Omenax

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT OMENAX® (OMENAX®)

Composition:

Active substance: omeprazole;

1 vial contains omeprazole sodium equivalent to omeprazole 40 mg;

Excipient: sodium hydroxide.

Pharmaceutical form. Powder for solution for injection.

Main physico-chemical properties: lyophilized powder ranging from white to almost white.

Pharmacotherapeutic group.

Drugs for treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors. Omeprazole. ATC code A02BC01.

Pharmacological properties.

Pharmacodynamics.

Omeprazole, a racemic mixture of two enantiomers, reduces gastric secretion of hydrochloric acid through a mechanism of highly targeted 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 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 enzyme H⁺, K⁺-ATPase (proton pump). This effect at the final stage of gastric juice hydrochloric acid formation is dose-dependent and provides highly effective suppression of both basal and stimulated acid secretion, regardless of the type of stimulation.

All pharmacodynamic effects can be explained by the influence of omeprazole 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 obtained 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, averaging 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 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 sustained remission of 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 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 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 prolonged treatment courses, a slightly increased frequency of gastric polyps has been reported. These changes are considered a physiological consequence of pronounced acid secretion suppression; 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.

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

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 omeprazole sulfone formation. Due to omeprazole's high affinity for CYP2C19, there is potential for competitive inhibition and metabolic drug-drug interactions with other CYP2C19 substrates. However, because of its low affinity for CYP3A4, omeprazole does not inhibit the metabolism of other CYP3A4 substrates. Furthermore, omeprazole does not inhibit major CYP enzymes.

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

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 single and repeated once-daily administration. Omeprazole is completely eliminated 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 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 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 juice hydrochloric acid secretion.

Patients with hepatic impairment.

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

Omenax® for intravenous use is indicated as an alternative to oral therapy in 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.

Concomitant administration of omeprazole, as well as other proton pump inhibitors (PPIs), with nelfinavir and atazanavir is contraindicated.

Interaction with other medicinal products and other forms of interaction.

Effect of omeprazole on the pharmacokinetics of other medicinal products.

Medicinal products whose absorption depends on gastric pH.

Suppression of gastric acid secretion during treatment with omeprazole and other PPIs may decrease or increase the absorption of medicinal products whose absorption is pH-dependent. As with other agents that reduce intragastric acidity, absorption of drugs such as ketoconazole, itraconazole, and erlotinib may be reduced, whereas absorption of drugs such as digoxin may be increased during omeprazole treatment. Concomitant administration of omeprazole (20 mg once daily) and digoxin in healthy volunteers increased digoxin bioavailability by 10% (up to 30% in two out of ten subjects).

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 mean exposure to nelfinavir by approximately 40%, and mean exposure to its pharmacologically active metabolite M8 decreased by approximately 75–90%. The 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/ritonavir 100 mg in healthy volunteers resulted in a 75% reduction in atazanavir exposure. Increasing the atazanavir dose to 400 mg did not compensate for the effect of omeprazole on atazanavir exposure. Concomitant administration of omeprazole (20 mg once daily) with atazanavir 400 mg/ritonavir 100 mg in healthy volunteers resulted in approximately 30% reduction in atazanavir exposure compared to atazanavir 300 mg/ritonavir 100 mg once daily.

Digoxin.

Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy volunteers increased digoxin bioavailability by 10%. Rare cases of digoxin toxicity have been reported. However, caution should be exercised when prescribing high doses of omeprazole to elderly patients. Therapeutic drug monitoring of digoxin should be intensified. Patients receiving concomitant digoxin should be closely monitored by a physician.

Clopidogrel.

In studies, clopidogrel (loading dose 300 mg followed by 75 mg daily) was administered alone and together with omeprazole (80 mg given simultaneously with clopidogrel) for 5 days. When clopidogrel and omeprazole were administered together, exposure to the active metabolite of clopidogrel decreased by 46% (day 1) and 42% (day 5). Mean inhibition of platelet aggregation decreased by 47% (after 24 hours) and 30% (day 5) when clopidogrel and omeprazole were used together. In another study, administration of clopidogrel and omeprazole at different times did not prevent their interaction, likely due to omeprazole's inhibitory effect on CYP2C19. Conflicting data on the clinical implications of this pharmacokinetic/pharmacodynamic (PK/PD) interaction regarding major cardiovascular events have been reported in studies. Therefore, concomitant use of omeprazole and clopidogrel should be avoided.

