Misoprostol

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MISOPROSTOL (Misoprostol)

Composition:

Active substance: misoprostol;

1 tablet contains 200 mcg of misoprostol in the form of misoprostol dispersion (1:100 in hypromellose);

Excipients: microcrystalline cellulose, sodium starch glycolate (type A), hydrogenated castor oil, hypromellose.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: hexagonal-shaped tablets, white in colour, with clear embossing of M and 3 and a dividing line on one flat side and slightly convex on the other side.

Pharmacotherapeutic group. Prostaglandins. Misoprostol. ATC code A02B B01.

Pharmacological properties.

Pharmacodynamics.

Misoprostol is an analogue of the natural prostaglandin E1, which promotes healing of peptic ulcers and relieves their symptoms.

Misoprostol protects the mucous membrane of the gastrointestinal tract (GIT) by inhibiting basal, stimulated, and nocturnal acid secretion, reducing the volume and proteolytic activity of gastric juice, and increasing bicarbonate secretion in mucus.

Pharmacokinetics.

Misoprostol is rapidly absorbed after oral administration. The maximum concentration (Cmax) of misoprostolic acid, the active metabolite, is reached in approximately 30 minutes. The elimination half-life of misoprostolic acid in plasma is 20−40 minutes. With repeated administration of 400 mcg twice daily, accumulation of misoprostolic acid in plasma does not occur.

Clinical characteristics.

Indications.

Treatment of gastric and duodenal ulcers, including those caused by the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with arthritis who are at risk but continue NSAID therapy.

Prevention of NSAID-induced ulcers.

Contraindications.

− Hypersensitivity to the active substance or to any of the other components of the medicinal product; known allergy to prostaglandins.

− Use in women of childbearing potential who are not using effective contraceptive measures.

− Pregnancy or use in women in whom pregnancy has not been excluded, or in women planning pregnancy, due to the fact that misoprostol increases uterine tone and contractions, which may lead to termination of pregnancy and partial or complete abortion. Use of misoprostol during pregnancy has been associated with fetal abnormalities (see sections "Special precautions", "Use during pregnancy or breastfeeding", "Side effects").

Interaction with other medicinal products and other forms of interaction.

Concomitant use of NSAIDs and misoprostol in individual cases may cause increased levels of transaminases and peripheral edema.

Misoprostol is predominantly metabolized via fatty acid oxidation systems and does not exhibit any adverse effect on the hepatic microsomal mixed-function oxidase enzyme system (P450).

Specific studies have not demonstrated clinically significant pharmacokinetic interactions with antipyrine or diazepam.

With repeated administration of misoprostol, a slight increase in propylolol concentration was observed (on average approximately 20% in AUC and 30% in Cmax). Studies on drug interactions between misoprostol and several NSAIDs did not demonstrate clinically significant effects on the pharmacokinetics of ibuprofen, diclofenac, piroxicam, acetylsalicylic acid, naproxen, or indomethacin.

During treatment with misoprostol, magnesium-containing antacids should be avoided, as they may exacerbate diarrhea caused by misoprostol.

Special precautions for use.

When prescribing the drug to women of childbearing potential, pregnancy must first be ruled out, and appropriate contraceptive measures must be used. If pregnancy is confirmed, the drug should be discontinued immediately (see sections "Contraindications", "Use during pregnancy or breastfeeding", "Adverse reactions").

These patients should only be prescribed misoprostol if they:

• are using effective contraceptive methods;
• have been informed of the risks associated with misoprostol use during pregnancy (see section "Contraindications").

Gastrointestinal bleeding, ulcers, and perforation have been observed in patients receiving NSAID therapy and taking misoprostol. In cases of peptic ulcers, even in the absence of gastrointestinal symptoms, therapy should be continued with caution, and if appropriate, endoscopy with biopsy should be performed prior to treatment to exclude the presence of malignancy in the upper gastrointestinal tract. These investigations should be repeated as necessary at appropriate intervals for ongoing monitoring.

Symptomatic responses to misoprostol do not exclude the presence of gastric malignancy.

Misoprostol should be used with caution in patients with conditions that may be associated with diarrhea, such as inflammatory bowel diseases. To minimize the risk of diarrhea, misoprostol should be taken with meals, and antacids containing magnesium should be avoided.

Misoprostol should be used with caution in patients with severe dehydration. The condition of such patients must be closely monitored.

Experience with the use of misoprostol in doses effective for promoting healing of gastric and duodenal ulcers indicates that the drug does not cause arterial hypotension. However, misoprostol should be used cautiously in patients with underlying diseases, as hypotension may lead to serious complications, such as cerebrovascular disorders, coronary artery disease, or severe peripheral vascular diseases, including arterial hypertension.

There is no evidence that misoprostol has a negative effect on glucose metabolism in patients with diabetes mellitus.

Important information about excipients

The medicinal product contains hydrogenated castor oil, which may cause gastrointestinal disturbances and diarrhea. Therefore, the drug should be used with particular caution in patients with inflammatory bowel diseases.

Use during pregnancy or breastfeeding

Women of childbearing potential must be informed of the teratogenic risk before initiating treatment. Treatment must not be started until pregnancy has been excluded. Women should be advised on the importance of adequate contraception during treatment. If pregnancy is suspected, treatment must be discontinued immediately.

