Ovestin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT OVESTINâ (OVESTINâ)

Composition:

Active ingredient: estriol;

1 vaginal suppository contains 0.5 mg of estriol;

Excipient: solid fat with additives (hard fat, macrogol cetyl stearyl ether, and glyceryl ricinoleate).

Pharmaceutical form. Vaginal suppositories.

Main physico-chemical characteristics: white torpedo-shaped suppositories; external surface and cross-section surface along the longitudinal axis are smooth.

Pharmacotherapeutic group. Natural and semi-synthetic estrogens.

ATC code G03C A04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

The medicinal product Ovestinâ contains the natural female hormone estriol. Unlike other estrogens, estriol is short-acting. It compensates for the reduced production of endogenous estrogens. In cases of atrophic vaginitis, locally administered estriol normalizes the urogenital epithelium and promotes restoration of normal vaginal microflora and physiological pH levels.

Treatment of vaginal symptoms of estrogen deficiency: vaginally administered estrogen alleviates symptoms of atrophic vaginitis caused by estrogen deficiency in postmenopausal women.

Clinical trial data

• Improvement in vaginal symptoms was observed within the first weeks of treatment.
• Vaginal bleeding following treatment with Ovestinâ occurred only rarely. If vaginal bleeding occurs during administration of Ovestinâ suppositories, patients should consult their physician. The cause of any vaginal bleeding occurring during treatment with medicinal products must always be investigated (see section "Special precautions for use").

Pharmacokinetics.

Absorption

Intravaginal administration of estriol ensures optimal bioavailability at the site of action. Estriol is also absorbed into the systemic circulation, as evidenced by a rapid increase in plasma concentration of unconjugated estriol.

Distribution

Maximum plasma concentration (Cmax) is reached within 1–2 hours after administration. After vaginal administration of 0.5 mg estriol, Cmax was approximately 100 pg/mL, minimum concentration (Cmin) was approximately 25 pg/mL, and average concentration (Caverage) was approximately 70 pg/mL. After 3 weeks of daily vaginal administration of 0.5 mg estriol, Caverage decreased to 40 pg/mL.

In a clinical study, the mean plasma level measured 12 hours after application of estriol cream during 12 weeks of treatment was 8.5 pg/mL (interquartile range 3.3–24.3). After administration three times per week for 21 months, the mean serum estriol level in patients with chronic disease was 5.5 pg/mL (interquartile range 1.9–10.2).

Biotransformation

Approximately 90% of estriol in plasma is bound to albumin and, unlike other estrogens, is almost not bound to sex hormone-binding globulin. Metabolic breakdown of estriol occurs primarily through conjugation and deconjugation during enterohepatic circulation.

Elimination

Since estriol is an end metabolite, it is primarily excreted in conjugated form in urine. Only a small fraction (approximately 2%) is excreted in feces, mainly as unconjugated estriol. The elimination half-life after vaginal administration is approximately 6–9 hours.

Clinical characteristics.

Indications.

• Treatment of symptoms of vaginal atrophy due to estrogen deficiency in postmenopausal women.
• Pre- and postoperative treatment of postmenopausal women undergoing vaginal surgery.
• As an adjunct in the diagnosis of equivocal cervical smear findings (class IIIa according to the Papanicolaou test) in postmenopausal women when pathological cells indicating epithelial atrophy are detected.

Contraindications.

• Known, current, past history of, 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 thrombophilic disorders (e.g., protein C, protein S or antithrombin deficiency; see section "Special precautions").
• Active or recent arterial thromboembolic disease (e.g., angina pectoris, myocardial infarction).
• Active liver disease or history of liver disease after which liver function tests have not returned to normal.
• Hypersensitivity to the active substance or to any of the excipients.
• Porphyria.

Interaction with other medicinal products and other forms of interaction.

Due to vaginal administration and minimal systemic absorption, clinically significant interactions with Ovestinâ are unlikely. However, interactions with other local vaginal products should be considered.

