Expiration date: 11/2025
Dosage form: pills
Composition per 1 tablet:
Active substance: ulipristal acetate 5.00 mg,
Other ingredients: microcrystalline cellulose 93.50 mg of mannitol
43.50 mg talc 4.00 mg Croscarmellose sodium 2.50 mg Magnesium stearate 1.50 mg.
Description: Round biconvex, white or nearly white with engraving «ES5» on one side.
Pharmacotherapeutic group: antigestagen
ATX code: G03
pharmacological properties
pharmacodynamics
Ulipristal - active when taken orally synthetic selective modulator progesterone receptor (SMLF), characterized by a tissue-specific partial antiprogesteronovym effect.
The endometrium
Ulipristal has a direct effect on the endometrium. When starting pri?mapreparata 5 mg during the menstrual cycle in most women (including patients with myoma) ends next menstrual bleeding, and the next It does not occur. When the reception of the drug is stopped, menstrual cycles generally It resumed for 4 weeks. Direct action on the endometrium results in specific for this class of drugs to changes in the endometrium, associated with antagonistic action on the progesterone receptors (ProgesteroneReceptor ModulatorAssociatedEndometrialChanges (PAEC)). Typically, histological changes represented an inactive and weakly proliferating epithelium accompanied by the asymmetry of stromal and epithelial growth, severe cystic expansion of glands with mixed estrogen (mitotic) and progestogen (Secretory) effects on the epithelium. These changes were observed in about 60% patients receiving ulipristal for 3 months. These changes are reversible and
disappear after cessation of treatment, they should not be taken as hyperplasia Endometrial.
Approximately 5% of patients of reproductive age with severe menstrual bleeding, endometrial thickness greater than 16 mm. In 10-15% of patients, receiving ulipristal, the endometrium may thicken (> ,, 16 mm) during treatment. it thickening disappears after discontinuation of the drug and resumption menstrual bleeding. If the endometrial thickening persists for 3 months after the end of treatment and recovery of the menstrual cycle, it should be conduct additional tests to rule out other diseases.
leiomyoma
Ulipristal has a direct effect on leiomyoma, suppressing cell proliferation and inducing apoptosis, which leads to a reduction in their size.
Pituitary
With daily admission ulipristala at a dose of 5 mg of ovulation suppression in Most patients, as evidenced by the maintenance of the concentration of progesterone at about 0.3 ng / ml.
With daily admission ulipristala 5 mg partially reduced concentration follicle stimulating hormone (FSH), but the concentration in plasma estradiol Blood in most patients maintained at mid mollicular phase and corresponds to that in the placebo group.
Ulipristal not affect the concentration of thyroxine binding globulin (TBG), adrenokortikotrogshogo hormone (ACTH) and plasma prolactin throughout 3 months of treatment.
Preclinical safety data
In preclinical studies of pharmacological safety, toxicity multiple doses and genotoxicity potential threats have been identified for the individual. Key findings in general toxicity studies are associated with the impact on receptors progesterone (as well as receptors for glucocorticoids when used in the preparation higher concentrations), with antiprogesteronovoy activity at exhibitions, close to a human therapeutic. In the 39-week study in monkeys with using low doses were identified changes similar to PAEC. Due to this ulipristal mechanism of action causes fetal death in rats and rabbits (in Multiple doses above 1 mg / kg), guinea pigs and monkeys. Safety drug It is not set for human embryo. At doses small enough to preserve pregnancy in animals revealed no teratogenic potential. studies reproduction in rats using dosages that provide the same exposure as that man found no evidence of effect on the reproductive capacity of animals
receiving ulipristal, as well as their offspring. Carcinogenicity studies have not been conducted.
Clinical efficacy and safety
Efficacy ulipristala fixed doses of 5 mg and 10 mg once a day was evaluated in two Phase 3 studies, which involved patients with very heavy menstrual bleeding caused by uterine fibroids.