Pregnancy

Misoprostol

Misoprostol is contraindicated in pregnant women, as it causes uterine contractions and may lead to termination of pregnancy, partial or complete abortion, fetal death, or congenital malformations. An approximately threefold increase in the risk of congenital abnormalities has been reported during the first trimester of pregnancy with misoprostol use compared to the 2% incidence in the control group. Prenatal exposure to misoprostol is associated with a significantly increased risk of congenital defects: Möbius syndrome (congenital facial paralysis leading to hypomimia, difficulties with sucking and swallowing, and eye movements, with or without limb defects), amniotic band syndrome (limb deformities and shortening, particularly clubfoot, acheiria, oligodactyly, cleft palate), and central nervous system abnormalities (cerebral and cranial anomalies such as anencephaly, hydrocephaly, cerebellar hypoplasia, neural tube defects). Other defects, including arthrogryposis, have also been observed.

Therefore, women should be informed of the teratogenic risk. If a patient wishes to continue the pregnancy after intrauterine exposure to misoprostol, a thorough ultrasound examination of the fetus should be performed, with special attention to the limbs and head.

The risk of uterine rupture increases with advancing gestational age, in women with a history of previous uterine surgery or cesarean section. A high number of previous pregnancies is also a risk factor for uterine rupture.

Breastfeeding period

Misoprostol is rapidly metabolized to misoprostolic acid, which is biologically active and passes into breast milk. Since misoprostolic acid may cause adverse effects such as diarrhea in breastfed infants, the medicinal product should not be used during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Since misoprostol may cause dizziness, patients are advised to refrain from driving or operating machinery.

Dosage and Administration.

Treatment of gastric ulcer, duodenal ulcer, peptic ulcer disease of the stomach, and NSAID-induced peptic ulcer:

800 mcg daily in two or four divided doses, taken with breakfast and/or each main meal and at bedtime.

Treatment should be initiated for at least 4 weeks, even if symptomatic relief occurs earlier. In most patients, ulcers heal within 4 weeks, but if necessary, treatment may continue for up to 8 weeks. If ulcer recurrence occurs, an additional course of treatment may be prescribed.

Prophylaxis of NSAID-induced peptic ulcer: 200 mcg twice daily, three times daily, or four times daily. Dosage should be individually adjusted for each patient according to clinical condition.

Renal impairment: available data indicate that dosage adjustment is not required for patients with impaired renal function.

Hepatic impairment: misoprostol is metabolized by fatty acid oxidation systems present throughout the body. Therefore, its metabolism and plasma levels are unlikely to be significantly affected in patients with hepatic impairment.

Elderly patients: the usual dose may be used.

Children: experience with the use of this drug in children is lacking.

Overdose.

The toxic dose of misoprostol in humans has not been established. Clinical signs that may indicate overdose include drowsiness, tremor, seizures, abdominal pain, diarrhea, fever, palpitations, hypotension, or bradycardia.

Symptomatic therapy is recommended.

Misoprostol has been reported to be used at a dosage of 1200 mcg daily for three months without significant adverse effects.

Adverse Reactions

All adverse reactions are listed by system organ class and frequency: 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).

Gastrointestinal disorders: very common – diarrhea*; common – abdominal pain*, constipation, dyspepsia, flatulence, nausea, vomiting.

Nervous system disorders: common – dizziness, headache.

Immune system disorders: frequency not known – anaphylactic reactions.

Skin and subcutaneous tissue disorders: very common – rash.

Reproductive system and breast disorders: uncommon – vaginal bleeding (including postmenopausal bleeding), intermenstrual bleeding, menstrual cycle disturbances, uterine cramps; rare – menorrhagia, dysmenorrhea; frequency not known – uterine bleeding.

Pregnancy, puerperium and perinatal period: rare – uterine rupture**; frequency not known – amniotic fluid embolism, abnormal uterine contraction, fetal death, incomplete abortion, preterm labor, delayed placental separation, uterine perforation.

Congenital, familial and genetic disorders: common – fetal malformations.

General disorders: frequency not known – chills; uncommon – fever.

* Diarrhea and abdominal pain were dose-related and usually occurred at the beginning of therapy and were self-limiting. There have been reports of rare cases of diarrhea leading to severe dehydration. Diarrhea symptoms may be minimized by administering a dose not exceeding 200 mcg with food and by avoiding magnesium-containing antacids.

** Uterine rupture has been infrequently reported following prostaglandin administration during the second and third trimesters of pregnancy. Uterine ruptures have occurred in women who have had multiple deliveries or in women with a scar from previous cesarean section.

Adverse reactions observed with misoprostol are similar to those observed with NSAIDs.

Over 15,000 patients in clinical trials received at least one dose of misoprostol. Adverse reactions occurred predominantly in the gastrointestinal tract. The adverse reaction profile with a frequency > 1% was consistent in both short-term (duration 4–12 weeks) and long-term (up to 1 year) clinical trials. The safety of long-term (more than 12 weeks) use of misoprostol has been demonstrated in several studies in which patients received continuous treatment for up to 1 year.

This does not include adverse or unusual changes in gastric mucosal morphology identified by gastric biopsy. There were no significant differences in the safety profile of misoprostol in patients aged 65 years and older compared to younger patients. The use of misoprostol in children has not been evaluated.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, and patients or their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of reach of children.

Packaging.

3 or 4 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.

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