Metabolism of estrogens (and progestogens) may be increased when used concomitantly with medicinal products capable of inducing enzymes involved in drug metabolism, particularly cytochrome P450 enzymes, such as anticonvulsants (e.g., phenobarbital, phenytoin, carbamazepine), antibacterial/antiviral agents (e.g., rifampicin, rifabutin, nevirapine, efavirenz), and herbal preparations containing St. John's wort (Hypericum perforatum).

Ritonavir and nelfinavir are known potent inhibitors, but they may exhibit enzyme-inducing properties when used concomitantly with steroid hormones.

Clinically significant increase in estrogen and progestogen metabolism may lead to reduced efficacy of Ovestinâ and changes in bleeding pattern.

Special precautions for use.

Hormone replacement therapy (HRT) for the treatment of estrogen deficiency symptoms in postmenopausal women should only be initiated when symptoms negatively affect quality of life. A careful assessment of risks and benefits should be performed at least annually, and HRT should be continued only as long as the benefits outweigh the risks.

Limited data are available regarding risks associated with HRT in the treatment of premature menopause. However, due to the lower absolute risk in younger women, the benefit-risk ratio is more favorable in this group compared to older women.

Medical examination / follow-up monitoring

Before initiating or re-initiating HRT, a thorough personal and family medical history should be reviewed. A physical examination (including pelvic and breast examination) should take into account the patient’s history and the contraindications and warnings associated with the drug (see sections "Contraindications" and "Special precautions for use"). Periodic medical check-ups should be performed throughout treatment, with frequency and type depending on individual patient characteristics. Women should be informed to report any changes in their breasts to their physician or nurse (see section "Breast cancer" below). Screening examinations, including imaging methods such as mammography, should be performed according to current screening practices, adjusted to meet the individual patient’s needs.

Conditions requiring medical monitoring

If any of the conditions listed below are currently present, have occurred in the past, or worsened during pregnancy or previous hormonal therapy, the patient requires additional monitoring. These conditions may recur or worsen during treatment with Ovestin®. Such conditions include:

• leiomyoma (fibroids) or endometriosis;
• risk factors for thromboembolic disorders (see "Venous thromboembolism");
• risk factors for estrogen-dependent tumors, e.g., first-degree family history of breast cancer;
• elevated blood pressure;
• liver disease (e.g., hepatocellular adenoma);
• diabetes mellitus with or without vascular complications;
• gallstone disease;
• migraine or severe headache;
• systemic lupus erythematosus;
• history of endometrial hyperplasia (see "Endometrial hyperplasia and cancer");
• epilepsy;
• bronchial asthma;
• otosclerosis.

Reasons for immediate discontinuation of treatment

HRT should be immediately discontinued if any contraindication is identified or 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

In women with an intact uterus, long-term systemic estrogen monotherapy increases the risk of endometrial hyperplasia and endometrial carcinoma.

When using Ovestin®, vaginal cream or suppositories, systemic exposure to estriol remains close to the normal postmenopausal range when administered twice weekly; therefore, combination with a progestogen is not recommended.

The safety of long-term (more than one year) or repeated use of locally administered vaginal estrogens with regard to endometrial effects is unknown. Therefore, treatment should be reviewed at least once a year when repeated use is considered.

Estrogen-only HRT may lead to premalignant or malignant transformation of residual endometriosis foci. Therefore, caution should be exercised when using this drug in women who have undergone hysterectomy for endometriosis if residual endometriosis foci are known to remain.

If bleeding or spotting occurs at any time during treatment, the cause should be investigated, which may require endometrial biopsy to exclude endometrial malignancy.

