Mifeton: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MIFETON (Mifeton)

Composition:

Active substance: mifepristone;

1 tablet contains 200 mg of mifepristone;

Excipients: microcrystalline cellulose, maize starch, povidone, sodium lauryl sulfate, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: round-shaped tablets of light yellow color with a score line on one side.

Pharmacotherapeutic group.

Medicinal products affecting the urogenital system and sex hormones. Antigestagens.

ATC code G03X B01.

Pharmacological Properties.

Pharmacodynamics.

Mifepristone is a synthetic steroid antiprogestogen (blocks the action of progesterone at the receptor level).

At oral doses of 3–10 mg/kg body weight, mifepristone inhibits the action 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 cervical dilation and effacement.

When mifepristone is 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 misoprostol orally (with amenorrhea up to 49 days), approximately 98% when combined with 1 mg gemeprost administered intravaginally (with amenorrhea up to 49 days), and approximately 95% when combined with 1 mg gemeprost administered intravaginally (with amenorrhea up to 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 misoprostol orally (with amenorrhea up to 49 days), the failure rate is slightly higher with a 200 mg dose of mifepristone compared to 600 mg.

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

The rate of complete expulsion with 200 mg and 600 mg mifepristone was 93.8% and 94.3%, respectively – with amenorrhea up to 57 days (n = 777), and 92.4% and 91.7%, respectively – with amenorrhea of 57–63 days (n = 896).
The rate of ongoing pregnancy with 200 mg and 600 mg mifepristone was 0.5% and 0.3%, respectively – with amenorrhea up to 57 days, and 1.3% and 1.6%, respectively – with amenorrhea of 57–63 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 indications 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 and allows for lower doses of prostaglandins.

When mifepristone alone is used to induce labor following intrauterine fetal demise, labor begins within 72 hours after the first dose in approximately 60% of cases. In such cases, there is no need to use 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, ant glucocorticoid activity of mifepristone is observed 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 antiandrogenic effects, but this has been observed only with prolonged administration of very high doses in animals.

Pharmacokinetics.

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.

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

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

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

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

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.

Mifetone and prostaglandins may be used for termination of pregnancy only if all requirements of national legislation are met.

Indications.

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

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

Potentiation of the effect of prostaglandin analogues in termination of pregnancy for medical indications (in the II–III trimesters of pregnancy).

Preparation and induction of labor in cases of intrauterine fetal death, when the use of prostaglandins or oxytocin is contraindicated.

Contraindications.

General contraindications

Chronic adrenal cortex insufficiency.

Hypersensitivity to the active substance or to any of the excipients of the drug.

Severe uncontrolled bronchial asthma.

Hereditary porphyria.

Contraindications for medical termination of intrauterine pregnancy

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

Pregnancy duration exceeding 49 days of amenorrhea.

Suspected ectopic pregnancy.

Presence of contraindications for the use of prostaglandins.

Contraindications for conservative softening and dilation of the cervix prior to surgical termination of pregnancy in the first trimester of pregnancy

Pregnancy not confirmed by USG or biological tests.

Pregnancy duration exceeding 84 days of amenorrhea.

Suspected ectopic pregnancy.

Contraindications for potentiation of the effect of prostaglandin analogues in termination of pregnancy for medical indications (in the II–III trimesters of pregnancy)

Presence of contraindications for the use of prostaglandins.

Contraindications for preparation and induction of labor in cases of intrauterine fetal death

Severe gestosis, pre-eclampsia, eclampsia, preterm or post-term pregnancy.

Interaction with other medicinal products and other forms of interaction.

Specific studies on interactions between mifepristone and other medicinal products have not been conducted.

Since mifepristone is metabolized via the CYP3A4 isoenzyme of the cytochrome P450 system, drugs such as ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (resulting in increased serum concentration of mifepristone). Rifampicin, dexamethasone, St. John’s Wort herbal preparations, and certain anticonvulsants (phenytoin, phenobarbital, carbamazepine) may stimulate mifepristone metabolism (reducing its serum concentration).

In vitro studies indicate that concomitant use of mifepristone may increase serum concentrations of drugs that are substrates of the CYP3A4 isoenzyme. 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, it is recommended to use mifepristone with caution in combination with medicinal products having a narrow therapeutic range that are substrates of the CYP3A4 isoenzyme (e.g. certain general anesthetics).

Due to the anti-glucocorticoid activity of mifepristone, the effectiveness of long-term corticosteroid therapy (including inhaled corticosteroids) may be reduced for 3–4 days after administration of Mifetone. In such cases, corticosteroid doses should be adjusted.

Theoretically, the efficacy of the method of medical termination of intrauterine pregnancy using mifepristone in combination with prostaglandins may be reduced when co-administered with non-steroidal anti-inflammatory drugs (NSAIDs) possessing anti-prostaglandin properties, particularly aspirin (acetylsalicylic acid). 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.

Special precautions for use.

Considering the abortive properties of mifepristone, it must not be administered to pregnant women who wish to carry the pregnancy to term.

