Xeloda

Xeloda

capecitabine

Manufacturer:

Roche

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Capecitabine.
Description
Active ingredient: capecitabine.
150 mg: Light peach, biconvex and oblong-shaped film-coated tablets containing 150 mg capecitabine. The tablets are engraved "XELODA" on one side and "150" on the other side.
500 mg: Peach, biconvex, and oblong-shaped film-coated tablets containing 500 mg capecitabine. The tablets are engraved "XELODA" on one side and "500" on the other side.
Action
Pharmacotherapeutic Group: Cystostatic agent. ATC Code: L01BC06.
Pharmacology: Pharmacodynamics: Mechanism of action:
Capecitabine is a fluoropyrimidine carbamate derivative, which was designed as an orally administered, tumour-activated and tumour-selective cytotoxic agent. Capecitabine is non-cytotoxic in vitro. However, in vivo, it is sequentially converted to the cytotoxic moiety, 5-fluorouracil (5-FU), which is further metabolised.
Formation of 5-FU is catalysed preferentially at the tumour site by the tumour-associated angiogenic factor thymidine phosphorylase (dThdPase), thereby minimising the exposure of healthy tissues to systemic 5-FU.
The sequential enzymatic biotransformation of capecitabine to 5-FU leads to higher concentrations of 5-FU within tumour tissues. Following oral administration of capecitabine to patients with colorectal cancer (N=8), the ratio of 5-FU concentration in colorectal tumours vs adjacent tissues was 3.2 (ranged from 0.9 to 8.0). The ratio of 5-FU concentration in tumour vs plasma was 21.4 (ranged from 3.9 to 59.9) whereas the ratio in healthy tissues to plasma was 8.9 (ranged from 3.0 to 25.8). Thymidine phosphorylase activity was 4 times greater in primary colorectal tumour than in adjacent normal tissue.
Several human tumours, such as breast, gastric, colorectal, cervical and ovarian cancers, have a higher level of thymidine phosphorylase (capable of converting 5'-DFUR [5'-deoxy-5-fluorouridine] to 5-FU) than corresponding normal tissues.
Normal cells and tumour cells metabolise 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 a covalently bound ternary complex. This binding inhibits the formation of thymidylate from uracil. 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. 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.
Clinical/Efficacy Studies: Colon and Colorectal cancer: Monotherapy in adjuvant colon cancer: Data from one multicenter, randomized, controlled phase 3 clinical trial in patients with stage III (Dukes C) colon cancer supports the use of Xeloda for the adjuvant treatment of patients with colon cancer (XACT Study: M66001). In this trial, 1987 patients were randomized to treatment with Xeloda (1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles for 24 weeks) or 5-FU and leucovorin (Mayo regimen: 20 mg/m2 leucovorin i.v. followed by 425 mg/m2 i.v. bolus 5-FU, on days 1 to 5, every 28 days for 24 weeks). Xeloda was at least equivalent to i.v. 5-FU/LV in disease-free survival (DFS) (p = 0.0001, non-inferiority margin 1.2). In the all-randomized population, tests for difference of Xeloda vs 5-FU/LV in DFS and overall survival (OS) showed hazard ratios of 0.88 (95% Cl 0.77-1.01; p = 0.068) and 0.86 (0.74 - 1.01; p = 0.060), respectively. The median follow up at the time of the analysis was 6.9 years.
Combination therapy in adjuvant colon cancer: Xeloda in combination with oxaliplatin (XELOX) for the adjuvant treatment of patients with colon cancer has been studied in a multicenter, randomized, controlled phase 3 clinical trial in patients with stage III (Dukes' C) colon cancer (NO16968 study). In this trial, 944 patients were randomized to 3-week cycles for 24 weeks with Xeloda (1000 mg/m2 twice daily for 2 weeks followed by a 1-week rest period) in combination with oxaliplatin (130 mg/m2 intravenous infusion over 2-hours on day 1 every 3 weeks); 942 patients were randomized to bolus 5-FU and leucovorin. In the primary analysis for DFS, in the ITT population, XELOX was shown to be significantly superior to 5-FU/LV HR=0.80, (95% CI 0.69, 0.93; p=0.0045). The 3-year DFS rate was 71% for XELOX versus 67% for 5-FU/LV. The analysis for the secondary endpoint of relapse free survival (RFS) supports these results with a HR of 0.78 (95% CI 0.67, 0.92; p=0.0024) for XELOX vs. 5-FU/LV. XELOX showed a trend towards superior OS with a HR of 0.87 (95% CI 0.72, 1.05; p=0.1486) which translates into a 13% reduction in risk of death. The 5-year OS rate was 78% for XELOX versus 74% for 5-FU/LV. The efficacy data provided is based on a median observation time of 59 months for OS and 57 months for DFS.
At 7 years median follow up, XELOX maintained a statistically significant superior disease-free survival HR=0.80 (95% CI 0.69, 0.93; p=0.0038), and relapse-free survival HR=0.78 (95% CI 0.67, 0.91; p=0.0015). The OS rate at 7 years was 73% in the XELOX arm and 67% in the 5-FU/LV arm. The additional two years of follow up after the primary analysis show an increase in the difference between survival rates from 3% to 6%.
Monotherapy in metastatic colorectal cancer: Data from two identically-designed, multicenter, randomized, controlled, phase 3 clinical trials support the use of Xeloda for first-line treatment of metastatic colorectal cancer (SO14695; SO14796). In these trials, 603 patients were randomized to treatment with Xeloda (1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles) and 604 patients were randomized to treatment with 5-FU and leucovorin (Mayo regimen: 20 mg/m2 leucovorin i.v. followed by 425 mg/m2 i.v. bolus 5-FU, on days 1 to 5, every 28 days).
The overall objective response rates in the all-randomised population (investigator assessment) were 25.7% (Xeloda) vs 16.7% (Mayo regimen); p<0.0002. The median time to progression was 140 days (Xeloda) vs 144 days (Mayo regimen). Median survival was 392 days (Xeloda) vs 391 days (Mayo regimen).
Combination therapy - first-line treatment of colorectal cancer: A multicenter, randomized, controlled phase 3 clinical study (NO16966) has been conducted for the use of Xeloda in combination with oxaliplatin or in combination with oxaliplatin and bevacizumab (BV) for the first-line treatment of metastastic colorectal cancer. The study contained two parts: an initial 2-arm part in which patients were randomized to two different treatment groups, including XELOX or FOLFOX-4, and a subsequent 2x2 factorial part with four different treatment groups, including XELOX + placebo (P), FOLFOX-4+P, XELOX+BV, and FOLFOX-4+BV. The treatment regimens are summarized in table 1 as follows. (See Table 1.)

