INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Mifepristone (Mifepristone)

Composition:

Active substance: mifepristone;

1 tablet contains 200 mg of mifepristone;

Excipients: maize starch, microcrystalline cellulose, povidone, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: round, biconvex tablets of light yellow color, with "M 1" embossed on one side.

Pharmacotherapeutic group. Agents affecting the genitourinary system and sex hormones. Antigestational agents. ATC code G03X B01.

Pharmacological Properties.

Pharmacodynamics.

Mifepristone is a synthetic steroid anti-progestogen agent (blocks the action of progesterone at the receptor level).

At oral doses of 3–10 mg/kg body weight, mifepristone inhibits the effect of endogenous or exogenous progesterone in various animal species (rats, mice, rabbits, monkeys). This effect manifests as interruption of pregnancy in rodents.

In women, mifepristone at doses exceeding 1 mg/kg body weight neutralizes the action of progesterone on the endometrium and myometrium. During pregnancy, mifepristone increases the sensitivity of the myometrium to prostaglandins, which induce uterine contractions. When administered in the first trimester of pregnancy, mifepristone promotes dilation and opening of the cervix.

When used in combination with prostaglandin analogues in early pregnancy, the success rate of terminating intrauterine pregnancy is approximately 95% (depending on the prostaglandin and its administration regimen), and expulsion of the gestational sac is accelerated.

The success rate of terminating intrauterine pregnancy is approximately 95% when 600 mg mifepristone is used in combination with 400 μg orally administered misoprostol (in cases of amenorrhea up to 49 days), approximately 98% when combined with 1 mg gemeprost administered intravaginally (in cases of amenorrhea up to 49 days), and approximately 95% when combined with 1 mg gemeprost administered intravaginally (in cases of amenorrhea lasting 50–63 days).

In 1.3–7.5% of cases, pregnancy termination fails with mifepristone in combination with prostaglandins (in 0–1.5% of cases pregnancy continues, in 1.3–4.6% of cases incomplete expulsion occurs, and in 0–1.4% of cases severe uterine bleeding develops, requiring hemostatic curettage).

When mifepristone is used in combination with 400 μg orally administered misoprostol (in cases of amenorrhea up to 49 days), the failure rate is slightly higher with a mifepristone dose of 200 mg compared to 600 mg.

When mifepristone is used in combination with 1 mg gemeprost administered intravaginally (in cases of amenorrhea up to 63 days), the failure rate is approximately the same with mifepristone doses of 200 mg and 600 mg:

The complete expulsion rates with mifepristone doses of 200 mg and 600 mg were 93.8% and 94.3%, respectively, in cases of amenorrhea up to 57 days (n = 777), and 92.4% and 91.7%, respectively, in cases of amenorrhea from 57 to 63 days (n = 896).
The rates of ongoing pregnancy with mifepristone doses of 200 mg and 600 mg were 0.5% and 0.3%, respectively, in cases of amenorrhea up to 57 days, and 1.3% and 1.6%, respectively, in cases of amenorrhea from 57 to 63 days.

Studies on combined use of mifepristone with other prostaglandins, apart from misoprostol and gemeprost, have not been conducted.

For termination of pregnancy for medical reasons in the second and third trimesters, mifepristone should be administered at a dose of 600 mg, followed by prostaglandin administration 36–48 hours later. This reduces the interval between induction and the onset of therapeutic abortion, as well as allows for lower prostaglandin doses.

When mifepristone is used alone to induce labor in cases of intrauterine fetal demise, labor begins within 72 hours after the first dose in approximately 60% of cases. In such cases, there is no need for prostaglandins or oxytocin.

Mifepristone binds to glucocorticoid receptors. Animal experiments have shown that mifepristone at doses of 10–25 mg/kg body weight inhibits the action of dexamethasone. In humans, anti-glucocorticoid activity of mifepristone occurs at doses exceeding 4.5 mg/kg body weight and manifests as compensatory elevation of adrenocorticotropic hormone (ACTH) and cortisol levels. Glucocorticoid bioactivity may be reduced for several days after a single 200 mg dose of mifepristone. The clinical significance of this is unclear, although nausea and vomiting may be exacerbated in some sensitive women.

Mifepristone exerts weak anti-androgenic effects, but this has been observed only after prolonged administration of very high doses in animals.

Pharmacokinetics.

Absorption

After a single oral dose of 600 mg, mifepristone is rapidly absorbed. The maximum plasma concentration (Cmax) is 1.98 mg/L, reached on average within 1.3 hours.

