CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Severe Renal Impairment (4.1)Hypersensitivity (4.2). Severe Renal Impairment (4.1). Hypersensitivity (4.2). 4.1Severe Renal Impairment. XELODA is contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min [Cockroft and Gault]) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].. 4.2Hypersensitivity XELODA is contraindicated in patients with known hypersensitivity to capecitabine or to any of its components. XELODA is contraindicated in patients who have known hypersensitivity to 5-fluorouracil.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Enzymes convert capecitabine to 5-fluorouracil (5-FU) in vivo. Both normal and tumor cells metabolize 5-FU to 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor, N5-10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form covalently bound ternary complex. This binding inhibits the formation of thymidylate from 2-deoxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that deficiency of this compound can inhibit cell division. Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. 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.. Most common adverse reactions (>=30%) were diarrhea, hand-and-foot syndrome, nausea, vomiting, abdominal pain, fatigue/weakness, and hyperbilirubinemia. Other adverse reactions, including serious adverse reactions, have been reported. (6)To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Adjuvant Colon Cancer. Table shows the adverse reactions occurring in >=5% of patients from one phase trial in patients with Dukes colon cancer who received at least one dose of study medication and had at least one safety assessment. total of 995 patients were treated with 1250 mg/m2 twice day of XELODA administered for weeks followed by 1-week rest period, and 974 patients were administered 5-FU and leucovorin (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU on days 1-5 every 28 days). The median duration of treatment was 164 days for capecitabine-treated patients and 145 days for 5-FU/LV-treated patients. total of 112 (11%) and 73 (7%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions. total of 18 deaths due to all causes occurred either on study or within 28 days of receiving study drug: (0.8%) patients randomized to XELODA and 10 (1.0%) randomized to 5-FU/LV.Table shows grade 3/4 laboratory abnormalities occurring in >=1% of patients from one phase trial in patients with Dukes colon cancer who received at least one dose of study medication and had at least one safety assessment.Table 4Percent Incidence of Adverse Reactions Reported in >=5% of Patients Treated With XELODA or 5-FU/LV for Colon Cancer in the Adjuvant Setting (Safety Population)Adjuvant Treatment for Colon Cancer (N=1969)XELODA(N=995)5-FU/LV(N=974)Body System/Adverse EventAll GradesGrade 3/4All GradesGrade 3/4Gastrointestinal Disorders Diarrhea47126514 Nausea342472 Stomatitis2226014 Vomiting152212 Abdominal Pain143162 Constipation9-11<1 Upper Abdominal Pain7<17<1 Dyspepsia6<15-Skin and Subcutaneous Tissue Disorders Hand-and-Foot Syndrome60179<1 Alopecia6-22<1 Rash7-8- Erythema615<1General Disorders and Administration Site Conditions Fatigue16<1161 Pyrexia7<19<1 Asthenia10<1101 Lethargy10<19<1Nervous System Disorders Dizziness6<16- Headache5<16<1 Dysgeusia6-9-Metabolism and Nutrition Disorders Anorexia9<111<1Eye Disorders Conjunctivitis5<16<1Blood and Lymphatic System Disorders Neutropenia2<185Respiratory Thoracic and Mediastinal Disorders Epistaxis2-5-Table 5Percent Incidence of Grade 3/4 Laboratory Abnormalities Reported in >=1% of Patients Receiving XELODA Monotherapy for Adjuvant Treatment of Colon Cancer (Safety Population) Adverse EventXELODA(n=995)Grade 3/4 %IV 5-FU/LV(n=974)Grade 3/4 Increased ALAT (SGPT)1.60.6 Increased calcium1.10.7 Decreased calcium2.32.2 Decreased hemoglobin1.01.2 Decreased lymphocytes13.013.0 Decreased neutrophilsThe incidence of grade 3/4 white blood cell abnormalities was 1.3% in the XELODA arm and 4.9% in the IV 5-FU/LV arm. 2.226.2 Decreased neutrophils/granulocytes2.426.4 Decreased platelets1.00.7 Increased bilirubinIt should be noted that grading was according to NCIC CTC Version (May, 1994). In the NCIC-CTC Version 1, hyperbilirubinemia grade indicates bilirubin value of 1.5 to 3.0 upper limit of normal (ULN) range, and grade a value of 3.0 ULN. The NCI CTC Version and above define grade bilirubin value of >3.0 to 10.0 ULN, and grade values >10.0 ULN. 206.3. 6.2 Metastatic Colorectal Cancer. MonotherapyTable shows the adverse reactions occurring in >=5% of patients from pooling the two phase trials in first line metastatic colorectal cancer. total of 596 patients with metastatic colorectal cancer were treated with 1250 mg/m2 twice day of XELODA administered for weeks followed by 1-week rest period, and 593 patients were administered 5-FU and leucovorin in the Mayo regimen (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU, on days 1-5, every 28 days). In the pooled colorectal database the median duration of treatment was 139 days for capecitabine-treated patients and 140 days for 5-FU/LV-treated patients. total of 78 (13%) and 63 (11%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions/intercurrent illness. total of 82 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 50 (8.4%) patients randomized to XELODA and 32 (5.4%) randomized to 5-FU/LV.Table 6Pooled Phase Colorectal Trials: Percent Incidence of Adverse Reactions in >=5% of PatientsAdverse EventXELODA(n=596)5-FU/LV(n=593)Total%Grade 3%Grade 4%Total%Grade 3%Grade 4%- Not observedNA Not ApplicableNumber of Patients With One Adverse Event9652994459Body System/Adverse EventGI Diarrhea5513261102 Nausea434-513<1 Vomiting274<1304<1 Stomatitis252<162141 Abdominal Pain359<1315- Gastrointestinal Motility Disorder10<1-7<1- Constipation141<1171- Oral Discomfort10--10-- Upper GI Inflammatory Disorders8<1-101- Gastrointestinal Hemorrhage61<131- Ileus641521Skin and Subcutaneous Hand-and-Foot Syndrome5417NA61NA Dermatitis271-261- Skin Discoloration7<1-5-- Alopecia6--21<1-General Fatigue/Weakness424-464- Pyrexia181-212- Edema151-91- Pain121-101- Chest Pain61-61<1Neurological Peripheral Sensory Neuropathy10--4-- Headache101-7-- DizzinessExcluding vertigo 8<1-8<1- Insomnia7--7-- Taste Disturbance61-11<11Metabolism Appetite Decreased263<1312<1 Dehydration72<1831Eye Eye Irritation13--10<1- Vision Abnormal5--2--Respiratory Dyspnea141-10<11 Cough7<118-- Pharyngeal Disorder5--5-- Epistaxis3<1-6-- Sore Throat2--6--Musculoskeletal Back Pain102-9<1- Arthralgia81-61-Vascular Venous Thrombosis83<162-Psychiatric Mood Alteration5--6<1- Depression5--4<1-Infections Viral5<1-5<1-Blood and Lymphatic Anemia802<1791<1 Neutropenia131246813Hepatobiliary Hyperbilirubinemia481851733. 6.3 Breast Cancer. In Combination with DocetaxelThe following data are shown for the combination study with XELODA and docetaxel in patients with metastatic breast cancer in Table and Table 8. In the XELODA and docetaxel combination arm the treatment was XELODA administered orally 1250 mg/m2 twice daily as intermittent therapy (2 weeks of treatment followed by week without treatment) for at least weeks and docetaxel administered as 1-hour intravenous infusion at dose of 75 mg/m2 on the first day of each 3-week cycle for at least weeks. In the monotherapy arm docetaxel was administered as 1-hour intravenous infusion at dose of 100 mg/m2 on the first day of each 3-week cycle for at least weeks. The mean duration of treatment was 129 days in the combination arm and 98 days in the monotherapy arm. total of 66 patients (26%) in the combination arm and 49 (19%) in the monotherapy arm withdrew from the study because of adverse reactions. The percentage of patients requiring dose reductions due to adverse reactions was 65% in the combination arm and 36% in the monotherapy arm. The percentage of patients requiring treatment interruptions due to adverse reactions in the combination arm was 79%. Treatment interruptions were part of the dose modification scheme for the combination therapy arm but not for the docetaxel monotherapy-treated patients.Table 7Percent Incidence of Adverse Events Considered Related or Unrelated to Treatment in >=5% of Patients Participating in the XELODA and Docetaxel Combination vs Docetaxel Monotherapy StudyAdverse EventXELODA 1250 mg/m2/bid With Docetaxel75 mg/m2/3 weeksDocetaxel100 mg/m2/3 weeks(n=251)(n=255)Total %Grade %Grade %Total %Grade %Grade %- Not observedNA Not ApplicableNumber of Patients With at Least One Adverse Event9976.529.19757.631.8Body System/Adverse EventGI Diarrhea6714<1485<1 Stomatitis6717<1435- Nausea457-362- Vomiting3541242- Constipation202-18-- Abdominal Pain30<3<1242- Dyspepsia14--81- Dry Mouth6<1-5--Skin and Subcutaneous Hand-and-Foot Syndrome6324NA81NA Alopecia416-427- Nail Disorder142-15-- Dermatitis8--111- Rash Erythematous9<1-5-- Nail Discoloration6--4<1- Onycholysis51-51- Pruritus4--5--General Pyrexia282-342- Asthenia264<1256- Fatigue224-276- Weakness162-112- Pain in Limb13<1-132- Lethargy7--62- Pain7<1-51- Chest Pain (non-cardiac)4<1-62- Influenza-like Illness5--5--Neurological Taste Disturbance16<1-14<1- Headache153-152- Paresthesia12<1-161- Dizziness12--8<1- Insomnia8--10<1- Peripheral Neuropathy6--101- Hypoaesthesia4<1-8<1-Metabolism Anorexia131-11<1- Appetite Decreased10--5-- Weight Decreased7--5-- Dehydration102-7<1<1Eye Lacrimation Increased12--7<1- Conjunctivitis5--4-- Eye Irritation5--1--Musculoskeletal Arthralgia152-243- Myalgia152-252- Back Pain12<1-113- Bone Pain8<1-102-Cardiac Edema33<2-34<31Blood Neutropenic Fever1631321516Respiratory Dyspnea142<1162- Cough131-22<1- Sore Throat122-11<1- Epistaxis7<1-6-- Rhinorrhea5--3-- Pleural Effusion21-74-Infection Oral Candidiasis7<1-8<1- Urinary Tract Infection6<1-4-- Upper Respiratory Tract4--51-Vascular Flushing5--5-- Lymphoedema3<1-51-Psychiatric Depression5--51-Table 8Percent of Patients With Laboratory Abnormalities Participating in the XELODA and Docetaxel Combination vs Docetaxel Monotherapy StudyAdverse EventXELODA 1250 mg/m2/bid With Docetaxel75 mg/m2/3 weeksDocetaxel100 mg/m2/3 weeks(n=251)(n=255)Body System/Adverse EventTotal %Grade 3%Grade 4%Total%Grade 3%Grade 4%Hematologic Leukopenia913724884233 Neutropenia/Granulocytopenia862049871066 Thrombocytopenia41212312 Anemia8073835<1 Lymphocytopenia994841984440Hepatobiliary Hyperbilirubinemia2072622. MonotherapyThe following data are shown for the study in stage IV breast cancer patients who received dose of 1250 mg/m2 administered twice daily for weeks followed by 1-week rest period. The mean duration of treatment was 114 days. total of 13 out of 162 patients (8%) discontinued treatment because of adverse reactions/intercurrent illness.Table 9Percent Incidence of Adverse Reactions Considered Remotely, Possibly or Probably Related to Treatment in >=5% of Patients Participating in the Single Arm Trial in Stage IV Breast CancerAdverse EventPhase Trial in Stage IV Breast Cancer(n=162)Body System/Adverse EventTotal%Grade 3%Grade 4%- Not observedNA Not ApplicableGIDiarrhea57123Nausea534-Vomiting374-Stomatitis247-Abdominal Pain204-Constipation151-Dyspepsia8--Skin and SubcutaneousHand-and-Foot Syndrome5711NADermatitis371-Nail Disorder7--GeneralFatigue418-Pyrexia121-Pain in Limb61-NeurologicalParesthesia211-Headache91-Dizziness8--Insomnia8--MetabolismAnorexia233-Dehydration741EyeEye Irritation15--MusculoskeletalMyalgia9--CardiacEdema91-BloodNeutropenia2622Thrombocytopenia2431Anemia7231Lymphopenia944415HepatobiliaryHyperbilirubinemia2292. 6.4Clinically Relevant Adverse Events in <5% of Patients. Clinically relevant adverse events reported in <5% of patients treated with XELODA either as monotherapy or in combination with docetaxel that were considered at least remotely related to treatment are shown below; occurrences of each grade and adverse event are provided in parentheses.. Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)Gastrointestinal:abdominal distension, dysphagia, proctalgia, ascites (0.1%), gastric ulcer (0.1%), ileus (0.3%), toxic dilation of intestine, gastroenteritis (0.1%)Skin Subcutan.:nail disorder (0.1%), sweating increased (0.1%), photosensitivity reaction (0.1%), skin ulceration, pruritus, radiation recall syndrome (0.2%)General:chest pain (0.2%), influenza-like illness, hot flushes, pain (0.1%), hoarseness, irritability, difficulty in walking, thirst, chest mass, collapse, fibrosis (0.1%), hemorrhage, edema, sedationNeurological:insomnia, ataxia (0.5%), tremor, dysphasia, encephalopathy (0.1%), abnormal coordination, dysarthria, loss of consciousness (0.2%), impaired balanceMetabolism:increased weight, cachexia (0.4%), hypertriglyceridemia (0.1%), hypokalemia, hypomagnesemiaEye:conjunctivitisRespiratory:cough (0.1%), epistaxis (0.1%), asthma (0.2%), hemoptysis, respiratory distress (0.1%), dyspneaCardiac:tachycardia (0.1%), bradycardia, atrial fibrillation, ventricular extrasystoles, extrasystoles, myocarditis (0.1%), pericardial effusionInfections:laryngitis (1.0%), bronchitis (0.2%), pneumonia (0.2%), bronchopneumonia (0.2%), keratoconjunctivitis, sepsis (0.3%), fungal infections (including candidiasis) (0.2%)Musculoskeletal:myalgia, bone pain (0.1%), arthritis (0.1%), muscle weaknessBlood Lymphatic:leukopenia (0.2%), coagulation disorder (0.1%), bone marrow depression (0.1%), idiopathic thrombocytopenia purpura (1.0%), pancytopenia (0.1%)Vascular:hypotension (0.2%), hypertension (0.1%), lymphoedema (0.1%), pulmonary embolism (0.2%), cerebrovascular accident (0.1%)Psychiatric:depression, confusion (0.1%)Renal:renal impairment (0.6%)Ear:vertigoHepatobiliary:hepatic fibrosis (0.1%), hepatitis (0.1%), cholestatic hepatitis (0.1%), abnormal liver function testsImmune System:drug hypersensitivity (0.1%). XELODA In Combination With Docetaxel (Metastatic Breast Cancer)Gastrointestinal:ileus (0.4%), necrotizing enterocolitis (0.4%), esophageal ulcer (0.4%), hemorrhagic diarrhea (0.8%)Neurological:ataxia (0.4%), syncope (1.2%), taste loss (0.8%), polyneuropathy (0.4%), migraine (0.4%)Cardiac:supraventricular tachycardia (0.4%)Infection:neutropenic sepsis (2.4%), sepsis (0.4%), bronchopneumonia (0.4%)Blood Lymphatic:agranulocytosis (0.4%), prothrombin decreased (0.4%)Vascular:hypotension (1.2%), venous phlebitis and thrombophlebitis (0.4%), postural hypotension (0.8%)Renal:renal failure (0.4%)Hepatobiliary:jaundice (0.4%), abnormal liver function tests (0.4%), hepatic failure (0.4%), hepatic coma (0.4%), hepatotoxicity (0.4%)Immune System:hypersensitivity (1.2%). 6.5Postmarketing Experience. The following adverse reactions have been observed in the postmarketing setting: angioedema, hepatic failure, lacrimal duct stenosis, acute renal failure secondary to dehydration including fatal outcome [see Warnings and Precautions (5.5)], cutaneous lupus erythematosus, corneal disorders including keratitis, toxic leukoencephalopathy, severe skin reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (TEN) [see Warnings and Precautions (5.7)], persistent or severe hand-and-foot syndrome can eventually lead to loss of fingerprints [see Warnings and Precautions (5.7) ]In instances of exposure to crushed XELODA tablets, the following adverse reactions have been reported: eye irritation and swelling, skin rash, diarrhea, paresthesia, headache, gastric irritation, vomiting, and nausea.

