XELODA- capecitabine tablet, film coated

Xeloda by

Drug Labeling and Warnings

Xeloda by is a Prescription medication manufactured, distributed, or labeled by State of Florida DOH Central Pharmacy. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

Metastatic Colorectal Cancer

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 4.

Table 4 Baseline Demographics of Controlled Colorectal Trials
Study 1Study 2
XELODA
(n=302)
5-FU/LV
(n=303)
XELODA
(n=301)
5-FU/LV
(n=301)
Age (median, years)64636464
Range(23-86)(24-87)(29-84)(36-86)
Gender
  Male (%)181 (60)197 (65)172 (57)173 (57)
  Female (%)121 (40)106 (35)129 (43)128 (43)
Karnofsky PS (median)90909090
Range(70-100)(70-100)(70-100)(70-100)
Colon (%)222 (74)232 (77)199 (66)196 (65)
Rectum (%)79 (26)70 (23)101 (34)105 (35)
Prior radiation therapy (%)52 (17)62 (21)42 (14)42 (14)
Prior adjuvant 5-FU (%)84 (28)110 (36)56 (19)41 (14)

The efficacy endpoints for the two phase 3 trials are shown in Table 5 and Table 6.

Table 5 Efficacy of XELODA vs 5-FU/LV in Colorectal Cancer (Study 1)
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)0.99
95% C.I. for Hazard Ratio(0.84-1.17)
Survival
(Median, days, 95% C.I.)380 (321-434)407 (366-446)
Hazard Ratio (XELODA/5-FU/LV)1.00
95% C.I. for Hazard Ratio(0.84-1.18)
Table 6 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)
(p-value)0.027
Time to Progression
(Median, days, 95% C.I.)137 (128-165)131 (102-156)
Hazard Ratio (XELODA/5-FU/LV)0.97
95% C.I. for Hazard Ratio(0.82-1.14)
Survival
(Median, days, 95% C.I.)404 (367-452)369 (338-430)
Hazard Ratio (XELODA/5-FU/LV)0.92
95% C.I. for Hazard Ratio(0.78-1.09)

Figure 2 Kaplan-Meier Curve for Overall Survival of Pooled Data (Studies 1 and 2)

Figure

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 5, Table 6, and Figure 2).

Breast Cancer

XELODA has been evaluated in clinical trials in combination with docetaxel (Taxotere®) and as monotherapy.

Breast Cancer Combination Therapy

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 anthracycline-containing 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 1-hour intravenous infusion administered in 3-week cycles. Patient demographics are provided in Table 7.

Table 7 Baseline Demographics and Clinical Characteristics XELODA and Docetaxel Combination vs Docetaxel in Breast Cancer Trial
XELODA + Docetaxel
(n=255)
Docetaxel
(n=256)
  • * Includes 10 patients in combination and 18 patients in monotherapy arms treated with an anthracenedione
  • Age (median, years)5251
    Karnofsky PS (median)9090
    Site of Disease
      Lymph nodes121 (47%)125 (49%)
      Liver116 (45%)122 (48%)
      Bone107 (42%)119 (46%)
      Lung95 (37%)99 (39%)
      Skin73 (29%)73 (29%)
    Prior Chemotherapy
      Anthracycline*255 (100%)256 (100%)
      5-FU196 (77%)189 (74%)
      Paclitaxel25 (10%)22 (9%)
    Resistance to an Anthracycline
      No resistance19 (7%)19 (7%)
      Progression on anthracycline therapy65 (26%)73 (29%)
      Stable disease after 4 cycles of anthracycline therapy41 (16%)40 (16%)
      Relapsed within 2 years of completion of anthracycline-adjuvant therapy78 (31%)74 (29%)
      Experienced a brief response to anthracycline therapy, with subsequent progression while on therapy or within 12 months after last dose51 (20%)50 (20%)
    No. of Prior Chemotherapy Regimens for Treatment of Metastatic Disease
      089 (35%)80 (31%)
      1123 (48%)135 (53%)
      243 (17%)39 (15%)
      30 (0%)2 (1%)

    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 8, Figure 3, and Figure 4.

    Table 8 Efficacy of XELODA and Docetaxel Combination vs Docetaxel Monotherapy
    Efficacy ParameterCombination TherapyMonotherapyp-valueHazard Ratio
  • * The response rate reported represents a reconciliation of the investigator and IRC assessments performed by the sponsor according to a predefined algorithm.
  • NA = Not Applicable
  • Time to Disease Progression
    Median Days1861280.00010.643
    95% C.I.(165-198)(105-136)
    Overall Survival
    Median Days4423520.01260.775
    95% C.I.(375-497)(298-387)
    Response Rate*32%22%0.009NA

    Figure 3 Kaplan-Meier Estimates for Time to Disease Progression XELODA and Docetaxel vs Docetaxel

    Figure

    Figure 4 Kaplan-Meier Estimates of Survival XELODA and Docetaxel vs Docetaxel

    Figure

    Breast Cancer Monotherapy

    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 9. 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 9 Baseline Demographics and Clinical Characteristics Single-Arm Breast Cancer Trial
    Patients With Measurable Disease
    (n=135)
    All Patients
    (n=162)
  • * Lung, pleura, liver, peritoneum
  • Includes 2 patients treated with an anthracenedione
  • Age (median, years)5556
    Karnofsky PS9090
    No. Disease Sites
      1-243 (32%)60 (37%)
      3-463 (46%)69 (43%)
      >529 (22%)34 (21%)
    Dominant Site of Disease
      Visceral*101 (75%)110 (68%)
      Soft Tissue30 (22%)35 (22%)
      Bone4 (3%)17 (10%)
    Prior Chemotherapy
      Paclitaxel135 (100%)162 (100%)
      Anthracycline122 (90%)147 (91%)
      5-FU110 (81%)133 (82%)
      Resistance to Paclitaxel103 (76%)124 (77%)
      Resistance to an Anthracycline55 (41%)67 (41%)
      Resistance to both Paclitaxel
        and an Anthracycline
    43 (32%)51 (31%)

    Antitumor responses for patients with disease resistant to both paclitaxel and an anthracycline are shown in Table 10.

