Omeprazole lyophilized powder for solution for infusion 40 mg vial No. 1

Translation of the instructions can be

Instruction

For medical use of the medicinal product

Omeprazole

(Omeprazole)

Composition:

Active ingredient: omeprazole;

1 bottle contains omeprazole sodium (as omeprazole) 40 mg;

excipients: disodium edetate, sodium hydroxide.

Dosage form.

Lyophilisate for solution for infusion.

Main physicochemical properties: lyophilized porous mass or powder from white to yellowish color.

Pharmacotherapeutic group.

Drugs for the treatment of ulcers and gastroesophageal reflux disease: proton pump inhibitors.

PBX code A02B C01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Omeprazole, a racemic mixture of two enantiomers, reduces gastric acid secretion by a highly targeted mechanism of action. Omeprazole inhibits gastric acid secretion by specifically targeting the proton pump in the parietal cells. The drug, when administered once daily, acts rapidly and provides control by reversible inhibition of gastric acid secretion.

Omeprazole is a weak base that accumulates and is converted to the active form in the highly acidic environment of the intracellular tubules of parietal cells, where it inhibits the enzyme H +, K + -ATPase (proton pump). This effect on the final stage of the process of hydrochloric acid formation of gastric juice depends on its dose and provides highly effective inhibition of both basal and stimulated secretion of hydrochloric acid, regardless of the type of stimulation.

pharmacodynamic effects

All pharmacodynamic effects can be explained by the effect of omeprazole on hydrochloric acid secretion.

Effect on gastric acid secretion

Intravenous administration of omeprazole causes a dose-dependent inhibition of gastric acid secretion in humans. In order to immediately reduce intragastric acidity to the same extent as that achieved by repeated oral doses of 20 mg, an intravenous dose of 40 mg is recommended as the first dose. This results in an immediate reduction in intragastric acidity and a subsequent maintenance of this reduction by an average of 90% for 24 hours, both after intravenous injection and intravenous infusion.

Inhibition of hydrochloric acid secretion is related to the area under the concentration-time curve (AUC) of omeprazole and is independent of the actual concentration of omeprazole in the blood plasma at a given time point.

No signs of tachyphylaxis were noted during treatment with omeprazole.

Effect on Helicobacter pylori

Helicobacter pylori is associated with the development of peptic ulcer disease, including duodenal and gastric ulcers. Helicobacter pylori is a major factor in the development of atrophic gastritis, which is associated with an increased risk of developing gastric cancer.

Eradication of Helicobacter pylori with omeprazole and antimicrobials is associated with high rates of healing and long-term remission of peptic ulcer disease.

Other effects associated with inhibition of gastric acid secretion

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. Chromogranin A (CgA) levels also increase in response to reduced gastric acidity. Elevated CgA levels may interfere with the evaluation of neuroendocrine tumors. It has been reported that proton pump inhibitor treatment should be discontinued 5 to 14 days before CgA measurement. Measurements should be repeated if levels have returned to normal by this time.

An increase in the number of ECL cells, possibly related to an increase in serum gastrin levels, has been observed in both children and adults during long-term treatment with omeprazole. These findings are not considered to be of clinical significance.

A slightly increased incidence of glandular cysts in the stomach has been reported during long-term treatment. These changes are a physiological consequence of the marked inhibition of hydrochloric acid secretion; this process is benign and probably reversible.

Reducing stomach acid with some medications, including proton pump inhibitors, increases the number of bacteria in the stomach that are normally present in the digestive tract. Treatment with acid-reducing medications may lead to a slightly increased risk of developing gastrointestinal infections caused by Salmonella and Campylobacter.

Pharmacokinetics.

distribution

The estimated volume of distribution in healthy volunteers is approximately 0.3 l/kg body weight. Omeprazole is approximately 97% bound to plasma proteins.

metabolism

Approximately 3% of Caucasians and 15-20% of Mongoloids lack a functional CYP2C19 enzyme; they are referred to as “poor metabolizers”. In these individuals, the metabolism of omeprazole is probably catalyzed mainly by the CYP3A4 enzyme. After repeated administration of omeprazole at a dose of 20 mg once daily, the mean area under the AUC curve in “poor metabolizers” was 5-10 times higher than in individuals with a functional CYP2C19 enzyme (in “extensive metabolizers”). The mean maximum plasma concentrations were also 3-5 times higher. However, these results do not affect the dosage of omeprazole.

