ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Adjuvant Colon Cancer. Table 11 shows the adverse events 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 events. 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 12 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 11Percent Incidence of Adverse Events 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 12Percent 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)IV 5-FU/LV(n=974)Grade 3/4 %Grade 3/4 Increased ALAT (SGPT)1.60.6 Increased calcium 1.10.7 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. Metastatic Colorectal Cancer. Table 13 shows the adverse events 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 events/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 13 Pooled Phase Colorectal Trials: Percent Incidence of Adverse Events 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. Breast Cancer Combination. The following data are shown for the combination study with XELODA and docetaxel in patients with metastatic breast cancer in Table 14 and Table 15. 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 events. The percentage of patients requiring dose reductions due to adverse events was 65% in the combination arm and 36% in the monotherapy arm. The percentage of patients requiring treatment interruptions due to adverse events 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 14Percent 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/bidWith Docetaxel75 mg/m2/3 weeksDocetaxel100 mg/m2/3 weeks(n=251)(n=255)Total%Grade 3%Grade 4%Total%Grade 3%Grade 4%- Not observedNA Not ApplicableNumber of Patients With at Least One Adverse Event9976.529.19757.631.8Body System/Adverse EventGI Diarrhea6714<1485<1 Stomatitis6717<143 5- Nausea457-362- Vomiting3541242- Constipation202-18-- Abdominal Pain30<3<1242- Dyspepsia14--81- Dry Mouth6<1-5--Skin and Subcutaneous Hand-and-Foot Syndrome6324NA8 1NA 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 <1-6 2- 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- Myalgia15 -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 Effusion2 -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 15Percent of Patients With Laboratory Abnormalities Participating in the XELODA and Docetaxel Combination vs Docetaxel Monotherapy StudyAdverse EventXELODA 1250 mg/m2/bidWith 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. Breast Cancer XELODA Monotherapy. The 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 events/intercurrent illness.Table 16Percent Incidence of Adverse Events 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. XELODA and Docetaxel in Combination. Shown below by body system are the clinically relevant adverse events in <5% of patients in the overall clinical trial safety database of 251 patients (Study Details) reported as related to the administration of XELODA in combination with docetaxel and that were clinically at least remotely relevant. In parentheses is the incidence of grade and occurrences of each adverse event.It is anticipated that the same types of adverse events observed in the XELODA monotherapy studies may be observed in patients treated with the combination of XELODA plus docetaxel.Gastrointestinal: ileus (0.39), necrotizing enterocolitis (0.39), esophageal ulcer (0.39), hemorrhagic diarrhea (0.80)Neurological: ataxia (0.39), syncope (1.20), taste loss (0.80), polyneuropathy (0.39), migraine (0.39)Cardiac: supraventricular tachycardia (0.39)Infection: neutropenic sepsis (2.39), sepsis (0.39), bronchopneumonia (0.39)Blood and Lymphatic: agranulocytosis (0.39), prothrombin decreased (0.39)Vascular: hypotension (1.20), venous phlebitis and thrombophlebitis (0.39), postural hypotension (0.80)Renal: renal failure (0.39)Hepatobiliary: jaundice (0.39), abnormal liver function tests (0.39), hepatic failure (0.39), hepatic coma (0.39), hepatotoxicity (0.39)Immune System: hypersensitivity (1.20). XELODA Monotherapy Metastatic Breast and Colorectal Cancer. Shown below by body system are the clinically relevant adverse events in <5% of patients in the overall clinical trial safety database of 875 patients (phase colorectal studies -- 596 patients, phase colorectal study -- 34 patients, phase breast cancer studies -- 245 patients) reported as related to the administration of XELODA and that were clinically at least remotely relevant. In parentheses is the incidence of grade or occurrences of each adverse event.Gastrointestinal: abdominal distension, dysphagia, proctalgia, ascites (0.1), gastric ulcer (0.1), ileus (0.3), toxic dilation of intestine, gastroenteritis (0.1)Skin and Subcutaneous: 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 and 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)Postmarketing: hepatic failure, lacrimal duct stenosis.

BOXED WARNING SECTION.

