OMETREN

Composition

active substance: omeprazole;
1 vial contains 42.6 mg of omeprazole sodium, which is equivalent to 40 mg of omeprazole;
excipient: sodium hydroxide;
1 ampoule of solvent contains: macrogol 400, citric acid monohydrate, water for injection.

Pharmaceutical form

Powder and solvent for solution for injection.
Main physical and chemical properties: white or almost white ‘briquette’ in a colourless vial. After dissolution: clear liquid, colourless to pale yellowish, free of particles.
Solvent ampoule: a colourless glass ampoule containing 10 ml of colourless, clear solution for injection.

Pharmacotherapeutic group

Medicines for the treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors. ATC code А02В С01.

Pharmacological properties

Pharmacodynamics.
Mechanism of action
Omeprazole, a racemic mixture of two enantiomers reduces gastric acid secretion through a highly targeted mechanism of action. Omeprazole is a specific inhibitor of the gastric proton pump (GPP) in parietal cells. Its effect on acid secretion is rapid and reversibly inhibits gastric acid secretion by single-dose treatment per day.
Omeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the intracellular canaliculi within the parietal cell, where it inhibits the enzyme Н⁺, К⁺-ATPase (proton pump). This effect at the final step of the gastric acid formation process is dose-dependent and provides for highly effective inhibition of both basal and stimulated hydrochloric acid secretion, regardless of the type of stimulation.
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 suppression of hydrochloric acid secretion in the human stomach. In order to immediately achieve a similar reduction of intragastric acidity as after repeated dosing with 20 mg orally, a first dose of 40 mg intravenously is recommended. This leads to an immediate decrease in intragastric acidity and further maintenance of this decrease by an average of 90% within 24 hours both after intravenous injection and after intravenous infusion.
Inhibition of hydrochloric acid secretion is associated with the area under the concentration-time curve (AUC) of omeprazole and does not depend on the actual concentration of omeprazole in the blood plasma at a given time.
No tachyphylaxis has been observed during treatment with omeprazole.
Effect on Helicobacter pylori
Helicobacter pylori is associated with peptic ulcer disease, including duodenal and gastric ulcer disease. Helicobacter pylori is a major factor in the development of atrophic gastritis which is associated with an increased risk of developing gastric cancer.
Eradication of Helicobacter pylori with omeprazole and antimicrobial drugs provides that rapidly healing of mucosal lesions and long-term remission of peptic ulcer disease.
Other effects associated with inhibition of hydrochloric acid secretion in the stomach
During long-term treatment, an increased incidence of gastric glandular cysts has been reported. These changes are the result of a pronounced inhibition of hydrochloric acid secretion and are benign and reversible.
During treatment with antisecretory medicines, serum gastrin levels increase in response to decreased acid secretion. Also, the level of chromogranin A (CgA) increases due to decreased gastric acidity. Elevated CgA levels can interfere with the study of neuroendocrine tumors. To prevent this effect, you should stop taking a proton pump inhibitor (PPI) 5 days before the CgA test. If the levels of chromogranin A and gastrin have not returned to the reference values after the initial measurements, the measurements should be repeated 14 days after discontinuation of omeprazole therapy.
During long-term treatment with omeprazole, an increase in the number of Entero chromaffin-like (ECL) cells in some patients (in children and adults), probably associated with increased serum gastrin levels, was observed. It is thought that the findings do not have a clinical meaning.
Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with acid-reducing medicines may lead to a slightly increased risk of developing digestive tract infections caused by Salmonella and Campylobacter.
Pharmacokinetics.
Distribution
The estimated volume of distribution in healthy subjects is approximately 0.3 l/kg body weight. Omeprazole is about 97% bound to plasma proteins.
Metabolism
Omeprazole is completely metabolised by the cytochrome P450 system (CYP). The major part of its metabolism is dependent on the polymorphically expressed CYP2C19, responsible for the formation of hydroxyomeprazole, the major metabolite in plasma. The remaining part is dependent on another specific isoform (CYP3A4), responsible for the formation of omeprazole sulphone. As a consequence of high affinity of omeprazole to CYP2C19, there is a potential for competitive inhibition and metabolic drug-drug interactions with other substrates for CYP2C19. However, due to low affinity to CYP3A4, omeprazole has no potential to inhibit the metabolism of other CYP3A4 substrates. In addition, omeprazole lacks an inhibitory effect on the main CYP enzymes.
Approximately 3% of the Caucasian race and 15-20% of the Mongolian race lack a functional CYP2C19 enzyme and are called “poor metabolisers”. In such individuals the metabolism of omeprazole is probably mainly catalysed by CYP3A4. After repeated once-daily administration of 20 mg omeprazole, the mean AUC was 5 to 10 times higher in “poor metabolisers” than in subjects having a functional CYP2C19 enzyme (“extensive metabolisers”). Mean peak plasma concentrations were also higher, by 3 to 5 times. These findings have no implications for the posology of omeprazole.
Elimination
Total plasma clearance is about 30-40 l/h after a single dose. The plasma elimination half-life of omeprazole is usually shorter than one hour both after single and repeated once-daily dosing. Omeprazole is completely eliminated from plasma between doses with no tendency for accumulation during once-daily administration. Almost 80% of the dose of omeprazole is excreted in the form of metabolites in the urine, and the rest is excreted in the feces, mainly by secretion with bile.
The area under the curve (AUC) in the plasma-time measurement of omeprazole is increased by repeated applications. This increase is dose-dependent and results in a non-linear dose-AUC relationship after repeated administration. That possibly due to a decrease in systemic cleavage caused by inhibition of CYP2C19 enzyme by omeprazole and / or its metabolites (eg, sulfone). No metabolite has been found to have any effect on gastric acid secretion.
Special patient groups
Patients with hepatic impairment
The metabolism of omeprazole in patients with hepatic impairment is slowed, which leads to an increase in AUC. When omeprazole was administered once daily, no tendency to accumulate the drug was observed.
Patients with impaired renal function
The pharmacokinetics of omeprazole, including systemic bioavailability and elimination rate, are unchanged in patients with reduced renal function.
Elderly patients
The rate of omeprazole metabolism in elderly patients (75-79 years) is slightly reduced.

