CAPEGARD 500 Tablets (Capecitabine)

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1 Published on: 10 Jul 2014 CAPEGARD 500 Tablets (Capecitabine) Black Box Warning: Capecitabine-Warfarin Interaction Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (International Normalized Ratio or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. A clinically important capecitabine-warfarin drug interaction was demonstrated in a clinical pharmacology trial. Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. Postmarketing reports have shown clinically significant increases in the prothrombin time and INR in patients who were stabilized on anticoagulants at the time capecitabine was introduced. These events occurred within several days and up to several months after initiating capecitabine therapy and, in a few cases, within 1 month after stopping capecitabine. These events occurred in patients with and without liver metastases. Age greater than 60 years and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy. Composition CAPEGARD 500 Tablets Each tablet contains: Capecitabine mg Dosage Form Oral tablet Pharmacology Pharmacodynamics Capecitabine is a non-cytotoxic fluoropyrimidine carbamate, which functions as an orally administered precursor of the cytotoxic moiety 5-fluorouracil (5-FU). Capecitabine is activated via several enzymatic steps. The enzyme involved in the final conversion to 5-FU, thymidine phosphorylase, is found in tumour tissues, but also in normal tissues, albeit usually at lower levels. In human cancer xenograft models, capecitabine demonstrated a synergistic effect in combination with docetaxel, which may be related to the upregulation of thymidine phosphorylase by docetaxel. Enzymes convert capecitabine to 5-FU in vivo. Both normal and tumour 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. Firstly, FdUMP and the folate cofactor, N5-10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a 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 a deficiency of this compound can inhibit cell division. Secondly, nuclear transcriptional enzymes can mistakenly

2 incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis. Since DNA and RNA are essential for cell division and growth, the effect of 5- FU may be to create a thymidine deficiency that provokes unbalanced growth and death of a cell. The effects of DNA and RNA deprivation are most marked on those cells that proliferate more rapidly and metabolize 5-FU at a more rapid rate. Pharmacokinetics Absorption Following oral administration to cancer patients, capecitabine reached peak blood levels in about 1.5 hours (T max ), with peak 5-FU levels occurring slightly later at 2 hours. Food reduced both the rate and extent of absorption of capecitabine, with the mean C max and AUC 0- decreased by 60% and 35%, respectively. The C max and AUC 0- of 5-FU were also reduced by food by 43% and 21%, respectively. Food delayed the T max of both the parent drug and 5-FU by 1.5 hours. After oral administration, capecitabine is rapidly and extensively absorbed, followed by extensive conversion to the metabolites, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR). Administration with food decreases the rate of capecitabine absorption, but only results in a minor effect on the AUC of 5'-DFUR, and on the AUC of the subsequent metabolite, 5-FU. At the dose of 1,250 mg/m 2 on day 14 with administration after food intake, the peak plasma concentrations (C max in μg/ml) for capecitabine, 5'-DFCR, 5'-DFUR, 5-FU and α-fluoro-β-alanine (FBAL) were 4.67, 3.05, 12.1, 0.95 and 5.46, respectively. The time to peak plasma concentrations (T max in hours) were 1.50, 2.00, 2.00, 2.00 and 3.34, respectively. The AUC 0- values in μg-h/ml were 7.75, 7.24, 24.6, 2.03 and 36.3, respectively. 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. Capecitabine has a low potential for pharmacokinetic interactions related to plasma protein binding. In vitro human plasma studies have determined that capecitabine, 5'-DFCR, 5'-DFUR and 5-FU are 54%, 10%, 62% and 10% protein-bound, mainly to albumin, respectively. Bioactivation and Metabolism Capecitabine is extensively metabolized enzymatically to 5-FU. In the liver, a 60 kda carboxylesterase hydrolyses much of the compound to 5'-DFCR. Cytidine deaminase, an enzyme found in most tissues, including tumours, subsequently converts 5'-DFCR to 5'-DFUR. The enzyme, thymidine phosphorylase, then hydrolyses 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 the surrounding normal tissues. Following oral administration of capecitabine, 7 days before surgery, in patients with colorectal cancer, the median ratio of 5-FU concentration in colorectal tumours 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

3 The enzyme, dihydropyrimidine dehydrogenase (DPD), 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, β-ureido-propionase cleaves FUPA to 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 (CY) P450 isoenzymes, 1A2, 2A6, 3A4, 2C19, 2D6 and 2E1. Excretion Capecitabine and its metabolites are predominantly excreted in the urine; 95.5% of the administered capecitabine dose is recovered in the urine. Faecal 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 the urine as unchanged drug. The elimination half-life (t1/2 in hours) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU and FBAL were 0.85, 1.11, 0.66, 0.76 and 3.23, respectively. Special Populations Presence or absence of liver metastasis at baseline, Karnofsky Performance Status, total bilirubin, serum albumin, aspartate amino transferase (ASAT) and alanine amino transferase (ALAT) had no statistically significant effect on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL. Effect of Age, Gender and Race on the Pharmacokinetics of Capecitabine Gender and 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. A 20% increase in age results in a 15% increase in the AUC of FBAL. This increase is likely due to a change in renal function. Following oral administration of 825 mg/m 2 capecitabine twice daily for 14 days, the Japanese patients had about 36% lower C max and 24% lower AUC for capecitabine than the Caucasian patients. The Japanese patients also had about 25% lower C max 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 Impairment Capecitabine has been evaluated in 13 patients with mild-to-moderate hepatic dysfunction due to liver metastases defined by a composite score, including bilirubin, AST/ALT and alkaline phosphatase following a single dose of capecitabine. Both the AUC 0- and C max of capecitabine increased by 60% in patients with hepatic dysfunction compared to patients with normal hepatic function. The AUC 0- and C max 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.

