Esmiya® [Ulipristal Acetate]

Pharmacological properties

ulipristal acetate is an oral synthetic selective modulator of progesterone receptors, characterized by a tissue-specific partial antiprogesterone effect.

Endometrium. Ulipristal acetate has a direct effect on the endometrium. With daily use at a dose of 5 mg and throughout the menstrual cycle, most patients (including patients with myoma) notice the cessation of menstruation until the end of therapy. After treatment, the menstrual cycle resumes within 4 weeks.

A direct effect on the endometrium in the histological classification is referred to as changes in the endometrium caused by the use of Progesterone Receptor Modulator Associated Endometrial Changes (PAEC). As a rule, histological changes are represented by inactive and weakly proliferating epithelium, which is accompanied by asymmetry of stroma and epithelium growth, expressed by cystic expansion of the glands with mixed estrogenic (mitotic) and progestogen (secretory) effects on the epithelium. Such changes were noted in ≈60% of patients who used ulipristal acetate for 3 months. These changes are reversible after discontinuation of therapy. The identification of such changes should not be mistaken for hyperplasia.

In ≈5% of patients of reproductive age with severe forms of menstrual bleeding, the thickening of the endometrium is 16 mm. When using ulipristal acetate in ≈10-15% of patients, the thickness of the endometrium can be 16 mm. This thickening disappears after completion of treatment and the resumption of menstruation. If the thickening of the endometrium persists for more than 3 months after the end of therapy and the resumption of menstruation, an additional examination should be performed to exclude concomitant pathology.

Leiomyoma Ulipristal acetate has a direct effect on leiomyoma, reducing its size by inhibiting cell proliferation and inducing apoptosis.

Pituitary. A daily dose of ulipristal acetate 5 mg suppresses ovulation in most patients, which is noticeable in the level of progesterone of ≈0.3 ng / ml.

The daily dose of ulipristal acetate 5 mg partially reduces the FSH content in blood plasma, however, the concentration of estradiol in blood plasma is maintained at the level of the middle follicular phase and corresponds to that in the placebo group.

Ulipristal acetate does not affect the concentration of thyroxin-binding globulin (TSH), ACTH or prolactin in blood plasma during 3 months of therapy.

Clinical efficacy and safety. Preoperative therapy. The efficacy of fixed single daily doses of ulipristal acetate 5 and 10 mg was evaluated in two randomized, double-blind, 13-week phase III trials, which included patients with very severe menstrual bleeding associated with uterine fibroids. Study 1 was double-blind and placebo-controlled. To participate in the study, patients with signs of anemia (Hb 10.2 g / dl) were selected, who received iron supplements (Fe²⁺) at a dose of 80 mg orally. In study 2, a comparison was made with leuprorelin (active control), which was prescribed 1 time per month at a dose of 3.75 mg IM. In this study, the double masking method (two placebo control) was used. In both studies, menstrual bleeding was assessed using the Pictorial Bleeding Assessment Chart (PBAC). A total score of PBAC 100 during the first 8 days after menstruation is considered a sign of increased menstrual blood loss.

In study 1, statistically significant differences were observed in the reduction of menstrual blood loss in favor of ulipristal acetate compared with placebo (Table 1), which led to a more rapid and effective correction of anemia compared with iron supplementation alone.Similarly, in patients using ulipristal acetate, a more pronounced decrease in the size of fibroids was observed according to the results of MRI.

In study 2, a decrease in menstrual blood loss was comparable in the group of patients who received ulipristal acetate and leuprorelin, a gonadotropin releasing hormone (GnRH) agonist. Most patients who received ulipristal acetate experienced a cessation of bleeding (amenorrhea) during the 1st week of therapy.

The size of the three largest fibroids was estimated using ultrasound at the end of the course of treatment (13th week) and during another 25 weeks of follow-up in patients who did not have a hysterectomy or myomectomy. The decrease in the size of the fibroids continued during the follow-up period in patients receiving ulipristal acetate, and in the leuprorelin group a certain resumption of growth of fibroids was revealed.

Table 1. The results of the primary and selective results of the secondary evaluation of performance indicators in clinical trials of phase III, n (%)

Index	Study 1			Study 2
	Placebo (n = 48)	Ulipristal acetate, 5 mg / day (n = 95)	Ulipristal acetate, 10 mg / day (n = 94)	Leiprorelin, 3.75 mg / month (n = 93)	Ulipristal acetate, 5 mg / day (n = 93)	Ulipristal acetate, 10 mg / day (n = 95)
Menstrual bleeding. Median RVAS at the beginning of the study	376	386	330	297	286	271
Menstrual bleeding. Week 13 change median	–59	–329	–326	–274	–268	–268
Patients with amenorrhea at week 13	3 (6,3)	69 (73,4)1	76 (81,7)2	74 (80,4)	70 (75,3)	85 (89,5)
Patients whose menstrual bleeding returned to normal (PBAC 75) at week 13	9 (18,8)	86 (91,5)1	86 (92,5)1	82 (89,1)	84 (90,3)	93 (97,9)
Median change in the volume of fibroids from the start of the study to the 13th weekand	(+3,0)	(–21,2)3	(–12,3)4	(–53,5)	(–35,6)	(–42,1)

^andIn study 1, the change in the total volume of fibroids compared with the initial value was evaluated using MRI. In study 2, the sizes of the three largest fibroids were determined using ultrasound. Values ​​in bold indicate significant differences when comparing ulipristal acetate and control. All differences noted were in favor of ulipristal acetate.

P values: ¹ 0,001; ² 0,037; ³ 0,002; ⁴ 0,006.

Long-term course therapy. The long-term efficacy of a single fixed dose of ulipristal acetate 5 or 10 mg was determined in two phase III studies that evaluated a maximum of four 3-month courses of therapy in patients with heavy menstrual bleeding associated with uterine fibroids. Study 3 was an open study evaluating the use of ulipristal acetate at a dose of 10 mg, in which, after each 3-month course of therapy, 10 days of double-blind progestin or placebo therapy followed. Study 4 was a randomized, double-blind, clinical trial evaluating the use of ulipristal acetate in doses of 5 or 10 mg.

Studies 3 and 4 showed efficacy in controlling the symptoms of uterine fibroids (for example, uterine bleeding) and reducing the size of fibroids after the 2nd and 4th course of treatment.

In study 3, treatment efficacy was observed for 18 months of multiple course therapy (4 courses with a dose of 10 mg 1 time per day): at the end of the 4th course of therapy, amenorrhea was registered in 89.7% of patients.

In study 4, amenorrhea was registered in 61.9 and 72.7% of patients at the end of the 1st and 2nd course of therapy (doses of 5 and 10 mg, respectively, p = 0.032), in 48.7 and 60.5% of patients amenorrhea was registered at the end of all four courses of therapy (doses of 5 and 10 mg, respectively; p = 0.027). According to estimates, at the end of the 4th course of therapy, amenorrhea was registered in 158 (69.6%) and 164 (74.5%) patients, respectively (p = 0.290) (Table 2).

Table 2. Results of primary and selective results of a secondary evaluation of performance indicators in long-term clinical trials of the III phase, n (%)

Index	After completion of the 2nd course of treatment (2 courses of 3 months)			After completion of the 4th course of treatment (4 courses of 3 months)
	Study 3and	Study 4		Isl