Gynest 0.01%w/w Cream
Excipients: Arachis oil and Benzoic acid For a full list of excipients, see Section 6.1 3 PHARMACEUTICAL FORM
4.1 Therapeutic indications
1. Hormone replacement therapy for treatment of atrophic vaginitis and 2. Treatment of pruritus vulvae and dyspareunia associated with atrophic 4.2 Posology and method of administration
Gynest Cream is an estrogen-only product for intravaginal use. No progestogen needs to be added (but please refer to section 4.4). Guidance on how to start therapy and maintenance Gynest Cream can be started any time after the manifestation of atrophic vaginitis or associated symptoms (eg dyspareunia, pruritus). The recommended initial daily dose is one applicator full per day. A maintenance dose of one applicator full twice a week may be used after restoration of the vaginal mucosa has been achieved. 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. Attempts to discontinue medication should be made at three to six month intervals following physical examination. Missed Dose: When a dose is inadvertently forgotten, resume dosing when the omission is realized. Gynest Cream is to be applied into the vagina, using an applicator. The applicator holds 5ml of cream containing 0.5mg estriol. The filled applicator should be inserted high into the vagina and emptied, preferably in the evening. Remove the cap from a new tube and use the top of the cap to pierce the metal seal on the tube. One end of the applicator is fitted with a plunger. Ensure the plunger is fully inserted into the applicator. Screw the other end of the applicator onto the tube. Squeeze the tube, so that the barrel of the applicator fills with cream. Unscrew the applicator and replace the cap on the tube. Lie down, with knees bent and spread apart. Gently insert the open end of the applicator well into the vagina. Push the plunger firmly but gently as far as it will go to empty the cream into the vagina. Keeping the plunger pressed down firmly, grip the applicator by the barrel and remove it. There is no relevant indication for use of Gynest in children 4.3 Contraindications
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 • Previous idiopathic or current venous thrombo-embolism (deep venous • Active or recent arterial thrombo-embolic disease (eg angina, myocardial • Acute liver disease, or a history of liver disease as long as liver function 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. 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. Before initiating or re-instituting 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 mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual. 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 risk factors for, thrombo-embolic disorders (see below) - Risk factors for estrogen dependent tumours, eg 1st degree heredity for - Diabetes mellitus with or without vascular involvement - A history of endometrial hyperplasia (see below) 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 The risk of endometrial hyperplasia and carcinoma is increased when systemic estrogens are administered alone for prolonged periods of time. 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. If break-through bleeding or spotting appears at any time on therapy, 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 product in women who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis. A randomised placebo-controlled trial, the Women’s Health Initiative (WHI) and epidemiological studies, including the Million Women Study (MWS) have reported an increased risk of breast cancer in women taking estrogens or estrogen-progestogen combinations or tibolone for HRT for several years (see Section 4.8). For all HRT, an 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. HRT is associated with a higher relative risk of developing venous thrombo-embolism (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. 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. 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 contraindicated. The women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT. The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all postoperative patients, scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where 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. Treatment should not be restarted until the woman is completely mobilised. 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-embolic symptom (eg, painful swelling of a leg, sudden pain in the chest, dyspnoea). There is no evidence from randomised controlled trials of cardiovascular benefit with continuous 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 increased risk of cardiovascular morbidity in 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 products. 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. Long-term (at least 5-10 years) use of estrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRT confers a different risk than estrogen-only products. 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 estrogens 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 of 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 MPA 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 increased by concomitant administration of drugs 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 raise 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. 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
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-toxic effect. 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. According to evidence from a large number of epidemiological studies and
one randomised placebo-controlled trial, the Women’s Health Initiative
(WHI), the overall risk of breast cancer increases with increasing duration of
HRT use in current or recent HRT users.
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: 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. For 1000 current or recent users of HRT, the number of additional cases 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. For users ofestrogen 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. 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: • about 16 cases of invasive breast cancer would be diagnosed in 5 years. 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 • 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. Skin and subcutaneous tissue disorders: chloasma; erythema multiforme; erythema nodosum; vascular purpura, urticaria, angioedema. 4.9 Overdose
Symptoms of overdose of estrogen therapy may include breast pain or tenderness, nausea, break-through bleeding, abdominal cramps and/or bloating. Vaginal lavage should be considered. If accidental ingestion of large quantities of the product occurs, an appropriate method of gastric emptying may be considered. 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. 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. 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. 5.2 Pharmacokinetic properties
Estriol is readily absorbed following intravaginal application. Peak serum estriol concentrations are generally observed within 2 hours following intravaginal application and remain elevated for 6 hours. Systemic bioavailability on vaginal administration is better than after oral administration. Intravaginal application of 1 mg estriol in women with senile atrophy of the vaginal epithelium results in serum levels similar to those seen after oral administration of 10 mg estriol. Plasma estriol levels increased from <90pmol/L (26 pg/mL) about fifty fold over a few hours after intravaginal administration of Gynest Cream. Eight to ten hours after administration, 50% of women still had estriol levels above 90pmol/L (26 pg/mL). Estriol circulates with the blood, about 14% free, 8% bound to SHBG and the rest bound to albumin. Primary metabolites of estriol include the 16-alpha-glucuronide, 3-glucuronide, 3-sulfate and 3-sulfate 16-alpha-glucuronide. More than 95% of estriol is excreted in the urine, predominantly in the form of glucuronides. 5.3 Preclinical safety data
No relevant information additional to that contained elsewhere in the Summary of Product Characteristics. 6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life
6.4 Special precautions for storage
6.5 Nature and contents of container
Aluminium tube with screw cap containing 80 g [or 78g]* cream supplied with a plastic vaginal applicator. 6.6 Special precautions for disposal
Please refer to Section 4.2 Posology and Method of Administration. 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 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. 7 MARKETING AUTHORISATION HOLDER

Date of first authorisation: 1 September 1995 10 DATE OF REVISION OF THE TEXT


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