Omeprazole-darnitsa

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT OMEPRAZOLE-DARNITSA (OMEPRASOLE-DARNITSA)

Composition:

Active substance: omeprazole;

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

Excipients: disodium edetate, sodium hydroxide.

Pharmaceutical form. Powder for solution for infusion.

Main physicochemical properties: white or almost white, porous, homogeneous lyophilized 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 is a racemic mixture of two enantiomers that reduces gastric acid secretion through a targeted mechanism of action. It is a specific inhibitor of the gastric proton pump (PPI) in parietal cells. It acts rapidly and causes controlled, reversible inhibition of gastric acid secretion when administered once daily.

Omeprazole is a weak base that concentrates and is converted into its active form in the acidic environment of intracellular canaliculi of parietal cells, where it inhibits the enzyme H⁺/K⁺-ATPase—the "acid pump." This effect on the final stage of gastric acid production is dose-dependent and provides highly effective suppression of both basal and stimulated acid secretion, regardless of the nature of the stimulus.

Pharmacodynamic effects

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

Effect on gastric acid secretion

Intravenous administration of omeprazole causes dose-dependent inhibition of gastric hydrochloric acid secretion in humans. To achieve immediately the same degree of intragastric acid suppression as with repeated oral administration of 20 mg, an initial intravenous dose of 40 mg is recommended. This results in immediate reduction of intragastric acidity and an average reduction of 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, rather than with the current plasma concentration.

No tachyphylaxis has been observed during treatment with omeprazole.

Effect on Helicobacter pylori (H. pylori)

Peptic ulcer disease, including duodenal ulcer and gastric ulcer, is associated with H. pylori and is considered a major factor in the development of gastritis. Together with gastric acid, H. pylori is a key 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 a high healing rate and long-term remission of peptic ulcers.

Other effects related to acid inhibition

During long-term treatment, a slightly increased frequency of gastric glandular cysts has been reported. These changes are a physiological consequence of acid secretion inhibition; the cysts are benign and reversible.

Reduced gastric acidity, caused by any agent 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, such as those caused by Salmonella and Campylobacter bacteria.

During treatment with antisecretory drugs, plasma gastrin concentration increases as a result of reduced hydrochloric acid secretion. Due to reduced hydrochloric acid secretion, levels of chromogranin A (CgA) increase. Elevated CgA levels may interfere with diagnostic tests for neuroendocrine tumors. Available published data suggest that PPI therapy should be discontinued 5 to 14 days before planned CgA measurements. This allows CgA levels, which may be falsely elevated during PPI use, to return to reference values.

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.

Pharmacokinetics.

Distribution

The apparent volume of distribution in healthy volunteers is approximately 0.3 L/kg body weight. Omeprazole is 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. Another part depends on another specific isoenzyme, CYP3A4, responsible for the formation of omeprazole sulfone. Due to omeprazole's high affinity for CYP2C19, competitive inhibition and metabolic interactions may occur between drugs that are substrates for CYP2C19. However, due to its low affinity for CYP3A4, omeprazole is not capable of inhibiting the metabolism of other CYP3A4 substrates. In addition, omeprazole does not inhibit the major CYP enzymes.

Approximately 3% of individuals of Caucasian descent and 15–20% of individuals of Mongoloid descent have a deficiency of functional CYP2C19 enzyme and are therefore referred to as "poor metabolizers." In these individuals, omeprazole metabolism is likely catalyzed mainly by CYP3A4. After repeated administration of 20 mg omeprazole once daily, the AUC in "poor metabolizers" was 5–10 times higher than in patients with functional CYP2C19 enzyme ("extensive metabolizers"). Mean peak plasma concentrations were 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 dosing. Omeprazole is completely cleared from plasma between doses, with no tendency toward accumulation when administered once daily. Nearly 80% of the dose is excreted in urine as metabolites; the remainder is excreted in feces via biliary secretion.

Linearity/Non-linearity

The AUC of omeprazole increases with repeated administration. This increase is dose-dependent and results in a non-linear relationship between AUC and dose after repeated dosing. This time- and dose-dependent effect is due to reduced first-pass metabolism and systemic clearance, likely caused by omeprazole and/or its metabolites (e.g., sulfone) inhibiting the CYP2C19 enzyme.

No effects of omeprazole metabolites on gastric acid secretion have been observed.

Special patient groups

Hepatic impairment

Omeprazole metabolism is impaired in patients with hepatic dysfunction, leading to increased AUC. Omeprazole did not show a tendency to accumulate when administered once daily.

Renal impairment

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

Elderly patients

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

Clinical characteristics.

Indications.

