Esmya® [Ulipristal]

Brand Gedeon Richter

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Clinical Pharmacology

Esmya has anti-progestogenic effect.

Pharmacodynamics

Ulipristal is a synthetic selective progesterone receptor modulator, characterized by a tissue-specific partial anti-progesterone effect, which is active when taken orally.

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 to this class of drugs, associated with an antagonistic effect on progesterone receptors (Progesterone Receptor Modulator Associated Endometrial Changes (PAEC)). As a rule, histological changes are represented by inactive and weakly proliferating epithelium, accompanied by asymmetry of growth of the stroma and epithelium, marked cystic expansion of the glands with mixed estrogenic (mitotic) and progestogenic (secretory) effects on the epithelium. Such changes were observed in approximately 60% of patients who received uliprystala acetate for 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 childbearing age with severe forms of menstrual bleeding endometrial thickness more than 16 mm. In 10–15% of patients receiving ulipristal acetate, 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 remains within 3 months after the end of treatment and the restoration of menstruation, 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 is partially reduced, however, the concentration of estradiol in the blood serum of 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 (TSH), 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 fetal death in rats, rabbits (with multiple doses above 1 mg / kg), guinea pigs and monkeys. The safety of the drug against a 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.
In studies conducted in mice and rats, no carcinogenic effect on ulipristal was detected.

Clinical efficacy and safety
The effectiveness of fixed doses of ulipristal 5 mg and 10 mg 1 time / day was evaluated in two studies of phase 3, which involved patients with very heavy menstrual bleeding caused by uterine myoma.
In comparison with placebo, a clinically significant decrease in the volume of menstrual blood loss was detected in patients taking ulipristal. 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 with the ulipristal group was comparable to the group receiving the GnRH agonist (leuprorelin). In the majority of patients receiving ulistrist, the bleeding stopped during the first week of administration (amenorrhea developed).

According to MRI, there was a significantly greater decrease in the size of uterine fibroids in the ulipristal group than in the placebo group. In patients who did not undergo hysterectomy or myomectomy, with ultrasound control at the end of treatment (week 13), a reduction in the size of the uterine myoma was evaluated. As a rule, it persisted for 25 weeks of follow-up in patients of the ulipristal group, whereas in the group treated with leuprorelin, there was a slight increase in the size of uterine fibroids.
In another study, Phase 3, in which patients received 2 courses of treatment 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 recorded during the first course was maintained during the second course. Taking into account the results of previous studies, the effectiveness of the drug in a dose of 5 mg during the first course of therapy will be the same during the second course of therapy, similar to the dose of 10 mg.

Despite the limited number of patients who completed the four 3-month course of treatment, the safety data obtained is 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, ulipristyl is rapidly absorbed, reaching approximately 1 hour after taking Cmax 23.5 ± 14.2 ng / ml and 50.0 ± 34.4 ng / ml, respectively. AUC0-∞ is 61.3 ± 31.7 and 134.0 ± 83.8 ng × h / ml, respectively. Ulipristal is quickly transformed into a pharmacologically active metabolite, 1 hour after administration, Cmax is 9.0 ± 4.4 ng / ml and 20.6 ± 10.9 ng / ml, AUC0-∞ - 26.0 ± 12.0 and 63.6 ± 30.1 ng × h / ml, respectively. Acceptance of 30 mg of ulipristal along with high-fat breakfast results in an average Cmax decrease of about 45%, lengthening the time to reach Cmax (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 pills.

Distribution
Ulipristal is highly (> 98%) bound to plasma proteins, including albumin, α-1-acid glycoprotein, high-density lipoproteins and low-density lipoproteins.
Ulipristal and its active N-demethylated metabolite pass into breast milk; the average AUCt ratio for milk / plasma is 0.74 ± 0.32 for ulipristal.

Metabolism
Ulipristal acetate 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 acetate is mediated by cytochrome P450, the effect of hepatic insufficiency on the elimination of ulipristal acetate is expected, which will lead to an increase in its effect.

Removal
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 acetate after a single dose of 5 mg or 10 mg is about 38 hours, the average clearance of about 100 l / h.In vitro data show that clinically significant concentrations of ulipristal acetate 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 acetate should not affect the clearance of drugs that are metabolized with the participation of these isoenzymes.
In vitro data shows that ulipristal acetate and its active metabolite are not substrates for P-glycoprotein (ABCB1).

Indications

Preoperative treatment of symptoms of uterine fibroids of moderate and severe in adult women of reproductive age over 18 years of age (duration of therapy is not more than 2 courses).

Composition

1 tablet contains:

Active substance: ulipristal acetate 5 mg;

Excipients: microcrystalline cellulose - 93.5 mg, mannitol - 43.5 mg, talc - 4 mg, croscarmellose sodium - 2.5 mg, magnesium stearate - 1.5 mg.

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Dosage and Administration

Inside, before eating.For the prevention of influenza and SARS (in contact with patients)
adults and children over 12 years old - 200 mg / day, children from 6 to 12 years old - 100 mg / day, children from 2 to 6 years old - 50 mg / day. The course is 10-14 days.
During the epidemic of influenza, the seasonal increase in the incidence of ARVI, for the prevention of exacerbation of chronic bronchitis and recurrence of herpes infection adults and children over 12 years old should be prescribed a single dose of 200 mg, children from 6 to 12 years old - 100 mg, children from 2 to 6 years old - 50 mg. The drug is taken 2 times a week for 3 weeks.
For the treatment of influenza and other acute respiratory viral infections without complications adults and children over 12 years old should be prescribed; 200 mg 4 times / day (every 6 hours), children 6 to 12 years old - 100 mg 4 times / day (every 6 hours), from 2 to 6 years - 50 mg 4 times / day (every 6 hours). The course is 5 days.
For the treatment of influenza and other acute respiratory viral infections complicated by bronchitis, pneumonia, adults and children over 12 years old; prescribed 200 mg 4 times / day (every 6 hours) for 5 days, then switch to 200 mg once a week for 4 weeks. For children from 6 to 12 years old, a single dose of the drug is 100 mg, from 2 to 6 years old - 50 mg; the drug is taken 4 times / day (every 6 hours) for 5 days, then transferred to the reception 1 time per week for 4 weeks.
With chronic bronchitis and recurrent herpes infection adults and children over the age of 12 are prescribed 200 mg 4 times / day (every 6 hours); children from 6 to 12 years old on 100 mg 4 times / day (every 6 hours), from 2 to 6 years old - 50 mg 4 times / day (every 6 hours) for 5-7 days; then a single dose 2 times a week for 4 weeks.
As part of complex therapyacute intestinal infections of rotavirus etiology children from 2 to 6 years old - 50 mg; from 6 to 12 years old - 100 mg, over 12 years old - 200 mg 4 times / day (every 6 hours) for 5 days.
Forprevention of postoperative infectious complications children from 2 to 6 years old - 50 mg; from 6 to 12 years old - 100 mg, over 12 years old and adults - 200 mg should be prescribed at a dose of 200 mg 2 days before surgery, then on the second and fifth day after surgery.

Adverse reactions

Seldom: allergic reactions.

Contraindications

- children's age up to 2 years;
- Hypersensitivity to the drug.

Pregnancy and Lactation

Use of the drug during pregnancy is possible only in cases where the intended benefit to the mother outweighs the potential risk to the fetus and newborn.