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Total plasma clearance is approximately 30-40 l/h after a single dose. The plasma half-life of omeprazole is usually less than 1 h after both single and repeated once-daily dosing. Omeprazole is completely eliminated from plasma between doses without a tendency to accumulate with once-daily dosing. Almost 80% of the omeprazole dose is excreted as metabolites in the urine, the remainder in the feces, mainly by biliary excretion.

The AUC of omeprazole increases with repeated administration of the drug. This increase is dose-dependent and provides a non-linear dependence of AUC on dose after repeated administration of the drug. This dependence on time and dose is due to a decrease in first-pass metabolism and systemic clearance, which is probably caused by inhibition of the CYP2C19 enzyme by omeprazole and / or its metabolites (for example, sulfone). None of the metabolites were found to affect the secretion of hydrochloric acid in gastric juice.

Special patient groups

Patients with liver dysfunction

The metabolism of omeprazole is slowed in patients with impaired liver function, leading to an increase in AUC. When omeprazole is administered once daily, no tendency for accumulation of the drug was observed.

Patients with renal impairment

The pharmacokinetics of omeprazole, including systemic availability and elimination rate, are not altered in patients with reduced renal function.

Elderly patients

The metabolic rate of omeprazole in elderly patients (75-79 years) is slightly reduced.

Clinical characteristics.

Indication.

Intravenous omeprazole is indicated as an alternative to oral therapy in the following cases.

adults

Contraindication.

Hypersensitivity to omeprazole, benzimidazoles or to any of the excipients.

Omeprazole, like other proton pump inhibitors (PPIs), should not be used concomitantly with nelfinavir.

Interaction with other drugs and other types of interactions.

Effect of omeprazole on the pharmacokinetics of other drugs

Drugs whose absorption depends on gastric pH

Suppression of gastric secretion during omeprazole therapy may reduce or increase the absorption of drugs whose absorption depends on gastric pH.

Nelfinavir, atazanavir

Decreased serum levels of atazanavir and nelfinavir have been reported with concomitant use of omeprazole, therefore concomitant use of these drugs is not recommended.

Co-administration of omeprazole (40 mg once daily) and atazanavir 300 mg/ritonavir 100 mg in healthy volunteers resulted in a significant decrease in atazanavir exposure (approximately 75% decrease in AUC, Cmax, and Cmin). Increasing the atazanavir dose to 400 mg did not compensate for the effect of omeprazole on atazanavir exposure. Co-administration of omeprazole (20 mg daily) with atazanavir 400 mg/ritonavir 100 mg in healthy volunteers decreased atazanavir exposure by approximately 30% compared to the exposure observed with atazanavir 300 mg/ritonavir 100 mg once daily without the use of these drugs at a dose of 20 mg/day. Concomitant use of omeprazole (40 mg daily) reduced the mean AUC, Cmax and Cmin of nelfinavir by 36-39%, and the mean AUC, Cmax and Cmin of the pharmacologically active metabolite M8 by 75-92%.

digoxin

When omeprazole (20 mg daily) was co-administered with digoxin in healthy volunteers, the bioavailability of digoxin increased by 10% (up to 30% in two out of ten subjects). Toxic effects of digoxin were rarely observed. However, caution should be exercised when prescribing high doses of omeprazole to elderly patients. Monitoring of the patient's blood digoxin concentration should be intensified.

In a study, clopidogrel (300 mg loading dose followed by 75 mg/day) was administered alone and in combination with omeprazole (80 mg given concurrently with clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was reduced by 46% (day 1) and 42% (day 5) when clopidogrel and omeprazole were co-administered. The mean inhibition of platelet aggregation was reduced by 47% (24 hours) and 30% (day 5) when clopidogrel and omeprazole were co-administered. Another study showed that co-administration of clopidogrel and omeprazole at different times did not eliminate their interaction, which is likely due to the inhibitory effect of omeprazole on CYP2C19. Studies have shown conflicting evidence regarding the clinical implications of this pharmacokinetic/pharmacodynamic interaction in terms of significant cardiovascular events. Therefore, concomitant use of omeprazole and clopidogrel is not recommended.

