ESTROFEM

Hormone replacement therapy (HRT) for estrogen deficiency symptoms in menopausal women [at least 6 months after the last period].

Prevention of postmenopausal osteoporosis in women with an increased risk of osteoporotic fracture and who have an intolerance or a contraindication to other treatments indicated in the prevention of osteoporosis.

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

Pregnancy

This medicine has no indication during pregnancy.

The discovery of a pregnancy during treatment with PROVAMES 2 mg, film-coated tablet requires immediate discontinuation of treatment.

To date, most epidemiological studies have not demonstrated any teratogenic or foetotoxic effect in pregnant women accidentally exposed to therapeutic doses of estrogens.

Breastfeeding

This medicine has no indication during breastfeeding.

Not applicable.

The following adverse effects have been observed during hormone replacement therapy for menopause (clinical studies):

Risk of breast cancer

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

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

The level of risk is dependent on the duration of treatment (see section 4.4).

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

Largest meta-analysis of prospective epidemiological studies

Estimation of the additional risk of breast cancer after 5 years of use in women with a BMI of 27 (kg/m 2 )

* Derived from baseline incidence rates in England in 2015 in developed countries in women having a BMI of 27 (kg/m 2 )

Note: given that the baseline incidence of breast cancer differs according to European Union (EU) countries, the number of additional breast cancer cases will vary proportionally.

Estimation of the additional risk of breast cancer after 10 years of use in women with a BMI of 27 (kg /m 2 )

* Derived from baseline incidence rates in England in 2015 in women with a BMI of 27 (kg/m 2 )

Note: given that the baseline incidence of breast cancer differs according to EU countries, the number of additional breast cancer cases will vary proportionally.

US WHI studies – additional risk of breast cancer after 5 years of use

‡ 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 women without a uterus did not show an increase in the risk of breast cancer.

Risk of endometrial cancer

In non-hysterectomized women, the risk is approximately 5 endometrial cancer diagnoses per 1000 women not using HRT.

In non-hysterectomized women, the use of estrogens alone is not recommended due to the increased risk of endometrial cancer (see section 4.4).

According to epidemiological studies, the risk of endometrial cancer varies from 5 to 55 additional diagnostic cases per 1000 women between 50 and 65 years of age, depending on the duration of use and the dose of estrogen used.

The combination of a progestogen with estrogen for at least 12 days per cycle prevents the increase in this risk. In the Million Women Study, the use of combined HRT (sequential or continuous) did not increase the risk of endometrial cancer (RR of 1.0 (0.8 – 1.2)).

Risk of ovarian cancer

The use of HRT by estrogens alone or by a combination of estrogens and progestogens has been associated with a slight increase in the risk of diagnosed ovarian cancer (see section 4.4).

A meta-analysis of 52 epidemiological studies reported an increased risk of ovarian cancer in women currently taking HRT compared to women who have never taken it (RR 1.43, 95% CI 1.31-1.56). In women aged 50 to 54 years, taking HRT for five years results in the appearance of one additional case per 2000 users. In women aged between 50 and 54 years who are not taking HRT, an ovarian cancer diagnosis will be made in approximately 2 women out of 2000 over a five-year period.

Risk of venous thromboembolism

HRT is associated with a 1.3 to 3-fold increase in the relative risk of a venous thromboembolic event, 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 4.4). The results of the WHI studies are presented below:

WHI studies - additional risk of VTE over 5 years of use

* Study in women without a uterus

Risk of coronary artery disease

The risk of coronary artery disease is slightly increased in users of estroprogestogen HRT beyond 60 years (see section 4.4).

Risk of ischemic stroke

The use of an HRT based on estrogens alone or an estroprogestogen combination is associated with up to a 1.5-fold increase in the relative risk of ischemic stroke. The risk of hemorrhagic stroke is not increased during 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 4.4).

Combined WHI studies - Additional risk of stroke* over 5 years of use

* no distinction was made between ischemic and hemorrhagic strokes

The following adverse effects, considered class effects, are reported during the administration of an estroprogestogen treatment:

· Estrogen-dependent benign or malignant tumors, such as endometrial cancer.

· Venous thromboembolic disease (i.e. pelvic or lower limb deep vein thrombosis, pulmonary embolism), more frequent in women on HRT than in non-users. For additional information, see sections 4.3 and 4.4.

· Myocardial infarction and stroke.

· Biliary disorders.

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

· Probable dementia (see section 4.4).

Reporting of suspected adverse effects

Reporting of suspected adverse effects after authorisation of the medicinal product is important. It allows continuous monitoring of the benefit/risk ratio of the medicinal product. Healthcare professionals report any suspected adverse effect via the national reporting system: French National Agency for Medicines and Health Products Safety (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr