XEMETAN is indicated for the adjuvant treatment of postmenopausal women with oestrogen receptor positive invasive
early breast cancer (EBC), following 2 – 3 years of initial adjuvant tamoxifen therapy.
XEMETAN is indicated for the treatment of advanced breast cancer in women with natural or induced postmenopausal
status whose disease has progressed following anti-oestrogen therapy. Efficacy has not been demonstrated in patients
with oestrogen receptor negative status
 

Posology
Adult and elderly patients
The recommended dose of XEMETAN is one 25 mg tablet to be taken once daily, preferably after a meal.
In patients with early breast cancer, treatment with XEMETAN should continue until completion of five years of combined
sequential adjuvant hormonal therapy (tamoxifen followed by XEMETAN), or earlier if tumour relapse occurs.
In patients with advanced breast cancer, treatment with XEMETAN should continue until tumour progression is evident.
No dose adjustments are required for patients with hepatic or renal insufficiency (see section 5.2).
Paediatric population
Not recommended for use in children
 

XEMETAN should not be administered to women with pre-menopausal endocrine status. Therefore, whenever clinically
appropriate, the post-menopausal status should be ascertained by assessment of LH, FSH and oestradiol levels.
XEMETAN should be used with caution in patients with hepatic or renal impairment.
XEMETAN tablets contain sucrose and should not be administered to patients with rare hereditary problems of fructose
intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency.
XEMETAN tablets contain methyl-p-hydroxybenzoate which may cause allergic reactions (possibly delayed).
XEMETAN is a potent oestrogen lowering agent, and a reduction in bone mineral density (BMD) and an increased
fracture rate have been observed following administration (see section 5.1). At the commencement of adjuvant treatment
with XEMETAN, women with osteoporosis or at risk of osteoporosis should have treatment baseline bone mineral health
assessment based on current clinical guidelines and practice. Patients with advanced disease should have their bone
mineral density assessed on a case-by-case basis. Although adequate data to show the effects of therapy in the
treatment of the bone mineral density loss caused by XEMETAN are not available, patients treated with XEMETAN should
be carefully monitored and treatment for, or prophylaxis of, osteoporosis should be initiated in at risk patients.
Routine assessment of 25 hydroxy vitamin D levels prior to the start of aromatase inhibitor treatment should be
considered, due to the high prevalence of severe deficiency in women with early breast cancer. Women with Vitamin D
deficiency should receive supplementation with Vitamin D
 

In vitro evidence showed that the drug is metabolised through cytochrome P450 CYP3A4 and aldoketoreductases (see
section 5.2) and does not inhibit any of the major CYP isoenzymes. In a clinical pharmacokinetic study, the specific
inhibition of CYP3A4 by ketoconazole showed no significant effects on the pharmacokinetics of exemestane.
In an interaction study with rifampicin, a potent CYP450 inducer, at a dose of 600 mg daily and a single dose of
exemestane 25 mg, the AUC of exemestane was reduced by 54% and Cmax by 41%. Since the clinical relevance of this
interaction has not been evaluated, the co-administration of drugs, such as rifampicin, anticonvulsants (e.g., phenytoin
and carbamazepine) and herbal preparations containing hypericum perforatum (St John's Wort) known to induce CYP3A4
may reduce the efficacy of XEMETAN.
XEMETAN should be used cautiously with drugs that are metabolised via CYP3A4 and have a narrow therapeutic
window. There is no clinical experience of the concomitant use of XEMETAN with other anticancer drugs.
XEMETAN should not be coadministered with oestrogen-containing medicines as these would negate its pharmacological
action
 

Pregnancy Category: X
Pregnancy
No clinical data on exposed pregnancies are available with XEMETAN. Studies on animals have shown reproductive
toxicity (see section 5.3). XEMETAN is therefore contraindicated in pregnant women.
Breast-feeding
It is not known whether exemestane is excreted into human milk. XEMETAN should not be administered to lactating
woman.
Women of perimenopausal status or child-bearing potential
The physician needs to discuss the necessity of adequate contraception with women who have the potential to become
pregnant including women who are perimenopausal or who have recently become postmenopausal, until their
postmenopausal status is fully established (see sections 4.3 and 4.4)
 