BOXED WARNING SECTION.

WARNING: XELODA-WARFARIN INTERACTION. XELODA Warfarin Interaction: Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. clinically important XELODA-Warfarin drug interaction was demonstrated in clinical pharmacology trial [see Warnings and Precautions (5.2) and Drug Interactions (7.1)]. Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking XELODA concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. Postmarketing reports have shown clinically significant increases in prothrombin time (PT) and INR in patients who were stabilized on anticoagulants at the time XELODA was introduced. These events occurred within several days and up to several months after initiating XELODA therapy and, in few cases, within month after stopping XELODA. These events occurred in patients with and without liver metastases. Age greater than 60 and diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.. WARNING: XELODA-WARFARIN INTERACTIONSee full prescribing information for complete boxed warning.Patients receiving concomitant XELODA and oral coumarin-derivative anticoagulants such as warfarin and phenprocoumon should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. Altered coagulation parameters and/or bleeding, including death, have been reported during concomitant use.Occurrence: Within several days and up to several months after initiating XELODA therapy; may also be seen within month after stopping XELODAPredisposing factors: age>60 and diagnosis of cancer. Occurrence: Within several days and up to several months after initiating XELODA therapy; may also be seen within month after stopping XELODA. Predisposing factors: age>60 and diagnosis of cancer.

