Myfotab

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MIFOTAB (MIFOTAB)

Composition:

Active substance: mifepristone;

1 tablet contains mifepristone 200 mg (0.2 g);

Excipients: maize starch, sodium starch glycolate (type A), calcium
hydrogen phosphate, colloidal anhydrous silicon dioxide, talc, magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: round, light yellow-green tablets with speckles and a score line on one side.

Pharmacotherapeutic group.

Sex hormones and drugs affecting the reproductive system. Antigestagens.

ATC code G03X B01.

Pharmacological Properties

Pharmacodynamics

Mifepristone is a synthetic steroid antiprogestogen (it 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 used in the first trimester of pregnancy, mifepristone promotes dilation and opening of the cervix.

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 (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 of 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 in cases of amenorrhea up to 49 days, the frequency of lack of effect 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 frequency of lack of effect is approximately the same with mifepristone doses of 200 mg and 600 mg:

• The frequency of complete expulsions with mifepristone doses of 200 mg and 600 mg 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 frequency of ongoing pregnancy with mifepristone doses of 200 mg and 600 mg 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 the 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 is administered at a dose of 600 mg, followed by prostaglandins 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 after intrauterine fetal death, 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 a compensatory increase in adrenocorticotropic hormone (ACTH) and cortisol levels. Glucocorticoid bioactivity may be reduced for several days after a single dose of 200 mg mifepristone. The clinical significance of this is unclear, although nausea and vomiting may be exacerbated in some sensitive women.

Mifepristone exerts a weak antiandrogenic effect, but this has been observed only after 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 = 1.98 mg/L) is 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), then accelerates. The mean elimination half-life is 18 hours. Receptor-binding assays have shown that the terminal-phase elimination 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), the absolute bioavailability is 69%.

98% of mifepristone in blood is protein-bound—primarily to albumin and predominantly to alpha-1-acid glycoprotein (binding to the latter 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 terminal 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.

Mifepristone 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 gestation (up to 49 days of amenorrhea) in combination with misoprostol.
• Conservative ripening and cervical dilation prior to surgical termination of pregnancy in the first trimester of pregnancy.
• Potentiation of prostaglandin analogs' action in termination of pregnancy for medical indications (in the II–III trimesters of pregnancy).
• Preparation and induction of labor in cases of intrauterine fetal demise when prostaglandins or oxytocin are contraindicated.

Contraindications.

General contraindications:

• Chronic adrenal 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 (US) or biological tests.
• Pregnancy duration exceeding 49 days of amenorrhea.
• Suspected ectopic pregnancy.
• Presence of contraindications to the use of prostaglandins.

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

• Pregnancy not confirmed by US or biological tests.
• Pregnancy duration exceeding 84 days of amenorrhea.
• Suspected ectopic pregnancy.

Contraindications for potentiation of prostaglandin analogs' action in termination of pregnancy for medical indications (in the II–III trimesters of pregnancy):

• Presence of contraindications to the use of prostaglandins.

Contraindications for preparation and induction of labor in cases of intrauterine fetal demise:

• Severe preeclampsia, eclampsia, preterm or post-term pregnancy.

Interaction with other medicinal products and other forms of interactions.

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 enhance mifepristone metabolism (reducing its serum concentration).

In vitro studies indicate that co-administration 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. Therefore, caution is recommended when using mifepristone in combination with medicinal products having a narrow therapeutic range that are substrates of the CYP3A4 isoenzyme (e.g., certain general anesthetics).

Due to mifepristone’s antiglucocorticoid activity, the efficacy of long-term corticosteroid therapy (e.g., inhaled corticosteroids) may be reduced for 3–4 days after administration of Mifotab. 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 non-steroidal anti-inflammatory drugs (NSAIDs) with anti-prostaglandin properties, including aspirin (acetylsalicylic acid), are used concomitantly. However, limited clinical data suggest that the use of NSAIDs on the day of prostaglandin administration does not negatively affect mifepristone or prostaglandin action on cervical ripening or uterine contractility, and does not reduce the clinical efficacy of the medical method of terminating intrauterine pregnancy.

Special precautions for use.

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

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

Medical termination of early intrauterine pregnancy

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

• The necessity of combined use of a prostaglandin, which is administered or taken during the second visit to the physician.
• The necessity of a follow-up visit to the physician (third visit) 14–21 days after taking Mifotab to confirm complete expulsion.
• If pregnancy termination with Mifotab fails, the abortion must be completed by another method.
• If a patient is pregnant with an intrauterine device in place, it must be removed prior to administration of Mifotab.
• Abortion may occur before prostaglandin administration (in approximately 3% of cases). This does not eliminate the need for a follow-up visit to the physician for examination of the uterine cavity and confirmation of complete expulsion.

Risks associated with this method:

• Lack of effect.

Since failure to terminate pregnancy occurs in 1.3–7.5% of cases with Mifotab, 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 efficacy of this method decreases with increasing maternal age and in patients with a history of previous deliveries.