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Non-inferiority of the XELOX-containing arms compared with the FOLFOX-4-containing arms in the overall comparison was demonstrated in terms of progression-free survival (PFS) in the eligible patient population and the intent-to-treat population (see table 2 as follows). The results indicate that XELOX is equivalent to FOLFOX-4 in terms of OS.A comparison of XELOX plus bevacizumab versus FOLFOX-4 plus bevacizumab was a pre-specified exploratory analysis. In this treatment subgroup comparison, XELOX plus bevacizumab was similar compared to FOLFOX-4 plus bevacizumab in terms of PFS (hazard ratio 1.01 [97.5% CI 0.84, 1.22]). The median follow up at the time of the primary analyses in the intent-to-treat population was 1.5 years; data from analyses following an additional 1 year of follow up are also included in the table 2 as follows. (See Table 2.)

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The CAIRO study was a raodomized, controlled phase III trial to study the use of Xeloda at a starting dose of 1000 mg/m2 for 2 weeks every 3 weeks in combination with irinotecan for the first-line treatment of patients with metastatic colorectal cancer. The efficacy in terms of Overall Response Rate (ORR), Progression Free Survival (PFS) and OS was similar to that reported in pivotal studies of 5-FU, leucovorin, and irinotecan (FOLFIRI).
Xeloda (at a starting dose of 800 mg/m2 for 2 weeks every 3 weeks) in combination with irinotecan and bevacizumab was studied for the first-line treatment of patients with metastatic colorectal cancer, in a multicentre, randomized, controlled phase II study (AIO KRK 0604) 128 patients were randomized to treatment with Xeloda combined with irinotecan (XELIRI) and bevacizumab: Xeloda (800 mg/m2 twice daily for two weeks followed by a 7-day rest period), irinotecan (200 mg/m2 as a 30 to 90 minute infusion on day 1 every 3 weeks), and bevacizumab (7.5 mg/kg as a 30 to 90 minute infusion on day 1 every 3 weeks); a total of 127 patients were randomised to treatment with Xeloda combined with oxaliplatin (XELOX) plus bevacizumab: Xeloda (1000 mg/m2 twice daily for two weeks followed by a 7-day rest period), oxaliplatin (130 mg/m2 as a 2 hour infusion on day 1 every 3 weeks), and bevacizumab (7.5 mg/kg as a 30 to 90 minute infusion on day 1 every 3 weeks). The mean duration of follow-up for the study population was 26.6 months. Progression-free survival at 6 months in the intent-to-treat population was 84% (XELIRI plus bevacizumab) versus 76% (XELOX plus bevacizumab). Overall response rate (complete response plus partial response) was 56% (XELIRI plus bevacizumab) versus 53% (XELOX plus bevacizumab). The median overall survival was 25.5 months (XELIRI plus bevacizumab) and 24.4 months (XELOX plus bevacizumab).
Combination therapy - Second-line treatment of colorectal cancer: Study NO16967 was a multicenter, randomized, controlled phase III trial that studied the use of Xeloda in combination with oxaliplatin for the second-line treatment of metastastic colorectal cancer. In this trial, 627 patients with metastatic colorectal carcinoma who have received prior treatment with irinotecan in combination with a fluoropyrimidine regimen as first-line therapy were randomized to treatment with XELOX or FOLFOX-4. For the dosing schedule of XELOX and FOLFOX-4 (without addition of placebo or bevacizumab), refer to Table 1. XELOX was demonstrated to be non-inferior to FOLFOX-4 in terms of progression-free survival in the per-protocol population and intent-to-treat population (see table 3 as follows). The results indicate that XELOX is equivalent to FOLFOX-4 in terms of OS. The median follow up at the time of the primary analyses in the intent-to-treat population was 2.1 years; data from analyses following an additional 6 months of follow up are also included in the table 3 as follows. (See Table 3.)

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A pooled analysis of the efficacy data from first-line (study NO16966; initial 2-arm part) and second line treatment (study NO16967) further support the non-inferiority results of XELOX versus FOLFOX-4 as obtained in the individual studies: progression-free survival in the per-protocol population (hazard ratio 1.00 [95% CI: 0.88; 1.14]) with a median progression-free survival of 193 days (XELOX; 508 patients) versus 204 days (FOLFOX-4; 500 patients). The results indicate that XELOX is equivalent to FOLFOX-4 in terms of OS (hazard ratio 1.01 [95% CI: 0.87; 1.17]) with a median OS of 468 days (XELOX) versus 478 days (FOLFOX-4).
Combination therapy - Oesophagogastric cancer: A multicenter, randomized, controlled phase 3 clinical trial (ML17032) in patients with advanced or metastatic gastric cancer studied the use of Xeloda for the first-line treatment of patients with advanced gastric cancer. In this trial, 160 patients were randomized to treatment with Xeloda (1000 mg/m2 twice daily for 2 weeks followed by a 7-day rest period) and cisplatin (80 mg/m2 as a 2-hour infusion every 3 weeks). A total of 156 patients were randomized to treatment with 5-FU (800 mg/m2 per day, continuous infusion on days 1 to 5 every 3 weeks) and cisplatn (80 mg/m2 as a 2-hour infusion on day 1, every 3 weeks). The primary objective of the study was met, Xeloda in combination with cisplatin was at least equivalent to 5-FU in combination with cisplatin in terms of progression-free survival in the per-protocol analysis. The result for duration of survival (OS) was similar to the result for progression-free survival (see Table 4 as follows).

