INSTRUCTIONS for medical use of the medicinal product OMEPRAZOLE (OMEPRAZOL)

Composition:

Active substance: omeprazole;

One vial contains 40 mg of omeprazole sodium (calculated as omeprazole);

Excipients: edetate disodium, sodium hydroxide.

Pharmaceutical form. Lyophilisate for solution for infusion.

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

Pharmacotherapeutic group.
Agents for treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors. ATC code A02BC01.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Omeprazole, a racemic mixture of two enantiomers, reduces gastric hydrochloric acid secretion through an extremely targeted mechanism of action. Omeprazole inhibits gastric acid secretion by specifically acting on the proton pump in parietal cells. When administered once daily, the drug acts rapidly and provides control through reversible suppression of gastric hydrochloric acid secretion.

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

Pharmacodynamic effects

All pharmacodynamic effects can be explained by omeprazole's effect on gastric acid secretion.

Effect on gastric acid secretion

Intravenous administration of omeprazole causes dose-dependent inhibition of gastric acid secretion in humans. To achieve an immediate reduction in intragastric acidity equivalent to that achieved with repeated oral doses of 20 mg, an initial intravenous dose of 40 mg is recommended. This results in an immediate reduction in intragastric acidity and sustained suppression of this parameter by approximately 90% over 24 hours, both after intravenous injection and intravenous infusion.

Inhibition of acid secretion correlates with the area under the concentration-time curve (AUC) of omeprazole and does not depend on the actual plasma concentration of omeprazole at any given time.

No signs of tachyphylaxis have been observed during omeprazole treatment.

Effect on Helicobacter pylori

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

Eradication of Helicobacter pylori using omeprazole in combination with antimicrobial agents is associated with high healing rates and prolonged remission in peptic ulcer disease.

Other effects related to inhibition of gastric acid secretion

During treatment with antisecretory agents, serum gastrin levels increase in response to reduced acid secretion. Additionally, due to decreased gastric acidity, chromogranin A (CgA) levels increase. Elevated CgA levels may interfere with diagnostic testing for neuroendocrine tumors. It has been reported that treatment with proton pump inhibitors should be discontinued 5–14 days before CgA measurement. Testing should be repeated if levels have not normalized by that time.

An increase in ECL-cell numbers, possibly related to elevated serum gastrin levels, has been observed in both children and adults during long-term omeprazole treatment. These findings are considered to have no clinical significance.

During prolonged treatment, a slightly increased frequency of gastric fundic gland polyps has been reported. These changes are considered a physiological consequence of pronounced inhibition of gastric acid secretion; the process is benign and likely reversible.

Reduction of gastric acidity by any means, including proton pump inhibitors, increases the number of bacteria normally present in the gastrointestinal tract. Treatment with acid-reducing agents may lead to a slightly increased risk of gastrointestinal infections caused by Salmonella and Campylobacter.

Pharmacokinetics.

Distribution

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

Metabolism

Omeprazole is completely metabolized by the cytochrome P450 (CYP) system. The majority of its metabolism depends on the polymorphically expressed CYP2C19, responsible for the formation of hydroxyomeprazole, the main metabolite in plasma. The remainder depends on another specific isoenzyme (CYP3A4), responsible for the formation of omeprazole sulfone. Due to omeprazole's high affinity for CYP2C19, there is a potential for competitive inhibition and metabolic drug-drug interactions with other CYP2C19 substrates. However, due to its low affinity for CYP3A4, omeprazole lacks the ability to inhibit the metabolism of other CYP3A4 substrates. Furthermore, omeprazole does not exert inhibitory effects on major CYP enzymes.

