FEMSEPT 50 µg/24 h Transdermal Patch 4Sachet

Transdermal system.

Estradiol hemihydrate ..................................................................................................................1,50 mg

For a transdermal patch of 15 cm2.

Excipients:

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

Experience with this treatment in women aged over 65 years is limited.

Dosage

Apply FEMSEPT once a week, i.e. replace the transdermal patch every 7 days.

To initiate or continue treatment for the indication of post-menopausal symptoms, the lowest effective dose should be used for the shortest possible duration (see section Warnings and precautions).

Treatment generally starts with FEMSEPT 50 micrograms/24 h. Depending on clinical response, the dosage may be adjusted to individual needs:

• if the chosen dose has not corrected the symptoms of estrogen deficiency, it should be increased,

• the onset of breast tenderness, metrorrhagia, fluid retention or bloating (persisting for more than 6 weeks) or irritability generally indicates that the dose is too high and should be modified.

FEMSEPT 50 micrograms/24 h may be used according to the following therapeutic regimen:

• Cyclic (discontinuous), for 21 to 28 days, followed by a treatment-free interval of 2 to 7 days. During this interval, withdrawal bleeding may occur.

• Continuous, without any treatment break. Continuous, non-cyclic treatment may be indicated where symptoms of estrogen deficiency strongly recur during the treatment-free interval.

If the prescription is for a woman not taking HRT, or for switching from a continuous combined HRT, treatment may be started on any day.

On the other hand, if the previous treatment is sequential HRT, the current treatment cycle must be completed before starting treatment with FEMSEPT 50 micrograms/24 h.

In women who have not undergone hysterectomy, a progestogen must be added for at least 12 days per cycle to oppose the development of estrogen-induced endometrial hyperplasia. Sequential progestogen treatment must be given according to the following scheme:

• If FEMSEPT 50 micrograms/24 h is administered cyclically (discontinuously), the progestogen will be administered for at least the last 12 days of estradiol treatment. Thus, there will be no hormonal administration during the free interval of each cycle.

• If FEMSEPT 50 micrograms/24 h is administered continuously, it is recommended to take the progestogen for at least 12 days each month (continuous sequential).

In both cases, bleeding may occur after stopping progestogen treatment.

In women who have had a hysterectomy, adding a progestogen is not recommended except in cases of a history of endometriosis.

Method of administration

Once the protective liner has been detached, FEMSEPT 50 micrograms/24 h must be applied immediately to the buttocks or abdomen at a site free of significant folds and not subject to friction from clothing.

The skin must be dry, must not be irritated, and must not be treated with oily or greasy products.

FEMSEPT 50 micrograms/24 h must not be applied to the breasts. It is recommended not to apply it 2 times in a row to the same site.

Maintain pressure of approximately 30 seconds over the entire transdermal system (warmth is essential to ensure good adhesion).

It is possible to shower or bathe while keeping the transdermal system in place.

As estradiol is degraded by ultraviolet rays, the transdermal system must not be exposed directly to sunlight.

In the event that the transdermal system comes loose (very hot water, excessive sweating, abnormal friction from clothing), it is recommended to reapply it to dry skin. If this is not possible, use a new transdermal system, which will be removed on the date originally planned. Then resume the transdermal system change schedule in accordance with the initial treatment regimen.

In case of forgetting to replace FEMSEPT 50 micrograms/24 h, a new transdermal system must be applied as soon as possible. Then resume the transdermal system change schedule in accordance with the initial treatment regimen. Forgetting to apply a patch may promote recurrence of symptoms and the occurrence of bleeding and spotting.

• Known hypersensitivity to the active substance or to any of the excipients listed in section Composition.

• Known or suspected breast cancer, or history of breast cancer.

• Known or suspected estrogen-dependent malignant tumours (example: endometrial cancer).

• Undiagnosed genital haemorrhage.

• Untreated endometrial hyperplasia.

• History of venous thromboembolic event or ongoing venous thromboembolic event (deep vein thrombosis, pulmonary embolism).

• Known thrombophilic disorders (example: deficiency in protein C, protein S or antithrombin) (see section Warnings and precautions).

• Recent or evolving arterial thromboembolic event (for example: angina, myocardial infarction).

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

• 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 the risks associated with HRT in the treatment of prematurely menopausal women is limited. Due to the low absolute risk in younger women, however, the benefit/risk ratio 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 during treatment; these abnormalities must be reported to the treating physician (see the paragraph "breast cancer" below). Examinations, including appropriate imaging examinations such as mammography, must be carried out according to current recommendations and adapted to each patient.

