Source: Health Products Regulatory Authority (IE) Revision Year: 2020 Publisher: Rottapharm Ltd, Damastown Industrial Park, Mulhuddart, Dublin 15, Ireland
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 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 ofthe 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 DERMESTRIL-Septem, in particular:
Therapy should be discontinued in case a contra-indication is discovered and in the following situations:
n 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 risk may remain elevated for at least 10 years.
The addition of a progestagen cyclically for at least 12 days per month/28 day cycle or continuous combined oestrogen-progestagen therapy in non-hysterectomised women prevents the excess risk associated with oestrogen-only HRT.
For patches releasing more than 50 micrograms/day the endometrial safety of added progestagens has not been demonstrated.
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 estrogen 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.
Combined oestrogen-progestagen therapy: The randomised placebo-controlled trial the Women’s Health Initiative study (WHI), and a meta-analysis of prospective epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined oestrogen-progestagen for HRT that becomes apparent after about 3 (1-4) years (see Section 4.8).
Oestrogen-only therapy: The 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 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 a history of VTE or 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 (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 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 therapy, the drug 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.
Combined oestrogen-progestagen therapy: The relative risk of CAD during use of combined oestrogen+progestagen 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 oestrogen+progestagen use is very low in healthy women close to menopause, but will rise with more advanced age.
Oestrogen-only: 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 hypertriglyceridemia 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.
Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or 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.
The metabolism of oestrogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamezapin) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).
Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones. Herbal preparations containing St John’s wort (Hypericum Perforatum) may induce the metabolism of oestrogens.
At transdermal administration, the first-pass effect in the liver is avoided and, thus, transdermally applied oestrogens might be less affected than oral hormones by enzyme inducers.
Clinically, an increased metabolism of oestrogens and progestagens may lead to decreased effect and changes in the uterine bleeding profile.
DERMESTRIL-Septemis not indicated during pregnancy. If pregnancy occurs during medication with
DERMESTRIL-Septemtreatment should be withdrawn immediately.
The results of most epidemiological studies to date relevant to inadvertent fetal exposure to oestrogens indicate no teratogenic or foetotoxic effects.
DERMESTRIL-Septem is not indicated during lactation.
No studies on the effects on the ability to drive and use machines have been performed.
More than 700 patients have been treated with the product in clinical trials.
Approximately 10 to 17% of the patients treated with DERMESTRIL-Septem in clinical trials experienced systemic adverse reactions, which were mild and transient. Breast tenderness was reported in 20-35% of patients. Local reactions at the application site, mostly mild erythema with or without pruritus, occurred in 10-25% of patients.
Serious undesirable effects associated with the use of hormone replacement therapy are also mentioned in section 4.4 Special warnings and precautions for use.
The table below reports undesirable effects that have been reported in users of hormone replacement therapy (HRT) by MedDRA system organ classes (MedDRA SOCs).
| System Organ Class | Common ADRs, (≥1/100, <1/10) | Uncommon ADRs, (≥1/1,000, <1/100) | Rare ADRs (<1/1,000) | Frequency unknown* |
|---|---|---|---|---|
| Infections and manifestations | Vaginal candidiasis | |||
| Immune system disorders | Hypersensitivity reaction | |||
| Metabolism and nutrition disorders | Weight increase or Weight decrease | |||
| Psychiatric disorders | Depressed mood | Anxiety Libido decreased or Libido increased | ||
| Nervous system disorders | Headache | Dizziness | Migraine | Probable dementia over the age of 65 (see section 4.4), chorea, exacerbation of epilepsy |
| Eye disorders | Visual disturbances | Contact lens intolerance | ||
| Cardiac disorders | Palpitations | |||
| Gastrointestinal disorders | Abdominal pain, Nausea | Dyspepsia | Bloating, Vomiting | Pancreatitis (in women with pre-existing hypertriglyceridaemia) Gastroesophageal reflux disease |
| Hepatobiliary disorders | Gall bladder disorder | Hepatic function abnormal, sometimes with jaundice | ||
| Skin and subcutaneous tissue disorders | Rash, Pruritus | Erythema nodosum, Urticaria | Hirsutism, acne | Angioedema, Erythema multiforme, Vascular purpura, Chloasma Application site reactions: erythema with or without pruritus |
| Musculoskeletal and connective tissue disorders | Muscle cramps | |||
| Reproductive system and breast disorders | Metrorrhagia, Uterine/Vaginal bleeding including Spotting | Breast pain, Breast tenderness | Dysmenorrhea, Vaginal discharge, Premestrual-like syndrome, Breast enlargement | Fibrocystic breast disease |
| General disorders and administration site conditions | Oedema | Fatigue | ||
| Neoplasms benign, malignant and unspecified (incl. cysts and polyps) | Breast cancera Oestrogen dependent neoplasms benign and malignant, e.g. endometrial cancerb, ovarian cancerc Increase in size of leiomyoma | |||
| Vascular disorders | Strokef Arterial thromboembolism, i.e. angina and myocardial infarctione . For further information see sections 4.3 and 4.4. Venous thromboembolismd, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism. For further information see sections 4.3 and 4.4. | |||
| Renal and urinary disorders | Urinary incontinence |
The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.
* Undesirable effects from spontaneous post-marketing reporting sources, which have not been observed in clinical trials.
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 (see section 4.4).
Absolute risk estimations based on results of the largest randomised placebo-controlled trial (WHI-study) and the largest meta-analysis ofprospective 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 | Incidence per 1000 never-users of HRT over a 5 year period (50-54 years)* | Risk ratio | Additional cases per 1000 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 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 year 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 oestrogen-only | |||
| 50-79 | 21 | 0.8 (0.7 – 1.0) | -4 (-6 – 0)*3 |
| CEE+MPA oestrogen & progestagen# | |||
| 50-79 | 17 | 1.2 (1.0 – 1.5) | +4 (0 – 9) |
*3 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 1000 women with an 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 1000 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 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 oestrogen-only*4 | |||
| 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) |
*4 Study in women with no uterus
The risk of coronary artery disease is slightly increased in users of combined oestrogen-progestagen HRT over the age of 60 (see section 4.4).
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, see section 4.4.
WHI studies combined – Additional risk of ischaemic stroke*5 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 over 5 years |
| 50-59 | 8 | 1.3 (1.1-1.6) | 3 (1-5) |
*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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.
Not applicable.
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