AROMASIN Tablets may cause fetal harm when administered to a
pregnant woman. Radioactivity related to 14C-exemestane
crossed the placenta of rats following oral administration of 1 mg/kg
exemestane. The concentration of exemestane and its metabolites was
approximately equivalent in maternal and fetal blood. When rats were
administered exemestane from 14 days prior to mating until either days 15 or 20
of gestation, and resuming for the 21 days of lactation, an increase in
placental weight was seen at 4 mg/kg/day (approximately 1.5 times the
recommended human daily dose on a mg/m2 basis). Prolonged
gestation and abnormal or difficult labor was observed at doses equal to or
greater than 20 mg/kg/day. Increased resorption, reduced number of live fetuses,
decreased fetal weight, and retarded ossification were also observed at these
doses. No malformations were noted when exemestane was administered to pregnant
rats during the organogenesis period at doses up to 810 mg/kg/day (approximately
320 times the recommended human dose on a mg/m2 basis).
Daily doses of exemestane, given to rabbits during organogenesis caused a
decrease in placental weight at 90 mg/kg/day (approximately 70 times the
recommended human daily dose on a mg/m2 basis).
Abortions, an increase in resorptions, and a reduction in fetal body weight were
seen at 270 mg/kg/day. There was no increase in the incidence of malformations
in rabbits at doses up to 270 mg/kg/day (approximately 210 times the recommended
human dose on a mg/m2 basis).
There are no studies in pregnant women using AROMASIN. AROMASIN is indicated
for postmenopausal women. If there is exposure to AROMASIN during pregnancy, the
patient should be apprised of the potential hazard to the fetus and potential
risk for loss of the pregnancy.
AROMASIN Tablets should not be administered to premenopausal
women. AROMASIN should not be coadministered with estrogen-containing agents as
these could interfere with its pharmacologic action.
The pharmacokinetics of exemestane have been investigated in
subjects with moderate or severe hepatic insufficiency (Childs-Pugh B or C).
Following a single 25-mg oral dose, the AUC of exemestane was approximately 3
times higher than that observed in healthy volunteers. The safety of chronic
dosing in patients with moderate or severe hepatic impairment has not been
studied. Based on experience with exemestane at repeated doses up to 200 mg
daily that demonstrated a moderate increase in non-life threatening adverse
events, dosage adjustment does not appear to be necessary.
The AUC of exemestane after a single 25-mg dose was approximately
3 times higher in subjects with moderate or severe renal insufficiency
(creatinine clearance less than 35 mL/min/1.73 m2) compared
with the AUC in healthy volunteers. The safety of chronic dosing in patients
with moderate or severe renal impairment has not been studied. Based on
experience with exemestane at repeated doses up to 200 mg daily that
demonstrated a moderate increase in non-life threatening adverse events, dosage
adjustment does not appear to be necessary.
In patients with early breast cancer the incidence of
hematological abnormalities of Common Toxicity Criteria (CTC) grade greater than or equal to 1 was lower
in the exemestane treatment group, compared with tamoxifen. Incidence of CTC
grade 3 or 4 abnormalities was low (approximately 0.1%) in both treatment
groups. Approximately 20% of patients receiving exemestane in clinical studies
in advanced breast cancer, experienced CTC grade 3 or 4 lymphocytopenia. Of
these patients, 89% had a pre-existing lower grade lymphopenia. Forty percent of
patients either recovered or improved to a lesser severity while on treatment.
Patients did not have a significant increase in viral infections, and no
opportunistic infections were observed. Elevations of serum levels of AST, ALT,
alkaline phosphatase and gamma glutamyl transferase less than greater than 5 times the upper value
of the normal range (i.e., greater than or equal to CTC grade 3) have been rarely reported in patients
treated for advanced breast cancer but appear mostly attributable to the
underlying presence of liver and/or bone metastases. In the comparative study in
advanced breast cancer patients, CTC grade 3 or 4 elevation of gamma glutamyl
transferase without documented evidence of liver metastasis was reported in 2.7%
of patients treated with AROMASIN and in 1.8% of patients treated with megestrol
In patients with early breast cancer, elevations in bilirubin, alkaline
phosphatase, and creatinine were more common in those receiving exemestane than
either tamoxifen or placebo. Treatment emergent bilirubin elevations (any CTC
grade) occurred in 5.3% of exemestane patients and 0.8% of tamoxifen patients on
the IES, and in 6.9% of exemestane treated patients vs. 0% of placebo treated
patients on the 027 study. CTC grade 3–4 increases in bilirubin occurred in 0.9%
of exemestane treated patients compared to 0.1% of tamoxifen treated patients.
