warnings and Precautions 5.9)] Hyperbilirubinemia [see Warnings and Precautions 5.10)] Most common adverse reactions in patients who received capecitabine as single agent for the adjuvant treatment for colon cancer (>=30%) were palmar-plantar erythrodysesthesia syndrome, diarrhea, and nausea. 6.1) Most common adverse reactions (>=30%) in patients with metastatic colorectal cancer who received capecitabine as single agent were anemia, diarrhea, palmar-plantar erythrodysesthesia syndrome, hyperbilirubinemia, nausea, fatigue, and abdominal pain. 6.1) Most common adverse reactions (>=30%) in patients with metastatic breast cancer who received capecitabine with docetaxel were diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, nausea, alopecia, vomiting, edema, and abdominal pain. 6.1) Most common adverse reactions (>=30%) in patients with metastatic breast cancer who received capecitabine as single agent were lymphopenia, anemia, diarrhea, hand-and-foot syndrome, nausea,fatigue, vomiting, and dermatitis. 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or www.accordhealthcare.us or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or www.accordhealthcare.us or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1Clinical 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 as single agent was evaluated in patients with Stage III colon cancer in X-ACT [see Clinical Studies 14.1)]. Patients received capecitabine 1,250 mg/m orally twice daily for the first 14 days of 21-day cycle (N=995) or leucovorin 20 mg/m intravenously followed by fluorouracil 425 mg/m as an intravenous bolus on days to of each 28-day cycle (N=974). Among patients who received capecitabine, the median duration of treatment was 5.4 months. Deaths due to all causes occurred in 0.8% of patients who received capecitabine on study or within 28 days of receiving study drug. Permanent discontinuation due to an adverse reaction occurred in 11% of patients who received capecitabine.Most common adverse reactions (>30%) were palmar-plantar erythrodysesthesia syndrome, diarrhea, and nausea.Tables and summarize the adverse reactions and laboratory abnormalities in X-ACT.Table2 Adverse Reactions (>= 10%) in Patients Who Received Capecitabine for Adjuvant Treatment of Colon Cancer in X-ACTAdverse ReactionCapecitabine (N=995)Fluorouracil Leucovorin (N=974)All Grades (%)Grade or (%)All Grades (%)Grade3 or (%)Skin and Subcutaneous TissuePalmar-plantar erythrodysesthesia syndrome60179<1GastrointestinalDiarrhea47126514Nausea342472Stomatitis2226014Vomiting152212Abdominal Pain143162General Fatigue16<1161Asthenia10<1101Lethargy10<19<1Clinically relevant adverse reactions in <10% of patients are presented below:Eye: conjunctivitis Gastrointestinal: constipation, upper abdominal pain, dyspepsia General: pyrexia Metabolism and Nutrition: anorexia Nervous System: dizziness, dysgeusia, headache Skin Subcutaneous Tissue: rash, alopecia, erythema Table Grade or Laboratory Abnormalities (>1%) in Patients Who Received Capecitabine as SingleAgent for Adjuvant Treatment of Colon Cancer in X- ACTLaboratory AbnormalityCapecitabine (n=995) Grade or %Fluorouracil Leucovorin (n=974) Grade or %Bilirubin increased206Lymphocytes decreased1313Neutrophils/granulocytes decreased2.426Calcium decreased2.32.2Neutrophils decreased2.226ALT increased 1.60.6Calcium increased1.10.7Hemoglobin decreased11.2Platelets decreased 10.7In Combination with Oxaliplatin-Containing RegimensThe safety of capecitabine 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 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 as single agent, with the exception of an increased incidence of neurosensory toxicity. Perioperative Treatment of Rectal CancerThe safety of capecitabine for the perioperative treatment of adults with locally advanced rectal cancer as component of chemoradiotherapy was derived from published literature [seeClinical Studies 14.1)] The safety of capecitabine for the perioperative treatment of adults with locally advanced rectal cancer as component of chemoradiotherapy was similar to those in patients treated with capecitabine as single agent, with the exception of an increased incidence of diarrhea. Metastatic Colorectal Cance Single AgentThe safety of capecitabine as single agent was evaluated in pooled metastatic colorectal cancer population (Study SO14695 and Study SO14796) [see Clinical Studies 14.1)] Patients received capecitabine 1,250 mg/m orally twice day for the first 14 days of 21-day cycle (N=596) or leucovorin 20 mg/m intravenously followed by fluorouracil 425 mg/m as an intravenous bolus on days to of each 28-day cycle (N=593). Among the patients who received capecitabine, the median duration of treatment was 4.6 months.Deaths due to all causes occurred in 8% of patients who received capecitabine on study or within 28 days ofreceiving study drug. Permanent discontinuation due to an adverse reaction or intercurrent illness occurred in13% of patients who received capecitabine.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 in Pooled Metastatic Colorectal Cancer Population (Study SO14695 and Study SO14796)- Not observedIncludes weaknessNA Not ApplicableClinically relevant adverse reactions in <10% of patients are presented below:Eye: abnormal vision Gastrointestinal: upper gastrointestinal tract inflammatory disorders, gastrointestinal hemorrhage, ileus General: chest pain Infections: viral Metabolism and Nutrition: dehydration Musculoskeletal: arthralgia Nervous System: dizziness (excluding vertigo), insomnia, taste disturbance Psychiatric: mood alteration, depression Respiratory, Thoracic, and Mediastinal: cough, pharyngeal disorder Skin and Subcutaneous Tissue: skin discoloration, alopecia Vascular: venous thrombosis In Combination with OxaliplatinThe safety of capecitabine 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 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 as single agent, with the exception of an increased incidence of peripheral neuropathy. Metastatic Breast CancerIn Combination with DocetaxelThe safety of capecitabine in combination with docetaxel was evaluated in patients with metastatic breast cancer in Study SO14999 [see Clinical Studies 14.2)]. Patients received capecitabine 1,250 mg/m orally twice daily for the first 14 days of 21-day cycle with docetaxel 75 mg/m as 1- hour intravenous infusion on day of each 21-day cycle for at least weeks or docetaxel 100 mg/m as 1-hour intravenous infusion on day of each 21-day cycle for at least weeks. Among patients who received capecitabine, the mean duration