4 Effect of Renal Impairment Following oral administration of 1,250 mg/m 2 capecitabine twice a day to cancer patients with varying degrees of renal impairment, patients with moderate (creatinine clearance = ml/min) and severe (creatinine clearance 80 ml/min). FBAL is a metabolite without antiproliferative activity. 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. Effect of Capecitabine on the Pharmacokinetics of Warfarin In patients with cancer, chronic administration of capecitabine (1,250 mg/m 2 b.i.d.) with a 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%. Effect of Antacids on the Pharmacokinetics of Capecitabine When an aluminium hydroxide- and magnesium hydroxide-containing antacid, was administered immediately after capecitabine (1,250 mg/m 2 ), the AUC and C max increased by 16% and 35%, respectively, for capecitabine and by 18% and 22%, respectively, for 5'-DFCR. No effect was observed on the other three major metabolites (5'-DFUR, 5-FU, FBAL) of capecitabine. Effect of Capecitabine on the Pharmacokinetics of Docetaxel and Vice Versa Capecitabine was found to have no effect on the pharmacokinetics of docetaxel (C max and AUC) and docetaxel has no effect on the pharmacokinetics of capecitabine and the 5-FU precursor, 5'-DFUR. Indications Colorectal Cancer CAPEGARD 500 Tablets are indicated as a single agent for adjuvant treatment in patients with Dukes' C colon cancer who have undergone complete resection of the primary tumour when treatment with fluoropyrimidine therapy alone is preferred. CAPEGARD 500 Tablets were non-inferior to 5-FU and leucovorin (5-FU/LV) for disease-free survival. CAPEGARD 500 Tablets are indicated for the first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown a survival benefit compared to 5-FU/LV alone. A survival benefit over 5-FU/LV has not been demonstrated with CAPEGARD 500 Tablets monotherapy. Use of CAPEGARD 500 Tablets instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage. Breast Cancer CAPEGARD 500 Tablets in combination with docetaxel are indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy. CAPEGARD 500 Tablets 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). Gastric Cancer CAPEGARD 500 Tablets are indicated for the first-line treatment of advanced gastric cancer in combination with a platinum- based regimen.

5 Dosage And Administration CAPEGARD 500 Tablets should be swallowed whole with water within 30 minutes after a meal. The dose of CAPEGARD 500 Tablets is calculated according to the body surface area. Standard Starting Dose Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer) The recommended dose of CAPEGARD 500 Tablets is 1,250 mg/m 2 administered orally twice daily (morning and evening; equivalent to 2,500 mg/m 2 total daily dose) for 2 weeks followed by a 1-week rest period; the tablets are given as 3-week cycles (see Table 1). Adjuvant treatment in patients with Dukes' C colon cancer is recommended for a total of 6 months. Table 1: CAPEGARD 500 Tablets Dose Calculation According to Body Surface Area Dose Level: 1,250 mg/m 2 Twice a Day Surface Area (m 2 ) Total Daily Dose* (mg) , , , ,000 Dose Level: 1,250 mg/m 2 Twice a Day Surface Area (m 2 ) Total Daily Dose* (mg) , , , , ,600

6 * Total Daily Dose divided by 2 to allow equal morning and evening doses Combination Therapy (Colon, Colorectal and Gastric Cancer) In combination treatment, the recommended starting dose of CAPEGARD 500 Tablets should be reduced to 800-1,000 mg/m 2 when administered twice daily for 14 days followed by a 7-day rest period, or to 625 mg/m 2 twice daily when administered continuously. The inclusion of biological medicinal products in a combination regimen has no effect on the starting dose of CAPEGARD 500 Tablets. Premedication to maintain adequate hydration and anti-emesis according to the cisplatin summary of product characteristics should be started prior to cisplatin administration for patients receiving the CAPEGARD 500 Tablets plus cisplatin combination. Premedication with anti-emetics according to the oxaliplatin summary of product characteristics is recommended for patients receiving the CAPEGARD 500 Tablets plus oxaliplatin combination. Adjuvant treatment in patients with stage III colon cancer is recommended for duration of 6 months. Breast Cancer In combination with docetaxel, the recommended dose of CAPEGARD 500 Tablets is 1,250 mg/m 2 twice daily for 2 weeks followed by a 1-week rest period, combined with docetaxel at 75 mg/m 2 as a 1-hour intravenous infusion every 3 weeks. Pre-medication with an oral corticosteroid such as dexamethasone, according to the docetaxel labelling, should be started prior to docetaxel administration for patients receiving the CAPEGARD 500 Tablets plus docetaxel combination. Table 1 displays the total daily dose of CAPEGARD 500 Tablets by body surface area. General Dose Management Guidelines CAPEGARD 500 Tablets dosage may need to be individualized to optimize patient management. Patients should be carefully monitored for toxicity and doses of CAPEGARD 500 Tablets should be modified as necessary to accommodate individual patient tolerance to treatment. Toxicity due to CAPEGARD 500 Tablets administration may be managed by symptomatic treatment, dose interruptions and adjustment of the CAPEGARD 500 Tablets dose. Once the dose has been reduced, it should not be increased at a later time. Doses of CAPEGARD 500 Tablets omitted for toxicity should not be replaced or restored; instead the patient should resume the planned treatment cycles. For those toxicities considered by the treating doctor to be unlikely to become serious or life-threatening, e.g. alopecia, altered taste, nail changes, treatment can be continued at the same dose without reduction or interruption. The dose of phenytoin and the dose of coumarin-derivative anticoagulants may need to be reduced when either drug is administered concomitantly with CAPEGARD 500 Tablets. Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer) The CAPEGARD 500 Tablets dose modification scheme as described below (see Table 2) is recommended for the management of adverse reactions. Table 2: Recommended Dose Modifications for CAPEGARD 500 Tablets

