Esmia - instructions for use, dose, side effects, contraindications

Active substanceUlipristalUlipristal

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Esmia®

pills inwards

GEDEON RICHTER, OJSC Hungary

Dosage form: & nbspPills.

Composition:

Composition per 1 tablet:

active substance: whitened acetate 5.00 mg;

Excipients: cellulose microcrystalline 93.50 mg, mannitol 43.50 mg, talc 4.00 mg, croscarmellose sodium 2.50 mg, magnesium stearate 1.50 mg.

Description:

Round biconvex tablets white or almost white with engraved "ES5" on one side.

Pharmacotherapeutic group:receptor progesterone modulator

ATX: & nbsp

G.03.A.D.02 Ulipristal

G.03.A.D Preparations for emergency contraception

Pharmacodynamics:

Ulipristal is an active selective synthetic selective modulator of progesterone receptors (SMPR), which is characterized by a tissue-specific partial antiprogestronic effect.

Endometrium

Ulipristal has a direct effect on the endometrium. At the beginning of daily intake of the drug at a dose of 5 mg during the menstrual cycle in most women (including patients with myoma) another menstrual bleeding ends, and the next does not occur. When the drug is stopped, the menstrual cycle usually resumes within 4 weeks. Direct action on the endometrium leads to changes in the endometrium specific for this class of drugs, associated with an antagonistic effect on the receptors of progesterone (Progesterone Receptor Modulator Associated Endometrial Changes (PAEC)). As a rule, histological changes are represented by inactive and weakly proliferating epithelium, accompanied by asymmetric growth of stroma and epithelium, marked cystic enlargement of glands with mixed estrogenic (mitotic) and progestogen (secretory) effects on the epithelium. Such changes were noted in about 60% of patients who received whitewashed within 3 months. These changes are reversible and disappear after discontinuation of treatment, they should not be taken for endometrial hyperplasia.

Approximately 5% of patients of reproductive age with severe forms of menstrual bleeding have an endometrium thickness of more than 16 mm. In 10-15% of patients receiving whitewashed, the endometrium can thicken (> 16 mm) during treatment. This thickening disappears after discontinuation of the drug and the resumption of menstrual bleeding. If the thickening of the endometrium persists longer than 3 months after the end of treatment and recovery of the menstrual cycle, an additional examination should be conducted to exclude other diseases.

Leiomyoma

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

Pituitary

With the daily administration of vilify at a dose of 5 mg, ovulation is suppressed in most patients, as indicated by the maintenance of a progesterone concentration of about 0.3 ng / ml.

With a daily intake of 5 mg of vilify the dose, the concentration of follicle-stimulating hormone (FSH) is partially reduced, but the concentration of estradiol in the blood plasma in most patients is maintained at the level of the middle follicular phase and corresponds to that in the placebo group.

Ulipristal does not affect the concentration of thyroxin-binding globulin (TSH), adrenocorticotropic hormone (ACTE) and prolactin in the blood plasma for 3 months of treatment.

Preclinical safety data

Pre-clinical studies of pharmacological safety, toxicity of multiple doses and genotoxicity of potential threats to humans have not been revealed. The main findings in studies of general toxicity are associated with the effect on progesterone receptors (as well as on glucocorticosteroid receptors when the drug is used at higher concentrations), with antiprogestronic activity at exposures close to therapeutic in humans.In a 39-week study on monkeys using low doses, changes similar to PACE were found. In connection with its mechanism of action whitewashed causes fetal death in rats, rabbits (at multiple doses above 1 mg / kg), guinea pigs and monkeys. The safety of the drug against the human embryo is not established. In doses small enough to preserve pregnancy in animals, teratogenic potential is not revealed. In studies of reproduction in rats using doses that provide the same exposure as in humans, there is no evidence of an effect on the reproductive capacity of animals receiving whitewashed, as well as their offspring.

In studies conducted in mice and rats, there was no evidence of carcinogenic action.

Clinical efficacy and safety

The efficacy of fixed doses of 5 mg and 10 mg once a day was evaluated in two phase 3 trials involving patients with very severe menstrual bleeding caused by uterine myoma.