Women must be informed that FEMSEPT 50 micrograms/24 h is not a contraceptive and does not restore fertility.

Conditions requiring monitoring

If any of the following conditions occurs, has occurred previously, and/or has worsened during a pregnancy or a previous hormonal treatment, the patient must be closely monitored and the benefit/risk ratio of HRT individually reassessed. The following conditions may reappear or worsen during treatment with FEMSEPT 50 micrograms/24 h, in particular:

• leiomyoma (uterine fibroid) or endometriosis,

• presence of thromboembolic risk factors (see below),

• risk factors for estrogen-dependent tumours, for example: 1er degree of hereditary predisposition for breast cancer,

•  arterial hypertension,

• hepatic disorders (for example: hepatic adenoma),

• diabetes with or without vascular involvement,

• biliary lithiasis,

• migraines or severe headaches,

• systemic lupus erythematosus,

• history of endometrial hyperplasia (see below),

• epilepsy,

• asthma,

• otosclerosis.

Contact allergy

As with any topical formulation, although this is extremely rare, contact sensitisation may occur. Women who present with contact sensitisation to any of the components of the patch must be warned that a severe hypersensitivity reaction may occur if exposure to the responsible product is maintained.

Immediate discontinuation of treatment

Treatment must be discontinued 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 endometrial cancer

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with prolonged administration of estrogens alone. The risk of endometrial cancer is 2 to 12 times higher compared to women not taking estrogens, depending on the duration of treatment and the estrogen dose used (see section Adverse effects).

After treatment discontinuation, the risk may remain elevated for at least 10 years.

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

Metrorrhagia and spotting may occur during the first months of treatment. The occurrence of irregular bleeding several months after the start of treatment or the persistence of bleeding after treatment has been stopped 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

Available data show an increased risk of breast cancer in women taking estroprogestogen treatment or those taking HRT based on estrogens alone, this risk depending on the duration of treatment.

Treatment with combined oestrogen-progestogen

The randomised placebo-controlled trial, the 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 oestrogen-progestogen HRT, appearing after approximately 3 (1-4) years of treatment (see section Adverse effects).

Treatment with oestrogens alone

The WHI study did not show an increased risk of breast cancer in hysterectomised women using oestrogens alone as HRT. Observational studies have generally reported a slight increase in the risk of diagnosed breast cancer, this risk being lower than in women using combined oestrogen-progestogen therapy (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.

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 is more likely to occur during the first year of treatment (see section Adverse effects).

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

The recognized risk factors for venous thromboembolic events are: use of estrogens, age, major surgery, prolonged immobilization, 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 a scheduled surgical procedure, a temporary interruption of the 4 treatment 6 weeks before the procedure is recommended. Treatment will only be reinstated once the patient has resumed normal mobility.

In women without a history of venous thrombosis but with a close family member having 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 must be carefully evaluated.

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 times in the risk of ischaemic stroke has been shown in women treated with a combination of oestrogen-progestogen or with oestrogens alone. The relative risk does not change with age or time since menopause. However, as 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).

Ovarian cancer

Ovarian cancer is much 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, which appears within five years of starting use and gradually decreases 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).

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 hypertriglyceridaemia should be monitored during hormone replacement therapy. Rare cases of major increases in triglyceride levels leading to pancreatitis have been observed under oestrogen therapy.

• Thyroid function should be monitored in patients receiving thyroid hormone replacement therapy during oestrogen treatment (see section Interactions).

• During estrogen treatment, an increase in plasma TBG (thyroid binding globulin) levels is observed, leading to an elevation of plasma total thyroid hormone levels measured by PBI (protein-bound iodine), total T4 (measured by column or by RIA (radioimmunoassay)) and 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 CBG (corticoid binding globulin) and SHBG (sex-hormone binding globulin) may be increased, resulting, respectively, in an increase in circulating corticosteroid and sex steroid levels. 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).

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

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

Elevation of ALT level

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

In women using medicinal products containing estrogens other than ethinylestradiol, such as estradiol, and the combination of 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 when co-administered with the following drug combinations: ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir. See section Interactions.

Associations requiring precautions for use

The metabolism of estrogens and progestogens may be increased by concomitant use of enzyme-inducing medicinal products, in particular cytochrome P450 isoenzymes, such as anticonvulsants (phenobarbital, phenytoin, carbamazepine, oxcarbazepine) 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) may alter the metabolism of estrogens and progestogens.

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.

Effects of estrogenic 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 may lead to reduced seizure control in women taking both medicinal products at the same time.

