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EXEMESTANE FAIR-MED HEALTHCARE 25MG FILM-COATED TABLETS

Active substance(s): EXEMESTANE

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1.

NAME OF THE MEDICINAL PRODUCT
Exemestane Fair-Med Healthcare 25 mg film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Exemestane
Each film coated tablet contains 25 mg exemestane.
For full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Film-coated tablet.
White to off-white, round compound cup film coated tablet, with “25” on one
side and plain on the reverse.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Exemestane is indicated for the adjuvant treatment of postmenopausal women
with oestrogen receptor positive invasive early breast cancer, following 2 – 3
years of initial adjuvant tamoxifen therapy.
Exemestane 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.

4.2

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

4.3

Contraindications
Exemestane is contraindicated in:
-

premenopausal women.

-

women who are pregnant or breastfeeding

patients with hypersensitivity to the active substance or to any of the
excipients.

4.4

Special warnings and precautions for use
Exemestane should not be administered to women with pre-menopausal
endocrine status. Therefore, whenever clinically appropriate, the postmenopausal status should be ascertained by assessment of LH, FSH and
oestradiol levels.
Exemestane should be used with caution in patients with hepatic or renal
impairment.
Exemestane is a potent oestrogen lowering agent, and a reduction in bone
mineral density and an increased fracture rate has been observed following
administration (see section 5.1). During adjuvant treatment with Exemestane,
women with osteoporosis or at risk of osteoporosis should have their bone
mineral density formally assessed by bone densitometry at the commencement

of treatment. Although adequate data to show the effects of therapy in the
treatment of the bone mineral density loss caused by Exemestane are not
available, treatment for osteoporosis should be initiated in at risk patients.
Patients treated with Exemestane should be carefully monitored.

4.5

Interaction with other medicinal products and other forms of interaction
In vitro evidence showed that the drug is metabolised through cytochrome
P450 (CYP) 3A4 and aldoketoreductases (see 5.2) and does not inhibit any of
the major CYP isoenzymes. In a clinical pharmacokinetic study, the specific
inhibition of CYP 3A4 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
600mg daily and a single dose of exemestane 25mg, 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 Exemestane.
Exemestane 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 Exemestane with other anticancer drugs.
Exemestane should not be co administered with oestrogen-containing
medicines as these would negate its pharmacological action.

4.6

Fertility, Pregnancy and lactation
Pregnancy
No clinical data on exposed pregnancies are available with Exemestane.
Studies on animals have shown reproductive toxicity (See section 5.3). The
potential risk for humans is unknown. Exemestane is therefore contraindicated
in pregnant women.
Lactation
It is not known whether exemestane is excreted into human milk. Exemestane
should not be used during breast-feeding.
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).

4.7

Effects on ability to drive and use machines
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.

4.8

Undesirable effects
Exemestane was generally well tolerated across all clinical studies conducted
with Exemestane 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 Exemestane 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).
The reported adverse reactions 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 (≥1/1000 to < 1/100), rare (≥1/10,000 to <1/1000)

System
class

organ Very
common Common
(≥1/10)
(≥1/100
<1/10)
Metabolism and
Anorexia
nutrition
disorders

Uncommon Rare
to (≥1/1000 to (≥1/10,000
<1/100)
to <1/1000)

Very
rare
(<1/10,000)

Psychiatric
Insomnia
disorders
Nervous system Headache
disorders
Vascular
disorders
Gastrointestinal
disorders

Hot flushes

Skin
and
subcutaneous
tissue disorders
Musculoskeletal
and
bone
disorders
General disorders
and
administration
site conditions

Increased
sweating

Nausea

Depression
Diziness,
Somnolence
carpal tunnel
syndrome

Abdominal
pain,
vomiting,
constipation,
dyspesia,
diarrhoea
Rash, alopecia

Joint
and Osteoporosis,
musculoskeletal
fracture
pain (*)
Fatigue
Pain,
peripheral
oedema

Asthenia

(*)

Includes: arthralgia, and less frequently pain in limb, osteoarthritis, back
pain, arthritis, myalgia and joint stiffness
Blood and lymphatic system disorders

