Instructions for Ovestin vaginal cream tube 15 g
Composition
active ingredient: estriol;
1 g of cream contains estriol 1 mg;
excipients: octyldodecanol, cetyl palmitate, glycerin, cetyl alcohol, stearyl alcohol, polysorbate 60, sorbitan stearate, lactic acid, chlorhexidine, sodium hydroxide, purified water.
Dosage form
Vaginal cream.
Main physicochemical properties: homogeneous, uniform mass of creamy consistency from white to almost white.
Pharmacotherapeutic group
Hormones of the sex glands and drugs used in pathologies of the genital sphere. Simple preparations of natural and semi-synthetic estrogens. ATX code G03C A04.
Pharmacological properties
Pharmacodynamics
Mechanism of action
Ovestin contains the natural female hormone estriol. Unlike other estrogens, estriol is short-acting, as it interacts with the nuclei of endometrial cells. It compensates for the loss of estrogen production in women during menopause and reduces the severity of menopausal symptoms. Estriol is particularly effective in the treatment of urogenital disorders. In case of atrophy of the lower parts of the urogenital tract, estriol normalizes the epithelium and helps restore normal microflora and physiological pH level in the vagina. As a result, the resistance of the urogenital tract epithelial cells to infection and inflammation increases, which leads to a decrease in such vaginal diseases and their symptoms as dyspareunia, dryness, itching, vaginal and urinary tract infections, urinary disorders and minor urinary incontinence.
Clinical trial information
According to information obtained during clinical trials, a reduction in menopausal symptoms occurred during the first weeks of treatment. Also, according to clinical trials, vaginal bleeding after treatment with Ovestin occurred only in rare cases. In case of vaginal bleeding during treatment with Ovestin vaginal cream, a woman should consult her doctor. All cases of vaginal bleeding during use of the drug should be investigated (see section "Special instructions").
Pharmacokinetics
Absorption
Intravaginal administration of estriol provides optimal bioavailability at the site of action. Estriol is also absorbed into the systemic circulation, as evidenced by a rapid increase in plasma concentrations of unconjugated estriol.
Distribution
The maximum plasma concentration (Cmax) develops 1-2 hours after application. After vaginal administration of 0.5 mg estriol, the Cmax value was approximately 100 pg/ml, the minimum plasma concentration (Cmin) was approximately 25 pg/ml, and the average concentration was approximately 70 pg/ml. After 3 weeks of daily vaginal administration of 0.5 mg estriol, the average concentration decreased to 40 pg/ml.
Biotransformation
Almost all (90%) of estriol in plasma is bound to albumin and, unlike other estrogens, almost no binding to sex hormone binding globulin. Estriol is metabolized mainly by conjugation and deconjugation during enterohepatic circulation.
Breeding
Since estriol is the end product of metabolism, it is mainly excreted in the urine in conjugated form. Only a small part (approximately 2%) is excreted in the feces, mainly as unconjugated estriol.
Indication
hormone replacement therapy (HRT) for the treatment of lower genitourinary tract atrophy associated with estrogen deficiency; pre- and postoperative treatment of postmenopausal women undergoing vaginal surgery; as an aid in diagnosis in doubtful cases of atrophic cervical smear.
Contraindication
Hypersensitivity to the active substance or to any of the excipients of the drug; established, past or suspected breast cancer; established or suspected estrogen-dependent malignant tumors (e.g. endometrial cancer); vaginal bleeding of unknown etiology; untreated endometrial hyperplasia; previous or current venous thromboembolism (VTE) (deep vein thrombosis, pulmonary embolism);
established thromboembolic disorders (e.g. protein C, protein S or antithrombin deficiency, see section "Special warnings and precautions for use");
Active or recent thromboembolic arterial disease (e.g. angina pectoris, myocardial infarction); acute liver disease or a history of liver disease after which liver function tests have not returned to normal; porphyria.
Interaction with other medicinal products and other types of interactions
Ritonavir and nelfinavir are known strong inhibitors, but they, on the contrary, exhibit inducing properties when used with steroid hormones.
A clinically significant increase in estrogen metabolism may lead to a decrease in the effectiveness of Ovestin and a change in the pattern of bleeding.
