Omeprotect

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

Composition:

Active substance: omeprazole;

1 vial contains sodium omeprazole equivalent to omeprazole 40 mg;

Excipients: sodium hydroxide.

1 ampoule of solvent contains polyethylene glycol 400; citric acid, monohydrate; water for injections.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white or practically white mass in a colorless vial.

Pharmacotherapeutic group.

Drugs 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 acid secretion through a mechanism of highly targeted action. Omeprazole inhibits gastric acid secretion by specifically affecting the proton pump in parietal cells. The drug acts rapidly when administered once daily and provides control through reversible suppression of gastric 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 enzyme H⁺, K⁺-ATPase (proton pump). This effect, occurring at the final stage of gastric 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 the effect of omeprazole on gastric acid secretion.

Effect on gastric acid secretion

Intravenous administration of omeprazole causes a 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, an initial intravenous dose of 40 mg is recommended. This results in an immediate reduction of 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 current 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 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 rates of ulcer healing and prolonged remission.

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 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 measuring CgA. Testing should be repeated if levels have not normalized by that time.

An increase in ECL cells, 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 long-term treatment, a slightly increased frequency of gastric polyps has been reported. These changes are 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 estimated 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 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 does not have 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 the CYP3A4 enzyme. After repeated administration of omeprazole at a dose of 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 mean maximum plasma concentration was 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. Nearly 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-dependency 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 acid secretion.

Special patient groups

Patients with hepatic impairment

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

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 for the following indications.

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 high-risk patients.
• 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.

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 forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Effect of omeprazole on the pharmacokinetics of other medicinal products

Medicinal products whose absorption is pH-dependent

Suppression of gastric secretion during treatment with omeprazole and other PPIs may reduce or increase the absorption of medicinal products whose absorption depends on gastric pH. As with other medicinal products that reduce intragastric 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 46% to 42% between days 1 and 5. The mean inhibition of platelet aggregation decreases from 47% to 30% between days 1 and 5 when clopidogrel and omeprazole are administered together. Administering 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 medicinal products that are also metabolized by CYP2C19 may be reduced, and systemic exposure to these agents may be increased. 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/daily maintenance dose 75 mg) 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 precautionary measure, concomitant use of omeprazole and clopidogrel should be avoided.

However, the clinical significance of this interaction remains unclear. There is no evidence of increased risk of cardiovascular events with concomitant use of clopidogrel and PPIs.

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 effect on (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 40 mg increases 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 treatment; and if the phenytoin dose is adjusted, monitoring and further dose adjustments should continue after discontinuation of omeprazole treatment.

Unknown mechanism

Saquinavir

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

Tacrolimus

Increased serum levels of tacrolimus have been reported with concomitant use of omeprazole. Enhanced 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 receiving concomitant PPIs. In cases where 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 enzymes, medicinal products known to inhibit the activity of CYP2C19 or CYP3A4, or both enzymes (such as clarithromycin and voriconazole), may lead to increased serum levels of omeprazole 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 also partially metabolized by CYP3A4, but does not inhibit this enzyme. Therefore, omeprazole does not affect the metabolism of medicinal products metabolized by CYP3A4, such as cyclosporine, lidocaine, quinidine, estradiol, erythromycin, and budesonide.

Inducers of CYP2C19 and/or CYP3A4

Medicinal products known to induce the activity of CYP2C19 or CYP3A4, or both enzymes (such as rifampicin and St. John's wort), may lead to decreased serum levels of omeprazole 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 melaena) and in suspected or confirmed gastric ulcer, malignancy must be excluded since treatment may alleviate symptoms 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 in combination 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. At the initiation or discontinuation of omeprazole treatment, potential interactions with medicinal products metabolized 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, 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.

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 manifest as serious symptoms such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias. Hypomagnesemia may also be asymptomatic and may not be diagnosed in time. In most patients, symptoms of hypomagnesemia resolve and levels normalize after magnesium supplementation and discontinuation of 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 spine, wrist, and hip fractures, especially in elderly patients and in the presence of predisposing risk factors. According to observational studies, PPIs may increase the overall risk of fractures by 10–40%. This increased risk may be partially related to other risk factors. Patients at risk of osteoporosis should receive 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 occur, 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 drug use may increase the risk of developing SCLE when using other PPIs.

Effect on laboratory test results

Elevated chromogranin A (CgA) levels may interfere with tests for detecting neuroendocrine tumors. To prevent this interference, omeprazole should be temporarily discontinued at least 5 days before measuring CgA levels. 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 who are taking the medicinal product for a prolonged period (particularly if treatment exceeds 1 year) should be under regular medical supervision.

Omeprazole may cause serious skin reactions. Symptoms may include: skin redness; blisters; rash.

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 been reported indicating no adverse effect 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 if the mother is taking the drug at therapeutic doses.

Ability to affect reaction speed when driving or operating machinery.

It is unlikely that omeprazole affects 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 medication is inappropriate, OmeProtect 40 mg is recommended to be administered intravenously once daily. For patients with Zollinger–Ellison syndrome, the recommended initial dose is 60 mg per day given intravenously. 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 medicinal product should 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 4 hours after reconstitution. The diluted solution of OmeProtect must not be stored in the refrigerator. Any unused solution should be discarded.

Instructions for Reconstitution of the Medicinal Product Prior to Administration

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

For Intravenous Infusions: Reconstitute the contents of each vial of OmeProtect containing 40 mg of omeprazole in 10 mL and then dilute 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 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 4 hours after reconstitution. The diluted solution of OmeProtect must not be stored in the 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 medicinal product in pediatric practice is limited; therefore, the drug should not be prescribed to this patient group.

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). Symptoms such as nausea, vomiting, dizziness, abdominal pain, diarrhea, and headache have been recorded. In rare cases, apathy, 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.

If necessary, symptomatic treatment should be administered.

In clinical trials, the drug was administered intravenously at doses up to 270 mg in a single day and up to 650 mg over three days, with no dose-dependent adverse reactions observed.

Adverse Reactions

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

Undesirable effects listed below were identified during clinical trials with omeprazole and in the post-marketing period. 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, such as 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 lead to 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:
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.

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

Renal function impairment

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

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

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

Keep out of the reach of children.

The reconstituted solution should be stored for no more than 12 hours in a refrigerator.

Incompatibilities.

This medicinal product should not be mixed with other medicinal products except those mentioned in the section "Method of administration and dosage."

Packaging.

1 vial of powder with 1 ampoule of solvent in a package.

Prescription status. By prescription only.

Manufacturer. ANFARM HELLAS S.A.

Manufacturer's address and location of operations.

61st km National Road Athens-Lamia, Schimatari Viotia 32009, Greece.