WARNING. 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 CLINICAL PHARMACOLOGY and PRECAUTIONS). 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis and Impairment of Fertility Adequate studies investigating the carcinogenic potential of XELODA 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.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. XELODA is relatively non-cytotoxic in vitro. This drug is enzymatically converted to 5-fluorouracil (5-FU) in vivo.. Bioactivation. Capecitabine is readily absorbed from the gastrointestinal tract. 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-deoxy-5-fluorouridine (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.Metabolic Pathway of capecitabine to 5-FU. Figure. Mechanism of Action. 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.. Pharmacokinetics in Colorectal Tumors and Adjacent Healthy Tissue. 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.. Human Pharmacokinetics. 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 elimination half-life of both parent capecitabine and 5-FU was about 3/4 of an hour. The inter-patient variability in the Cmax and AUC of 5-FU was greater than 85%.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).. Absorption, Distribution, Metabolism and Excretion. 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 PRECAUTIONS and DOSAGE AND ADMINISTRATION). Plasma 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%).Capecitabine is extensively metabolized enzymatically to 5-FU. The 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.Capecitabine 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.A clinical phase study evaluating 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.. Special Populations. 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 DOSAGE AND ADMINISTRATION).. Hepatic Insufficiency. XELODA 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 PRECAUTIONS and DOSAGE AND ADMINISTRATION).. Renal Insufficiency. Following 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 CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION). Drug-Drug Interactions. Anticoagulants. In 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 PRECAUTIONS: Drug-Drug Interactions).. Drugs Metabolized by Cytochrome P450 Enzymes. In vitro enzymatic studies with human liver microsomes indicated that capecitabine and its metabolites (5-DFUR, 5-DFCR, 5-FU, and FBAL) had no inhibitory effects on substrates of cytochrome P450 for the major isoenzymes such as 1A2, 2A6, 3A4, 2C9, 2C19, 2D6, and 2E1.. Antacid. When 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.XELODA has low potential for pharmacokinetic interactions related to plasma protein binding.

CLINICAL STUDIES SECTION.

CLINICAL STUDIES. General. The 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.. Adjuvant Colon Cancer. multicenter randomized, controlled phase clinical trial in patients with Dukes colon cancer 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 1. The baseline characteristics were well-balanced between arms. Table Baseline 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). 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 2).Table Summary 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 53 months. The hazard ratio for DFS for XELODA compared to 5-FU/LV was 0.87 (95% C.I. 0.76 1.00). 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. Survival data were not mature at the time of the analysis with median follow-up of 53 months. The comparison of overall survival did not reach statistical significance for the test of difference (HR 0.88, 95% C.I. 0.74 1.05; = 0.169).Table Efficacy of XELODA vs 5-FU/LV in Adjuvant Treatment of Colon CancerApproximately 85% had 3-year DFS information All Randomized PopulationXELODA(n=1004)5-FU/LV(n=983)Median follow-up (months)53533-year Disease-free Survival Rates66.062.9Hazard Ratio(XELODA/5-FU/LV)(95% C.I. for Hazard Ratio),p-valueLog-rank test for differences of XELODA vs 5-FU/LV 0.87(0.76 1.00)p 0.055Figure Kaplan-Meier Estimates of Disease-Free Survival (All Randomized Population)XELODA has been demonstrated to be non-inferior to 5-FU/LV. Figure. Metastatic Colorectal Cancer. Data 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 4.Table Baseline 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 and Table 6.Table Efficacy 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)0.9995% C.I. for Hazard Ratio(0.84-1.17)Survival(Median, days, 95% C.I.)380 (321-434)407 (366-446)Hazard Ratio (XELODA/5-FU/LV)1.0095% C.I. for Hazard Ratio(0.84-1.18)Table Efficacy 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)0.9795% C.I. for Hazard Ratio(0.82-1.14)Survival(Median, days, 95% C.I.)404 (367-452)369 (338-430)Hazard Ratio (XELODA/5-FU/LV)0.9295% C.I. for Hazard Ratio(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 5, Table 6, and Figure 2). Figure. Breast Cancer. XELODA has been evaluated in clinical trials in combination with docetaxel (Taxotere(R)) and as monotherapy.. Breast Cancer Combination Therapy. The 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 7.Table Baseline 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 8, Figure 3, and Figure 4.Table 8Efficacy 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. Figure. Breast Cancer Monotherapy. The 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 9. 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 Baseline 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 10.Table 10Response 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 9). The median time to progression was 90 days and the median survival was 306 days.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. 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. XELODA is contraindicated in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency. XELODA is also contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min [Cockroft and Gault]) (see CLINICAL PHARMACOLOGY: Special Populations).

DESCRIPTION SECTION.

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 20C.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.

