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INDICATONS AND USAGE
Colorectal Cancer
- XELODA is indicated as a single agent for adjuvant treatment in patients with Dukes’ C colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. XELODA was non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Although neither XELODA nor combination chemotherapy prolongs overall survival (OS), combination chemotherapy has been demonstrated to improve disease-free survival compared to 5-FU/LV. Physicians should consider these results when prescribing single-agent XELODA in the adjuvant treatment of Dukes’ C colon cancer.
- XELODA is indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown a survival benefit compared to 5-FU/LV alone. A survival benefit over 5-FU/LV has not been demonstrated with XELODA monotherapy. Use of XELODA instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.
Breast Cancer
- XELODA in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.
- XELODA monotherapy is also indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated, eg, patients who have received cumulative doses of 400 mg/m2 of doxorubicin or doxorubicin equivalents. Resistance is defined as progressive disease while on treatment, with or without an initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant regimen.
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METASTATIC BREAST CANCER – MONOTHERAPY
Antitumor responses for patients with disease resistant to both paclitaxel and an anthracycline are shown in Table 10 in the full prescribing information.
Response Rates in Doubly-Resistant Patients
Single-Arm Breast Cancer TrialTaken from Table 10 in the full prescribing information
Resistance to Both Paclitaxel and an Anthracycline (n=43) CR 0 PR1 11 CR + PR1 11 Response Rate1
(95% C.I.)25.6%
(13.5, 41.2)Duration of Response,1
Median in days2
(Range)154
(63-233)1Includes 2 patients treated with an anthracenedione
2From date of first response
Efficacy of XELODA and Docetaxel Combination vs Docetaxel Monotherapy
Taken from Table 8 in the full prescribing information
Efficacy Parameter Combination Therapy Monotherapy p-value Hazard Ratio Time to Disease Progression
Median Days
95% C.I186
(165-198)128
(105-136)0.0001 0.643 Overall Survival>
Median Days
95% C.I.442
(375-497)352
(298-387)0.0126 0.775 Response Rate1 32% 22% 0.009 NA2 1The response rate reported represents a reconciliation of the investigator and IRC assessments performed by the sponsor according to a predefined algorithm.
2NA = Not Applicable
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METASTATIC COLORECTAL CANCER – MONOTHERAPY
The efficacy endpoints for the two phase 3 trials are shown in Tables 5 and 6 in the full prescribing information.
Efficacy of XELODA vs 5-FU/LV in Colorectal Cancer
(Study 1)Taken from Table 5 in the full prescribing information.
XELODA
(n=302)5-FU/LV
(n=303)Overall Response Rate
(%, 95% C.I.)21 (16-26) 11 (8-15) (p-value) 0.0014 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 Ratio0.99
(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 Ratio1.00
(0.84-1.18)Efficacy of XELODA vs 5-FU/LV in Colorectal Cancer
(Study 2)Taken from Table 6 in the full prescribing information.
XELODA
(n=301)5-FU/LV
(n=301)Overall Response Rate
(%, 95% C.I.)21 (16-26) 14 (10-18) (p-value) 0.027 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 Ratio0.97
(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 Ratio0.92
(0.78-1.09)
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ADVERSE REACTIONS
WARNING
XELODA Warfarin Interaction: Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. A clinically important XELODA-Warfarin drug interaction was demonstrated in a clinical pharmacology trial (see CLINICAL PHARMACOLOGY and PRECAUTIONS). Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking XELODA concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. Postmarketing reports have shown clinically significant increases in prothrombin time (PT) and INR in patients who were stabilized on anticoagulants at the time XELODA was introduced. These events occurred within several days and up to several months after initiating XELODA therapy and, in a few cases, within 1 month after stopping XELODA. These events occurred in patients with and without liver metastases. Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.In pivotal trials across the 3 monotherapy indications at the recommended dose:
Grade 3 and 4 adverse events for Xeloda monotherapy
Adverse Event aCRC1 mCRC1 mBC2 Hand-foot syndrome (HFS) 17% 17% 11% Diarrhea 12% 15% 15% Stomatitis 2% 3% 3% Neutropenia <1% 3% 4% Hyperbilirubinemia 20% 23% 11% *1250 mg/m2 orally twice daily for 2 weeks followed by a 1-week rest period.
