FEMSEPTEVO 50 µg/7 µg/24 h Transdermal Patch 4Sachet

Transdermal system.

This device consists of a transdermal matrix, octagonal in shape, transparent, flexible, with rounded edges, placed on a larger, detachable protective backing.

Estradiol hemihydrate ........................................................................................................................... 1,500 mg

Levonorgestrel ........................................................................................................................................ 0,525 mg

For a transdermal patch of 15 cm2.

One transdermal device delivers 50 micrograms of estradiol hemihydrate and 7 micrograms of levonorgestrel per 24 hours.

For the full list of excipients, see section Composition.

Excipients:

Hormone Replacement Therapy (HRT) for the symptoms of oestrogen deficiency in women who are more than one year postmenopausal.

Experience with this treatment in women older than 65 years is limited.

Dosage

For transdermal use.

FEMSEPTEVO should be applied once a week, i.e. the device is replaced every 7 days.

FEMSEPTEVO is a HRT continuous combined, with no treatment break: as soon as the patient removes a device, she must immediately apply the next one. Forgetting to change a patch on the scheduled date may increase the occurrence of intercurrent bleeding and spotting.

In women who are amenorrhoeic and not receiving any HRT, or in women already treated with another continuous combined HRT, treatment with FEMSEPTEVO may be started at any time.

In contrast, women on sequential HRT should start treatment with FEMSEPTEVO just after the end of their withdrawal bleed.

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

Method of administration

FEMSEPTEVO should be applied to clean, dry, healthy skin (not irritated or abraded), free of cream, lotion or oily products.

FEMSEPTEVO must be applied to a site without significant skin folds, for example the buttocks or hips, and which is not subject to clothing friction (avoid the waistline and tight clothing which may detach the transdermal system).

FEMSEPTEVO must not be applied to the breasts or in their vicinity. It is recommended not to apply it twice in a row to the same site. A free interval of at least one week must be respected between applications to the same site.

After opening the sachet, half of the protective liner must be detached, taking care not to place fingers on the adhesive part of the transdermal system, which must be applied immediately to the skin. Then the other part of the protective liner must be detached and firm pressure must be applied to the patch with the palm of the hand for at least 30 seconds, pressing especially on the edges. Pressure and the warmth of the hand are essential to ensure optimal adhesion of the system.

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

In the event that a transdermal system detaches prematurely, i.e. before the 7th day (due to significant physical activity, hyperhidrosis, abnormal clothing friction), it must be replaced with a new system. To facilitate good treatment adherence, it is recommended to change the patch on the date initially planned and to resume the change schedule in accordance with the initial regimen.

Once applied, the transdermal system must be protected by clothing to avoid direct sun exposure.

Removal of the transdermal system must be done gently so as not to irritate the skin. If some adhesive remains on the skin, it can be removed by gently rubbing with an oily cream or lotion.

After use, FEMSEPTEVO must be folded in two (adhesive surface against adhesive surface) before being discarded.

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

• Known or suspected estrogen-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 (for example, protein C, protein S or antithrombin deficiency, see section Warnings and precautions) ;

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

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

• Known hypersensitivity to one of the active substances or to one 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.

Data concerning the risks associated with HRT in the treatment of premature menopause are limited. However, due to the low absolute risk in young women, the benefit/risk ratio in this population 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 tools (for example 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 pregnancy or a previous hormone treatment, the patient should be closely monitored. The following conditions may reappear or worsen during treatment with FEMSEPTEVO, in particular:

• leiomyoma (uterine fibroid) or endometriosis;

• 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;

• 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 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 carcinoma

• In women with an intact uterus, the risk of endometrial hyperplasia and carcinoma is increased when oestrogens alone are administered over long periods. The reported increase in the risk of endometrial cancer in users of oestrogens alone is 2 to 12 times higher than in non-users, depending on the duration of treatment and the oestrogen dose (see section Adverse effects). After treatment is stopped, this risk may remain elevated for at least 10 years.

