Estetrol

Estetrol is not recommended in women with moderate or severe renal impairment.

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.

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:

• Leiomyoma (uterine fibroids) or endometriosis;
• Risk factors for thromboembolic disorders (see below);
• Risk factors for oestrogen dependent tumours, e.g. 1^st degree heredity for breast cancer;
• Hypertension;
• Liver disorders (e.g. liver adenoma);
• Diabetes mellitus with or without vascular involvement;
• Cholelithiasis;
• Migraine or (severe) headache;
• Systemic lupus erythematosus;
• A history of endometrial hyperplasia;
• Epilepsy;
• Asthma;
• Otosclerosis.

Venous thromboembolism

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.

Estetrol is not indicated during pregnancy. If pregnancy occurs during treatment, it should be withdrawn immediately.

Studies in animals have shown reproductive toxicity. 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.

Estetrol is not indicated during lactation.

Fertility

Estetrol is not indicated in women of child-bearing potential.

Estetrol has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

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.

Tabulated list of adverse drug reactions

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:

^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

Description of selected adverse reactions

Breast cancer risk

• An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestagen therapy for more than 5 years.
• The increased risk in users of oestrogen-only therapy is lower than that seen in users of oestrogen-progestagen combinations.
• The level of risk is dependent on the duration of use.
• Absolute risk estimations based on results of the largest randomised placebo-controlled trial (WHI-study) and the largest meta-analysis of prospective epidemiological studies are presented.

Largest meta-analysis of prospective epidemiological studies

Estimated additional risk of breast cancer after 5 years' use in women with BMI 27 (kg/m²):

^* 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):

^* 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:

^* 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.

Endometrial cancer risk

• Postmenopausal women with a uterus

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.

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)).

Ovarian cancer

Use of oestrogen-only or combined oestrogen-progestagen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed.

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.

Risk of venous thromboembolism

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. Results of the Women's Health Initiative (WHI) studies are presented:

WHI Studies - Additional risk of VTE over 5 years' use:

^* Study in women with no uterus

Risk of coronary artery disease

• The risk of coronary artery disease is slightly increased in users of combined oestrogen-progestagen HRT over the age of 60.

Risk of ischaemic stroke

• The use of oestrogen-only and oestrogen + progestagen therapy is associated with an up to 1.5-fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT.
• This relative risk is not dependent on age or on duration of use, but as the baseline risk is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age.

WHI studies combined - Additional risk of ischaemic stroke* over 5 years' use:

^* no differentiation was made between ischaemic and haemorrhagic stroke.