†1255 mg/m2 orally twice daily for 2 weeks followed by a 1-week rest period.
- Rates of HFS and diarrhea were similar across the 3 studies; stomatitis was infrequently observed.
- XELODA is associated with minimal neutropenia and alopecia (1.2%).1
In the combination therapy pivotal trial at the recommended dose:
Grade 3 and 4 adverse events for Xeloda monotherapy plus docetaxel in metastatic breast cancer
Adverse Event Xeloda
+Docetaxel1Docetaxel
Monotherapy2Hand-foot syndrome (HFS) 24% 1% Diarrhea 15% 6% Stomatitis 18% 5% Neutropenia 16% 21% Hyperbilirubinemia 9% 4% †XELODA 1250 mg/m2 BID x14 days followed by 1 week off plus docetaxel 75 mg/m2 1-hr IV every 3 weeks.
§Docetaxel 100 mg/m2 1-hr IV every 3 weeks.
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DOSAGE AND ADMINISTRATION
XELODA Dose Calculation According to Body Surface Area
Taken from Table 17 in the full prescribing information.
Dose Level 1250 mg/m2
Twice a DayNumber of Tablets to be Taken at Each Dose (Morning and Evening) Surface Area
(m2)Total Daily
Dose* (mg)150 mg 500 mg ≤1.25 3000 0 3 1.26-1.37 3300 1 3 1.38-1.51 3600 2 3 1.52-1.65 4000 0 4 1.66-1.77 4300 1 4 1.78-1.91 4600 2 4 1.92-2.05 5000 0 5 2.06-2.17 5300 1 5 ≥2.18 5600 2 5 *Total Daily Dose divided by 2 to allow equal morning and evening doses
Dose Management Guidelines
XELODA dosage may need to be individualized to optimize patient management. Patients should be carefully monitored for toxicity and doses of XELODA should be modified as necessary to accommodate individual patient tolerance to treatment (see CLINICAL STUDIES). Toxicity due to XELODA administration may be managed by symptomatic treatment, dose interruptions and adjustment of XELODA dose. Once the dose has been reduced it should not be increased at a later time.
The dose of phenytoin and the dose of coumarin-derivative anticoagulants may need to be reduced when either drug is administered concomitantly with XELODA (see PRECAUTIONS: Drug-Drug Interactions).
XELODA dose modification scheme as described below (see Tables 18 and 19 in full prescribing information) is recommended for the management of adverse events.
XELODA in Combination With Docetaxel Dose Reduction Schedule
Taken from Table 18 in the full prescribing information
Toxicity
NCIC Grades*Grade 2 Grade 3 Grade 4 1st appearance Grade 2 occurring during the 14 days of XELODA treatment: interrupt XELODA treatment until resolved to grade 0-1. Treatment may be resumed during the cycle at the same dose of XELODA. Doses of XELODA missed during a treatment cycle are not to be replaced. Prophylaxis for toxicities should be implemented where possible.
Grade 2 persisting at the time the next XELODA/docetaxel treatment is due: delay treatment until resolved to grade 0-1, then continue at 100% of the original XELODA and docetaxel dose. Prophylaxis for toxicities should be implemented where possible.Grade 3 occurring during the 14 days of XELODA treatment: interrupt the XELODA treatment until resolved to grade 0-1. Treatment may be resumed during the cycle at 75% of the XELODA dose. Doses of XELODA missed during a treatment cycle are not to be replaced. Prophylaxis for toxicities should be implemented where possible.
Grade 3 persisting at the time the next XELODA/docetaxel treatment is due: delay treatment until resolved to grade 0-1.
For patients developing grade 3 toxicity at any time during the treatment cycle, upon resolution to grade 0-1, subsequent treatment cycles should be continued at 75% of the original XELODA dose and at 55 mg/m2 of docetaxel. Prophylaxis for toxicities should be implemented where possible.Discontinue treatment unless treating physician considers it to be in the best interest of the patient to continue with XELODA at 50% of original dose. 2nd appearance of same toxicity Grade 2 occurring during the 14 days of XELODA treatment: interrupt XELODA treatment until resolved to grade 0-1. Treatment may be resumed during the cycle at 75% of original XELODA dose. Doses of XELODA missed during a treatment cycle are not to be replaced. Prophylaxis for toxicities should be implemented where possible.