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Data from a randomised multicentre, phase 3 study (REAL-2) comparing capecitabine to 5-FU and oxaliplatin to cisplatin in patients with advanced oesophagogastric cancer supports the use of Xeloda for the first-line treatment of advanced oesophagogastric cancer. In this trial, 1002 patients were randomised in a 2x2 factorial design to one of the following 4 arms: ECF: epirubicin (50 mg/m2 as a bolus on day 1 every 3 weeks), cisplatin (60 mg/m2 as a two hour infusion on day 1 every 3 weeks) and 5-FU (200 mg/m2 daily given by continuous infusion via a central line).
ECX: epirubicin (50 mg/m2 as a bolus on day 1 every 3 weeks), cisplatin (60 mg/m2 as a two hour infusion on day 1 every 3 weeks), and Xeloda (625 mg/m2 twice daily continuously).
EOF: epirubicin (50 mg/m2 as a bolus on day 1 every 3 weeks), oxaliplatin (130 mg/m2 given as a 2 hour infusion on day 1 every three weeks), and 5-FU (200 mg/m2 daily given by continuous infusion via a central line).
EOX: epirubicin (50 mg/m2 as a bolus on day 1 every 3 weeks), oxaliplatin (130 mg/m2 given as a 2 hour infusion on day 1 every three weeks), and Xeloda (625 mg/m2 twice daily continuously).
The primary efficacy analyses in the per protocol population demonstrated non-inferiority in OS for capecitabine- vs 5-FU-based regimens (hazard ratio 0.86, 95% CI: 0.8 to 0.99) and for oxaliplatin- vs cisplatin-based regimens (hazard ratio 0.92, 95% CI: 0.8 to 1.1). The median OS was 10.9 months in capecitabine-based regimens and 9.6 months in 5-FU based regimens. The median OS was 10.0 months in cisplatin-based regimens and 10.4 months in oxaliplatin-based regimens.
Combination therapy - Gastric cancer: An open-label, randomized, multicenter (South Korea, China and Taiwan) phase 3 study (CLASSIC) comparing capecitabine plus oxaliplatin (XELOX) to observation only, following D2 resection of stage II and III gastric adenocarcinoma, was conducted for use of adjuvant XELOX for completely resected gastric cancer. Patients received oral capecitabine twice daily on a 3-week cycle consisting of 2 weeks treatment followed by 1 week without treatment and intravenous oxaliplatin on day 1 of each cycle or observation only (no adjuvant chemotherapy). The study treatment phase was scheduled for a total of 8 cycles (24 weeks). A follow-up phase continued until date of death or the last date the patient was known to be alive, or until 2 years after the full efficacy analysis had taken place.
A total of 1035 patients were randomized into the study (ITT population: XELOX = 520, observation = 515). The primary efficacy endpoint of 3-year DFS was met at the preplanned interim analysis after 266 DFS events and following the recommendation of the IDMC (Independent Data Monitoring Committee) to fully evaluate the study. A statistically significant benefit for the XELOX arm over the observation only arm was observed: HR=0.56 (95% CI 0.44, 0.72, p<0.0001). At the time of clinical cut-off a greater proportion of patients in the XELOX arm were without an event compared to patients in the observation arm: 79.6% versus 68.3%.
The HR for the secondary endpoint, OS was 0.72 (95% CI 0.52, 1.00; p=0.0493), however as only 14% of patients reported an OS event at the time of clinical cut-off, the data are relatively immature.
The final five year follow up DFS analysis showed almost identical results in terms of treatment effect and absolute event-free rates at 3-years HR=0.58 (95% CI 0.47, 0.72; p<0.0001). The HR observed for OS, at final analysis, was 0.66 (95% CI 0.51, 0.85; p=0.015).
Xeloda has also been used in combination with oxaliplatin for the treatment of advanced gastric cancer. Studies with Xeloda monotherapy indicate that Xeloda has activity in advanced gastric cancer.
Colon, colorectal and advanced gastric cancer: meta-analysis A meta-analysis of six clinical trials (studies SO14695, SO14796, M66001, NO16966, NO16967, M17032) investigated the question whether Xeloda can replace 5-FU in mono- and combination treatment in gastrointestinal cancer. The pooled analysis includes 3097 patients treated with Xeloda-containing regimens and 3074 patients treated with 5-FU-containing regimens. The hazard ratio for OS was 0.94 (95% CI: 0.89; 1.00, p=0.0489) with Xeloda-containing regimens indicating that they are non-inferior to 5-FU-containing regimens.
Combination therapy - breast cancer: Xeloda in combination with docetaxel for treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy, including an anthracycline was studied in a multicenter, randomized, controlled phase 3 clinical trial (SO14999). In this trial, 255 patients were randomized to treatment with Xeloda (1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period) and docetaxel (75 mg/m2 as a 1-hour intravenous infusion every 3 weeks). A total of 256 patients were randomized to treatment with docetaxel alone (100 mg/m2 as a 1-hour intravenous infusion every 3 weeks). Survival was superior in the Xeloda+docetaxel combination arm (p=0.0126). Median survival was 442 days (Xeloda+docetaxel) vs 352 days (docetaxel alone). The overall objective response rates in the all-randomized population (investigator assessment) were 41.6% (Xeloda+docetaxel) vs 29.7% (docetaxel alone); p=0.0058. Time to disease progression or death was superior in the Xeloda+docetaxel combination arm (p<0.0001). The median time to progression was 186 days (Xeloda+docetaxel) vs 128 days (docetaxel alone).
Monotherapy - Breast carcinoma: Two multicenter phase 2 clinical trials were conducted to determine the use of Xeloda monotherapy for treatment of patients with locally advanced or metastatic breast cancer after failure of a taxane and an anthracycline-containing chemotherapy regimen or for whom further anthracycline therapy is not indicated. In these trials, a total of 236 patients were treated with Xeloda (1250 mg/m2 twice daily for 2 weeks followed by 1-week rest period). The overall objective response rates (investigator assessment) were 20% (first trial) and 25% (second trial). The median time to progression was 93 and 98 days. Median survival was 384 and 373 days.
Immunogenicity: Not applicable.
Pharmacokinetics: Absorption: After oral administration, capecitabine is rapidly and extensively absorbed, followed by extensive conversion to the metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-DFUR. Administration with food decreases the rate of capecitabine absorption, but has only a minor effect on the areas under the curve (AUC) of 5'-DFUR and the subsequent metabolite 5-FU. At the dose of 1250 mg/m2 on day 14 with administration after food intake, the peak plasma concentrations (Cmax in μg/ml) for capecitabine, 5'-DFCR, 5'-DFUR, 5-FU and FBAL were 4.47, 3.05, 12.1, 0.95 and 5.46 respectively. The times to peak plasma concentrations (Tmax in hours) were 1.50, 2.00, 2.00, 2.00 and 3.34. The AUC0-∞ values in μg·h/ml were 7.75, 7.24, 24.6, 2.03 and 36.3.
Distribution: 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.
Metabolism: Capecitabine is first metabolised by hepatic carboxylesterase to 5'-DFCR, which is then converted to 5'-DFUR by cytidine deaminase, principally located in the liver and tumour tissues.
Formation of 5-FU occurs preferentially at the tumour site by the tumour-associated angiogenic factor dThdPase, thereby minimising the exposure of healthy body tissues to systemic 5-FU.
The plasma AUC of 5-FU is 6 to 22 times lower than that following an i.v. bolus of 5-FU (dose of 600 mg/m2). The metabolites of capecitabine become cytotoxic only after conversion to 5-FU and anabolites of 5-FU (see Pharmacology: Pharmacodynamics: Mechanism of Action under Actions).
5-FU is further catabolized to the inactive metabolites dihydro-5-fluoruracil (FUH2), 5-fluoro-ureidopropionic acid (FUPA) and α-fluoro-β-alanine (FBAL) via dihydropyrimidine dehydrogenase (DPD), which is rate limiting.
Elimination: The elimination half-lives (t½ 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. The pharmacokinetics of capecitabine have been evaluated over a dose range of 502 - 3514 mg/m2/day. The parameters of capecitabine, 5'-DFCR and 5'-DFUR measured on days 1 and 14 were similar. The AUC of 5-FU was 30-35% higher on day 14, but did not increase subsequently (day 22). At therapeutic doses, the pharmacokinetics of capecitabine and its metabolites were dose proportional, except for 5-FU.
After oral administration capecitabine metabolites are primarily recovered in the urine. Most (95.5%) of administered capecitabine dose is recovered in 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 urine as unchanged drug.
Combination therapy: Phase I studies evaluating the effect of Xeloda on the pharmacokinetics of either docetaxel or paclitaxel and vice versa showed no effect by Xeloda on the pharmacokinetics of docetaxel or paclitaxel (Cmax and AUC) and no effect by docetaxel or paclitaxel on the pharmacokinetics of 5'-DFUR (the most important metabolite of capecitabine).
Pharmacokinetics in Special Populations: A population pharmacokinetic analysis was carried out after Xeloda treatment of 505 patients with colorectal cancer dosed at 1250 mg/m2 twice daily. Gender, presence or absence of liver metastasis at baseline, Karnofsky Performance Status, total bilirubin, serum albumin, ASAT and ALAT had no statistically significant effect on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL.
Hepatic impairment due to liver metastases: No clinically significant effect on the bioactivation and pharmacokinetics of capecitabine was observed in cancer patients with mildly to moderately impaired liver function due to liver metastases (see Special Dosage Instructions under Dosage & Administration).
No formal pharmacokinetic study has been conducted and no population pharmacokinetic data was collected in patients with severe hepatic impairment.
Renal impairment: Based on a pharmacokinetic study in cancer patients with mild to severe renal impairment, there is no evidence for an effect of creatinine clearance on the pharmacokinetics of intact drug and 5-FU. Creatinine clearance was found to influence the systemic exposure to 5'-DFUR (35% increase in AUC when creatinine clearance decreases by 50%) and to FBAL (114% increase in AUC when creatinine clearance decreases by 50%). FBAL is a metabolite without antiproliferative activity; 5'-DFUR is the direct precursor of 5-FU (see Special dosage instructions under Dosage & Administration).
Geriatric Population: Based on the population pharmacokinetic analysis, which included patients with a wide range of ages (27 to 86 years) and included 234 (46%) patients greater or equal to 65, age has no influence on the pharmacokinetics of 5'-DFUR and 5-FU. The AUC of FBAL increased with age (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 (see Special Dosage Instructions under Dosage & Administration and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations: Renal impairment under Actions).
Race: Based on population pharmacokinetic analysis of 455 white patients (90.1%), 22 black patients (4.4%) and 28 patients of other race or ethnicity (5.5%), the pharmacokinetics of Xeloda in black patients were not different compared to white patients.
Toxicology: Nonclinical Safety: Carcinogenicity: A two-year mouse carcinogenicity study produced no evidence of carcinogenicity by capecitabine.
Genotoxocity: Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). However, similar to other nucleoside analogues (ie, 5-FU), capecitabine was clastogenic in human lymphocytes (in vitro) and a positive trend occurred in mouse bone marrow micronucleus tests (in vivo).
Reproductive Toxicity: Oral administration of capecitabine to pregnant mice during the period of organogenesis at a 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. Oral administration of capecitabine to pregnant monkeys during the period of organogenesis at a 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.
Impairment of Fertility: In a study of fertility and general reproductive performance in mice, oral capecitabine doses of 760 mg/kg/day disturbed estrus and consequently caused a decrease in female fertility. In mice that became pregnant, no fetuses survived this dose. The disturbance in estrus was reversible. In males, this dose caused degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids. In separate pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values about 0.7 times the corresponding values in patients administered the recommended daily dose.
Other: Not applicable.
Indications/Uses
Breast Cancer: Xeloda in combination with docetaxel is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline. Xeloda is also indicated as monotherapy for the treatment of patients with locally advanced or metastatic breast cancer after failure of a taxane and an anthracycline-containing chemotherapy regimen or for whom further anthracycline therapy is not indicated.
Xeloda is indicated in combination with lapatinib ditosylate for the treatment of patients with advanced or metastatic breast cancer whose tumors over express HER2 and who have received prior therapy including an anthracycline, a taxane and trastuzumab.
Colon, Colorectal cancer: Xeloda is indicated for the treatment of patients with metastatic colorectal carcinoma.
Xeloda is indicated as adjuvant treatment of patients following surgery of Stage III (Duke's Stage C) colon cancer.
Oesophagogastric Cancer: Xeloda is indicated as first-line treatment of patients with advanced oesophagogastric cancer in combination with a platinum-based regimen.
Dosage/Direction for Use
Standard dosage: Xeloda tablets should be swallowed whole with water within 30 minutes after a meal. Xeloda tablets should not be crushed or cut (see Postmarketing Experience under Adverse Reactions). If patients cannot swallow Xeloda tablets whole and tablets must be crushed or cut, this should be done by a professional trained in the safe handling of cytotoxic drugs (see Special Instructions for Use, Handling and Disposal under Cautions for Usage).
Monotherapy: Colon, Colorectal and breast cancer The recommended monotherapy starting dose of Xeloda is 1250 mg/m2 administered twice daily (morning and evening; equivalent to 2500 mg/m2 total daily dose) for 2 weeks followed by a 7-day rest period.
Combination therapy: Breast Cancer: In combination with docetaxel: In combination with docetaxel, the recommended dose of Xeloda is 1250 mg/m2 twice daily for 2 weeks followed by a 7-day rest period, combined with docetaxel at 75 mg/m2 as a 1-hour intravenous infusion every 3 weeks.
Pre-medication according to the docetaxel labelling, should be started prior to docetaxel administration for patients receiving the Xeloda plus docetaxel combination.
In combination with lapatinib ditosylate: In combination with lapatinib ditosylate, the recommended dose of Xeloda is 2000 mg/m2/day administered orally in 2 doses 12 hours apart for 14 days (Day 1-14) in a repeating 21 day cycle combined with lapatinib ditosylate 1250 mg (5 tablets) given orally once daily from Day 1-21. (See manufacturer's prescribing information for lapatinib ditosylate for further information).
Colon, colorectal cancer: In combination with oxaliplatin and/or bevacizumab: In combination with oxaliplatin and/or bevacizumab the recommended dose of Xeloda is 1000 mg/m2 twice daily for 2 weeks followed by a 7-day rest period. The first dose of Xeloda is given on the evening of day 1 and the last dose is given on the morning of day 15. Given as a 3-weekly schedule, on day 1 every 3 weeks bevacizumab is administered as a 7.5 mg/kg intravenous infusion over 30-90 minutes followed by oxaliplatin administered as a 130 mg/m2 intravenous infusion over 2 hours.
Premedication to maintain adequate hydration and anti-emesis according to the oxaliplatin product information should be started prior to oxaliplatin administration for patients receiving the Xeloda plus oxaliplatin combination. Adjuvant treatment in patients with stage III colon cancer is recommended for a total of 6 months.
Gastric Cancer: In combination with platinum-based regimen: In combination with a platinum-based compound the recommended dose of Xeloda for the treatment of advanced gastric cancer is 1000 mg/m2 administered twice daily for 14 days followed by a 7 day rest period. The first dose of Xeloda should be given on the evening of day 1 and the last dose should be given on the morning of day 15. If epirubicin is added to this regimen the recommended dose of Xeloda is 625 mg/m2 twice daily continuously. Epirubicin at a dose of 50 mg/m2 should be given as a bolus on day 1 every 3 weeks. The platinum based compound (cisplatin at a dose of 60 mg/m2 (triple regimen) - 80 mg/m2 (double regimen) or oxaliplatin at a dose of 130 mg/m2) should be given on day 1 as a 2 hour intravenous infusion every 3 weeks.
Premedication to maintain adequate hydration and anti-emesis according to the cisplatin/oxaliplatin summary of product characteristics should be started prior to cisplatin/oxaliplatin administration for patients receiving the Xeloda plus cisplatin/oxaliplatin combination.
Dose calculation: Xeloda dose is calculated according to body surface area .The following tables show the standard and reduced dose calculations (see section "Dosage adjustments during treatment" as follows) for a starting dose of Xeloda of either 1250 mg/m2 or 1000 mg/m2. (See Table 5 and Table 6.)