7 Toxicity NCIC Grades* Grade 1 1st appearance 2nd appearance 3rd appearance 4th appearance 1st appearance 2nd appearance 3rd appearance 1st appearance During a Course of Therapy Maintain Dose Level Grade 2 Interrupt until resolved to grade 0-1 Discontinue treatment permanently Grade 3 Interrupt until resolved to grade 0-1 Discontinue treatment permanently Grade 4 Discontinue permanently OR If the physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade 0-1 Dose Adjustment for Next Treatment (% of Starting Dose) Maintain Dose Level 100% 75% 50% - 75% 50% - 50%

8 * National Cancer Institute of Canada Common Toxicity Criteria were used except for the hand-and-foot syndrome In Combination with Docetaxel (Metastatic Breast Cancer) Dose modifications of CAPEGARD 500 Tablets for toxicity should be made according to Table 2 above. At the beginning of a treatment cycle, if a treatment delay is indicated for either CAPEGARD 500 Tablets 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 CAPEGARD 500 Tablets for the treatment of metastatic breast cancer is shown in Table 3. Table 3: Docetaxel Dose Reduction Schedule in Combination with CAPEGARD 500 Tablets Toxicity NCIC Grades* Grade 2 Grade 3 Grade 4 1st appearance Delay treatment until resolved to grade 0-1; Resume treatment with original dose of 75 mg/m 2 docetaxel Delay treatment until resolved to grade 0-1; Resume treatment with 55 mg/m 2 of docetaxel. Discontinue treatment with docetaxel 2nd appearance Delay treatment until resolved to grade 0-1; Resume treatment with 55 mg/m 2 of docetaxel. Discontinue treatment with docetaxel - 3rd appearance Discontinue treatment with docetaxel - - * National Cancer Institute of Canada Common Toxicity Criteria were used except for hand-and-foot syndrome Haematology Patients with baseline neutrophil counts of < /L and/or thrombocyte counts of < /L should not be

9 treated with CAPEGARD 500 Tablets. If unscheduled laboratory assessments during a treatment cycle show that the neutrophil count drops below /L or that the platelet count drops below /L, treatment with CAPEGARD 500 Tablets should be interrupted. Dose Modifications for Toxicity When CAPEGARD 500 Tablets Are Used As a 3-Weekly Cycle in Combination with Other Medicinal Products Dose modifications for toxicity when CAPEGARD 500 Tablets is used as a 3 weekly cycle in combination with other medicinal products should be made according to table 2 above for CAPEGARD 500 Tablets and according to the appropriate summary of product characteristics for the other medicinal product(s). At the beginning of a treatment cycle, if a treatment delay is indicated for either CAPEGARD 500 Tablets or the other medicinal product(s), then administration of all therapy should be delayed until the requirements for restarting all medicinal products are met. During a treatment cycle for those toxicities considered by the treating doctor not to be related to CAPEGARD 500 Tablets, CAPEGARD 500 Tablets should be continued and the dose of the other medicinal product should be adjusted according to the appropriate Prescribing Information. If the other medicinal product(s) have to be discontinued permanently, CAPEGARD 500 Tablets treatment can be resumed when the requirements for restarting CAPEGARD 500 Tablets are met. This advice is applicable to all indications and to all special populations. Dose Modifications for Toxicity When CAPEGARD 500 Tablets Are Used Continuously in Combination with Other Medicinal Products Dose modifications for toxicity when CAPEGARD 500 Tablets are used continuously in combination with other medicinal products should be made according to Table 2 above for capecitabine and according to the appropriate summary of product characteristics for the other medicinal product(s). Dose Adjustments for Special Populations Hepatic Impairment Insufficient safety and efficacy data are available in patients with hepatic impairment to provide a dose adjustment recommendation. No information is available on hepatic impairment due to cirrhosis or hepatitis. Renal Impairment CAPEGARD 500 Tablets are contraindicated in patients with severe renal impairment (creatinine clearance <30 ml/min at baseline). The incidence of grade 3 or 4 adverse reactions in patients with moderate renal impairment (creatinine clearance: ml/min at baseline) is increased, compared to the overall population. In patients with moderate renal impairment at baseline, a dose reduction to 75% for a starting dose of 1,250 mg/m 2 is recommended. In patients with moderate renal impairment at baseline, no dose reduction is required for a starting dose of 1,000 mg/m 2. In patients with mild renal impairment (creatinine clearance: ml/min at baseline), no adjustment of the starting dose is recommended. Careful monitoring and prompt treatment interruption is recommended if the patient develops a grade 2, 3 or 4 adverse events during treatment and subsequent dose adjustment as outlined in Table 2 above. If the calculated creatinine clearance decreases during treatment to a value <30 ml/min, CAPEGARD 500 Tablets should be discontinued. These dose adjustment recommendations for renal impairment apply both to monotherapy and combination use. Geriatric During CAPEGARD 500 Tablets monotherapy, no adjustment of the starting dose is needed. However, grade 3 or 4

