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Instructions / Instruction for use: Ulipristal (Ulipristal)

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Pharmacological group

Estrogens, gestagens; Their homologues and antagonists

Code CAS 126784-99-4

Characteristics of Ulipristal

Selective modulator of progesterone receptors.

Ulipristala acetate - crystalline powder from white to yellow. Molecular weight 475.6.

Pharmacology

Pharmacological action is anti-gestagenic.

Pharmacodynamics

Ulipristal is an active selective synthetic modulator of progesterone receptors, which is characterized by a tissue-specific partial antiprogestronic effect.

Endometrium. Ulipristal has a direct effect on the endometrium. When ulipristala beginning daily administration of 5 mg for the majority of the menstrual cycle in women (including patients with myoma) ends regular menstrual bleeding, and the following does not occur. When the reception is over, the menstrual cycle usually resumes within 4 weeks. The direct action on the endometrium results in specific for this class of drugs to changes in the endometrium, associated with an antagonistic effect on the progesterone receptors (Progesterone Receptor Modulator Associated Endometrial Changes (PAEC). In general, histological changes are presented inactive and weakly proliferating epithelium and accompanied asymmetry stromal growth and epithelium, severe cystic glands extension mixed estrogenic (mitotic) and progestagenic (secretory) effects on epithelia. Such changes were observed in approximately 60% of PAC entok receiving ulipristal within 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 reproductive age with severe forms of menstrual bleeding have an endometrium thickness of more than 16 mm. In 10-15% of patients receiving ulcers, the endometrium can thicken (> 16 mm) during treatment. This thickening disappears after stopping taking vaginal and resuming menstrual bleeding. If the thickening of the endometrium persists for 3 months after the end of treatment and recovery of the menstrual cycle, an additional examination should be conducted to exclude other diseases.

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

Pituitary. With the daily administration of vipers in a dose of 5 mg, ovulation is suppressed in most patients, as indicated by the maintenance of a progesterone concentration of about 0.3 ng / ml.

With a daily intake ulipristala 5 mg partially reduced FSH concentration, however estradiol plasma concentration is maintained in most patients at mid follicular phase, and corresponds to that in the placebo group.

Ulipristal does not affect the concentration of thyroxin-binding globulin, ACTH, and prolactin in the blood plasma for 3 months of treatment.

Preclinical safety data.

Pre-clinical studies of pharmacological safety, toxicity of multiple doses and genotoxicity of potential threats to humans have not been revealed. Key findings in the research associated with the systemic toxicity influence on the progesterone receptors (as well as the receptors corticosteroids (glucocorticoids) at the application of drugs (medicament) at higher concentrations) with anti-progesterone activity at exposures similar to therapeutic in humans. In a 39-week study in monkeys using low doses, changes similar to PACE were found. In connection with its mechanism of action, vulture causes fetal death in rats, rabbits (at multiple doses above 1 mg / kg), guinea pigs and monkeys. Security has not been established against the human embryo. In doses small enough to preserve pregnancy in animals, teratogenic potential is not revealed. In reproduction studies in rats using dosages that provide the same exposure as in man, revealed no evidence of an effect on reproductive performance of animals receiving ulipristal, as well as their progeny.

In studies conducted in mice and rats, there was no evidence of carcinogenic action.

Clinical efficacy and safety.

Efficacy ulipristala fixed doses of 5 and 10 mg once a day 1 was evaluated in two phase 3 trials, which involved a patient with a very heavy menstrual bleeding caused by uterine myoma.

In comparison with placebo, a clinically significant decrease in the amount of menstrual blood loss was found in patients taking ulcers. This allowed faster and more effective correction of anemia than with the appointment of only iron preparations. Reduction of menstrual blood loss in patients receiving ulipristal was comparable to the group receiving GnRH agonist (gonadotropin releasing hormone) (leuprorelin). In the majority of patients who received vomit, the bleeding stopped during the first week of admission (amenorrhea developed).

According to MRI (magnetic resonance imaging), patients receiving ulcers had a significantly larger decrease in uterine fibroids than in the placebo group. Patients who have not been performed a hysterectomy or myomectomy, ultrasonography (ultrasound) control at the end of the treatment (13th week) was estimated decrease in the size of uterine fibroids. As a rule, it persisted for 25 weeks of follow-up in patients receiving ulcers, whereas in the group receiving leuprorelin, there was a slight increase in the size of uterine fibroids.

In yet another Phase 3 study, in which patients received 2 cycles of 10 mg of vaginoplasty for 3 months, the incidence of amenorrhea was comparable at the end of both courses of therapy. The decrease in the volume of leiomyoma registered during the first course was preserved during the 2nd course.