After administration of low doses (20 mg), the absolute bioavailability of mifepristone is 69%.

Distribution

98% of mifepristone in blood is bound to plasma proteins—albumin and predominantly to alpha-1-acid glycoprotein (AAG) (binding to AAG is saturable). Due to this specific binding, the volume of distribution and plasma clearance of mifepristone are inversely proportional to the plasma concentration of AAG.

Biological Transformation

The main metabolic pathway of oxidative biotransformation of mifepristone in the liver involves N-demethylation and final hydroxylation of the 17-propynyl side chain.

Elimination

The pharmacokinetics of mifepristone is nonlinear. After the distribution phase, elimination of mifepristone initially proceeds slowly (plasma concentration decreases by half within 12–72 hours), then accelerates. The mean elimination half-life (t1/2) is 18 hours. Receptor-binding assays have shown that the terminal-phase t1/2 of mifepristone and its metabolites capable of binding to progesterone receptors is up to 90 hours.

Mifepristone is excreted predominantly in feces. After administration of radiolabeled 600 mg mifepristone, 10% of radioactivity was excreted in urine and 90% in feces.

Clinical Characteristics.

Mifepristone and a prostaglandin analogue may be used for termination of pregnancy only if all requirements of national legislation are met.

Indications.

Medical termination of intrauterine pregnancy in early gestation (up to 49 days of amenorrhea) in combination with misoprostol.
Conservative cervical ripening and dilation prior to surgical termination of pregnancy in the first trimester.
Potentiation of prostaglandin analogues for termination of pregnancy for medical indications (in the second and third trimesters of pregnancy).
Preparation and induction of labor in cases of intrauterine fetal demise when the use of prostaglandins or oxytocin is contraindicated.

Contraindications.

General contraindications:

Chronic adrenal cortical insufficiency.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Severe uncontrolled bronchial asthma.

Hereditary porphyria.

Contraindications for medical termination of intrauterine pregnancy:

Pregnancy not confirmed by ultrasound examination (USG) or biological tests.

Gestational age exceeding 49 days of amenorrhea.

Suspected ectopic pregnancy.

Presence of contraindications to the use of prostaglandins.

Contraindications for conservative cervical ripening and dilation prior to surgical termination of pregnancy in the first trimester:

Pregnancy not confirmed by ultrasound examination (USG) or biological tests.

Gestational age exceeding 84 days of amenorrhea.

Suspected ectopic pregnancy.

Contraindications for potentiation of prostaglandin analogues in termination of pregnancy for medical indications (in the second and third trimesters of pregnancy):

Presence of contraindications to the use of prostaglandins.

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interaction

Theoretically, the efficacy of the method of terminating intrauterine pregnancy using mifepristone in combination with prostaglandins may be reduced when nonsteroidal anti-inflammatory drugs (NSAIDs) with anti-prostaglandin properties, including aspirin (acetylsalicylic acid), are used concomitantly. However, limited clinical data indicate that the use of NSAIDs on the day of prostaglandin administration does not negatively affect the action of mifepristone or prostaglandin on cervical ripening or uterine contractility, and does not reduce the clinical efficacy of the method of medical termination of intrauterine pregnancy.

Pharmacokinetic interactions

Effect of other medicinal products on mifepristone

Concomitant administration of mifepristone with the CYP3A4 inhibitor itraconazole increased the area under the plasma concentration-time curve (AUC) of mifepristone by a factor of 2.6, and exposure to its metabolites 22-hydroxymifepristone and N-demethylmifepristone by 5.1 and 1.5 times, respectively. Cmax increased by 1.5 times for mifepristone and by 1.8 times for 22-hydroxymifepristone, while decreasing to 0.7 times for N-demethylmifepristone. Increased exposure is expected when mifepristone is administered concomitantly with a strong CYP3A4 inhibitor (Cmax increases by 1.5 times). However, this is unlikely to be of clinical significance. There is no need to adjust the dose when mifepristone is administered concomitantly with a CYP3A4 inhibitor (e.g., itraconazole, ketoconazole, erythromycin, or grapefruit juice).

It has been shown that concomitant administration of mifepristone with the CYP3A4 inducer rifampicin reduces the AUC of mifepristone by a factor of 6.3, and its metabolites 22-hydroxymifepristone and N-demethylmifepristone by 20 times and 5.9 times, respectively. Thus, reduced efficacy can be expected when mifepristone is administered concomitantly with a CYP3A4 inducer (e.g., rifampicin, dexamethasone, St. John’s wort, and certain anticonvulsants such as phenytoin, phenobarbital, carbamazepine).

