Gastrotek

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT GASTROTEC® GASTROTEC

Composition:

Active ingredient: misoprostol;

One tablet contains 0.2 mg of misoprostol in the form of misoprostol dispersion (1:100 in hypromellose);

Excipients: microcrystalline cellulose, hydrogenated castor oil, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide.

Pharmaceutical form. Tablets.

Main physico-chemical characteristics: white or almost white tablets with a yellowish-greyish tint, round flat cylindrical in shape, with a bevelled edge.

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

Pharmacological properties.

Pharmacodynamics.

Gastrotec**®** is a synthetic analogue of natural prostaglandin E1, which promotes healing of peptic ulcers and relieves their symptoms. The drug 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.

Gastrotec**®** is rapidly absorbed after oral administration. The maximum concentration (Cmax) of misoprostolic acid, the active metabolite, is reached within approximately 30 minutes. The elimination half-life of misoprostol 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, particularly 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 ulcers caused by NSAID use.

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 who are 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 lactation", "Adverse reactions").

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 propylanolol concentration (on average approximately 20% in AUC and 30% in Cmax) has been observed. Studies on drug interactions between misoprostol and several NSAIDs did not demonstrate clinically significant effects on the kinetics of ibuprofen, diclofenac, piroxicam, acetylsalicylic acid, naproxen, or indomethacin.

During treatment with misoprostol, magnesium-containing antacids should be avoided, as this may exacerbate misoprostol-induced diarrhea.

Special precautions for use

When prescribing the medicinal product to women of childbearing potential, pregnancy must first be excluded, and appropriate contraceptive measures must be used. If pregnancy is confirmed, the medicinal product must be discontinued immediately (see sections "Contraindications", "Use during pregnancy or breastfeeding", "Side effects").

Patients should be advised to take misoprostol only if they:

− are using effective contraceptive methods;

− are informed about 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 patients with ulcers, even in the absence of gastrointestinal symptoms, therapy should be continued with caution. Endoscopy and biopsy may be indicated before treatment to exclude malignancy in the upper gastrointestinal tract. These examinations should be repeated at appropriate intervals as necessary 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 disease. To minimize the risk of diarrhea, misoprostol should be taken with food, and antacids containing magnesium should be avoided.

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

Experience with the use of misoprostol at 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 disease, 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 product should be used with particular caution in patients with inflammatory bowel disease.

The medicinal product contains 14.4 mg of sodium per dose. Caution is advised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding

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

Pregnancy

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. Exposure to misoprostol during the first trimester of pregnancy is associated with a significantly increased risk of congenital defects: Möbius sequence (e.g., paralysis of cranial nerves VI and VII), amniotic band syndrome (limb deformities and shortening, especially clubfoot, acardia, oligodactyly, cleft palate), and central nervous system abnormalities (cerebral and cranioencephalic anomalies such as anencephaly, hydrocephaly, cerebellar hypoplasia, neural tube defects). Other defects have also been observed, including arthrogryposis.

Therefore, women must be informed about the teratogenic risk. If a patient wishes to continue the pregnancy after in utero exposure to misoprostol, a thorough ultrasound examination of the fetus is required, with special attention to the limbs and head.

The risk of uterine rupture increases with advancing gestational age, in patients 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, the biologically active substance, which is excreted 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 the speed of reactions 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 duodenal ulcer, gastric ulcer, 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 up to 8 weeks. If the ulcer recurs, an additional course of treatment may be prescribed.

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

Renal impairment: Available data indicate that dose adjustment in patients with renal impairment is not required.

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 medicinal product 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, dyspnea, abdominal pain, diarrhea, fever, palpitations, hypotension, or bradycardia.

Symptomatic therapy is recommended.

There have been reports of misoprostol administered 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 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the 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 muscle spasms; rare – menorrhagia, dysmenorrhea; frequency not known – uterine bleeding.

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

Congenital, familial and genetic disorders: frequency not known – fetal malformations.

General disorders: rare – chills; uncommon – malaise.

* Diarrhea and abdominal pain were dose-related, usually occurred at the beginning of therapy, and were localized. There have been reports of rare cases of diarrhea leading to severe dehydration. Diarrhea symptoms may be minimized by administering a dose of no more than 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 occurred in women who 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 frequency > 1% was consistent in both short-term (duration 4–12 weeks) and long-term (up to 1 year) clinical trials. The safety of prolonged (more than 12 weeks) misoprostol use 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 after gastric biopsy. There were no significant differences in the safety profile of misoprostol between 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 a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 2 years.

Storage conditions.

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

Keep out of the reach of children.

Packaging.

10 tablets in a blister; 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and location of its business activities.

13, Boryspylska Street, Kyiv, 02093, Ukraine.