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Elleste Solo MX 80 micrograms Transdermal Patch


Elleste Solo MX 80 contains 2.5mg of estradiol (as hemihydrate) and each patch
delivers approximately 80 micrograms of estradiol per 24 hours
For excipients, see 6.1


Transdermal patch.
Elleste Solo MX 80 is a self adhesive, flexible transdermal patch comprising a layer
of clear adhesive sandwiched between a translucent patch and a metallised polyester
backing. Elleste Solo MX 80 is a rectangular shape with rounded corners and has an
active surface area of 28.5cm².




Therapeutic indications
Hormone replacement therapy (HRT) for estrogen deficiency symptoms in perimenopausal and post-menopausal women.
Prevention of osteoporosis in postmenopausal women at high risk of future fractures
who are intolerant of, or contraindicated for, other medicinal products approved for
the prevention of osteoporosis (see also Section 4.4).
The experience of treating women older than 65 years is limited.


Posology and method of administration
Elleste Solo MX 80 Transdermal Patch is an estrogen-only product for transdermal
Climacteric Symptoms:

For initiation and continuation of treatment of peri- and postmenopausal symptoms,
the lowest effective dose for the shortest duration (see also Section 4.4) should be
used. Therapy should be initiated with Elleste Solo MX 40 in women who have
menopausal symptoms. The dosage may be increased if required by using Elleste
Solo MX 80.
Prevention of Osteoporosis
Treatment should be with Elleste Solo MX 80
Dosage Schedule (for both indications):
Therapy may start at any time in women with established amenorrhoea or who are
experiencing long intervals between spontaneous menses. In women who are
menstruating, it is advised that therapy starts within five days of the start of bleeding.
Patients changing from a cyclical or continuous sequential preparation should
complete the cycle, and after a withdrawal bleed, may then change to Elleste Solo
MX 80. Patients changing from a continuous combined preparation may start therapy
at any time if amenorrhoea is established, or otherwise start within five days of the
start of bleeding.
One Elleste Solo MX 80 transdermal patch should be applied twice weekly on a
continuous basis. Each patch should be removed after 3 to 4 days and replaced with a
new patch applied to a slightly different site. Patches should be applied to clean, dry
and intact areas of skin below the waist on the lower back or buttocks. Elleste Solo
MX 80 should not be applied on or near the breasts.
Elleste Solo MX 80 should be given continuously and, in women with an intact
uterus, a progestogen is recommended and should be added for at least 12-14 days
each cycle. The benefits of the lower risk of endometrial hyperplasia and endometrial
cancer, due to adding progestogen, should be weighed against the increased risk of
Breast cancer, (See Sections 4.4 and 4.8). Unless there is a previous diagnosis of
endometriosis, it is not recommended to add a progestogen in hysterectomised
If the patch is not replaced at the normal time, it should be changed as soon as
There is an increased likelihood of break-through bleeding and spotting when a patch
is not replaced at the normal time.
Elleste Solo MX 80 is not indicated in children.



Known, past or suspected breast cancer;
Known or suspected oestrogen-dependent malignant tumours, (e.g. endometrial
Undiagnosed genital bleeding;
Untreated endometrial hyperplasia;
Active thrombophlebitis;
Previous idiopathic or current venous thromboembolism (deep vein thrombosis,
pulmonary embolism);
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, myocardial infarction);
Acute liver disease, or a history of liver disease as long as liver function tests have
failed to return to normal;
Dubin-Johnson and Rotor Syndromes (or monitor closely);
Known hypersensitivity to the active substances or to any of the excipients;


Special warnings and 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.
Medical examination/follow-up
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
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 Elleste Solo MX 80, in particular:

Risk factors for estrogen dependent tumours, e.g. 1st degree heredity for breast
cancer (see below);


Diabetes mellitus with or without vascular involvement;


Migraine or (severe) headache;




A history of, or risk of factors for, thromboembolic disorders (see below);