of treatment was 4.2 months. Permanent discontinuation due to an adverse reaction occurred in 26% of patients who received capecitabine.Dosage interruptions due to an adverse reaction occurred in 79% of patients who received capecitabine 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 with Docetaxel for Metastatic Breast Cancer in Study SO14999Adverse ReactionCapecitabine with Docetaxel(N=251)Docetaxel(N=255)All Grades (%)Grade (%)Grade (%)All Grades (%)Grade (%)Grade (%)GastrointestinalDiarrhea6714<1485<1Stomatitis6717<1435-Nausea457-362-Vomiting3541242-Abdominal pain303<1242-Constipation202-18--Dyspepsia14--81-Skin and Subcutaneous TissuePalmar-plantarerythrodysesthesiasyndrome6324NA81NAAlopecia416-427-Nail disorder142-15--CardiacEdema33<2-34<31GeneralPyrexia282-342-Asthenia264<1256-Fatigue224-276-Weakness162-112-Pain in Limb13<1-132-Blood and Lymphatic SystemNeutropenic fever1631321516Nervous SystemTaste disturbance16<1-14<1-Headache153-152-Paresthesia12<1-161-Dizziness12--8<1-Musculoskeletal and Connective TissueArthralgia152-243-Myalgia152-252-Back Pain12<1-113-Respiratory, Thoracic and MediastinalDyspnea142<1162-Cough131-22<1-Sore Throat122-11<1-Metabolism and NutritionAnorexia13<1-11<1-Appetite decreased10--5--Dehydration102-7<1<1EyeLacrimation increased12--7<1-- Not observedNA Not ApplicableClinically relevant adverse reactions in <10% of patients are presented below:Blood and Lymphatic System: agranulocytosis, prothrombin decreased Cardiac: supraventricular tachycardia Eye: conjunctivitis, eye irritation Gastrointestinal: ileus, necrotizing enterocolitis, esophageal ulcer, hemorrhagic diarrhea, dry mouth General: chest pain (non-cardiac), lethargy, pain, influenza-like illness Hepatobiliary: jaundice, abnormal liver function tests, hepatic failure, hepatic coma, hepatotoxicity Immune System: hypersensitivity Infection: hypoesthesia, neutropenic sepsis, sepsis, bronchopneumonia, oral candidiasis, urinary tract infection Metabolism and Nutrition: weight decreased Musculoskeletal and Connective Tissue: bone pain Nervous System: insomnia, peripheral neuropathy, ataxia, syncope, taste loss, polyneuropathy, migraine Psychiatric: depression Renal and Urinary: renal failure Respiratory, Thoracic and Mediastinal: upper respiratory tract infection, pleural effusion, epistaxis, rhinorrhea Skin and Subcutaneous Tissue: pruritis, rash erythematous, dermatitis, nail discoloration, onycholysis Vascular: lymphedema, hypotension, venous phlebitis and thrombophlebitis, postural hypotension, flushing Table summarizes the laboratory abnormalities in this trial.Table Laboratory Abnormalities (>=20%) in Patients Who Received Capecitabine with Docetaxel forMetastatic Breast Cancer in Study SO14999Laboratory AbnormalityCapecitabine with Docetaxel(N=251)Docetaxel(N=255)All Grades(%)Grade 3(%)Grade 4(%)All Grades(%)Grade 3(%)Grade 4(%)HematologicLymphocytopenia994841984440Leukopenia913724884233Neutropenia862049871066Anemia8073835<1Thrombocytopenia41212312HepatobiliaryHyperbilirubinemia2072622Single AgentThe safety of capecitabine as single agent was evaluated in patients with metastatic breast cancer in StudySO14697 [see Clinical Studies (14.2)]. Patients received capecitabine 1,250 mg/m 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 for Metastatic Breast Cancerin Study SO14697Adverse ReactionCapecitabine(n=162)All Grades (%)Grade3 (%)Grade4 (%)Blood and Lymphatic SystemLymphopenia944415Anemia7231Neutropenia2622Thrombocytopenia2431GastrointestinalDiarrhea57123Nausea534-Vomiting374-Stomatitis247-Abdominal pain204-Constipation151-Skin and Subcutaneous TissueHand-and-foot syndrome5711NADermatitis371-GeneralFatigue418-Pyrexia121-Metabolism and NutritionAnorexia233-HepatobiliaryHyperbilirubinemia2292Nervous SystemParesthesia211-EyeEye irritation15--- Not observedNA Not ApplicablePooled Safety PopulationClinically relevant adverse reactions in <10% of patients who received capecitabine as single agent are presented below.Blood Lymphatic System: leukopenia, coagulation disorder, bone marrow depression, pancytopenia Cardiac: tachycardia, bradycardia, atrial fibrillation, myocarditis, edema Ear: vertigo Eye: conjunctivitis Gastrointestinal: abdominal distension, dysphagia, proctalgia, gastric ulcer, ileus, gastroenteritis, dyspepsia General: chest pain, influenza-like illness, hot flushes, pain, thirst, fibrosis, hemorrhage, edema, pain in limb Hepatobiliary: hepatic fibrosis, hepatitis, cholestatic hepatitis, abnormal liver function tests Immune System: drug hypersensitivity Infections: bronchitis, pneumonia, keratoconjunctivitis, sepsis, fungal infections Metabolism and Nutrition: cachexia, hypertriglyceridemia, hypokalemia, hypomagnesemia, dehydration Musculoskeletal and Connective Tissue: myalgia, arthritis, muscle weakness Nervous System: insomnia, ataxia, tremor, dysphasia, encephalopathy, dysarthria, impaired balance, headache, dizzinessPsychiatric: depression, confusion Renal and Urinary: renal impairment Respiratory, Mediastinal and Thoracic: cough, epistaxis, respiratory distress, dyspnea Skin and Subcutaneous Tissue: nail disorder, sweating increased, photosensitivity reaction, skin ulceration, pruritus, radiation recall syndromeVascular: hypotension, hypertension, lymphedema, pulmonary embolism Unresectable or Metastatic Gastric, Esophageal, or Gastroesophageal Junction CancerThe safety of capecitabine 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 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. The safety of capecitabine 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 for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma was consistent with the known safety profile of capecitabine. Pancreatic CancerThe safety of capecitabine for the adjuvant treatment of adults with pancreatic adenocarcinoma as componentof combination chemotherapy regimen was derived from the published literature [see Clinical Studies 14.4)]. The safety of capecitabine for the adjuvant treatment of adults with pancreatic adenocarcinoma as componentof combination chemotherapy regimen was consistent with the known safety profile of capecitabine.. Table . 6.2Postmarketing Experience The following adverse reactions have been identified during post-approval use of capecitabine. 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 keratitis Hepatobiliary: hepatic failure Immune System Disorders: angioedema Nervous System: toxic leukoencephalopathy Renal Urinary: acute renal failure secondary to dehydration including fatal outcome Skin 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.