Compared with placebo, a clinically significant decrease in the amount of menstrual blood loss was found in patients taking whitewashed. This allowed faster and more effective correction of anemia than with the appointment of only iron preparations. Reduction of menstrual blood loss in patients of the group was vindictive was comparable to the group receiving agonist gonadotropin-releasing hormone (leuprorelin). Most patients who received whitewashed, bleeding stopped during the first week of admission (developing amenorrhea).

According to the data of magnetic resonance imaging in the group, there was a much larger decrease in the size of uterine fibroids than in the placebo group. In patients who did not undergo a hysterectomy or myomectomy, a decrease in the size of uterine fibroids was assessed in the ultrasound at the end of treatment (week 13). As a rule, it persisted for 25 weeks of follow-up in the patients of the group vilified, whereas 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 cycles of 10 mg of 10 mg for 3 months, the incidence of amenorrhea was comparable at the end of both courses of therapy.The decrease in the volume of leiomyoma recorded during the first course was preserved 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, similarly to a dose of 10 mg.

Despite the limited number of patients completing four 3-month courses of treatment, the safety data obtained are 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 whitewashed quickly absorbed, reaching about 1 hour after taking the maximum concentration (C_max) 23.5 ± 14.2 ng / ml and 50.0 ± 34.4 ng / ml, respectively. Area under the curve "concentration-time" (AUC) is 61.3 ± 31.7 and 134.0 ± 83.8 ng-h / ml, respectively. Ulipristal quickly transformed into a pharmacologically active metabolite, while 1 hour after taking C_max is 9.0 ± 4.4 ng / ml and 20.6 ± 10.9 ng / ml, AUC 26.0 ± 12.0 and 63.6 ± 30.1 ng-h / ml, respectively. The reception of the overdue in a dose of 30 mg together with a breakfast with a high fat content leads to a decrease in the average C_max by about 45%, the elongation of the time to reach the maximum concentration (t_max) from the median 0.75 h to 3 h and 25% increase AUC, in comparison with reception on an empty stomach. 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 tablets.

Distribution

Ulipristal to a high degree (> 98%) binds to plasma proteins, including albumin, a-1-acid glycoprotein, high-density lipoproteins and low-density lipoproteins.

Ulipristal and his active N-detylated metabolite penetrate into breast milk; average ratio AUC_t for milk / plasma is 0.74 ± 0.32 for vilification.

Metabolism

Ulipristal quickly turns into a vjyj-N-demethylated and then in di-N- demethylated metabolites. Data in vitro 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 the vigil was mediated by cytochrome P450, it is expected that the peptic insufficiency will affect the excretion of vigilance, which will lead to an increase in its effect.

Excretion

The main way of excretion is through the intestine, less than 10% of the substance is excreted by the kidneys. The final elimination half-life after a single dose of 5 mg or 10 mg is approximately 38 hours, with an average clearance of about 100 l / h. Data in vitro show that in clinically significant concentrations whitewashed and its active metabolite does not inhibit isoenzymes CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4 and do not induce an isoenzyme CYP1A2. Thus, the use of vandalism should not affect the clearance of drugs that are metabolized with the participation of these isoenzymes.

Data in vitro show that whitewashed and its active metabolite are not substrates of P-glycoprotein (ABCB1).

Indications:

Preoperative therapy for symptoms of uterine fibroids of medium severity and severe degree in adult women of reproductive age is over 18 years. Duration of therapy - no more than 2 courses.

Contraindications:

- Hypersensitivity to vulgaris or any of the excipients.

- Pregnancy and the period of breastfeeding.

- Bleeding from the vagina of unclear etiology or for reasons not related to uterine myoma.

- Cancer of the uterus, cervix, ovary or breast.

- Duration of therapy more than 2 courses.

- Age <18 years.

- Bronchial asthma, a severe form that can not be corrected by oral glucocorticosteroids.

Carefully:

Renal and / or liver failure; bronchial asthma

Pregnancy and lactation:

Pregnancy

Ulipristol is contraindicated in pregnancy.

Data on the use of overpriced in pregnant women are absent or limited.

Although there has been no teratogenic potential in animal studies, data on reproductive toxicity are not sufficient.