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/m2/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. 12.1 Mechanism of Action. Enzymes convert capecitabine to 5-fluorouracil (5-FU) in vivo. Both normal and tumor cells metabolize 5-FU to 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor, N5-10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form covalently bound ternary complex. This binding inhibits the formation of thymidylate from 2-deoxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that deficiency of this compound can inhibit cell division. Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis.. 12.3 Pharmacokinetics. AbsorptionFollowing oral administration of 1255 mg/m2 BID to cancer patients, capecitabine reached peak blood levels in about 1.5 hours (Tmax) with peak 5-FU levels occurring slightly later, at hours. Food reduced both the rate and extent of absorption of capecitabine with mean Cmax and AUC0- decreased by 60% and 35%, respectively. The Cmax and AUC0- of 5-FU were also reduced by food by 43% and 21%, respectively. Food delayed Tmax of both parent and 5-FU by 1.5 hours [see Warnings and Precautions (5), Dosage and Administration (2), and Drug-Food Interaction (7.2)].The pharmacokinetics of XELODA and its metabolites have been evaluated in about 200 cancer patients over dosage range of 500 to 3500 mg/m2/day. Over this range, the pharmacokinetics of XELODA and its metabolite, 5-DFCR were dose proportional and did not change over time. The increases in the AUCs of 5-DFUR and 5-FU, however, were greater than proportional to the increase in dose and the AUC of 5-FU was 34% higher on day 14 than on day 1. The interpatient variability in the Cmax and AUC of 5-FU was greater than 85%.. 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%). XELODA has low potential for pharmacokinetic interactions related to plasma protein binding.. Bioactivation and MetabolismCapecitabine is extensively metabolized enzymatically to 5-FU. In the liver, 60 kDa carboxylesterase hydrolyzes much of the compound to 5-deoxy-5-fluorocytidine (5-DFCR). Cytidine deaminase, an enzyme found in most tissues, including tumors, subsequently converts 5-DFCR to 5-DFUR. The enzyme, thymidine phosphorylase (dThdPase), then hydrolyzes 5-DFUR to the active drug 5-FU. Many tissues throughout the body express thymidine phosphorylase. Some human carcinomas express this enzyme in higher concentrations than surrounding normal tissues. Following oral administration of XELODA days before surgery in patients with colorectal cancer, the median ratio of 5-FU concentration in colorectal tumors to adjacent tissues was 2.9 (range from 0.9 to 8.0). These ratios have not been evaluated in breast cancer patients or compared to 5-FU infusion.Metabolic Pathway of capecitabine to 5-FUThe enzyme dihydropyrimidine dehydrogenase hydrogenates 5-FU, the product of capecitabine metabolism, to the much less toxic 5-fluoro-5, 6-dihydro-fluorouracil (FUH2). Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, -ureido-propionase cleaves FUPA to -fluoro--alanine (FBAL) which is cleared in the urine.In vitro enzymatic studies with human liver microsomes indicated that capecitabine and its metabolites (5-DFUR, 5-DFCR, 5-FU, and FBAL) did not inhibit the metabolism of test substrates by cytochrome P450 isoenzymes 1A2, 2A6, 3A4, 2C19, 2D6, and 2E1.. Figure. ExcretionCapecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered capecitabine dose is recovered in urine. Fecal excretion is minimal (2.6%). The major metabolite excreted in urine is FBAL which represents 57% of the administered dose. About 3% of the administered dose is excreted in urine as unchanged drug. The elimination half-life of both parent capecitabine and 5-FU was about 0.75 hour.. Effect of Age, Gender, and Race on the Pharmacokinetics of CapecitabineA population analysis of pooled data from the two large controlled studies in patients with metastatic colorectal cancer (n=505) who were administered XELODA at 1250 mg/m2 twice day indicated that gender (202 females and 303 males) and race (455 white/Caucasian patients, 22 black patients, and 28 patients of other race) have no influence on the pharmacokinetics of 5-DFUR, 5-FU and FBAL. Age has no significant influence on the pharmacokinetics of 5-DFUR and 5-FU over the range of 27 to 86 years. 20% increase in age results in 15% increase in AUC of FBAL [see Warnings and Precautions (5.11) and Dosage and Administration (2.4)].Following oral administration of 825 mg/m2 capecitabine twice daily for 14 days, Japanese patients (n=18) had about 36% lower Cmax and 24% lower AUC for capecitabine than the Caucasian patients (n=22). Japanese patients had also about 25% lower Cmax and 34% lower AUC for FBAL than the Caucasian patients. The clinical significance of these differences is unknown. No significant differences occurred in the exposure to other metabolites (5-DFCR, 5-DFUR, and 5-FU).. Effect of Hepatic InsufficiencyXELODA has been evaluated in 13 patients with mild to moderate hepatic dysfunction due to liver metastases defined by composite score including bilirubin, AST/ALT and alkaline phosphatase following single 1255 mg/m2 dose of XELODA. Both AUC0- and Cmax of capecitabine increased by 60% in patients with hepatic dysfunction compared to patients with normal hepatic function (n=14). The AUC0- and Cmax of 5-FU were not affected. In patients with mild to moderate hepatic dysfunction due to liver metastases, caution should be exercised when XELODA is administered. The effect of severe hepatic dysfunction on XELODA is not known [see Warnings and Precautions (5.11) and Use in Special Populations (8.6)]. Effect of Renal InsufficiencyFollowing oral administration of 1250 mg/m2 capecitabine twice day to cancer patients with varying degrees of renal impairment, patients with moderate (creatinine clearance 30 to 50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment showed 85% and 258% higher systemic exposure to FBAL on day compared to normal renal function patients (creatinine clearance >80 mL/min). Systemic exposure to 5-DFUR was 42% and 71% greater in moderately and severely renal impaired patients, respectively, than in normal patients. Systemic exposure to capecitabine was about 25% greater in both moderately and severely renal impaired patients [see Dosage and Administration (2.4), Contraindications (4.2), Warnings and Precautions (5.5), and Use in Special Populations (8.7)].. Effect of Capecitabine on the Pharmacokinetics of WarfarinIn four patients with cancer, chronic administration of capecitabine (1250 mg/m2 bid) with single 20 mg dose of warfarin 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% [see Boxed Warning and Drug Interactions (7.1)]. Effect of Antacids on the Pharmacokinetics of CapecitabineWhen Maalox(R) (20 mL), an aluminum hydroxide- and magnesium hydroxide-containing antacid, was administered immediately after XELODA (1250 mg/m2, n=12 cancer patients), AUC and Cmax increased by 16% and 35%, respectively, for capecitabine and by 18% and 22%, respectively, for 5-DFCR. No effect was observed on the other three major metabolites (5-DFUR, 5-FU, FBAL) of XELODA.. Effect of Allopurinol on CapecitabinePublished literature reported that concomitant use with allopurinol may decrease conversion of capecitabine to the active metabolites, FdUMP and FUTP; however, the clinical significance was not fully characterized.. Effect of Capecitabine on the Pharmacokinetics of Docetaxel and Vice VersaA Phase study evaluated the effect of XELODA on the pharmacokinetics of docetaxel (Taxotere(R)) and the effect of docetaxel on the pharmacokinetics of XELODA was conducted in 26 patients with solid tumors. XELODA was found to have no effect on the pharmacokinetics of docetaxel (Cmax and AUC) and docetaxel has no effect on the pharmacokinetics of capecitabine and the 5-FU precursor 5-DFUR.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Adjuvant Colon Cancer. multicenter randomized, controlled phase clinical trial in patients with Dukes colon cancer (X-ACT) provided data concerning the use of XELODA for the adjuvant treatment of patients with colon cancer. The primary objective of the study was to compare disease-free survival (DFS) in patients receiving XELODA to those receiving IV 5-FU/LV alone. In this trial, 1987 patients were randomized either to treatment with XELODA 1250 mg/m2 orally twice daily for weeks followed by 1-week rest period, given as 3-week cycles for total of cycles (24 weeks) or IV bolus 5-FU 425 mg/m2 and 20 mg/m2 IV leucovorin on days to 5, given as 4-week cycles for total of cycles (24 weeks). Patients in the study were required to be between 18 and 75 years of age with histologically-confirmed Dukes stage colon cancer with at least one positive lymph node and to have undergone (within weeks prior to randomization) complete resection of the primary tumor without macroscopic or microscopic evidence of remaining tumor. Patients were also required to have no prior cytotoxic chemotherapy or immunotherapy (except steroids), and have an ECOG performance status of or (KPS >= 70%), ANC >= 1.5x109/L, platelets >= 100x109/L, serum creatinine <= 1.5 ULN, total bilirubin <= 1.5 ULN, AST/ALT <= 2.5 ULN and CEA within normal limits at time of randomization.The baseline demographics for XELODA and 5-FU/LV patients are shown in Table 10. The baseline characteristics were well-balanced between arms.Table 10Baseline DemographicsXELODA(n=1004)5-FU/LV(n=983)Age (median, years)6263Range(25-80)(22-82)Gender Male (n, %)542 (54)532 (54) Female (n, %)461 (46)451 (46)ECOG PS (n, %)849 (85)830 (85) (n, %)152 (15)147 (15)Staging Primary Tumor PT1 (n, %)12 (1)6 (0.6) PT2 (n, %)90 (9)92 (9) PT3 (n, %)763 (76)746 (76) PT4 (n, %)138 (14)139 (14) Other (n, %)1 (0.1)0 (0)Staging Lymph Node pN1 (n, %)695 (69)694 (71) pN2 (n, %)305 (30)288 (29) Other (n, %)4 (0.4)1 (0.1)All patients with normal renal function or mild renal impairment began treatment at the full starting dose of 1250 mg/m2 orally twice daily. The starting dose was reduced in patients with moderate renal impairment (calculated creatinine clearance 30 to 50 mL/min) at baseline [see Dosage and Administration (2.4)]. Subsequently, for all patients, doses were adjusted when needed according to toxicity. Dose management for XELODA included dose reductions, cycle delays and treatment interruptions (see Table 11).Table 11Summary of Dose Modifications in X-ACT StudyXELODAN 9955-FU/LVN 974Median relative dose intensity (%)9392Patients completing full course of treatment (%)8387Patients with treatment interruption (%)155Patients with cycle delay (%)4629Patients with dose reduction (%)4244Patients with treatment interruption, cycle delay, or dose reduction (%)5752The median follow-up at the time of the analysis was 83 months (6.9 years). The hazard ratio for DFS for XELODA compared to 5-FU/LV was 0.88 (95% C.I. 0.77 1.01) (see Table 12 and Figure 1). Because the upper 2-sided 95% confidence limit of hazard ratio was less than 1.20, XELODA was non-inferior to 5-FU/LV. The choice of the non-inferiority margin of 1.20 corresponds to the retention of approximately 75% of the 5-FU/LV effect on DFS. The hazard ratio for XELODA compared to 5-FU/LV with respect to overall survival was 0.86 (95% C.I. 0.74 1.01). The 5-year overall survival rates were 71.4% for XELODA and 68.4% for 5-FU/LV (see Figure 2).Table 12Efficacy of XELODA vs 5-FU/LV in Adjuvant Treatment of Colon CancerApproximately 93.4% had 5-year DFS information All Randomized PopulationXELODA(n=1004)5-FU/LV(n=983)Median follow-up (months)83835-year Disease-free Survival Rates (%)Based on Kaplan-Meier estimates 59.154.6Hazard Ratio(XELODA/5-FU/LV)(95% C.I. for Hazard Ratio)0.88(0.77 1.01)p-valueTest of superiority of XELODA vs 5-FU/LV (Wald chi-square test) = 0.068Figure Kaplan-Meier Estimates of Disease-Free Survival (All Randomized Population)XELODA has been demonstrated to be non-inferior to 5-FU/LV. Figure Kaplan-Meier Estimates of Overall Survival (All Randomized Population). Figure 1. Figure 2. 14.2Metastatic Colorectal Cancer. GeneralThe recommended dose of XELODA was determined in an open-label, randomized clinical study, exploring the efficacy and safety of continuous therapy with capecitabine (1331 mg/m2/day in two divided doses, n=39), intermittent therapy with capecitabine (2510 mg/m2/day in two divided doses, n=34), and intermittent therapy with capecitabine in combination with oral leucovorin (LV) (capecitabine 1657 mg/m2/day in two divided doses, n=35; leucovorin 60 mg/day) in patients with advanced and/or metastatic colorectal carcinoma in the first-line metastatic setting. There was no apparent advantage in response rate to adding leucovorin to XELODA; however, toxicity was increased. XELODA, 1250 mg/m2 twice daily for 14 days followed by 1-week rest, was selected for further clinical development based on the overall safety and efficacy profile of the three schedules studied.. MonotherapyData from two open-label, multicenter, randomized, controlled clinical trials involving 1207 patients support the use of XELODA in the first-line treatment of patients with metastatic colorectal carcinoma. The two clinical studies were identical in design and were conducted in 120 centers in different countries. Study was conducted in the US, Canada, Mexico, and Brazil; Study was conducted in Europe, Israel, Australia, New Zealand, and Taiwan. Altogether, in both trials, 603 patients were randomized to treatment with XELODA at dose of 1250 mg/m2 twice daily for weeks followed by 1-week rest period and given as 3-week cycles; 604 patients were randomized to treatment with 5-FU and leucovorin (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU, on days to 5, every 28 days).In both trials, overall survival, time to progression and response rate (complete plus partial responses) were assessed. 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 for XELODA and 5-FU/LV patients are shown in Table 13.Table 13Baseline Demographics of Controlled Colorectal TrialsStudy 1Study 2XELODA(n=302)5-FU/LV(n=303)XELODA(n=301)5-FU/LV(n=301)Age (median, years)64636464Range(23-86)(24-87)(29-84)(36-86)Gender Male (%)181 (60)197 (65)172 (57)173 (57) Female (%)121 (40)106 (35)129 (43)128 (43)Karnofsky PS (median)90909090Range(70-100)(70-100)(70-100)(70-100)Colon (%)222 (74)232 (77)199 (66)196 (65)Rectum (%)79 (26)70 (23)101 (34)105 (35)Prior radiation therapy (%)52 (17)62 (21)42 (14)42 (14)Prior adjuvant 5-FU (%)84 (28)110 (36)56 (19)41 (14)The efficacy endpoints for the two phase trials are shown in Table 14 and Table 15.Table 14Efficacy of XELODA vs 5-FU/LV in Colorectal Cancer (Study 1)XELODA(n=302)5-FU/LV(n=303)Overall Response Rate(%, 95% C.I.)21 (16-26)11 (8-15)(p-value)0.0014Time to Progression(Median, days, 95% C.I.)128 (120-136)131 (105-153)Hazard Ratio (XELODA/5-FU/LV)95% C.I. for Hazard Ratio0.99(0.84-1.17)Survival(Median, days, 95% C.I.)380 (321-434)407 (366-446)Hazard Ratio (XELODA/5-FU/LV)95% C.I. for Hazard Ratio1.00(0.84-1.18)Table 15Efficacy of XELODA vs 5-FU/LV in Colorectal Cancer (Study 2)XELODA(n=301)5-FU/LV(n=301)Overall Response Rate(%, 95% C.I.)21 (16-26)14 (10-18)(p-value)0.027Time to Progression(Median, days, 95% C.I.)137 (128-165)131 (102-156)Hazard Ratio (XELODA/5-FU/LV)95% C.I. for Hazard Ratio0.97(0.82-1.14)Survival(Median, days, 95% C.I.)404 (367-452)369 (338-430)Hazard Ratio (XELODA/5-FU/LV)95% C.I. for Hazard Ratio0.92(0.78-1.09)Figure Kaplan-Meier Curve for Overall Survival of Pooled Data (Studies and 2)XELODA was superior to 5-FU/LV for objective response rate in Study and Study 2. The similarity of XELODA and 5-FU/LV in these studies was assessed by examining the potential difference between the two treatments. In order to assure that XELODA has clinically meaningful survival effect, statistical analyses were performed to determine the percent of the survival effect of 5-FU/LV that was retained by XELODA. The estimate of the survival effect of 5-FU/LV was derived from meta-analysis of ten randomized studies from the published literature comparing 5-FU to regimens of 5-FU/LV that were similar to the control arms used in these Studies and 2. The method for comparing the treatments was to examine the worst case (95% confidence upper bound) for the difference between 5-FU/LV and XELODA, and to show that loss of more than 50% of the 5-FU/LV survival effect was ruled out. It was demonstrated that the percent of the survival effect of 5-FU/LV maintained was at least 61% for Study and 10% for Study 1. The pooled result is consistent with retention of at least 50% of the effect of 5-FU/LV. It should be noted that these values for preserved effect are based on the upper bound of the 5-FU/LV vs XELODA difference. These results do not exclude the possibility of true equivalence of XELODA to 5-FU/LV (see Table 14, Table 15, and Figure 3).. Figure 3. 14.3Breast Cancer. XELODA has been evaluated in clinical trials in combination with docetaxel (Taxotere(R)) and as monotherapy.. In Combination With DocetaxelThe dose of XELODA used in the phase clinical trial in combination with docetaxel was based on the results of phase study, where range of doses of docetaxel administered in 3-week cycles in combination with an intermittent regimen of XELODA (14 days of treatment, followed by 7-day rest period) were evaluated. The combination dose regimen was selected based on the tolerability profile of the 75 mg/m2 administered in 3-week cycles of docetaxel in combination with 1250 mg/m2 twice daily for 14 days of XELODA administered in 3-week cycles. The approved dose of 100 mg/m2 of docetaxel administered in 3-week cycles was the control arm of the phase study.XELODA in combination with docetaxel was assessed in an open-label, multicenter, randomized trial in 75 centers in Europe, North America, South America, Asia, and Australia. total of 511 patients with 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. Two hundred and fifty-five (255) patients were randomized to receive XELODA 1250 mg/m2 twice daily for 14 days followed by week without treatment and docetaxel 75 mg/m2 as 1-hour intravenous infusion administered in 3-week cycles. In the monotherapy arm, 256 patients received docetaxel 100 mg/m2 as 1-hour intravenous infusion administered in 3-week cycles. Patient demographics are provided in Table 16.Table 16Baseline Demographics and Clinical Characteristics XELODA and Docetaxel Combination vs Docetaxel in Breast Cancer TrialXELODA Docetaxel(n=255)Docetaxel(n=256)Age (median, years)5251Karnofsky PS (median)9090Site of Disease Lymph nodes121 (47%)125 (49%) Liver116 (45%)122 (48%) Bone107 (42%)119 (46%) Lung95 (37%)99 (39%) Skin73 (29%)73 (29%)Prior Chemotherapy AnthracyclineIncludes 10 patients in combination and 18 patients in monotherapy arms treated with an anthracenedione 255 (100%)256 (100%) 5-FU196 (77%)189 (74%) Paclitaxel25 (10%)22 (9%)Resistance to an Anthracycline No resistance19 (7%)19 (7%) Progression on anthracycline therapy65 (26%)73 (29%) Stable disease after cycles of anthracycline therapy41 (16%)40 (16%) Relapsed within years of completion of anthracycline-adjuvant therapy78 (31%)74 (29%) Experienced brief response to anthracycline therapy, with subsequent progression while on therapy or within 12 months after last dose51 (20%)50 (20%)No. of Prior Chemotherapy Regimens for Treatment of Metastatic Disease 089 (35%)80 (31%) 1123 (48%)135 (53%) 243 (17%)39 (15%) 30 (0%)2 (1%)XELODA in combination with docetaxel resulted in statistically significant improvement in time to disease progression, overall survival and objective response rate compared to monotherapy with docetaxel as shown in Table 17, Figure 4, and Figure 5.Table 17Efficacy of XELODA and Docetaxel Combination vs Docetaxel MonotherapyEfficacy ParameterCombination TherapyMonotherapyp-valueHazard RatioTime to Disease ProgressionMedian Days1861280.00010.64395% C.I.(165-198)(105-136)Overall SurvivalMedian Days4423520.01260.77595% C.I.(375-497)(298-387)Response RateThe response rate reported represents reconciliation of the investigator and IRC assessments performed by the sponsor according to predefined algorithm.32%22%0.009NANA Not Applicable Figure Kaplan-Meier Estimates for Time to Disease Progression XELODA and Docetaxel vs DocetaxelFigure Kaplan-Meier Estimates of Survival XELODA and Docetaxel vs Docetaxel. Figure 4. Figure 5. MonotherapyThe antitumor activity of XELODA as monotherapy was evaluated in an open-label single-arm trial conducted in 24 centers in the US and Canada. total of 162 patients with stage IV breast cancer were enrolled. The primary endpoint 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. XELODA was administered at dose of 1255 mg/m2 twice daily for weeks followed by 1-week rest period and given as 3-week cycles. The baseline demographics and clinical characteristics for all patients (n=162) and those with measurable disease (n=135) are shown in Table 18. 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.Table 18Baseline Demographics and Clinical Characteristics Single-Arm Breast Cancer TrialPatients With Measurable Disease(n=135)All Patients(n=162)Age (median, years)5556Karnofsky PS9090No. Disease Sites 1-243 (32%)60 (37%) 3-463 (46%)69 (43%) >529 (22%)34 (21%)Dominant Site of Disease VisceralLung, pleura, liver, peritoneum 101 (75%)110 (68%) Soft Tissue30 (22%)35 (22%) Bone4 (3%)17 (10%)Prior Chemotherapy Paclitaxel135 (100%)162 (100%) AnthracyclineIncludes patients treated with an anthracenedione 122 (90%)147 (91%) 5-FU110 (81%)133 (82%) Resistance to Paclitaxel103 (76%)124 (77%) Resistance to an Anthracycline 55 (41%)67 (41%) Resistance to both Paclitaxel and an Anthracycline 43 (32%)51 (31%)Antitumor responses for patients with disease resistant to both paclitaxel and an anthracycline are shown in Table 19.Table 19Response Rates in Doubly-Resistant Patients Single-Arm Breast Cancer TrialResistance to Both Paclitaxel and an Anthracycline(n=43)CR0PRIncludes patients treated with an anthracenedione 11CR PR 11Response Rate (95% C.I.)25.6%(13.5, 41.2)Duration of Response, Median in daysFrom date of first response (Range)154(63-233)For the subgroup of 43 patients who were doubly resistant, the median time to progression was 102 days and the median survival was 255 days. 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 18). The median time to progression was 90 days and the median survival was 306 days.

DESCRIPTION SECTION.