BOXED WARNING SECTION.

Clinically significant increases in prothrombin time (PT) and international normalized ratio (INR) have been reported in patients who were on stable doses of vitamin antagonist at the time capecitabine was introduced. These events occurred within several days and up to several months after initiating capecitabine and, in few cases, within month after stopping capecitabine. 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 (7.2)]. WARNING: INCREASED RISK OF BLEEDING WITH CONCOMITANT USE OF VITAMIN ANTAGONISTSSee full prescribing information for complete boxed warning.Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking capecitabine concomitantly with oral vitamin antagonists. (5.1, 7.2)Monitor international normalized ratio (INR) more frequently and adjust the dose of the vitamin antagonist as appropriate. (7.2).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Adequate studies investigating the carcinogenic potential of capecitabine have not been conducted. Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). Capecitabine was clastogenic in vitro to human peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow (micronucleus test). Fluorouracil causes mutations in bacteria and yeast. Fluorouracil also causes chromosomal abnormalities in the mouse micronucleus test in vivo. In studies of fertility and general reproductive performance in female mice, oral capecitabine doses of 760 mg/kg/day (about 2300 mg/m 2/day) disturbed estrus and consequently caused decrease in fertility. In mice that became pregnant, no fetuses survived this dose. The disturbance in estrus was reversible. In males, this dose caused degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids. In separate pharmacokinetic studies, this dose in mice produced 5-DFUR AUC values about 0.7 times the corresponding values in patients administered the recommended daily dose.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1Mechanism 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, 5-10-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/m 2/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 max and AUC of fluorouracil was greater than 85%. AbsorptionFollowing oral administration of capecitabine 1,255 mg/m orally twice daily (the recommended dosage when used as single agent), the median max 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 max and AUC to INF of capecitabine was decreased by 60% and 34%, respectively. The mean max and AUC to INF of fluorouracil were also decreased by 37 and 12%, respectively. The max 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 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, 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 825 mg/m orally twice daily for 14 days (0.66 times the recommended dosage), the max and AUC of capecitabine decreased by 36% and 24%, respectively in Japanese patients (n=18) compared to White patients (n=22). The max and AUC of FBAL decreased by approximately 25% and 34%, respectively in Japanese patients compared to White patients; however, the clinical significance of these differences is unknown. No clinically significant differences in the pharmacokinetics of 5-DFCR, 5-DFUR or fluorouracil were observed.Patients with Renal ImpairmentTable Effect of Renal Impairment on the Pharmacokinetics of Capecitabine, 5-DFUR, and FBALRenal Impairment Changes in AUC Capecitabine5-DFUR FBAL 5-FUCLcr 30 to 50mL/minIncreased by 25%Increased by 42%Increased by 85%No relevant changeCLcr <30 mL/minIncreased by 25%Increased by 71%Increased by 258%Increased by 24%a Compared to patients with CLcr >80 mL/min Following administration ofcapecitabine 1,250 mg/m2 orally twice daily; day observations Capecitabine metabolite CLcr= Creatine Clearance, AUC= Area under the plasma concentration-time curvePatients with Hepatic ImpairmentAUC to INF and max 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 StudiesEffect of Capecitabine on Warfarin: In four patients with cancer, chronic administration of capecitabine 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 (capecitabine1,000 mg/m2 twice daily for 14 days) increased celecoxib (sensitive CYP2C9 substrate) AUC by 28%, max by24% and trough by 30%. Effect of Antacids on Capecitabine: When an aluminum hydroxide- and magnesium hydroxide- containing antacid was administered immediately after capecitabine dose of 1,250 mg/m2 in patients with cancer, AUC and max increased by 16% and 35%, respectively, for capecitabine and by 18% and 22%, respectively, for 5-DFCR. No effect was observed on the other three major metabolites (5-DFUR, fluorouracil, FBAL) of capecitabine. Effect of Allopurinol on Capecitabine: Concomitant use with allopurinol may decrease conversion of capecitabine to the active metabolites, FdUMP and FUTP. Effect of Capecitabine on Docetaxel and Effect of Docetaxel on Capecitabine: capecitabine had no effect on the pharmacokinetics of docetaxel (C max and AUC) and docetaxel has no effect on the pharmacokinetics of capecitabine and the fluorouracil precursor 5-DFUR. In Vitro 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 no function DPYD variants) 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 due to increased systemic exposure to capecitabine. 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. Four DPYD variants have been associated with impaired DPD activity in White populations, especially when present as homozygous or compound heterozygous variants: c.1905+1G>A DPYD 2A), c.1679T>G DPYD13), c.2846A>T, and c.1129-5923C>G (Haplotype B3). DPYD2A and DPYD13 are no function variants, and c.2846A>T and c.1129-5923C>G are decreased function variants. The decreased function DPYD variant c.557A>G is observed in individuals of African ancestry. This is not complete listing of all DPYD variants that may result in DPD deficiency [see Warnings and Precautions 5.2)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Colorectal Cancer. Adjuvant Treatment of Colon CancerSingle AgentThe efficacy of capecitabine 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 >1.5x10 9/L, platelets >100x10 9/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=1987) were randomized to capecitabine 1,250 mg/m orally twice daily for the first 14 days of 21-day cycle for total of cycles or fluorouracil 425 mg/m and leucovorin 20 mg/m intravenously on days to of each 28-day cycle for total of cycles. The capecitabine 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-ACTCapecitabine (n=1004)Fluorouracil Leucovorin (n=983)Age (median, years)6263Range(25 to 80)(22 to 82)Sex Male (%)5454 Female (%)4646ECOG performance Status (%)8585 (%)1515Staging Primary Tumor PT1 (%)10.6 PT2 (%)99 PT3 (%)7676 PT4 (%)1414 Other (%)0.10Staging Lymph Node pN1 (%)6971 pN2 (%)3029 Other (n, %)0.40.1Efficacy 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 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 compared to fluorouracil leucovorin with respect to overall survival was 0.86 (95% CI0.74, 1.01). The 5- year overall survival rates were 71% for capecitabine and 68% for fluorouracil leucovorin.Table 10 Efficacy Results in X-ACTa (All Randomized Population)Efficacy ParametersCapecitabine(N=1004)Fluorouracil Leucovorin(N=983)5-year Disease-free Survival Rate 59%55%Hazard Ratio0.88(95% CI)(0.77, 1.01)p-value p 0.068a Approximately 93.4% had 5-year DFS information Based on Kaplan-Meier estimates 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 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 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 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 metastaticcolorectal cancer. Patients were randomized to capecitabine 1,250 mg/m twice daily for first 14 days of 21-day cycle or leucovorin 20 mg/m intravenously followed by fluorouracil 425 mg/m 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 SO14796Study SO14695Study SO14796Capecitabine (N=302)Fluorouracil Leucovorin(N=303)Capecitabine (N=301)Fluorouracil Leucovorin(N=301)Age (median, years)64636464Range(23 to 86)(24 to 87)(29 to 84)(36 to 86)SexMale, %60655757Female, %40354343Karnofsky PS(median)90909090Range(70 to 100)(70 to 100)(70 to 100)(70 to 100)Colon, %74776665Rectum, %26233435Prior radiation therapy, %17211414Prior adjuvant fluorouracil, %28361914Efficacy 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(N=302)Fluorouracil+ Leucovorin(N=303)Overall Response Rate% (95% CI)21 (16, 26)11 (8, 15)p-value 0.0014Time to ProgressionMedian, months (95% CI)4.2 (3.9, 4.5)4.3 (3.4, 5.0)Hazard Ratio0.9995% CI(0.84, 1.17)Overall SurvivalMedian, months (95% CI)12.5 (10.5, 14.3)13.4 (12.0, 14.7)Hazard Ratio1.0095% CI(0.84, 1.18)Table 13 Efficacy Results for First-Line Treatment of Metastatic Colorectal Cancer (Study SO14796)Capecitabine(N=301)Fluorouracil+ Leucovorin(N=301)Overall Response Rate% (95% CI)21 (16, 26)14 (10, 18)p-value0.027Time to ProgressionMedian, months (95% CI)4.5 (4.2, 5.5)4.3 (3.4, 5.1)Hazard Ratio0.9795% CI(0.82, 1.14)Overall SurvivalMedian, months (95% CI)13.3 (12.1, 14.8)12.1 (11.1,14.1)Hazard Ratio0.9295% 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. 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, 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 difference.Figure Kaplan-Meier Curve for Overall Survival of Pooled Data (Studies SO14695 and SO14796) In Combination with OxaliplatinThe efficacy of capecitabine 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.. Figure 1. Figure . Figure . 14.2Metastatic Breast Cancer. In Combination With DocetaxelThe efficacy of capecitabine 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 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 +Docetaxel (N=255)Docetaxel (N=256)Age (median, years)5251Karnofsky Performance Status (median)9090Site of DiseaseLymph nodes, %4749Liver, %4548Bone, %4246Lung, %3739Skin, %2929Prior ChemotherapyAnthracycline1,%100100Fluorouracil,%7774Paclitaxel, %109Resistance to an AnthracyclineNo resistance, %77Progression on anthracycline therapy, %2629Stable disease after cycles of anthracycline therapy, %1616Relapsed within years of completion ofanthracycline- adjuvant therapy, %3129Experienced brief response to anthracycline therapy, with subsequent progression while on therapy or within12 months after last dose, %2020No. of Prior Chemotherapy Regimens for Treatment of Metastatic Disease0, %35311, %48532, %17153, %011Includes 10 patients in combination and 18 patients in single agent arms treated with an anthracenedione Efficacy results are shown in Table 15, Figure and Figure 5.Table 15 Efficacy Results in Metastatic Breast Cancer (Study SO14999)Efficacy ParameterCapecitabine Docetaxel(N=255)Docetaxel(N=256)Timeto Disease ProgressionMedian, months6.14.295% CI(5.4, 6.5)(3.5, 4.5)Hazard Ratio0.643p-value0.0001Overall SurvivalMedian, months14.511.695% CI(12.3, 16.3)(9.8, 12.7)Hazard Ratio0.775p-value0.0126Response Rate132%22%1The 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 (StudySO14999)Figure Kaplan-Meier Estimates of Survival in Metastatic Breast Cancer (Study SO14999)Single AgentThe efficacy of capecitabine 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/m 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 1,255 mg/m 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 WithMeasurable Disease (N=135)All Patients (N=162)Age (median, years)5556Karnofsky Performance Status9090No. Disease Sites1 to 2, %32373 to 4, %4643>5, %2221Dominant Site of DiseaseVisceral 1, 7568Soft Tissue, %2222Bone, %310Prior ChemotherapyPaclitaxel, %100100Anthracycline2,%9091Fluorouracil,%8182Resistance to Paclitaxel, %7677Resistance to an Anthracycline 2, 4141Resistance to both Paclitaxel and anAnthracycline 2, 32311Lung, pleura, liver, peritoneum 2Includes patients treated with an anthracenedione Efficacy for Study SO14697 are shown in Table 17.Table 17 Efficacy Results in Metastatic Breast Cancer (Study SO14697)Efficacy ParameterResistance to Both Paclitaxel andanAnthracycline(N=43)Response Rate (95% CI)25.6%(13.5, 41.2)Complete Response0%Partial Response 11%Durationof Response Median, months (Range)5.1 (2.1-7.7)1 Includes patients treated with an anthracenedione From date of first response For 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.. Figure . Figure . 14.3 Gastric, Esophageal, or Gastroesophageal Junction Cancer The efficacy of capecitabine 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 was 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 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 was evaluated in the ToGA trial [NCT01041404], an open-label, multicenter, randomized trial where the primary efficacy measure was overall survival.. 14.4 Pancreatic Cancer The efficacy of capecitabine for the adjuvant treatment of adults with pancreatic adenocarcinoma as component of combination chemotherapy regimen was derived from study in the published literature.Capecitabine was evaluated in ESPAC-4 trial, two-group, open-label, multicenter, randomized trial, where the major efficacy outcome measure was overall survival.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Capecitabine is contraindicated in patients with history of severe hypersensitivity reaction to fluorouracil orcapecitabine [see Adverse Reactions 6.1)] . History of severe hypersensitivity reactions to fluorouracil or capecitabine 4) History of severe hypersensitivity reactions to fluorouracil or capecitabine 4).

