Ovestin (Estriol), vaginal suppositories

Active substance:

Estriol 0.5 mg

Excipients:

Vitepsol S58 2.4995 g

Ovestin contains estriol, an analogue of the natural female hormone. It makes up for estrogen deficiency in postmenopausal women and alleviates postmenopausal symptoms. Estriol is most effective in the treatment of urogenital disorders. In case of atrophy of the mucous membrane of the lower urinary tract, estriol helps normalize the epithelium of the genitourinary tract and helps restore normal microflora and physiological pH in the vagina.

As a result, it increases the resistance of the urinary tract epithelial cells to infection and inflammation, reducing complaints such as pain during intercourse, dryness and itching in the vagina, reduces the likelihood of vaginal infections and urinary tract infections, helps to normalize urination and prevents urinary incontinence.

Unlike other estrogens, estriol has a short period of action, since it is retained in the nuclei of endometrial cells for a short period of time. It is assumed that a single administration of a daily dose does not cause endometrial proliferation. Therefore, cyclic administration of progestogen is not required and withdrawal bleeding does not occur. In addition, it has been shown that estriol does not increase mammographic density.

Pharmacokinetics

Intravaginal administration of estriol ensures optimal bioavailability at the site of action. Estriol is also absorbed and enters the general bloodstream, which is manifested by a rapid increase in the concentration of unbound estriol in plasma. The maximum plasma concentration is observed 1-2 hours after administration.

In plasma, almost all (90%) of estriol is bound to albumin and, unlike other estrogens, it is practically not bound to sex hormone-binding globulin. Estriol metabolism consists mainly in the transition to a conjugated and unconjugated state in the intestinal-hepatic circulation. Estriol, being the end product of metabolism, is mainly excreted in the urine in a bound form. Only a small fraction (± 2%) is excreted in the feces, mainly in the form of unbound estriol. The half-life is approximately 6–9 hours.

After vaginal administration of 0.5 mg of estriol, the maximum concentration of Cmax is approximately 100 pg / ml, the minimum concentration of Cmin is approximately 25 pg / ml, and the average concentration of Cmp is approximately 70 pg / ml. After 3 weeks of daily administration of 0.5 mg of vaginal estriol, the Cav value decreased to 40 pg / ml.

• Hormone replacement therapy (HRT) for the treatment of atrophy of the lower urinary tract mucosa associated with estrogen deficiency in postmenopausal women.
• Pre- and postoperative therapy of women in the postmenopausal period with surgical interventions with vaginal access.
• As an auxiliary diagnostic tool for obtaining an atrophic picture of a cervical smear.

Ovestin is contraindicated in pregnancy and lactation (breastfeeding).

• An identified, past, or suspected breast cancer.
• Diagnosed or suspected estrogen-dependent tumors (e.g., endometrial cancer).
• Vaginal bleeding of unknown etiology.
• Untreated endometrial hyperplasia.
• The presence of venous thrombosis at present and in the anamnesis (deep vein thrombosis, pulmonary thromboembolism).
• Confirmed thrombophilia (e.g., protein C, protein S, or antithrombin deficiency).
• Thrombosis (venous and arterial) and thromboembolism currently or in history (including deep vein thrombosis, pulmonary thromboembolism, myocardial infarction, stroke), cerebrovascular disorders; conditions preceding thrombosis (including transient ischemic attacks, angina pectoris) at present or in history.
• An acute liver disease or a history of liver disease, after which liver function indicators have not returned to normal.
• The established hypersensitivity to the active substance or to any of the excipients of the drug.
• Porphyria.

Carefully

• Leiomyoma (uterine fibroids) or endometriosis.
• Risk factors for thromboembolism.
• Risk factors for estrogen-dependent tumors, for example, the 1st degree of heredity for breast cancer.
• Arterial hypertension.
• Benign liver tumors (e.g., liver adenoma).
• Diabetes mellitus with or without diabetic angiopathy.
• Cholelithiasis.
• Jaundice (including a history of previous pregnancy).
• Liver failure.
• Migraine or (severe) headache.
• Systemic lupus erythematosus.
• History of endometrial hyperplasia.
• Epilepsy.
• Bronchial asthma.
• Otosclerosis.
• Familial hyperlipoproteinemia.
• Pancreatitis

As with any other drug that is applied to the surface of the mucous membranes, Ovestin® suppositories can sometimes cause local irritation or itching. Sometimes sensitivity, tension, pain, an increase in the size of the mammary glands can be noted. These adverse reactions are usually short-lived and transient, but at the same time may indicate the use of too high a dose.

Also found: acyclic spotting, bleeding "breakthrough", metrorrhagia.

Other adverse reactions that have occurred with estrogen monotherapy or combination therapy with estrogens and progestogens have been reported.

Violations of the liver and biliary tract:

- Cholelithiasis.

Benign, malignant and unspecified neoplasms (including cysts and polyps):

- Benign and malignant estrogen-dependent neoplasia, incl. endometrial cancer.

Mental disorders:

- Dementia at the beginning of HRT in a continuous mode after 65 years (see the section "Special Instructions").