Monitoring and possible adjustment of the HRT dose are recommended during enzyme-inducer treatment and after its discontinuation.

Estrogen intake may alter the results of certain laboratory tests such as: liver, thyroid, adrenal and renal function tests, plasma levels of (carrier) proteins such as corticosteroid-binding globulin (CBG) and lipid/lipoprotein fractions, carbohydrate metabolism parameters, and coagulation and fibrinolysis parameters. The changes generally remain within the normal range.

Pharmacodynamic interactions

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

In women using medicinal products containing estrogens other than ethinylestradiol, such as estradiol, and the combination of 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 when co-administered with the following drug combinations: ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section Warnings and precautions).

Pregnancy

This medicinal product has no indication during pregnancy.

Discovery of a pregnancy during treatment with FEMSEPT 50 µg/24 h, transdermal system 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

This medicine has no indication during breastfeeding.

FEMSEPT has no known effect on the ability to drive vehicles or use machines.

The table below presents the adverse reactions observed with FEMSEPT or other HRT containing 17β-estradiol.

System	Very common	Common	Uncommon	Rare	Very rare	Frequency
System organ class	(> 1/10)	(≥ 1/100,	(≥ 1/1000,	(≥ 1/10 000,	(< 1/10 000)	Not known
Class		< 1/10)	< 1/100)	< 1/1 000)
(MedDRA)
Benign, malignant and unspecified tumours (including cysts and polyps)						Breast cancer
Infections and infestations		Vaginitis, vaginal candidiasis,
Immune system disorders				Hypersensitivity	Urticaria, Anaphylactic reaction
Metabolism and nutrition disorders					Decreased tolerance to carbohydrates
Psychiatric disorders		Depression, mood disorders, Nervousness, insomnia		Libido disorders
Nervous system disorders	Headache		Migraine, vertigo	Paresthesias	Chorea
Eye disorders					Intolerance to contact lenses
Vascular disorders			Increase in blood pressure	Venous thromboembolism
Gastrointestinal disorders		Nausea, dyspepsia, diarrhea, abdominal pain, bloating	Vomiting
Hepato-biliary disorders				Gallbladder disorders, gallstones
Skin and subcutaneous tissue disorders	Erythema, pruritus	Acne, pruritus, dryness of the skin	Skin discolouration	Alopecia	Skin necrosis, hirsutism
Musculoskeletal and systemic disorders		Back pain		Myasthenia		Pain in the extremities
Disorders of the reproductive system and breast	Breast tenderness and pain, dysmenorrhea, menstrual disorders	Breast enlargement, menorrhagia, leukorrhea, irregular vaginal bleeding, uterine spasms, endometrial hyperplasia		Uterine leiomyomas, paratubal cysts, endocervical polyps		Fibrocystic breast disease
General disorders and administration site conditions	Application site reactions (1)	Pain, asthenia, peripheral edema, weight changes
Investigations			Increased transaminase levels

(1) Skin reactions at the application site are less frequent if the transdermal system is applied to the upper outer part of the buttocks, changing the application site each time.

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 an estrogen-progestogen combination for more than 5 years.

• The increase in risk is lower in users of oestrogens alone compared with users of oestroprogestogen combinations.

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

• Absolute risk estimates 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 the start of HRT (years)	Incidence per 1000 women not using HRT over 5 (50-54 years) years*	Relative Risk	Number of additional cases for 1000 HRT users after 5 years
Estrogens alone
50	13.3	1,2	2.7
Estroprogestogen combinations
50	13.3	1.6	8,0

*Derived from base incidence rates in England in 2015 in developed countries of women with a BMI of 27 (kg/m2)

Note: since the base incidence of breast cancer varies from one country to another in the EU, the number of additional cases of breast cancer will vary proportionally.

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

Age at start of HRT (years)	Incidence per 1 000 patients who have never taken HRT over a period of 10 years (50-59 years) *	Relative Risk	Number of additional cases per 1000 HRT users after 10 years
HRT with oestrogens alone
50	26.6	1,3	7.1
Oestroprogestogen combinations
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 breast cancer cases will vary proportionally.

WHI study in the United States – Additional risk of breast cancer 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 for 1000 HRT users over 5 years (CI 95%)
Oestrogens alone (conjugated equine oestrogens)
50-79	21	0,8 (0,7–1,0)	-4 (-6–0)*
Oestroprogestogen combinations (CEE + MPA)#
50-79	17	1,2 (1,0–1,5)	+4 (0–9)

# When the analysis was limited to women who had not used HRT before the study, no increase in risk was observed during the first 5 years of treatment: after 5 years, the risk was higher than in non-users.