Taking into account the results of previous studies, the effectiveness of the drug at a dose of 5 mg during the first course of therapy will be the same during the second course of therapy, similarly to a dose of 10 mg.

Despite the limited number of patients completing four 3-month courses of treatment, the safety data obtained are sufficient to justify one additional 3-month course of therapy in the preoperative period.

Pharmacokinetics

Suction. After a single oral dose of 5 or 10 mg of vulture is quickly absorbed, reaching about 1 hour after taking Cmax (23.5 ± 14.2) and (50 ± 34.4) ng / ml, respectively. AUC0-∞ is (61.3 ± 31.7) and (134, ± 83.8) ng · h / ml, respectively. Ulipristal is rapidly transformed into a pharmacologically active metabolite, and after 1 h after administration, Cmax is (9 ± 4.4) and (20.6 ± 10.9) ng / ml, AUC (area under the concentration-time curve) 0 -∞ - (26 ± 12) and (63.6 ± 30.1) ng · h / ml, respectively. Receiving ulipristala 30 mg with breakfast with high fat reduces the average Cmax approximately 45% increase in median Tmax of 0.75 hours to 3 hours and a 25% increase of AUC0-∞, as compared with the fasted. 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 pills.

Distribution. Ulipristal highly (> 98%) binds to plasma proteins, including albumin, α1-acid glycoprotein, HDL (high density lipoproteins) and LDL (low density lipoproteins). Ulipristal and its active N-demethylated metabolite penetrate into breast milk; The average ratio AUC (area under the concentration-time curve) τ for milk / plasma is (0.74 ± 0.32) for vandal.

Metabolism. Ulipristal 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 with the participation of the 3A4 isoenzyme (CYP3A4). Proceeding from the fact that the metabolism of vypristopitala is mediated by cytochrome P450, it is expected that hepatic insufficiency will affect the excretion of vigilance, which will lead to an increase in its effect.

Excretion. The main way of excretion is through the intestine, less than 10% of the substance is excreted by the kidneys. The final T1 / 2 vigil after a single intake of 5 or 10 mg is approximately 38 hours, the average clearance is about 100 l / h. In vitro data indicate that clinically significant concentrations ulipristal and its active metabolite do not inhibit isozymes CYP1A2 (cytochrome P450), 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4 isoenzyme and do not induce CYP1A2 (cytochrome P450). Thus, the use of vandamycin should not affect the clearance of drugs that are metabolized with the participation of these isoenzymes.

The in vitro data show that the overgrowth and its active metabolite are not substrates of P-gp.

Application of Ulipristal

Preoperative therapy of symptoms of uterine fibroids of medium severity and severe degree in adult women of reproductive age over 18 years. Duration of therapy - no more than 2 courses.

Contraindications

Hypersensitivity to vandalitis; Pregnancy and the period of breastfeeding; Bleeding from the vagina of an unclear etiology or for reasons not related to uterine myoma; Cancer of the uterus, cervix, ovary or breast; Duration of therapy more than 2 courses; Age <18 years; Bronchial asthma, severe form, not amenable to oral glucocorticosteroids (glucocorticosteroids).

Restrictions for use

Renal and / or liver failure; bronchial asthma.

pregnancy and lactation

Ulimprust is contraindicated in pregnancy.

Data on the use of overpriced in pregnant women are absent or limited. Although there has been no teratogenic potential in animal studies, data on reproductive toxicity is not enough.

In animal studies, it has been shown that vilified milk permeates into breast milk. Ulipristal penetrates into the human breast milk. The impact of vandalizing on newborns and young children has not been studied, therefore, it is impossible to exclude the risk for children during breastfeeding. Ulipristal is contraindicated during breastfeeding.

The action category for fetus by FDA is X.

Side effects

Security Profile Overview

Safety was assessed in 602 women with uterine fibroids who received 5 or 10 mg of ulcers during phase 3 studies. The most frequent observed phenomenon in clinical trials was amenorrhea (80.8%), which is considered the desired outcome.

The most frequent adverse reaction was the appearance of tides. The vast majority of adverse reactions were mild or moderate (93.6%), did not lead to cessation of treatment (99.5%), and were resolved independently.

The safety of two courses of treatment with 10 mg of narco-ulcer, each lasting 3 months, was evaluated in a phase 3 study involving women with uterine fibroids. The data obtained are comparable with the safety profile in the course of treatment within a single course.

