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Mechanism Of Action
Enzymes convert capecitabine to 5-fluorouracil (5-FU) in vivo. Both normal and tumor cells metabolize 5-FU to 5-fluoro-2'-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor, N5-10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form 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. 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.
Following oral administration of 1255 mg/m² BID to cancer patients, capecitabine reached peak blood levels in about 1.5 hours (Tmax) with peak 5-FU levels occurring slightly later, at 2 hours. Food reduced both the rate and extent of absorption of capecitabine with mean Cma x and AUC0-∞ decreased by 60% and 35%, respectively. The Cmax and AUC0-∞ of 5-FU were also reduced by food by 43% and 21%, respectively. Food delayed Tmax of both parent and 5-FU by 1.5 hours [see WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION, and Drug-Food Interaction].
The pharmacokinetics of XELODA and its metabolites have been evaluated in about 200 cancer patients over a dosage range of 500 to 3500 mg/m²/day. Over this range, the pharmacokinetics of XELODA and its metabolite, 5'-DFCR were dose proportional and did not change over time. The increases in the AUCs of 5'-DFUR and 5-FU, however, were greater than proportional to the increase in dose and the AUC of 5-FU was 34% higher on day 14 than on day 1. The interpatient variability in the Cma x and AUC of 5-FU was greater than 85%.
Plasma protein binding of capecitabine and its metabolites is less than 60% and is not concentration-dependent. Capecitabine was primarily bound to human albumin (approximately 35%). XELODA has a low potential for pharmacokinetic interactions related to plasma protein binding.
Bioactivation and Metabolism
Capecitabine is extensively metabolized enzymatically to 5-FU. In the liver, a 60 kDa carboxylesterase hydrolyzes much of the compound to 5'-deoxy-5-fluorocytidine (5'-DFCR). Cytidine deaminase, an enzyme found in most tissues, including tumors, subsequently converts 5'-DFCR to 5'-DFUR. The enzyme, thymidine phosphorylase (dThdPase), then hydrolyzes 5'DFUR to the active drug 5-FU. Many tissues throughout the body express thymidine phosphorylase. Some human carcinomas express this enzyme in higher concentrations than surrounding normal tissues. Following oral administration of XELODA 7 days before surgery in patients with colorectal cancer, the median ratio of 5-FU concentration in colorectal tumors to adjacent tissues was 2.9 (range from 0.9 to 8.0). These ratios have not been evaluated in breast cancer patients or compared to 5-FU infusion.
Metabolic Pathway of capecitabine to 5-FU
The enzyme dihydropyrimidine dehydrogenase hydrogenates 5-FU, the product of capecitabine metabolism, to the much less toxic 5-fluoro-5, 6-dihydro-fluorouracil (FUH2). Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, β-ureido-propionase cleaves FUPA to α-fluoro-β-alanine (FBAL) which is cleared in the urine.
In vitro enzymatic studies with human liver microsomes indicated that capecitabine and its metabolites (5'-DFUR, 5'-DFCR, 5-FU, and FBAL) did not inhibit the metabolism of test substrates by cytochrome P450 isoenzymes 1A2, 2A6, 3A4, 2C19, 2D6, and 2E1.
Capecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered capecitabine dose is recovered in urine. Fecal excretion is minimal (2.6%). The major metabolite excreted in urine is FBAL which represents 57% of the administered dose. About 3% of the administered dose is excreted in urine as unchanged drug. The elimination half-life of both parent capecitabine and 5-FU was about 0.75 hour.
Effect of Age, Gender, and Race on the Pharmacokinetics of Capecitabine
A population analysis of pooled data from the two large controlled studies in patients with metastatic colorectal cancer (n=505) who were administered XELODA at 1250 mg/m² twice a day indicated that gender (202 females and 303 males) and race (455 white/Caucasian patients, 22 black patients, and 28 patients of other race) have no influence on the pharmacokinetics of 5'DFUR, 5-FU and FBAL. Age has no significant influence on the pharmacokinetics of 5'-DFUR and 5-FU over the range of 27 to 86 years. A 20% increase in age results in a 15% increase in AUC of FBAL [see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION].
