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EVOREL 50

Active substance(s): ESTRADIOL / ESTRADIOL

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
EVOREL 50

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each Evorel 50 patch contains estradiol 3.20 mg.

3

PHARMACEUTICAL FORM
Evorel is a square shaped, transparent, self-adhesive transdermal therapeutic
system (patch) of surface area 16sq. cm and 0.2 mm thickness, for application
to the skin surface. It consists of a monolayered adhesive matrix throughout
which 17β estradiol is uniformly distributed. The adhesive matrix is protected
on the outside surface (from clothes etc.) by a polyethylene teraphthalate
backing foil, while the adhesive surface of the patch is covered by a polyester
sheet (the release liner) which is removed before placing the patch on the body
surface. This release liner has an S-shaped incision which facilitates easy
removal from the patch.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in
peri- 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 Section 4.4)
The experience treating women older than 65 years is limited.

4.2

Posology and method of administration
Adults
Evorel is an oestrogen-only HRT patch applied to the skin twice weekly.
For initiation and continuation of treatment of menopausal symptoms, the lowest
effective dose for the shortest duration (see also Section 4.4) should be used.
For women with an intact uterus progestogen should normally be added to Evorel for
the prevention of adverse endometrial effects, e.g. hyperplasia and cancer. The
regimen may be either cyclic or continuous sequential.
Only progestogens approved for addition to oestrogen treatment may be prescribed
(e.g. oral norethisterone, 1 mg/day or medroxyprogesterone acetate, 2.5 mg/day) and
should be added for at least 12-14 days every month/28 day cycle.
Unless there is a previous diagnosis of endometriosis, it is not recommended to add a
progestogen in hysterectomised women.
Treatment of oestrogen deficiency symptoms
Therapy should be started with one Evorel 50 patch (delivering 50 micrograms of
estradiol/24 hours) and the dose adjusted after the first month if necessary depending
on efficacy and signs of over-oestrogenisation (eg breast tenderness). For
maintenance therapy the lowest effective dose should be used; a maximum dose of
100 micrograms of estradiol/24 hours should not be exceeded.

Prevention of post-menopausal osteoporosis
Therapy should be started with Evorel 50. The dose may be adjusted depending on
efficacy and signs of over-oestrogenisation (eg breast tenderness). Note, however,
that the efficacy of Evorel 25 for the prevention of post-menopausal osteoporosis has
not been demonstrated. For maintenance therapy, the lowest effective dose should be
used. A dose of 100micrograms of estradiol/24 hours should not be exceeded.
Guidance on how to start therapy:
Post-menopausal women currently not on HRT may start Evorel at any time.
Peri-menopausal women who are still having regular menstrual cycles and are not
currently on HRT should start Evorel within 5 days of the start of bleeding. Perimenopausal women with irregular menstrual cycles, for whom pregnancy has been
excluded, can start Evorel at any time.
Switching from other HRT
The switch from another oestrogen-only therapy in post-menopausal women to
Evorel may occur at any time.
Women on a continuous combined regimen wishing to switch from another oestrogen
to Evorel may do so at any time.
Women on a cyclic or continuous sequential regimen wishing to switch from a
sequential combined HRT preparation to Evorel may do so at the end of a cycle of the
current therapy or after a 7 day hormone free interval.
Method of Administration
Evorel should be applied to the skin as soon as it is removed from the wrapper.
Recommended application sites are on clean, dry, healthy, intact skin and each
application should be made to a slightly different area of skin on the trunk below
waistline. Evorel should not be applied on or near the breasts.

Evorel should remain in place during bathing and showering. Should it fall off during
bathing or showering the patient should wait until cutaneous vasodilation ceases
before applying a replacement patch to avoid potential excessive absorption. Should
a patch fall off at other times it should be replaced immediately.
Patients can be advised to use baby oil to help remove any gum/glue which may
remain on their skin after patch removal.
Missed dose
If the patient forgets to change their patch, they should change it as soon as possible
and apply the next one at the normal time. However, if it is almost time for the next
patch, the patient should skip the missed one and go back to their regular schedule.
Only one patch should be applied at a time.
There is an increased likelihood of break-through bleeding and spotting when a patch
is not replaced at the normal time.
Children
Evorel is not indicated in children.
Elderly
Data are insufficient in regard to the use of Evorel in the elderly (>65 years old).
Route of administration