11 DESCRIPTION. XELODA (capecitabine) is fluoropyrimidine carbamate with antineoplastic activity. It is an orally administered systemic prodrug of 5-deoxy-5-fluorouridine (5-DFUR) which is converted to 5-fluorouracil.The chemical name for capecitabine is 5-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine and has 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 20oC.XELODA is 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 XELODA include: anhydrous lactose, croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate and purified water. The peach or light peach film coating contains hydroxypropyl methylcellulose, talc, titanium dioxide, and synthetic yellow and red iron oxides.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Take XELODA with water within 30 min after meal (2.1)Monotherapy: 1250 mg/m2 twice daily orally for weeks followed by one week rest period in 3-week cycles (2.2)Adjuvant treatment is recommended for total of months (8 cycles) (2.2)In combination with docetaxel, the recommended dose of XELODA is 1250 mg/m2 twice daily for weeks followed by 7-day rest period, combined with docetaxel at 75 mg/m2 as 1-hour IV infusion every weeks (2.2)XELODA dosage may need to be individualized to optimize patient management (2.3)Reduce the dose of XELODA by 25% in patients with moderate renal impairment (2.4). Take XELODA with water within 30 min after meal (2.1). Monotherapy: 1250 mg/m2 twice daily orally for weeks followed by one week rest period in 3-week cycles (2.2). Adjuvant treatment is recommended for total of months (8 cycles) (2.2). In combination with docetaxel, the recommended dose of XELODA is 1250 mg/m2 twice daily for weeks followed by 7-day rest period, combined with docetaxel at 75 mg/m2 as 1-hour IV infusion every weeks (2.2). XELODA dosage may need to be individualized to optimize patient management (2.3). Reduce the dose of XELODA by 25% in patients with moderate renal impairment (2.4). 2.1Important Administration Instructions. XELODA tablets should be swallowed whole with water within 30 minutes after meal. XELODA is cytotoxic drug. Follow applicable special handling and disposal procedures.1 If XELODA 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. XELODA dose is calculated according to body surface area.. 2.2 Standard Starting Dose. Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer) The recommended dose of XELODA is 1250 mg/m2 administered orally twice daily (morning and evening; equivalent to 2500 mg/m2 total daily dose) for weeks followed by 1-week rest period given as 3-week cycles (see Table 1).Adjuvant treatment in patients with Dukes colon cancer is recommended for total of months [ie, XELODA 1250 mg/m2 orally twice daily for weeks followed by 1-week rest period, given as 3-week cycles for total of cycles (24 weeks)].Table 1XELODA Dose Calculation According to Body Surface AreaDose Level 1250 mg/m2 Twice DayNumber of Tablets to be Taken at Each Dose (Morning and Evening)Surface Area(m2)Total Daily DoseTotal Daily Dose divided by to allow equal morning and evening doses (mg)150 mg500 mg<= 1.253000031.26-1.373300131.38-1.513600231.52-1.654000041.66-1.774300141.78-1.914600241.92-2.055000052.06-2.17530015>= 2.18560025. In Combination With Docetaxel (Metastatic Breast Cancer)In combination with docetaxel, the recommended dose of XELODA is 1250 mg/m2 twice daily for weeks followed by 1-week rest period, combined with docetaxel at 75 mg/m2 as 1-hour intravenous infusion every weeks. Pre-medication, according to the docetaxel labeling, should be started prior to docetaxel administration for patients receiving the XELODA plus docetaxel combination. Table displays the total daily dose of XELODA by body surface area and the number of tablets to be taken at each dose.. 2.3Dose Management Guidelines. GeneralXELODA dosage may need to be individualized to optimize patient management. Patients should be carefully monitored for toxicity and doses of XELODA should be modified as necessary to accommodate individual patient tolerance to treatment [see Clinical Studies (14)]. Toxicity due to XELODA administration may be managed by symptomatic treatment, dose interruptions and adjustment of XELODA dose. Once the dose has been reduced, it should not be increased at later time. Doses of XELODA omitted for toxicity are not replaced or restored; instead the patient should resume the planned treatment cycles.The dose of phenytoin and the dose of coumarin-derivative anticoagulants may need to be reduced when either drug is administered concomitantly with XELODA [see Drug Interactions (7.1)].. Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)XELODA dose modification scheme as described below (see Table 2) is recommended for the management of adverse reactions.Table 2Recommended Dose Modifications of XELODAToxicity NCIC GradesNational Cancer Institute of Canada Common Toxicity Criteria were used except for the hand-and-foot syndrome [see Warnings and Precautions (5)]. During Course of TherapyDose Adjustment for Next Treatment (% of starting dose)Grade 1Maintain dose levelMaintain dose levelGrade 2-1st appearanceInterrupt until resolved to grade 0-1100%-2nd appearance75%-3rd appearance50%-4th appearanceDiscontinue treatment permanently-Grade 3-1st appearanceInterrupt until resolved to grade 0-175%-2nd appearance50%-3rd appearanceDiscontinue treatment permanently-Grade 4-1st appearanceDiscontinue permanentlyORIf physician deems it to be in the patients best interest to continue, interrupt until resolved to grade 0-150%. In Combination With Docetaxel (Metastatic Breast Cancer) Dose modifications of XELODA for toxicity should be made according to Table above for XELODA. At the beginning of treatment cycle, if treatment delay is indicated for either XELODA or docetaxel, then administration of both agents should be delayed until the requirements for restarting both drugs are met.The dose reduction schedule for docetaxel when used in combination with XELODA for the treatment of metastatic breast cancer is shown in Table 3.Table 3Docetaxel Dose Reduction Schedule in Combination with XELODAToxicity NCIC GradesNational Cancer Institute of Canada Common Toxicity Criteria were used except for hand-and-foot syndrome [see Warnings and Precautions (5)]. Grade 2Grade 3Grade 41st appearanceDelay treatment until resolved to grade 0-1; Resume treatment with original dose of 75 mg/m2 docetaxelDelay treatment until resolved to grade 0-1;Resume treatment at 55 mg/m2 of docetaxel.Discontinue treatment with docetaxel2nd appearanceDelay treatment until resolved to grade 0-1; Resume treatment at 55 mg/m2 of docetaxel.Discontinue treatment with docetaxel-3rd appearanceDiscontinue treatment with docetaxel--. 2.4Adjustment of Starting Dose in Special Populations. Renal ImpairmentNo adjustment to the starting dose of XELODA is recommended in patients with mild renal impairment (creatinine clearance 51 to 80 mL/min [Cockroft and Gault, as shown below]). In patients with moderate renal impairment (baseline creatinine clearance 30 to 50 mL/min), dose reduction to 75% of the XELODA starting dose when used as monotherapy or in combination with docetaxel (from 1250 mg/m2 to 950 mg/m2 twice daily) is recommended [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. Subsequent dose adjustment is recommended as outlined in Table and Table (depending on the regimen) if patient develops grade to adverse event [see Warnings and Precautions (5.5)]. The starting dose adjustment recommendations for patients with moderate renal impairment apply to both XELODA monotherapy and XELODA in combination use with docetaxel.Cockroft and Gault Equation:Creatinine clearance for males =(140 age [yrs]) (body wt [kg])(72) (serum creatinine [mg/dL])Creatinine clearance for females 0.85 male value. Geriatrics Physicians should exercise caution in monitoring the effects of XELODA in the elderly. Insufficient data are available to provide dosage recommendation.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. XELODA is supplied as biconvex, oblong film-coated tablets for oral administration. Each light peach-colored tablet contains 150 mg of capecitabine and each peach-colored tablet contains 500 mg of capecitabine.. Tablets: 150 mg and 500 mg (3). Tablets: 150 mg and 500 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Anticoagulants: Monitor anticoagulant response (INR or prothrombin time) frequently in order to adjust the anticoagulant dose as needed. (5.2, 7.1)Phenytoin: Monitor phenytoin levels in patients taking XELODA concomitantly with phenytoin. The phenytoin dose may need to be reduced. (7.1)Leucovorin: The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin. (7.1)CYP2C9 substrates: Care should be exercised when XELODA is coadministered with CYP2C9 substrates. (7.1)Allopurinol: Avoid the use of allopurinol during treatment with XELODA.Food reduced both the rate and extent of absorption of capecitabine. (2, 7.2, 12.3). Anticoagulants: Monitor anticoagulant response (INR or prothrombin time) frequently in order to adjust the anticoagulant dose as needed. (5.2, 7.1). Phenytoin: Monitor phenytoin levels in patients taking XELODA concomitantly with phenytoin. The phenytoin dose may need to be reduced. (7.1). Leucovorin: The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin. (7.1). CYP2C9 substrates: Care should be exercised when XELODA is coadministered with CYP2C9 substrates. (7.1). Allopurinol: Avoid the use of allopurinol during treatment with XELODA.. Food reduced both the rate and extent of absorption of capecitabine. (2, 7.2, 12.3). 7.1 Drug-Drug Interactions. AnticoagulantsAltered coagulation parameters and/or bleeding have been reported in patients taking XELODA concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon [see Boxed Warning]. These events occurred within several days and up to several months after initiating XELODA therapy and, in few cases, within month after stopping XELODA. These events occurred in patients with and without liver metastases. In drug interaction study with single-dose warfarin administration, there was significant increase in the mean AUC of S-warfarin [see Clinical Pharmacology (12.3)]. The maximum observed INR value increased by 91%. This interaction is probably due to an inhibition of cytochrome P450 2C9 by capecitabine and/or its metabolites.. PhenytoinThe level of phenytoin should be carefully monitored in patients taking XELODA and phenytoin dose may need to be reduced [see Dosage and Administration (2.3)]. Postmarketing reports indicate that some patients receiving XELODA and phenytoin had toxicity associated with elevated phenytoin levels. Formal drug-drug interaction studies with phenytoin have not been conducted, but the mechanism of interaction is presumed to be inhibition of the CYP2C9 isoenzyme by capecitabine and/or its metabolites.. LeucovorinThe concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil.. CYP2C9 substratesOther than warfarin, no formal drug-drug interaction studies between XELODA and other CYP2C9 substrates have been conducted. Care should be exercised when XELODA is coadministered with CYP2C9 substrates.. AllopurinolConcomitant use with allopurinol may decrease concentration of capecitabines active metabolites [see Clinical Pharmacology (12.3)], which may decrease XELODA efficacy. Avoid the use of allopurinol during treatment with XELODA. 7.2Drug-Food Interaction. Food was shown to reduce both the rate and extent of absorption of capecitabine [see Clinical Pharmacology (12.3)]. In all clinical trials, patients were instructed to administer XELODA within 30 minutes after meal. It is recommended that XELODA be administered with food [see Dosage and Administration (2)].

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Pregnancy TestingPregnancy testing is recommended for females of reproductive potential prior to initiating XELODA.. Contraception. FemalesXELODA can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment and for months following the final dose of XELODA.. MalesBased on genetic toxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for months following the final dose of XELODA [see Nonclinical Toxicology (13.1)]. InfertilityBased on animal studies, XELODA may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Physicians should pay particular attention to monitoring the adverse effects of XELODA in the elderly [see Warnings and Precautions (5.10)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 150 mgColor:Light peachEngraving:XELODA on one side and 150 on the other150 mg tablets are packaged in bottles of 60 (NDC 0004-1100-20), individually packaged in carton.. 500 mgColor:PeachEngraving:XELODA on one side and 500 on the other500 mg tablets are packaged in bottles of 120 (NDC 0004-1101-50), individually packaged in carton.. Storage and HandlingStore at 25C (77F); excursions permitted to 15 to 30C (59 to 86F). [See USP Controlled Room Temperature]. KEEP TIGHTLY CLOSED.XELODA is cytotoxic drug. Follow applicable special handling and disposal procedures.1 Any unused product should be disposed of in accordance with local requirements, or drug take back programs.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. XELODA (capecitabine) is nucleoside metabolic inhibitor with antineoplastic activity indicated for:Adjuvant Colon Cancer (1.1)-Patients with Dukes colon cancer Metastatic Colorectal Cancer (1.1)-First-line as monotherapy when treatment with fluoropyrimidine therapy alone is preferred Metastatic Breast Cancer (1.2)-In combination with docetaxel after failure of prior anthracycline-containing therapy-As monotherapy in patients resistant to both paclitaxel and an anthracycline-containing regimen Adjuvant Colon Cancer (1.1)-Patients with Dukes colon cancer -Patients with Dukes colon cancer. Metastatic Colorectal Cancer (1.1)-First-line as monotherapy when treatment with fluoropyrimidine therapy alone is preferred -First-line as monotherapy when treatment with fluoropyrimidine therapy alone is preferred. Metastatic Breast Cancer (1.2)-In combination with docetaxel after failure of prior anthracycline-containing therapy-As monotherapy in patients resistant to both paclitaxel and an anthracycline-containing regimen -In combination with docetaxel after failure of prior anthracycline-containing therapy. -As monotherapy in patients resistant to both paclitaxel and an anthracycline-containing regimen. 1.1Colorectal Cancer. XELODA is indicated as single agent for adjuvant treatment in patients with Dukes colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. XELODA was non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Physicians should consider results of combination chemotherapy trials, which have shown improvement in DFS and OS, when prescribing single-agent XELODA in the adjuvant treatment of Dukes colon cancer.XELODA is indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown survival benefit compared to 5-FU/LV alone. survival benefit over 5-FU/LV has not been demonstrated with XELODA monotherapy. Use of XELODA instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.. XELODA is indicated as single agent for adjuvant treatment in patients with Dukes colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. XELODA was non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Physicians should consider results of combination chemotherapy trials, which have shown improvement in DFS and OS, when prescribing single-agent XELODA in the adjuvant treatment of Dukes colon cancer.. XELODA is indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown survival benefit compared to 5-FU/LV alone. survival benefit over 5-FU/LV has not been demonstrated with XELODA monotherapy. Use of XELODA instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.. 1.2Breast Cancer. XELODA in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.XELODA monotherapy is also indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated (e.g., patients who have received cumulative doses of 400 mg/m2 of doxorubicin or doxorubicin equivalents). Resistance is 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 regimen.. XELODA in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.. XELODA monotherapy is also indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated (e.g., patients who have received cumulative doses of 400 mg/m2 of doxorubicin or doxorubicin equivalents). Resistance is 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 regimen.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. Diarrhea Inform 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 XELODA. Advise patients on the use of antidiarrheal treatments (e.g., loperamide) to manage diarrhea [see Warnings and Precautions (5.2)]. CardiotoxicityAdvise patients of the risk of cardiotoxicity and to immediately contact their healthcare provider or to go to an emergency room for new onset of chest pain, shortness of breath, dizziness, or lightheadedness [see Warnings and Precautions (5.3)]. Dihydropyrimidine Dehydrogenase DeficiencyAdvise patients to notify their healthcare provider if they have known DPD deficiency. Advise patients if they have complete or near complete absence of DPD activity they are at an increased risk of acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by XELODA (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity) [see Warnings and Precautions (5.4)].. Dehydration and Renal Failure Instruct patients experiencing grade or higher dehydration (IV fluids indicated 24 hours) to stop taking XELODA immediately and to call their healthcare provider to correct the dehydration. Advise patients to not restart XELODA until rehydrated and any precipitating causes have been corrected or controlled [see Warnings and Precautions (5.5)]. Important Administration InstructionsAdvise patients to swallow XELODA tablets whole with water within 30 minutes of meal. Advise patients and caregivers not to crush or cut XELODA tablets. Advise patients if they cannot swallow XELODA tablets whole, to inform their healthcare provider [see Dosage and Administration (2.1)].. Hypersensitivity and Angioedema Advise patients that XELODA 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 XELODA and immediately contact their healthcare provider or to go to an emergency room. [see Adverse Reactions (6)].. Nausea Instruct patients experiencing grade nausea (food intake significantly decreased but able to eat intermittently) or greater to stop taking XELODA immediately and to contact their healthcare provider for management of nausea [see Adverse Reactions (6.1)].. VomitingInstruct patients experiencing grade vomiting (2 to episodes in 24-hour period) or greater to stop taking XELODA immediately and to contact their healthcare provider for management of vomiting [see Adverse Reactions (6.1)].. Hand-and-Foot SyndromeInstruct patients experiencing grade hand-and-foot syndrome (painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patients activities of daily living) or greater to stop taking XELODA immediately and to contact their healthcare provider. Inform patients that initiation of symptomatic treatment is recommended, and hand-and-foot syndrome can lead to loss of fingerprints which could impact personal identification [see Adverse Reactions (6.1)].. Stomatitis Inform patients experiencing grade stomatitis (painful erythema, edema or ulcers of the mouth or tongue, but able to eat) or greater to stop taking XELODA immediately and to contact their healthcare provider [see Adverse Reactions (6.1)].. Fever and Neutropenia Inform patients who develop fever of 100.5F or greater or other evidence of potential infection to contact their healthcare provider [see Adverse Reactions (6.1)].. Embryo-Fetal ToxicityAdvise females of reproductive potential of the potential risk to fetus and to use effective contraception during treatment with XELODA and for months after the last dose. Advise females to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.6), Use in Specific Populations (8.1 and 8.3)].Advise male patients with female partners of reproductive potential to use effective contraception during treatment with XELODA and for months after the last dose [see Use in Specific Populations (8.3)].. LactationAdvise females not to breastfeed during treatment with XELODA and for weeks after the last dose [see Use in Specific Populations (8.2)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere is no information regarding the presence of capecitabine in human milk, or on its effects on milk production or the breast-fed infant. Capecitabine metabolites were present in the milk of lactating mice [see Data]. Because of the potential for serious adverse reactions from capecitabine exposure in breast-fed infants, advise women not to breastfeed during treatment with XELODA and for weeks after the final dose.. DataLactating mice given single oral dose of capecitabine excreted significant amounts of capecitabine metabolites into the milk.

