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Mechanism of action

Cell growth of breast cancer can
be estrogen dependent. Aromatase is the main enzyme that converts
androgens to estrogens in pre- and post-menopausal women. While the main
The source of estrogen (mainly estradiol) is the ovary in premenopausal women.
the main source of circulating estrogen in postmenopausal women comes from
conversion of adrenal and ovarian androgens (androstenedione and testosterone)
estrogens (estrone and estradiol) by the aromatase enzyme in peripheral tissues

The exemestane is irreversible,
Steroidal aromatase inactivator, structurally related to natural substrate
androstenedione. It acts as a false substrate for the aromatase enzyme, and is
treated to an intermediate that irreversibly binds to the active site of the
enzyme, causing its inactivation, an effect also called "suicide inhibition".
Exemestane significantly reduces estrogen levels in the blood
postmenopausal, but has no detectable effect on the adrenal biosynthesis of
corticosteroids or aldosterone. Exemestane has no effect on other enzymes
involved in the steroidogenic pathway up to a concentration of at least 600-fold
higher than that inhibiting the aromatase enzyme.


Effect on estrogen

Several doses of exemestane
0.5 to 600 mg / day were administered to postmenopausal women with
advanced breast cancer. Plasma estrogens (estradiol, estrone and estrone)
sulfate) were observed from a daily dose of 5 mg of
exemestane, with a maximal suppression of at least 85% to 95% achieved at a
25 mg dose. Exemestane 25 mg a day reduced the aromatization of the whole body
measured by radiolabeled androstenedione injection) to 98% in postmenopausal women
women with breast cancer. After a single dose of 25 mg exemestane, the maximum
the suppression of circulating estrogens occurred 2 to 3 days after the administration and
persisted for 4 to 5 days.

Effect on corticosteroids

In trials involving several doses up to 200 mg per day,
the selectivity of exemestane was evaluated by examining its effect on adrenal steroids.
Exemestane has no negative effect on the secretion of cortisol or aldosterone at the beginning or end of treatment.
response to ACTH regardless of the dose. Thus, no glucocorticoid or mineralocorticoid
replacement therapy is necessary with treatment with exemestane.

Other effects on the endocrine system

Exemestane does not bind significantly to steroids
receptors, with the exception of a slight affinity for the androgen receptor (0.28%
compared to dihydrotestosterone). The binding affinity of its
17dihydrometabolite for the androgen receptor, however, is 100 times that of
the parent compound. Daily doses of exemestane up to 25 mg had no significant effect.
effect on circulating levels of androstenedione, dehydroepiandrosterone
sodium sulphate or 17-hydroxyprogesterone and have been associated with slight decreases in
Circulating levels of testosterone. Increased testosterone and
Androstenedione levels were observed at daily doses of 200 mg or more. A
dose-related decrease in sex hormone binding globulin (SHBG) was
observed with daily doses of exemestane of 2.5 mg or more. Light, not dependent
increased serum levels of luteinizing hormone (LH) and follicle stimulating hormone
(FSH) were observed even at low doses as a result of feedback
at the level of the pituitary gland. Exemestane 25 mg daily had no significant effect on
thyroid function (free triiodothyronine (FT3), free thyroxine (FT4) and
stimulating hormone of the thyroid (TSH)).

Effects of coagulation and lipids

In the 027 study of postmenopausal women having had an early breast
cancer treated with exemestane (N = 73) or placebo (N = 73), there was no change in
the coagulation parameters activate the partial thromboplastin time (APTT),
prothrombin time (PT) and fibrinogen. Plasma HDL cholesterol decreased
6-9% in patients treated with exemestane; total cholesterol, LDL cholesterol,
triglycerides, apolipoprotein-A1, apolipoprotein-B and lipoprotein-a
unchanged. An 18% increase in homocysteine ​​levels was also observed in
patients treated with exemestane compared with a 12% increase seen with placebo.


