WARNINGS
ARIMIDEX can cause fetal harm when administered
to a pregnant woman. Anastrozole has been found to cross
the placenta following oral administration of 0.1 mg/kg
in rats and rabbits (about 3/4 and 1.5 times the recommended
human dose, respectively, on a mg/m2 basis). Studies in
both rats and rabbits at doses equal to or greater than
0.1 and 0.02 mg/kg/day, respectively (about 3/4 and 1/3,
respectively, the recommended human dose on a mg/m2 basis),
administered during the period of organogenesis showed
that anastrozole increased pregnancy loss (increased pre-
and/or post-implantation loss, increased resorption, and
decreased numbers of live fetuses); effects were dose-related
in rats. Placental weights were significantly increased
in rats at doses of 0.1 mg/kg/day or more.
Evidence of fetotoxicity, including delayed fetal development
(i.e., incomplete ossification and depressed fetal body
weights), was observed in rats administered doses of 1
mg/kg/day (which produced plasma anastrozole Cssmax and
AUC0-24 hr that were 19 times and 9 times higher than
the respective values found in healthy post-menopausal
humans at the recommended dose). There was no evidence
of teratogenicity in rats administered doses up to 1.0
mg/kg/day. In rabbits, anastrozole caused pregnancy failure
at doses equal to or greater than 1.0 mg/kg/day (about
16 times the recommended human dose on a mg/m2 basis);
there was no evidence of teratogenicity in rabbits administered
0.2 mg/kg/day (about 3 times the recommended human dose
on a mg/m2 basis).
There are no adequate and well-controlled studies in pregnant
women using ARIMIDEX. If ARIMIDEX 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 or potential risk for loss of the
pregnancy.
PRECAUTIONS
General
Before starting treatment with ARIMIDEX, pregnancy
must be excluded (see
WARNINGS
).
ARIMIDEX should be administered under the supervision
of a qualified physician experienced in the use of anticancer
agents.
Laboratory Tests
Three-fold elevations of mean serum gamma glutamyl
transferase (GT) levels have been observed among patients
with liver metastases receiving ARIMIDEX or megestrol
acetate. These changes were likely related to the progression
of liver metastases in these patients, although other
contributing factors could not be ruled out.
Drug Interactions
(See CLINICAL PHARMACOLOGY) Anastrozole inhibited
in vitro metabolic reactions catalyzed by cytochromes
P450 1A2, 2C8/9, and 3A4 but only at relatively high concentrations.
Anastrozole did not inhibit P450 2A6 or the polymorphic
P450 2D6 in human liver microsomes. Anastrozole did not
alter the pharmacokinetics of antipyrine. Although there
have been no formal interaction studies other than with
antipyrine, based on these in vivo and in vitro studies,
it is unlikely that co-administration of a 1-mg dose of
ARIMIDEX with other drugs will result in clinically significant
drug inhibition of cytochrome P450-mediated metabolism
of the other drugs.
Drug/Laboratory Test Interactions
No clinically significant changes in the results
of clinical laboratory tests have been observed.
Carcinogenesis, Mutagenesis, and Impairment of
Fertility
Carcinogenesis: No long-term animal studies have
been conducted to assess the carcinogenic potential of
ARIMIDEX.
Mutagenesis: ARIMIDEX has not been shown
to be mutagenic in in vitro tests (Ames and E. coli bacterial
tests, CHO-K1 gene mutation assay) or clastogenic either
in vitro (chromosome aberrations in human lymphocytes)
or in vivo (micronucleus test in rats).
Impairment of Fertility: Studies to
investigate the effect of ARIMIDEX on fertility have not
been conducted; however, chronic studies indicated hypertrophy
of the ovaries and the presence of follicular cysts in
rats administered doses equal to or greater than 1 mg/kg/day
(which produced plasma anastrozole Cssmax and AUC0-24
hr that were 19 times and 9 times higher than the respective
values found in healthy post-menopausal humans at the
recommended dose). In addition, hyperplastic uteri were
observed in chronic studies of female dogs administered
doses equal to or greater than 1 mg/kg/day (which produced
plasma anastrozole Cssmax and AUC0-24 hr that were 22
times and 16 times higher than the respective values found
in post-menopausal humans at the recommended dose). It
is not known whether these effects on the reproductive
organs of animals are associated with impaired fertility
in humans.
Pregnancy
Pregnancy Category D: (See
WARNINGS
).
Nursing Mothers
It is not known if anastrozole is excreted in
human milk. Because many drugs are excreted in human milk,
caution should be exercised when ARIMIDEX is administered
to a nursing woman (see
WARNINGS
).
Pediatric Use
The safety and efficacy of ARIMIDEX in pediatric
patients have not been established.
Geriatric Use
Fifty percent of patients in studies 0004 and 0005 were
65 or older. Response rates and time to progression were
similar for the over 65 and younger patients.
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