Following oral administration of 825 mg/m² capecitabine twice daily for 14 days, Japanese patients (n=18) had about 36% lower Cmax and 24% lower AUC for capecitabine than the Caucasian patients (n=22). Japanese patients had also about 25% lower Cmax and 34% lower AUC for FBAL than the Caucasian patients. The clinical significance of these differences is unknown. No significant differences occurred in the exposure to other metabolites (5'-DFCR, 5'DFUR, and 5-FU).
Effect of Hepatic Insufficiency
XELODA 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 1255 mg/m² dose of XELODA. Both AUC0-∞ and Cma x of capecitabine increased by 60% in patients with hepatic dysfunction compared to patients with normal hepatic function (n=14). The AUC0-∞ and Cmax of 5-FU were not affected. In patients with mild to moderate hepatic dysfunction due to liver metastases, caution should be exercised when XELODA is administered. The effect of severe hepatic dysfunction on XELODA is not known [see WARNINGS AND PRECAUTIONS and Use in Special Populations].
Effect of Renal Insufficiency
Following oral administration of 1250 mg/m² capecitabine twice a day to cancer patients with varying degrees of renal impairment, patients with moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine clearance < 30 mL/min) renal impairment showed 85% and 258% higher systemic exposure to FBAL on day 1 compared to normal renal function patients (creatinine clearance > 80 mL/min). Systemic exposure to 5'-DFUR was 42% and 71% greater in moderately and severely renal impaired patients, respectively, than in normal patients. Systemic exposure to capecitabine was about 25% greater in both moderately and severely renal impaired patients [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and Use in Special Populations].
Effect of Capecitabine on the Pharmacokinetics of Warfarin
In four patients with cancer, chronic administration of capecitabine (1250 mg/m² bid) 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 4 patients increased by 2.8-fold, and the maximum observed mean INR value was increased by 91% [see BOXED WARNING and DRUG INTERACTIONS].
Effect of Antacids on the Pharmacokinetics of Capecitabine
When Maalox® (20 mL), an aluminum hydroxide-and magnesium hydroxide-containing antacid, was administered immediately after XELODA (1250 mg/m², n=12 cancer patients), AUC and Cma x increased by 16% and 35%, respectively, for capecitabine and by 18% and 22%, respectively, for 5'-DFCR. No effect was observed on the other three major metabolites (5'-DFUR, 5-FU, FBAL) of XELODA.
Effect of Capecitabine on the Pharmacokinetics of Docetaxel and Vice Versa
A Phase 1 study evaluated the effect of XELODA on the pharmacokinetics of docetaxel (Taxotere®) and the effect of docetaxel on the pharmacokinetics of XELODA was conducted in 26 patients with solid tumors. XELODA was found to have no effect on the pharmacokinetics of docetaxel (Cma x and AUC) and docetaxel has no effect on the pharmacokinetics of capecitabine and the 5-FU precursor 5'-DFUR.
Adjuvant Colon Cancer
A multicenter randomized, controlled phase 3 clinical trial in patients with Dukes' C colon cancer (X-ACT) provided data concerning the use of XELODA for the adjuvant treatment of patients with colon cancer. The primary objective of the study was to compare disease-free survival (DFS) in patients receiving XELODA to those receiving IV 5-FU/LV alone. In this trial, 1987 patients were randomized either to treatment with XELODA 1250 mg/m² orally twice daily for 2 weeks followed by a 1-week rest period, given as 3-week cycles for a total of 8 cycles (24 weeks) or IV bolus 5-FU 425 mg/m² and 20 mg/m² IV leucovorin on days 1 to 5, given as 4week cycles for a total of 6 cycles (24 weeks). Patients in the study were required to be between 18 and 75 years of age with histologically-confirmed Dukes' stage C colon cancer with at least one positive lymph node and to have undergone (within 8 weeks prior to randomization) complete resection of the primary tumor without macroscopic or microscopic evidence of remaining tumor. Patients were also required to have no prior cytotoxic chemotherapy or immunotherapy (except steroids), and have an ECOG performance status of 0 or 1 (KPS ≥ 70%), ANC ≥ 1.5x109/L, platelets ≥ 100x109/L, serum creatinine ≤ 1.5 ULN, total bilirubin ≤ 1.5 ULN, AST/ALT ≤ 2.5 ULN and CEA within normal limits at time of randomization.