    Table 10 Response Rates in Doubly-Resistant Patients Single-Arm Breast Cancer Trial
    Resistance to Both Paclitaxel and an Anthracycline
    (n=43)
  • * Includes 2 patients treated with an anthracenedione
  • From date of first response
  • CR0
    PR*11
    CR + PR*11
    Response Rate*
    (95% C.I.)
    25.6%
    (13.5, 41.2)
    Duration of Response,*
    Median in days
    (Range)
    154
    (63-233)

    For the subgroup of 43 patients who were doubly resistant, the median time to progression was 102 days and the median survival was 255 days. The objective response rate in this population was supported by 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 9). The median time to progression was 90 days and the median survival was 306 days.

  • INDICATIONS 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.
  • CONTRAINDICATIONS

    XELODA is contraindicated in patients with known hypersensitivity to capecitabine or to any of its components. XELODA is contraindicated in patients who have a known hypersensitivity to 5-fluorouracil. XELODA is contraindicated in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency. XELODA is also contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min [Cockroft and Gault]) (see CLINICAL PHARMACOLOGY: Special Populations).

  • WARNINGS

    Renal Insufficiency

    Patients with moderate renal impairment at baseline require dose reduction (see DOSAGE AND ADMINISTRATION). Patients with mild and moderate renal impairment at baseline should be carefully monitored for adverse events. Prompt interruption of therapy with subsequent dose adjustments is recommended if a patient develops a grade 2 to 4 adverse event as outlined in Table 18 in DOSAGE AND ADMINISTRATION.

    Coagulopathy

    See Boxed WARNING.

    Diarrhea

    XELODA can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. In 875 patients with either metastatic breast or colorectal cancer who received XELODA monotherapy, the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range from 1 to 369 days). The median duration of grade 3 to 4 diarrhea was 5 days. National Cancer Institute of Canada (NCIC) grade 2 diarrhea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhea as an increase of 7 to 9 stools/day or incontinence and malabsorption, and grade 4 diarrhea as an increase of ≥10 stools/day or grossly bloody diarrhea or the need for parenteral support. If grade 2, 3 or 4 diarrhea occurs, administration of XELODA should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1. Following a reoccurrence of grade 2 diarrhea or occurrence of any grade 3 or 4 diarrhea, subsequent doses of XELODA should be decreased (see DOSAGE AND ADMINISTRATION). Standard antidiarrheal treatments (eg, loperamide) are recommended.

    Necrotizing enterocolitis (typhlitis) has been reported.

    Geriatric Patients

    Patients ≥80 years old may experience a greater incidence of grade 3 or 4 adverse events (see PRECAUTIONS: Geriatric Use). In 875 patients with either metastatic breast or colorectal cancer who received XELODA monotherapy, 62% of the 21 patients ≥80 years of age treated with XELODA experienced a treatment-related grade 3 or 4 adverse event: diarrhea in 6 (28.6%), nausea in 3 (14.3%), hand-and-foot syndrome in 3 (14.3%), and vomiting in 2 (9.5%) patients. Among the 10 patients 70 years of age and greater (no patients were >80 years of age) treated with XELODA in combination with docetaxel, 30% (3 out of 10) of patients experienced grade 3 or 4 diarrhea and stomatitis, and 40% (4 out of 10) experienced grade 3 hand-and-foot syndrome.

    Among the 67 patients ≥60 years of age receiving XELODA in combination with docetaxel, the incidence of grade 3 or 4 treatment-related adverse events, treatment-related serious adverse events, withdrawals due to adverse events, treatment discontinuations due to adverse events and treatment discontinuations within the first two treatment cycles was higher than in the <60 years of age patient group.

    In 995 patients receiving XELODA as adjuvant therapy for Dukes' C colon cancer after resection of the primary tumor, 41% of the 398 patients ≥65 years of age treated with XELODA experienced a treatment-related grade 3 or 4 adverse event: hand-and-foot syndrome in 75 (18.8%), diarrhea in 52 (13.1%), stomatitis in 12 (3.0%), neutropenia/granulocytopenia in 11 (2.8%), vomiting in 6 (1.5%), and nausea in 5 (1.3%) patients. In patients ≥65 years of age (all randomized population; capecitabine 188 patients, 5-FU/LV 208 patients) treated for Dukes' C colon cancer after resection of the primary tumor, the hazard ratios for disease-free survival and overall survival for XELODA compared to 5-FU/LV were 1.01 (95% C.I. 0.80 – 1.27) and 1.04 (95% C.I. 0.79 – 1.37), respectively.

    Pregnancy

    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.

  • PRECAUTIONS

    General

    Patients receiving therapy with XELODA should be monitored by a physician experienced in the use of cancer chemotherapeutic agents. Most adverse events are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced (see DOSAGE AND ADMINISTRATION).

    Combination With Other Drugs

    Use of XELODA in combination with irinotecan has not been adequately studied.

    Hand-and-Foot Syndrome

    Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) is a cutaneous toxicity. Median time to onset was 79 days (range from 11 to 360 days) with a severity range of grades 1 to 3 for patients receiving XELODA monotherapy in the metastatic setting. Grade 1 is characterized by any of the following: numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt normal activities. Grade 2 hand-and-foot syndrome 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 hand-and-foot syndrome is defined as moist desquamation, ulceration, blistering or severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living. If grade 2 or 3 hand-and-foot syndrome occurs, administration of XELODA should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-and-foot syndrome, subsequent doses of XELODA should be decreased (see DOSAGE AND ADMINISTRATION).

    Cardiotoxicity

    The cardiotoxicity observed with XELODA includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy. These adverse events may be more common in patients with a prior history of coronary artery disease.

    Dihydropyrimidine Dehydrogenase Deficiency

    Rarely, unexpected, severe toxicity (eg, stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5-fluorouracil has been attributed to a deficiency of dihydropyrimidine dehydrogenase (DPD) activity. A link between decreased levels of DPD and increased, potentially fatal toxic effects of 5-fluorouracil therefore cannot be excluded.

