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 Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Adjuvant 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 1,250 mg/m2 twice day of capecitabine 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 to 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 capecitabine 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 Percent Incidence of Adverse Reactions Reported in >=5% of Patients Treated with Capecitabine or 5-FU/LV for Colon Cancer in the Adjuvant Setting (Safety Population)Adjuvant Treatment for Colon Cancer (N=1,969)Capecitabine (N=995)5-FU/LV (N=974)Body System/Adverse EventAll GradesGrade 3/4All GradesGrade 3/4Gastrointestinal DisordersDiarrhea47126514Nausea342472Stomatitis2226014Vomiting152212Abdominal Pain143162Constipation9-11<1Upper Abdominal Pain7<17<1Dyspepsia6<15-Skin and Subcutaneous Tissue DisordersHand-and-Foot Syndrome60179<1Alopecia6-22<1Rash7-8-Erythema615<1General Disorders and Administration Site ConditionsFatigue16<1161Pyrexia7<19<1Asthenia10<1101Lethargy10<19<1Nervous System DisordersDizziness6<16-Headache5<16<1Dysgeusia6-9-Metabolism and Nutrition DisordersAnorexia9<111<1Eye DisordersConjunctivitis5<16<1Blood and Lymphatic System DisordersNeutropenia2<185Respiratory Thoracic and Mediastinal DisordersEpistaxis2-5-Table Percent Incidence of Grade 3/4 Laboratory Abnormalities Reported in >=1% of Patients Receiving Capecitabine Monotherapy for Adjuvant Treatment of Colon Cancer (Safety Population)Adverse EventCapecitabine (n=995) Grade 3/4 %IV 5-FU/LV (n=974) Grade 3/4 %Increased ALAT (SGPT)1.60.6Increased Calcium1.10.7Decreased Calcium2.32.2Decreased Hemoglobin1.01.2Decreased Lymphocytes13.013.0Decreased NeutrophilsThe incidence of grade 3/4 white blood cell abnormalities was 1.3% in the capecitabine arm and 4.9% in the IV 5-FU/LV arm. 2.226.2Decreased Neutrophils/Granulocytes2.426.4Decreased Platelets1.00.7Increased 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 Monotherapy:Table 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 1,250 mg/m2 twice day of capecitabine 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 to 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 capecitabine and 32 (5.4%) randomized to 5-FU/LV.Table Pooled Phase Colorectal Trials: Percent Incidence of Adverse Reactions in >=5% of PatientsAdverse EventCapecitabine (n=596)5-FU/LV (n=593)Total %Grade %Grade %Total %Grade %Grade %Number of Patients with One Adverse Event9652994459Body System/Adverse EventGIDiarrhea5513261102Nausea434-513<1Vomiting274<1304<1Stomatitis252<162141Abdominal Pain359<1315-Gastrointestinal Motility Disorder10<1-7<1-Constipation141<1171-Oral Discomfort10--10--Upper GI Inflammatory Disorders8<1-101-Gastrointestinal Hemorrhage61<131-Ileus641521Skin and SubcutaneousHand-and-Foot Syndrome5417NA61NADermatitis271-261-Skin Discoloration7<1-5--Alopecia6--21<1-GeneralFatigue/Weakness424-464-Pyrexia181-212-Edema151-91-Pain121-101-Chest Pain61-61<1NeurologicalPeripheral Sensory Neuropathy10--4--Headache101-7--DizzinessExcluding vertigo- Not ObservedNA Not Applicable 8<1-8<1-Insomnia7--7--Taste Disturbance61-11<11MetabolismAppetite Decreased263<1312<1Dehydration72<1831EyeEye Irritation13--10<1-Vision Abnormal5--2--RespiratoryDyspnea141-10<11Cough7<118--Pharyngeal Disorder5--5--Epistaxis3<1-6--Sore Throat2--6--MusculoskeletalBack Pain102-9<1-Arthralgia81-61-VascularVenous Thrombosis83<162-PsychiatricMood Alteration5--6<1-Depression5--4<1-InfectionsViral5<1-5<1-Blood and LymphaticAnemia802<1791<1Neutropenia131246813HepatobiliaryHyperbilirubinemia481851733. 6.3 Breast Cancer In Combination with Docetaxel:The following data are shown for the combination study with capecitabine and docetaxel in patients with metastatic breast cancer in Table and Table 8. In the capecitabine and docetaxel combination arm the treatment was capecitabine administered orally 1,250 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 Percent Incidence of Adverse Events Considered Related or Unrelated to Treatment in >=5% of Patients Participating in the Capecitabine and Docetaxel Combination vs Docetaxel Monotherapy StudyAdverse EventCapecitabine 1,250 mg/m2/bid with Docetaxel 75 mg/m2/3 weeks (n=251)Docetaxel 100 mg/m2/3 weeks (n=255)Total %Grade %Grade %Total %Grade %Grade %Number of Patients with at Least One Adverse Event9976.529.19757.631.8Body System/Adverse EventGIDiarrhea6714<1485<1Stomatitis6717<1435-Nausea457-362-Vomiting3541242-Constipation202-18--Abdominal Pain30<3<1242-Dyspepsia14--81-Dry Mouth6<1-5--Skin and SubcutaneousHand-and-Foot Syndrome6324NA81NAAlopecia416-427-Nail Disorder142-15--Dermatitis8--111-Rash Erythematous9<1-5--Nail Discoloration6--4<1-Onycholysis51-51-Pruritus4--5--GeneralPyrexia282-342-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--NeurologicalTaste Disturbance16<1-14<1-Headache153-152-Paresthesia12<1-161-Dizziness12--8<1-Insomnia8--10<1-Peripheral Neuropathy6--101-Hypoaesthesia4<1-8<1-MetabolismAnorexia131-11<1-Appetite Decreased10--5--Weight Decreased7--5--Dehydration102-7<1<1EyeLacrimation Increased12--7<1-Conjunctivitis5--4--Eye Irritation5--1--MusculoskeletalArthralgia152-243-Myalgia152-252-Back Pain12<1-113-Bone Pain8<1-102-CardiacEdema33<2-34<31BloodNeutropenic Fever1631321516RespiratoryDyspnea142<1162-Cough131-22<1-Sore Throat122-11<1-Epistaxis7<1-6--Rhinorrhea5--3--Pleural Effusion21-74-InfectionOral Candidiasis7<1-8<1-Urinary Tract Infection6<1-4--Upper Respiratory Tract4--51-VascularFlushing 5--5--Lymphoedema3<1-51-PsychiatricDepression5--51-- Not observed NA=Not applicableTable Percent of Patients with Laboratory Abnormalities Participating in the Capecitabine and Docetaxel Combination vs Docetaxel Monotherapy StudyAdverse EventCapecitabine 1,250 mg/m2/bid with Docetaxel 75 mg/m2/3 weeks (n=251)Docetaxel 100 mg/m2/3 weeks (n=255)Body System/Adverse EventTotal %Grade %Grade %Total %Grade %Grade %HematologicLeukopenia913724884233Neutropenia/Granulocytopenia862049871066Thrombocytopenia41212312Anemia8073835<1Lymphocytopenia994841984440HepatobiliaryHyperbilirubinemia2072622Monotherapy:The following data are shown for the study in stage IV breast cancer patients who received dose of 1,250 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 Percent 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 %Grade %GIDiarrhea57123Nausea534-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- Not observed NA=Not applicable. 6.4 Clinically Relevant Adverse Events in <5% of Patients Clinically relevant adverse events reported in <5% of patients treated with capecitabine 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 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%)Capecitabine 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 and 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%). 6.5 Postmarketing 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 capecitabine tablets, the following adverse reactions have been reported: eye irritation and swelling, skin rash, diarrhea, paresthesia, headache, gastric irritation, vomiting, and nausea.