The baseline demographics for XELODA and 5-FU/LV patients are shown in Table 10. The baseline characteristics were well-balanced between arms.
Table 10 : Baseline Demographics
|Age (median, years) Range||62 (25-80)||63 (22-82)|
|Male (n, %)||542 (54)||532 (54)|
|Female (n, %)||461 (46)||451 (46)|
|0 (n, %)||849 (85)||830 (85)|
|1 (n, %)||152 (15)||147 (15)|
|Staging - Primary Tumor|
|PT1 (n, %)||12 (1)||6 (0.6)|
|PT2 (n, %)||90 (9)||92 (9)|
|PT3 (n, %)||763 (76)||746 (76)|
|PT4 (n, %)||138 (14)||139 (14)|
|Other (n, %)||1 (0.1)||0 (0)|
|Staging - Lymph Node|
|pN1 (n, %)||695 (69)||694 (71)|
|pN2 (n, %)||305 (30)||288 (29)|
|Other (n, %)||4 (0.4)||1 (0.1)|
All patients with normal renal function or mild renal impairment began treatment at the full starting dose of 1250 mg/m² orally twice daily. The starting dose was reduced in patients with moderate renal impairment (calculated creatinine clearance 30 to 50 mL/min) at baseline [see DOSAGE AND ADMINISTRATION]. Subsequently, for all patients, doses were adjusted when needed according to toxicity. Dose management for XELODA included dose reductions, cycle delays and treatment interruptions (see Table 11).
Table 11 : Summary of Dose Modifications in X-ACT Study
N = 995
N = 974
|Median relative dose intensity (%)||93||92|
|Patients completing full course of treatment (%)||83||87|
|Patients with treatment interruption (%)||15||5|
|Patients with cycle delay (%)||46||29|
|Patients with dose reduction (%)||42||44|
|Patients with treatment interruption, cycle delay, or dose reduction (%)||57||52|
The median follow-up at the time of the analysis was 83 months (6.9 years). The hazard ratio for DFS for XELODA compared to 5-FU/LV was 0.88 (95% C.I. 0.77 – 1.01) (see Table 12 and Figure 1). Because the upper 2-sided 95% confidence limit of hazard ratio was less than 1.20, XELODA was non-inferior to 5-FU/LV. The choice of the non-inferiority margin of 1.20 corresponds to the retention of approximately 75% of the 5-FU/LV effect on DFS. The hazard ratio for XELODA compared to 5-FU/LV with respect to overall survival was 0.86 (95% C.I. 0.74 – 1.01). The 5-year overall survival rates were 71.4% for XELODA and 68.4% for 5FU/LV (see Figure 2).