In patients with advanced breast cancer thrombocytopenia and leucopenia
have been rarely reported. An occasional decrease in lymphocytes has been
observed in approximately 20% of patients receiving Exemestane, particularly
in patients with pre-existing lymphopenia; however, mean lymphocyte values
in these patients did not change significantly over time and no corresponding
increase in viral infections was observed. These effects have not been
observed in patients treated in early breast cancer studies.
Hepatobiliary disorders
Elevation of liver function test parameters including enzymes, bilirubin and
alkaline phosphatase have been observed.
The table below presents the frequency of pre-specified adverse events and
illnesses in the early breast cancer study (IES), irrespective of causality,
reported in patients receiving trial therapy and up to 30 days after cessation of
trial therapy.

Adverse events Exemestane
and illnesses
(N = 2249)

Tamoxifen
(N = 2279)

Hot flushes
Fatigue
Headache
Insomnia
Sweating
increased
Gynaecological
Dizziness
Nausea
Osteoporosis
Vaginal
haemorrhage
Other
primary
cancer
Vomiting
Visual disturbance
Thromboembolism
Osteoporotic
fracture
Myocardial
infarction

491 (21.8%)
367 (16.3%)
305 (13.6%)
290 (12.9%)
270 (12.0%)

457 (20.1%)
344 (15.1%)
255 (11.2%)
204 (9.0%)
242 (10.6%)

235 (10.5%)
224 (10.0%)
200 (8.9%)
116 (5.2%)
90 (4.0%)

340 (14.9%)
200 (8.8%)
208 (9.1%)
66 (2.9%)
121 (5.3%)

84 (3.6%)

125 (5.3%)

50 (2.2%)
45 (2.0%)
16 (0.7%)
14 (0.6%)

54 (2.4%)
53 (2.3%)
42 (1.8%)
12 (0.5%)

13 (0.6%)

4 (0.2%)

In the IES study, the frequency of ischemic cardiac events in the exemestane
and tamoxifen treatment arms was 4.5% versus 4.2%, respectively. No
significant difference was noted for any individual cardiovascular event
including hypertension (9.9% versus 8.4%), myocardial infarction (0.6%
versus 0.2%) and cardiac failure (1.1% versus 0.7%).
In the IES study, exemestane was associated with a greater incidence of
hypercholesterolemia compared with tamoxifen (3.7% vs. 2.1%).
In a separate double blinded, randomized study of postmenopausal women
with early breast cancer at low risk treated with exemestane (N=73) or placebo
(N=73) for 24 months , exemestane was associated with an average 7-9%
mean reduction in plasma HDL-cholesterol, versus a 1% increase on placebo.
There was also a 5-6% reduction in apolipoprotein A1 in the exemestane
group versus 0-2% for placebo. The effect on the other lipid parameters
analysed (total cholesterol, LDL cholesterol, triglycerides, apolipoprotein-B
and lipoprotein-a) was very similar in the two treatment groups . The clinical
significance of these results is unclear.

In the IES study, gastric ulcer was observed at a higher frequency in the
exemestane arm compared to tamoxifen (0.7% versus <0.1%). The majority of
patients on exemestane with gastric ulcer received concomitant treatment with
non-steroidal anti-inflammatory agents and/or had a prior history.
Adverse reactions from post-marketing experience
Hepatobiliary disorders: Hepatitis, cholestatic hepatitis
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.

