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One tablet of drug of Esmiya includes 5 mg of an ulipristal of acetate – active ingredient.
As excipients medicine contains: 43,5 mg – Mannitolum; 93,5 mg – microcrystallic cellulose; 4 mg – talc; 1,5 mg — magnesium stearate; 2,5 mg — croscarmellose sodium.
Medicine of Esmiya (Esmya) is issued in the form of tablets at which one party there is an engraving of "ES5". One packaging can contain 28 or 84 tablets.
Pharmacodynamics and pharmacokinetics
Esmiya's (Esmya) drug contains substance — ulipristat a synthetic origin, being the selection modulator of progesteronovy receptors and differing in tkanespetsifichny selective antiprogesteronovy action.
Ulipristal is characterized by direct impact on an endometria. At most of women, at use of 5 mg of drug daily throughout a menstrual cycle including having myoma, there does not come the menstrual bleeding, subsequent to this cycle. At the termination of reception of tablets, the menstrual cycle is, as a rule, recovered for a month.
Direct impact of drug on an endometria is connected with some of its specific changes characteristic of this class of medicines and provoked by antagonistic action to progesteronovy receptors. At 60% of the women accepting ulipristat for 3 months, histologic changes are shown by poorly proliferating inactive epithelium with the accompanying asymmetry of its growth and growth of a stroma, and also cystous expansion of glands with progestagenny and oestrogenic impacts on an epithelium. These changes have reversible character with disappearance on the termination of a course of treatment and have no relation to an endometria hyperplasia.
At 10–15% of the women passing therapy using an ulipristal growth of an endometria which reached a thickening more than 16 mm was observed. This thickening also independently disappears on the end of treatment and return of normal menstrual bleedings. If for 3 months after drug withdrawal, the thickening of an endometria does not come to a condition of norm, it is necessary to pass additional inspections for the purpose of an exception or confirmation of other pathologies.
Ulipristal induces apoptosis and oppresses cellular proliferation, thereby making the direct impact on leiomyomas leading to their reduction.
Daily reception of 5 mg of an ulipristal leads to the guaranteed oppression of an ovulation at most of the women accepting it that confirms maintenance of level of content of progesterone on a mark of 0,3 ng/ml. Also, daily reception of this dose of drug partially reduces concentration of FSG, at the same time leaving contents in an oestradiol blood plasma at the level of an average follicular phase.
During 3-month therapy ulipristat does not exert impact on quantity in a blood plasma of AKTG, prolactin, tiroksinsvyazyvayushchy globulin.
In the conducted preclinical trials on animals, at reception of repeated doses, threat of toxicity and genotoxicity of drug for the person was not revealed. The death of fruits of animals at reception of doses was noted more than 1 mg/kg in this connection, safety of an ulipristal in relation to an embryo of the person is not established. In small doses which allowed to keep pregnancy at animals teratogenic action was not observed. Also, on data outputs of researches, there are no direct proofs of influence of drug on reproductive ability of animals and their posterity.
Clinical trials of safety and Esmiya's efficiency in daily doses of 5 and 10 mg, were carried out on female volunteers with the menstrual bleedings of difficult character provoked by a hysteromyoma. In comparison with group of placebo clinically significant decrease in volume of the blood loss connected with periods was noted, at the patients receiving ulipristat that allowed to carry out faster effective correction of anemia, than at use of one iron preparations. At patients of group of reception of an ulipristal, lowering of volume of blood loss, was comparable to group of patients accepting Leyprorelin (GNRG agonist). In most cases Esmiya's reception led to the termination of bleeding for the first week of treatment (the amenorrhea developed). Researches MRT in this group, were shown by considerable reduction of a hysteromyoma, in comparison with group of placebo. Carrying out ultrasonography control on the termination of a course of treatment (the 13th week), for the purpose of establishment of decrease in the sizes of a hysteromyoma, showed preservation of its parameters in group of an ulipristal within 25 weeks, in comparison with some increase in its sizes in Leyprorelin's group.
After reception of an ulipristal in a single dose of 5 mg, there is a fast absorption of drug, to achievement of Cmax in 60 minutes at the level — 23,5±14,2 ng/ml and plasma concentration of 61,3±31,7 ng/ml. Ulipristal is exposed to fast transformation with allocation pharmacological of an active metabolite, at the same time in 60 minutes Cmax in 9±4,4 ng/ml and plasma concentration of 26±12 ng/ml is reached.
At reception of 30 mg of Esmiya during a breakfast with a large amount of fats, lowering of Cmax, till 3 o'clock increase in Tmax and 25% increase of plasma concentration, both the ulipristal, and its metabolite, unlike reception on an empty stomach observed 45%. At daily reception of tablets this effect is not considered as significant.
With proteins of plasma ulipristat communicates for 98% and even more.
The metabolism occurs with the participation of P450 cytochrome about allocation final di-N-demetilirovannogo metabolites.
It is more removed by intestines, in smaller (about 10%) kidneys. T1/2 in a dose of 5 mg, about 38 hours, with average clearance about 100 l/h.
Indications to use
Preoperative treatment of manifestations of a hysteromyoma of average and heavy severity, at the women of reproductive age who reached 18 years lasting not more than 3 months.