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

Adults:

• for the treatment of duodenal ulcers;
• for the prevention of recurrence of duodenal ulcers;
• for the treatment of gastric ulcers;
• for the prevention of recurrence of gastric ulcers;
• in combination with appropriate antibiotics for eradication of H. pylori in peptic ulcer disease;
• for the treatment of gastric and duodenal ulcers associated with use of nonsteroidal anti-inflammatory drugs (NSAIDs);
• for the prevention of gastric and duodenal ulcers associated with NSAID use in patients at risk;
• for the treatment of reflux esophagitis;
• for long-term management of patients with inactive reflux esophagitis;
• for the treatment of symptomatic gastroesophageal reflux disease;
• for the treatment of Zollinger-Ellison syndrome.

Contraindications.

Hypersensitivity to the active substance, substituted benzimidazoles, or to any of the excipients of the medicinal product.

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

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

Nelfinavir, atazanavir

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

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

Concomitant use of omeprazole and atazanavir is not recommended. Coadministration 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 administration of omeprazole (20 mg daily) and digoxin in healthy volunteers increased the bioavailability of digoxin 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 monitoring of digoxin should be intensified.

Clopidogrel

In healthy volunteers, a pharmacokinetic (PK)/pharmacodynamic (PD) interaction was observed between clopidogrel (loading dose 300 mg/daily maintenance dose 75 mg) and omeprazole (80 mg daily orally), 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.

Results from observational and clinical studies on the clinical outcomes of this PK/PD interaction regarding major cardiovascular events have been conflicting. Concomitant use of omeprazole and clopidogrel should be avoided.

Other medicinal products

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

Medicinal products metabolized by CYP2C19

Omeprazole moderately inhibits CYP2C19 (the main enzyme responsible for omeprazole metabolism). Therefore, 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.

Cilostazol

In healthy volunteers, administration of omeprazole 40 mg increased the maximum plasma concentration (Cmax) and AUC of cilostazol by 18% and 26%, respectively, and of one of its active metabolites by 29% and 69%, respectively.

Phenytoin

Monitoring of phenytoin plasma concentrations is recommended during the first two weeks after initiation of omeprazole therapy. If phenytoin dosage adjustment is required, monitoring and further dose adjustments should continue after discontinuation of omeprazole treatment.

Unknown mechanism

Saquinavir

Concomitant administration 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 serum levels of tacrolimus have been reported with concomitant use of omeprazole. Intensified monitoring of tacrolimus concentrations and renal function (creatinine clearance) is required, with dose adjustment of tacrolimus if necessary.

MTX (methotrexate)

Elevated methotrexate levels have been reported in some patients when coadministered with 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 that inhibit the activity of CYP2C19 or CYP3A4 (such as clarithromycin and voriconazole) may lead to increased omeprazole plasma levels due to reduced metabolic rate. Concomitant administration 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.

Inducers of CYP2C19 and/or CYP3A4

Medicinal products that induce the activity of CYP2C19 and/or CYP3A4 (such as rifampicin and St. John's wort) may lead to decreased omeprazole plasma levels due to accelerated metabolism.

Special precautions for use.

Omeprazole may cause serious skin reactions. Symptoms may include: redness of the skin, blisters, and/or rash.

If an allergic reaction occurs, discontinue use of the medicinal product and seek immediate medical attention.

In the presence of any alarming symptoms (e.g., significant unintentional weight loss; frequent vomiting; dysphagia; hematemesis or melena) and in diagnosed or suspected gastric ulcer, malignancy must be ruled out, as treatment with this medicinal product may mask symptoms and delay correct diagnosis.

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

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

Omeprazole is a CYP2C19 inhibitor. When starting or stopping 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.

PPI treatment 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 present with serious symptoms such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias. Hypomagnesemia may also be asymptomatic and thus may not be promptly diagnosed. In most patients, symptoms resolve and magnesium levels normalize after magnesium supplementation and discontinuation of the PPI.

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

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

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 PPI use increases the risk of developing SCLE with other PPIs.

Renal function impairment

Acute tubulointerstitial nephritis (ATIN) has been reported in patients taking omeprazole, occurring at any time during therapy (see section "Adverse reactions"). ATIN 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 tests for detecting neuroendocrine tumors. To avoid this interference, omeprazole should be temporarily discontinued at least 5 days before measuring CgA levels.

Patients undergoing long-term treatment (particularly if therapy exceeds 1 year) should be under regular medical supervision.

Important information on excipients.

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

Use during pregnancy or breastfeeding.

Pregnancy

Data from prospective epidemiological studies indicate no adverse effects of omeprazole on pregnancy or fetal/neonatal health. Omeprazole may be used during pregnancy.

