DERMESTRIL SEPTEM 75 µg/24 h Transdermal patch 4 sachets

Transdermal system. Each system is transparent, colourless, slightly opaque and elliptical in shape. An identification code is printed on it and it is covered by a rectangular transparent protective liner.

Estradiol hemihydrate................................................................................................................................7,74 mg

Equivalent to estradiol................................................................................................................................7,50 mg

For a transdermal system of 33,75 cm²

One transdermal system releases 75 micrograms of estradiol per 24 hours.

Excipients:

Hormone replacement therapy (HRT) for the symptoms of oestrogen deficiency in postmenopausal women whose last menstrual period was at least 6 months ago.

The experience with this treatment in women aged over 65 years is limited

Dosage

DERMESTRIL SEPTEM is an estrogen-only transdermal system, applied to the skin once a week in order to ensure a continuous supply of estradiol to the body; thus, each used system is removed after 7 days and replaced with a new one.

Three strengths of DERMESTRIL SEPTEM are available: DERMESTRIL SEPTEM 25, 50 and 75.

To start or continue treatment for postmenopausal symptoms, the minimum effective dose should be used for the shortest duration possible (see section Warnings and precautions).

Treatment generally starts with DERMESTRIL SEPTEM 25 micrograms/24 hours.

If, after 1 to 2 months of treatment with DERMESTRIL SEPTEM 25 micrograms/24 hours, applied once a week, the symptoms of oestrogen deficiency have not decreased, a higher strength of DERMESTRIL SEPTEM may be used.

If undesirable effects or symptoms of overdose occur (for example a feeling of breast tension and/or metrorrhagia), the dosage must be reduced.

In women who have not had a hysterectomy, a progestogen authorised as an adjunct to oestrogen treatment must be added for at least 12 to 14 days per month/cycle of 28 days to oppose the development of oestrogen-induced endometrial hyperplasia (see section Warnings and precautions).

In women who have undergone a hysterectomy, it is not recommended to combine a progestogen with hormone replacement oestrogen treatment, except in the case of a history of endometriosis.

In a woman not taking HRT, treatment with DERMESTRIL SEPTEM can be started at any time.

In a woman already taking a cyclic or sequential oestrogen/progestogen treatment, the current treatment cycle must be completed before starting treatment with DERMESTRIL SEPTEM. The appropriate time to start treatment with DERMESTRIL SEPTEM is the first day of withdrawal bleeding.

In a woman already taking a continuous combined oestrogen/progestogen treatment, treatment with DERMESTRIL SEPTEM can be started directly.

Method of administration

Apply DERMESTRIL SEPTEM to the skin of the hips, upper buttocks, lumbar or abdominal region and press firmly over the entire surface and edges to ensure maximum adhesion.

The rate of estradiol released by DERMESTRIL SEPTEM depends on the absorption capacity of the skin. Thus, as the site of application influences the release of estradiol, application to another skin region located higher than the recommended regions is not advised.

At the application site, the skin must be clean, dry, not greasy, without redness or irritation. Body sites with significant skin folds or that are subject to friction during movement should be avoided.

DERMESTRIL SEPTEM not must not be applied on or near the breasts.

Transdermal devices must not be applied 2 times in a row to the same site.

If the transdermal device is correctly applied, it will adhere to the skin for a full week without problems. In case of premature detachment, use a new transdermal device which will be removed on the date initially planned. The initial treatment schedule will then be resumed.

If the device is not changed on the date initially planned, it must be replaced as soon as possible, then changed again in accordance with the initial treatment schedule.

Forgetting a device may promote the occurrence of bleeding and spotting.

If the transdermal device is correctly applied, it is possible to shower or take a bath. However, it may detach in the case of a very hot bath or sauna. In this case, it must be replaced with a new transdermal device (as indicated above). Sauna use should preferably be scheduled on the day the transdermal device is changed.

