Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK
For the treatment of postmenopausal symptoms, Hormone Replacement Therapy (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 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.
Assessment of each woman prior to taking hormone replacement therapy (and at regular intervals thereafter) should include a personal and family medical history. Physical examination should be guided by this and by the contraindications (see Section 4.3) and warnings (see Section 4.4) for this product. During assessment of each individual woman, clinical examination of the breasts and pelvic examination should be performed where clinically indicated rather than as a routine procedure. Women should be encouraged to participate in the national cervical cancer screening programme (cervical cytology) and the national breast cancer screening programme (mammography) as appropriate for their age. Breast awareness should also be encouraged and women advised to report any changes in their breasts to their doctor or nurse.
Some women may be unsuitable for treatment with ESTRING vaginal delivery system, in particular those with short narrow vaginas due to previous surgery, or the effects of vaginal atrophy, or those with a degree of uterovaginal prolapse severe enough to prevent retention of the ring.
In addition, any woman with symptoms/signs of abnormal vaginal discharge, vaginal discomfort, or any vaginal bleeding should be examined fully, to exclude ulceration, infection, or unresponsive atrophic vaginitis. Minor signs of irritation are often transient.
Any woman experiencing persistent or severe discomfort due to the presence of the ring or excessive movement of the ring should be withdrawn from treatment. Patients with signs of ulceration or severe inflammation due to unresponsive atrophic vaginitis should also be withdrawn from treatment.
There have been rare reports of ring adherence to the vaginal wall, making ring removal difficult. Some cases have required surgical removal of vaginal rings.
Patients with vaginal infection should be treated appropriately. In the case of systemic therapy, ESTRING vaginal delivery system treatment may continue without interruption. However, removal of ESTRING vaginal delivery system should be considered while using other vaginal preparations.
There have been incidences of both the ring falling out and movement of the ring, generally at defaecation. Therefore, if the woman is constipated she should remove the ring before defaecation. There may also be other instances when some women wish to remove the ring, e.g. prior to sexual intercourse.
Patients on long-term corticosteroid treatment or those with conditions causing poor skin integrity, e.g. Cushing’s Disease, may be unsuitable for treatment as they may have vaginal atrophy unresponsive to oestrogen therapy.
The pharmacokinetic profile of ESTRING vaginal delivery system shows that there is low systemic absorption of estradiol (see Section 5.2), however, being a HRT product the following need to be considered, especially for long term or repeated use of this product.
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 ESTRING vaginal delivery system, in particular:
The pharmacokinetic profile of ESTRING shows that there is very low systemic absorption of estradiol during treatment (see Section 5.2). Due to this, the recurrence or aggravation of the above mentioned conditions is less likely than with systemic oestrogen treatment.
Therapy should be discontinued in case a contra-indication is discovered and in the following situations:
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 ESTRING.
In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods.
For oestrogen products for vaginal application of which the systemic exposure to oestrogen remains within the normal postmenopausal range ESTRING vaginal delivery system, it is not recommended to add a progestagen.
As a general rule, oestrogen replacement therapy should not be prescribed for longer than one year without another physical, including gynaecological examination being performed.
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.
The woman should be advised to contact her doctor in case bleeding or spotting occurs during treatment with ESTRING. If bleeding or spotting appears at any time on therapy, 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, 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.
The following risks have been associated with systemic HRT and apply to a lesser extent for oestrogen products for vaginal application of which the systemic exposure to the oestrogen remains within the normal postmenopausal range. However, they should be considered in case of long term or repeated use of this product.
The overall evidence suggests an increased risk of breast cancer, in women taking combined oestrogen-progestogen and possibly also oestrogen-only systemic HRT, that is dependent on the duration of taking HRT.
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.
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 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 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).
Randomised controlled data found no increased risk of CAD in hysterectomised women using systemic oestrogen-only therapy.
Systemic oestrogen-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).
Oestrogens may cause fluid retention and therefore patients with cardiac or renal dysfunction should be carefully observed.
Exogenous oestrogens may induce or exacerbate symptoms of angioedema, particularly in patients with hereditary angioedema.
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 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-1-antitrypsin, ceruloplasmin).
The low systemic absorption of estradiol with vaginal administration (see Section 5.2 Pharmacokinetic Properties) may result in less pronounced effects on plasma binding proteins than with oral hormones.
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.
In rare cases benign, and in even rarer cases malignant liver tumours leading in isolated cases to life-threatening intra-abdominal haemorrhage have been observed after the use of hormonal substances such as those contained in ESTRING. If severe upper abdominal complaints, enlarged liver or signs of intra-abdominal haemorrhage occur, a liver tumour should be considered in the differential diagnosis.
