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EPIESTROL-SEPTUM 25 MICROGRAMS/24HOURS TRANSDERMAL PATCH
NAME OF THE MEDICINAL PRODUCT
EPIESTROL®-Septem 25 micrograms/24hours Transdermal Patch
QUALITATIVE AND QUANTITATIVE COMPOSITION
One transdermal patch contains:
2.58 mg of estradiol hemihydrate equivalent to 2.5 mg estradiol/11.25 cm2
delivering 25 μg of estradiol in 24 hours.
For a full list of excipients, see section 6.1.
Transdermal patch. Each patch is transparent, colourless, slightly opaque with
an elliptical shape and a printed identification code, and covered by a
rectangular, transparent protective liner.
Hormone replacement therapy (HRT) for estrogen deficiency symptoms in women at
least 6 months since last menses.
The experience of treating women older than 65 years is limited.
Posology and method of administration
EPIESTROL-Septem is an estrogen-only patch applied to the skin once
weekly in order to ensure a continuous supply of estradiol to the body; thus
each used system is removed after seven days and replaced by a new one.
Three strengths of EPIESTROL®-Septem are available, i.e. EPIESTROL®Septem 25, 50, 75.
For initiation and continuation of treatment of postmenopausal symptoms, the
lowest effective dose for the shortest duration (see also Section 4.4) should be
Treatment is usually initiated with EPIESTROL®-Septem 25.
If after a treatment of 1-2 months with EPIESTROL®-Septem 25 applied once
weekly the symptoms of estrogen deficiency appear not to be neutralised, a
higher dosage can be given.
In case of undesirable effects or symptoms of overdose (e.g. breast tenderness
and/or vaginal bleeding), the dose should be reduced.
In women with an intact uterus, a progestagen approved for addition to
estrogen treatment must be additionally administered for at least 12-14 days
every month/28 day cycle to oppose the development of an estrogenstimulated hyperplasia of the endometrium (see Section 4.4 Special Warnings
and Special Precautions for Use).
Unless there is a previous diagnosis of endometriosis, it is not recommended
to add a progestagen in hysterectomised women.
Two therapeutic regimens can be used:
a) Cyclic: EPIESTROL®-Septem is dosed cyclically with a treatment-free
interval, usually 21 days on and 7 days off. The progestagen is usually
added for 12-14 days of the cycle. Withdrawal bleeding may appear during
b) Continuous sequential: EPIESTROL®-Septem is dosed continuously. The
progestagen is usually added for 12-14 days (or more) of every 28 day
cycle, in a sequential manner.
Continuous sequential treatment may be recommended in cases when
marked symptoms of estrogen deficiency recur during the treatment-free
Withdrawal bleeding may occur when the progestagen is withdrawn.
The treatment with EPIESTROL®-Septem may be initiated at any convenient
time for women who are not currently on any estrogen therapy. Women
currently using cyclic or sequential estrogen/progestagen therapy should
complete the on-going treatment cycle before beginning treatment with
EPIESTROL®-Septem; the appropriate time to begin treatment with
EPIESTROL®-Septem would be the first day of a withdrawal bleeding.
Women who are already using continuous combined estrogen/progestagen
therapy may be switched to EPIESTROL®-Septem directly.
Method of administration
Apply EPIESTROL®-Septem to the skin of the hip, upper quadrant of the
buttock, lumbar region or abdomen and press firmly over the whole surface
and along the edges to ensure good adhesion.
The absorption capacity of the skin is the rate-determining factor in the release
of estradiol from EPIESTROL®-Septem. The application on another (higher)
skin region than on the mentioned preferred regions is not recommended, as
this might have an influence on the release of estradiol.
The skin of the application site should be clean, dry, not-greasy and free of
redness or irritation. Areas of the body which form folds or are subject to
friction during movement should be avoided.
EPIESTROL®-Septem should not be applied on or near the breasts.
Patches should not be applied twice consecutively to the same skin site.
