Omeprazole-farmak

№ UA/18270/01/01 INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT OMEPRAZOLE-FARMAK

Composition:

active substance: omeprazole;

1 vial contains 42.6 mg of omeprazole sodium, 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 and homogeneous lyophilized powder.

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 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 accumulates and is converted into its active form in the acidic environment of the intracellular canaliculi of parietal cells, where it inhibits the H+/K+-ATPase enzyme—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 results in a dose-dependent inhibition of gastric hydrochloric acid secretion in humans. To achieve immediately the same degree of intragastric acidity reduction as with repeated oral administration of 20 mg, an initial intravenous dose of 40 mg is recommended. This leads to immediate reduction in 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 actual plasma concentration at any given time.

No tachyphylaxis has been observed during omeprazole treatment.

Effect on Helicobacter pylori (H. pylori)

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

Other Effects Related to Acid Suppression

During long-term treatment, a slightly increased incidence 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 may lead to a slightly increased risk of gastrointestinal infections, such as those caused by Salmonella and Campylobacter, and in hospitalized patients, possibly also those caused by Clostridium difficile.

During treatment with antisecretory agents, plasma gastrin concentrations increase as a result of reduced hydrochloric acid secretion. Due to reduced hydrochloric acid secretion, chromogranin A (CgA) levels 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.

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 isoform, CYP3A4, responsible for the formation of omeprazole sulfone. Due to omeprazole's high affinity for CYP2C19, competitive inhibition and metabolic interactions between drugs that are substrates for CYP2C19 are possible. However, due to its low affinity for CYP3A4, omeprazole is not capable of inhibiting the metabolism of other CYP3A4 substrates. Furthermore, omeprazole does not exert inhibitory effects on the main 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 primarily catalyzed 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. These data have no implications for omeprazole dosing.

Elimination

Total plasma clearance is approximately 30–40 L/hour after a single dose. The plasma half-life of omeprazole is typically less than 1 hour, both after single and repeated once-daily dosing. 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, the remainder via biliary secretion in feces.

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-dependence 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 conditions.

Adults:

• Treatment of duodenal ulcers;
• Prevention of recurrence of duodenal ulcers;
• Treatment of gastric ulcers;
• Prevention of recurrence of gastric ulcers;
• In combination with appropriate antibiotics for eradication of Helicobacter pylori (H. pylori) in peptic ulcer disease;
• Treatment of NSAID-associated gastric and duodenal ulcers;
• Prevention of NSAID-associated gastric and duodenal ulcers in patients at risk;
• Treatment of reflux esophagitis;
• Long-term management of patients with healed reflux esophagitis;
• Treatment of symptomatic gastroesophageal reflux disease;
• 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 PPIs, must not be used concomitantly with nelfinavir (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 acid 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) reduced the mean AUC of nelfinavir by approximately 40% and the mean AUC of its pharmacologically active metabolite M8 by 75–90%. The interaction may also be due to inhibition of CYP2C19 activity.

Concomitant use of omeprazole with atazanavir is not recommended. Co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg in healthy volunteers resulted in a 75% reduction in atazanavir AUC. Increasing the atazanavir dose to 400 mg did not compensate for the effect of omeprazole on atazanavir AUC. 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 AUC 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%. Cases of digoxin toxicity have been rarely reported. However, caution should be exercised when prescribing high doses of omeprazole to elderly patients. Therapeutic monitoring of digoxin should be intensified.

Clopidogrel

A pharmacokinetic (PK)/pharmacodynamic (PD) interaction between clopidogrel (loading dose 300 mg / maintenance dose 75 mg daily) and omeprazole (80 mg daily orally) was observed in healthy volunteers, resulting in a mean 46% reduction in AUC of the active metabolite of clopidogrel and a mean 16% reduction in maximum inhibitory effect (ADP-induced) on platelet aggregation.

Conflicting data on the clinical significance of this PK/PD interaction regarding major cardiovascular events have been reported in observational and clinical studies. 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 with posaconazole and erlotinib should be avoided.

Medicinal products metabolized by CYP2C19

Omeprazole exerts a moderate inhibitory effect on 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.

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

Mechanism unknown

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

MTX (Methotrexate)

Elevated 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 known to inhibit the activity of CYP2C19 or CYP3A4 (such as clarithromycin and voriconazole) may lead to increased omeprazole serum levels due to reduced metabolic rate. Concomitant administration of voriconazole resulted in more than a two-fold increase in omeprazole AUC. 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 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, frequent vomiting, dysphagia, hematemesis, or melena) or in patients with diagnosed or suspected gastric ulcer, malignancy should be ruled out, as treatment with the drug may mask symptoms and delay correct diagnosis.

Concomitant use of atazanavir with proton pump inhibitors (PPIs) is not recommended. If co-administration of atazanavir with omeprazole 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 inhibit gastric acid secretion, may reduce absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with low body weight or risk factors for reduced vitamin B12 absorption during long-term therapy.

Omeprazole is an inhibitor of CYP2C19. At the beginning or end of omeprazole treatment, potential interactions with medicinal products metabolized 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 is associated with a slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter, and possibly also Clostridium difficile in hospitalized patients.

