Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2022 Publisher: Besins Healthcare (UK) Ltd, Lion Court, 25 Procter Street, Holborn, London, WC1V 6NY, United Kingdom
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.
IMVAGGIS 0.03 mg pessary must not be combined with estrogen preparations for systemic treatment, as there are no studies of safety and risks with estrogen concentrations attained in combination treatment.
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.
Vaginal infections should be treated with the appropriate medication before the start of treatment with IMVAGGIS 0.03 mg pessary.
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 IMVAGGIS 0.03 mg pessary, in particular:
Therapy should be discontinued in case a contraindication is discovered, and in the following situations:
An increased risk of endometrial hyperplasia or uterine cancer has not been attributed to treatment with estriol by vaginal use.
In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when systemic estrogens are administered alone for prolonged periods.
For estrogen products for vaginal application of which the systemic exposure to estrogen is very low, it is not recommended to add a progestagen.
Endometrial safety of long-term (more than one year) or repeated use of local vaginally administered estrogen is uncertain. Therefore, if repeated, treatment should be reviewed at least annually.
Unopposed estrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore caution is advised when using this product in women who have undergone hysterectomy because of endometriosis, especially if they are known to have residual endometriosis. If bleeding or spotting appears at any time on therapy, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.
The following risks have been associated with systemic HRT and apply to a lesser extent for estrogen products for vaginal application of which the systemic exposure to the estrogen is very low. However, they should be considered in case of long term or repeated use of this product.
Epidemiological evidence from a large meta-analysis suggests no increase in risk of breast cancer in women with no history of breast cancer taking low dose vaginally applied estrogens. It is unknown if low dose vaginal estrogens stimulate recurrence 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 systemic HRT, which becomes apparent within 5 years of use and diminishes over time after stopping.
Systemic 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 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).
Randomised controlled data found no increased risk of CAD in hysterectomised women using systemic estrogen-only therapy.
Systemic estrogen-only therapy is 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. Women with pre-existing hypertriglyceridemia, should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.
Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.
Estrogens 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 biologically 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 estrogen-only HRT after the age of 65.
Note:
IMVAGGIS 0.03 mg pessary cannot be used for contraception.
The excipient butylhydroxytoluene may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.
Due to the vaginal administration and minimal systemic absorption, it is unlikely that any clinically relevant drug interactions will occur with IMVAGGIS 0.03 mg pessary. However interactions with other locally applied vaginal treatments should be considered.
If IMVAGGIS 0.03 mg pessary is used simultaneously with condoms made of latex it can decrease the tensile strength and thus impair the safety of condoms.
The use of IMVAGGIS 0.03 mg pessary is not indicated during pregnancy. If pregnancy occurs during medication with IMVAGGIS 0.03 mg pessary, treatment should be withdrawn immediately.
The results of most epidemiological studies to date relevant to inadvertent fetal exposure to estrogens indicate no teratogenic or fetotoxic effects. However, no clinical data on fetal exposure following vaginal administration of estriol are available. Given the high estriol concentrations in human pregnancy, any fetal exposure to estriol due to the use of low-dose pessaries is to be regarded as negligible.
IMVAGGIS 0.03 mg pessary is not indicated during lactation. However, very low doses of vaginally applied estriol are unlikely to interfere with lactation.
Treatment with IMVAGGIS 0.03 mg pessary has no influence on the ability to drive and use machines.
At the beginning of treatment, when the vaginal epithelial layers are still atrophic, local At the beginning of treatment, when the vaginal epithelial layers are still atrophic, local irritation may occur as a sensation of heat, pain and/or itching but the undesirable effects are often transient and of mild intensity.
The reported undesirable effects have been classified according to frequency of appearance:
| System Organ Class | Common (≥1/100 to <1/10) | Uncommon (≥1/1,000 to <1/100) |
|---|---|---|
| Gastrointestinal disorders | anorectal discomfort | |
| Renal and urinary disorders | dysuria | |
| Reproductive system and breast disorders | vulvovaginal burning, pruritus and pain | vaginal discharge |
The following risks have been associated with systemic HRT and apply to a lesser extent for estrogen products for vaginal application of which the systemic exposure to estrogen is very low.
Use of systemic 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 systemic 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.
Systemic 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 HRT (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) |
* Study in women with no uterus
The use of systemic HRT 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 over 5 years |
|---|---|---|---|
| 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 systemic oestrogen/progestagen treatment:
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 yellow card scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
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