Mifeton in combination with prostaglandins should be used only under medical prescription and supervision, and solely in specialized healthcare facilities equipped to provide immediate gynecological assistance.

Since specific studies have not been conducted, Mifeton is not recommended for patients with renal insufficiency, hepatic insufficiency, or nutritional deficiency.

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, which should be 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 Mifeton 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 administration of Mifeton;
abortion may occur before prostaglandin administration (in approximately 3% of cases). This does not exclude the need for a follow-up visit to the physician for examination of the uterine cavity and confirmation of complete expulsion.

Risks associated with the method

Lack of effect.

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

In rare cases, surgical intervention may be required due to incomplete expulsion. The efficacy of the method decreases with a history of previous deliveries and increasing age.

Bleeding.

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

Bleeding may begin shortly 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 administration of the prostaglandin analogue (approximately 3% of cases). However, this does not eliminate the need for a follow-up visit to confirm complete expulsion and absence of uterine remnants.

Patients should not travel far from the healthcare facility until complete expulsion is confirmed. They should be given detailed information on where and to whom to turn in case of any problems, 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 intensive uterine bleeding requiring hemostatic curettage may occur in 0–1.4% of cases, particular attention should be paid to patients with coagulation disorders, hypocoagulation, or anemia. Decisions regarding medical or surgical management should be made with the involvement of a hematologist consultant.

Infections.

There have been reports of rare cases 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 such as fever and other obvious symptoms), following medical abortion using 200 mg mifepristone followed by unsanctioned intravaginal administration of oral misoprostol tablets. Physicians should consider the possibility of 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 36–48 hours (no later) after Mifeton administration.

Risks associated with the method

Bleeding.

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

Since intensive uterine bleeding requiring hemostatic curettage may occur in approximately 1% of cases, particular 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 expected return of menstruation were observed.

To exclude the potential effect of mifepristone on a subsequent pregnancy, conception should be avoided 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.

Rare serious cardiovascular complications (myocardial infarction and/or coronary artery spasm and acute hypotension) have been reported after administration of a prostaglandin analogue. Therefore, the drug should be prescribed with caution to patients with risk factors for cardiovascular diseases (e.g., age over 35 years 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 drug's action and possible adverse effects, 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 abortive effect of mifepristone prevented evaluation of the compound's teratogenic properties. With sub-abortive doses of mifepristone, isolated malformations were observed in rabbits, but the frequency was too low to be considered mifepristone-related. Malformations were not observed in rats or mice.

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. However, these limited data do not allow assessment of the teratogenic potential of mifepristone in humans.

Considering the above:

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

Mifeton is a lipophilic compound that may theoretically pass into breast milk, although this is not definitively known. Therefore, mifepristone use 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 reaction rate 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, nausea, vomiting, and cramps, patients are advised to refrain from driving or operating machinery until they are certain these reactions are absent.

Method of Administration and Dosage

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

Amenorrhea up to 49 days

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

14–21 days after administration of Mifeton, a clinical examination and ultrasound (US) should be performed, and beta-hCG (human chorionic gonadotropin) levels should be measured 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 ongoing 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 termination of pregnancy in the first trimester

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

Potentiation of prostaglandin analogs' effect in medically indicated termination of pregnancy (in the second and third trimesters)

600 mg of mifepristone (3 tablets of 200 mg each) taken orally as a single dose in the presence of a physician. 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 prostaglandin administration.

Preparation and induction of labor in cases of intrauterine fetal demise

Administer 600 mg of mifepristone orally once daily (3 tablets of 200 mg each) for two consecutive days in the presence of a physician. 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 may reduce the effectiveness of mifepristone; in such cases, a new oral dose of 600 mg of mifepristone is recommended.

Children

There is no experience with the use of the 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.

Adverse Reactions

Adverse reactions are categorized according to frequency as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000).

Frequency not known (cannot be estimated from available data; based on post-marketing reports; since reports of these reactions were voluntary and the size of the population is unknown, it is not possible to reliably estimate the frequency of these events, therefore they are classified as adverse reactions with unknown frequency).

Central Nervous System

Rare: headache.

Gastrointestinal System

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

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

Skin and Subcutaneous Tissue

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 following medical abortion using 200 mg mifepristone followed by unsanctioned intravaginal administration of misoprostol tablets intended for oral use.

Vascular System

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: heavy uterine bleeding (in approximately 5% of patients), which required hemostatic curettage in 0–1.4% of cases.

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

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

1 tablet or 3 tablets per blister, 10 blisters (1x10) or 1 blister (1x3) per cardboard box.

Prescription status. Prescription only.

Manufacturer.

ACME FORMULATION PVT. LTD.

aCME FORMULATION PVT. LTD.

Manufacturer's address and place of business.

Ropar Road, Nalagarh, District Solan, Himachal Pradesh, 174101, India

Ropar Road, Nalagarh, District Solan, Himachal Pradesh, 174101 India

Marketing Authorization Holder.

M.BIOTECH LIMITED

Address of Marketing Authorization Holder.

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom