ESTRING 7.5 microgram/24 hours

Treatment for atrophic vaginitis, (due to oestrogen deficiency) in postmenopausal women.

ESTRING vaginal delivery system is an oestrogen-only product for vaginal use.

Adults including elderly people (≥ 65 years old)

One ring to be inserted into the upper third of the vagina. Once inserted it is left in the vagina continuously for 90 days and replaced by a new ring as appropriate. For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (See also Section 4.4) should be used. The maximum recommended duration of continuous therapy is two years.

Therapy may start at any time in women with established amenorrhoea or who are experiencing long intervals between spontaneous menses. Patients changing from a cyclical or continuous sequential preparation should complete the cycle, after a withdrawal bleed, and then change to ESTRING vaginal delivery system. Patients changing from a continuous combined preparation may start therapy at any time.

For oestrogen products for vaginal application of which the systemic exposure to the oestrogen remains within the normal postmenopausal range (ESTRING vaginal delivery system), it is not recommended to add a progestagen (see also section 4.4).

To put ESTRING into the vagina

• Choose a comfortable position

• With one hand, the folds of skin around the vagina are opened.

• With the other hand, press the ring into an oval shape.

• The ring is pushed into the vagina as far as it will go, upwards and backwards towards the small of the back.

To take out ESTRING

• Choose a comfortable position.

• Place a finger into the vagina and hook around the ring.

• The ring is gently pulled out - downwards and forwards.

Comprehensive advice for removal and reinsertion of the ring are provided in the Patient Information Leaflet, which is included in every pack.

Paediatric population

ESTRING vaginal delivery system is not recommended for use in the paediatric population.

• Known, past or suspected breast cancer;

• Known or suspected oestrogen-dependent malignant tumours (e.g., endometrial cancer);

• Undiagnosed genital bleeding;

• Untreated endometrial hyperplasia;

• Previous or current venous thromboembolism (deep venous thrombosis, pulmonary embolism);

• Known thrombophilic disorders (e.g., protein C, protein S, or antithrombin deficiency, see section 4.4);

• Active or recent arterial thromboembolic disease (e.g., angina, myocardial infarction);

• Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal;

• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1;

• Porphyria.

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.

Medical examination/follow-up

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.

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 treatment with ESTRING vaginal delivery system, in particular:

• Leiomyoma (uterine fibroids) or endometriosis

• Risk factors for thromboembolic disorders (see below)

• Risk factors for oestrogen dependent tumours, e.g., 1^st 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 below)

• Epilepsy

• Asthma

• Otosclerosis

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.

Reasons for immediate withdrawal of therapy

Therapy should be discontinued in case a contra-indication 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

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 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.

Breast cancer

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 oestrogens. It is unknown if low dose vaginal oestrogens stimulate recurrence of breast cancer.

Ovarian 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 systemic HRT, which becomes apparent within 5 years of use and diminishes over time after stopping.

Venous thromboembolism

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).

Coronary artery disease (CAD)

Oestrogen only

Randomised controlled data found no increased risk of CAD in hysterectomised women using systemic oestrogen-only therapy.

Ischaemic stroke

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).

Other conditions

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 hereditary and acquired 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) 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).

Paediatric population

Interaction studies have only been performed in adults.

Pregnancy

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.

Breast-feeding

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:

^# post-marketing experience

The following adverse reactions have been associated with oral and/or transdermal oestrogen therapy:

Class effects associated with systemic HRT

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.

Ovarian 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.

Risk of venous thromboembolism

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

* Study in women with no uterus

Risk of coronary artery disease

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).

Risk of ischaemic stroke

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

* No differentiation was made between ischaemic and haemorrhagic stroke

Other adverse reactions have been reported in association with systemic oestrogen/progestogen treatment.

• Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura

• Probable dementia over the age of 65 (see section 4.4)

• Gallbladder disease

Reporting of suspected adverse reactions

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.

ESTRING is intended for intravaginal use and the dose of estradiol is very low. Overdose is therefore unlikely, but if it occurs, treatment is symptomatic.

Pharmacotherapeutic group: Natural and semisynthetic oestrogens, plain,

ATC code: G03C A03

Treatment of vaginal oestrogen deficiency symptoms: Vaginally applied oestrogen alleviates the symptoms of vaginal atrophy due to oestrogen deficiency in postmenopausal women.