    Hepatic Insufficiency

    Patients with mild to moderate hepatic dysfunction due to liver metastases should be carefully monitored when XELODA is administered. The effect of severe hepatic dysfunction on the disposition of XELODA is not known (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

    Hyperbilirubinemia

    In 875 patients with either metastatic breast or colorectal cancer who received at least one dose of XELODA 1250 mg/m2 twice daily as monotherapy for 2 weeks followed by a 1-week rest period, grade 3 (1.5-3 × ULN) hyperbilirubinemia occurred in 15.2% (n=133) of patients and grade 4 (>3 × ULN) hyperbilirubinemia occurred in 3.9% (n=34) of patients. Of 566 patients who had hepatic metastases at baseline and 309 patients without hepatic metastases at baseline, grade 3 or 4 hyperbilirubinemia occurred in 22.8% and 12.3%, respectively. Of the 167 patients with grade 3 or 4 hyperbilirubinemia, 18.6% (n=31) also had postbaseline elevations (grades 1 to 4, without elevations at baseline) in alkaline phosphatase and 27.5% (n=46) had postbaseline elevations in transaminases at any time (not necessarily concurrent). The majority of these patients, 64.5% (n=20) and 71.7% (n=33), had liver metastases at baseline. In addition, 57.5% (n=96) and 35.3% (n=59) of the 167 patients had elevations (grades 1 to 4) at both prebaseline and postbaseline in alkaline phosphatase or transaminases, respectively. Only 7.8% (n=13) and 3.0% (n=5) had grade 3 or 4 elevations in alkaline phosphatase or transaminases.

    In the 596 patients treated with XELODA as first-line therapy for metastatic colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was similar to the overall clinical trial safety database of XELODA monotherapy. The median time to onset for grade 3 or 4 hyperbilirubinemia in the colorectal cancer population was 64 days and median total bilirubin increased from 8 µm/L at baseline to 13 µm/L during treatment with XELODA. Of the 136 colorectal cancer patients with grade 3 or 4 hyperbilirubinemia, 49 patients had grade 3 or 4 hyperbilirubinemia as their last measured value, of which 46 had liver metastases at baseline.

    In 251 patients with metastatic breast cancer who received a combination of XELODA and docetaxel, grade 3 (1.5 to 3 × ULN) hyperbilirubinemia occurred in 7% (n=17) and grade 4 (>3 × ULN) hyperbilirubinemia occurred in 2% (n=5).

    If drug-related grade 2 to 4 elevations in bilirubin occur, administration of XELODA should be immediately interrupted until the hyperbilirubinemia resolves or decreases in intensity to grade 1. NCIC grade 2 hyperbilirubinemia is defined as 1.5 × normal, grade 3 hyperbilirubinemia as 1.5 to 3 × normal and grade 4 hyperbilirubinemia as >3 × normal. (See recommended dose modifications under DOSAGE AND ADMINISTRATION.)

    Hematologic

    In 875 patients with either metastatic breast or colorectal cancer who received a dose of 1250 mg/m2 administered twice daily as monotherapy for 2 weeks followed by a 1-week rest period, 3.2%, 1.7%, and 2.4% of patients had grade 3 or 4 neutropenia, thrombocytopenia or decreases in hemoglobin, respectively. In 251 patients with metastatic breast cancer who received a dose of XELODA in combination with docetaxel, 68% had grade 3 or 4 neutropenia, 2.8% had grade 3 or 4 thrombocytopenia, and 9.6% had grade 3 or 4 anemia.

    Carcinogenesis, Mutagenesis and Impairment of Fertility

    Adequate studies investigating the carcinogenic potential of XELODA have not been conducted. Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). Capecitabine was clastogenic in vitro to human peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow (micronucleus test). Fluorouracil causes mutations in bacteria and yeast. Fluorouracil also causes chromosomal abnormalities in the mouse micronucleus test in vivo.

    Impairment of Fertility

    In studies of fertility and general reproductive performance in mice, oral capecitabine doses of 760 mg/kg/day disturbed estrus and consequently caused a decrease in 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.

    Information for Patients (see Patient Package Insert)

    Patients and patients' caregivers should be informed of the expected adverse effects of XELODA, particularly nausea, vomiting, diarrhea, and hand-and-foot syndrome, and should be made aware that patient-specific dose adaptations during therapy are expected and necessary (see DOSAGE AND ADMINISTRATION). Patients should be encouraged to recognize the common grade 2 toxicities associated with XELODA treatment.

    Diarrhea

    Patients experiencing grade 2 diarrhea (an increase of 4 to 6 stools/day or nocturnal stools) or greater should be instructed to stop taking XELODA immediately. Standard antidiarrheal treatments (eg, loperamide) are recommended.

    Nausea

    Patients experiencing grade 2 nausea (food intake significantly decreased but able to eat intermittently) or greater should be instructed to stop taking XELODA immediately. Initiation of symptomatic treatment is recommended.

    Vomiting

    Patients experiencing grade 2 vomiting (2 to 5 episodes in a 24-hour period) or greater should be instructed to stop taking XELODA immediately. Initiation of symptomatic treatment is recommended.

    Hand-and-Foot Syndrome

    Patients experiencing grade 2 hand-and-foot syndrome (painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patients' activities of daily living) or greater should be instructed to stop taking XELODA immediately.

    Stomatitis

    Patients experiencing grade 2 stomatitis (painful erythema, edema or ulcers of the mouth or tongue, but able to eat) or greater should be instructed to stop taking XELODA immediately. Initiation of symptomatic treatment is recommended (see DOSAGE AND ADMINISTRATION).

    Fever and Neutropenia

    Patients who develop a fever of 100.5°F or greater or other evidence of potential infection should be instructed to call their physician.

    Drug-Food Interaction

    In all clinical trials, patients were instructed to administer 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 (see DOSAGE AND ADMINISTRATION).

    Drug-Drug Interactions

    Antacid

    The effect of an aluminum hydroxide- and magnesium hydroxide-containing antacid (Maalox) on the pharmacokinetics of XELODA was investigated in 12 cancer patients. There was a small increase in plasma concentrations of XELODA and one metabolite (5'-DFCR); there was no effect on the 3 major metabolites (5'-DFUR, 5-FU and FBAL).

    Anticoagulants

    Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored closely with great frequency and the anticoagulant dose should be adjusted accordingly (see Boxed WARNING and CLINICAL PHARMACOLOGY). 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 1 month after stopping XELODA. These events occurred in patients with and without liver metastases. In a drug interaction study with single-dose warfarin administration, there was a significant increase in the mean AUC of S-warfarin. The maximum observed INR value increased by 91%. This interaction is probably due to an inhibition of cytochrome P450 2C9 by capecitabine and/or its metabolites (see CLINICAL PHARMACOLOGY).

    CYP2C9 substrates

    Other than warfarin, no formal drug-drug interaction studies between XELODA and other CYP2C9 substrates have been conducted. Care should be exercised when XELODA is coadministered with CYP2C9 substrates.

