4.1 Therapeutic indications

1.      Hormone replacement therapy for treatment of atrophic vaginitis and kraurosis in post-menopausalpostmenopausal women.

2.      Treatment of pruritus vulvae and dyspareunia associated with atrophic vaginal epithelium.

4.3 Contraindications            Contra-indications

·         HypersensitivityKnown hypersensitivity to estriol or to any of the excipients.

·         Known, past or suspected cancer of the breast

·         Known or suspected estrogen-dependent malignant tumours (eg endometrial cancer)

·         Undiagnosed genital bleeding

·         Untreated endometrial hyperplasia

·         Previous idiopathic or current venous thrombo-embolismthromboembolism (deep venous thrombosis, pulmonary embolism)

·         Known thrombophilic disorders (eg protein C, protein S, or antithrombin deficiency, see section 4.4)

·         Active or recent arterial thrombo-embolicthromboembolic disease (eg angina, myocardial infarction)

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

·         Porphyria.

4.4 Special warnings and precautions for use

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.

Gynest Cream contains arachis oil (peanut oil) and should not be applied by patients known to be allergic to peanuts (see Section 4.3). As there is a possible relationship between allergy to peanuts and allergy to soya, patients with soya allergy should also avoid Gynest Cream.

Medical examination/follow-up

Before initiating or re-institutingreinstituting 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 contra-indications 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 eg mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

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 Gynest Cream, in particular:

-          Leiomyoma (uterine fibroids) or endometriosis

-          A history of, or riskRisk factors for, thrombo-embolic thromboembolic disorders (see below)

-          Risk factors for estrogen dependent tumours, eg 1^st degree heredity for breast cancer

-          Hypertension

-          Liver disorders (eg 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

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

TheIn women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when systemic estrogens are administered alone for prolonged periods of time. The reported increase in endometrial cancer risk among estrogen-only users varies from 2 to12-fold greater compared with non-users, depending on the duration of treatment and estrogen dose (see section 4.8). After stopping treatment risk may remain elevated for at least 10 years.

The addition of a progestogen cyclically for at least 12 days per month/28 day cycle or continuous combined estrogen-progestogen therapy in non-hysterectomised women prevents the excess risk associated with estrogen-only HRT.

The endometrial safety of long-term or repeated use of topical vaginal estrogens is uncertain. Therefore, if repeated, treatment should be reviewed at least annually, with a special consideration given to any symptoms of endometrial hyperplasia or carcinoma.

Break-through bleeding and spotting may occur during the first months of treatment. If break-through bleeding or spotting appears at anyafter some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

Unopposed estrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, caution is advised when using this productTherefore, the addition of progestogens to estrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis.

Breast cancer

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

Combined estrogen-progestogen therapy

·         The randomised placebo-controlled trial, the (Women’s Health Initiative study (WHI)), and epidemiological studies, including the Million Women Study (MWS) are consistent in finding an increased risk of breast cancer in women taking combined estrogen-progestogen for HRT that becomes apparent after about 3 years (see Section 4.8)

Estrogen-only therapy

·         The Women’s Health Initiative (WHI) trial found no increase in the risk of breast cancer in hysterectomised women using estrogen-only HRT. Observational studies have mostly reported an increased a small increase in risk of having breast cancer in women taking estrogens or diagnosed that is substantially lower than that found in users of estrogen-progestogen combinations or tibolone for HRT for several years (see Section 4.8).

For all HRT, anThe excess risk becomes apparent within a few years of use and increases with duration of intake but returns to baseline within a few (at most five) years after stopping treatment.

In the MWS, the relative risk of breast cancer with conjugated equine estrogens (CEE) or estradiol (E2) was greater when a progestogen was added, either sequentially or continuously, and regardless of type of progestogen. There was no evidence of a difference in risk between the different routes of administration.

In the WHI study, the continuous combined conjugated equine estrogen and medroxyprogesterone acetate (CEE + MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.

HRT, especially estrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Ovarian cancer

Venous thrombo-embolism

HRT Ovarian cancer is much rarer than breast cancer. Long-term (at least 5-10 years) use of estrogen-only HRT products has been associated with a higher relativeslightly increased risk of ovarian cancer (see section 4.8). Some studies including the WHI trial suggest that the long-term use of combined HRT may confer a similar, or slightly smaller, risk (see section 4.8).

Venous thromboembolism

·         HRT is associated with a 1.3 to 3-fold risk of developing venous thrombo-embolismthromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a two- to threefold higher risk for users compared with non-users. For non-users it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate =4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate =9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later. (see Section 4.8).

Generally recognized risk factors for VTE include a personal history or family history, severe obesity (BMI > 30 kg/m²) and systemic lupus erythematosus (SLE). There is no consensus about the possible role of varicose veins in VTE.

·         Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. and HRT may add to this risk. Personal or strong family history of thrombo-embolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as HRT is therefore contraindicated. The women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT. in these patients (see section 4.3).