DESCRIPTION SECTION.

11 DESCRIPTION. Capecitabine is nucleoside metabolic inhibitor. The chemical name is 5-deoxy-5-fluoro-N- [(pentyloxy) carbonyl]-cytidine and has molecular formula of 15H 22FN 3O and molecular weight of 359.35. Capecitabine has the following structural formula: Capecitabine is white to off-white crystalline powder with an aqueous solubility of 26 mg/mL at 20C.Capecitabine tablets, USP are supplied as biconvex, oblong film-coated tablets for oral administration. Each light peach-colored tablet contains 150 mg capecitabine and each peach-colored tablet contains 500 mg capecitabine. The inactive ingredients in capecitabine tablets include: anhydrous lactose, croscarmellose sodium, hypromellose, microcrystalline cellulose and magnesium stearate. The peach or light peach film coating contains hypromellose, purified talc, titanium dioxide and ferric oxide red and ferric oxide yellow.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Adjuvant Treatment of Colon Cancer Single agent: 1,250 mg/m 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/m orally twice daily for the first 14 days of each 21-day cycle for maximum of cycles in combination with oxaliplatin 130 mg/m administered intravenously on day of each cycle. 2.1) Perioperative Treatment of Rectal Cancer With Concomitant Radiation Therapy: 825 mg/m orally twice daily 2.1) Without Radiation Therapy: 1,250 mg/m orally twice daily 2.1) Unresectable or Metastatic Colorectal Cancer: Single agent: 1,250 mg/m twice daily orally for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity. 2.1) In Combination with Oxaliplatin: 1,000 mg/m orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with oxaliplatin 130 mg/m administered intravenously on day of each cycle. 2.1) Advanced or Metastatic Breast Cancer: Single agent: 1,000 mg/m or 1,250 mg/m2 twice daily orally for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity. 2.2) In combination with docetaxel: 1,000 mg/m 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/m administered intravenously on day of each cycle 2.2) Unresectable or Metastatic Gastric, Esophageal, or Gastroesophageal Junction Cancer 625 mg/m orally twice daily on days to 21 of each 21-day cycle for maximum of cycles in combination with platinum-containing chemotherapy. 2.3) OR 850 mg/m or 1,000 mg/m orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with oxaliplatin 130 mg/m administered intravenously on day of each cycle. 2.3) HER2-overexpressing metastatic adenocarcinoma of the gastroesophageal junction or stomach 1,000 mg/m orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with cisplatin and trastuzumab. 2.3) Pancreatic cancer 830 mg/m orally twice daily for the first 21 days of each 28-day cycle for maximum of cycles in combination with gemcitabine 1,000 mg/m administered intravenously on days 1, 8, and 15 of each cycle. 2.4) Refer to Sections 2.5 and 2.6 for information related to dosage modifications for adverse reactions and renal impairment 2.5 and 2.6). 2.1 Recommended Dosage for Colorectal Cancer. Adjuvant Treatment of Colon CancerSingle AgentThe recommended dosage of capecitabine tablets are 1,250 mg/m2 orally twice daily for the first 14 days of each21-day cycle for maximum of cycles.In Combination with Oxaliplatin-Containing RegimensThe recommended dosage of capecitabine tablets are 1,000 mg/m2 orally twice daily for the first 14 days of each21-day cycle for maximum of cycles in combination with oxaliplatin 130 mg/m2 administered intravenously onday of each cycle.Refer to the oxaliplatin prescribing information for additional dosing information as appropriate.Perioperative Treatment of Rectal CancerThe recommended dosage of capecitabine is 825 mg/m2 orally twice daily when administered with concomitantradiation therapy and 1,250 mg/m2 orally twice daily when administered without radiation therapy as part of aperi-operative combination regimen.Unresectable or Metastatic Colorectal CancerSingle AgentThe recommended dosage of capecitabine tablets are 1,250 mg/m2 orally twice daily for the first 14 days of a21-day cycle until disease progression or unacceptable toxicity.In Combination with OxaliplatinThe recommended dosage of capecitabine tablets are 1,000 mg/m2 orally twice daily for the first 14 days of each21-day cycle until disease progression or unacceptable toxicity in combination with oxaliplatin 130 mg/m2administered intravenously on day of each cycle.Refer to the Prescribing Information for oxaliplatin for additional dosing information as appropriate. 2.2Recommended Dosage for Breast Cancer. Advanced or Metastatic Breast CancerSingle AgentThe recommended dosage of capecitabine tablets are 1,000 mg/m or 1,250 mg/m orally twice daily for the first 14 days of 21-day cycle until disease progression or unacceptable toxicity. Individualize the dose and dosingschedule of capecitabine tablets based on patient risk factors and adverse reactions.In Combination with DocetaxelThe recommended dosage of capecitabine tablets are 1,000 mg/m or 1,250 mg/m orally twice daily for the first 14 days of 21-day cycle until disease progression or unacceptable toxicity in combination with docetaxel 75mg/m administered intravenously on day of each cycle. Refer to the Prescribing Information for docetaxel for additional dosing information as appropriate. 2.3Recommended Dosage for Gastric, Esophageal, or Gastroesophageal Junction Cancer. The recommended dosage of capecitabine tablets for unresectable or metastatic gastric, esophageal, orgastroesophageal junction cancer is: 625 mg/m orally twice daily on days to 21 of each 21-day cycle for maximum of cycles in combination with platinum-containing chemotherapy. OR 850 mg/m2 or 1,000 mg/m orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with oxaliplatin 130 mg/m 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/m orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with cisplatin and trastuzumab. Refer to the Prescribing Information for agents used in combination for additional dosing information as appropriate. 2.4Recommended Dosage for Pancreatic Cancer. The recommended dosage of capecitabine tablets are 830 mg/m2 orally twice daily for the first 21 days of each28-day cycle until disease progression, unacceptable toxicity, or for maximum cycles in combination withgemcitabine 1,000 mg/m administered intravenously on days 1, 8, and 15 of each cycle. Refer to Prescribing Information for gemcitabine for additional dosing information as appropriate.. 2.5 Dosage Modifications for Adverse Reactions Monitor patients for adverse reactions and modify dosages of capecitabine tablets as described in Table 1. Do notreplace missed doses of capecitabine tablets; instead resume capecitabine tablets with the next planned dosage.When capecitabine tablets is administered with docetaxel, withhold capecitabine tablets and docetaxel until therequirements for resuming both capecitabine tablets and docetaxel are met. Refer to the Prescribing Informationfor docetaxel for additional dosing information as appropriate.Table Recommended Dose Modifications of Adverse Reactions SeverityDosage Modification Resume at Same orReduced Dose(Percent of Current Dose)Grade 21st appearanceWithhold until resolved to grade to 1.100%2nd appearance75%3rd appearance50%4th appearancePermanently discontinue.-Grade 31st appearanceWithhold until resolved to grade to 1.75%2nd appearance50%3rd appearancePermanently discontinue.-Grade 41st appearancePermanently 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 thanthree times the upper limit of normal), using the percent of current dose as shown in column of Table [see Warnings and Precautions 5.10)]. 2.6 Dosage Modification For Renal Impairment Reduce the dose of capecitabine tablets by 25% for patients with creatinine clearance (CLcr) of 30 to 50 mL/minas determined by Cockcroft-Gault equation. dosage has not been established in patients with severe renalimpairment (CLcr <30 mL/min) [see Use in Specific Populations 8.6)] . 2.7 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 crushcapecitabine 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 misseddose and continue with the next scheduled dose.Capecitabine tablets is hazardous drug. Follow applicable special handling and disposal procedures.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Capecitabine tablets, USP film-coated: 150 mg: biconvex, oblong shaped, light peach colored, debossed with 150 on one side and plain on other side. 500 mg: biconvex, oblong shaped, peach colored, debossed with 500 on one side and plain on other side.. Tablets: 150 mg and 500 mg 3) Tablets: 150 mg and 500 mg 3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Allopurinol: Avoid concomitant use of allopurinol with capecitabine. 7.1) Leucovorin: Closely monitor for toxicities when capecitabine is coadministered with leucovorin. 7.1) CYP2C9 substrates: Closely monitor for adverse reactions when CYP2C9 substrates are coadministered with capecitabine. 7.2) Vitamin antagonists: Monitor INR more frequently and dose adjust oral vitamin antagonist as appropriate Phenytoin: Closely monitor phenytoin levels in patients taking capecitabine concomitantly with phenytoin and adjust the phenytoin dose as appropriate. 7.2) Nephrotoxic drugs: Closely monitor for signs of renal toxicity when capecitabine is used concomitantly with nephrotoxic drugs. 7.3) 7.1 Effect of Other Drugs on Capecitabine. 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. 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.. 7.2Effect of Capecitabine on Other Drugs CYP2C9 SubstratesCapecitabine increased exposure of CYP2C9 substrates [see Clinical Pharmacology 12.3)], which may increase the risk of adverse reactions related to these substrates. Closely monitor for adverse reactions of CYP2C9 substrates where minimal concentration changes may lead to serious adverse reactions when used concomitantly with capecitabine (e.g., anticoagulants, antidiabetic drugs). Vitamin AntagonistsCapecitabine 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. Monitor INR more frequently and refer to the prescribing information of oral vitamin antagonist for dosage adjustment, as appropriate, when capecitabine is used concomitantly with vitamin antagonist.PhenytoinCapecitabine may increases exposure of phenytoin, which may increase the risk of adverse reactions related to phenytoin. Closely monitor phenytoin levels and refer to the prescribing information of phenytoin for dosage adjustment, as appropriate, when capecitabine is used concomitantly with phenytoin. 7.3 Nephrotoxic Drugs Due of the additive pharmacologic effect, concomitant use of capecitabine with other drugs known to cause renal toxicity may increase the risk of renal toxicity [see Warnings and Precautions 5.6)]. Closely monitor for signs of renal toxicity when capecitabine is used concomitantly with nephrotoxic drugs (e.g. platinum salts, irinotecan, methotrexate, intravenous bisphosphonates).