Breastfeeding

Omeprazole passes into breast milk, but the likelihood of effects on the infant is low when used at therapeutic doses.

Fertility

Animal studies with the racemic mixture of omeprazole showed no effect on fertility.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

Adults

Alternative to Oral Therapy

For patients for whom oral administration of the medicinal product is not feasible, intravenous administration of omeprazole 40 mg once daily is recommended. For patients with Zollinger–Ellison syndrome, the recommended initial dose 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 into two equal parts and administered twice daily.

The medicinal product should be administered only by intravenous infusion over 20–30 minutes; it must not be given by any other route.

Reconstitution of the Medicinal Product Prior to Administration

For intravenous infusions, the contents of each vial containing 40 mg of omeprazole should be dissolved in approximately 5 mL of solvent and then immediately diluted to a final volume of 100 mL. A 9 mg/mL (0.9%) sodium chloride infusion solution or a 50 mg/mL (5%) glucose infusion solution should be used. The stability of omeprazole depends on the pH of the infusion solution; therefore, other solvents or volumes must not be used for dilution.

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 of the medicinal product 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, Omeprazole-Darnitsia should not be administered to this patient population.

Overdose.

Data on the effects of omeprazole overdose in humans are limited. Cases of doses up to 560 mg of omeprazole have been reported in scientific publications, and there have been isolated reports of single oral doses of omeprazole up to 2400 mg (120 times higher than the usual recommended clinical dose). Symptoms reported include nausea, vomiting, dizziness, abdominal pain, diarrhea, and headache. In isolated cases, lethargy, depression, and confusion have also been reported. However, all these symptoms were transient, and no serious consequences were reported. The elimination rate of the drug was not altered (first-order kinetics) with increasing dose. In case of overdose, symptomatic treatment should be administered.

In clinical studies, intravenous administration of the medicinal product at doses up to 270 mg in one day and up to 650 mg over three days did not result in any dose-dependent adverse reactions.

Adverse reactions.

The most common adverse effects (in 1–10 % of patients) are headache, abdominal pain, constipation, diarrhoea, bloating and nausea/vomiting.

During clinical trials of omeprazole or post-marketing use, the following adverse drug reactions have been reported (or suspected). These were found not to be dose-dependent. All adverse reactions are listed by system organ classes and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Eye disorders: rare — blurred vision.

Ear and labyrinth disorders: uncommon — vertigo.

Respiratory, thoracic and mediastinal disorders: rare — bronchospasm.

Gastrointestinal disorders: common — abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting; rare — dry mouth, stomatitis, gastrointestinal candidiasis; frequency not known — 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.

Renal and urinary disorders: rare — interstitial nephritis; frequency not known — tubulointerstitial nephritis (with possible progression to renal failure).

Metabolism and nutrition disorders: rare — hyponatraemia; frequency not known — hypomagnesaemia, severe hypomagnesaemia may lead to hypocalcaemia. Hypomagnesaemia may cause hypokalaemia.

Nervous system disorders: common — headache; uncommon — dizziness, paraesthesia, somnolence; rare — taste disturbance.

Psychiatric disorders: uncommon — insomnia; rare — agitation, confusion, depression; very rare — aggression, hallucinations.

Blood and lymphatic system disorders: rare — leucopenia, thrombocytopenia; very rare — agranulocytosis, pancytopenia.

Immune system disorders: rare — hypersensitivity reactions, including fever, angioedema and anaphylactic reactions/shock.

Skin and subcutaneous tissue disorders: uncommon — dermatitis, pruritus, rash, urticaria; rare — photosensitivity, alopecia; very rare — Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme; 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.

Reproductive system and breast disorders: very rare — gynaecomastia.

General disorders and administration site conditions: uncommon — malaise, peripheral oedema; rare — increased sweating.

In isolated cases, irreversible visual disturbances have been reported in seriously ill patients receiving omeprazole as intravenous injection, particularly at high doses, but a causal relationship has not been established.

Reporting of suspected adverse reactions.

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

Shelf life. 2 years.

Storage conditions.

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

Keep out of the reach and sight of children.

Incompatibilities (if applicable).

Do not mix with other solvents except those specified in the section "Directions for use and dosage".

Packaging. 1 vial per pack.

Prescription status. Prescription only.

Manufacturer. Laboratorios Normon S.A., Spain.

Manufacturer's address.

Ronda de Valdecarrizo, 6, Tres Cantos, 28760, Spain.

Marketing Authorisation Holder.

JSC "Pharmaceutical company "Darnytsia".

Address of the Marketing Authorisation Holder.

13, Boryspilska Street, Kyiv, 02093, Ukraine.