10 treatment-related adverse reactions were more frequent in patients who were 60 years of age compared to younger patients. When CAPEGARD 500 Tablets were used in combination with other medicinal products, elderly patients (aged 65 years) experienced more grade 3 and grade 4 adverse drug reactions, including those leading to discontinuation, compared to younger patients. Careful monitoring of patients 60 years of age is advisable. In Combination with Docetaxel An increased incidence of grade 3 or 4 treatment-related adverse reactions and treatment-related serious adverse reactions were observed in patients 60 years of age. For patients 60 years of age, a starting dose reduction of CAPEGARD 500 Tablets to 75% (950 mg/m 2 twice daily) is recommended. If no toxicity is observed in patients 60 years of age treated with a reduced CAPEGARD 500 Tablets starting dose in combination with docetaxel, the dose of CAPEGARD 500 Tablets may be cautiously escalated to 1,250 mg/m 2 twice daily. In Combination with Irinotecan For patients 65 years of age, a starting dose reduction of CAPEGARD 500 Tablets to 800 mg/m 2 twice daily is recommended. Paediatric There is no relevant use of CAPEGARD 500 Tablets in the paediatric population for the indications of colon, colorectal, gastric and breast cancer. Contraindications History of severe and unexpected reactions to fluoropyrimidine therapy. In patients with a known hypersensitivity to CAPEGARD 500 Tablets or to any of its components. CAPEGARD 500 Tablets are contraindicated in patients who have a known hypersensitivity to 5-FU. In patients with known DPD deficiency. During pregnancy and lactation. In patients with severe leucopenia, neutropenia or thrombocytopenia. In patients with severe hepatic impairment. In patients with severe renal impairment (creatinine clearance Treatment with sorivudine or its chemically related analogues, such as brivudine. If contraindications exist to any of the medicinal products in the combination regimen, that medicinal product should not be used. Warnings And Precautions Drug Interactions Interaction studies have only been performed in adults. Interactions with Other Medicinal Products CYP450 2C9 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 2C9 substrates (e.g. phenytoin). Coumarin-derivative Anticoagulants Altered coagulation parameters and/or bleeding have been reported in patients taking capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. These reactions occurred within several days and up to several months after initiating capecitabine therapy and, in a few cases, within 1 month after stopping

11 capecitabine. In a clinical pharmacokinetic interaction study, after a single 20 mg dose of warfarin, capecitabine treatment increased the AUC of S-warfarin by 57%, with a 91% increase in the INR value. Since metabolism of R-warfarin was not affected, these results indicate that capecitabine down-regulates isozyme 2C9, but has no effect on isozymes 1A2 and 3A4. Patients taking coumarin-derivative anticoagulants concomitantly with capecitabine should be monitored regularly for alterations in their coagulation parameters (INR or prothrombin time) and the anti-coagulant dose adjusted accordingly. Phenytoin Increased phenytoin plasma concentrations resulting in symptoms of phenytoin intoxication in single cases have been reported during concomitant use of capecitabine with phenytoin. Patients taking phenytoin concomitantly with capecitabine should be regularly monitored for increased phenytoin plasma concentrations. Folinic Acid A combination study with capecitabine and folinic acid indicated that folinic acid has no major effect on the pharmacokinetics of capecitabine and its metabolites. However, folinic acid has an effect on the pharmacodynamics of capecitabine and its toxicity may be enhanced by folinic acid: the maximum tolerated dose of capecitabine alone using the intermittent regimen is 3,000 mg/m 2 per day whereas it is only 2,000 mg/m 2 per day when capecitabine was combined with folinic acid (30 mg orally b.i.d.). Sorivudine and Analogues A clinically significant drug-drug interaction between sorivudine and 5-FU, resulting from the inhibition of DPD by sorivudine, has been described. This interaction, which leads to increased fluoropyrimidine toxicity, is potentially fatal. Therefore, capecitabine must not be administered concomitantly with sorivudine or its chemically related analogues, such as brivudine. There must be at least a 4-week waiting period between end of treatment with sorivudine or its chemically related analogues such as brivudine and the start of capecitabine therapy. Antacid The effect of an aluminium hydroxide- and magnesium hydroxide-containing antacid on the pharmacokinetics of capecitabine was investigated. There was a small increase in plasma concentrations of capecitabine and one metabolite (5'-DFCR); there was no effect on the three major metabolites (5'-DFUR, 5-FU and FBAL). Allopurinol Interactions with allopurinol have been observed for 5-FU, with, possibly, decreased efficacy of 5-FU. Concomitant use of allopurinol with capecitabine should be avoided. Interferon Alpha-2a The maximum tolerated dose of capecitabine was 2,000 mg/m 2 per day when combined with interferon alpha-2a (3 MIU/m 2 per day) compared to 3,000 mg/m 2 per day when capecitabine was used alone. Radiotherapy The maximum tolerated dose of capecitabine alone using the intermittent regimen is 3,000 mg/m 2 per day, whereas, when combined with radiotherapy for rectal cancer, the maximum tolerated dose of capecitabine is 2,000 mg/m 2 per day using either a continuous schedule, or given daily Monday through Friday during a 6-week course of radiotherapy. Oxaliplatin No clinically significant differences in exposure to capecitabine or its metabolites, and free platinum or total platinum occurred when capecitabine was administered in combination with oxaliplatin or in combination with oxaliplatin and bevacizumab. Bevacizumab There was no clinically significant effect of bevacizumab on the pharmacokinetic parameters of capecitabine or its metabolites in the presence of oxaliplatin.