Approximately 3% of individuals of Caucasian ethnicity and 15–20% of individuals of Mongoloid ethnicity lack functional CYP2C19 enzyme; they are classified as "poor metabolizers." In these individuals, omeprazole metabolism may be primarily catalyzed by CYP3A4. After repeated administration of omeprazole 20 mg once daily, the mean AUC value in "poor metabolizers" is 5–10 times higher than in individuals with functional CYP2C19 ("extensive metabolizers"). Mean maximum plasma concentrations were also higher—by 3–5 times. However, these findings do not affect omeprazole dosing.

Elimination

Total plasma clearance is approximately 30–40 L/h after a single dose. The elimination half-life of omeprazole in plasma is generally less than 1 hour, both after single and repeated once-daily administration. Omeprazole is completely cleared from plasma between doses, with no tendency for accumulation when administered once daily. Approximately 80% of the dose is excreted in urine as metabolites, and the remainder is excreted in feces, primarily via biliary secretion.

The AUC of omeprazole increases with repeated administration. This increase is dose-dependent and results in a nonlinear relationship between AUC and dose after repeated dosing. This time- and dose-dependent relationship is attributed to reduced presystemic metabolism and systemic clearance, possibly due to inhibition of the CYP2C19 enzyme by omeprazole and/or its metabolites (e.g., sulfone). No metabolite has been shown to affect gastric acid secretion.

Special patient populations

Patients with hepatic impairment

Omeprazole metabolism is slowed in patients with impaired liver function, leading to increased AUC. However, with once-daily administration of omeprazole, no tendency toward drug accumulation has been observed.

Patients with renal impairment

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

Elderly patients

The rate of omeprazole metabolism is slightly reduced in elderly patients (75–79 years of age).

Clinical characteristics.

Indications.

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

Adults

Treatment of duodenal ulcer.
Prevention of recurrence of duodenal ulcer.
Treatment of gastric ulcer.
Prevention of recurrence of gastric ulcer.
In combination with appropriate antibiotics for eradication of Helicobacter pylori (H. pylori) in peptic ulcer disease.
Treatment of gastric and duodenal ulcers associated with use of nonsteroidal anti-inflammatory drugs (NSAIDs).
Prevention of gastric and duodenal ulcers associated with NSAID use in patients at risk.
Treatment of reflux esophagitis.
Long-term management 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.

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

Interaction with other medicinal products and other forms of interactions.

Effect of omeprazole on the pharmacokinetics of other medicinal products

Medicinal products whose absorption is pH-dependent

Suppression of gastric secretion during omeprazole therapy may decrease or increase the absorption of medicinal products whose absorption depends on gastric pH.

Nelfinavir, atazanavir

Reduced serum levels of atazanavir and nelfinavir have been observed with concomitant use of omeprazole; therefore, co-administration of these agents is not recommended. Concomitant administration of omeprazole (40 mg once daily) and atazanavir 300 mg/ritonavir 100 mg in healthy volunteers resulted in a significant reduction in atazanavir exposure (decrease in AUC, Cmax, and Cmin by approximately 75%). Increasing the atazanavir dose to 400 mg did not compensate for the effect of omeprazole on atazanavir exposure. Concomitant administration of omeprazole (20 mg daily) with atazanavir 400 mg/ritonavir 100 mg in healthy volunteers reduced atazanavir exposure by approximately 30% compared to exposure observed with atazanavir 300 mg/ritonavir 100 mg once daily without omeprazole 20 mg daily. Concomitant use of omeprazole (40 mg daily) reduced mean AUC, Cmax, and Cmin values of nelfinavir by 36–39%, and mean AUC, Cmax, and Cmin values of its pharmacologically active metabolite M8 by 75–92%.

Digoxin

When omeprazole (20 mg daily) and digoxin were co-administered in healthy volunteers, digoxin bioavailability increased by 10% (up to 30% in two out of ten participants). Digoxin toxicity has been reported rarely. However, caution should be exercised when administering high doses of omeprazole to elderly patients. Monitoring of digoxin blood levels should be intensified.