    Phenytoin

    The level of phenytoin should be carefully monitored in patients taking XELODA and phenytoin dose may need to be reduced (see DOSAGE AND ADMINISTRATION: Dose Management Guidelines). Postmarketing reports indicate that some patients receiving XELODA and phenytoin had toxicity associated with elevated phenytoin levels. Formal drug-drug interaction studies with phenytoin have not been conducted, but the mechanism of interaction is presumed to be inhibition of the CYP2C9 isoenzyme by capecitabine and/or its metabolites (see PRECAUTIONS: Drug-Drug Interactions: Anticoagulants).

    Leucovorin

    The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil.

    Pregnancy

    Teratogenic Effects

    Category D (see WARNINGS). Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with XELODA.

    Nursing Women

    Lactating mice given a single oral dose of capecitabine excreted significant amounts of capecitabine metabolites into the milk. Because of the potential for serious adverse reactions in nursing infants from capecitabine, it is recommended that nursing be discontinued when receiving XELODA therapy.

    Pediatric Use

    The safety and effectiveness of XELODA in persons <18 years of age have not been established.

    Geriatric Use

    Physicians should pay particular attention to monitoring the adverse effects of XELODA in the elderly (see WARNINGS: Geriatric Patients).

  • ADVERSE REACTIONS

    Adjuvant Colon Cancer

    Table 11 shows the adverse events occurring in ≥5% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment. A total of 995 patients were treated with 1250 mg/m2 twice a day of XELODA administered for 2 weeks followed by a 1-week rest period, and 974 patients were administered 5-FU and leucovorin (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU, on days 1-5, every 28 days). The median duration of treatment was 164 days for capecitabine-treated patients and 145 days for 5-FU/LV-treated patients. A total of 112 (11%) and 73 (7%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse events. A total of 18 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 8 (0.8%) patients randomized to XELODA and 10 (1.0%) randomized to 5-FU/LV.

    Table 12 shows grade 3/4 laboratory abnormalities occurring in ≥1% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment.

    Table 11 Percent Incidence of Adverse Events Reported in ≥5% of Patients Treated With XELODA or 5-FU/LV for Colon Cancer in the Adjuvant Setting (Safety Population)
    Adjuvant Treatment for Colon Cancer (N=1969)
    XELODA
    (N=995)
    5-FU/LV
    (N=974)
    Body System/
    Adverse Event
    All GradesGrade 3/4All GradesGrade 3/4
    Gastrointestinal Disorders
      Diarrhea47126514
      Nausea342472
      Stomatitis2226014
      Vomiting152212
      Abdominal Pain143162
      Constipation9-11<1
      Upper Abdominal Pain7<17<1
      Dyspepsia6<15-
    Skin and Subcutaneous Tissue Disorders
      Hand-and-Foot Syndrome60179<1
      Alopecia6-22<1
      Rash7-8-
      Erythema615<1
    General Disorders and Administration Site Conditions
      Fatigue16<1161
      Pyrexia7<19<1
      Asthenia10<1101
      Lethargy10<19<1
    Nervous System Disorders
      Dizziness6<16-
      Headache5<16<1
      Dysgeusia6-9-
    Metabolism and Nutrition Disorders
      Anorexia9<111<1
    Eye Disorders
      Conjunctivitis5<16<1
    Blood and Lymphatic System Disorders
      Neutropenia2<185
    Respiratory Thoracic and Mediastinal Disorders
      Epistaxis2-5-
    Table 12 Percent Incidence of Grade 3/4 Laboratory Abnormalities Reported in ≥1% of Patients Receiving XELODA Monotherapy for Adjuvant Treatment of Colon Cancer (Safety Population)
    Adverse EventXELODA
    (n=995)
    IV 5-FU/LV
    (n=974)
    Grade 3/4 %Grade 3/4 %
  • * The incidence of grade 3/4 white blood cell abnormalities was 1.3% in the XELODA arm and 4.9% in the IV 5-FU/LV arm.
  • It should be noted that grading was according to NCIC CTC Version 1 (May, 1994). In the NCIC-CTC Version 1, hyperbilirubinemia grade 3 indicates a bilirubin value of 1.5 to 3.0 × upper limit of normal (ULN) range, and grade 4 a value of > 3.0 × ULN. The NCI CTC Version 2 and above define a grade 3 bilirubin value of >3.0 to 10.0 × ULN, and grade 4 values >10.0 × ULN.
  •   Increased ALAT (SGPT)1.60.6
      Increased calcium 1.10.7
      Decreased calcium2.32.2
      Decreased hemoglobin1.01.2
      Decreased lymphocytes13.013.0
      Decreased neutrophils*2.226.2
      Decreased neutrophils/granulocytes2.426.4
      Decreased platelets1.00.7
      Increased bilirubin206.3

    Metastatic Colorectal Cancer

    Table 13 shows the adverse events occurring in ≥5% of patients from pooling the two phase 3 trials in first line metastatic colorectal cancer. A total of 596 patients with metastatic colorectal cancer were treated with 1250 mg/m2 twice a day of XELODA administered for 2 weeks followed by a 1-week rest period, and 593 patients were administered 5-FU and leucovorin in the Mayo regimen (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU, on days 1-5, every 28 days). In the pooled colorectal database the median duration of treatment was 139 days for capecitabine-treated patients and 140 days for 5-FU/LV-treated patients. A total of 78 (13%) and 63 (11%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse events/intercurrent illness. A total of 82 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 50 (8.4%) patients randomized to XELODA and 32 (5.4%) randomized to 5-FU/LV.

    Table 13 Pooled Phase 3 Colorectal Trials: Percent Incidence of Adverse Events in ≥5% of Patients
    Adverse EventXELODA
    (n=596)
    5-FU/LV
    (n=593)
    Total
    %
    Grade 3
    %
    Grade 4
    %
    Total
    %
    Grade 3
    %
    Grade 4
    %
    – Not observed
    NA = Not Applicable
  • * Excluding vertigo
  • Number of Patients With > One Adverse Event9652994459
    Body System/Adverse Event
    GI
      Diarrhea5513261102
      Nausea434513<1
      Vomiting274<1304<1
      Stomatitis252<162141
      Abdominal Pain359<1315
      Gastrointestinal Motility Disorder10<17<1
      Constipation141<1171
      Oral Discomfort1010
      Upper GI Inflammatory Disorders8<1101
      Gastrointestinal Hemorrhage61<131
      Ileus641521
    Skin and Subcutaneous
      Hand-and-Foot Syndrome5417NA61NA
      Dermatitis271261
      Skin Discoloration7<15
      Alopecia621<1
    General
      Fatigue/Weakness424464
      Pyrexia181212
      Edema15191
      Pain121101
      Chest Pain6161<1
    Neurological
      Peripheral Sensory Neuropathy104
      Headache1017
      Dizziness*8<18<1
      Insomnia77
      Taste Disturbance6111<11
    Metabolism
      Appetite Decreased263<1312<1
      Dehydration72<1831
    Eye
      Eye Irritation1310<1
      Vision Abnormal52
    Respiratory
      Dyspnea14110<11
      Cough7<118
      Pharyngeal Disorder55
      Epistaxis3<16
      Sore Throat26
    Musculoskeletal
      Back Pain1029<1
      Arthralgia8161
    Vascular
      Venous Thrombosis83<162
    Psychiatric
      Mood Alteration56<1
      Depression54<1
    Infections
      Viral5<15<1
    Blood and Lymphatic
      Anemia802<1791<1
      Neutropenia131246813
    Hepatobiliary
      Hyperbilirubinemia481851733