If the patch is correctly applied, it will adhere to the skin for the required oneweek period without problems. In the event that a patch does come off, it
should be replaced with a new patch for the rest of the one-week dosing
period. The patch should then be changed again at the regular time to reestablish the patient’s routine schedule. Similarly, if the patch is not changed
on the scheduled day, it should be replaced as soon as possible and changed
again on the next scheduled day. Forgetting to apply a new patch at the
scheduled time may increase the likelihood of break-through bleeding and
If the patch is correctly applied, the patient may bathe or shower. However,
the patch may become detached after a very hot bath or sauna. If this occurs,
the patch should be replaced with a new one (as described above). Possibly the
sauna should be planned for a day scheduled for the change of the patch.
Known, past or suspected breast cancer;
Known or suspected estrogen-dependent malignant tumours
Undiagnosed genital bleeding;
Untreated endometrial hyperplasia;
Previous or current venous thromboembolism (deep venous thrombosis,
Known thrombophilic disorders (e.g. protein C, protein S, or
antithrombin deficiency, see section 4.4);
Active or recent arterial thromboembolic disease (e.g. angina,
Acute liver disease, or a history of liver disease as long as liver function
tests have failed to return to normal;
Known hypersensitivity to the active substances or to any of the
Special warnings and special precautions for use
For the treatment of postmenopausal symptoms, HRT should only be initiated
for symptoms that adversely affect quality of life. In all cases, a careful
appraisal of the risks and benefits should be undertaken at least annually and
HRT should only be continued as long as the benefit outweighs the risk.
Evidence regarding the risks associated with HRT in the treatment of premature
menopause is limited. Due to the low level of absolute risk in younger women,
however, the balance of benefits and risks for these women may be more
favourable than in older women.
Before initiating or reinstituting HRT, a complete personal and family
medical history should be taken. Physical (including pelvic and breast)
examination should be guided by this and by the contraindications and
warnings for use. During treatment, periodic check-ups are
recommended of a frequency and nature adapted to the individual
woman. Women should be advised what changes in their breasts should
be reported to their doctor or nurse (see ‘Breast cancer’ below).
Investigations, including appropriate imaging tools, e.g. mammography,
should be carried out in accordance with currently accepted screening
practices, modified to the clinical needs of the individual.
Conditions which need supervision
If any of the following conditions are present, have occurred previously
and/or have been aggravated during pregnancy or previous hormone
treatment, the patient should be closely supervised. It should be taken
into account that these conditions may recur or be aggravated during
treatment with EPIESTROL®-Septem, in particular:
leiomyoma (uterine fibroids) or endometriosis
risk factors for thromboembolic disorders (see below)
risk factors for estrogen dependent tumours, e.g. 1st degree heredity for
liver disorders (e.g. liver adenoma)
diabetes mellitus with or without vascular involvement
migraine or (severe) headache
systemic lupus erythematosus
a history of endometrial hyperplasia (see below)
Reasons for immediate withdrawal of therapy:
Therapy should be discontinued in case a contra-indication is discovered and in
the following situations:
jaundice or deterioration in liver function
significant increase in blood pressure
new onset of migraine-type headache
In women with an intact uterus the risk of endometrial hyperplasia and
carcinoma is increased when oestrogens are administered alone for
prolonged periods. The reported increase in endometrial cancer risk
among oestrogen-only users varies from 2-to 12-fold greater compared
with non-users, depending on the duration of treatment and oestrogen
dose (see section 4.8). After stopping treatment risk may remain
elevated for at least 10 years.
The addition of a progestagen cyclically for at least 12 days per
month/28 day cycle or continuous combined oestrogen-progestagen
therapy in non-hysterectomised women prevents the excess risk
associated with oestrogen-only HRT.
For patches releasing more than 50 μg/day the endometrial safety of
added progestagens has not been demonstrated.
Break-through bleeding and spotting may occur during the first months
of treatment. If break-through bleeding or spotting appears after some
time on therapy, or continues after treatment has been discontinued, the
reason should be investigated, which may include endometrial biopsy to
exclude endometrial malignancy.