• Known or suspected breast cancer or history of breast cancer;

• Known or suspected oestrogen-dependent malignant tumours (example: endometrial cancer);

• Undiagnosed genital bleeding;

• Untreated endometrial hyperplasia;

• History of venous thromboembolic event or current venous thromboembolic event (deep vein thrombosis, pulmonary embolism);

• Known thrombophilic disorders (such as deficiency in protein C, protein S or antithrombin, see section Warnings and precautions) ;

• Recent or current arterial thromboembolic event (example: angina, myocardial infarction);

• Acute liver disease or history of liver disease, until liver function tests return to normal;

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

• Porphyria.

In the indication for treatment of menopausal symptoms, HRT should only be initiated if the symptoms are perceived by the patient as impairing her quality of life. In all cases, reassessment of the benefit/risk ratio should be performed at least once a year. HRT may be continued as long as the benefit exceeds the risk incurred.

Evidence of risks associated with HRT in the treatment of women with premature menopause is limited. Due to the low absolute risk in younger women, however, the benefit/risk balance may be more favourable than in older women.

Clinical examination and monitoring

Before starting or restarting hormone replacement therapy (HRT), it is essential to perform a complete clinical and gynaecological examination (including collection of personal and family medical history), taking into account contraindications and precautions for use. Throughout the duration of treatment, regular examinations will be carried out, their nature and frequency being adapted to each patient.

Women must be informed of the type of breast abnormalities that may occur under treatment; these abnormalities must be reported to the treating physician (see paragraph "Breast cancer" below). Examinations, including appropriate imaging examinations such as mammography, must be performed according to current recommendations and adapted to each patient.

Conditions requiring monitoring

If any of the following conditions occur, have occurred previously, and/or worsened during a pregnancy or a previous hormonal treatment, the patient should be closely monitored. The following conditions may recur or worsen during treatment with DERMESTRIL SEPTEM, in particular:

• leiomyoma (uterine fibroid) or endometriosis;

• presence of thromboembolic risk factors (see below);

• risk factors for oestrogen-dependent tumours, for example: 1 degree of relatives with breast cancer;

• arterial hypertension;

• hepatic disorders (for example: hepatic adenoma);

• diabetes with or without vascular involvement;

• gallstone disease;

• migraines or severe headaches;

• systemic lupus erythematosus;

• history of endometrial hyperplasia (see below);

• epilepsy;

• asthma;

• otosclerosis.

Immediate discontinuation of treatment

Treatment must be stopped immediately in the event of the occurrence of a contraindication or in the following cases:

• jaundice or impairment of liver function;

• significant increase in blood pressure;

• unusual migraine-type headache;

• pregnancy.

Endometrial hyperplasia and carcinoma

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with prolonged administration of estrogens alone. An increased risk of endometrial cancer has been reported in women using estrogens alone. This increase is 2 to 12 times higher compared with women not taking estrogens, depending on the duration of treatment and the estrogen dose used (see section Adverse effects). After stopping treatment, the risk may remain elevated for at least 10 years.

In women who have not had a hysterectomy, the addition of a progestogen cyclically for at least 12 days per month / cycle of 28 days, or taking a continuous combined estrogen-progestogen treatment, prevents the increased risk associated with estrogens alone as HRT.

The endometrial safety of daily doses above 50 micrograms of transdermal estradiol combined with a progestogen has not been studied.

Metrorrhagia and "spotting" may occur during the first months of treatment. The occurrence of irregular bleeding several months after starting treatment, or persistent bleeding after stopping treatment, should prompt investigation for an underlying pathology. This may require an endometrial biopsy to rule out malignant pathology.

Estrogen stimulation may lead to malignant or premalignant transformation of residual endometriosis foci. The addition of a progestogen to estrogen should be considered in cases of residual endometriosis foci in women who have undergone hysterectomy for endometriosis.

Breast cancer

The available data as a whole show an increased risk of breast cancer in women taking estrogen-progestogen treatment, or in those taking HRT based on estrogens alone, this risk depending on the duration of treatment.

Combined estrogen-progestogen treatment

• The randomised placebo-controlled Women's Health Initiative study (WHI) and a meta-analysis of prospective epidemiological studies both show an increased risk of breast cancer in women treated with combined estrogen-progestogen HRT, appearing after about 3 (1-4) years of treatment (see section Adverse effects).

