Esmia, tablets 5 mg, 28 pcs.

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

Endometrium

Ulypristal has a direct effect on the endometrium. When the drug is started daily at a dose of 5 mg during the menstrual cycle, most women (including patients with myoma) end their next menstrual bleeding and the next bleeding does not occur. When the drug is discontinued, the menstrual cycle usually resumes within 4 weeks.

Direct action on the endometrium results in endometrial changes specific to this class of drugs due to antagonistic action 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 asymmetric growth of stroma and epithelium, pronounced cystic expansion of glands with mixed estrogenic (mitotic) and progestagenic (secretory) effects on epithelium. These changes were noted in about 60% of patients who received ulipristal acetate for 3 months. These changes are reversible and disappear after discontinuation of treatment and should not be mistaken for endometrial hyperplasia.

About 5% of patients of childbearing age with severe menstrual bleeding have an endometrial thickness greater than 16 mm. In 10-15% of patients receiving ulipristal acetate, the endometrium may thicken (>16 mm) during treatment. This thickening disappears when the drug is discontinued and menstrual bleeding resumes. If endometrial thickening remains for 3 months after the end of treatment and recovery of menstrual periods, further evaluation should be performed to rule out other diseases.

Leiomyoma

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

Pituitary

The daily administration of ulipristal at a dose of 5 mg suppresses ovulation in most patients, as evidenced by maintaining progesterone concentrations at about 0.3 ng/mL.
Daily administration of ulipristal at a dose of 5 mg partially reduces FSH concentrations, but serum estradiol concentrations in most patients are maintained at mid-follicular phase levels and correspond to those in the placebo group.
Ulipristal does not affect plasma thyroxine-binding globulin (TSH), ACTH and prolactin concentrations for 3 months of treatment.

Preclinical safety data

Preclinical studies of pharmacological safety, multiple dose toxicity and genotoxicity have not identified any potential threats to humans.

The main findings in general toxicity studies are related to effects on progesterone receptors (as well as on GCS receptors when the drug is used in higher concentrations), with antiprogesterone activity at exposures close to therapeutic in humans. A 39-week study in monkeys using low doses showed changes similar to RAES. Due to its mechanism of action, ulipristal 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 has not been established.

In doses low enough to maintain pregnancy in animals, teratogenic potential has not been identified. Reproduction studies in rats using doses that provide the same exposure as in humans found no evidence of effects on the reproductive capacity of animals receiving ulipristal or their offspring.

In studies conducted in mice and rats, no carcinogenic effects of ulipristal have been identified.

Clinical efficacy and safety

The efficacy of fixed-dose ulipristal 5 mg and 10 mg once daily was evaluated in two phase 3 studies involving patients with very severe menstrual bleeding caused by uterine myoma.

Compared with placebo, there was a clinically significant reduction in menstrual bleeding volume in patients taking ulipristal. This allowed quicker and more effective correction of anemia than when only iron preparations were prescribed. The reduction in menstrual blood loss in patients in the ulipristal group was comparable to the group receiving the GnRH agonist (leuprorelin). In most patients receiving ulipristal, bleeding stopped within the first week of use (amenorrhea developed).

In MRI data, there was a significantly greater reduction in uterine myoma size in the ulipristal group than in the placebo group. In patients who did not undergo hysterectomy or myomectomy, a decrease in uterine myoma size was assessed at ultrasound follow-up at the end of treatment (week 13). This was generally maintained through 25 weeks of follow-up in patients in the ulipristal group, whereas a slight increase in uterine myoma size was noted in the group receiving leuprorelin.

In another Phase 3 study in which patients received 2 courses of 10-mg ulipristal therapy for 3 months each, the incidence of amenorrhea was comparable at the end of both courses of therapy. The reduction in leiomyoma volume recorded during the first course was maintained during the second course. Based on previous studies, the efficacy of 5 mg in the first course would be the same in the second course, similar to the 10 mg dose.

In spite of the limited number of patients who completed four 3-month courses of therapy, the safety data are sufficient to justify one additional 3-month course of therapy in the preoperative period.

