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Xeloda

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Xeloda

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

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 [see DOSAGE AND ADMINISTRATION].

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.

Coagulopathy

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 DRUG INTERACTIONS].

Cardiotoxicity

The cardiotoxicity observed with XELODA includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy. These adverse reactions 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.

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 reactions. 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 2 [see DOSAGE AND ADMINISTRATION, Use in Specific Populations, and CLINICAL PHARMACOLOGY].

Pregnancy

XELODA may cause fetal harm when given to a pregnant woman. Capecitabine caused embryolethality and teratogenicity in mice and embryolethality in monkeys when administered during organogenesis. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving XELODA, the patient should be apprised of the potential hazard to the fetus [see Use In Specific Populations].

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].

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 x ULN) hyperbilirubinemia occurred in 15.2% (n=133) of patients and grade 4 ( > 3 x 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 Ám/L at baseline to 13 Ám/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 x ULN) hyperbilirubinemia occurred in 7% (n=17) and grade 4 ( > 3 x 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 DOSAGE AND ADMINISTRATION].

Hematologic

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 < 1.5 x 109/L and/or thrombocyte counts of < 100 x 109/L should not be treated with XELODA. If unscheduled laboratory assessments during a treatment cycle show grade 3 or 4 hematologic toxicity, treatment with XELODA should be interrupted.

Geriatric Patients

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 < 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.

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 Use In Specific Populations and CLINICAL PHARMACOLOGY].

Combination With Other Drugs

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

Patient Counseling Information

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]. 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.

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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, 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 female mice, oral capecitabine doses of 760 mg/kg/day (about 2300 mg/m /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.

Use In Specific Populations

Pregnancy: Category D

XELODA can cause fetal harm when administered 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 of XELODA in pregnant women. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving XELODA, the patient should be apprised of the potential hazard to the fetus. Women should be advised to avoid becoming pregnant while receiving treatment with XELODA [see WARNINGS AND PRECAUTIONS].

Nursing Mothers

Lactating mice given a single oral dose of capecitabine excreted significant amounts of capecitabine metabolites into the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from capecitabine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of XELODA in pediatric patients have not been established. No clinical benefit was demonstrated in two single arm trials in pediatric patients with newly diagnosed brainstem gliomas and high grade gliomas. In both trials, pediatric patients received an investigational pediatric formulation of capecitabine concomitantly with and following completion of radiation therapy (total dose of 5580 cGy in 180 cGy fractions). The relative bioavailability of the investigational formulation to XELODA was similar.

The first trial was conducted in 22 pediatric patients (median age 8 years, range 5-17 years) with newly diagnosed non-disseminated intrinsic diffuse brainstem gliomas and high grade gliomas. In the dose-finding portion of the trial, patients received capecitabine with concomitant radiation therapy at doses ranging from 500 mg/m² to 850 mg/m² every 12 hours for up to 9 weeks. After a 2 week break, patients received 1250 mg/m capecitabine every 12 hours on Days 1-14 of a 21-day cycle for up to 3 cycles. The maximum tolerated dose (MTD) of capecitabine administered concomitantly with radiation therapy was 650 mg/m² every 12 hours. The major dose limiting toxicities were palmar-plantar erythrodysesthesia and alanine aminotransferase (ALT) elevation.

The second trial was conducted in 34 additional pediatric patients with newly diagnosed nondisseminated intrinsic diffuse brainstem gliomas (median age 7 years, range 3-16 years) and 10 pediatric patients who received the MTD of capecitabine in the dose-finding trial and met the eligibility criteria for this trial. All patients received 650 mg/m capecitabine every 12 hours with concomitant radiation therapy for up to 9 weeks. After a 2 week break, patients received 1250 mg/m² capecitabine every 12 hours on Days 1-14 of a 21-day cycle for up to 3 cycles.

There was no improvement in one-year progression-free survival rate and one-year overall survival rate in pediatric patients with newly diagnosed intrinsic brainstem gliomas who received capecitabine relative to a similar population of pediatric patients who participated in other clinical trials.

The adverse reaction profile of capecitabine was consistent with the known adverse reaction profile in adults, with the exception of laboratory abnormalities which occurred more commonly in pediatric patients. The most frequently reported laboratory abnormalities (per-patient incidence > 40%) were increased ALT (75%), lymphocytopenia (73%), leukopenia (73%), hypokalemia (68%), thrombocytopenia (57%), hypoalbuminemia (55%), neutropenia (50%), low hematocrit (50%), hypocalcemia (48%), hypophosphatemia (45%) and hyponatremia (45%).

Geriatric Use

Physicians should pay particular attention to monitoring the adverse effects of XELODA in the elderly [see WARNINGS AND PRECAUTIONS].

Hepatic Insufficiency

Exercise caution when patients with mild to moderate hepatic dysfunction due to liver metastases are treated with XELODA. The effect of severe hepatic dysfunction on XELODA is not known [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Renal Insufficiency

Patients with moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine clearance 30 mL/min) renal impairment showed higher exposure for capecitabine, 5-FDUR, and FBAL than in those with normal renal function [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION, and CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 12/23/2013
This monograph has been modified to include the generic and brand name in many instances.

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