Drowsiness, somnolence, asthenia and dizziness have been reported with the use of the drug. Patients should be advised
that, if these events occur, their physical and/or mental abilities required for operating machinery or driving a car may be
impaired
 

a. Summary of the safety profile
XEMETAN was generally well tolerated across all clinical studies conducted with XEMETAN at a standard dose of 25
mg/day, and undesirable effects were usually mild to moderate.
The withdrawal rate due to adverse events was 7.4% in patients with early breast cancer receiving adjuvant treatment
with XEMETAN following initial adjuvant tamoxifen therapy. The most commonly reported adverse reactions were hot
flushes (22%), arthralgia (18%) and fatigue (16%).
The withdrawal rate due to adverse events was 2.8% in the overall patient population with advanced breast cancer. The
most commonly reported adverse reactions were hot flushes (14%) and nausea (12%).
Most adverse reactions can be attributed to the normal pharmacological consequences of oestrogen deprivation (e.g., hot
flushes).
b. Tabulated summary of adverse reactions
The reported adverse reactions from clinical studies and post-marketing experience are listed below by system organ
class and by frequency.
Frequencies are defined as: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare
(≥1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data)

c. Description of selected adverse reactions
Not Applicable
d. Paediatric population
Not recommended for use in children.
e. Other special populations
Age
No significant correlation between the systemic exposure of XEMETAN and the age of subjects has been observed.
Renal impairment
In patients with severe renal impairment (CLcr <30 ml/min) the systemic exposure to exemestane was 2 times higher
compared with healthy volunteers.
Given the safety profile of exemestane, no dose adjustment is considered to be necessary.
Hepatic impairment
In patients with moderate or severe hepatic impairment the exposure of exemestane is 2-3 fold higher compared with
healthy volunteers. Given the safety profile of exemestane, no dose adjustment is considered to be necessary

Clinical trials have been conducted with XEMETAN given up to 800 mg in a single dose to healthy female volunteers and
up to 600 mg daily to postmenopausal women with advanced breast cancer; these dosages were well tolerated. The
single dose of XEMETAN that could result in life-threatening symptoms is not known. In rats and dogs, lethality was
observed after single oral doses equivalent respectively to 2000 and 4000 times the recommended human dose on a
mg/m2 basis. There is no specific antidote to overdosage and treatment must be symptomatic. General supportive care,
including frequent monitoring of vital signs and close observation of the patient, is indicated
 

Pharmacotherapeutic group: steroidal aromatase inhibitor; anti-neoplastic agent
ATC: L02BG06
Mechanism of action
Exemestane is an irreversible, steroidal aromatase inhibitor, structurally related to the natural substrate androstenedione.
In post-menopausal women, oestrogens are produced primarily from the conversion of androgens into oestrogens through
the aromatase enzyme in peripheral tissues. Oestrogen deprivation through aromatase inhibition is an effective and
selective treatment for hormone dependent breast cancer in postmenopausal women. In postmenopausal women,
XEMETAN p.o. significantly lowered serum oestrogen concentrations starting from a 5 mg dose, reaching maximal
suppression (>90%) with a dose of 10-25 mg. In postmenopausal breast cancer patients treated with the 25 mg daily
dose, whole body aromatization was reduced by 98%.
Exemestane does not possess any progestogenic or oestrogenic activity. A slight androgenic activity, probably due to the
17-hydro derivative, has been observed mainly at high doses. In multiple daily doses trials, XEMETAN had no detectable
effects on adrenal biosynthesis of cortisol or aldosterone, measured before or after ACTH challenge, thus demonstrating
its selectivity with regard to the other enzymes involved in the steroidogenic pathway.
Glucocorticoid or mineralocorticoid replacements are therefore not needed. A non dose-dependent slight increase in
serum LH and FSH levels has been observed even at low doses: this effect is, however, expected for the pharmacological
class and is probably the result of feedback at the pituitary level due to the reduction in oestrogen levels that stimulate the
pituitary secretion of gonadotropins also in postmenopausal women.
Clinical efficacy and safety
Adjuvant treatment of early breast cancer
In a multicentre, randomised, double-blind study (IES), conducted in 4724 postmenopausal patients with oestrogenreceptor-positive or unknown primary breast cancer, patients who had remained disease-free after receiving adjuvant
tamoxifen therapy for 2 to 3 years were randomised to receive 3 to 2 years of XEMETAN (25 mg/day) or tamoxifen (20 or
30 mg/day) to complete a total of 5 years of hormonal therapy.
IES 52-month median follow-up
After a median duration of therapy of about 30 months and a median follow-up of about 52 months, results showed that
sequential treatment with XEMETAN after 2 to 3 years of adjuvant tamoxifen therapy was associated with a clinically and
statistically significant improvement in disease-free survival (DFS) compared with continuation of tamoxifen therapy.
Analysis showed that in the observed study period XEMETAN reduced the risk of breast cancer recurrence by 24%
compared with tamoxifen (hazard ratio 0.76; p = 0.00015). The beneficial effect of exemestane over tamoxifen with
respect to DFS was apparent regardless of nodal status or prior chemotherapy.
XEMETAN also significantly reduced the risk of contralateral breast cancer (hazard ratio 0.57, p = 0.04158).
In the whole study population, a trend for improved overall survival was observed for exemestane (222 deaths) compared
to tamoxifen (262 deaths) with a hazard ratio 0.85 (log-rank test: p = 0.07362), representing a 15% reduction in the risk of
death in favour of exemestane. A statistically significant 23% reduction in the risk of dying (hazard ratio for overall survival
0.77; Wald chi square test: p = 0.0069) was observed for exemestane compared to tamoxifen when adjusting for the prespecified prognostic factors (i.e., ER status, nodal status, prior chemotherapy, use of HRT and use of bisphosphonates).
52 month main efficacy results in all patients (intention to treat population) and oestrogen receptor positive
patients