Therapeutic indications

Ometren intravenous medicine is indicated as an alternative to oral therapy in the following cases.
Adults:

• Treatment of duodenal ulcers;
• Prevention of relapses of duodenal ulcers;
• Treatment of gastric ulcers;
• Prevention of relapse of stomach ulcers;
• In combination with appropriate antibiotics for eradication of Helicobaсter 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 oesophagitis;
• Long-term treatment of patients with inactive reflux esophagitis;
• Treatment of symptomatic gastro-oesophageal reflux disease;
• Treatment of Zollinger-Ellison syndrome.

Contraindications

Omeprazole should not be used in cases with hypersensitivity to omeprazole substituted benzimidazoles and other components in its content.
Omeprazole, like other proton pump inhibitors (PPIs) should 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

Effects of omeprazole on the pharmacokinetics of other medicinal products
Medicinal products whose absorption depends on gastric pH
Gastric acid suppression during treatment with omeprazole and other PPIs might decrease or increase the absorption of medicinal products with a gastric pH dependent absorption. As with other medicinal products that decrease intragastric acidity, the absorption of medicinal products such as ketoconazole, itraconazole and erlotinib can decrease and the absorption of digoxin can increase during treatment with omeprazole. Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (up to 30% in two out of ten subjects).
Nelfinavir, atazanavir
The plasma levels of nelfinavir and atazanavir are decreased in case of co-administration with omeprazole.
Concomitant administration of omeprazole and nelfinavir is contraindicated. Concomitant administration of omeprazole (40 mg once daily) reduced the average exposure of nelfinavir by approximately 40%, and the average exposure of the pharmacologically active metabolite M8 was reduced by approximately 75-90%. The interaction may also be due to inhibition of CYP2C19 activity.
Concomitant administration of omeprazole with atazanavir is not recommended. Co-administration of omeprazole (40 mg once a day) and atazanavir 300 mg / ritonavir 100 mg in healthy volunteers led to a 75% reduction in atazanavir exposure. Increasing the atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure. The co-administration of omeprazole (20 mg once daily) with atazanavir 400 mg/ritonavir 100 mg to healthy volunteers resulted in a decrease of approximately 30% in the atazanavir exposure as compared to atazanavir 300 mg/ritonavir 100 mg once daily.
Digoksin
Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10%. Digoxin toxicity has been rarely reported. However caution should be given when omeprazole is administered at high doses in elderly patients. Therapeutic drug monitoring of digoxin should be strengthened. In the case of concomitant use with digoxin, patients should be closely monitored by a doctor.
Clopidogrel
During the study, clopidogrel (loading dose – 300 mg, then 75 mg per day) was administered as monotherapy and with omeprazole (80 mg concomitantly with clopidogrel) for 5 days. With concomitant administration of clopidogrel and omeprazole, the exposure of the active metabolite of clopidogrel was decreased by 46% (day 1) and 42% (day 5). The inhibition of platelet aggregation was decreased by 47% on average (after 24 hours) and by 30% (day 5), when clopidogrel and omeprazole were administered together. Another study showed that administering clopidogrel and omeprazole at different times does not prevent this interaction, which is likely due to the inhibitory effect of omeprazole on CYP2C19. Contradictory data on clinical effects of pharmacokinetic/pharmacodynamic interaction in terms of major cardiovascular diseases have been reported in observational and clinical studies. Thus, concomitant use of omeprazole and clopidogrel should be avoided.
Other medicinal products
The absorption of posaconazole, erlotinib, ketoconazol and itraconazol is significantly reduced and thus clinical efficacy may be impaired. Concomitant use of the medicine with posaconazole and erlotinib should be avoided.
Medicinal products metabolised by CYP2C19
Omeprazole is a moderate inhibitor of CYP2C19, the main enzyme that metabolises omeprazole. Thus, the metabolism of concomitant drugs that are also metabolised by CYP2C19 may be reduced and the systemic exposure of these drugs may increase. Examples of such drugs are R-warfarin and other vitamin K antagonists, cilostazol, diazepam and phenytoin.
Cilostazol
In healthy subjects, administration of omeprazole at a dose of 40 mg increased the maximum plasma concentration (C_max) and AUC of cilostazol by 18% and 26%, respectively, and one of its active metabolites by 29% and 69%, respectively.
Phenytoin
Monitoring phenytoin plasma concentration is recommended during the first two weeks after initiating omeprazole treatment and, if a phenytoin dose adjustment is made, monitoring and a further dose adjustment should be performed upon ending omeprazole treatment.
Unknown interaction mechanism
Saquinavir
Concomitant administration of omeprazole with saquinavir/ritonavir resulted in increased plasma levels up to approximately 70% for saquinavir associated with good tolerability in HIV-infected patients.
Tacrolimus
If omeprazole and tacrolimus are used together, an increase in plasma level of tacrolimus has been reported. Supported impression of tacrolimus concentrations, including renal function (creatinine clearance), should be carried out and, if necessary, tacrolimus dose adjusted.
Methotrexate
In some patients, methotrexate levels have been reported to be increased when given with proton pump inhibitors. In the application of high-dose methotrexate, omeprazole administration may need to be temporarily discontinued.
Effects of other medications on the pharmacokinetics of omeprazole
Inhibitors of CYP2C19 and/or CYP3A4
Since omeprazole is metabolised by the enzymes CYP2C19 and CYP3A4, medications known to inhibit the activity of CYP2C19 or CYP3A4 or both (such as clarithromycin and voriconazole) may lead to increase omeprazole serum levels as a result of a slower rate of metabolism. Concomitant use of voriconazole led to a more than double increase in omeprazole exposure. As high doses of omeprazole have been well-tolerated adjustment of the omeprazole dose is not generally required. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated.
Omeprazole is partly metabolised also by CYP3A4, but omeprazole does not inhibit this enzyme. Thus, omeprazole does not affect the metabolism of medicines metabolised by CYP3A4, such as cyclosporin, lignocaine, quinidine, oestradiol, erythromycin and budesonide.
Inducers of CYP2C19 and/or CYP3A4
Medications known to induce the activity of CYP2C19 or CYP3A4, or both enzymes (e.g. Rifampicin and St. John’s wort) may lead to a decrease in the serum level of omeprazole due to an acceleration of its metabolism.

