Instructions for use OVESTIN® (OVESTIN)
To treat menopausal symptoms, HRT should only be started for symptoms that adversely affect quality of life. In all cases, it is necessary to conduct a thorough assessment of the risks and benefits of treatment at least once a year, and HRT should be continued only for a period of time until the benefits outweigh the risks.
Before starting or resuming HRT, a detailed individual and family history should be established. Based on the obtained medical history, contraindications and warnings for use, it is necessary to conduct a clinical examination (including examination of the pelvic organs and mammary glands). During treatment, it is recommended to conduct periodic medical examinations, the frequency and nature of which vary from person to person. Women should be informed about the need to report changes in the mammary glands to their doctor. Tests, including mammography, must be performed in accordance with currently accepted screening standards.
Therapy should be discontinued if a contraindication is identified and if the following conditions occur:
- jaundice or impaired liver function, significant increase in blood pressure, resumption of migraine-type headaches, pregnancy, endometrial hyperplasia.
When used intravaginally to prevent stimulation of the endometrium, the daily dose should not exceed 0.5 mg of estriol (1 application of cream or 1 suppository). This maximum dose should not be used for more than 4 weeks.
Breast cancer
Based on randomized, placebo-controlled, Women's Health Initiative (WHI) trials, and epidemiological studies including the Million Women Study (MWS), an increased risk of breast cancer was reported in women taking estrogens, estrogen-progestogen combinations, or tribolone. for HRT for several years. For all HRT, the increased risk becomes noticeable after several years of use and increases with duration of use, but returns to baseline levels a few (maximum 5) years after stopping treatment.
In the MWS study, the relative risk of mammary cancer with conjugated equine estrogens (CEE) or estradiol (E2) was higher when a progestogen was added, both cyclically and continuously, and regardless of the type of progestogen. There is no evidence of differences in risk between different routes of administration.
In the WHI study, a continuous combination of conjugated equine estrogen and medroxyprogesterone acetate (CEE + MPA) was associated with mammary tumors that were slightly larger and more likely to have local lymph node metastases compared with placebo.
It is unknown whether such a risk is associated with the use of Ovestin. A recent population-based case-control study of 3345 women with invasive breast cancer and 3454 controls showed that estriol use, unlike other estrogens, was not associated with an increased risk of breast cancer. Therefore, when deciding whether to use HRT, it is very important to carefully assess the risk of developing breast cancer and the benefits of therapy.
Venous thromboembolism (VTE)
HRT is associated with a higher relative risk of developing VTE - deep vein thrombosis or pulmonary embolism. One randomized controlled trial and epidemiological studies have found that the risk for women receiving HRT is 2-3 times higher than for non-users. It is unknown whether the use of Ovestin is associated with the same risk.
Commonly recognized risk factors for VTE include personal or family history, severe obesity (BMI >30 kg/m2) and systemic lupus erythematosus. There is no consensus regarding the possible role of varicose veins in the development of VTE.
Patients with a history of VTE or known thromboembolic conditions are at increased risk of VTE. HRT may increase this risk. In order to exclude a predisposition to blood clots, it is necessary to examine an individual and family history of thromboembolism or recurrent spontaneous miscarriage. Until a thorough assessment of thromboembolic factors has been carried out, the initiation of anticoagulant treatment or the use of HRT in such patients should be considered a contraindication. For women already receiving anticoagulant treatment, careful consideration of the benefit-risk balance of HRT is required.
The risk of VTE may increase with prolonged immobilization of the patient, extensive trauma, or a large volume of surgical intervention. After surgery, special attention should be paid to preventive measures to prevent VTE. In cases where prolonged immobilization is unavoidable after elective surgery (especially after abdominal surgery or orthopedic surgery on the lower extremities), if possible, temporary cessation of HRT should be considered 4-6 weeks before surgery. If the drug Ovestin is used for indications related to pre- and postoperative therapy, then it is necessary to provide preventive treatment to prevent thrombosis.
If VTE develops after starting treatment with Ovestin, treatment should be discontinued. Patients should be advised to seek immediate medical attention if they experience a symptom of a potential thromboembolism (eg, painful leg swelling, sudden chest pain, shortness of breath).