ESTRING vaginal delivery system is a vaginal ring, which delivers approximately 7.5 microgram/24 hours of 17 ß -estradiol for 3 months. ESTRING vaginal delivery system is only suitable for the treatment of urogenital complaints due to oestrogen deficiency. Its pharmacokinetic profile shows that it is not suitable for postmenopausal complaints which require a systemically active dose of oestrogen (e.g., vasomotor symptoms), neither is it suitable for osteoporosis prevention.

The active ingredient, synthetic 17ß -estradiol, is chemically and biologically identical to endogenous human estradiol. The estradiol from the vaginal ring substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms. It acts locally to restore vaginal pH and to eliminate or reduce symptoms and signs of post-menopausal urogenital oestrogen deficiency.

ESTRING vaginal delivery system presumably increases local estradiol target concentrations, while maintaining very low and stable systemic plasma concentrations. There is limited clinical trial data beyond 2 years and therefore the maximum recommended duration of continuous therapy is 2 years.

The pharmacokinetic properties of estradiol in humans are well known and depend, in large part, on the extent to which estradiol is taken up by the systemic circulation. The clinical effects of ESTRING are therefore governed by the release characteristics of the vaginal ring delivery system.

Absorption

After a brief initial peak, the release of estradiol from ESTRING vaginal delivery system is constant (7.5 microgram/24 h), for at least 90 days, as governed by Fick's law of diffusion. As a consequence of the initial release, peak plasma levels of estradiol reach about 55 pg/mL (C_max) within 3 hours (T_max) when the patient applies the first ring to a previously untreated, atrophic vagina. This initial peak dissipates rapidly, and plasma estradiol concentrations return to postmenopausal levels (defined as <20 pg/mL) within 4 hours, and achieve a constant level of approximately 10 pg/mL or less within 2-3 days. This level is maintained for the duration of the 90-day treatment period and is below the serum estradiol levels typically seen with use of transdermal oestrogen therapy (approximately 40 to 70 pg/mL). No data are available on the absolute bioavailability of estradiol from ESTRING.

Distribution

The distribution of exogenous oestrogens is similar to that of endogenous oestrogens. Circulating, unbound oestrogens are known to modulate pharmacological response. Oestrogens circulate in blood bound to sex-hormone binding globulin (SHBG) and albumin. A dynamic equilibrium exists between the conjugated and the unconjugated forms of estradiol and estrone, which undergo rapid interconversion.

Biotransformation

Estradiol is mainly metabolized in the liver. Its main metabolites are estriol, estrone, and their conjugates. The plasma half life of estradiol is 1-2 hours. Metabolic plasma clearance varies between 450-625 ml/min/m². The metabolites are mainly excreted via the kidneys as glucuronides and sulfates. Oestrogens also undergo enterohepatic circulation. The vaginal delivery of oestrogens avoids first-pass metabolism and there is limited systemic absorption.

Elimination

The urinary excretion of total estradiol in the 24-hour urine, 4 and 12 weeks post-application of estradiol vaginal ring in a Phase 1 study was 7.23 ± 4.82 nmoles and 8.20 ± 5.45 nmoles, respectively.

Linearity/non-linearity

Estradiol follows apparent linear kinetics for systemic concentrations up to 550 pmoles/L following administration of vaginal ring containing doses of 2 to 400 mg.

The toxicity profile of estradiol is well known. There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Studies on the silicone elastomer indicated that it was non-toxic in in-vitro studies, and non-pyrogenic, non-irritant, and non-sensitizing in short term in-vivo tests. Long-term implantation induced encapsulation equal to or less than the negative control (polyethylene). No toxic reaction or tumour formation was observed with the silicone elastomer.

Silicone elastomer Q7-4735 A

Silicone elastomer Q7-4735 B

Silicone Fluid

Barium sulfate

Not applicable.

2 years.

Do not store above 25° C.

Each ring is individually packed in a heat-sealed rectangular pouch consisting of, from outside to inside: Polyester/Aluminium foil/Low density Poly-ethylene. Each pouch is provided with a tear-off notch on one side and is packed into a cardboard carton.

After use the ring still contains some of the active hormonal ingredient, which may be harmful to the environment. Therefore, the used ring should be placed within the original pouch or a plastic bag, then sealed and discarded safely. Used rings should not be flushed down the toilet nor placed in liquid waste disposal systems. Any used or unused medicinal product or waste material should be disposed of according to local requirements.