Therefore, in the case of medical termination of an ongoing intrauterine pregnancy, for a patient receiving a strong or moderate CYP3A4 inducer, it is recommended to administer a single oral dose of 600 mg (i.e., 3 tablets of 200 mg each), followed by administration of a prostaglandin analogue (misoprostol 400 μg orally or gemeprost 1 mg vaginally) 36–48 hours later.

Effect of mifepristone on other medicinal products

In vitro and in vivo data indicate that mifepristone is a CYP3A4 inhibitor. Concomitant administration of mifepristone may lead to increased serum concentrations of drugs metabolized by CYP3A4. Due to the slow elimination of mifepristone from the human body, this interaction may persist for a prolonged period after administration of the drug. For this reason, mifepristone should be used with caution in combination with medicinal products having a narrow therapeutic index that are substrates of the CYP3A4 isoenzyme (e.g., certain general anesthetics).

Due to the anti-glucocorticosteroid activity of mifepristone, the efficacy of long-term corticosteroid therapy (e.g., inhaled corticosteroids) may be reduced for 3–4 days after administration of mifepristone. In such cases, corticosteroid doses should be adjusted accordingly.

Special precautions for use

Considering the abortifacient properties of mifepristone, it must not be administered to pregnant women who wish to continue their pregnancy.

Since specific studies have not been conducted, the medicinal product Mifepristone is not recommended for patients with renal impairment, hepatic impairment, or nutritional deficiency.

Mifepristone in combination with prostaglandins should be used only under medical supervision and prescribed by a physician, and only in specialized healthcare facilities equipped to provide immediate gynecological assistance.

Medical termination of early intrauterine pregnancy

This method requires active participation by the woman, and she must be informed about the following rules:

The necessity of combined use of a prostaglandin analogue, which is taken or administered during the second visit to the physician.
The necessity of a follow-up visit to the physician (third visit) 14–21 days after taking Mifepristone to confirm complete expulsion.
If pregnancy termination with Mifepristone fails, abortion must be completed by another method.
If the patient is pregnant with an intrauterine device in place, it must be removed before administering Mifepristone.

Risks associated with this method:

Ineffectiveness

Since pregnancy termination with Mifepristone fails in 1.3–7.5% of cases, a follow-up visit to the physician is mandatory to verify complete expulsion.

In rare cases of incomplete expulsion, surgical intervention may be required.

The effectiveness of the method decreases in the presence of prior deliveries and with increasing age.

Bleeding

Patients should be informed about the possibility of prolonged vaginal bleeding (on average for 12 days or more after administration of Mifepristone), which may be heavy. Bleeding occurs in nearly all patients and is not always proof of complete expulsion.

Bleeding may begin very quickly after misoprostol intake or later:

In 60% of cases, expulsion occurs within 4 hours after misoprostol intake;
In the remaining 40% of cases, expulsion occurs between 24 and 72 hours after misoprostol intake.

Rarely, expulsion may occur before taking the prostaglandin analogue (approximately 3% of cases). However, this does not exclude the need for a follow-up visit to confirm complete expulsion and absence of uterine remnants.

Patients should not travel long distances from the healthcare facility until complete expulsion is confirmed. They should be provided with detailed information on where and to whom to turn in case of any complications, particularly in the event of heavy vaginal bleeding. Heavy bleeding is defined as bleeding lasting longer than 12 days and/or bleeding heavier than normal menstrual flow.

Since severe uterine bleeding requiring hemostatic curettage may occur in 0–1.4% of cases, special attention should be paid to patients with coagulation disorders, hypocoagulation, or anemia. Decisions regarding the use of medical or surgical methods should be made with the involvement of a hematologist consultant.

Infections

There have been isolated reports of severe or even fatal infectious-toxic shock caused by pathogenic microorganisms Clostridium sordellii endometritis and Escherichia coli (with or without typical signs of infection), following medical abortion using 200 mg mifepristone followed by unsanctioned intravaginal administration of misoprostol tablets intended for oral use. Physicians should be aware of the potential for such potentially fatal complications.

Conservative preparation and cervical dilation prior to surgical termination of pregnancy in the first trimester

To ensure maximum therapeutic efficacy, surgical abortion should be performed within 36–48 hours (no later) after administration of Mifepristone.