In comparison with placebo was clinically significant reduction in the volume of menstrual blood loss in patients treated with ulipristal. This allowed quickly and more effectively carry out the correction of anemia than in the appointment only iron supplements. The reduction of menstrual blood loss in the group of patients ulipristala was comparable to the group receiving an agonist of gonadotropin-releasing hormone (leylrorelin). The majority of patients receiving ulipristal bleeding It was stopped in the first week of admission (developed amenorrhea).
According to the magnetic resonance imaging in ulipristala group it was significantly greater reduction in the size of uterine fibroids than in the placebo group. Patients, which has not been performed hysterectomy or myomectomy under ultrasound control at the end of of treatment (Week 13) was estimated decrease in the size of uterine fibroids. Typically, it It persisted throughout the 25 weeks of follow-up in the group of patients ulipristala, whereas in the group treated with leuprorelin, showed some increase in size of uterine fibroids.
Pharmacokinetics
Suction
After a single oral administration dose of 5 mg or 10 mg ulipristal rapidly absorbed, reaches approximately 1 hour after taking the maximum concentration (Sta *) 23,5 ±14.2 ng / ml and 50.0 ± 34.4 ng / ml, respectively. The area under the curve "concentration-time" (AUCo-oo) is 61,3 ± 31,7 and 134,0 ± 83,8 ng-hr / mL, respectively. Ulipristal quickly It transformed into the pharmacologically active metabolite, wherein the through 1 hour after Hour Cmax was 9,0 ± 4,4 ng / ml and 20,6 ± 10,9 ng / ml, AUCo-oo26,0 ± 12,0 and 63,6 s = 30.1 ng-hr / mL, respectively. Admission sale stuck at a dose of 30 mg with breakfast with high fat reduces the average Cmax approximately 45% elongation time to reach maximum concentration (tmax) of the mean of 0.75 hours to 3 hours and 25% increase AUCo-oo, compared with taking on an empty stomach. The same results were obtained active MOHo-N-demethylated metabolite. This kinetic effect of food
It is not regarded as significant for the daily use of pills in there stuck.
Distribution
Ulipristal highly (> 98% ,,) associated with plasma proteins, including albumin, a-1-acid glycoprotein, lipoproteins, high density lipoproteins and low density.
Metabolism
Ulipristal is fast becoming a MOHO-N-demethylated and then di-N-demethylated metabolites. These invitropokazyvayut that this process occurs in the cytochrome P450 system, with the participation of isoenzyme ZA4 (CYP3A4). Based on the fact that ulipristala metabolism mediated by cytochrome P450, is expected to influence hepatic deficiency ulipristala excretion, leading to an increase in its effect.
breeding
The main excretion route - through the intestine, at least 10% of the material excreted by the kidneys.
Terminal half-life after a single ulipristala receiving 5 mg or 10 mg approximately 38 hours, the average clearance of about 100 l / h. These invitropokazyvayut, that clinically relevant concentrations ulipristal and its active metabolite not inhibit isozymes CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and ZA4 not induce isoenzyme CYP1A2. Thus, the use ulipristala should not affect the
clearance of drugs that are metabolized by the participation data isoenzymes.
Invitro data show that ulipristal and its active metabolite are not P-glycoprotein substrates (AVSV1).
Testimony:
Preoperative treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age over 18 years, no longer than 3 months.
Contraindications
- hypersensitivity to ulipristal or any of the excipients
- Pregnancy and lactation
- Bleeding from the vagina of unknown aetiology or for reasons connected with uterine myoma
- uterine cancer, cervical, ovarian or breast
- Duration of therapy over 3 months (due to the lack of data on safety at a long-term use)
- Age <18 ,, = "" p = ""> ,,
- Bronchial asthma, severe, not treatable with oral correction glucocorticosteroids
Precautions: renal and / or hepatic insufficiency, bronchial asthma.
