NAME OF THE MEDICINAL PRODUCT

Estring 7.5 microgram/24 hours, vaginal delivery system

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vaginal ring contains:

Estradiol Hemihydrate 2.0 mg, corresponding to 1.94 mg estradiol.

Each ring releases estradiol at an average amount of 7.5 microgram per 24 hours, over a period of 90 days.

For the full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Vaginal delivery system.

A slightly opaque ring, made of a silicone elastomer, with a whitish core, containing a drug reservoir of Estradiol Hemihydrate. The product has the following dimensions. Outer diameter - 55 mm; cross sectional diameter - 9 mm; core diameter - 2 mm.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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

4.2    Posology and method of administration

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

Adults including older 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.

Estring vaginal delivery system is a local therapy and in women with an intact uterus, progestogen treatment is not necessary (however see Section 4.4, Special Warnings and Precautions for Use, Endometrial Hyperplasia).

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.

4.3 Contraindications

•    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.

Special warnings and precautions for use

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 effect of 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.

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. 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 below)

•    Epilepsy

•    Asthma

•    Otosclerosis

The pharmacokinetic profile of Estring shows that there is very low 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. 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 remain elevated for at least 10 years.

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 on 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 Estring.

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.

Risk estimates have been drawn from systemic exposure and it is not known how these apply to local treatments.

Breast cancer

The overall evidence suggests an increased risk of breast cancer in women taking combined oestrogen-progestogen and possibly also oestrogen-only HRT, that is dependent on the duration of taking HRT.

The WHI trial found no increase in the 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 that found in users of oestrogen-progestogen combinations (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.

A relationship between breast cancer risk and low dose local vaginal oestrogen therapy is uncertain.

HRT, especially oestrogen-progestogen 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 (see section 4.8). Some studies including the WHI trial suggest that the long-term use of combined HRTs may confer a similar, or slightly smaller, risk (see Section 4.8).

Risk estimates have been drawn from systemic exposure and it is not known how these apply to local treatments.

Venous thromboembolism

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)

There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined oestrogen-progestogen or oestrogen-only HRT.

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

Risk estimates have been drawn from systemic exposure and it is not known how these apply to local treatments.

Ischaemic stroke

Combined oestrogen-progestogen 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).

Risk estimates have been drawn from systemic exposure and it is not known how these apply to local treatments.

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 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.

4.5 Interaction with other medicinal products and other forms of interaction

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).

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).

Paediatric Population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

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.

4.7 Effects on ability to drive and use machines

Estring has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

See also section 4.4.

Adverse reactions due to local therapy with Estring which were reported with a frequency of 1/1000 or more in Estring clinical trials are listed as follows:

System Organ Class	Common > 1/100 to < 1/10	Uncommon 1/1000 to <1/100
Infections and infestations	Urinary tract infection, vaginal infection
Immune system disorders		Hypersensitivity
Gastrointestinal disorders	Abdominal pain, abdominal pain lower, abdominal discomfort, anorectal discomfort
Skin and subcutaneous tissue disorders	Pruritus generalised, hyperhidrosis
Renal and urinary disorders	Bladder discomfort
Reproductive system and breast disorders	Vulvovaginal discomfort, pruritus genitalis

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

System Organ Class	Common > 1/100 to < 1/10	Uncommon >1/1000 to <1/100
Infections and infestations		Vaginitis, including vaginal candidiasis
Immune system disorders		Hypersensitivity
Psychiatric disorders	Depression	Changes in libido, mood disturbances
Nervous system disorders		Dizziness, headache, migraine, anxiety
Eye disorders		Intolerance to contact

		lenses
Vascular disorders		Venous thrombosis, pulmonary embolism
Gastrointestinal disorders		Nausea, bloating, abdominal pain
Hepatobiliary disorders		Gallbladder disease
Skin and subcutaneous tissue disorders	Alopecia	Chloasma/melasma, hirsutism, pruritus, rash
Musculoskeletal, and connective tissue disorders	Arthralgias, leg cramps
Reproductive system and breast disorders	Abnormal uterine bleeding (breakthrough bleeding/spotting), breast pain, breast tenderness, breast enlargement, breast discharge, leukorrhoea	Change in menstrual flow, change in cervical ectropion and secretion
General disorders and administration site conditions		Oedema
Investigations	Changes in weight (increase or decrease), increased triglycerides

Breast cancer risk

Risk estimates have been drawn from systemic exposure and it is not known how

these apply to local treatments.

•    An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestogen 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-progestogen 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 and 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 and 95% CI	Additional cases per 1000 HRT users over 5 years (95% CI)
		CEE oestrog	en-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

{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.

Ovarian cancer

Risk estimates have been drawn from systemic exposure and it is not known how these apply to local treatments.

Long-term use of oestrogen-only and combined oestrogen-progestogen HRT has been associated with a slightly increased risk of ovarian cancer. In the Million Women Study 5 years of HRT resulted in 1 extra case per 2500 users.

Risk of venous thromboembolism

Risk estimates have been drawn from systemic exposure and it is not known how these apply to local treatments.

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)
Oral combined oestrogen-progestogen
50-59	4	2.3 (1.2 -4.3)	5 (1 - 13)

* Study in women with no uterus

Risk of coronary artery disease

Risk estimates have been drawn from systemic exposure and it is not known how these apply to local treatments.

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

Risk estimates have been drawn from systemic exposure and it is not known how these apply to local treatments.

The use of oestrogen-only and oestrogen + progestogen 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 * 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 oestrogen/progestogen treatment. Risk estimates have been drawn from systemic exposure and it is not known how these apply to local treatments:

•    Skin and subcutaneous disorders: 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

4.9 Overdose

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Natural and semisynthetic oestrogens, plain. ATC Code G03C A03

Estring vaginal delivery system is a vaginal ring, which delivers approximately 7.5 microgram/24 hours of 17 B-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 17B-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 postmenopausal 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.

5.2 Pharmacokinetic properties

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 (Cmax) within 3 hours (Tmax) 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 sulphates. 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.

Linearitv/non-linearitv

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.

5.3    Preclinical safety data

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 tumor formation was observed with the silicone elastomer.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Silicone elastomer Q7-4735 A Silicone elastomer Q7-4735 B Silicone Fluid Barium sulphate

6.2 Incompatibilities

Not applicable.

Shelf life

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

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.

6.6 Special precautions for disposal

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.

7    MARKETING AUTHORISATION HOLDER

Pfizer Limited Ramsgate Road Sandwich Kent

CT13 9NJ UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 00057/1424

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

29/07/2013

10    DATE OF REVISION OF THE TEXT

17/10/2014