Clopidogrel

In a study, clopidogrel (loading dose 300 mg followed by 75 mg/day) was administered alone and in combination with omeprazole (80 mg administered simultaneously with clopidogrel) for 5 days. Exposure to the active metabolite of clopidogrel decreased by 46% (day 1) and 42% (day 5) with concomitant administration of clopidogrel and omeprazole. The mean extent of platelet aggregation inhibition with concomitant use of clopidogrel and omeprazole decreased by 47% (after 24 hours) and 30% (day 5). Another study demonstrated that administering clopidogrel and omeprazole at different times did not eliminate their interaction, likely due to the inhibitory effect of omeprazole on CYP2C19. Clinical studies have yielded conflicting data regarding the clinical significance of this pharmacokinetic/pharmacodynamic interaction in terms of major cardiovascular events. Therefore, concomitant use of omeprazole and clopidogrel is not recommended.

Other medicinal products

Absorption of ampicillin, posaconazole, erlotinib, ketoconazole, itraconazole, and iron is significantly reduced, and thus their clinical efficacy may be decreased. Concomitant use with posaconazole and erlotinib should be avoided.

Medicinal products metabolized by CYP2C19

Interaction is possible with drugs metabolized in the liver via the cytochrome P450 enzyme system. Plasma concentrations of diazepam, phenytoin, nifedipine, disulfiram, cilostazol, aminopyrine, antipyrine, warfarin, and other vitamin K antagonists may increase. Such increases are generally not clinically significant with usual doses of omeprazole. However, monitoring of patients is recommended at the start and upon discontinuation of treatment, and dose adjustments of phenytoin, diazepam, warfarin, and disulfiram may be necessary.

Cilostazol

Administration of omeprazole 40 mg led to increases in Cmax and AUC of cilostazol by 18% and 26%, respectively, and of one of its active metabolites by 29% and 69%.

Phenytoin

Monitoring of plasma phenytoin concentrations is recommended during the first two weeks after initiating omeprazole therapy. If phenytoin dose adjustment is required, monitoring and further dose adjustments are needed after discontinuation of omeprazole treatment.

Unknown mechanism

Saquinavir

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

Tacrolimus

Concomitant use of tacrolimus and omeprazole may increase tacrolimus serum concentrations. Enhanced monitoring of tacrolimus levels and renal function (creatinine clearance) is required, and dose adjustment of tacrolimus may be necessary.

Methotrexate

Elevated methotrexate levels have been reported in some patients receiving concomitant proton pump inhibitors. When high-dose methotrexate is required, temporary discontinuation of omeprazole should be considered.

Effect of other medicinal products on the pharmacokinetics of omeprazole

Inhibitors of CYP2C19 and/or CYP3A4

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. Because high doses of omeprazole are generally well tolerated, dose adjustment of omeprazole is usually not required. However, dose adjustment should be considered for patients with severe hepatic impairment and in cases requiring long-term treatment.

Omeprazole is also partially metabolized by CYP3A4 but does not inhibit this enzyme. Therefore, 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 induce CYP2C19, CYP3A4, or both enzymes (such as rifampicin and St. John's wort) may reduce omeprazole serum levels by accelerating its metabolism.

The efficacy of prednisolone and cyclosporine may be reduced, and cyclosporine dosage adjustments may sometimes be necessary.

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

Special precautions for use

In the presence of any alarming symptom (e.g., significant involuntary weight loss, recurrent vomiting, dysphagia, hematemesis or melena) and in suspected or confirmed gastric ulcer, malignancy must be ruled out, as treatment may reduce symptom severity and delay diagnosis.

Concomitant use of atazanavir with proton pump inhibitors is not recommended. If a combination of atazanavir with a proton pump inhibitor cannot be avoided, careful clinical monitoring (e.g., viral load) is recommended, along with an increased dose of atazanavir to 400 mg with 100 mg ritonavir; the omeprazole dose should not exceed 20 mg.