To prevent endometrial stimulation, the daily dose should not exceed 1 suppository (0.5 mg estriol). This maximum dose should not be used for longer than several weeks (maximum 4 weeks). Epidemiological studies have shown that long-term low-dose oral estriol (but not vaginal estriol) may increase the risk of endometrial carcinoma. This risk increases proportionally with duration of treatment and disappears within one year after discontinuation. The increased risk primarily involves less invasive, highly differentiated tumors.

The following risks have been associated with systemic HRT and are less relevant to Ovestin® vaginal cream and suppositories, which, when used twice weekly, result in systemic estriol exposure close to the normal postmenopausal range. However, these risks should be considered in cases of long-term or repeated use of this medicinal product.

Breast cancer

Results from a large meta-analysis of epidemiological studies indicate that low-dose vaginal estrogen use does not increase the risk of breast cancer in women without prior history of the disease. The risk of recurrence in women with a history of breast cancer is unknown.

It is unclear whether estriol carries the same risk. In several population-based case-control studies, estriol use, unlike other estrogens, was not associated with an increased risk of breast cancer. However, the clinical significance of these data is unknown.

Ovarian cancer

Ovarian cancer is much rarer than breast cancer. A large meta-analysis of epidemiological studies suggests a slightly increased risk in women receiving systemic estrogen-only HRT, which becomes evident after five years of use and decreases after treatment cessation.

Vein thromboembolism (VTE)

Systemic hormone replacement therapy increases the risk of VTE (i.e., deep vein thrombosis or pulmonary embolism) by 1.3–3 times. This risk is highest during the first year of HRT and subsequently declines (see section "Adverse reactions").

Patients with known conditions associated with thrombophilic disorders have an increased risk of VTE, and HRT may further increase this risk. Therefore, HRT is contraindicated in such patients (see section "Contraindications"). General risk factors for VTE include: estrogen use, advanced age, major surgery, prolonged immobilization, obesity (body mass index > 30 kg/m²), pregnancy, postpartum period, systemic lupus erythematosus, and cancer. The role of varicose veins in VTE development is not clearly established.

As with all postoperative patients, preventive measures should be taken to avoid VTE after surgery. If prolonged immobilization is unavoidable following elective surgery, HRT should be temporarily discontinued 4–6 weeks before surgery and resumed only after full mobility is restored.

Women without personal history of VTE but with a first-degree relative who experienced thrombosis at a young age should be offered screening after thorough counseling about its limitations (such screening detects only a portion of thrombophilic disorders). If inherited thrombophilic disorders associated with thrombosis in family members or serious disorders (e.g., antithrombin, protein S or protein C deficiency, or combinations thereof) are identified, HRT is contraindicated.

In women already on long-term anticoagulant therapy, the benefit-risk ratio of treatment should be carefully evaluated.

If VTE occurs after starting treatment with Ovestin®, the drug should be discontinued immediately. Patients should be informed to seek immediate medical attention if they experience symptoms suggestive of thromboembolism (e.g., painful leg swelling, sudden chest pain, dyspnea).

Ischemic heart disease (IHD)

Estrogen-only

Randomized controlled trials have not shown an increased risk of IHD in women with hysterectomy who received systemic HRT containing estrogen only.

Ischemic stroke

Systemic estrogen therapy increases the risk of ischemic stroke by 1.5 times. The relative risk does not vary with age or time since menopause. Since the absolute risk of ischemic stroke increases significantly with age, the overall risk in women receiving HRT also increases with age (see section "Adverse reactions").

Concomitant use of hepatitis C treatments

In clinical trials where patients with hepatitis C virus (HCV) infection received treatment with ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, ALT elevations >5 times the upper limit of normal occurred significantly more frequently in women receiving ethinylestradiol-containing products. In women receiving other estrogens (e.g., estradiol, estriol, conjugated estrogens), ALT elevations were similar to those in women not receiving estrogens. However, due to the limited number of women receiving these other estrogens, caution should be exercised when co-administering Ovestin® with this combination therapy.

Other conditions

Estrogens may cause fluid retention; therefore, careful monitoring is required in patients with cardiac or renal dysfunction.