4.9

Overdose
Clinical trials have been conducted with Exemestane 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 Exemestane 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 overdosing and
treatment must be symptomatic. General supportive care, including frequent
monitoring of vital signs and close observation of the patient, is indicated.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: hormone antagonists and related agents, enzyme
inhibitors.
ATC: L02BG06
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, Exemestane 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, Exemestane 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.
Adjuvant Treatment of Early Breast Cancer
In a multicentre, randomised, double-blind study, conducted in 4724
postmenopausal patients with oestrogen-receptor-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
Exemestane (25 mg/day) or tamoxifen (20 or 30 mg/day) to complete a total of
5 years of hormonal therapy.
After a median duration of therapy of about 30 months and a median followup of about 52 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 disease-free
survival (DFS) compared with continuation of tamoxifen therapy. Analysis
showed that in the observed study period Exemestane 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.
Exemestane 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 favor 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).
Main efficacy results in all patients (intention to treat population) and
oestrogen receptor positive patients are summarised in the table below:
Endpoint Exemestane
Tamoxifen
Hazard Ratio p-value*
Population Events /N (%) Events /N (%) (95% CI)
Disease-free survival a
All patients 354
/2352 453
/2372 0.76 (0.67-0.88) 0.00015
(15.1%)
(19.1%)
ER+ patients 289
/2023 370
/2021 0.75 (0.65-0.88) 0.00030
(14.3%)
(18.3%)
Contralateral breast cancer
All patients 20 /2352 (0.9%) 35 /2372 (1.5%) 0.57 (0.33-0.99) 0.04158
ER+ patients 18 /2023 (0.9%) 33 /2021 (1.6%) 0.54 (0.30-0.95) 0.03048
Breast cancer free survival b
All patients 289
/2352 373
/2372 0.76 (0.65-0.89) 0.00041
(12.3%)
(15.7%)
ER+ patients 232
/2023 305
/2021 0.73 (0.62-0.87) 0.00038
(11.5%)
(15.1%)
Distant recurrence free survival c
All patients 248
/2352 297
/2372 0.83 (0.70-0.98) 0.02621
(10.5%)
(12.5%)
ER+ patients 194 /2023 (9.6%) 242
/2021 0.78 (0.65-0.95) 0.01123
(12.0%)
Overall survivald
All patients 222 /2352 (9.4%) 262
/2372 0.85 (0.71-1.02) 0.07362
(11.0%)
ER+ patients 178 /2023 (8.8%) 211
/2021 0.84 (0.68-1.02) 0.07569
(10.4%)
* Log-rank test; ER+ patients = oestrogen receptor positive patients;
a

Disease-free survival is defined as the first occurrence of local or distant
recurrence, contralateral breast cancer, or death from any cause;

b

Breast cancer free survival is defined as the first occurrence of local or
distant recurrence, contralateral breast cancer or breast cancer death;
c

Distant recurrence free survival is defined as the first occurrence of distant
recurrence or breast cancer death;
d

Overall survival is defined as occurrence of death from any cause.

In the additional analysis for the subset of patients with oestrogen receptor
positive or unknown status, the unadjusted overall survival hazard ratio was
0.83 (log-rank test: p = 0.04250), representing a clinically and statistically
significant 17% reduction in the risk of dying.
Results from a bone sub study demonstrated that women treated with
Exemestane 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 Exemestane compared with tamoxifen
(4.5% and 3.3% correspondingly, p=0.038).
Results from an endometrial sub study indicate that after 2 years of treatment
there was a median 33% reduction of endometrial thickness in the
Exemestane-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 Exemestane.
Treatment of Advanced Breast Cancer
In a randomised peer reviewed controlled clinical trial, Exemestane 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.

5.2

Pharmacokinetic properties
Absorption :
After oral administration of Exemestane 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.
Metabolism and excretion:
Exemestane is metabolised by oxidation of the methylene moiety on the 6
position by CYP 3A4 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 Exemestane
and the age of subjects has been observed.
Renal insufficiency:
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 insufficiency:.
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.

5.3

Preclinical safety data
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 vivo studies.
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 tumors 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.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet core:
Mannitol (E421)
Copovidone
Crospovidone
Microcrystalline Cellulose
Silica, colloidal anhydrous
Sodium Starch Glycolate (Type A)
Magnesium Stearate(E470b)
Film coating:
Hypromellose (E464)

Macrogol 400
Titanium Dioxide(E171)

6.2

Incompatibilities
Not applicable.

6.3

Shelf life

3 years

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container
PVC-PVdC/Aluminium blisters of:
15, 20, 30, 90, 100, 120 and 200 (Blisters of 10 & 15) film-coated tablets.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Any unused product or waste should be disposed of in accordance with local
requirements

7

MARKETING AUTHORISATION HOLDER
Fair-Med Healthcare GmbH
Planckstrasse 13
22765 Hamburg
Germany

8

MARKETING AUTHORISATION NUMBER(S)
PL 20242/0014

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
19/10/2011

10

DATE OF REVISION OF THE TEXT
23/08/2013

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Source: Medicines and Healthcare Products Regulatory Agency

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