Xeloda: Package Insert and Label Information

XELODA- capecitabine tablet, film coated
Genentech, Inc.

WARNING: XELODA-WARFARIN INTERACTION

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 Warnings and Precautions (5.2) and Drug Interactions (7.1)] . 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.

1 INDICATIONS AND USAGE

1.1 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). Physicians should consider results of combination chemotherapy trials, which have shown improvement in DFS and 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.

1.2 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 (e.g., 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.

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions

XELODA tablets should be swallowed whole with water within 30 minutes after a meal. XELODA is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 If XELODA tablets must be cut or crushed, this should be done by a professional trained in safe handling of cytotoxic drugs using appropriate equipment and safety procedures. XELODA dose is calculated according to body surface area.

2.2 Standard Starting Dose

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

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 (see Table 1).

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 1 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 mg 500 mg
*
Total Daily Dose divided by 2 to allow equal morning and evening doses
≤ 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

In Combination With Docetaxel (Metastatic Breast Cancer)

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 1 displays the total daily dose of XELODA by body surface area and the number of tablets to be taken at each dose.

2.3 Dose Management Guidelines

General

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 (14)]. 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 [see Drug Interactions (7.1)].

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

XELODA dose modification scheme as described below (see Table 2) is recommended for the management of adverse reactions.

Table 2 Recommended Dose Modifications of XELODA
Toxicity NCIC Grades * During a Course of Therapy Dose 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 Warnings and Precautions (5)].
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 treatment permanently -
Grade 4
-1st appearance Discontinue permanentlyORIf physician deems it to be in the patient’s best interest to continue, interrupt until resolved to grade 0-1 50%

In Combination With Docetaxel (Metastatic Breast Cancer)

Dose modifications of XELODA for toxicity should be made according to Table 2 above for XELODA. At the beginning of a treatment cycle, if a treatment delay is indicated for either XELODA or docetaxel, then 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 in Table 3.

Table 3 Docetaxel Dose Reduction Schedule in Combination with XELODA
Toxicity NCIC Grades * Grade 2 Grade 3 Grade 4
*
National Cancer Institute of Canada Common Toxicity Criteria were used except for hand-and-foot syndrome [see Warnings and Precautions (5)].
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 - -

2.4 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 [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. 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 [see Warnings and Precautions (5.5)]. 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:

Creatinine clearance for males = (140 — age [yrs]) (body wt [kg])
(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.

3 DOSAGE FORMS AND STRENGTHS

XELODA is supplied as biconvex, oblong film-coated tablets for oral administration. Each light peach-colored tablet contains 150 mg of capecitabine and each peach-colored tablet contains 500 mg of capecitabine.

4 CONTRAINDICATIONS

4.1 Severe Renal Impairment

XELODA is contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min [Cockroft and Gault]) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

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