After oral administration to healthy menopause
In women, the plasma concentrations of exemestane decrease polyexponentially with
mean terminal half-life of approximately 24 hours. The pharmacokinetics of exemestane
proportional to the dose after single (10-200 mg) or repeated (0.5 to
50 mg). After repeated administration of daily doses of 25 mg exemestane,
unchanged drug concentrations are similar to levels measured after a single
dose. Pharmacokinetic parameters in postmenopausal women with advanced breast cancer
cancer after single or repeated doses were compared to those of
postmenopausal women in good health. After repeated administration, the average oral dose
clearance in women with advanced breast cancer was 45% lower than that obtained orally.
in healthy postmenopausal women, with a corresponding systemic increase
exposure. Mean values ​​of AUC after repeated dose administration in women with breast cancer
(75.4 ng • h / mL) were approximately twice as high as in healthy women (41.4
ng • h / mL).


After oral administration, exemestane appears to have been
absorbed more quickly in women with breast cancer than in healthy women,
average tmax of 1.2 hours in women with breast cancer and 2.9 hours in
healthy women. About 42% of radiolabeled exemestane was absorbed by
The digestive tract. A high-fat breakfast increased the AUC and Cmax of
the exemestane of 59% and 39%, respectively, compared with the state of fasting.


Exemestane is widely distributed in the tissues.
Exemestane is 90% bound to plasma proteins and the bound fraction is
independent of the total concentration. Albumin and α11 acid glycoprotein
both contribute to binding. The distribution of exemestane and its
metabolites in blood cells is negligible.


Exemestane is extensively metabolized, with levels of
unchanged drug in plasma representing less than 10% of the total
radioactivity. The first steps in the metabolism of exemestane are oxidation
of the methylene group in position 6 and reduction of the 17-keto group with
subsequent formation of many secondary metabolites. Each metabolite count
only for a limited amount of drug-related material. Metabolites are
aromatase inactive or inhibited with decreased potency relative to parent
drug. A metabolite may have androgenic activity (see CLINICAL PHARMACOLOGY).
Studies using human liver preparations indicate that cytochrome P 450 3A4 (CYP)
3A4) is the main isoenzyme involved in the oxidation of exemestane.
Exemestane is also metabolized by aldoketoreductases.


After the administration of radiolabelled exemestane to
Postmenopausal women in good health, cumulative amounts of radioactivity excreted
in urine and feces were similar (42 ± 3% in urine and 42 ± 6% in faeces on one
Collection period of one week). The amount of drug excreted unchanged in the urine was
less than 1% of the dose.

Specific Populations


Healthy postmenopausal women aged 43 to 68 years were
studied in pharmacokinetic trials. Age-related changes in exemestane
pharmacokinetics has not been observed in this age range.

Gender MAN or WOMAN

The pharmacokinetics of exemestane after
the administration of a single 25 mg tablet to men in good health and fasting (mean age: 32 years).
years) were similar to the pharmacokinetics of exemestane in healthy fasting subjects
menopausal women (mean age 55 years).


The influence of race on the pharmacokinetics of exemestane
not evaluated.

Hepatic impairment

The pharmacokinetics of exemestane have been studied
in subjects with moderate or severe hepatic impairment (Childs-Pugh B or C).
After a single oral dose of 25 mg, the AUC of exemestane was about 3
times higher than that observed in healthy volunteers.

Renal failure

The AUC of exemestane after a single dose of 25 mg was
about 3-fold higher in subjects with moderate or severe renal insufficiency
insufficiency (creatinine clearance <35 mL / min / 1.73 m²) compared to
AUC in healthy volunteers.


The pharmacokinetics of exemestane have not been studied
in pediatric patients.

Drugs interactions

Exemestane does not inhibit any of the major CYP
isoenzymes, including CYP 1A2, 2C9, 2D6, 2E1 and 3A4.

In a pharmacokinetic interaction study of 10 healthy subjects
Postmenopausal volunteers pretreated with rifampicin 600 inducing CYP 3A4
mg daily for 14 days, followed by a single dose of 25 mg exemestane, the average
Plasma Cmax and AUC 0 – Plasma from exemestane were decreased by 41% and 54%,

In a clinical pharmacokinetic study, the coadministration of
Ketoconazole, a potent inhibitor of CYP 3A4, has no significant effect on
pharmacokinetics of exemestane. Although no other formal drug interaction
studies with inhibitors have been conducted, significant effects on exemestane
the clearance of CYP isoenzyme inhibitors seems unlikely.