12 Food Interaction In all clinical trials, patients were instructed to take capecitabine within 30 minutes after a meal. Since current safety and efficacy data are based upon administration with food, it is recommended that capecitabine be administered with food. Administration with food decreases the rate of capecitabine absorption. General Patients receiving therapy with capecitabine should be monitored by a doctor. Most adverse reactions are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced. Dose-limiting Toxicities Dose limiting toxicities include diarrhoea, abdominal pain, nausea, stomatitis and hand-foot syndrome (hand-foot skin reaction, Palmar-Plantar erythrodysaesthesia). Most adverse reactions are reversible and do not require permanent discontinuation of therapy, although doses may need to be withheld or reduced. Diarrhoea Patients with severe diarrhoea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. Standard anti-diarrhoeal treatments (e.g. loperamide) may be used. NCIC-CTC grade 2 diarrhoea is defined as an increase of 4-6 stools/day or nocturnal stools, and grade 3 diarrhoea as an increase of 7-9 stools/day or incontinence and malabsorption. Grade 4 diarrhoea is an increase of 10 stools/day or grossly bloody diarrhoea or the need for parenteral support. If grade 2, 3 or 4 diarrhoea occurs, administration of capecitabine should be immediately interrupted until the diarrhoea resolves or decreases in intensity to grade 1. Following a reoccurrence of grade 2 diarrhoea or occurrence of any grade 3 or 4 diarrhoea, subsequent doses of capecitabine should be decreased. Necrotizing enterocolitis (typhlitis) has been reported. Dehydration Dehydration should be prevented or corrected at the onset. Patients with anorexia, asthenia, nausea, vomiting or diarrhoea may rapidly become dehydrated. If grade 2 (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 applied should be applied for the precipitating adverse event as necessary. Hypocalcaemia or Hypercalcaemia Hypocalcaemia or hypercalcaemia has been reported during capecitabine treatment. Caution must be exercised in patients with pre-existing hypocalcaemia or hypercalcaemia. Central or Peripheral Nervous System Disease Caution must be exercised in patients with central or peripheral nervous system disease, e.g. brain metastasis or neuropathy. Diabetes Mellitus or Electrolyte Disturbances Caution must be exercised in patients with diabetes mellitus or electrolyte disturbances, as these may be aggravated during capecitabine treatment. 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. Cardiotoxicity Cardiotoxicity has been associated with fluoropyrimidine therapy, including myocardial infarction, angina, dysrhythmias, cardiogenic shock, sudden death and electrocardiographic changes (including very rare cases of QT prolongation). These adverse reactions may be more common in patients with a prior history of coronary artery disease. Cardiac arrhythmias (including ventricular fibrillation, torsades de pointes, and bradycardia), angina pectoris, myocardial infarction, heart failure and cardiomyopathy have been reported in patients receiving capecitabine. Caution must be exercised in patients