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Dosage adjustments during treatment: General: Toxicity due to Xeloda administration may be managed by symptomatic treatment and/or modification of the Xeloda dose (treatment interruption or dose reduction). Once the dose has been reduced it should not be increased at a later time.
For those toxicities considered by the treating physician to be unlikely to become serious or life-threatening treatment can be continued at the same dose without reduction or interruption.
Dosage modifications are not recommended for Grade 1 events. Therapy with Xeloda should be interrupted if a Grade 2 or 3 adverse drug reaction (ADR) occurs. Once the ADR has resolved or decreased in intensity to Grade 1, Xeloda therapy may be restarted at full dose or as adjusted according to Table 3. If a Grade 4 ADR occurs, therapy should be discontinued or interrupted until the ADR has resolved or decreased to Grade 1, and therapy should be restarted at 50% of the original dose. Patients taking Xeloda should be informed of the need to interrupt treatment immediately if moderate or severe toxicity occurs. Doses of Xeloda omitted for toxicity are not replaced.
Haematology: Patients with baseline neutrophil counts of <1.5 X 109/L and/or thrombocyte counts of <100 X 109/L should not be treated with Xeloda. If unscheduled laboratory assessments during a treatment cycle show grade 3 or 4 haematologic toxicity, treatment with Xeloda should be interrupted.
The following table shows the recommended dose modifications following toxicity related to with Xeloda: (See Table 7.)