Clinical studies

Adjuvant treatment of early stage breast cancer

The intergroup study exemestane 031 (IES) was a
multinational, randomized, double-blind, multi-center study comparing exemestane
(25 mg / day) compared to tamoxifen (20 or 30 mg / day) in postmenopausal women with
breast cancer. Patients who remained free from the disease after receiving an adjuvant
Tamoxifen for 2 to 3 years were randomized to receive 3 additional doses.
or 2 years of AROMASIN or tamoxifen to complete a total of 5 years of hormone therapy.

The main objective of the study was to determine
if, in terms of disease-free survival, it was more efficient to switch to
AROMASIN rather than continue tamoxifen treatment for the rest of the five
years. Disease-free survival was defined as the time elapsed between randomization and time
local or distant recurrence of breast cancer, contralateral invasive breast cancer
cancer, or the death of any cause.

The secondary objectives were to compare the two schemas
in terms of overall survival and long-term tolerability. Contralateral time
invasive breast cancer and remote relapse-free survival have also been

A total of 4724 patients with intent to treat (ITT)
The analyzes were randomized according to AROMASIN (exemestane tablets) at 25 mg once daily (N =
2352) or continue to receive tamoxifen once a day at the same dose
before randomization (N = 2372). Demographics and initial tumor
the characteristics are presented in Table 5. Previous treatment with breast cancer is recommended.
summarized in Table 6.

Table 5: Demographic and basic tumors
Features of the IES study on postmenopausal women in early breast
Cancer (ITT population)

Parameter exemestane
(N = 2352)
(N = 2372)
Age (years): median age 63.0 (38.0 – 96.0) 63.0 (31.0 – 90.0)
Race, n (%):
Caucasian 2315 (98.4) 2333 (98.4)
Hispanic 13 (0.6) 13 (0.5)
Asian 10 (0.4) 9 (0.4)
Black 7 (0.3) 10 (0.4)
Other / not reported 7 (0.3) 7 (0.3)
Nodal status, n (%):
Negative 1217 (51.7) 1228 (51.8)
Positive 1051 (44.7) 1044 (44.0)
1-3 positive nodes 721 (30.7) 708 (29.8)
4-9 positive nodes 239 (10.2) 244 (10.3)
> 9 positive nodes 88 (3.7) 86 (3,6)
Not reported 3 (0,1) 6 (0.3)
Unknown or missing 84 (3,6) 100 (4.2)
Histological type, n (%):
Infiltration channel 1777 (75.6) 1830 (77.2)
Invasive lobular 341 (14.5) 321 (13.5)
Other 231 (9.8) 213 (9.0)
Unknown or missing 3 (0,1) 8 (0.3)
Receiver status *, n (%):
ER and PgR positive 1331 (56.6) 1319 (55.6)
ER positive and PgR negative / unknown 677 (28.8) 692 (29.2)
ER Unknown and PgR Positive ** / Unknown 288 (12.2) 291 (12.3)
ER negative and positive PgR 6 (0.3) 7 (0.3)
ER negative and PgR negative / unknown (no positive) 48 (2.0) 58 (2,4)
Missing 2 (0,1) 5 (0.2)
Size of the tumor, n (%):
≤ 0.5 cm 58 (2.5) 46 (1,9)
> 0.5 – 1.0 cm 315 (13.4) 302 (12.7)
> 1.0 – 2 cm 1031 (43.8) 1033 (43.5)
> 2.0 – 5.0 cm 833 (35.4) 883 (37.2)
> 5.0 cm 62 (2.6) 59 (2.5)
Not reported 53 (2.3) 49 (2.1)
Tumor category, n (%):
G1 397 (16.9) 393 (16.6)
G2 977 (41.5) 1007 (42.5)
G3 454 (19.3) 428 (18.0)
G4 23 (1.0) 19 (0.8)
Unknown / Not evaluated / Not reported 501 (21.3) 525 (22.1)
* The results for receiver status include the results of the
post-randomization trials on samples of subjects for which the status of the receptor
was unknown at the randomization.
** Only one subject in the exemestane group had an unknown ER status and was positive
PgR status.

