OVESTIN Estriol 1 mg / g Cream 15g

Hormone replacement therapy (HRT) for the treatment of atrophy of the lower urogenital tract related to estrogen deficiency.
Pre- and postoperative therapy in postmenopausal women undergoing vaginal surgery.
A diagnostic aid in case of a doubtful atrophic cervical smear.

Atrophy of the Lower Urogenital Tract: 1 application/day for the 1st week, followed by a gradual reduction, based on relief of symptoms, until a maintenance dosage (eg, 1 application twice a week) is reached.
Pre- and Postoperative Therapy in Postmenopausal Women Undergoing Vaginal Surgery: 1 application/day 2 weeks before surgery; 1 application twice a week 2 weeks after surgery.
Diagnostic Aid in Case of a Doubtful Atrophic Cervical Smear: 1 application on alternate days in the week before taking the next smear.
Application: Ovestin cream should be administered intravaginally by means of a calibrated applicator before retiring at night.
1 application (applicator filled to the ring mark) contains Ovestin cream 0.5 g which corresponds to estriol 0.5 mg.
Instructions for Use: Apply the vaginal cream before retiring at night. Remove cap from the tube, invert it and use the sharp point to open tube. Screw the end of the applicator onto the tube and squeeze tube to fill the applicator with the cream until the plunger stops. Unscrew applicator from tube and replace cap on tube. To apply cream, lie down, insert end of applicator deep into the vagina and slowly push plunger all the way in until applicator is empty.
After use, pull plunger out of barrel and wash both in warm, soapy water. Do not use detergents. Rinse well afterwards. Do not put the applicator in hot or boiling water.
A missed dose should be administered as soon as remembered, unless the missed dose is noticed at the day of the next dose. In the latter case, the missed dose should be skipped and the regular dosing scheme continued. Two doses must never be administered on the same day.
For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration of time should be used (see Precautions). In women not taking HRT or women who switch from a continuous combined HRT product, treatment with Ovestin may be started on any day. Women who switch from cyclic HRT regimen should start Ovestin treatment 1 week after completion of the cycle.

Known hypersensitivity to estriol or to any of the excipients of Ovestin. Known, past or suspected breast cancer; known or suspected estrogen-dependent malignant tumors eg, endometrial cancer; undiagnosed vaginal bleeding; untreated endometrial hyperplasia; previous or current venous thromboembolism (deep venous thrombosis, pulmonary embolism); known thrombophilic disorders eg, protein C, protein S or antithrombin deficiency (see Precautions); active or recent arterial thromboembolic disease eg, angina, myocardial infarction; active liver disease, or a history of liver disease as long as liver function tests failed to return to normal; porphyria.
Use in pregnancy & lactation: Ovestin is not indicated during pregnancy. If pregnancy occurs during medication with Ovestin, treatment should be withdrawn immediately. The results of most epidemiological studies to date relevant to inadvertent fetal exposure to estrogens indicate no teratogenic or fetotoxic effects.
Ovestin is not indicated during lactation. Estriol is excreted in breast milk and may decrease milk production.

