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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.
Medical examination/follow-up: Before initiating or reinstituting hormone therapy, a complete personal and family medical history should be obtained. Physical (including pelvic and breast) examination should be guided by this and by 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 the doctor or nurse. 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.
The pharmacokinetic profile of Vagifem shows that there is very low systemic absorption of estradiol during treatment (see Pharmacology: Pharmacokinetics under Actions), however, being a HRT product, the following needs to be considered, especially for long-term or repeated use of this product.
Conditions which need supervision: 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 oestrogen treatment, in particular: Leiomyoma (uterine fibroids) or endometriosis; risk factors for thromboembolic disorders (see as follows); risk factors for oestrogen-dependent tumours, e.g. 1st 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 (see as follows); epilepsy; asthma; otosclerosis.
The pharmacokinetic profile of Vagifem shows that there is very low absorption of estradiol during treatment (see Pharmacology: Pharmacokinetics under Actions). Due to this, the recurrence or aggravation of the above mentioned conditions is less likely than with systemic oestrogen treatment.
Reasons for immediate withdrawal of therapy: Therapy should be discontinued in case a contraindication is discovered and in the following situations: Jaundice or deterioration in liver function, significant increase in blood pressure, new onset of migraine-type headache, pregnancy.
Vagifem is a locally acting low dose estradiol preparation and therefore the occurrence of the below mentioned conditions is less likely than with systemic oestrogen treatment.
Endometrial hyperplasia and carcinoma: Women with an intact uterus with abnormal bleeding of unknown aetiology or women with an intact uterus who have previously been treated with unopposed oestrogens should be examined with special care in order to exclude hyperstimulation/malignancy of the endometrium before initiation of treatment with Vagifem.
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 systemic oestrogen-only users varies from 2- to 12-fold compared with non-users, depending on both duration of treatment and on oestrogen dose. After stopping treatment, risk remains elevated for at least 10 years.
During Vagifem treatment, a minor degree of systemic absorption may occur in some patients, especially during the first two weeks of once daily administration.
However, average plasma E2 concentrations [Cave(0-24)] at all evaluated days remained within the normal postmenopausal range in all subjects (see Pharmacology: Pharmacokinetics under Actions).
Endometrial safety of long-term (more than one year) or repeated use of local vaginally administered oestrogen is uncertain. Therefore, if repeated, treatment should be reviewed at least annually, with special consideration given to any symptoms of endometrial hyperplasia or carcinoma.
As a general rule, oestrogen replacement therapy should not be prescribed for longer than one year without another physical, including gynaecological examination, being performed.
If bleeding or spotting appears at any time during therapy, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.
The woman should be advised to contact her doctor in case bleeding or spotting occurs during treatment with Vagifem.
Unopposed oestrogen 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.
Breast cancer: 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 WHI trial found no increase in 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 substantially lower than found in users of oestrogen-progestagen combinations.
The excess risk becomes apparent within a few years of use but returns to baseline within a few (at most 5) years after stopping treatment.
A relationship between breast cancer risk and low-dose local vaginal oestrogen therapy is uncertain.
HRT, especially oestrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Ovarian cancer: Ovarian cancer is much rarer than breast cancer. Long-term (at least 5-10 years) use of oestrogen-only HRT products has been associated with a slightly increased risk of ovarian cancer. Some studies including the WHI trial suggest that the long-term use of combined HRT may confer a similar or slightly smaller risk (see Adverse Reactions).
A relationship between ovarian cancer risk and low dose local vaginal oestrogen therapy is uncertain.
Venous thromboembolism: HRT is associated with a 1.3- to 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 Adverse Reactions).
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 Contraindications).
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.
A relationship between venous thromboembolism and low dose local vaginal oestrogen therapy is uncertain.
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 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' (eg, 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).
Coronary artery disease (CAD): 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.
Randomised controlled data found no increased risk of CAD in hysterectomised women using oestrogen-only therapy.
Ischaemic stroke: 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 increases with age (see Adverse Reactions).
A relationship between ischaemic stroke and low-dose local vaginal oestrogen therapy is uncertain.
Other Conditions: Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed.
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. The relationship between pre-existing hypertriglyceridaemia and low dose local vaginal oestrogen therapy is unknown.
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 radioimmunoassay). 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-1-antitrypsin, ceruloplasmin).
The minimal systemic absorption of estradiol with local vaginal administration (see Pharmacology: Pharmacokinetics under Actions) is likely to result in less pronounced effects on plasma binding proteins than with systemic hormones.
HRT does not improve cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined or oestrogen-only HRT after the age of 65.
Intravaginal applicators may cause minor local trauma, especially in women with serious vaginal atrophy.
Effects on ability to drive and use machines: No effects known.