    Breast Cancer Combination

    The following data are shown for the combination study with XELODA and docetaxel in patients with metastatic breast cancer in Table 14 and Table 15. In the XELODA and docetaxel combination arm the treatment was XELODA administered orally 1250 mg/m2 twice daily as intermittent therapy (2 weeks of treatment followed by 1 week without treatment) for at least 6 weeks and docetaxel administered as a 1-hour intravenous infusion at a dose of 75 mg/m2 on the first day of each 3-week cycle for at least 6 weeks. In the monotherapy arm docetaxel was administered as a 1-hour intravenous infusion at a dose of 100 mg/m2 on the first day of each 3-week cycle for at least 6 weeks. The mean duration of treatment was 129 days in the combination arm and 98 days in the monotherapy arm. A total of 66 patients (26%) in the combination arm and 49 (19%) in the monotherapy arm withdrew from the study because of adverse events. The percentage of patients requiring dose reductions due to adverse events was 65% in the combination arm and 36% in the monotherapy arm. The percentage of patients requiring treatment interruptions due to adverse events in the combination arm was 79%. Treatment interruptions were part of the dose modification scheme for the combination therapy arm but not for the docetaxel monotherapy-treated patients.

    Table 14 Percent Incidence of Adverse Events Considered Related or Unrelated to Treatment in ≥5% of Patients Participating in the XELODA and Docetaxel Combination vs Docetaxel Monotherapy Study
    Adverse EventXELODA 1250 mg/m2/bid
    With Docetaxel
    75 mg/m2/3 weeks
    Docetaxel
    100 mg/m2/3 weeks
    (n=251)(n=255)
    Total
    %
    Grade 3
    %
    Grade 4
    %
    Total
    %
    Grade 3
    %
    Grade 4
    %
    – Not observed
    NA = Not Applicable
    Number of Patients With at Least One Adverse Event9976.529.19757.631.8
    Body System/Adverse Event
    GI
      Diarrhea6714<1485<1
      Stomatitis6717<143 5
      Nausea457362
      Vomiting3541242
      Constipation20218
      Abdominal Pain30<3<1242
      Dyspepsia1481
      Dry Mouth6<15
    Skin and Subcutaneous
      Hand-and-Foot Syndrome6324NA8 1NA
      Alopecia416427
      Nail Disorder14215
      Dermatitis8111
      Rash Erythematous9<15
      Nail Discoloration64 <1
      Onycholysis5151
      Pruritus4 5
    General
      Pyrexia282342
      Asthenia264<1256
      Fatigue224276
      Weakness162112
      Pain in Limb13<1132
      Lethargy762
      Pain7<151
      Chest Pain (non-cardiac)4 <16 2
      Influenza-like Illness55
    Neurological
      Taste Disturbance16<114<1
      Headache153152
      Paresthesia12<1161
      Dizziness128<1
      Insomnia810<1
      Peripheral Neuropathy6101
      Hypoaesthesia4 <1 8<1
    Metabolism
      Anorexia13111<1
      Appetite Decreased105
      Weight Decreased75
      Dehydration1027<1<1
    Eye
      Lacrimation Increased127<1
      Conjunctivitis54
      Eye Irritation51
    Musculoskeletal
      Arthralgia152243
      Myalgia15 2 252
      Back Pain12<1113
      Bone Pain8<1102
    Cardiac
      Edema33<234<31
    Blood
      Neutropenic Fever1631321516
    Respiratory
      Dyspnea142<1162
      Cough13122<1
      Sore Throat12211<1
      Epistaxis7<16
      Rhinorrhea53
      Pleural Effusion2 1 74
    Infection
      Oral Candidiasis7<18<1
      Urinary Tract Infection6<14
      Upper Respiratory Tract4 51
    Vascular
      Flushing55
      Lymphoedema3 <151
    Psychiatric
      Depression551
    Table 15 Percent of Patients With Laboratory Abnormalities Participating in the XELODA and Docetaxel Combination vs Docetaxel Monotherapy Study
    Adverse EventXELODA 1250 mg/m2/bid
    With Docetaxel
    75 mg/m2/3 weeks
    Docetaxel
    100 mg/m2/3 weeks
    (n=251)(n=255)
    Body System/Adverse EventTotal
    %
    Grade 3
    %
    Grade 4
    %
    Total
    %
    Grade 3
    %
    Grade 4
    %
    Hematologic
      Leukopenia913724884233
      Neutropenia/Granulocytopenia862049871066
      Thrombocytopenia41212312
      Anemia8073835<1
      Lymphocytopenia994841984440
    Hepatobiliary
      Hyperbilirubinemia2072622

    Breast Cancer XELODA Monotherapy

    The following data are shown for the study in stage IV breast cancer patients who received a dose of 1250 mg/m2 administered twice daily for 2 weeks followed by a 1-week rest period. The mean duration of treatment was 114 days. A total of 13 out of 162 patients (8%) discontinued treatment because of adverse events/intercurrent illness.