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 favorable than in older women.
Medical Examination/Follow-Up: Before initiation 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 contraindications 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 breast should be reported to the physician or nurse (see 'Breast Cancer' as follows). 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 Ovestin, in particular: Leiomyoma (uterine fibroids) or endomteriosis, risk factors for thromboembolic disorders (see as follows), risk factors for estrogen-dependent tumors (eg, 1st degree hereditary 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 as follows), epilepsy, asthma, otosclerosis.
Reasons for Immediate Withdrawal of Therapy: Therapy should be discontinued in case a contraindication 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: In order to prevent endometrial stimulation, the daily dose should not exceed 1 application (estriol 0.5 mg) nor should this maximum dose be used for longer than several weeks. One (1) epidemiological study has shown that long-term treatment with a low-dose of oral estriol, but not vaginal estriol, may increase the risk for endometrial cancer. This risk increased with the duration of treatment and disappeared within 1 year after the treatment was terminated. The increased risk mainly concerned less invasive and highly differentiated tumors. Vaginal bleeding during medication should always be investigated. The patient should be informed to contact a physician if vaginal bleeding occurs.
Breast Cancer: Hormone replacement therapy may increase mammographic density. This may complicate the radiological detection of breast cancer. Clinical studies reported that the likelihood of developing increased mammographic density was lower in subjects treated with estriol than in subjects treated with other estrogens.
The overall incidence suggests an increased risk of breast cancer in women taking combined estrogen-progestogen and possibly also estrogen-only HRT, that is dependent on duration of taking HRT.
Combined Estrogen-Progestogen Therapy: The randomized 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 Adverse Reactions).
Estrogen-Only Therapy: The 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 Adverse Reactions).
The excess risk becomes apparent within a few years of use but returns to baseline within a few (at most 5) years after stopping treatment.
It is unknown whether Ovestin carries the same risk. In a recent population-based case control study in 3345 women with invasive breast cancer and 3454 controls, estriol was found not to be associated with an increased risk of breast cancer, in contrast to other estrogens. However, the clinical implication of these findings are as yet unknown. Therefore, it is important that the risk of being diagnosed with breast cancer is discussed with the patient and weighed against the known benefits of HRT.
Ovarian Cancer: 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 slightly increased risk of ovarian cancer. Some studies including the Women's Health Initiative (WHI) trial suggest that long-term use of combined HRTs may confer a similar or slightly smaller risk (see Adverse Reactions). It is uncertain whether long-term use of low potency estrogens eg, Ovestin confers a different risk than other estrogen-only products.
Venous Thromboembolism: Hormone replacement therapy is associated with a 1.3- to 3-fold risk of developing venous thromboembolism (VTE) ie, deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the 1st year of HRT than later (see Adverse Reactions). These studies did not include Ovestin and in the absence of data, it is unknown whether Ovestin carries the same risk.
Patients with known thrombophilic states have increased risk of VTE and HRT may add to this risk. Hormone replacement therapy is therefore contraindicated in these patients (see Contraindications).
Generally recognized risk factors for VTE include use of estrogens, older age, major surgery, prolonged immobilization, obesity (body mass index >30 kg/m²), pregnancy/postpartum period, systemic lupus erythematosus (SLE) and cancer. There is no consensus about the role of varicose veins in VTE.
As in all postoperative patients, prophylactic measures need be considered to prevent VTE following surgery. If prolonged immobilization is to follow elective surgery, temporarily stopping HRT 4-6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilised.
If Ovestin is used for the indication pre- and postoperative therapy, consideration should be given to prophylactic treatment against thrombosis.
In women with no personal history of VTE but with a 1st degree relative with a history of thrombosis at a young age, screening may be offered after careful counseling 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 anticoagulant treatment require careful consideration of the benefit-risk use of HRT.
Discontinue if VTE develops after initiating Ovestin therapy. Patients should be told to contact their physician immediately when they are aware of a potential thromboembolic symptom (eg, painful swelling of a leg, sudden pain in the chest, dyspnea).
Coronary Artery Disease (CAD): There is no evidence from randomized 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 Therapy: The relative risk of CAD during use of combined estrogen-progestagen 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: Randomized controlled data found no increased risk of CAD in hysterectomised women using estrogen-only therapy.
Ischemic Stroke: Combined estrogen-progestogen and estrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischemic 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 Adverse Reactions).
Other Conditions: Estrogens may cause fluid retention and therefore patients with cardiac or renal dysfunction should be carefully observed.
Estriol is a weak gonadotrophin inhibitor without other significant effects on the endocrine system.
Hormone replacement therapy 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.
Ovestin cream contains cetyl alcohol and stearyl alcohol. This may cause local skin reactions (eg, contact dermatitis).

From literature and safety surveillance monitoring, the following adverse reactions have been reported: General Disorders and Administration Site Conditions: Application site irritation and pruritus.
Reproductive System and Breast Disorders: Breast discomfort and pain.
These adverse reactions are usually transient but may also be indicative of a high dosage.
Other adverse reactions have been reported in association with estrogen-only and estrogen-progestogen combined treatment: Estrogen-dependent neoplasms benign and malignant eg, endometrial cancer (see Contraindications and Precautions); gall bladder disease.
Skin and Subcutaneous Disorders: Chloasma, erythema multiforme, erythema nodosum, vascular purpura; probable dementia for patients >65 years (see Precautions).
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 <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 Precautions). Results of the largest randomized placebo-controlled trial (WHI study) and largest epidemiological study (MWS) are presented in Tables 1 and 2, respectively. (See Tables 1 and 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 MWS, 5 years of HRT resulted in 1 extra case per 2500 users.
Risk of Venous Thromboembolism: HRT is associated with a 1.3- to 3-fold increased relative risk of developing venous thromboembolism (VTE), ie deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of using HRT (see Precautions). Results of the WHI studies are presented in Table 3. (See Table 3.)




Risk of Coronary Artery Disease: The risk of coronary artery disease is slightly increased in users of combined estrogen-progestogen HRT >60 years. (see Precautions).
Risk of Ischemic Stroke: The use of estrogen-only and estrogen-progestogen therapy is associated with an up to 1.5-fold increased relative risk of ischemic stroke. The risk of hemorrhagic 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 Table 4).

No examples of interactions between Ovestin and other medicines have been reported in clinical practice. Although data are limited, interactions between Ovestin and other medicinal products may occur. The following interactions have been described with use of combined oral contraceptives which may also be relevant for Ovestin.
The metabolism of estrogens may be increased by concomitant use of substances known to induce drug-metabolizing enzymes, specifically cytochrome P-450 enzymes eg, anticonvulsants (eg, hydantoins, barbiturates, carbamazepine), anti-infectives (eg, griseofulvin, rifamycins, the antiretroviral agents nevirapine and efavirenz) and herbal preparations containing St. John's wort (Hypericum perforatum).
Ritonavir and nelfinavir, although known as strong inhibitors by contrast, exhibit inducing properties when used concomitantly with steroid hormones.
Clinically, an increased metabolism of estrogens may lead to decreased effectiveness of Ovestin and changes in uterine bleeding profile.
Estriol may possibly increase the pharmacological effects of corticosteroids, succinylcholine, theophyllines and troleandomycin.