Results from the IES bone substudy demonstrated that women treated with XEMETAN following 2 to 3 years of tamoxifen
treatment experienced moderate reduction in bone mineral density. In the overall study, the treatment emergent fracture
incidence evaluated during the 30 months treatment period was higher in patients treated with XEMETAN compared with
tamoxifen (4.5% and 3.3% correspondingly, p = 0.038).
Results from the IES endometrial substudy indicate that after 2 years of treatment there was a median 33% reduction of
endometrial thickness in the XEMETAN-treated patients compared with no notable variation in the tamoxifen-treated
patients. Endometrial thickening, reported at the start of study treatment, was reversed to normal (<5 mm) for 54% of
patients treated with XEMETAN.
IES 87-month median follow-up
After a median duration of therapy of about 30 months and a median follow-up of about 87 months, results showed that
sequential treatment with exemestane after 2 to 3 years of adjuvant tamoxifen therapy was associated with a clinically and
statistically significant improvement in DFS compared with continuation of tamoxifen therapy. Results showed that in the
observed study period XEMETAN significantly reduced the risk of breast cancer recurrence by 16% compared with
tamoxifen (hazard ratio 0.84; p = 0.002).
Overall, the beneficial effect of exemestane over tamoxifen with respect to DFS was apparent regardless of nodal status
or prior chemotherapy or hormonal therapy. Statistical significance was not maintained in a few sub-groups with small
sample sizes. These showed a trend favouring exemestane in patients with more than 9 nodes positive, or previous
chemotherapy CMF. In patients with nodal status unknown, previous chemotherapy other, as well as unknown/missing
status of previous hormonal therapy a non statistically significant trend favouring tamoxifen was observed.
In addition, exemestane also significantly prolonged breast cancer-free survival (hazard ratio 0.82, p = 0.00263), and
distant recurrence-free survival (hazard ratio 0.85, p = 0.02425).
XEMETAN also reduced the risk of contralateral breast cancer, although the effect was no longer statistically significant in
this observed study period (hazard ratio 0.74, p = 0.12983). In the whole study population, a trend for improved overall
survival was observed for exemestane (373 deaths) compared to tamoxifen (420 deaths) with a hazard ratio 0.89 (log
rank test: p = 0.08972), representing an 11% reduction in the risk of death in favour of exemestane. When adjusting for
the pre-specified prognostic factors (i.e., ER status, nodal status, prior chemotherapy, use of HRT and use of
bisphosphonates), a statistically significant 18% reduction in the risk of dying (hazard ratio for overall survival 0.82; Wald
chi square test: p = 0.0082) was observed for exemestane compared to tamoxifen in the whole study population.
In the additional analysis for the subset of patients with oestrogen receptor positive or unknown status, the unadjusted
overall survival hazard ratio was 0.86 (log-rank test: p = 0.04262), representing a clinically and statistically significant 14%
reduction in the risk of dying.
Results from a bone sub-study indicate that treatment with exemestane for 2 to 3 years following 3 to 2 years of tamoxifen
treatment increased bone loss while on treatment (mean % change from baseline for BMD at 36 months: -3.37 [spine], -
2.96 [total hip] for exemestane and -1.29 [spine], -2.02 [total hip], for tamoxifen). However, by the end of the 24 month
post treatment period there were minimal differences in the change in BMD from baseline for both treatment groups, the
tamoxifen arm having slightly greater final reductions in BMD at all sites (mean % change from baseline for BMD at 24
months post treatment -2.17 [spine], -3.06 [total hip] for exemestane and -3.44 [spine], -4.15 [total hip] for tamoxifen).
The all fractures reported on-treatment and during follow-up was significantly higher in the exemestane group than on
tamoxifen (169 [7.3%] versus 122 [5.2%]; p = 0.004), but no difference was noted in the number of fractures reported as
osteoporotic.
Treatment of advanced breast cancer
In a randomised peer reviewed controlled clinical trial, XEMETAN at the daily dose of 25 mg has demonstrated
statistically significant prolongation of survival, Time to Progression (TTP), Time to Treatment Failure (TTF) as compared
to a standard hormonal treatment with megestrol acetate in postmenopausal patients with advanced breast cancer that
had progressed following, or during, treatment with tamoxifen either as adjuvant therapy or as first-line treatment for
advanced disease
 