• Bleeding.

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

Patients should not travel long distances from a medical facility until complete expulsion is confirmed. They should be given detailed instructions on where and to whom to turn in case of any complications, particularly in the event of heavy vaginal bleeding.

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, hypocoagulability, or anemia. Decisions regarding medical or surgical management should be made in consultation with a hematologist.

• Infections.

Isolated cases of severe or even fatal infectious-toxic shock caused by pathogenic microorganisms such as Clostridium sordellii endometritis and Escherichia coli (with or without typical signs of infection such as fever) have been reported after 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 cervical ripening and dilation prior to surgical termination of first-trimester pregnancy

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

Risks associated with this method:

• Bleeding.

Patients should be informed about the possibility of vaginal bleeding (sometimes heavy) after taking Mifotab. They should also be aware that abortion may occur before surgical intervention (although the likelihood is minimal), and they must be given detailed instructions 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, hypocoagulability, or severe anemia.

• Other risks associated with surgical intervention.

Use for all indications

The use of this medication 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 observed.

To avoid potential effects of mifepristone on a subsequent pregnancy, conception should be avoided during the following menstrual cycle. Therefore, reliable contraception should be initiated as early as possible after mifepristone administration.

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

Isolated serious cardiovascular complications have been reported after intramuscular administration of prostaglandin analogs. Therefore, caution should be exercised when prescribing these drugs to patients with pre-existing cardiovascular diseases or risk factors for such conditions.

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

Prostaglandins must be administered in an inpatient setting. To prevent possible acute complications, the patient should be observed in a medical facility capable of providing immediate gynecological care for at least 3 hours after prostaglandin administration. The patient must be thoroughly informed about the drug's action and possible adverse effects and must know where and to whom to turn in case of any problems.

Use during pregnancy or breastfeeding.

In preclinical animal studies, the abortifacient effect of mifepristone prevented evaluation of the compound's teratogenic properties. Isolated malformations were observed in animals after administration of mifepristone at sub-abortive doses, but the frequency was too low to attribute them definitively to mifepristone. Malformations were not observed in rats or mice.

In clinical practice, isolated cases of 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.

Given the above:

• Patients must be informed that since pregnancy termination with Mifotab may occasionally fail, and considering the unknown risk to the fetus, a follow-up visit to the physician is mandatory.
• If a continuing pregnancy is diagnosed during the follow-up visit, the patient should be offered an alternative 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.

Mifepristone is a lipophilic compound that may theoretically pass into breast milk, although this has not been definitively established. Therefore, mifepristone use should be avoided during breastfeeding.

Ability to affect 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 do not occur.

Method of Administration and Dosage

Medical termination of intrauterine pregnancy in early gestation (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 – 400 mcg of misoprostol orally. The patient must remain under medical supervision for at least 3 hours after prostaglandin administration.

14–21 days after administration of Mifotab, a clinical examination and ultrasound (US) should be performed, along with measurement of beta-hCG (human chorionic gonadotropin) levels to confirm complete abortion 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, additional ultrasound examination should be performed.

The presence of vaginal bleeding at this stage may indicate incomplete abortion 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 under medical supervision. Surgical abortion should be performed 36–48 hours later (but not later).

Enhancement of prostaglandin analogue effects in medically indicated termination of pregnancy (in the second–third trimesters)

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 prostaglandin administration.

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.

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 (≥ 1/10000, < 1/1000), very rare (< 1/10000).

From the nervous system.

• Rare: headache.

From the gastrointestinal tract.

• Very common: nausea, vomiting, diarrhea (these adverse effects are frequently observed during prostaglandin use).
• Common: gastrointestinal spasms (mild or moderate in severity).

From the skin and subcutaneous tissues.

• Uncommon: hypersensitivity reactions, including skin rashes (0.2%).
• Rare: urticaria, erythroderma, nodular erythema, toxic epidermal necrolysis.
• Very rare: angioneurotic edema.

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: there have been reports of 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 apparent symptoms of infection), following medical abortion using 200 mg mifepristone followed by unauthorized intravaginal administration of misoprostol tablets intended for oral use.

Vascular system.

• Uncommon: arterial hypotension (0.25%).

General disorders and local reactions.

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

From the reproductive system and mammary glands.

• 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 in 0–1.4% of cases requires hemostatic curettage.
• Rare: 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, cases of uterine rupture have been reported following prostaglandin use (predominantly in multiparous women and women with a uterine scar from previous cesarean section).

Shelf life. 3 years.

Storage conditions.

Store in a dry, light-protected place at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

3 tablets in a blister; 1 blister per cardboard box.

Prescription category.

Prescription only.

Manufacturer.

Novast Laboratories Ltd, China.

Novast Laboratories Ltd, China.

Manufacturer's address and location of operations.

1 Guangjing Road, Free Trade Zone, NETDA, Nantong, - 226009, China.

1 Guangxing Road, Free Trade Zone, NETDA, Nantong, - 226009, China (CHN).