Women with a history of hypertriglyceridemia require special monitoring, as rare cases of marked increases in plasma triglyceride levels leading to pancreatitis have been reported during estrogen therapy in such patients.

Exogenous estrogens may induce or exacerbate symptoms of hereditary or acquired angioedema.

Estrogens increase levels of thyroxine-binding globulin, leading to increased total circulating thyroid hormone levels, measured as protein-bound iodine, T4 (by chromatographic separation or radioimmunoassay), or T3 (by radioimmunoassay). T3 resin uptake is reduced, reflecting increased thyroxine-binding globulin (TBG). Free T4 and T3 concentrations remain unchanged. Levels of other plasma binding proteins may also increase, such as corticosteroid-binding globulin (CBG) and sex hormone-binding globulin (SHBG), leading to increased circulating levels of corticosteroids and sex steroids, respectively. Free or biologically active hormone concentrations remain unchanged. Levels of other plasma proteins may also increase (e.g., angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

There are no data indicating improvement in cognitive function with HRT. However, some evidence suggests an increased risk of possible dementia in women who initiate continuous combined HRT or estrogen-only therapy at age 65 or older.

When used at recommended maintenance doses, Ovestin® suppositories do not affect the results of hormonal laboratory tests.

Ovestin®, vaginal suppositories, contain macrogol cetostearyl ether and glyceryl ricinoleate in their composition.

Macrogol cetostearyl ether and glyceryl ricinoleate may cause local skin reactions.

Use during pregnancy or breastfeeding.

Pregnancy

Ovestin® is not used during pregnancy. If a woman becomes pregnant while taking Ovestin®, treatment should be discontinued immediately. Results from most epidemiological studies conducted to date relevant to assessing the effects of accidental estrogen exposure on the fetus do not indicate teratogenic or fetotoxic effects.

Breastfeeding period

Ovestin® should not be used during breastfeeding, as estriol passes into breast milk and may reduce milk production.

Fertility

Ovestin® is intended only for the treatment of women in the postmenopausal period (natural or surgically induced).

Ability to affect reaction speed when driving or operating machinery.

Ovestin® does not affect the ability to drive or operate machinery.

Method of Administration and Dosage

Ovestin contains only estrogen and therefore can be administered vaginally to women with or without a uterus.

Doses

At the beginning or during continuation of treatment for estrogen deficiency symptoms in postmenopausal women, the lowest effective dose for the shortest duration should be used (see section "Special Instructions").

• For atrophy of the lower urogenital tract: 1 suppository daily for the first weeks (no more than 4 weeks), followed by gradual dose reduction to a maintenance dose (no more than 1 suppository twice weekly), depending on the degree of symptom relief.
• For pre- and postoperative treatment of postmenopausal women undergoing vaginal surgical procedures: 1 suppository daily for 2 weeks before surgery; 1 suppository twice weekly for 2 weeks after surgery.
• As an adjunctive aid in diagnosis when a suspicious atrophic cervical smear is obtained: 1 suppository every other day for one week prior to obtaining the next smear.

If a dose is missed, the patient should administer the missed dose as soon as remembered, unless it is already the day of the next scheduled dose. In the latter case, the missed dose should be skipped and the regular dosing schedule resumed. Two doses must not be administered on the same day.

Method of Administration

Ovestin vaginal suppositories should be administered into the vagina in the evening before bedtime. The patient should insert the suppository as deeply as possible into the vagina while lying down.

When Ovestin, vaginal cream or suppositories, is used twice weekly, systemic exposure to estriol remains within the normal postmenopausal range; therefore, combination with a progestogen is not recommended (see section "Special Instructions").

For women who are not currently receiving hormone replacement therapy (HRT), or those switching from continuous combined HRT, treatment with Ovestin can be initiated at any time. Women switching from a cyclic or continuous sequential HRT regimen should start Ovestin the day after completion of their previous treatment cycle.