DOSAGE AND ADMINISTRATION. 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. XELODA tablets should be swallowed with water within 30 minutes after meal. 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 17 displays the total daily dose by body surface area and the number of tablets to be taken at each dose.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 17XELODA Dose Calculation According to Body Surface AreaDose Level 1250 mg/m2 Twice DayNumber of Tablets to be Taken atEach Dose (Morning and Evening)Surface Area(m2)Total DailyDoseTotal Daily Dose divided by to allow equal morning and evening doses (mg)150 mg500 mg<= 1.25 3000031.26-1.37 3300131.38-1.51 3600231.52-1.65 4000041.66-1.77 4300141.78-1.91 4600241.92-2.05 5000052.06-2.17 530015>= 2.18560025. Dose Management Guidelines. XELODA 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). 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.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 PRECAUTIONS: Drug-Drug Interactions).XELODA dose modification scheme as described below (see Table 18 and Table 19) is recommended for the management of adverse events. Table 18 XELODA in Combination With Docetaxel Dose Reduction ScheduleToxicityNCIC GradesNational Cancer Institute of Canada Common Toxicity Criteria were used except for hand-and-foot syndrome (see PRECAUTIONS). Grade 2Grade 3Grade 41st appearanceGrade occurring during the 14 days of XELODA treatment: interrupt XELODA treatment until resolved to grade 0-1. Treatment may be resumed during the cycle at the same dose of XELODA. Doses of XELODA missed during treatment cycle are not to be replaced. Prophylaxis for toxicities should be implemented where possible. Grade persisting at the time the next XELODA/docetaxel treatment is due: delay treatment until resolved to grade 0-1, then continue at 100% of the original XELODA and docetaxel dose. Prophylaxis for toxicities should be implemented where possible.Grade occurring during the 14 days of XELODA treatment: interrupt the XELODA treatment until resolved to grade 0-1. Treatment may be resumed during the cycle at 75% of the XELODA dose. Doses of XELODA missed during treatment cycle are not to be replaced. Prophylaxis for toxicities should be implemented where possible. Grade persisting at the time the next XELODA/docetaxel treatment is due: delay treatment until resolved to grade 0-1. For patients developing grade toxicity at any time during the treatment cycle, upon resolution to grade 0-1, subsequent treatment cycles should be continued at 75% of the original XELODA dose and at 55 mg/m2 of docetaxel. Prophylaxis for toxicities should be implemented where possible.Discontinue treatment unless treating physician considers it to be in the best interest of the patient to continue with XELODA at 50% of original dose.2nd appearance of same toxicityGrade occurring during the 14 days of XELODA treatment: interrupt XELODA treatment until resolved to grade 0-1. Treatment may be resumed during the cycle at 75% of original XELODA dose. Doses of XELODA missed during treatment cycle are not to be replaced. Prophylaxis for toxicities should be implemented where possible. Grade persisting at the time the next XELODA/docetaxel treatment is due: delay treatment until resolved to grade 0-1. For patients developing 2nd occurrence of grade toxicity at any time during the treatment cycle, upon resolution to grade 0-1, subsequent treatment cycles should be continued at 75% of the original XELODA dose and at 55 mg/m2 of docetaxel. Prophylaxis for toxicities should be implemented where possible. Grade occurring during the 14 days of XELODA treatment: interrupt the XELODA treatment until resolved to grade 0-1. Treatment may be resumed during the cycle at 50% of the XELODA dose. Doses of XELODA missed during treatment cycle are not to be replaced. Prophylaxis for toxicities should be implemented where possible. Grade persisting at the time the next XELODA/docetaxel treatment is due: delay treatment until resolved to grade 0-1. For patients developing grade toxicity at any time during the treatment cycle, upon resolution to grade 0-1, subsequent treatment cycles should be continued at 50% of the original XELODA dose and the docetaxel discontinued. Prophylaxis for toxicities should be implemented where possible. Discontinue treatment.3rd appearance of same toxicityGrade occurring during the 14 days of XELODA treatment: interrupt XELODA treatment until resolved to grade 0-1. Treatment may be resumed during the cycle at 50% of the original XELODA dose. Doses of XELODA missed during treatment cycle are not to be replaced. Prophylaxis for toxicities should be implemented where possible. Grade persisting at the time the next XELODA/docetaxel treatment is due: delay treatment until resolved to grade 0-1. For patients developing 3rd occurrence of grade toxicity at any time during the treatment cycle, upon resolution to grade 0-1, subsequent treatment cycles should be continued at 50% of the original XELODA dose and the docetaxel discontinued. Prophylaxis for toxicities should be implemented where possible.Discontinue treatment.4th appearance of same toxicityDiscontinue treatment.Dose modification for the use of XELODA as monotherapy is shown in Table 19.Table 19 Recommended Dose Modifications With XELODA MonotherapyToxicity NCIC GradesNational Cancer Institute of Canada Common Toxicity Criteria were used except for the hand-and-foot syndrome (see PRECAUTIONS). During Course of TherapyDose Adjustment for Next Treatment (% of starting dose)o Grade Maintain dose levelMaintain dose levelo Grade -1st appearanceInterrupt until resolved to grade 0-1100%-2nd appearanceInterrupt until resolved to grade 0-175%-3rd appearanceInterrupt until resolved to grade 0-150%-4th appearanceDiscontinue treatment permanentlyo Grade -1st appearanceInterrupt until resolved to grade 0-175%-2nd appearanceInterrupt until resolved to grade 0-150%-3rd appearanceDiscontinue treatment permanentlyo Grade -1st appearanceDiscontinue permanently OR If physician deems it to be in the patients best interest to continue, interrupt until resolved to grade 0-150%Dosage modifications are not recommended for grade events. Therapy with XELODA should be interrupted upon the occurrence of grade or adverse experience. Once the adverse event has resolved or decreased in intensity to grade 1, then XELODA therapy may be restarted at full dose or as adjusted according to Table 18 and Table 19. If grade experience occurs, therapy should be discontinued or interrupted until resolved or decreased to grade 1, and therapy should be restarted at 50% of the original dose. Doses of XELODA omitted for toxicity are not replaced or restored; instead the patient should resume the planned treatment cycles.. Adjustment of Starting Dose in Special Populations. Hepatic Impairment. In patients with mild to moderate hepatic dysfunction due to liver metastases, no starting dose adjustment is necessary; however, patients should be carefully monitored. Patients with severe hepatic dysfunction have not been studied.. Renal Impairment. No 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 CLINICAL PHARMACOLOGY: Special Populations). Subsequent dose adjustment is recommended as outlined in Table 18 and Table 19 if patient develops grade to adverse event (see WARNINGS). The starting dose adjustment recommendations for patients with moderate renal impairment apply both to XELODA monotherapy and XELODA in combination use with docetaxel.Cockroft and Gault Equation: (140 age [yrs]) (body wt [kg])Creatinine clearance for males -------------------------- (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.