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The following are the recommended dose modifications for toxicity when Xeloda and docetaxel are used in combination: (See Table 8.)

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Specific dose adjustment in combination with docetaxel: Xeloda and/or docetaxel dose modifications should be made according to the general dose modification scheme above, if nothing else is stated regarding specific dose adjustments. For those toxicities considered 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. At the beginning of a treatment cycle, if either a docetaxel or a Xeloda treatment delay is indicated, both docetaxel and Xeloda administration should be delayed until the requirements for restarting both drugs are met. If docetaxel has to be discontinued, Xeloda treatment can be resumed when the requirements for restarting Xeloda are met.
Hematology: Treatment should only be re-administered when the neutrophil count is <1.5 x 109/l (Grade 0 - 1). Patients with neutropenia <0.5 x 109/l (Grade 4) for more than 1 week, or febrile (>38°C) neutropenia, should have the docetaxel dosage reduced from 75 mg/m2 to 55 mg/m2. If Grade 4 neutropenia or febrile neutropenia occurs at 55 mg/m2 docetaxel, docetaxel should be discontinued. Patients with baseline neutrophil counts of <1.5 x 109/l and/or thrombocyte counts of <1.0 x 109/l should not be treated with the Xeloda/docetaxel combination.
Hypersensitivity: Patients who develop severe hypersensitivity reactions (hypotension with a decrease of ≥20 mm Hg, or bronchospasm, or generalised rash/erythema) should stop treatment immediately and be given appropriate therapy. These patients should not be re challenged with the drug suspected to have caused hypersensitivity.
Peripheral neuropathy: For 1st appearance of Grade 2 toxicity, reduce the docetaxel dose to 55 mg/m2. If Grade 3 toxicity appears, discontinue docetaxel treatment. In both instances follow the above dose modification scheme for Xeloda.
Fluid retention: Severe (Grade 3 or 4) toxicity such as pleural effusion, pericardial effusion or ascites which is possibly related to docetaxel should be closely monitored. In case of appearance of such toxicity docetaxel treatment should be discontinued, Xeloda treatment may be continued without dose modification.
Hepatic impairment: Docetaxel should generally not be given to patients with serum bilirubin above the upper limit of normal. The following modifications should be applied to the docetaxel dose in the event of abnormal values for ASAT, ALAT, and/or alkaline phosphatase levels: (See Table 9.)

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Once the docetaxel dose is reduced for a given cycle, no further dose reduction is recommended for subsequent cycles unless worsening of the parameters is observed. In case of recovery of liver function tests after previous reduction of the docetaxel dose, the docetaxel dose can be re-escalated to the previous dose level.
Dehydration: Dehydration should be prevented or corrected at the onset. Patients with anorexia, asthenia, nausea, vomiting or diarrhea may rapidly become dehydrated. If Grade 2 (or higher) dehydration occur, Xeloda treatment should be immediately interrupted and the dehydration corrected. Treatment should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled. Dose modifications applied should be those for the precipitating adverse event in accordance with the above guidelines.
Reductions to 75% and 50% of Xeloda dose: For patients receiving Xeloda monotherapy or Xeloda in combination with docetaxel, the following tables show the dosage at 75% and 50%, calculated according to the body surface area: (See Table 10.)

