For the treatment of postmenopausal symptoms, HRT 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 hormone replacement therapy, 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 Velbienne, in particular:
Therapy should be discontinued in case a contraindication is discovered and in the following situations:
In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among estrogen-only users varies from 2- to 12-fold greater compared with non-users, depending on the duration of treatment and estrogen dose (see section 4.8). After stopping treatment risk may remain elevated for at least 10 years.
The addition of a progestogen cyclically for at least 12 days/28 day cycle or continuous combined estrogenprogestogen therapy in non-hysterectomised women prevents the excess risk associated with estrogenonly HRT.
Break-through bleeding and spotting may occur during the first months of treatment. If breakthrough 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.
The overall evidence shows an increased risk of breast cancer in women taking combined estrogenprogestogen or estrogen-only HRT, that is dependent on the duration of taking HRT.
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 estrogen-progestogen 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 estrogen-only or combined estrogen-progestogen 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 estrogens, older age, major surgery, prolonged immobilization, obesity (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 be considered to prevent VTE following surgery. If prolonged immobilization 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 counseling 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 therapy, the drug should be discontinued. Patients should be told to contact their doctorsimmediatelywhen they are aware of a potential thromboembolic symptom (eg, painful swelling of a leg, sudden pain in the chest, dyspnea).
There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined estrogen-progestogen HRT.
The relative risk of CAD during use of combined estrogen-progestogen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to estrogenprogestogen use is very low in healthy women close to menopause, but will rise with more advanced age.
Randomised controlled data found no increased risk of CAD in hysterectomised women using estrogenonly therapy.
Combined estrogen-progestogen and estrogen-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).
Estrogens may cause fluid retention, and therefore, patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients of estradiol valerate and dienogest is increased.
In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.
During clinical trials with patients treated for hepatitis C virus (HCV) infections with the combination regimen ombitasvir/paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiolcontaining medicinal products such as CHCs. Additionally, also in patients treated with glecaprevir/pibrentasvir, 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, 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 coadministration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir and also the regimen glecaprevir/pibrentasvir. See section 4.5.
The tablet contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Note: The prescribing information of concomitant medication should be consulted to identify potential interactions.
The metabolism of estrogen and dienogest may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. barbiturates, phenytoin, primidone, carbamezapin) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz) and possibly also felbamate, griseofulvin, oxcarbazepine, topiramate and products containing the herbal remedy St. John’s Wort (hypericum perforatum).
Clinically, an increased metabolism of estrogen and dienogest may lead to decreased effect and changes in the uterine bleeding profile.
Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction is generally seen within a few weeks. After cessation of drug therapy, the enzyme induction may be sustained for about 4 weeks.
When co-administered with sex hormones, many combinations of HIV protease inhibitors and nonnucleoside reverse transcriptase inhibitors, including combinations with HCV inhibitors, , can increase or decrease plasma concentrations of the estrogen or dienogest or both. In some cases, the net effect of these changes may be clinically relevant.
Therefore, the prescribing information of co-administered HIV/HCV medications should be consulted to identify potential interactions and any related recommendations.
Strong and moderate CYP3A4 inhibitors, such as azole antifungals (e.g. fluconazole, itraconazole, ketoconazole, voriconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem, and grapefruit juice can increase plasma concentrations of the estrogen or dienogest, or both.
During clinical trials with the HCV combination drug regimen ombitasvir/paritaprevir/ritonavir with and without dasabuvir, 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 CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, 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 combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir and also the regimen with glecaprevir/pibrentasvir (see section 4.4).
The use of sex steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins, e.g. corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism, and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range. For more information see section 4.4, “Other conditions”.
Velbienne is not indicated during pregnancy. If pregnancy occurs during medication with Velbienne, treatment should be withdrawn immediately.
For dienogest no clinical data on exposed pregnancies are available. Studies in animals have not shown reproductive toxicity which could be related to the progestogenic effects of dienogest (see section 5.3). The potential risk for humans is unknown. The results of most epidemiological studies to date relevant to inadvertent foetal exposure to combinations of estrogens with other progestogens indicate no teratogenic or foetotoxic effect.
Velbienne is not indicated during lactation.
No studies on the effects on the ability to drive and use machines have been performed. No effects on ability to drive and use of machines have been observed in users of estradiol valerate 1 mg/dienogest 2 mg.