Unopposed estrogen stimulation may lead to premalignant or malignant
transformation in the residual foci of endometriosis. Therefore, the
addition of progestagens to estrogen replacement therapy should be
considered in women who have undergone hysterectomy because of
endometriosis, if they are known to have residual endometriosis.
The overall evidence suggests an increased risk of breast cancer in women
taking combined oestrogen-progestagen and possibly also oestrogen-only
HRT, that is dependent on the duration of taking HRT.
Combined oestrogen-progestagen therapy
The randomised placebo-controlled trial the Women’s Health Initiative
study (WHI), and epidemiological studies are consistent in finding an
increased risk of breast cancer in women taking combined oestrogenprogestagen for HRT that becomes apparent after about 3 years (see Section
The WHI trial found no increase in the risk of breast cancer in
hysterectomised women using oestrogen-only HRT. Observational studies
have mostly reported a small increase in risk of having breast cancer
diagnosed that is substantially lower than that found in users of oestrogenprogestagen combinations (see section 4.8).
The excess risk becomes apparent within a few years of use but returns to
baseline within a few (at most five) years after stopping treatment.
HRT, especially oestrogen-progestagen combined treatment, increases the
density of mammographic images which may adversely affect the radiological
detection of breast cancer.
Ovarian cancer is much rarer than breast cancer. Long-term (at least 5-10
years) use of oestrogen-only HRT products has been associated with a slightly
increased risk of ovarian cancer (see section 4.8). Some studies including the
WHI trial suggest that the long-term use of combined HRTs may confer a
similar, or slightly smaller, risk (see Section 4.8).
HRT is associated with a 1.3-3 fold risk of developing venous
thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary
embolism. The occurrence of such an event is more likely in the first
year of HRT than later (see Section 4.8).
Patients with a history of VTE or known thrombophilic states have an
increased risk of VTE and HRT may add to this risk. HRT is therefore
contraindicated in these patients (see section 4.3).
Generally recognised risk factors for VTE include, use of oestrogens,
older age, major surgery, prolonged immobilisation, obesity (BMI > 30
kg/m2), pregnancy/postpartum period, systemic lupus erythematosus
(SLE), and cancer. There is no consensus about the possible role of
varicose veins in VTE.
As in all postoperative patients, prophylactic measures need be
considered to prevent VTE following surgery. If prolonged
immobilisation is to follow elective surgery temporarily stopping HRT
4 to 6 weeks earlier is recommended. Treatment should not be restarted
until the woman is completely mobilised.
In women with no personal history of VTE but with a first degree
relative with a history of thrombosis at young age, screening may be
offered after careful counselling regarding its limitations (only a
proportion of thrombophilic defects are identified by screening). If a
thrombophilic defect is identified which segregates with thrombosis in
family members or if the defect is ‘severe’ (e.g, antithrombin, protein
S, or protein C deficiencies or a combination of defects)
DERMESTRIL-Septem should only be used after careful risk/benefit
Women already on chronic anticoagulant treatment require careful
consideration of the benefit-risk of use of HRT.
If VTE develops after initiating therapy, the drug should be
discontinued. Patients should be told to contact their doctors
immediately when they are aware of a potential thromboembolic
symptom (e.g. painful swelling of a leg, sudden pain in the chest,
Coronary artery disease (CAD)
There is no evidence from randomised controlled trials of protection
against myocardial infarction in women with or without existing CAD
who received combined oestrogen-progestagen or oestrogen-only
Combined oestrogen-progestagen therapy:
The relative risk of CAD during use of combined oestrogen+progestagen HRT
is slightly increased. As the baseline absolute risk of CAD is strongly
dependent on age, the number of extra cases of CAD due to
oestrogen+progestagen use is very low in healthy women close to menopause,
but will rise with more advanced age.
Randomised controlled data found no increased risk of CAD in
hysterectomised women using oestrogen-only therapy.