GERIATRIC USE SECTION.

5.10Hyperbilirubinemia. Hyperbilirubinemia can occur with capecitabine. In the 875 patients with metastatic breast or colorectal cancer who received capecitabine 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 increasedalkaline 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 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. 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 with docetaxel, grade hyperbilirubinemia occurred in 7% and grade hyperbilirubinemia occurred in 2%. Withhold capecitabine 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)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Capecitabine tablets, USP 150 mg and 500 mg are supplied as follows: NDC 68001-487-06: 150 mg: biconvex, oblong shaped, light peach colored, film coated tablets, debossed with 150 on one side and plain on other side; available in bottles of 60 with child-resistant closure. NDC 68001-488-07: 500 mg: biconvex, oblong shaped, peach colored, film coated tablets, debossed with 500 on one side and plain on other side; available in bottles of 120 with child-resistant closure.Storage and HandlingStore at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature]. KEEP TIGHTLY CLOSED. Capecitabine is hazardous drug. Follow applicable special handling and disposal procedures.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Capecitabine is nucleoside metabolic inhibitor indicated for:Colorectal Cancer 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) Breast Cancer 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) 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) 1.1 Colorectal Cancer. Capecitabine tablets, USP 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. Capecitabine tablets, USP are indicated for the: 1.2 Breast Cancer. Capecitabine tablets USP 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.. Capecitabine tablets USP are indicated for the: . 1.3 Gastric, Esophageal, or Gastroesophageal Junction Cancer Capecitabine tablets USP are indicated for the: treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junctioncancer as component of combination chemotherapy regimen. treatment of adults with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinomawho have not received prior treatment for metastatic disease as component of combination regimen.. 1.4 Pancreatic Cancer Capecitabine tablets USP are indicated for the adjuvant treatment of adults with pancreatic adenocarcinoma asa component of combination chemotherapy regimen.

MECHANISM OF ACTION SECTION.

12.1Mechanism 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, 5-10-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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Adequate studies investigating the carcinogenic potential of capecitabine have not been conducted. Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). Capecitabine was clastogenic in vitro to human peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow (micronucleus test). Fluorouracil causes mutations in bacteria and yeast. Fluorouracil also causes chromosomal abnormalities in the mouse micronucleus test in vivo. In studies of fertility and general reproductive performance in female mice, oral capecitabine doses of 760 mg/kg/day (about 2300 mg/m 2/day) disturbed estrus and consequently caused decrease in fertility. In mice that became pregnant, no fetuses survived this dose. The disturbance in estrus was reversible. In males, this dose caused degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids. In separate pharmacokinetic studies, this dose in mice produced 5-DFUR AUC values about 0.7 times the corresponding values in patients administered the recommended daily dose.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Administer uridine triacetate within 96 hours for management of capecitabine overdose.Although no clinical experience using dialysis as treatment for capecitabine overdose has been reported, dialysis may be of benefit in reducing circulating concentrations of 5-DFUR, low- molecular-weight metabolite of the parent compound.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. 150 mg 60 tablets500 mg 120 tablets. Capecitabine Tablets 150mg 60s Bottle Label. Capecitabine Tablets 150mg Pharmez. Capecitabine Tablets 500mg 120s Bottle Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of capecitabine 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 5580 cGy in 180 cGy fractions). The relative bioavailability of the investigational formulation to capecitabine 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%).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The AUC of capecitabine and its metabolite 5-DFCR increases proportionally over dosage range of 500 mg/m 2/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 max and AUC of fluorouracil was greater than 85%. AbsorptionFollowing oral administration of capecitabine 1,255 mg/m orally twice daily (the recommended dosage when used as single agent), the median max 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 max and AUC to INF of capecitabine was decreased by 60% and 34%, respectively. The mean max and AUC to INF of fluorouracil were also decreased by 37 and 12%, respectively. The max 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 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, 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 825 mg/m orally twice daily for 14 days (0.66 times the recommended dosage), the max and AUC of capecitabine decreased by 36% and 24%, respectively in Japanese patients (n=18) compared to White patients (n=22). The max and AUC of FBAL decreased by approximately 25% and 34%, respectively in Japanese patients compared to White patients; however, the clinical significance of these differences is unknown. No clinically significant differences in the pharmacokinetics of 5-DFCR, 5-DFUR or fluorouracil were observed.Patients with Renal ImpairmentTable Effect of Renal Impairment on the Pharmacokinetics of Capecitabine, 5-DFUR, and FBALRenal Impairment Changes in AUC Capecitabine5-DFUR FBAL 5-FUCLcr 30 to 50mL/minIncreased by 25%Increased by 42%Increased by 85%No relevant changeCLcr <30 mL/minIncreased by 25%Increased by 71%Increased by 258%Increased by 24%a Compared to patients with CLcr >80 mL/min Following administration ofcapecitabine 1,250 mg/m2 orally twice daily; day observations Capecitabine metabolite CLcr= Creatine Clearance, AUC= Area under the plasma concentration-time curvePatients with Hepatic ImpairmentAUC to INF and max 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 StudiesEffect of Capecitabine on Warfarin: In four patients with cancer, chronic administration of capecitabine 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 (capecitabine1,000 mg/m2 twice daily for 14 days) increased celecoxib (sensitive CYP2C9 substrate) AUC by 28%, max by24% and trough by 30%. Effect of Antacids on Capecitabine: When an aluminum hydroxide- and magnesium hydroxide- containing antacid was administered immediately after capecitabine dose of 1,250 mg/m2 in patients with cancer, AUC and max increased by 16% and 35%, respectively, for capecitabine and by 18% and 22%, respectively, for 5-DFCR. No effect was observed on the other three major metabolites (5-DFUR, fluorouracil, FBAL) of capecitabine. Effect of Allopurinol on Capecitabine: Concomitant use with allopurinol may decrease conversion of capecitabine to the active metabolites, FdUMP and FUTP. Effect of Capecitabine on Docetaxel and Effect of Docetaxel on Capecitabine: capecitabine had no effect on the pharmacokinetics of docetaxel (C max and AUC) and docetaxel has no effect on the pharmacokinetics of capecitabine and the fluorouracil precursor 5-DFUR. In Vitro 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.

