Xeloda Information
Xeloda () 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 . 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.
Xeloda () Dosage And Administration
Xeloda () tablets should be swallowed whole with water within 30 minutes after a meal. Xeloda () dose is calculated according to body surface area.
Xeloda () 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.
Xeloda () Warnings And Precautions
General
Patients receiving therapy with Xeloda () should be monitored by a physician experienced in the use of cancer chemotherapeutic agents. Most adverse reactions are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced .
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 . Standard antidiarrheal treatments (eg, loperamide) are recommended.
Necrotizing enterocolitis (typhlitis) has been reported.
In 875 patients with either metastatic breast or colorectal cancer who received at least one dose of Xeloda () 1250 mg/m 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 3 to 4 elevations in bilirubin occur, administration of Xeloda () should be immediately interrupted until the hyperbilirubinemia decreases to ≤3.0 X ULN see recommended dose modifications under .
In 875 patients with either metastatic breast or colorectal cancer who received a dose of 1250 mg/m 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.
Patients with baseline neutrophil counts of
Patients ≥80 years old may experience a greater incidence of grade 3 or 4 adverse reactions. 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 reactions, treatment-related serious adverse reactions, withdrawals due to adverse reactions, treatment discontinuations due to adverse reactions and treatment discontinuations within the first two treatment cycles was higher than in the
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.
Xeloda () Adverse Reactions
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Xeloda () 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/m basis).
Xeloda () Description
Xeloda () (capecitabine) is a fluoropyrimidine carbamate with antineoplastic activity. It is an orally administered systemic prodrug of 5'-deoxy-5-fluorouridine (5'-DFUR) which is converted to 5-fluorouracil.
The chemical name for capecitabine is 5'-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine and has a molecular weight of 359.35. Capecitabine has the following structural formula:
Capecitabine is a white to off-white crystalline powder with an aqueous solubility of 26 mg/mL at 20°C.
Xeloda () is supplied as biconvex, oblong film-coated tablets for oral administration. Each light peach-colored tablet contains 150 mg capecitabine and each peach-colored tablet contains 500 mg capecitabine. The inactive ingredients in Xeloda () include: anhydrous lactose, croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate and purified water. The peach or light peach film coating contains hydroxypropyl methylcellulose, talc, titanium dioxide, and synthetic yellow and red iron oxides.
Xeloda () Clinical Pharmacology
Xeloda () Clinical Studies
A multicenter randomized, controlled phase 3 clinical trial in patients with Dukes' C colon cancer (X-ACT) provided data concerning the use of Xeloda () for the adjuvant treatment of patients with colon cancer. The primary objective of the study was to compare disease-free survival (DFS) in patients receiving Xeloda () to those receiving IV 5-FU/LV alone. In this trial, 1987 patients were randomized either to treatment with Xeloda () 1250 mg/m orally twice daily for 2 weeks followed by a 1-week rest period, given as 3-week cycles for a total of 8 cycles (24 weeks) or IV bolus 5-FU 425 mg/m and 20 mg/m IV leucovorin on days 1 to 5, given as 4-week cycles for a total of 6 cycles (24 weeks). Patients in the study were required to be between 18 and 75 years of age with histologically-confirmed Dukes' stage C colon cancer with at least one positive lymph node and to have undergone (within 8 weeks prior to randomization) complete resection of the primary tumor without macroscopic or microscopic evidence of remaining tumor. Patients were also required to have no prior cytotoxic chemotherapy or immunotherapy (except steroids), and have an ECOG performance status of 0 or 1 (KPS ≥ 70%), ANC ≥ 1.5×10/L, platelets ≥ 100×10/L, serum creatinine ≤ 1.5 ULN, total bilirubin ≤ 1.5 ULN, AST/ALT ≤ 2.5 ULN and CEA within normal limits at time of randomization.
The baseline demographics for Xeloda () and 5-FU/LV patients are shown in . The baseline characteristics were well-balanced between arms.
All patients with normal renal function or mild renal impairment began treatment at the full starting dose of 1250 mg/m orally twice daily. The starting dose was reduced in patients with moderate renal impairment (calculated creatinine clearance 30 to 50 mL/min) at baseline . Subsequently, for all patients, doses were adjusted when needed according to toxicity. Dose management for Xeloda () included dose reductions, cycle delays and treatment interruptions (see ).
The median follow-up at the time of the analysis was 83 months (6.9 years). The hazard ratio for DFS for Xeloda () compared to 5-FU/LV was 0.88 (95% C.I. 0.77 – 1.01) (see and ). Because the upper 2-sided 95% confidence limit of hazard ratio was less than 1.20, Xeloda () was non-inferior to 5-FU/LV. The choice of the non-inferiority margin of 1.20 corresponds to the retention of approximately 75% of the 5-FU/LV effect on DFS. The hazard ratio for Xeloda () compared to 5-FU/LV with respect to overall survival was 0.86 (95% C.I. 0.74 – 1.01). The 5-year overall survival rates were 71.4% for Xeloda () and 68.4% for 5-FU/LV (see .
Figure 2 Kaplan-Meier Estimates of Overall Survival (All Randomized Population)
Xeloda () How Supplied/storage And Handling
150 mg
Color: Light peach
Engraving: Xeloda () on one side and 150 on the other 150 mg tablets are packaged in bottles of 60 (NDC 0004-1100-20).
500 mg
Color: Peach
Engraving: Xeloda () on one side and 500 on the other 500 mg tablets are packaged in bottles of 120 (NDC 0004-1101-50).
Storage and Handling
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.
Care should be exercised in the handling of Xeloda () . Xeloda () tablets should not be cut or crushed. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of tablets. If powder from broken Xeloda () tablets contacts the skin, wash the skin immediately and thoroughly with soap and water. If Xeloda () contacts the mucous membranes, flush thoroughly with water.
Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published.
Xeloda () Patient Counseling Information
(see )
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 . As described below, patients taking Xeloda () should be informed of the need to interrupt treatment immediately if moderate or severe toxicity occurs. Patients should be encouraged to recognize the common grade 2 toxicities associated with Xeloda () treatment.
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