Source: European Medicines Agency (EU) Revision Year: 2026 Publisher: Gedeon Richter Plc., Gyömrői út 19-21., 1103 Budapest, Hungary
The percentage of vaginal bleeding was 66.8% and of disordered proliferative endometrium was 5.4% in the pivotal phase 3 study in non-hysterectomised women with at least 12 months since last menses treated with estetrol 18.9 mg continuously combined with progesterone (P4) 100 mg (see also section 4.8). Higher P4 doses or another progestogen approved for addition to oestrogen treatment may be used, however, safety and tolerability data in combination with estetrol are not available.
For the treatment of postmenopausal symptoms, estetrol should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually, and HRT should only be continued as long as the benefit outweighs the risk.
Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women.
Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see 'Breast cancer' below). Investigations, including appropriate imaging tools, e.g. mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.
If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with estetrol, in particular:
Therapy should be discontinued in case a contra-indication is discovered and in the following situations:
In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among oestrogen-only users varies from 2- to 12-fold greater compared with non-users, depending on the duration of treatment and oestrogen dose (see section 4.8). After stopping treatment, the risk may remain elevated for at least 10 years.
The addition of a progestogen in continuous combined oestrogen-progestagen therapy in non-hysterectomised women prevents the excess risk associated with oestrogen-only HRT.
Break-through bleeding and spotting may occur during the first months of treatment. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.
Unopposed oestrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestagens to oestrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis.
The overall evidence shows an increased risk of breast cancer in women taking combined oestrogen- progestagen or oestrogen-only HRT, that is dependent on the duration of taking HRT.
The Women's Health Initiative (WHI) trial found no increase in the risk of breast cancer in hysterectomised women using oestrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is substantially lower than that found in users of oestrogen-progestagen combinations (see section 4.8).
Results from a large meta-analysis showed that after stopping treatment, the excess risk will decrease with time and the time needed to return to baseline depends on the duration of prior HRT use. When HRT was taken for more than 5 years, the risk may persist for 10 years or more.
HRT, especially oestrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Ovarian cancer is much rarer than breast cancer.
Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking oestrogen-only or combined oestrogen-progestagen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping.
Some other studies, including the WHI trial, suggest that use of combined HRTs may be associated with a similar or slightly smaller risk (see section 4.8).
HRT is associated with a 1.3-3-fold risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than later (see section 4.8).
Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients (see section 4.3).
Generally recognised risk factors for VTE include, use of oestrogens, older age, major surgery, prolonged immobilisation, obesity (body mass index (BMI) ≥30 kg/m²), pregnancy/postpartum period, systemic lupus erythematosus (SLE), and cancer. There is no consensus about the possible role of varicose veins in VTE.
As in all postoperative patients, prophylactic measures need to be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery temporarily stopping HRT 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilised.
In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is 'severe' (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated.
Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.
If VTE develops after initiating HRT, the medicinal product should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).
There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined oestrogen-progestagen or oestrogen-only HRT.
Randomised controlled data found no increased risk of CAD in hysterectomised women using oestrogen-only therapy.
Combined oestrogen-progestagen and oestrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see section 4.8).
Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed.
Women with pre-existing hypertriglyceridaemia should be followed closely during oestrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.
Exogenous oestrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.
Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), thyroxine (T4) levels (by column or by radio- immunoassay) or triiodothyronine (T3) levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).
HRT use does not improve cognitive function. There is some evidence of increased risk of probable dementia in women who start using continuous combined or oestrogen-only HRT after the age of 65.
During clinical trials with patients treated for hepatitis C virus (HCV) infections with the combination regimen ombitasvir/paritaprevir/ritonavir and dasabuvir with and without ribavirin, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medicinal products such as combined hormonal contraceptives (CHCs). Additionally, also in patients treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, and ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co- administration with the following combination drug regimens: ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir. See section 4.5.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially 'sodium-free'.
Estetrol is predominantly glucuronised by UDP-glucuronosyltransferase (UGT) 2B7 enzyme. No clinically relevant interaction was observed with estetrol and the strong UGT inhibitor valproic acid. Cytochrome P450 (CYP450) enzymes do not play a major role in the metabolism of estetrol. An interaction of estetrol with substances known to induce or inhibit CYP450 enzymes is therefore unlikely.
Based on in vitro inhibition studies, an interaction of estetrol with the metabolism of other active substances is unlikely.
During clinical trials with the HCV combination drug regimen ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, ALT elevations greater than 5 times the ULN were significantly more frequent in women using ethinylestradiol-containing medicinal products such as CHCs. Additionally, also with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs.
Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, and ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the following combination drug regimens: ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section 4.4).
FYLREVY is not indicated during pregnancy. If pregnancy occurs during treatment, it should be withdrawn immediately.
Studies in animals have shown reproductive toxicity (see section 5.3). Based on animal experience, harmful effects due to hormonal action of the active substance cannot be excluded.
The results of most epidemiological studies to date relevant to inadvertent foetal exposure to oestrogens indicate no teratogenic or foetotoxic effects.
FYLREVY is not indicated during lactation.
FYLREVY is not indicated in women of child-bearing potential.
FYLREVY has no or negligible influence on the ability to drive and use machines.
The most frequent adverse drug reactions reported in non-hysterectomised postmenopausal women with at least 12 months since last menses exposed to estetrol together with progesterone included endometrial thickening (>4 mm, 71.3%), vaginal haemorrhage (66.8%) and disordered proliferative endometrium (DPE) (5.4%). The other most frequent adverse drug reactions reported in women with or without a uterus were breast tenderness (8.7%) and breast pain (5.6%). Apart from uterus-related adverse drug reactions, there was no other difference in the safety profile in women with or without a uterus.