Alkaline phosphatase elevations of any CTC grade occurred in 15.0% of exemestane
treated patients on the IES compared to 2.6% of tamoxifen treated patients, and
in 13.7% of exemestane treated patients compared to 6.9% of placebo treated
patients on study 027. Creatinine elevations occurred in 5.8% of exemestane
treated patients and 4.3% of tamoxifen treated patients on the IES and in 5.5%
of exemestane treated patients and 0% of placebo treated patients on study
Reductions in bone mineral density (BMD) over time are seen with exemestane
use. Table 7 describes changes in BMD from baseline to 24 months in patients
receiving exemestane compared to patients receiving tamoxifen (IES) or placebo
(027). Concomitant use of bisphosphonates, Vitamin D supplementation and Calcium
was not allowed.
Table 7: Percent Change in BMD from Baseline to 24 months, Exemestane vs. Control*
* For patients who had 24-month data.
|Lumbar spine (%)
|Femoral neck (%)
Exemestane is extensively metabolized by CYP 3A4, but
coadministration of ketoconazole, a potent inhibitor of CYP 3A4, has no
significant effect on exemestane pharmacokinetics. Significant pharmacokinetic
interactions mediated by inhibition of CYP isoenzymes therefore appear unlikely.
Co-medications that induce CYP 3A4 (e.g., rifampicin, phenytoin, carbamazepine,
phenobarbital, or St. John's wort) may significantly decrease exposure to
exemestane. Dose modification is recommended for patients who are also receiving
a potent CYP 3A4 inducer (see DOSAGE AND ADMINISTRATION and
Drug/Laboratory Tests Interactions
No clinically relevant changes in the results of clinical
laboratory tests have been observed.
Carcinogenesis, Mutagenesis, Impairment of
A 2-year carcinogenicity study in mice at doses of 50, 150 and
450 mg/kg/day exemestane (gavage), resulted in an increased incidence of
hepatocellular adenomas and/or carcinomas in both genders at the high dose
level. Plasma AUCs(0–24hr) at the high dose were 2575 ±
386 and 5667 ± 1833 ng.hr/mL in males and females (approx. 34 and 75 fold the
AUC in postmenopausal patients at the recommended clinical dose). An increased
incidence of renal tubular adenomas was observed in male mice at the high dose
of 450 mg/kg/day. Since the doses tested in mice did not achieve an MTD,
neoplastic findings in organs other than liver and kidneys remain unknown.
A separate carcinogenicity study was conducted in rats at the doses of 30,
100 and 315 mg/kg/day exemestane (gavage) for 92 weeks in males and 2 years in
females. No evidence of carcinogenic activity up to the highest dose tested of
315 mg/kg/day was observed in females. The male rat study was inconclusive since
it was terminated prematurely at Week 92. At the highest dose, plasma AUC(0–24hr) levels in male (1418 ± 287 ng.hr/mL) and female (2318
± 1067 ng.hr/mL) rats were 19 and 31 fold higher than those measured in
postmenopausal cancer patients, receiving the recommended clinical dose.
Exemestane was not mutagenic in vitro in bacteria (Ames test) or mammalian
cells (V79 Chinese hamster lung cells). Exemestane was clastogenic in human
lymphocytes in vitro without metabolic activation but was not clastogenic in
vivo (micronucleus assay in mouse bone marrow). Exemestane did not increase
unscheduled DNA synthesis in rat hepatocytes when tested in vitro.
In a pilot reproductive study in rats, male rats were treated with doses of
125–1000 mg/kg/day exemestane, beginning 63 days prior to and during
cohabitation. Untreated female rats showed reduced fertility when mated to males
treated with greater than or equal to 500 mg/kg/day exemestane (greater than or equal to 200 times the recommended human dose on
a mg/m2 basis). In a separate study, exemestane was given
to female rats at 4–100 mg/kg/day beginning 14 days prior to mating and through
day 15 or 20 of gestation. Exemestane increased the placental weights at greater than or equal to 4
mg/kg/day greater than or equal to 1.5 times the human dose on a mg/m2 basis).
Exemestane showed no effects on ovarian function, mating behavior, and
conception rate in rats given doses up to 20 mg/kg/day (approximately 8 times
the recommended human dose on a mg/m2 basis), however,
decreases in mean litter size and fetal body weight, along with delayed
ossification were evidenced at greater than or equal to 20 mg/kg/day. In general toxicology studies,
changes in the ovary, including hyperplasia, an increase in the incidence of
ovarian cysts and a decrease in corpora lutea were observed with variable
frequency in mice, rats and dogs at doses that ranged from 3–20 times the human
dose on a mg/m2 basis.
Pregnancy Category D
AROMASIN is only indicated in postmenopausal women. However,
radioactivity related to exemestane appeared in rat milk within 15 minutes of
oral administration of radiolabeled exemestane. Concentrations of exemestane and
its metabolites were approximately equivalent in the milk and plasma of rats for
24 hours after a single oral dose of 1 mg/kg 14C-exemestane. It is not known whether exemestane is excreted
in human milk. Because many drugs are excreted in human milk, caution should be
exercised if a nursing woman is inadvertently exposed to AROMASIN (see WARNINGS).
The safety and effectiveness of AROMASIN in pediatric patients
have not been evaluated.
The use of AROMASIN in geriatric patients does not require