Faslodex is metabolized by CYP 3A4 in vitro. Clinical studies of the effect of strong CYP 3A4
inhibitors on the pharmacokinetics of fulvestrant have not been performed.
Carcinogenesis, Mutagenesis and Impairment of Fertility
A two-year carcinogenesis study was conducted in female and male rats, at intramuscular doses of 15
mg/kg/30 days, 10 mg/rat/30 days and 10 mg/rat/15 days. These doses correspond to approximately 1-, 3-, and 5-fold
(in females) and 1.3-, 1.3-, and 1.6-fold (in males) the systemic exposure [AUC0-30 days]] achieved in
women receiving the recommended dose of 250 mg/month. An increased incidence of benign ovarian granulosa cell tumors
and testicular Leydig cell tumors was evident, in females dosed at 10 mg/rat/15 days and males dosed at 15 mg/rat/30
days, respectively. Induction of such tumors is consistent with the pharmacology-related endocrine feedback
alterations in gonadotropin levels caused by an antiestrogen.
Faslodex was not mutagenic or clastogenic in multiple in vitro tests with and without the addition
of a mammalian liver metabolic activation factor (bacterial mutation assay in strains of Salmonella typhimurium and
Escherichia coli, in vitro cytogenetics study in human lymphocytes, mammalian cell mutation assay in mouse lymphoma
cells and in vivo micronucleus test in rat.
In female rats, fulvestrant administered at doses > 0.01 mg/kg/day (approximately one-hundredth of
the human recommended dose based on body surface area [BSA], for 2 weeks prior to and for 1 week following mating,
caused a reduction in fertility and embryonic survival. No adverse effects on female fertility and embryonic survival
were evident in female animals dosed at 0.001 mg/kg/day (approximately one-thousandth of the human dose based on
BSA). Restoration of female fertility to values similar to controls was evident following a 29-day withdrawal period
after dosing at 2 mg/kg/day (twice the human dose based on BSA). The effects of fulvestrant on the fertility of
female rats appear to be consistent with its anti-estrogenic activity. The potential effects of fulvestrant on the
fertility of male animals were not studied but in a 6-month toxicology study, male rats treated with intramuscular
doses of 15 mg/kg/30 days, 10 mg/rat/30 days, or 10 mg/rat/15 days fulvestrant showed a loss of spermatozoa from the
seminiferous tubules, seminiferous tubular atrophy, and degenerative changes in the epididymides. Changes in the
testes and epididymides had not recovered 20 weeks after cessation of dosing. These fulvestrant doses correspond to
approximately 2-, 3-, and 3-fold the systemic exposure [AUC0-30 days] achieved in women.
Pregnancy Category D: .
In studies in female rats at doses > 0.01 mg/kg/day (IM; approximately one-hundredth of the human
recommended dose based on body surface area [BSA]), fulvestrant caused a reversible reduction in female fertility, as
well as effects on embryo/fetal development consistent with its anti-estrogenic activity. Faslodex caused an
increased incidence of fetal abnormalities in rats (tarsal flexure of the hind paw at 2 mg/kg/day IM; twice the human
dose on BSA) and non-ossification of the odontoid and ventral tubercle of the first cervical vertebra at doses >
0.1 mg/kg/day IM (approximately one-tenth of the human dose on BSA) when administered during the period of
organogenesis. Rabbits failed to maintain pregnancy when dosed with 1 mg/kg/day fulvestrant IM (twice the human dose
on BSA) during the period of organogenesis. Further, in rabbits dosed at 0.25 mg/kg/day (about one-half the human
dose on BSA), increases in placental weight and post-implantation loss were observed but, there were no observed
effects on fetal development. Faslodex was associated with an increased incidence of fetal variations in rabbits
(backwards displacement of the pelvic girdle, and 27 pre-sacral vertebrae at 0.25 mg/kg/day IM; one-half the human
dose on BSA) when administered during the period of organogenesis. Because pregnancy could not be maintained in the
rabbit following doses of fulvestrant of 1 mg/kg/day and above, this study was inadequate to fully define the
possible adverse effects on fetal development at clinically relevant exposures.
Faslodex is found in rat milk at levels significantly higher (approximately 12-fold) than plasma
after administration of 2 mg/kg. Drug exposure in rodent pups from fulvestrant-treated lactating dams was estimated
as 10% of the administered dose. It is not known if fulvestrant is excreted in human milk. Because many drugs are
excreted in human milk, and because of the potential for serious adverse reactions from FASLODEX in nursing infants,
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 efficacy of FASLODEX in pediatric patients have not been established.
When tumor response was considered by age, objective responses were seen in 24% and 22% of patients
under 65 years of age and in 16% and 11% of patients 65 years of age and older, who were treated with FASLODEX in the
European and North American trials, respectively.