·         The risk of VTE may be temporarily increased with Generally recognised risk factors for VTE include use of estrogens, older age, major surgery, prolonged immobilisation, major trauma or major surgery. 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, scrupulous attention should be given to prophylactic measures need be considered to prevent VTE following surgery. WhereIf prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4 to 6 weeks earlier, if possible.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’ (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 thrombo-embolicthromboembolic symptom (eg, painful swelling of a leg, sudden pain in the chest, dyspnoea).

Coronary artery disease (CAD)

·         There is no evidence from randomised controlled trials of cardiovascular benefit protection against myocardial infarction in women with continuousor without existing CAD who received combined conjugated estrogens and medroxyprogesterone acetate (MPA). Two large clinical trials (WHI and HERS i.e. Heart and estrogen/progestin Replacement Study) showed a possible-progestogen or estrogen-only HRT.

·         Combined estrogen-progestogen therapy

The relative risk of CAD during use of combined estrogen+progestogen HRT is slightly increased risk of cardiovascular morbidity in . As the first year of use and no overall benefit. For other HRT products there are only limited data from randomised controlled trials examining effects in cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT productsbaseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to estrogen+progestogen use is very low in healthy women close to menopause, but will rise with more advanced age.

Stroke

One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated estrogens and MPA. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 11 per 1000 women aged 60-69 years. It is estimated that for women who use conjugated estrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.

Ovarian cancer

·           Long-term (at least 5-10 years) use of estrogen-only HRT productsEstrogen-only therapy

Randomised controlled data found no increase of CAD in hysterectomised women has been using estrogen-only therapy.

Ischaemic Stroke

·         Combined estrogen-progestogen and estrogen-only therapy are associated with an increasedup 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 ovarian cancerstroke is strongly age-dependent, the overall risk of stroke in some epidemiological studies. It is uncertain whether long-term use of combined HRT confers a different risk than estrogen-only products.women who use HRT will increase with age (see section 4.8)

Other conditions

·         Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients in Gynest Cream is increased.

·         Women with pre-existing hypertriglyceridaemia 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.

·         Oral estrogensEstrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or 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 biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-l-antitrypsin, ceruloplasmin).

With vaginal administration, stimulation of the liver by the first-pass effect is avoided and thus, transvaginal estrogens might affect hormone binding proteins and other serum proteins produced by the liver less than oral hormones.

·         There is no conclusive evidence for improvement ofHRT use 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 CEE and MPAor estrogen-only HRT after the age of 65. It is unknown whether the findings apply to younger post-menopausal women or other HRT products.

4.5 Interaction with other medicinal products and other forms of interaction

The serum concentration and efficacy of estrogen could be reduced and its metabolism of estrogens may be increased by concomitant administrationuse of drugssubstances known to induce drug metabolising enzymes, specifically CYP 450 enzymes, such as anticonvulsants (eg phenobarbital, phenytoin, carbamazepine) and anti-infectives (eg rifampicin, rifabutin, nevirapine, efavirenz) and also bosentan.

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 raiseinduce the metabolism of estrogens. With intravaginal administration, the first-pass effect in the liver is avoided and thus, estriol given intravaginally might be less affected by enzyme inducers than oral hormones.

Clinically, an increased metabolism of estrogens may lead to decreased effect. and changes in the uterine bleeding profile.

Contact between contraceptive diaphragms or condoms and the cream must be avoided since the rubber may be damaged by this preparation.

Estrogen-containing oral contraceptives have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered due to induction of lamotrigine glucuronidation. This may reduce seizure control. Although the potential interaction between estrogen-containing hormone replacement therapy and lamotrigine has not been studied, it is expected that a similar interaction exists, which may lead to a reduction in seizure control among women taking both drugs together. Therefore, dose adjustment of lamotrigine may be necessary.

4.6 Pregnancy and lactation

Pregnancy

 Gynest Cream is not indicated during pregnancy. If pregnancy occurs during use of Gynest Cream, treatment should be withdrawn immediately.

There are no clinical data on exposed pregnancies.

The results of most epidemiological studies to date, relevant to inadvertent foetal exposure to estrogens indicate no teratogenic or foeto-toxicfoetotoxic effect.

Lactation

Gynest Cream is not indicated during lactation.

4.7 Effects on ability to drive and use machines

 No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable effects

No undesirable effects were reported in two open, uncontrolled clinical trials of short duration involving 47 women.

However, in a double-blind, placebo controlled clinical trial of 30 women treated with Gynest, the following undesirable effects were reported in the estriol pessary treatment group more frequently than in the placebo group:

Breast pain, micturition frequency increased, vaginal discharge, cystitis, leg pain, pre-menstrual tension, lower abdominal pain, palpitations and depression.

The following adverse reactions, associated with estrogen treatment, may occur during estriol overdose: breast pain or tenderness, nausea, break-through bleeding, abdominal cramps and/or bloating.

Breast Cancercancer risk

·         An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined estrogen-progestogen therapy for more than 5 years.

·         Any increased risk in users of estrogen-only therapy is substantially lower than that seen in users of estrogen-progestogen combinations.

