Esmya tablets 5mg #28

Pharmacological properties:
Ulipristal - when taken orally active synthetic selective modulator progesterone receptor (SMLF) partially characterized tissue-specific antiprogesteronovym effect.

Endometrium:
Ulipristal has a direct effect on the endometrium. At the beginning priёmapreparata 5 mg per menstrual cycle in most women (including patients with myoma) ends next menstrual bleeding, and the next does not occur. When taking the drug stops the menstrual cycle is usually resumed for 4 weeks. The direct action on the endometrium results in specific for this class of drugs endometrial changes associated with antagonistic action on the  progesterone receptors (ProgesteroneReceptor ModulatorAssociatedEndometrialChanges (PAEC)). Typically, histologic changes presented inactive and weakly proliferating epithelium accompanied by the asymmetry of stromal and epithelial growth, severe cystic expansion glands with mixed estrogen (mitotic) and progestogen (Secretory) the effect on the epithelium. Such changes were observed in approximately 60% patients receiving ulipristal for 3 months. These changes are reversible and disappear after cessation of treatment, should not be taken for hyperplasia endometrium.

Approximately 5% of patients of reproductive age with severe menstrual bleeding endometrial thickness greater than 16 mm. In 10-15% of patients, receiving ulipristal endometrium may thicken (> 16 mm) in the course of treatment. Is This 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 the leiomyoma, suppressing cell proliferation and inducing apoptosis, which leads to a reduction in their size.

Pituitary:
With daily admission ulipristala 5 mg is suppressed ovulation. The majority of 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 of estradiol in the plasma. Blood in most patients maintained at mid follicular 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 levels during 3 months of treatment.

Preclinical safety data:
In preclinical studies of pharmacological safety, toxicity multiple doses and genotoxicity potential threats to humans have been identified. Key findings in general toxicity studies related to the effects on receptors progesterone (as well as glucocorticosteroid receptors when using the drug in higher concentrations), with antiprogesteronovoy activity at exhibitions, close to a human therapeutic. In the 39-week study in monkeys with use of low doses were identified changes similar to PAEC. In connection with their ulipristal mechanism of action causes fetal death in rats and rabbits (in Multiple doses above 1 mg / kg), guinea pigs and monkeys. Safety drug against human embryo is not installed. At doses small enough to preserve Pregnancy, teratogenic potential was not detected. Studies Reproduction in rats using dosages providing such exposure, as in man, found no evidence of effect on the  reproductive ability of animals receiving ulipristal, as well as their offspring. Carcinogenicity studies have not been conducted.

Clinical efficacy and safety:
Efficacy ulipristala fixed dose of 5 mg and 10 mg once a day evaluated in two Phase 3 studies, which involved patients with very heavy menstrual bleeding caused by fibroids of the uterus. Compared 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. Decrease in menstrual blood loss in patients group ulipristala was comparable to the group receiving agonist of gonadotropin-releasing hormone (leylrorelin). Most patients treated with ulipristal, bleeding was eliminated during the first week (developed amenorrhea). According to MRI in the group was significantly ulipristala greater reduction in size of uterine fibroids than in the placebo group. Patients, which not had a hysterectomy or myomectomy, with ultrasonic control at the end of treatment (Week 13) was estimated reduction in size of uterine fibroids. As a rule, it persisted throughout the 25 weeks of follow-up in patients group ulipristala, whereas in the group treated with leuprorelin, showed some increase in size of uterine fibroids.

Pharmacokinetics:

Absorption: After a single oral administration dose of 5 mg or 10 mg ulipristal rapidly absorbed, reaching about 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 converted into a pharmacologically active metabolite, with 1 hour after Admission Cmax is 9,0 ± 4,4 ng / ml and 20,6 ± 10,9 ng / ml, AUCo-oo26,0 ± 12,0 and 63.6 = 30.1 s ng-hr / mL, respectively. Admission sale stuck at a dose of 30 mg with breakfast high fat reduces the average Cmax approximately 45% elongation
time to reach maximum concentration (tmax) of the median 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 is not regarded as significant for the daily use of tablets in there stuck.

Distribution: Ulipristal highly (> 98%) binds to plasma proteins, including albumin, and 1-acid glycoprotein, lipoproteins, and high density lipoprotein density.

