Instructions for use ESMYA® (ESMYA®)

With the right approach in the early stages of development of myomatous nodes, drug treatment can give the desired results. It is also prescribed as preparatory measures before surgery. One of the means that allows you to achieve excellent results are Esmiya tablets . They are a new generation drug and were introduced (Hungary) just a few years ago - in 2014. In accordance with the reviews of patients about “Esmiya” for fibroids , the drug made it possible to preserve the uterus in a number of cases, eliminating the need for its removal. The operations themselves after treatment with this drug were less traumatic and as safe as possible.

Please note: you can only get complete instructions for using Esmiya for fibroids from your doctor. He will determine the dosage and schedule of administration after conducting diagnostic studies to identify the type of myomatous nodes and their size. Do not self-medicate: the drug has a number of contraindications and side effects and, if taken incorrectly, can cause irreparable harm to your body.

What is Esmiya?

The drug for the treatment of uterine fibroids "Esmiya" is hormonal, antigestagenic and is produced in the form of white tablets for internal oral administration. Its active ingredient is ulipristal, a selective modulator of progesterone receptors that can have a direct effect on the uterine endometrium and suppress the production of progestrogen. An excess of this hormone is most often the cause of the development of myomatous nodes. Ulipristal has an effect on leiomyomas, suppressing the process of cell reproduction by division and programming their apoptosis, due to which the size of the tumor decreases.

Instructions for use ESMYA® (ESMYA®)

Ulipristal acetate is an orally active synthetic selective progesterone receptor modulator characterized by a partial tissue-specific antiprogesterone effect.

Endometrium

Ulipristal acetate has a direct effect on the endometrium. If daily use of the drug at a dose of 5 mg is started during the menstrual cycle, in most women (including patients with uterine fibroids), the next menstruation continues, and subsequent menstruation does not occur until treatment is suspended. After the end of treatment, the menstrual cycle resumes (usually within 4 weeks).

Direct action on the endometrium results in class-specific histological changes in the endometrium called RAEC (progesterone receptor modulator-associated endometrial changes). As a rule, the histological picture is represented by an inactive and weakly proliferating epithelium, accompanied by asymmetry of growth of the stroma and epithelium, which leads to pronounced cystic expansion of the glands with mixed estrogenic (mitotic) and progestin (secretory) effects on the epithelium. Such changes were observed in approximately 60% of patients receiving ulipristal acetate for 3 months. Such changes are reversible after cessation of treatment. Identification of such changes should not be mistaken for endometrial hyperplasia.

In approximately 5% of patients of reproductive age with heavy menstrual bleeding, endometrial thickening exceeds 16 mm. In approximately 10-15% of patients receiving ulipristal acetate, the endometrium may thicken (>16 mm) during the first 3 months of treatment. In the case of repeated courses of therapy, endometrial thickening was observed with less frequency (4.9% of patients after the second course of therapy and 3.5% after the fourth). This thickening disappears after stopping the drug and returning to menstruation. If endometrial thickening persists after the resumption of menstruation during periods of interruption of therapy or 3 months after the end of courses of therapy, a standard examination should be performed to exclude other diseases.

Uterine fibroids

Ulipristal acetate has a direct effect on uterine fibroids, reducing their size by suppressing cell proliferation and inducing apoptosis.

Pituitary

With daily use of ulipristal acetate at a dose of 5 mg, ovulation is suppressed in most patients, as evidenced by maintaining progesterone concentrations at about 0.3 ng/ml.

With daily use of ulipristal acetate at a dose of 5 mg, FSH levels are partially reduced, but the concentration of estradiol in the blood serum in most patients is maintained at the level of the mid-follicular phase and corresponds to that in the placebo group.

Ulipristal acetate does not affect serum concentrations of thyroxine-binding globulin (TBG), ACTH, or prolactin.

Clinical efficacy and safety

Use in the preoperative period:

The efficacy of fixed single doses of ulipristal acetate 5 mg and 10 mg was assessed in two randomized, double-blind, 13-week phase III studies that included patients with extremely heavy menstrual bleeding associated with uterine fibroids.

There were statistically significant differences in the reduction in menstrual blood loss, which were higher in patients receiving ulipristal acetate compared to those receiving placebo, thereby ulipristal acetate provided a faster and more effective correction of anemia compared to iron monotherapy. The reduction in menstrual blood loss was comparable for the groups of patients receiving ulipristal acetate and the GnRH agonist (leuprorelin). In most patients receiving ulipristal acetate, bleeding stopped within the first week of treatment (amenorrhea).