Cardiac ischemia
Randomized controlled trials have not confirmed the positive effect of continuous use of a combination of conjugated estrogens and medroxyprogesterone acetate on the state of the cardiovascular system. Two large clinical trials (WHI and HERS, i.e. Heart Study and Estrogen-Progestogen Replacement Therapy) showed a possible increase in the risk of cardiovascular disease during the first year of use and did not show an overall benefit. For other HRT drugs, only limited data are available from randomized controlled trials assessing effects on cardiovascular disease incidence or mortality in such patients. Therefore, it is not certain that these results also apply to other HRT drugs.
Stroke
It was found that there is an increased risk of ischemic stroke in healthy women during treatment with continuous use of a combination of conjugated estrogens and medroxyprogesterone acetate. It is unknown whether this risk applies to other HRT drugs, including Ovestin.
Ovarian cancer
Long-term (at least 5-10 years) use of estrogen-only HRT in women who have had uterine surgery has been associated with an increased risk of ovarian cancer in several epidemiological studies. There is no certainty that long-term use of combined HRT or low-potency estrogens (for example, Ovestin) is characterized by a different degree of risk than the use of drugs containing only estrogen.
Other states
Estrogens can cause fluid retention and therefore patients with impaired renal function and cardiovascular insufficiency should be closely monitored. Patients with end-stage chronic renal failure should be closely monitored as circulating levels of the active substances of Ovestin are expected to increase.
Estriol is a weak gonadotropin inhibitor and has no other significant effects on the endocrine system.
There has been no convincing evidence of improvement in cognitive function with HRT.
In case of vaginal infections, concomitant specific treatment is recommended.
Ovestin®
— To treat menopausal symptoms, HRT should only be prescribed for symptoms that adversely affect quality of life. In all cases, a thorough assessment of the risks and benefits of treatment should be carried out at least once a year, and HRT should be continued only as long as the benefits outweigh the risks.
— There is limited evidence of the risks of HRT when treating premature menopause. Due to the lower absolute risk in younger women, the benefit-risk ratio is more favorable in them than in older women.
Medical examination/observation
— Before starting or resuming HRT, it is necessary to obtain a detailed individual and family history. Guided by the obtained medical history, contraindications and warnings for use, it is necessary to conduct a clinical examination, including examination of the pelvic organs and mammary glands. During treatment, it is recommended to conduct periodic medical examinations, the frequency and nature of which vary from person to person. Women should be informed about the need to tell their doctor about changes in the mammary glands (see “Breast cancer” below). Investigations, including appropriate imaging modalities such as mammography, should be performed in accordance with currently accepted examination standards and on a case-by-case basis.
Reasons for immediate discontinuation of therapy:
Therapy should be discontinued if contraindications are identified and if the following conditions occur:
- Jaundice or deterioration of liver function;
- Significant increase in blood pressure;
— The occurrence of migraine-type headaches;
- Pregnancy.
Endometrial hyperplasia and carcinoma
— To prevent stimulation of the endometrium, the daily dose of the drug should not be divided into several doses and should not exceed 8 mg of estriol. In addition, one epidemiological study found that long-term use of low-dose estriol may increase the risk of endometrial cancer. The risk increases with the duration of treatment and returns to baseline values one year after discontinuation of the drug. Basically, the risk of minimally invasive and well-differentiated tumors increases.
For women with an intact uterus, the following precautions are recommended:
- The entire daily dose must be taken at once;
— The patient should be informed of the need to contact the attending physician if vaginal bleeding begins (this symptom in all cases requires examination);
- With long-term treatment, the condition of the endometrium must be assessed at least once a year, or progestogens must be prescribed for at least 12-14 days of each calendar month.
When deciding whether to control the condition of the endometrium or to prescribe progestogens, the increased risk of breast cancer with combined therapy with estrogens and progestogens should be taken into account. There is currently no evidence that estrogen monotherapy increases the risk of breast cancer.
Mammary cancer
— Hormone replacement therapy may increase mammographic density. This can make radiological detection of breast cancer more difficult. Clinical studies have shown that the likelihood of developing increased mammographic density was lower in patients treated with estriol than in patients treated with other estrogens.