Application features
For the treatment of postmenopausal symptoms, HRT should only be initiated if symptoms are bothersome and have a negative impact on quality of life. In any case, a careful assessment should be made at least annually to accurately determine the risks and benefits, and HRT should only be continued as long as the benefits of treatment outweigh the risks.
Medical examination/follow-up by a doctor
Before starting or resuming HRT, a complete personal and family history should be taken. The medical examination (including pelvic and breast examination) should take into account the patient's medical history and the contraindications and precautions for use of the drug. Periodic medical examinations of the patient are recommended during the course of treatment, the frequency and nature of which depend on the individual characteristics. Women should be informed about what changes in the breasts they should report to their doctor or nurse. It is recommended that examinations, including mammography, be carried out in accordance with current screening practices, adjusted to the needs of the individual patient.
Conditions that require medical attention
If the following conditions are present or have been present and/or worsened during pregnancy or previous hormonal therapy, the patient should be closely monitored. It should be noted that these conditions may recur or worsen during treatment with Ovestin, including:
leiomyoma (uterine fibroids) or endometriosis; thromboembolic disorders or risk factors (see below); risk factors for estrogen-dependent tumors, such as 1st degree heredity for breast cancer; high blood pressure; liver disease (e.g. hepatoadenoma); diabetes mellitus with or without vascular disorders; gallstone disease; migraine or severe headache; systemic lupus erythematosus; history of endometrial hyperplasia (see below); epilepsy; asthma; otosclerosis.
Reasons for immediate discontinuation of treatment
HRT should be discontinued immediately if any of the contraindications are identified, as well as in the following situations:
jaundice or worsening liver function; significant increase in blood pressure; new onset of migraine-type headache; pregnancy.
Endometrial hyperplasia and cancer
To prevent the development of endometrial hyperplasia, the daily dose should not exceed 1 dose contained in the applicator (0.5 mg estriol), and this maximum dose should not be used for more than several weeks. In one epidemiological study, it was demonstrated that long-term treatment with low-dose estriol orally, but not vaginally, may increase the risk of endometrial cancer. The risk increases depending on the duration of treatment and disappears within one year after the end of treatment. The increased risk mainly concerns less invasive and well-differentiated tumors. All cases of vaginal bleeding during use of the drug should be investigated. The patient should be informed about the need to consult a doctor in case of vaginal bleeding.
Breast cancer
Based on the overall body of evidence, an increased risk of breast cancer is expected in women who have taken combined estrogen-progestogen and possibly also estrogen-only HRT, depending on the duration of HRT use.
Combined estrogen-progestogen therapy
An increased risk of breast cancer in women taking combined estrogen-progestogen HRT has been reported in the randomized placebo-controlled Women's Health Initiative (WHI) trial and in epidemiological studies, which became apparent after approximately 3 years (see section 4.8).
Estrogen-only therapy
The WHI trial did not find an increased risk of breast cancer in hysterectomised women using oestrogen-only HRT. Observational studies have mainly reported a small increased risk of breast cancer, which is much lower than in users of combined oestrogen-progestagen products (see section 4.8).
The increased risk becomes noticeable after several years of use, but returns to baseline levels several years (maximum 5) after stopping treatment.
HRT, especially the use of estrogen-progestogen combinations, increases the density of mammographic images, which may negatively affect the quality of X-ray detection of breast cancer. Limited data suggest that there is no increased risk of breast cancer with the use of Ovestin vaginal cream.
Ovarian cancer is much less common than breast cancer. Long-term (at least 5-10 years) estrogen monotherapy (as HRT) has been associated with a small increased risk of ovarian cancer. Some studies, including the WHI, suggest that long-term combined HRT is associated with a similar or slightly lower risk (see Adverse Reactions). It is not known whether long-term use of low-potency estrogens (such as estriol) poses a different risk than other estrogen-only preparations.
Venous thromboembolism (VTE)
Hormone replacement therapy (HRT) is associated with a 1.3- to 3-fold increased risk of developing VTE, i.e. deep vein thrombosis or pulmonary embolism. The risk of developing these events is greater during the first year of HRT than thereafter (see section 4.8).
