Omeprazole

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Omeprazole (Omeprazole)

Composition:

Active substance: omeprazole;

1 vial contains sodium omeprazole equivalent to omeprazole 40 mg;

Excipients: mannitol, disodium edetate, meglumine, sodium bisulphite, sodium hydroxide.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white or practically white lyophilized mass or powder.

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 inhibition of gastric juice hydrochloric acid secretion.

Omeprazole is a weak base that accumulates and is converted into its active form in the highly acidic environment of the intracellular canaliculi of parietal cells, where it inhibits the H⁺, K⁺-ATPase enzyme (proton pump). This effect on the final step of gastric acid formation is dose-dependent and results in highly effective suppression 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 immediately reduce intragastric acidity to a level comparable to that achieved with repeated oral doses of 20 mg, the recommended initial intravenous dose is 40 mg. This leads to 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 plasma 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 H. pylori

H. pylori is associated with the development of peptic ulcer disease, including duodenal and gastric ulcers. H. pylori is a primary factor in the development of gastritis.

H. pylori, together with gastric hydrochloric acid, is a major factor in the development of peptic ulcer disease. H. pylori is also a primary factor in the development of atrophic gastritis, which is associated with an increased risk of gastric cancer.

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

Other effects related to inhibition of gastric acid secretion

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. Additionally, due to decreased gastric acidity, chromogranin A (CgA) levels rise. 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 measuring CgA. 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 courses, a slightly increased frequency of gastric 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.

Reducing gastric juice 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 is approximately 0.3 L/kg body weight. Omeprazole is approximately 97% bound to plasma proteins.

Metabolism and elimination

Omeprazole is completely metabolized by the cytochrome P450 (CYP) system. The majority of its metabolism depends on the polymorphically expressed CYP2C19, responsible for forming hydroxyomeprazole, the main metabolite in plasma. The remainder depends on another specific isoenzyme (CYP3A4), responsible for forming omeprazole sulfone. Due to omeprazole's high affinity for CYP2C19, there is potential for competitive inhibition and metabolic drug-drug interactions 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 inhibit major CYP enzymes.

Approximately 3% of individuals of Caucasian ethnicity and 15–20% of individuals of Mongoloid ethnicity lack functional CYP2C19 enzyme; these individuals are classified as "poor metabolizers." In these individuals, omeprazole metabolism may be predominantly catalyzed by the CYP3A4 enzyme. After repeated administration of omeprazole at 20 mg once daily, the mean AUC value in "poor metabolizers" is 5–10 times higher than in individuals with functional CYP2C19 enzyme ("extensive metabolizers"). The average maximum plasma concentration is also 3–5 times higher. 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 one 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 an omeprazole 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 due to reduced presystemic metabolism and systemic clearance, possibly caused by inhibition of the CYP2C19 enzyme by omeprazole and/or its metabolites (e.g., sulfone). None of the metabolites have been shown to affect gastric juice hydrochloric acid secretion.

Special patient populations

Patients with hepatic impairment

Omeprazole metabolism is slowed in patients with impaired liver function, leading to increased AUC. However, no tendency toward accumulation of the drug was observed when omeprazole was administered once daily.

Patients with renal impairment

The pharmacokinetics of omeprazole, including systemic bioavailability and elimination rate, are unchanged in patients with impaired 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 conditions.

Adults

• Treatment of duodenal ulcer.
• Prevention of duodenal ulcer recurrence.
• Treatment of gastric ulcer.
• Prevention of gastric ulcer recurrence.
• In combination with appropriate antibiotics for eradication of Helicobacter pylori (H. pylori) in peptic ulcer disease.
• Treatment of gastric and duodenal ulcers associated with nonsteroidal anti-inflammatory drug (NSAID) use.
• Prevention of gastric and duodenal ulcers associated with NSAID use in high-risk patients.
• Treatment of reflux esophagitis.
• Long-term management of patients with non-erosive 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 and atazanavir (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions.