Pharmacokinetics

Absorption

After a single oral dose of 5 mg or 10 mg, ulipristal is rapidly absorbed, reaching a Cmax of 23±14.2 ng/mL approximately 1 h after ingestion.5±14.2 ng/mL and 50.0±34.4 ng/mL, respectively. The AUC0-∞ is 61.3±31.7 and 134.0±83.8 ng×h/mL, respectively. Ulipristal is rapidly converted to a pharmacologically active metabolite, with a Cmax of 9.0±4.4 ng/mL and 20.6±10.9 ng/mL 1 hour after administration and an AUC0-∞ of 26.0±12.0 and 63.6±30.1 ng×h/mL, respectively. Administration of ulipristal at a dose of 30 mg together with a high-fat breakfast resulted in a decrease in mean Cmax of approximately 45%, a prolongation of time to reach Cmax (from a median of 0.75 hours to 3 hours), and a 25% increase in AUC0-∞, compared with fasting administration. The same results were obtained for the active mono-N-demethylated metabolite. This kinetic effect of food is not considered significant for daily ulipristal tablets.

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 penetrate into breast milk; the average AUCt ratio for milk/plasma is 0.74±0.32 for ulipristal.

Metabolism

Ulipristal acetate is rapidly converted to mono-N-demethylated and then to di-N-demethylated metabolites. In vitro data show that this process occurs in the cytochrome P450 system involving isoenzyme 3A4 (CYP3A4). Based on the fact that metabolism of ulipristal acetate is mediated by cytochrome P450, the effect of hepatic insufficiency on excretion of ulipristal acetate is expected to increase exposure.

The main route of excretion is through the intestine, less than 10% of the substance is excreted by the kidneys. The final T1/2 of ulipristal acetate after a single dose of 5 mg or 10 mg is approximately 38 h, the average clearance is about 100 l/h.

In vitro data show that at clinically relevant concentrations, 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 show that ulipristal acetate and its active metabolite are not substrates of P-glycoprotein (ABCB1).

Indications

Preoperative therapy for symptoms of moderate to severe uterine myoma in adult women of reproductive age over 18 years (duration of therapy – no more than 2 courses).

Active ingredient

Composition

1 tablet contains:

the active ingredient:

ulipristal acetate 5 mg,

auxiliary substances:

microcrystalline cellulose, 93.5 mg,

mannitol – 43.5 mg, talc – 4 mg,

croscarmellose sodium – 2.5 mg,

magnesium stearate – 1.5 mg.

How to take, the dosage

Esmia is prescribed orally, 1 tablet 1 time per day. regardless of meals for no more than 3 months. Treatment should be started during the first week of the menstrual cycle.

There are no data on treatment over 3 months or repeated courses of therapy, so the duration of treatment should not exceed 3 months.
If the next intake is missed, take an ulipristal acetate tablet as soon as possible. If the dose is missed for more than 12 hours, the missed tablet should not be taken and the usual regimen should be resumed.

In patients with mild to moderate renal impairment, no dose adjustment is required. Ulipristal acetate is not recommended for use in patients with severe renal impairment if continuous monitoring is not possible.

Dose adjustment is not required in patients with mild hepatic impairment. Ulipristal acetate is not recommended for use in patients with moderate or severe hepatic impairment if continuous monitoring is not possible.

The use of ulipristal acetate for appropriate indications in children is not indicated. The safety and efficacy of ulipristal acetate have been established only for women 18 years of age and older.

Interaction

Possible effects of other drugs on the effect of ulipristal acetate

Hormonal contraceptives

Ulipristal acetate has a steroid structure and acts as a selective modulator of progesterone receptors with a predominant inhibitory effect against progesterone receptors. Thus, hormonal contraceptives and gestagens may reduce the effectiveness of ulipristal acetate through competitive effects on the progesterone receptor. Therefore, concomitant use of drugs containing gestagens is not recommended.

CYP3A4 isoenzyme inhibitors

The Cmax and AUC of ulipristal were increased 1.2 and 2.9 times, respectively; the AUC of the active metabolite ulipristal acetate increased 1.5 times, while the Cmax of the active metabolite decreased (0.52 times). In healthy female volunteers, ketoconazole (400 mg once daily, 7 days), a potent CYP3A4 inhibitor, increased Cmax and AUC of ulipristal 2-fold and 5.9-fold, respectively.

There was a 2.4-fold increase in the AUC of the active metabolite of ulipristal while its Cmax decreased (0.53-fold change). No dose adjustment is required when using ulipristal in patients receiving weak CYP3A4 isoenzyme inhibitors. Co-administration of medium potency inhibitors or potent CYP3A4 isoenzyme inhibitors with ulipristal is not recommended.