Systemic lupus erythematosus, SLE;


Liver disorders (e.g. liver adenoma);


Leiomyoma (uterine fibroids) or endometriosis;






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:
- Hepatitis, jaundice, liver enlargement or deterioration in liver function
Significant increase in blood pressure or blood pressure above systolic 160 mmHg or
diastolic 95 mmHg; Serious neurological effects including unusual severe, prolonged
headache especially if first time or getting progressively worse or sudden partial or
complete loss of vision or sudden disturbance of hearing or other perceptual disorders
or dysphasia or bad fainting attack or collapse or first unexplained epileptic seizure or
weakness, motor disturbances, very marked numbness suddenly affecting one side or
one part of body;

sudden severe chest pain (even if not radiating to left arm);


sudden breathlessness (or cough with blood-stained sputum);


unexplained swelling or severe pain in calf of one leg;


severe stomach pain;


prolonged immobility after surgery or leg injury.


New onset of migraine-type headache



Endometrial Hyperplasia and carcinoma

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 progestogen 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.

The endometrial safety of added progestogen has not been studied for Elleste Solo
MX 80.
The reduction in risk to the endometrium should be weighed against the increase in
the risk of breast cancer of added progestogen (See 'Breast cancer' below, and in
Section 4.8)
Breakthrough bleeding and spotting may occur during the first months of treatment. If
breakthrough 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 transformation in the
residual foci of endometriosis. Therefore, the addition of progestogens to estrogen
replacement therapy should be considered in women who have undergone
hysterectomy because of endometriosis, if they are known to have residual
endometriosis (but see above).
Breast Cancer
The overall evidence suggests an increased risk of breast cancer in women taking
combined oestrogenprogestage 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 oestrogen-progestagen for HRT
that becomes apparent after about 3 years (see Section 4.8)

Oestrogen-only therapy

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 estrogen-progestogen combined treatment, increases the density of
mammographic images which may adversely affect the radiological detection of
breast cancer.
Venous Thromboembolism
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)
Generally recognised risk factors for VTE include use of oestrogens, older age, major
surgery, prolonged immobilisation, obesity (BMI>30 kg/m2), pregnancy/postpartum
period and 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.
Patients with 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
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) HRT is contraindicated.
Those women already on 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 doctor immediately when
they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg,
sudden pain in the chest, dyspnea).
Coronary Artery Disease
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 HRT.

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.
Ischaemic Stroke
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).
Ovarian 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).
Other Conditions
Oestrogens may cause fluid retention and therefore patients with cardiac or renal
dysfunction should be carefully observed. Patients with terminal renal insufficiency
should be closely observed, since it is expected that the level of circulating active
ingredients in Elleste Solo MX 80 is increased.
Women with pre-existing hypertriglyceridaemia 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.
Oestrogens 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 biologically active
hormone concentrations are unchanged. Other plasma proteins may be increased
(angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

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.

In rare cases benign, and in even rarer cases malignant liver tumours leading in
isolated cases to life-threatening intra-abdominal haemorrhage have been observed
after the use of hormonal substances such as those contained in Elleste Solo MX 80.
If severe upper abdominal complaints, enlarged liver or signs of intra-abdominal
haemorrhage occur, a liver tumour should be considered in the differential diagnosis.
Women who may be at risk of pregnancy should be advised to adhere to nonhormonal contraceptive methods.
The requirement for oral anti-diabetics or insulin can change as a result of the effect
on glucose tolerance.


Interaction with other medicinal products and other forms of interaction
Oestrogens antagonise the effects of phenindione.
The metabolism of oestrogens may be increased by concomitant use of substances
known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes,
such as anticonvulsants, (e.g. carbamezapine, phenobarbitol, phenytoin) and antiinfectives, (e.g. rifampicin, rifabutin, nevirapine, or efavirenz).
Ritonavir and nelfinavir, although known 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 oestrogens.
Oestrogens have also been found to interact with the following drugs:
Coumarins, lamotrigine, and selegiline.
At transdermal administration, the first-pass effect in the liver is avoided and, thus,
transdermally applied oestrogens might be less affected than oral hormones by
enzyme inducers.
Clinically, an increased metabolism of oestrogens may lead to decreased effect and
changes in the uterine bleeding profile.