Estrogen-alone treatment

• The WHI study did not show an increased risk of breast cancer in hysterectomised women using estrogens alone as HRT. Observational studies have generally reported a slight increase in the risk of diagnosed breast cancer, this risk being lower than in users of estrogen-progestogen combinations (see section Adverse effects).

The results of a large meta-analysis showed that after stopping treatment, the additional risk decreases over time, and the time needed for it to return to normal depends on the duration of HRT use. When HRT has been taken for more than 5 years, the risk may persist for 10 years or more.

HRT, particularly combined estrogen/progestogen treatments, increases breast density on mammography, which could hinder the diagnosis of breast cancer.

Ovarian cancer

Ovarian cancer is rarer than breast cancer. Epidemiological data from a large meta-analysis suggest a slight increase in risk in women taking HRT with estrogens alone or with a combination of estrogens and progestogens, appearing within five years of starting use and gradually decreasing after stopping treatment. Other studies, including the WHI (Women's Health Initiative) trial, suggest that a similar or slightly lower risk may be associated with the use of combined HRT (see section Adverse effects).

Venous thromboembolic events

• HRT is associated with a 1,3 to 3 times higher risk of venous thromboembolic events (deep vein thrombosis or pulmonary embolism). This event occurs mostly during the first year of treatment (see section Adverse effects).

• Patients with a history of venous thromboembolism or a known thrombophilia have an increased risk of venous thromboembolic events. HRT could increase this risk. In these patients, the use of HRT is contraindicated (see section Contraindications).

• The recognised risk factors for venous thromboembolic events are: use of oestrogens, advanced age, major surgery, prolonged immobilisation, obesity (BMI > 30 kg/m²), pregnancy / postpartum, systemic lupus erythematosus (SLE), cancer. On the other hand, there is no consensus on the possible role of varicose veins in venous thromboembolic events.

• In order to prevent any post-operative venous thromboembolic risk, the usual prophylactic measures must be strictly applied. In the case of prolonged immobilisation following scheduled surgery, a temporary interruption of treatment 4 to 6 weeks before the procedure is recommended. Treatment should only be resumed once the patient has regained normal mobility.

• In women without a history of venous thrombosis but with a close family member who has a history of thrombosis at a young age, tests may be offered, while informing them of their limitations (only certain types of thrombophilic disorders are identified by these tests). If a thrombophilic disorder linked to thromboses in family members is identified, or if the disorder is severe (for example antithrombin, protein S or protein C deficiency, or a combination of disorders), HRT is contraindicated.

• In women already receiving long-term anticoagulant treatment, the benefit/risk ratio of HRT should be carefully assessed.

• The occurrence of a thromboembolic event requires discontinuation of HRT. Patients should be informed of the need to contact their doctor immediately if signs suggestive of thrombosis occur, such as a painful swollen leg, sudden chest pain or dyspnoea.

Coronary heart disease

Randomised controlled studies have not demonstrated protection against myocardial infarction in women with or without pre-existing coronary heart disease treated with an oestro-progestogen combination or with oestrogens alone.

Treatment with an oestro-progestogen combination

The relative risk of coronary heart disease is slightly increased during treatment with an oestro-progestogen combination. Since the baseline absolute risk of coronary heart disease depends strongly on age, the number of additional cases of coronary heart disease due to the oestro-progestogen combination is very low in healthy women close to menopause, but increases with age.

Treatment with oestrogens alone

Randomised controlled studies have not demonstrated an increased risk of coronary heart disease in hysterectomised women using oestrogens alone.

Cerebrovascular accidents

An increase of up to 1,5-fold in the risk of ischaemic stroke has been shown in women treated with an oestro-progestogen combination or with oestrogens alone. The relative risk does not change with age or time since menopause. However, since the baseline absolute risk of stroke is strongly dependent on age, the overall risk of stroke in women using HRT will increase with age (see section Adverse effects).

Other special warnings and precautions for use

• As estrogens may cause fluid retention, patients with renal or cardiac insufficiency must be closely monitored.

• Women with pre-existing hypertriglyceridemia must be closely monitored during hormone replacement therapy. Rare cases of significant increases in triglyceride levels leading to pancreatitis have been observed under estrogen therapy.