* WHI study in hysterectomised women, which did not show an increased risk of breast cancer.

Endometrial Cancer Risk

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 due to the increased risk of endometrial cancer (see section Warnings and precautions).

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

Adding a progestogen to estrogen-only treatment for at least 12 days per cycle prevents the increase in risk. In the MWS study, use of combined HRT (sequential or continuous) for 5 years did not increase the risk of endometrial cancer (RR = 1,0 (0,8–1,2)).

Ovarian Cancer Risk

Use of estrogen-only HRT or of a combination of estrogens and progestogens has been associated with a slight increase in the risk of diagnosed ovarian cancer (see section Warnings and precautions).

A meta-analysis of 52 epidemiological studies reported an increased risk of ovarian cancer in women currently taking HRT compared with women who have never taken it (RR 1,43, CI 95% 1,31-1,56). In women aged 50 to 54 years, taking HRT for five years results in one additional case per 2000 users. In women aged 50 to 54 years who do not take HRT, a diagnosis of ovarian cancer will be made in approximately 2 women out of 2000 over a period of five years.

Risk of venous thromboembolic event

HRT is associated with a 1,3 to 3-fold increase in the relative risk of venous thromboembolic events, i.e. deep vein thrombosis or pulmonary embolism. The probability of such an event occurring 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 events over 5 years of treatment

Age (years)	Incidence for 1000 women in the placebo arm over 5 years	Relative risk (CI 95%)	Number of additional cases for 1 000 HRT users
Oral estrogens alone*
50-59	7	1,2 (0,6-2,4)	1 (-3–10)
Oral estroprogestogen combinations
50-59	4	2,3 (1,2–4,3)	5 (1-13)

* Study in hysterectomised women

Risk of coronary heart disease

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

Risk of ischaemic stroke

Use of HRT based on estrogens alone or an estrogen-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 relative 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* over 5 years of treatment

Age (years)	Incidence per 1 000 women in the placebo arm over 5 years	Relative risk (CI 95 %)	Number of additional cases for 1 000 HRT users over 5 years
50-59	8	1,3 (1,1-1,6)	3 (1-5)

* No distinction was made between ischaemic and haemorrhagic strokes.

The following adverse effects are reported with administration of estroprogestogen treatment (class effects):

• Gallbladder disorders.

• Skin and subcutaneous tissue disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura.

• Probable dementia beyond the age of 65 years (see section Warnings and precautions).

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/

The effects of an overdose are generally breast tension, abdominopelvic swelling, anxiety, irritability. These signs disappear upon removal of the device.

Pharmacotherapeutic class: ESTROGENS, ATC code: G03CA03 (G: Genito-urinary system and sex hormones)

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.

FEMSEPT releases estradiol, in unchanged form and in physiological quantity, into the bloodstream at 50 µg/24 h.

FEMSEPT 50 µg/24 h raises the estradiol concentration to a level similar to that obtained in the early and mid follicular phases. The mean estradiol/estrone ratios are those observed in women before menopause.

Information on clinical studies :

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

This transdermal system releases, on average, 50 micrograms of estradiol per day for 7 days.

Serum estradiol concentrations are proportional to the amount administered. Approximately 18 hours after application of a 50, 75 or 100 system, concentrations reach mean peaks of 79, 120 and 148 pg/mL respectively.

The decline after the peak is slight, and mean concentrations are 42, 54 and 71 pg/mL for the 50, 75 and 100 systems respectively (coefficient of variability 27 to 40%).

However, it should be noted that inter-individual variations in absorption may be observed, as with any transdermal administration of estradiol (see section Warnings and precautions). Twelve hours after removal of the device, the serum estradiol concentration returns to baseline value.

Estradiol is mainly bound to SHBG in plasma.

Estradiol is mainly metabolized in the liver. The most important metabolites are estrone and its conjugates (glucuronides, sulfates); they are much less active than estradiol.

Most metabolites are excreted in the urine as glucuronates and sulfates. Estrogenic metabolites also undergo enterohepatic recycling.

The toxicological profile of estradiol is known. There is no preclinical data relevant to the prescriber other than those mentioned in the other sections of the summary of product characteristics (SmPC).

3 years.

To be stored at a temperature not exceeding 30°C.

See section Dosage and administration.

List II

Marketing authorisation (AMM)

CIP 3400934610783 (4 sachets).

Price:

5,87 euros (4 sachets).

Social Security reimbursement at 65%.
Collection.