Application of pregnancy and during breastfeeding
Pregnancy
Ulipristal is contraindicated in pregnancy.
on the application of data ulipristala in pregnant women are not available or are limited.
Despite the fact that in the course of research on animals is not teratogenic potential identified, data relating to the reproductive toxicity insufficient.
Period breastfeeding
In animal studies it has shown that ulipristal passes into breast milk. It is unknown whether ulipristal penetrates the female breast milk and therefore it is impossible
eliminate the risk for children during the breastfeeding period. Ulipristal is contraindicated during breastfeeding.
Dosing and Administration
Inside one tablet 1 time per day regardless of the meal for no more than 3 months.
Treatment should begin during the first week of the menstrual cycle.
There are no data on the treatment of more than 3 months, or repeated courses of treatment, therefore, the duration of treatment should not exceed 3 months.
When you miss pills should take a tablet of the drug as possible Esmya faster. If the appointment is missed by more than 12 hours, the missed tablet is not
It accepted, and should be easy to resume the normal reception mode.
Special groups of patients
kidney failure
In patients with mild or moderate renal insufficiency correction doses are not required. Esmya is not recommended for use in patients with severe renal insufficiency when it is impossible for ongoing monitoring (see. See "Special Instructions").
Liver failure
In patients with mild hepatic insufficiency dose adjustment is required. Esmya is not recommended for use in patients with moderate or severe hepatic insufficiency when it is impossible for ongoing monitoring (See. "Special Instructions" section).
Children
Application Esmya preparation of the relevant indications in children is not provided. Safety and efficacy established only for ulipristal Women 18 years and older.
Side effect
Security Profile Overview
Ulipristal Safety was evaluated in 393 women with uterine fibroids treated with 5 mg or 10 mg ulipristala during phase III studies. The most commonly observed phenomenon in clinical studies was amenorrhea (82.2%), which is considered desired outcome.
The most frequent adverse event was the appearance of "hot flashes." overwhelming Most adverse reactions were mild or lungs (94.9%), did not lead to cessation of drug treatment (99.3%) and resolved on their own.
List of adverse reactions
In two studies of phase III in patients with uterine fibroids patients receiving the drug in Within 3 months, reported the following adverse reactions. adverse adverse reactions are presented by system-organ classes in accordance with the MedDRAi classification with the frequency of occurrence: very common (> 1/10 ,,), often (by > ,, 1/100 to <1 ,, = "" 10 = ""> ,, 1/1000 to <1 ,, = "" 100 = ""> ,, 1/10000 to <1 ,, = "" 1000 = "" p = ""> ,, rare (<1 ,, 10000 = "" p = ""> ,,
Within each frequency band side reactions are presented in order decreasing seriousness.
mental disorders
Frequent: emotional disorders.
Uncommon: anxiety.
Disorders of the nervous system
Common: headache * (* - see the "Description of selected adverse reactions" section.).
Infrequent: dizziness.
Violations of the metabolism and nutrition
Uncommon: weight gain
Violations of the organ of hearing and labyrinth disorders
Common: vertigo.
Disorders of the respiratory system, organs, thoracic and mediastinal disorders
Infrequent: epistaxis.
Disorders of the gastrointestinal tract
Common: abdominal pain, nausea.
Uncommon: dyspepsia, dry mouth, flatulence, constipation.
Disorders of the skin and subcutaneous tissue
Frequent: acne, increased sweating.
Infrequent: skin lesions.
Violations by mygiechnoy skeletal system and connective tissue
Common: pain in the bones and muscles.
Uncommon: back pain.
Violations of the kidney and urinary tract
Infrequent: urinary incontinence.
Violations of the genital and breast
Very Frequent: amenorrhea, endometrial thickening *, "tides" *.
Frequent: metrorrhagia *, ovarian cyst *, tension / breast tenderness, pelvic pain.