Grade 2 persisting at the time the next XELODA/docetaxel treatment is due: delay treatment until resolved to grade 0-1.
For patients developing 2nd occurrence of grade 2 toxicity at any time during the treatment cycle, upon resolution to grade 0-1, subsequent treatment cycles should be continued at 75% of the original XELODA dose and at 55 mg/m2 of docetaxel. Prophylaxis for toxicities should be implemented where possible.Grade 3 occurring during the 14 days of XELODA treatment: interrupt the XELODA treatment until resolved to grade 0-1. Treatment may be resumed during the cycle at 50% of the XELODA dose. Doses of XELODA missed during a treatment cycle are not to be replaced. Prophylaxis for toxicities should be implemented where possible.
Grade 3 persisting at the time the next XELODA/docetaxel treatment is due: delay treatment until resolved to grade 0-1.
For patients developing grade 3 toxicity at any time during the treatment cycle, upon resolution to grade 0-1, subsequent treatment cycles should be continued at 50% of the original XELODA dose and the docetaxel discontinued. Prophylaxis for toxicities should be implemented where possible.Discontinue treatment. 3rd appearance of same toxicity =Grade 2 occurring during the 14 days of XELODA treatment: interrupt XELODA treatment until resolved to grade 0-1. Treatment may be resumed during the cycle at 50% of the original XELODA dose. Doses of XELODA missed during a treatment cycle are not to be replaced. Prophylaxis for toxicities should be implemented where possible.
Grade 2 persisting at the time the next XELODA/docetaxel treatment is due: delay treatment until resolved to grade 0-1.
For patients developing 3rd occurrence of grade 2 toxicity at any time during the treatment cycle, upon resolution to grade 0-1, subsequent treatment cycles should be continued at 50% of the original XELODA dose and the docetaxel discontinued. Prophylaxis for toxicities should be implemented where possible.Discontinue treatment. 4th appearance of same toxicity Discontinue treatment. *National Cancer Institute of Canada Common Toxicity Criteria were used except for hand-and-foot syndrome (see PRECAUTIONS).
Dose modification for the use of XELODA as monotherapy is shown in Table below.
Recommended Dose Modifications With XELODA Monotherapy
Taken from Table 19 in the full prescribing information.
Toxicity
NCIC Grades*During a Course of Therapy Dose Adjustment for Next Treatment (% of starting dose) • Grade 1 Maintain dose level Maintain dose level • Grade 2 –1st appearance Interrupt until resolved to grade 0 – 1 100% –2nd appearance Interrupt until resolved to grade 0 – 1 75% –3rd appearance Interrupt until resolved to grade 0 – 1 50% –4th appearance Discontinue treatment permanently • Grade 3 –1st appearance Interrupt until resolved to grade 0 – 1 75% –2nd appearance Interrupt until resolved to grade 0 – 1 50% –3rd appearance Discontinue treatment permanently • Grade 4 –1st appearance Discontinue permanently
OR
If physician deems it to be in the patient’s best interest to continue, interrupt until resolved to grade 0 – 150% *National Cancer Institute of Canada Common Toxicity Criteria were used except for the hand-and-foot syndrome (see PRECAUTIONS).
Dosage modifications are not recommended for grade 1 events. Therapy with XELODA should be interrupted upon the occurrence of a grade 2 or 3 adverse experience. Once the adverse event has resolved or decreased in intensity to grade 1, then XELODA therapy may be restarted at full dose or as adjusted according to Tables 18 and 19 in the full prescribing information. If a grade 4 experience occurs, therapy should be discontinued or interrupted until resolved or decreased to grade 1, and therapy should be restarted at 50% of the original dose. Doses of XELODA omitted for toxicity are not replaced or restored; instead the patient should resume the planned treatment cycles.
