ESMYA PILL 5 MG

Latin name
Esmya

pills

Composition

1 pill contains:
active ingredient: ulipristal acetate 5 mg,
excipients: microcrystalline cellulose - 93.5 mg, mannitol - 43.5 mg, talc - 4 mg, croscarmellose sodium - 2.5 mg, Magnesium stearate - 1.5 mg.

Packing

28 tablets.

Mechanism of action

Ulipristal is a synthetic selective Progesterone receptor modulator, characterized by a tissue-specific partial anti-progesterone effect, which is active when taken orally.

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

Pituitary
With daily intake of ulipristal at a dose of 5 mg, ovulation is suppressed in most patients, as evidenced by the maintenance of progesterone concentration at about 0.3 ng / ml.
With daily intake of ulipristal at a dose of 5 mg, the concentration of FSH partially decreases, however, the concentration of estradiol in the blood serum in most patients is maintained at the level of the average follicular phase and corresponds to that in the placebo group.
Ulipristal does not affect the concentration of thyroxin-binding globulin (TSH), ACTH and prolactin in the blood plasma during 3 months of treatment.

Preclinical safety data
In preclinical studies of pharmacological safety, toxicity of multiple doses and genotoxicity of potential threats to humans have not been identified.
The main findings in general toxicity studies are related to the effect on progesterone receptors (as well as GCS receptors when the drug is used in higher concentrations), with anti-progesterone activity at exposures close to therapeutic in humans. In a 39-week low-dose monkey study, changes similar to RAEC were identified. In connection with its mechanism of action, the snorpal causes fetal death in rats, rabbits (with multiple doses above 1 mg / kg), guinea pigs and monkeys. The safety of the drug in relation to the human embryo has not been established. At doses small enough to preserve pregnancy in animals, no teratogenic potential was detected. In reproduction studies in rats using doses that provide the same exposure as in humans, no evidence was found to influence the reproductive ability of animals receiving uliprystyle, as well as on their offspring.
In studies conducted in mice and rats, no carcinogenic effect on ulipristal was detected.

Clinical efficacy and safety
The effectiveness of fixed doses of ulipristal 5 mg and 10 mg 1 time / day was evaluated in two studies of phase 3, which involved patients with very heavy menstrual bleeding caused by uterine myoma.
In comparison with placebo, a clinically significant decrease in the volume of menstrual blood loss was detected in patients taking ulipristal. This made it possible to quickly and more efficiently correct anemia than when prescribing only iron preparations. The reduction in menstrual blood loss in patients with the ulipristal group was comparable to the group receiving the GnRH agonist (leuprorelin). In the majority of patients receiving ulipristal, the bleeding stopped during the first week of administration (amenorrhea developed).

According to MRI, there was a significantly greater reduction in the size of uterine fibroids in the ulipristal group than in the placebo group. In patients who did not undergo hysterectomy or myomectomy, with ultrasound control at the end of treatment (week 13), a reduction in the size of the uterine myoma was evaluated. As a rule, it persisted for 25 weeks of follow-up in patients of the ulipristal group, whereas in the group treated with leuprorelin, there was a slight increase in the size of uterine fibroids.
In another study, Phase 3, in which patients received 2 courses of therapy with ulipristal 10 mg lasting 3 months, the frequency of amenorrhea was comparable at the end of both courses of therapy. The decrease in leiomyoma recorded during the first course was maintained during the second course. Taking into account the results of previous studies, the effectiveness of the drug in a dose of 5 mg during the first course of therapy will be the same during the second course of therapy, similar to the dose of 10 mg.

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

Pharmacokinetics
Suction
After a single oral dose of 5 mg or 10 mg, ulipristal is rapidly absorbed, reaching approximately 1 hour after taking Cmax 23.5 &№177; 14.2 ng / ml and 50.0 &№177; 34.4 ng / ml, respectively. AUC0-∞ is 61.3 &№177; 31.7 and 134.0 &№177; 83.8 ng &№215; h / ml, respectively. Ulipristal is rapidly transformed into a pharmacologically active metabolite, 1 hour after administration, Cmax is 9.0 &№177; 4.4 ng / ml and 20.6 &№177; 10.9 ng / ml, AUC0-∞ - 26.0 &№177; 12.0 and 63.6 &№177; 30.1 ng &№215; h / ml, respectively. Acceptance of 30 mg of ulipristal along with high-fat breakfast results in an average Cmax decrease of about 45%, lengthening the time to reach Cmax (from a median of 0.75 hours to 3 hours) and a 25% increase in AUC0-∞ compared to fasting. The same results were obtained for the active mono-N-demethylated metabolite.This kinetic effect of food is not regarded as significant for daily pills.