Combined oestrogen-progestagen and oestrogen-only therapy are
associated with an up to 1.5-fold increase in risk of ischaemic stroke.
The relative risk does not change with age or time since menopause.
However, as the baseline risk of stroke is strongly age-dependent, the
overall risk of stroke in women who use HRT will increase with age
(see section 4.8).
Estrogens may cause fluid retention, and therefore patients with cardiac
or renal dysfunction should be carefully observed.
Women with pre-existing hypertriglyceridemia should be followed
closely during estrogen replacement or hormone replacement therapy,
since rare cases of large increases of plasma triglycerides leading to
pancreatitis have been reported with estrogen therapy in this condition.
Estrogens increase thyroid binding globulin (TBG), leading to increased
circulating total thyroid hormone, as measured by protein-bound iodine
(PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by
radio-immunoassay). T3 resin uptake is decreased, reflecting the
elevated TBG. Free T4 and free T3 concentrations are unaltered. Other
binding proteins may be elevated in serum, i.e. corticoid binding
globulin (CBG), sex-hormone-binding globulin (SHBG) leading to
increased circulating corticosteroids and sex steroids, respectively. Free
or biological active hormone concentrations are unchanged. Other
plasma proteins may be increased (angiotensinogen/renin substrate,
HRT use does not improve cognitive function. There is some evidence
of increased risk of probable dementia in women who start using
continuous combined or oestrogen-only HRT after the age of 65.
Interaction with other medicinal products and other forms of interaction
The metabolism of estrogens may be increased by concomitant use of
substances known to induce drug-metabolising enzymes, specifically
cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital,
phenytoin, carbamezapin) and anti-infectives (e.g. rifampicin, rifabutin,
Ritonavir and nelfinavir, although known as strong inhibitors, by contrast
exhibit inducing properties when used concomitantly with steroid hormones.
Herbal preparations containing St John’s wort (Hypericum Perforatum) may
induce the metabolism of estrogens.
At transdermal administration, the first-pass effect in the liver is avoided and,
thus, transdermally applied estrogens might be less affected than oral
hormones by enzyme inducers.
Clinically, an increased metabolism of estrogens and progestagens may lead to
decreased effect and changes in the uterine bleeding profile.
Pregnancy and lactation
EPIESTROL®-Septem is not indicated during pregnancy. If pregnancy occurs
during medication with EPIESTROL®-Septem treatment should be withdrawn
The results of most epidemiological studies to date relevant to inadvertent fetal
exposure to estrogens indicate no teratogenic or foetotoxic effects.
EPIESTROL®-Septem is not indicated during lactation.
Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been
More than 700 patients have been treated with the product in clinical trials.
Approximately 10 to 17% of the patients treated with EPIESTROL®-Septem in
clinical trials experienced systemic adverse reactions, which were mild and
transient. Breast tenderness was reported in 20-35% of patients. Local reactions
at the application site, mostly mild erythema with or without pruritus, occurred
in 10-25% of patients.
Serious undesirable effects associated with the use of hormone replacement
therapy are also mentioned in section 4.4 Special warnings and precautions for
The table below reports undesirable effects, that have been reported in users of
hormone replacement therapy (HRT) by MedDRA system organ classes
Uncommon ADRs, Rare ADRs
System Organ Class
(≥1/1,000, <1/100) (<1/1,000)
Immune system disorders
Metabolism and nutrition Weight increase or
Nervous system disorders Headache
Gastrointestinal disorders Abdominal pain,
Skin and subcutaneous Rash, Pruritus
Reproductive system and Uterine/Vaginal
Libido decreased or
Visual disturbances Contact lens intolerance
Breast pain, Breast Dysmenorrhea,
General disorders and
The most appropriate MedDRA term is used to describe a certain reaction and its
synonyms and related conditions.
Breast cancer risk
An up to 2-fold increased risk of having breast cancer diagnosed is
reported in women taking combined oestrogen-progestagen therapy for
more than 5 years.
Any increased risk in users of oestrogen-only therapy is substantially
lower than that seen in users of oestrogen-progestagen combinations.