Other medicines

The absorption of ampicillin, posaconazole, erlotinib, ketoconazole, itraconazole and iron is significantly reduced and therefore clinical efficacy may be reduced. Concomitant use with posaconazole and erlotinib should be avoided.

Drugs metabolized by CYP2C19

Interaction with drugs metabolized in the liver by the cytochrome P450 enzyme system is possible. Plasma concentrations of diazepam, phenytoin, nifedipine, disulfiram, cilostazol, aminopyrine, antipyrine, warfarin and other vitamin K antagonists may increase. As a rule, such an increase is not clinically significant when using usual doses of omeprazole. However, it is recommended to monitor patients at the beginning of treatment and when stopping the drug, and if necessary, change the doses of phenytoin, diazepam, warfarin and disulfiram.

Cilostazol

The use of omeprazole at a dose of 40 mg led to an increase in C max and AUC of cilostazol by 18% and 26%, respectively, and one of its active metabolites by 29% and 69%.

phenytoin

Monitoring of phenytoin plasma concentrations is recommended during the first two weeks after starting treatment with the drug, and in case of dose adjustment of phenytoin, monitoring and further dose adjustment are required after the end of treatment with omeprazole.

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saquinavir

Concomitant use of omeprazole with saquinavir/ritonavir results in a 70% increase in plasma levels of saquinavir and is well tolerated by HIV-infected patients.

tacrolimus

Concomitant use of tacrolimus and omeprazole may increase serum tacrolimus concentrations. Close monitoring of tacrolimus concentrations and renal function (creatinine clearance) is required, and the tacrolimus dose should be adjusted if necessary.

methotrexate

Increased methotrexate levels have been reported in some patients when co-administered with proton pump inhibitors. If high doses of this drug are required, temporary withdrawal of omeprazole should be considered.

Effect of other drugs on the pharmacokinetics of omeprazole

CYP2C19 and/or CYP3A4 inhibitors

Since omeprazole is metabolized by CYP2C19 and CYP3A4, drugs that inhibit CYP2C19, CYP3A4, or both enzymes (such as clarithromycin and voriconazole) may increase omeprazole serum levels by slowing its metabolism. Since high doses of omeprazole are well tolerated, no dose adjustment is generally necessary for these drugs. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated.

Omeprazole is also partially metabolized by CYP3A4, but does not inhibit this enzyme. Thus, omeprazole does not affect the metabolism of drugs that are metabolized by CYP3A4, such as cyclosporine, lidocaine, quinidine, estradiol, erythromycin, and budesonide.

CYP2C19 and/or CYP3A4 inducers

Drugs that induce CYP2C19, CYP3A4, or both enzymes (such as rifampicin and St. John's wort) may lead to decreased serum levels of this drug by accelerating its metabolism.

The effectiveness of prednisolone and cyclosporine may be reduced, so it is sometimes necessary to adjust the dose of cyclosporine.

No clinically significant interactions with omeprazole were observed when antacids, amoxicillin, digoxin, theophylline, cyclosporine, lidocaine, quinidine, estradiol, erythromycin, budesonide, metoprolol or propranolol were administered concomitantly.

Application features.

If any alarming symptom is present (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melena) and if gastric ulcer is suspected or present, malignancy should be ruled out, as treatment may reduce symptoms and delay diagnosis.

Omeprazole, like all drugs that inhibit the secretion of hydrochloric acid in the stomach, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be taken into account in patients with cachexia or risk factors for reduced absorption of vitamin B12 during long-term therapy.

Omeprazole is an inhibitor of CYP2C19. When initiating or ending treatment with omeprazole, the possibility of interactions with medicinal products metabolised by CYP2C19 should be considered. An interaction has been observed between clopidogrel and omeprazole. The clinical significance of this interaction remains unclear. As a precautionary measure, the concomitant use of these medicinal products and clopidogrel should be avoided.