— Pooled evidence suggests an increased risk of breast cancer in women receiving combination therapy with estrogens and progestogens and possibly estrogen monotherapy.
— In women receiving combination therapy with estrogens and progestogens for more than 5 years, there was a 2-fold increase in the risk of breast cancer.
— With estrogen monotherapy, any increase in risk is significantly lower than when combined with progestogens.
— The level of risk depends on the duration of HRT.
— It is unknown whether Ovestin® poses the same risk. A recent population-based case-control study of 3345 women with invasive breast cancer and 3454 controls showed that estriol use, unlike other estrogens, was not associated with an increased risk of breast cancer. It is therefore important that the risk of developing breast cancer is discussed with the patient and weighed against the known benefits of HRT.
Ovarian cancer
— Ovarian cancer develops much less frequently than breast cancer. Long-term estrogen monotherapy (at least 5-10 years) was associated with a small increase in the risk of ovarian cancer. Some studies suggest that combined HRT may increase the risk of ovarian cancer in a similar or small way. It is not known whether the risk of long-term use of low-potency estrogens (such as Ovestin®) differs from that of monotherapy with other estrogens.
Venous thromboembolism
— HRT is associated with an increased risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism, 1.3 - 3 times. VTE is more likely to occur during the first year of HRT use than later in life. A similar risk is not known for Ovestin®.
— In patients with confirmed thrombophilia, the risk of VTE is high, and HRT may further increase it. In this regard, HRT is contraindicated for such women (see section “Contraindications”).
— Commonly recognized risk factors for VTE include estrogen use, older age, major surgery, prolonged immobilization, obesity (BMI > 30 kg/m2), pregnancy/puerperium, systemic lupus erythematosus, and cancer. Not regarding the possible role of varicose veins in the development of VTE. After any surgical intervention, VTE prophylaxis is necessary. If prolonged immobilization is associated with elective surgery, it is necessary to temporarily discontinue HRT 4-6 weeks before surgery. Treatment should be resumed after the woman begins to walk.
— If Ovestin® is prescribed as “pre- and postoperative treatment,” the issue of thrombosis prevention should be considered.
— In the absence of a history of VTE, but in the presence of thrombosis at a young age in the patient’s closest relatives, she can be offered a screening examination, having previously discussed all its limitations (screening can only identify a number of thrombophilic disorders). If a thrombophilic defect is detected that does not correspond to the disease in relatives, or if a “severe” defect is detected (for example, deficiency of antithrombin, protein S or protein C, or a combination of these defects), HRT is contraindicated.
— For women already receiving anticoagulant treatment, careful consideration of the benefit-risk ratio of HRT is required.
— If VTE develops after starting treatment with Ovestin®, then treatment with the drug must be stopped. Patients should be informed to seek immediate medical attention if they experience possible signs of thromboembolism (eg, painful leg swelling, sudden chest pain, shortness of breath).
Coronary heart disease (CHD)
— In randomized controlled trials, there were no results that would indicate that combination therapy with estrogens and progestogens and estrogen monotherapy can prevent the development of myocardial infarction in women with and without coronary artery disease.
Estrogen monotherapy:
— According to randomized controlled trials in women with a removed uterus, the risk of coronary heart disease does not increase with estrogen monotherapy.
— The risk of coronary heart disease increases slightly with combined HRT with estrogens and progestogens in patients over 60 years of age.
Ischemic stroke
— Combination therapy with estrogens and progestogens and monotherapy with estrogens are associated with a 1.5-fold increase in the risk of ischemic stroke. The relative risk does not change with age or time after menopause. However, the baseline risk of stroke is highly dependent on age, and the overall risk of stroke with HRT increases with age. The risk of hemorrhagic stroke does not increase with HRT;
Other states
— Estrogens can cause fluid retention, so patients with impaired renal function and cardiovascular insufficiency should be under close medical supervision.
— Estriol is a weak gonadotropin antagonist and does not have other significant effects on the endocrine system.
— Cognitive function does not improve with HRT. Evidence was obtained of an increased risk of developing dementia in women who began using combination therapy or monotherapy in a continuous mode after 65 years of age.
