Ovanelia (Suppositories) Instructions for Use

Marketing Authorization Holder

Otisipharm, JSC (Russia)

Manufactured By

Altpharm LLC (Russia)

ATC Code

G03CA04 (Estriol)

Active Substance

Estriol (Ph.Eur. European Pharmacopoeia)

Dosage Form

Ovanelia

Vaginal suppositories 0.5 mg: 10, 15 or 20 pcs.

Dosage Form, Packaging, and Composition

Vaginal suppositories from white to yellowish-white, torpedo-shaped, without visible inclusions and inhomogeneities; a longitudinal section may have an air core and/or a funnel-shaped depression.

Excipients: Witepsol S58 – 2499.5 mg.

5 pcs. – contour cell packs (2) – cardboard packs.
5 pcs. – contour cell packs (3) – cardboard packs.
5 pcs. – contour cell packs (4) – cardboard packs.

Clinical-Pharmacological Group

Estrogenic drug

Pharmacotherapeutic Group

Estrogen

Pharmacological Action

Estriol is an analogue of the natural female hormone. It compensates for estrogen deficiency in postmenopausal women and alleviates postmenopausal symptoms. Estriol is most effective in treating urogenital disorders. In case of atrophy of the mucosa of the lower urogenital tract, Estriol helps normalize the epithelium of the urogenital tract and promotes the restoration of normal microflora and physiological pH in the vagina. As a result, it increases the resistance of epithelial cells of the urogenital tract to infection and inflammation, reducing complaints such as pain during intercourse, dryness, itching in the vagina, reduces the likelihood of vaginal infections and urinary tract infections, helps normalize urination and prevents urinary incontinence.

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

Pharmacokinetics

Intravaginal administration of estriol provides optimal bioavailability at the site of action. Estriol is also absorbed and enters the systemic circulation, which is manifested by a rapid increase in the concentration of unbound estriol in plasma. C_max in plasma is observed 1-2 hours after administration. After vaginal application of 0.5 mg of estriol, the maximum concentration C_max is approximately 100 pg/ml, the minimum concentration C_min is about 25 pg/ml, and the average concentration C_avg is about 70 pg/ml. After 3 weeks of daily application of 0.5 mg of vaginal estriol, the C_avg value decreased to 40 pg/ml. In plasma, almost all (90%) Estriol is bound to albumin and, unlike other estrogens, is practically not bound to sex hormone-binding globulin. The metabolism of estriol consists mainly of conversion to conjugated and unconjugated states during enterohepatic circulation. Estriol, being the end product of metabolism, is mainly excreted in the urine in bound form. Only a small part (± 2%) is excreted in the feces, mainly in the form of unbound estriol. T_1/2 is approximately 6-9 hours.

Indications

As HRT (according to the dosage form used): for the treatment of atrophy of the mucosa of the lower urinary and genital tracts due to estrogen deficiency in postmenopausal women; pre- and postoperative treatment of postmenopausal women during vaginal surgery; as an auxiliary diagnostic aid when an atrophic picture of a cervical smear is obtained.

ICD codes

Dosage Regimen

Administer intravaginally.

Insert one 0.5 mg suppository daily.

For initial treatment of atrophic vaginitis, use one suppository daily for two to three weeks.

Following initial therapy, transition to a maintenance dose of one suppository twice weekly.

For pre- and postoperative care in postmenopausal women, administer one suppository daily for two weeks prior to surgery.

Resume treatment two weeks after the surgical procedure.

As a diagnostic aid for an atrophic cervical smear, use one suppository daily for seven days prior to repeat testing.

Apply the suppository at bedtime for optimal retention and local effect.

Wash hands before and after administration.

Remove the suppository from its foil packaging immediately before use.

Assume a comfortable lying position for insertion.

Insert the suppository deeply into the vagina.

Discontinue use and consult a physician if vaginal bleeding of unknown origin occurs.

Regularly reassess the continued need for therapy.

Adverse Reactions

Possible local irritation or itching.

Sometimes sensitivity, tension, soreness, and enlargement of the mammary glands may 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.

Acyclic bloody discharge, breakthrough bleeding, and metrorrhagia have also been reported.

Contraindications

Hypersensitivity to estriol, breast cancer (established, history of, or suspected), diagnosed estrogen-dependent tumors or suspicion of them (e.g., endometrial cancer), vaginal bleeding of unknown etiology, untreated endometrial hyperplasia, presence of venous thrombosis currently and in history (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 embolism, myocardial infarction, stroke), cerebrovascular disorders; conditions preceding thrombosis (including transient ischemic attacks, angina) currently or in history, acute liver disease or a history of liver disease after which liver function tests have not returned to normal; porphyria.

