Omez

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT OMZOL (OmZOL)

Composition:

Active substance: omeprazole;

One vial contains 42.6 mg of omeprazole sodium equivalent to 40 mg of omeprazole;

Excipients: sodium hydroxide, disodium edetate (EDTA).

Pharmaceutical form. Powder for solution for infusion.

Main physicochemical properties: the vial contains a porous and homogeneous lyophilized powder, white or almost white in color.

Pharmacotherapeutic group.
Agents 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 hydrochloric acid secretion 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 hydrochloric acid secretion.

Mechanism of action.

Omeprazole is a weak base. After entering the body, omeprazole accumulates and is converted into its active form in the highly acidic environment of secretory canaliculi of parietal cells—precisely where inhibition of the enzyme H⁺K⁺-ATPase (the proton pump) is required. This leads to suppression of both basal and stimulated gastric acid secretion.

Pharmacodynamic effects.

All pharmacodynamic effects can be explained by the effect of omeprazole on hydrochloric acid secretion.

Effect on gastric hydrochloric acid secretion.

Intravenous administration of omeprazole causes a dose-dependent inhibition of gastric hydrochloric 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 of intragastric acidity and sustained suppression of this parameter by approximately 90% over 24 hours, both after intravenous injection and intravenous infusion.

Inhibition of hydrochloric 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 moment.

No signs of tachyphylaxis have been observed during omeprazole treatment.

Effect on Helicobacter pylori.

In some cases, peptic ulcer disease is associated with the presence of H. pylori. H. pylori infection is a major 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 highly effective and leads to long-term remission of peptic ulcer disease.

Other effects related to inhibition of gastric hydrochloric 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. Treatment with proton pump inhibitors (PPIs) 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 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 fundic gland polyps has been reported. These changes are considered a physiological consequence of pronounced inhibition of hydrochloric acid secretion; the process is benign and likely reversible.

Reduction of gastric acidity by any means, including PPIs, increases the number of bacteria normally present in the gastrointestinal tract. Treatment with acid-reducing agents slightly increases the risk of gastrointestinal infections caused by Salmonella and Campylobacter.

Pharmacokinetics.

Distribution.

The estimated volume of distribution is approximately 0.3 L/kg 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 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 descent and 15–20% of individuals of Mongoloid descent lack functional CYP2C19 enzyme; these individuals are referred to as poor metabolizers. In these individuals, omeprazole metabolism may be predominantly catalyzed by CYP3A4. 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 (extensive metabolizers). Mean maximum plasma concentrations are 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 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. Nearly 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 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 effects of any metabolites on gastric hydrochloric acid secretion have been demonstrated.

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 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 not altered in patients with impaired renal function.

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

Clinical characteristics.

Indications.

• 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) associated with 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.
• Maintenance therapy in patients after treatment of reflux esophagitis.
• Symptomatic treatment of gastroesophageal reflux disease (GERD).
• Treatment of Zollinger–Ellison syndrome.

Contraindications.

Hypersensitivity to omeprazole, to other substituted benzimidazoles, or to any of the excipients of the medicinal product.

Omez, like other PPIs, should not be used concomitantly with nelfinavir or 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 decrease or increase the absorption of medicinal products whose absorption depends on gastric pH. As with other agents that reduce gastric 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 daily) and digoxin increased digoxin bioavailability by 10%.

Nelfinavir, atazanavir

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

Concomitant use of omeprazole and nelfinavir is contraindicated.

Concomitant use of omeprazole (40 mg once daily) reduced the average exposure to nelfinavir by approximately 40%, and the average 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 with atazanavir is not recommended.

Concomitant use of omeprazole (40 mg once daily) with atazanavir 300 mg or ritonavir 100 mg 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 use of omeprazole (20 mg once daily) with atazanavir 400 mg or ritonavir 100 mg resulted 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 daily) and digoxin increased digoxin bioavailability by 10%. Cases of digoxin toxicity have been rarely reported. However, caution should be exercised when prescribing high doses of omeprazole to elderly patients. Therapeutic drug monitoring of digoxin blood levels should be intensified.