In addition, patients receiving ulipristal acetate had a more pronounced reduction in fibroid size according to MRI results.

Myoma size was assessed by ultrasound at the end of treatment (week 13) and for an additional 25 weeks of follow-up in patients who did not undergo hysterectomy or myomectomy. The reduction in fibroid size was generally maintained during this follow-up period in patients initially treated with ulipristal acetate, and some regrowth of fibroids was detected in the leuprorelin group.

Table 1. Results of primary and selected results of secondary evaluation of efficacy indicators in phase III clinical trials

Study 1.

Study 2.

a In Study 1, change from baseline in total fibroid volume was assessed by MRI. In Study 2, the sizes of the 3 largest fibroids were determined using ultrasound. Values ​​in bold indicate significant differences when comparing ulipristal acetate and control. All differences noted were in favor of ulipristal acetate.

P values: 1 = <0.001, 2 = 0.037, 3 = <0.002, 4 = <0.006.

Intermittent therapy

The effectiveness of repeated courses of single fixed doses of ulipristal acetate 5 mg or 10 mg was determined in two phase III studies that assessed a maximum of four 3-month courses of therapy in patients with heavy menstrual bleeding associated with uterine fibroids. Study 3 was an open-label study evaluating ulipristal acetate 10 mg, in which each 3-month course of therapy was followed by 10 days of double-blind progestin or placebo therapy. Study 4 was a randomized, double-blind clinical trial evaluating ulipristal acetate at doses of 5 or 10 mg.

Studies 3 and 4 showed efficacy in controlling uterine fibroid symptoms (eg, uterine bleeding) and reducing fibroid size after 2 and 4 courses of treatment.

In Study 3, treatment efficacy was observed over >18 months of multiple intermittent courses of therapy (4 courses using a dose of 10 mg once a day), and at the end of the 4th course of therapy, 89.7% of patients had amenorrhea.

In study 4, 61.9% and 72.7% of patients had amenorrhea at the end of courses 1 and 2 (doses of 5 mg and 10 mg, respectively, p = 0.032); in 48.7% and 60.5% of patients, amenorrhea was registered at the end of all four courses of therapy (doses of 5 mg and 10 mg, respectively, p = 0.027). According to the assessment, at the end of the 4th course of therapy, amenorrhea was registered in 158 (69.6%) and 164 (74.5%) patients, respectively (p = 0.290).

Table 2. Results of primary and selected results of secondary evaluation of efficacy indicators in long-term clinical trials of phase III

After completion of the second course of treatment (2 times 3 months of treatment)

After completion of the fourth course of treatment (4 times 3 months of treatment)

a The 2nd course of therapy score corresponds to 2nd course of therapy plus one menstrual bleed.

b Patients with missing values ​​were excluded from the analysis.

c N and % are presented taking into account dropped out patients.

d Controlled bleeding was defined as no episodes of heavy bleeding and a maximum of 8 days of bleeding (excluding spotting days) during the last 2 months of therapy.

Results of studies assessing the effect on the endometrium

In all phase III studies (including studies of intermittent course therapy), among 789 patients, 7 cases of hyperplasia (0.89%) were recorded, confirmed by the results of pathomorphological examination. In the intervals between courses of treatment and upon the resumption of menstruation, in most cases, spontaneous disappearance of all previously recorded changes in the endometrium occurred. During subsequent courses of therapy, the incidence of hyperplasia did not increase. The reported frequencies are consistent with those in control groups and the prevalence reported in the literature for premenopausal women in this age group (mean age 40 years).

Contraindications:

• Allergic reaction to ulipristal or additional substances;
• Malignant neoplasms of the uterus, ovaries, cervix;
• Malignant neoplasms of the mammary glands;
• Pregnancy and lactation;
• The patient's age is up to eighteen years;
• Vaginal bleeding of unknown nature or not due to myomatous nodes;
• Severe form of bronchial asthma;
• Long-term therapy, more than two courses.

Esmiya fibroids are treated with caution in cases of renal and/or liver failure.

Mode of application

The maximum effect from taking Esmiya can only be achieved by strictly following the doctor’s instructions. He calculates the dosage and draws up a dosage regimen based on diagnostic test data and the patient’s individual indicators. On average, the course of treatment with this drug is up to three months, during which the dosage can be adjusted depending on:

• behavior of myomatous nodes;
• identified side effects;
• tolerability of the drug by the patient.