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Special dosage instructions: Pediatric use: The safety and efficacy of Xeloda in children and adolescents (<18 years) have not been established.
Geriatric use: For Xeloda monotherapy, no adjustment of the starting dose is needed. However, severe Grade 3 or 4 treatment-related ADRs were more frequent in patients over 80 years of age compared to younger patients.
When Xeloda was used in combination with other antineoplastic agents, geriatric patients (≥65 years) experience more Grade 3 and Grade 4 ADRs and ADRs that led to discontinuation, than younger patients. Careful monitoring of elderly patients is advisable.
In combination with docetaxel: an increased incidence of Grade 3 or 4 treatment-related ADRs and treatment-related serious ADRs was observed in patients 60 years of age or more. For patients 60 years of age or more treated with the combination of Xeloda plus docetaxel, a starting dose reduction of Xeloda to 75% (950 mg/m2 twice daily) is recommended. For dosage calculations, see Table 5.
In combination with irinocetan: for patients 65 years of age or more, a starting dose reduction of Xeloda to 800 mg/m2 twice daily is recommended.
Renal impairment: In patients with moderate renal impairment (creatinine clearance 30 - 50 mL/min [Cockroft and Gault]) at baseline, a dose reduction to 75% for a starting dose of 1250 mg/m2 is recommended. In patients with mild renal impairment (creatinine clearance 51 - 80 mL/min), no adjustment in starting dose is recommended.
Careful monitoring and prompt treatment interruption is recommended if the patient develops a Grade 2, 3, or 4 ADRs with subsequent dose adjustment as outlined in Table 7 above (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions). If the calculated creatinine clearance decreases during treatment to a value below 30 mL/min, Xeloda should be discontinued. The dose adjustment recommendations for patients with moderate renal impairment apply both to monotherapy and combination use. For dosage calculations, see Table 5 and Table 6.
Hepatic Impairment: In patients with mild to moderate hepatic impairment due to liver metastases, no starting dose adjustment is necessary. However, such patients should be carefully monitored (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions and Precautions). Patients with severe hepatic impairment have not been studied.
Overdosage
The manifestations of acute overdose include nausea, vomiting, diarrhea, mucositis, gastrointestinal irritation and bleeding and bone marrow depression.
Medical management of overdose should include customary therapeutic and supportive medical interventions aimed at correcting the presenting clinical manifestations and preventing their possible complications.
Contraindications
Xeloda is contraindicated in patients with a known hypersensitivity to capecitabine or to any of its excipients.
Xeloda is contraindicated in patients who have a history of severe and unexpected reactions to fluoropyrimidine therapy or with known hypersensitivity to fluorouracil.
Xeloda is contraindicated in patients with known complete absence of dihydropyrimidine dehydrogenase (DPD) activity (see Precautions).
Xeloda should not be administered concomitantly with sorivudine or its chemically related analogues, such as brivudine (see Interactions).
Xeloda is contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min).
If contraindications exist to any of the agents in a combination regimen, that agent should not be used.
Special Precautions
Warnings: Diarrhea: Xeloda can induce diarrhea, which can sometimes be severe. Patients with severe diarrhea should be carefully monitored and, if they become dehydrated, should be given fluid and electrolyte replacement. Standard anti-diarrhea treatments (e.g. loperamide) should be initiated, as medically appropriate, as early as possible. Dose reduction should be applied as necessary (see Dosage & Administration).
Dehydration: Dehydration should be prevented or corrected at the onset. Patients with anorexia, asthenia, nausea, vomiting or diarrhea may rapidly become dehydrated.
Dehydration may cause acute renal failure, especially in patients with pre-existing compromised renal function or when capecitabine is given concomitantly with known nephrotoxic agents. Fatal outcome of renal failure has been reported in these situations, see Postmarketing Experience under Adverse Reactions.
If Grade 2 (or higher) dehydration occurs, Xeloda treatment should be immediately interrupted and the dehydration corrected. Treatment should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled. Dose modifications should be applied for the precipitating ADR as necessary (see Dosage & Administration).
Dihydropyrimidine dehydrogenase (DPD) deficiency: Rarely, unexpected, severe toxicity (e.g. stomatitis, diarrhea, mucosal inflammation, neutropenia and neurotoxicity) associated with 5-FU has been attributed to a deficiency of DPD activity, an enzyme involved in fluorouracil degradation.
Patients with certain homozygous or certain compound heterozygous mutations in the DPYD gene locus that cause complete or near complete absence of DPD activity, are at the highest risk for severe, life-threatening, or fatal adverse reactions caused by fluorouracil. These patients should not be treated with Xeloda. No dose has been proven safe for patients with complete absence of DPD activity (see Contraindications).
Patients with certain heterozygous DPYD variants (eg. DPYD*2A variant) that may cause partial DPD deficiency have been shown to have increased risk of severe toxicity when treated with capecitabine. For patients with partial DPD deficiency where the benefits of Xeloda are considered to outweigh the risks (taking into account the suitability of an alternative non-fluoropyrimidine chemotherapeutic regimen), these patients must be treated with extreme caution, initially with a substantial dose reduction and frequent subsequent monitoring and dose adjustment according to toxicity.
Testing for DPD deficiency should be considered based on the local availability and current guidelines.
In patients with unrecognised DPD deficiency treated with capecitabine as well as patients who test negative for specific DPYD variations, life-threatening toxicities manifesting as acute overdose may occur. In the event of grade 2-4 acute toxicity, treatment must be discontinued immediately. Permanent discontinuation should be considered based on clinical assessment of the onset, duration and severity of the observed toxicities (see Overdosage).
Precautions: The spectrum of cardiotoxicity observed with Xeloda is similar to that of other fluorinated pyrimidines. This includes myocardial infarction, angina, dysrhythmias, cardiac arrest, cardiac failure and electrocardiographic changes. These ADRs may be more common in patients with a prior history of coronary artery disease.
Xeloda can induce severe skin reactions such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis (TEN), see Postmarketing Experience under Adverse Reactions. Xeloda should be permanently discontinued in patients who experience a severe skin reaction possibly attributable to Xeloda treatment.
Xeloda can induce hand-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy induced acral erythema) which is a cutaneous toxicity. Persistent or severe hand-foot syndrome (grade 2 and above) can eventually lead to loss of fingerprints, which could impact patient identification. For patients receiving Xeloda monotherapy in the metastatic setting, the median time to onset of 79 days, range from 11 to 360 days), with a severity range of Grades 1 to 3.
Grade 1 hand-foot syndrome is defined by numbness, dysesthesia/paresthesia, tingling, or erythema of the hands and/or feet and/or discomfort which does not disrupt normal activities. Grade 2 is defined as painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient's activities of daily living. Grade 3 is defined as moist desquamation, ulceration, blistering or severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living. If Grade 2 or 3 hand-foot syndrome occurs, administration of Xeloda should be interrupted until the event resolves or decreases in intensity to Grade 1. Following Grade 3 hand-foot syndrome, subsequent doses of Xeloda should be decreased (see Dosage & Administration). When Xeloda and cisplatin are used in combination, use of Vitamin B6 (pyridoxine) is not advised for the symptomatic or secondary prophylactic treatment of hand-foot syndrome, because of published reports that it may decrease the efficacy of cisplatin. There is some evidence that dexpanthenol is effective for hand-foot syndrome prophylaxis in patients treated with Xeloda.
Xeloda can induce hyperbilirubinemia. Administration of Xeloda 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 may be resumed when bilirubin decreases to >3.0 x ULN or hepatic aminotransferases decrease to ≤2.5 x ULN.
Care should be exercised when Xeloda is co-administered with drugs, which are metabolized by cytochrome P450 2C9 such as for example warfarin or phenytoin. Patients receiving concomitant Xeloda and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored closely and the anticoagulant dose adjusted accordingly. Patients taking phenytoin concomitantly with Xeloda should be regularly monitored for increased phenytoin plasma concentrations (see Interactions).
General: Patients treated with Xeloda should be carefully monitored for toxicity. Most ADRs are reversible and do not require permanent discontinuation of therapy, although doses may have to be withheld or reduced (see Dosage & Administration).
Drug Abuse and Dependence: Not applicable.
Ability to Drive and Use Machines: Xeloda has moderate influence on the ability to drive and use machines. Patients should be advised to use caution when driving or using machines if they experience ADRs such as dizziness, fatigue, and or nausea during treatment with Xeloda (see Adverse Reactions).
Renal Impairment: Physicians should exercise caution when Xeloda is administered to patients with impaired renal function. As seen with 5-FU the incidence of treatment-related Grade 3 or 4 ADRs was higher in patients with moderate renal impairment (creatinine clearance 30-50 mL/min) (see Special Dosage Instructions under Dosage & Administration).
Hepatic Impairment: Patients with hepatic impairment should be carefully monitored when Xeloda is administered. The effect of hepatic impairment not due to liver metastases or severe hepatic impairment on the disposition of Xeloda is not known (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions and Special Dosage Instructions under Dosage & Administration).
Use in Children: The safety and efficacy of Xeloda in pediatric patients below the age of 18 have not been established.
Use in Elderly: Among patients with colorectal cancer aged 60-79 years receiving Xeloda monotherapy in the metastatic setting, the incidence of gastrointestinal toxicity was similar to that in the overall population. In patients aged 80 years or older, a larger percentage experienced reversible Grade 3 or 4 gastrointestinal ADRs, such as diarrhea, nausea and vomiting (see Special Dosage Instructions under Dosage & Administration). When Xeloda was used in combination with other agents geriatric patients (≥ 65 years) experienced more Grade 3 and Grade 4 ADRs and ADRs that led to discontinuation than younger patients. An analysis of safety data in patients equal to or greater than 60 years of age treated with Xeloda plus docetaxel combination therapy showed an increase in the incidence of treatment-related Grade 3 and 4 ADRs, treatment-related serious ADRs and early withdrawals from treatment due to ADRs compared to patients less than 60 years of age.
Use In Pregnancy & Lactation
Female and Males of Reproductive Potential: Fertility: Based on evidence from animal studies, Xeloda may impair fertility in females and males of reproductive potential (see Pharmacology: Toxicology: Reproductive Toxicity and Impairment of Fertility under Actions).
Contraception: Females: Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Xeloda. An effective method of contraception should be used during treatment and for 6 months after the last dose of Xeloda. If the patient becomes pregnant while receiving Xeloda, the potential hazard to the fetus must be explained.
Males: Based on genetic toxicity findings, male patients with female partners of reproductive potential should use effective contraception during treatment and for 3 months following the last dose of Xeloda.
Pregnancy: There are no studies in pregnant women using Xeloda; however, based on the pharmacological and toxicological properties of Xeloda, it can be assumed that Xeloda may cause fetal harm if administered to pregnant women. In reproductive toxicity studies in animals, capecitabine administration caused embryolethality and teratogenicity. These findings are expected effects of fluoropyrimidine derivatives. Capecitabine should be considered a potential human teratogen. Xeloda should not be used during pregnancy (see Pharmacology: Toxicology: Reproductive Toxicity under Actions). If Xeloda is used during pregnancy or if the patient becomes pregnant while receiving this drug, the patient must be apprised of the potential hazard to the fetus.
Lactation: It is not known whether Xeloda is excreted in human milk. No studies have been conducted to assess the impact of Xeloda on milk production or its presence in human breast milk. In a study of single oral administration of Xeloda to lactating mice, a significant amount of capecitabine metabolites was detected in the milk. As the potential for harm to the nursing infant is unknown, breastfeeding should be discontinued during treatment with Xeloda and for 2 weeks after the final dose.
Adverse Reactions
Clinical Trials: Adverse drug reactions (ADRs) considered by the investigator to be possibly, probably, or remotely related to the administration of Xeloda have been obtained from clinical studies conducted with Xeloda monotherapy (in adjuvant therapy of colon cancer, in metastatic colorectal cancer and metastatic breast cancer), and clinical studies conducted with Xeloda in combination with different chemotherapy regimens for multiple indications. ADRs are added to the appropriate category in the tables below according to the highest incidence from the pooled analysis of seven clinical trials. Within each frequency grouping ADRs are listed in descending order of seriousness. Frequencies are defined as very common ≥ 1/10, common ≥ 5/100 to < 1/10 and uncommon ≥ 1/1000 to < 1/100.
Xeloda monotherapy: Safety data of Xeloda monotherapy were reported for patients who received adjuvant treatment for colon cancer and for patients who received treatment for metastatic breast cancer or metastatic colorectal cancer. The safety information includes data from a phase III trial in adjuvant colon cancer (995 patients treated with Xeloda and 974 treated with i.v. 5-FU/LV) and from 4 phase II trials in female patients with breast cancer (N=319) and 3 trials (1 phase II and 2 phase III trials) in male and female patients with colorectal cancer (N=630).The safety profile of Xeloda monotherapy is comparable in patients who received adjuvant treatment for colon cancer and in those who received treatment for metastatic breast cancer or metastatic colorectal cancer. The intensity of ADRs was graded according to the toxicity categories of the NCIC CTC Grading System. (See Table 11.)