CYP3A4 isoenzyme inducers
Using powerful CYP3A4 inducer rifampicin (300 mg 2 times per day, 9 days) in healthy female volunteers there was significant reduction of Cmax and AUC of ulipristal and its active metabolite by more than 90%. There was also a 2.2-fold decrease in the T1/2 of ulipristal, which corresponds to a decrease in its exposure by a factor of approximately 10. Concomitant use of ulipristal and potent CYP3A4 inducers (e.g., rifampicin, rifabutin, carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, primidone, St John’s wort, efavirenz, nevirapine, ritonavir – during long-term use) is not recommended.

Drugs affecting gastric juice pH

The use of ulipristal (10 mg/day) together with proton pump inhibitor esomeprazole (20 mg 1 time/day for 6 days) leads to decreased mean Cmax by 65%, prolonged Tmax (from median 0.75 h to 1.0 h) and a 13% increase in mean AUC. This effect of gastric juice pH-raising medications is not considered clinically relevant for daily ulipristal acetate tablets.

Possible effects of ulipristal acetate on the effects of other medications

Hormonal contraceptives

. Ulipristal may interfere with the effects of hormonal contraceptives (gestagen-containing pills only, gestagen-releasing systems, or combined oral contraceptives) and gestagen drugs used for other indications. Therefore, concomitant use of drugs containing gestagen is not recommended. Gestagen-containing drugs should not be used for 12 days after discontinuation of ulipristal treatment.

P-glycoprotein substrates

In vitro data show that in clinically relevant concentrations, ulipristal acetate can be an inhibitor of P-glycoprotein (P-gp) during absorption in the gastrointestinal wall. Simultaneous use of ulipristal and P-gp substrate has not been studied, so the possibility of interactions cannot be excluded. In vivo data indicate that administration of ulipristal (10 mg tablet) 1.5 hours before administration of the P-gp substrate fexofenadine (60 mg) has no clinically significant effect on the pharmacokinetics of fexofenadine. Thus, an interval of at least 1.5 hours between ulipristal and P-gp substrates (e.g., dabigatran etexilate, digoxin, fexofenadine) is recommended. The patient must tell the attending physician about all medications she takes, even if they are over-the-counter.

Special Instructions

Ulipristal acetate is prescribed only after careful examination. Pregnancy should be excluded prior to treatment.
Contraception
Due to the possibility of undesirable interactions, concomitant use of gestagen-containing drugs alone, gestagen-releasing systems or combined oral contraceptives is not recommended. Although most women who received therapeutic doses of ulipristal experienced anovulation, the additional use of a non-hormonal method of contraception during treatment is recommended.

Renal impairment
There is no evidence to suggest that renal impairment may significantly interfere with ulipristal excretion. The use of ulipristal acetate without continuous monitoring in patients with severe renal impairment is not recommended, as no specific studies have been performed.

Hepatic impairment
There is no experience with therapeutic use of ulipristal acetate in patients with hepatic impairment. It is expected that hepatic insufficiency may affect the excretion of ulipristal acetate, resulting in increased exposure to the drug. This is not significant in patients with mild hepatic impairment. It is not recommended that ulipristal acetate be administered to patients with moderate to severe hepatic impairment if continuous monitoring is not possible.

Companion therapy
Concomitant use of ulipristal and moderate CYP3A4 inhibitors (e.g., erythromycin, grapefruit juice, verapamil) or potent inhibitors (e.g., ketoconazole, ritonavir, nefazodone, itraconazole, telithromycin, clarithromycin) is not recommended.
Co-administration of ulipristal with potent CYP3A4 inducers (e.g., rifampicin, rifabutin, carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, primidone, St John’s wort, efavirenz, nevirapine, ritonavir – with long-term use) is not recommended.

Endometrial changes
Ulipristal acetate has specific pharmacodynamic effects on the endometrium. An increase in endometrial thickness may be noted. If endometrial thickening persists for 3 months after the end of treatment and resumption of menstruation, further examination should be performed to rule out other diseases.
In patients receiving ulipristal, histological examination may show changes in the endometrial structure. These changes are reversible upon completion of treatment. These histologic changes are labeled as endometrial changes due to progesterone receptor antagonistic effects (PAEC) and should not be mistaken for endometrial hyperplasia. No more than two courses of therapy are recommended. The duration of each course should not exceed 3 months, since the risk of adverse effects on the endometrium with longer therapy is unknown.