Risks associated with this method:

Bleeding.

Patients should be informed about the possibility of vaginal bleeding (sometimes heavy) after administration of Mifepristone. They should also be aware that abortion may occur before surgical intervention (although the likelihood is minimal), and they should be given detailed information on where and to whom to turn in such a case (to verify complete expulsion) or in case of any complications.

Since severe uterine bleeding requiring hemostatic curettage may occur in approximately 1% of cases, special attention should be paid to patients with coagulation disorders, hypocoagulation, or severe anemia.

Other risks associated with surgical intervention.

Use for all indications

Administration of the drug requires determination of the Rh factor to prevent Rh alloimmunization, as well as implementation of other general measures accompanying pregnancy termination.

During clinical trials, cases of new pregnancy occurring between expulsion and the expected return of menstruation were reported.

To exclude the potential effect of mifepristone on a subsequent pregnancy, it is recommended to avoid conception during the following menstrual cycle. Therefore, reliable contraceptive methods should be used as early as possible after mifepristone administration.

In suspected acute adrenal insufficiency, dexamethasone should be administered. 1 mg of dexamethasone neutralizes the effect of 400 mg of mifepristone.

There have been reports of serious cardiovascular complications (myocardial infarction and/or coronary artery spasm and acute arterial hypotension) following administration of a prostaglandin analogue. Therefore, the drug should be prescribed with caution to patients with risk factors for cardiovascular disease (e.g., age 35 years or older with chronic smoking, hyperlipidemia, diabetes) or existing cardiovascular conditions should be managed cautiously.

Severe skin adverse reactions have been reported with mifepristone use, including toxic epidermal necrolysis and acute generalized exanthematous pustulosis (see section "Adverse reactions"). Treatment with mifepristone should be immediately discontinued in patients who develop severe skin adverse reactions. Re-administration of mifepristone is not recommended.

Mifepristone should be used with caution in patients with bronchial asthma, as it may provoke exacerbation.

Prostaglandins must be administered under inpatient conditions. To prevent possible acute complications, the patient should be observed in a healthcare facility equipped to provide immediate gynecological assistance for at least 3 hours after prostaglandin administration. The patient should be thoroughly informed about the action and possible adverse effects of the drugs and provided with detailed instructions on where and to whom to turn in case of any complications.

Use during pregnancy or breastfeeding.

In preclinical animal studies, the abortifacient effect of mifepristone prevented evaluation of the teratogenic properties of the compound. When mifepristone was administered at sub-abortifacient doses, isolated malformations were observed in rabbits, but the frequency was too low to be considered mifepristone-induced. No malformations were observed in rats, mice, or monkeys.

In clinical practice, isolated cases of lower limb malformations (limb absence, clubfoot) have been reported after mifepristone use as monotherapy or in combination with prostaglandins. One possible mechanism may be amniotic band syndrome. However, these limited data do not allow assessment of the teratogenic potential of mifepristone in humans.

Considering the above:

Patients should be informed that, since pregnancy termination with Mifepristone sometimes fails and due to the unknown risk to the fetus, a follow-up visit to the physician is mandatory.
If ongoing pregnancy is diagnosed during the follow-up visit, the patient should be offered another method of pregnancy termination (with her consent).
If the patient wishes to continue the pregnancy, the existing limited medical data do not justify mandatory termination. In such cases, regular ultrasound examinations should be performed, with special attention to fetal development.

Mifepristone is a lipophilic compound that may pass into breast milk in small amounts. Therefore, mifepristone should be avoided during breastfeeding.

Fertility

Mifepristone does not affect fertility. It is entirely possible for a woman to become pregnant immediately after completion of the abortion process. Therefore, it is important to inform the patient about the necessity of starting contraceptive methods immediately after confirmation of pregnancy termination.

Ability to influence the speed of reactions when driving or operating machinery.

Studies on the effect of mifepristone on the ability to drive or operate machinery have not been conducted. However, since mifepristone may cause adverse effects such as dizziness, patients are advised to refrain from driving or operating machinery until they are certain they do not experience such reactions.

Method of Administration and Dosage

Medical termination of early intrauterine pregnancy (up to 49 days of amenorrhea) in combination with misoprostol

Amenorrhea up to 49 days:

600 mg of mifepristone (3 tablets of 200 mg) taken orally as a single dose under medical supervision. 36–48 hours later, administer a prostaglandin analogue—misoprostol 400 mcg orally. The patient must remain under medical supervision for at least 3 hours after administration of the prostaglandin.