• Cyclic addition of a progestogen for at least 12 days per month/cycle of 28 days or continuous combined oestrogen-progestogen treatment in women without a hysterectomy prevents the excess risk associated with HRT based on oestrogens alone.

• Uterine bleeding and spotting may occur during the first months of treatment. The occurrence of irregular bleeding several months after starting treatment, or persistence of bleeding after treatment is stopped, should prompt investigation for an underlying pathology. This may require an endometrial biopsy to rule out malignant pathology.

Breast cancer

Overall data show an increased risk of breast cancer in women taking a combined oestrogen-progestogen regimen or in those taking HRT with oestrogens alone, this risk depending on the duration of HRT use.

Combined oestrogen‑progestogen treatment

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

Estrogen-only therapy

The WHI study did not show an increased risk of breast cancer in hysterectomized women treated with estrogen alone. 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 much rarer than breast cancer.

Epidemiological data from a large meta-analysis suggest a slight increase in risk in women taking HRT with estrogen alone or with a combination of estrogen and progestogen, which appears within five years of starting use of the product 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).

Venous thromboembolism

HRT is associated with a 1,3- to 3-fold risk of developing venous thromboembolism (VTE), 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 Adverse effects).

Patients with a known thrombophilic condition have an increased risk of VTE, and HRT may increase this risk. HRT is therefore contraindicated in these patients (see section Contraindications).

Generally recognized risk factors for VTE include estrogen use, advanced age, major surgery, prolonged immobilization, obesity (BMI > 30 kg/m2), the pregnancy/postpartum period, systemic lupus erythematosus (SLE) and cancer. There is no consensus regarding the potential role of varicose veins in VTE.

As in all postoperative patients, prophylactic measures should be considered to prevent VTE after surgery. If prolonged immobilization is to follow elective surgery, temporary discontinuation of HRT 4 to 6 weeks beforehand is recommended. Treatment should not be resumed until the patient has fully regained mobility.

In women with no personal history of VTE but with a first-degree relative who had thrombosis at a young age, screening may be offered after a thorough review of its limitations (only certain thrombophilic abnormalities are identified by screening).

If thrombophilic abnormalities associated with thrombosis in family members or considered to be 'severe' are identified (for example, antithrombin, protein S or protein C deficiency, or a combination of abnormalities), HRT is contraindicated.

Women already on chronic anticoagulant treatment should undergo a careful assessment of the benefit/risk ratio of HRT use.

If VTE develops after treatment has started, treatment must be stopped. Patients should be advised to contact their doctor immediately if they suspect a potential thromboembolic symptom (in particular painful swelling of the leg, sudden chest pain, dyspnea).

Coronary heart disease

There are no randomized controlled trial data demonstrating protection against myocardial infarction in women with or without existing coronary artery disease receiving estro-progestogen or estrogen-only HRT.

The relative risk of coronary artery disease during use of combined estro-progestogen HRT is slightly increased. Since the baseline absolute risk of coronary heart disease is strongly age-dependent, the number of additional cases due to combined estrogen and progestogen use is very low in healthy women close to menopause, but it increases with age.

Ischaemic stroke

Combined estro-progestogen treatment and estrogen-only treatment are associated with an increased risk of ischemic stroke of up to a factor of 1,5. The relative risk does not change with age or with time since menopause. However, since the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women using HRT increases 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 should be closely monitored.

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

Exogenous oestrogens may induce or exacerbate symptoms of hereditary or acquired angioedema.

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 resin is decreased, reflecting the increase in TBG. 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 increased circulating levels of corticosteroids and sex steroids. 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 does not improve cognitive function. Some data indicate an increased risk of probable dementia in women starting continuous combined or estrogen-only 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 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. 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 is advised 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.

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) 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. Therefore, the metabolism of estrogens and progestogens 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 medicines at the same time.

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

FEMSEPTEVO has no indication during pregnancy. Discovery of a pregnancy during treatment with FEMSEPTEVO requires immediate discontinuation of treatment.