PREGNANCY SECTION.

5.6Renal Toxicity. Serious renal failure, sometimes fatal, can occur with capecitabine. Renal impairment or coadministration of capecitabine 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. Withhold capecitabine and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence [see Dosage and Administration 2.5)].

RECENT MAJOR CHANGES SECTION.

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

REFERENCES SECTION.

15 REFERENCES. 1. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationCapecitabine Tablets(KAP-e-SYE-ta-been)150 mg and 500 mgWhat is the most important information should know about capecitabine tabletsCapecitabine can cause serious side effects, including: Increased risk of bleeding when taking capecitabine with blood thinner medicines, such as warfarin. Taking Capecitabine with these medicines can cause changes in how fast your blood clots and can cause bleedingthat can lead to death. This can happen as soon as few days after you start taking capecitabine, or later during treatment, and possibly within month after you stop taking capecitabine. This can happen in people whose cancer has spread to the liver (liver metastasis) and in people whose cancer has not spread to the liver. Before taking capecitabine, tell your healthcare provider if you are taking warfarin or another blood thinner medicine. If you take warfarin or another blood thinner that is like warfarin during treatment with capecitabine, your healthcare provider should do blood tests more often, to check how fast your blood clots during and after you stop treatment with capecitabine. Your healthcare provider may change your dose of the blood thinner medicine if needed. Tell your healthcare provider right away if you develop any signs or symptoms of bleeding. See What are the possible side effects of capecitabine for more information about side effects.What are capecitabine tablets Capecitabine tablets are prescription medicine used to treat people with: kind of cancer called colon or rectal (colorectal) cancer. Capecitabine tablets may be used: alone or in combination with other chemotherapy medicines in people with colon cancer that has spread to lymph nodes in the area close to the colon (Stage III colon cancer), to help prevent your cancer from coming back after you have had surgery. adults with rectal cancer, around the time of your surgery, as part of chemotherapy and radiation (chemoradiation) treatment when your rectal cancer has spread to nearby tissues (locally advanced). alone or in combination with other chemotherapy medicines, when your colorectal cancer cannot be removed by surgery or has spread to other areas of your body (metastatic). kind of cancer called breast cancer. Capecitabine tablets may be used in people with breast cancer that is advanced or has spread to other parts of the body (metastatic): alone if you are not able to receive an anthracycline medicine or taxane-containing chemotherapy. in combination with docetaxel when you have received anthracycline containing chemotherapy and it is no longer working. Kinds of cancer called stomach (gastric), esophageal, or gastroesophageal junction (GEJ) cancer. Capecitabine tablets may be used in adults: in combination with other chemotherapy medicines when your cancer of the stomach, esophagus, or GEJ cannot be removed by surgery or has spread to other parts of the body (metastatic). when your cancer of the stomach, esophagus, or GEJ is metastaticadeno carcinoma, and: is HER2-positive, and you have not received treatment with capecitabine in combination with other treatments for your metastatic cancer. kind of cancer called pancreatic cancer. Capecitabine tablets may be used to treat adults in combination with other chemotherapy medicines, to help prevent your pancreatic cancer from coming back after you have had surgery.It is not known if capecitabine tablets are safe and effective in children.Do not take capecitabine tablets if you: have had severe allergic reaction to fluorouracil or capecitabine. See the end of this leaflet for complete list of ingredients in capecitabine tablets.Talk to your healthcare provider before taking capecitabine tablets if you are notsure.Before taking capecitabine tablets, tell your healthcare provider about all your medical conditions, including if you: See What is the most important information should know about capecitabine tablets. have had heart problems.have kidney or liver problems.are pregnant or plan to become pregnant. Capecitabine tablets can harm your unborn baby.Females who are able to become pregnant: Your healthcare provider should do pregnancy test before you start treatment with capecitabine tablets. Use an effective method of birth control (contraception) during treatment and for months after your last dose of capecitabine tablets. Talk to your healthcare provider about birth control choices that may be right for you during treatment with capecitabine tablets. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with capecitabine tablets.Males who have female partners who are able to become pregnant should use effective birth control during treatment and for months after your last dose of capecitabine. are breastfeeding or plan to breastfeed. It is not known if capecitabine passes into your breast milk. Do not breastfeed during treatment with capecitabine and for week after your last dose of capecitabineTell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Capecitabine tablets may affect the way other medicines work, and other medicines may affect the way capecitabine tablets works.How should take capecitabine tablets Take capecitabine tablets exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much capecitabine tablets to take and when to take it. The numberof days that you will take capecitabine tablets during each treatment cycle and the number of days in eachtreatment cycle depends on the type of cancer you are being treated for. Take capecitabine tablets times day at the same time each day, about 12 hours apart. Take capecitabine tablets within 30 minutes after finishing meal. Swallow capecitabine tablets whole with water. Do not chew, cut, or crush capecitabine tablets. See Eye irritation, skin rash and other side effects with exposure to crushed capecitabine tablets in the section called What are the possible side effects of capecitabine tablets If you cannot swallow capecitabine tablets whole, tell your healthcare provider. Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment withcapecitabine tablets if you develop side effects. Do not take products that contain folic acid or folate analog products, for example, leucovorin or levoleucovorin, during treatment with capecitabine tablets, unless your healthcare provider instructs you totake it. If you vomit after taking dose of capecitabine tablets, do not take another dose at that time. Wait and takeyour next dose of capecitabine tablets at your scheduled time. If you miss dose of capecitabine tablets, just skip the dose and then take your next dose at your scheduledtime. If you take too much capecitabine tablets, call your healthcare provider or go to the nearest hospitalemergency room right awayWhat are the possible side effects of capecitabine tablets Capecitabine tablets may cause serious side effects including:See What is the most important information should know about capecitabine tablets. Serious side effects in people with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency. People with certain changes in gene called DPYD may have deficiency of the DPD enzyme. Some of these people may not produce enough DPD enzyme, and some of these people may not produce the DPD enzyme at all. People who do not produce any DPD enzyme are at increased risk of sudden side effects that come onearly during treatment with capecitabine tablets and can be serious, and sometimes lead to death. Call yourhealthcare provider right away if you develop any of the followingsymptoms and they are severe, including: sores of the mouth, tongue, throat and esophagus (mucositis) diarrhea low white blood cell counts nervous system problems. People with some DPD enzyme may have an increased risk of serious side effects with capecitabinetablets treatment that can sometimes lead to death.Your healthcare provider should talk with you about DPYD testing to look for DPD deficiency. Heart problems. Capecitabine tablets can cause heart problems including: heart attack and decreased blood flow to the heart, chest pain, irregular heartbeats, changes in the electrical activity of your heart seen on an electrocardiogram(ECG), problems with your heart muscle, heart failure, and sudden death. You may have an increased risk of heartproblems with capecitabine tablets if you have history of narrowing or blockage of the coronary arteries(coronary artery disease). Stop taking capecitabine tablets and call your healthcare provider right away if you getany of the following symptoms: chest pain dizzinessshortness of breath lightheadedness Diarrhea. Diarrhea is common with capecitabine tablets and can sometimes be severe. Stop taking capecitabine