Children

The drug is not intended for use in children.

Overdose

In women and girls, ingestion of a large quantity of the drug may result in nausea, vomiting, and withdrawal bleeding. There is no specific antidote. If necessary, symptomatic treatment should be administered.

Adverse reactions.

Adverse reactions occur in 3–10% of patients undergoing treatment. They may indicate an excessive dose. In most cases, adverse reactions resolve after the first weeks of treatment. The frequency of adverse reactions may vary depending on the indication, administered dose, and concomitant use of other medicinal products.

The following frequency categories are used to assess adverse reactions: 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 not known (cannot be estimated from the available data).

Based on literature data and post-marketing safety surveillance, the following adverse reactions have been documented with the use of Ovestin®:

These adverse effects are usually transient, but may also indicate the use of a very high dose of the drug.

Other adverse reactions have also been observed during treatment with estrogen/progestogen.

• Benign and malignant estrogen-dependent neoplasms, e.g., endometrial carcinoma (see sections "Contraindications" and "Special precautions" for additional information).
• Gallbladder disease.
• Skin and subcutaneous tissue disorders: chloasma, erythema multiforme, nodular erythema, hemorrhagic purpura.
• Possible dementia in women aged 65 years and older (see section "Special precautions").

Class effects associated with systemic HRT

The following risks have been associated with the use of systemic HRT and are of less relevance to the drug Ovestin®, vaginal cream and suppositories, in which twice-weekly application results in systemic exposure to estriol remaining close to the normal postmenopausal range.

Risk of breast cancer

It has been documented that women receiving combined HRT with estrogen and progestogen for more than 5 years have an approximately two-fold increased risk of developing breast cancer.

In patients receiving estrogen-only therapy, the degree of increased risk is somewhat lower than in patients taking combined estrogen and progestogen HRT.

The level of risk depends on the duration of treatment (see section "Special precautions").

Results from the largest randomized placebo-controlled trial (WHI) and the largest epidemiological study, the "Million Women Study" (MWS), are presented below. The "Million Women Study" (MWS) estimated the additional risk of developing breast cancer after 5 years of treatment.

WHI study in the USA – additional risk of breast cancer development after 5 years of use

Ovarian cancer

The use of systemic HRT is associated with a slightly increased risk of ovarian cancer diagnosis (see section "Special precautions for use").

A meta-analysis of 52 epidemiological studies showed an increased risk of developing ovarian cancer in women currently using systemic HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31–1.56). In women aged 50 to 54 years, using HRT for 5 years results in one additional case per 2000 women. Among women aged 50 to 54 years who do not use HRT, ovarian cancer is diagnosed in 2 out of 2000 women over a 5-year period.

VENOUS THROMBOEMBOLIC (VTE) RISK

The risk of venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism, is increased by 1.3 to 3 times with systemic HRT. The development of VTE is most likely during the first year of HRT (see section "Special precautions for use"). The relevant results from the WHI study are presented below.

WHI study – additional risk of VTE after 5 years of use

Risk of ischemic stroke development

Systemic estrogen monotherapy is associated with a 1.5-fold increased risk of ischemic stroke. The risk of hemorrhagic stroke does not increase during HRT use.

The relative risk is independent of age or duration of treatment; however, since the baseline risk largely depends on age, the overall risk of stroke in women receiving HRT will increase with age (see section "Special instructions").

Combined data from WHI studies – additional risk of ischemic stroke* after 5 years of treatment

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization of a medicinal product is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at 2–25 °C in a dry, light-protected place.

Keep out of reach of children.

Packaging.

5 suppositories per blister; 3 blisters per cardboard box.

Availability. Over-the-counter (without prescription).

Manufacturer.

Unither Industries.

Manufacturer's address and site of operation.

Zone Industrielle des Malcurles, 03800 Gannat, France.