13 with history of significant cardiac disease, arrhythmias and angina pectoris. DPD Deficiency Rarely, unexpected, severe toxicity (e.g., stomatitis, diarrhoea, neutropenia and neurotoxicity) associated with 5-FU has been attributed to a deficiency of DPD activity. A link between decreased levels of DPD and increased, potentially fatal toxic effects of 5-FU, therefore, cannot be excluded. In patients with unrecognized DPD deficiency treated with capecitabine, life-threatening toxicities manifesting as acute overdose may occur. In the event of grade 2-4 acute toxicity, treatment must be discontinued immediately until observed toxicity resolves. Permanent discontinuation should be considered based on clinical assessment of the onset, duration and severity of the observed toxicities. Ophthalmologic Complications Patients should be carefully monitored for ophthalmologic complications such as keratitis and corneal, especially if they have a prior history of eye. Treatment of eye should be initiated as clinically appropriate. Lactose As this medicinal product contains anhydrous lactose as an excipient, patients with rare hereditary problems of galactose intolerance, the Lapp-lactase deficiency or glucose-galactose malabsorption should not take this medicine. Hand-Foot Syndrome Hand-foot syndrome (also known as hand-foot skin reaction or Palmar-Plantar erythrodysaesthesia or chemotherapyinduced acral erythema). Grade 1 hand- foot syndrome is defined as numbness, dysaesthesia/ paraesthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort, which does not disrupt the patient's normal activities. Grade 2 hand-foot syndrome is painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient's activities of daily living. Grade 3 hand-foot syndrome is moist desquamation, ulceration, blistering and severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living. If grade 2 or 3 hand-foot syndrome occurs, administration of capecitabine should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-foot syndrome, subsequent doses of capecitabine should be decreased. When capecitabine and cisplatin are used in combination, the use of vitamin B6 (pyridoxine) is not advised for symptomatic or secondary prophylactic treatment of hand-foot syndrome, because of published reports that it may decrease the efficacy of cisplatin. Hyperbilirubinaemia In 875 patients with either metastatic breast or colorectal cancer who received at least one dose of capecitabine 1,250 mg/m 2 twice daily as monotherapy for 2 weeks followed by a 1-week rest period, grade 3 (1.5-3 x upper limit of normal ) hyperbilirubinaemia occurred in 15.2% (n=133) of patients and grade 4 (>3 x ULN) hyperbilirubinaemia 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 3 or 4 hyperbilirubinaemia occurred in 22.8% and 12.3%, respectively. Of the 167 patients with grade 3 or 4 hyperbilirubinaemia, 18.6% (n=31) also had post-baseline elevations (grades 1 to 4, without elevations at baseline) in alkaline phosphatase and 27.5% (n=46) had post-baseline elevations in transaminases at any time (not necessarily concurrent). The majority of these patients, i.e. 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 1 to 4) at both pre-baseline and post-baseline in alkaline phosphatase or transaminases, respectively. Only 7.8% (n=13) and 3.0% (n=5) had grade 3 or 4 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 3 or 4 hyperbilirubinaemia was similar to the overall clinical trial safety database of capecitabine monotherapy. The median time to

14 onset for grade 3 or 4 hyperbilirubinaemia in the colorectal cancer population was 64 days and median total bilirubin increased from 8 -m/l at baseline to 13 -m/l during treatment with capecitabine. Of the 136 colorectal cancer patients with grade 3 or 4 hyperbilirubinaemia, 49 patients had grade 3 or 4 hyperbilirubinaemia as their last measured value, of which 46 had liver metastases at baseline. In 251 patients with metastatic breast cancer who received a combination of capecitabine and docetaxel, grade 3 (1.5-3 x ULN) hyperbilirubinaemia occurred in 7% (n=17) and grade 4 (>3 x ULN) hyperbilirubinaemia occurred in 2% (n=5). If drug-related grade 3 to 4 elevations in bilirubin occur, administration of capecitabine should be immediately interrupted until the hyperbilirubinaemia decreases to 3.0 x ULN. Haematologic In 875 patients with either metastatic breast or colorectal cancer who received a dose of 1,250 mg/m 2 administered twice daily as monotherapy for 2 weeks followed by a 1-week rest period, 3.2%, 1.7%, and 2.4% of patients had grade 3 or 4 neutropenia, thrombocytopenia or decreases in haemoglobin, respectively. In 251 patients with metastatic breast cancer who received a dose of capecitabine in combination with docetaxel, 68% had grade 3 or 4 neutropenia, 2.8% had grade 3 or 4 thrombocytopenia, and 9.6% had grade 3 or 4 anaemia. Patients with baseline neutrophil counts of < /L and/or thrombocyte counts of < /L should not be treated with capecitabine. If unscheduled laboratory assessments during a treatment cycle show grade 3 or 4 haematologic toxicity, treatment with capecitabine should be interrupted. Combination with Other Drugs Use of capecitabine in combination with irinotecan has not been adequately studied. Renal Impairment Patients with moderate renal impairment at baseline require dose reduction. 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 a patient develops a grade 2-4 adverse event as outlined in Table 2. The incidence of grade 3 or 4 adverse reactions in patients with moderate renal impairment (creatinine clearance: ml/min) is increased compared to the overall population. Hepatic Impairment In the absence of safety and efficacy data in patients with hepatic impairment, capecitabine use should be carefully monitored in patients with mild-to-moderate liver dysfunction, regardless of the presence or absence of liver metastasis. Administration of capecitabine should be interrupted if treatment-related elevations in bilirubin of >3.0 x ULN or treatment-related elevations in hepatic aminotransferases (ALT, AST) of >2.5 x ULN occur. Treatment with capecitabine monotherapy may be resumed when bilirubin decreases to 3.0 x ULN or hepatic aminotransferases decrease to 2.5 x ULN. The effect of severe hepatic dysfunction on the disposition of capecitabine is not known In animal studies effects on fertility were observed. Pregnancy Pregnancy Category D There are no studies in pregnant women using capecitabine; however, it should be assumed that capecitabine may cause foetal harm if administered to pregnant women. In reproductive toxicity studies in animals, capecitabine administration caused embryo-lethality and teratogenicity. These findings are expected effects of fluoropyrimidine derivatives. Capecitabine is contraindicated during pregnancy. Women of Childbearing Potential/Contraception in Males and Females Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with