Effect of omeprazole on the pharmacokinetics of other medicinal products

Medicinal products whose absorption is pH-dependent

Suppression of gastric acid secretion during treatment with omeprazole and other PPIs may reduce or increase the absorption of drugs whose absorption is pH-dependent. As with other agents that reduce gastric acidity, absorption of drugs such as ketoconazole, itraconazole, and erlotinib may be decreased, whereas absorption of drugs such as digoxin may be increased during omeprazole treatment. It has been reported that concomitant administration of omeprazole (20 mg once daily) and digoxin increases digoxin bioavailability by 10%.

Nelfinavir, atazanavir

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

Concomitant use of omeprazole and nelfinavir is contraindicated.

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

Concomitant use of omeprazole and atazanavir is contraindicated.

Concomitant administration of omeprazole (40 mg once daily) with atazanavir 300 mg or ritonavir 100 mg results in a 75% reduction in atazanavir exposure. Increasing the atazanavir dose to 400 mg does not compensate for the effect of omeprazole on atazanavir exposure. Concomitant use of omeprazole (20 mg once daily) with atazanavir 400 mg or ritonavir 100 mg results in approximately a 30% reduction in atazanavir exposure compared to atazanavir 300 mg or ritonavir 100 mg once daily.

Digoxin

Concomitant treatment with omeprazole (20 mg once daily) and digoxin increases digoxin bioavailability by 10%. Cases of digoxin-induced toxicity have been rarely reported. However, caution should be exercised when prescribing high doses of omeprazole to elderly patients. Therapeutic drug monitoring of digoxin should be intensified.

Clopidogrel

When clopidogrel and omeprazole are used concomitantly, exposure to the active metabolite of clopidogrel decreases from day 1 to day 5 from 46% to 42%. The mean inhibition of platelet aggregation decreases from 47% to 30% from day 1 to day 5 when clopidogrel and omeprazole are administered together. Administration of clopidogrel and omeprazole at different times does not prevent their interaction, which is likely due to the inhibitory effect of omeprazole on CYP2C19. Conflicting data have been reported regarding the clinical significance of this PK/PD interaction in terms of major cardiovascular events.

Other medicinal products

Absorption of posaconazole, erlotinib, ketoconazole, and itraconazole is significantly reduced; therefore, clinical efficacy may be diminished. Concomitant use with posaconazole and erlotinib should be avoided.

Medicinal products metabolized by CYP2C19

Omeprazole is a moderate inhibitor of CYP2C19, the main enzyme responsible for omeprazole metabolism. Thus, metabolism of concomitantly administered drugs that are also metabolized by CYP2C19 may be reduced, and systemic exposure to these drugs may increase. Examples include R-warfarin and other vitamin K antagonists, cilostazol, diazepam, and phenytoin.

Studies in healthy volunteers have demonstrated a pharmacokinetic/pharmacodynamic interaction between clopidogrel (loading dose – 300 mg / maintenance dose – 75 mg daily) and omeprazole (80 mg daily orally, i.e., a dose four times higher than the standard daily dose), resulting in a mean reduction of 46% in exposure to the active metabolite of clopidogrel and a mean reduction of 16% in maximum inhibitory effect (ADP-induced) on platelet aggregation. As a precaution, concomitant use of omeprazole and clopidogrel should be avoided.

However, the clinical relevance of this interaction remains unclear. There is no evidence of an increased risk of adverse cardiovascular outcomes with concomitant use of clopidogrel and PPIs, including esomeprazole.

Several observational studies have shown conflicting results regarding whether the risk of cardiovascular thromboembolic events increases when patients receive clopidogrel together with PPIs.

It has been reported that administration of clopidogrel in combination with acetylsalicylic acid and esomeprazole, compared to clopidogrel monotherapy, resulted in a nearly 40% reduction in exposure to the active metabolite of clopidogrel. However, the maximum inhibitory activity against (ATP-induced) platelet aggregation was similar in groups receiving clopidogrel alone and in combination with acetylsalicylic acid and esomeprazole, likely due to the concomitant administration of low-dose acetylsalicylic acid.

Cilostazol

Administration of omeprazole at a dose of 40 mg increases the Cmax and AUC of cilostazol by 18% and 26%, respectively, and of one of its active metabolites by 29% and 69%, respectively.

Phenytoin

Plasma phenytoin concentration monitoring is recommended during the first two weeks after initiation of omeprazole therapy; and if the phenytoin dose is adjusted, monitoring and further dose adjustments should be performed after discontinuation of omeprazole treatment.

