Composition, form of production and packaging
? The cream is vaginal in the form of a homogeneous mass from white to almost white, with a specific odor.
1 g
estriol 1 mg
Excipients: octyl dodecanol, cetyl palmitate, glycerol, cetyl alcohol, stearyl alcohol, polysorbate, sorbitan stearate, lactic acid, chlorhexidine dihydrochloride, sodium hydroxide, purified water.
15 g - aluminum tubes (1) complete with applicator - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
PHARMACHOLOGIC EFFECT
An estrogen preparation. Analogue of the natural female hormone. It replenishes the estrogen deficiency in postmenopausal women and weakens postmenopausal symptoms. The most effective in treating genitourinary disorders. With atrophy of the mucous membrane of the lower sections of the urogenital tract, estriol contributes to the normalization of the epithelium of the genito-urinary tract and helps restore normal microflora and physiological pH in the vagina. Increases the resistance of epithelial cells of the genito-urinary tract to infections and inflammation, reducing complaints such as soreness in intercourse, dryness, itching in the vagina, reduces the likelihood of vaginal infections and urinary tract infections, helps normalize urination, 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 dose of a daily dose does not cause endometrial proliferation. Therefore, cyclic progestogen administration is not required and no withdrawal bleeding occurs. In addition, it was shown that estriol does not increase the mammographic density.
PHARMACOKINETICS
Suction
When the drug is administered orally, as well as topically, estriol is rapidly and almost completely absorbed.
C max estriol in plasma is achieved 1-2 hours after intravaginal application.
Distribution
In plasma, almost all (90%) of estriol is bound to albumin and, in contrast to other estrogens, is virtually unrelated to globulin that binds sex hormones (SHBG).
Excretion
The excretion of estriol (in a bound form) is carried out mainly by the kidneys; about 2% is excreted through the intestine in an unchanged form. Excretion of metabolites with urine begins within a few hours after application of the drug and lasts 18 hours.
INDICATIONS
- hormone replacement therapy (HRT) for the treatment of atrophy of the mucous membrane of the lower sections of the genito-urinary tract associated with estrogen deficiency;
- pre- and post-operative treatment of women in the postmenopausal period with vaginal operations;
- with a diagnostic purpose for unclear results of cervical cervical examination (suspicion of a tumor process) against atrophic changes.
DOSING MODE
The cream should be injected into the vagina with a calibrated applicator at night (before bedtime).
1 application (applicator, filled to the ring mark) contains 500 mg of cream, which corresponds to 500 Ојg of estriol.
In the treatment of atrophy of the mucous membrane of the lower sections of the genito-urinary tract, 1 application / day during the first weeks (maximum 4 weeks), followed by a gradual dose reduction, based on relief of symptoms, until a maintenance dose is reached (i.e., 1 application 2 times a week) .
With pre- and postoperative therapy of women in the postmenopausal period, with surgical interventions with vaginal access - 1 application / day for 2 weeks before the operation; 1 application 2 times a week for 2 weeks after the operation.
With a diagnostic purpose for unclear results of cervical cervical examination - 1 application every other day for a week before taking the next smear.
If a dose is missed, the missed dose should be entered on the same day as the patient recalls this (the dose should not be administered 2 times / day). In the future, the applications are carried out in accordance with the usual dosing scheme.
At the beginning or continuation of the treatment of postmenopausal symptoms, it is necessary to use the lowest effective dose for the shortest period of time.
In women who do not receive HRT, or women who are transferred from a continuous intake of an oral combination drug for HRT, treatment with Ovestin can begin any day. Women who switch from cyclic regimens for HRT should begin treatment with Ovestin В® cream 1 week after the withdrawal of HRT.
Instructions for use for patients
1. The cream is injected into the vagina for the night (before going to bed).
2. Remove the cap from the tube, turn 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 prone position, the end of the applicator is inserted deep into the vagina and slowly pressed against the piston until it stops, injecting the cream.
After the drug is injected from the cylinder, remove the piston and rinse the cylinder and the piston with warm water and soap. Do not use detergents. After that, the cylinder and the piston are abundantly rinsed with clean water.
Do not lower the applicator into hot or boiling water.
SIDE EFFECT
As with any other drug that is applied to the surface of mucous membranes, Ovestin В® cream can sometimes cause local irritation or itching.
Sometimes there may be a sensitivity, tension, tenderness, increase in the size of the mammary glands. These undesirable reactions are usually short and transitory, but at the same time may indicate the use of too high a dose.
Acyclic spotting, breakthrough bleeding, and metrorrhagia are also noted.
With HRT using estrogen-progestogen-containing drugs, the following side effects were also observed, the relationship of which with the use of Ovestin is not proved:
- benign and malignant estrogen-dependent neoplasias (endometrial and breast cancer);
- Venous thromboembolism (deep vein thrombosis of the legs or pelvis, pulmonary embolism) occurs more often with HRT than with no therapy;
- Myocardial infarction, stroke;
- cholelithiasis;
- cutaneous and subcutaneous diseases (chloasma, erythema multiforme, erythema nodosum, hemorrhagic purpura);
- dementia;
- increased libido.