Infrequent: metrorrhagia, ovarian cysts rupture, vaginal discharge, and an increase in discomfort in the mammary glands.
General disorders and administration site in
Common: edema, fatigue.
Infrequent: asthenia.
Changes in laboratory and instrumental investigations
Frequent: increasing the concentration of cholesterol in the blood.
Infrequent: increased concentration of triglycerides in the blood.
Description of the individual adverse events
The thickening of the endometrium
In 10-15% of patients receiving ulipristal, thickening of the endometrium may occur (> ,, 16 mm by ultrasound or MRI at the end of treatment). This phenomenon is reversible
after cessation of treatment and restoration of the menstrual cycle. Moreover, reversible changes in the endometrium, designated as PAEC differ from endometrial hyperplasia. The pathologist should be informed about the reception ulipristal patient during histological examination at hysterectomy or endometrial biopsy.
"Tides"
"Tides" were observed in 12.7% of patients, but the frequency is varied in different studies. In a study with their active control rate was 24% (10,5% moderate or severe) for ulipristala group and 60.4% (39.6% moderate or severe) for leuprorelin group. In the placebo-controlled study, the frequency of "Tide" amounted to 1.0% for ulipristala and 0% for placebo.
Headache
Headache mild to moderate occurred in 6.4% of patients.
Ovarian cyst
At 1.5% of the patients during treatment with functional ovarian cysts have been found, who disappeared spontaneously within a few weeks.
Uterine bleeding
Patients with heavy menstrual bleeding due to uterine leiomyoma, They are at risk of increased bleeding, which may require surgery. There were several such reports in the course of therapy,
and after 2-3 months after treatment ulipristal th.
Overdose
Data on overdose ulipristala limited.
Single doses of 200 mg and 50 mg doses daily for 10 days designate a limited number of volunteers, with no marked or severe serious adverse reactions.
Interaction with other drugs
The possible influence of other drugs on the action ulipristal
Hormonal contraceptives
Ulipristal has steroidal structure and acts as a selective modulator predominantly progesterone receptor inhibitory effect on progesterone receptors. Thus, gestagens and hormonal contraceptives may reduce the effectiveness of ulipristala by competitive effects on the receptor progesterone. Therefore, it is not recommended the simultaneous use of drugs,
containing progestins.
Inhibitors of CYP3A4
After applying a moderate inhibitor of CYP3A4 Erythromycin
propionate (500 mg, 2 times a day for 9 days) in healthy female volunteers Stach and AUCulipristala indicators rose by 1.2 and 2.9 times, respectively, the value AUCaktivnogo ulipristala metabolite increased 1.5 times, while Sschah active metabolite decreased (at 0.52 times). The combined use of high-power inhibitors isoenzyme CYP3A4 (ketoconazole, ritonavir, nefazodone) may lead a greater increase ulipristala concentration in blood plasma. No dose adjustment when ulipristala application in patients receiving weak inhibitors of isoenzyme CYP3A4, is not required. The combined use of moderate or potent inhibitors CYP3A4 isoenzyme with ulipristalom not recommended.
Inducers of CYP3A4
In patients receiving inducers of CYP3A4 isoenzyme, can be observed ulipristala decreased concentration in the blood plasma. The combined use of ulipristala and potent inducers of CYP3A4 isoenzyme (rifampicin, carbamazepine, phenytoin, St. John's wort preparations) is not recommended.
Agents affecting gastric pH
Application ulipristala (10 mg / day) together with a proton pump inhibitor esomeprazole (20 mg 1 time per day for 6 days) reduces the average whisk 65% elongation (median of 0.75 hours to 1.0 hours) and a higher average AUCna 13%. Such action of drugs that increase the pH of gastric juice without It considered clinically significant for the daily use of pills ulipristala Possible impact on the action ulipristala drugihlekarstvennyh drugs
Hormonal contraceptives
Ulipristal may interfere with the action of hormonal contraceptives (only gestagensoderzhaschih pills progestogen-releasing systems or combined oral contraceptives) and progestogen drugs used for other indications. Therefore, the use of concomitant medication containing the progestogen without recommended. Gestagensoderzhaschie drugs should not be used within 12 days
ulipristalom after cessation of treatment.