Unknown mechanism

Saquinavir

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

Tacrolimus

Increased blood tacrolimus levels have been reported with concomitant use of omeprazole. Intensified monitoring of tacrolimus concentration 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 when administered concomitantly with proton pump inhibitors. When high-dose methotrexate therapy 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 enzymes, drugs known to inhibit the activity of CYP2C19 or CYP3A4, or both enzymes (such as clarithromycin and voriconazole), may lead to increased omeprazole plasma levels due to reduced metabolic rate. Concomitant use of voriconazole resulted in more than a twofold increase in omeprazole exposure. Since high doses of omeprazole are generally well tolerated, dose adjustment of omeprazole is usually not required. However, dose adjustment should be considered in patients with severe hepatic impairment and during long-term treatment.

Omeprazole is partially metabolized by CYP3A4 as well, 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 known to induce the activity of CYP2C19 or CYP3A4, or both enzymes (such as rifampicin and St. John’s wort), may lead to decreased omeprazole plasma levels due to accelerated metabolism.

Special precautions for use.

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

Concomitant use of omeprazole with atazanavir is contraindicated.

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 increasing the atazanavir dose 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. At the beginning or end of omeprazole treatment, potential interactions with medicinal products metabolized via 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, concomitant use of omeprazole and clopidogrel should be avoided.

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

In patients who have taken PPIs, including omeprazole, for at least 3 months, severe hypomagnesemia has occurred (in most cases, patients had been taking the drug for approximately 1 year). Hypomagnesemia may present with serious symptoms such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias. Hypomagnesemia may also be asymptomatic and thus may not be diagnosed promptly. In most patients, symptoms of hypomagnesemia resolve and levels normalize after administration of magnesium supplements and discontinuation of the PPI.

In patients planned for long-term PPI therapy or concomitant use of digoxin or other medicinal products that may cause reduced magnesium levels (e.g., diuretics), serum magnesium concentration should be measured before starting PPI therapy and periodically during treatment.

PPIs, particularly when used at high doses and for prolonged periods (>1 year), may slightly increase the risk of fractures of the spine, wrist, and hip, especially in elderly patients and those with predisposing factors. According to observational studies, PPIs may increase the overall risk of fractures by 10–40%. This increased risk may partly be related to other risk factors. Patients at risk of osteoporosis should receive appropriate management according to current clinical guidelines and should take vitamin D and calcium at recommended doses.

Subacute cutaneous lupus erythematosus (SCLE)

PPI use has occasionally been associated with the development of SCLE. If skin manifestations appear, particularly in sun-exposed areas and accompanied by arthralgia, patients should seek immediate medical advice and discontinuation of omeprazole should be considered. A history of SCLE following PPI use may increase the risk of SCLE with other PPIs.

Renal function

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.

Effect on laboratory test results

Elevated chromogranin A (CgA) levels may interfere with diagnostic tests for neuroendocrine tumors. To prevent this interference, omeprazole should be temporarily discontinued 5 days before CgA testing. If CgA and gastrin levels have not returned to the reference range after initial measurements, these parameters should be re-measured 14 days after discontinuation of the drug.

Patients receiving long-term treatment (particularly when treatment duration exceeds 1 year) should be under regular medical supervision.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

Studies have reported no adverse effects of omeprazole on pregnancy or fetal/neonatal health. Omeprazole may be used during pregnancy.

Omeprazole passes into breast milk, but the risk of effects on the infant is unlikely when the mother uses the medicinal product at therapeutic doses.

Ability to influence reaction speed when driving or operating machinery.

Omeprazole is unlikely to affect the ability to drive or operate machinery. 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 dose is 60 mg administered intravenously once daily. 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.

The drug must be administered only intravenously and must not be given by any other route.

The solution must be used immediately after preparation, but no later than within 4 hours. The diluted omeprazole solution must not be stored in a refrigerator. Any unused solution should be discarded.

Instructions for Reconstitution Prior to Administration

For intravenous injection: The contents of each vial of Omeprazole containing 40 mg of omeprazole should be dissolved in 10 mL of sterile water for injection. The solution for intravenous injection should be administered slowly over 5 minutes.