CONTRAINDICATIONS
- established, history of or suspected breast cancer;
- diagnosed estrogen-dependent tumors or suspected of them (eg, endometrial cancer);
bleeding from the vagina of an unclear etiology;
- untreated endometrial hyperplasia;
- the presence of venous thrombosis at present and in the anamnesis;
active or recently transferred thromboembolic disease of the arteries (eg, angina pectoris, myocardial infarction);
- liver disease in the acute stage or liver disease in history, after which the liver function indicators did not return to normal;
- porphyria;
- established hypersensitivity to the active substance or to any of the excipients of the drug.
With caution
If any of the following conditions are present or if this condition was previously noted and / or worsened during previous pregnancies or previous hormonal treatment, then such a patient should be under the direct supervision of a physician. It should be borne in mind that these conditions can recur or worsen during treatment with Ovestin В® , especially if there are:
- Leiomyoma (uterine fibroids) or endometriosis;
- transferred thromboembolic disorders or existing risk factors for such disorders;
- risk factors for estrogen-dependent tumors, for example, the first degree of heredity for breast cancer;
- arterial hypertension;
- benign liver tumors (eg, liver adenoma);
- diabetes mellitus with the presence or absence of a vascular component;
- cholelithiasis;
- jaundice (including anamnesis during previous pregnancy);
- liver failure;
- Migraine or severe headache;
- systemic lupus erythematosus;
- Endometrial hyperplasia in the anamnesis;
- epilepsy;
- asthma;
otosclerosis;
- familial hyperlipoproteinemia;
- pancreatitis.
PREGNANCY AND LACTATION
Ovestin В® is contraindicated in pregnancy. In case of pregnancy during therapy with Ovestin В® , treatment should be immediately canceled.
The results of most epidemiological studies conducted so far on the unintended impact of estrogen on the fetus indicate the absence of teratogenic or fetotoxic effects.
Ovestin В® is not recommended for use during breastfeeding. Estriol is excreted in breast milk and can reduce the formation of milk.
APPLICATION FOR FUNCTIONS OF THE LIVER
Estrogens can cause fluid retention, and therefore patients with impaired renal function should be under close medical supervision. In the terminal stage of chronic renal failure, there should be a special control in connection with the possible increase in the level of circulating active components of Ovestin.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
The drug is contraindicated in case of liver disease in the acute stage or liver disease in an anamnesis, after which the liver function indices did not return to normal.
With hepatic insufficiency, use the drug with caution.
SPECIAL INSTRUCTIONS
For the treatment of postmenopausal symptoms, HRT should only be started with symptoms that adversely affect the quality of life. In all cases, it is necessary to carry out a thorough assessment of the risk and benefits of treatment at least once a year. HRT should only be continued for a period of time when the benefit exceeds the risk.
Medical Examination / Surveillance
Before starting or resuming HRT, it is necessary to establish a detailed individual and family history. Based on anamnesis, contraindications and warnings on the use of the drug, 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 are individual, but not less than once a year. Women should be informed of the need to inform the doctor about changes in the mammary glands. Studies, including mammography, should be conducted in accordance with generally accepted survey standards.
Therapy should be discontinued if there is a contraindication and / or when the following conditions occur:
- jaundice and / or worsening of liver function;
- a significant increase in blood pressure;
- resumption of a migraine headache;
- Pregnancy.
Endometrial hyperplasia
To prevent stimulation of the endometrium, the daily dose should not exceed 1 application (500 Ојg estriol). Do not use this maximum dose for more than 4 weeks.
Breast Cancer
Based on the results of a randomized, placebo-controlled study under the Women's Health Initiative (WHI) and epidemiological studies including the Million-Female Study (MWS), an increased risk of breast cancer was reported in women taking estrogens, estrogen-progestogen-containing combinations or tibolone for HRT for several years. For all HRT, the increased risk becomes noticeable after several years of use and increases with the duration of admission, but returns to baseline after a few (maximum 5) years after discontinuation of treatment.
In the MWS study, the relative risk of breast cancer when using conjugated equine estrogens (CEE) or estradiol (E2) was higher when progestogen was added, both in cyclic and continuous administration, regardless of the type of progestogen. There is no confirmation of a change in the degree of risk with different modes of administration.
In the WHI study, the use of a combined preparation of conjugated equine estrogen and medroxyprogesterone acetate (CEE + MPA) was associated with the onset of breast cancer, which was somewhat larger in size and more often metastasized in the local lymph nodes compared with placebo.
With regard to Ovestin, such a risk is not known. In a recent population-based case-control study involving 3,345 women with invasive breast cancer and 3,454 women in the control group, it was shown that estriol, unlike other estrogens, was not associated with an increased risk of developing breast cancer. In this regard, it is important that the patient is aware of the risk of developing breast cancer in relation to the known benefit of HRT.