tablets and call your healthcare provider right away if the number of bowel movements you have in day increases by or more bowel movements than what is usual for you, or if you have bowel movements at night. Ask your healthcare provider about what medicines you can take to treat your diarrhea. Stop taking capecitabine tablets if you have severe bloody diarrhea with severe abdominal pain and fever and call you healthcare provider right away. Decreased white blood cells, platelets, and red blood cell counts.Decreased white blood cells, platelets, and red blood cell counts can happen with capecitabine tablets and can sometimes be severe. Your healthcare provider will do blood tests during treatment with capecitabine tablets to check your blood cell counts. If your white blood cell count is very low, you are at increased risk for infection. Call your healthcare provider right away if you develop fever of 100.5F or greater or have other signs and symptoms of infection. Increased level of bilirubin in your blood and liver problems. Increased bilirubin in your blood is common with capecitabine tablets and can also sometimes be severe. Your healthcare provider will check you for these problems during treatment with capecitabine tablets. Tell your healthcare provider right away if you develop yellowing of your skin or the white part of your eyes. Eye irritation, skin rash and other side effects with exposure to crushed capecitabine tablets. If you come into contact with (you are exposed to) crushed capecitabine tablets, you may develop side effects including: eye irritation and swelling feeling like pins and needles in your hands skin rash headache diarrhea stomach irritation nausea and vomiting Do not chew, cut, or crush capecitabine tablets. See How should take capecitabine tablets. If for any reason your tablets must be cut or crushed, this must be done by your pharmacist or healthcare provider.Your healthcare provider may decide to decrease your dose, or temporarily or permanently stop capecitabine tablets if you have serious side effects with capecitabine tablets.The most common side effects in people with colon cancer who take capecitabine tablets alone to help prevent it from coming back include: hand and foot syndrome, diarrhea, and nausea.The most common side effects in people with metastatic colorectal carcinomawho take capecitabine tablets alone include: decreased red blood cell count diarrhea nausea hand and foot syndrome tiredness increased bilirubin level in your blood stomach-area (abdominal) pain The most common side effects in people with metastatic breast cancer who take capecitabine tablets in combination with docetaxel include: diarrhea hair loss mouth sores or mouth inflammation swelling hand and foot syndrome stomach-area (abdominal) pain nausea and vomiting The most common side effects in people with metastatic breast cancer who take capecitabine tablets alone include: Capecitabine tablets may cause fertility problems in females and males. This may affect the ability to have child.Talk to your healthcare provider if you have concerns about fertility.These are not all the possible side effects of capecitabine tablets.Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store capecitabine tablets Store capecitabine tablets at room temperature between 68F to 77F (20C to 25C).Keep capecitabine tablets in tightly closed container.Ask your healthcare provider or pharmacist how to safely throw away any unused capecitabine tablets.Keep capecitabine tablets and all medicines out of the reach of children. General information about the safe and effective use of capecitabine tablets. Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use capecitabine tablets for condition for which it was not prescribed. Do not give capecitabine tablets to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about capecitabine tablets that is written for health professionals.What are the ingredients in capecitabine tabletsActive ingredient: capecitabineInactive ingredients: anhydrous lactose, croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate and purified water. The peach or light peach film coating contains hydroxypropylmethylcellulose, talc, titanium dioxide and synthetic yellow and red iron oxides.For more information, go to www.accordhealthcare.us or call Accord Healthcare at 1-866-941-7875.This Patient Information has been approved by the U.S. Food and Drug Administration.All trade names drug products are the property of their respective owners.For full Taxotere prescribing information, please refer to Taxotere Package Insert.All trade names drug products are the property of their respective owners.Manufactured By: Intas Pharmaceuticals Limited, Ahmedabad 380 054, India. For BluePoint LaboratoriesIssued 03/23. have had heart problems.. have kidney or liver problems.. are pregnant or plan to become pregnant. Capecitabine tablets can harm your unborn baby.. Females who are able to become pregnant: Your healthcare provider should do pregnancy test before you start treatment with capecitabine tablets. Use an effective method of birth control (contraception) during treatment and for months after your last dose of capecitabine tablets. Talk to your healthcare provider about birth control choices that may be right for you during treatment with capecitabine tablets. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with capecitabine tablets.. are breastfeeding or plan to breastfeed. It is not known if capecitabine passes into your breast milk. Do not breastfeed during treatment with capecitabine and for week after your last dose of capecitabine. See What is the most important information should know about capecitabine tablets. Serious side effects in people with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency. People with certain changes in gene called DPYD may have deficiency of the DPD enzyme. Some of these people may not produce enough DPD enzyme, and some of these people may not produce the DPD enzyme at all. any of the following symptoms: chest pain dizzinessshortness of breath lightheadedness Diarrhea. Diarrhea is common with capecitabine tablets and can sometimes be severe. Stop taking capecitabine tablets and call your healthcare provider right away if the number of bowel movements you have in day increases by or more bowel movements than what is usual for you, or if you have bowel movements at night. Ask your healthcare provider about what medicines you can take to treat your diarrhea. Stop taking capecitabine tablets if you have severe bloody diarrhea with severe abdominal pain and fever and call you healthcare provider right away. chest pain dizziness. shortness of breath lightheadedness Diarrhea. Diarrhea is common with capecitabine tablets and can sometimes be severe. Stop taking capecitabine tablets and call your healthcare provider right away if the number of bowel movements you have in day increases by or more bowel movements than what is usual for you, or if you have bowel movements at night. Ask your healthcare provider about what medicines you can take to treat your diarrhea. Stop taking capecitabine tablets if you have severe bloody diarrhea with severe abdominal pain and fever and call you healthcare provider right away. tablets to check your blood cell counts. If your white blood cell count is very low, you are at increased risk for infection. Call your healthcare provider right away if you develop fever of 100.5F or greater or have other signs and symptoms of infection.. eye irritation and swelling feeling like pins and needles in your hands. skin rash headache. diarrhea stomach irritation nausea and vomiting Do not chew, cut, or crush capecitabine tablets. See How should take capecitabine tablets. If for any reason your tablets must be cut or crushed, this must be done by your pharmacist or healthcare provider.. Your healthcare provider may decide to decrease your dose, or temporarily or permanently stop capecitabine tablets if you have serious side effects with capecitabine tablets.. The most common side effects in people with colon cancer who take capecitabine tablets alone to help prevent it from coming back include: hand and foot syndrome, diarrhea, and nausea.. The most common side effects in people with metastatic colorectal carcinoma. who take capecitabine tablets alone include: decreased red blood cell count diarrhea nausea. hand and foot syndrome tiredness. increased bilirubin level in your blood stomach-area (abdominal) pain The most common side effects in people with metastatic breast cancer who take capecitabine tablets in combination with docetaxel include: diarrhea hair loss. mouth sores or mouth inflammation swelling. hand and foot syndrome stomach-area (abdominal) pain nausea and vomiting The most common side effects in people with metastatic breast cancer who take capecitabine tablets alone include: Store capecitabine tablets at room temperature between 68F to 77F (20C to 25C).. Keep capecitabine tablets in tightly closed container.. Ask your healthcare provider or pharmacist how to safely throw away any unused capecitabine tablets.