Patients with established medical conditions associated with thrombophilic disorders are at increased risk of VTE, and hormone replacement therapy may increase this risk. Therefore, hormone replacement therapy is contraindicated in such patients (see Contraindications). Risk factors for VTE include estrogen use, older age, major surgery, prolonged immobilization, obesity (body mass index > 30 kg/m2), pregnancy, the postpartum period, systemic lupus erythematosus, and cancer. There is no consensus on the role of varicose veins in the development of VTE.
As with all postoperative patients, precautions should be taken to prevent VTE. If prolonged immobilization is unavoidable after elective surgery, it is recommended that hormone replacement therapy be temporarily discontinued 4 to 6 weeks prior to surgery. Such therapy should not be resumed until the woman is fully ambulatory.
Women with no history of VTE but a first-degree relative with a history of thrombosis at a young age may be offered screening after careful counseling about its limitations (only a fraction of thrombophilic disorders are detected by screening). If there is an established hereditary thrombophilic condition that is associated with thrombosis in family members, or if the condition is severe (e.g., antithrombin, protein S, or protein C deficiency, or a combination of disorders), HRT is contraindicated.
For women already on ongoing anticoagulant treatment, the benefit-risk balance of hormone replacement therapy should be carefully weighed.
If VTE occurs after initiation of treatment with Ovestin, treatment with the drug should be discontinued. Patients should be advised to seek immediate medical attention if they experience symptoms of possible thromboembolism (e.g. painful swelling of a leg, sudden chest pain, shortness of breath).
Coronary heart disease (CHD)
Randomized controlled trials have shown no evidence that combined estrogen-progestin or estrogen-only hormone replacement therapy protects against myocardial infarction in women with or without coronary artery disease.
Combined estrogen-progestogen therapy
The relative risk of CHD is slightly increased with combined estrogen-progestogen HRT. Since the underlying absolute risk of CHD is largely age-dependent, the number of additional cases of CHD due to estrogen-progestogen use is very small in healthy women approaching menopause, but increases with age.
Estrogen only
Based on these randomized controlled trials, no increased risk of CHD was found in hysterectomized women using estrogen-only HRT.
Ischemic stroke
There is evidence that with combined estrogen-progestogen or estrogen-only therapy, the risk of ischemic stroke increases by 1.5 times. The relative risk does not change with age or time since menopause. However, since the baseline absolute risk of ischemic stroke is significantly age-dependent, the overall risk of stroke in women taking HRT increases with age (see section "Adverse reactions").
Other states
Estrogens can cause fluid retention in the body, so patients with impaired cardiac or renal function should be carefully monitored.
Estrogens increase the concentration of thyroxine-binding globulin (TBG), which leads to an increase in the total amount of circulating thyroid hormone, as measured by the level of protein-bound iodine, T4 (measured by column analysis or RIA), or T3 (measured by RIA). The level of T3-resin complex capture is reduced, reflecting the increased levels of TSH. The concentrations of free T3 and T4 are not changed. The serum levels of other binding proteins, i.e., corticosteroid-binding globulin (CBG) and sex hormone-binding globulin (SHBG), may also be increased, leading to a corresponding increase in the concentrations of circulating corticosteroids and sex hormones. The concentrations of free or biologically active hormones remain unchanged. Levels of other plasma proteins (angiotensin-renin substrate, α-1-antitrypsin, ceruloplasmin) may increase.
HRT does not improve cognitive function. There is some evidence of an increased risk of possible dementia in women who start continuous combined or estrogen-only HRT after age 65.
The use of Ovestin vaginal cream at the recommended maintenance dose does not affect the results of endocrine function tests.
Ovestin cream contains cetyl alcohol and stearyl alcohol. They may cause local skin reactions (e.g. contact dermatitis).
Ability to influence reaction speed when driving vehicles or other mechanisms
Ovestin does not affect the ability to drive or operate machinery.
Use during pregnancy or breastfeeding
Fertility
Ovestin is only intended for the treatment of women in the postmenopausal period (natural and surgically induced).
Pregnancy
Ovestin is not used during pregnancy. If a woman becomes pregnant during treatment with Ovestin, the drug should be discontinued immediately. The results of epidemiological studies conducted to date on the effects of estrogens on the fetus do not indicate the presence of teratogenic or fetotoxic effects.
Breastfeeding period
Ovestin is not used during breastfeeding. Estriol passes into breast milk and may reduce milk production.
Method of administration and doses
The drug Ovestin contains only estrogen, so it can be used both in women with a preserved uterus and in women after hysterectomy.