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/m2/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. The manifestations of acute overdose would include nausea, vomiting, diarrhea, gastrointestinal irritation and bleeding, and bone marrow depression. Medical management of overdose should include customary supportive medical interventions aimed at correcting the presenting clinical manifestations. Although no clinical experience using dialysis as treatment for XELODA overdose has been reported, dialysis may be of benefit in reducing circulating concentrations of 5-DFUR, low-molecular-weight metabolite of the parent compound.Single doses of XELODA were not lethal to mice, rats, and monkeys at doses up to 2000 mg/kg (2.4, 4.8, and 9.6 times the recommended human daily dose on mg/m2 basis).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 150 mg Tablet Bottle Carton. NDC 0004-1100-20Xeloda(R) (capecitabine)Tablets150 mgEach tablet contains 150 mgcapecitabine.Rx only60 tabletsGenentech10210268. PRINCIPAL DISPLAY PANEL 150 mg Tablet Bottle Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of XELODA in pediatric patients have not been established. No clinical benefit was demonstrated in two single arm trials in pediatric patients with newly diagnosed brainstem gliomas and high grade 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 XELODA was similar.The first trial was conducted in 22 pediatric patients (median age years, range 5-17 years) with newly diagnosed non-disseminated intrinsic diffuse brainstem gliomas and high grade gliomas. In the dose-finding portion of the trial, patients received capecitabine with concomitant radiation therapy at doses ranging from 500 mg/m2 to 850 mg/m2 every 12 hours for up to weeks. After 2 week break, patients received 1250 mg/m2 capecitabine every 12 hours on Days 1-14 of 21-day cycle for up to cycles. The maximum tolerated dose (MTD) of capecitabine administered concomitantly with radiation therapy was 650 mg/m2 every 12 hours. The major dose limiting toxicities were palmar-plantar erythrodysesthesia and alanine aminotransferase (ALT) elevation.The second trial was conducted in 34 additional pediatric patients with newly diagnosed non-disseminated intrinsic diffuse brainstem gliomas (median age years, range 3-16 years) and 10 pediatric patients who received the MTD of capecitabine in the dose-finding trial and met the eligibility criteria for this trial. All patients received 650 mg/m2 capecitabine every 12 hours with concomitant radiation therapy for up to weeks. After 2 week break, patients received 1250 mg/m2 capecitabine every 12 hours on Days 1-14 of 21-day cycle for up to cycles.There was no improvement in one-year progression-free survival rate and one-year overall survival rate in pediatric patients with newly diagnosed intrinsic brainstem gliomas who received capecitabine relative to similar population of pediatric patients who participated in other clinical trials.The adverse reaction profile of capecitabine was consistent with the known adverse reaction profile in 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%), leukopenia (73%), hypokalemia (68%), thrombocytopenia (57%), hypoalbuminemia (55%), neutropenia (50%), low hematocrit (50%), hypocalcemia (48%), hypophosphatemia (45%) and hyponatremia (45%).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionFollowing oral administration of 1255 mg/m2 BID to cancer patients, capecitabine reached peak blood levels in about 1.5 hours (Tmax) with peak 5-FU levels occurring slightly later, at hours. Food reduced both the rate and extent of absorption of capecitabine with mean Cmax and AUC0- decreased by 60% and 35%, respectively. The Cmax and AUC0- of 5-FU were also reduced by food by 43% and 21%, respectively. Food delayed Tmax of both parent and 5-FU by 1.5 hours [see Warnings and Precautions (5), Dosage and Administration (2), and Drug-Food Interaction (7.2)].The pharmacokinetics of XELODA and its metabolites have been evaluated in about 200 cancer patients over dosage range of 500 to 3500 mg/m2/day. Over this range, the pharmacokinetics of XELODA and its metabolite, 5-DFCR were dose proportional and did not change over time. The increases in the AUCs of 5-DFUR and 5-FU, however, were greater than proportional to the increase in dose and the AUC of 5-FU was 34% higher on day 14 than on day 1. The interpatient variability in the Cmax and AUC of 5-FU was greater than 85%.. 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%). XELODA has low potential for pharmacokinetic interactions related to plasma protein binding.. Bioactivation and MetabolismCapecitabine is extensively metabolized enzymatically to 5-FU. In the liver, 60 kDa carboxylesterase hydrolyzes much of the compound to 5-deoxy-5-fluorocytidine (5-DFCR). Cytidine deaminase, an enzyme found in most tissues, including tumors, subsequently converts 5-DFCR to 5-DFUR. The enzyme, thymidine phosphorylase (dThdPase), then hydrolyzes 5-DFUR to the active drug 5-FU. Many tissues throughout the body express thymidine phosphorylase. Some human carcinomas express this enzyme in higher concentrations than surrounding normal tissues. Following oral administration of XELODA days before surgery in patients with colorectal cancer, the median ratio of 5-FU concentration in colorectal tumors to adjacent tissues was 2.9 (range from 0.9 to 8.0). These ratios have not been evaluated in breast cancer patients or compared to 5-FU infusion.Metabolic Pathway of capecitabine to 5-FUThe enzyme dihydropyrimidine dehydrogenase hydrogenates 5-FU, the product of capecitabine metabolism, to the much less toxic 5-fluoro-5, 6-dihydro-fluorouracil (FUH2). Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, -ureido-propionase cleaves FUPA to -fluoro--alanine (FBAL) which is cleared in the urine.In vitro enzymatic studies with human liver microsomes indicated that capecitabine and its metabolites (5-DFUR, 5-DFCR, 5-FU, and FBAL) did not inhibit the metabolism of test substrates by cytochrome P450 isoenzymes 1A2, 2A6, 3A4, 2C19, 2D6, and 2E1.. Figure. ExcretionCapecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered capecitabine dose is recovered in urine. Fecal excretion is minimal (2.6%). The major metabolite excreted in urine is FBAL which represents 57% of the administered dose. About 3% of the administered dose is excreted in urine as unchanged drug. The elimination half-life of both parent capecitabine and 5-FU was about 0.75 hour.. Effect of Age, Gender, and Race on the Pharmacokinetics of CapecitabineA population analysis of pooled data from the two large controlled studies in patients with metastatic colorectal cancer (n=505) who were administered XELODA at 1250 mg/m2 twice day indicated that gender (202 females and 303 males) and race (455 white/Caucasian patients, 22 black patients, and 28 patients of other race) have no influence on the pharmacokinetics of 5-DFUR, 5-FU and FBAL. Age has no significant influence on the pharmacokinetics of 5-DFUR and 5-FU over the range of 27 to 86 years. 20% increase in age results in 15% increase in AUC of FBAL [see Warnings and Precautions (5.11) and Dosage and Administration (2.4)].Following oral administration of 825 mg/m2 capecitabine twice daily for 14 days, Japanese patients (n=18) had about 36% lower Cmax and 24% lower AUC for capecitabine than the Caucasian patients (n=22). Japanese patients had also about 25% lower Cmax and 34% lower AUC for FBAL than the Caucasian patients. The clinical significance of these differences is unknown. No significant differences occurred in the exposure to other metabolites (5-DFCR, 5-DFUR, and 5-FU).. Effect of Hepatic InsufficiencyXELODA has been evaluated in 13 patients with mild to moderate hepatic dysfunction due to liver metastases defined by composite score including bilirubin, AST/ALT and alkaline phosphatase following single 1255 mg/m2 dose of XELODA. Both AUC0- and Cmax of capecitabine increased by 60% in patients with hepatic dysfunction compared to patients with normal hepatic function (n=14). The AUC0- and Cmax of 5-FU were not affected. In patients with mild to moderate hepatic dysfunction due to liver metastases, caution should be exercised when XELODA is administered. The effect of severe hepatic dysfunction on XELODA is not known [see Warnings and Precautions (5.11) and Use in Special Populations (8.6)]. Effect of Renal InsufficiencyFollowing oral administration of 1250 mg/m2 capecitabine twice day to cancer patients with varying degrees of renal impairment, patients with moderate (creatinine clearance 30 to 50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment showed 85% and 258% higher systemic exposure to FBAL on day compared to normal renal function patients (creatinine clearance >80 mL/min). Systemic exposure to 5-DFUR was 42% and 71% greater in moderately and severely renal impaired patients, respectively, than in normal patients. Systemic exposure to capecitabine was about 25% greater in both moderately and severely renal impaired patients [see Dosage and Administration (2.4), Contraindications (4.2), Warnings and Precautions (5.5), and Use in Special Populations (8.7)].. Effect of Capecitabine on the Pharmacokinetics of WarfarinIn four patients with cancer, chronic administration of capecitabine (1250 mg/m2 bid) with single 20 mg dose of warfarin 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% [see Boxed Warning and Drug Interactions (7.1)]. Effect of Antacids on the Pharmacokinetics of CapecitabineWhen Maalox(R) (20 mL), an aluminum hydroxide- and magnesium hydroxide-containing antacid, was administered immediately after XELODA (1250 mg/m2, n=12 cancer patients), AUC and Cmax increased by 16% and 35%, respectively, for capecitabine and by 18% and 22%, respectively, for 5-DFCR. No effect was observed on the other three major metabolites (5-DFUR, 5-FU, FBAL) of XELODA.. Effect of Allopurinol on CapecitabinePublished literature reported that concomitant use with allopurinol may decrease conversion of capecitabine to the active metabolites, FdUMP and FUTP; however, the clinical significance was not fully characterized.. Effect of Capecitabine on the Pharmacokinetics of Docetaxel and Vice VersaA Phase study evaluated the effect of XELODA on the pharmacokinetics of docetaxel (Taxotere(R)) and the effect of docetaxel on the pharmacokinetics of XELODA was conducted in 26 patients with solid tumors. XELODA was found to have no effect on the pharmacokinetics of docetaxel (Cmax and AUC) and docetaxel has no effect on the pharmacokinetics of capecitabine and the 5-FU precursor 5-DFUR.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on findings in animal reproduction studies and its mechanism of action, XELODA can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. Limited available human data are not sufficient to inform the drug-associated risk during pregnancy. In animal reproduction studies, administration of capecitabine to pregnant animals during the period of organogenesis caused embryo lethality and teratogenicity in mice and embryo lethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving the recommended dose respectively [see Data]. Apprise pregnant women of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Data. Animal 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.

REFERENCES SECTION.

