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Composition:


active ingredient: omeprazole;


1 bottle contains omeprazole sodium equivalent to omeprazole 40 mg;


excipient: sodium carbonate anhydrous.


Dosage form. Lyophilizate for solution for injection.


Basic physical and chemical properties: freeze-dried powder from white to light yellow color, without visible inclusions.


Pharmacotherapeutic group.


Remedies for the treatment of peptic ulcer disease and gastroesophageal reflux disease. Proton pump inhibitors. Omeprazole. ATX code A02B C01.


Pharmacological properties.


Pharmacodynamics.


Mechanism of action


Omeprazole, a racemic mixture of two enantiomers, reduces the secretion of hydrochloric acid in the stomach due to an extremely targeted mechanism of action. Omeprazole inhibits the secretion of hydrochloric acid in the stomach by specifically affecting the proton pump in parietal cells. The drug, when used 1 time a day, acts quickly and provides control by reversible inhibition of the secretion of hydrochloric acid in gastric juice.


Omeprazole is a weak base that accumulates and turns into the active form in the very acidic environment of the intracellular tubules of parietal cells, where it inhibits the enzyme H+, K+-ATPase (proton pump). This effect at the final stage of the process of formation of hydrochloric acid in gastric juice is dose-dependent and provides highly effective inhibition of both basal and stimulated hydrochloric acid secretion, 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 the secretion of hydrochloric acid in the stomach


Intravenous administration of omeprazole causes dose-dependent inhibition of hydrochloric acid secretion in the human stomach. In order to immediately similarly reduce intragastric acidity, which is achieved by using repeated doses of the drug of 20 mg orally, intravenous administration of 40 mg of the drug is recommended as the first dose. This leads to an immediate decrease in intragastric acidity and further retention of this indicator of reduction by an average of 90% within 24 hours, both after intravenous injection and after intravenous infusion.


Inhibition of hydrochloric acid secretion is associated with the area under the plasma concentration – time (AUC) curve of omeprazole and does not depend on the actual plasma concentration of omeprazole at a given time.


No signs of tachyphylaxis were observed during treatment with omeprazole.


Effects on Helicobacter pylori (H. pylori)


H. pylori is associated with the development of peptic ulcer disease, including duodenal and gastric ulcers. H. pylori is a major factor in the development of gastritis. H. pylori, together with hydrochloric acid of gastric juice, is a major factor in the development of peptic ulcer disease. H. pylori is a major factor in the development of atrophic gastritis, which is associated with an increased risk of stomach cancer.


Eradication Of H. pylori with omeprazole and antimicrobials is associated with high levels of healing and long-term remission of peptic ulcer disease.


Other effects associated with inhibition of hydrochloric acid secretion in the stomach


During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. Also, due to low gastric acidity, the level of chromogranin a (CgA) increases. Increased CgA levels may interfere with screening for neuroendocrine tumors. It has been reported that treatment with proton pump inhibitors (PPIs) should be discontinued 5-14 days before CGA determination. The determination should be repeated if the levels have not returned to normal by this time.


An increase in the number of ECL cells, possibly associated with an increase in serum gastrin levels, is observed in both children and adults during long-term treatment with omeprazole. These data are considered to have no clinical significance.


During a long course of treatment, a slightly increased incidence of glandular cysts in the stomach has been reported. These changes are a physiological consequence of a pronounced inhibition of hydrochloric acid secretion; this process is benign and probably reversible.


Reducing the acidity of gastric juice by any means, including PPIs, increases the number of bacteria in the stomach that are usually present in the gastrointestinal tract. Treatment with acid-lowering medications Slightly increases the risk of gastrointestinal infections caused by Salmonella and Campylobacter.


Pharmacokinetics.


Distribution


The estimated volume of distribution is approximately 0.3 L / kg of body weight. Omeprazole binds approximately 97% to plasma proteins.