DRUG INTERACTIONS SECTION.

Drug-Drug Interactions.

GENERAL PRECAUTIONS SECTION.

General. Patients receiving therapy with XELODA should be monitored by physician experienced in the use of cancer chemotherapeutic agents. Most adverse events are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced (see DOSAGE AND ADMINISTRATION).

GERIATRIC USE SECTION.

Geriatric Use. Physicians should pay particular attention to monitoring the adverse effects of XELODA in the elderly (see WARNINGS: Geriatric Patients).

HOW SUPPLIED SECTION.

HOW SUPPLIED. XELODA is supplied as biconvex, oblong film-coated tablets, available in bottles as follows:150 mgcolor: light peachengraving: XELODA on one side, 150 on the other500 mgcolor: peachengraving: XELODA on one side, 500 on the other They are supplied by State of Florida DOH Central Pharmacy as follows:NDCStrengthQuantity/FormColorSource Prod. Code53808-0411-1500 mg30 Tablets in Blister Packlight peach0004-1101. Storage Conditions. Store at 25C (77F); excursions permitted to 15 to 30C (59 to 86F). [See USP Controlled Room Temperature]. KEEP TIGHTLY CLOSED.For full Taxotere prescribing information, please refer to Taxotere Package Insert.This product was Manufactured By:Hoffmann-La Roche Inc.340 Kingsland StreetNutley, NJ 07110And Repackaged By:State of Florida DOH Central Pharmacy104-2 Hamilton Park DriveTallahassee, FL 32304United States.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Colorectal 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). Although neither XELODA nor combination chemotherapy prolongs overall survival (OS), combination chemotherapy has been demonstrated to improve disease-free survival compared to 5-FU/LV. Physicians should consider these results 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). Although neither XELODA nor combination chemotherapy prolongs overall survival (OS), combination chemotherapy has been demonstrated to improve disease-free survival compared to 5-FU/LV. Physicians should consider these results 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. Breast 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, eg, 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, eg, 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.

Information for Patients (see Patient Package Insert) Patients and patients caregivers should be informed of the expected adverse effects of XELODA, particularly nausea, vomiting, diarrhea, and hand-and-foot syndrome, and should be made aware that patient-specific dose adaptations during therapy are expected and necessary (see DOSAGE AND ADMINISTRATION). Patients should be encouraged to recognize the common grade toxicities associated with XELODA treatment.

NURSING MOTHERS SECTION.

Nursing Women. Lactating mice given single oral dose of capecitabine excreted significant amounts of capecitabine metabolites into the milk. Because of the potential for serious adverse reactions in nursing infants from capecitabine, it is recommended that nursing be discontinued when receiving XELODA therapy.

