Nosological classification (ICD-10)
Description of the dosage form
Round biconvex tablets of white or almost white color with “ES5” engraving on one side.
Ulipristal is an active, orally administered synthetic, selective progesterone receptor modulator, characterized by a tissue-specific partial anti-progesterone effect.
Endometrium Ulipristal has a direct effect on the endometrium. At the beginning of the daily intake of the drug in a dose of 5 mg during the menstrual cycle in most women (including patients with myoma), the next menstrual bleeding ends, and the next does not occur. When the drug is stopped, the menstrual cycle usually resumes within 4 weeks. A direct effect on the endometrium leads to changes in the endometrium that are specific for this class of drugs, associated with an antagonistic effect on progesterone receptors (Progesterone Receptor Modulator Associated Endometrial Changes (PAEC). Typically, histological changes are represented by an inactive and weakly proliferating epithelium and are accompanied by stromal growth asymmetry and epithelium, pronounced cystic enlargement of the glands with mixed estrogenic (mitotic) and progestogenic (secretory) influences on the epithelium. Such changes were noted approximately 60% of patients receiving ulipristal within 3 months. These changes are reversible and disappear after cessation of treatment, they should not be mistaken for endometrial hyperplasia.
Approximately 5% of patients of reproductive age with severe forms of menstrual bleeding endometrial thickness more than 16 mm. In 10–15% of patients receiving ulipristal, the endometrium may thicken (>16 mm) during treatment. This thickening disappears after discontinuation of the drug and the resumption of menstrual bleeding. If endometrial thickening persists for 3 months after the end of treatment and the restoration of the menstrual cycle, an additional examination should be conducted to rule out other diseases.
Leiomyoma. 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 the majority of 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 plasma 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, 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 associated with 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 the death of fruits 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 has been identified. Reproduction studies in rats using doses that provide the same exposure as humans did not show evidence of an effect on the reproductive ability of animals receiving uliprystyle, as well as on their offspring. Carcinogenicity studies have not been conducted.
Clinical efficacy and safety. The effectiveness of fixed doses of ulipristal 5 and 10 mg 1 time per day was evaluated in 2 phase III studies, in which patients with very heavy menstrual bleeding caused by uterine myoma participated. In comparison with placebo, a clinically significant decrease in the volume of menstrual blood loss was detected in patients who had taken the snail powder. 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 receiving ulipristal was comparable to the group receiving the GnRH agonist (leuprorelin). In most patients who received ulistrist, the bleeding stopped during the 1st week of administration (amenorrhea developed). According to MRI, patients receiving ulipristal had a significantly greater reduction in the size of uterine fibroids than in the placebo group. In patients who did not undergo hysterectomy or myomectomy, a decrease in the size of the uterine myomas was evaluated by ultrasound control at the end of treatment (13th week). As a rule, it was maintained for 25 weeks of follow-up in patients receiving ulipristal, while in the group treated with leuprorelin, there was a slight increase in the size of uterine fibroids.
As part of another phase III study, during 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 registered during the 1st course was maintained during the 2nd course.
Taking into account the results of previous studies, the effectiveness of the drug in a dose of 5 mg during the 1st course of therapy will be the same during the 2nd course of therapy, similar to the dose of 10 mg.
Despite the limited number of patients who completed four 3-month courses of treatment, the safety data obtained are sufficient to substantiate one additional 3-month course of therapy in the preoperative period.
Suction. After a single oral dose of 5 or 10 mg of ulipristal is rapidly absorbed, reaching approximately 1 hour after taking it Cmax (23.5 ± 14.2) and (50 ± 34.4) ng / ml, respectively. AUC0 – ∞ is (61.3 ± 31.7) and (134, ± 83.8) ng · h / ml, respectively. Ulipristal is quickly transformed into a pharmacologically active metabolite, with 1 h after administration, Cmax is (9 ± 4.4) and (20.6 ± 10.9) ng / ml, AUC0 – ∞ – (26 ± 12) and (63 , 6 ± 30.1) ng · h / ml, respectively. Reception of ulipristal at a dose of 30 mg, along with a high-fat breakfast, leads to a decrease in the average Cmax by about 45%, an increase in Tmax 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 intake of ulipristal tablets.
Distribution. Ulipristal to a high degree (>98%) is bound to plasma proteins, including albumin, α1-acid glycoprotein, HDL and LDL.