14–21 days after administration of mifepristone, a clinical examination and ultrasound (US) should be performed, along with determination of beta-hCG (human chorionic gonadotropin) levels to confirm complete expulsion and cessation of vaginal bleeding. If bleeding persists (even if mild) after the follow-up visit, the patient's condition should be reassessed within a few days. If a progressing pregnancy is suspected, an additional ultrasound should be performed.

The presence of vaginal bleeding at this stage may indicate incomplete expulsion or an undiagnosed ectopic pregnancy. In such cases, appropriate measures should be taken.

If a continuing pregnancy is diagnosed during the follow-up visit, the patient should be offered an alternative method of pregnancy termination.

Conservative softening and dilation of the cervix prior to surgical abortion in the first trimester of pregnancy

200 mg of mifepristone (1 tablet of 200 mg) taken orally as a single dose under medical supervision. Surgical abortion should be performed 36–48 hours (but no later) after mifepristone administration.

Enhancement of prostaglandin analogue effects for termination of pregnancy due to medical indications (in the second and third trimesters of pregnancy)

600 mg of mifepristone (3 tablets of 200 mg) taken orally as a single dose under medical supervision. 36–48 hours later, prostaglandins should be administered at the required intervals. The patient must remain under medical supervision for at least 3 hours after administration of prostaglandins.

Preparation and induction of labor in cases of intrauterine fetal demise

600 mg of mifepristone (3 tablets of 200 mg) taken orally once daily for two consecutive days under medical supervision. If labor does not begin within 72 hours after the first dose of mifepristone, standard methods of labor induction should be used.

Vomiting within 45 minutes after administration of mifepristone may reduce the effectiveness of the drug; in such cases, a new oral dose of 600 mg of mifepristone is recommended.

Children

There is no experience with the use of this drug in children.

Overdose

Cases of mifepristone overdose have not been reported.

In the event of significant overdose, symptoms of adrenal insufficiency may occur. Treatment is symptomatic. Dexamethasone may be administered.

Side effects

Adverse reactions are categorized according to frequency as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from available data; based on post-marketing reports, as reports were voluntary and the number of patients is unknown, making it impossible to reliably estimate the frequency of these events).

Nervous system disorders

Rare: headache.

Gastrointestinal disorders

Very common: nausea, vomiting, diarrhea (these adverse reactions are frequently observed with prostaglandin use).

Common: gastrointestinal spasms (mild or moderate in severity).

Skin and subcutaneous tissue disorders

Uncommon: hypersensitivity reactions, including skin rashes (0.2%).

Rare: urticaria, erythroderma, nodular erythema, toxic epidermal necrolysis.

Very rare: angioneurotic edema.

Frequency not known: acute generalized exanthematous pustulosis.

Infections and infestations

Common: post-abortion infections. Suspected or confirmed infections (endometritis, pelvic inflammatory disease) were observed in less than 5% of patients.

Very rare: isolated cases of severe or even fatal infectious-toxic shock caused by pathogenic microorganisms Clostridium sordellii endometritis and Escherichia coli (with or without chills and other obvious signs of infection) have been reported after medical abortion using 200 mg mifepristone followed by unauthorized intravaginal administration of misoprostol tablets intended for oral use.

Vascular disorders

Uncommon: arterial hypotension (0.25%).

General disorders and administration site conditions

Rare: malaise, vagal symptoms (hot flushes, dizziness, chills), chills.

Reproductive system and breast disorders

Very common: uterine contractions or spasms (in 10–45% of patients) occurring within several hours after prostaglandin administration.

Common: intense uterine bleeding (in approximately 5% of patients), requiring hemostatic curettage in 0–1.4% of cases.

Rare: in cases of medically indicated termination of pregnancy in the second trimester, as well as induction of labor due to intrauterine fetal death in the third trimester, cases of uterine rupture have been reported after prostaglandin use (predominantly in multiparous women and women with a uterine scar from previous cesarean section).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life.

2 years.

Storage conditions.

Store in the original packaging, protected from light, at a temperature not exceeding 30 °C.

Keep out of reach of children.

Packaging.

1 or 3 tablets in a blister, 1 blister per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

China Resources Zizhu Pharmaceutical Co., Ltd.

Manufacturer's address and place of business.

Chaoyang North Road 27, Chaoyang District, Beijing, 100024, People's Republic of China.

No. 27, Chaoyang North Road, Chaoyang District, Beijing, 100024, People's Republic of China.