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

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 06/2021 Patient InformationXELODA(R) (zeh-LOE-duh)(capecitabine)tabletsWhat is the most important information should know about XELODAXELODA can cause serious side effects, including:XELODA can interact with blood thinner medicines, such as warfarin (COUMADIN(R)). Taking XELODA with these medicines can cause changes in how fast your blood clots and can cause bleeding that can lead to death. This can happen as soon as few days after you start taking XELODA, or later during treatment, and possibly even within month after you stop taking XELODA. Your risk may be higher because you have cancer, and if you are over 60 years of age.Before taking XELODA, tell your healthcare provider if you are taking warfarin (COUMADIN) or another blood thinner-medicine.If you take warfarin (COUMADIN) or another blood thinner that is like warfarin (COUMADIN) during treatment with XELODA, your healthcare provider should do blood tests often, to check how fast your blood clots during and after you stop treatment with XELODA. Your healthcare provider may change your dose of the blood thinner medicine if needed. See What are the possible side effects of XELODA for more information about side effects.What is XELODAXELODA is prescription medicine used to treat people with:cancer of the colon that has spread to lymph nodes in the area close to the colon (Dukes stage), after they have surgery.cancer of the colon or rectum (colorectal) that has spread to other parts of the body (metastatic), as your first treatment of your cancer at this stage.breast cancer that has spread to other parts of the body (metastatic) together with another medicine called docetaxel after treatment with certain other anti-cancer medicines have not worked.breast cancer that spread to other parts of the body and has not improved after treatment with paclitaxel and certain other anti-cancer medicines, or who cannot receive any more treatment with certain anti-cancer medicines.It is not known if XELODA is safe and effective in children.Do not take XELODA if you:have severe kidney problemsare allergic to capecitabine, 5-fluorouracil, or any of the ingredients in XELODA. See the end of this leaflet for complete list of ingredients in XELODA.Talk to your healthcare provider before taking XELODA if you are not sure if you have any of the conditions listed above.Before taking XELODA, tell your healthcare provider about all your medical conditions, including if you:See What is the most important information should know about XELODAhave had heart problemshave kidney or liver problemshave been told that you lack the enzyme DPD (dihydropyrimidine dehydrogenase).are pregnant or plan to become pregnant. XELODA can harm your unborn baby. Your healthcare provider should do pregnancy test before you start treatment with XELODA. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with XELODA.Females who are able to become pregnant should use effective birth control during treatment and for months after the final dose. Talk to your healthcare provider about birth control choices that may be right for you during treatment with XELODA.Males who have female partners who are able to become pregnant should use effective birth control during treatment and for months after the final dose. are breastfeeding or plan to breastfeed. It is not known if XELODA passes into your breast milk. Do not breastfeed during treatment with XELODA and for weeks after the final dose.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. XELODA may affect the way other medicines work, and other medicines may affect the way XELODA works.Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine.How should take XELODATake XELODA exactly as your healthcare provider tells you to take it.Your healthcare provider will tell you how much XELODA to take and when to take it.Take XELODA times day, time in the morning and time in the evening.Take XELODA within 30 minutes after finishing meal.Swallow XELODA tablets whole with water. Do not crush or cut XELODA tablets. If you cannot swallow XELODA tablets whole, tell your healthcare provider.Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with XELODA if you develop side effects.If you take too much XELODA, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of XELODAXELODA can cause serious side effects including:See What is the most important information should know about XELODA Diarrhea. Diarrhea is common with XELODA and can sometimes be severe. Stop taking XELODA and call your healthcare provider right away if the number of bowel movements you have in day increases by or more bowel movements than is usual for you or bowel movements at night. Ask your healthcare provider about what medicines you can take to treat your diarrhea. If you have severe bloody diarrhea with severe abdominal pain and fever, stop taking Xeloda and call your healthcare provider or go to the nearest hospital emergency room right away.Heart problems. XELODA 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. Stop taking XELODA and call your healthcare provider or go to the nearest hospital emergency room right away if you get any new symptoms of heart problem including: chest painshortness of breathdizzinesslightheadednessLoss of too much body fluid (dehydration) and kidney failure. Dehydration can happen with XELODA and may cause sudden kidney failure that can lead to death. You are at higher risk if you have kidney problems before taking XELODA and also take other medicines that can cause kidney problems.Nausea, and vomiting are common with XELODA. If you lose your appetite, feel weak, and have nausea, vomiting, or diarrhea, you can quickly become dehydrated.Stop taking XELODA and call your healthcare provider right away if you:vomit or more times in day.are only able to eat or drink little now and then, or not at all due to nausea.have diarrhea. See diarrhea above. Severe skin and mouth reactions.XELODA can cause severe skin reactions that may lead to death. Tell your healthcare provider right away if you develop skin rash, blister and peeling of your skin. Your healthcare provider may tell you to stop taking XELODA if you have serious skin reaction. Do not take XELODA again if this happens.XELODA can also cause hand and foot syndrome. Hand and foot syndrome is common with XELODA and can cause you to have numbness and changes in sensation in your hands and feet, or cause redness, pain, swelling of your hands and feet. Stop taking XELODA and call your healthcare provider right away if you have any of these symptoms and you are not able to do your usual activities.Hand and foot syndrome can lead to loss of fingerprints which could impact your identification.you may get sores in your mouth or on your tongue when taking XELODA. Stop taking XELODA and call your healthcare provider if you get painful redness, swelling, or ulcers in your mouth or tongue, or if you are having problems eating.Increased level of bilirubin in your blood and liver problems. Increased bilirubin in your blood is common with XELODA and can also sometimes be severe. Your healthcare provider will check you for these problems during treatment with XELODA.Decreased white blood cells, platelets, and red blood cell counts. Your healthcare provider will do blood tests during treatment with XELODA 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.People 80 years of age or older may be more likely to develop severe or serious side effects with XELODA.The most common side effects of XELODA include:diarrheahand and foot syndromenauseavomitingstomach-area (abdominal) painweakness and tirednessincreased amounts of red blood cell breakdown products (bilirubin) in your bloodSevere allergic reactions can happen with XELODA. Tell your healthcare provider if you have ever had an allergic reaction to capecitabine or 5-fluorouracil. See Do not take XELODA if you:. Stop taking XELODA and call your healthcare provider right away or go to an emergency room if you have any of the following symptoms of severe allergic reaction:red itchy welts on your skin (hives)rashskin rednessitchingswelling of your face, lips, tongue or throattrouble swallowing or breathingXELODA 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 XELODA.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store XELODAStore XELODA at room temperature between 68F to 77F (20C to 25C).Keep XELODA in tightly closed container.Ask your healthcare provider or pharmacist how to safely throw away any unused XELODA.Keep XELODA and all medicines out of the reach of children.General information about the safe and effective use of XELODA.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use XELODA for condition for which it was not prescribed. Do not give XELODA 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 XELODA that is written for health professionals.What are the ingredients in XELODAActive ingredient: capecitabineInactive ingredients: anhydrous lactose, croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate and purified water. The peach or light peach film coating contains hydroxypropyl methylcellulose, talc, titanium dioxide, and synthetic yellow and red iron oxides.For more information, go to http://www.gene.com/patients/medicines/xeloda or call 1-877-436-3683.Distributed by:Genentech USA, Inc.A Member of the Roche Group1 DNA WaySouth San Francisco, CA 94080-4990XELODA(R) is registered trademark of Hoffmann-La Roche, Inc.(C) 2021 Genentech, Inc. All rights reserved.. XELODA can interact with blood thinner medicines, such as warfarin (COUMADIN(R)). Taking XELODA with these medicines can cause changes in how fast your blood clots and can cause bleeding that can lead to death. This can happen as soon as few days after you start taking XELODA, or later during treatment, and possibly even within month after you stop taking XELODA. Your risk may be higher because you have cancer, and if you are over 60 years of age.Before taking XELODA, tell your healthcare provider if you are taking warfarin (COUMADIN) or another blood thinner-medicine.If you take warfarin (COUMADIN) or another blood thinner that is like warfarin (COUMADIN) during treatment with XELODA, your healthcare provider should do blood tests often, to check how fast your blood clots during and after you stop treatment with XELODA. Your healthcare provider may change your dose of the blood thinner medicine if needed. Before taking XELODA, tell your healthcare provider if you are taking warfarin (COUMADIN) or another blood thinner-medicine.. If you take warfarin (COUMADIN) or another blood thinner that is like warfarin (COUMADIN) during treatment with XELODA, your healthcare provider should do blood tests often, to check how fast your blood clots during and after you stop treatment with XELODA. Your healthcare provider may change your dose of the blood thinner medicine if needed.. cancer of the colon that has spread to lymph nodes in the area close to the colon (Dukes stage), after they have surgery.. cancer of the colon or rectum (colorectal) that has spread to other parts of the body (metastatic), as your first treatment of your cancer at this stage.. breast cancer that has spread to other parts of the body (metastatic) together with another medicine called docetaxel after treatment with certain other anti-cancer medicines have not worked.. breast cancer that spread to other parts of the body and has not improved after treatment with paclitaxel and certain other anti-cancer medicines, or who cannot receive any more treatment with certain anti-cancer medicines.. have severe kidney problems. are allergic to capecitabine, 5-fluorouracil, or any of the ingredients in XELODA. See the end of this leaflet for complete list of ingredients in XELODA.. have had heart problems. have kidney or liver problems. have been told that you lack the enzyme DPD (dihydropyrimidine dehydrogenase).. are pregnant or plan to become pregnant. XELODA can harm your unborn baby. Your healthcare provider should do pregnancy test before you start treatment with XELODA. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with XELODA.Females who are able to become pregnant should use effective birth control during treatment and for months after the final dose. Talk to your healthcare provider about birth control choices that may be right for you during treatment with XELODA.Males who have female partners who are able to become pregnant should use effective birth control during treatment and for months after the final dose. Females who are able to become pregnant should use effective birth control during treatment and for months after the final dose. Talk to your healthcare provider about birth control choices that may be right for you during treatment with XELODA.. Males who have female partners who are able to become pregnant should use effective birth control during treatment and for months after the final dose.. are breastfeeding or plan to breastfeed. It is not known if XELODA passes into your breast milk. Do not breastfeed during treatment with XELODA and for weeks after the final dose.. Take XELODA exactly as your healthcare provider tells you to take it.. Your healthcare provider will tell you how much XELODA to take and when to take it.. Take XELODA times day, time in the morning and time in the evening.. Take XELODA within 30 minutes after finishing meal.. Swallow XELODA tablets whole with water. Do not crush or cut XELODA tablets. If you cannot swallow XELODA tablets whole, tell your healthcare provider.. Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with XELODA if you develop side effects.. If you take too much XELODA, call your healthcare provider or go to the nearest hospital emergency room right away.. Diarrhea. Diarrhea is common with XELODA and can sometimes be severe. Stop taking XELODA and call your healthcare provider right away if the number of bowel movements you have in day increases by or more bowel movements than is usual for you or bowel movements at night. Ask your healthcare provider about what medicines you can take to treat your diarrhea. If you have severe bloody diarrhea with severe abdominal pain and fever, stop taking Xeloda and call your healthcare provider or go to the nearest hospital emergency room right away.. Heart problems. XELODA 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. Stop taking XELODA and call your healthcare provider or go to the nearest hospital emergency room right away if you get any new symptoms of heart problem including: chest pain. shortness of breath. dizziness. lightheadedness. Loss of too much body fluid (dehydration) and kidney failure. Dehydration can happen with XELODA and may cause sudden kidney failure that can lead to death. You are at higher risk if you have kidney problems before taking XELODA and also take other medicines that can cause kidney problems.Nausea, and vomiting are common with XELODA. If you lose your appetite, feel weak, and have nausea, vomiting, or diarrhea, you can quickly become dehydrated.Stop taking XELODA and call your healthcare provider right away if you:vomit or more times in day.are only able to eat or drink little now and then, or not at all due to nausea.have diarrhea. See diarrhea above. vomit or more times in day.. are only able to eat or drink little now and then, or not at all due to nausea.. have diarrhea. See diarrhea above.. Severe skin and mouth reactions.XELODA can cause severe skin reactions that may lead to death. Tell your healthcare provider right away if you develop skin rash, blister and peeling of your skin. Your healthcare provider may tell you to stop taking XELODA if you have serious skin reaction. Do not take XELODA again if this happens.XELODA can also cause hand and foot syndrome. Hand and foot syndrome is common with XELODA and can cause you to have numbness and changes in sensation in your hands and feet, or cause redness, pain, swelling of your hands and feet. Stop taking XELODA and call your healthcare provider right away if you have any of these symptoms and you are not able to do your usual activities.Hand and foot syndrome can lead to loss of fingerprints which could impact your identification.you may get sores in your mouth or on your tongue when taking XELODA. Stop taking XELODA and call your healthcare provider if you get painful redness, swelling, or ulcers in your mouth or tongue, or if you are having problems eating.. XELODA can cause severe skin reactions that may lead to death. Tell your healthcare provider right away if you develop skin rash, blister and peeling of your skin. Your healthcare provider may tell you to stop taking XELODA if you have serious skin reaction. Do not take XELODA again if this happens.. XELODA can also cause hand and foot syndrome. Hand and foot syndrome is common with XELODA and can cause you to have numbness and changes in sensation in your hands and feet, or cause redness, pain, swelling of your hands and feet. Stop taking XELODA and call your healthcare provider right away if you have any of these symptoms and you are not able to do your usual activities.. Hand and foot syndrome can lead to loss of fingerprints which could impact your identification.. you may get sores in your mouth or on your tongue when taking XELODA. Stop taking XELODA and call your healthcare provider if you get painful redness, swelling, or ulcers in your mouth or tongue, or if you are having problems eating.. Increased level of bilirubin in your blood and liver problems. Increased bilirubin in your blood is common with XELODA and can also sometimes be severe. Your healthcare provider will check you for these problems during treatment with XELODA.. Decreased white blood cells, platelets, and red blood cell counts. Your healthcare provider will do blood tests during treatment with XELODA 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.. diarrhea. hand and foot syndrome. nausea. vomiting. stomach-area (abdominal) pain. weakness and tiredness. increased amounts of red blood cell breakdown products (bilirubin) in your blood. red itchy welts on your skin (hives). rash. skin redness. itching. swelling of your face, lips, tongue or throat. trouble swallowing or breathing. Store XELODA at room temperature between 68F to 77F (20C to 25C).. Keep XELODA in tightly closed container.. Ask your healthcare provider or pharmacist how to safely throw away any unused XELODA.

SPL UNCLASSIFIED SECTION.

1.1Colorectal Cancer. XELODA is indicated as single agent for adjuvant treatment in patients with Dukes colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. XELODA was non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Physicians should consider results of combination chemotherapy trials, which have shown improvement in DFS and OS, when prescribing single-agent XELODA in the adjuvant treatment of Dukes colon cancer.XELODA is indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown survival benefit compared to 5-FU/LV alone. survival benefit over 5-FU/LV has not been demonstrated with XELODA monotherapy. Use of XELODA instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.. XELODA is indicated as single agent for adjuvant treatment in patients with Dukes colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. XELODA was non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Physicians should consider results of combination chemotherapy trials, which have shown improvement in DFS and OS, when prescribing single-agent XELODA in the adjuvant treatment of Dukes colon cancer.. XELODA is indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown survival benefit compared to 5-FU/LV alone. survival benefit over 5-FU/LV has not been demonstrated with XELODA monotherapy. Use of XELODA instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.

STORAGE AND HANDLING SECTION.