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 Absorption:Following oral administration of 1,255 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 capecitabine and its metabolites have been evaluated in about 200 cancer patients over dosage range of 500 to 3,500 mg/m2/day. Over this range, the pharmacokinetics of capecitabine 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%.Distribution: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 has low potential for pharmacokinetic interactions related to plasma protein binding.Bioactivation and Metabolism:Capecitabine 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 capecitabine 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-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.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.Excretion: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. 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 Capecitabine:A population analysis of pooled data from the two large controlled studies in patients with metastatic colorectal cancer (n=505) who were administered capecitabine at 1,250 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 Insufficiency:Capecitabine 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 1,255 mg/m2 dose of capecitabine. 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 capecitabine is administered. The effect of severe hepatic dysfunction on capecitabine is not known [see Warnings and Precautions (5.11) and Use in Special Populations (8.6)].Effect of Renal Insufficiency:Following oral administration of 1,250 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 Warfarin:In four patients with cancer, chronic administration of capecitabine (1,250 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 Capecitabine: When Maalox(R) (20 mL), an aluminum hydroxide- and magnesium hydroxide-containing antacid, was administered immediately after capecitabine (1,250 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 capecitabine.Effect of Allopurinol on Capecitabine:Published 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 Versa:A Phase study evaluated the effect of capecitabine on the pharmacokinetics of docetaxel (Taxotere(R)) and the effect of docetaxel on the pharmacokinetics of capecitabine was conducted in 26 patients with solid tumors. Capecitabine 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.. Metabolic Pathway of Capecitabine to 5-FU. metabolicpathway.jpg.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1 Adjuvant Colon Cancer A multicenter randomized, controlled phase clinical trial in patients with Dukes colon cancer (X-ACT) provided data concerning the use of capecitabine 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 capecitabine to those receiving IV 5-FU/LV alone. In this trial, 1,987 patients were randomized either to treatment with capecitabine 1,250 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 >=1.5 109/L, platelets >=100 109/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 capecitabine and 5-FU/LV patients are shown in Table 10. The baseline characteristics were well-balanced between arms.Table 10 Baseline DemographicsCapecitabine (n=1,004)5-FU/LV (n=983)Age (median, years)Range62(25 to 80)63(22 to 82)Gender Male (n, %) Female (n, %)542 (54)461 (46)532 (54)451 (46)ECOG PS (n, %) (n, %)849 (85)152 (15)830 (85)147 (15)Staging Primary Tumor PT1 (n, %) PT2 (n, %) PT3 (n, %) PT4 (n, %) Other (n, %)12 (1)90 (9)763 (76)138 (14)1 (0.1)6 (0.6)92 (9)746 (76)139 (14)0 (0)Staging Lymph Node pN1 (n, %) pN2 (n, %) Other (n, %)695 (69)305 (30)4 (0.4)694 (71)288 (29)1 (0.1)All patients with normal renal function or mild renal impairment began treatment at the full starting dose of 1,250 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 capecitabine included dose reductions, cycle delays and treatment interruptions (see Table 11).Table 11 Summary of Dose Modifications in X-ACT StudyCapecitabine (n=995)5-FU/LV (n=974)Median 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 capecitabine compared to 5-FU/LV was 0.88 (95% C.I. 0.77 to 1.01) (see Table 12 and Figure 1). Because the upper 2-sided 95% confidence limit of hazard ratio was less than 1.20, capecitabine 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 capecitabine compared to 5-FU/LV with respect to overall survival was 0.86 (95% C.I. 0.74 to 1.01). The 5-year overall survival rates were 71.4% for capecitabine and 68.4% for 5-FU/LV (see Figure 2).Table 12 Efficacy of Capecitabine vs 5-FU/LV in Adjuvant Treatment of Colon CancerApproximately 93.4% had 5-year DFS information All Randomized PopulationCapecitabine (n=1,004)5-FU/LV (n=983)Median Follow-Up (Months)83835-Year Disease-Free Survival Rates (%)Based on Kaplan-Meier estimates59.154.6Hazard Ratio (Capecitabine/5-FU/LV) (95% C.I. for Hazard Ratio)p-valueTest of superiority of capecitabine vs 5-FU/LV (Wald chi-square test) 0.88(0.77 to 1.01)p=0.068Figure Kaplan-Meier Estimates of Disease-Free Survival (All Randomized Population)a Figure Kaplan-Meier Estimates of Overall Survival (All Randomized Population). diseasefreesurvival1.jpg. overallsurvival2.jpg. 14.2 Metastatic Colorectal Cancer General:The recommended dose of capecitabine was determined in an open-label, randomized clinical study, exploring the efficacy and safety of continuous therapy with capecitabine (1,331 mg/m2/day in two divided doses, n=39), intermittent therapy with capecitabine (2,510 mg/m2/day in two divided doses, n=34), and intermittent therapy with capecitabine in combination with oral leucovorin (LV) (capecitabine 1,657 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 capecitabine; however, toxicity was increased. Capecitabine, 1,250 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.Monotherapy:Data from two open-label, multicenter, randomized, controlled clinical trials involving 1,207 patients support the use of capecitabine 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 capecitabine at dose of 1,250 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 capecitabine and 5-FU/LV patients are shown in Table 13.Table 13 Baseline Demographics of Controlled Colorectal TrialsStudy 1Study 2Capecitabine (n=302)5-FU/LV (n=303)Capecitabine (n=301)5-FU/LV (n=301)Age (median, years)Range64(23 to 86)63(24 to 87)64(29 to 84)64(36 to 86)Gender Male (%) Female (%)181 (60)121 (40)197 (65)106 (35)172 (57)129 (43)173 (57)128 (43)Karnofsky PS (median)Range90(70 to 100)90(70 to 100)90(70 to 100)90(70 to 100)Colon (%)Rectum (%)222 (74)79 (26)232 (77)70 (23)199 (66)101 (34)196 (65)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 14 Efficacy of Capecitabine vs 5-FU/LV in Colorectal Cancer (Study 1)Capecitabine (n=302)5-FU/LV (n=303)Overall Response Rate (%, 95% C.I.)21 (16 to 26)11 (8 to 15)(p-value)0.0014Time to Progression (Median, days, 95% C.I.)128 (120 to 136)131 (105 to 153)Hazard Ratio (capecitabine/5-FU/LV)95% C.I. for Hazard Ratio0.99(0.84 to 1.17)Survival (Median, days, 95% C.I.)380 (321 to 434)407 (366 to 446)Hazard Ratio (capecitabine/5-FU/LV)95% C.I. for Hazard Ratio1.00(0.84 to 1.18)Table 15 Efficacy of Capecitabine vs 5-FU/LV in Colorectal Cancer (Study 2)Capecitabine (n=301)5-FU/LV (n=301)Overall Response Rate (%, 95% C.I.)21 (16 to 26)14 (10 to 18)(p-value)0.027Time to Progression (Median, days, 95% C.I.)137 (128 to 165)131 (102 to 156)Hazard Ratio (capecitabine/5-FU/LV)95% C.I. for Hazard Ratio0.97(0.82 to 1.14)Survival (Median, days, 95% C.I.)404 (367 to 452)369 (338 to 430)Hazard Ratio (capecitabine/5-FU/LV)95% C.I. for Hazard Ratio0.92(0.78 to 1.09)Figure Kaplan-Meier Curve for Overall Survival of Pooled Data (Studies and 2)Capecitabine was superior to 5-FU/LV for objective response rate in Study and Study 2. The similarity of capecitabine and 5-FU/LV in these studies was assessed by examining the potential difference between the two treatments. In order to assure that capecitabine 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 capecitabine. 