XELODA Dose Calculation According to Body Surface Area
Taken from Table 17 in the full prescribing information.
Dose Level 1250 mg/m2
Twice a DayNumber of Tablets to be Taken at Each Dose (Morning and Evening) Surface Area
(m2)Total Daily
Dose* (mg)150 mg 500 mg ≤1.25 3000 0 3 1.26-1.37 3300 1 3 1.38-1.51 3600 2 3 1.52-1.65 4000 0 4 1.66-1.77 4300 1 4 1.78-1.91 4600 2 4 1.92-2.05 5000 0 5 2.06-2.17 5300 1 5 ≥2.18 5600 2 5 *Total Daily Dose divided by 2 to allow equal morning and evening doses
Dose Management Guidelines
XELODA dosage may need to be individualized to optimize patient management. Patients should be carefully monitored for toxicity and doses of XELODA should be modified as necessary to accommodate individual patient tolerance to treatment (see CLINICAL STUDIES). Toxicity due to XELODA administration may be managed by symptomatic treatment, dose interruptions and adjustment of XELODA dose. Once the dose has been reduced it should not be increased at a later time.
The dose of phenytoin and the dose of coumarin-derivative anticoagulants may need to be reduced when either drug is administered concomitantly with XELODA (see PRECAUTIONS: Drug-Drug Interactions).
XELODA dose modification scheme as described below (see Tables 18 and 19 in full prescribing information) is recommended for the management of adverse events.
XELODA in Combination With Docetaxel Dose Reduction Schedule
Taken from Table 18 in the full prescribing information
Toxicity
NCIC Grades*Grade 2 Grade 3 Grade 4 1st appearance Grade 2 occurring during the 14 days of XELODA treatment: interrupt XELODA treatment until resolved to grade 0-1. Treatment may be resumed during the cycle at the same dose of XELODA. Doses of XELODA missed during a treatment cycle are not to be replaced. Prophylaxis for toxicities should be implemented where possible.
Grade 2 persisting at the time the next XELODA/docetaxel treatment is due: delay treatment until resolved to grade 0-1, then continue at 100% of the original XELODA and docetaxel dose. Prophylaxis for toxicities should be implemented where possible.Grade 3 occurring during the 14 days of XELODA treatment: interrupt the XELODA treatment until resolved to grade 0-1. Treatment may be resumed during the cycle at 75% of the XELODA dose. Doses of XELODA missed during a treatment cycle are not to be replaced. Prophylaxis for toxicities should be implemented where possible.
Grade 3 persisting at the time the next XELODA/docetaxel treatment is due: delay treatment until resolved to grade 0-1.
For patients developing grade 3 toxicity at any time during the treatment cycle, upon resolution to grade 0-1, subsequent treatment cycles should be continued at 75% of the original XELODA dose and at 55 mg/m2 of docetaxel. Prophylaxis for toxicities should be implemented where possible.Discontinue treatment unless treating physician considers it to be in the best interest of the patient to continue with XELODA at 50% of original dose. 2nd appearance of same toxicity Grade 2 occurring during the 14 days of XELODA treatment: interrupt XELODA treatment until resolved to grade 0-1. Treatment may be resumed during the cycle at 75% of original XELODA dose. Doses of XELODA missed during a treatment cycle are not to be replaced. Prophylaxis for toxicities should be implemented where possible.
Grade 2 persisting at the time the next XELODA/docetaxel treatment is due: delay treatment until resolved to grade 0-1.
For patients developing 2nd occurrence of grade 2 toxicity at any time during the treatment cycle, upon resolution to grade 0-1, subsequent treatment cycles should be continued at 75% of the original XELODA dose and at 55 mg/m2 of docetaxel. Prophylaxis for toxicities should be implemented where possible.Grade 3 occurring during the 14 days of XELODA treatment: interrupt the XELODA treatment until resolved to grade 0-1. Treatment may be resumed during the cycle at 50% of the XELODA dose. Doses of XELODA missed during a treatment cycle are not to be replaced. Prophylaxis for toxicities should be implemented where possible.
Grade 3 persisting at the time the next XELODA/docetaxel treatment is due: delay treatment until resolved to grade 0-1.