Special warnings and precautions for use

In the presence of any alarming symptom (e.g. significant weight loss not caused by diet; frequent vomiting; dysphagia; vomiting with blood or melena) and in the presence of a diagnosed or suspected gastric ulcer, malignant disease should be excluded, as taking the medicine may mask its symptoms and delay the correct diagnosis.
Co-administration of atazanavir with omeprazole is not recommended. If the combination of atazanavir and omeprazole is unavoidable, close clinical monitoring (e.g. viral load) is recommended in combination with an increase in the dose of atazanavir to 400 mg per 100 mg of ritonavir; the dose of omeprazole should not exceed 20 mg.
Omeprazole, as all acid-blocking medicinal products, may reduce the absorption of vitamin B₁₂ (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with reduced body reserves or risk factors due to reduced vitaminThis should be considered in patients with low body weight or risk factors for decreased vitamin B₁₂ absorption during long-term therapy.
Omeprazole is a CYP2C19 inhibitor. When starting or ending treatment with omeprazole, the potential for interactions with medicinal products metabolised through CYP2C19 should be considered. An interaction is observed between clopidogrel and omeprazole. The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of omeprazole and clopidogrel should be avoided.
The administration of omeprazole slightly increases the risk of developing gastrointestinal infections such as Salmonella and Campylobacter.
Patients who have been taking PPIs, including omeprazole, for at least 3 months may develop severe hypomagnesaemia (in most cases of hypomagnesaemia, patients have been using the drug for about 1 year). Hypomagnesaemia can manifest as serious symptoms such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia. Hypomagnesaemia can also be asymptomatic and may not be diagnosed in time. In most patients, the symptoms of hypomagnesaemia disappear and the condition returns to normal after the use of magnesium supplements and discontinuation of omeprazole.
In patients who are planning long-term administration of omeprazole or concomitant administration of digoxin or other medicines that may cause a decrease in magnesium content (e.g. diuretics), it is necessary to determine the serum magnesium concentration before administration of omeprazole and periodically during treatment.
Omeprazole, especially when used in high doses and for a long time (> 1 year), slightly increases the risk of fractures of the spine, wrist and hip, especially in elderly people and in the presence of risk factors. According to observational studies, omeprazole may increase the overall risk of fractures by 10-40%. This increase in risk may be partly due to other factors. Patients at risk of osteoporosis should receive care according to current clinical guidelines and they should have an adequate intake of vitamin D and calcium.
Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported very rarely and rarely, respectively in association with omeprazole treatment.
Subacute cutaneous lupus erythematosus (SCLE)
The administration of omeprazole can sometimes be associated with the occurrence of SCLE. If skin lesions occur, especially in areas exposed to sunlight and accompanied by arthralgia, you should immediately consult a doctor and consider discontinuing omeprazole. The presence of a history of SCLE, which developed after the administration of omeprazole, may increase the risk of SCLE when using other PPIs.
Renal impairment
Acute tubulointerstitial nephritis (TIN) has been observed in patients taking omeprazole and may occur at any point during omeprazole therapy (see section «Undesirable effects»). Acute tubulointerstitial nephritis can progress to renal failure.