OVERDOSAGE SECTION.

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 500 mg Tablet Label. NDC 53808-0411-1Xeloda(R)(capecitabine)Tablets500 mgEach tablet contains500 mg capecitabine.. PRINCIPAL DISPLAY PANEL.

PEDIATRIC USE SECTION.

Pediatric Use. The safety and effectiveness of XELODA in persons <18 years of age have not been established.

PRECAUTIONS SECTION.

PRECAUTIONS. General. Patients receiving therapy with XELODA should be monitored by physician experienced in the use of cancer chemotherapeutic agents. Most adverse events are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced (see DOSAGE AND ADMINISTRATION).. Combination With Other Drugs. Use of XELODA in combination with irinotecan has not been adequately studied.. Hand-and-Foot Syndrome. 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. 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).. Cardiotoxicity. The cardiotoxicity observed with XELODA includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy. These adverse events may be more common in patients with prior history of coronary artery disease.. Dihydropyrimidine Dehydrogenase Deficiency. Rarely, unexpected, severe toxicity (eg, stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5-fluorouracil has been attributed to deficiency of dihydropyrimidine dehydrogenase (DPD) activity. link between decreased levels of DPD and increased, potentially fatal toxic effects of 5-fluorouracil therefore cannot be excluded.. Hepatic 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 CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).. Hyperbilirubinemia. 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 resolves or decreases in intensity to grade 1. NCIC grade hyperbilirubinemia is defined as 1.5 normal, grade hyperbilirubinemia as 1.5 to x normal and grade hyperbilirubinemia as >3 normal. (See recommended dose modifications under DOSAGE AND ADMINISTRATION.). 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.. Carcinogenesis, Mutagenesis and Impairment of Fertility Adequate studies investigating the carcinogenic potential of XELODA 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.. Impairment of Fertility. In studies of fertility and general reproductive performance in mice, oral capecitabine doses of 760 mg/kg/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.. Information for Patients (see Patient Package Insert) Patients and patients caregivers should be informed of the expected adverse effects of XELODA, particularly nausea, vomiting, diarrhea, and hand-and-foot syndrome, and should be made aware that patient-specific dose adaptations during therapy are expected and necessary (see DOSAGE AND ADMINISTRATION). Patients should be encouraged to recognize the common grade toxicities associated with XELODA treatment.. Diarrhea. Patients experiencing grade diarrhea (an increase of to stools/day or nocturnal stools) or greater should be instructed to stop taking XELODA immediately. Standard antidiarrheal treatments (eg, loperamide) are recommended.. Nausea Patients experiencing grade nausea (food intake significantly decreased but able to eat intermittently) or greater should be instructed to stop taking XELODA immediately. Initiation of symptomatic treatment is recommended.. Vomiting. Patients experiencing grade vomiting (2 to episodes in 24-hour period) or greater should be instructed to stop taking XELODA immediately. Initiation of symptomatic treatment is recommended.. Hand-and-Foot Syndrome. 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 should be instructed to stop taking XELODA immediately.. Stomatitis. Patients experiencing grade stomatitis (painful erythema, edema or ulcers of the mouth or tongue, but able to eat) or greater should be instructed to stop taking XELODA immediately. Initiation of symptomatic treatment is recommended (see DOSAGE AND ADMINISTRATION).. Fever and Neutropenia. Patients who develop fever of 100.5F or greater or other evidence of potential infection should be instructed to call their physician.. Drug-Food Interaction. In all clinical trials, patients were instructed to administer XELODA within 30 minutes after meal. Since current safety and efficacy data are based upon administration with food, it is recommended that XELODA be administered with food (see DOSAGE AND ADMINISTRATION).. Drug-Drug Interactions. Antacid. The effect of an aluminum hydroxide- and magnesium hydroxide-containing antacid (Maalox) on the pharmacokinetics of XELODA was investigated in 12 cancer patients. There was small increase in plasma concentrations of XELODA and one metabolite (5-DFCR); there was no effect on the major metabolites (5-DFUR, 5-FU and FBAL).. Anticoagulants. 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 CLINICAL PHARMACOLOGY). Altered coagulation parameters and/or bleeding have been reported in patients taking XELODA concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. 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. 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 (see CLINICAL PHARMACOLOGY).. CYP2C9 substrates. Other 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.. Phenytoin. The level of phenytoin should be carefully monitored in patients taking XELODA and phenytoin dose may need to be reduced (see DOSAGE AND ADMINISTRATION: Dose Management Guidelines). 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 (see PRECAUTIONS: Drug-Drug Interactions: Anticoagulants).. Leucovorin. The 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.. Pregnancy. Teratogenic Effects. Category (see WARNINGS). Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with XELODA.. Nursing Women. Lactating mice given single oral dose of capecitabine excreted significant amounts of capecitabine metabolites into the milk. Because of the potential for serious adverse reactions in nursing infants from capecitabine, it is recommended that nursing be discontinued when receiving XELODA therapy.. Pediatric Use. The safety and effectiveness of XELODA in persons <18 years of age have not been established.. Geriatric Use. Physicians should pay particular attention to monitoring the adverse effects of XELODA in the elderly (see WARNINGS: Geriatric Patients).

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PATIENT INFORMATION (TEXT ONLY). Read this leaflet before you start taking XELODA(R) [zeh-LOE-duh] and each time you refill your prescription in case the information has changed. This leaflet contains important information about XELODA. However, this information does not take the place of talking with your doctor. This information cannot cover all possible risks and benefits of XELODA. Your doctor should always be your first choice for discussing your medical condition and this medicine.What is XELODAXELODA is medicine you take by mouth (orally). XELODA is changed in the body to 5-fluorouracil (5-FU). In some patients with colon, rectum or breast cancer, 5-FU stops cancer cells from growing and decreases the size of the tumor. XELODA is used to treat:-cancer of the colon after surgery-cancer of the colon or rectum (colorectal cancer) that has spread to other parts of the body (metastatic colorectal cancer). You should know that in studies, other medicines showed improved survival when they were taken together with 5-FU and leucovorin. In studies, XELODA was no worse than 5-FU and leucovorin taken together but did not improve survival compared to these two medicines.-breast cancer that has spread to other parts of the body (metastatic breast cancer) together with another medicine called docetaxel (Taxotere(R))-breast cancer that has spread to other parts of the body and has not improved after treatment with other medicines such as paclitaxel (Taxol(R)) and anthracycline-containing medicine such as Adriamycin(TM) and doxorubicinWhat is the most important information about XELODAXELODA may increase the effect of other medicines used to thin your blood such as warfarin (Coumadin(R)). It is very important that your doctor knows if you are taking blood thinner such as warfarin because XELODA may increase the effect of this medicine and could lead to serious side effects. If you are taking blood thinners and XELODA, your doctor needs to check more often how fast your blood clots and change the dose of the blood thinner, if needed.Who should not take XELODA1. DO NOT TAKE XELODA IF YOU-are nursing baby. Tell your doctor if you are nursing. XELODA may pass to the baby in your milk and harm the baby.-are allergic to 5-fluorouracil-are allergic to capecitabine or to any of the ingredients in XELODA-have been told that you lack the enzyme DPD (dihydropyrimidine dehydrogenase)2. TELL YOUR DOCTOR IF YOU-take blood thinner such as warfarin (Coumadin). This is very important because XELODA may increase the effect of the blood thinner. If you are taking blood thinners and XELODA, your doctor needs to check more often how fast your blood clots and change the dose of the blood thinner, if needed.-take phenytoin (Dilantin(R)). Your doctor needs to test the levels of phenytoin in your blood more often or change your dose of phenytoin.-are pregnant or think you may be pregnant. XELODA may harm your unborn child. -have kidney problems. Your doctor may prescribe different medicine or lower the XELODA dose.-have liver problems. You may need to be checked for liver problems while you take XELODA.-have heart problems because you could have more side effects related to your heart.-take the vitamin folic acid. It may affect how XELODA works.How should take XELODATake XELODA exactly as your doctor tells you to. Your doctor will prescribe dose and treatment plan that is right for you. Your doctor may want you to take both 150 mg and 500 mg tablets together for each dose. If so, you must be able to identify the tablets. Taking the wrong tablets could cause an overdose (too much medicine) or underdose (too little medicine). The 150 mg tablets are light peach in color with 150 on one side. The 500 mg tablets are peach in color with 500 on one side. Your doctor may change the amount of medicine you take during your treatment. Your doctor may prescribe XELODA Tablets with Taxotere or docetaxel injection.-XELODA is taken in daily doses, morning dose and an evening dose-Take XELODA tablets within 30 minutes after the end of meal (breakfast and dinner)-Swallow XELODA tablets with water-If you miss dose of XELODA, do not take the missed dose at all and do not double the next dose. Instead, continue your regular dosing schedule and check with your doctor.-XELODA is usually taken for 14 days followed by 7-day rest period (no drug), for 21-day cycle. Your doctor will tell you how many cycles of treatment you will need.-If you take too much XELODA, contact your doctor or local poison control center or emergency room right away.What should avoid while taking XELODA-Women should not become pregnant while taking XELODA. XELODA may harm your unborn child. Use effective birth control while taking XELODA. Tell your doctor if you become pregnant.-Do not breast-feed. XELODA may pass through your milk and harm your baby.-Men should use birth control while taking XELODAWhat are the most common side effects of XELODAThe most common side effects of XELODA are:-diarrhea, nausea, vomiting, sores in the mouth and throat (stomatitis), stomach area pain (abdominal pain), upset stomach, constipation, loss of appetite, and too much water loss from the body (dehydration). These side effects are more common in patients age 80 and older.-hand-and-foot syndrome (palms of the hands or soles of the feet tingle, become numb, painful, swollen or red), rash, dry, itchy or discolored skin, nail problems, and hair loss-tiredness, weakness, dizziness, headache, fever, pain (including chest, back, joint, and muscle pain), trouble sleeping, and taste problemsThese side effects may differ when taking XELODA with Taxotere. Please consult your doctor for possible side effects that may be caused by taking XELODA with Taxotere.If you are concerned about these or any other side effects while taking XELODA, talk to your doctor.Stop taking XELODA immediately and contact your doctor right away if you have the side effects listed below, or other side effects that concern you. Your doctor can then adjust XELODA to dose that is right for you or stop your XELODA treatment for while. This should help to reduce the side effects and stop them from getting worse.