General. 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.
Hepatic Insufficiency. 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.
Renal Insufficiency. 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 <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.
Laboratory Tests. In patients with early breast cancer the incidence of hematological
abnormalities of Common Toxicity Criteria (CTC) grade ≥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 > 5 times the
upper value of the normal range (i.e., ≥ 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
acetate.
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 027.
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. Control1
Drug Interactions. 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 CLINICAL PHARMACOLOGY).
Drug/Laboratory Tests Interactions. No clinically relevant changes in the
results of clinical laboratory tests have been observed.
Carcinogenesis, Mutagenesis, Impairment of Fertility. 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
≥500 mg/kg/day exemestane (≥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 ≥4 mg/kg/day (≥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 ≥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. Pregnancy Category D. See WARNINGS.
Nursing Mothers. 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).
Pediatric Use. The safety and effectiveness of AROMASIN in pediatric patients
have not been evaluated.
Geriatric Use. The use of AROMASIN in geriatric patients does not require
special precautions.