Metabolism and elimination


Omeprazole is completely metabolized by the cytochrome P450 (CYP) system. Most of its metabolism depends on polymorphically expressed CYP2C19, which is responsible for the formation of hydroxyomeprazole, the main metabolite of the substance in blood plasma. The rest depends on another specific isoform (CYP3A4) responsible for the formation of omeprazole sulfone. Due to the high affinity of omeprazole with CYP2C19, there is a possibility of competitive inhibition and metabolic Inter-drug interaction with other CYP2C19 substrates. However, due to its low affinity for CYP3A4, omeprazole does not have the ability to inhibit the metabolism of other CYP3A4 substrates. In addition, omeprazole does not have an inhibitory effect on the main CYP enzymes.


Approximately 3% of the Caucasian race and 15-20% of the Mongoloid race do not have the functional enzyme CYP2C19; they are classified as so-called "slow metabolizers". In these individuals, omeprazole metabolism may be catalyzed primarily by the CYP3A4 enzyme. After repeated administration of omeprazole at a dose of 20 mg 1 time per day, the average AUC value in "slow metabolizers" is 5-10 times higher than in individuals with the functional enzyme CYP2C19 (in "fast metabolizers"). The average maximum plasma concentrations are also 3-5 times higher. However, these results do not affect the dosage of omeprazole.


Output


Total plasma clearance is approximately 30-40 L/H after a single dose. The plasma half-life of omeprazole is usually less than 1 hour, both after a single and repeated use of the drug 1 time a day. Omeprazole is completely eliminated from the blood plasma between doses without a tendency to accumulate when it is used 1 time a day. Almost 80% of the omeprazole dose is excreted as metabolites in the urine, and the rest is excreted in the faeces, mainly by bile secretion.


The AUC of omeprazole increases with repeated use of the drug. This increase depends on the dose of the drug and provides a non-linear dependence of AUC on the dose after repeated use of the drug. This time-dose dependence is due to a decrease in presystemic metabolism and systemic clearance, which may be caused by inhibition of the CYP2C19 enzyme by omeprazole and/or its metabolites (for example, sulfone). No effect of any metabolites on the secretion of hydrochloric acid in gastric juice was found.


Special patient groups


Patients with impaired liver function


Omeprazole metabolism in patients with impaired liver function is slowed, which leads to an increase in AUC. When using omeprazole 1 time a day, there was no tendency to accumulate the drug.


Patients with impaired renal function


The pharmacokinetics of omeprazole, including systemic bioavailability and rate of elimination, do not change in patients with reduced renal function.


Elderly patients


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


Clinical characteristics.


Indications.


Omeprazole for intravenous administration is indicated as an alternative to oral therapy in the following cases.


Adults


Treatment of duodenal ulcers.


Prevention of recurrent duodenal ulcers.


Treatment of stomach ulcers.


Prevention of recurrent stomach ulcers.


In combination with appropriate antibiotics for the eradication of Helicobacter pylori (H. pylori) for peptic ulcer disease.


Treatment of gastric and duodenal ulcers associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs).


Prevention of gastric and duodenal ulcers associated with the use of NSAIDs in patients at risk.


Treatment of reflux esophagitis.


Long-term treatment of patients with inactive reflux esophagitis.


Treatment of symptomatic gastroesophageal reflux disease.


Treatment of Zollinger – Ellison syndrome.


Contraindications.


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


Omeprazole, like other PPIs, should not be used concomitantly with nelfinavir and atazanavir.


Interactions with other drugs and other types of interactions.


Effect of omeprazole on the pharmacokinetics of other drugs


Medications whose absorption depends on the pH of the stomach


Inhibition of gastric secretion during treatment with omeprazole and other drugs from the PPI group may reduce or increase the absorption of drugs, the absorption of which depends on the pH of the stomach. As with other drugs that reduce intragastric acidity, the absorption of drugs such as ketoconazole, itraconazole, and erlotinib may decrease, while the absorption of drugs such as digoxin may increase during treatment with omeprazole. Concomitant use of omeprazole (20 mg per day) and digoxin in healthy volunteers increased the bioavailability of digoxin by 10 % (in two out of ten subjects – up to 30 %).


Nelfinavir, atazanavir


Plasma levels of nelfinavir and atazanavir are reduced when co-administered with omeprazole.


Concomitant use of omeprazole and nelfinavir is contraindicated.


Concomitant administration of omeprazole (40 mg once daily) reduced the average exposure to nelfinavir by approximately 40 %, and the average exposure to the pharmacologically active metabolite M8 decreased by approximately 75-90 %. The interaction may also be due to inhibition of CYP2C19 activity.