As a rule, the dosage of the drug is 5–10 mg, once a day. It is advisable to take it in the 2nd half of the day at the same time. It is prohibited to combine Esmiya with hormonal contraceptives containing gestagens.

Esmiya

The drug (ulipristal) is an orally active synthetic selective modulator of progesterone receptors (SMPR), characterized by a tissue-specific partial antiprogesterone effect.

Ulipristal has a direct effect on the endometrium. When starting a daily dose of 5 mg of the drug during the menstrual cycle, most women (including patients with fibroids) end up with one menstrual bleeding, and the next one does not occur. When the drug is stopped, the menstrual cycle usually resumes within 4 weeks. Direct action on the endometrium leads to class-specific changes in the endometrium associated with an antagonistic effect on progesterone receptors (Progesterone Receptor Modulator Associated Endometrial Changes (PAEC)). As a rule, histological changes are represented by an inactive and weakly proliferating epithelium, accompanied by asymmetry of growth of the stroma and epithelium, pronounced cystic expansion of the glands with mixed estrogenic (mitotic) and progestogenic (secretory) effects on the epithelium. Such changes were observed in approximately 60% of patients receiving ulipristal acetate for 3 months. These changes are reversible and disappear after cessation of treatment and should not be mistaken for endometrial hyperplasia.

In approximately 5% of patients of reproductive age with severe forms of menstrual bleeding, the thickness of the endometrium is more than 16 mm. In 10-15% of patients receiving ulipristal, the endometrium may thicken (> 16 mm) during treatment. This thickening disappears after stopping the drug and resuming menstrual bleeding. If endometrial thickening persists longer than 3 months after completion of treatment and restoration of the menstrual cycle, additional examination should be performed to exclude other diseases.

The drug has a direct effect on leiomyomas, suppressing cell proliferation and inducing apoptosis, which leads to a decrease in their size.

Pituitary

When taking ulipristal daily at a dose of 5 mg, ovulation is suppressed in most patients, as evidenced by maintaining progesterone concentrations at about 0.3 ng/ml.

When taking ulipristal daily at a dose of 5 mg, the concentration of FSH is partially reduced, but the concentration of estradiol in the blood serum in most patients is maintained at the level of the mid-follicular phase and corresponds to that in the placebo group.

Ulipristal does not affect the concentration of thyroxine-binding globulin (TBG), ACTH and prolactin in the blood plasma during 3 months of treatment.

The efficacy of fixed doses of ulipristal 5 mg and 10 mg once daily was assessed in two phase 3 studies in patients with very heavy menstrual bleeding caused by uterine fibroids.

Compared with placebo, a clinically significant reduction in the volume of menstrual blood loss was detected in patients taking ulipristal. This made it possible to quickly and more effectively correct anemia than when prescribing iron supplements alone. The reduction in menstrual blood loss in patients in the ulipristal group was comparable to the group receiving the GnRH agonist (leuprorelin). In most patients receiving ulipristal, bleeding stopped during the first week of treatment (amenorrhea developed).

According to MRI, there was a significantly greater reduction in uterine fibroid size in the ulipristal group than in the placebo group. In patients who did not undergo hysterectomy or myomectomy, a decrease in the size of uterine fibroids was assessed by ultrasound control at the end of treatment (week 13). As a rule, it persisted throughout the 25-week follow-up in patients in the ulipristal group, while in the group receiving leuprorelin there was a slight increase in the size of uterine fibroids.

In another Phase 3 study, in which patients received 2 courses of ulipristal 10 mg for 3 months, the incidence of amenorrhea was comparable at the end of both courses of therapy. The reduction in leiomyoma volume recorded during the first course was maintained during the second course. Taking into account the results of previous studies, the effectiveness of the drug at a dose of 5 mg during the first course of therapy will be the same during the second course of therapy, similar to a dose of 10 mg.

Despite the limited number of patients completing four 3-month courses of treatment, the safety data obtained were sufficient to justify one additional 3-month course of therapy in the preoperative period.

The effect of Esmiya on the female body

As already mentioned, Esmiya fibroid tablets have a direct effect on the uterine endometrium. It is expressed in a change in the epithelium, which becomes weak and inactive. When taking 5 mg daily, starting from the first day of menstruation, after four to five days, the bleeding stops and there is no bleeding for the next month. The cycle is restored one month after stopping the drug. Numerous studies have shown that the medicine for fibroids "Esmiya" is not toxic even with long-term use.
There is no data on the effect of its active substance ulipristal on the fetus, since studies in this direction have not been conducted. The drug was tested on patients who suffered from intense menstruation, accompanied by pronounced pain symptoms, caused by fibroids. It was noted not only a decrease in the intensity of bleeding already in the first week of use, but also a decrease in the size of myomatous neoplasms.

