Mizotab

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MIZOTAB (MISOTAB)

Composition:

Active substance: misoprostol;

1 tablet contains 200 mcg (0.2 mg) of misoprostol;

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

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white, round tablets with a break line on one side.

Pharmacotherapeutic group. Drugs used in gynecology. Prostaglandins.

ATC code G02AD06.

Pharmacological properties.

Pharmacodynamics.

Misoprostol is a synthetic prostaglandin E1 analogue.

Misoprostol induces contractions of the smooth muscle fibers of the myometrium and cervical dilation. The ability of misoprostol to stimulate uterine contractions facilitates cervical dilation and evacuation of the uterine cavity.

The drug exerts a weak stimulatory effect on the smooth musculature of the gastrointestinal tract. High doses of misoprostol inhibit gastric juice secretion.

Misoprostol has no clinically significant effect on prolactin, gonadotropin levels, thyroid-stimulating hormone, growth hormone, thyroxine, cortisol, creatinine, platelet aggregation, lung function, or the cardiovascular system.

Pharmacokinetics.

After oral administration, misoprostol is rapidly absorbed. Concomitant administration with food reduces the bioavailability of misoprostol (fatty food significantly reduces absorption without affecting the duration of absorption).

It is metabolized in the gastrointestinal tract wall and liver to the pharmacologically active diesterified metabolite—misoprostolic acid. Time to reach peak metabolite concentration is 15–30 minutes. Peak concentration of misoprostol is 6.08±1.64 mg/mL, and of misoprostolic acid—499 mg/mL. The elimination half-life of misoprostolic acid is at least 30 minutes. No accumulation occurs.

Increasing the misoprostol dose from 200 to 400 mcg results in a doubling of plasma concentration of misoprostolic acid.

It is excreted predominantly by the kidneys.

Clinical characteristics.

Indications.

Termination of early pregnancy (up to 49 days) from the first day of the last menstrual period (in combination with mifepristone).

Contraindications.

Hypersensitivity to the components of the drug, cardiovascular diseases, liver and kidney diseases, conditions associated with prostaglandin dependency or contraindications to the use of prostaglandins (glaucoma, bronchial asthma, arterial hypertension), endocrinopathies and endocrine system disorders, including diabetes mellitus, adrenal dysfunction, hormone-dependent tumors, anemia, lactation period, use of intrauterine contraceptive devices (IUDs) (the IUD must be removed prior to administration), suspected ectopic pregnancy, pediatric age.

Special safety precautions.

Due to the abortifacient properties of misoprostol, it should not be used by women with viable pregnancy who intend to continue the pregnancy. Cases of uterine hyperstimulation and uterine rupture after the first trimester have been reported; in such cases, the dose of misoprostol should be reduced.

Rare but serious cardiovascular events have been reported following administration of prostaglandins, including misoprostol. Therefore, the drug should be used with caution in women with risk factors for or existing cardiovascular diseases.

There have been reports of seizure occurrence during treatment with prostaglandins and prostaglandin analogs; thus, this drug should be used with caution in patients with a history of epilepsy.

The use of prostaglandins or their analogs may be associated with a risk of bronchospasm, which should be considered when administering the drug to patients with a history of bronchial asthma.

Interaction with other medicinal products and other types of interactions.

Acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs should not be used within one week after taking this drug. Long-term use of rifampicin, isoniazid, anticonvulsants, antidepressants, cimetidine, acetylsalicylic acid, indomethacin, and phenobarbital-group drugs, smoking more than 10 cigarettes per day, and alcohol abuse significantly enhance the metabolism of misoprostol and reduce its serum levels.

Special precautions for use.

Before carrying out a medical abortion, ectopic pregnancy must be ruled out and pregnancy confirmed.

For termination of early pregnancy, misoprostol should be used in combination with mifepristone (it must not be used alone).

When used in combination with mifepristone, the drug should be administered under medical supervision. It may only be used in hospitals where emergency curettage and blood transfusion are available. The patient must remain under medical supervision in the hospital for 4–6 hours after administration of the drug.

Prior to administration, the patient should be informed about the drug’s action and possible adverse effects.

Medical termination of early intrauterine pregnancy.

This method requires active participation of the woman, who must be informed about the following guidelines:

• The necessity of combined use with mifepristone.
• The necessity of a follow-up visit to the physician 14–21 days after taking the drug to confirm complete expulsion.
• If pregnancy termination with misoprostol fails, the abortion must be completed by another method.
• If the patient became pregnant with an intrauterine device (IUD) in place, the IUD must be removed before administration of misoprostol.
• After discharge from the medical facility, the patient should be informed about possible signs and symptoms she may experience and provided with information about healthcare facilities to contact if needed.

The following risks associated with medical abortion should be considered and information about them provided to the woman:

Failure to achieve effect.

Since in 7% of cases pregnancy cannot be terminated by medical abortion, a follow-up visit to the physician is mandatory to confirm complete expulsion.

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

Bleeding.

Patients should be informed about the possibility of prolonged vaginal bleeding (on average lasting 10–16 days or more after administration of mifepristone and misoprostol), which may be heavy. Bleeding occurs in almost all patients and is not always proof of complete expulsion. Persistent bleeding may be a sign of incomplete abortion.

Patients should not travel far from a medical facility until complete expulsion is confirmed. They should be given detailed information about whom and where to contact in case of any problems, particularly in the event of heavy vaginal bleeding.

A follow-up visit to the physician must be scheduled within 14–21 days after administration of mifepristone and misoprostol to verify whether complete abortion has occurred and vaginal bleeding has ceased.