Clopidogrel

In a crossover clinical study, clopidogrel (loading dose 300 mg followed by 75 mg daily) was administered alone and with omeprazole (80 mg administered simultaneously with clopidogrel) for 5 days. When clopidogrel and omeprazole were used together, exposure to the active metabolite of clopidogrel decreased by 46% (day 1) and by 42% (day 5). Mean inhibition of platelet aggregation decreased by 47% (at 24 hours) and by 30% (day 5) when clopidogrel and omeprazole were administered together. Another study demonstrated that administering clopidogrel and omeprazole at different times did not eliminate their interaction, likely due to omeprazole's inhibitory effect on CYP2C19. Clinical studies have yielded conflicting data regarding the clinical significance of this pharmacokinetic/pharmacodynamic interaction in terms of major cardiovascular events. As a precautionary measure, concomitant use of omeprazole and clopidogrel should be avoided.

Other medicinal products

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

In a study evaluating clopidogrel use in combination with aspirin and omeprazole versus clopidogrel monotherapy, exposure to the active metabolite of clopidogrel was reduced by nearly 40%. However, maximum inhibitory activity against (ADP-induced) platelet aggregation was similar in groups receiving clopidogrel alone or in combination with aspirin and omeprazole, likely due to the concomitant administration of low-dose aspirin.

Cilostazol

In a crossover study, administration of omeprazole 40 mg increased 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 2 weeks after initiating omeprazole treatment. If phenytoin dose adjustment is required, monitoring and further dose adjustments should continue after discontinuation of omeprazole therapy.

Unknown mechanism

Saquinavir

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

Tacrolimus

Increased blood levels of tacrolimus have been reported with concomitant use of omeprazole. Intensified monitoring of tacrolimus concentrations, as well as renal function (creatinine clearance), is required, and dose adjustment of tacrolimus may be necessary.

Increased methotrexate levels have been reported in some patients receiving concomitant PPIs. 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 enzymes, medicinal products that inhibit the activity of CYP2C19 or CYP3A4, or both enzymes (such as clarithromycin and voriconazole), may cause increased omeprazole serum levels due to slowed metabolism. Concomitant use of voriconazole resulted in more than a two-fold 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 for 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 that induce the activity of CYP2C19 or CYP3A4, or both enzymes (such as rifampicin and St. John's wort), may cause decreased omeprazole serum levels due to accelerated metabolism.

Special precautions.

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 excluded, as treatment may alleviate symptoms and delay diagnosis.

Concomitant use of atazanavir with PPIs is not recommended. If co-administration of atazanavir with a PPI cannot be avoided, careful clinical monitoring (e.g., viral load measurement) is recommended, along with increasing the dose of atazanavir to 400 mg with 100 mg ritonavir; the dose of omeprazole 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 treatment, potential interactions with drugs 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.

PPI therapy slightly increases the 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 remain undiagnosed for some time. In most patients, symptoms of hypomagnesemia resolve and magnesium 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.

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

Some published studies have found that PPI therapy may be associated with a small increased risk of osteoporosis-related fractures. 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 developing osteoporosis should receive appropriate management according to current clinical guidelines and should take vitamin D and calcium at recommended doses.

However, other similar observational studies have not detected an increased risk.

Studies with omeprazole and esomeprazole have not shown an association between PPI use and osteoporotic fractures.

Despite the fact that a causal relationship between omeprazole/esomeprazole and osteoporotic fractures has not been proven, patients at risk of progressive osteoporosis or osteoporotic fractures are recommended to undergo appropriate clinical monitoring according to current clinical guidelines for this condition.

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 immediately consult a physician and discontinuation of omeprazole should be considered. A history of SCLE following PPI use may increase the risk of developing SCLE when using other PPIs.

Omeprazole may cause serious skin reactions, symptoms of which may include: skin redness, blisters, rash.

Serious skin adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis, have been reported rarely and very rarely during omeprazole treatment and may be life-threatening or even fatal.

Renal function impairment

Acute tubulointerstitial nephritis (TIN) has been observed in patients taking omeprazole and may occur at any time during omeprazole therapy (see section "Special precautions"). Acute tubulointerstitial nephritis may progress to renal failure.

If TIN is suspected, omeprazole should be discontinued and appropriate treatment initiated immediately.