With caution

Use with caution (under careful medical supervision) if any of the following diseases or conditions are present, or these diseases or conditions were noted previously and/or worsened during previous pregnancies or previous hormonal treatment (as they may recur or worsen during treatment with estriol): leiomyoma (uterine fibroids) or endometriosis; risk factors for thromboembolism; risk factors for estrogen-dependent tumors, e.g., 1st degree heredity for breast cancer; arterial hypertension; benign liver tumors (e.g., liver adenoma); diabetes mellitus with or without diabetic angiopathy; cholelithiasis; jaundice (including history during previous pregnancy); hepatic insufficiency; migraine or (severe) headache; systemic lupus erythematosus; history of endometrial hyperplasia; epilepsy; bronchial asthma; otosclerosis; familial hyperlipoproteinemia; pancreatitis.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Estriol is contraindicated in acute liver disease or a history of liver disease after which liver function tests have not returned to normal.

In hepatic insufficiency, Estriol should be used with caution.

Use in Renal Impairment

Estrogens can cause fluid retention, so patients with impaired renal function should be under careful control.

Pediatric Use

Not intended for use in children and adolescents under 18 years of age.

Geriatric Use

There is evidence of an increased risk of possible dementia (senile dementia) in women who started combined HRT or estrogen monotherapy in a continuous regimen after 65 years of age.

Special Precautions

Therapy should be discontinued if contraindications are identified or if the following conditions occur: jaundice or worsening liver function; significant increase in blood pressure; onset of migraine-type headache; pregnancy.

Aggregated evidence indicates an increased risk of breast cancer in women receiving combined estrogen-progestogen therapy and possibly estrogen monotherapy.

With estrogen monotherapy, any increase in risk is substantially lower than when combined with progestogens.

The level of risk depends on the duration of HRT.

It is important that the risk of developing breast cancer is discussed with the patient and weighed against the known benefits of HRT.

Women should be informed of the need to report any breast changes to their doctor.

In patients with confirmed thrombophilia, the risk of VTE is high, and HRT may further increase it. Therefore, HRT is contraindicated in such women.

Generally recognized risk factors for VTE include estrogen use, advanced age, major surgery, prolonged immobilization, obesity (BMI >30 kg/m²), pregnancy/postpartum period, systemic lupus erythematosus, and cancer. There is no consensus regarding the possible role of varicose veins in the development of VTE. VTE prophylaxis should be carried out after any surgical intervention. If prolonged immobilization is associated with elective surgery, HRT should be temporarily discontinued 4-6 weeks before surgery. Treatment should be resumed after the woman starts walking.

If Estriol is used as pre- and postoperative treatment, thrombosis prophylaxis should be considered.

In the absence of a history of VTE, but if there is a history of thrombosis at a young age in the patient’s first-degree relatives, she may be offered screening, after discussing all its limitations (screening can only detect a number of thrombophilic disorders). If a thrombophilic defect is detected that does not match the disease in relatives, or if a serious defect is found (e.g., antithrombin, protein S or protein C deficiency, or a combination of these defects), HRT is contraindicated.

For women who are already receiving anticoagulant treatment, a careful consideration of the benefit-risk ratio of HRT is required.

If VTE develops after starting treatment with estriol, treatment must be discontinued. Patients should be informed of the need to immediately consult a doctor if they feel possible signs of thromboembolism (e.g., painful leg swelling, sudden chest pain, shortness of breath).

Combined estrogen-progestogen therapy and estrogen monotherapy are associated with a 1.5-fold increase in the risk of ischemic stroke. The relative risk does not change with age and time since menopause. However, the baseline risk of stroke is highly age-dependent, and the overall risk of stroke during HRT increases with age.

There is evidence of an increased risk of possible dementia (senile dementia) in women who started combined HRT or estrogen monotherapy in a continuous regimen after 65 years of age.

Drug Interactions

The metabolism of estrogens may be enhanced when used in combination with compounds that induce drug-metabolizing enzymes, especially cytochrome P450 isoenzymes, 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 the metabolism of estrogens.

Increased metabolism of estrogens may lead to a decrease in their clinical effect.

Estriol enhances the effect of lipid-lowering drugs; weakens the effects of male sex hormones, anticoagulants, antidepressants, diuretic, antihypertensive, hypoglycemic drugs.

Drugs for general anesthesia, narcotic analgesics, anxiolytics, some antihypertensive drugs, and ethanol reduce the effectiveness of estradiol.

Folic acid and thyroid preparations enhance the effects of estriol.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.