Table 12 : Efficacy of
XELODA vs 5-FU/LV in Adjuvant Treatment of Colon Cancera
|All Randomized Population||XELODA
|Median follow-up (months)||83||83|
|5-year Disease-free Survival Rates (%)b||59.1||54.6|
|(XELODA/5 -FU/LV) (95% C.I. for Hazard Ratio)||(0.77 -1.01)|
|p-valuec||p = 0.068|
|aApproximately 93.4% had 5-year DFS information
bBased on Kaplan-Meier estimates
cTest of superiority of XELODA vs 5-FU/LV (Wald chi-square test)
Figure 1 : Kaplan-Meier
Estimates of Disease-Free Survival (All Randomized Population)a
Figure 2 : Kaplan-Meier
Estimates of Overall Survival (All Randomized Population)
Metastatic Colorectal Cancer
The recommended dose of XELODA was determined in an open-label, randomized clinical study, exploring the efficacy and safety of continuous therapy with capecitabine (1331 mg/m²/day in two divided doses, n=39), intermittent therapy with capecitabine (2510 mg/m²/day in two divided doses, n=34), and intermittent therapy with capecitabine in combination with oral leucovorin (LV) (capecitabine 1657 mg/m²/day in two divided doses, n=35; leucovorin 60 mg/day) in patients with advanced and/or metastatic colorectal carcinoma in the first-line metastatic setting. There was no apparent advantage in response rate to adding leucovorin to XELODA; however, toxicity was increased. XELODA, 1250 mg/m² twice daily for 14 days followed by a 1-week rest, was selected for further clinical development based on the overall safety and efficacy profile of the three schedules studied.
Data from two open-label, multicenter, randomized, controlled clinical trials involving 1207 patients support the use of XELODA in the first-line treatment of patients with metastatic colorectal carcinoma. The two clinical studies were identical in design and were conducted in 120 centers in different countries. Study 1 was conducted in the US, Canada, Mexico, and Brazil; Study 2 was conducted in Europe, Israel, Australia, New Zealand, and Taiwan. Altogether, in both trials, 603 patients were randomized to treatment with XELODA at a dose of 1250 mg/m² twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles; 604 patients were randomized to treatment with 5-FU and leucovorin (20 mg/m² leucovorin IV followed by 425 mg/m² IV bolus 5-FU, on days 1 to 5, every 28 days).
In both trials, overall survival, time to progression and response rate (complete plus partial responses) were assessed. Responses were defined by the World Health Organization criteria and submitted to a blinded independent review committee (IRC). Differences in assessments between the investigator and IRC were reconciled by the sponsor, blinded to treatment arm, according to a specified algorithm. Survival was assessed based on a non-inferiority analysis.
The baseline demographics for XELODA and 5-FU/LV patients are shown in Table 13.
Table 13 : Baseline
Demographics of Controlled Colorectal Trials
|Study 1||Study 2|
|Age (median, years) Range||64
|Female (%)||121 (40)||106
|Karnofsky PS (median) Range||90
|Prior radiation therapy (%)||52
|Prior adjuvant 5-FU (%)||84
The efficacy endpoints for the two phase 3 trials are shown in Table 14 and Table 15.
Table 14 : Efficacy of
XELODA vs 5-FU/LV in Colorectal Cancer (Study 1)
|Overall Response Rate (%, 95% C.I.)||21 (16-26)||11 (8-15)|
|Time to Progression (Median, days, 95% C.I.)||128 (120-136)||131 (105-153)|
|Hazard Ratio (XELODA/5 -FU/LV) 95% C.I. for Hazard Ratio||0.99 (0.84-1.17)|
|Survival (Median, days, 95% C.I.)||380 (321-434)||407 (366-446)|
|Hazard Ratio (XELODA/5 -FU/LV) 95% C.I. for Hazard Ratio||1.00 (0.84-1.18)|
Table 15 : Efficacy of XELODA vs 5-FU/LV in Colorectal
Cancer (Study 2)
|XELODA (n=301)||5-FU/LV (n=301)|
|Overall Response Rate (%, 95% C.I.)||21 (16-26)||14 (10-18)|
|Time to Progression (Median, days, 95% C.I.)||137 (128-165)||131 (102-156)|
|Hazard Ratio (XELODA/5 -FU/LV) 95% C.I. for Hazard Ratio||0.97 (0.82-1.14)|
|Survival (Median, days, 95% C.I.)||404 (367-452)||369 (338-430)|
|Hazard Ratio (XELODA/5 -FU/LV) 95% C.I. for Hazard Ratio||0.92 (0.78-1.09)|
Figure 3 : Kaplan-Meier
Curve for Overall Survival of Pooled Data (Studies 1 and 2)