Bleeding
Patients should be informed that treatment with ulipristal acetate usually results in a significant reduction in menstrual bleeding or amenorrhea during the first 10 days of treatment. If excessive bleeding persists, the patient should see her doctor. As a rule, the menstrual cycle resumes within 4 weeks after the end of treatment.

Fertility
Most women who took ulipristal acetate at therapeutic doses experienced anovulation. However, fertility with long-term use of ulipristal acetate has not been studied.

Impact on driving and operating ability
Ulipristal may have minimal effect on driving and operating ability, as light dizziness may occur after ulipristal administration.

Contraindications

Side effects

Safety of ulipristal acetate was evaluated in 393 women with uterine myomas receiving 5 mg or 10 mg of ulipristal acetate in phase III studies. The most frequently observed event in the clinical trials was amenorrhea (82.2%), which is considered a desirable outcome.

The most common adverse reaction was the occurrence of hot flashes. The vast majority of adverse reactions were mild to moderate (94.9%), did not lead to discontinuation of treatment with the drug (99.3%) and resolved on their own.

The following adverse reactions were reported in two phase III studies in patients with uterine myomas who received the drug for 3 months. Adverse adverse reactions are presented by systemic organ class according to the MedDRA classification and with frequency of occurrence: very common (≥1/10); common (≥1/100 to

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

Psychiatric: often, emotional disturbances; infrequently, anxiety.

Nervous system disorders: often – headache* (* – see Description of individual adverse reactions); infrequent – dizziness.

Metabolism: infrequent – weight gain.

Hearing and balance disorders: often – vertigo.

Respiratory system: infrequent – nasal bleeding.

Gastrointestinal system: often – abdominal pain, nausea; infrequent – dyspepsia, dry mouth, flatulence, constipation.

Skin and subcutaneous tissue: often – acne, increased sweating; rarely – skin lesions.

Muscular system: often – bone and muscle pain; infrequent – back pain.

Urinary system disorders: infrequent – urinary incontinence.

As to the reproductive system and the mammary glands: very often – amenorrhea, endometrial thickening*, hot flashes*; often – metrorrhagia*, ovarian cyst*, breast tightness/pain, pelvic pain; infrequently – rupture of ovarian cyst, vaginal discharge, increase and discomfort in the breast area.

As for the body in general: often – edema, increased fatigue; infrequently – asthenia.

Laboratory measures: frequently – increased concentration of cholesterol in blood; infrequently – increased concentration of triglycerides in blood.

Description of some adverse reactions

Endometrial thickening

In 10-15% of patients who received ulipristal acetate, endometrial thickening (>16 mm according to ultrasound or MRI at the end of treatment) may occur. This phenomenon is reversible once treatment is discontinued and the menstrual cycle resumes.

In addition, reversible changes in the endometrium, referred to as PAEC, are different from endometrial hyperplasia. The pathomorphologist should be informed about the patient’s intake of ulipristal acetate when performing a histologic study for a hysterectomy or endometrial biopsy.

Tides

Tides were reported in 12.7% of patients, but their frequency varied from study to study. In the active-control study, their incidence was 24% (10.5% moderate or severe) for the ulipristal acetate group and 60.4% (39.6% moderate or severe) for the leuproline group. In the placebo-controlled study, the incidence of flushes was 1.0% for ulipristal acetate and 0% for placebo.

Headache

Mild to moderate headache occurred in 6.4% of patients.

Ovarian cysts

In 1.5% of patients, functional ovarian cysts were detected during treatment and disappeared spontaneously within a few weeks.

Uterine bleeding

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

Overdose

There are limited data on ulipristal acetate overdose.

Single doses of up to 200 mg and daily doses of 50 mg for 10 days were administered to a limited number of volunteers and no serious or serious adverse reactions were noted.

Pregnancy use

Ulipristal acetate is contraindicated in pregnancy. There are no or limited data on the use of ulipristal acetate in pregnant women. Although no teratogenic potential has been identified in animal studies, there are insufficient data regarding reproductive toxicity.

In animal studies, ulipristal acetate has been shown to be excreted with breast milk. It is not known whether ulipristal acetate is excreted with women’s breast milk, so a risk to children during breastfeeding cannot be excluded. Ulipristal acetate is contraindicated during breastfeeding.