Breastfeeding period

In animal studies, it has been shown that whitewashed penetrates into breast milk. Ulipristal penetrates into the human breast milk. The effect of the drug on newborns and young children has not been studied, so it is impossible to exclude the risk for children during breastfeeding. Ulipristal contraindicated during breastfeeding.

Dosing and Administration:

Inside, one tablet once a day, regardless of food intake for no more than 3 months.

One-time repeated carrying out of a 3-month course of therapy is allowed. Repeated course of therapy should be started no earlier than the second menstrual cycle after the end of the first course, during the first week.

There are no data on the safety of long-term courses of therapy, so the duration of treatment should not exceed two courses lasting 3 months. In case of missing a pill, you should take the Esmia® tablet as soon as possible. If the reception is missed for more than 12 hours, then the missed tablet is not accepted, and simply resume the normal reception mode.

Special groups of patients

Renal insufficiency

In patients with mild or moderate renal failure, dose adjustment is not required. The drug Esmia® is not recommended for use in patients with severe renal failure if it is not possible to continuously monitor (see section "Special instructions").

Liver failure

In patients with mild hepatic insufficiency, dose adjustment is not required. The drug Esmia® is not recommended for use in patients with moderate or severe hepatic insufficiency if it is not possible to continuously monitor (see section "Special instructions").

Children

The use of the drug Esmia® according to the corresponding indications in children is not provided.The safety and efficacy of vandalism are established only for women 18 years of age and older.

Side effects:

Security Profile Overview

Safety was assessed in 602 women with uterine fibroids receiving 5 mg or 10 mg of ulcers during Phase 3 studies. The most frequent observed phenomenon in clinical trials was amenorrhea (80.8%), which is considered the desired outcome.

The most frequent adverse reaction was the appearance of "tides". The vast majority of adverse reactions were mild or moderate (93.6%), did not lead to discontinuation of drug treatment (99.5%) and were resolved independently.

The safety of two 10 mg weekly treatment courses, each lasting 3 months, was evaluated in a Phase 3 study involving women with uterine fibroids. The data obtained are comparable with the safety profile in the course of treatment within a single course.

List of adverse reactions

In 3 Phase 3 studies, the following adverse reactions were reported in patients with uterine myomas who received the drug for 3 months. Adverse adverse reactions are presented according to the system-organ classes according to the classification MedDRA and with frequency of occurrence: very often (> 1/10); often (from> 1/100 to <1/10); infrequently (from> 1/1000 to <1/100); rarely (from> 1/10 000 to <1/1000); very rarely (<1/10 000); unknown (can not be estimated based on available data).

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

Disorders of the psyche

Infrequent: anxiety, emotional disorders.

Disturbances from the nervous system

Frequent: headache * (* - see section "Description of individual adverse reactions"). Infrequent: dizziness.

Disorders from the metabolism and nutrition

Infrequent: weight gain.

Hearing disorders and labyrinthine disorders

Frequent: vertigo.

Disturbances from the respiratory system, chest and mediastinal organs

Infrequent: epistaxis.

Disorders from the gastrointestinal tract

Frequent: abdominal pain, nausea.

Infrequent: indigestion, dry mouth, flatulence, constipation.

Disturbances from the skin and subcutaneous tissues

Frequent: acne, excessive sweating.

Infrequent: alopecia, dry skin.

Disturbances from musculoskeletal system and connective tissue Frequent: pain in the bones and muscles.

Infrequent: back pain.

Disorders from the kidneys and urinary tract

Infrequent: incontinence.

Violations of the genitals and mammary gland Very frequent: amenorrhea, thickening of the endometrium *.

Frequent: "hot flashes" *, pelvic pain, ovarian cyst *, tensions or tenderness of the mammary glands.

Infrequent: metrorrhagia, rupture of the ovarian cyst, vaginal discharge, an increase and discomfort in the mammary glands.

General disorders and disorders at the site of administration

Frequent: swelling, fatigue.

Infrequent: asthenia.

Changes in laboratory and instrumental studies

Frequent: increased cholesterol concentration in the blood.

Infrequent: increased concentration of triglycerides in the blood.

Description of individual adverse reactions

Endometrial Thickening

In 10-15% of patients who received whitewashed, endometrial thickening may occur (> 16 mm according to ultrasound or MRI data at the end of treatment). This phenomenon is reversible after discontinuation of treatment and the resumption of the menstrual cycle.