For intravenous infusion: The contents of each vial of Omeprazole containing 40 mg of omeprazole should be reconstituted with 10 mL of solvent and then further diluted 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; therefore, other solvents or different volumes should not be used for dilution.

The intravenous infusion should be administered over 20–30 minutes.

The solution must be used immediately after preparation, but no later than within 4 hours. The diluted omeprazole solution must not be stored in a refrigerator.

Any unused product or waste material should be disposed of in accordance with local requirements.

Special Patient Populations

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 administration of the drug in pediatric practice is limited; therefore, the drug should not be administered to this patient population.

Overdose

Information on the consequences of omeprazole overdose in humans is limited. Cases of administration up to 560 mg have been reported. There have also been isolated reports of single oral doses of omeprazole reaching 2400 mg (120 times higher than the usual recommended clinical dose). Reported symptoms include nausea, vomiting, dizziness, abdominal pain, diarrhea, and headache. 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.

In case of necessity, symptomatic treatment should be administered.

In clinical trials, intravenous doses of up to 270 mg in a single day and up to 650 mg over three days have been administered without causing any dose-dependent adverse reactions.

Side effects.

The most commonly reported adverse reactions (1–10% of patients) are headache, abdominal pain, constipation, diarrhea, flatulence, and nausea/vomiting.

During clinical trials with omeprazole and in the post-marketing period, the undesirable effects listed below have been identified. None of these events were considered dose-dependent. The adverse reactions listed below are classified by frequency and by system organ classes (SOC). Frequency is defined according to the following categories: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), and not known (cannot be estimated from available data).

Blood and lymphatic system disorders:
Rare: leukopenia, thrombocytopenia;
Very rare: agranulocytosis, pancytopenia.

Immune system disorders:
Rare: hypersensitivity reactions, e.g., fever, angioedema, and anaphylactic reactions/shock.

Metabolism and nutrition disorders:
Rare: hyponatremia;
Very rare: hypomagnesemia, severe hypomagnesemia which may lead to hypocalcemia; hypomagnesemia may also result in hypokalemia.

Psychiatric disorders:
Uncommon: insomnia;
Rare: agitation, confusion, depression;
Very rare: aggression, hallucinations.

Nervous system disorders:
Common: headache;
Uncommon: dizziness, paraesthesia, somnolence;
Rare: taste disturbance.

Eye disorders:
Rare: blurred vision.

Ear and labyrinth disorders:
Uncommon: vertigo.

Respiratory, thoracic and mediastinal disorders:
Rare: bronchospasm.

Gastrointestinal disorders:
Common: abdominal pain, constipation, diarrhea, flatulence, nausea/vomiting, fundic gland polyps (benign);
Rare: dry mouth, stomatitis, gastrointestinal candidiasis, microscopic colitis.

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

Skin and subcutaneous tissue disorders:
Uncommon: dermatitis, pruritus, rash, urticaria;
Rare: alopecia, photosensitivity;
Very rare: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN);
Frequency not known: subacute cutaneous lupus erythematosus.

Musculoskeletal and connective tissue disorders:
Uncommon: fractures of the hip, wrist, or spine;
Rare: arthralgia, myalgia;
Very rare: muscle weakness.

Renal and urinary disorders:
Frequency not known: tubulointerstitial nephritis (with possible progression to renal failure).

Reproductive system and breast disorders:
Very rare: gynecomastia.

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

There have been isolated reports of irreversible visual disturbances in critically ill patients who received omeprazole intravenously, particularly at high doses; however, a causal relationship has not been established.

Shelf life. 2 years.

Storage conditions.

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

Shelf life of reconstituted solution: up to 4 hours at a temperature not exceeding 25°C.

Storage period of the powder after reconstitution: up to 24 hours.

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

Incompatibilities.

This medicinal product must not be mixed with other medicinal products except those mentioned in the section "Dosage and administration".

Packaging.

1 or 10 vials per cardboard box.

Prescription category. Prescription only.

Manufacturer. Shandong Yuxing Pharmaceutical Co., Ltd.

Manufacturer's address and place of business.
Luoci Street, west central section, Luozhuang District, Linyi City, People's Republic of China.