15 capecitabine. If the patient becomes pregnant while receiving capecitabine, the potential hazard to the foetus must be explained. An effective method of contraception should be used during treatment. Lactation It is not known whether capecitabine is excreted in human breast milk. In lactating mice, considerable amounts of capecitabine and its metabolites were found in milk. Breastfeeding should be discontinued while receiving treatment with capecitabine. Paediatric Use The safety and effectiveness of capecitabine in persons <18 years of age have not been established. Geriatric Use Patients 80 years of age may experience a greater incidence of grade 3 or 4 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 a treatment-related grade 3 or 4 adverse event as follows: diarrhoea in 6 (28.6%), nausea in 3 (14.3%), hand-foot syndrome in 3 (14.3%), and vomiting in 2 (9.5%) patients. Among the 10 patients 70 years of age (no patients were >80 years of age) treated with capecitabine in combination with docetaxel, 30% (3 out of 10) of patients experienced grade 3 or 4 diarrhoea and stomatitis, and 40% (4 out of 10) experienced grade 3 hand-foot syndrome. Among the 67 patients 60 years of age receiving capecitabine in combination with docetaxel, the incidence of grade 3 or 4 treatment-related adverse reactions, and 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' C colon cancer after resection of the primary tumour, 41% of the 398 patients 65 years of age treated with capecitabine experienced a treatment-related grade 3 or 4 adverse event as follows: hand-foot syndrome in 75 (18.8%), diarrhoea in 52 (13.1%), stomatitis in 12 (3.0%), neutropenia/granulocytopenia in 11 (2.8%), vomiting in 6 (1.5%), and nausea in 5 (1.3%) patients. In patients 65 years of age (all-randomized population; capecitabine, 188 patients; 5-FU/LV, 208 patients) treated for Dukes' C colon cancer after resection of the primary tumour, the hazard ratios for disease-free survival and overall survival for capecitabine, compared to 5-FU/LV, were 1.01 (95% CI: ) and 1.04 (95% CI: ), respectively. Fertility There is no data on capecitabine and its impact on fertility. The capecitabine pivotal studies included females of childbearing potential and males only if they agreed to use an acceptable method of birth control to avoid pregnancy for the duration of the study and for a reasonable period thereafter. Effects on the Ability to Drive and Use Machines Capecitabine has minor or moderate influence on the ability to drive and use machines. Capecitabine may cause dizziness, fatigue and nausea. Undesirable Effects Summary of the Safety Profile The overall safety profile of capecitabine is based on data from over 3,000 patients treated with capecitabine as monotherapy or capecitabine in combination with different chemotherapy regimens in multiple indications. The safety profiles of capecitabine monotherapy for the metastatic breast cancer, metastatic colorectal cancer and adjuvant colon cancer populations are comparable. The most commonly reported and/or clinically relevant treatment-related adverse drug reactions (ADRs) were

16 gastrointestinal (especially diarrhoea, nausea, vomiting, abdominal pain, and stomatitis), hand-foot syndrome (Palmar-Plantar erythrodysaesthesia), fatigue, asthenia, anorexia, cardiotoxicity, increased renal dysfunction in those with pre-existing compromised renal function, and thrombosis/embolism. Tabulated Summary of ADRs ADRs considered by the investigator to be possibly, probably, or remotely related to the administration of capecitabine are listed in Table 4 for capecitabine given as monotherapy and in Table 5 for capecitabine given in combination with different chemotherapy regimens in multiple indications. The following headings are used to rank the ADRs by frequency: very common ( 1/10), common ( 1/100 to <1/10), uncommon ( 1/1,000 to <1/100), rare ( 1/10,000 to <1/1,000), and very rare (<1/10,000). Within each frequency grouping, the ADRs are presented in order of decreasing seriousness. Capecitabine Monotherapy Table 4 lists the ADRs associated with the use of capecitabine monotherapy, based on a pooled analysis of safety data from three major studies, including over 1,900 patients (Studies M66001, SO14695 and SO14796). The ADRs are added to the appropriate frequency grouping according to the overall incidence from the pooled analysis. Table 4: Summary of Related ADRs Reported in Patients Treated with Capecitabine Monotherapy Body System Very Common All Grades Common All Grades Uncommon,Severe and/or Lifethreatening (Grade 3-4) or Considered Medically Relevant Infections and infestations - Herpes viral infection,nasopharyngitis Lower respiratory tract infection Sepsis, urinary tract infection, cellulitis, tonsillitis, pharyngitis, laryngitis, bronchitis,oral candidiasis, influenza, gastroenteritis, fungal infection, infection, tooth abscess, pneumonia, bronchopneumonia, keratoconjunctivitis, fungal infections (including candidiasis) Neoplasm benign, malignant and unspecified - - Lipoma

17 Blood and lymphatic system Immune system - Neutropenia, Anaemia Febrile neutropenia, Pancytopenia, Granulocytopenia, Thrombocytopenia, Leucopenia, Lymphocytopenia, Haemolytic anaemia, INR increased/prothrombin time prolonged, Coagulation disorder, Bone marrow depression, Idiopathic thrombocytopenia purpura - - Hypersensitivity Metabolism and nutrition Anorexia Dehydration,, Weight decreased or increased, Cachexia Diabetes, hypokalaemia, appetite disorder, malnutrition, hypertriglyceridaemia, hypomagnesemia Psychiatric Nervous system - Insomnia, depression, taste disturbance - Headache, Lethargy Dizziness, Paraesthesia Dysgeusia Confusional state, panic attack, depressed mood, libido decreased, mood alteration Aphasia, memory impairment, ataxia, syncope, balance disorder, sensory disorder, neuropathy peripheral, tremor, dysphasia, encephalopathy, abnormal coordination, dysarthria, loss of consciousness, impaired balance Eye - Lacrimation increased, Conjunctivitis,Eye irritation Visual acuity reduced, Diplopia