Other medicinal products.

Absorption of posaconazole, erlotinib, ketoconazole, and itraconazole is significantly reduced, and thus 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 increase. Examples include R-warfarin and other vitamin K antagonists, cilostazol, diazepam, and phenytoin.

Study results in healthy volunteers demonstrated PK/PD 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 precaution, concomitant use of omeprazole and clopidogrel should be avoided. However, the clinical significance of this interaction remains unclear.

Based on results from one randomized (but incomplete) study (comparing placebo and omeprazole 20 mg in patients treated with clopidogrel and acetylsalicylic acid) and non-randomized post-hoc analyses of data from large randomized clinical outcome studies, there is no evidence of increased risk of adverse cardiovascular outcomes with concomitant use of clopidogrel and PPIs, including esomeprazole.

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

In a study involving healthy volunteers evaluating clopidogrel together with the combination of acetylsalicylic acid and esomeprazole compared to clopidogrel monotherapy, exposure to the active metabolite of clopidogrel decreased by nearly 40%. However, maximum inhibitory activity against (ATP-induced) platelet aggregation was similar in groups receiving clopidogrel alone and clopidogrel in combination with acetylsalicylic acid and esomeprazole, likely due to the concomitant administration of low-dose acetylsalicylic acid.

Cilostazol.

In a crossover study, administration of omeprazole 40 mg to healthy volunteers increased the maximum concentration and AUC of cilostazol by 18% and 26%, respectively, and one of its active metabolites by 29% and 69%, respectively.

Phenytoin.

Plasma phenytoin concentration monitoring is recommended during the first 2 weeks after initiation of omeprazole treatment; and if phenytoin dose adjustment is required, monitoring and further dose adjustments should be performed after discontinuation of omeprazole.

Unknown mechanism.

Saquinavir.

Concomitant use of omeprazole with saquinavir/ritonavir led to an increase in saquinavir plasma levels by approximately 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. If 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, medicinal products known to inhibit the activity of CYP2C19 or CYP3A4, or both enzymes (such as clarithromycin and voriconazole), may lead to increased omeprazole serum levels due to slowed metabolism. 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 in cases where long-term treatment is indicated.

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.

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 omeprazole serum 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) or in suspected or confirmed gastric ulcer, malignancy must be ruled out, as treatment may reduce symptom severity and delay diagnosis.

In healthy volunteers, a pharmacokinetic/pharmacodynamic interaction between clopidogrel (loading dose – 300 mg/day; maintenance dose – 75 mg/day) and omeprazole (80 mg orally per day, i.e., a dose four times higher than the standard daily dose) was observed, 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.

Concomitant use of atazanavir with proton pump inhibitors is contraindicated. 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 initiation or completion of omeprazole therapy, potential interactions with medicinal products metabolized by CYP2C19 should be considered. An interaction occurs 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.

Use of PPIs, particularly at high doses and for prolonged periods (>1 year), is associated with a slightly increased risk of fractures of the hip, wrist, and spine, primarily in elderly patients or those with other risk factors. According to study data, PPIs increase the overall fracture risk by 10–40%. In some cases, this is associated with the presence of other risk factors in the patient. Patients at risk of osteoporosis should receive appropriate treatment and adequate supplementation with vitamin D and calcium.

As with any long-term treatment, especially when the duration of omeprazole therapy exceeds 1 year, patients require medical supervision and regular laboratory monitoring of serum magnesium and calcium levels.

In patients taking PPIs, including omeprazole, for at least 3 months, significant hypomagnesemia may occur (in most cases, patients had been taking the drug for approximately 1 year).