Metabolism. Ulipristal quickly turns into a mono-N-demethylated and then a di-N-demethylated metabolite. 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 is mediated by cytochrome P450, the effect of liver failure on the excretion of ulipristal is expected, which will lead to an increase in its effect.
Derivation. 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 after a single dose of 5 or 10 mg is approximately 38 h, the average clearance is about 100 l / h. In vitro data show that clinically significant concentrations of ulipristal and its active metabolite do not inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 isoenzymes and do not induce CYP1A2 isoenzyme. Thus, the use of ulipristal should not affect the clearance of drugs that are metabolized with the participation of these isoenzymes. In vitro data shows that sniperista and its active metabolite are not substrates of P-glycoprotein (P-gp).
Indications drug Esmia ®
Preoperative treatment of moderate and severe uterine fibroid symptoms in adult women of reproductive age over 18 years. The duration of therapy is not more than 2 courses.
hypersensitivity to stulis or any of the excipients;
pregnancy and breastfeeding;
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 for more than 2 courses;
bronchial asthma (severe, not amenable to correction with oral GCS);
age under 18 years.
With care: renal and / or liver failure; bronchial asthma.
Use during pregnancy and lactation
Ulipristal contraindicated during pregnancy. Data on the use of ulipristal in pregnant women are missing or limited. Although no teratogenic potential has been identified in animal studies, reproductive toxicity data are insufficient.
In animal studies, it has been shown that ulpristyle passes into breast milk. It is not known whether ulipristal penetrates into breast milk, therefore, the risk to children during breastfeeding cannot be excluded. Ulipristal contraindicated during breastfeeding.
Security Profile Overview
Safety of ulipristal was evaluated in 602 women with uterine fibroids who received 5 or 10 mg of ulipristal during phase III studies. Amenorrhea (80.8%), 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 (93.6%), did not lead to discontinuation of drug treatment (99.5%) and resolved on their own.
The safety of two courses of treatment with ulipristal 10 mg, each lasting 3 months, was evaluated in a phase III study involving women with uterine myomas. The obtained data are comparable with the safety profile during treatment in one course.
List of adverse reactions
During the 3rd phase III study 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 * see “Description of individual adverse reactions”.
General disorders and disorders at the injection site: often – edema, fatigue; infrequently – asthenia.
Changes in laboratory and instrumental studies: 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 receiving ulipristal, endometrial thickening may occur (>16 mm, according to an ultrasound or MRI at the end of treatment). This phenomenon is reversible after stopping treatment and resuming the menstrual cycle. In addition, reversible changes in the endometrium, referred to as RAEC, differ from endometrial hyperplasia. The pathologist must be informed that the patient has received ulipristal when performing a histological examination for endometrial hysterectomy or biopsy.
Tides It was noted in 9.8% 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 receiving ulipristal and 60.4% (39.6% moderate or severe) for receiving leuprorelin. In a placebo-controlled study, the frequency of tides was 1% for ulipristal and 0% for placebo.
Headache. Mild or moderate was observed in 6.8% of patients.
Ovarian cyst. In 1.2% 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 after 2–3 months after the end of treatment with ulipristal.
Possible effects of other drugs on the action of ulipristal
Hormonal contraceptives. Ulipristal 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 by competitive effects on the progesterone receptor. Therefore, the simultaneous use of drugs containing gestagens is not recommended.
Inhibitors of the isoenzyme CYP3A4. After using a moderate inhibitor of the CYP3A4 isoenzyme – erythromycin propionate (500 mg 2 times a day for 9 days) – in healthy female volunteers, the Cmax and AUC values of ulipristal increased 1.2 and 2.9 times, respectively; The AUC value of the active metabolite of ulipristal increased by 1.5 times, while the Cmax of the active metabolite decreased (by 0.52 times).
The use of ketoconazole (400 mg 1 time per day, 7 days), a potent inhibitor of CYP3A4, in healthy female volunteers, the Cmax and AUC values of ulipristal increased 2 and 5.9 times, respectively. There was an increase in AUC for the active metabolite of ulipristal by 2.4 times with a decrease in 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 moderate and potent inhibitors of CYP3A4 isoenzyme with ulipristalom is recommended.
Inductors of isoenzyme CYP3A4. The use of rifampicin, a potent inducer of CYP3A4 (300 mg, 2 times a 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%. Also, a decrease in T1 / 2 ulipristala 2.2 times, which corresponds to a decrease in its exposure by about 10 times. Concomitant use ulipristala and powerful inducers of CYP3A4 (for example, rifampicin, rifabutin, carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, primidone, Hypericum perforatum, efavirenz, nevirapine, ritonavir, – long-term use on the background) are not recommended.