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 stopping the drug.

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

Use during pregnancy or breastfeeding.

Research findings indicate no adverse effects of omeprazole on pregnancy or fetal/neonatal health. Omeprazole may be used during pregnancy.

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

Ability to affect reaction speed when driving or operating machinery.

It is unlikely that the medicinal product affects the ability to drive or operate machinery.

However, considering that adverse reactions (dizziness, somnolence, hallucinations, reversible confusion) may occur in sensitive patients during treatment, such patients should refrain from driving or operating machinery requiring concentration during treatment.

Method of Administration and Dosage

Dosage

Alternative to Oral Therapy

For patients for whom oral formulation 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 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 into two equal parts and administered twice daily.

The drug 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 3 hours after preparation. The diluted omeprazole solution must not be refrigerated. Unused solution should be discarded.

Instructions for Reconstitution Prior to Administration

For Intravenous Infusion: Reconstitute the contents of each vial containing 40 mg omeprazole with 10 mL, 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 drug should be administered as an intravenous infusion over 20–30 minutes.

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

The solution must be used immediately after preparation, but no later than 3 hours after preparation. The diluted omeprazole solution must not be refrigerated.

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 of age)

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). Symptoms such as nausea, vomiting, dizziness, abdominal pain, diarrhea, and headache have been observed. In isolated 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.

In case of necessity, 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 three days 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.

The following adverse drug reactions were identified during clinical studies. None of these events were considered dose-dependent.

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 (≥1/10000 to <1/1000), very rare (<1/10000), not known (cannot be estimated from available data).

Body systems	Adverse reactions
Blood and lymphatic system	rare: leucopenia, thrombocytopenia very rare: agranulocytosis, pancytopenia
Immune system	rare: hypersensitivity reactions, including fever, angioedema, and anaphylactic reactions/shock
Metabolism and nutrition	rare: hyponatremia very rare: hypomagnesemia; severe hypomagnesemia may lead to hypocalcemia; hypomagnesemia may also cause hypokalemia
Psychiatric	uncommon: insomnia, rare: agitation, confusion, depression very rare: aggression, hallucinations
Nervous system	common: headache uncommon: dizziness, paraesthesia, somnolence rare: taste disturbance
Eye disorders	rare: blurred vision
Ear and labyrinth disorders	uncommon: vertigo
Respiratory, thoracic and mediastinal system	rare: bronchospasm
Gastrointestinal system	common: abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting, fundic gland polyps (benign) rare: dry mouth, stomatitis, gastrointestinal candidiasis, microscopic colitis
Hepatobiliary system	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	uncommon: dermatitis, pruritus, rash, urticaria rare: alopecia, photosensitivity very rare: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis frequency unknown: subacute cutaneous lupus erythematosus
Musculoskeletal, connective tissue and bone	uncommon: fractures of hip, wrist or spine rare: arthralgia, myalgia very rare: muscle weakness
Renal and urinary system	rare: tubulointerstitial nephritis (with possible progression to renal failure)
Reproductive system and breast	very rare: gynecomastia
General disorders and administration site reactions	uncommon: malaise, peripheral edema, increased sweating

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

Reporting of adverse reactions following marketing authorization is of significant importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage period after reconstitution:

The chemical and physical stability of the reconstituted solution has been demonstrated for 12 hours at 25 °C after dilution with 0.9 % sodium chloride solution, and for 6 hours after dilution with 5 % glucose solution. From a microbiological standpoint, the reconstituted solution should be used immediately, unless reconstitution has been carried out under controlled and aseptic conditions, validated by appropriate methods.

Storage conditions.

Keep the vial in the outer carton at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Incompatibilities. This medicinal product must not be mixed with other solvents or diluents than those specified in the section “Dosage and administration”.

Packaging.

1 or 10 vials per carton.

Prescription status. Prescription only.

Manufacturer.

Sofarimex – Industria Quimica e Farmaceutica, S.A.
Sofarimex – Chemical and Pharmaceutical Industry, S.A.

Manufacturer's address and place of business.

Av. das Industrias – Alto do Colaride, Cacem, 2735-213, Portugal
Av. das Industrias – Alto do Colaride, Cacem, 2735-213, Portugal.