Concomitant use of omeprazole with atazanavir is not recommended.


Concomitant administration of omeprazole (40 mg once daily) and atazanavir at a dose of 300 mg or ritonavir at a dose of 100 mg resulted in a 75% reduction in exposure to atazanavir. Increasing the dose of atazanavir to 400 mg did not compensate for the effect of omeprazole on atazanavir exposure. Concomitant administration of omeprazole (20 mg 1 time daily) with atazanavir 400 mg or ritonavir 100 mg in healthy volunteers resulted in an approximately 30% reduction in exposure to atazanavir compared to atazanavir 300 mg or compared to ritonavir 100 mg 1 time daily.


Digoxin


Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy volunteers increased the bioavailability of digoxin by 10 %. Cases of toxicity caused by digoxin use have rarely been reported. However, caution should be exercised when prescribing high doses of omeprazole to elderly patients. Therapeutic drug monitoring of digoxin should be strengthened. If used concomitantly with digoxin, patients should be closely monitored by a doctor.

Clopidogrel


During the study, clopidogrel (a loading dose of 300 mg followed by a dose of 75 mg per day) was used as monotherapy and with omeprazole (80 mg simultaneously with clopidogrel) for 5 days. When clopidogrel and omeprazole were co-administered, exposure to the active metabolite of clopidogrel was reduced by 46 % (day 1) and 42 % (day 5). Mean inhibition of platelet aggregation decreased by 47 % (after 24 hours) and by 30 % (day 5) when clopidogrel and omeprazole were used together. In another study, it was shown that taking clopidogrel and omeprazole at different times did not interfere with their interaction, which is probably due to the inhibitory effect of omeprazole on CYP2C19.  Therefore, you should refrain from concomitant use of omeprazole and clopidogrel.


Other medicines


The absorption of posaconazole, erlotinib, ketoconazole, and Itraconazole is significantly reduced, so clinical efficacy may be weakened. Concomitant use of the drug with posaconazole and erlotinib should be avoided.


Drugs that are metabolized with the participation of CYP2C19


Omeprazole is a moderate inhibitor of CYP2C19, the main enzyme that metabolizes omeprazole. Thus, the metabolism of concomitant drugs that are also metabolized with the participation of CYP2C19 may decrease, and the systemic exposure of these drugs may increase. Examples of such drugs are R-warfarin and other vitamin K antagonists, cilostazol, diazepam, and phenytoin.


In healthy volunteers, there was a pharmacokinetic/pharmacodynamic interaction between clopidogrel (loading dose – 300 mg/daily maintenance dose – 75 mg) and omeprazole (80 mg per day orally, that is, a dose 4 times higher than the standard daily dose), which led to a decrease in the exposure of the active metabolite of clopidogrel by an average of 46% and a decrease in the maximum inhibitory effect (ADP-induced) of platelet aggregation by an average of 16 %. As a precautionary measure, concomitant use of omeprazole and clopidogrel should be avoided.


However, it remains unclear to what extent this interaction may have clinical significance.


Cilostazol


In healthy volunteers, administration of omeprazole at a dose of 40 mg increased the Cmax and AUC of cilostazol by 18% and 26%, respectively, and one of its active metabolites – by 29% and 69%, respectively.


Phenytoin


Monitoring of the concentration of phenytoin in blood plasma is recommended during the first 2 weeks after the start of treatment with omeprazole; if the dose of phenytoin has been adjusted, monitoring and further dose adjustment of the drug should be carried out after the end of treatment with omeprazole.


Unknown interaction mechanism


Saquinavir


Concomitant use of omeprazole with saquinavir/ritonavir resulted in an increase in plasma saquinavir levels of approximately 70 %, which was associated with proper tolerability in HIV-infected patients.


Tacrolimus


An increase in serum tacrolimus levels has been reported with concomitant use of omeprazole. It is necessary to conduct intensive monitoring of Tacrolimus concentration, as well as renal function (creatinine clearance) and, if necessary, adjust the dosage of Tacrolimus.


Methotrexate


Elevated methotrexate levels have been reported in some patients when co-administered with PPIs. If it is necessary to use methotrexate in high doses, consideration should be given to temporarily discontinuing omeprazole.