Distribution
Ulipristal is highly (> 98%) bound to plasma proteins, including albumin, α-1-acid glycoprotein, high-density lipoproteins and low-density lipoproteins.
Ulipristal and its active N-demethylated metabolite pass into breast milk; the average AUCt ratio for milk / plasma is 0.74 &№177; 0.32 for ulipristal.

Metabolism
Ulipristal acetate is rapidly converted to mono-N-demethylated and then to di-N-demethylated metabolites. In vitro data show that this process occurs in the cytochrome P450 system with the participation of the 3A4 isoenzyme (CYP3A4). Based on the fact that the metabolism of ulipristal acetate is mediated by cytochrome P450, the effect of hepatic insufficiency on the elimination of ulipristal acetate is expected, which will lead to an increase in its effect.

Removal
The main route of elimination is through the intestines, less than 10% of the substance is excreted by the kidneys. The final T1 / 2 ulipristal acetate after a single dose of 5 mg or 10 mg is about 38 hours, the average clearance of about 100 l / h. In vitro data show that clinically significant concentrations of ulipristal acetate and its active metabolite do not inhibit CYP1A2 isoenzymes, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 and do not induce CYP1A2 isoenzyme. Thus, the use of ulipristal acetate should not affect the clearance of drugs that are metabolized with the participation of these isoenzymes.
In vitro data shows that ulipristal acetate and its active metabolite are not substrates for P-glycoprotein (ABCB1).

Preoperative treatment of symptoms of uterine fibroids of moderate and severe adult women of reproductive age over 18 years of age (duration of therapy is not more than 2 courses).

hypersensitivity to ulipristal acetate or any of the excipients of Esmya;
bleeding from the vagina of unknown etiology or for reasons unrelated to uterine myoma;
cancer of the uterus, cervix, ovary, or breast;
duration of therapy over 3 months (due to the lack of safety data with longer use);
bronchial asthma, a severe form that cannot be corrected by oral GCS;
pregnancy;
lactation period;
age up to 18 years.
Precautions should be prescribed the drug for renal and / or liver failure, bronchial asthma.

Ulipristal acetate is contraindicated during pregnancy. Data on the use of ulipristal acetate in pregnant women are missing or limited. Although no teratogenic potential has been identified in animal studies, reproductive toxicity data are insufficient.

Animal studies have shown that ulipristal acetate is excreted in breast milk. It is not known whether ulipristal acetate is excreted with female breast milk, so the risk to children during breastfeeding cannot be excluded. Ulipristal acetate is contraindicated during breastfeeding.

Esmya is prescribed by mouth for 1 pill 1 time / day. regardless of food intake for no more than 3 months. Treatment should begin within the first week of the menstrual cycle.
There is no data on treatment over 3 months or repeated courses of therapy, therefore the duration of treatment should not exceed 3 months.
In the case of skipping the next reception, you should take a pill of ulipristal acetate as soon as possible. If the intake is missed for more than 12 hours, then the missed pill is not taken, and the normal mode of administration should be resumed.

In patients with mild or moderate renal insufficiency, dose adjustment is not required. Ulipristal acetate is not recommended for use in patients with severe renal insufficiency if continuous monitoring is not possible.

In patients with mild liver failure, dose adjustment is not required. Ulipristal acetate is not recommended for use in patients with severe or severe hepatic impairment when it is impossible to continuously monitor.

The use of nulipristal acetate for the appropriate indications in children is not provided. The safety and effectiveness of ulipristal acetate are established only for women 18 years and older.

The safety of ulipristal acetate was evaluated in 393 women with uterine myomas who received 5 mg or 10 mg of ulipristal acetate during phase III studies.Amenorrhea (82.2%), which is considered to be the desired outcome, was the most common occurrence in clinical trials.

The most frequent adverse reaction was the appearance of hot flashes. The vast majority of adverse reactions were mild or moderate (94.9%), did not lead to discontinuation of drug treatment (99.3%) and resolved on their own.

During the two phase III studies in patients with uterine fibroids who received the drug for 3 months, the following adverse reactions were reported. Adverse adverse reactions are represented by system-organ classes according to the MedDRA classification and with the frequency of occurrence: very often (≥1 / 10); often (≥1 / 100 to

Within each frequency group, adverse reactions are presented in decreasing order of severity.

On the part of the psyche: often - emotional disorders; infrequently - anxiety.