Some laboratory tests can be influenced by oestrogens such as tests for thyroid
function or glucose tolerance, (see Section 4.4).


Fertility, pregnancy and lactation
Elleste Solo MX 80 is not indicated during pregnancy. If pregnancy occurs during
medication with Elleste Solo MX 80, treatment should be withdrawn immediately.
The results of most epidemiological studies to date relevant to inadvertent foetal
exposure to estrogens indicate no teratogenic or foetotoxic effects.
Elleste Solo MX 80 is not indicated during lactation.


Effects on ability to drive and use machines


Undesirable effects
Elleste Solo MX 80 is generally well tolerated. The most frequent side effects,
(reported in 10 to 20 % of patients, on at least one occasion, in clinical trials with
Elleste Solo MX 80) which do not normally prevent continued treatment include:
breast tenderness, headaches and breakthrough bleeding. Some patients experience
mild and transient local erythema at the site of application with or without itching;
this usually disappears rapidly on removal of the patch. The overall incidence of
general patch irritation in clinical studies is less than 5 %. In a clinical study 3 % of
102 patients showed well defined erythema (Draize scale) 30 minutes after patch
removal. No instances of permanent skin damage have been reported. If unacceptable
topical side effects do occur discontinuation of treatment should be considered.
The following adverse reactions have been reported with Elleste Solo MX 80 and/or
oestrogen therapy:

Very Common Common
< 1/10


Rare ADRs
< 1/1000

System Organ

Very Rare
< 1/10,000


Infections and
benign, malignant
and unspecified
(incl. cysts and
Metabolism and

Frequency Not Known



Breast cancer*; Endometrial
neoplasm*; Uterine

Sodium retention; Fluid


retention; Weight


Mood altered (elation or
depression); Libido disorder

Nervous system

Cerebrovascular accident*;
Dementia*; Migraine;
Dizziness; Chorea;
Exertional headache


Eye disorders

Astigmatism; Visual
impairment; Contact lens

Cardiac disorders

Myocardial infarction*


Embolism venous*;
Hypertension; Thrombosis;


Pancreatitis; Nausea;
Vomiting; Abdominal pain;


Cholelithiasis; Jaundice
cholestatic; Gallbladder

Skin and
tissue disorders

Chloasma (may persist
when drug
Erythema multiforme;
Erythema nodosum;
Vascular purpura; Rash;
Alopecia; Hirsutism

and connective
tissue disorders

Muscle spasms

Renal and
urinary disorders

Cystitis-like symptom

system and breast


Endometriosis; Vaginal
haemorrhage; Ectropion of
cervix; Cervical discharge;
Uterine cervical erosion;
Breast pain;
enlargement; Breast
discharge; Premenstrual

familial and
genetic disorders
General disorders



site conditions
Glucose tolerance


Breast Cancer

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

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’
Age range

Additional cases per 1000
never-users of HRT over a 5
year period*2

Risk ratio &

Additional cases per 1000
HRT users over 5 years

Oestrogen only HRT




Combined oestrogen-progestagen




#Overall risk ratio. The risk ratio is not constant but will increase with increasing duration on
Note: Since the background incidence of breast cancer differs by EU country, the number of
additional cases of breast cancer will also change proportionately.

*2 Taken from baseline incidence rates in developed countries
US WHI studies - additional risk of breast cancer after 5 years’ use
Age range (yrs)

Incidence per 1000
women in placebo
arm over 5 years

Risk ratio & 95%CI
Additional cases per
1000 HRT

users over 5 years

CEE oestrogen-only




CEE+MPA oestrogen & progestagen‡





‡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.
*3 WHI study in women with no uterus, which did not show an increase in risk of
breast cancer

Endometrial cancer
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)).