The level of risk is dependent on the duration of use (see section 4.4).
Results of the largest randomised placebo-controlled trial (WHI-study)
and largest epidemiological study (MWS) are presented.
Million Women study– Estimated additional risk of breast cancer after 5 years’
Additional cases per 1000 HRT users over 5
over a 5 year
Oestrogen only HRT
*2 Taken from baseline incidence rates in developed countries.
# Overall risk ratio. The risk ratio is not constant but will increase with increasing
duration on use
Note: Since the background incidence of breast cancer differs by EU country, the
number of additional cases of breast cancer differs by EU country, the number of
additional cases of breast cancer will also change proportionately.
US WHI studies - additional risk of breast cancer after 5 years’ use
Incidence per Risk ratio & Additional cases per 1000 HRT users over 5
range 1000 women
(years) in placebo arm
over 5 years
0.8 (0.7 – 1.0) -4 (-6 – 0)*3
CEE+MPA oestrogen & progestagen§
1.2 (1.0 – 1.5) +4 (0 – 9)
*3 WHI study in women with no uterus, which did not show an increase in risk of
§ When the analysis was restricted to women who had not used HRT prior to the
study there was no increased risk apparent during the first 5 years of treatment:
after 5 years the risk was higher than in non-users.
Endometrial cancer risk
Postmenopausal women with a uterus
The endometrial cancer risk is about 5 in every 1000 women with an uterus not using
In women with a uterus, use of oestrogen-only HRT is not recommended because it
increases the risk of endometrial cancer (see section 4.4). Depending on the duration
of oestrogen-only use and oestrogen dose, the increase in risk of endometrial cancer in
epidemiology studies varied from between 5 and 55 extra cases diagnosed in every
1000 women between the ages of 50 and 65.
Adding a progestagen to oestrogen-only therapy for at least 12 days per cycle can
prevent this increased risk. In the Million Women Study the use of five years of
combined (sequential or continuous) HRT did not increase risk of endometrial cancer
(RR of 1.0 (0.8-1.2)).
Long-term use of oestrogen-only and combined oestrogen-progestagen HRT has been
associated with a slightly increased risk of ovarian cancer. In the Million Women
Study 5 years of HRT resulted in 1 extra case per 2500 users.
Risk of venous thromboembolism
HRT is associated with a 1.3-3-fold increased relative risk of developing venous
thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The
occurrence of such an event is more likely in the first year of using HT (see section
4.4). Results of the WHI studies are presented:
WHI Studies - Additional risk of VTE over 5 years’ use
Incidence per Risk ratio & Additional cases per 1000 HRT users
(years) in placebo arm
over 5 years
1 (-3 – 10)
Oral combined oestrogen-progestagen
2.3 (1.2 – 4.3) 5 (1 - 13)
* 4 Study in women with no uterus
Risk of coronary artery disease
o The risk of coronary artery disease is slightly increased in users of combined
oestrogen-progestagen HRT over the age of 60 (see section 4.4).
Risk of ischaemic stroke
The use of oestrogen-only and oestrogen + progestagen therapy is associated with
an up to 1.5 fold increased relative risk of ischaemic stroke. The risk of
haemorrhagic stroke is not increased during use of HRT.
This relative risk is not dependent on age or on duration of use, but as the
baseline risk is strongly age-dependent, the overall risk of stroke in women who
use HRT will increase with age, see section 4.4.
WHI studies combined - Additional risk of ischaemic stroke*5 over 5 years’
Incidence per Risk ratio & Additional cases per 1000 HRT users
range 1000 women
(years) in placebo arm
over 5 years
*5 No differentiation was made between ischaemic and haemorrhagic stroke
Other adverse reactions have been reported in association with oestrogen/progestagen
Gall bladder disease.
Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema
nodosum, vascular purpura.
Probable dementia over the age of 65 (see section 4.4).
Acute toxicity studies did not indicate a risk of acute adverse effects in case of
inadvertent intake of a multiple of the daily therapeutic dose.
