A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Xeloda Warnings, Precautions, Pregnancy, Nursing, Abuse - Capecitabine
Xeloda Warnings, Precautions, Pregnancy, Nursing, Abuse - Capecitabine
WARNINGS
Coagulopathy
Altered coagulation parameters and/or bleeding have been reported in
patients taking XELODA concomitantly with coumarin-derivative anticoagulants
such as warfarin and phenprocoumon. These events occurred within several
days and up to several months after initiating XELODA therapy and, in
a few cases, within one month after stopping XELODA. These events occurred
in patients with and without liver metastases. Patients taking coumarin-derivative
anticoagulants concomitantly with XELODA should be monitored regularly
for alterations in their coagulation parameters (PT or INR) (see DRUG
INTERACTIONS section).
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. The median time to first occurrence of grade
2-4 diarrhea was 31 days (range from 1 to 322 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 ³10 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
grade 3 or 4 diarrhea, subsequent doses of XELODA should be decreased
(see DOSAGE AND ADMINISTRATION).
Standard antidiarrheal treatments (e.g., loperamide) are recommended.
Necrotizing enterocolitis (typhlitis) has been reported.
Geriatric Patients (gastrointestinal toxicity)
Patients ³80 years old may experience
a greater incidence of gastrointestinal grade 3 or 4 adverse events (see
PRECAUTIONS
: Geriatric Use). Among the 14 patients
80 years of age and greater treated with capecitabine, three (21.4%),
three (21.4%) and one (7.1%) patients experienced reversible grade 3 or
4 diarrhea, nausea and vomiting, respectively.
Among the 313 patients age 60 to 79 years old, the incidence of gastrointestinal
toxicity was similar to that in the overall population.
Pregnancy
XELODA may cause fetal harm when given to a pregnant woman. Capecitabine
at doses of 198 mg/kg/day during organogenesis caused teratogenic 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. Teratogenic
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 in pregnant women using XELODA. If the drug is used during pregnancy,
or if the patient becomes pregnant while receiving this drug, the patient
should be apprised of the potential hazard to the fetus. Women of childbearing
potential should be advised to avoid becoming pregnant while receiving
treatment with XELODA.
PRECAUTIONS
General
Patients receiving therapy with XELODA should be monitored by a physician
experienced in the use of cancer chemotherapeutic agents. Most adverse
events are reversible and do not need to result in discontinuation although
doses may need to be withheld or reduced (see DOSAGE
AND ADMINISTRATION).
Hand-and-Foot Syndrome: Hand-and-foot syndrome (palmarplantar
erythrodysesthesia or chemotherapy induced acral erythema) is characterized
by the following: numbness, dysesthesia/paresthesia, tingling, painless
or painful swelling, erythema, desquamation, blistering, and severe pain.
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 and 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).
Cardiac: There has been cardiotoxicity associated with
fluorinated pyrimidine therapy, including myocardial infarction, angina,
dysrhythmias, cardiogenic shock, sudden death and electrocardiograph changes.
These adverse events may be more common in patients with a prior history
of coronary artery disease.
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 CLINICAL
PHARMACOLOGY and DOSAGE AND
ADMINISTRATION).
Hyperbilirubinemia: Grade 3 or 4 hyperbilirubinemia occurred
in 17% (n=97) of 570 patients with either metastatic breast or colorectal
cancer who received a dose of 2510 mg/m2 daily for 2 weeks
followed by a 1-week rest period. Of 339 patients who had hepatic metastases
at baseline and 231 patients without hepatic metastases at baseline, grade
3 or 4 hyperbilirubinemia occurred in 21.2% and 10.4%, respectively. Seventy-four
(76%) of the 97 patients with grade 3 or 4 hyperbilirubinemia also had
concurrent elevations in alkaline phosphatase and/or hepatic transaminases;
6% of these were grade 3 or 4. Only 4 patients (4%) had elevated hepatic
transaminases without a concurrent elevation in alkaline phosphatase.
If drug related grade 2-4 elevations in bilirubin occur, administration
of XELODA should be immediately interrupted until the hyperbilirubinemia
resolves or decreases in intensity to grade 1. NCIC grade 2 hyperbilirubinemia
is defined as 1.5 x normal, grade 3 hyperbilirubinemia as 1.5-3 x normal
and grade 4 hyperbilirubinemia as >3 x normal. (See recommended dose modifications
under DOSAGE AND ADMINISTRATION.)
Renal Insufficiency: There is little experience in patients
with renal impairment. Physicians should exercise caution when XELODA
is administered (see DOSAGE AND ADMINISTRATION).
Hematologic: In 570 patients with either metastatic breast
or colorectal cancer who received a dose of 2510 mg/m2 administered
daily for 2 weeks followed by a 1-week rest period, 4%, 2%, and 3% of
patients had grade 3 or 4 neutropenia, thrombocytopenia and decreases
in hemoglobin, respectively.
Carcinogenesis, Mutagenesis and Impairment of Fertility
Long-term studies in animals to evaluate the carcinogenic potential of
capecitabine 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 mice, oral capecitabine doses of 760 mg/kg/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.
Information for Patients
See PATIENT INFORMATION section.
Drug-Food Interaction
In all clinical trials, patients were instructed to administer XELODA
within 30 minutes after a meal. Since current safety and efficacy data
are based upon administration with food, it is recommended that XELODA
be administered with food (see DOSAGE
AND ADMINISTRATION).
Drug-Drug Interactions
See DRUG INTERACTIONS section.
Pregnancy
Teratogenic Effects
Category D (see WARNINGS
). Women
of childbearing potential should be advised to avoid becoming pregnant
while receiving treatment with XELODA.
Nursing Women
It is not known whether the 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, it is recommended that nursing be
discontinued when receiving XELODA therapy.
Pediatric Use
The safety and effectiveness of XELODA in persons <18 years of age have
not been established.
Geriatric Use
No separate studies have been conducted to examine the effect of age
on the pharmacokinetics of capecitabine and its metabolites. Patients
³80 years old may experience a greater
incidence of gastrointestinal grade 3 or 4 adverse events (see WARNINGS
).
Among the 14 patients 80 years of age and greater treated with capecitabine,
21.4%, 21.4% and 71 % experienced grade 3 or 4 diarrhea, nausea and vomiting,
respectively. Among the 313 patients 60 to 79 years old, the incidence
was similar to the overall population.
The elderly may be pharmacodynamically more sensitive to the toxic effects
of 5-FU. Physicians should pay particular attention to monitoring the
adverse effects of XELODA in the elderly.
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