Absorption
After oral administration of XEMETAN tablets, exemestane is absorbed rapidly. The fraction of the dose absorbed from
the gastrointestinal tract is high. The absolute bioavailability in humans is unknown, although it is anticipated to be limited
by an extensive first pass effect. A similar effect resulted in an absolute bioavailability in rats and dogs of 5%. After a
single dose of 25 mg, maximum plasma levels of 18 ng/ml are reached after 2 hours. Concomitant intake with food
increases the bioavailability by 40%.
Distribution
The volume of distribution of exemestane, not corrected for the oral bioavailability, is ca 20000 l. The kinetics is linear and
the terminal elimination half-life is 24 h. Binding to plasma proteins is 90% and is concentration independent. Exemestane
and its metabolites do not bind to red blood cells.
Exemestane does not accumulate in an unexpected way after repeated dosing.
Elimination
Exemestane is metabolised by oxidation of the methylene moiety on the 6 position by CYP3A4 isoenzyme and/or
reduction of the 17-keto group by aldoketoreductase followed by conjugation. The clearance of exemestane is ca 500 l/h,
not corrected for the oral bioavailability.
The metabolites are inactive or the inhibition of aromatase is less than the parent compound.
The amount excreted unchanged in urine is 1% of the dose. In urine and faeces equal amounts (40%) of 14C-labeled
exemestane were eliminated within a week.
Special populations
Age
No significant correlation between the systemic exposure of XEMETAN and the age of subjects has been observed.
Renal impairment
In patients with severe renal impairment (CLcr <30 ml/min) the systemic exposure to exemestane was 2 times higher
compared with healthy volunteers.
Given the safety profile of exemestane, no dose adjustment is considered to be necessary.
Hepatic impairment
In patients with moderate or severe hepatic impairment the exposure of exemestane is 2-3 fold higher compared with
healthy volunteers. Given the safety profile of exemestane, no dose adjustment is considered to be necessary
 

Toxicological studies
Findings in the repeat dose toxicology studies in rat and dog were generally attributable to the pharmacological activity of
exemestane, such as effects on reproductive and accessory organs. Other toxicological effects (on liver, kidney or central
nervous system) were observed only at exposures considered sufficiently in excess of the maximum human exposure
indicating little relevance to clinical use.
Mutagenicity
Exemestane was not genotoxic in bacteria (Ames test), in V79 Chinese hamster cells, in rat hepatocytes or in the mouse
micronucleus assay. Although exemestane was clastogenic in lymphocytes in vitro, it was not clastogenic in two in
vivostudies.
Reproductive toxicology
Exemestane was embryotoxic in rats and rabbits at systemic exposure levels similar to those obtained in humans at 25
mg/day. There was no evidence of teratogenicity.
Carcinogenicity
In a two-year carcinogenicity study in female rats, no treatment-related tumours were observed. In male rats the study
was terminated on week 92, because of early death by chronic nephropathy. In a two-year carcinogenicity study in mice,
an increase in the incidence of hepatic neoplasms in both genders was observed at the intermediate and high doses (150
and 450 mg/kg/day). This finding is considered to be related to the induction of hepatic microsomal enzymes, an effect
observed in mice but not in clinical studies. An increase in the incidence of renal tubular adenomas was also noted in
male mice at the high dose (450 mg/kg/day). This change is considered to be species- and gender-specific and occurred
at a dose which represents 63-fold greater exposure than occurs at the human therapeutic dose. None of these observed
effects is considered to be clinically relevant to the treatment of patients with exemestane
 

Tablet core: Microcrystalline cellulose powder, Crospovidone, Polysorbate, Acetone, Mannitol, Colloidal Anhydrous Silica
and Magnesium Stearate.
Sugar-coating: Sucrose, Gum Acacia, Purified Talc, Titanium dioxide, Purified Water, Opaglos and Isopropyl alcohol
 

Not applicable
 

Store below 30°C.
KEEP OUT OF THE REACH OF CHILDREN
 

White opaque, thermoformable PVdC coated PVC film and Aluminium foil hard tampered, printing on dull side PVDC
coated.
Box of 2 strip of 15 Tablets each
 

No special requirements