4.3

4.4

Transdermal use.
Contraindications


Known, current or past, or suspected breast cancer



Known or suspected oestrogen-dependent malignant tumours (eg
endometrial cancer) or pre-malignant tumours (e.g. untreated atypical
endometrial hyperplasia)



Undiagnosed genital bleeding



Previous idiopathic or current venous thrombo-embolism (deep venous
thrombosis, pulmonary embolism)



Active or recent past arterial thrombo-embolic disease (eg
cerebrovascular accident angina, myocardial infarction)



Acute liver disease, or a history of liver disease as long as liver
function tests have failed to return to normal



Known thrombophilic conditions (e.g.protein C, Protein S or
antithrombin deficiency see section 4.4).



Known hypersensitivity to the active substances or to any of the
excipients



Porphyria

Special warnings and precautions for use
For the treatment of menopausal 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 re-instituting 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 contra-indications 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
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 Evorel, in particular:
Leiomyoma (uterine fibroids) or endometriosis
A history of, or risk factors for, thrombo-embolic disorders (see below)
Risk factors for oestrogen dependent tumours, eg 1st degree heredity for breast cancer
Hypertension
Liver disorders (eg liver adenoma)
Diabetes mellitus with or without vascular involvement
Cholelithiasis
Migraine or (severe) headache
Systemic lupus erythematosus
A history of endometrial hyperplasia (see below)
Epilepsy
Asthma
Otosclerosis
Hereditary angioedema
Mastopathy
Conditions which require monitoring while on oestrogen therapy:


Oestrogens may cause fluid retention. Cardiac or renal dysfunction should be
carefully observed



Disturbances or mild impairment of liver function



History of cholestatic jaundice



Pre-existing hypertriglyceridaemia. Rare cases of large increases of plasma
triglycerides leading to pancreatitis have been reported with oestrogen
therapy in this condition

Reasons for immediate withdrawal of therapy:
Therapy should be discontinued if 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