Violations of the genitals and mammary gland:

- Increased libido.

Disorders from the skin and subcutaneous tissues:

- Chloasma, erythema multiforme, erythema nodosum, hemorrhagic purpura.

There is data on the development of the risk of breast cancer, ovarian cancer, the risk of venous thromboembolism, the risk of coronary heart disease, the risk of ischemic stroke (for more information, see the “Special Instructions” section).

Ovestin suppositories should be administered into the vagina at night before bedtime.

• In the treatment of atrophy of the mucous membrane of the lower urinary tract:

1 suppository per day during the first weeks, followed by a gradual dose reduction, based on symptom relief, until a maintenance dose is reached (i.e. 1 suppository twice a week).

• Pre- and postoperative therapy of women in the postmenopausal period during surgical interventions with vaginal access:

1 suppository per day for 2 weeks before surgery; 1 suppository twice a week for 2 weeks after surgery.

• For diagnostic purposes with unclear results of cytological examination of the cervix:

1 suppository every other day for a week before taking the next smear.

The missed dose must be entered on the same day, as soon as the patient remembers this (the dose should not be administered twice a day). Further applications are carried out in accordance with the usual dosing schedule.

When starting or continuing treatment of postmenopausal symptoms, the lowest effective dose should be used for the shortest time possible.

In women who do not receive HRT, or women who are transferred from continuous oral administration of the combined preparation for HRT, treatment with Ovestin® can be started any day. Women who switch to a cyclic regimen of HRT drugs should begin treatment with Ovestin® one week after withdrawal of HRT drugs.

Pills

The drug is administered orally.

If the delay was more than 12 hours, you should skip one dose and continue to take the drug at the usual time.
The tablets are taken with water, preferably at the same time every day. The daily dose should be taken in one dose (see section "Special instructions"). In women who have not previously received HRT or have taken HRT in a continuous combined regimen, treatment with Ovestin® can be started at any time. In women taking HRT in an intermittent regimen, Ovestin® should be prescribed one week after the completion of the cycle.

Ovestin® Cream should be injected into the vagina using a calibrated applicator before bedtime. 

1 application (applicator filled to the annular mark) contains 0.5 g of cream, which corresponds to 0.5 mg of estriol. 

• In the treatment of atrophy of the mucous membrane of the lower urinary tract: 

• 1 application per day during the first weeks (maximum 4 weeks), followed by a gradual dose reduction, based on the dynamics of the symptoms, until a maintenance dose is reached (ie 1 administration twice week). 
• Pre- and postoperative therapy of women in the postmenopausal period with surgical interventions by vaginal access: 
• 1 application per day for 2 weeks before surgery; 1 application twice a week for 2 weeks after surgery. 
• For diagnostic purposes, with unclear results of a cytological examination of the cervix: 1 application every other day for a week before taking the next smear. 

Instructions for use for patients 

1. The cream is injected into the vagina at night before bedtime. 
2. Remove the cap from the tube, flip the cap over and use a sharp 
rod to open the tube. 
3. Screw the applicator onto the tube.  
4. Squeeze the tube to fill the applicator with cream until the piston stops. 
5. Unscrew the applicator from the tube and close the tube with a cap. 
6. In the “lying” position, the cream is introduced, the end of the applicator is inserted deep into the vagina and slowly press on the piston until it stops. 
 
After administration of the drug, the piston is removed from the cylinder and the cylinder and piston are washed with warm water and soap. Do not use detergents. After that, the cylinder and piston are rinsed liberally with clean water. 

DO NOT DROP THE APPLICATOR IN HOT OR BOILING WATER. 

The missed dose must be entered on the same day as soon as the patient remembers this (the dose should not be administered twice a day). Further applications are carried out in accordance with the usual dosing schedule. When starting or continuing treatment of menopausal symptoms, the lowest effective dose should be used for the shortest period of time. 

In women who do not receive HRT, or women who are transferred from continuous oral administration of the combined preparation for HRT, treatment with Ovestin® cream can be started any day. Women who switch to a 
cyclical regimen of HRT preparations should begin treatment with Ovestin® cream one week after withdrawal of HRT preparations. 

• For the treatment of menopausal symptoms of HRT, it is necessary to start only in relation to symptoms that adversely affect the quality of life. In all cases, it is necessary to conduct a thorough assessment of the risk and benefits of treatment at least once a year, and HRT should only be continued for as long as the benefit exceeds the risk.
• There is limited evidence of a risk of HRT in the treatment of premature menopause. Due to the low absolute risk in younger women, the benefit-risk ratio is more favorable for them than for older women.

Medical Examination / Surveillance

• Before starting or resuming HRT, a detailed individual and family history should be collected. Based on the received 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, periodic medical examinations are recommended, the frequency and nature of which are individual. Women should be informed about the need to inform the doctor about changes in the mammary glands (see below the subsection "Breast Cancer"). Studies, including appropriate imaging methods, such as mammography, must be carried out in accordance with the currently accepted examination standards and depending on each specific case.

Reasons for immediate discontinuation of therapy

Therapy should be discontinued if a contraindication is detected and if the following conditions occur:

- Jaundice or impaired liver function.