XELODA was superior to 5-FU/LV for objective response rate in Study 1 and Study 2. The similarity of XELODA and 5-FU/LV in these studies was assessed by examining the potential difference between the two treatments. In order to assure that XELODA has a clinically meaningful survival effect, statistical analyses were performed to determine the percent of the survival effect of 5-FU/LV that was retained by XELODA. The estimate of the survival effect of 5-FU/LV was derived from a meta-analysis of ten randomized studies from the published literature comparing 5-FU to regimens of 5-FU/LV that were similar to the control arms used in these Studies 1 and 2. The method for comparing the treatments was to examine the worst case (95% confidence upper bound) for the difference between 5-FU/LV and XELODA, and to show that loss of more than 50% of the 5-FU/LV survival effect was ruled out. It was demonstrated that the percent of the survival effect of 5-FU/LV maintained was at least 61% for Study 2 and 10% for Study 1. The pooled result is consistent with a retention of at least 50% of the effect of 5-FU/LV. It should be noted that these values for preserved effect are based on the upper bound of the 5-FU/LV vs XELODA difference. These results do not exclude the possibility of true equivalence of XELODA to 5-FU/LV (see Table 14, Table 15, and Figure 3).
XELODA has been evaluated in clinical trials in combination with docetaxel (Taxotere®) and as monotherapy.
In Combination With Docetaxel
The dose of XELODA used in the phase 3 clinical trial in combination with docetaxel was based on the results of a phase 1 study, where a range of doses of docetaxel administered in 3-week cycles in combination with an intermittent regimen of XELODA (14 days of treatment, followed by a 7-day rest period) were evaluated. The combination dose regimen was selected based on the tolerability profile of the 75 mg/m² administered in 3-week cycles of docetaxel in combination with 1250 mg/m² twice daily for 14 days of XELODA administered in 3-week cycles. The approved dose of 100 mg/m² of docetaxel administered in 3-week cycles was the control arm of the phase 3 study.
XELODA in combination with docetaxel was assessed in an open-label, multicenter, randomized trial in 75 centers in Europe, North America, South America, Asia, and Australia. A total of 511 patients with metastatic breast cancer resistant to, or recurring during or after an anthracyclinecontaining therapy, or relapsing during or recurring within 2 years of completing an anthracycline-containing adjuvant therapy were enrolled. Two hundred and fifty-five (255) patients were randomized to receive XELODA 1250 mg/m² twice daily for 14 days followed by 1 week without treatment and docetaxel 75 mg/m² as a 1-hour intravenous infusion administered in 3-week cycles. In the monotherapy arm, 256 patients received docetaxel 100 mg/m² as a 1hour intravenous infusion administered in 3-week cycles. Patient demographics are provided in Table 16.
Table 16 : Baseline Demographics and Clinical
Characteristics XELODA and Docetaxel Combination vs Docetaxel in Breast Cancer
|XELODA + Docetaxel
|Age (median, years)||52||51|
|Karnofsky PS (median)||90||90|
|Site of Disease|
|Lymph nodes||121 (47%)||125 (49%)|
|Liver||116 (45%)||122 (48%)|
|Bone||107 (42%)||119 (46%)|
|Lung||95 (37%)||99 (39%)|
|Skin||73 (29%)||73 (29%)|
|Anthracycline1||255 (100%)||256 (100%)|
|5-FU||196 (77%)||189 (74%)|
|Paclitaxel||25 (10%)||22 (9%)|
|Resistance to an Anthracycline|
|No resistance||19 (7%)||19 (7%)|
|Progression on anthracycline therapy||65 (26%)||73 (29%)|
|Stable disease after 4 cycles of anthracycline therapy||41 (16%)||40 (16%)|
|Relapsed within 2 years of completion of anthracycline-adjuvant therapy||78 (31%)||74 (29%)|
|Experienced a brief response to anthracycline therapy, with subsequent progression while on therapy or within 12 months after last dose||51 (20%)||50 (20%)|
|No. of Prior Chemotherapy Regimens for Treatment of Metastatic Disease|
|0||89 (35%)||80 (31%)|
|1||123 (48%)||135 (53%)|
|2||43 (17%)||39 (15%)|
|3||0 (0%)||2 (1%)|
|1Includes 10 patients in combination and 18 patients in monotherapy arms treated with an anthracenedione|
XELODA in combination with docetaxel resulted in statistically significant improvement in time to disease progression, overall survival and objective response rate compared to monotherapy with docetaxel as shown in Table 17, Figure 4, and Figure 5.