Treatment with proton pump inhibitors may lead to a slightly increased risk of developing gastrointestinal infections such as Salmonella and Campylobacter.

Cases of severe hypomagnesemia have been reported in patients taking proton pump inhibitors (PPIs) such as omeprazole for at least three months, and in most cases for a year. Hypomagnesemia can have serious manifestations such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias, but its development may be gradual and go unnoticed. In most patients with hypomagnesemia, the condition improved after magnesium replacement therapy and discontinuation of the PPI.

For patients who are expected to be on long-term treatment or who are taking PPIs with digoxin or drugs that can cause hypomagnesemia (e.g., diuretics), it may be advisable to measure magnesium levels before starting PPI therapy and periodically during treatment.

Proton pump inhibitors, especially when used at high doses and for long periods (1 year), may slightly increase the risk of hip, wrist, and spine fractures, mainly in elderly patients or those with other risk factors. Results of review studies suggest that proton pump inhibitors may increase the overall risk of fractures by 10-40%. This increase may be due to other risk factors to some extent. Patients at risk of osteoporosis should be treated according to current clinical guidelines; they should also receive adequate vitamin D and calcium.

Impact on laboratory test results

Omeprazole may increase the concentration of chromogranin A (CgA). An increase in CgA may affect the results of examinations for the detection of neuroendocrine tumors. To prevent this effect, it is necessary to temporarily stop taking omeprazole 5 days before the CgA test.

As with any long-term treatment, especially when the period of treatment with omeprazole exceeds 1 year, patients should be under constant supervision.

Use during pregnancy or breastfeeding.

pregnancy

The results of the studies indicate that there is no undesirable effect of omeprazole on pregnancy or the health of the fetus/newborn child. Omeprazole can be used during pregnancy.

Breastfeeding

Omeprazole passes into breast milk, but is unlikely to affect the baby if used in therapeutic doses.

fertility

Oral administration of the racemic mixture of omeprazole in animal studies did not affect reproductive function.

The ability to influence the reaction speed when driving vehicles or other mechanisms.

It is unlikely that omeprazole affects the ability to drive or use machines. Side effects such as dizziness and visual disturbances may occur. If such disorders occur, patients should not drive or use machines.

Method of administration and doses.

dosage

Alternative to oral therapy

For patients for whom oral administration is unacceptable, omeprazole 40 mg once daily intravenously is recommended. For patients with Zollinger-Ellison syndrome, the recommended starting dose of omeprazole, which should be administered intravenously, is 60 mg per day. Higher daily doses may be required and the dose should be adjusted individually. If the dose exceeds 60 mg per day, it should be divided equally into two doses and administered 2 times a day.

Omeprazole should be administered intravenously as an infusion over 20-30 minutes.

Instructions for reconstitution of the drug before administration

The entire contents of the vial should be dissolved in approximately 5 ml of solvent and then immediately diluted to 100 ml with solvent. 0.9% sodium chloride solution or 5% glucose solution should be used. The stability of omeprazole depends on the pH of the infusion solution, therefore no other solvent or other amount should be used for dilution.

preparation

1. Using a syringe, withdraw 5 ml of infusion solution from a 100 ml bottle or infusion bag.

2. Add this volume to the vial of lyophilized omeprazole, mix thoroughly, making sure that all of the drug has dissolved.

3. Withdraw all of the omeprazole solution from the vial back into the syringe.

4. Transfer the solution to an infusion bag or bottle.

5. Repeat steps 1-4 to ensure that the entire volume of omeprazole is transferred from the vial to the infusion bag or bottle.

1. Attach the double-ended needle adapter to the injection membrane of the infusion bag.

Attach the other end of the needle to the vial of lyophilized omeprazole.

2. Dissolve the lyophilisate from the vial by pumping the infusion solution back and forth between the infusion bag and the vial.

3. Make sure that all the drug has dissolved.

The resulting solution should be used for intravenous infusion over 20-30 minutes.

Any residue or waste should be disposed of in accordance with local requirements.

