- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Guidance on how to start therapy and maintenanceGynest 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.
Administration: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
Medical examination/follow-upBefore initiating or reinstituting 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 supervisionIf 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- Risk factors for thromboembolic disorders (see below)- Risk factors for estrogen dependent tumours, eg 1st 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 carcinomaIn women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when 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 after 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, 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 cancerThe 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 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 a small increase in risk of having breast cancer diagnosed that is substantially lower than that found in users of estrogen-progestogen combinations (see Section 4.8). The excess risk becomes apparent within a few years of use and returns to baseline within a few (at most five) years after stopping treatment.HRT, especially estrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Ovarian cancerOvarian 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 slightly 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 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 estrogens, 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 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' (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 thromboembolic 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 protection against myocardial infarction in women with or without existing CAD who received combined estrogen-progestogen or estrogen-only HRT.• Combined estrogen-progestogen therapyThe relative risk of CAD during use of combined estrogen+progestogen HRT is slightly increased. As the baseline 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. • Estrogen-only therapyRandomised controlled data found no increase of CAD in hysterectomised women using estrogen-only therapy.
Ischaemic Stroke• Combined estrogen-progestogen and estrogen-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)
Other conditions• Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. • 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.• 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.• 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 estrogen-only HRT after the age of 65.
PregnancyGynest Cream is not indicated during pregnancy. If pregnancy occurs during use of Gynest Cream, treatment should be withdrawn immediately.The results of most epidemiological studies to date, relevant to inadvertent foetal exposure to estrogens indicate no teratogenic or foetotoxic effect.
LactationGynest Cream is not indicated during lactation.
Breast cancer 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 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)|
|#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. *Taken from baseline incidence rates in developed countries|
|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)|
|50-79||21||0.8 (0.7 1.0)||-4 (-6 0)*|
|CEE + MPA Combined estrogen & progestogen#|
|50-79||14||1.2 (1.0 1.5)||+4 (0-9)|
|#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. *WHI study in women with no uterus, which did not show an increase in risk of breast cancer|
Endometrial cancer riskPostmenopausal women with a uterusThe 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 cancerLong-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 thromboembolismHRT 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
|Age range (years)||Incidence per 1000 women in placebo arm over 5 years||Risk ratio and 95% CI||Additional cases per 1000 HRT users|
|50-59||7||1.2 (0.6 2.4)||1 (-3 10)*|
|Oral combined estrogen-progestogen|
|50-59||4||2.3 (1.2 4.3)||5 (1-13)|
|*Study in women with no uterus|
Risk of coronary artery diseaseThe 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 strokeThe 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 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|
|50-59||8||1.3 (1.1 1.6)||3 (1-5)|
|*No differentiation was made between ischaemic and haemorrhagic stroke|
Clinical trial informationImprovement 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.
Marlborough Pharmaceuticals Ltd
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