Source: Health Products Regulatory Authority (IE) Revision Year: 2016 Publisher: Pfizer Healthcare Ireland, 9 Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24
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 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 Totelle 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 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.
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 suggests an increased risk of breast cancer in women taking combined oestrogen-progestagen and possibly also oestrogen-only HRT, that is dependent on the duration of taking HRT.
The randomized placebo-controlled trial (the Women’s Health Initiative study (WHI)), and 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 years (see section 4.8).
The excess risk becomes apparent within a few years of use but returns to baseline within a few (at most five) years after stopping treatment.
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 the use of combined HRTs may 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 (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 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.
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.
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).
Should a stroke occur or be suspected, oestrogens should be discontinued immediately.
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 radioimmunoassay) 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.
Exogenous oestrogens may induce or exacerbate symptoms of angioedema, particularly in patients with hereditary angioedema.
Oestrogen therapy should be used with caution in women with hypoparathyroidism, as oestrogen-induced hypocalcemia may occur.
This medicinal product contains lactose and sucrose. Patients with rare hereditary problems of galactose intolerance, fructose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
The metabolism of oestrogens and progestagens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants, anti-infectives, dexamethasone and herbal preparations containing St John’s Wort (Hypericum perforatum). Strong CYP3A4 inducers such as phenobarbital, phenytoin, carbamazepine, rifampicin and dexamethasone may reduce plasma concentrations of 17ß-estradiol.
Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones. Clinically, an increased metabolism of oestrogens and progestagens may lead to decreased effect and changes in the uterine bleeding profile.
CYP3A4 inhibitors such as cimetidine, erythromycin and ketoconazole may increase plasma concentrations of 17ß-estradiol and may result in increased risk of side effects.
In vitro studies have shown that trimegestone may inhibit cytochrome P450 2C19 (CYP2C19). The clinical relevance is not known; however trimegestone may moderately increase the plasma concentrations of drugs metabolised via CYP2C19 such as citalopram, imipramine, and diazepam. Similar in vitro studies with cytochrome P450 3A4 (CYP3A4), which is partially responsible for trimegestone metabolism, have demonstrated a low potential for an interaction.
Patients receiving concomitant telaprevir should be monitored for signs of oestrogen deficiency.
Totelle is not indicated during pregnancy.
If pregnancy occurs during medication with Totelle, treatment should be withdrawn immediately. For trimegestone no clinical data on exposed pregnancies are available. Studies in animals have shown reproductive toxicity (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 oestrogens with other progestagens indicate no teratogenic or foetotoxic effect.
Totelle is not indicated during lactation.
Not relevant.
The adverse reactions listed in the table are based on post-marketing spontaneous (reporting rate), clinical trials and class-effects. Breast pain is a very common adverse event reported in 10% of patients.
These frequencies are based on conjugated equine oestrogens plus medroxyprogesterone acetate (MPA) data.
| System Organ Class | Very common ADRs (≥1/10) | Common ADRs (≥1/100 to <1/10) | Uncommon ADRs (≥1/1,000 to <1/100) | Rare ADRs (≥1/10,000 to <1/1,000) | Very Rare ADRs (<1/10,000) |
|---|---|---|---|---|---|
| Infections and infestations | None | Vaginitis | Vaginal candidiasis | None | None |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | None | None | None | Breast cancer, Fibrocystic breast changes, Ovarian cancer, Growth potentiation of benign meningioma | Endometrial cancer, Enlargement of hepatic hemangiomas |
| Immune system disorders | None | None | None | Anaphylactic/ anapylactoid reactions, including urticaria and angioedema | None |
| Metabolism and nutrition disorders | None | None | None | Glucose intolerance | Exacerbation of porphyria, Hypocalcemia |
| Psychiatric disorders | None | Depression | Changes in libido, Mood disturbances, Dementia | Irritability | None |
| Nervous system disorders | None | None | Dizziness, Headache, Migraine, Anxiety | Stroke, Exacerbation of epilepsy | Exacerbation of chorea |
| Eye disorders | None | None | Intolerance to contact lenses | None | Retinal vascular thrombosis |
| Cardiac disorders | None | None | None | Myocardial infarction | None |
| Vascular disorders | None | None | Venous thrombosis, Pulmonary embolism | Superficial thrombophlebitis | None |
| Respiratory, thoracic and mediastinal disorders | None | None | None | Exacerbation of asthma | None |
| Gastrointestinal disorders | None | None | Nausea, Bloating, Abdominal pain | Vomiting, Pancreatitis, Ischaemic colitis | None |
| Hepatobiliary disorders | None | None | Gallbladder disease | None | Cholestatic jaundice |
| Skin and subcutaneous tissue disorders | None | None | Alopecia, Acne, Pruritus | Chloasma/ melasma, Hirsutism, Rash | Erythema multiforme, Erythema nodosum |
| Musculoskeletal and connective tissue disorders | None | Arthralgias, Leg cramps | None | None | None |
| Reproductive system and breast disorders | Breast pain | Breakthrough bleeding/ spotting, Dysmenorrhea, Breast tenderness/ enlargement/ discharge | Change in menstrual flow, Change in cervical ectropion and secretion | Galactorrhoea, Increased size of uterine leiomyomata | Endometrial hyperplasia |
| General disorders and administration site conditions | None | None | Oedema | None | None |
| Investigations | None | Changes in weight (increase or decrease), Increased triglycerides | None | None | Increase in blood pressure |
Million Women Study – Estimated additional risk of breast cancer after 5 years' use:
| Age range (years) | Additional cases per 1,000 never-users of HRT over a 5-year period*2 | Risk ratio# | Additional cases per 1,000 HRT users over 5 years (95% CI) |
|---|---|---|---|
| Oestrogen only HRT | |||
| 50-65 | 9-12 | 1.2 | 1-2 (0-3) |
| Combined oestrogen-progestagen | |||
| 50-65 | 9-12 | 1.7 | 6 (5-7) |
# Overall risk ratio. The risk ratio is not constant but will increase with increasing duration on use.
Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately.
*2 Taken from baseline incidence rates in developed countries.
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)*3 |
| CEE+MPA oestrogen & progestagen‡ | |||
| 50-79 | 17 | 1.2 (1.0 – 1.5) | +4 (0 – 9) |
‡ 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.
*3 WHI study in women with no uterus, which did not show an increase in risk of breast cancer.
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 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 1,000 women in placebo arm over 5 years | Risk ratio & 95% CI | Additional cases per 1,000 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 plus 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.
Other adverse reactions have been reported in association with oestrogen/progestagen treatment:
Skin and subcutaneous tissue disorders: vascular purpura.
Clinical studies have not been conducted in the paediatric population.
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.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