Vials of lyophilisate (without cardboard box) can be stored under normal external lighting for up to 24 hours.

Reconstituted solution: Chemical and physical in-use stability has been demonstrated for 12 hours at 25°C after reconstitution with 0.9% sodium chloride solution and for 6 hours at 25°C after reconstitution with 5% glucose solution.

From a microbiological point of view, the product should be used immediately, unless reconstitution takes place in controlled and aseptic conditions, confirmed by validated methods.

Special categories of patients

Kidney dysfunction

Dose adjustment is not required for patients with renal impairment.

Liver dysfunction

For patients with impaired liver function, a daily dose of 10-20 mg may be sufficient.

Elderly patients (65 years)

Dose adjustment is not required for elderly patients.

Children.

Experience with the use of this drug for intravenous administration in pediatric practice is limited.

Overdose.

There is limited information on the effects of omeprazole overdose in humans. Cases of use of the drug in doses up to 560 mg have been described; there are also isolated reports of oral administration of single doses of omeprazole reaching 2400 mg (120 times the usual recommended clinical dose). Nausea, vomiting, dizziness, abdominal pain, diarrhea and headache have been reported. Apathy, depression and confusion have also been reported in isolated cases.

The symptoms described were transient, no serious effects were reported. The rate of drug elimination did not change (first-order kinetics) with increasing drug doses. If necessary, symptomatic treatment should be carried out.

There is data on intravenous administration of the drug in doses up to 270 mg for one day and up to 650 mg for three days, which did not lead to the appearance of any dose-dependent adverse reactions.

Adverse reactions.

The most common adverse reactions are headache, abdominal pain, constipation, diarrhea, flatulence, and nausea/vomiting.

From the blood system: leukopenia, thrombocytopenia, agranulocytosis, pancytopenia.

Immune system disorders: Hypersensitivity reactions, such as fever, angioedema and anaphylactic reaction/shock.

Metabolic disorders: hyponatremia, hypomagnesemia, severe hypomagnesemia can lead to hypocalcemia, hypomagnesemia can also cause hypokalemia.

On the part of the psyche: insomnia, agitation, confusion, depression, aggression, hallucinations.

From the nervous system: headache, dizziness, paresthesia, drowsiness, taste disturbance.

From the organs of vision: blurred vision.

On the part of the organs of hearing: vertigo.

Respiratory system: bronchospasm.

Gastrointestinal tract: abdominal pain, constipation, diarrhea, flatulence, nausea/vomiting, dry mouth, stomatitis, gastrointestinal candidiasis, microscopic colitis.

Hepatobiliary system: increased liver enzymes, hepatitis with or without jaundice, hepatic failure, encephalopathy in patients with liver disease.

Skin: dermatitis, itching, rash, urticaria, alopecia, photosensitivity, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN).

Musculoskeletal system: fracture of the hip, wrist or spine (see section "Special warnings and precautions for use"), arthralgia, myalgia, muscle weakness.

From the urinary system: interstitial nephritis.

From the reproductive system: gynecomastia.

General disorders and administration site conditions: malaise, peripheral edema, increased sweating.

In isolated cases, irreversible visual impairment has been reported in seriously ill patients receiving omeprazole as an intravenous injection, especially in high doses, but a causal relationship has not been established.

Expiration date.

2 years.

Storage conditions.

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

Keep out of reach of children.

Incompatibility.

Omeprazole should not be mixed with other medicinal products except those mentioned in the "Method of administration" section.

Packaging.

1 bottle per pack.

Vacation category.

According to the recipe.

Producer.

"Pharmex Group" LLC.

Location of the manufacturer and address of its place of business.

Ukraine, 08301, Kyiv region, Boryspil city, Shevchenko st., building 100.

All cases of adverse reactions must be reported to the manufacturer:

LLC "PHARMEX GROUP", Ukraine, 08301, Kyiv region, Boryspil city, Shevchenko st., building 100, tel.: +38 (044) 391-19-19, fax: +38 (044) 391-19-18, or via the form on the website: http://www.pharmex.com.ua/farmakonadzor