Ovarian cancer
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:
WHI Studies - Additional risk of VTE over 5 years’ use

Age range (years)


Risk ratio and

per 1000 women in


placebo arm over 5

Additional cases per
1000 HRT users over
5 years

Oral oestrogen-only*4


1.2 (0.6-2.4)

1 (-3 – 10)

2.3 (1.2 – 4.3)

5 (1 - 13)

Oral combined oestrogen-progestagen

*4 Study in women with no uterus
Risk of coronary artery disease

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’ use

Age range (years)


Risk ratio and

per 1000 women in


Additional cases per
1000 HRT users over
5 years

placebo arm over 5




*5 no differentiation was made between ischaemic and haemorrhagic stroke


This is not likely due to the mode of administration. If it is necessary to stop delivery
then the patch can be removed and plasma estradiol levels will fall rapidly.




Pharmacodynamic properties
Pharmacotherapeutic group:
Natural and semisynthetic oestrogens, plain.

ATC Code G03C A
The active ingredient, synthetic 17 -estradiol, is chemically and biologically identical
to endogenous human estradiol. It substitutes for the loss of oestrogen production in
menopausal women, and alleviates menopausal symptoms. Oestrogens prevent bone
loss following menopause or ovariectomy.


Oestrogen deficiency at menopause is associated with an increasing bone turnover
and decline in bone mass. The effect of oestrogens on the bone mineral density is
dose-dependent. Protection appears to be effective for as long as treatment is
After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated
Evidence from the WHI trial and meta-analysed trials shows that current use of HRT,
alone or in combination with a progestagen – given to predominantly healthy women
– reduces the risk of hip, vertebral, and other osteoporotic fractures. HRT may also
prevent fractures in women with low bone density and/or established osteoporosis,
but the evidence for that is limited.


Pharmacokinetic properties
Estradiol is absorbed from the patch across the stratum corneum and is delivered
systemically at a low but constant rate throughout the period of application (3 to 4
days). The estimated delivery of estradiol is approximately 80 g/day for Elleste Solo
MX 80.


Steady state plasma estradiol concentrations have been demonstrated in the range
from Cmin 34 pg/ml to Cmax 62 pg/ml for the Elleste Solo MX 80 patch (including
baseline levels) and these are maintained throughout the dose interval (for up to four
days). Absorption rate may vary between individual patients. After removal of the last
patch plasma estradiol and estrone concentrations return to baseline values in less
than 24 hours.
Estradiol is mainly metabolized in the liver. Its main metabolites are estriol, estrone,
and their conjugates. The plasma half life of estradiol is 1-2 hours. Metabolic plasma
clearance varies between 450-625 ml/min/m2. The metabolites are mainly excreted
via the kidneys as glucuronides and sulphates. Oestrogens also undergo enterohepatic


Preclinical safety data
No additional information is available.




List of excipients
Acrylic adhesive (Dow Corning MG-0560)
Acrylic emulsion (Acrysol 33),
Backing: Polyester film (Scotchpak 9733)
Release liner: Siliconised aluminised polyester.


Not applicable.


Shelf life
3 years.


Special precautions for storage
Do not store above 25°C. Store in the original package.


Nature and contents of container
Sachet made out of laminate comprising of paper (clay coated), bonding layer of
LDPE, aluminium foil and heat seal layer of LDPE.containing one transdermal patch.
Each carton contains eight patches, sufficient for one 28 day cycle and a patient
leaflet. An additional pack containing two patches may also be available.


Special precautions for disposal
Detailed instructions for use are provided in the patient leaflet.


Meda Pharmaceuticals Ltd
Skyway House
Parsonage Road
Bishop’s Stortford
CM22 6PU


PL 15142/0059





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Source: Medicines and Healthcare Products Regulatory Agency

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