    Table 16 Percent Incidence of Adverse Events Considered Remotely, Possibly or Probably Related to Treatment in ≥5% of Patients Participating in the Single Arm Trial in Stage IV Breast Cancer
    Adverse EventPhase 2 Trial in Stage IV Breast Cancer
    (n=162)
    Body System/Adverse EventTotal
    %
    Grade 3
    %
    Grade 4
    %
    – Not observed
    NA = Not Applicable
    GI
    Diarrhea57123
    Nausea534
    Vomiting374
    Stomatitis247
    Abdominal Pain204
    Constipation151
    Dyspepsia8
    Skin and Subcutaneous
    Hand-and-Foot Syndrome5711NA
    Dermatitis371
    Nail Disorder7
    General
    Fatigue418
    Pyrexia121
    Pain in Limb61
    Neurological
    Paresthesia211
    Headache91
    Dizziness8
    Insomnia8
    Metabolism
    Anorexia233
    Dehydration741
    Eye
    Eye Irritation15
    Musculoskeletal
    Myalgia9
    Cardiac
    Edema91
    Blood
    Neutropenia2622
    Thrombocytopenia2431
    Anemia7231
    Lymphopenia944415
    Hepatobiliary
    Hyperbilirubinemia2292

    XELODA and Docetaxel in Combination

    Shown below by body system are the clinically relevant adverse events in <5% of patients in the overall clinical trial safety database of 251 patients (Study Details) reported as related to the administration of XELODA in combination with docetaxel and that were clinically at least remotely relevant. In parentheses is the incidence of grade 3 and 4 occurrences of each adverse event.

    It is anticipated that the same types of adverse events observed in the XELODA monotherapy studies may be observed in patients treated with the combination of XELODA plus docetaxel.

    Gastrointestinal: ileus (0.39), necrotizing enterocolitis (0.39), esophageal ulcer (0.39), hemorrhagic diarrhea (0.80)

    Neurological: ataxia (0.39), syncope (1.20), taste loss (0.80), polyneuropathy (0.39), migraine (0.39)

    Cardiac: supraventricular tachycardia (0.39)

    Infection: neutropenic sepsis (2.39), sepsis (0.39), bronchopneumonia (0.39)

    Blood and Lymphatic: agranulocytosis (0.39), prothrombin decreased (0.39)

    Vascular: hypotension (1.20), venous phlebitis and thrombophlebitis (0.39), postural hypotension (0.80)

    Renal: renal failure (0.39)

    Hepatobiliary: jaundice (0.39), abnormal liver function tests (0.39), hepatic failure (0.39), hepatic coma (0.39), hepatotoxicity (0.39)

    Immune System: hypersensitivity (1.20)

    XELODA Monotherapy Metastatic Breast and Colorectal Cancer

    Shown below by body system are the clinically relevant adverse events in <5% of patients in the overall clinical trial safety database of 875 patients (phase 3 colorectal studies — 596 patients, phase 2 colorectal study — 34 patients, phase 2 breast cancer studies — 245 patients) reported as related to the administration of XELODA and that were clinically at least remotely relevant. In parentheses is the incidence of grade 3 or 4 occurrences of each adverse event.

    Gastrointestinal: abdominal distension, dysphagia, proctalgia, ascites (0.1), gastric ulcer (0.1), ileus (0.3), toxic dilation of intestine, gastroenteritis (0.1)

    Skin and Subcutaneous: nail disorder (0.1), sweating increased (0.1), photosensitivity reaction (0.1), skin ulceration, pruritus, radiation recall syndrome (0.2)

    General: chest pain (0.2), influenza-like illness, hot flushes, pain (0.1), hoarseness, irritability, difficulty in walking, thirst, chest mass, collapse, fibrosis (0.1), hemorrhage, edema, sedation

    Neurological: insomnia, ataxia (0.5), tremor, dysphasia, encephalopathy (0.1), abnormal coordination, dysarthria, loss of consciousness (0.2), impaired balance

    Metabolism: increased weight, cachexia (0.4), hypertriglyceridemia (0.1), hypokalemia, hypomagnesemia

    Eye: conjunctivitis

    Respiratory: cough (0.1), epistaxis (0.1), asthma (0.2), hemoptysis, respiratory distress (0.1), dyspnea

    Cardiac: tachycardia (0.1), bradycardia, atrial fibrillation, ventricular extrasystoles, extrasystoles, myocarditis (0.1), pericardial effusion

    Infections: laryngitis (1.0), bronchitis (0.2), pneumonia (0.2), bronchopneumonia (0.2), keratoconjunctivitis, sepsis (0.3), fungal infections (including candidiasis) (0.2)

    Musculoskeletal: myalgia, bone pain (0.1), arthritis (0.1), muscle weakness

    Blood and Lymphatic: leukopenia (0.2), coagulation disorder (0.1), bone marrow depression (0.1), idiopathic thrombocytopenia purpura (1.0), pancytopenia (0.1)

    Vascular: hypotension (0.2), hypertension (0.1), lymphoedema (0.1), pulmonary embolism (0.2), cerebrovascular accident (0.1)

    Psychiatric: depression, confusion (0.1)

    Renal: renal impairment (0.6)

    Ear: vertigo

    Hepatobiliary: hepatic fibrosis (0.1), hepatitis (0.1), cholestatic hepatitis (0.1), abnormal liver function tests

    Immune System: drug hypersensitivity (0.1)

    Postmarketing: hepatic failure, lacrimal duct stenosis

  • OVERDOSAGE

    The manifestations of acute overdose would include nausea, vomiting, diarrhea, gastrointestinal irritation and bleeding, and bone marrow depression. Medical management of overdose should include customary supportive medical interventions aimed at correcting the presenting clinical manifestations. Although no clinical experience using dialysis as a treatment for XELODA overdose has been reported, dialysis may be of benefit in reducing circulating concentrations of 5'-DFUR, a low–molecular-weight metabolite of the parent compound.

    Single doses of XELODA were not lethal to mice, rats, and monkeys at doses up to 2000 mg/kg (2.4, 4.8, and 9.6 times the recommended human daily dose on a mg/m2 basis).

  • DOSAGE AND ADMINISTRATION

    The recommended dose of XELODA is 1250 mg/m2 administered orally twice daily (morning and evening; equivalent to 2500 mg/m2 total daily dose) for 2 weeks followed by a 1-week rest period given as 3-week cycles. XELODA tablets should be swallowed with water within 30 minutes after a meal. In combination with docetaxel, the recommended dose of XELODA is 1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period, combined with docetaxel at 75 mg/m2 as a 1-hour intravenous infusion every 3 weeks. Pre-medication, according to the docetaxel labeling, should be started prior to docetaxel administration for patients receiving the XELODA plus docetaxel combination. Table 17 displays the total daily dose by body surface area and the number of tablets to be taken at each dose.

    Adjuvant treatment in patients with Dukes' C colon cancer is recommended for a total of 6 months, ie, 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).