On the part of the nervous system: often - headache * (* - see Description of individual adverse reactions); infrequently - dizziness.

On the part of metabolism: infrequently - an increase in body weight.

From the organ of hearing and balance: often - vertigo.

On the part of the respiratory system: infrequently - nosebleeds.

On the part of the digestive system: often - abdominal pain, nausea; infrequently - dyspepsia, dry mouth, flatulence, constipation.

On the part of the skin and subcutaneous tissue: often - acne, excessive sweating; infrequently - skin lesions.

From the musculoskeletal system: often - pain in the bones and muscles; infrequently - back pain.

On the part of the urinary system: infrequently - urinary incontinence.

On the part of the reproductive system and mammary glands: very often - amenorrhea, thickening of the endometrium *, hot flashes *; often - metrorrhagia *, ovarian cyst *, breast tension / tenderness, pelvic pain; Infrequently, ovarian cyst rupture, vaginal discharge, an increase in and discomfort in the mammary glands.

On the part of the body as a whole: often - edema, fatigue; infrequently - asthenia.

From the laboratory indicators: often - increasing the concentration of cholesterol in the blood; infrequently - an increase in the concentration of triglycerides in the blood.

Description of individual adverse reactions

Endometrial thickening

In 10–15% of patients who received ulipristal acetate, endometrial thickening may occur (> 16 mm by ultrasound or MRI at the time of termination of treatment).This phenomenon is reversible after stopping treatment and resuming the menstrual cycle.

In addition, reversible changes in the endometrium, referred to as PAEC, differ from endometrial hyperplasia. The pathologist must be informed that the patient has received ulipristal acetate when conducting a histological examination for hysterectomy or endometrial biopsy.

Tides

Tides were observed in 12.7% of patients, but their frequency varied in different studies. In the study with active control, their frequency was 24% (10.5% moderate or severe) for the ulipristal acetate group and 60.4% (39.6% moderate or severe) for the leuprorelin group. In a placebo-controlled study, the frequency of tides was 1.0% for ulipristal acetate and 0% for placebo.

Headache

Mild to moderate headache was observed in 6.4% of patients.

Ovarian cyst

In 1.5% of patients, during the treatment, functional ovarian cysts were detected, which spontaneously disappeared within a few weeks.

Uterine bleeding

Patients with severe menstrual bleeding caused by uterine leiomyoma are at risk of increased blood loss, which may require surgery. There were several such reports, both during therapy, and 2-3 months after the end of treatment, ulapristal acetate.

Ulipristal acetate is prescribed only after a thorough examination. Pregnancy should be excluded prior to treatment.
Contraception
In connection with the possibility of undesirable interactions, concomitant use of only gestagen-containing preparations, progestogen-releasing systems, or combined oral contraceptives is not recommended. Although the majority of women who received therapeutic doses of ulipristal, anovulation was observed, the additional use of a non-hormonal method of contraception during treatment was recommended.

Renal failure
There is no reason to believe that renal failure can significantly affect the removal of ullipristal. It is not recommended to use ulipristal acetate without constant observation in patients with severe renal insufficiency, since special studies have not been conducted.

Liver failure
There is no experience of therapeutic use of ulipristal acetate in patients with hepatic insufficiency. It is expected that hepatic impairment may affect the removal of ulipristal acetate, which will increase the impact of the drug. This is not essential for patients with mild hepatic insufficiency. It is not recommended to administer ulipristal acetate in patients with moderate or severe hepatic impairment if continuous monitoring is not possible.

Concomitant therapy
The concomitant use of ulipristal and medium-strength CYP3A4 inhibitors (for example, Erythromycin, grapefruit juice, verapamil) or potent inhibitors (for example, Ketoconazole, ritonavir, nefazodone, itraconazole, telithromycin, clarithromycin) is not recommended.
We do not recommend joint application ulipristala and potent inducers of CYP3A4 (eg, rifampicin, rifabutin, Carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, primidone, Hypericum perforatum, efavirenz, nevirapine, ritonavir - against a background of long-term use).

Endometrial changes
Ulipristal acetate has a specific pharmacodynamic effect on the endometrium. There may be an increase in the thickness of the endometrium. If endometrial thickening persists for 3 months after the end of treatment and the resumption of menstruation, an additional examination should be conducted to rule out other diseases.
In patients receiving ulisperis, histological examination may experience changes in the structure of the endometrium. Such changes are reversible upon completion of treatment. These histological changes are referred to as changes in the endometrium associated with an antagonistic effect on progesterone receptors (PAEC), and they should not be mistakenly assessed as endometrial hyperplasia. It is recommended that no more than two courses of therapy. The duration of each course should not exceed 3 months, since the risk of undesirable effects on the endometrium during longer therapy is unknown.