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 capecitabine, 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 capecitabine difference. These results do not exclude the possibility of true equivalence of capecitabine to 5-FU/LV (see Table 14, Table 15, and Figure 3).. kaplanmeiersurvival3.jpg. 14.3 Breast Cancer Capecitabine has been evaluated in clinical trials in combination with docetaxel (Taxotere(R)) and as monotherapy.In Combination With Docetaxel:The dose of capecitabine 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 capecitabine (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 1,250 mg/m2 twice daily for 14 days of capecitabine 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.Capecitabine 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 capecitabine 1,250 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 16 Baseline Demographics and Clinical Characteristics Capecitabine and Docetaxel Combination vs Docetaxel in Breast Cancer TrialCapecitabine Docetaxel (n=255)Docetaxel(n=256)Age (median, years)5251Karnofsky PS (median)9090Site of DiseaseLymph NodesLiverBoneLungSkin121 (47%)116 (45%)107 (42%)95 (37%)73 (29%)125 (49%)122 (48%)119 (46%)99 (39%)73 (29%)Prior ChemotherapyAnthracyclineIncludes 10 patients in combination and 18 patients in monotherapy arms treated with an anthracenedione. 5-FUPaclitaxel255 (100%)196 (77%)25 (10%)256 (100%)189 (74%)22 (9%)Resistance to an AnthracyclineNo 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 1 389 (35%)123 (48%)43 (17%)0 (0%)80 (31%)135 (53%)39 (15%)2 (1%)Capecitabine 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 17 Efficacy of Capecitabine and Docetaxel Combination vs Docetaxel MonotherapyEfficacy ParameterCombination TherapyMonotherapyp-valueHazard RatioTime to Disease Progression Median Days 95% C.I.186(165 to 198)128(105 to 136)0.00010.643Overall Survival Median Days 95% C.I.442(375 to 497)352(298 to 387)0.01260.775Response 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 Capecitabine and Docetaxel vs DocetaxelFigure Kaplan-Meier Estimates of Survival Capecitabine and Docetaxel vs DocetaxelMonotherapy:The antitumor activity of capecitabine 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. Capecitabine was administered at dose of 1,255 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 18 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 to 3 to >543 (32%)63 (46%)29 (22%)60 (37%)69 (43%)34 (21%)Dominant Site of Disease VisceralLung, pleura, liver, peritoneum Soft Tissue Bone101 (75%)30 (22%)4 (3%)110 (68%)35 (22%)17 (10%)Prior Chemotherapy Paclitaxel AnthracyclineIncludes patients treated with an anthracenedione 5-FU 135 (100%)122 (90%)110 (81%)162 (100%)147 (91%)133 (82%) Resistance to Paclitaxel Resistance to an Anthracycline Resistance to Both Paclitaxel and an Anthracycline 103 (76%)55 (41%)43 (32%)124 (77%)67 (41%)51 (31%)Antitumor responses for patients with disease resistant to both paclitaxel and an anthracycline are shown in Table 19.Table 19 Response 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.)From date of first response 25.6%(13.5, 41.2)Duration of Response,Median in Days (Range)154(63 to 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.. kaplanmeierdisease4.jpg. kaplanmeiersurvival5.jpg.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oTake capecitabine with water within 30 min after meal. (2.1)oMonotherapy: 1,250 mg/m2 twice daily orally for weeks followed by one week rest period in 3-week cycles. (2.2)oAdjuvant treatment is recommended for total of months (8 cycles). (2.2)oIn combination with docetaxel, the recommended dose of capecitabine is 1,250 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)oCapecitabine dosage may need to be individualized to optimize patient management. (2.3)oReduce the dose of capecitabine by 25% in patients with moderate renal impairment. (2.4). oTake capecitabine with water within 30 min after meal. (2.1). oMonotherapy: 1,250 mg/m2 twice daily orally for weeks followed by one week rest period in 3-week cycles. (2.2). oAdjuvant treatment is recommended for total of months (8 cycles). (2.2). oIn combination with docetaxel, the recommended dose of capecitabine is 1,250 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). oCapecitabine dosage may need to be individualized to optimize patient management. (2.3). oReduce the dose of capecitabine by 25% in patients with moderate renal impairment. (2.4). 2.1 Important Administration Instructions Capecitabine tablets should be swallowed whole with water within 30 minutes after meal. Capecitabine is cytotoxic drug. Follow applicable special handling and disposal procedures1. If capecitabine tablets must be cut or crushed, this should be done by professional trained in safe handling of cytotoxic drugs using appropriate equipment and safety procedures. Capecitabine 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 capecitabine is 1,250 mg/m2 administered orally twice daily (morning and evening; equivalent to 2,500 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 [i.e., capecitabine 1,250 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 Capecitabine Dose Calculation According to Body Surface AreaDose Level 1,250 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<=1.253,000031.26 to 1.373,300131.38 to 1.513,600231.52 to 1.654,000041.66 to 1.774,300141.78 to 1.914,600241.92 to 2.055,000052.06 to 2.175,30015>=2.185,60025In Combination With Docetaxel (Metastatic Breast Cancer):In combination with docetaxel, the recommended dose of capecitabine is 1,250 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 capecitabine plus docetaxel combination. Table displays the total daily dose of capecitabine by body surface area and the number of tablets to be taken at each dose.. 2.3 Dose Management Guidelines General: Capecitabine dosage may need to be individualized to optimize patient management. Patients should be carefully monitored for toxicity and doses of capecitabine should be modified as necessary to accommodate individual patient tolerance to treatment [see Clinical Studies (14)]. Toxicity due to capecitabine administration may be managed by symptomatic treatment, dose interruptions and adjustment of capecitabine dose. Once the dose has been reduced it should not be increased at later time. Doses of capecitabine 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 capecitabine [see Drug Interactions (7.1)].Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer):Capecitabine dose modification scheme as described below (see Table 2) is recommended for the management of adverse reactions.Table Recommended Dose Modifications of CapecitabineToxicity 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 to 1100%-2nd appearance75%-3rd appearance50%-4th appearanceDiscontinue treatment permanently-Grade 3-1st appearanceInterrupt until resolved to grade to 175%-2nd appearance50%-3rd appearanceDiscontinue treatment permanently-Grade 4-1st appearanceDiscontinue permanently OR If physician deems it to be in the patients best interest to continue, interrupt until resolved to grade to 150%In Combination With Docetaxel (Metastatic Breast Cancer):Dose modifications of capecitabine for toxicity should be made according to Table above for capecitabine. At the beginning of treatment cycle, if treatment delay is indicated for either capecitabine 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 capecitabine for the treatment of metastatic breast cancer is shown in Table 3.Table Docetaxel Dose Reduction Schedule in Combination with CapecitabineToxicity NCIC GradesNational Cancer Institute of Canada Common Toxicity Criteria were used except for the hand-and-foot syndrome [see Warnings and Precautions (5)].Grade 2Grade 3Grade 41st appearanceDelay treatment until resolved to grade to 1; Resume treatment with original dose of 75 mg/m2 docetaxelDelay treatment until resolved to grade to 1; Resume treatment at 55 mg/m2 of docetaxelDiscontinue treatment with docetaxel2nd appearanceDelay treatment until resolved to grade to 1; Resume treatment at 55 mg/m2 of docetaxelDiscontinue treatment with docetaxel-3rd appearanceDiscontinue treatment with docetaxel--. 