    Table 17 XELODA Dose Calculation According to Body Surface Area
    Dose Level 1250 mg/m2
    Twice a Day
    Number of Tablets to be Taken at
    Each Dose (Morning and Evening)
    Surface Area
    (m2)
    Total Daily
    Dose* (mg)
    150 mg500 mg
  • * Total Daily Dose divided by 2 to allow equal morning and evening doses
  • ≤ 1.25 300003
    1.26-1.37 330013
    1.38-1.51 360023
    1.52-1.65 400004
    1.66-1.77 430014
    1.78-1.91 460024
    1.92-2.05 500005
    2.06-2.17 530015
    ≥ 2.18560025

    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 Table 18 and Table 19) is recommended for the management of adverse events.

    Table 18 XELODA in Combination With Docetaxel Dose Reduction Schedule
    Toxicity
    NCIC Grades*
    Grade 2Grade 3Grade 4
  • * National Cancer Institute of Canada Common Toxicity Criteria were used except for hand-and-foot syndrome (see PRECAUTIONS).
  • 1st appearanceGrade 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 toxicityGrade 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 toxicityGrade 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 toxicityDiscontinue treatment.

    Dose modification for the use of XELODA as monotherapy is shown in Table 19.

    Table 19 Recommended Dose Modifications With XELODA Monotherapy
    Toxicity
    NCIC Grades*
    During a Course of TherapyDose Adjustment for Next Treatment (% of starting dose)
  • * National Cancer Institute of Canada Common Toxicity Criteria were used except for the hand-and-foot syndrome (see PRECAUTIONS).
  •     Grade 1Maintain dose levelMaintain dose level
        Grade 2
    -1st appearanceInterrupt until resolved to grade 0-1100%
    -2nd appearanceInterrupt until resolved to grade 0-175%
    -3rd appearanceInterrupt until resolved to grade 0-150%
    -4th appearanceDiscontinue treatment permanently
        Grade 3
    -1st appearanceInterrupt until resolved to grade 0-175%
    -2nd appearanceInterrupt until resolved to grade 0-150%
    -3rd appearanceDiscontinue treatment permanently
        Grade 4
    -1st appearanceDiscontinue permanently
    OR
    If physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade 0-1
    50%

    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 Table 18 and Table 19. 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.

    Adjustment of Starting Dose in Special Populations

    Hepatic Impairment

    In patients with mild to moderate hepatic dysfunction due to liver metastases, no starting dose adjustment is necessary; however, patients should be carefully monitored. Patients with severe hepatic dysfunction have not been studied.

    Renal Impairment

    No adjustment to the starting dose of XELODA is recommended in patients with mild renal impairment (creatinine clearance = 51 to 80 mL/min [Cockroft and Gault, as shown below]). In patients with moderate renal impairment (baseline creatinine clearance = 30 to 50 mL/min), a dose reduction to 75% of the XELODA starting dose when used as monotherapy or in combination with docetaxel (from 1250 mg/m2 to 950 mg/m2 twice daily) is recommended (see CLINICAL PHARMACOLOGY: Special Populations). Subsequent dose adjustment is recommended as outlined in Table 18 and Table 19 if a patient develops a grade 2 to 4 adverse event (see WARNINGS). The starting dose adjustment recommendations for patients with moderate renal impairment apply both to XELODA monotherapy and XELODA in combination use with docetaxel.

    Cockroft and Gault Equation:

                                                         (140 - age [yrs]) (body wt [kg])

    Creatinine clearance for males = —————————————

                                                         (72) (serum creatinine [mg/dL])

    Creatinine clearance for females = 0.85 × male value

    Geriatrics

    Physicians should exercise caution in monitoring the effects of XELODA in the elderly. Insufficient data are available to provide a dosage recommendation.

  • HOW SUPPLIED

    XELODA is supplied as biconvex, oblong film-coated tablets, available in bottles as follows:

    150 mg

    color:         light peach
    engraving:   XELODA on one side, 150 on the other

    500 mg

    color:         peach
    engraving:   XELODA on one side, 500 on the other

    They are supplied by State of Florida DOH Central Pharmacy as follows:

    NDCStrengthQuantity/FormColorSource Prod. Code
    53808-0411-1500 mg30 Tablets in a Blister Packlight peach0004-1101

    Storage Conditions

    Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature]. KEEP TIGHTLY CLOSED.

    For full Taxotere prescribing information, please refer to Taxotere Package Insert.

    This product was Manufactured By:
    Hoffmann-La Roche Inc.
    340 Kingsland Street
    Nutley, NJ 07110


    And Repackaged By:

    State of Florida DOH Central Pharmacy
    104-2 Hamilton Park Drive
    Tallahassee, FL 32304
    United States

  • PATIENT INFORMATION (TEXT ONLY)

    Read this leaflet before you start taking XELODA® [zeh-LOE-duh] and each time you refill your prescription in case the information has changed. This leaflet contains important information about XELODA. However, this information does not take the place of talking with your doctor. This information cannot cover all possible risks and benefits of XELODA. Your doctor should always be your first choice for discussing your medical condition and this medicine.

    What is XELODA?

    XELODA is a medicine you take by mouth (orally). XELODA is changed in the body to 5-fluorouracil (5-FU). In some patients with colon, rectum or breast cancer, 5-FU stops cancer cells from growing and decreases the size of the tumor.

    XELODA is used to treat:

    What is the most important information about XELODA?

    XELODA may increase the effect of other medicines used to thin your blood such as warfarin (Coumadin®). It is very important that your doctor knows if you are taking a blood thinner such as warfarin because XELODA may increase the effect of this medicine and could lead to serious side effects. If you are taking blood thinners and XELODA, your doctor needs to check more often how fast your blood clots and change the dose of the blood thinner, if needed.

    Who should not take XELODA?

    1. DO NOT TAKE XELODA IF YOU

    2. TELL YOUR DOCTOR IF YOU

    How should I take XELODA?

    Take XELODA exactly as your doctor tells you to. Your doctor will prescribe a dose and treatment plan that is right for you. Your doctor may want you to take both 150 mg and 500 mg tablets together for each dose. If so, you must be able to identify the tablets. Taking the wrong tablets could cause an overdose (too much medicine) or underdose (too little medicine). The 150 mg tablets are light peach in color with 150 on one side. The 500 mg tablets are peach in color with 500 on one side. Your doctor may change the amount of medicine you take during your treatment. Your doctor may prescribe XELODA Tablets with Taxotere or docetaxel injection.