Effect of other drugs on the pharmacokinetics of omeprazole


CYP2C19 and/or CYP3A4 inhibitors


Since omeprazole is metabolized by the enzymes CYP2C19 and CYP3A4, drugs that are known to inhibit the activity of CYP2C19 or CYP3A4, or both enzymes (such as clarithromycin and voriconazole), can cause an increase in serum levels of omeprazole as a result of slowing its metabolic rate. Concomitant use of voriconazole resulted in a more than twofold increase in omeprazole exposure. Since high doses of omeprazole were well tolerated, no dose adjustment of omeprazole is usually required. However, dose adjustment should be considered in patients with severe hepatic insufficiency 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 metabolized by CYP3A4, such as cyclosporine, lidocaine, quinidine, estradiol, erythromycin and budesonide.


Inducers of CYP2C19 and/or CYP3A4


Drugs that are known to induce the activity of CYP2C19 or CYP3A4, or both enzymes (such as rifampicin and St. John's wort), can cause a decrease in serum omeprazole levels as a result of accelerating its metabolic rate.


Application features.


If there is any alarming symptom (for example, significant involuntary weight loss, recurrent vomiting, dysphagia, bloody vomiting or Melena) and if a stomach ulcer is suspected or present, malignant tumors should be excluded, since treatment may reduce the severity of symptoms and delay the diagnosis.


Concomitant use of atazanavir with PPIs is not recommended. If the combination of atazanavir with PPIs cannot be avoided, careful clinical monitoring (for example, viral load) is recommended in combination with an increase in the dose of atazanavir to 400 mg per 100 mg of ritonavir; the dose of omeprazole should not exceed 20 mg.


Omeprazole, like all medications that inhibit the secretion of hydrochloric acid in gastric juice, can reduce the absorption of vitamin B12 (cyancobalamin) through hypo - or achlorhydria. This should be taken into account when treating patients with cachyxia or risk factors for reduced vitamin B12 absorption during long-term therapy.


Omeprazole is an inhibitor of CYP2C19. at the beginning or end of treatment with omeprazole, the possibility of interaction with drugs metabolized with the participation of CYP2C19 should be considered. the interaction is observed between clopidogrel and omeprazole. The clinical significance of this interaction remains unclear. As a precautionary measure, concomitant use of omeprazole and clopidogrel should be avoided.


PPI treatment Slightly increases the risk of gastrointestinal infections such as Salmonella and Campylobacter.


The use of PPIs, especially in high doses and for a long time (> 1 year), slightly increases the risk of hip, wrist and spine fractures, mainly in elderly patients or in the presence of other risk factors. According to studies, PPIs increase the risk of fractures by 10-40 %. In some cases, this is due to the presence of other risk factors in the patient. Patients at risk of osteoporosis should be provided with appropriate treatment and adequate administration of vitamin D and calcium.


As with any long-term treatment, especially when the treatment period with omeprazole exceeds 1 year, patients need medical supervision and regular laboratory determination of serum magnesium and calcium levels.


Patients taking PPIs, including omeprazole, for at least 3 months may experience significant hypomagnesemia (in most cases of hypomagnesemia, patients have used the drug for approximately 1 year).


After discontinuation of the drug, serum magnesium levels returned to normal. The clinical picture of hypomagnesemia is characterized by: increased neuromuscular excitability, which is manifested by spasm of the muscles of the hands and feet, motor arousal; tachycardia, cardiac arrhythmia, increased blood pressure; dystrophic disorders in the form of trophic erosions and skin ulcers. The criterion for establishing the diagnosis of hypomagnesemia is a decrease in the concentration of magnesium in the blood serum less than 1 meq/l. In addition, there have been cases where hypomagnesemia has led to the development of hypocalcemia due to inhibition of parathyroid hormone secretion in conditions of low magnesium content in the body. Some patients experienced severe hypocalcemia and hypomagnesemia, with the development of convulsive syndrome, cardiac arrhythmias, tetany, mental disorders and severe vomiting, which led to a violation of the electrolyte balance.