Esmya®

Ulipristal is prescribed only after a thorough examination. Pregnancy should be excluded before starting treatment. If pregnancy is suspected before starting a new course of therapy, an appropriate test must be performed.

Contraception

Due to the possibility of undesirable interactions, the concomitant use of only gestagen-containing drugs, gestagen-releasing systems or combined oral contraceptives is not recommended. Most women experience anovulation when using ulipristal; additional use of a non-hormonal method of contraception during treatment is recommended.

Endometrial changes

Ulipristal has a specific pharmacodynamic effect on the endometrium, leading to histological changes in the endometrium characteristic of this class, which are designated as RAEC. These changes disappear after cessation of treatment and should not be misdiagnosed as endometrial hyperplasia (see section "Pharmacodynamics"). In addition, reversible thickening of the endometrium may be observed during treatment.

When conducting repeated courses of treatment, periodic monitoring of the condition of the endometrium is recommended, including an annual ultrasound examination performed after the resumption of menstrual bleeding during periods of interruption of therapy.

If there is persistent thickening of the endometrium after the resumption of menstrual bleeding during periods of interruption of therapy or 3 months after the end of courses of therapy and/or a change in the nature of bleeding (see section “Pattern of bleeding”), an appropriate examination should be carried out to exclude other diseases, for example, malignancy , including endometrial biopsy.

If hyperplasia (without atypia) is detected, monitoring is recommended in accordance with standard clinical practice (for example, follow-up after 3 months). In the case of atypical hyperplasia, evaluation and management of the patient should be carried out in accordance with the principles of standard clinical practice.

The duration of each course of treatment should not exceed 3 months, since the risk of undesirable effects on the endometrium is unknown if therapy is carried out without interruption.

Nature of bleeding

Patients should be informed that treatment with ulipristal usually results in a significant reduction in menstrual blood loss or amenorrhea during the first 10 days of treatment. If excessive bleeding continues, the patient should consult a doctor. As a rule, the menstrual cycle resumes within 4 weeks after the end of treatment.

Appropriate evaluation, including endometrial biopsy, should be performed to exclude other diseases (eg, endometrial malignancy) if, after an initial decrease in bleeding intensity or the onset of amenorrhea, a persistent change or unexpected bleeding pattern (eg, intermenstrual bleeding) is detected during repeated courses of treatment.

The maximum studied duration of drug use is 4 courses.

Kidney failure

There is no reason to believe that renal failure may significantly affect the elimination of ulipristal. Due to the lack of special studies, the use of Esmya® is not recommended in patients with severe renal failure if it is impossible to carefully monitor their condition.

Liver damage

During the period of post-registration use of the drug, cases of liver damage and liver failure were reported (see section “Contraindications”).

Liver function tests should be checked before starting treatment. Do not start taking the drug if the activity of transaminases (alanine aminotransferase (ALT) or aspartate aminotransferase (AST)) exceeds the upper limit of normal (ULN) by more than 2 times (isolated or in combination with an increase in bilirubin concentration >2 x ULN).

During course therapy, liver function indicators must be monitored monthly during the first two courses of treatment. In the future, liver function tests should be checked before each new course of treatment and as clinically indicated.

If during treatment the patient develops signs and symptoms indicating liver damage (fatigue, asthenia, nausea, vomiting, pain in the right hypochondrium, anorexia, jaundice), the drug should be discontinued and the patient should be immediately examined, including liver function tests.

Patients whose transaminase activity (ALT or AST) exceeds the upper limit of normal by more than 3 times during treatment should stop taking the drug and be closely monitored.

Additional monitoring of liver function tests should be carried out 2-4 weeks after stopping the drug.

Concomitant therapy

Concomitant use of ulipristal and moderate-potent CYP3A4 inhibitors (eg, erythromycin, grapefruit juice, verapamil) or potent inhibitors (eg, ketoconazole, ritonavir, nefazodone, itraconazole, telithromycin, clarithromycin) is not recommended.

Concomitant use of ulipristal and strong inducers of CYP3A4 (for example, rifampicin, rifabutin, carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, primidone, St. John's wort, efavirenz, nevirapine, with long-term use of ritonavir) is not recommended.

Fertility

Most women experience anovulation when using ulipristal, but fertility has not been studied with long-term use of ulipristal.