2.4 Adjustment of Starting Dose in Special Populations Renal Impairment:No adjustment to the starting dose of capecitabine 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 capecitabine starting dose when used as monotherapy or in combination with docetaxel (from 1,250 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 capecitabine monotherapy and capecitabine 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 valueGeriatrics:Physicians should exercise caution in monitoring the effects of capecitabine in the elderly. Insufficient data are available to provide dosage recommendation.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS oAnticoagulants: Monitor anticoagulant response (INR or prothrombin time) frequently in order to adjust the anticoagulant dose as needed. (5.2, 7.1)oPhenytoin: Monitor phenytoin levels in patients taking capecitabine concomitantly with phenytoin. The phenytoin dose may need to be reduced. (7.1)oLeucovorin: The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin. (7.1)oCYP2C9 Substrates: Care should be exercised when capecitabine is co-administered with CYP2C9 substrates. (7.1)oAllopurinol: Avoid the use of allopurinol during treatment with capecitabine. oFood reduced both the rate and extent of absorption of capecitabine. (2, 7.2, 12.3). oAnticoagulants: Monitor anticoagulant response (INR or prothrombin time) frequently in order to adjust the anticoagulant dose as needed. (5.2, 7.1). oPhenytoin: Monitor phenytoin levels in patients taking capecitabine concomitantly with phenytoin. The phenytoin dose may need to be reduced. (7.1). oLeucovorin: The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin. (7.1). oCYP2C9 Substrates: Care should be exercised when capecitabine is co-administered with CYP2C9 substrates. (7.1). oAllopurinol: Avoid the use of allopurinol during treatment with capecitabine. oFood reduced both the rate and extent of absorption of capecitabine. (2, 7.2, 12.3). 7.1 Drug-Drug Interactions Anticoagulants:Altered coagulation parameters and/or bleeding have been reported in patients taking capecitabine 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 capecitabine therapy and, in few cases, within month after stopping capecitabine. 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.Phenytoin:The level of phenytoin should be carefully monitored in patients taking capecitabine and phenytoin dose may need to be reduced [see Dosage and Administration (2.3)]. Postmarketing reports indicate that some patients receiving capecitabine 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.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.CYP2C9 Substrates:Other than warfarin, no formal drug-drug interaction studies between capecitabine and other CYP2C9 substrates have been conducted. Care should be exercised when capecitabine is co-administered with CYP2C9 substrates.Allopurinol:Concomitant use with allopurinol may decrease concentration of capecitabines active metabolites [see Clinical Pharmacology (12.3)], which may decrease capecitabine efficacy. Avoid the use of allopurinol during treatment with capecitabine.. 7.2 Drug-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 capecitabine within 30 minutes after meal. It is recommended that capecitabine be administered with food [see Dosage and Administration (2)].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE Capecitabine is nucleoside metabolic inhibitor with antineoplastic activity indicated for: oAdjuvant Colon Cancer (1.1) -Patients with Dukes colon cancer oMetastatic Colorectal Cancer (1.1) -First-line as monotherapy when treatment with fluoropyrimidine therapy alone is preferred oMetastatic 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. oAdjuvant Colon Cancer (1.1) -Patients with Dukes colon cancer oMetastatic Colorectal Cancer (1.1) -First-line as monotherapy when treatment with fluoropyrimidine therapy alone is preferred oMetastatic 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. 1.1 Colorectal Cancer oCapecitabine 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. Capecitabine 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 capecitabine in the adjuvant treatment of Dukes colon cancer.oCapecitabine 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 capecitabine monotherapy. Use of capecitabine instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.. oCapecitabine 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. Capecitabine 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 capecitabine in the adjuvant treatment of Dukes colon cancer.. oCapecitabine 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 capecitabine monotherapy. Use of capecitabine instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.. 1.2 Breast Cancer oCapecitabine in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.oCapecitabine 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.. oCapecitabine in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.. oCapecitabine 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 capecitabine. Advise patients on the use of antidiarrheal treatments (e.g., loperamide) to manage diarrhea [see Warnings and Precautions (5.2)]. Cardiotoxicity: Advise 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 Deficiency:Advise 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 capecitabine (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 capecitabine immediately and to call their healthcare provider to correct the dehydration. Advise patients to not restart capecitabine until rehydrated and any precipitating causes have been corrected or controlled [see Warnings and Precautions (5.5)].Important Administration Instructions:Advise patients to swallow capecitabine tablets whole with water within 30 minutes of meal. Advise patients and caregivers not to crush or cut capecitabine tablets. Advise patients if they cannot swallow capecitabine tablets whole, to inform their healthcare provider [see Dosage and Administration (2.1)].Hypersensitivity and Angioedema:Advise patients that capecitabine may cause severe hypersensitivity reactions and angioedema. Advise patients who have known hypersensitivity to capecitabine or 5-fluorouracil to inform their healthcare provider [see Contraindications (4)]. Instruct patients who develop hypersensitivity reactions or mucocutaneous symptoms (e.g., urticaria, rash, erythema, pruritus, or swelling of the face, lips, tongue or throat which make it difficult to swallow or breathe) to stop taking capecitabine and immediately contact their healthcare provider or to go to an emergency room. [see Adverse Reactions (6)].Nausea:Instruct patients experiencing