Adjuvant Treatment of Early Breast Cancer
AROMASIN tolerability in postmenopausal women with early breast cancer was evaluated
in two well-controlled trials: the IES study (see CLINICAL STUDIES) and the 027
study (a randomized, placebo-controlled, double-blind, parallel group study specifically
designed to assess the effects of exemestane on bone metabolism, hormones, lipids
and coagulation factors over 2 years of treatment).
Certain adverse events, expected based on the known pharmacological properties and
side effect profiles of test drugs, were actively sought through a positive checklist.
Signs and symptoms were graded for severity using CTC in both studies. Within the
IES study, the presence of some illnesses/conditions was monitored through a positive
checklist without assessment of severity. These included myocardial infarction,
other cardiovascular disorders, gynecological disorders, osteoporosis, osteoporotic
fractures, other primary cancer, and hospitalizations.
The median duration of adjuvant treatment was 27.4 months and 27.3 months for patients
receiving AROMASIN or tamoxifen, respectively, within the IES study and 23.9 months
for patients receiving AROMASIN or placebo within the 027 study. Median duration
of observation after randomization for AROMASIN was 34.5 months and for tamoxifen
was 34.6 months. Median duration of observation was 30 months for both groups in
the 027 study.
AROMASIN was generally well tolerated and adverse events were usually mild to moderate.
Within the IES study discontinuations due to adverse events occurred in 6.3% and
5.1% of patients receiving AROMASIN and tamoxifen, respectively, and in 12.3% and
4.1% of patients receiving exemestane or placebo within study 027. Deaths due to
any cause were reported for 1.3% of the exemestane-treated patients and 1.4% of
the tamoxifen-treated patients within the IES study. There were 6 deaths due to
stroke on the exemestane arm compared to 2 on tamoxifen. There were 5 deaths due
to cardiac failure on the exemestane arm compared to 2 on tamoxifen.
The incidence of cardiac ischemic events (myocardial infarction, angina and myocardial
ischemia) was 1.6% in exemestane treated patients and 0.6% in tamoxifen treated
patients in the IES study. Cardiac failure was observed in 0.4% of exemestane treated
patients and 0.3% of tamoxifen treated patients.
Treatment-emergent adverse events and illnesses including all causalities and occurring
with an incidence of ≥5% in either treatment group of the IES study during or within
one month of the end of treatment are shown in Table 8.
Table 8. Incidence (%) of Adverse Events of all Grades1
and Illnesses Occurring in ( ≥5%) of Patients in Any Treatment Group in Study
IES in Postmenopausal Women with Early Breast Cancer
In the IES study, as compared to tamoxifen, AROMASIN was associated with a higher
incidence of events in the musculoskeletal disorders and in the nervous system disorders,
including the following events occurring with frequency lower than 5% (osteoporosis
[4.6% vs. 2.8%], osteochondrosis and trigger finger [0.3% vs 0 for both events],
paresthesia [2.6% vs. 0.9%], carpal tunnel syndrome [2.4% vs. 0.2%], and neuropathy
[0.6% vs. 0.1%]. Diarrhea was also more frequent in the exemestane group (4.2% vs.
2.2%). Clinical fractures were reported in 94 patients receiving exemestane (4.2%)
and 71 patients receiving tamoxifen (3.1%). After a median duration of therapy of
about 30 months and a median follow-up of about 52 months, gastric ulcer was observed
at a slightly higher frequency in the AROMASIN group compared to tamoxifen (0.7%
versus <0.1%). The majority of patients on AROMASIN with gastric ulcer received
concomitant treatment with non-steroidal anti-inflammatory agents and/or had a prior
history.
Tamoxifen was associated with a higher incidence of muscle cramps [3.1% vs. 1.5%],
thromboembolism [2.0% vs. 0.9%], endometrial hyperplasia [1.7% vs. 0.6%], and uterine
polyps [2.4% vs. 0.4%].
Common adverse events occurring on study 027 are described in Table 9.
Table 9: Incidence of Selected Treatment-Emergent Adverse Events of all CTC Grades*
Occurring in ≥ 5% of Patients in Either Arm on Study 027
Treatment of Advanced Breast Cancer
A total of 1058 patients were treated with exemestane 25 mg once daily in the clinical
trials program. Exemestane was generally well tolerated, and adverse events were
usually mild to moderate. Only one death was considered possibly related to treatment
with exemestane; an 80-year-old woman with known coronary artery disease had a myocardial
infarction with multiple organ failure after 9 weeks on study treatment. In the
clinical trials program, only 3% of the patients discontinued treatment with exemestane
because of adverse events, mainly within the first 10 weeks of treatment; late discontinuations
because of adverse events were uncommon (0.3%).
In the comparative study, adverse reactions were assessed for 358 patients treated
with AROMASIN and 400 patients treated with megestrol acetate. Fewer patients receiving
AROMASIN discontinued treatment because of adverse events than those treated with
megestrol acetate (2% vs. 5%). Adverse events that were considered drug related
or of indeterminate cause included hot flashes (13% vs. 5%), nausea (9% vs. 5%),
fatigue (8% vs. 10%), increased sweating (4% vs. 8%), and increased appetite (3%
vs. 6%). The proportion of patients experiencing an excessive weight gain (>10%
of their baseline weight) was significantly higher with megestrol acetate than with
AROMASIN (17% vs. 8%). Table 10 shows the adverse events of all CTC grades, regardless
of causality, reported in 5% or greater of patients in the study treated either
with AROMASIN or megestrol acetate.
Table 10. Incidence (%) of Adverse Events of all Grades*
and Causes
Occurring in ≥5% of Advanced Breast Cancer Patients
In Each Treatment Arm in the Comparative Study
Less frequent adverse events of any cause (from 2% to 5%) reported in the comparative
study for patients receiving AROMASIN 25 mg once daily were fever, generalized weakness,
paresthesia, pathological fracture, bronchitis, sinusitis, rash, itching, urinary
tract infection, and lymphedema.
Additional adverse events of any cause observed in the overall clinical trials program
(N =1058) in 5% or greater of patients treated with exemestane 25 mg once daily
but not in the comparative study included pain at tumor sites (8%), asthenia (6%)
and fever (5%). Adverse events of any cause reported in 2% to 5% of all patients
treated with exemestane 25 mg in the overall clinical trials program but not in
the comparative study included chest pain, hypoesthesia, confusion, dyspepsia, arthralgia,
back pain, skeletal pain, infection, upper respiratory tract infection, pharyngitis,
rhinitis, and alopecia.
Post-marketing Experience
The following adverse reactions have been identified during post approval use of Aromasin. Because reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Cases of hepatitis including cholestatic hepatitis have been observed in clinical trials and reported through post-marketing surveillance.