Metabolism: Ulipristal rapidly converted to MOHO-N-desmethyl and then di-N-demethylated metabolites. These invitropokazyvayut that this process occurs system involving cytochrome P450 isoenzyme ZA4 (CYP3A4). Based on the fact that ulipristala metabolism mediated by cytochrome P450, is expected to influence hepatic failure to ulipristala excretion, leading to an increase in its effect.

Breeding: The main route of excretion - through the intestines, less than 10% of the substance 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 show, 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 clearance of drugs that are metabolized with the participation of the data isoenzymes.

Invitro data indicate that ulipristal and its active metabolite are not substrates of P-glycoprotein (AVSV1).

Indications for use:
Preoperative treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age over 18 years of not more than 3 months.

Contraindications:

• Ulipristalu or hypersensitivity to any of the excipients
• Pregnancy and breast-feeding
• Vaginal bleeding of unknown aetiology or for reasons unrelated to uterine myoma
• Cancer of the uterus, cervix, ovary or breast
• Duration of therapy for more than 3 months (due to the lack of data on safety over prolonged use)
• Age <18 years
• Bronchial asthma, a severe form, can not be corrected with oral glucocorticosteroids
• Precautions: renal and / or hepatic insufficiency, bronchial asthma.
• Pregnancy and lactation

Pregnancy:
Ulipristal is contraindicated in pregnancy. Data on the use in pregnant ulipristala absent or limited. Despite the fact that in the course of research on animals is not teratogenic potential found, data relating to the reproductive toxicity insufficient. Breastfeeding in animal studies demonstrated that ulipristal passes into breast milk. It is not known whether ulipristal in human breast milk, so it is impossible eliminate the risk for children during breastfeeding. 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 treatment for more than 3 months, or repeated courses of therapy, so duration of treatment should not exceed 3 months. When you miss a pill should be taken as a pill drug can Esmiya® faster. If the receipt is missing for more than 12 hours, the missed pills not
accepted, and should simply resume normal reception.

Special groups of patients:

Renal failure: In patients with mild or moderate renal insufficiency correction doses are not required. Esmiya® drug is not recommended for use in patients with severe renal failure when it is impossible for ongoing monitoring (see "Special Instructions").

Liver failure: In patients with mild hepatic insufficiency dose adjustment is required. Esmiya® drug is not recommended for use in patients with moderate or severe hepatic impairment when it is impossible for ongoing monitoring
(See. Section "Special Instructions").

Children: Use of the drug Esmiya® relevant indications in children is not provided. Safety and efficacy ulipristala set only for women 18 years and older.

Side effects:
Profile Security: Safety was evaluated in ulipristala 393 women with uterine fibroids treated with 5 mg or 10 mg ulipristala during Phase III studies. The most frequently observed phenomenon in clinical trials was amenorrhea (82.2%), which is considered the desired outcome.

The most common adverse reaction was the emergence of "hot flashes." Overwhelming most adverse events were mild or lungs (94.9%) did not lead to cessation of treatment (99.3%) and resolved on their own.

The list of adverse reactions:
In two studies of phase III in patients with uterine fibroids treated with the drug in within 3 months, reported the following adverse reactions. Adverse adverse reactions are presented by system-organ class in accordance with the
MedDRAi classification with the frequency of occurrence: very common (> 1/10); often (from > 1/100 to <1/10); infrequently (from> 1/1000 to <1/100); rarely (from> 1/10000 to <1/1000); very much rare (<1/10000); not known (can not be estimated from the available data).
Within each frequency band side reactions are presented in order of decreasing seriousness.
Mental disorders
Frequent: emotional disorders.
Uncommon: anxiety.
Disorders of the nervous system
Common: headache * (* - see. See "Description of the individual adverse reactions").
Uncommon: dizziness.
Violations by metabolism and nutrition
Uncommon: weight gain
Violations by the organ of hearing and labyrinthine disorders
Frequent: vertigo.
Violations of the respiratory system, the chest and mediastinum
Infrequent: epistaxis.
Disorders of the gastrointestinal tract
Common: abdominal pain, nausea.
Uncommon: dyspepsia, dry mouth, flatulence, constipation.
Violations of the skin and subcutaneous tissue
Common: 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 by the kidneys and urinary tract
Infrequent: urinary incontinence.
Violations by the genital and breast cancer
Very Frequent: amenorrhea, endometrial thickening *"tides"*.
Frequent: * metrorrhagia, ovarian cyst *, tension / breast tenderness, pelvic pain.
Infrequents: metrorrhagia, ovarian cyst rupture, vaginal discharge, and an increase in discomfort in the mammary glands.
General disorders and at the injection site: Frequent: edema, fatigue.
Infrequent: asthenia.

