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Prescribing Information

Safety First

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Safety First

Boxed WARNING and Contraindications

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. 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.

XELODA is contraindicated in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency, severe renal impairment, or known hypersensitivity to capecitabine or to any of its components or to 5-fluorouracil.

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Dosing modification1

Dose Management Guidelines

Optimizing outcomes by individualizing dosing

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. 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. Doses of XELODA omitted for toxicity are not replaced or restored; instead the patient should resume the planned treatment cycles.

The dose of phenytoin and the dose of coumarin-derivative anticoagulants may need to be reduced when either drug is administered concomitantly with XELODA.

Monotherapy

(Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer,Metastatic Breast Cancer)

XELODA dose modification scheme as described below is recommended for the management of adverse reactions.

Recommended Dose Modifications of XELODA

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 75%
3rd appearance 50%
4th appearance Discontinue treatment permanently. —
Grade 3
1st appearance Interrupt until resolved to grade 0-1. 75%
2nd appearance 50%
3rd appearance Discontinue 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 0-1.		 50%

*National Cancer Institute of Canada Common Toxicity Criteria were used, except for the hand-and-foot syndrome.

In Combination with Docetaxel (Metastatic Breast Cancer)

Dose modifications of XELODA for toxicity should be made according to the above chart for XELODA. At the beginning of a treatment cycle, if a treatment delay is indicated for either XELODA or docetaxel, administration of both agents should be delayed until the requirements for restarting both drugs are met.

The dose reduction schedule for docetaxel when used in combination with XELODA for the treatment of metastatic breast cancer is shown below.

Docetaxel Dose Reduction Schedule in Combination with XELODA

Toxicity
NCIC Grades*		 Grade 2 Grade 3 Grade 4
1st appearance Delay treatment until resolved to grade 0-1; resume treatment with original dose of 75 mg/m2 docetaxel. Delay treatment until resolved to grade 0-1; resume treatment at 55 mg/m2 of docetaxel. Discontinue treatment with docetaxel.
2nd appearance Delay treatment until resolved to grade 0-1; resume treatment at 55 mg/m2 of docetaxel. Discontinue treatment with docetaxel —
3rd appearance Discontinue treatment with docetaxel. — —

*National Cancer Institute of Canada Common Toxicity Criteria were used, except for hand-and-foot syndrome.

Adjustment of Starting Dose in Special Populations

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 and Clinical Pharmacology. Subsequent dose adjustment is recommended as outlined in Table 2 and Table 3 (depending on the regimen) if a patient develops a grade 2 to 4 adverse event. The starting dose adjustment recommendations for patients with moderate renal impairment apply to both 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 x 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.

Important treatment considerations — dose modifications

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. 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. Please consult XELODA Prescribing Information for recommended dose modifications.

View XELODA Safety Profile

References

  1. Xeloda [package insert]. South San Francisco, CA: Genentech USA, Inc; 2011.

Indications

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). Physicians should consider results of combination chemotherapy trials, which have shown improvement in DFS and overall survival (OS), 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.

XELODA monotherapy is 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.

XELODA in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.

Boxed WARNING and Additional Important Safety Information

Boxed WARNING
Warfarin Interaction — Coagulopathy

  • 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.
  • 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 have been observed 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 infrequently 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.
  • XELODA is contraindicated in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency, or severe renal impairment. XELODA is also contraindicated in patients with known hypersensitivity to capecitabine or to any of its components or to 5-fluorouracil.
  • Additional serious adverse reactions include diarrhea, cardiotoxicity, hand-and-foot syndrome, and hyperbilirubinemia. XELODA can cause fetal harm. Advise women of the potential risk to the fetus. Do not treat patients with neutrophil counts <1.5 x 109/L or thrombocyte counts <100 x 109/L.
  • The most common adverse reactions (≥30%) reported with XELODA were diarrhea, hand-and-foot syndrome, nausea, vomiting, abdominal pain, fatigue/weakness, and hyperbilirubinemia. Other adverse reactions, including serious adverse reactions, have been reported.

Monotherapy in Adjuvant Colon Cancer

In a phase 3 study of XELODA monotherapy in colon cancer in the adjuvant setting, serious adverse events (grade 3/4) occurring in ≥5% of patients receiving either XELODA or 5-FU/LV (%;%) were increase in bilirubin (20;7), hand-foot syndrome (17;<1), decrease in lymphocytes (13;13), diarrhea (12;14), decrease in neutrophils/granulocytes (3;27), decrease in neutrophils (3;27), stomatitis (2;14), and neutropenia (<1;5). The most common adverse events for all grades occurring in ≥30% of patients receiving either XELODA or 5-FU/LV were hand-foot syndrome (60;9), diarrhea (47;65), nausea (34;47), and stomatitis (22;60). 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.

Monotherapy in mCRC

In two phase 3 trials of XELODA monotherapy in metastatic colorectal cancer, serious adverse events (grade 3/4) occurring in ≥5% of patients receiving either XELODA or 5-FU/LV (%;%) were hyperbilirubinemia (23;6), hand-foot syndrome (17;1), diarrhea (15;12), abdominal pain (<10;5), vomiting (<5;<5), ileus (5;3), stomatitis (<3;15), and neutropenia (3;21). The most common adverse events for all grades occurring in ≥30% of patients receiving either XELODA or 5-FU/LV were anemia (80;79), diarrhea (55;61), hand-foot syndrome (54;6), hyperbilirubinemia (48;17), nausea (43;51), fatigue/weakness (42;46), abdominal pain (35;31), vomiting (27;30), appetite decrease (26;31), stomatitis (25;62), and neutropenia (13;46). 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.

Monotherapy in mBC

In a single arm study of XELODA monotherapy in metastatic breast cancer, serious adverse events (grade 3/4) occurring in ≥5% of patients receiving XELODA (%) were lymphopenia (59), diarrhea (15), hand-foot syndrome (11), hyperbilirubinemia (11), fatigue (8), stomatitis (7), and dehydration (5). The most common adverse events for all grades occurring in ≥30% of patients receiving XELODA were lymphopenia (94), anemia (72), diarrhea (57), hand-foot syndrome (57), nausea (53), fatigue (41), dermatitis (37), and vomiting (37).

Combination Therapy with Docetaxel in mBC

In a phase 3 study of XELODA combination therapy (XELODA plus docetaxel) in metastatic breast cancer, serious adverse events (grade 3/4) occurring at a ≥2% higher incidence in patients receiving XELODA plus docetaxel vs docetaxel alone (%;%) were lymphocytopenia (89;84), hand-foot syndrome (24;1), stomatitis (<18;5), diarrhea (<15;<6), anemia (10;<6), hyperbilirubinemia (9;4), nausea (7;2), vomiting (5;2), constipation (2;0), and nail disorder (2;0). The most common adverse events for all grades occurring at a ≥5% higher incidence in patients receiving XELODA plus docetaxel vs docetaxel alone were diarrhea (67;48), stomatitis (67;43), hand-foot syndrome (63;8), nausea (45;36), thrombocytopenia (41;23), vomiting (35;24), abdominal pain (30;24), hyperbilirubinemia (20;6), weakness (16;11), dyspepsia (14;8), lacrimation increase (12;7), and appetite decrease (10;5).

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