Severe hypomagnesemia has been reported in patients treated with PPIs, including omeprazole, for at least 3 months (in most cases, hypomagnesemia occurred after approximately 1 year of treatment). Hypomagnesemia may manifest as serious symptoms such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias. Hypomagnesemia may also be asymptomatic and may therefore remain undiagnosed for some time. In most patients, symptoms resolve and magnesium levels normalize after magnesium supplementation and discontinuation of PPI therapy.

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 initiating PPI therapy and periodically during treatment.

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

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

Subacute cutaneous lupus erythematosus (SCLE)

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

Renal function 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 and appropriate treatment initiated immediately.

Effect on laboratory test results

Elevated chromogranin A (CgA) levels may interfere with diagnostic tests for neuroendocrine tumors. To avoid this interference, omeprazole should be temporarily discontinued 5 days before CgA measurement. If CgA and gastrin levels do not return to normal reference ranges after initial testing, measurements should be repeated 14 days after discontinuation of the drug.

Patients receiving long-term treatment (especially longer than 1 year) should be under regular medical supervision.

This medicinal product contains less than 1 mmol/dose (23 mg/dose) of sodium, 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/newborn health. Omeprazole may be used during pregnancy.

Breastfeeding

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

Fertility

Studies in animals using the racemic mixture of omeprazole showed no effect on fertility.

Ability to affect reaction speed when driving or operating machinery

Omeprazole-Farmak is unlikely to affect the ability to drive or operate machinery. Adverse reactions such as dizziness and visual disturbances may occur. If such effects occur, patients should refrain from driving or operating machinery.

Administration and Dosage

Dosage

Alternative to Oral Therapy

For patients for whom oral administration of the drug is unsuitable, intravenous 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 must be administered intravenously only and must not be given by any other route.

The solution must be used immediately after preparation, but no later than within 3 hours. The diluted omeprazole solution must not be stored in a refrigerator. Any unused solution should be discarded.

Instructions for Reconstitution Prior to Administration

For Intravenous Infusion: 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. Use either 9 mg/mL (0.9 %) sodium chloride solution for infusion or 50 mg/mL (5 %) glucose solution for infusion. The stability of omeprazole depends on the pH of the infusion solution; therefore, other solvents or volumes must not be used for dilution. After reconstitution, the solution should be colorless, clear, and practically free from visible particles.

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

The solution must be used immediately after preparation, but no later than within 3 hours. The diluted omeprazole solution must not be stored in a refrigerator.

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

Special Patient Populations

Renal Impairment

Dose adjustment is not required in patients with renal impairment.

Hepatic Impairment

In patients with hepatic impairment, a daily dose of 10–20 mg may be sufficient.

Elderly Patients (>65 years)

Dose adjustment is not required in elderly patients.

Children

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

Overdose

Very limited data are available regarding the effects of omeprazole overdose in humans. Doses up to 560 mg of omeprazole have been reported in the literature, and there have been isolated reports of single oral doses reaching 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 have been reported. Elimination rate of the drug did not change (first-order kinetics) with increasing dose. Symptomatic treatment should be administered if necessary.

In clinical studies, intravenous administration of omeprazole at doses 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 common adverse effects (in 1–10% of patients) are headache, abdominal pain, constipation, diarrhea, bloating, and nausea/vomiting.

During clinical trials of omeprazole or post-marketing use, the following adverse reactions have been identified (or suspected). These were found not to be dose-dependent. Adverse reactions are classified into groups according to their frequency and affected organ or body system, and are categorized by frequency as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data).

MedDRA SOC / frequency	Adverse reaction
Blood and lymphatic system disorders
Uncommon	Leukopenia, thrombocytopenia
Very rare	Agranulocytosis, pancytopenia
Immune system disorders
Uncommon	Hypersensitivity reactions, including fever, angioedema, and anaphylactic reactions/shock
Metabolism and nutrition disorders
Uncommon	Hypnatremia
Frequency unknown	Hypomagnesemia; severe hypomagnesemia may lead to hypocalcemia. Hypomagnesemia, which may result in hypokalemia
Psychiatric disorders
Uncommon	Insomnia
Uncommon	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, diarrhoea, flatulence, nausea/vomiting, fundic gland polyps (benign)
Rare	Dry mouth, stomatitis, gastrointestinal candidiasis
Frequency unknown	Microscopic colitis
Hepatobiliary disorders
Uncommon	Elevated 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, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS)
Very rare	Multiform erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis
Frequency unknown	Subacute cutaneous lupus erythematosus
Musculoskeletal and connective tissue disorders
Uncommon	Femur, wrist or spine fractures
Rare	Arthralgia, myalgia
Very rare	Muscle weakness
Renal and urinary disorders
Rare	Tubulointerstitial nephritis (with possible progression to renal failure)
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 vision 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 suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should 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.

Do not use the medicinal product after the expiry date stated on the packaging.

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

Keep out of reach and sight of children.

Incompatibilities

This medicinal product must not be mixed with solvents other than those specified in the section "Instructions for use and dosage".

Packaging. 1 vial per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak" (processing of bulk product manufactured by Laboratorios Normon S.A., Spain).

Manufacturer's address and location of operation.
74 Kyrylivska Street, Kyiv, 04080, Ukraine