grade nausea (food intake significantly decreased but able to eat intermittently) or greater to stop taking capecitabine immediately and to contact their healthcare provider for management of nausea [see Adverse Reactions (6.1)]. Vomiting:Instruct patients experiencing grade vomiting (2 to episodes in 24-hour period) or greater to stop taking capecitabine immediately and to contact their healthcare provider for management of vomiting [see Adverse Reactions (6.1)]. Hand-and-Foot Syndrome:Instruct 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 capecitabine immediately and to contact their healthcare provider. Inform patients that initiation of symptomatic treatment is recommended, and hand-and-foot syndrome can lead to loss of fingerprints which could 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 capecitabine 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 Toxicity:Advise females of reproductive potential of the potential risk to fetus and to use effective contraception during treatment with capecitabine 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 capecitabine and for months after the last dose [see Use in Specific Populations (8.3)].Lactation:Advise females not to breastfeed during treatment with capecitabine and for weeks after the last dose [see Use in Specific Populations (8.2)].Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922C50000412/02Revised May 2021.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Absorption:Following oral administration of 1,255 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 capecitabine and its metabolites have been evaluated in about 200 cancer patients over dosage range of 500 to 3,500 mg/m2/day. Over this range, the pharmacokinetics of capecitabine 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%.Distribution: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 has low potential for pharmacokinetic interactions related to plasma protein binding.Bioactivation and Metabolism:Capecitabine 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 capecitabine 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-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.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.Excretion: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. 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 Capecitabine:A population analysis of pooled data from the two large controlled studies in patients with metastatic colorectal cancer (n=505) who were administered capecitabine at 1,250 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 Insufficiency:Capecitabine 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 1,255 mg/m2 dose of capecitabine. 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 capecitabine is administered. The effect of severe hepatic dysfunction on capecitabine is not known [see Warnings and Precautions (5.11) and Use in Special Populations (8.6)].Effect of Renal Insufficiency:Following oral administration of 1,250 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 Warfarin:In four patients with cancer, chronic administration of capecitabine (1,250 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 Capecitabine: When Maalox(R) (20 mL), an aluminum hydroxide- and magnesium hydroxide-containing antacid, was administered immediately after capecitabine (1,250 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 capecitabine.Effect of Allopurinol on Capecitabine:Published 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 Versa:A Phase study evaluated the effect of capecitabine on the pharmacokinetics of docetaxel (Taxotere(R)) and the effect of docetaxel on the pharmacokinetics of capecitabine was conducted in 26 patients with solid tumors. Capecitabine 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.. Metabolic Pathway of Capecitabine to 5-FU. metabolicpathway.jpg.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information Capecitabine Tablets USP(kap sye ta been)Rx Only What is the most important information should know about capecitabine Capecitabine can cause serious side effects, including: oCapecitabine can interact with blood thinner medicines, such as warfarin (COUMADIN(R)). Taking capecitabine 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 capecitabine, or later during treatment, and possibly even within month after you stop taking capecitabine. Your risk may be higher because you have cancer, and if you are over 60 years of age. oBefore taking capecitabine, tell your healthcare provider if you are taking warfarin (COUMADIN) or another blood thinner-medicine. oIf you take warfarin (COUMADIN) or another blood thinner that is like warfarin (COUMADIN) during treatment with capecitabine, your healthcare provider should do blood tests often, to check how fast your blood clots during and after you stop treatment with capecitabine. Your healthcare provider may change your dose of the blood thinner medicine if needed. See What are the possible side effects of capecitabine for more information about side effects.What is capecitabine Capecitabine is prescription medicine used to treat people with: oCancer of the colon that has spread to lymph nodes in the area close to the colon (Dukes stage), after they have surgery. oCancer 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. oBreast cancer that spread to other parts of the body (metastatic) together with another medicine called docetaxel after treatment with certain other anticancer medicines have not worked. oBreast cancer that has 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 capecitabine is safe and effective in children.Do not take capecitabine if you: oHave severe kidney problems. oAre allergic to capecitabine, 5-fluorouracil, or any of its ingredients in capecitabine. See the end of this leaflet for complete list of ingredients in capecitabine. Talk to your healthcare provider before taking capecitabine if you are not sure if you have any of the conditions listed above.Before taking capecitabine, tell your healthcare provider about all your medical conditions, including if you: See What is the most important information should know about capecitabine oHave had heart problems.oHave kidney or liver problems.oHave been told that you lack the enzyme DPD (dihydropyrimidine dehydrogenase). oAre pregnant or plan to become pregnant. Capecitabine can harm your unborn baby. Your healthcare provider should do pregnancy test before you start treatment with capecitabine. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with capecitabine. oFemales 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 capecitabine. oMales who have female partners who are able to become pregnant should use effective birth control during treatment and for months after the final dose.oAre breastfeeding or plan to breastfeed. It is not known if capecitabine passes into your breast milk. Do not breastfeed during treatment with capecitabine and for two 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. Capecitabine may affect the way other medicines work, and other medicines may affect the way capecitabine 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 capecitabine oTake capecitabine exactly as your healthcare provider tells you to take it.oYour healthcare provider will tell you how much capecitabine to take and when to take it.oTake capecitabine times day, time in the morning and time in the evening.oTake capecitabine within 30 minutes after finishing meal.oSwallow capecitabine tablets whole with water. Do not crush or cut capecitabine tablets. If you cannot swallow capecitabine tablets whole, tell your healthcare provider.oYour healthcare provider may change your dose, temporarily stop, or permanently shop treatment with capecitabine if you develop side effects.oIf you take too much capecitabine, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of capecitabine Capecitabine can cause serious side effects including: oSee What is the most important information should know about capecitabine. oDiarrhea. Diarrhea is common with capecitabine and can sometimes be severe. Stop taking capecitabine 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 capecitabine and call your healthcare provider or go to the nearest hospital emergency room right away. oHeart problems. Capecitabine 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 capecitabine 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: ochest pain oshortness of breathodizziness olightheadednessoLoss of too much body fluid (dehydration) and kidney failure. Dehydration can happen with capecitabine and may cause sudden kidney failure that can lead to death. You are at higher risk if you have kidney problems before taking capecitabine and also take other medicines that can cause kidney problems. Nausea, and vomiting are common with capecitabine. If you lose your appetite, feel weak, and have nausea, vomiting, or diarrhea, you can quickly become dehydrated. Stop taking capecitabine and call your healthcare provider right away if you: oVomit or more times in day. oAre only able to eat or drink little now and then, or not at all due to nausea. oHave diarrhea. See diarrhea above. oSevere skin and mouth reactions. oCapecitabine 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 capecitabine if you have serious skin reaction. Do not take capecitabine again if this happens. oCapecitabine can also cause hand and foot syndrome. Hand and foot syndrome is common with capecitabine 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 capecitabine and call your healthcare provider right away if you have any of these symptoms and you are not able to do your usual activities. oHand and foot syndrome can lead to loss of fingerprints which could impact your identification.oYou may get sores in your mouth or on your tongue when taking capecitabine. Stop taking capecitabine 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.oIncreased level of bilirubin in your blood and liver problems. Increased bilirubin in your blood is common with capecitabine and can also sometimes be severe. Your healthcare provider will check you for these problems during treatment with capecitabine. oDecreased white blood cells, platelets, and red blood cell counts. Your healthcare provider will do blood tests during treatment with capecitabine 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 capecitabine.The most common side effects of capecitabine include: odiarrhea ohand and foot syndrome onausea ovomitingostomach-area (abdominal) pain oweakness and tiredness oincreased amounts of red blood cell breakdown products (bilirubin) in your bloodSevere allergic reactions can happen with capecitabine. Tell your healthcare provider if you have ever had an allergic reaction to capecitabine or 5-fluorouracil. See Do not take capecitabine if you:. Stop taking capecitabine 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: ored itchy welts on your skin (hives)orashoskin rednessoitchingoswelling of your face, lips, tongue or throatotrouble swallowing or breathingCapecitabine may cause fertility problems in females and males. This may affect the ability to have child. Talk to your healthcare provider if you have concerns about fertility. These are not all the possible side effects of capecitabine.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store capecitabine oStore capecitabine at room temperature between 68F to 77F (20C to 25C).oKeep capecitabine in tightly closed container. oAsk your healthcare provider or pharmacist how to safely throw away any unused capecitabine. Keep Capecitabine Tablets and all medicines out of the reach of children.General information about the safe and effective use of capecitabine. Medicines are sometimes prescribed for purposes other than those listed in patient information leaflets. Do not use capecitabine for condition for which it was not prescribed. Do not give capecitabine to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about capecitabine that is written for health professionals.What are the ingredients in Capecitabine Tablets Active ingredient: capecitabine USPInactive ingredients: croscarmellose sodium, magnesium stearate and silicified microcrystalline cellulose. In addition to the ingredients listed above, each tablet contains Opadry II (Pink). Opadry II (Pink) contains FD&C Blue Indigo Carmine Aluminum Lake, FD&C Red 40 Allura Red AC Aluminum Lake, FD&C Yellow Sunset Yellow FCF Aluminum Lake, hypromellose, macrogol, polydextrose, titanium dioxide, and triacetin.For more information, call Hikma Pharmaceuticals USA Inc. at 1-800-962-8364.This Patient Information has been approved by the U.S. Food and Drug Administration.Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922C50000412/02Revised May 2021. What is the most important information should know about capecitabine oCapecitabine can interact with blood thinner medicines, such as warfarin (COUMADIN(R)). Taking capecitabine 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 capecitabine, or later during treatment, and possibly even within month after you stop taking capecitabine. Your risk may be higher because you have cancer, and if you are over 60 years of age. oBefore taking capecitabine, tell your healthcare provider if you are taking warfarin (COUMADIN) or another blood thinner-medicine. oIf you take warfarin (COUMADIN) or another blood thinner that is like warfarin (COUMADIN) during treatment with capecitabine, your healthcare provider should do blood tests often, to check how fast your blood clots during and after you stop treatment with capecitabine. Your healthcare provider may change your dose of the blood thinner medicine if needed. oCancer of the colon that has spread to lymph nodes in the area close to the colon (Dukes stage), after they have surgery. oCancer 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. oBreast cancer that spread to other parts of the body (metastatic) together with another medicine called docetaxel after treatment with certain other anticancer medicines have not worked. oBreast cancer that has 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. oHave severe kidney problems. oAre allergic to capecitabine, 5-fluorouracil, or any of its ingredients in capecitabine. See the end of this leaflet for complete list of ingredients in capecitabine. oHave had heart problems.. oHave kidney or liver problems.. oHave been told that you lack the enzyme DPD (dihydropyrimidine dehydrogenase). oAre pregnant or plan to become pregnant. Capecitabine can harm your unborn baby. Your healthcare provider should do pregnancy test before you start treatment with capecitabine. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with capecitabine. oFemales 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 capecitabine. oMales who have female partners who are able to become pregnant should use effective birth control during treatment and for months after the final dose.. oAre breastfeeding or plan to breastfeed. It is not known if capecitabine passes into your breast milk. Do not breastfeed during treatment with capecitabine and for two weeks after the final dose.. oTake capecitabine exactly as your healthcare provider tells you to take it.. oYour healthcare provider will tell you how much capecitabine to take and when to take it.. oTake capecitabine times day, time in the morning and time in the evening.. oTake capecitabine within 30 minutes after finishing meal.. oSwallow capecitabine tablets whole with water. Do not crush or cut capecitabine tablets. If you cannot swallow capecitabine tablets whole, tell your healthcare provider.. oYour healthcare provider may change your dose, temporarily stop, or permanently shop treatment with capecitabine if you develop side effects.. oIf you take too much capecitabine, call your healthcare provider or go to the nearest hospital emergency room right away.. oSee What is the most important information should know about capecitabine. oDiarrhea. Diarrhea is common with capecitabine and can sometimes be severe. Stop taking capecitabine 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 capecitabine and call your healthcare provider or go to the nearest hospital emergency room right away. oHeart problems. Capecitabine 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 capecitabine 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: ochest pain oshortness of breath. odizziness olightheadedness. oLoss of too much body fluid (dehydration) and kidney failure. Dehydration can happen with capecitabine and may cause sudden kidney failure that can lead to death. You are at higher risk if you have kidney problems before taking capecitabine and also take other medicines that can cause kidney problems. Nausea, and vomiting are common with capecitabine. If you lose your appetite, feel weak, and have nausea, vomiting, or diarrhea, you can quickly become dehydrated. Stop taking capecitabine and call your healthcare provider right away if you: oVomit or more times in day. oAre only able to eat or drink little now and then, or not at all due to nausea. oHave diarrhea. See diarrhea above. oSevere skin and mouth reactions. oCapecitabine 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 capecitabine if you have serious skin reaction. Do not take capecitabine again if this happens. oCapecitabine can also cause hand and foot syndrome. Hand and foot syndrome is common with capecitabine 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 capecitabine and call your healthcare provider right away if you have any of these symptoms and you are not able to do your usual activities. oHand and foot syndrome can lead to loss of fingerprints which could impact your identification.. oYou may get sores in your mouth or on your tongue when taking capecitabine. Stop taking capecitabine 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.. oIncreased level of bilirubin in your blood and liver problems. Increased bilirubin in your blood is common with capecitabine and can also sometimes be severe. Your healthcare provider will check you for these problems during treatment with capecitabine. oDecreased white blood cells, platelets, and red blood cell counts. Your healthcare provider will do blood tests during treatment with capecitabine 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.. odiarrhea ohand and foot syndrome onausea ovomiting. ostomach-area (abdominal) pain oweakness and tiredness oincreased amounts of red blood cell breakdown products (bilirubin) in your blood. ored itchy welts on your skin (hives). orash. oskin redness. oitching. oswelling of your face, lips, tongue or throat. otrouble swallowing or breathing. oStore capecitabine at room temperature between 68F to 77F (20C to 25C).. oKeep capecitabine in tightly closed container. oAsk your healthcare provider or pharmacist how to safely throw away any unused capecitabine.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oLactation: Advise women not to breastfeed. (8.2)oFemales and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of capecitabine. Advise males with female partners of reproductive potential to use effective contraception. (8.3)oGeriatric: Greater incidence of adverse reactions. Monitoring required. (8.5)oHepatic Impairment: Monitoring is recommended in patients with mild to moderate hepatic impairment. (8.6)oRenal Impairment: Reduce capecitabine starting dose in patients with moderate renal impairment. (2.4, 8.7, 12.3). oLactation: Advise women not to breastfeed. (8.2). oFemales and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of capecitabine. Advise males with female partners of reproductive potential to use effective contraception. (8.3). oGeriatric: Greater incidence of adverse reactions. Monitoring required. (8.5). oHepatic Impairment: Monitoring is recommended in patients with mild to moderate hepatic impairment. (8.6). oRenal Impairment: Reduce capecitabine starting dose in patients with moderate renal impairment. (2.4, 8.7, 12.3). 8.1 Pregnancy Risk Summary:Based on findings in animal reproduction studies and its mechanism of action, capecitabine can cause fetal harm when administered to 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% to 4% and 15% to 20%, respectively. Data: Animal Data: Oral 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 Summary:There is no information regarding the presence of capecitabine in human milk, or on its effects on milk production or the breastfed 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 breastfed infants, advise women not to breastfeed during treatment with capecitabine and for weeks after the final dose. Data: Lactating 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 Testing: Pregnancy testing is recommended for females of reproductive potential prior to initiating capecitabine. Contraception: Females: Capecitabine 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 capecitabine. Males: Based on genetic toxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for months following the last dose of capecitabine [see Nonclinical Toxicology (13.1)]. Infertility: Based on animal studies, capecitabine may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use The safety and effectiveness of capecitabine in pediatric patients have not been established. 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 5,580 cGy in 180 cGy fractions). The relative bioavailability of the investigational formulation to capecitabine was similar.The first trial was conducted in 22 pediatric patients (median age years, range to 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 1,250 mg/m2 capecitabine every 12 hours on Days to 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 to 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 1,250 mg/m2 capecitabine every 12 hours on Days to 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 capecitabine in the elderly [see Warnings and Precautions (5.10)].. 8.6 Hepatic Insufficiency Exercise caution when patients with mild to moderate hepatic dysfunction due to liver metastases are treated with capecitabine. The effect of severe hepatic dysfunction on capecitabine is not known [see Warnings and Precautions (5.11) and Clinical Pharmacology (12.3)].. 