Omeprazole, like all medicinal products that suppress gastric acid secretion, may reduce absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with cachexia or risk factors for reduced vitamin B12 absorption during long-term therapy.

Omeprazole is an inhibitor of CYP2C19. Potential interactions with medicinal products metabolized by CYP2C19 should be considered at the beginning or after completion of omeprazole treatment. An interaction has been observed between clopidogrel and omeprazole. The clinical significance of this interaction remains unclear. As a precaution, concomitant use of omeprazole and clopidogrel should be avoided.

Treatment with proton pump inhibitors (PPIs) may lead to a slightly increased risk of 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 over a year. Hypomagnesemia may present with serious symptoms such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia, but its onset may be gradual and remain unnoticed. In most patients with hypomagnesemia, condition improved after magnesium replacement therapy and discontinuation of PPI.

For patients expected to undergo long-term treatment or those taking PPIs with digoxin or medications capable of causing 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 prolonged periods (>1 year), may slightly increase the risk of fractures of the hip, wrist, and spine, primarily in elderly patients or those with other risk factors. Results of observational studies suggest that proton pump inhibitors may increase the overall risk of fractures by 10–40%. This increase may be partly attributable to other risk factors. Patients at risk of osteoporosis should be managed according to current clinical guidelines and should also receive adequate vitamin D and calcium intake.

Effect on laboratory test results

Use of omeprazole may increase chromogranin A (CgA) levels. Elevated CgA levels may interfere with diagnostic tests for neuroendocrine tumors. To avoid this interference, omeprazole should be temporarily discontinued 5 days before measuring CgA levels.

As with any long-term therapy, especially when treatment duration with omeprazole exceeds 1 year, patients should be under continuous monitoring.

Renal function impairment

Acute tubulointerstitial nephritis (ATIN) has been observed in patients taking omeprazole and may occur at any time during omeprazole therapy (see section "Adverse reactions"). Acute tubulointerstitial nephritis may progress to renal failure. If ATIN is suspected, omeprazole should be discontinued and appropriate treatment initiated immediately.

Use during pregnancy or breastfeeding

Pregnancy

Study results indicate no adverse effects of omeprazole on pregnancy or fetal/newborn health. Omeprazole may be used during pregnancy.

Breastfeeding

Omeprazole passes into breast milk, but is unlikely to affect the infant when used at therapeutic doses.

Fertility

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

Ability to influence reaction speed when driving or operating machinery

Omeprazole is unlikely to affect the ability to drive or operate machinery. However, adverse reactions such as dizziness and visual disturbances may occur. If such disorders occur, patients should not drive or operate machinery.

Method of Administration and Dosage

Dosage

Alternative to Oral Therapy

For patients for whom oral administration of the drug is unsuitable, intravenous administration of omeprazole 40 mg once daily is recommended. For patients with Zollinger-Ellison syndrome, the recommended initial intravenous dose of omeprazole is 60 mg per day. Higher daily doses may be required; therefore, the dose should be individually adjusted. If the daily dose exceeds 60 mg, it should be divided equally into two doses and administered twice daily.

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

Instructions for Reconstituting the Drug Prior to Administration

The entire contents of the vial should be dissolved in approximately 5 mL of diluent and then immediately diluted to 100 mL with diluent. Use either 0.9% sodium chloride solution or 5% glucose solution. The stability of omeprazole depends on the pH of the infusion solution; therefore, no other diluent or volume should be used.

Preparation

Using a syringe, withdraw 5 mL of infusion solution from a 100-mL infusion bottle or bag.
Add this volume to the vial containing lyophilized omeprazole, mix thoroughly, ensuring complete dissolution of the drug.
Withdraw the entire omeprazole solution from the vial into the syringe.
Transfer the solution to the infusion bag or bottle.
Repeat steps 1–4 to ensure that the entire omeprazole volume has been transferred from the vial to the infusion bag or bottle.