Venous thromboembolism
HRT is associated with a higher relative risk of venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. In one randomized controlled trial and in epidemiological studies it was found that the risk for women receiving HRT is 2-3 times higher than for patients who did not receive such treatment. It has been established that for women not using HRT, the number of cases of VTE that can occur during a 5-year period is about 3 cases per 1,000 women aged 50-59 years and 8 cases per 1000 women aged 60-69 years. In healthy women using HRT for 5 years, the number of additional cases of VTE within 5 years should be 2-6 cases (on average 4) for every 1000 women aged 50-59 years and 5-15 cases (on average 9) for every 1000 women aged 60-69 years. VTE is most likely during the first year of HRT than at a later date. With regard to Ovestin, such a risk is unknown.
Usually recognized risk factors for VTE are the appropriate individual or family history, high-grade obesity (BMI> 30 kg / m 2 ) and SLE. There is no consensus on the role of varicose veins in the development of VTE.
Patients with a VTE in the anamnesis or with established thromboembolic conditions have an increased risk of VTE. HRT may increase this risk. In order to exclude a predisposition to the formation of blood clots, it is necessary to carefully collect individual and family history of thromboembolism or repeated spontaneous miscarriage. Until a thorough evaluation of thromboembolic factors is made, anticoagulant treatment or HRT should not be started. For women who are already receiving anticoagulant treatment, careful consideration of the HRT benefit / risk ratio is required.
The risk of VTE may increase with prolonged immobilization of the patient, extensive trauma, a large amount of surgical intervention. After a surgical operation, special attention should be given to preventive measures to prevent VTE. In cases where prolonged immobilization is unavoidable after an optional operation, especially after abdominal surgery or orthopedic surgery on the lower extremities, it is possible, if possible, to temporarily discontinue HRT 4 to 6 weeks before surgery. If the drug Ovestin В® is used according to the indication "pre- and post-operative treatment of women in the postmenopausal period with vaginal access operations," it is necessary to provide preventive treatment to prevent thrombosis.
If after the start of treatment with Ovestin В® , VTE develops, then the drug should be discontinued. Patients should be informed of the need for immediate medical attention if they feel a symptom of potential thromboembolism (eg, painful swelling of the foot, sudden chest pain, shortness of breath).
Ovarian Cancer
Long-term (no less than 5-10 years) monotherapy with estrogen (as HRT) in women who underwent uterine surgery is associated with an increased risk of ovarian cancer, which has been established in several epidemiological studies. It has not been proven that prolonged combined HRT or monotherapy with low-level estrogen (eg, Ovestin В® ) has another risk.
Other states
Estrogens can cause fluid retention, and therefore patients with impaired renal function and cardiovascular failure should be under close medical supervision. In the terminal stage of chronic renal failure, there should be a special control in connection with the possible increase in the level of circulating active components of Ovestin.
Estriol is a weak inhibitor of gonadotropin and has no other significant effects on the endocrine system.
There is no convincing confirmation of the improvement in cognitive function. The WHI trial received evidence of an increased risk of possible dementia in women who began to use continuously a combination of conjugated estrogens and MRA in a continuous regime after 65 years. It is not known whether these results apply to younger women in postmenopausal women using other drugs for HRT.
In the presence of vaginal infections, concomitant specific treatment is recommended.
OVERDOSE
Acute toxicity of estriol in animals is very low. Overdosage with Ovestin В® for vaginal administration is unlikely. However, in case of contact with large amounts of the drug in the gastrointestinal tract may develop nausea, vomiting, and cessation of bleeding in women.
Treatment: No specific antidote. If necessary, symptomatic treatment.
DRUG INTERACTION
In clinical practice were observed interaction between the drug Ovestin В® and other drugs.
Estrogen metabolism may be enhanced when used in combination with compounds that induce the enzymes involved in the metabolism of drugs, in particular isozymes of cytochrome P450, for example, such as anticonvulsants (e.g., phenobarbital, phenytoin, carbamazepine) and antimicrobial agents (e.g. rifampicin, rifabutin, nevirapine, efavirenz).
Ritonavir and nelfinavir exhibit inducing properties when used in combination with steroid hormones.
Herbal preparations containing St. John's wort (Hypericum perforatum), may induce estrogen metabolism.
Increased estrogen metabolism may lead to a decrease in their clinical effect.
Estriol enhances the effect of lipid-lowering drugs.
It reduces the effects of male sex hormones, anticoagulants, antidepressants, diuretics, antihypertensive, hypoglycemic drugs.
Medicines for general anesthesia, opioid analgesics, anxiolytics, some antihypertensive drugs, ethanol reduces the effectiveness of the drug.
Folic acid, and thyroid medication enhances the action of estriol.
TERMS OF RELEASE FROM PHARMACY
The drug is approved for use as a means of OTC.
TERMS AND CONDITIONS OF STORAGE
The preparation should be stored in a dry place, protected from light and the reach of children at a temperature of from 2 В° to 30 В° C; Do not freeze. Shelf life - 3 years.