Storage and HandlingStore at 25C (77F); excursions permitted to 15 to 30C (59 to 86F). [See USP Controlled Room Temperature]. KEEP TIGHTLY CLOSED.XELODA is cytotoxic drug. Follow applicable special handling and disposal procedures.1 Any unused product should be disposed of in accordance with local requirements, or drug take back programs.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise women not to breastfeed. (8.2)Females and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of XELODA. Advise males with female partners of reproductive potential to use effective contraception. (8.3)Geriatric: Greater incidence of adverse reactions. Monitoring required. (8.5)Hepatic Impairment: Monitoring is recommended in patients with mild to moderate hepatic impairment. (8.6)Renal Impairment: Reduce XELODA starting dose in patients with moderate renal impairment (2.4, 8.7, 12.3). Lactation: Advise women not to breastfeed. (8.2). Females and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of XELODA. Advise males with female partners of reproductive potential to use effective contraception. (8.3). Geriatric: Greater incidence of adverse reactions. Monitoring required. (8.5). Hepatic Impairment: Monitoring is recommended in patients with mild to moderate hepatic impairment. (8.6). Renal Impairment: Reduce XELODA starting dose in patients with moderate renal impairment (2.4, 8.7, 12.3). 8.1 Pregnancy. Risk SummaryBased on findings in animal reproduction studies and its mechanism of action, XELODA can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. Limited available human data are not sufficient to inform the drug-associated risk during pregnancy. In animal reproduction studies, administration of capecitabine to pregnant animals during the period of organogenesis caused embryo lethality and teratogenicity in mice and embryo lethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving the recommended dose respectively [see Data]. Apprise pregnant women of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Data. Animal 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 in human milk, or on its effects on milk production or the breast-fed infant. Capecitabine metabolites were present in the milk of lactating mice [see Data]. Because of the potential for serious adverse reactions from capecitabine exposure in breast-fed infants, advise women not to breastfeed during treatment with XELODA 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. Pregnancy TestingPregnancy testing is recommended for females of reproductive potential prior to initiating XELODA.. Contraception. FemalesXELODA can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment and for months following the final dose of XELODA.. MalesBased on genetic toxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for months following the final dose of XELODA [see Nonclinical Toxicology (13.1)]. InfertilityBased on animal studies, XELODA may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use. The safety and effectiveness of XELODA in pediatric patients have not been established. No clinical benefit was demonstrated in two single arm trials in pediatric patients with newly diagnosed brainstem gliomas and high grade 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 XELODA was similar.The first trial was conducted in 22 pediatric patients (median age years, range 5-17 years) with newly diagnosed non-disseminated intrinsic diffuse brainstem gliomas and high grade gliomas. In the dose-finding portion of the trial, patients received capecitabine with concomitant radiation therapy at doses ranging from 500 mg/m2 to 850 mg/m2 every 12 hours for up to weeks. After 2 week break, patients received 1250 mg/m2 capecitabine every 12 hours on Days 1-14 of 21-day cycle for up to cycles. The maximum tolerated dose (MTD) of capecitabine administered concomitantly with radiation therapy was 650 mg/m2 every 12 hours. The major dose limiting toxicities were palmar-plantar erythrodysesthesia and alanine aminotransferase (ALT) elevation.The second trial was conducted in 34 additional pediatric patients with newly diagnosed non-disseminated intrinsic diffuse brainstem gliomas (median age years, range 3-16 years) and 10 pediatric patients who received the MTD of capecitabine in the dose-finding trial and met the eligibility criteria for this trial. All patients received 650 mg/m2 capecitabine every 12 hours with concomitant radiation therapy for up to weeks. After 2 week break, patients received 1250 mg/m2 capecitabine every 12 hours on Days 1-14 of 21-day cycle for up to cycles.There was no improvement in one-year progression-free survival rate and one-year overall survival rate in pediatric patients with newly diagnosed intrinsic brainstem gliomas who received capecitabine relative to similar population of pediatric patients who participated in other clinical trials.The adverse reaction profile of capecitabine was consistent with the known adverse reaction profile in 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%), leukopenia (73%), hypokalemia (68%), thrombocytopenia (57%), hypoalbuminemia (55%), neutropenia (50%), low hematocrit (50%), hypocalcemia (48%), hypophosphatemia (45%) and hyponatremia (45%).. 8.5 Geriatric Use. Physicians should pay particular attention to monitoring the adverse effects of XELODA in the elderly [see Warnings and Precautions (5.10)].. 8.6Hepatic Insufficiency. Exercise caution when patients with mild to moderate hepatic dysfunction due to liver metastases are treated with XELODA. The effect of severe hepatic dysfunction on XELODA is not known [see Warnings and Precautions (5.11) and Clinical Pharmacology (12.3)]. 8.7Renal Insufficiency. Patients with moderate (creatinine clearance 30 to 50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment showed higher exposure for capecitabine, 5-DFUR, and FBAL than in those with normal renal function [see Contraindications (4.2), Warnings and Precautions (5.5), Dosage and Administration (2.4), and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Coagulopathy: May result in bleeding, death. Monitor anticoagulant response (e.g., INR) and adjust anticoagulant dose accordingly. (5.1)Diarrhea: May be severe. Interrupt XELODA treatment immediately until diarrhea resolves or decreases to grade 1. Recommend standard antidiarrheal treatments. (5.2)Cardiotoxicity: Common in patients with prior history of coronary artery disease. (5.3)Increased Risk of Severe or Fatal Adverse Reactions in Patients with Low or Absent Dihydropyrimidine Dehydrogenase (DPD) Activity: Withhold or permanently discontinue XELODA in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No XELODA dose has been proven safe in patients with absent DPD activity. (5.4) Dehydration and Renal Failure: Interrupt XELODA treatment until dehydration is corrected. Potential risk of acute renal failure secondary to dehydration. Monitor and correct dehydration. (5.5). Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception. (5.6, 8.1, 8.3)Mucocutaneous and Dermatologic Toxicity: Severe mucocutaneous reactions, Steven-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), have been reported. XELODA should be permanently discontinued in patients who experience severe mucocutaneous reaction during treatment. XELODA may induce hand-and-foot syndrome. Persistent or severe hand-and-foot syndrome can lead to loss of fingerprints which could impact patient identification. Interrupt XELODA treatment until the hand-and-foot syndrome event resolves or decreases in intensity. (5.7)Hyperbilirubinemia: Interrupt XELODA treatment immediately until the hyperbilirubinemia resolves or decreases in intensity. (5.8)Hematologic: Do not treat patients with neutrophil counts <1.5 109/L or thrombocyte counts <100 109/L. If grade 3-4 neutropenia or thrombocytopenia occurs, stop therapy until condition resolves. (5.9). Coagulopathy: May result in bleeding, death. Monitor anticoagulant response (e.g., INR) and adjust anticoagulant dose accordingly. (5.1). Diarrhea: May be severe. Interrupt XELODA treatment immediately until diarrhea resolves or decreases to grade 1. Recommend standard antidiarrheal treatments. (5.2). Cardiotoxicity: Common in patients with prior history of coronary artery disease. (5.3). Increased Risk of Severe or Fatal Adverse Reactions in Patients with Low or Absent Dihydropyrimidine Dehydrogenase (DPD) Activity: Withhold or permanently discontinue XELODA in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No XELODA dose has been proven safe in patients with absent DPD activity. (5.4) Dehydration and Renal Failure: Interrupt XELODA treatment until dehydration is corrected. Potential risk of acute renal failure secondary to dehydration. Monitor and correct dehydration. (5.5). Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception. (5.6, 8.1, 8.3). Mucocutaneous and Dermatologic Toxicity: Severe mucocutaneous reactions, Steven-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), have been reported. XELODA should be permanently discontinued in patients who experience severe mucocutaneous reaction during treatment. XELODA may induce hand-and-foot syndrome. Persistent or severe hand-and-foot syndrome can lead to loss of fingerprints which could impact patient identification. Interrupt XELODA treatment until the hand-and-foot syndrome event resolves or decreases in intensity. (5.7). Hyperbilirubinemia: Interrupt XELODA treatment immediately until the hyperbilirubinemia resolves or decreases in intensity. (5.8). Hematologic: Do not treat patients with neutrophil counts <1.5 109/L or thrombocyte counts <100 109/L. If grade 3-4 neutropenia or thrombocytopenia occurs, stop therapy until condition resolves. (5.9). 5.1Coagulopathy. Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored closely with great frequency and the anticoagulant dose should be adjusted accordingly [see Boxed Warning and Drug Interactions (7.1)]. 5.2Diarrhea. XELODA can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. In 875 patients with either metastatic breast or colorectal cancer who received XELODA monotherapy, the median time to first occurrence of grade to diarrhea was 34 days (range from to 369 days). The median duration of grade to diarrhea was days. National Cancer Institute of Canada (NCIC) grade diarrhea is defined as an increase of to stools/day or nocturnal stools, grade diarrhea as an increase of to stools/day or incontinence and malabsorption, and grade diarrhea as an increase of >=10 stools/day or grossly bloody diarrhea or the need for parenteral support. If grade 2, or diarrhea occurs, administration of XELODA should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade [see Dosage and Administration (2.3)]. Standard antidiarrheal treatments (e.g., loperamide) are recommended.Necrotizing enterocolitis (typhlitis) has been reported.. 5.3Cardiotoxicity. The cardiotoxicity observed with XELODA includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy. These adverse reactions may be more common in patients with prior history of coronary artery disease.. 5.4Dihydropyrimidine Dehydrogenase Deficiency. Based on postmarketing reports, patients with certain homozygous or certain compound heterozygous mutations in the DPD gene that result in complete or near complete absence of DPD activity are at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by XELODA (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions caused by XELODA. Withhold or permanently discontinue XELODA based on clinical assessment of the onset, duration and severity of the observed toxicities in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No XELODA dose has been proven safe for patients with complete absence of DPD activity. There is insufficient data to recommend specific dose in patients with partial DPD activity as measured by any specific test.. 5.5Dehydration and Renal Failure. Dehydration has been observed and may cause acute renal failure which can be fatal. Patients with pre-existing compromised renal function or who are receiving concomitant XELODA with known nephrotoxic agents are at higher risk. Patients with anorexia, asthenia, nausea, vomiting or diarrhea may rapidly become dehydrated. Monitor patients when XELODA is administered to prevent and correct dehydration at the onset. If grade (or higher) dehydration occurs, XELODA treatment should be immediately interrupted and the dehydration corrected. Treatment should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled. Dose modifications should be applied for the precipitating adverse event as necessary [see Dosage and Administration (2.3) ].Patients with moderate renal impairment at baseline require dose reduction [see Dosage and Administration (2.4)]. Patients with mild and moderate renal impairment at baseline should be carefully monitored for adverse reactions. Prompt interruption of therapy with subsequent dose adjustments is recommended if patient develops grade to adverse event as outlined in Table [see Dosage and Administration (2.3), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].. 5.6 Embryo-Fetal Toxicity. Based on findings from animal reproduction studies and its mechanism of action, XELODA may cause fetal harm when given to pregnant woman [see Clinical Pharmacology (12.1)]. Limited available data are not sufficient to inform use of XELODA in pregnant women. 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 respectively [see Use in Specific Populations (8.1)]. Apprise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment and for months following the last dose of XELODA [see Use in Specific Populations (8.3)].. 5.7Mucocutaneous and Dermatologic Toxicity. Severe mucocutaneous reactions, some with fatal outcome, such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis (TEN) can occur in patients treated with XELODA [see Adverse Reactions (6.4) ]. XELODA should be permanently discontinued in patients who experience severe mucocutaneous reaction possibly attributable to XELODA treatment.Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) is cutaneous toxicity. Median time to onset was 79 days (range from 11 to 360 days) with severity range of grades to for patients receiving XELODA monotherapy in the metastatic setting. Grade is characterized by any of the following: numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt normal activities. Grade hand-and-foot syndrome is defined as painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patients activities of daily living. Grade hand-and-foot syndrome is defined as moist desquamation, ulceration, blistering or severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living. Persistent or severe hand-and-foot syndrome (grade and above) can eventually lead to loss of fingerprints which could impact patient identification. If grade or hand-and-foot syndrome occurs, administration of XELODA should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade hand-and-foot syndrome, subsequent doses of XELODA should be decreased [see Dosage and Administration (2.3)].. 5.8Hyperbilirubinemia. In 875 patients with either metastatic breast or colorectal cancer who received at least one dose of XELODA 1250 mg/m2 twice daily as monotherapy for weeks followed by 1-week rest period, grade (1.5-3 ULN) hyperbilirubinemia occurred in 15.2% (n=133) of patients and grade (>3 ULN) hyperbilirubinemia occurred in 3.9% (n=34) of patients. Of 566 patients who had hepatic metastases at baseline and 309 patients without hepatic metastases at baseline, grade or hyperbilirubinemia occurred in 22.8% and 12.3%, respectively. Of the 167 patients with grade or hyperbilirubinemia, 18.6% (n=31) also had postbaseline elevations (grades to 4, without elevations at baseline) in alkaline phosphatase and 27.5% (n=46) had postbaseline elevations in transaminases at any time (not necessarily concurrent). The majority of these patients, 64.5% (n=20) and 71.7% (n=33), had liver metastases at baseline. In addition, 57.5% (n=96) and 35.3% (n=59) of the 167 patients had elevations (grades to 4) at both prebaseline and postbaseline in alkaline phosphatase or transaminases, respectively. Only 7.8% (n=13) and 3.0% (n=5) had grade or elevations in alkaline phosphatase or transaminases.In the 596 patients treated with XELODA as first-line therapy for metastatic colorectal cancer, the incidence of grade or hyperbilirubinemia was similar to the overall clinical trial safety database of XELODA monotherapy. The median time to onset for grade or hyperbilirubinemia in the colorectal cancer population was 64 days and median total bilirubin increased from um/L at baseline to 13 um/L during treatment with XELODA. Of the 136 colorectal cancer 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 251 patients with metastatic breast cancer who received combination of XELODA and docetaxel, grade (1.5 to x ULN) hyperbilirubinemia occurred in 7% (n=17) and grade (>3 ULN) hyperbilirubinemia occurred in 2% (n=5).If drug-related grade to elevations in bilirubin occur, administration of XELODA should be immediately interrupted until the hyperbilirubinemia decreases to <=3.0 ULN [see recommended dose modifications under Dosage and Administration (2.3)].. 5.9 Hematologic. In 875 patients with either metastatic breast or colorectal cancer who received dose of 1250 mg/m2 administered twice daily as monotherapy for weeks followed by 1-week rest period, 3.2%, 1.7%, and 2.4% of patients had grade or neutropenia, thrombocytopenia or decreases in hemoglobin, respectively. In 251 patients with metastatic breast cancer who received dose of XELODA in combination with docetaxel, 68% had grade or neutropenia, 2.8% had grade or thrombocytopenia, and 9.6% had grade or anemia.Patients with baseline neutrophil counts of <1.5 109/L and/or thrombocyte counts of <100 109/L should not be treated with XELODA. If unscheduled laboratory assessments during treatment cycle show grade or hematologic toxicity, treatment with XELODA should be interrupted.. 5.10Geriatric Patients. Patients >=80 years old may experience greater incidence of grade or adverse reactions. In 875 patients with either metastatic breast or colorectal cancer who received XELODA monotherapy, 62% of the 21 patients >=80 years of age treated with XELODA experienced treatment-related grade or adverse event: diarrhea in (28.6%), nausea in (14.3%), hand-and-foot syndrome in (14.3%), and vomiting in (9.5%) patients. Among the 10 patients 70 years of age and greater (no patients were >80 years of age) treated with XELODA in combination with docetaxel, 30% (3 out of 10) of patients experienced grade or diarrhea and stomatitis, and 40% (4 out of 10) experienced grade hand-and-foot syndrome.Among the 67 patients >=60 years of age receiving XELODA in combination with docetaxel, the incidence of grade or treatment-related adverse reactions, treatment-related serious adverse reactions, withdrawals due to adverse reactions, treatment discontinuations due to adverse reactions and treatment discontinuations within the first two treatment cycles was higher than in the <60 years of age patient group.In 995 patients receiving XELODA as adjuvant therapy for Dukes colon cancer after resection of the primary tumor, 41% of the 398 patients >=65 years of age treated with XELODA experienced treatment-related grade or adverse event: hand-and-foot syndrome in 75 (18.8%), diarrhea in 52 (13.1%), stomatitis in 12 (3.0%), neutropenia/granulocytopenia in 11 (2.8%), vomiting in (1.5%), and nausea in (1.3%) patients. In patients >=65 years of age (all randomized population; capecitabine 188 patients, 5-FU/LV 208 patients) treated for Dukes colon cancer after resection of the primary tumor, the hazard ratios for disease-free survival and overall survival for XELODA compared to 5-FU/LV were 1.01 (95% C.I. 0.80 1.27) and 1.04 (95% C.I. 0.79 1.37), respectively.. 5.11Hepatic Insufficiency. Patients with mild to moderate hepatic dysfunction due to liver metastases should be carefully monitored when XELODA is administered. The effect of severe hepatic dysfunction on the disposition of XELODA is not known [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].. 5.12Combination With Other Drugs. Use of XELODA in combination with irinotecan has not been adequately studied.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Adjuvant Treatment of Colon Cancer. Single AgentThe safety of XELODA as single agent was evaluated in patients with Stage III colon cancer in X-ACT [see Clinical Studies (14.1)]. Patients received XELODA 1,250 mg/m2 orally twice daily for the first 14 days of 21-day cycle (N=995) or leucovorin 20 mg/m2 intravenously followed by fluorouracil 425 mg/m2 as an intravenous bolus on days to of each 28-day cycle (N=974). Among patients who received XELODA, the median duration of treatment was 5.4 months. Deaths due to all causes occurred in 0.8% of patients who received XELODA on study or within 28 days of receiving study drug. Permanent discontinuation due to an adverse reaction occurred in 11% of patients who received XELODA.Most common adverse reactions (>30%) were palmar-plantar erythrodysesthesia syndrome, diarrhea, and nausea.Tables and summarize the adverse reactions and laboratory abnormalities in X-ACT.Table 2Adverse Reactions (>=10%) in Patients Who Received XELODA for Adjuvant Treatment of Colon Cancer in X-ACTAdverse ReactionXELODA(N=995)Fluorouracil Leucovorin(N=974)All Grades(%)Grade or (%)All Grades(%)Grade or (%)Skin and Subcutaneous TissuePalmar-plantar erythrodysesthesia syndrome60179<1GastrointestinalDiarrhea47126514Nausea342472Stomatitis2226014Vomiting152212Abdominal pain143162GeneralFatigue16<1161Asthenia10<1101Lethargy10<19<1Clinically relevant adverse reactions in <10% of patients are presented below:Eye: conjunctivitisGastrointestinal: constipation, upper abdominal pain, dyspepsiaGeneral: pyrexiaMetabolism and Nutrition: anorexiaNervous System: dizziness, dysgeusia, headacheSkin Subcutaneous Tissue: rash, alopecia, erythemaTable 3Grade or Laboratory Abnormalities (>1%) in Patients Who Received XELODA as Single Agent for Adjuvant Treatment of Colon Cancer in X-ACTLaboratory Abnormality XELODA(N=995)Fluorouracil Leucovorin(N=974)Grade or 4Grade or 4(%)(%)Bilirubin increased206Lymphocytes decreased1313Neutrophils/granulocytes decreased2.426Calcium decreased2.32.2Neutrophils decreased2.226ALT increased1.60.6Calcium increased1.10.7Hemoglobin decreased11.2Platelets decreased10.7. In Combination with Oxaliplatin-Containing RegimensThe safety of XELODA 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 XELODA 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 XELODA as single agent, with the exception of an increased incidence of neurosensory toxicity.. Perioperative Treatment of Rectal CancerThe safety of XELODA for the perioperative treatment of adults with locally advanced rectal cancer as component of chemoradiotherapy was derived from published literature [see Clinical Studies (14.1)]. The safety of XELODA for the perioperative treatment of adults with locally advanced rectal cancer as component of chemoradiotherapy was similar to those in patients treated with XELODA as single agent, with the exception of an increased incidence of diarrhea.. Metastatic Colorectal Cancer. Single AgentThe safety of XELODA as single agent was evaluated in pooled metastatic colorectal cancer population (Study SO14695 and Study SO14796) [see Clinical Studies (14.1)]. Patients received XELODA 1,250 mg/m2 orally twice day for the first 14 days of 21-day cycle (N=596) or leucovorin 20 mg/m2 intravenously followed by fluorouracil 425 mg/m2 as an intravenous bolus on days to of each 28-day cycle (N=593). Among the patients who received XELODA, the median duration of treatment was 4.6 months.Deaths due to all causes occurred in 8% of patients who received XELODA on study or within 28 days of receiving study drug. Permanent discontinuation due to an adverse reaction or intercurrent illness occurred in 13% of patients who received XELODA. 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 XELODA in Pooled Metastatic Colorectal Cancer Population (Study SO14695 and Study SO14796)Adverse ReactionXELODAFluorouracil Leucovorin(N=596)(N=593)All Grades(%)Grade 3(%)Grade 4(%)All Grades(%)Grade 3(%)Grade 4(%)- Not observedNA Not ApplicableBlood and Lymphatic System Anemia802<1791<1 Neutropenia131246813Gastrointestinal Diarrhea5513261102 Nausea434-513<1 Abdominal pain359<1315- Vomiting274<1304<1 Stomatitis252<162141 Constipation141<1171- Gastrointestinal motility disorder10<1-7<1- Oral discomfort10--10--Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia syndrome5417NA61NA Dermatitis271-261-Hepatobiliary Hyperbilirubinemia481851733General FatigueIncludes weakness 424-464- Pyrexia181-212- Edema151-91- Pain121-101-Metabolism and Nutrition Decreased appetite263<1312<1Respiratory Thoracic and Mediastinal Dyspnea141-10<11Eye Eye irritation13--10<1-Nervous System Peripheral sensory neuropathy10--4-- Headache101-7--Musculoskeletal Back pain102-9<1-Clinically relevant adverse reactions in <10% of patients are presented below:Eye: abnormal visionGastrointestinal: upper gastrointestinal tract inflammatory disorders, gastrointestinal hemorrhage, ileus General: chest painInfections: viralMetabolism and Nutrition: dehydrationMusculoskeletal: arthralgiaNervous System: dizziness (excluding vertigo), insomnia, taste disturbancePsychiatric: mood alteration, depressionRespiratory, Thoracic, and Mediastinal: cough, pharyngeal disorderSkin and Subcutaneous Tissue: skin discoloration, alopeciaVascular: venous thrombosis. In Combination with OxaliplatinThe safety of XELODA 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 XELODA 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 XELODA as single agent, with the exception of an increased incidence of peripheral neuropathy.. Metastatic Breast Cancer In Combination with DocetaxelThe safety of XELODA in combination with docetaxel was evaluated in patients with metastatic breast cancer in Study SO14999 [see Clinical Studies (14.2)]. Patients received XELODA 1,250 mg/m2 orally twice daily for the first 14 days of 21-day cycle with docetaxel 75 mg/m2 as 1-hour intravenous infusion on day of each 21-day cycle for at least weeks or docetaxel 100 mg/m2 as 1-hour intravenous infusion on day of each 21-day cycle for at least weeks. Among patients who received XELODA, the mean duration of treatment was 4.2 months. Permanent discontinuation due to an adverse reaction occurred in 26% of patients who received XELODA. Dosage interruptions due to an adverse reaction occurred in 79% of patients who received XELODA 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 5Adverse Reactions (>=10%) in Patients Who Received XELODA with Docetaxel for Metastatic Breast Cancer in Study SO14999Adverse ReactionXELODA with DocetaxelDocetaxel(N=251)(N=255)All Grades(%)Grade 3(%)Grade 4(%)All Grades(%)Grade 3(%)Grade 4(%)- Not observedNA Not ApplicableGastrointestinalDiarrhea6714<1485<1Stomatitis6717<1435-Nausea457-362-Vomiting3541242-Abdominal pain303<1242-Constipation202-18--Dyspepsia14--81-Skin and Subcutaneous TissuePalmar-plantar erythrodysesthesia syndrome6324NA81NAAlopecia416-427-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-Clinically relevant adverse reactions in <10% of patients are presented below:Blood and Lymphatic System: agranulocytosis, prothrombin decreased Cardiac: supraventricular tachycardia Eye: conjunctivitis, eye irritationGastrointestinal: ileus, necrotizing enterocolitis, esophageal ulcer, hemorrhagic diarrhea, dry mouthGeneral: chest pain (non-cardiac), lethargy, pain, influenza-like illnessHepatobiliary: jaundice, abnormal liver function tests, hepatic failure, hepatic coma, hepatotoxicityImmune System: hypersensitivityInfection: hypoesthesia, neutropenic sepsis, sepsis, bronchopneumonia, oral candidiasis, urinary tract infectionMetabolism and Nutrition: weight decreasedMusculoskeletal and Connective Tissue: bone painNervous System: insomnia, peripheral neuropathy, ataxia, syncope, taste loss, polyneuropathy, migrainePsychiatric: depressionRenal and Urinary: renal failureRespiratory, Thoracic and Mediastinal: upper respiratory tract infection, pleural effusion, epistaxis, rhinorrheaSkin and Subcutaneous Tissue: pruritis, rash erythematous, dermatitis, nail discoloration, onycholysis Vascular: lymphedema, hypotension, venous phlebitis and thrombophlebitis, postural hypotension, flushingTable summarizes the laboratory abnormalities in this trial.Table 6Laboratory Abnormalities (>=20%) in Patients Who Received XELODA with Docetaxel for Metastatic Breast Cancer in Study SO14999Laboratory AbnormalityXELODA with Docetaxel Docetaxel (N=251)(N=255)All Grades(%)Grade 3(%)Grade 4(%)All Grades(%)Grade 3(%)Grade 4(%)HematologicLymphocytopenia994841984440Leukopenia913724884233Neutropenia862049871066Anemia8073835<1Thrombocytopenia41212312HepatobiliaryHyperbilirubinemia2072622. Single AgentThe safety of XELODA as single agent was evaluated in patients with metastatic breast cancer in Study SO14697 [see Clinical Studies (14.2)]. Patients received XELODA 1,250 mg/m2 orally twice daily for the first 14 days of 21-day cycle. The mean duration of treatment was 3.7 months.Permanent discontinuation due to an adverse reaction or intercurrent illness occurred in 8% of patients.Most common adverse reactions (>30%) were lymphopenia, anemia, diarrhea, hand-and-foot syndrome, nausea, fatigue, vomiting, and dermatitis.Table summarizes the adverse reactions in Study SO14697.Table 7Adverse Reactions (>=10%) in Patients Who Received XELODA for Metastatic Breast Cancer in Study SO14697Adverse ReactionXELODA(n=162)All Grades(%)Grade 3(%)Grade 4(%) = Not observed NA Not ApplicableBlood and Lymphatic SystemLymphopenia944415Anemia7231Neutropenia2622Thrombocytopenia2431GastrointestinalDiarrhea57123Nausea534-Vomiting374-Stomatitis247-Abdominal pain204-Constipation151-Skin and Subcutaneous TissueHand-and-foot syndrome5711NADermatitis371-GeneralFatigue418-Pyrexia121-Metabolism and NutritionAnorexia233-HepatobiliaryHyperbilirubinemia2292Nervous SystemParesthesia211-EyeEye irritation15--. Pooled Safety PopulationClinically relevant adverse reactions in <10% of patients who received XELODA as single agent are presented below. Blood Lymphatic System: leukopenia, coagulation disorder, bone marrow depression, pancytopeniaCardiac: tachycardia, bradycardia, atrial fibrillation, myocarditis, edemaEar: vertigoEye: conjunctivitisGastrointestinal: abdominal distension, dysphagia, proctalgia, gastric ulcer, ileus, gastroenteritis, dyspepsiaGeneral: chest pain, influenza-like illness, hot flushes, pain, thirst, fibrosis, hemorrhage, edema, pain in limbHepatobiliary: hepatic fibrosis, hepatitis, cholestatic hepatitis, abnormal liver function testsImmune System: drug hypersensitivityInfections: bronchitis, pneumonia, keratoconjunctivitis, sepsis, fungal infectionsMetabolism and Nutrition: cachexia, hypertriglyceridemia, hypokalemia, hypomagnesemia, dehydrationMusculoskeletal and Connective Tissue: myalgia, arthritis, muscle weaknessNervous System: insomnia, ataxia, tremor, dysphasia, encephalopathy, dysarthria, impaired balance, headache, dizzinessPsychiatric: depression, confusionRenal and Urinary: renal impairmentRespiratory, Mediastinal and Thoracic: cough, epistaxis, respiratory distress, dyspneaSkin and Subcutaneous Tissue: nail disorder, sweating increased, photosensitivity reaction, skin ulceration, pruritus, radiation recall syndromeVascular: hypotension, hypertension, lymphedema, pulmonary embolism. Unresectable or Metastatic Gastric, Esophageal, or Gastroesophageal Junction CancerThe safety of XELODA 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 XELODA 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 XELODA.The safety of XELODA 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 XELODA for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma was consistent with the known safety profile of XELODA.. Pancreatic CancerThe safety of XELODA for the adjuvant treatment of adults with pancreatic adenocarcinoma as component of combination chemotherapy regimen was derived from the published literature [see Clinical Studies (14.4)]. The safety of XELODA for the adjuvant treatment of adults with pancreatic adenocarcinoma as component of combination chemotherapy regimen was consistent with the known safety profile of XELODA.