After discontinuation of the drug, serum magnesium levels returned to normal. Clinical features of hypomagnesemia include increased neuromuscular excitability, manifested as carpopedal spasms, motor agitation; tachycardia, cardiac arrhythmias, elevated blood pressure; and dystrophic disorders such as trophic skin erosions and ulcers. The diagnostic criterion for hypomagnesemia is a serum magnesium concentration below 1 mEq/L. Additionally, cases have been reported where hypomagnesemia led to hypocalcemia due to suppressed parathyroid hormone secretion under conditions of low magnesium levels in the body. In some patients, severe hypocalcemia and hypomagnesemia were observed, with development of seizure syndrome, cardiac rhythm disturbances, tetany, psychiatric disorders, and severe vomiting, leading to electrolyte imbalance.

During treatment with antisecretory drugs, plasma gastrin concentration increases as a result of reduced hydrochloric acid secretion. Due to decreased acid secretion, chromogranin A (CgA) levels increase. Elevated CgA levels may interfere with diagnostic tests for neuroendocrine tumors. To prevent such interference, PPIs should be discontinued 5 days before measuring CgA levels. If CgA and gastrin levels have not returned to reference values after initial measurements, the tests should be repeated 14 days after discontinuation of PPI therapy.

Subacute cutaneous lupus erythematosus (SCLE)

PPI use may be associated with very rare cases of SCLE. If skin lesions develop, particularly on sun-exposed areas, and are accompanied by arthralgia, the patient should seek immediate medical attention, and the healthcare provider should consider discontinuing omeprazole. A history of SCLE following previous PPI treatment increases the risk of developing SCLE upon subsequent use of other PPIs.

Renal function impairment

Acute interstitial nephritis (AIN) has been observed in patients taking omeprazole and may occur at any time during omeprazole therapy (see section "Adverse reactions"). Acute interstitial nephritis may progress to renal failure.

If AIN is suspected, omeprazole should be discontinued immediately and appropriate treatment initiated without delay.

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

Use during pregnancy or breastfeeding

The efficacy and safety of omeprazole in pregnant women have not been established; therefore, the drug is not recommended during pregnancy.

Omeprazole passes into breast milk, but its effect on the infant is unknown; therefore, use of the drug is not recommended during breastfeeding.

Ability to affect reaction speed when driving or operating machinery

It is unlikely that omeprazole affects 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, Omenax® 40 mg is recommended to be administered intravenously once daily. For patients with Zollinger-Ellison syndrome, the recommended initial dose of Omenax® to be administered intravenously 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.

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

For intravenous injection, the contents of each Omenax® 40 mg vial should be dissolved in 10 mL of sterile water (or 0.9% sodium chloride solution) for injection. The solution for intravenous injection should be administered slowly (over 5 minutes).

Instructions for Reconstituting the Drug Prior to Administration

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

Preparation.

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

Alternative Method for Preparing the Infusion Solution in a Flexible Container.

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

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

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

Renal Impairment.

Dosage 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).

Dosage adjustment is not required in elderly patients.

Children.

Experience with intravenous administration of omeprazole in pediatric practice is limited; therefore, the drug should not be prescribed to this age 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 dose). Symptoms reported 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 serious consequences have been reported. 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, intravenous administration of up to 270 mg in a single day and up to 650 mg over 3 days did not result in any dose-dependent adverse reactions.

Adverse reactions.

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

The undesirable effects listed below were observed during clinical studies. None of these events were considered dose-dependent.

In isolated cases, irreversible vision impairment has been reported in critically ill patients receiving omeprazole as intravenous injection, especially at high doses; however, a causal relationship has not been established.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is very important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions through the national reporting system.

Shelf life. 2 years.

Storage conditions.

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

Storage period of the powder after opening: up to 24 hours at a temperature not exceeding 25 ºC.

Stability of reconstituted solution: up to 4 hours at a temperature not exceeding 25 ºC.

Incompatibilities.

The medicinal product must not be mixed with other medicinal products except those mentioned in the section “Posology and method of administration”.

Packaging.

1 vial containing powder in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

DEMO S.A. Pharmaceutical Industry.

Manufacturer’s address and location of operations.

21st km National Road Athens - Lamia, Kryoneri Attica, 14568, Greece.