For patients developing grade 3 toxicity at any time during the treatment cycle, upon resolution to grade 0-1, subsequent treatment cycles should be continued at 50% of the original XELODA dose and the docetaxel discontinued. Prophylaxis for toxicities should be implemented where possible.Discontinue treatment. 3rd appearance of same toxicity =Grade 2 occurring during the 14 days of XELODA treatment: interrupt XELODA treatment until resolved to grade 0-1. Treatment may be resumed during the cycle at 50% of the original XELODA dose. Doses of XELODA missed during a treatment cycle are not to be replaced. Prophylaxis for toxicities should be implemented where possible.
Grade 2 persisting at the time the next XELODA/docetaxel treatment is due: delay treatment until resolved to grade 0-1.
For patients developing 3rd occurrence of grade 2 toxicity at any time during the treatment cycle, upon resolution to grade 0-1, subsequent treatment cycles should be continued at 50% of the original XELODA dose and the docetaxel discontinued. Prophylaxis for toxicities should be implemented where possible.Discontinue treatment. 4th appearance of same toxicity Discontinue treatment. *National Cancer Institute of Canada Common Toxicity Criteria were used except for hand-and-foot syndrome (see PRECAUTIONS).
Dose modification for the use of XELODA as monotherapy is shown in Table below.
Recommended Dose Modifications With XELODA Monotherapy
Taken from Table 19 in the full prescribing information.
Toxicity
NCIC Grades*During a Course of Therapy Dose Adjustment for Next Treatment (% of starting dose) • Grade 1 Maintain dose level Maintain dose level • Grade 2 –1st appearance Interrupt until resolved to grade 0 – 1 100% –2nd appearance Interrupt until resolved to grade 0 – 1 75% –3rd appearance Interrupt until resolved to grade 0 – 1 50% –4th appearance Discontinue treatment permanently • Grade 3 –1st appearance Interrupt until resolved to grade 0 – 1 75% –2nd appearance Interrupt until resolved to grade 0 – 1 50% –3rd appearance Discontinue treatment permanently • Grade 4 –1st appearance Discontinue permanently
OR
If physician deems it to be in the patient’s best interest to continue, interrupt until resolved to grade 0 – 150% *National Cancer Institute of Canada Common Toxicity Criteria were used except for the hand-and-foot syndrome (see PRECAUTIONS).
Dosage modifications are not recommended for grade 1 events. Therapy with XELODA should be interrupted upon the occurrence of a grade 2 or 3 adverse experience. Once the adverse event has resolved or decreased in intensity to grade 1, then XELODA therapy may be restarted at full dose or as adjusted according to Tables 18 and 19 in the full prescribing information. If a grade 4 experience occurs, therapy should be discontinued or interrupted until resolved or decreased to grade 1, and therapy should be restarted at 50% of the original dose. Doses of XELODA omitted for toxicity are not replaced or restored; instead the patient should resume the planned treatment cycles.
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PREGNANCY CATEGORY D
Pregnancy Category D
Teratogenic Effects
Category D. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with XELODA.
XELODA may cause fetal harm when given to a pregnant woman. Capecitabine at doses of 198 mg/kg/day during organogenesis caused malformations and embryo death in mice. In separate pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values about 0.2 times the corresponding values in patients administered the recommended daily dose. Malformations in mice included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail and dilation of cerebral ventricles. At doses of 90 mg/kg/day, capecitabine given to pregnant monkeys during organogenesis caused fetal death. This dose produced 5'-DFUR AUC values about 0.6 times the corresponding values in patients administered the recommended daily dose. There are no adequate and well-controlled studies in pregnant women using XELODA. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with XELODA.
- Xeloda Prescribing Information (PDF)
- Xeloda Tablets (150 mg) MSDS (PDF)
- Xeloda Tablets (500 mg) MSDS (PDF)
- Mechanism of Action: 5-FU Concentrations in Tumor After Xeloda (PDF)
- Mechanism of Action: TP Concentration in Tumor and Normal Tissue after Xeloda (PDF)
- Mechanism of Action: Treatment for Breast Cancer & Colorectal Cancer with Xeloda (PDF)