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment. The exposure of capecitabine increases in patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the safety and pharmacokinetics of XELODA is unknown [see Clinical Pharmacology (12.3)]. Monitor patients with hepatic impairment more frequently for adverse reactions.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Population-based exposure-effect analyses demonstrated positive association between AUC of fluorouracil and grade 3-4 hyperbilirubinemia.

PHARMACOGENOMICS SECTION.

12.5 Pharmacogenomics. The DPYD gene encodes the enzyme DPD, which is responsible for the catabolism of >80% of fluorouracil. Approximately 3-5% 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 XELODA. 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 XELODA.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 (DPYD 13), 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)].

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of XELODA. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Eye: lacrimal duct stenosis, corneal disorders including keratitisHepatobiliary: hepatic failureImmune System Disorders: angioedemaNervous System: toxic leukoencephalopathyRenal Urinary: acute renal failure secondary to dehydration including fatal 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.

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).

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. The exposure of capecitabine and its inactive metabolites (5-DFUR and FBAL) increases in patients with CLcr <50 mL/min as determined by Cockcroft-Gault [see Clinical Pharmacology (12.3)]. Reduce the dosage for patients with CLcr of 30 to 50 mL/min [see Dosage and Administration (2.6)]. There is limited experience with XELODA in patients with CLcr <30 mL/min, and dosage has not been established in those patients. If no treatment alternative exists, XELODA 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.