In addition, reversible changes in the endometrium, referred to as PACE, differ from endometrial hyperplasia. The pathologist should be informed of the patient's admission of a vaginal discharge during a histological examination with hysterectomy or endometrial biopsy.

* "Tides"

"Tides" were noted in 9.8% of patients, but their frequency varied in different research. In a study with active control, their incidence was 24% (10.5% of the average or severe severity) for the group vilified and 60.4% (39.6% of moderate or severe severity) for the leuprorelin group. In a placebo-controlled study, the frequency of "hot flashes" was 1.0% for vandal and 0% for placebo.

In the framework of the open phase 3 study, the frequency of "hot flashes" was 4.3% in the group of vandals.

Headache

Headache of mild or moderate degree was noted in 6.8% of patients.

*Ovarian cyst

In 1.2% of patients during the treatment, functional ovarian cysts were found that spontaneously disappeared within a few weeks.

Uterine bleeding

Patients with severe menstrual bleeding due to uterine leiomyoma are at increased risk of blood loss, which may require surgical intervention. There have been several such reports, both during therapy and 2-3 months after the end of treatment with vandalism.

Overdose:

Data on overdose of over-sight is limited.

Single doses up to 200 mg and daily doses of 50 mg for 10 days were administered to a limited number of volunteers, without serious or serious adverse reactions.

Interaction:

The possible influence of other drugs on the action of whip Hormonal contraceptives

Ulipristal has a steroid structure and acts as a selective modulator of progesterone receptors with a predominant inhibitory effect on the receptors of progesterone. Thus, hormonal contraceptives and gestagens can reduce the effectiveness of vandalizing by competing with the progesterone receptor. Therefore, simultaneous use of preparations containing gestagens is not recommended.

Inhibitor inhibitors CYP3A4

After using an inhibitor of the average isoenzyme capacity CYP3A4 erythromycin propionate (500 mg twice daily for 9 days) in healthy female volunteers indicators C_max and AUC vypristupala increased by 1.2 and 2.9 times, respectively; the AUC value of the active metabolite increased 1.5 times, while C_max of the active metabolite decreased (by 0.52 times).Against the background of the use of ketoconazole (400 mg once a day, 7 days), a powerful inhibitor of CYP3A4, in healthy female volunteers of the study there was an increase in the C_max and AUC was overpriced at 2 and 5.9 times, respectively. There was an increase in the AUC for the active metabolite, which exceeded 2.4 times with a decrease in its C_max (a change of 0.53 times). Dose adjustments in the use of vaginal discharge in patients receiving weak inhibitors of the CYP3A4 isoenzyme are not required. The combined use of medium-strength inhibitors or potent inhibitors of the isoenzyme CYP3A4 with ulcers is not recommended.

Inductors of isoenzyme CYP3A4

Against the background of the use of a powerful inductor CYP3A4 rifampicin (300 mg twice daily, 9 days) in healthy female volunteers, there was a marked decrease in C_max and AUC and its active metabolite more than 90%. Also, there was a decrease in the half-life of vandalitis by 2.2 times, which corresponds to a decrease in its exposure by about 10 times. The concomitant use of vandal and powerful inductors CYP3A4 (for example, rifampicin, rifabutin, carbamazepine, oxcarbazepine, phenytoin, phosphenytoin,phenobarbital, primidon, St. John's wort, efavirenz, nevirapine, ritonavir - against long-term use) is not recommended.

Drugs affecting the pH of gastric juice

The use of ulcers (10 mg / day) together with the proton pump inhibitor esomeprazole (20 mg once a day for 6 days) leads to a decrease in the mean C_max by 65%, elongation t_max (from a median of 0.75 hours to 1.0 hours) and an increase in the mean AUC on 13%. Such action of drugs that increase the pH of gastric juice, is not considered clinically significant for daily intake of vaginal tablets.

Possible influence of other drugs on the effect of other drugs

Hormonal contraceptives

Ulipristal can interfere with the action of hormonal contraceptives (only gestagen-containing tablets, gestagen-releasing systems or combined oral contraceptives) and progestogen drugs used for other indications. Therefore, the concomitant use of medications containing gestagen is not recommended. Gestagen-containing drugs should not be used within 12 days after the cessation of treatment by illicit drug.