    What should I avoid while taking XELODA?

    What are the most common side effects of XELODA?

    The most common side effects of XELODA are:

    These side effects may differ when taking XELODA with Taxotere. Please consult your doctor for possible side effects that may be caused by taking XELODA with Taxotere.

    If you are concerned about these or any other side effects while taking XELODA, talk to your doctor.

    Stop taking XELODA immediately and contact your doctor right away if you have the side effects listed below, or other side effects that concern you. Your doctor can then adjust XELODA to a dose that is right for you or stop your XELODA treatment for a while. This should help to reduce the side effects and stop them from getting worse.

    Your doctor may tell you to lower the dose or to stop XELODA treatment for a while. If caught early, most of these side effects usually improve after you stop taking XELODA. If they do not improve within 2 to 3 days, call your doctor again. After your side effects have improved, your doctor will tell you whether to start taking XELODA again and what dose to take. Adjusting the dose of XELODA to be right for each patient is an important part of treatment.

    How should I store and use XELODA?

    General advice about prescription medicines:

    Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use XELODA for a condition for which it was not prescribed. Do not give XELODA to other people, even if they have the same symptoms you have. It may harm them.

    This leaflet summarizes the most important information about XELODA. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about XELODA that is written for health professionals.

    XELODA is a registered trademark of Hoffmann – La Roche Inc.

  • Patient Information

    XELODA® (capecitabine) TABLETS

    Read this leaflet before you start taking XELODA® [zeh-LOE-duh] and each time you refill your prescription in case the information has changed. This leaflet contains important information about XELODA. However, this information does not take the place of talking with your doctor. This information cannot cover all possible risks and benefits of XELODA. Your doctor should always be your first choice for discussing your medical condition and this medicine.

    What is XELODA?

    XELODA is a medicine you take by mouth (orally). XELODA is changed in the body to 5-fluorouracil (5-FU). In some patients with colon, rectum or breast cancer, 5-FU stops cancer cells from growing and decreases the size of the tumor.

    XELODA is used to treat:

    What is the most important information about XELODA?

    XELODA may increase the effect of other medicines used to thin your blood such as warfarin (Coumadin®). It is very important that your doctor knows if you are taking a blood thinner such as warfarin because XELODA may increase the effect of this medicine and could lead to serious side effects. If you are taking blood thinners and XELODA, your doctor needs to check more often how fast your blood clots and change the dose of the blood thinner, if needed.

    Who should not take XELODA?

    1. DO NOT TAKE XELODA IF YOU

    2. TELL YOUR DOCTOR IF YOU

    How should I take XELODA?

    Take XELODA exactly as your doctor tells you to. Your doctor will prescribe a dose and treatment plan that is right for you. Your doctor may want you to take both 150 mg and 500 mg tablets together for each dose. If so, you must be able to identify the tablets. Taking the wrong tablets could cause an overdose (too much medicine) or underdose (too little medicine). The 150 mg tablets are light peach in color with 150 on one side. The 500 mg tablets are peach in color with 500 on one side. Your doctor may change the amount of medicine you take during your treatment. Your doctor may prescribe XELODA Tablets with Taxotere or docetaxel injection.

    What should I avoid while taking XELODA?

    What are the most common side effects of XELODA?

    The most common side effects of XELODA are:

    These side effects may differ when taking XELODA with Taxotere. Please consult your doctor for possible side effects that may be caused by taking XELODA with Taxotere.

    If you are concerned about these or any other side effects while taking XELODA, talk to your doctor.

    Stop taking XELODA immediately and contact your doctor right away if you have the side effects listed below, or other side effects that concern you. Your doctor can then adjust XELODA to a dose that is right for you or stop your XELODA treatment for a while. This should help to reduce the side effects and stop them from getting worse.

    Your doctor may tell you to lower the dose or to stop XELODA treatment for a while. If caught early, most of these side effects usually improve after you stop taking XELODA. If they do not improve within 2 to 3 days, call your doctor again. After your side effects have improved, your doctor will tell you whether to start taking XELODA again and what dose to take. Adjusting the dose of XELODA to be right for each patient is an important part of treatment.

    How should I store and use XELODA?

    General advice about prescription medicines:

    Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use XELODA for a condition for which it was not prescribed. Do not give XELODA to other people, even if they have the same symptoms you have. It may harm them.

    This leaflet summarizes the most important information about XELODA. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about XELODA that is written for health professionals.

    XELODA is a registered trademark of Hoffmann – La Roche Inc.

    Figure

    Representative sample of labeling (see the HOW SUPPLIED section for complete listing):

  • PRINCIPAL DISPLAY PANEL - 500 mg Tablet Label

    NDC: 53808-0411-1

    Xeloda®
    (capecitabine)
    Tablets

    500 mg

    Each tablet contains
    500 mg capecitabine.

    PRINCIPAL DISPLAY PANEL
  • INGREDIENTS AND APPEARANCE
    XELODA 
    capecitabine tablet, film coated
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 53808-0411(NDC:0004-1101)
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    CAPECITABINE (UNII: 6804DJ8Z9U) (capecitabine - UNII:6804DJ8Z9U) CAPECITABINE500 mg
    Inactive Ingredients
    Ingredient NameStrength
    ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)  
    CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
    HYPROMELLOSE 2208 (15000 CPS) (UNII: Z78RG6M2N2)  
    CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    WATER (UNII: 059QF0KO0R)  
    HYPROMELLOSE (UNII: 3NXW29V3WO)  
    TALC (UNII: 7SEV7J4R1U)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    FERRIC OXIDE RED (UNII: 1K09F3G675)  
    FERRIC OXIDE YELLOW (UNII: EX438O2MRT)  
    Product Characteristics
    ColorPINK (light peach) Scoreno score
    ShapeOVALSize11mm
    FlavorImprint Code XELODA;500
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 53808-0411-130 in 1 BLISTER PACK
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA02089607/01/2009
    Labeler - State of Florida DOH Central Pharmacy (829348114)
    Establishment
    NameAddressID/FEIBusiness Operations
    State of Florida DOH Central Pharmacy829348114repack

  • Trademark Results [Xeloda]

    Mark Image

    Registration | Serial
    Company
    Trademark
    Application Date
    XELODA
    XELODA
    75241696 2200434 Live/Registered
    Hoffmann-La Roche Inc.
    1997-02-13

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