The safety of estetrol was assessed in one phase 2 and two phase 3 clinical trials (Trial 1 and Trial 2) that included 2 606 postmenopausal women (1 290 were treated with estetrol 14.2 mg or 18.9 mg alone, 463 were treated with placebo and 853 with at least 12 months since last menses were treated with estetrol 18.9 mg continuously combined with P4 100 mg).
Adverse drug reactions observed during clinical trials are listed in Table 1 and classified according to frequency and system organ class. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000) very rare (<1/10 000) and not known (cannot be estimated from the available data).
Table 1. Adverse drug reactions:
| System organ class | Very common | Common | Uncommon |
|---|---|---|---|
| Infections and infestations | Vulvovaginal candidiasis | ||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Uterine leiomyoma | ||
| Nervous system disorders | Dizziness | ||
| Vascular disorders | Venous thromboembolism | ||
| Gastrointestinal disorders | Abdominal pain lowera, Abdominal pain, Abdominal distension, Nausea, Constipation | ||
| Skin and subcutaneous tissue disorders | Urticaria | ||
| Musculoskeletal and connective tissue disorders | Pain in extremity | ||
| Reproductive system and breast disorders | Vaginal haemorrhageb, Endometrial thickening | Disordered proliferative endometrium, Breast pain, Breast tenderness, Nipple pain, Uterine spasm, Vaginal discharge, Vulvovaginal pruritus | Endometrial hyperplasia, Endometrial polypc, Adenomyosis, Breast massd, Breast swellinge, Ovarian cyst |
| General disorders and administration site conditions | Asthenia | Peripheral swelling | |
| Investigations | Weight increased |
a Includes pelvic pain
b Includes uterine haemorrhage and intermenstrual bleeding
c Includes cervical polyp and uterine polyp
d Includes Phyllodes tumour, breast cyst, breast scan abnormal
e Includes breast enlargement, breast engorgement
Largest meta-analysis of prospective epidemiological studies
Estimated additional risk of breast cancer after 5 years' use in women with BMI 27 (kg/m²):
| Age at start HRT (years) | Incidence per 1 000 never-users of HRT over a 5-year period (50-54 years)* | Risk ratio | Additional cases per 1 000 HRT users after 5 years |
|---|---|---|---|
| Oestrogen-only HRT | |||
| 50 | 13.3 | 1.2 | 2.7 |
| Combined oestrogen-progestagen | |||
| 50 | 13.3 | 1.6 | 8.0 |
* Taken from baseline incidence rates in England in 2015 in women with BMI = 27 (kg/m²)
Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately.
Estimated additional risk of breast cancer after 10 years' use in women with BMI 27 (kg/m²):
| Age at start HRT (years) | Incidence per 1 000 never-users of HRT over a 10-year period (50-59 years)* | Risk ratio | Additional cases per 1 000 HRT users after 10 years |
|---|---|---|---|
| Oestrogen-only HRT | |||
| 50 | 26.6 | 1.3 | 7.1 |
| Combined oestrogen-progestagen | |||
| 50 | 26.6 | 1.8 | 20.8 |
* Taken from baseline incidence rates in England in 2015 in women with BMI = 27 (kg/m²)
Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately.
US WHI studies - additional risk of breast cancer after 5 years' use:
| Age range (years) | Incidence per 1 000 women in placebo arm over 5 years | Risk ratio & 95% CI | Additional cases per 1 000 HRT users over 5 years (95% CI) |
|---|---|---|---|
| CEE oestrogen-only | |||
| 50-79 | 21 | 0.8 (0.7 – 1.0) | -4 (-6 – 0)* |
| CEE+MPA oestrogen & progestagen‡ | |||
| 50-79 | 17 | 1.2 (1.0 – 1.5) | +4 (0 – 9) |
* WHI study in women with no uterus, which did not show an increase in risk of breast cancer
‡ When the analysis was restricted to women who had not used HRT prior to the study there was no increased risk apparent during the first 5 years of treatment: after 5 years the risk was higher than in non-users.
The endometrial cancer risk is about 5 in every 1 000 women with a uterus not using HRT.
In women with a uterus, use of oestrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4).
Depending on the duration of oestrogen-only use and oestrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1 000 women between the ages of 50 and 65.
Adding a progestagen to oestrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study the use of five years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer (RR of 1.0 (0.8-1.2)).
Use of oestrogen-only or combined oestrogen-progestagen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed (see section 4.4).
A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31-1.56). For women aged 50 to 54 years taking 5 years of HRT, this results in about 1 extra case per 2 000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2 000 will be diagnosed with ovarian cancer over a 5-year period.
HRT is associated with a 1.3-3-fold increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of using HT (see section 4.4). Results of the Women's Health Initiative (WHI) studies are presented:
WHI Studies - Additional risk of VTE over 5 years' use:
| Age range (years) | Incidence per 1 000 women in placebo arm over 5 years | Risk ratio & 95% CI | Additional cases per 1 000 HRT users |
|---|---|---|---|
| Oral oestrogen-only* | |||
| 50-59 | 7 | 1.2 (0.6 – 2.4) | 1 (-3 – 10) |
| Oral combined oestrogen-progestagen | |||
| 50-59 | 4 | 2.3 (1.2 – 4.3) | 5 (1 – 13) |
* Study in women with no uterus
Risk of coronary artery disease
WHI studies combined - Additional risk of ischaemic stroke* over 5 years' use:
| Age range (years) | Incidence per 1 000 women in placebo arm over 5 years | Risk ratio & 95% CI | Additional cases per 1 000 HRT users over 5 years |
|---|---|---|---|
| 50-59 | 8 | 1.3 (1.1 – 1.6) | 3 (1 – 5) |
* no differentiation was made between ischaemic and haemorrhagic stroke.
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 listed in Appendix V.
Not applicable.
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