Substrates of P-glycoprotein

Data in vitro show that in clinically significant concentrations whitewashed in the process of absorption in the wall of the gastrointestinal tract may be an inhibitor of P-glycoprotein (P-gp). Simultaneous use of jam and substrate P-gp It has not been investigated, therefore, the probability of interactions can not be ruled out. Data in vivo indicate that the administration of the illicit (tablet 10 mg) for 1.5 hours before receiving the substrate P-gp fexofenadine (60 mg) does not have a clinically significant effect on the pharmacokinetics of fexofenadine. Thus, it is recommended to observe an interval of not less than 1.5 hours between reception of overprints and substrates P-gp (for example, dabigatran etexilate, digoxin, fexofenadine). The patient should inform the attending physician about all medications that she takes, even if they are dispensed without a prescription.

Special instructions:

Ulipristal is prescribed only after a thorough examination. Pregnancy should be excluded before treatment begins.

Contraception

Due to the possibility of unwanted interactions, the 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 ulcers, anovulation was observed, additional use of non-hormonal method of contraception during treatment was recommended.

Renal insufficiency

There is no reason to believe that renal insufficiency can significantly affect the excretion of ulcers. It is not recommended to apply whitewashed without constant observation in patients with severe renal insufficiency, since no special studies have been conducted.

Liver failure

There is no experience of therapeutic use of ulcers in patients with hepatic insufficiency. It is expected that liver failure can affect the excretion of ulcers, which will lead to an increase in the effect of the drug. This is unimportant for patients with mild hepatic insufficiency. It is not recommended to appoint whitewashed Patients with moderate or severe hepatic impairment when it is not possible to continuously monitor.

Concomitant therapy

It is not recommended concomitant use of vandal and inhibitors CYP3A4 (eg, erythromycin, grapefruit juice, verapamil) or potent inhibitors (eg, ketoconazole, ritonavir, nefazodone, itraconazole, telithromycin, clarithromycin).

It is not recommended to use the combined use of jam and powerful inductors CYP3A4 (eg, rifampicin, rifabutin, carbamazepine, oxcarbazepine, phenytoin, phosphenytoin, phenobarbital, primidon, St. John's wort, efavirenz, nevirapine, ritonavir - against long-term use).

Changes in the endometrium

Ulipristal has a specific pharmacodynamic effect on the endometrium. An increase in the thickness of the endometrium may be noted. If the thickening of the endometrium persists longer than 3 months after the end of treatment and the resumption of the menstrual cycle, an additional examination should be conducted to exclude other diseases. Patients receiving whitewashed, with histological examination, changes in the structure of the endometrium may be observed. Such changes are reversible after the completion of treatment. These histological changes are referred to as endometrial changes associated with the antagonistic effect on the progesterone receptors (PACE),and they should not be mistakenly evaluated as endometrial hyperplasia. It is recommended to conduct 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 against a background of longer therapy is unknown.

Bleeding

Patients should be informed that treatment with ulcers usually results in 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. Typically, the menstrual cycle resumes within 4 weeks after the end of the course of treatment.

Fertility

Most women who took whitewashed in therapeutic doses, anovulation was observed. However, fertility with prolonged use of vandalitis has not been studied.

Effect on the ability to drive transp. cf. and fur:Impact on the ability to drive vehicles and mechanisms. Ulipristal can have a minimal impact on the ability to drive vehicles and mechanisms, since after taking vigilant can experience slight dizziness.

Form release / dosage:

Tablets, 5 mg.

Packaging:For 14 tablets in a blister of PVC / PE / PVDH films of orange color and aluminum foil. For 2 or 6 blisters in a cardboard box together with instructions for use.

Storage conditions:

In the dark place at a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002000

Date of registration:13.02.2013

The owner of the registration certificate:GEDEON RICHTER, OJSC GEDEON RICHTER, OJSC Hungary

Manufacturer: & nbsp

GEDEON RICHTER, Ltd. Hungary

Representation: & nbspGEDEON RICHTER OJSC GEDEON RICHTER OJSC Hungary

Information update date: & nbsp20.10.2015

Illustrated instructions

Instructions

Esmia® (Esmya®)