18 Ear and labyrinth Cardiac Vascular - - Vertigo,Ear pain - - Angina unstable, angina pectoris, myocardial ischaemia, atrial fibrillation, arrhythmia, tachycardia, bradycardia, sinus tachycardia, palpitations, ventricular extrasystoles, extrasystoles, myocarditis, pericardial effusion - Thrombophlebitis Deep vein thrombosis, hypertension, petechiae, hypotension, hot flush, peripheral coldness, lymphoedema, pulmonary embolism, cerebrovascular accident Respiratory, thoracic and mediastinal - Dyspnoea, epistaxis, cough, rhinorrhoea, pharyngeal disorder, pleural effusion Pulmonary embolism, pneumothorax, haemoptysis, asthma, dyspnoea exertional, respiratory distress

19 Gastrointestinal Diarrhoea, vomiting, nausea, stomatitis, abdominal pain Gastrointestinal haemorrhage, constipation, upper abdominal pain, dyspepsia, flatulence, dry mouth Intestinal obstruction, Ascites, enteritis, gastritis, dysphagia, abdominal pain lower, abdominal distension oesophagitis, abdominal discomfort, proctalgia, ascites, ileus, toxic dilation of intestine, gastroenteritis, gastric ulcers, gastrooesophageal reflux disease, colitis, blood in stool Hepatobiliary - Hyperbilirubinaemia, Liver function test abnormalities Jaundice, hepatic fibrosis, hepatitis, abnormal liver function tests Skin and subcutaneous tissue Palmar-Plantar erythrodysaesthesia syndrome Rash, alopecia, erythema, dry skin, pruritus, skin hyper-pigmentation, rash macular, skin desquamation, dermatitis, pigmentation disorder, nail disorder, sweating increased, photosensitivity reaction Blister, skin ulcer, rash, urticaria, photosensitivity reaction, Palmar erythema, swelling of face, purpura, radiation recall syndrome, skin ulceration Muskuloskeletal and connective tissue - Pain in extremity, Back pain, Arthralgia Joint swelling, bone pain, facial pain, musculoskeletal stiffness, muscular weakness, myalgia, arthritis Renal and urinary - - Hydronephrosis, urinary incontinence, haematuria, nocturia, blood creatinine increased, renal impairment

20 Reproductive system and breast - - Vaginal haemorrhage General and administration site conditions Fatigue, asthenia Pyrexia, oedema peripheral, malaise, chest pain Oedema, chills, influenza like illness, rigors, body temperature increased, pain, hot flushes, hoarseness, irritability, difficulty in walking, thirst, chest mass, collapse, fibrosis, haemorrhage, sedation Capecitabine in Combination Therapy Table 5 lists the ADRs associated with the use of capecitabine in combination with different chemotherapy regimens in multiple indications, based on safety data from over 3,000 patients. The ADRs were added to the appropriate frequency grouping (very common or common) according to the highest incidence seen in any of the major clinical trials and were only added when they were seen in addition to those seen with capecitabine monotherapy or seen at a higher frequency grouping compared to capecitabine monotherapy (see Table 4). Uncommon ADRs reported for capecitabine in combination therapy are consistent with the ADRs reported for capecitabine monotherapy or reported for monotherapy with the combination medicinal product (in literature and/or respective summary of product characteristics). Some of the ADRs are reactions commonly seen with the combination medicinal product (e.g. peripheral sensory neuropathy with docetaxel or oxaliplatin, hypertension seen with bevacizumab); however, an exacerbation by capecitabine therapy cannot be excluded. Table 5: Summary of Related ADRs Reported in Patients Treated with Capecitabine in Combination Treatment in Addition to Those Seen with Capecitabine Monotherapy or Seen at a Higher Frequency Grouping Compared to Capecitabine Monotherapy Body System Very Common All Grades Common All Grades

21 Infections and infestations - Herpes zoster, urinary tract infection, oral candidiasis, upper respiratory tract infection, rhinitis, influenza, infection +, oral herpes, neutropenic sepsis, sepsis, bronchopneumonia Blood and lymphatic system Neutropenia +, leucopenia +, anaemia +, neutropenic fever +, thrombocytopenia Bone marrow depression, febrile neutropenia +, agranulocytosis, prothrombin decreased Immune system - Hypersensitivity Metabolism and nutrition Appetite decreased Hypokalaemia, Hyponatraemia, Hypomagnesaemia, Hypocalcaemia, Hyperglycaemia Psychiatric - Sleep disorder, anxiety Nervous system Eye Paraesthesia, dysaesthesia, peripheral neuropathy, peripheral sensory neuropathy, dysgeusia, headache Lacrimation increased Neurotoxicity, tremor, neuralgia, hypersensitivity reaction, hypoaesthesia, taste loss, polyneuropathy, migraine Visual, dry eye, eye pain, visual impairment, vision blurred Ear and labyrinth - Tinnitus, hypoacusis