- A significant increase in blood pressure.

- The occurrence of a headache like migraine.

- Pregnancy.

Endometrial hyperplasia and carcinoma

• To prevent endometrial stimulation, the daily dose of the drug should not exceed 1 suppository (0.5 mg of estriol). Do not use this maximum dose for more than 4 weeks. In addition, one epidemiological study found that long-term administration of low-dose estriol when administered orally but not intravaginally may increase the risk of endometrial cancer. The risk increases with increasing duration of treatment and returns to baseline values ������one year after discontinuation of the drug. Basically, the risk of minimally invasive and highly differentiated tumors increases. Vaginal bleeding in all cases requires examination. The patient should be informed about the need to contact your doctor if vaginal bleeding begins.

Mammary cancer

• Hormone replacement therapy (HRT) can increase mammographic density. This can complicate the radiological detection of breast cancer. Clinical studies have shown that the probability of an increase in mammographic density is lower in women receiving estriol treatment than in women receiving other estrogen treatment.
• Generalized evidence suggests an increased risk of breast cancer in women receiving combination therapy with estrogens and progestogens and, possibly, monotherapy with estrogens.
• Women receiving combination therapy with estrogens and progestogens for more than 5 years have a 2-fold increase in the risk of breast cancer.
• With estrogen monotherapy, the increased risk is significantly lower than with their combination with progestogens.
• The level of risk depends on the duration of HRT.
• It is not known whether Ovestin® presents the same risk. A recent case-control population study involving 3345 women with invasive breast cancer and 3454 women in the control group showed that the use of estriol, unlike other estrogens, was not associated with an increased risk of developing breast cancer. Therefore, it is important that the risk of developing breast cancer be discussed with the patient and correlated with 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 slight increase in the risk of ovarian cancer. The results of some studies suggest that combined HRT may increase the risk of ovarian cancer in a similar or insignificant manner. It is not known whether the risk of prolonged intake of low-level estrogens (such as Ovestin®) differs from that of monotherapy with other estrogens.

Venous thromboembolism

• HRT is associated with an increased risk of venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism, 1.3 to 3 times. The likelihood of developing VTE is higher during the first year of HRT use than at a later date. It is not known whether Ovestin® has the same risk.
• In patients with confirmed thrombophilia, the risk of VTE is high, and HRT can further increase it. In this regard, HRT is contraindicated for such women.
• Commonly recognized risk factors for VTE are estrogen intake, old age, extensive surgery, prolonged immobilization, obesity (BMI> 30 kg / m2), pregnancy / postpartum period, systemic lupus erythematosus, and cancer. There is no consensus on 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 a planned operation, it is necessary to temporarily cancel HRT 4-6 weeks before the operation. Treatment should be resumed after the woman begins to walk.
• For women who are already receiving anticoagulant treatment, careful consideration of the benefit-risk ratio of HRT is required.
• If Ovestin® is prescribed as a “pre- and postoperative treatment ...”, the prevention of thrombosis should be considered.
• In the absence of VTE in the anamnesis, but in the presence of thrombosis at a young age, the patient’s closest relatives can be offered to conduct a screening examination, after discussing all its limitations (screening allows you to identify only a number of thrombophilic disorders). When detecting a thrombophilic defect that does not correspond to the disease in relatives, or if a “severe” defect (for example, deficiency of antithrombin, protein S or protein C, or a combination of these defects) is detected, HRT is contraindicated.
• If VTE develops after the start of treatment with Ovestin®, then drug treatment must be discontinued. Patients should be informed of the need to immediately consult a doctor if they feel possible signs of thromboembolism (for example, painful swelling of the legs, sudden chest pain, shortness of breath).

Coronary heart disease (CHD)

• In randomized controlled trials, no results were obtained that would indicate that combination therapy with estrogens and progestogens and monotherapy with estrogens can prevent the development of myocardial infarction in women with and without coronary heart 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

• Combined therapy with estrogens and progestogens and monotherapy with estrogens are associated with an increase in the risk of ischemic stroke by 1.5 times. The relative risk does not change with age and with time after the onset of menopause. However, the initial risk of stroke is highly dependent on age, and the overall risk of stroke with HRT increases with age. The risk of hemorrhagic stroke in HRT does not increase.

Other conditions

• Estrogens can cause fluid retention, and therefore patients with impaired renal function and cardiovascular failure should be closely monitored.
• Estriol is a weak gonadotropin antagonist and has no other significant effects on the endocrine system.
• Cognitive function on the background of HRT does not improve. There is evidence of an increased risk of dementia in women who have started to use combination therapy or monotherapy in a continuous mode after 65 years.

Influence on the ability to drive a car and other mechanisms.

The effect of the drug Ovestin® on concentration and attention was not noted.

Vaginal suppositories 0.5 mg. 5 suppositories in double-sided blister strip packaging made of PVC / PE. 3 contour packaging along with instructions for use are placed in a cardboard box. 

At a temperature of 2-25 ° C in a dry, dark place.

Keep out of the reach of children.