List of adverse reactions

In three phase 3 studies, the following adverse reactions were reported in patients with uterine fibroids who had been stuck for up to 3 months. Adverse adverse reactions are presented according to the system-organ classes according to the MedDRA classification and with the frequency of occurrence: very often (≥1 / 10); Often (from ≥1 / 100 to <1/10); Infrequently (from ≥1 / 1000 to <1/100); Rarely (from ≥1 / 10000 to <1/1000); Very rarely (<1/10000); Unknown (can not be estimated based on available data).

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

Disorders of the psyche: infrequently, anxiety, emotional disorders.

From the nervous system: often - headache *; Infrequently - dizziness.

From the side of metabolism and nutrition: infrequently - an increase in body weight.

From the side of the hearing organ and labyrinthine disturbances: often - vertigo.

From the respiratory system, chest and mediastinum: infrequently - epistaxis.

From the digestive tract: often - pain in the abdomen, nausea; Infrequently - dyspepsia, dry mouth, flatulence, constipation.

From the skin and subcutaneous tissues: often - acne, increased sweating; Infrequently - alopecia, dry skin.

From the musculoskeletal system and connective tissue: often - pain in the bones and muscles; Infrequently - back pain.

From the side of the kidneys and urinary tract: infrequently - urinary incontinence.

From the genitals and the breast: very often - amenorrhea, thickening of the endometrium *; Often - hot flashes *, pelvic pain, ovarian cyst *, tension / tenderness of the mammary glands; Infrequently - metrorrhagia, rupture of the ovarian cyst, vaginal discharge, an increase and discomfort in the mammary glands.

* See "Description of selected adverse reactions".

General disorders and disorders at the injection site: often - swelling, fatigue; Infrequently, asthenia.

Changes in laboratory and instrumental studies: often - increasing the concentration of cholesterol in the blood; Infrequently, an increase in the concentration of triglycerides in the blood.

Description of individual adverse reactions

Thickening of the endometrium. In 10-15% of patients who received ulcers, an endometrial thickening (> 16 mm, according to ultrasound or MRI at the end of treatment) may occur. This phenomenon is reversible after cessation of treatment and the resumption of the menstrual cycle.

In addition, reversible changes in the endometrium, referred to as PACE, differ from endometrial hyperplasia. The pathologist should be informed of the patient's admission during a histological examination with a hysterectomy or endometrial biopsy.

Tides. They were noted in 9.8% of patients, but their frequency varied in different studies. In the study with active control, their incidence was 24% (10.5% of the average or severe severity) for those receiving ulcers and 60.4% (39.6% of moderate or severe severity) for those receiving leuprorelin. In a placebo-controlled study, the frequency of hot flashes was 1% for vandal and 0% for placebo.

In the framework of the open phase 3 study, the frequency of the tides was 4.3% in the group vilified.

Headache. Headache of mild or moderate degree was noted in 6.8% of patients.

Ovarian cyst. In 1.2% of patients, functional ovarian cysts were found during treatment, which spontaneously disappeared within a few weeks.

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

Interaction

Possible impact of other drugs on the action of treason

Hormonal contraceptives. Ulipristal has a steroid structure and acts as a selective modulator of progesterone receptors with a predominant inhibitory effect on the receptors of progesterone. Thus, hormonal contraceptives and gestagens can reduce the effectiveness of vandalitis by competing with the progesterone receptor. Therefore, simultaneous use of preparations containing gestagens is not recommended.

Inhibitors of the isoenzyme CYP3A4. After applying moderate isoenzyme CYP3A4 inhibitor erythromycin propionate (500 mg, 2 times a day for 9 days) in healthy female volunteers Cmax and AUC figures ulipristala raised to 1.2 and 2.9 times, respectively; The AUC value of the active metabolite increased 1.5 times, while the Cmax of the active metabolite decreased (by 0.52 times).

Against the background of ketoconazole (400 mg 1 time a day, 7 days), a potent inhibitor of CYP3A4, in healthy female volunteers studies showed an increase in Cmax and AUC figures ulipristala 2 and 5.9 times respectively. There was an increase in the AUC for the active metabolite, which exceeded 2.4 times with a decrease in its Cmax (a change of 0.53 times).

Correction of the dose with the use of ulcers in patients receiving weak inhibitors of the isoenzyme CYP3A4 is not required. The combined use of moderate or strong inhibitors of the isoenzyme CYP3A4 with ulcers is not recommended.

Inductors of the isoenzyme CYP3A4. Against the background of strong CYP3A4 inducer rifampicin (300 mg 2 times a day for 9 days) in healthy female volunteers, a marked decrease in Cmax and AUC figures ulipristala and its active metabolite by over 90%. Also, there was a decrease in T1 / 2 whitened 2.2 times, which corresponds to a decrease in its exposure by about 10 times. Concomitant use ulipristala and strong inducers of CYP3A4 (for example, rifampicin, rifabutin, carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, primidone, St. John's wort, efavirenz, nevirapine, ritonavir, - long-term use on the background) are not recommended.