During treatment with antisecretory drugs, the concentration of gastrin in the blood plasma increases as a result of a decrease in the secretion of hydrochloric acid. Due to a decrease in hydrochloric acid secretion, the level of SDA increases. An increase in the concentration of SDA may affect the results of studies to detect neuroendocrine tumors. To prevent such exposure, it is necessary to stop taking PPIs 5 days before determining the level of SDA. If SDA and gastrin levels do not return to control values after initial measurements, the measurement should be repeated 14 days after discontinuation of PPI treatment.


Subacute cutaneous lupus erythematosus (PSHV)


The use of PPIs may be associated with very rare cases of PSHV. If damage occurs, especially in areas of the skin exposed to the sun, and if it is accompanied by arthralgia, the patient should seek immediate medical attention, and a healthcare professional should consider discontinuing omeprazole. The patient's history of PSHV after previous PPI treatment increases the risk of PSHV in the case of other PPI use.

This medicine contains 1.93 mmol (or 44.52 mg)/dose of sodium. Caution should be exercised when using the drug in patients who use a sodium-controlled diet.


Use during pregnancy or lactation.


In epidemiological studies, the results of more than 1,000 pregnant women whose delivery was successful indicate that there is no undesirable effect of omeprazole on pregnancy or the health of the fetus/newborn child. Omeprazole can only be used during pregnancy when, in the opinion of the doctor, the expected benefit to the mother exceeds the possible risk to the fetus.


Omeprazole is excreted in small amounts in breast milk, but its effect on the child is unknown. Therefore, breast-feeding should be discontinued for the duration of use of the drug.


Ability to influence the reaction rate when driving vehicles or other mechanisms.


It is unlikely that the drug affects the ability to drive a car or work with other mechanisms.


Given that sensitive patients may experience adverse reactions (dizziness, drowsiness, hallucinations, reversible confusion, etc.) when using the drug, such patients should refrain from driving vehicles or working with other mechanisms that require concentration of attention during the period of taking the drug.


Dosage and administration.


Dosage


Alternative to oral therapy


Patients for whom the oral form of the drug is unacceptable are recommended to use omeprazole 40 mg 1 time a day intravenously. For patients with Zollinger – Ellison syndrome, the recommended starting dose of the drug, which is administered intravenously, is 60 mg per day. There may be a need for higher daily doses, so the dose should be selected individually. If the dose exceeds 60 mg per day, it should be divided equally into 2 parts and taken 2 times a day.


The drug should only be administered intravenously and should not be administered in any other way.


The solution should be used immediately after preparation, but not later than 3 hours later. Dilute omeprazole solution should not be stored in the refrigerator. The unused solution should be destroyed.


Instructions for restoring the drug before Administration


For intravenous injections, the contents of each vial containing 40 mg of omeprazole are dissolved in 10 ml of sterile water for injection. The drug in the form of intravenous injections should be administered slowly (within 5 minutes).


For intravenous infusions, the contents of each vial containing 40 mg of omeprazole are reduced to 10 ml and adjusted to 100 ml with 0.9% sodium chloride solution or 5% glucose solution. The stability of omeprazole depends on the pH of the infusion solution, so no other solvents or other amounts should be used for dilution.


The drug in the form of an intravenous infusion is administered for 20-30 minutes.


The solution should be used immediately after preparation, but not later than 3 hours later. Dilute omeprazole solution should not be stored in the refrigerator.


Any unused product or waste must be disposed of in accordance with local regulations.


Special categories of patients


Impaired renal function


Dose adjustment is not required in patients with impaired renal function.


Impaired liver function


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


Elderly patients (>65 years)


Dose adjustment is not required in elderly patients.


Children.


The experience of using the drug for intravenous administration in pediatric practice is limited, so you should not prescribe the drug to this category of patients.


Overdose.


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


The described symptoms were temporary and there were no reports of serious consequences. The rate of elimination of the drug did not change (first-order Kinetics) with increasing doses of the drug.


In clinical studies, intravenous administration of the drug was used in doses up to 270 mg for one day and up to 650 mg for three days, which did not lead to any dose-dependent adverse reactions.


Treatment. There is no specific antidote. It is poorly excreted by dialysis. Gastric lavage, symptomatic and supportive therapy are indicated.


Tags: Omeprazole