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

Fertility
The majority of women who took ulipristal acetate at therapeutic doses, anovulation was observed. However, fertility with long-term use of ulipristal acetate has not been studied.

Ulipristal can have a minimal impact on the ability to drive vehicles and machinery, because after taking the ulipristal, slight dizziness may be observed.

Possible effects of other drugs on the action of ulipristal acetate
Hormonal contraceptives
Ulipristal acetate has a steroid structure and acts as a selective modulator of progesterone receptors with a predominant inhibitory effect on progesterone receptors. Thus, hormonal contraceptives and progestogens can reduce the effectiveness of ulipristal acetate by competitive effects on the progesterone receptor. Therefore, the simultaneous use of drugs containing gestagens is not recommended.

Inhibitors of the isoenzyme CYP3A4
After the use of a moderate-power inhibitor of CYP3A4 isoenzyme erythromycin propionate (500 mg 2 times / day for 9 days) in healthy female volunteers, Cmax and AUC ulipristal increased by 1.2 and 2.9 times, respectively; The AUC value of the active metabolite of ulipristal acetate increased 1.5 times, while the Cmax of the active metabolite decreased (0.52 times). The use of ketoconazole (400 mg 1 time / day, 7 days), a potent CYP3A4 inhibitor, in healthy female volunteers showed an increase in Cmax and AUC ulipristal by 2 and 5.9 times, respectively. There was an increase in AUC for the active metabolite of ulipristal by 2.4 times while reducing its Cmax (a change of 0.53 times). Dose adjustment in the use of ulipristal in patients receiving mild inhibitors of the CYP3A4 isoenzyme is not required. The combined use of medium-power inhibitors or potent inhibitors of CYP3A4 isoenzyme with ulipristal is not recommended.

Inductors of isoenzyme CYP3A4
The use of rifampicin, a powerful inducer of CYP3A4 (300 mg, 2 times / day, 9 days), in healthy female volunteers, showed a marked decrease in Cmax and AUC of ulipristal and its active metabolite by more than 90%. A decrease in T1 / 2 of ulipristal by 2.2 times was also noted, which corresponds to a decrease in its exposure by about 10 times. Concomitant use ulipristala and powerful inducers of CYP3A4 (e.g., rifampicin, rifabutin, carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, primidone, Hypericum perforatum, efavirenz, nevirapine, ritonavir, - long-term use on the background) are not recommended.

Drugs affecting the pH of gastric juice
The use of ulipristal (10 mg / day) together with a proton pump inhibitor esomeprazole (20 mg 1 time / day for 6 days) results in a decrease in the average Cmax by 65%, a lengthening of Tmax (from a median of 0.75 h to 1.0 h) and an increase in the average AUC by 13%. Such an effect of drugs that increase the pH of gastric juice is not considered clinically significant for the daily intake of ulipristal acetate tablets.
Possible effect of ulipristal acetate on the effect of other drugs

Hormonal contraceptives
Ulipristal may interfere with the action of hormonal contraceptives (only gestagen-containing tablets, progestogen release systems, or combined oral contraceptives) and progestogen drugs used for other reasons. Therefore, the concomitant use of drugs containing gestagen is not recommended. Progestin-containing drugs should not be used for 12 days after stopping uripristal.

Substrates of P-glycoprotein
In vitro data show that in clinically significant concentrations of uliprystal acetate during absorption in the wall of the gastrointestinal tract, it can be an inhibitor of P-glycoprotein (P-gp). The simultaneous use of ulipristal and P-gp substrate has not been studied, so the likelihood of interactions cannot be excluded. In vivo data suggest that taking ulipristal (a 10 mg tablet) 1.5 hours before taking the P-gp substrate Fexofenadine (60 mg) does not have a clinically significant effect on the pharmacokinetics of Fexofenadine. Thus, it is recommended to observe the interval of at least 1.5 hours between taking ulipristal and P-gp substrates (for example, dabigatran etexilate, Digoxin, fexofenadine). The patient should inform the doctor about all medicines that she takes, even if they are available without a prescription.

Data on overdose of ulipristal acetate is limited.
A single dose of up to 200 mg and a daily dose of 50 mg for 10 days were administered to a limited number of volunteers, and no serious or serious adverse reactions were noted.

Storage conditions
In the dark place at a temperature of no higher than 30 ° C. Keep out of the reach of children!