Table 6: Previous Treatment of Breast Cancer in Patients
the IES study on postmenopausal women with early stage breast cancer (ITT)

Parameter exemestane
(N = 2352)
(N = 2372)
Type of surgery, n (%):
Mastectomy 1232 (52.4) 1242 (52.4)
Breast conservation 1116 (47.4) 1123 (47.3)
Unknown or missing 4 (0.2) 7 (0.3)
Breast radiotherapy, n (%):
Yes 1524 (64.8) 1523 (64.2)
No 824 (35.5) 843 (35.5)
Not reported 4 (0.2) 6 (0.3)
Prior therapy, n (%):
Chemotherapy 774 (32.9) 769 (32.4)
Hormone replacement therapy 567 (24.1) 561 (23.7)
bisphosphonates 43 (1,8) 34 (1,4)
Duration of treatment with tamoxifen at randomization (months):
Median (extent) 28.5 (15.8 – 52.2) 28.4 (15.6 – 63.0)
Tamoxifen dose, n (%):
20 mg 2270 (96.5) 2287 (96.4)
30 mg * 78 (3,3) 75 (3.2)
Not reported 4 (0.2) 10 (0.4)
* The dose of 30 mg was used only in Denmark, where this dose
was the standard of care.

After a median treatment duration of 27 months and with
median follow-up of 34.5 months, 520 events were reported, including 213 in the
AROMASIN and 307 in the tamoxifen group (Table 7).

Table 7: Main events related to endpoints (ITT population)

Event First events
NOT (%)
(N = 2352)
(N = 2372)
Loco-regional recurrence 34 (1,45) 45 (1.90)
Remote recurrence 126 (5,36) 183 (7.72)
Second primary breast cancer 7 (0.30) 25 (1.05)
Death – breast cancer 1 (0.04) 6 (0.25)
Death – another reason 41 (1.74) 43 (1,81)
Death – missing / unknown 3 (0,13) 5 (0.21)
Ipsilateral breast cancer 1 (0.04) 0
Total number of events 213 (9.06) 307 (12.94)

Survival without disease in the
intention to treat has been statistically significantly improved (risk study)
Ratio (HR) = 0.69, 95% CI: 0.58, 0.82, p = 0.00003, Table 8, Figure 1) in the
AROMASIN compared to tamoxifen. In the positive hormone receptor
subpopulation representing approximately 85% of patients in the study, free from
Survival was also statistically significantly improved (HR = 0.65, 95% CI:
0.53, 0.79, p = 0.00001) in the AROMASIN arm relative to the tamoxifen arm.
Consistent results were observed in subgroups of lymph node patients
negative or positive disease, and patients who had or had not received prior

A global update on survival at
Median follow-up at 119 months revealed no significant difference between the two
groups, with 467 deaths (19.9%) in the AROMASIN group and 510 deaths
(21.5%) in the tamoxifen group.

Table 8: Results of effectiveness of the IES study in
Postmenopausal women with early stage breast cancer

Risk ratio (95% CI) p-value (log-rank test)
ITT population
Disease-free survival 0.69 (0.58-0.82) 0.00003
Contralateral breast cancer 0.32 (0.15-0.72) 0.00340
Remote Survival Without Recurrence 0.74 (0.62-0.90) 0.00207
Overall survival 0.91 (0.81-1.04) 0.16 *
ER and / or PgR positive
Disease-free survival 0.65 (0.53-0.79) 0.00001
Contralateral breast cancer 0.22 (0.08-0.57) 0.00069
Remote Survival Without Recurrence 0.73 (0.59-0.90) 0.00367
Overall survival 0.89 (0.78-1.02) 0.09065 *
* Not adjusted for many

Figure 1: Without disease
Survival in the IES study on postmenopausal women with early stage breast cancer (ITT)

Without disease
Survival in the IES study on postmenopausal women with early-stage breast cancer - Stock Illustration

Advanced chest treatment

Exemestane 25 mg administered
once a day has been evaluated in a randomized, double-blind, multicenter,
multinational comparative study and in two single-center multicentric
Postmenopausal women with advanced breast cancer presenting with disease progression
after treatment with tamoxifen for treatment of metastatic disease or adjuvant therapy.
Some patients have also received prior cytotoxic therapy, either as adjuvant
treatment or for metastatic disease.