Substrates of P-glycoprotein
These invitropokazyvayut that ulipristal at clinically relevant concentrations During absorption in the wall of the gastrointestinal tract may be an inhibitor of P-glycoprotein (P-gp). Thus, concomitant use may ulipristala increase the concentration of other drugs - P-gp- substrates in plasma blood. In the absence of clinical data and the simultaneous use of ulipristala
substrates of P-gp (dabigatran etexilate, digoxin) is not recommended. The patient should tell your doctor about all the medications she takes, even if they are sold without prescription.
Special instructions
Ulipristal is prescribed only after thorough examination. Prior to treatment should be exclude pregnancy.
Contraception
In connection with the possibility of adverse interactions concomitant use only gestagensoderzhaschih drugs progestogen-releasing systems or combined oral contraceptives is not recommended. Although the majority of women treated ulipristala therapeutic doses, was observed anovulation, recommended additional use of non-hormonal method of contraception during treatment.
kidney failure
There is no reason to assume that kidney failure can significantly influence the ulipristala removal is not recommended without a permanent ulipristal observation in patients with severe renal failure patients, as special studies have not been conducted.
Liver failure
No experience ulipristala therapeutic use in patients with hepatic failure. That liver failure is expected may influence ulipristala excretion, leading to a strengthening of the drug. It is not essential
for patients with liver failure mild. Not recommended ulipristal appoint patients with moderate or severe hepatic failure if it is impossible for ongoing monitoring.
concomitant therapy
Ulipristal is not recommended for the use of patients receiving P-gp substrates
(Dabigatran etexilate, digoxin).
Concomitant use of moderate or potent inhibitors of CYP3A4 and ulipristala not recommended.
Concomitant use ulipristala and powerful inducers of CYP3A4 (Rifampicin, carbamazepine, phenytoin, Hypericum perforatum preparations) are not
recommended.
endometrial Changes
Ulipristal has a specific pharmacodynamic action on the endometrium.
There may be an increase in endometrial thickness. If the endometrial thickening It persists for 3 months after the end of treatment and the resumption of menstrual
cycle should conduct additional tests to rule out other diseases.
In patients receiving ulipristal may histologically observed changes in the structure of the endometrium. These changes are reversible after completion treatment. These histologic changes are referred to as changes in the endometrium, associated with antagonistic action on the progesterone receptor (PAEC), and they do not It must be erroneously judged as endometrial hyperplasia. In the absence safety data Long-term use (more than 3 months), or repeated courses of treatment the risk of adverse effects on the endometrium in the case continuation of treatment is unknown. Therefore, the treatment duration should not exceed
3 months
Bleeding
Patients should be informed that treatment usually ulipristalom It leads to a significant reduction in menstrual blood loss or amenorrhea within
the first 10 days of treatment. When continuing excessive bleeding patient should be seek medical attention. Typically, the menstrual cycle is resumed for 4 weeks
after the end of treatment.
fertility
The majority of women who took ulipristal at therapeutic doses, there was anovulation. However, fertility long-term use has not been studied ulipristala.
Effects on ability to drive vehicles and mechanisms
Ulipristal may have a minimal effect on the ability to drive vehicles and mechanisms, as after taking ulipristala can observed a slight dizziness.
Release Form
Tablets of 5 mg. On 14 tablets in a blister of PVC / PE / PVDC film and orange aluminum foil. In 2 or 6 blisters in a cardboard box with instructions application.
Storage conditions
In the dark place at a temperature no higher than 30 ° C. Keep out of the reach of children!
Shelf life: 2 years.
Do not use the drug after the expiry date.