LAN, 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 Cmax by 65% elongation Tmax (median of 0.75 hours to 1 hour) and increase The average AUC is 13%. This effect of drugs that increase the pH of gastric juice, is not considered clinically significant for the daily intake of pills vyskopstala.

The possible influence of the illicit influence of other drugs

Hormonal contraceptives. Ulipristal may interfere with the action of hormonal contraceptives (only gestagensoderzhaschie tablets gestagenvysvobozhdayuschie systems or combined oral contraceptives) and progestogen preparations used for other indications. Therefore, the concomitant use of drugs containing gestagen is not recommended. Gestagen-containing medicines should not be used within 12 days after the cessation of treatment with ulcers.

Substrates P-gp. In vitro data show that in clinically significant concentrations of ulcers during suction in the wall, the gastrointestinal tract may be an inhibitor of P-gp. Simultaneous use of the substratum and P-gp substrate has not been investigated, therefore the probability of interactions can not be ruled out. In vivo data indicate that the reception ulipristala (tablet 10 mg) for 1.5 hours prior to receiving the P-gp substrate fexofenadine (60 mg) was no clinically significant effect on the pharmacokinetics of fexofenadine. Thus, it is recommended to observe an interval of at least 1.5 h between taking vaginal and P-gp substrates (eg dabigatran etexilate, digoxin, fexofenadine). The patient should inform the attending physician about all the drugs that she receives, even if they are dispensed without a prescription.

Overdose

Data on overdose of overdue is limited.

Single doses up to 200 mg and daily doses of 50 mg for 10 days were administered to a limited number of volunteers, without serious or serious adverse reactions.

Routes of administration

Inside.

Precautions

Ulipristal is prescribed only after a thorough examination. Pregnancy should be excluded before treatment begins.

Contraception. Due to the possibility of unwanted interactions, concomitant use of only gestagen-containing drugs, gestagen-releasing systems or combined oral contraceptives is not recommended. Although the majority of women who received therapeutic doses were exposed to anovulation, an additional use of non-hormonal method of contraception during treatment was recommended.

Renal insufficiency. There is no reason to assume that renal insufficiency can significantly affect the excretion of ulcers. It is not recommended to use ulpristal without constant observation in patients with severe renal insufficiency. Special studies have not been conducted.

Liver failure. There is no experience of therapeutic use of ulcers in patients with hepatic insufficiency. It is expected that hepatic insufficiency may affect the elimination of ulipristala that will strengthen the effects of drugs. This is not relevant for patients with mild liver failure. It is not recommended to appoint ulcers to patients with moderate or severe hepatic impairment when it is not possible to continuously monitor.

Concomitant therapy. Not recommended ulipristala concomitant use of CYP3A4 inhibitors and the average force (e.g. erythromycin, grapefruit juice, verapamil) or potent inhibitors (e.g. ketoconazole, ritonavir, nefazodone, itraconazole, telithromycin, clarithromycin).

We do not recommend joint application ulipristala and strong inducers of CYP3A4 (eg rifampicin, rifabutin, carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, primidone, St. John's wort, efavirenz, nevirapine, ritonavir - against a background of long-term use).

Changes in the endometrium. Ulipristal has a specific pharmacodynamic effect on the endometrium. An increase in the thickness of the endometrium may be noted. If the thickening of the endometrium persists for 3 months after the end of treatment and the resumption of the menstrual cycle, an additional examination should be conducted to exclude other diseases. In patients receiving ulcers, histological examination may show changes in the structure of the endometrium. Such changes are reversible after the completion of treatment. These histological changes are referred to as endometrial changes associated with the antagonistic effect on PACE, and they should not be erroneously evaluated as endometrial hyperplasia. It is recommended to conduct no more than 2 courses of therapy. The duration of each course should not exceed 3 months, since the risk of undesirable effects on the endometrium against a background of longer therapy is unknown.

Bleeding. Patients should be informed that treatment with ulcers usually results in a significant reduction in menstrual blood loss or amenorrhea during the first 10 days of treatment. With persistent excessive bleeding, the patient should consult a doctor. As a rule, the menstrual cycle resumes within 4 weeks after the end of the course of treatment.

Fertility. Anastilation was observed in the majority of women who took ulcers in therapeutic doses. However, fertility with long-term use of vandalitis has not been studied.

Impact on the ability to drive vehicles and mechanisms. Ulipristal can have minimal impact on the ability to drive vehicles and mechanisms, because After taking vaginal can be observed slight dizziness.

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