• Exogenous estrogens may cause or worsen symptoms of hereditary or acquired angioedema.

• During oestrogen treatment, an increase in plasma levels of thyroid-binding globulin (TBG) is observed, leading to an elevation of plasma levels of total thyroid hormones measured by PBI (protein-bound iodine), of total T4 (measured by column or RIA (radioimmunoassay)) and of total T3 (measured by RIA). The uptake of T3 on the resin is decreased, reflecting the increase in TBG. The concentrations of the free fractions of T4 and T3 remain unchanged. Serum levels of other binding proteins such as corticoid-binding globulin (CBG) and sex-hormone-binding globulin (SHBG) may be increased, resulting in increased circulating levels of corticoids and sex steroids, respectively. The concentrations of the free or active fractions of the hormones remain unchanged. Other plasma proteins may also be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

• HRT use does not improve cognitive function. Data suggest an increased risk of probable dementia in women starting continuous combined or oestrogen-alone treatment after 65 years.

Increase in ALT levels

In clinical trials of treatment of hepatitis C virus (HCV) infection with the combination ombitasvir/paritaprevir/ritonavir and dasabuvir with and without ribavirin, elevations of ALT above 5 times the upper limit of normal (ULN) were significantly more frequent in women using medicinal products containing ethinylestradiol, such as CHCs. Elevations of ALT were also observed in patients treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir using medicinal products containing ethinylestradiol, such as CHCs.

 In women using medicinal products containing oestrogens other than ethinylestradiol, such as oestradiol, the frequency of ALT elevations with ombitasvir/paritaprevir/ritonavir and dasabuvir with and without ribavirin was similar to that observed in women not using any oestrogen; however, given the limited number of women taking these other oestrogens, caution is advised when co-administered with the combination ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir. See section Interactions.

The metabolism of oestrogens may be increased by concomitant use of enzyme-inducing medicinal products, in particular cytochrome P450 isoenzymes, such as anticonvulsants (phenobarbital, phenytoin, carbamazepine) and anti-infectives (rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir and nelfinavir, although known as potent enzyme inhibitors, paradoxically have inducing properties when used with steroid hormones.

Herbal preparations containing St John's wort (Hypericum perforatum) could alter estrogen metabolism.

Transdermal administration avoids the hepatic first-pass effect; consequently, the metabolism of estrogens administered by this route may be less affected by enzyme inducers than by the oral route.

Increased metabolism of estrogens and progestogens may lead to a decrease in therapeutic effect and a change in the uterine bleeding profile.

Effect of estrogen HRT on other medicinal products

Hormonal contraceptives containing estrogens 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 hormone replacement therapy and lamotrigine has not been studied, a similar interaction is expected, which could lead to reduced seizure control in women taking both medicinal products at the same time.

Pharmacodynamic interactions

Direct-acting antivirals (DAAs) and medicinal products containing ethinylestradiol, such as CHCs.

During clinical trials on the treatment of HCV infection with the drug combination ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, elevations of ALT above 5 times the upper limit of normal (ULN) were significantly more frequent in women using medicinal products containing ethinylestradiol, such as CHCs. Furthermore, even in patients treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir, ALT elevations were observed in women using medicinal products containing ethinylestradiol, such as CHCs.

 

Direct-acting antivirals (DAAs) and medicinal products containing estrogens other than ethinylestradiol, such as estradiol.

 In women using medicinal products containing estrogens other than ethinylestradiol, such as estradiol, and ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, the frequency of ALT elevations was similar to that observed in women not using any estrogen; however, given the limited number of women taking these other estrogens, caution should be exercised in case of co-administration with the drug combination ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section Warnings and precautions).

Pregnancy

DERMESTRIL SEPTEM has no indication during pregnancy.

Discovery of a pregnancy during treatment with DERMESTRIL SEPTEM requires immediate discontinuation of treatment.

To date, most epidemiological studies have not shown a teratogenic or fetotoxic effect in pregnant women inadvertently exposed to therapeutic doses of estrogens.

Breast-feeding

DERMESTRIL SEPTEM has no indication during breastfeeding.

No studies have been performed to demonstrate effects on the ability to drive vehicles and use machines.