Alternative Method for Preparing Infusion Solution in a Flexible Container

Attach a double-ended transfer needle to the infusion bag’s injection port. Connect the other end of the needle to the vial containing lyophilized omeprazole.
Dissolve the lyophilized powder by alternately transferring the infusion solution back and forth between the infusion bag and the vial.
Ensure complete dissolution of the drug.

The prepared solution should be used for intravenous infusion within 20–30 minutes.

Any unused portion or waste material must be disposed of according to local requirements.

Vials containing the lyophilized powder (without the cardboard box) may be stored under normal room lighting for up to 24 hours.

Reconstituted Solution:

Chemical and physical stability after container opening has been demonstrated for 12 hours at 25°C when reconstituted with 0.9% sodium chloride solution and for 6 hours at 25°C when reconstituted with 5% glucose solution.

From a microbiological standpoint, the product should be used immediately, except when reconstitution has been carried out under controlled and aseptic conditions, validated by appropriate methods.

Special Patient Categories

Renal Impairment

Dose adjustment is not required in patients with renal impairment.

Hepatic Impairment

In patients with hepatic impairment, a daily dose of 10–20 mg may be sufficient.

Elderly Patients (>65 years)

Dose adjustment is not required in elderly patients.

Children

Experience with intravenous omeprazole administration in pediatric practice is limited.

Overdose

Information on the consequences of omeprazole overdose in humans is limited. Cases of doses up to 560 mg have been reported. There are also isolated reports of single oral doses of omeprazole reaching 2400 mg (120 times higher than the usual recommended clinical dose). Symptoms such as nausea, vomiting, dizziness, abdominal pain, diarrhea, and headache have been recorded. In isolated cases, lethargy, depression, and confusion have also been reported.

The described symptoms were transient, and no reports of serious outcomes have been received. The elimination rate of the drug did not change (first-order kinetics) with increasing doses. Symptomatic treatment should be administered if necessary.

There are data on intravenous administration of up to 270 mg in a single day and up to 650 mg over three days, which did not result in any dose-dependent adverse reactions.

Adverse Reactions

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

Blood system disorders: leucopenia, thrombocytopenia, agranulocytosis, pancytopenia.

Immune system disorders: hypersensitivity reactions, such as fever, angioneurotic edema, and anaphylactic reactions/shock.

Metabolic and nutritional disorders: hyponatremia, hypomagnesemia. Severe hypomagnesemia may lead to hypocalcemia. Hypomagnesemia may also cause hypokalemia.

Psychiatric disorders: insomnia, agitation, confusion, depression, aggression, hallucinations.

Nervous system disorders: headache, dizziness, paraesthesia, somnolence, taste disturbance.

Eye disorders: blurred vision.

Ear and labyrinth disorders: vertigo.

Respiratory system disorders: bronchospasm.

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

Hepatobiliary disorders: increased liver enzymes, hepatitis with or without jaundice, hepatic failure, encephalopathy in patients with pre-existing liver disease.

Skin and subcutaneous tissue disorders: dermatitis, pruritus, rash, urticaria, alopecia, photosensitivity, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN).

Musculoskeletal and connective tissue disorders: fractures of the hip, wrist, or spine (see section "Special precautions"), arthralgia, myalgia, muscle weakness.

Renal and urinary disorders: tubulointerstitial nephritis (with possible progression to renal failure).

Reproductive system disorders: gynecomastia.

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

In isolated cases, irreversible visual disturbances have been reported in critically ill patients who received intravenous omeprazole, particularly at high doses; however, a causal relationship has not been established.

Shelf life: 2 years.

Storage conditions:

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibilities:

Omeprazole must not be mixed with other medicinal products except as specified in the section "Dosage and administration".

Packaging: 1 vial per carton.

Prescription status: Prescription only.

Manufacturer:

LLC "FARMEKS GROUP"

Manufacturer's address and place of business:

100, Shevchenka St., Boryspil, Kyiv Oblast, 08301, Ukraine