Changes in laboratory and instrumental studies:
Frequent: increase in the concentration of cholesterol in the blood.
Infrequent: increased concentration of triglycerides in the blood.
Description of the individual adverse events

Thickening of the endometrium:
In 10-15% of patients receiving ulipristal may be thickening of the endometrium (> 16 mm by ultrasound or MRI at the end of treatment). This effect is reversible after treatment and resuming the menstrual cycle. Moreover, reversible changes in the endometrium, as denoted PAEC differ from endometrial hyperplasia. The pathologist should be informed of admission ulipristala patient during histological examination at hysterectomy or endometrial biopsy.

"Tides": "Tides" were observed in 12.7% of patients, but their frequency varied in different studies. In a study with their active control rate was 24% (10,5% moderate or severe) for the group ulipristala and 60.4% (39.6%  moderate or severe) for leuprorelin group. In placebo-controlled study, the incidence "Tide" amounted to 1.0% for ulipristala and 0% for placebo.

Headache: Headache mild or moderate degree was observed in 6.4% of patients.

Ovarian cyst: In 1.5% of patients during treatment were found functional ovarian cysts, which spontaneously disappeared within a few weeks.

Uterine bleeding: Patients with heavy menstrual bleeding due to uterine leiomyoma, are at risk of increased bleeding, which may require surgery. There have been several such messages in the course of therapy, and 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 ulipristala

Hormonal contraceptives:
Ulipristal has steroidal structure and acts as a selective modulator predominantly progesterone receptor inhibitory effect on progesterone receptor. Thus, gestagens and hormonal contraceptives may reduce the effectiveness ulipristala by competitive effects on receptor progesterone. It is therefore not recommended 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 figures and Stach AUCulipristala rose by 1.2 and 2.9 times, respectively; value AUCaktivnogo ulipristala metabolite increased 1.5 times, while sschah active metabolite decline (0.52 times). The combined use of powerful inhibitors of CYP3A4 (ketoconazole, ritonavir nefazodone) may lead a greater increase in the plasma concentration ulipristala blood. Dose adjustment when ulipristala application in patients receiving a weak inhibitor of isoenzyme CYP3A4, is not required. The combined use of moderate or potent inhibitors
CYP3A4 isoenzyme with ulipristalom not recommended.

Inducers of CYP3A4:
Patients receiving inductors isoenzyme CYP3A4, can be observed ulipristala decreased concentration in the blood plasma. The combined use of ulipristala and powerful inducers of isoenzyme CYP3A4 (rifampicin,  carbamazepine, phenytoin, drugs Hypericum perforatum) is not recommended. Drugs affecting the pH of gastric juice 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 effects of drugs that increase the pH of gastric juice is not considered clinically significant for the daily use of pills ulipristala The possible impact on the action ulipristala drugihlekarstvennyh drugsHormonal 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 concomitant administration of drugs containing the progestogen without recommended. Gestagensoderzhaschie drugs should not be used within 12 days.

Bleeding:
Patients should be informed that the treatment is usually ulipristalom leads to a significant decrease in menstrual blood loss during or amenorrhea the first 10 days of treatment. With continuing excessive bleeding patient should seek medical advice. Typically, the menstrual cycle is resumed for 4 weeks after treatment.

Fertility:
The majority of women who took ulipristal at therapeutic doses, there was anovulation. However, long-term use fertility ulipristala not been studied. Effect on the ability to drive vehicles and mechanisms Ulipristal may have a minimal effect on the ability to drive vehicles and machinery, as after taking ulipristala can observed slight dizziness.

Product form:
Tablets of 5 mg. 14 tablets in a blister of PVC / PE / PVDC film and orange aluminum foil. 2 or 6 blisters in a cardboard box with instructions application.

Storage conditions:
In the dark place at a temperature not exceeding 30° C. Keep out of reach of children!

Shelf-life:
2 years. Do not use the drug after the expiry date.

Manufacturer:
JSC "Gedeon Richter" Hungary

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