Women who may be at risk of pregnancy should be advised to adhere to non-hormonal contraceptive methods.
The requirement for oral anti-diabetics or insulin can change as a result of the effect on glucose tolerance.
As the oestrogen is administered within the vagina and due to the low levels released, it is unlikely that any clinically relevant drug interactions will occur with ESTRING vaginal delivery system.
However, the prescriber should be aware that 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, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz). At vaginal administration, the first-pass effect in the liver is avoided and, thus, vaginally applied oestrogens might be less affected than oral hormones by enzyme inducers.
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.
Clinically, an increased metabolism of oestrogens may lead to decreased effect and changes in the uterine bleeding profile.
Removal of ESTRING vaginal delivery system should be considered when using other vaginal preparations (See Section 4.4 Special Warnings and Precautions for Use).
Interaction studies have only been performed in adults.
ESTRING is not recommended during pregnancy and in women of childbearing potential. If pregnancy occurs during medication with ESTRING vaginal delivery system treatment should be withdrawn immediately.
The results of most epidemiological studies to date relevant to inadvertent foetal exposure to oestrogens indicate no teratogenic or foetotoxic effects.
Estring should not be used during breast-feeding.
ESTRING has no or negligible influence on the ability to drive and use machines.
See also section 4.4.
Adverse reactions due to local therapy with ESTRING which were reported in ESTRING clinical trials with a frequency of 1/1000 or more, or were reported as post-marketing experience are listed below:
Common ≥1/100 to <1/10
Uncommon ≥1/1000 to <1/100
Rare ≥1/10000 to <1/1000
Common: Urinary tract infection, vaginal infection
Uncommon: Hypersensitivity
Common: Abdominal pain, abdominal pain lower, abdominal discomfort, anorectal discomfort
Common: Pruritus generalised, hyperhidrosis
Common: Bladder discomfort
Common: Vulvovaginal discomfort, pruritus genitalis
Rare: Vaginal erosion#/Vaginal ulceration#, Vaginal adhesion#
# post-marketing experience
The following adverse reactions have been associated with oral and/or transdermal oestrogen therapy:
Uncommon: Vaginitis, including vaginal candidiasis
Uncommon: Hypersensitivity
Common: Depression
Uncommon: Changes in libido, mood disturbances
Uncommon: Dizziness, headache, migraine, anxiety
Uncommon: Intolerance to contact lenses
Uncommon: Venous thrombosis, pulmonary embolism
Uncommon: Nausea, bloating, abdominal pain
Uncommon: Gallbladder disease
Common: Alopecia
Uncommon: Chloasma/melasma, hirsutism, pruritus, rash
Common: Arthralgias, leg cramps
Common: Abnormal uterine bleeding (breakthrough bleeding/spotting), breast pain, breast tenderness, breast enlargement, breast discharge, leukorrhoea
Uncommon: Change in menstrual flow, change in cervical ectropion and secretion
Uncommon: Oedema
Common: Changes in weight (increase or decrease), increased triglycerides
The following risks have been associated with systemic HRT and apply to a lesser extent for oestrogen products for vaginal application of which the systemic exposure to oestrogen remains within the normal postmenopausal range.
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,
Any increased risk in users of oestrogen-only therapy is substantially 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),
Results of the largest randomised placebo-controlled trial (WHI-study) and largest epidemiological study (MWS) are presented.
Million Women study– Estimated additional risk of breast cancer after 5 years' use:
| Age range (years) | Additional cases per 1000 never-users of HRT over a 5 year period* | Risk ratio & 95%CI# | Additional cases per 1000 HRT users over 5 years (95%CI) |
|---|---|---|---|
| Oestrogen only HRT | |||
| 50-65 | 9-12 | 1.2 | 1-2 (0-3) |
| Combined oestrogen-progestogen | |||
| 50-65 | 9-12 | 1.7 | 6 (5-7) |
* Taken from baseline incidence rates in developed countries.
# 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.
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)* |
| CEE+MPA oestrogen & progestogen | |||
| 50-79 | 17 | 1.2 (1.0–1.5) | +4 (0–9) |
* WHI study in women with no uterus, which did not show an increase in risk of breast cancer
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 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 and 95%CI | Additional cases per 1000 HRT users |
|---|---|---|---|
| Oral oestrogen-only* | |||
| 50-59 | 7 | 1.2 (0.6-2.4) | 1 (-3 – 10) |
The risk of coronary artery disease is slightly increased in users of combined oestrogen-progestogen HRT over the age of 60 (see section 4.4).
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 and 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/progestogen 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 at: 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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