In cases of ongoing pregnancy, an ultrasound examination (US) or determination of serum human chorionic gonadotropin (hCG) levels should be performed to assess fetal viability. In cases of prolonged bleeding, when incomplete abortion or ongoing pregnancy is confirmed, appropriate measures should be taken and the woman should be offered termination of pregnancy by another method.

Since in 5% of cases severe uterine bleeding requiring hemostatic curettage may occur, particular attention should be paid to patients with coagulation disorders, hypocoagulability, or anemia. Decisions regarding the use of medical or surgical methods should be made with the involvement of a hematologist consultant.

Infections.

As with other types of abortion, rare cases of severe or even fatal infectious-toxic shock have been reported after administration of mifepristone and misoprostol. Physicians must consider the possibility of such potentially fatal complications. In particular, persistent fever of 38°C or higher, severe abdominal pain, or pelvic pain after medical abortion may be signs of infection.

Increased risk of septic complications caused by pathogenic microorganisms Clostridium sordellii and Streptococcus should be considered if the patient reports abdominal pain or discomfort, or general malaise (including weakness, nausea, vomiting, or diarrhea) within 24 hours after misoprostol administration.

Very rare fatal cases have been reported in patients who had no fever with or without abdominal pain but presented with leukocytosis, tachycardia, hemoconcentration, and general malaise. Most of these cases occurred after medical abortion using mifepristone followed by unauthorized intravaginal administration of orally formulated misoprostol tablets.

There is no experience with the use of the drug in adolescents.

Use during pregnancy or breastfeeding.

The drug may be used in pregnant women only for termination of pregnancy; in all other cases, it is contraindicated during pregnancy.

In clinical practice, isolated cases of limb malformations (absent limbs, clubfoot) and cranial nerve abnormalities (hypomimia, impaired sucking and swallowing, impaired eye movements) have been reported after use of misoprostol. Based on available data, the risk of fetal malformations cannot be excluded.

Patients must be informed about the potential risks of misoprostol.

Considering the above:

• Patients must be informed that, since pregnancy termination with misoprostol 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, limited medical data available do not justify mandatory termination of pregnancy. In such cases, regular ultrasound examinations should be performed, with special attention paid to fetal development.

Lactation period.

Misoprostol is partially metabolized in the mother’s body into misoprostolic acid, which is biologically active and passes into breast milk. Misoprostol should not be used during breastfeeding.

Ability to affect reaction rate while driving or operating machinery.

Not established.

Dosage and Administration.

Healthy pregnant women with amenorrhea of 49 days or less should take 3 tablets (600 mg) of mifepristone orally on an empty stomach or 2 hours after a meal. 36–48 hours after taking the 3 tablets (600 mg) of mifepristone, 2 tablets (400 mcg) of misoprostol should be taken on an empty stomach.

Children.

There is no experience with the use of the drug in adolescents.

Overdose.

Toxicity of misoprostol in humans has not been observed. Clinical signs that may indicate an overdose include drowsiness, tremor, seizures, abdominal pain, fever, increased heart rate, arterial hypotension, or bradycardia. Symptomatic therapy is recommended.

Adverse reactions.

Adverse reactions observed during the use of misoprostol.

Gastrointestinal system: nausea, vomiting, diarrhea, abdominal pain.

Reproductive system and mammary glands: uterine contractions, vaginal bleeding.

General and local reactions: headache, dizziness, malaise, fever.

Adverse reactions associated with the combined use of misoprostol and mifepristone, classified by frequency and system organ class, are presented in the table.

According to frequency, adverse reactions are categorized 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), and frequency not known (cannot be estimated based on available data).

Adverse reactions with the combined use of mifepristone and misoprostol.

Adverse reactions associated with the use of mifepristone and misoprostol, classified as uncommon:

Reproductive system and breast disorders: haemorrhagic shock, salpingitis.

Infections and infestations: infections.

Vascular disorders: hot flushes.

Skin and subcutaneous tissue disorders: skin rashes/itching.

Adverse reactions associated with the use of mifepristone and misoprostol, classified as rare and very rare:

Gastrointestinal disorders: gastrointestinal haemorrhage.

Nervous system disorders: epileptic seizures, neurogenic tinnitus.

Reproductive system and breast disorders: bilateral ovarian neoplasms, intrauterine adhesions, ovarian cyst rupture, breast abscess, hematosalpinx, uterine rupture.

General disorders and administration site conditions: anaphylaxis, periorbital oedema.

Infections and infestations: toxic shock syndrome.

Vascular disorders: thrombophlebitis, arterial hypotension.

Cardiac disorders: myocardial infarction, Adams-Stokes syndrome.

Respiratory system disorders: bronchospasm, bronchial asthma.

Skin and subcutaneous tissue disorders: toxic epidermal necrolysis, urticaria.

Pregnancy, puerperium and perinatal conditions: vesicular mole, ectopic pregnancy, amniotic band syndrome, gestational trophoblastic tumour, atheroplacental apoplexy.

Hepatobiliary disorders: altered liver function tests, liver failure.

Blood and lymphatic system disorders: thrombocytopenic purpura, thrombocytopenia, systemic lupus erythematosus.

Renal disorders: renal failure.

Benign, malignant and unspecified neoplasms (including cysts and polyps): elevated alpha-fetoprotein levels, elevated carcinoembryonic antigen levels.

Musculoskeletal and connective tissue disorders: extremity spasms.

Eye disorders: ophthalmoplegia.

Psychiatric disorders: mania.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

2 or 10 tablets in a blister; 1 blister per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Novast Laboratories Ltd.

Novast Laboratories Ltd.

Manufacturer's address and place of business.

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

1 Guangjing Road, Free Trade Zone, NETDA, Nantong, - 2260009, China (CHN)