-Diarrhea: if you have an additional bowel movements each day beyond what is normal or any diarrhea at night-Vomiting: if you vomit more than once in 24-hour time period-Nausea: if you lose your appetite, and the amount of food you eat each day is much less than usual-Stomatitis: if you have pain, redness, swelling or sores in your mouth-Hand-and-Foot Syndrome: if you have pain, swelling or redness of your hands or feet that prevents normal activity-Fever or Infection: if you have temperature of 100.5F or greater, or other signs of infectionYour doctor may tell you to lower the dose or to stop XELODA treatment for while. If caught early, most of these side effects usually improve after you stop taking XELODA. If they do not improve within to days, call your doctor again. After your side effects have improved, your doctor will tell you whether to start taking XELODA again and what dose to take. Adjusting the dose of XELODA to be right for each patient is an important part of treatment.How should store and use XELODA-Never share XELODA with anyone-Store XELODA at normal room temperature (about 65 to 85F)-Keep XELODA and all other medicines out of the reach of children-If you take too much XELODA by mistake, contact your doctor or local poison control center or emergency room right awayGeneral advice about prescription medicines:Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. 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.This leaflet summarizes the most important information about XELODA. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about XELODA that is written for health professionals.XELODA is registered trademark of Hoffmann La Roche Inc.. -cancer of the colon after surgery. -cancer of the colon or rectum (colorectal cancer) that has spread to other parts of the body (metastatic colorectal cancer). You should know that in studies, other medicines showed improved survival when they were taken together with 5-FU and leucovorin. In studies, XELODA was no worse than 5-FU and leucovorin taken together but did not improve survival compared to these two medicines.. -breast cancer that has spread to other parts of the body (metastatic breast cancer) together with another medicine called docetaxel (Taxotere(R)). -breast cancer that has spread to other parts of the body and has not improved after treatment with other medicines such as paclitaxel (Taxol(R)) and anthracycline-containing medicine such as Adriamycin(TM) and doxorubicin. -are nursing baby. Tell your doctor if you are nursing. XELODA may pass to the baby in your milk and harm the baby.. -are allergic to 5-fluorouracil. -are allergic to capecitabine or to any of the ingredients in XELODA. -have been told that you lack the enzyme DPD (dihydropyrimidine dehydrogenase). -take blood thinner such as warfarin (Coumadin). This is very important because XELODA may increase the effect of the blood thinner. If you are taking blood thinners and XELODA, your doctor needs to check more often how fast your blood clots and change the dose of the blood thinner, if needed.. -take phenytoin (Dilantin(R)). Your doctor needs to test the levels of phenytoin in your blood more often or change your dose of phenytoin.. -are pregnant or think you may be pregnant. XELODA may harm your unborn child. -have kidney problems. Your doctor may prescribe different medicine or lower the XELODA dose.. -have liver problems. You may need to be checked for liver problems while you take XELODA.. -have heart problems because you could have more side effects related to your heart.. -take the vitamin folic acid. It may affect how XELODA works.. -XELODA is taken in daily doses, morning dose and an evening dose. -Take XELODA tablets within 30 minutes after the end of meal (breakfast and dinner). -Swallow XELODA tablets with water. -If you miss dose of XELODA, do not take the missed dose at all and do not double the next dose. Instead, continue your regular dosing schedule and check with your doctor.. -XELODA is usually taken for 14 days followed by 7-day rest period (no drug), for 21-day cycle. Your doctor will tell you how many cycles of treatment you will need.. -If you take too much XELODA, contact your doctor or local poison control center or emergency room right away.. -Women should not become pregnant while taking XELODA. XELODA may harm your unborn child. Use effective birth control while taking XELODA. Tell your doctor if you become pregnant.. -Do not breast-feed. XELODA may pass through your milk and harm your baby.. -Men should use birth control while taking XELODA. -diarrhea, nausea, vomiting, sores in the mouth and throat (stomatitis), stomach area pain (abdominal pain), upset stomach, constipation, loss of appetite, and too much water loss from the body (dehydration). These side effects are more common in patients age 80 and older.. -hand-and-foot syndrome (palms of the hands or soles of the feet tingle, become numb, painful, swollen or red), rash, dry, itchy or discolored skin, nail problems, and hair loss. -tiredness, weakness, dizziness, headache, fever, pain (including chest, back, joint, and muscle pain), trouble sleeping, and taste problems. -Diarrhea: if you have an additional bowel movements each day beyond what is normal or any diarrhea at night. -Vomiting: if you vomit more than once in 24-hour time period. -Nausea: if you lose your appetite, and the amount of food you eat each day is much less than usual. -Stomatitis: if you have pain, redness, swelling or sores in your mouth. -Hand-and-Foot Syndrome: if you have pain, swelling or redness of your hands or feet that prevents normal activity. -Fever or Infection: if you have temperature of 100.5F or greater, or other signs of infection. -Never share XELODA with anyone. -Store XELODA at normal room temperature (about 65 to 85F). -Keep XELODA and all other medicines out of the reach of children. -If you take too much XELODA by mistake, contact your doctor or local poison control center or emergency room right away.