Pregnancy

Endometrial hyperplasia
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, the risk may remain
elevated for at least 10 years. Oestrogen-only therapy from 1 to 5 years in women
with a uterus has been estimated to increase the risk of endometrial cancer 3-fold
(from a baseline lifetime risk of about 3% for a woman aged 50 years), with effects
persisting for several years after oestrogen is stopped. The addition of a progestogen
for 12-14 days per cycle or continuous combined oestrogen/progestogen therapy in
non-hysterectomised women greatly reduces this risk.
Although progestogen treatment for at least 10 days per cycle reduces the risk of
endometrial hyperplasia, which may be a precursor to endometrial cancer, 12-14 days
per cycle is recommended to maximise endometrial protection. Such a sequential
oestrogen/oestrogen-progestogen regimen results in cyclic bleeding in the majority of
women.
For Evorel 75 and 100 the endometrial safety of added progestogens has not been
studied.
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 oestrogen stimulation may lead to premalignant or malignant
transformation in the residual foci of endometriosis. Therefore, the addition of a
progestogen to oestrogen replacement therapy should be considered in women who
have undergone hysterectomy because of endometriosis if they are known to have
residual endometriosis.
Breast cancer
The overall evidence suggests an increased risk of breast cancer in women taking
combined oestrogen-progestogen and possibly also oestrogen-only HRT, that is
dependent on the duration of taking HRT.
Combined oestrogen-progestogen 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-progestogen 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 lower than that found
in users of oestrogen-progestogen 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 oestrogenprogestogen combined treatment, increases the density of mammographic images
which may adversely affect the radiological detection of breast cancer.
Ovarian cancer
Ovarian cancer is much rarer than breast cancer. Epidemiological evidence from a
large meta-analysis suggests a slightly increased risk in women taking oestrogen-only
or combined oestrogen-progestogen HRT, which becomes apparent within 5 years of
use and diminishes over time after stopping. Some other studies, including the WHI
trial, suggest that the use of combined HRTs may be associated with a similar or
slightly smaller risk (see Section 4.8).
Venous thrombo-embolism
HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. One randomised
controlled trial and epidemiological studies found a two- to threefold higher risk for
users compared with non-users. For non-users it is estimated that the number of cases
of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59
years and 8 per 1000 women aged 60-69 years. It is estimated that in healthy women
who use combined oral HRT for 5 years, the number of additional cases of VTE over
a 5 year period will be between 2 and 6 (best estimate =4) per 1000 women aged 5059 years and between 5 and 15 (best estimate =9) per 1000 women aged 60-69 years.
The occurrence of such an event is more likely in the first year of HRT than later.
Generally recognised risk factors for VTE include a personal history or family
history, use of oestrogens, older age, severe obesity (BMI > 30 kg/m2),
pregnancy/postpartum period, cancer and systemic lupus erythematosus (SLE). There
is no consensus about the possible role of varicose veins in VTE.
Patients with a history of VTE or known thrombophilic states have an increased risk
of VTE. HRT may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to
exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic
factors has been made or anticoagulant treatment initiated, use of HRT in such
patients should be viewed as contra-indicated. The women already on anticoagulant
treatment require careful consideration of the benefit-risk of use of HRT.
The risk of VTE may be temporarily increased with prolonged immobilisation, major
trauma or major surgery. As in all postoperative patients, scrupulous attention should
be given to prophylactic measures to prevent VTE following surgery. Where
prolonged immobilisation is liable to follow elective surgery, particularly abdominal
or orthopaedic surgery to the lower limbs, consideration should be given to
temporarily stopping HRT 4 to 6 weeks earlier, if possible. Treatment should not be
restarted until the woman is completely mobilised.
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
thrombo-embolic symptom (eg, painful swelling of a leg, sudden pain in the chest,
dyspnoea).
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 HRT.
Oestrogen-only: Randomised controlled data found no increased risk of CAD in
hysterectomised women using oestrogen-only therapy. Combined oestrogenprogestogen therapy: The relative risk of CAD during use of combined oestrogenprogestogen HRT is slightly increased. The absolute risk of CAD is strongly
dependent on age. The number of extra cases of CAD due to oestrogen-progestogen
use is very low in healthy women close to menopause, but will rise with more
advanced age.
Stroke
One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an
increased risk of ischaemic stroke in healthy women during treatment with
continuous combined conjugated oestrogens and and medroxyprogesterone acetate
(MPA). For women who do not use HRT, it is estimated that the number of cases of
stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59
years and 11 per 1000 women aged 60-69 years. It is estimated that for women who
use conjugated oestrogens and MPA for 5 years, the number of additional cases will
be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between
1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether
the increased risk also extends to other HRT products.
Combined oestrogen-progestogen 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 or duration of use. 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.
Other conditions
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 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, alpha-l-antitrypsin, ceruloplasmin).
Chloasma may occasionally occur, especially in women with a history of chloasma
gravidarum. Women with a tendency to chloasma should minimise exposure to the
sun or ultraviolet radiation whilst taking HRT.
Dementia
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.
Evorel is not to be used for contraception. Women of child-bearing potential should
be advised to use non-hormonal contraceptive methods to avoid pregnancy.

4.5.

Interaction with other medicinal products and other forms of
interaction

The metabolism of oestrogens and progestogens 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, carbamazepine) and anti-infectives (e.g., rifampicin,
rifabutin, nevirapine, efavirenz) and also bosentan.
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
raise the metabolism of oestrogens and progestogens.
With transdermal administration, the first-pass effect in the liver is avoided
and thus, transdermally applied oestrogens and progestogens might be less
affected by enzyme inducers than oral hormones.
Clinically, an increased metabolism of oestrogens and progestogens may lead
to decreased effect and changes in the uterine bleeding profile.
Estrogen-containing oral contraceptives have been shown to significantly
decrease plasma concentrations of lamotrigine when co-administered due to
induction of lamotrigine glucuronidation. This may reduce seizure control.
Although the potential interaction between estrogen-containing hormone
replacement therapy and lamotrigine has not been studied, it is expected that a
similar interaction exists, which may lead to a reduction in seizure control
among women taking both drugs together. Therefore, dose adjustment of
lamotrigine may be necessary.
4.6

Fertility, pregnancy and lactation
Pregnancy
Evorel is not indicated during pregnancy. If pregnancy occurs during use of
Evorel, treatment should be withdrawn immediately.
There are no clinical data on exposed pregnancies.
Studies in animals have not shown reproductive toxicity.
The results of most epidemiological studies to date relevant to inadvertent
foetal exposure to oestrogens indicate no teratogenic or foetotoxic effect.
Lactation
Evorel is not indicated during lactation.