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Skin fissures were reported to be at least remotely related to Xeloda in less than 2% of the patients in seven completed clinical trials (N= 949).
The following ADRs represent known toxicities with fluoropyrimidine therapy and were reported to be at least remotely related to Xeloda in less than 5% of patients in seven completed clinical trials (N = 949): Gastrointestinal disorder: dry mouth, flatulence, ADRs related to inflammation/ulceration of mucous membranes such as esophagitis, gastritis, duodenitis, colitis, gastrointestinal hemorrhage.
Cardiac disorders: edema lower limb, cardiac chest pain including angina, cardiomyopathy, myocardial ischemia/infarction, cardiac failure, sudden death, tachycardia, atrial arrhythmias including atrial fibrillation, and ventricular extrasystoles.
Nervous system disorders: taste disturbance, insomnia, confusion, encephalopathy, and cerebellar signs such as ataxia, dysarthria, impaired balance, abnormal coordination. - Infections and infestations: ADRs related to bone marrow depression, immune system compromise, and/or disruption of mucous membranes such as local and fatal systemic infections (including bacterial, viral, fungal etiologies) and sepsis.
Blood and lymphatic system disorders: anemia, bone marrow depression/ pancytopenia.
Skin and subcutaneous tissue disorders: pruritus, localized exfoliation, skin hyperpigmentation, nail disorders, photosensitivity reactions, radiation recall syndrome.
General disorders and administration site conditions: pain in limb, chest pain (non-cardiac).
Eye: eye irritation.
Respiratory: dyspnoea, cough.
Musculoskeletal: back pain, myalgia, arthralgia.
Psychiatric disorders: depression.
Hepatic failure and cholestatic hepatitis have been reported during clinical trials and post-marketing exposure. A causal relationship with Xeloda treatment has not been established.
Xeloda in combination therapy: Table 12 lists ADRs associated with the use of Xeloda in combination therapy with different chemotherapy regimens in multiple indications and occurred in addition to those seen with monotherapy and/or at a higher frequency grouping. The safety profile was similar across all indications and combination regimens. These reactions occurred in ≥5% of patients treated with Xeloda in combination with other chemotherapies. Adverse drug reactions are added to the appropriate category in the table below according to the highest incidence seen in any of the major clinical trials. Some of the adverse reactions are reactions commonly seen with chemotherapy (e.g. peripheral sensory neuropathy with docetaxel or oxaliplatin), or with bevacizumab (e.g. hypertension); however, an exacerbation by Xeloda therapy cannot be excluded. (See Table 12.)