Dosage
When initiating or continuing treatment for symptoms of estrogen deficiency in postmenopausal women, the lowest effective dose should be used for the shortest possible period of time (see section "Special warnings and precautions for use").
With atrophy of the lower parts of the genitourinary tract:
1 dose of the drug per day for the first few weeks (maximum up to 4 weeks) with subsequent gradual reduction to a maintenance dose (for example, a maximum of 1 dose of the drug 2 times a week) depending on the degree of symptom reduction.
For pre- and postoperative treatment of postmenopausal women undergoing vaginal surgery:
1 dose of the drug per day for 2 weeks before surgery; 1 dose of the drug 2 times a week for 2 weeks after surgery.
As an aid for diagnosis when obtaining an atrophic cervical smear pattern:
1 dose of the drug every other day for a week before taking the next smear.
If a dose is missed, the dose should be taken as soon as possible, unless it is due on the day of the next dose. In the latter case, the missed dose should not be taken and treatment should be continued as usual.
YOU CANNOT ADMINISTER 2 DOSES OF THE MEDICATION IN ONE DAY.
Method of application
Ovestin cream should be inserted into the vagina using a calibrated applicator. Apply in the evening before bedtime.
1 dose of the drug (applicator filled to the ring mark) contains 0.5 g of Ovestin cream, which corresponds to 0.5 mg of estriol.
Instructions for use of the drug by the patient
Remove the cap from the tube, turn the cap over and use the sharp protrusion on it to open the tube. Screw the end of the applicator onto the tube. Make sure that the piston is fully inserted into the cylinder. Slowly squeeze the tube to fill the applicator with cream until the piston stops at the red ring, see the arrows in the picture below. Unscrew the applicator from the tube and close it with the cap. To introduce the cream, lie down and insert the end of the applicator deep into the vagina. Slowly press the piston until the applicator is completely empty. After use, remove the piston from the cylinder, overcoming noticeable resistance, and wash the cylinder and piston in warm soapy water. Do not use detergents. Rinse thoroughly after washing. DO NOT PUT THE APPLICATOR IN HOT OR BOILING WATER. The applicator should be assembled by fully inserting the piston into the cylinder, overcoming resistance where it is felt.
When the tube is empty, the applicator should be disposed of.
Children
The drug is not used in children.
Overdose
In case of accidental ingestion of a large amount of the drug, women may experience nausea, vomiting and bleeding as a withdrawal syndrome. There is no specific antidote. If necessary, symptomatic treatment should be carried out.
Adverse reactions
Adverse reactions usually occur in 3-10% of patients receiving treatment. This may indicate that the dose of the drug is too high. Adverse reactions usually disappear within the first weeks of treatment.
The frequency of adverse reactions may vary depending on the indications for use, dosage of the drug and combination with other drugs.
The frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to <1/10); uncommon (≥ 1/1000 to <1/100); rare (≥ 1/10,000 to <1/1000); very rare (<1/10,000); frequency unknown (cannot be estimated from the available data).
The following adverse reactions have been reported in the literature and during post-marketing surveillance, the frequency of which was unknown:
From the side of metabolism and nutrition - fluid retention.
Gastrointestinal tract: nausea.
On the part of the reproductive system and mammary glands - discomfort and pain in the mammary glands, chest pain, postmenopausal bleeding, vaginal discharge.
Systemic disorders and reactions at the injection site – irritation and itching at the injection site, flu-like illness.
Other adverse reactions have also occurred with treatment with a combined estrogen and progestogen preparation.
Benign and malignant estrogen-dependent neoplasms, such as endometrial cancer (see sections "Contraindications" and "Special instructions").
Gallbladder disease.
Skin and subcutaneous tissue disorders: chloasma, erythema multiforme, erythema nodosum, hemorrhagic purpura.
Dementia is possible at the age of 65 years (see section "Special instructions").
Risk of developing breast cancer
The risk of developing breast cancer was almost doubled in women who took combined estrogen-progestogen HRT for more than 5 years.
The risk with estrogen-only therapy is much lower than with combined estrogen and progestogen therapy as HRT.
The risk depends on the duration of use of the drug (see section "Special instructions for use").
The results of the largest WHI study and the largest epidemiological study (MWS) are presented below.