Omeprazole should be discontinued in case of suspected TIN, and appropriate treatment should be promptly initiated.
Influence on test results
During treatment with antisecretory medicines, the concentration of gastrin in the blood plasma increases as a result of decreased hydrochloric acid secretion. Due to the decrease in hydrochloric acid secretion, the level of chromogranin A (CgA) increases. An increase in CgA concentration may affect the results of tests for the detection of neuroendocrine tumours. To prevent such an effect, stop taking omeprazole for 5 days before the CgA test. If the levels of CgA and gastrin do not return to the reference values after the initial measurements, the measurements should be repeated in 14 days after discontinuation of Ometren.
Patients who have been using omeprazole for a long period of time (especially when treatment lasts for more than 1 year) should be under regular medical supervision.
This medicine contains less than 1 mmol (23 mg)/dose of sodium, i.e. it is practically free of sodium.

Use during pregnancy or breastfeeding.
Pregnancy
The prospective epidemiological studies indicate that omeprazole has no adverse effects on pregnant women and on the fetus or neonatal health. Omeprazole can be used during pregnancy.
Breast-feeding period
Omeprazole passes into breast milk, but it is not expected to have an effect on the child when used in therapeutic doses.
Fertility
The results of animal studies of omeprazole racemic mixtures indicate that omeprazole has no effect on fertility.

Effects on ability to drive and use machines
Omeprazole is not likely to affect the ability to drive or use machines. Adverse reactions such as dizziness and visual disturbances may occur. The patients who are affected by these adverse effect, should not drive or use machines.

Posology and method of administration

Posology
Alternative to oral therapy
In patients for whom the oral form of the medicinal product is unacceptable, it is recommended to use Ometren 40 mg once daily intravenously. For patients with Zollinger-Ellison syndrome, the recommended initial dose of omeprazole to be administered intravenously is 60 mg per day. Higher daily doses may be required, and therefore the dose should be selected individually. If the dose exceeds 60 mg per day, it should be divided equally into two parts and administered 2 times per day. The medicine should be administered intravenously as an infusion over 20-30 minutes.
Reconstitution of the product before administration
Dissolve the lyophilised powder contained in the vial in 10 ml of solvent (solvent ampoule is included) before intravenous injection. The solution should be administered slowly, for at least 2 minutes. Dissolve Ometren before use. The resulting solution is stable for 4 hours at room temperature (not higher than 25 ^оС).
Before intravenous drip administration, the preparation should be dissolved in 0.9% sodium chloride or 5% glucose solution. The contents of one vial should be dissolved in a volume of approximately 5 ml and then immediately diluted to a volume of up to 100 ml. The stability of omeprazole depends on the pH of the solution. Make sure that all the medicine is dissolved. The resulting solution should be used for intravenous infusion within 20-30 minutes.
Before general anaesthesia to prevent aspiration of gastric contents, administer intravenous Ometren 40 mg 1 hour before surgery.
Any unused product or waste should be disposed of in accordance with local requirements.
Special categories of patients
Impaired renal function
Dose adjustment is not needed in patients with impaired renal function.
Hepatic impairment
In patients with impaired hepatic function, a daily dose of 10-20 mg may be sufficient.
Elderly patients (> 65 years)
No dose adjustment is required in elderly patients.