SPL UNCLASSIFIED SECTION.

Bioactivation. Capecitabine is readily absorbed from the gastrointestinal tract. 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-deoxy-5-fluorouridine (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.Metabolic Pathway of capecitabine to 5-FU.

STORAGE AND HANDLING SECTION.

Storage Conditions. Store at 25C (77F); excursions permitted to 15 to 30C (59 to 86F). [See USP Controlled Room Temperature]. KEEP TIGHTLY CLOSED.For full Taxotere prescribing information, please refer to Taxotere Package Insert.This product was Manufactured By:Hoffmann-La Roche Inc.340 Kingsland StreetNutley, NJ 07110And Repackaged By:State of Florida DOH Central Pharmacy104-2 Hamilton Park DriveTallahassee, FL 32304United States.

TERATOGENIC EFFECTS SECTION.

Teratogenic Effects. Category (see WARNINGS). Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with XELODA.

WARNINGS SECTION.

WARNINGS. Renal Insufficiency. Patients with moderate renal impairment at baseline require dose reduction (see DOSAGE AND ADMINISTRATION). Patients with mild and moderate renal impairment at baseline should be carefully monitored for adverse events. Prompt interruption of therapy with subsequent dose adjustments is recommended if patient develops grade to adverse event as outlined in Table 18 in DOSAGE AND ADMINISTRATION. Coagulopathy. See Boxed WARNING.. Diarrhea. 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 1. Following reoccurrence of grade diarrhea or occurrence of any grade or diarrhea, subsequent doses of XELODA should be decreased (see DOSAGE AND ADMINISTRATION). Standard antidiarrheal treatments (eg, loperamide) are recommended.Necrotizing enterocolitis (typhlitis) has been reported.. Geriatric Patients. Patients >=80 years old may experience greater incidence of grade or adverse events (see PRECAUTIONS: Geriatric Use). 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 events, treatment-related serious adverse events, withdrawals due to adverse events, treatment discontinuations due to adverse events 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.. Pregnancy XELODA may cause fetal harm when given to pregnant woman. Capecitabine at doses of 198 mg/kg/day during organogenesis caused malformations and embryo death in mice. In separate pharmacokinetic studies, this dose in mice produced 5-DFUR AUC values about 0.2 times the corresponding 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. At doses of 90 mg/kg/day, capecitabine given to pregnant monkeys during organogenesis caused fetal death. This dose produced 5-DFUR AUC values about 0.6 times the corresponding values in patients administered the recommended daily dose. There are no adequate and well-controlled studies in pregnant women using XELODA. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with XELODA.