4.7.

Effects on Ability to Drive and Use Machines
In normal use, Evorel would not be expected to have any effect on the ability
to drive or use machinery.

4.8

Undesirable effects
The safety of Evorel was evaluated in 2584 subjects who participated in 15
clinical trials and received at least one administration of Evorel. Subjects were
also asked about application site signs and symptoms in 8 of the 15 clinical
trials (N = 1739 subjects). Based on safety data from these clinical trials, the
most commonly reported (≥5% incidence) adverse drug reactions (ADRs)
were (with % incidence): application site rash (20.8%), application site
pruritus (19.8%), application site erythema (8.5%), headache (7.8%), and
breast pain (6.6%).
Including the above-mentioned ADRs, the following table displays ADRs that
have been reported with the use of Evorel from either clinical trial or postmarketing experiences. The displayed frequency categories use the following
convention:
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); and not known (cannot be estimated from the available
clinical trial data).
Adverse Drug Reactions
Infections and Infestations
Uncommon

Genital candidiasis

Neoplasms benign, malignant and unspecified (including cysts and polyps)
Rare
Frequency not known

Breast cancer
Endometrial cancer

Immune System Disorders
Uncommon

Hypersensitivity

Psychiatric disorders
Common

Depressed mood

Nervous system disorders
Common
Rare
Frequency not known

Migraine, Dizziness, Headache
Epilepsy
Cerebrovascular accident

Cardiac disorders
Uncommon
Frequency not known

Palpitations
Myocardial infarction

Vascular disorders
Rare
Frequency not known

Thrombosis
Deep vein thrombosis

Respiratory, Thoracic and Mediastinal Disorders
Frequency not known

Pulmonary embolism

Gastrointestinal disorders
Common
Uncommon
Rare

Abdominal pain, Diarrhoea, Nausea
Flatulence
Abdominal distension

Hepato-biliary disorders
Rare

Cholelithiasis

Skin and subcutaneous tissue disorders
Common
Frequency not known

Pruritus, Rash
Angioedema

Musculoskeletal and Connective Tissue Disorders
Common
Uncommon

Arthralgia
Myalgia

Reproductive system and breast disorders
Common
Uncommon

Breast pain, Metrorrhagia
Breast enlargement, Dysmenorrhoea

General disorders and administration site conditions
Very Common
Common

Application site pruritus*, Application site rash*
Pain, Application site erythema*, Application site oedema*,
Application site reaction
Oedema, Generalised oedema, Oedema peripheral

Uncommon
Investigations
Common
Weight increased
* Additional adverse drug reactions reported in clinical trials of Evorel
(estradiol only).

The table below reports additional undesirable effects that have been reported
in users of other hormone replacement therapy (HRT) by MedDRA system
organ classes (MedDRA SOCs).
Metabolism and nutrition disorders

Common

Weight decrease

Psychiatric disorders

Rare

Anxiety, Libido decreased, Libido increased

Eye disorders

Uncommon
Rare

Visual disturbances
Contact lens intolerance

Gastrontestinal disorders

Common
Uncommon
Rare

Nausea
Dyspepsia
Vomiting

Skin and subcutaneous tissue

Uncommon
Rare

Erythema nodosum,
Hirsutism, Acne

Musculoskeletal and connective tissue disorders

Rare

Muscle cramps

Reproductive system and breast disorders

Uncommon
Rare

Breast tenderness
Vaginal discharge, Premenstrual like syndrome

General disorders and administration conditions

Rare

Fatigue

Other adverse reactions have been reported in association with
oestrogen/progestogen treatment:





Gall bladder disease.
Skin and subcutaneous disorders: chloasma, erythema multiforme,
Vascular purpura.
Probable dementia over the age of 65 (see section 4.4).

Serious undesirable effects associated with the use of hormone replacement therapy
are also mentioned in section 4.4 Special warnings and precautions for use
Breast Cancer
According to evidence from a large number of epidemiological studies and one
randomised placebo-controlled trial, the Women’s Health Initiative (WHI), the
overall risk of breast cancer increases with increasing duration of HRT use in current
or recent HRT users. 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.
For oestrogen plus progestogen combined HRT, several epidemiological studies have
reported an overall higher risk for breast cancer than with oestrogens alone.
Results of the largest randomised placebo-controlled trial (WHI-study) and largest
epidemiological study (MWS) are presented below:
Million Women study– Estimated additional risk of breast cancer after 5 years’
use
Age range
(years)

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 (95% CI)

Oestrogen only HRT
1.2
1-2 (0 - 3)
Combined oestrogen-progestagen
50-65
9-12
1.7
6 (5 - 7)
*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.
50-65

9-12

US WHI studies - additional risk of breast cancer after 5 year’s use

Age range
(years)

Incidence per 1000
women in placebo arm
over 5 years

Risk ratio & 95%CI

Additional cases per 1000
HRT users over 5 years
(95% CI)

CEE oestrogen only
0.8 (0.7-1.0)
-4 (-6 - 0)*3
CEE + MPA oestrogen & progestagens §
50-79
17
1.2 (1.0-1.5)
+4 (0 - 9)
*3 WHI study in women with no uterus, which did not show an increase of breast cancer.
§ 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.
50-79

21

Endometrial Cancer
In women with an intact uterus, the risk of endometrial hyperplasia and
endometrial cancer increases with increasing duration of use of unopposed
oestrogens. According to data from epidemiological studies, the best estimate
of the risk is that for women not using HRT, about 5 in every 1000 are
expected to have endometrial cancer diagnosed between the ages of 50 and 65.
Depending on the duration of treatment and oestrogen dose, the reported
increase in endometrial cancer risk among unopposed oestrogen users varies
from 2- to 12-fold greater compared with non-users. Adding a progestogen to
oestrogen-only therapy greatly reduces 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
Use of oestrogen-only or combined oestrogen-progestogen HRT has been associated
with a slightly increased risk of having ovarian cancer diagnosed (see Section 4.4).
A meta-analysis from 52 epidemiological studies reported an increased risk of
ovarian cancer in women currently using HRT compared to women who have never
used HRT (RR 1.43, 95% CI 1.31-1.56). For women aged 50 to 54 years taking 5
years of HRT, this results in about 1 extra case per 2000 users. In women aged 50 to
54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian
cancer over a 5-year period.
Adverse events which have been reported in association with oestrogen/ progestogen
treatment :
Venous thrombo-embolism, ie deep leg or pelvic venous thrombosis and pulmonary
embolism, is more frequent among hormone HRT users than among non-users. For
further information see Section 4.3 Contra-indications and 4.4 Special warnings and
precautions for use.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal
product is important. It allows continued monitoring of the benefit/risk balance
of the medicinal product. Healthcare professionals are asked to report any
suspected adverse reactions via the Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard.
4.9

Overdose
By virtue of the mode of administration of Evorel, overdosage is unlikely, but effects
can if necessary be reversed by removal of the patch. The most commonly observed

symptoms of overdose with oestrogen therapy are breast pain or tenderness, nausea,
vomiting and breakthrough bleeding, abdominal cramps or bloating. There is no
specific antidote and treatment should be symptomatic.

5.

PHARMACOLOGICAL PROPERTIES

5.1.