SPL UNCLASSIFIED SECTION.

1.1 Colorectal Cancer. Capecitabine tablets, USP 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. Capecitabine tablets, USP are indicated for the:.

TERATOGENIC EFFECTS SECTION.

Risk SummaryBased on findings in animal reproduction studies and its mechanism of action [see Clinical Pharmacology 12.1)], capecitabine can cause fetal harm when administered to pregnant woman. Available human data with capecitabine 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.

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) 8.1Pregnancy. Risk SummaryBased on findings in animal reproduction studies and its mechanism of action [see Clinical Pharmacology 12.1)], capecitabine can cause fetal harm when administered to pregnant woman. Available human data with capecitabine 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 breast-fed infant. 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 and for weeks after the final 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 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.ContraceptionFemalesAdvise females of reproductive potential to use effective contraception during treatment with capecitabine and for months after the last dose. Males Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraceptionduring treatment with capecitabine and for months after the last dos [see Nonclinical Toxicology (13.1)] InfertilityBased on animal studies, capecitabine may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)] . 8.4 Pediatric Use. The safety and effectiveness of capecitabine in pediatric patients have not been established.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 5580 cGy in 180 cGy fractions). The relative bioavailability of the investigational formulation to capecitabine 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 7938 patients with colorectal cancer who were treated with capecitabine, 33% were older than 65 years. Of the 4536 patients with metastatic breast cancer who were treated with capecitabine, 18% were older than 65 years.Of 1951 patients with gastric, esophageal, or gastrointestinal junction cancer who were treated with capecitabine, 26% were older than 65 years.Of 364 patients with pancreatic cancer who received adjuvant treatment with capecitabine, 47% were 65 yearsor 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 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)]. 8.6Renal 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 in patients with CLcr <30 mL/min, and dosage has not been established in those patients. If no treatment alternative exists, capecitabine 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. 8.7Hepatic Impairment. The exposure of capecitabine increases in patients with mild to moderate hepatic impairment. The effect ofsevere hepatic impairment on the safety and pharmacokinetics of capecitabine is unknown [see Clinical Pharmacology 12.3)]. Monitor patients with hepatic impairment more frequently for adverse reactions.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Serious Adverse Reactions from Dihydropyrimidine Dehydrogenase (DPD) Deficiency: Patients with certain homozygous or compound heterozygous variants in the DPYD gene are at increased risk for acute early-onset toxicity and serious, including fatal, adverse reactions due to capecitabine (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Capecitabine is not recommended for use in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete absence of DPD activity. Withhold or permanently discontinue based on clinical assessment. No capecitabine dose has been proven safe in patients with complete absence of DPD activity. 5.2) Cardiotoxicity: May be more common in patients with prior history of coronary artery disease. Withhold capecitabine for cardiotoxicity as appropriate. The safety of resumption of capecitabine in patients with cardiotoxicity that has resolved has not been established. (2.5, 5.3) Diarrhea: Withhold capecitabine 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. Monitor hydration status and kidney function at baseline and as clinically indicated. Withhold capecitabine 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. Withhold capecitabine 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 in patients who experience severe cutaneous adverse reaction. 5.7) Palmar-Plantar Erythrodysesthesia Syndrome: Withhold capecitabine 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 is not recommended in patients with baseline neutrophil counts <1.5 109/L or platelet counts <100 109/L. For grade or myelosuppression, withhold capecitabine 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 isGrade 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) 5.1Increased Risk of Bleeding With Concomitant Use of Vitamin Antagonists. Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking capecitabine 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 was introduced. These events occurred within several days and up to several months after initiating capecitabine and, in few cases, within month after stopping capecitabine.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)]. 5.2Serious Adverse Reactions 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 (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity (partial DPD deficiency) may also have increased risk of serious, including fatal, adverse reactions. Capecitabine is not recommended for use in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency. Withhold or permanently discontinue capecitabine based on clinical assessment of the onset, duration, and severity of the observed adverse reactions in patients with evidence of acute early- onset or unusually severe reactions, which may indicate complete DPD deficiency. No capecitabine dose has been proven safe for patients with complete DPD deficiency. There are insufficient data to recommend specific dose in patients with partial DPD deficiency. Consider testing for genetic variants of DPYD prior to initiating capecitabine to reduce the risk of serious adverse reactions if the patients clinical status permits and based on clinical judgement [see Clinical Pharmacology( 12.5)] Serious adverse reactions may still occur even if no DPYD variants are identified. An FDA-authorized test for the detection of genetic variants of DPYD to identify patients at risk of serious adverse reactions due to increased systemic exposure to capecitabine 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). 5.3Cardiotoxicity Cardiotoxicity can occur with capecitabine. Myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy have been reported with capecitabine. These adverse reactions may be more common in patients with prior history of coronary artery disease.Withhold capecitabine for cardiotoxicity as appropriate [see Dosage and Administration (2.5)]. The safety of resumption of capecitabine in patients with cardiotoxicity that has resolved have not been established. 5.4Diarrhea. Diarrhea, sometimes severe, can occur with capecitabine. In 875 patients with metastatic breast or colorectal cancer who received capecitabine 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 and then resume at same or reduced dose or permanently discontinue based on severity and occurrence [see Dosage and Administration (2.5)]. 5.5Dehydration Dehydration can occur with capecitabine. Patients with anorexia, asthenia, nausea, vomiting, or diarrhea may be at an increased risk of developing dehydration with capecitabine. Optimize hydration before starting capecitabine. Monitor hydration status and kidney function at baseline and as clinically indicated. Withhold capecitabine and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence [see Dosage and Administration (2.5)]. 5.6Renal Toxicity. Serious renal failure, sometimes fatal, can occur with capecitabine. Renal impairment or coadministration of capecitabine 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. Withhold capecitabine and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence [see Dosage and Administration 2.5)]. 5.7Serious Skin Toxicities. Severe mucocutaneous reactions, some with fatal outcome, such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis (TEN) can occur in patients treated with capecitabine [see Adverse Reactions (6.2) . Monitor for new or worsening serious skin reactions. Permanently discontinue capecitabine for severe cutaneous adverse reactions. . 5.8Palmar-Plantar Erythrodysesthesia Syndrome Palmar-plantar erythrodysesthesia syndrome (PPES) can occur with capecitabine. In patients with metastatic breast or colorectal cancer who received capecitabine as single agent, the median time to onset of grades to PPES was 2.6 months (range: 11 days to year). Withhold capecitabine and then resume at same or reduced dose or permanently discontinue based on severity and occurrence [see Dosage and Administration 2.5)]. 5.9Myelosuppression. Myelosuppression can occur with capecitabine.In the 875 patients with metastatic breast or colorectal cancer who received capecitabine 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 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 andabdominal pain.Monitor complete blood count at baseline and before each cycle. Capecitabine is not recommended if baseline neutrophil count <1.5 10 9/L or platelet count <100 10 9/L. For grade to myelosuppression, withhold capecitabine and then resume at same or reduced dose, or permanently discontinue, based on occurrence [see Dosage and Administration 2.5)]. 5.10Hyperbilirubinemia. Hyperbilirubinemia can occur with capecitabine. In the 875 patients with metastatic breast or colorectal cancer who received capecitabine 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 increasedalkaline 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 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. 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 with docetaxel, grade hyperbilirubinemia occurred in 7% and grade hyperbilirubinemia occurred in 2%. Withhold capecitabine 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 can cause fetal harm when administered to pregnant woman. Insufficient data is available on capecitabine 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 dosageof 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 and for months following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with capecitabine and for months following the last dose [see Use in Specific Populations 8.1, 8.3)]. 5.12Eye 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.