More than 700 patients were treated with this product during clinical trials.

During clinical trials, approximately 10 to 17% of patients treated with DERMESTRIL SEPTEM experienced mild and transient systemic adverse effects. Breast tenderness was reported in 20 to 35% of patients. Local reactions at the application site, consisting mostly of mild erythema with or without pruritus, occurred in 10 to 25% of patients.

Serious adverse effects associated with the use of hormone replacement therapy are also mentioned in section Warnings and precautions.

The table below presents adverse effects reported in users of hormone replacement therapy (HRT), classified according to the MedDRA system organ class.

System organ class	Common (≥ 1/100 to <1/10)	Uncommon (≥ 1/1 000 to < 1/100)	Rare (< 1/1 000)	Frequency not known*
Infections and infestations		Vaginal candidiasis
Immune system disorders		Hypersensitivity reaction
Metabolism and nutrition disorders	Weight increase, weight decrease
Psychiatric disorders		Depressed mood	Anxiety, decreased libido or increased libido
Nervous system disorders	Headache	Vertigo	Migraine	Probable dementia after 65 years (see section Warnings and precautions), chorea, worsening of epilepsy
Eye disorders		Visual disorders	Intolerance to contact lenses
Cardiac disorders		Palpitations
Gastrointestinal disorders	Abdominal pain, nausea	Dyspepsia	Flatulence, vomiting	Pancreatitis (in women with pre-existing hypertriglyceridaemia), gastro-oesophageal reflux
Hepatobiliary disorders		Gallbladder disorder		Impaired liver function, sometimes with jaundice
Skin and subcutaneous tissue disorders	Rash, pruritus	Erythema nodosum, urticaria	Hirsutism, acne	Angioedema, erythema multiforme, vascular purpura, chloasma, reactions at the application site: erythema with or without pruritus
Musculoskeletal and systemic disorders			Muscle cramps
Disorders of the reproductive system and breast	Metrorrhagia, uterine/vaginal bleeding including spotting	Breast pain, breast tension	Dysmenorrhea, vaginal discharge, premenstrual syndrome, breast hypertrophy	Fibrocystic breast disease
General disorders and administration site conditions		Oedema	Fatigue
Benign, malignant and unspecified neoplasms (incl cysts and polyps)				Breast cancera, benign or malignant estrogen-dependent tumours: endometrial cancerb, ovarian cancerc, increase in the size of a leiomyoma
Vascular disorders				Cerebrovascular accidentf, arterial thromboembolic disease, for example angina and myocardial infarctione. For additional information, see sections Contraindications and Warnings and precautions). Venous thromboembolic diseased, for example pelvic or lower limb deep vein thrombosis, pulmonary embolism. For additional information, see sections Contraindications and Warnings and precautions.
Renal and urinary disorders				Urinary incontinence

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions

*Adverse effects from spontaneous post-marketing reports that were not observed in clinical studies.

Risk of breast cancer

• An increase of up to 2 times in the risk of breast cancer has been reported in women who have taken a combined oestrogen-progestogen preparation for more than 5 years.

• The increase in risk is lower in users of oestrogens alone compared with users of combined oestrogen-progestogen preparations.

• The level of risk depends on the duration of treatment (see section Warnings and precautions)

• Estimates of absolute risk based on the results of the largest randomised placebo-controlled trial (WHI study) and the largest meta-analysis of prospective epidemiological studies are presented below.

Largest meta-analysis of prospective epidemiological studies

Estimate of additional risk of breast cancer after 5 years of treatment in women with a BMI of 27 (kg/m²)

Age at start of HRT (years)	Incidence for 1 000 patients who have never taken HRT over a period of 5 years (50-54 years)*	Relative risk	Number of additional cases for 1 000 HRT users after 5 years
Oestrogen-only HRT
50	13,3	1,2	2,7
Oestrogen-progestogen combination
50	13,3	1,6	8,0
* Derived from baseline incidence rates in England in 2015 in women with a BMI of 27 (kg/m²) Note: since the baseline incidence of breast cancer differs between European Union (EU) countries, the number of additional cases of breast cancer will vary proportionally.