Overdosage is unlikely with transdermal application. Nausea, vomiting and
withdrawal bleeding may occur in some women. There is no specific antidote
and treatment should be symptomatic. The patch(es) should be removed.
ATC code: G03CA03
Urogenital system and sex hormones
The active ingredient, synthetic 17β-estradiol, is chemically and biologically
identical to endogenous human estradiol. It substitutes for the loss of estrogen
production in menopausal women, and alleviates menopausal symptoms.
Clinical trial Information
Relief of menopausal symptoms was achieved during the first few weeks of
The average half-life of estradiol in plasma is about one hour. Plasma
clearance is 650-900 liter/day/m2. Estradiol is metabolised mainly in the liver,
the most important metabolites are estriol, estrone and their conjugates
(glucuronides, sulphates), which are much less active than estradiol. The
metabolites of estradiol are eliminated mainly by the kidney as glucuronides
and sulphates. The metabolites of estradiol are also found in faeces, due to an
Following cutaneous application of EPIESTROL®-Septem, estradiol is
released from the drug-containing adhesive matrix through the skin and
reaches the systemic circulation directly, avoiding first-pass metabolism by the
liver. Consequently, the estradiol:estrone ratio in plasma, which falls to values
below 1 after the menopause and during oral estrogen replacement therapy,
return to pre-menopausal levels (approximately 1) with transdermal estradiol.
The nominal daily in vivo release rate of EPIESTROL®-Septem 25 is 25µg of
estradiol; the system is active for one week. This release rate results in
physiological estradiol serum concentrations, i.e. in the range of those
observed during the premenopausal early follicular phase, which are
constantly maintained throughout the patch application period.
Physiological concentrations of estradiol were achieved 6 hours after
application of EPIESTROL®-Septem 25 in postmenopausal women, with
average concentrations over 147pmol/l after 12 hours.
Following repeated applications of EPIESTROL®-Septem 25 patches at one
week intervals, mean maximum serum estradiol concentrations of 169pmol/l
were obtained at steady-state. The serum concentration of estradiol remained
within the physiological levels of premenopausal women throughout the seven
days of application and returned to baseline within 12-24 hours after removal
of the patch.
The average concentration of estradiol in steady-state conditions was
95pmol/l. The Cmin of estradiol, shown to be at the steady state, was 48pmol/l.
Preclinical safety data
Animal studies with estradiol have shown expected estrogenic effects. There
are no preclinical data of relevance to the prescriber that are additional to those
already included in other sections of the SPC.
Local tolerance studies performed in the rabbit have demonstrated the good
skin tolerability of the transdermal patch after single and repeated applications.
The patch did not show any sensitisation potential in the guinea pig.
List of excipients
Adhesive matrix: acrylic copolymers (Durotak 387-2353; Durotak 387-2287)
Backing foil: polyethylene terephthalate
Special precautions for storage
Do not store above 25°C.
EPIESTROL®-Septem should be stored in an intact sachet.
Nature and contents of container
EPIESTROL®-Septem 25 is packed in a cardboard box containing 4 or 12
transdermal delivery systems sealed individually in protective sachets
consisting of 4 layers: Surlyn, heat-sealable material (inner layer), aluminium
foil, polyethylene and paper (outer layer).
Not all pack sizes may be marketed.
Special precautions for disposal
Tear open the sachet at the indentation (do not use scissors to avoid damaging
the patch) and remove the patch. Hold the patch between the thumb and index
finger at the corner of the pull-off-tag. Detach the protective liner with the
other hand and discard it.
Do not touch the adhesive side of the patch. Apply the patch to the skin
holding between the thumb and index finger the part still covered by the
protective liner. Detach the remaining part of the protective liner and press
firmly for about 10 seconds on the whole surface of the patch.
Pass a finger along the edges to assure good adhesion.
After use, the patch should be folded with the adhesive part inside and
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MARKETING AUTHORISATION NUMBER(S)
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
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