8.7 Renal 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 oCoagulopathy: May result in bleeding, death. Monitor anticoagulant response (e.g., INR) and adjust anticoagulant dose accordingly. (5.1) oDiarrhea: May be severe. Interrupt capecitabine treatment immediately until diarrhea resolves or decreases to grade 1. Recommend standard antidiarrheal treatments. (5.2)oCardiotoxicity: Common in patients with prior history of coronary artery disease. (5.3)oIncreased Risk of Severe or Fatal Adverse Reactions in Patients with Low or Absent Dihydropyrimidine Dehydrogenase (DPD) Activity: Withhold or permanently discontinue capecitabine in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No capecitabine dose has been proven safe in patients with absent DPD activity. (5.4)oDehydration and Renal Failure: Interrupt capecitabine treatment until dehydration is corrected. Potential risk of acute renal failure secondary to dehydration. Monitor and correct dehydration. (5.5)oEmbryo-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)oMucocutaneous and Dermatologic Toxicity: Severe mucocutaneous reactions, Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), have been reported. Capecitabine should be permanently discontinued in patients who experience severe mucocutaneous reaction during treatment. Capecitabine 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 capecitabine treatment until the hand-and-foot syndrome event resolves or decreases in intensity. (5.7)oHyperbilirubinemia: Interrupt capecitabine treatment immediately until the hyperbilirubinemia resolves or decreases in intensity. (5.8)oHematologic: 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). oCoagulopathy: May result in bleeding, death. Monitor anticoagulant response (e.g., INR) and adjust anticoagulant dose accordingly. (5.1) oDiarrhea: May be severe. Interrupt capecitabine treatment immediately until diarrhea resolves or decreases to grade 1. Recommend standard antidiarrheal treatments. (5.2). oCardiotoxicity: Common in patients with prior history of coronary artery disease. (5.3). oIncreased Risk of Severe or Fatal Adverse Reactions in Patients with Low or Absent Dihydropyrimidine Dehydrogenase (DPD) Activity: Withhold or permanently discontinue capecitabine in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No capecitabine dose has been proven safe in patients with absent DPD activity. (5.4). oDehydration and Renal Failure: Interrupt capecitabine treatment until dehydration is corrected. Potential risk of acute renal failure secondary to dehydration. Monitor and correct dehydration. (5.5). oEmbryo-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). oMucocutaneous and Dermatologic Toxicity: Severe mucocutaneous reactions, Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), have been reported. Capecitabine should be permanently discontinued in patients who experience severe mucocutaneous reaction during treatment. Capecitabine 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 capecitabine treatment until the hand-and-foot syndrome event resolves or decreases in intensity. (5.7). oHyperbilirubinemia: Interrupt capecitabine treatment immediately until the hyperbilirubinemia resolves or decreases in intensity. (5.8). oHematologic: 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). 5.1 Coagulopathy 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)].. 5.2 Diarrhea Capecitabine 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 capecitabine 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 capecitabine 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.. 5.3 Cardiotoxicity The cardiotoxicity observed with capecitabine 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.. 5.4 Dihydropyrimidine 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 capecitabine (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 capecitabine.Withhold or permanently discontinue capecitabine 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 capecitabine 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.. 5.5 Dehydration 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 capecitabine with known nephrotoxic agents are at higher risk. Patients with anorexia, asthenia, nausea, vomiting or diarrhea may rapidly become dehydrated. Monitor patients when capecitabine is administered to prevent and correct dehydration at the onset. If grade (or higher) dehydration occurs, capecitabine 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, capecitabine may cause fetal harm when given to pregnant woman [see Clinical Pharmacology (12.1)]. Limited available data are not sufficient to inform use of capecitabine 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 capecitabine [see Use in Specific Populations (8.3)].. 5.7 Mucocutaneous 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 capecitabine [see Adverse Reactions (6.4)]. Capecitabine should be permanently discontinued in patients who experience severe mucocutaneous reaction possibly attributable to capecitabine 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 capecitabine 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 capecitabine should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade hand-and-foot syndrome, subsequent doses of capecitabine should be decreased [see Dosage and Administration (2.3)].. 5.8 Hyperbilirubinemia In 875 patients with either metastatic breast or colorectal cancer who received at least one dose of capecitabine 1,250 mg/m2 twice daily as monotherapy for weeks followed by 1-week rest period, grade (1.5 to x 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 capecitabine as first-line therapy for metastatic colorectal cancer, the incidence of grade or hyperbilirubinemia was similar to the overall clinical trial safety database of capecitabine monotherapy. The median time to onset for grade or hyperbilirubinemia in the colorectal cancer population was 64 days and median total bilirubin increased from micromol/L at baseline to 13 micromol/L during treatment with capecitabine. 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 capecitabine 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 capecitabine 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 1,250 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 capecitabine 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 capecitabine. If unscheduled laboratory assessments during treatment cycle show grade or hematologic toxicity, treatment with capecitabine should be interrupted.. 5.10 Geriatric 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 capecitabine monotherapy, 62% of the 21 patients >=80 years of age treated with capecitabine 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 capecitabine 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 capecitabine 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 capecitabine as adjuvant therapy for Dukes colon cancer after resection of the primary tumor, 41% of the 398 patients >=65 years of age treated with capecitabine 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 capecitabine compared to 5-FU/LV were 1.01 (95% C.I. 0.80 to 1.27) and 1.04 (95% C.I. 0.79 to 1.37), respectively.. 5.11 Hepatic Insufficiency Patients with mild to moderate hepatic dysfunction due to liver metastases should be carefully monitored when capecitabine is administered. The effect of severe hepatic dysfunction on the disposition of capecitabine is not known [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].. 5.12 Combination With Other Drugs Use of capecitabine in combination with irinotecan has not been adequately studied.