Estimate of additional risk of breast cancer after 10 years of treatment in women with a BMI of 27 (kg/m²)

Age at start of HRT (years)	Incidence for 1 000 patients who have never taken HRT over a period of 10 years (50-59 years)*	Relative risk	Number of additional cases for 1 000 HRT users after 10 years
Oestrogen-only HRT
50	26,6	1,3	7,1
Oestrogen-progestogen combination
50	26,6	1,8	20,8
* Derived from baseline incidence rates in England in 2015 in women with a BMI of 27 (kg/m²) Note: since the baseline incidence of breast cancer differs between EU countries, the number of additional cases of breast cancer will vary proportionally.

WHI study in the United States: additional risk of breast cancer over 5 years of treatment

Age (years)	Incidence for 1 000 women not using HRT over 5 years *3	Relative risk #	Number of additional cases for 1 000 HRT users over 5 years (CI 95%)
Oestrogens alone (conjugated equine oestrogens)
50-79	21	0,8 (0,7-1,0)	-4 (-6 – 0) *3
Oestrogen-progestogen combination CEE + MPA #
50-79	17	1,2 (1,0-1,5)	+4 (0-9)
*3 The WHI study in hysterectomised women did not show an increased risk of breast cancer # When the analysis was limited to women who had not used HRT before the study, no increased risk was observed during the first 5 years of treatment: after 5 years, the risk was higher than in non-users

Endometrial cancer risk

Non-hysterectomised postmenopausal women

The risk of endometrial cancer is approximately 5 per 1000 women with an intact uterus who do not use HRT. In women with an intact uterus, the use of oestrogen-only HRT is not recommended as it increases the risk of endometrial cancer (see section Warnings and precautions)

In epidemiological studies, the increased risk of endometrial cancer depended on the duration of oestrogen-only treatment and the oestrogen dose, and ranged from 5 to 55 additional cases diagnosed per 1 000 women aged 50 to 65 years.

Adding a progestogen to oestrogen-only treatment for at least 12 days per cycle prevents this increased risk. In the Million Women Study, use for 5 years of combined HRT (sequential or continuous) did not increase the risk of endometrial cancer (RR of 1,0 (0,8 – 1,2)).

Ovarian cancer

The use of oestrogen-only HRT or an oestrogen-progestogen combination has been associated with a small increased risk of diagnosed ovarian cancer (see section Warnings and precautions). A meta-analysis of 52 epidemiological studies showed an increased risk of ovarian cancer in women taking HRT compared to women who have never taken HRT treatment (RR of 1,43, CI 95% 1,31-1,56). In women aged 50 to 54 years taking HRT for 5 years, this results in approximately 1 additional cases per 2000 users. In women aged 50 to 54 years not taking HRT, approximately 2 women out of 2000 will have ovarian cancer diagnosed over a period of 5 years.

Risk of venous thromboembolic event

HRT is associated with a 1,3 to 3-fold increase in the relative risk of occurrence of a venous thromboembolic event, i.e. deep vein thrombosis or pulmonary embolism.

The probability of occurrence of such an event is higher during the first year of HRT use (see section Warnings and precautions). The results of the WHI studies are presented below:

WHI studies: additional risk of venous thromboembolic event over 5 years of treatment

Age (years)	Incidence per 1000 women in the placebo arm over 5 years	Relative risk (CI 95%)	Number of additional cases per 1000 HRT users
Oral estrogens alone *4
50-59	7	1,2 (0,6-2,4)	1 (-3 – 10)
Oral estro-progestogen combination
50-59	4	2,3 (1,2 – 4,3)	5 (1 - 13)
*4 Study in hysterectomised women

Risk of coronary heart disease

The risk of coronary heart disease is slightly increased in users of estro-progestogen HRT beyond 60 years (see section Warnings and precautions).

Risk of ischaemic stroke

The use of HRT based on estrogens alone or an estro-progestogen combination is associated with an increase of up to 1,5-fold in the relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased with the use of HRT.