Carrying out therapy by medicine of Esmiya is contraindicated:
- at hypersensitivity of the patient to an ulipristal or other components of tablets;
- at vulval bleedings of not diagnosed nature or for the reasons which do not have relations to a hysteromyoma;
- at malignant tumors of a neck of uterus, ovaries, uterus, mammary glands;
- at heavy bronchial asthma which will not respond to treatment peroral GKS;
- at not achievement of age of 18 years;
- during the feeding periods breast and pregnancies;
- in case of the presumable course of therapy exceeding 3 months (because of lack of reliable data about influence of an ulipristal on an organism, throughout more this term).
- pathologies of kidneys and/or liver;
- bronchial asthma.
Bodies of a gastrointestinal tract:
- nasal bleedings.
Integuments and hypodermic fabrics:
Skeletal and muscular system:
- morbidity of muscles and bones;
- pain in a back.
Urinogenital system and mammary glands:
- urine incontience;
- endometria thickening;
- formation of oothecomas;
- pelvic pain;
- morbidity, increase, intensity of mammary glands;
- vulval allocations;
- rupture of an oothecoma.
- increase in body weight;
- increased fatigue;
- increase in content in blood of cholesterol and triglycerides.
During clinical trials observed the most frequent collateral manifestations among which 10–15% were occupied by the endometria thickening which in most cases is independently passing after treatment cancellation; 12-13% — inflow; 6,4% — headaches of easy or moderate weight; 1,5% — the oothecomas disappearing spontaneously for several weeks; uterine bleedings which in certain cases demand surgical intervention.
Esmiya, application instruction
The instruction recommends one-time daily reception of the 1st tablet for Esmiya orally (inside), in independence of food.
Time of the beginning of therapy is limited first week of a menstrual cycle. During this period it is necessary to begin to take Esmiya's pill, it is desirable at the same time days.
At the admission of time of reception of the next tablet, it is necessary to accept it as soon as possible, for 12 hours. In case of exceeding of this limit of time, miss this reception and continue a course of treatment from the subsequent tablet in due time.
Because of lack of experience of use of Esmiya throughout time exceeding 3 months, this term is the only thing admissible for therapy.
Full data on a possibility of overdose by Esmiya's drug and the subsequent to it negative manifestations, for this time do not exist. It is thoroughly known that reception of single 200 mg of a dose of drug and daily 50 mg of a dose, within 10 days, did not lead to serious or serious conditions of the patient.
Hormonal contraceptive drugs, also as well as Esmiya influence progesteronovy receptors and can lower effects of each other in this connection, their combined use is not recommended.
The combined Esmiya's reception and inhibitors of an isoenzyme CYP3A4 moderate (Erythromycin) and powerful (Nefazodon, Ritonavir, Ketokonazol) actions, can provoke significant increase in plasma concentration of an ulipristal. For this reason their combined use is not recommended. Reception of inhibitors of an isoenzyme of CYP3A4 of weak action significantly does not influence Esmiya's pharmacokinetics in this connection, does not demand correction of a dose of the last.
Reception of inductors of an isoenzyme of CYP3A4, leads to lowering of plasma maintenance of an ulipristal. Therefore parallel use of inductors of an isoenzyme of CYP3A4 of powerful action (The rifampicin, Phenytoinum, Carbamazepine, means including the St. John's Wort which is made a hole) is not recommended.
During absorption in walls of a gastrointestinal tract ulipristat it is capable to inhibit P-gp, thereby increasing plasma concentration of P-gp substrates. In this regard joint appointment of Esmiya and P-gp substrates is not recommended (Digoxin, Dabigatran).
Further the clinical use of Esmiya can reveal other interactions of medicines.
The patient preparing for passing of therapy with Esmiya's use is obliged to report to the attending physician about all means accepted by it, as from the prescription, and nonprescription list.
Terms of sale
In drugstores of Russia, for medicine acquisition of Esmiya, it is required to show the recipe of the doctor.
It is necessary to store tablets of drug of Esmiya in original packaging, at a surrounding temperature to 30 °C.
Period of validity
At observance of storage conditions of drug the term of its validity makes 2 years.
Medicine of Esmiya can be appointed only after carrying out careful inspection, for the purpose of confirmation of indications, an exception of contraindications and pregnancy.
During therapy recommend to use additional barrier methods of contraception as efficiency of hormonal contraceptives can be reduced, as well as effect of the drug.
Though there are no authentic data on influence of a renal failure on removal of an ulipristal, do not recommend its reception by patients with this disease, in particular in a severe form, without supervision of the doctor. These recommendations are applicable also for patients with a liver failure of average and heavy severity as influence of this pathology on removal of an ulipristal is supposed.
Duration of therapy should not exceed 3 months.
The patients accepting Esmiya have to be informed that effect of drug usually is followed by considerable decrease in menstrual blood loss or leads to an amenorrhea for 10 days of therapy. On the expiration of this term, in case of the continuing plentiful blood loss, it is necessary to see a doctor. Generally the normal menstrual cycle returns in a month after treatment cancellation.
At most of the patients passing treatment by Esmiya's drug anovulation was observed. Nevertheless, fertility at therapy ulipristaly is not studied.
Coincidence on the ATH code of the 4th level:
The analogs of an ulipristal entering into one pharmacological group and similar but not identical on the main action, are provided by the following drugs:
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