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Hypersensitivity reactions (2%) and cardiac ischaemia/infarction (3%) have been reported commonly for Xeloda in combination with other chemotherapy but in less than 5% of patients.
Rare or uncommon ADRs reported for Xeloda in combination with other chemotherapy are consistent with the ADRs reported for Xeloda monotherapy or the combination product monotherapy (see prescribing information for the combination product).
Laboratory Abnormalities: The following table displays laboratory abnormalities observed in 995 patients (adjuvant colon cancer) and 949 patients (metastatic breast and colorectal cancer), regardless of relationship to treatment with Xeloda. (See Table 13.)

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Postmarketing Experience: The following ADRs have been identified during post-marketing experience with Xeloda based on spontaneous case reports and literature cases. Adverse drug reactions are listed according to system organ classes in MedDRA and the corresponding frequency category estimation for each adverse drug reaction is based on the following convention: very common (≥ 1/10); common (≥ 5/100 to < 1/10); and uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (≥ 1/1,000 to < 1/100); unknown (cannot be estimated from the available data). (See Table 14.)

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Exposure to crushed or cut Xeloda tablets: In the instance of exposure to crushed or cut Xeloda tablets, the following ADRs have been reported: eye irritation, eye swelling, skin rash, headache, paresthesia, diarrhea, nausea, gastric irritation, and vomiting.
Drug Interactions
Coumarin anticoagulants: Altered coagulation parameters and/or bleeding have been reported in patients taking Xeloda concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. These events occurred within several days and up to several months after initiating Xeloda therapy and, in a few cases, within one month after stopping Xeloda. In a clinical interaction study, after a single 20 mg dose of warfarin, Xeloda treatment increased the AUC of S-warfarin by 57% with a 91% increase in INR value. These results suggest an interaction, probably due to an inhibition of the cytochrome P450 2C9 isoenzyme system by capecitabine. Patients taking coumarin-derivative anticoagulants concomitantly with Xeloda should be monitored regularly for alterations in their coagulation parameters (PT or INR) and the anti-coagulant dose adjusted accordingly (see Precautions).
Cytochrome P-450 2C9 substrates: No formal drug-drug interaction studies with capecitabine and other drugs known to be metabolized by the cytochrome P450 2C9 isoenzyme have been conducted. Care should be exercised when Xeloda is co-administered with these drugs.
Phenytoin: Increased phenytoin plasma concentrations have been reported during concomitant use of Xeloda with phenytoin. 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 system by capecitabine (see Coumarin anticoagulants as previously mentioned). Patients taking phenytoin concomitantly with Xeloda should be regularly monitored for increased phenytoin plasma concentrations.
Drug-food interaction: In all clinical trials, patients were instructed to take Xeloda within 30 minutes after a meal. Since current safety and efficacy data are based upon administration with food, it is recommended that Xeloda be administered with food.
Antacid: The effect of an aluminium hydroxide and magnesium hydroxide-containing antacid on the pharmacokinetics of Xeloda was investigated in cancer patients. There was a small increase in plasma concentrations of capecitabine and one metabolite (5'DFCR); there was no effect on the 3 major metabolites (5'DFUR, 5-FU and FBAL).
Leucovorin (folinic acid): The effect of leucovorin on the pharmacokinetics of Xeloda was investigated in cancer patients. Leucovorin has no effect on the pharmacokinetics of capecitabine and its metabolites. However, leucovorin has an effect on the pharmacodynamics of Xeloda and its toxicity may be enhanced by leucovorin.
Sorivudine and analogues: A clinically significant drug-drug interaction between sorivudine and 5-FU, resulting from the inhibition of dihydropyrimidine dehydrogenase by sorivudine, has been described in the literature. This interaction, which leads to increased fluoropyrimidine toxicity, is potentially fatal. Therefore, Xeloda should not be administered concomitantly with sorivudine or its chemically related analogues, such as brivudine (see Contraindications). There must be at least a 4-week waiting period between the end of treatment with sorivudine or its chemically related analogues such as brivudine and start of Xeloda therapy.
Oxaliplatin: No clinically significant differences in exposure to capecitabine or its metabolites , free platinum or total platinum occur when capecitabine and oxaliplatin were administered in combination, with or without bevacizumab.
Bevacizumab: There was no clinically significant effect of bevacizumab on the pharmacokinetic parameters of capecitabine or its metabolites.
Caution For Usage
Special Instructions for Use, Handling and Disposal: Disposal of Unused/Expired Medicines: The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Use established "collection systems", if available in the location.
Special handling using appropriate equipment and disposal procedures, should be taken as Xeloda is a cytotoxic drug. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Storage
Do not store above 30°C.
ATC Classification
L01BC06 - capecitabine ; Belongs to the class of antimetabolites, pyrimidine analogues. Used in the treatment of cancer.
Presentation/Packing
FC tab 150 mg (light peach, biconvex and oblong-shaped; the tablets are engraved "XELODA" on one side and "150" on the other side) x 60's. 500 mg (peach, biconvex, and oblong-shaped; the tablets are engraved "XELODA" on one side and "500" on the other side) x 120's.
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