·         The According to evidence from a large number of epidemiological studies and onelevel of risk is dependent on the duration of use (see section 4.4).

·         Results of the largest randomised placebo-controlled trial, the Women’s Health Initiative (WHI), (WHI-study) and largest epidemiological study (MWS) are presented.

Million Women study – Estimated additional risk of breast cancer after 5 years’ use

US WHI studies – Additional risk of breast cancer after 5 years’ use

Endometrial cancer risk

Postmenopausal women with a uterus

The endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT.

In women with a uterus, use of estrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4).

Depending on the duration of estrogen-only use and estrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 women between the ages of 50 and 65.

Adding a progestogen to estrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study the use of five years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer (RR of 1.0 (0.8-1.2)).

Ovarian cancer

Long-term use of estrogen-only and combined estrogen-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

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

Risk of coronary artery disease

The risk of coronary artery disease is slightly increased in users of combined estrogen-progestogen HRT over the age of 60 (see section 4.4).

Risk of ischaemic stroke

 The use of estrogen-only and estrogen + 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 breast cancer increases with increasing duration of HRT use in current or recent HRT usersstroke in women who use HRT will increase with age, see section 4.4.

For estrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which >80% of HRT use was estrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95%CI 1.21 – 1.49) and 1.30 (95%CI 1.21 – 1.40), respectively.

For estrogen plus progestogen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with estrogens alone.

The MWS reported that, compared to never users, the use of various types of estrogen-progestogen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of estrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40) or use of tibolone (RR=1.45; 95%CI 1.25-1.68).

The WHI trial reported a risk estimate of 1.24 (95%CI 1.01 – 1.54) after 5.6 years of use of estrogen-progestogen combined HRT (CEE + MPA) in all users compared with placebo.

The absolute risks calculated from the MWS and the WHI trial are presented below:

The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:

Ø   For women not using HRT, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.

Ø   For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be

Ø   For users of estrogen-only replacement therapy

·            between 0 and 3 (best estimate = 1.5) for 5 years’ use

·            between 3 and 7 (best estimate = 5) for 10 years’ use.

Ø   For users of estrogen plus progestogen combined HRT,

·            between 5 and 7 (best estimate = 6) for 5 years’ use

between 18 and 20 (best estimate = 19) for 10 years’ use.

WHI studies combined – Additional risk of ischaemic stroke* over 5 years’ use

The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to estrogen-progestogen combined HRT (CEE + MPA) per 10,000 women years.

According to calculations from the trial data, it is estimated that:

Ø   For 1000 women in the placebo group,

·            about 16 cases of invasive breast cancer would be diagnosed in 5 years.

Ø   For 1000 women who used estrogen + progestogen combined HRT (CEE + MPA), the number of additional cases would be

·            between 0 and 9 (best estimate = 4) for 5 years’ use.

The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see section 4.4).

Other adverse events which have been reported in association with estrogen/progestogen treatment are:

·            Estrogen-dependent neoplasms benign and malignant; eg endometrial cancer; breast cancer.

·            Venous thrombo-embolism. Deep leg or pelvic venous thrombosis and pulmonary embolism are more frequent among HRT users than among non- users. For further information, see Section 4.3 Contra-indications and 4.4 Special Warnings and Precautions for Use.

Myocardial infarction and stroke.

·         Gall bladder disease.

·         Skin and subcutaneous tissue disorders: chloasma; erythema multiforme; erythema nodosum; vascular purpura, urticaria, angioedema.

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

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Natural and semisynthetic estrogens, plain; ATC Code: G03CA04

The active ingredient, synthetic estriol, is chemically and biologically identical to endogenous human estriol. It substitutes for the loss of estrogen production in menopausal women and alleviates menopausal symptoms.

Estriol, a weak estrogen, is a natural metabolite of estradiol, the predominant estrogen. Estriol exerts estrogenicity by binding to estrogen receptors, present in the female genital tract. Estriol, oral or vaginal, similar to estradiol, corrects lowered proliferation and abnormal physiology in the atrophic vaginal epithelium seen in estrogen deficient states, such as after natural or surgical menopause. In contrast, the histology of the endometrium after using Gynest Cream rarely shows minor signs of proliferation in previously atrophic endometria.

Clinical trial information

Improvement of vaginal epithelial cytology was noted in 47 subjects with vaginal atrophy in two clinical trials with daily administration of Gynest Cream after 2 weeks in one trial and after 4 weeks in the other trial.

6.6 Special precautions for disposal

Please refer to Section 4.2 Posology and Method of Administration.

After each use, clean the applicator:

Pull the plunger from the barrel with a sharp tug. Clean barrel and plunger with mild soap and warm (not boiling) water. Rinse well. Reinsert the plunger into the barrel for next use.

A replacement applicator (the Ortho^âGynest Vaginal Applicator) can be obtained at pharmacies.

Empty tubes may be disposed of in household waste. Return tubes with drug remaining to your pharmacy for destruction. Do not dispose of unused drug in household waste or flush it down the toilet.

10 DATE OF REVISION OF THE TEXT

2^nd10^th June 20092011