Table 17 : Efficacy of XELODA and Docetaxel
Combination vs Docetaxel Monotherapy
|Efficacy Parameter||Combination Therapy||Monotherapy||p-value||Hazard Ratio|
|Time to Disease Progression|
|Median Days 95% C.I.||186
|Median Days 95% C.I.||442
|1The response rate reported represents a reconciliation of
the investigator and IRC assessments performed by the sponsor according to a
2NA = Not Applicable
Figure 4 : Kaplan-Meier
Estimates for Time to Disease Progression XELODA and Docetaxel vs Docetaxel
Figure 5 : Kaplan-Meier
Estimates of Survival XELODA and Docetaxel vs Docetaxel
The antitumor activity of XELODA as a monotherapy was evaluated in an open-label single-arm trial conducted in 24 centers in the US and Canada. A total of 162 patients with stage IV breast cancer were enrolled. The primary endpoint was tumor response rate in patients with measurable disease, with response defined as a ≥ 50% decrease in sum of the products of the perpendicular diameters of bidimensionally measurable disease for at least 1 month. XELODA was administered at a dose of 1255 mg/m² twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles. The baseline demographics and clinical characteristics for all patients (n=162) and those with measurable disease (n=135) are shown in Table 18. Resistance was defined as progressive disease while on treatment, with or without an initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant chemotherapy regimen.
Table 18 : Baseline Demographics and Clinical
Characteristics Single-Arm Breast Cancer Trial
|Patients With Measurable Disease
|Age (median, years)||55||56|
|No. Disease Sites|
|1-2||43 (32%)||60 (37%)|
|3-4||63 (46%)||69 (43%)|
|> 5||29 (22%)||34 (21%)|
|Dominant Site of Disease|
|Visceral1||101 (75%)||110 (68%)|
|Soft Tissue||30 (22%)||35 (22%)|
|Bone||4 (3%)||17 (10%)|
|Paclitaxel||135 (100%)||162 (100%)|
|Anthracycline2||122 (90%)||147 (91%)|
|5-FU||110 (81%)||133 (82%)|
|Resistance to Paclitaxel||103 (76%)||124 (77%)|
|Resistance to an Anthracycline2||55 (41%)||67 (41%)|
|Resistance to both Paclitaxel and an Anthracycline2||43 (32%)||51 (31%)|
|1Lung, pleura, liver, peritoneum
2Includes 2 patients treated with an anthracenedione
Antitumor responses for patients with disease resistant to both paclitaxel and an anthracycline are shown in Table 19.
Table 19 : Response Rates in
Doubly-Resistant Patients Single-Arm Breast Cancer Trial
|Resistance to Both Paclitaxel and an Anthracycline (n=43)|
|CR + PR1||11|
|Response Rate1(95% C.I.)||25.6% (13.5, 41.2)|
|Duration of Response,1Median in days2(Range)||154 (63-233)|
|1Includes 2 patients treated with an anthracenedione
2From date of first response
For the subgroup of 43 patients who were doubly resistant, the median time to progression was 102 days and the median survival was 255 days. The objective response rate in this population was supported by a response rate of 18.5% (1 CR, 24 PRs) in the overall population of 135 patients with measurable disease, who were less resistant to chemotherapy (see Table 18). The median time to progression was 90 days and the median survival was 306 days.
Last reviewed on RxList: 3/20/2015
This monograph has been modified to include the generic and brand name in many instances.
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