Drugs that affect the pH of gastric juice. The use of ulipristal (10 mg / day) together with a proton pump inhibitor — esomeprazole (20 mg once a day for 6 days) —– results in a decrease in the average Cmax by 65%, Tmax elongation (from a median of 0.75 h to 1 h) and an increase in the average AUC by 13%. Such an effect of drugs that increase the pH of the gastric juice is not considered clinically significant for the daily intake of ulipristal tablets.
Possible influence of snails on the effect of other drugs
Hormonal contraceptives. Ulipristal may interfere with the action of hormonal contraceptives (progestin-containing pills, progestogen-releasing systems, or combined oral contraceptives) and progestogen preparations used for other reasons. Therefore, the concomitant use of drugs containing gestagen is not recommended. Progestin-containing drugs should not be used within 12 days after stopping uripristal.
Substrates P-gp. In vitro data show that, at clinically significant concentrations, the ulipristal during absorption in the wall of the gastrointestinal tract may be an inhibitor of 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 (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 an 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 attending physician of all medications that she takes, even if they are available without a prescription.
Dosage and administration
Inside, on 1 tab. Once a day, regardless of the meal, for no more than 3 months.
A one-time repeated holding of a 3-month course of therapy is allowed. A second course of therapy should begin no earlier than the 2nd menstrual cycle after the end of the 1st course, during the first week.
There are no data on the safety of long-term courses of therapy, therefore the duration of treatment should not exceed two courses of 3 months duration.
If you miss a pill, you should take a pill of Esmya ® as soon as possible. If the intake is missed for more than 12 hours, then the missed tablet is not taken, and you should simply resume the normal mode of administration.
Special patient groups
Renal failure. In patients with mild or moderate renal insufficiency, dose adjustment is not required. The drug Esmya ® is not recommended for use in patients with severe renal insufficiency if it is impossible to continuously monitor (see “Special instructions”).
Liver failure. In patients with mild hepatic insufficiency dose adjustment is not required. Esmya ® is not recommended for use in patients with moderate or severe hepatic impairment if continuous monitoring is not possible (see “Special Instructions”).
Children. The use of Esmia ® according to the appropriate indications in children is not provided. Safety and effectiveness of ulipristal are established only for women aged 18 years and older.
Data on overdose of ulipristal is limited.
Single doses of up to 200 mg and daily doses of 50 mg were administered to a limited number of volunteers for 10 days, with no serious or serious adverse reactions noted.
Ulipristal is appointed 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 drugs, gestagen-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 ullistal. It is not recommended to use ulipristal without constant supervision in patients with severe renal failure,
Liver failure. There is no experience of therapeutic use of ulipristal in patients with liver failure. It is expected that liver failure may affect the elimination of ulipristal, which will lead to increased drug action. This is not essential for patients with mild hepatic insufficiency. It is not recommended to prescribe ulipristal to patients with moderate or severe liver failure when it is impossible to continuously monitor.
Concomitant Therapy 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 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 the menstrual cycle, an additional examination should be conducted to rule out other diseases. In patients receiving ulisperis, histological examination may be observed 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 RAEC, and they should not be mistakenly assessed as endometrial hyperplasia. It is recommended that no more than 2 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 the treatment with ulipristal usually leads to a significant reduction in menstrual blood loss or amenorrhea during the first 10 days of treatment. With persistent 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 received snail powder in therapeutic doses, anovulation was observed. However, fertility with prolonged use of ulipristal has not been studied.
Influence on ability to drive vehicles and mechanisms. Ulipristal can have a minimal impact on the ability to drive vehicles and mechanisms
Tablets, 5 mg. At 14 tab. in a blister of PVC / PE / PVDC film of orange color and aluminum foil. 2 or 6 blisters are placed in a cardboard box.
Gideon Richter OJSC. 1103 Budapest, ul. Demrei, 19-21, Hungary.
The claims of consumers should be sent to the address: Moscow Representative Office of Gedeon Richter OJSC. 119049 Moscow, 4th Dobryninsky per., 8.
Tel: (495) 363-39-50; fax: (495) 363-39-49.
Pharmacy sales terms
The storage conditions of the drug Esmia ®
Keep out of the reach of children.
The shelf life of the drug Esmia ®
Do not use after the expiration date printed on the package.