The following table (System Organ Class MedDRA v. 8.0) attributes frequencies to the undesirable effects of estradiol valerate 1 mg/dienogest 2 mg. These frequencies are based on the frequencies of adverse events, which were recorded in 4 phase III clinical studies (n = 538 women) and considered as at least possibly related to estradiol valerate 1 mg/dienogest 2 mg treatment.
| System Organ Class MedDRA v. 8.0 | Common ≥1/100, <1/10 | Uncommon ≥1/1,000, <1/100 |
|---|---|---|
| Metabolism and nutrition disorders | Weight increase | |
| Psychiatric disorders | Depression, Anorexia nervosa, Aggression, Somnolence, Insomnia, Nervousness, Anorgasmia, Libido decreased | |
| Nervous system disorders | Headache | Migraine, Dizziness, Paresthesia, Hyperkinesia |
| Vascular disorders | Venous thrombosis (Leg pain), Thrombophlebitis, Hypertension, Epistaxis | |
| Gastrointestinal disorders | Nausea | Abdominal pain, Diarrhea, Vomiting, Constipation, Flatulence, Dry mouth |
| Hepatobiliary disorders | Biliary pain | |
| Skin and subcutaneous tissue disorders | Psoriasis, Acne, Pruritus, Sweating increased, Dry skin | |
| Musculoskeletal and connective tissue disorders | Myalgia, Cramps legs | |
| Reproductive system and breast disorders | Uterine/Vaginal bleeding including Spotting (bleeding irregularities usually subside during continued treatment), Breast pain, Hot flushes | Endometrial disorder, Vaginal candidiasis, Dysmenorrhea, Pruritus genital |
| General disorders and administration site conditions | Generalized edema/Face edema/Edema Fatigue |
An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined estrogen-progestogen therapy for more than 5 years.
The increased risk in users of estrogen-only therapy is substantially lower than that seen in users of estrogen-progestogen combinations.
The level of risk is dependent on the duration of use (see section 4.4).
Absolute risk estimations based on results of the largest randomized 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):
| Age at start HRT (years) | Incidence per 1000 never-users of HRT over a 5 years period (50-54 years)** | Risk ratio | Additional cases per 1000 HRT users after 5 years |
|---|---|---|---|
| Estrogen only HRT | |||
| 50 | 13.3 | 1.2 | 2.7 |
| Combined estrogen-progestogen | |||
| 50 | 13.3 | 1.6 | 8.0 |
* Taken form 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 1000 never-users of HRT over a 10 years period (50-59 years)* | Risk ratio | Additional cases per 1000 HRT users after 10 years |
|---|---|---|---|
| Oestrogen only HRT | |||
| 50 | 26.6 | 1.3 | 7.1 |
| Combined oestrogen-progestogen | |||
| 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 1000 women in placebo arm over 5 years | Risk ratio & 95%CI | Additional cases per 1000 HRT users over 5 years (95% CI) |
|---|---|---|---|
| CEE estrogen only | |||
| 50-79 | 21 | 0.8 (0.7-1.0) | -4 (-6-0)* |
| CEE+MPA estrogen & progestagen¹ | |||
| 50-79 | 17 | 1.2 (1.0-1.5) | +4 (0-9) |
CEE: conjugated equine estrogens. MPA: medroxiprogesterone acetate
* WHI study in women with no uterus, which did not show an increase in risk of breast cancer
¹ 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 1000 women with a uterus not using HRT.
In women with a uterus, use of eestrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4).
Depending on the duration of estrogen-only use and estrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 women between the ages of 50 and 65.
Adding a progestogen to estrogen-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 estrogen-only or combined estrogen-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 2000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2000 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 WHI studies are presented.
WHI Studies- Additional risk of VTE over 5 years’use:
| Age range (years) | Incidence per 1000 women in placebo arm over 5 years | Risk ratio & 95%CI | Additional cases per 1000 HRT users |
|---|---|---|---|
| Oral estrogen only* | |||
| 50-59 | 7 | 1.2 (0.6-2.4) | 1 (-3 – 10) |
| Oral combined estrogen-progestogen | |||
| 50-59 | 4 | 2.3 (1.2 – 4.3) | 5 (1 – 13) |
* Study in women with no uterus
The risk of coronary artery disease is slightly increased in users of combined estrogen-progestogen HRT over the age of 60 (see section 4.4).
The use of estrogen-only and estrogen-progestogen 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, see section 4.4.
WHI Studies combined – Additional risk of ischaemic stroke* over 5 years’use:
| Age range (years) | Incidence per 1000 women in placebo arm over 5 years | Risk ratio & 95%CI | Additional cases per 1000 HRT users (95% CI) |
|---|---|---|---|
| 50-59 | 8 | 1.3 (1.1-1.6) | 3 (1-5) |
* no differentiation was made between ischaemic and haemorrhagic stroke
Other adverse reactions have been reported in association with estrogen-progestogen treatment:
In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema (see section 4.4).
Reporting suspected adverse reactions after authorization 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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