Pharmacodynamic Properties
ATC code: G03CA03
Estradiol hemihydrate:
The active ingredient, synthetic 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.
Clinical trial information:
Relief of menopausal symptoms was achieved to a similar degree during the
first few weeks of treatment with Evorel 50 and Evorel 100.
Prevention of osteoporosis
Oestrogen deficiency at menopause is associated with increasing bone
turnover and decline in bone mass. The effect of oestrogens on the bone
mineral density (BMD) is dose-dependent; the relationship is not linear,
however. Protection appears to be effective as long as treatment is continued.
After discontinuation of HRT, bone mass is lost at a rate similar to that in
untreated women.
Evidence from the WHI trial and meta-analysed trials shows that current use
of HRT, alone or in combination with a progestogen – 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.
In a clinical trial of two years duration comparing Evorel 50 and 100 to
placebo, the increase in lumbar spine bone mineral density (BMD) with Evorel
50 was 4.46 ± 4.04 % (mean±SD). With Evorel 100, the gain in lumbar spine
bone density was 5.93 ± 4.34 %.
The percentage of women who maintained or gained BMD in the lumbar spine
with Evorel 50 was 84% and with Evorel 100, 92.5%.
Evorel also had an effect on hip BMD. The increase in BMD in the femoral
neck with Evorel 50 was 1.26 ± 2.86 % and with Evorel 100, 1.61±0.53 %.
The percentage of women maintaining or gaining BMD in the femoral neck
was 65 and 63.5 %, respectively. In the total hip, the increase in BMD was
2.17 ± 2.33 % with Evorel 50 and 2.82±0.51 % with Evorel 100. The

percentage of women maintaining or gaining BMD in the total hip was 93 and
82.5 %, respectively.
5.2.

Pharmacokinetic Properties
The estradiol hemihydrate of the patch is taken up through the skin as
estradiol. Estradiol is metabolised primarily in the liver to estrone, which has
weak estrogenic activity. Estrone is either conjugated with glucuronic or
sulphuric acid or reconverted to estradiol. Conjugates are excreted mainly by
the kidneys. In contrast to oral preparations, the estradiol / estrone ratio on use
of Evorel is in the physiological range below 2, similar to that in premenopausal women.
Estradiol circulates in the blood bound to sex hormone binding globulin (3545%) and albumin (60-65%).
Estradiol is metabolised mainly in the liver by the P450 enzyme system. (see
Section 4.5 Interactions).
Due to the transdermal administration, there is no noticeable first-pass effect.
Pharmacokinetic parameters for the four sizes of Evorel patches are shown in
the following table.
Evorel 25
Evorel 50
Evorel 75
Serum estradiol (pmol/L; mean+/-SD)
Cmax
C96h
Cavg

5.3.

151±
64±
96±

69
27
35

277±
113±
173±

121
47
68

473±
176±
271±

Evorel 100
286
112
161

655±
226±
382±

Preclinical Safety Data
Preclinical effects were observed at exposures considered sufficiently in
excess of the maximum human exposure, or were related to an exaggerated
pharmacological effect, or were related to differences between species
regarding hormonal regulation/metabolism and indicate little relevance to
clinical use.
Subchronic skin irritation studies in rabbits and dermal sensitisation tests in
guinea pigs have been performed. The studies show that the estradiol
transdermal patch is an irritant and that estradiol contributes to the irritancy. It
is recognised that test studies on rabbits over-predict skin irritation which
occurs in humans.
The dermal sensitisation test shows that Evorel is not a skin sensitiser.

447
125
232

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Adhesive acrylic polymer (Duro-Tak 387-2287)
Guar gum
Hostaphan MN19 (polyester film - removed before application)

6.2.

Incompatibilities
None known.

6.3

Shelf life
24 months for the product as packed for sale.

6.4.

Special Precautions for Storage
Do not store above 25°C.

6.5.

Nature and Contents of Container
Each Evorel 50 patch is presented in a sealed protective pouch. The pouches
are packed in a cardboard carton. (Pack sizes 2, 8, 10, 24, 26, 30, 48, 60
patches).
Evorel 50 is available in a combination pack as Evorel Pak. Evorel Pak
contains 8 x Evorel 50 Patches (PL/0242/0223) and 12 x 1 mg Micronor
HRT/norethisterone tablets (PL/0242/0241).

6.6.

Instruction for Use/Handling
Not applicable.

7

MARKETING AUTHORISATION HOLDER
Janssen-Cilag Ltd
50 -100 Holmers Farm Way
High Wycombe
Buckinghamshire
HP12 4EG
UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 00242/0223

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
26/07/2006

10

DATE OF REVISION OF THE TEXT
26/06/2017

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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