Million Women Study (MWS) – estimated additional risk of breast cancer after 5 years of treatment
| Age group (years) | Additional cases per 1000 people not receiving HRT, registered over 5 years* | Risk ratio # | Additional cases per 1000 people receiving HRT, reported over 5 years (95% CI) |
| Estrogen-only HRT | | | |
| 50−65 | 9-12 | 1.2 | 1-2 (0-3) |
| Combined estrogen-progestogen HRT | | | |
| 50-65 | 9-12 | 1.7 | 6 (5-7) |
# Overall risk ratio. The risk ratio is not a constant value, it increases with increasing duration of use.
* Since the baseline incidence of breast cancer varies across EU countries, the number of additional cases of breast cancer will also vary proportionally.
WHI study in the US – additional risk of breast cancer after 5 years of treatment
| Age group (years) | Number of cases per 1000 women in the placebo group over 5 years* | Hazard ratio and 95% CI | Additional cases per 1000 people receiving HRT over 5 years (95% CI) |
| HRT with estrogen only EHR | | | |
| 50−79 | 21 | 0.8 (0.7-1.0) | -4 (-6−0)* |
| Combined estrogen-progestogen HRT CEE + MPA≠ | | | |
| 50−79 | 17 | 1.2 (1.0−1.5) | +4 (0−9) |
≠ When the analysis was restricted to women who had not used HRT before the study, there was no increase in risk during the first 5 years of treatment; after 5 years the risk was higher than in women who had not received treatment.
*WHI study in women with a removed uterus, which did not show an increased risk of breast cancer.
Ovarian cancer
Long-term use of estrogen-only and combined estrogen-progestogen HRT is associated with a small increased risk of ovarian cancer. In the Million Women Study, 5 years of HRT use resulted in 1 additional case per 2500 people treated.
Risk of developing VTE
When using HRT, the relative risk of VTE, i.e. deep vein thrombosis or pulmonary embolism, increases by 1.3-3 times (see section "Special instructions"). The results of the WHI studies are presented below.
WHI study – additional risk of VTE after 5 years of use
| Age group (years) | Number of cases per 1000 women in the placebo group over 5 years* | Hazard ratio and 95% CI | Additional cases per 1000 people receiving HRT over 5 years (95% CI) |
| Oral estrogen-only HRT* | | | |
| 50-59 | 7 | 1.2 (0.6−2.4) | 1 (-3−10) |
| Oral combined estrogen-progestogen HRT | | | |
| 50-59 | 4 | 2.3 (1.2−4.3) | 5 (1−13) |
*Study in women with a removed uterus.
Risk of developing coronary heart disease
The risk of developing coronary heart disease is slightly increased when combined estrogen-progestogen HRT is used in women aged 60 years and older (see section "Special warnings and precautions for use").
Risk of developing ischemic stroke
The use of estrogen alone and combined estrogen-progestagen therapy is associated with a 1.5-fold increased relative risk of ischemic stroke. The risk of hemorrhagic stroke is not increased during HRT.
This relative risk does not depend on age or duration of use, but because the baseline risk is strongly age-dependent, the overall risk of stroke increases with increasing age in HRT users (see section 4.4).
Combined WHI studies – additional risk of ischemic stroke* after 5 years of use
| Age group (years) | Number of cases per 1000 women in the placebo group over 5 years | Hazard ratio and 95% CI | Additional cases per 1000 people receiving HRT over 5 years (95% CI) |
| 50-59 | 8 | 1.3 (1.1−1.6) | 3 (1−5) |
*Differentiation between ischemic and hemorrhagic stroke was not performed.
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after a medicine has been authorised is important. This allows the benefit-risk balance of the medicine to be monitored. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
Expiration date
3 years.
Storage conditions
Store at a temperature not exceeding 25 °C out of the reach of children.
Do not freeze.
Packaging
15 g of cream in an aluminum tube with a polyethylene cap. The applicator consists of a styrene-acrylonitrile cylinder and a polyethylene piston. 1 tube complete with an applicator in a cardboard box.
Vacation category
Without a prescription.
Producer
Aspen Bad Oldesloh GmbH.
Location of the manufacturer and its business address
Industristrasse 32 - 36, 23843 Bad Oldesloe, Germany.