This risk does not depend on age or duration of treatment, but as the baseline risk is strongly age-dependent, the overall risk of stroke in women using HRT increases with age (see section Warnings and precautions)

Combined WHI studies – additional risk of stroke *5 over 5 years of treatment

Age (years)	Incidence per 1000 women in the placebo arm over 5 years		Relative risk (CI 95%)	Number of additional cases per 1000 HRT users over 5 years
50-59	8	1,3 (1,1-1,6)	3 (1-5)
*5 No distinction was made between ischaemic and haemorrhagic strokes

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 national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr.

Overdose is unlikely with transdermal application. Nausea, vomiting, drowsiness, dizziness and withdrawal bleeding may occur in some women. There is no specific antidote and treatment should be symptomatic. The transdermal system should be removed.

The information mentioned above also applies to children.

Pharmacotherapeutic class: ESTROGENS, ATC code: G03CA03.

The active substance, synthetic 17β-estradiol, is chemically and biologically identical to human endogenous estradiol. It replaces the cessation of estrogen production in postmenopausal women and relieves the climacteric symptoms of menopause.

Information on clinical studies:

• Relief of symptoms related to oestrogen deficiency and bleeding profile 

Relief of menopausal symptoms was obtained from the first weeks of treatment.

The elimination half-life of plasma estradiol is approximately 1 hour. Plasma clearance ranges from 650 to 900 l/day/m². Estradiol is mainly metabolised in the liver. The most important metabolites are estriol, estrone and their conjugates (glucuronates, sulfates). These metabolites are much less active than estradiol. They are eliminated mainly by the kidney as glucuronates and sulfates but are also found in faeces, due to the existence of the enterohepatic cycle.

After application of the DERMESTRIL SEPTEM transdermal system, the estradiol released by the adhesive matrix passes directly into the systemic circulation after crossing the skin, thus avoiding the hepatic first-pass effect. Thus, with the transdermal system, the plasma estradiol/estrone ratio, which is less than 1 after menopause and during oral estrogen replacement therapy, returns to values of the order of those observed in premenopause (close to 1).

DERMESTRIL SEPTEM 75 micrograms/24 hours releases in vivo 75 micrograms of estradiol per day for one week, which produces physiological serum estradiol concentrations, i.e. identical to those observed at the beginning of the follicular phase in premenopause. These concentrations are maintained throughout the duration of application of the transdermal system.

Physiological estradiol concentrations are reached 6 hours after application of DERMESTRIL SEPTEM 75 micrograms/24 hours, in postmenopausal women. After 12 hours, mean estradiol concentrations are greater than 367 pmol/L.

After repeated administration of DERMESTRIL SEPTEM 75 micrograms/24 hours, the maximum serum estradiol concentration is on average 404 pmol/L at steady state.

The serum estradiol concentration is maintained at values close to those of a premenopausal woman during the 7 days of application, returning to a baseline value 12 to 24 hours after removal of the transdermal system.

The mean estradiol concentration at steady state is 242 pmol/L.

The Cmin of estradiol, measured at steady state, is 125 pmol/L.

Studies conducted in animals with estradiol demonstrated the expected estrogenic effects. There is no preclinical data useful to the prescriber other than that already mentioned in the other sections of the Summary of Product Characteristics.

After single and repeated administration, local tolerance studies carried out in rabbits demonstrated good skin tolerance of the transdermal system. No sensitization potential was found in guinea pigs.

2 years

Store in the closed sachets and at a temperature not exceeding 25°C.

Tear the sachet along the pre-cut edge (do not use scissors, so as not to damage the system) and remove the system.

Hold the system between the thumb and index finger, at the small surface formed by the pre-detachable tab.

Remove the largest part of the protective liner with the other hand and discard it.

Do not place fingers on the adhesive surface of the transdermal system.

Apply the system by holding it between the thumb and index finger at the small surface formed by the pre-detachable tab.

Remove the remaining part of the protective liner and press firmly over the entire surface of the system for about 10 seconds.

Run a finger over the edges to ensure optimal adhesion.

After use, the transdermal system must be folded adhesive side inward and discarded.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

List II

Marketing authorisation (AMM)

CIP 3400935239518 (4 sachets).

Price:

5,87 euros (4 sachets).

Social Security reimbursement at 65%.
Collection.