Children.
The experience of using omeprazole for intravenous administration in paediatric practice is limited, so omeprazole should not be prescribed to this category of patients.

Overdose

There are very limited data on the effects of omeprazole overdose in humans. Cases of doses up to 560 mg of omeprazole have been described and single reports of a single oral dose of 2400 mg of omeprazole (120 times the usual recommended clinical dose) have been received. Nausea, vomiting, dizziness, abdominal pain, diarrhoea and headache have been reported. Apathy, depression and confusion have also been reported in isolated cases.
The described symptoms are transient. The elimination rate does not change (first-order kinetics) with increasing dose.
Treatment. There is no specific antidote. It is poorly excreted by dialysis. Gastric lavage, symptomatic and supportive therapy are indicated.

Undesirable effects

The most common adverse effects (1-10% of patients) are headache, abdominal pain, constipation, diarrhoea, flatulence and nausea/vomiting.
The frequency ratings of the undesirable effects listed below according to the system organ class are defined 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), Not known (cannot be estimated from the available data).
Eye disorders: Rare – blurred vision.
Hearing and vestibular system: Uncommon – vertigo.
Respiratory system, chest and mediastinal organs: Rare – bronchospasm.
Gastrointestinal tract: Common – abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting, fundic gland polyps (benign); Rare – dry mouth, stomatitis, gastrointestinal candidiasis; Not known – 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.
Renal and urinary system: Rare – tubulointerstitial nephritis (with possible progression to renal failure).
Metabolism and nutrition disorders: Rare – hyponatraemia; Not known – hypomagnesemia; severe hypomagnesemia may cause hypocalcemia, hypomagnesemia can also cause hypokalemia.
Nervous system: Common – headache; Uncommon – dizziness, paraesthesia, somnolence; Rare – taste disorders.
Psychiatric disorders: Uncommon – insomnia; Rare – agitation, confusion, depression; Very rare – aggression, hallucinations.
Blood and lymphatic system: Rare – leukopenia, thrombocytopenia; Very rare – agranulocytosis, pancytopenia.
Immune system: Rare – hypersensitivity reactions e.g. fever, angioedema and anaphylactic reaction/shock.
Skin and subcutaneous tissue: Uncommon – dermatitis, pruritus, rash, urticaria; Rare – alopecia, photosensitivity, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms; Very rare – erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN); Not known – subacute cutaneous lupus erythematosus.
Musculoskeletal system and connective tissue: Uncommon – fracture of the hip, wrist or spine; Rare – arthralgia, myalgia; Very rare – muscular weakness.
Reproductive system and breast disorders: Very rare – gynaecomastia.
General disorders and administration site reactions: Uncommon – malaise, peripheral oedema; Rare – increased sweating.
In isolated cases, irreversible visual impairment has been reported in critically ill patients receiving omeprazole as an intravenous injection, especially in high doses, but the causal relationship has not been established.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals and the patients or their legal guardians/carers are asked to report any suspected adverse reactions and lack of efficacy of the medicinal product to the State Expert Center of the Ministry of Health of Ukraine at the link: https://aisf.dec.gov.ua

Shelf life

2 years.

Storage conditions

Store in the original package in order to protect from light.
Store at a temperature not exceeding 25 ^оС. Keep out of the reach of children.

Incompatibilities

This medicinal product should not be mixed with other solvents, except as specified in the section «Posology and method of administration».

Packaging

1 vial with powder and 1 ampoule with solvent. 1 vial of powder with 1 ampoule of solvent (10 ml) in a cardboard box.

Prescription status

Available on prescription.

Manufacturer

ANFARM HELLAS S.A.

Manufacturer’s location and address of the place of operation

61st km NAT. RD. ATHENS-LAMIA, Schimatari Viotias, 32009, Greece.