Included as part of the "PRECAUTIONS" Section
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].
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
BOX WARNING and DRUG INTERACTIONS].
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 [see DOSAGE AND ADMINISTRATION]. Standard antidiarrheal treatments (eg,
loperamide) are recommended.
Necrotizing enterocolitis (typhlitis) has been reported.
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
Based on postmarketing reports, patients with certain homozygous or certain compound heterozygous
mutations in the DPD gene that result in complete or near complete absence of DPD activity are at
increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions
caused by XELODA (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial
DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions caused
Withhold or permanently discontinue XELODA based on clinical assessment of the onset, duration and
severity of the observed toxicities in patients with evidence of acute early-onset or unusually severe
toxicity, which may indicate near complete or total absence of DPD activity. No XELODA dose has
been proven safe for patients with complete absence of DPD activity. There is insufficient data to
recommend a specific dose in patients with partial DPD activity as measured by any specific test.
Dehydration And Renal Failure
Dehydration has been observed and may cause acute renal failure which can be fatal. Patients with preexisting
compromised renal function or who are receiving concomitant XELODA with known
nephrotoxic agents are at higher risk. Patients with anorexia, asthenia, nausea, vomiting or diarrhea may
rapidly become dehydrated. Monitor patients when XELODA is administered to prevent and correct
dehydration at the onset. If grade 2 (or higher) dehydration occurs, XELODA treatment should be
immediately interrupted and the dehydration corrected. Treatment should not be restarted until the patient
is rehydrated and any precipitating causes have been corrected or controlled. Dose modifications
should be applied for the precipitating adverse event as necessary [see DOSAGE AND ADMINISTRATION].
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].
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].
Mucocutaneous And Dermatologic Toxicity
Severe mucocutaneous reactions, some with fatal outcome, such as Stevens-Johnson syndrome and
Toxic Epidermal Necrolysis (TEN) can occur in patients treated with XELODA [see ADVERSE REACTIONS]. XELODA should be permanently discontinued in patients who experience a severe
mucocutaneous reaction possibly attributable to XELODA treatment.
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].
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 Ã ULN) hyperbilirubinemia occurred in 15.2% (n=133) of patients and grade 4 (>3 Ã
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
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 Âµm/L at baseline to 13 Âµm/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 Ã ULN) hyperbilirubinemia occurred in 7% (n=17) and grade 4 (>3 Ã 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 Ã ULN [see Recommended Dose
Modifications under DOSAGE AND ADMINISTRATION].
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.
Patients with baseline neutrophil counts of <1.5 Ã 10 /L and/or thrombocyte counts of <100 Ã 10 /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.
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-andfoot
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
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.
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 FDA-approved Patient Labeling)
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 and to call their physician immediately if moderate or severe toxicity occurs. Patients
should be encouraged to recognize the common grade 2 toxicities associated with XELODA treatment
See FDA-approved patient labeling (Patient Information).
Dihydropyrimidine Dehydrogenase Deficiency
Patients should be advised to notify their healthcare provider if they have a known DPD deficiency.
Advise patients if they have complete or near complete absence of DPD activity they are at an increased
risk of acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by
XELODA (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity) [see WARNINGS AND PRECAUTIONS].
Patients experiencing grade 2 diarrhea (an increase of 4 to 6 stools/day or nocturnal stools) or greater
or experiencing severe bloody diarrhea with severe abdominal pain and fever should be instructed to
stop taking XELODA and to call their physician immediately. Standard antidiarrheal treatments (eg,
loperamide) are recommended.
Patients experiencing grade 2 or higher dehydration should be instructed to stop taking XELODA
immediately and the dehydration corrected. Treatment should not be restarted until the patient is
rehydrated and any precipitating causes have been corrected or controlled.
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
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.
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. Initiation of symptomatic treatment is recommended.
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 and to call their
physician. Initiation of symptomatic treatment is recommended.
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 immediately.
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/m2 /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
Use In Specific Populations
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].
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.
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 dosefinding
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/m2 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/m2 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%).
Physicians should pay particular attention to monitoring the adverse effects of XELODA in the elderly
[see WARNINGS AND PRECAUTIONS].
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].
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-DFUR, and FBAL than in those
with normal renal function [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION, and CLINICAL PHARMACOLOGY].