The main purpose of the
three studies were evaluating the objective response rate (complete response (CR)
and partial response (PR)). The time required for tumor progression and overall survival was
also evaluated in the comparative test. Response rates were assessed on the basis of
The criteria of the World Health Organization (WHO) and the comparative study have been
submitted to an external blind patient review committee
treatment. In the comparative study, 769 patients were randomized to receive
AROMASIN (exemestane tablets) 25 mg once daily (N = 366) or megestrol acetate
40 mg four times daily (N = 403). Demographic and basic characteristics are
presented in Table 9.

Table 9: Demographics and
Basic characteristics of the comparative study of postmenopausal women
with advanced breast cancer whose disease had progressed after tamoxifen

Parameter AROMASIN
(N = 366)
Megestrol acetate
(N = 403)
Median age (range) 65 (35-89) 65 (30-91)
ECOG performance status
0 167 (46%) 187 (46%)
1 162 (44%) 172 (43%)
2 34 (9%) 42 (10%)
Receiver status
ER and / or PgR + 246 (67%) 274 (68%)
ER and PgR unknown 116 (32%) 128 (32%)
Previous Tamoxifen Respondents 68 (19%) 85 (21%)
NE for response to previous tamoxifen 46 (13%) 41 (10%)
Site of metastases
Visceral ± other sites 207 (57%) 239 (59%)
Os only 61 (17%) 73 (18%)
Soft fabric only 54 (15%) 51 (13%)
Bones and soft tissues 43 (12%) 38 (9%)
Measurable disease 287 (78%) 314 (78%)
Previous treatment with tamoxifen
Adjuvant or Neoadjuvant 145 (40%) 152 (38%)
Advanced disease, result
CR, PR or SD ≥ 6 months 179 (49%) 210 (52%)
SD <6 months, PD or NE 42 (12%) 41 (10%)
Previous chemotherapy
For advanced disease ± adjuvant 58 (16%) 67 (17%)
Adjuvant only 104 (28%) 108 (27%)
No chemotherapy 203 (56%) 226 (56%)

Efficiency results from the
Table 10 shows the comparative study. Objective response rates observed
in both treatment arms showed that AROMASIN was no different than the megestrol
acetate. Response rates to AROMASIN in both single arm trials were 23.4%.
and 28.1%.

Table 10: Results of effectiveness of the comparative study
postmenopausal women with advanced breast cancer whose disease had
Progressive after Tamoxifen therapy

Response characteristics AROMASIN
(N = 366)
Megestrol acetate
(N = 403)
Objective response rate = CR + PR (%) 15.0 12.4
Response rate difference (AR-MA) 2.6
95% of C.I. 7.5, -2.3
CR (%) 2.2 1.2
PR (%) 12.8 11.2
SD ≥ 24 weeks (%) 21.3 21.1
Median duration of response (weeks) 76.1 71.0
Median PTT (weeks) 20.3 16.6
Risk report (AR-MA) 0.84
Abbreviations: CR = complete response, PR = partial response, SD = stable disease (no change), TTP = delay before tumor progression, C.I. = confidence interval, MA = megestrol acetate, AR = AROMASIN

There were too few deaths
occurring through treatment groups to draw conclusions about overall survival
differences. The Kaplan-Meier curve for the delay of tumor progression in the
The comparative study is illustrated in Figure 2.

Figure 2: Time of progression of the tumor in the comparative
Study on postmenopausal women with advanced breast cancer whose disease had
Progressive after Tamoxifen treatment

    Temporal progression of the tumor in the comparative
Study on postmenopausal women with advanced breast cancer whose disease had
Progressive after tamoxifen treatment - Stock Illustration

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