Clinical data on a large number of exposed pregnancies have not revealed any adverse effects of levonorgestrel on the fetus.

To date, most epidemiological studies have not demonstrated a teratogenic or foetotoxic effect in pregnant women inadvertently exposed to therapeutic doses of estrogens and progestogens.

Breast-feeding

This medicine has no indication during breastfeeding.

Fertility

Not applicable

FEMSEPTEVO has no effect on the ability to drive vehicles and use machines.

The most frequently reported adverse reactions (> 10%) under treatment with FEMSEPTEVO during clinical trials were skin reactions at the application site, breast tenderness and metrorrhagia or spotting. Skin reactions, mostly of mild intensity, generally disappear within two to three days after removal of the device. In the majority of cases, reported breast tenderness was of mild to moderate intensity and tended to decrease over time during treatment.

Other adverse reactions are those usually observed with estrogen and progestogen treatments.

System organ class	Frequent undesirable effects (≥ 1/100, < 1/10)	Uncommon undesirable effects (≥ 1/1 000, < 1/100)	Rare adverse effects (≥ 1/10 000, < 1/1 000)
General disorders and administration site conditions		Water retention/oedema/weight gain or loss, fatigue, lower limb cramps
Nervous system disorders	Headache	Dizziness, migraine
Gastrointestinal disorders	Dyspepsia	Bloating, abdominal cramps, nausea	Biliary lithiasis, cholestatic jaundice
Cardiovascular disorders		Arterial hypertension
Disorders of the reproductive system and breast	Mastodynia	Endometrial hyperplasia, benign changes of breast tissue	Increase in size of a uterine fibroid
Psychiatric disorders		Depression

Risk of breast cancer

An increased risk of breast cancer, which can rise to a factor of 2, is observed in women taking a combined estrogen-progestogen therapy for more than 5 years.

The increase in risk is lower in users of estrogens alone compared with users of combined estrogen-progestogen therapies.

The level of risk depends on the duration of use (see section Warnings and precautions).

Absolute risk estimates based on the results of the largest randomised controlled trial versus placebo (WHI study) and the largest meta-analysis of prospective epidemiological studies (MWS) 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 per 1 000 non-users of HRT over a period of 5 years (50-54 years)*	Risk ratio	Additional cases per 1 000 HRT users after 5 years
Estrogens alone
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: as the baseline incidence of breast cancer differs from one country to another within 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 non-users of HRT over a period of 10 years (50-59 years)*	Risk ratio	Additional cases per 1 000 HRT users after 10 years
Estrogens alone
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: as the baseline incidence of breast cancer differs from one country to another within the EU, the number of additional cases of breast cancer will vary proportionally.

WHI studies in the United States: additional risk of breast cancer after 5 years of use

Age range (years)	Incidence for 1 000 women in the placebo arm over 5 years	Risk ratio and CI at 95 %	Additional cases for 1 000 HRT users over 5 years (CI at 95 %)
CEE estrogen only
50-79	21	0,8 (0,7 – 1,0)	-4 (-6 – 0)*
CEE+MPA estrogen and progestogen‡
50-79	14	1,2 (1,0 – 1,5)	+4 (0 – 9)
*WHI study in women without a uterus, which 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 1 000 women without a hysterectomy not using HRT.

In women with an intact uterus, the use of estrogens alone is not recommended because it increases the risk of endometrial cancer (see section Warnings and precautions).

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

Adding a progestogen to estrogen-only treatment for at least 12 days per cycle may prevent this increased risk. In the Million Women Study, five 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

HRT use with estrogens alone or with 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 had 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 about 2 women out of 2000 over a five-year period.

Risk of venous thromboembolic disease

HRT is associated with a 1,3 to 3-fold increased risk of developing venous thromboembolic disease, i.e., deep vein thrombosis or pulmonary embolism. The probability 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:

WHI studies: additional risk of venous thromboembolic disease over 5 years of use

Age range (years)	Incidence for 1 000 women in the placebo arm over 5 years	Risk ratio and CI at 95 %	Additional cases per 1 000 HRT users
Oral estrogen only*
50-59	7	1,2 (0,6-2,4)	1 (-3-10)
Oral estrogen-progestogen combination
50-59	4	2,3 (1,2-4,3)	5 (1-13)
*Study in women without a uterus.

Risk of coronary heart disease

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

Risk of ischaemic stroke

The use of estrogen-only treatment and estrogen-progestogen treatment is associated with an increase of up to a factor of 1,5 in the relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased with HRT use.

As this relative risk does not depend on age or duration of use, but 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 ischaemic stroke* over 5 years of use

Age range (years)	Incidence for 1 000 women in the placebo arm over 5 years	Risk ratio and CI at 95 %	Additional cases in 1 000 women using HRT over 5 years
50-59	8	1,3 (1,1-1,6)	3 (1-5)
*no distinction has been established between ischaemic and haemorrhagic strokes.

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

• Biliary disorders.

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

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

Given the mode of administration, a significant overdose is unlikely.

The effects of an overdose are generally breast tension, abdominopelvic swelling, anxiety, irritability, nausea and vomiting.

In case of overdose, only removal of the transdermal system is necessary.

Pharmacotherapeutic class: Progestogens and oestrogens in combination, levonorgestrel and oestrogens (Genito-urinary system and sex hormones), ATC code: G03FA11.

FEMSEPTEVO is a combination continuous combined, of estradiol hemihydrate and levonorgestrel.

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

Levonorgestrel: oestrogens stimulate endometrial growth and increase the risk of endometrial hyperplasia and endometrial cancer. The addition of a progestogen in non-hysterectomised women substantially reduces the risk of oestrogen-induced endometrial hyperplasia.

Information on clinical studies

Relief of symptoms related to oestrogen deficiency and bleeding:

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

FEMSEPTEVO is a continuous combined HRT whose objective is to avoid withdrawal bleeding associated with cyclic or sequential HRT.

Amenorrhoea was observed in 59 to 68% of women after 10 to 12 months of treatment. Irregular bleeding and/or spotting occurred in 28 to 39% of women during the first three months of treatment and in 37% of the 10th at 12th months of treatment.

Transdermal administration avoids the first-pass hepatic effect observed with the oral route. Estradiol reaches the systemic circulation unchanged and in physiological quantities. Therapeutic estradiol concentrations are comparable to those observed in the follicular phase.

After continuous application of FEMSEPTEVO, maximum plasma estradiol concentrations (Cmax) reach 82 pg/ml and the mean plasma concentration (Cmean) is approximately 34 pg/ml. The minimum plasma concentration (Cmin) at the end of the 7 days of application is 27 pg/ml. After removal of the transdermal system, estradiol concentrations return to their initial value within 12 to 24 hours.

The maximum plasma concentration (Cmax) of levonorgestrel is reached within 3 to 4 days and is approximately 113 pg/ml at steady state. The mean plasma concentration of levonorgestrel (Cmean) over a period of 7 days is approximately 88 pg/ml and the minimum plasma concentration (Cmin) is 72 pg/ml.

Following transcutaneous passage, levonorgestrel binds to plasma proteins, to albumin (50 %) and to sex hormone-binding globulin (SHBG) (47,5 %). Levonorgestrel has a greater affinity for SHBG than other progestogens commonly used.

In animals, estradiol has embryolethal effects at relatively low doses; malformations of the urogenital tract and feminisation of male fetuses have been observed. Levonorgestrel has embryolethal effects in animals and, at high doses, a virilising effect on female fetuses. Due to important differences between animal species and between animals and humans, the predictive value of preclinical results is limited for the treatment of women with estrogens.

3 years.

Store at a temperature not exceeding 30ºC.

Refer to section Dosage and administration

No special requirements.

List I

Marketing authorisation (AMM)

CIP 3400936759459 (4 Sach).

Price:

8,82 euros (4 Sach).

Social Security reimbursement at 65%.
Collection.